Bismuth Nanoparticles Increase Effectiveness of Proton Therapy of Ehrlich Carcinoma.

We studied the antitumor activity of the combined use of local proton irradiation in two modes (10 and 31 Gy) with preliminary intra-tumoral injection of two types of bismuth nanoparticles differing in surface coating: coated with the amphiphilic molecule Pluronic-F127 or Silane-PEG (5 kDa)-COOH polymer. Nanoparticles were used in doses of 0.75 and 1.5 mg/mouse. In two independent series on experimental tumor model (solid Ehrlich carcinoma), bismuth nanoparticles of both modifications injected directly into the tumor enhanced the antitumor effects of proton therapy. Moreover, the radiosensitizing effect of bismuth nanoparticles administered via this route increased with the increasing the doses of nanoparticles and the doses of radiation exposure. In our opinion, these promising data obtained for the first time extend the possibilities of treating malignant neoplasms.

[Indocyanine green angiography in assessment of parathyroid remnant perfusion after subtotal parathyroidectomy: a case report]. / Angiografiya s indotsianinom zelenym v otsenke perfuzii ostatka tkani parashchitovidnoi zhelezy pri subtotal'noi paratireoidektomii: klinicheskoe nablyudenie.

A 72-year-old female patient with chronic kidney disease stage presented with multiple parathyroid adenomas and tertiary hyperparathyroidism. SPECT/CT with 99mTc-MIBI revealed accumulation of radiopharmaceuticals in 2 out of 4 parathyroid glands. Ultrasound established localization of all parathyroid glands. Subtotal parathyroidectomy with excision of 3 glands and resection of half of the fourth gland was performed. Intraoperative indocyanine green angiography was performed to identify all parathyroid glands and remnant perfusion. There was normal parathyroid function after 6 months.

Genetic and therapeutic landscapes in cohort of pancreatic adenocarcinomas: next-generation sequencing and machine learning for full tumor exome analysis.

About 7% of all cancer deaths are caused by pancreatic cancer (PCa). PCa is known for its lowest survival rates among all oncological diseases and heterogenic molecular profile. Enormous amount of genetic changes, including somatic mutations, exceeds the limits of routine clinical genetic laboratory tests and further stagnates the development of personalized treatments. We aimed to build a mutational landscape of PCa in the Russian population based on full exome next-generation sequencing (NGS) of the limited group of patients. Applying a machine learning model on full exome individual data we received personalized recommendations for targeted treatment options for each clinical case and summarized them in the unique therapeutic landscape.

Biological Response of Chinese Hamster B14-150 Cells to Sequential Combined Exposure to Protons and 12C Ions.

Proton and ion radiation therapy, when used both as single radiation and in mixed radiation mode, have a number of advantages over the conventional γ-therapy that are determined by physical characteristics of accelerated particles. The paper presents the results of an in vitro study of the effectiveness of sequential exposures of Chinese hamster tumor cells B14-150 to proton (p) and 12C ion beams. We used 4 irradiation schemes differing by the sequence of exposure and the contribution of each radiation to the total dose. Synergism was shown for 12C ions dose contribution of 45% (taking into account the coefficient of relative biological efficiency) and the sequence 12C→p.

[Extent of resection in patients with glioblastoma]. / Stepen' khirurgicheskoi rezektsii pri glioblastome.

OBJECTIVE: To investigate the impact of resection quality on subsequent survival of patients with glioblastoma. MATERIAL AND METHODS: There were 141 patients with morphologically confirmed glioblastoma (grade 4). Fractionation with the prescribed dose of 2 and 3 Gy was alternately used (pairwise modeling strategy). Total resection was performed in 29.8% of patients (EOR: 100%; n=42), subtotal - 56.7% (EOR: 70-99%; n=80). Extent of resection 1-69% was registered in 19 patients (13.5%). RESULTS: As of December 2022, 124 out of 141 patients (87.9%) were diagnosed with primary progression, 101 (71.6%) ones died. We analyzed the threshold role of EOR. The most informative level was 70% (p=0.002). EOR 100% was followed by median overall survival about 32.2 months (95% Cl: 15.3-49.1), EOR 70-99% - 21.3 months (95% Cl: 15.1-27.5), EOR 1-69% - 10.3 months (95% Cl: 3.8-16.9; p=0.003). Fractionation mode with the prescribed dose of 3 Gy partially eliminated significance of EOR (p=0.148) in contrast to standard fractionation (p=0.015). Tumor growth in the interval between surgery and radiotherapy (REP) reduces significance of EOR (p=0.042). Inclusion of second-line therapy with bevacizumab in multivariate analysis model (OR=0.488; p=0.002) makes EOR less significant (OR=0.749; p=0.085) in contrast to REP (OR=2.482; p<0.0001). CONCLUSION: To date, the principle of maximum safe resection remains fundamental in neurosurgery. EOR about 70% is sufficient regarding overall survival, but total resection should be sought if possible.

