Targeted next-generation sequencing of 21 candidate genes in hereditary ovarian cancer patients from the Republic of Bashkortostan.

About 5-10% of all ovarian cancer cases show familial clustering, and some 15-25% of familial ovarian cancer cases are mediated by high-penetrance mutations in the BRCA1 and BRCA2 genes. Only few other genes have been identified for familial ovarian cancer.We conducted targeted next-generation sequencing of the protein coding region of 21 candidate genes, including UTR regions, in genomic DNA samples of 48 patients with familial ovarian cancer from the Republic of Bashkortostan. We identified deleterious variants in BRCA1, BRCA2, CHEK2, MSH6 and NBN in a total of 16 patients (33%). The NBN truncating variant, p.W143X, had not previously been reported. Seven patients (15%) were carriers of the c.5266dupC variant in BRCA1, supporting a Russian origin of this founder allele. An additional 15 variants of uncertain clinical significance were observed. We conclude that our gene panel explains about one-third of familial ovarian cancer risk in the Republic of Bashkortostan.

The Burden of Residual SymptOms That Complicate the Life of Patients Who Have Suffered a new Coronavirus Infection (THROW study).

Aim      To evaluate the prevalence of residual symptoms in patients hospitalized for novel coronavirus infection at 8 months after discharge and the severity of such symptoms depending on demographic characteristics, concurrent diseases, and specific features of the acute period of COVID-19.Material and methods  This study included the patients who were managed for novel coronavirus infection in a COVID-19 hospital and provided their consent to participate in the study (98 patients). At 8 months after discharge from the hospital, a structured telephone interview was performed.Results Only 40 % of patients treated for COVID-19 did not have any complaints at 8 months after discharge from the hospital. The most frequent complaints in the long term were fatigue (30.5 %), weakness (28.4 %), shortness of breath (23.2 %), arthralgia (22.1 %), myalgia (17.9 %), and anosmia (15.8 %). The background of chronic diseases and obesity, percentage of lung damage according to CT data, and the requirement for oxygen support during the acute period in our sample were not related with the presence of symptoms in the long term. The presence and severity of symptoms during the long term were not determined by the clinical condition, volume of lung damage, or requirement for oxygen support but were related with the gender and severity of inflammation upon admission.Conclusion      Independent predictors for persistence of symptoms in the patient sample with severe novel coronavirus infection during the long term included chest and joint pain during the stay in the hospital, female gender, and increased levels of C-reactive protein upon admission.

Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane.

Background: Capecitabine is an approved standard therapy for anthracycline- and taxane-pretreated locally advanced or metastatic breast cancer (BC). Vinflunine has demonstrated single-agent activity in phase II studies in this setting and activity and tolerability when combined with capecitabine. We compared the combination of vinflunine plus capecitabine (VC) with single-agent capecitabine. Patients and methods: Patients with locally recurrent/metastatic BC previously treated or resistant to an anthracycline and resistant to taxane therapy were randomly assigned to either vinflunine (280 mg/m2, day 1) plus oral capecitabine [825 mg/m2 twice daily (b.i.d.), days 1-14] every 3 weeks (q3w) or single-agent oral capecitabine (1250 mg/m2 b.i.d., days 1-14) q3w. The primary end point was progression-free survival (PFS) assessed by an independent review committee. The study had 90% power to detect a 30% improvement in PFS. Results: Overall, 770 patients were randomised. PFS was significantly longer with VC than with capecitabine alone [hazard ratio, 0.84, 95% confidence interval (CI), 0.71-0.99; log-rank P = 0.043; median 5.6 versus 4.3 months, respectively]. Median overall survival was 13.9 versus 11.7 months with VC versus capecitabine alone, respectively (hazard ratio, 0.98; 95% CI, 0.83-1.15; log-rank P = 0.77). No difference in quality of life was observed between the two treatment arms. The most common adverse events (NCI CTCAE version 3.0) in the combination arm were haematological and gastrointestinal. Grade 4 neutropenia was more frequent with VC (12% versus 1% with capecitabine alone); febrile neutropenia occurred in 2% versus 0.5%, respectively. Hand-foot syndrome was less frequent with VC (grade 3: 4% versus 19% for capecitabine alone). Peripheral neuropathy was uncommon in both arms (grade 3: 1% versus 0.3%). Conclusions: Vinflunine combined with capecitabine demonstrated a modest improvement in PFS and an acceptable safety profile compared with capecitabine alone in patients with anthracycline- and taxane-pretreated locally recurrent/metastatic BC. ClinicalTrials.gov: NCT01095003.

[The search for new candidate genes involved in ovarian cancer pathogenesis by exome sequencing].

