Oncolytic viral therapy for gliomas: Advances in the mechanisms and approaches to delivery.

Glioma is a diverse category of tumors originating from glial cells encompasses various subtypes, based on the specific type of glial cells involved. The most aggressive is glioblastoma multiforme (GBM), which stands as the predominant primary malignant tumor within the central nervous system in adults. Despite the application of treatment strategy, the median survival rate for GBM patients still hovers around 15 months. Oncolytic viruses (OVs) are artificially engineered viruses designed to selectively target and induce apoptosis in cancer cells. While clinical trials have demonstrated encouraging results with intratumoral OV injections for some cancers, applying this approach to GBM presents unique challenges. Here we elaborate on current trends in oncolytic viral therapy and their delivery methods. We delve into the various methods of delivering OVs for therapy, exploring their respective advantages and disadvantages and discussing how selecting the optimal delivery method can enhance the efficacy of this innovative treatment approach.

[Pain and quality of life after laparoscopic transabdominal preperitoneal hernioplasty with different ways of fixing the peritoneum. Results of early completion randomized clinical trial]. / Bolevoi sindrom i kachestvo zhizni posle laparoskopicheskoi transabdominal'noi preperitoneal'noi gernioplastiki s raznymi sposobami fiksatsii bryushiny. Rezul'taty dosrochno zavershennogo randomizirovannogo klinicheskogo issledovaniya.

OBJECTIVE: To compare and statistically evaluate the severity of pain syndrome and quality of life depending on the method of fixation of the parietal peritoneum during laparoscopic hernia repair (suture fixation or the use of tack fixation). METHODS: A randomized clinical trial was conducted from May to June 2021 at the Lomonosov Moscow State University Medical Center. It was planned to observe patients for a year. In the first group, the fixation of the parietal peritoneum was performed using suture fixation, in the second group, the peritoneal flap was fixed using a fixation device. In the course of statistical data processing, it was planned to study the dependence of the duration of the operation, the severity of the pain syndrome in the early postoperative period, the frequency of complications, the quality of life of patients in the postoperative period on the chosen method of the fixation of the parietal peritoneum. RESULTS: At the initial stage of the study, 8 patients with inguinal hernias were selected in the first group during randomization, and 6 patients were selected in the second group. Each patient of the second group in the early postoperative period had a more pronounced local pain, protective muscle tension in the projection of fixation of the parietal peritoneum with tacks, which was accompanied by negative psychoemotional reactions, an increase in the dose of analgesic drugs. Due to the revealed features of the early postoperative period in patients of second group, it was considered unethical and inappropriate to continue the study within the protocol. CONCLUSION: The results obtained do not allow us to draw statistically supported conclusions. The solution of the problem of the peritoneal flap fixation method is possible in two ways: abandoning stapler fixation in favor of suture or conducting additional clinical studies with an analysis of the impact of the choice of peritoneal fixation technique not only on acute and chronic postoperative pain, but on quality of life in the early and delayed postoperative periods.

[PD-L1 expression in EBV-associated gastric carcinomas]. / Ekspressiya PD-L1 v EBV-assotsiirovannom rake zheludka.

OBJECTIVE: Assessment of the incidence of PD-L1 expression in EBV-associated gastric adenocarcinomas, as well as clarification of the clinical and morphological characteristics and median survival of patients with PD-L1-positive EBV-associated gastric cancer. MATERIAL AND METHODS: Samples of surgical material from 127 patients with stomach cancer were studied. Each sample was stained by in situ hybridization using primers for the Epstein-Barr virus-encoded small RNAs (EBER). Expression of PD-L1 was assessed immunohistochemically (PD-L1 SP263, PD-L1 SP142). The results obtained were compared with the main clinical and morphological characteristics of gastric cancer and median survival of patients. RESULTS: The detection rate of PD-L1 SP263 and PD-L1 SP142 in EBV-associated gastric adenocarcinoma in our sample was 100% and 76.9% respectively, thus, PD-L1 expression (SP263, SP142) is significantly more frequently detected in EBV-associated gastric carcinomas. It was found that patients with positive expression of PD-L1 in EBV-associated gastric carcinomas are younger (mean age 56.3 years for SP263 and 55.6 years for SP142), belonging to male gender. In addition, this group is dominated by proximal localization of tumors, ulcerative form of growth, tubular histological type, intermediate subtype according to P. Lauren. These characteristics do not depend on the antibody clone: positive expression of SP142 and SP 263 was detected in the same patients with a few exceptions. The overall median survival of patients with positive PD-L1 status SP263 in EBV-associated gastric carcinomas was 35 months, for patients with positive PD-L1 status SP142 - 25 months. Median survival of SP142 PD-L1 positive patients is higher than overall median survival of PD-L1 negative patients in EBV-associated gastric carcinomas. It was found that PD-L1 status in EBV-associated gastric cancer is not a significant prognostic factor. CONCLUSION: A single PD-L1 status does not significantly affect the prognosis in patients with gastric cancer, including those in the group of EBV-associated carcinomas, and can only be considered in conjunction with 'classic' clinical and morphological characteristics, primarily with the stage of the tumor process, since they determine the prognostic properties of the tumor.

