The aim is to study some mechanisms of regulation of apoptosis and self-organization in the mitochondria in the heart cells in female mice during the growth of experimental melanoma B16/ F10 linked ...with chronic neurogenic pain as comorbid pathology. Materials and methods The work has been performed in female mice of the C57BL/6 strain (n=168).The following experimental groups have been presented: the group of intact mice (n=21), the control group (n=21) to reproduce chronic neurogenic pain (CNP), the comparison group (n=63) with a standard growth of melanoma B16/F10 and the main group (n=63) with CNP + melanoma B16 / F10. In mitochondria the following concentrations have been determined by the ELISA method: cytochrome C (ng/mg protein), caspase-9 (ng/mg protein), Bcl-2 (ng/mg protein), AIF (ng/mg protein) and calcium (mmol/g protein). The Statistica 10.0 software was used for statistical analysis. Results As against the intact values, the standard growth of melanoma reduced in the mitochondria of the heart cells the level of calcium in week 1-2 by 2.9 and 6.7 times, respectively, the AIF content in week 2-3 by 1.4 times (p < 0.05) and 2 times, respectively; Bcl-2 after 1-2 weeks by 1.7 and 2.9 times, while cytochrome C and caspase 9 remained stable throughout the entire period of the melanoma growth. CNP induced a decrease in the level of Ca2+ by 3.2 times, that in Bcl-2 by 1.3 times (p <0.05), in caspase 9 by 1.5 times and an increase in the AIF content by 2.3 times compared with the intact values. After 1 week of the melanoma growth against the background of CNP the levels of Ca2 + and caspase 9 increased by 5.3 times and 2.4 times relative to the control values, in the subsequent periods of the melanoma growth, Ca2+ decreased almost to undetectable values. AIF, Bcl2, and cytochrome C changed abruptly, but by the end of the experiment they were at a low level with a 5.2-fold decrease in AIF, and a 2.2-fold decrease in Bcl-2 and cytochrome C content. Conclusions The standard growth of B16/F10 melanoma in female mice is accompanied by a decline in the respiratory and energy function of the heart cell mitochondria. The growth of melanoma, stimulated by CNP as comorbid pathology, exacerbates the mitochondrial dysfunction, suppresses the activity of apoptosis factors and leads to the development of myocardial infarction in the vast majority of animals, accompanied by compensatory mitochondrial aggregation and chemiluminescence.
Aims A high incidence of breast cancer is observed in all countries throughout the world, and this dictates the use of aggressive antitumor drugs. The toxogenic effect of anthracycline drugs on the ...cardiovascular system under conditions of oncological pathology determines the need to expand the diagnostic capabilities for detecting cardiotoxicity, including searching for signal morphological markers in blood serum. The aim of this work is to study the structure of solid-state films of blood serum in patients with breast cancer at the stages of their chemotherapeutic treatment to identify signal criteria for cardiotoxicity. Materials and methods Studies were conducted in 25 patients with primary breast cancer (BC) with an extent of spread of the tumor process corresponding to T2-4N0-1M0. Polychemotherapy (PCT) was carried out in a neoadjuvant regimen, which included doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) supported by echocardiography examinations and ECG monitoring. Morphological testing of solid-state blood serum samples was carried out using the Shatokhina-Shabalin method of wedge-shaped dehydration both before PCT and in the course thereof. Samples were visualized with the Leica DMLS2 microscope with a magnification from x20 to x90. Results Before starting the PCT course, in the serum facias, in 55% of the cases detected has been the loss of the radial symmetry system and the formation of pathological types, including the "double" facias that is a criterion of systemic intoxication. Local markers of comorbid states with a detection rate of up to 40% of intoxication, impaired vascular elasticity, sclerosis, hypertension and ischemia have been identified. After 3 courses of PCT including anthracyclines, the occurrence rate of formation of these pathological criteria increased by 1.7 times; the occurrence rate of myocardial trophic disorder markers was found to be higher. At stages 5-6 of the treatment course, in 80% of the cases, some signal signs of the cumulative effect of anthracyclines associated with impaired cardiac rhythmogenesis were detected in the facias structure. Conclusions Inhibition of tumor growth under PCT including anthracyclines is accompanied by structural deformation of the systemic and local self-organization of blood serum. An intensification of crystallogenesis of inflammation pathological proteins, sclerosis, intoxication, hypertension, stagnation angiospasm and cardiac arrhythmias makes it possible to assess the intensity of drug cardiotoxicity using the identifying markers, predict long-term effects of PCT and a possibility of their prevention.
