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Abstract Background Lung cancer, which is diagnosed two to three times more frequently in patients over the age of 70, is a leading cause of cancer-specific mortality. Given the elevated risk of morbidity and mortality, surgical intervention may not always be the most appropriate primary treatment option. This study aims to evaluate specific risk factors associated with postoperative morbidity and mortality in elderly patients and to optimize patient selection therefore improving surgical outcomes. Patients and methods The study encompassed a cohort of 73 patients aged 75 and above who underwent surgical treatment for non-small cell lung cancer (NSCLC) at the Department of Thoracic Surgery of the P. Hertsen Moscow Oncological Research Institute between 2015 and 2021. All patients underwent preoperative evaluation, including PET/CT staging and functional assessment, carried out by a multidisciplinary team comprising thoracic surgeons, anesthesiologists, and other medical specialists. Results The investigation revealed a postoperative mortality rate of 5.5% and a postoperative morbidity incidence of 16.4%, with occurrences of atrial fibrillation in 41.6%, persistent air leak in 33.3%, and pneumonia in 25% of complicated cases. At the one-year follow-up, 88% of patients remained free from relapse, whereas at three years, this rate stood at 66%. During the follow-up period, 16 patients (22%) passed away, with a median survival duration of 44 months. Survival rates at one year, three years, and five years were 71%, 66%, and 35%, respectively. Multivariate analysis disclosed several significant factors predicting a complex postoperative period, including stage IIIb (p = 0.023), pN1 (p = 0.049), pN2 (p = 0.030), and central location (p = 0.007). Additionally, overall survival was primarily influenced by a Charlson comorbidity index of 6 (p = 0.044), stage Ia2 (p = 0.033), and the necessity for thoracotomy (p = 0.045). Conclusion Each case of lung cancer in patients aged 75 and older necessitates an individualized approach. Given the higher mortality rate relative to younger patients, comprehensive risk assessment and preoperative management of underlying comorbidities are imperative, with the involvement of anesthesiologists, intensive care physicians, cardiologists, and other relevant specialists as needed.

Aim: To access efficacy and safety of the upright proton therapy for the skull-base chordomas and chondrosarcomas. Materials and methods: The study encompasses single-center experience of proton therapy in chordomas (CA) and chondrosarcomas (CSA) of skull-base localization. We evaluate overall survival, local control and toxicity. Tumor response was assessed in accordance with RANO criteria. Treatment-related toxicity was evaluated with the help of CTCAE v 5.0 scale. Results: Proton therapy in the upright position was utilized for 51pts (patients) with CA-CSA (40 pts with chordoma and 11pts with chondrosarcoma) at the A. Tsyb Medical Radiological Research Center in 2016–2023. Median tumor volume constituted 30 cm3 (IQR (interquartile range) 15–41 cm3). Median total dose was 70 GyRBE. Median number of fractions was 35. Overall survival (OS) at 1-, 2- and 3-year rates reached 98.0 %, 88.6 % and 82.7 %, respectively. Median follow-up time was 36 months. The 1-, 2- and 3-year local control (LC) rates constituted, respectively, 98 %, 78.6 % and 66.3 %. Prior surgery showed statistically significant association with better prognosis (p = 0.023). Brainstem-to-tumor dose coverage compromise became the major pattern of LC failure (p = 0.03). The late radiation toxicity reactions included temporal lobe necrosis grade 2 in 2 pts, xerostomia grade 1 in 1pt, radiation cataract grade 2 in 1pt and persistent headache grade 2 in 4 pts. Severe late toxicity reactions were observed in 2 cases (4 %): 1 myelitis grade 3 and brainstem damage grade 5 in 1pt. Conclusion: Local control was achieved in the majority of patients receiving the scanning-beam upright proton therapy for skull-base CA-CSA. The LC rates after a surgery-radiotherapy combination treatment were higher compared with irradiation alone. Pattern of failure is mostly brainstem-tumor dose compromise. The high OS and LC rates were accompanied by low toxicity incidence. Even in complex case of the skull base CA-CSA upright proton therapy shows promising clinical outcomes.