[Correlations between vessel stiffness and biomarkers of senescent cell in elderly patients].

Aim    To study the association between vascular wall stiffness and known markers for accumulation of senescent cells in blood, cells, and tissues of old patients.Material and methods    This study included male and female patients aged 65 years and older who were referred to an elective surgical intervention, that included a surgical incision in the area of the anterior abdominal wall or large joints and met the inclusion and exclusion criteria. For all patients, traditional cardiovascular (CV) risk factors and arterial wall stiffness (pulse wave velocity, PWV) were evaluated. Also, biomaterials (peripheral blood, skin, subcutaneous adipose tissue) were collected during the surgery and were used for isolation of several cell types and subsequent histological analysis to determine various markers of senescent cells.Results    The study included 80 patients aged 65 to 90 years. The correlation analysis identified the most significant indexes that reflected the accumulation of senescent cells at the systemic, tissue, and cellular levels (r>0.3, р<0.05) and showed positive and negative correlations with PWV. The following blood plasma factors were selected as the markers of ageing: insulin-like growth factor 1 (IGF-1), fibroblast growth factor 21 (FGF-21), and vascular endothelium adhesion molecule 1 (VCAM-1). A significant negative correlation between PWV and IGF-1 concentration was found. Among the tissue markers, P16INK, the key marker for tissue accumulation of senescent cells, predictably showed a positive correlation (r=0.394, p<0.05). A medium-strength correlation with parameters of the 96-h increment of mesenchymal stromal cells and fibroblasts and a weak correlation with IL-6 as a SASP (specific senescent-associated secretory phenotype) were noted. Results of the multifactorial linear regression analysis showed that the blood plasma marker, VCAM-1, and the cell marker, 96-h increment of fibroblasts, were associated with PWV regardless of the patient's age.Conclusion    Stiffness of great arteries as measured by PWV significantly correlates with a number of plasma, tissue, and cellular markers for accumulation of senescent cells. This fact suggests PWV as a candidate for inclusion in the panel of parameters for evaluation and monitoring of the biological age during the senolytic therapy.

[Study of gastric adenocarcinomas association with the Epstein-Barr virus-encoded small RNAs]. / Issledovanie assotsiatsii adenokartsinom zheludka s malymi virusnymi RNK virusa Epshteina­Barr.

OBJECTIVE: Assessment of the incidence of EBV-associated gastric adenocarcinomas in a sample of Russian patients, as well as clarification of the clinical and morphological characteristics and median survival of patients with EBV-associated gastric cancer. MATERIAL AND METHODS: We used samples of surgical material from 282 patients with a verified diagnosis of gastric cancer. Each sample was stained by in situ hybridization using primers for the Epstein-Barr virus-encoded small RNAs (EBER). The results obtained were compared with the main clinical and morphological characteristics of gastric cancer. RESULTS: The detection rate of EBV-associated gastric adenocarcinoma in our sample was 9.57%. EBER-positive tumors much more often (p=0.021) belong to the intermediate type according to the P. Lauren classification (66.67%) in comparison with EBER-negative tumors (38.82%). EBER-positive tumors significantly more often (p=0.035) belong to high-grade tumors - 75.00% in comparison with EBER-negative tumors (52.13%). The overall median survival of all patients with EBER-positive tumors (53.5 months) was higher compared to the overall median survival of all patients with EBER-negative tumors - 36.5 months (p=0.5379). The median survival of patients with EBER-positive stage III tumors (30.0 months) was also higher compared to that for patients with EBER-negative tumors - 20.0 months (p=0.5622). It was found that a single EBER status is not a significant prognostic factor (HR=1.0143; CI: 0.9897-1.0196). CONCLUSION: Separately taken EBER-status is not a significant independent prognostic factor and can be considered only in conjunction with the «classical¼ clinical and morphological characteristics, primarily with the stage of the tumor process, since it is they that determine the prognostic properties of the tumor.

[Outcomes of various techniques of mesh prosthesis fixation in laparoscopic hernia repair]. / Rezul'taty razlichnykh metodik fiksatsii setchatogo proteza pri laparoskopicheskoi gernioplastiki (TAPP).