12076
Background: Numerous pharmacogenetic studies have identified genetic polymorphisms (SNPs) associated with an increased risk of anthracycline-mediated cardiotoxicity (AMC). The purpose was to ...search for SNP-SNP interactions associated with the risk of cardiotoxic manifestations caused by anthracycline therapy in breast cancer patients. Methods: The study included 256 Caucasian patients (median age - 55 years) with a diagnosis of breast cancer with normal cardiovascular system parameters at baseline, who were treated with anthracyclines in 2019-2020. For SNP genotyping of c.4544G > A rs8187710 (ABCC2), c.1744C > T rs11549465 ( HIF1A), g.22125504G > C rs1333049 ( CDKN2A/ B) and c.214T > C rs4673 ( CYBA). DNA was extracted from blood by using DNA-sorb-B (AmpliSens, Russia). HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by the Sanger method on a Genetic Analyzer 3500 (ABI, USA). Results: During the follow-up period 21 (8.2%) patients developed signs of subacute (changes developed within several weeks after the last course of therapy) or early chronic anthracycline mediated cardiotoxicity (changes developed within a year after completion of anthracycline therapy). Using the multifactorial dimension reduction method. We obtained a 4-locus model of SNP-SNP interactions c.4544G > A rs8187710 ( ABCC2) x g.22125504G > C rs1333049 ( CDKN2A/B) x c.214T > C rs4673 ( CYBA) x g.23708527G > A rs28714259 which has high prognostic properties. The specificity of the test based on the 4-locus model was 68%, the sensitivity was 100%, and the overall accuracy was 71%. The results of the analysis of SNP-SNP interactions indicate the greatest contribution of rs4673 and rs28714259 to the predisposition to AMC. The first ones yet into antagonistic interactions with rs28714259, rs1333049 and rs11549465, the second with rs8187710, rs11549465 and rs4673. On the contrary rs11549465 and rs1333049 contribute to a synergistic effect. Conclusions: The 4-locus model discovered in this study can form the basis of prognostic tests that predict early the risks of developing AMC in cancer patients, which in the future allow to personalize and select the most optimal treatment regimen.
12077
Background: Anthracyclines are highly effective chemotherapeutic agents, used for a wide variety of malignancies. Despite their antitumor efficacy there is a risk of cardiotoxic manifestations ...that reduce the time and quality of life of patients. The purpose was to study the effectiveness of molecular genetic tests based on rs4673 CYBA genotyping (c.242C > T) and measurement of plasma paraoxonase 1 (PON1) level in patients with breast cancer (BC) for predicting and diagnosing anthracycline-mediated cardiotoxicity (AMC). Methods: The study included 256 Caucasian patients (median age - 55 years) with a diagnosis of breast cancer normal cardiovascular system parameters at baseline, who were treated with anthracyclines in 2019-2020. For rs4673 genotyping, DNA was extracted from the blood by using DNA-sorb-B (AmpliSens, Russia). HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by the Sanger method on a Genetic Analyzer 3500 (ABI, USA). The concentration of PON1 in blood plasma was measured at baseline and after 4 course of chemotherapy with anthracyclines using ELISA kits (Cloud-Clone Corp., China/USA). Results: During the follow-up period 21 (8.2%) patients developed signs of subacute (changes developed within several weeks after the last course of therapy) or early chronic AMC (changes developed within a year after completion of anthracycline therapy). In the group of patients without AMC the frequency of the minor allele rs4673 (c.214C > T CYBA) was 0.38, the frequency of genotypes C/C was 0.4, C/T - 0.43, and T/T - 0.17. The risk of AMC increased by 6.49 times in the presence of the rs4673 polymorphic allele (p = 0.002). The area under the ROC curve of the test based on rs4673 genotyping was 71.9%. The concentration of PON1 after the 4 courses of chemotherapy increased by 19.57% in the group of patients without cardiotoxic manifestations (p = 0.018) and in the group of patients with AMC by 20.23% (p = 0.007) as compared to the initial level. Besides, after 4 courses of chemotherapy the PON1 level was higher in patients with AMC by 25.08% (p = 0.026) than in patients without cardiovascular complications. The sensitivity of the test based on the measurement of the PON1 level in the blood plasma after 4 courses of chemotherapy was 100%, the specificity was 70.8% with a cut-off value of 2.9 ng/ml. Conclusions: This study has showed that genotyping of patients for the rs4673 polymorphism allows pre-stratification of the risk group white determination of the PON1 level in blood plasma after 4 courses of chemotherapy gives the opportunity to identify patients with AMC and promptly correct the chosen treatment.