Extensive chest wall defects occur in 28% of all sternal resection cases and are a major challenge in thoracic surgery. These cases are generally considered “critical defects” requiring primary or secondary reconstruction using various types of flaps, mesh repairs, bone autografts, or endoprosthesis. The past decade witnessed rapid advances in the application of personalized endoprostheses in thoracic surgery. Surgeons began to use carbon or titanium grafts for personalized sternum replacement. The main advantages of these implants are superior cosmetic effect, biocompatibility, and low risk of infection. Herein, we present a case of a 55-year-old patient with an indication for extended sternum resection due to metastatic thyroid cancer. The patient underwent extended sternum resection, followed by the implantation of a personalized microporous titanium sternum equipped with graspers for atraumatic rib fixation.

Background: Radiation-induced liver disease (RILD) is a severe complication arising from radiotherapy, particularly when treating abdominal malignancies such as hepatocellular carcinoma. The liver’s critical role in systemic metabolism and its proximity to other abdominal organs make it highly susceptible to radiation-induced damage. This vulnerability significantly limits the maximum safe therapeutic dose of radiation, thereby constraining the overall efficacy of radiotherapy. Among the various modalities, electron beam therapy has gained attention due to its ability to precisely target tumors while minimizing exposure to surrounding healthy tissues. However, despite its advantages, the long-term impacts of electron beam exposure on liver tissue remain inadequately understood, particularly concerning chronic injury and fibrosis driven by sustained oxidative stress. Objectives: to investigate the molecular and cellular mechanisms underlying the radioprotective effects of vitamin C in a model of radiation-induced liver disease. Methods: Male Wistar rats (n = 120) were randomly assigned to four groups: control, fractionated local electron irradiation (30 Gy), pre-treatment with vitamin C before irradiation, and vitamin C alone. The study evaluated the effects of electron beam radiation and vitamin C on liver tissue through a comprehensive approach, including biochemical analysis of serum enzymes (ALT, AST, ALP, and bilirubin), cytokine levels (IL-1β, IL-6, IL-10, and TNF-α), and oxidative stress markers (MDA and SOD). Histological and morphometric analyses were conducted on liver tissue samples collected at 7, 30, 60, and 90 days, which involved standard staining techniques and advanced imaging, including light and electron microscopy. Gene expression of Bax, Bcl-2, and caspase-3 was analyzed using real-time PCR. Results: The present study demonstrated that fractional local electron irradiation led to significant reductions in body weight and liver mass, as well as marked increases in biochemical markers of liver damage (ALT, AST, ALP, and bilirubin), inflammatory cytokines (IL-1β, IL-6, and TNF-α), and oxidative stress markers (MDA) in the irradiated group. These changes were accompanied by substantial histopathological alterations, including hepatocyte degeneration, fibrosis, and disrupted microvascular circulation. Pre-treatment with vitamin C partially mitigated these effects, reducing the severity of the liver damage, oxidative stress, and inflammation, and preserving a more favorable balance between hepatocyte proliferation and apoptosis. Overall, the results highlight the potential protective role of vitamin C in reducing radiation-induced liver injury, although the long-term benefits require further investigation. Conclusions: The present study highlights vitamin C’s potential as a radioprotective agent against electron beam-induced liver damage. It effectively reduced oxidative stress, apoptosis, and inflammation, particularly in preventing the progression of radiation-induced liver fibrosis. These findings suggest that vitamin C could enhance radiotherapy outcomes by minimizing liver damage, warranting further exploration into its broader clinical applications.