[Indocyanine green in liver tumor resection]. / Primenenie ICG na etapakh planirovaniya i realizatsii rezektsii pecheni po povodu opukholei.

Primary liver cancer and colorectal cancer liver metastases are among the leading causes of cancer-related mortality worldwide. Surgery is one of the main methods of treatment to achieve the best results in overall and recurrence-free survival. The main objectives in this surgery are preoperative planning, assessment of functional viability of liver parenchyma and total resection with low complication rate. Post-resection liver failure is one of the most formidable and often fatal complication following functional failure of liver remnant. Thus, preoperative assessment of liver functional reserves is a necessary step for adequate selection of patients and safe surgery. Passive liver tests, such as biochemical parameters or clinical scales, do not accurately reflect the actual functional component of liver parenchyma. The most accurate method is dynamic quantitative test of liver, such as indocyanine green clearance. The authors discuss the practical aspects of preoperative assessment of liver functional reserves using indocyanine green, as well as the concept and technical foundations of fluorescent imaging in hepatobiliary surgery.

[Indocyanine green fluorescence angiography in transoral endoscopic thyroidectomy for papillary thyroid cancer]. / Primenenie fluorestsentnoi angiografii s indotsianinom zelenym v transoral'noi endoskopicheskoi tireoidektomii pri papillyarnom rake shchitovidnoi zhelezy.

OBJECTIVE: To evaluate the effectiveness of ICG angiography in patients with papillary thyroid cancer (PTC) undergoing transoral endoscopic thyroidectomy (TOETVA) and selective neck dissection (level VI). MATERIAL AND METHODS: A retrospective analysis included 20 patients with PTC who underwent TOETVA with selective neck dissection (level VI) between September and December 2022. ICG was administered intravenously (5 mg ´ 3 times). We analyzed parathyroid glands by visual examination and ICG angiography. Fluorescence of all glands was assessed. RESULTS: Twenty patients underwent ICG angiography during TOETVA. A total of 68 parathyroid glands were identified. Only 76.5% (52/68) of parathyroid glands were identified at initial visual examination. ICG angiography additionally localized 12 glands that improved detection to 94.1% (64/68). At least one well-vascularized parathyroid gland was demonstrated by ICG angiography in 16 patients. In all these patients, serum parathyroid hormone was normal in 1 and 10 days after surgery. Two out of four patients who failed to identify a well-vascularized parathyroid gland developed transient hypoparathyroidism. There were no intraoperative and postoperative complications associated with ICG angiography. CONCLUSION: ICG angiography was simple, safe and effective for better identification and preservation of parathyroid glands in patients with PTC undergoing TOETVA. This method was valuable for assessing the viability and function of parathyroid glands and predicting postoperative hypocalcemia.

[Isolated endovascular liver chemoperfusion for liver metastases of uveal melanoma]. / Sposob izolirovannoi endovaskulyarnoi khimioperfuzii pecheni pri metastazakh uveal'noi melanomy v pechen'.

Isolated hepatic perfusion is one of the possible approaches for unresectable liver metastases of uveal melanoma. This technique is rare in modern oncology because of extremely difficult technique and high risk of intra- and postoperative complications. Thus, minimizing surgical trauma and increasing safety and reproducibility of this technique are important. There were 36 procedures of isolated «open¼ hepatic perfusion. The authors describe the first experience of endovascular hepatic perfusion. Advantages and clinical prospects of this method are shown.

Effect of Collagen and GelMA on Preservation of the Costal Chondrocytes' Phenotype in a Scaffold in vivo.

