Vladimir M. Moiseyenko

Background. Despite improved outcomes with immune checkpoint inhibitors in first- or second-line advanced non-small-cell lung cancer (NSCLC) settings, a significant patient population has emerged that either does not respond to or progresses during anti-PD-(L)1-containing therapy. Following progression on platinum-based chemotherapy and PD-(L)1 inhibitor therapies, treatment options for patients with NSCLC are limited. Aim. To evaluate the clinical efficacy and safety of ceralasertib combined with durvalumab for the treatment of advanced or metastatic NSCLC without actionable genomic alterations. Materials and methods. This multicenter, single-arm, phase II study (NCT05941897; randomized clinical trial No. 88, dated February 21, 2023) conducted in Russia enrolled patients with EGFR and ALK wild-type NSCLC who had progressed on first- or second-line platinum-doublet chemotherapy and anti-PD-(L)1 immunotherapy. Eligible patients received oral ceralasertib 240 mg twice daily for 7 consecutive days followed by durvalumab 1500 mg as an intravenous infusion in continuous 28-day treatment cycles until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included disease control rate at 18 weeks (DCR), progression-free survival (PFS), duration of response, overall survival (OS), and safety. Results. Between June 2023 and July 2025, 55 patients were screened, of whom 39 received ceralasertib plus durvalumab. The median follow-up time was approximately 9 months. The confirmed ORR was 10.3% (4/39; 95% confidence interval [CI] 2.9–24.2), and DCR was 53.8% (21/39; 95% CI 37.2–69.9). Median PFS was 6.41 months (95% CI 3.71–8.28) and median OS was 18.04 months (95% CI 8.84–23.23). Adverse events (AEs) were reported in 31 patients (79.5%), with 11 (28.2%) experiencing grade ≥3 events. The most common AEs were nausea (53.8%), vomiting (23.1%), respiratory tract infection (20.5%), anemia (15.4%), asthenia (15.4%), fatigue (15.4%), and diarrhea (12.8%). No treatment-related serious adverse events or deaths occurred. Conclusion. The combination of ceralasertib and durvalumab demonstrated a manageable safety profile with clinical activity (as evidenced by PFS and OS) in second- or third-line treatment of patients with advanced or metastatic NSCLC without actionable genomic alterations. These findings support further investigation of this combination in selected patient populations.

Tumor microenvironment acidity represents a fundamental hallmark of cancer that promotes tumor progression, invasion, immune evasion, and treatment resistance. Objective . This study investigates the antitumor mechanisms of sodium bicarbonate-induced alkalization on mouse colon adenocarcinoma CT26 cells and human melanoma cells. Material and Methods . Cells were treated with varying sodium bicarbonate concentrations (50–119 mM) to assess effects on viability, metabolism, migration, and cell death pathways. Results . Results demonstrated immediate concentration-dependent extracellular pH elevation that decreased after 24 hours due to metabolic adaptation. Both cell lines exhibited dose-dependent cytotoxicity with an IC50 of approximately 80–90 mM, yet minimal apoptosis was detected via Annexin V/PI staining, suggesting alternative cell death mechanisms. Sodium bicarbonate signifcantly impaired cellular migration in wound healing assays, coinciding with mitochondrial depolarization as evidenced by reduced Mito Red fuorescence. Metabolic analysis revealed increased consumption of glucose and glutamine alongside elevated lactate production, indicating metabolic reprogramming in response to alkalization stress. While lysosomal accumulation increased with treatment (measured by Lyso Green), canonical autophagy markers (LC3B and p62) showed no signifcant changes, suggesting classical autophagy pathways are not primarily involved. Conclusion . These fndings indicate that sodium bicarbonate-induced alkalization triggers tumor cell death through mechanisms beyond conventional apoptosis and autophagy, potentially involving lysosome-mediated cell death or alkaliptosis. The study provides mechanistic insights supporting sodium bicarbonate as a potential adjuvant therapy that targets the tumor microenvironment’s acidity, with implications for enhancing conventional cancer treatments through pH modulation. Further research is needed to fully elucidate the precise cell death pathways involved.

In the context of global demographic aging, colorectal cancer is increasingly diagnosed in elderly and very old patients, representing a significant medical and social challenge, while the lack of data due to this group's underrepresentation in clinical trials results in variability in treatment approaches. This review aims to systematize current knowledge to formulate a personalized management strategy for such patients. Key aspects include the specific features of colorectal cancer in the elderly, the mandatory use of a Comprehensive Geriatric Assessment for risk stratification and treatment personalization, and the adaptation of surgical and pharmacological methods considering age-related changes in pharmacology and safety profiles. The most effective model is recognized as one that integrates the principles of geriatrics and oncology, optimizing the benefit-risk ratio and improving treatment outcomes and patients' quality of life.