Radiotherapy is one of the risk factors for radiation-induced premature ovarian failure and infertility in cancer patients. The development of methods for ovarian radioprotection remains relevant. Moreover, electrons are a little-studied and promising method of radiation with the least toxic effect on normal tissues. The assessment of intracellular mechanisms regulating the protective effects of leukocyte-poor platelet-rich plasma in a model of radiation-induced premature ovarian failure caused by electron irradiation. Wistar rats were divided into four groups, namely a control group, irradiation group (electron exposure), irradiation + leukocyte-poor platelet-rich plasma group, and only leukocyte-poor platelet-rich plasma group. Fragments of ovaries were removed and hormonal, oxidant, histological, and morphometric studies were carried out. The cell cycle of ovarian follicles and the inflammatory and vascular response were assessed using immunohistochemistry. The activity of MAPK, ERK, and PI3K pathways was also assessed using the RT-qPCR. We found that electron irradiation causes a decrease in the functional activity of the ovaries and the death of follicular cells through apoptosis. The administration of LP-PRP led to a partial restoration of the cytokine balance. In addition, minor ovarian damage and mild inflammation were observed in this group. Leukocyte-poor platelet-rich plasma components have anti-inflammatory, angiogenetic, and radioprotective effects, reducing the activation of the NOX4, caspase and cytokine cascades, and inflammatory response severity through the MAPK/p38/JNK signaling pathway. This leads to the induction of endogenous antioxidant protection, the repair of post-radiation follicular damage, and slowing down the development of radiation-induced premature ovarian failure after electron irradiation.

Previously, we showed the antitumor activity of the new NOS/PDK inhibitor T1084 (1-isobutanoyl-2-isopropylisothiourea dichloroacetate). The present study included an assessment of in vitro cytotoxicity against human malignant and normal cells according to the MTT-test and in vivo antitumor effects in solid tumor models in comparison with precursor compounds T1023 (NOS inhibitor; 1-isobutanoyl-2-isopropylisothiourea hydrobromide) and Na-DCA (PDK inhibitor; sodium dichloroacetate), using morphological, histological, and immunohistochemical methods. The effects of T1084 and T1023 on the in vitro survival of normal (MRC-5) and most malignant cells (A375, MFC-7, K562, OAW42, and PC-3) were similar and quantitatively equal. At the same time, melanoma A375 cells showed 2–2.5 times higher sensitivity (IC50: 0.39–0.41 mM) to the cytotoxicity of T1023 and T1084 than other cells. And only HeLa cells showed significantly higher sensitivity to the cytotoxicity of T1084 compared to T1023 (IC50: 0.54 ± 0.03 and 0.81 ± 0.02 mM). Comparative studies of the in vivo antitumor effects of Na-DCA, T1023, and T1084 on CC-5 cervical cancer and B-16 melanoma in mice were conducted with subchronic daily i.p. administration of these agents at an equimolar dose of 0.22 mmol/kg (33.6, 60.0, and 70.7 mg/kg, respectively). Cervical cancer CC-5 fairly quickly evaded the effects of both Na-DCA and T1023. So, from the end of the first week of Na-DCA or T1023 treatment, the tumor growth inhibition (TGI) began to decrease from 40% to an insignificant level by the end of the observation. In contrast, in two independent experiments, CC-5 showed consistently high sensitivity to the action of T1084: a significant antitumor effect with high TGI (43–58%) was registered throughout the observation, without any signs of neoplasia adaptation. The effect of precursor compounds on melanoma B-16 was either minimal (for Na-DCA) or moderate (for T1023) with TGI only 33%, which subsequently decreased by the end of the experiment. In contrast, the effect of T1084 on B-16 was qualitatively more pronounced and steadily increasing; it was accompanied by a 3-fold expansion of necrosis and dystrophy areas, a decrease in proliferation, and increased apoptosis of tumor cells. Morphologically, the T1084 effect was 2-fold superior to the effects of T1023—the TGI index reached 59–62%. This study suggests that the antitumor effects of T1084 develop through the interaction of NOS-dependent and PDK-dependent pathophysiological effects of this NOS/PDK inhibitor. The NOS inhibitory activity of T1084 exerts an anti-angiogenic effect on neoplasia. At the same time, the PDK inhibitory activity of T1084 enhances the cytotoxicity of induced intratumoral hypoxia and suppresses the development of neoplasia adaptation to anti-angiogenic stress. Such properties allow T1084 to overcome tumor resistance and realize a stable synergistic antitumor effect.