OBJECTIVE: To compare early and long-term results of various mesh prosthesis fixation methods in laparoscopic inguinal hernia repair. MATERIAL AND METHODS: It is a prospective clinical non-randomized trial. The study included 212 patients. Conventional stapler fixation (112 patients), self-gripping mesh implants (48 patients) and n-butyl cyanoacrylate adhesive fixation (52 patients) were compared. We estimated surgery time, pain syndrome severity in early and long-term postoperative period, postoperative morbidity and recurrence rate were evaluated. RESULTS: Early postoperative morbidity, activation of patients and hospital-stay were similar in all groups. Pain syndrome within 6 postoperative hours in the first group exceeded the same parameter in the second group by 1.23 times (95% CI 1.15-1.31, p<0.05) and by 1.19 times in the third group (95% CI 1.12-1.26, p<0.05). Within 12 hours, pain syndrome in the first group was 1.27 times more severe compared to the third group (95% CI 1.20-1.34, p<0.05). Pain syndrome in long-term period was similar in all groups. In the first group, one recurrence was detected (0.9%). CONCLUSION: There were no significant between-group differences. However, we found the correlation of postoperative pain syndrome with mesh implant fixation technique.

[Persistence of Epstein-Barr virus antigens in gastric cancer: characteristic of inflammatory cellular reactions in tumor]. / Persistentsiya antigenov virusa Epshteina­Barr pri rake zheludka: kharakteristika vospalitel'nykh kletochnykh reaktsii v opukholi.

THE AIM OF THE STUDY: Is to establish the relationship between the persistence of viral antigens of the Epstein-Barr virus (EBV) and the cellular composition of the immune microenvironment of tumor tissue and the mucous membrane of peritumoral area in gastric cancer. MATERIAL AND METHODS: We used samples of surgical material from 55 patients with a verified diagnosis of gastric cancer. The expression of CD4, CD8, CD68, CD1a and LMP-1 was assessed. The results were assessed by the morphometric method. We selected three fields of view (magnification x200) in tumor tissue and in peritumoral areas separately and counted an absolute number of cells with positive staining with further calculation of the average number of cells and the median. RESULTS: LMP-1-negative tumors with LMP-1 expression in epithelium of peritumoral area were characterized by the highest density of CD4+ lymphocyte infiltration in the central part of the tumor; the highest density of CD8+ lymphocyte infiltration in the mucous membrane of peritumoral area (p=0.0190); the highest density of infiltration by macrophages in the mucous membrane of peritumoral area (p=0.2492); the highest density of infiltration by CD1a+ cells in the mucous membrane of peritumoral area (p=0.1503). The highest density of infiltration with CD1a+ cells was characteristic for LMP-1-positive and LMP-1-negative tumors (p=0.0813). The persistence of the LMP-1 viral antigen in the glandular epithelium of the peritumoral area in our sample does not have a statistically significant effect on the prognosis of the disease (RR=1.7718; p=0.0885) but there is a tendency towards a negative predictive value. CONCLUSION: High density of infiltration of glandular epithelium of peritumoral area with the expression of LMP-1 by CD4+ and CD8+ lymphocytes is most likely associated with the activation of the cellular immune response and may be one of the signs of the persistence of viral antigens. It was shown for the first time that the phenomenon of persistence of the LMP-1 viral antigen is characterized by a trend towards negative predictive value for patients with gastric cancer.

[Comparison of efficiency and safety of laparoscopic manual esophagoenterostomy and esophagoenterostomy with mechanical anastomotic devices after laparoscopic gastrectomy for stomach cancer]. / Sravnenie bezopasnosti i effektivnosti primeneniya metodiki ruchnogo intrakorporal'nogo ezofagoenteroanastomoza i apparatnogo ezofagoenteroanastomoza s ispol'zovaniem lineinykh sshivayushchikh apparatov posle laparoskopicheskoi gastrektomii po povodu raka zheludka.