Tumor thrombosis in extremity soft tissue sarcomas Katelnitskaya, Oksana V.; Nepomnyashchaya, Evgeniya M.; Ausheva, Tatiana V. ...
Journal of clinical oncology,
06/2022, Letnik:
40, Številka:
16_suppl
Journal Article
Recenzirano
e23551
Background: Malignant tumors of bones and soft tissues often reach large sizes, compress and invade the major vessels, leading to the development of venous thrombosis. Venous thrombosis is ...difficult to distinguish from tumor thrombosis in the preoperative period. However, the management differs. Both conditions require anticoagulant therapy, but tumor thrombosis requires expanding intervention with the thrombus removal and major venous resection. The major vessel involvement complicates surgery. It is much more difficult to achieve negative resection margins. The risk of damage to the main vessels during tumor mobilization increases and, as a result, the risk of hemorrhagic complications increases as well. An interdisciplinary approach reduces the risk of surgical complications and helps achieve radical tumor resection. Our purpose was to analyze the rates of tumor thrombosis in malignant tumors of bones and soft tissues and evaluate the results of surgical treatment. Methods: 115 patients (mean age 46 years) with malignant tumors of bones and soft tissues received surgical treatment in 2020-2021. The most common histological subtypes were synovial sarcoma (25.3%), pleomorphic sarcoma (18.2%), and liposarcoma (15.6%). Venous thrombosis of the lower extremity veins was diagnosed at the stage of preoperative preparation in 17 patients (14.8%), the femoral segment was more often affected (70.6%). All patients received anticoagulant therapy. The tumor genesis of a thrombus was confirmed intraoperatively in 7 patients. Thus, the incidence of tumor thrombosis in malignant tumors of bones and soft tissues was 6%. All patients underwent tumor removal, thrombectomy, and the femoral or iliac venous segment resection. Results: The following complications were observed in the postoperative period: seroma - 5 cases (29.4%), lymphorrhea - 12 (70.5%), swelling of the lower limb - 12 cases (70.5%). Conclusions: Tumor thrombosis in malignant tumors of bones and soft tissues of the lower extremities is not a rare complication, it requires timely diagnosis and an expanded intervention to achieve negative resection margins and reduce the risk of embolism.
e21587
Background: The purpose of this study was to assess the effect of a strain 100 of a new group of rotavirus of Reoviridae family on the growth of transplantable B16/F10 melanoma in mice and the ...survival of the animals. Methods: We studied the strain 100 of a new group of rotavirus of Reoviridae family (RVK) ( http://jbks.ru/archive/issue-10/article-6 ). RVK 100 is a live attenuated non-pathogenic virus growing on pig embryo kidney cell culture with concentration 5·10
9
per 1 ml. The dynamics of melanoma growth and the survival of tumor-bearing animals receiving RVK were studied in 25 male mice divided into 5 equal groups, each n = 5. RVK was administered intramuscularly and orally once a week 0.3 mL and 25 µL, respectively: to groups 1-2 21 days prior to the tumor inoculation, a total of 4 injections (“vaccination” regimen); to groups 3-4 – 7 days after tumor inoculation with the onset of tumor nodes, a total of 3 injections (“treatment” regimen); group 5 included controls receiving 0.85% NaCl solution. Groups 1 and 3 received live RVK, groups 2 and 4 - RVK inactivated by UV radiation. Results: Survival of mice in groups 1-2 receiving both live and inactivated RVK in the “vaccination” regimen was increased statistically significantly: in group 1, Me = 25 days after melanoma transplantation (LQ 24; UQ 30), in group 2 Me = 26 days (LQ 25; UQ 30), in controls Me = 14 days (LQ 10; UQ 22); p = 0.032 and p = 0.0079, respectively. RVK administration in the “treatment” regimen did not cause such changes. While mice of group 3 receiving the live strain 100 showed a tendency to higher survival, compared to controls (Me = 23 days, LQ 22; UQ 24, p = 0.056), the administration of inactivated RVK (group 4) did not significantly improve the survival of animals, compared to controls (Me = 22 days (LQ 21; UQ 33, p = 0.151). Conclusions: Improved survival of animals with B16/F10 melanoma after the RVK administration indicates the virus ability to slow down tumor growth and confirms our previously published data on the RVK strain 228, although, in contrast to it, the strain 100 is able to increase the survival rate of tumor-bearing mice only when used in the “vaccination” regimen, which refers mainly to the inactivated virus. Since the inactivation of the RVK strain 100 eliminates its effect when used in the “treatment”, but not “vaccination” regimen, it seems to be associated with an immunostimulatory effect but not with an oncolytic one.