Introduction. In retroperitoneal sarcomas with invasion of the large или major vessels, large-scale multivisceral resections with vascular reconstruction is a technical necessity. Despite the successes of oncovascular surgery, aspects of planning and performance of such surgical interventions remain insufficiently studied. Aim. Retrospective analysis and summary of our own experience of vascular reconstructions in retroperitoneal sarcomas. Materials and methods. The study included 80 patients (median age 52.5 years, 65 % men, 35 % women) who underwent 88 surgical procedures due to primary (35 (39.8 %) cases) and recurrent (53 (30.2 %) cases) tumors. Preoperative planning was based on clinical examination, imaging and morphological verification data with subsequent multidisciplinary discussion. In 44.3 % of cases liposarcomas were diagnosed, in 22.7 % – leiomyosarcomas. Vascular invasion was classified in accordance with the M.H. Schwarzbach et al. (2006) classification. Type I invasion was observed in 15.9 % patients, type II – in 45.5 %, type III – in 39.6 %. Efficacy of preoperative planning, immediate and long-term oncological and vascular surgical results were evaluated. Results. Preoperative diagnostic methods were characterized by high sensitivity but moderate specificity: 94.7 and 68.6 %, respectively (area under the curve (AUC) = 0.712 (95 % confidence interval 0.698–0.811). In 96.6 % of cases, vascular reconstructions were performed as a prosthetic replacement (57 cases), vascular patch plastic (16 cases) or vascular suture (12 cases), and in the arterial invasion group graft interposition was the most common (83.7 % cases). In surgeries on the target vessels, R0 resection was achieved. Radical resection (R0) on the margins of tumor lesion was confirmed in 79 (89.8 %) cases. During long-term observation period, specific vascular complications (thrombosis, occlusion) were reported in 10 (12.05 %) patients. Long-term results of treatment were followed-up in 69 (86.25 %) patients. Follow-up duration varied between 3 and 92 months (median 23 months). Local recurrence developed in 18.8 % of patients after R0 resection and in 85.7% after R1/R2 resection. Tumor progression was verified in 24 (39.3 %) patients. Conclusion. Multivisceral resection with reconstruction of the major vessels in retroperitoneal sarcomas improve survival and decrease the rate of local recurrences. Planning and performance of such procedures require multidisciplinary approach. Despite encouraging results, some fundamental aspects of the problem remain unsolved and necessitate further investigation.

The efficacy of immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) varies widely across patients. Growing evidence indicates that the gut microbiome, through its interaction with the tumor microenvironment, may influence the response to immunotherapy. To investigate this, we analyzed fecal and tumor samples from 63 patients with inoperable NSCLC undergoing ICI therapy. Based on microbiome profiling using 16S rRNA sequencing, patients were grouped according to treatment benefit, defined as progression-free survival (PFS) of six months or longer. Associations between α-diversity indices, microbial composition at the genus and phylum levels, and a composite Sum Index of Binary Abundance (SIBA) were examined in relation to clinical outcomes. Higher microbial α-diversity was linked to improved response to ICIs (p-value = 0.0078 for the Chao1 index). Multiple specific taxa, such as Ruminococcus gauvreauii (p-value = 2 × 10⁻⁴), Ruminiclostridium 9 (p-value = 8 × 10⁻⁴), and [Eubacterium] ventriosum (p-value = 9 × 10⁻⁴), were enriched in patients with favorable outcomes, whereas Oscillibacter and the Eubacterium hallii group were associated with disease progression (p-value = 2 × 10⁻³ and 9 × 10⁻³, respectively). The SIBA index, which reflects the absence of multiple beneficial bacterial taxa, proved to be a stronger predictor of treatment response than individual taxa alone. Median SIBA values were 18 vs. 24 in patients benefiting from IO therapy compared to non-responders (p-value = 9 × 10⁻⁷). These findings suggest that gut microbiome diversity and composition are closely tied to immunotherapy outcomes in NSCLC. Composite microbial metrics like SIBA may enhance predictive accuracy and inform personalized treatment approaches.

Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcinomas arising in BRCA1 mutation carriers almost always carry alterations of the TP53 gene thus providing an opportunity to address this question. The analysis of consecutive BC patients treated by NACT revealed a higher pCR rate in BRCA1-driven vs. BRCA1-wildtype BCs (13/24 (54%) vs. 29/192 (15%), p < 0.0001). Twelve pre-/post-NACT tissue pairs obtained from BRCA1 mutation carriers were available for the study. While TP53 mutation was identified in all chemonaive tumors, droplet digital PCR (ddPCR) analysis of the post-NACT tumor bed revealed the persistence of this alteration in all seven pCR-non-responders but in none of five pCR responders. Eleven patients provided to the study post-NACT tissue samples only; next-generation sequencing (NGS) analysis revealed mutated TP53 copies in all six cases without pCR but in none of five instances of pCR. In total, TP53 mutation was present in post-NACT tissues in all 13 cases without pCR, but in none of 10 patients with pCR (p < 0.000001). Therefore, the lack of visible tumor cells in the post-NACT tumor bed is indeed a reliable indicator of the complete elimination of transformed clones. Failure of ultrasensitive methods to identify patients with minimal residual disease among pCR responders suggests that the result of NACT is a categorical rather than continuous variable, where some patients are destined to be cured while others ultimately fail to experience tumor eradication.