The aim of the study was to compare type I collagen-based and methacryloyl gelatin-based (GelMA) hydrogels by their ability to form hyaline cartilage in animals after subcutaneous implantation of scaffolds. Materials and Methods: Chondrocytes were isolated from the costal cartilage of newborn rats using 0.15% collagenase solution in DMEM. The cells was characterized by glycosaminoglycan staining with alcian blue. Chondrocyte scaffolds were obtained from 4% type I porcine atelocollagen and 10% GelMA by micromolding and then implanted subcutaneously into the withers of two groups of Wistar rats. Histological and immunohistochemical studies were performed on days 12 and 26 after implantation. Tissue samples were stained with hematoxylin and eosin, alcian blue; type I and type II collagens were identified by the corresponding antibodies. Results: The implanted scaffolds induced a moderate inflammatory response in both groups when implanted in animals. By day 26 after implantation, both collagen and GelMA had almost completely resorbed. Cartilage tissue formation was observed in both animal groups. The newly formed tissue was stained intensively with alcian blue, and the cells were positive for both types of collagen. Cartilage tissue was formed among muscle fibers. Conclusion: The ability of collagen type I and GelMA hydrogels to form hyaline cartilage in animals after subcutaneous implantation of scaffolds was studied. Both collagen and GelMA contributed to formation of hyaline-like cartilage tissue type in animals, but the chondrocyte phenotype is characterized as mixed. Additional detailed studies of possible mechanisms of chondrogenesis under the influence of each of the hydrogels are needed.

[Isolated liver perfusion with melphalan followed by pembrolizumab therapy for unresectable metastases of uveal melanoma to the liver]. / Sposob izolirovannoi perfuzii pecheni melfalanom s posleduyushchei terapiei pembrolizumabom v lechenii nerezektabel'nykh metastazov uveal'noi melanomy, ogranichennykh pechen'yu.

Uveal melanoma accounts for 80% of all ocular melanomas, and 30-60% of patients have metastases to the liver. A few patients are candidates for liver resection, and this disease is associated with poor prognosis. There are few data on optimal management of metastatic uveal melanoma. Isolated hepatic perfusion is a perspective method for regional treatment of inoperable metastatic liver lesions with uveal melanoma. We present a patient with uveal melanoma who underwent previous enucleation of the eye. Cancer progressed 15 years later as an isolated inoperable metastatic liver lesion. The patient underwent isolated liver perfusion with melphalan, hyperthermia and oxygenation. Subsequently, the patient received systemic therapy with pembrolizumab. Partial response was achieved 1 month after the procedure. There was no progression for 20 months after surgery under systemic therapy with pembrolizumab. Thus, isolated liver chemoperfusion with melphalan is advisable in these patients.

[Early progression of glioblastoma before radiotherapy]. / Rannee progressirovanie do luchevoi terapii pri glioblastome.

OBJECTIVE: To analyze the influence of continued growth of glioblastoma between surgery and radiotherapy on subsequent survival. MATERIAL AND METHODS: Fractionation with a prescribed dose of 2 and 3 Gy was alternately applied using a pairwise modeling strategy in 140 patients with morphologically confirmed glioblastoma (grade 4). Early progression of disease between microsurgery and radiotherapy was diagnosed in 60 patients, and no tumor growth was noted in 80 patients. RESULTS: The minimum period of early progression was 0.33 months, maximum - 4.27 months (median 1.1 (95.0% CI: 0.9-1.3)). The most significant predictors of early progression were resection quality (p<0.0001), large residual tumor (p=0.003) and no MGMT promoter methylation (p=0.001). IDH1 status did not affect early progression. In residual tumor ≥1.2 cm3, the median period of early progression was 1.9 months (n=70; 95% Cl: 1.3-2.5), <1.2 cm3 - 3.5 months (n=70; p=0.019). After resection of less than 76% of tumor, this value was 1.1 months (n=28), ≥76% - 3.1 months (n=112; p=0.006). Without tumor growth, the median overall survival was 33.41 months (n=80; 95% Cl: 27.1-39.7), with early progression - 16.03 months (n=60; 95% Cl: 13.5-18.6; p<0.0001). This predictor was significant for fractionation with a prescribed dose of 3 Gy (p<0.0001) and standard radiotherapy (2 Gy; p=0.028). By December 2022, 26 out of 40 patients without early progression survived two years after treatment (3 Gy) (65%, median not reached). In case of fractionation with a prescribed dose of 2 Gy, 20 patients survived this period (50%, median reached). CONCLUSION: Almost half of patients with newly diagnosed glioblastoma develop early progression between microsurgery and radiotherapy. Therefore, patients with and without early progression should be probably assigned to different prognostic groups regarding overall survival.

Anti-Tumor Efficacy of Photodynamic Therapy of Solid Tumors in Laboratory Animals with Guanidine and Biguanidine Derivatives of Chlorine e6.

We evaluated antitumor efficacy of photodynamic therapy of murine Ehrlich carcinoma and rat sarcoma M-1 with new photosensitizers 131-N-(4-aminobutyl)amydo chlorine e6 (1), 132-(5-guanidylbutanamido)-chlorine e6 (2), and 132-(5-biguanidylbutanamido)-chlorine e6 (3). The inhibiting effect of the photodynamic therapy was evaluated by the following parameters: tumor growth inhibition, complete regression of the tumors, and absolute growth rate of the tumor nodes in animals with the continued neoplasia growth. The criterion of cure was the absence of tumors up to 90 days after the therapy. It is shown that the studied photosensitizers have high antitumor activity in the photodynamic therapy of the Ehrlich carcinoma and sarcoma M-1.