Aggressiveness and age of manifestation of medullary thyroid cancer depend on the risk level of germline RET mutations. For high-risk mutations, preventive thyroidectomy is recommended at young age. In recent years, endoscopic operations for thyroid cancer were introduced in clinical practice. But such experience in pediatrics is very limited. We present a case report of a male patient, 6-year-old with the high-risk germline mutation С634R in RET gene. Close relatives (mother, cousin, and native sister) of the proband, were treated for medullary thyroid cancer. Also, his grandmother on the maternal line and her native brother died at the age of 38 and 37 years because of medullary thyroid cancer progression. Since 3 years old, our patient was under regular exams. At the age of six, calcitonin level was 8 ng/mL, and no evidence of pathology on ultrasound. According to recommendations of American Thyroid Association from 2015 (ATA 2015), preventive thyroidectomy was planned. This operation was performed by transoral vestibular approach. Oral nutrition started on the first day after the operation and the patient was discharged from the hospital. No major complications were observed. Transitory paresthesia and slight edema of the submental compartment were noticed. Consider this, endoscopic operation on the thyroid gland can be performed, as a preventive procedure, for RET gene germline mutation carriers in young age. This method helps avoid scars on the skin of the anterior neck.

Chemotherapy is among the main classical approaches to the treatment of oncologic diseases. Its efficiency has been comprehensively proven by clinical examinations; however, the low selectivity of chemotherapeutic agents limits the possibilities of this method, making it necessary to search for new approaches to the therapy of oncologic diseases. Photodynamic therapy is the least invasive method and a very efficient alternative for the treatment of malignant tumors; however, its efficiency depends on the depth of light penetration into the tissue and on the degree of oxygenation of the treatment zone. In this work, a hitherto unknown conjugate of a natural bacteriochlorin derivative and doxorubicin was obtained. In vitro and in vivo studies showed a more pronounced activity of the conjugate against MCF-7 and 4T1 cells and its higher tumorotropicity in animal tumor-bearing animals compared to free anthracycline antibiotic. The suggested conjugate implements the advantages of photodynamic therapy and chemotherapy and has great potential in cancer treatment.

Objective: The use of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET-СT) to determine the initial stage and assess the response to treatment for aggressive lymphomas is considered standard. Evaluation of bone marrow infiltration in PET-CT with 18F-FDG usually makes it possible to distinguish normal regenerating bone marrow after chemotherapy by the characteristic nature of absorption. Case report: A 54-year-old patient diagnosed with diffuse large B-cell lymphoma (DLBCL) with lesions of the lymph nodes and bone marrow of the focal form with osteodestruction of the lytic type. Therapy at the A.F.Tsyba MRRC – 6 cycles of R-CHOP, completed in December 2022. Results: The PET-CT - 2 cycles is completely normalized. The February 2023, PET-CT showed an increase in the level of metabolism in one of the foci of osteodestruction in the pelvic bones. The biopsy, March 2023, absence of signs of DLBCL. PET-CT, June 2023, the increase of contrast accumulation in previously identified foci. Trepan biopsy in July 2023 – a picture of hematopoiesis foci in the bone marrow, a statement of remission. PET-CT scan in December 2023 confirming the remission of the disease. Conclusion: False-positive PET-CT results in the era of rituximab began to be detected with greater frequency, therefore, their assessment and correct interpretation, as well as additional clarification using other available techniques, are necessary in modern clinical practice to choose tactics for further therapy.