E21049 Background: Local and international recommendations for anticancer treatment are formed and changed based on the results of clinical trials. A feature of most clinical trials is the strict criteria used to select “safe” patients without severe comorbidities. In real world practice, significant portion of patients do not meet all of these criteria (32%) [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586241/], which raises a significant question about the consistency of treatment results demonstrated in studies with data obtained in routine clinical practice (RCP). The purpose of this work was to compare the results of treatment of patients with unrespectable NSCLC receiving first-line drug therapy in RCP and in the framework of international clinical trials using the method of pseudo-randomization (propency score analysis). Methods: The current analysis included 344 patients with inoperable NSCLC who received first-line drug therapy as part of RCP and 90 patients included in various non-TKI clinical trials irrespectively of IO use 2018-2019.Firstly, a direct comparison of performance indicators was done (progression-free survival) using the Kaplan-Meier method for all patients included in the study.At the second stage, in order to eliminate the influence of the imbalance of prognostic factors, a regression analysis was carried out. To form balanced cohorts, we used the propensity score matching analysis.The propensity to progression was assessed using logistic regression analysis in each individual patient, taking into account the basic clinical characteristics: age, gender, ECOG, histological form, regional lymph nodes, presence of distant metastases (mts), stage of the disease, mts of the lung parenchyma, liver mts, pleural mts, bone lesions, adrenal mts, mts lesions of distant lymph nodes, mts lesions of other areas, mts lesions of the brain, number of metastasis zones, components of the first-line therapy regimen. Patients of both arms treatment were matched in a 1:1 ratio based on their progression propensity score in increments of 0.15.After matching two homogeneous groups of patients were formed: 83 in the RCP group and 84 in the clinical trial therapy group. Results: In a direct comparison of the results of the treatment, progression-free survival in the group of patient who underwent treatment in clinical trials was significantly higher than within the RCP (6.4 months 95% CI 5.9–6.9 vs. 13.3 months 95% CI 8.1–18.5; log rank p < 0.000).propensity score matching analysis showed a significantly longer time to progression in the clinical trials group of 13.3 months, 95% CI 8.3-18.3 versus 6.3 months. 95% CI 4.8-7.7; log rank p < 0.000. Conclusions: Results obtained in clinical trial are substantially better than seen in RCP, this should be taken into consideration when extrapolating new research findings.

Introduction. Intratumor heterogeneity is one of the key reasons for unfavourable prognosis in malignant tumors. Astrocytic tumors are known to develop therapy resistance inevitably during the course of disease. One of possible reason is tumor heterogeneity. Purpose. The aim of this work was to assess the intratumor morphologic and molecular heterogeneity in diffuse astrocytoma, anaplastic astrocytomas and primary glioblastomas. Material and methods. We conducted morphologic (n=22) and molecular-genetic (n=8) analysis of surgical specimens obtained from primarily operated glioblastoma giv (gb), anaplastic astrocytomas giii (aa) and diffuse astrocytoma gii (da) patients aged 18 years and older in whom total or subtotal tumor resection was performed. Tissue sampling for the analysis was performed from 5 equidistant areas of each tumor. Morphologic diagnosis was established according to who classification of central nervous system tumors (2007/2016). Mgmt, c-kit, top2a, pdgfr-α, ercc1, vegf genes mrnaexpression was assessed by rt-pcr. Idh1 and idh2 mutational status was evaluated by allele-specific pcr. Results. Morphologic heterogeneity was evident in 72,7 % tumors (16/22) overall. Heterogeneity was observed in 68,8 % (11/16) of gb, 80 % (4/5) of aa and in the only case of da. In 50 % of cases at least 3 different morphologic variants were seen in different areas of the tumor. This morphologic heterogeneity presented as the combination of different grades of anaplasia (gii – giv) in one tumor. Molecular profile was assessed in 48 expression analysis of genes: mgmt, c-kit, top2a, pdgfr-α, ercc1, vegf from 8 patients. Intratumoral molecular heterogeneity was revealed in 41,7 % of cases (20/48). Conclusion. The presence of intratumoral heterogeneity should be taken into account during surgery for adequate tumor sampling for histologic and molecular analysis which is critical for proper assessment of prognosis and following treatment planning.