Abstract only
e23522
Background: The disruptions in redox homeostasis in the nonmalignant tissues surrounding neoplasm can promote the tumor progression. The aim of this work was to assess the ...changes of the redox-regulatory system in the tumor and tumor-surrounding tissues in STS patients (pts) under the influence of a mofified metod of NC. Methods: The activity of glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), content of reduced glutathione (GSH) and malondialdehyde (MDA) were determined by spectrophotometric methods. All markers were measured in the samples of tumor, peritumoral area and healthy tissues (taken along the line of resection) obtained during the surgery from 42 STS pts (T2a-bN0M0). The control group consisted of 21 primary pts who underwent resection only. Patients of the experimental group (21) received NC comprising systemic and local administration of antitumor drugs. Doxorubicin (40 mg/m
2
) was injected intravenously on the 1st and 7th days with autologous red blood cells as drug carriers; at the same time, cyclophosphamide (600 mg/m
2
) and methotrexate (40 mg/m
2
) were injected along the tumor periphery, on autologous plasma as a carrier. After 14 days, tumor removal surgery performed. All STS pts received standard postoperative chemoradiotherapy. Results: The level of GSH in tumor without NC treatment was higher than in the healthy and peritumoral tissue (by 2.3-2.5 times), and the activity of all glutathione-dependent enzymes was higher by 53.0-147.0 % (p = 0.0413-0.00124). The content of MDA in tumor was lower than in other tissues by 30.0-46.0 % (p = 0.00061). We did not find any differences between the healthy and peritumoral areas. In tumor samples of the experimental group, we also observed statistically significant increase in the level of GSH (by 2.8–3.0 times) and activation of GPO (by 37.3-95.8 %) and GR (by 2.0-3.2 times) vs. other tissues. However, after NC, the studied samples showed an increase in GSH by 3.1–3.8 times (p = 0.0143–0.00112), compared with the corresponding control samples. Also, the activity of GPO (by 54.5 %) and GsT (by 38.9 %) was significantly increased in peritumoral tissue vs similar area in the control group. After NC, the content of MDA was reduced in the healthy and tumor tissues vs control by 52.0 % (p = 0.0074) and 30.6 % (p = 0.04815), respectively. Clinical efficacy of NC was confirmed by reduced tumor volume in most patients by 30-40 %; the 5-year monitoring of STS pts showed that local recurrence and metastasis occurred in 14 of 21 pts in the control group, and in 6 of 21 in the main group (p = 0.0294). Conclusions: The NC treatment modifies the redox balance in the tumor-surrounding tissues and, as a result, decreases the oxidation damages in the healthy tissues. This effect, apparently, is an additional factor that improves the effectiveness of the proposed NC method.