AimThis study presents an analysis (efficacy and toxicity) of outcomes in patients with esthesioneuroblastoma after pencil beam proton therapy with a fixed beamline in the upright position.BackgroundEsthesioneuroblastoma (ENB) is an extremely rare tumor of sinonasal area located in critical proximity to vital structures. Proton therapy (PT) is often considered the optimal radiation treatment for head-and-neck tumors, although of limited availability. Upright PT delivered using fixed pencil beamline and rotating chair is a fairly promising option.MethodsThis is a single-center experience describing the outcomes of PT in 14 patients with ENB treated between January 2016 and October 2022; half of the cases had a history of previous irradiation. The therapy was applied using a fixed pencil beamline with 6D-chair for positioning. The median dose was 63 GyRBE (total range 48–70 GyRBE; based on 1.1 RBE multiplier for protons) with 2.0 GyRBE per fraction. The mean gross tumor volume was 109.5 cm3 (17.1–257.7 cm3). Patient demography, pathology, treatment parameters and toxicity data were analyzed. Radiation-induced reactions were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v 4.0.ResultsThe median follow-up time was 28 months. The 1- and 2-year locoregional control rates constituted 100% and 88.9%, respectively; the median duration of local control was 52 months. The 1- and 2-year progression-free survival (PFS) rates constituted 92.9% and 75.0%, respectively; the median PFS duration was 52 months. The 1- and 2-year overall survival (OS) rates constituted 92.9% and 84.4%, respectively. Two patients died of non-cancer-related causes (coronavirus-induced pneumonia) and 1 patient died of tumor progression. All patients tolerated PT well without any treatment gaps. Serious late toxicity reactions included glaucoma in 1 patient and cataract in 2 patients, in over half a year since irradiation.ConclusionPT with upright design of the unit affords promising outcomes in terms of disease control and toxicity rates in ENB, a sinonasal tumor of complicated localization.

Based on studies that focused on the effect of SARS-CoV-2 on human tissues, not only pulmonary invasion was revealed, but also impaired testicular function. Thus, the study of the mechanisms of influence of SARS-CoV-2 on spermatogenesis is still relevant. Of particular interest is the study of pathomorphological changes in men of different age groups. The purpose of this study was to evaluate immunohistochemical changes in spermatogenesis during SARS-CoV-2 invasion in different age groups. In our study, for the first time, a cohort of COVID-19-positive patients of different age groups was collected, and the following were conducted––confocal microscopy of the testicles and immunohistochemical evaluation of spermatogenesis disorders in SARS-CoV-2 invasion with antibodies to the spike protein, the nucleocapsid protein of the SARS-CoV-2 virus, and angiotensin convertase type 2. An IHC study and confocal microscopy of testicular autopsies from COVID-19-positive patients revealed an increase in the number of S-protein- and nucleocapsid-positively stained spermatogenic cells, which indicates SARS-CoV-2 invasion into them. A correlation was found between the number of ACE2-positive germ cells and the degree of hypospermatogenesis, and in the group of patients with confirmed coronavirus infection older than 45 years, the decrease in spermatogenic function was more pronounced than in the cohort of young people. Thus, our study found a decrease in both spermatogenic and endocrine (Leydig cells) testicular functions in patients with COVID-19 infection. In the elderly, these changes were significantly higher than in the group of young patients.

Background: Research on the subject of the influence of SARS-CoV-2 mechanisms on human homeostasis remains an actual problem. Particular interest is the study of pathomorphological changes in the appendix in children with COVID-19. Objectives: Aim of this study: morphological and molecular biological evaluation of the appendix in children of different age groups with COVID-19. Methods: Groups were formed on the basis of anamnestic, clinical, and morphological data: I (n = 42; aged 2 to 18 years, average age—10.8 ± 4.79)—with an established clinical diagnosis: coronavirus infection (COVID-19; PCR+); II (n = 55; aged 2 to 18 years, average age—9.7 ± 4.77)—with a confirmed clinical diagnosis of acute appendicitis; collected before the onset of the COVID-19 pandemic in 2017–2019; and III (n = 38; aged 2 to 18 years, average age—10.3 ± 4.62)—the control group. Histological and immunohistochemical studies were conducted using primary antibodies to CD3, CD4, CD68, CD163, CD20, and CD138 and to pro-inflammatory (IL-1, IL-6) and anti-inflammatory (IL-4, IL-10) cytokines. Results: In most samples of appendixes in children with COVID-19, signs of destructive phlegmonous–ulcerative and gangrenous appendicitis were discovered. An increase in CD3+, CD4+, CD68+, CD163+, and CD20+ CD138+ immunocompetent cells was found in the appendix of children with COVID-19. As well, there was an increase in pro-inflammatory (IL-1, IL-6) and anti-inflammatory (IL-4, IL-10) cytokines. Conclusions: The aforementioned pathological and immunohistochemical changes were more pronounced in the group of children aged 6–12 years (childhood).