Preclinical Study of Therapeutic Efficacy of a New Russian Radiopharmaceutical 177Lu-DOTA-PSMA.

The therapeutic efficacy of a Russian radiopharmaceutical 177Lu-DOTA-PSMA was studied in vivo using male BALB/c nu/nu (nude) mice with prostate carcinoma 22Rv1 xenografts by tumor growth inhibition criterion. The mean tumor volumes in mice treated with 177Lu-DOTA-PSMA were significantly lower than in animals of the control group. There were no significant differences in the values of tumor growth inhibition between the groups of animals receiving 3.7 or 7.4 MBq of 177Lu-DOTA-PSMA.

In Vitro Antiviral Activity of a New Indol-3-carboxylic Acid Derivative Against SARS-CoV-2.

The coronavirus disease (COVID-19) pandemic has brought into sharp relief the threat posed by coronaviruses and laid the foundation for a fundamental analysis of this viral family, as well as a search for effective anti-COVID drugs. Work is underway to update existent vaccines against COVID-19, and screening for low-molecular-weight anti-COVID drug candidates for outpatient medicine continues. The opportunities and ways to accelerate the development of antiviral drugs against other pathogens are being discussed in the context of preparing for the next pandemic. In 2012-2015, Tsyshkova et al. synthesized a group of water-soluble low-molecular-weight compounds exhibiting an antiviral activity, whose chemical structure was similar to that of arbidol. Among those, there were a number of water-soluble compounds based on 5-methoxyindole-3-carboxylic acid aminoalkyl esters. Only one member of this rather extensive group of compounds, dihydrochloride of 6-bromo-5-methoxy-1-methyl-2-(1-piperidinomethyl)-3-(2-diethylaminoethoxy) carbonylindole, exhibited a reliable antiviral effect against SARS-CoV-2 in vitro. At a concentration of 52.0 µM, this compound completely inhibited the replication of the SARS-CoV-2 virus with an infectious activity of 106 TCID50/mL. The concentration curves of the analyzed compound indicate the specificity of its action. Interferon-inducing activity, as well as suppression of syncytium formation induced by the spike protein (S-glycoprotein) of SARS-CoV-2 by 89%, were also revealed. In view of its synthetic accessibility - high activity (IC50 = 1.06 µg/mL) and high selectivity index (SI = 78.6) - this compound appears to meets the requirements for the development of antiviral drugs for COVID-19 prevention and treatment.

Post-Irradiation Recovery of B14-150 Fibrosarcoma Cells after Combined Irradiation with Low and High Linear Energy Transfer.

The use of radiation with low and high linear energy transfer (LET) in the same treatment regimen is promising in terms of increasing the efficiency and reducing the severity of radiation complications. Here we studied combined effect of protons (LET≈3 keV/µm) and heavy recoils (HR) induced by 14.5 MeV neutrons (LET≈290 keV/µm) on B14-150 fibrosarcoma cells. Comparison of the 4 irradiation schemes with different high-LET/low-LET dose ratios and the irradiation sequences revealed higher effectiveness of the combined action in the HR→protons sequence and with increasing HR dose contribution to 40% of the total dose. The observed effects were due to differences in the recovery of damages induced in cells by radiations with low and high LET.

[Vertical resections for larynx cancer with preservation of the thyroid cartridge plates]. / Vertikal'nye rezektsii pri rake gortani s sokhraneniem plastin shchitovidnogo khryashcha.

This article presents a method of organ-preserving surgical treatment of laryngeal cancer, which has been developed and used since 1991 at the Tsyba Medical Radiological Research Center, Branch of the National Medical Research Center of Radiology of the Ministry of Health of Russia. The indications for this method are tumors affecting the middle part of the larynx, limiting its mobility, extending to the anterior commissure, laryngeal ventricle, vestibular fold, lower larynx and one arytenoid cartilage, but retaining mobility in the scooper-cricoid articulation. OBJECTIVE: To increase the functional safety of the larynx and improve the quality of life of patients with laryngeal cancer by using the developed method of organ-preserving surgical intervention in combined treatment. MATERIAL AND METHODS: The study included 197 patients who were operated on by the same method for a primary tumor or in connection with a relapse of the disease. At the first stage, all primary patients underwent a course of radiation or chemoradiation therapy 40-50 Gy. In 78 patients with recurrent laryngeal cancer who underwent resection of the larynx, the previous treatment was carried out in the form of a full course of radiation or chemoradiation therapy with a above 60 Gy. RESULTS: Wound healing by primary intention in patients with preoperative irradiation was observed in 92.4% of cases. With resections for a primary tumor, restoration of functions was observed in 115 (96.6%) patients, and with resections of recurrent tumors - in 71 (91%) patients. Three-year disease-free survival in these patients was 74.4%. CONCLUSION: The presented data showed the high efficiency of the method. This is evidenced by the course of the postoperative period, functional and oncological results are comparable, and in some cases exceed those of other researchers.