e23552
Background: Surgery with negative resection margins is now considered the main treatment for retroperitoneal sarcomas improving the survival and quality of life of patients. The most common ...obstacle to surgery with R0 resection in locally advanced tumors is the involvement of the great vessels. The purpose of this study was to analyze the results of surgical treatment in patients with locally advanced retroperitoneal sarcomas involving the inferior vena cava or iliac veins. Methods: The study included 34 cancer patients who underwent tumor resection with major vessel resection in 2015-2021. The mean tumor size was 15.5 cm (from 6 to 41 cm). The most common tumors were moderately differentiated liposarcoma (38%) and pleomorphic liposarcoma (26%). Results: Resection of the inferior vena cava was performed in 19 cases, resection of the iliac segment - 15. Circular vein resection without reconstruction was performed in 5 patients, wedge resection - 7, segmental resection with end-to-end anastomosis - 1, replacement of the venous segment with a prosthesis - 25. Resection of adjacent organs was required in 26.5% of surgical interventions. According to the final pathoanatomical examination, the rate of complete tumor resections (R0-1) was 88.2%. During the 30-day postoperative period, mortality and complication rates were acceptable, 29% and 0%, respectively. During the follow-up period, the median disease-free survival was 13 months, and the median overall survival was not reached. Conclusions: Surgical interventions expanded due to resection of the major veins in locally advanced retroperitoneal sarcomas allow achieving a high rate of radical tumor resection and improving relapse-free and overall survival rates.
e23556
Background: The system of insulin-like growth factors (IGF) is involved in the pathogenesis of many malignant tumors. At the same time, the specificity of this system in recurrent soft tissue ...sarcomas is unknown. The purpose of this study was to analyze the IGF system in tumors and their peritumoral areas in men with recurrent soft tissue sarcomas. Methods: The study included 26 men aged 57.8±6.2 years with primary (n = 12, group 1, controls) and recurrent (n = 14, group 2, main group) soft tissue sarcoma of the extremities, T2bN0M0. Grade 1 tumors were diagnosed in 6 patients of group 1 and in 7 patients of group 2, while the other patients had G3 or G4 tumors. 95% of tumors were liposarcomas. All patients of group 2 had previously underwent surgical and radiation treatment for primary sarcomas and their relapses (up to 2 episodes), with the last surgery more than 1 year ago. Levels of the IGF system components were determined in tumor (T) and peritumoral (PT) tissues by ELISA, and ratios of IGF(T)/IGF(PT) were calculated. Results: Levels of the IGF system components in patients of group 1 were similar in T and PT. In group 2, levels of IGF1 and IGFВР2 in T were respectively 2.2 and 1.6 times (p < 0.05) lower than in PT, but did not differ significantly from the levels in group 1. The IGF1(T)/IGF1(PT) ratio in patients of group 2 was 1.8 times (p < 0.05) lower than in group 1. PT levels of IGF2 in group 2 depended on the tumor grade: they were 1.5 times (p < 0.05) higher in G1 than in G3-G4, while no such dependence was observed in T. Conclusions: The levels of the IGF system components in recurrent soft tissue sarcomas in older men had some peculiarities. Unlike primary sarcomas with similar levels of the studied components of the IGF system in tumors and in peritumoral tissues, recurrent tumors contained less IGF1 and IGFBP2 than the corresponding peritumoral areas. The levels of IGF2 in the peritumoral tissues of recurrent tumors depended on the tumor grade.
Abstract only
e13504
Background: Numerous pharmacogenetic studies have led to the identification of genetic polymorphisms associated not only with the development of cardiovascular disease, but also ...increase the risk of complications due to the use of anthracycline drugs, widely used in the treatment of cancer. The purpose of this study was to assess the prevalence of rs28714259 polymorphism and to study possible correlation with anthracycline-mediated cardiotoxicity (AMC). Methods: The study included 173 Caucasian patients (median age 55 years) with a diagnosis of breast cancer without diagnosed cardiovascular pathology who underwent treatment in the RRIO, Rostov-on-Don in 2019. For genotyping of SNP rs28714259, DNA was extracted from blood using DNA-sorb-B (AmpliSens, Russia) and HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by Sanger sequencing with a Genetic Analyzer 3500 (ABI, USA). The obtained results were compared with European population (1000 Genome). Results: 13 patients (7.5%) with an early-onset of chronic AMC were founded after three courses of chemotherapy. The allelic frequency rs28714259 was 0.079, the frequency of AG genotypes was 0.135, and AA was 0.012. It was shown that the presence of this SNP leads to an increase risk of cardiovascular pathology at an early stage by more than 4 times (OR = 4.186, p = 0.006). In addition, when comparing with the European population, the highest probability of developing early-onset chronic AMC was determined for patients with the AA genotype (more than 22 times, p = 0.001). Conclusions: In this study, a statistically significant association of rs28714259 presence with developing early-onset chronic AMC was revealed, which seems promising for the early determination of the risk group in the management of cancer patients.
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