Ovarian cancer is one of the most insidious of tumors among gynecological cancers in the world. BRCA1 and BRCA2 mutations are associated with high risk of ovarian cancer; however, they are causative only in a fraction of cases. The search for new genes would expand our understanding of the mechanisms underlying malignant ovarian tumors and could help to develop new methods of early diagnosis and treatment of the disease. The present study involved exome sequencing of eight DNA samples extracted from the blood of ovarian cancer patients. As a result of the study, 53057 modifications in one sample were identified on average. Of them, 222 nucleotide sequence modifications in DNA located in exons and splice sites of 203 genes were selected. On the basis of the function of these genes in the cell and their involvement in carcinogenesis, 40 novel candidate genes were selected. These genes are involved in cell cycle control, DNA repair, apoptosis, regulation of cell invasion, proliferation and growth, transcription, and also immune response and might be involved in development of ovarian cancer.

[The immunosuppressive microenvironment of malignant gliomas].

The dogma of the central nervous system (CNS) as an immune-privileged site has been substantially revised in recent years. CNS is an immunocompetent organ and actively interacts with the immune system. Microglia plays a leading role in a CNS immune response. However, in malignant gliomas, there is M2-polarization of microglia acquiring immunosuppressive and tumor-supportive properties. It occurs under the influence of tumor cytokines, such as transforming growth factor-ß, interleukin-10, and prostaglandin E2. M2-polarized microglia exhibits reduced phagocytic activity, changes in the expression of many cellular determinants, or inverse of their functions, STAT3 activation, and production of immunosuppressive cytokines that suppress the function of cytotoxic CD8+ T cells or CD4+ T-helper cells type I. Myeloid-derived suppressor cells and regulatory T-lymphocytes, which have been recruited from peripheral blood into tumor tissue, also have immunosuppressive properties. The development of new treatment options for malignant gliomas must consider the role of the microenvironment in maintaining tumor vitality and progression.

[Glial brain tumor stem cells].

The review gives the present views on the origin, identification markers, and specific features of the phenotype of glioma stem cells, considers how the latter interact with the cells of the microenvironment in the perivascular niches. Many signaling pathways that determine properties, such a higher invasive and angiogenic ability, a marked metabolic shift toward glycolysis, and resistance to radio- and chemotherapy, are shown to be activated in the glioma stem cells. The exposure of the latter may contribute to the improvement of the results of treatment for malignant gliomas.

[Gene disorders and molecular genetic subtypes of malignant gliomas].

Malignant brain tumors are noteworthy for a lot of genetic disorders that show itself as decreased or increased gene function of different genes and lead to tumor development. The differences in the molecular genetic profile can identify several subtypes of malignant gliomas, which are distinguished by both their clinical course and susceptibility to drugs. This can be the basis for developing individualized therapy options in patients with malignant gliomas.

A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant KRAS metastatic colorectal cancer.

BACKGROUND: Targeted agents presently available for mutant KRAS metastatic colorectal cancer (mCRC) are bevacizumab and aflibercept. We evaluated the efficacy and safety of conatumumab (an agonistic monoclonal antibody against human death receptor 5) and ganitumab (a monoclonal antibody against the type 1 insulin-like growth factor receptor) combined with standard FOLFIRI chemotherapy as a second-line treatment in patients with mutant KRAS mCRC. PATIENTS AND METHODS: Patients with mutant KRAS metastatic adenocarcinoma of the colon or rectum refractory to fluoropyrimidine- and oxaliplatin-based chemotherapy were randomized 1 : 1 : 1 to receive intravenous FOLFIRI plus conatumumab 10 mg/kg (Arm A), ganitumab 12 mg/kg (Arm B), or placebo (Arm C) Q2W. The primary end point was progression-free survival (PFS). RESULTS: In total, 155 patients were randomized. Median PFS in Arms A, B, and C was 6.5 months (HR, 0.69; P = 0.147), 4.5 months (HR, 1.01; P = 0.998), and 4.6 months, respectively; median overall survival was 12.3 months (HR, 0.89; P = 0.650), 12.4 months (HR, 1.27; P = 0.357), and 12.0 months; and objective response rate was 14%, 8%, and 2%. The most common grade ≥3 adverse events in Arms A/B/C included neutropenia (30%/25%/18%) and diarrhea (18%/2%/10%). CONCLUSIONS: Conatumumab, but not ganitumab, plus FOLFIRI was associated with a trend toward improved PFS. Both combinations had acceptable toxicity.

[Radiotherapy of malignant brain gliomas using teniposide].

Efficacy of radiochemotherapy of malignantly-converted brain gliomas using teniposide was evaluated in a randomized prospective study. Combined use of cytostatics and irradiation appeared safe, tolerable and significantly more effective than radiotherapy alone as assessed by local control of tumor and survival.