Oncology during the New Coronavirus Infection Pandemic.

The COVID-19 pandemic has served as a catalyst for a whole layer of scientific research, including in Russia, where, since 2020, international multicenter studies have been conducted on the impact of the coronavirus infection on the course of oncological diseases, as well as on the development and application of new clinical methods in oncology. In the years 2020-2022, new methods of nuclear medicine based on the targeted effect of ionizing radiation of radiopharmaceuticals began to be actively developed, in particular, new domestic radiopharmaceuticals (RPs) for diagnostics and therapy and methods of intra-arterial radioembolization developed by RPs with 90Y and 188Re of primary and metastatic tumors of various localization. New methods of radiation therapy have been introduced into clinical practice, including remote radiation therapy with "fast" neutrons, which makes it possible to overcome the resistance of a tumor to radiation and drug treatment. In addition, the search for and introduction into clinical practice of new approaches in the field of gene therapy and the use of oncolytic viruses continues. Platforms for complex pharmacogenomic analysis based on global knowledge and deep machine learning are being used in Russia, allowing for the precise selection of the most effective therapy. New multidisciplinary technologies are being developed.

[Single-Domain Antibodies Used to Pretreat the Human Urinary Proteome in Cancer Biomarker Testing].

A number of single-domain antibodies (nanobodies) obtained previously to major marker blood proteins were tested as tools to preprocess urine samples from patients with bladder cancer. Nanobody-based tools demonstrated unique possibilities for noninvasive diagnostic studies along with other conventional methods, such as electrophoresis and, in prospect, mass spectrometric analysis. A testing of 22 samples from bladder cancer patients showed that the development of bladder cancer is accompanied by an increase in the urine contents of major blood proteins, including those known as potential bladder cancer biomarkers. New nanobody-based immunosorbents allow both specific enrichment and specific removal of particular antigenic proteins and subproteomes associated with them from a biological fluid. The isolation of immune complexes from the urine of a particular patient is of particular interest. An initial study of the complexes showed not only increased contents of IgA and IgG at advanced stages of the disease, but also many other components, which provide potential biomarkers of the pathological process in a particular patient. It is intended to use the approaches proposed in this work in a future larger-scale study of urine samples from patients with bladder cancer at different stages of the disease in order to identify new promising biomarkers of bladder cancer.

Calculation of the Biological Efficiency of the Proton Component from 14.8 MeV Neutron Irradiation in Computational Biology with Help of Video Cards.

Fast neutron therapy, which previously has demonstrated effective results, but along with a large number of complications, can again be considered a promising treatment method in the treatment of cancer. One of the ways of analyzing the relative biological efficiency and accurate biological dose of fast neutrons in body tissues is to improve the algorithms of computational biology and mathematical modeling. A high-performance computing code was written which allows to estimate in real-time mode the biological dose of the proton component from the action of neutron radiation with an energy of 14.8 MeV. A comparative analysis of the computing performance on various video cards was also performed.

Minimally Manipulated Bone Marrow-Derived Cells Can Be Used for Tissue Engineering In Situ and Simultaneous Formation of Personalized Tissue Models.

Red bone marrow and autologous bone tissue (bone fragments and bone chips) of the donor were harvested intraoperatively during autoplasty of talus bone defect. Titanium chips were obtained by grinding a fragment of a microporous titanium-coated hip arthroplasty (Zimmer). Bone marrow mononuclear cells were isolated in the operating room, and bone and titanium fragments were incubated with a suspension of mononuclear cells. The quality of revitalization was assessed by fluorescence microscopy and histological examination after culturing of adherent cells on the bone and titanium fragments. During culturing on bone chips, bone marrow mononuclear fraction cells demonstrated significantly higher metabolic activity than bone marrow cells (p=0.04). Mononuclear fraction cells were also capable of stable colonization of titanium fragments with the formation of composite tissue model.