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Background: Ras oncogene mutations leading to hyperactivation of the MAPK/ERK signaling pathway occur in 25% of all human tumors, and for gastrointestinal tumors, the frequency of Ras mutations amounts to 60%. The introduction of a Ras-GTPase inhibitor into clinical practice would increase the effectiveness of the treatment of socially significant diseases such as stomach and intestinal cancer. Aim: To select the optimal dose with a subsequent assessment of the safety of iRAS when administered to patients with gastrointestinal tract tumors, including those with peritoneal carcinomatosis. Materials and methods: This was a prospective open-label non-randomized phase I study for the assessment of safety and tolerability, with an adaptive design and determination of the maximally tolerated dose of the iRAS. Three dose levels were used (0.45 mg/kg, 0.9 mg/kg, 1.8 mg/kg) according to the "3 + 3" scheme. The study included 11 patients after surgery for stomach or colorectal cancer. The patients were administered PIPAC therapy with iRAS twice with a 7-days interval. The study duration was 28 ± 1 days. During the study, the patient monitoring included physical examination, assessment of vital signs, electrocardiography and echocardiography, laboratory parameters (hematology, clinical chemistry, coagulation tests, and urine analysis). Results: The anti-tumor iRAS agent demonstrated satisfactory tolerability of all doses studied, including the maximal 1.8 mg/kg dose. Vital sign and laboratory abnormalities were clinically non-significant and did not require additional therapeutic interventions. Statistically significant abnormalities were registered for total protein (p = 0.00028), white blood cell counts (p = 0.007), lymphocyte counts (p = 0.0008), and a number of other blood parameters; however, most of these abnormalities were within the physiological normal ranges. Vital signs such as electrocardiography and echocardiography parameters remained stable throughout the entire follow-up period (28 days after administration of the drug). There were short-term rises in body temperature, minor pains in the postoperative scar area. Conclusion: This trial of safety and tolerability of iRAS showed that no cases of dose-limiting toxicity in the studied dose range. The 1.8 mg/kg dose can be recommended for further clinical studies.

Aim. To determine clinical features and some mechanisms of osteosarcopenia development in patients with chronic pancreatitis (CP). Materials and methods. A casecontrol study was conducted on the basis of the Saratov State Clinical Hospital 5 in 20152018 of patients with CP. In a study of 161 patients with CP included, the control group 30 healthy individuals. Patients were divided into groups according to the etiology of CP: 79 with toxic-metabolic CP, 82 with biliary CP. To determine the risks of low-energy fractures, 154 patients were tested with the Fracture risk assessment tool (FRAX). Along with the standard examination, 30 patients with CP dual-energy X-ray absorptiometry was performed. To assess the state of skeletal muscles, body mass index was determined, hand-held dynamometry was performed, and a set of Short Physical Performance Battery (SPPB) tests was used. Along with the assessment of traditional risk factors for osteosarcopenia gender, age, state of reproductive function in women, body mass index, functional state of the pancreas (pancreas) the quantitative content of interleukins (IL)-2, 6, 8 in in colonic biopsies was analyzed by enzyme-linked immunosorbent assay (ELISA). Results. Bone disorders, according to densitometry, was detected in 70.0% of patients with CP, in 13.3% of the control group. Presarcopenia was detected in 62 (38.5%) patients with CP, sarcopenia in 34 (21.1%), in the control group presarcopenia and sarcopenia were not detected. Sarcopenia was statistically significantly more common in toxic-metabolic CP than in biliary CP (2=11.6; p0.001). Correlations of the lumbar spine T-score and IL-6 (r=-0.29; p=0.03), IL-8 (r=-0.29; p=0.04) were revealed. Correlations between sarcopenia and the concentration of cytokines in the in the colon mucosa in CP were determined (IL-2: r=0.44; p0.001; IL-6: r=0.48; p0.001; IL-8: r=0.42; p0.001). Conclusion. The development of osteopenia and sarcopenia syndromes in CP is interrelated and associated with both traditional risk factors and an increased concentration of cytokines in the in the colon mucosa.