OBJECTIVE: To compare laparoscopic manual esophagoenterostomy and esophagoenterostomy with mechanical stapling anastomotic devices after laparoscopic gastrectomy for stomach cancer. MATERIAL AND METHODS: There were 34 patients who underwent laparoscopic gastrectomy for stomach in 2015-2018. Roux-en-Y esophagoenterostomy was used to reconstruct the gastrointestinal tract. Manual anastomoses were performed in 18 patients (group 1), stapled anastomoses (endogia 45 mm, covidien, mansfield, ma, usa) - in 16 patients (group 2). There was no randomization. Surgery duration, length of icu-stay, terms of enteral nutrition initiation, postoperative complications, hospital-stay were analyzed. RESULTS: Mean duration of surgery in the first group was 217 (184-302) min, in the second group - 201 (162-311) min. Duration of surgery in the first group was 1.08-fold higher than in the second group (95% CI 1.03-1.13, p=0.05). Mean blood loss was 145 ml in both groups. Mean icu-stay was 20.2 (17-42) hours in the first group and 21.1 (16.2-46) hours in the second group (ratio 0.96, 95% CI 0.92-1.01, p=0.06). Total enteral feeding (sipping) was initiated on the third day in both groups. Mean postoperative hospital-stay was 9.21 (6-13) days in the first group and 9.23 (6-12 days) days in the second group (ratio 0.99, 95% CI 0,95-1.02, p=0.06). Postoperative morbidity was 5.5% in the first group and 6.25% in the second group. CONCLUSION: Laparoscopic manual esophagoenterostomy proposed by our surgical team does not have disadvantages in comparison with stapling anastomotic devices and these methods may be alternative to each other.

[Comparison of minimal invasive technologies for treatment of infected pancreatic necrosis]. / Sravnitel'naia otsenka minimal'no invazivnykh metodik lecheniia infitsirovannogo pankreonekroza.

AIM: the assessment of the role of minimally invasive interventional procedures in the treatment of patients with infected pancreatic necrosis and their safety, as well as comparison of the results of the most common modern minimally invasive techniques among themselves. METHODS: The results of treatment of 310 patients are presented with infected destructive pancreatitis from 2013 to 2018 on the basis of the city clinical hospital named after I.V. Davydovsky. The patients were divided into three groups: in the first one (n=170) patients underwent puncture followed by drainage of necrotic foci under ultrasound and CT control, in the second (n=98) patients underwent sanation of foci completely by laparoscopic access, in the third (n=42) a series of retroperitoneoscopy was used for the same purpose. RESULTS: In 114 (67.1%) cases, patients from the first group did not require further surgical intervention. The results of percutaneous drainage were successful. The average length of hospital stay in the first group was 27 days, in the second and third groups - 31 days (the ratio in the 2nd and 3rd groups was 1.03 (95% CI 0.97-1.08; p<0.05)). In the course of treatment, complications were identified in 35 (35.7%) patients in the 2nd and 17 (40.4%) patients in the 3rd group (ratio 0.88 (95% CI 0.82-0.94)). There were 22 (7.1%) deaths. The causes of death were: 1 (0.3%) of the patient had arrosive bleeding, 2 (0.7%) had duodenal fistulas, 19 (6.1%) multiple organ failure against the background of widespread retroperitoneal phlegmon. CONCLUSION: The efficacy of treatment of infected pancreatic necrosis depends on the possibility of full drainage of the necrotic focus, regardless of approach. Minimally invasive techniques can reduce intraoperative trauma by reducing the wound surface, which contribute to develop systemic inflammatory response syndrome.

[Ventral hernias and extracellular matrix of connective tissue]. / Ventral'nye gryzhi i ékstratselliuliarnyi matriks soedinitel'noi tkani.

Ventral hernia is still one of the most common reason for scheduled and emergency surgery. The review is designed to reveal relationships between metabolism in extracellular matrix of connective tissue and pathogenesis of ventral hernias. These data will be valuable to develop a personalized approach to the treatment of these patients.

[Early ileostomy closure in patients with rectal cancer. Primary results of the randomized controlled multicenter trial]. / Rannee zakrytie ileostom u bol'nykh rakom priamoi kishki. Pervye rezul'taty randomizirovannogo mul'titsentrovogo issledovaniia.

AIM: To evaluate safety of early closure of ileostomy in patients with rectal cancer after primary surgery. MATERIAL AND METHODS: The trial included patients from several medical centers without signs of anastomotic leakage. CT-proctography or rectoscopy were performed in 8 days after primary surgery to confirm integrity of the anastomoses. Exclusion criteria were factors affecting normal tissue regeneration (diabetes mellitus, steroid drugs prescription, etc.). Patients with intact anastomoses and no exclusion criteria were randomized into 2 groups: group 1 (n=31) with early closure of ileostomy (in 8-13 days after surgery) and group 2 (n=34) with delayed closure (after 12 weeks). All data were analyzed. RESULTS: Postoperative morbidity was similar in both groups (6.45% vs. 5.88%, p=0.08). However, less duration of reconstructive surgery was noted in group 1 (50 (27-126) min vs. 71 min (31-134). This value was 1.42 times less in the main group (95% CI 1.30-1.52; p=0.02). CONCLUSION: Early closure of ileostomy in patients after surgery for rectal cancer is feasible and does not result increased postoperative morbidity. This approach may be considered as an alternative to delayed closure. However, further researches devoted to analysis of ileostomy-associated complications and quality of life are necessary.