Development of new techniques for multimodal treatment and diagnostics of various neoplasms and the improvement of current techniques can significantly increase the life expectancy of patients with carcinomas of the colon and abdominal-cavity organs, since prevention of various side effects of radiation therapy is one of the main problems of oncological care. Electron irradiation is one of the most promising types of radiation therapy. There are no data on proliferation and apoptosis of the colon epithelium after irradiation with electrons, especially in different modes (single and summary). Morphological evaluation of apoptosis and proliferation of colonic epithelium after local irradiation with electrons were conducted at doses of 2 Gy (Gray) and 25 Gy. Colon fragments from sexually mature Wistar rats (n = 50, body weight 200 ± 10 g) were divided into three groups: I—control (n = 10); II—experimental group (n = 20; local single electron irradiation at a dose of 2 Gy); III—experimental group (n = 30) with local fractional irradiation with electrons at a total dose of 25 Gy. They were studied using light microscopy using hematoxylin and eosin staining and immunohistochemical reactions with antibodies to Ki-67 and caspase-3 (Cas3). Morphological disorders were accompanied by increased expression of pro-apoptotic molecules (caspase-3), and the period of regeneration by proliferative marker (Ki-67). Colon electron irradiation led to disturbances in the histoarchitecture of varying severity, and an increase in cell apoptosis was observed (increased expression of caspase-3 and decrease in Ki-67). In addition, modulation of the PI3K/AKT and MAPK/ERK signalling pathways was detected. The most pronounced destructive changes were observed in the group of 25 Gy fractionated electron irradiation.

Non-invasive methods for determining blood hemoglobin (Hb) concentration are urgently needed to avoid the painful and time-consuming process of invasive venous blood sampling. Many such methods rely on assessing the average attenuation of light over a tissue area where hemoglobin is the dominant chromophore, without separating those areas corresponding to vessels and bloodless tissue. In this study, we investigate whether it is possible to determine hemoglobin levels in the blood by assessing the changes in light intensity when passing through large vessels in comparison to adjacent tissues, using this as a Hb level predictor. Using Monte Carlo light transport modeling, we evaluate the accuracy of determining hemoglobin levels via light intensity contrast and vessel widths estimated in the transmittance illumination geometry and estimate the influence of physiologically significant parameters such as vessel depth, dermis vascularization, and melanin content in the epidermis on the blood Hb prediction error. The results show that physiological variations in tissue parameters limit the mean absolute error of this method to ~15 g/L for blood Hb levels varying in the 60–160 g/L range, which finding is also supported by experimental data obtained for volunteers with different total blood Hb levels that have been determined invasively. We believe the application of new approaches to the non-invasive assessment of Hb levels will lead to the creation of reliable and accurate devices that are applicable in point-of-care and clinical practice.