[Correlation between the effect of chemotherapy on complement conformation and on CA-125 antigen in the blood plasma of patients with ovarian carcinoma].

Correlation was investigated between blood-plasma levels of C3(H2)O (conformation pattern of C3 component of the complement) and tumor-associated marker CA-125 in patients with ovarian cancer before and after chemotherapy. Since a drop in CA-125 level after chemotherapy was associated with similar changes in C3(H2)O fraction, it seems reasonable to suggest that change in conformation of C3 is a response of the immune system to cancer.

[Hydroxymethyluracil in the correction of adverse effects caused by chemotherapy of malignant neoplasms]. / Oksimetiluratsil kak korrektor oslozhnenii khimioterapii zlokachestvennykh opukholei.

Hydroxymethyluracil (HMU) in a dose of 1.5-3 g/day produces a stimulant effect upon leukopoiesis and granulocytopoiesis in cases of toxic neutropenia caused by chemotherapy. In the same dose range, HMU produces immunostimulant action in patients with immune deficit caused by oncopathology and chemotherapy.

[Conformational changes in C3 levels of complement during storage of blood from Hodgkin's disease patients and from healthy people]. / Konformatsionnye izmeneniia C3-komponenta komplementa pri khranenii krovi bol'nykh limfogranulematozom i zdorovykh liudei.

Storage-related differences in C3 level of blood complement and its hydrolized form--C3(H2O)--were identified in Hodgkin's disease patients and healthy donors, by immunoenzymatic analysis using murine monoclonal antibodies. Both C3 and C3(H2O) levels in blood serum of patients varied with time and were significantly different from those in health subjects; they correlated with EDTA concentration. After a second thawing of plasma in patients, there were no traces left of C3(H2O).

[The effect of erythromycin on immunity in immunodeficiency]. / Vliianie éritromitsina na immunitet pri immunodefitsite.

The effect of 12.5 and 25 mg/kg doses of erythromycin on the immunity of intact mice and in cyclophosphan- and azathioprine-induced immunodeficiency was studied. Erythromycin has no effect on the number of antibody-forming cells in the spleen of intact and immunocompromised with cyclophosphan animals. It increases their number against the background of azathioprine. Immunosuppression may change the character of the effect of erythromycin on delayed hypersensitivity. Erythromycin stimulates phagocyte activity in intact animals and in immunosuppression.

[The effect of gentamycin on immunity in immunodeficiency and the action of immunomodulators]. / Vliianie gentamitsina na immunitet pri immunodefitsite i deistvie immunomoduliatorov.

The effect of 3 and 6 mg/kg gentamicin on the immunity of intact mice and cyclophosphan- and azathioprine-induced immunodeficiency was studied. Gentamicin deepens the severe suppression of antibody genesis against the background of cyclophosphan and azathioprine, inhibits the reaction of GZT in intact mice. The antibiotic does not prevent stimulation of AOK production by methyluracil and prodigiosan, and does not change the effect of immunostimulators on GZT in immunosuppression. Gentamicin has no effect on the phagocytic activity of neutrophils and macrophages in intact animals. The character of the effect of the antibiotic on phagocytosis depends on the genesis of immunosuppression. The effectiveness of gentamicin in experimental infection is maintained in immunosuppression also.

[The immunotropic properties of rifampicin and their correction]. / Immunotropnye svoistva rifampitsina i ikh korrektsiia.

The effect of rifampicin on antibody genesis depends on the dose, duration, and time of its administration in relation to the antigen, as well as on the character of immunosuppression. The antibiotic has no effect on delayed hypersensitivity and stimulates the activity of phagocytes, predominantly that of neutrophils. The effectiveness of rifampicin in experimental infection is maintained in treatment with cyclophosphane and azathioprine. When administered in combination with rifampicin and cytostatics methyluracil possesses a broader spectrum of immunostimulating activity than that of prodigiosin and levamisole.

[Immunity during ampicillin administration against a background of immunosuppression]. / Immunitet pri vvedenii ampitsillina na fone immunosupressii.

The effect of 50 and 100 mg/kg doses of ampicillin, immunocompromised by cyclophan and azathioprine, on immunity of intact mice was studied. Ampicillin did not change the number of antibody-forming cells (AFC) and delayed hypersensitivity (DHS) in immunosuppression. It inhibited spontaneous oxidant metabolism of neutrophils and macrophages against the background of azathioprine. The therapeutic effect of ampicillin was maintained under such conditions. In intact animals the antibiotic did not change the number of AFC, increased DHS expression, and reduced the spontaneous index of macrophage activation in the nitroblue tetrazolium test.