The effects of residual radiation from atomic bombs have been considered to be minimal because of its low levels of external radioactivity. However, studies involving atomic bomb survivors exposed to only residual radiation in Hiroshima and Nagasaki have indicated possible adverse health effects. Thus, we investigated the biological effects of radioactive dust of manganese dioxide 56 (56MnO2), a major radioisotope formed in soil by neutron beams from a bomb. Previously, we investigated C57BL mice exposed to 56MnO2 and found pulmonary gene expression changes despite low radiation doses. In this study, we examined the effects in a radiation-sensitive strain of mice, BALB/c, and compared them with those in C57BL mice. The animals were exposed to 56MnO2 particles at two radioactivity levels and examined 3 and 65 days after exposure. The mRNA expression of pulmonary pathophysiology markers, including Aqp1, Aqp5, and Smad7, and radiation-sensitive genes, including Bax, Phlda3, and Faim3, was determined in the lungs. The radiation doses absorbed in the lungs ranged from 110 to 380 mGy; no significant difference was observed between the two strains. No exposure-related pathological changes were observed in the lungs of any group. However, the mRNA expression of Aqp1 was significantly elevated in C57BL mice but not in BALB/c mice 65 days after exposure, whereas no changes were observed in external γ-rays (2 Gy) in either strain. In contrast, Faim3, a radiation-dependently downregulated gene, was reduced by 56MnO2 exposure in BALB/c mice but not in C57BL mice. These data demonstrate that inhalation exposure to 56MnO2 affected the expression of pulmonary genes at doses

This research presents a novel synthetic photosensitizer for the photodynamic therapy (PDT) of malignant tumors: meso-tetra(3-pyridyl) bacteriochlorin, which absorbs at 747 nm (in the long-wavelength region of the spectrum) and is stable when stored in the dark. H2Py4BC demonstrates pronounced photoinduced activity in vitro against tumor cells of various geneses (IC50 varies from 21 to 68 nM for HEp2, EJ, S37, CT26, and LLC cultured cells) and in vivo provides pronounced antitumor efficacy in the treatment of mice bearing small or large S37, Colo26, or LLC metastatic tumors, as well as in the treatment of rats bearing RS-1 liver cholangioma. As a result, total regression of primary tumor nodules and cure of 40 to 100% of the animals was proven by the experiment criteria, MRI, and histological analysis. Meso-tetra(3-pyridyl) bacteriochlorin quickly penetrates and accumulates in the tumor tissue and internal organs of mice, and after 24 h, 80% of the dye is excreted from the skin in addition to 87–92% from the liver, kidneys, and spleen.

Fast neutron therapy has been used for decades. In conjunction with recent advances in photonic techniques, fast neutrons are no longer of much oncologic interest, which is not unequivocally positive, given their undoubted therapeutic value. This mini-review recalls the history of medical research on fast neutrons, considers their physical and radiobiological properties alongside their benefits for cancer treatment, and discusses their place in modern radiation oncology.

Solid pseudopapillary neoplasm (SPN) of the pancreas is an extremely rare tumor, associated with favorable prognosis and long-term survival in patients with advanced disease. However, limited data exist on systemic therapy for such patients. Herein, we present a case of a young woman with a history of SPN, who progressed after multiple surgical resections and chemotherapy regimens. The immunohistochemistry (IHC) showed overexpression of estrogen receptors (ER) and progesterone receptors (PR) in tumor tissue. The patient started to receive tamoxifen and showed a durable response to endocrine therapy.

The development of new effective and safe vasopressors is one of the ways to increase the effectiveness of the treatment of hypotensive disorders, the severe forms of which remain a common cause of death in all countries of the world. Previously, we synthesized the original compound T1059, a selective inhibitor of eNOS/iNOS which has a pronounced vasoconstrictive effect. Here we show its vasopressor activity in models of the early stage of acute hemorrhagic shock in rats and dogs, as part of preclinical studies. The results indicate NOS inhibitor T1059 as a potent long-acting vasopressor. Its single parenteral administration in sufficiently safe doses (1/50–1/9 LD10), caused in rats and dogs a rapid increase in vascular tone, accompanied by a prolonged hypertensive effect (within 90–120 min in rats, and within 115 min in dogs). The repeated administration of T1059 at low doses (1/3 of the first dose) made it possible to considerably (by at least 60 min) prolong a significant vasopressor effect. In all schemes, T1059 administration considerably inhibited the development of threatening cardiorespiratory disorders and significantly (p = 0.0026–0.0098) increased the short-term survival of experimental animals, formally extending the duration of the “golden hour” by 2 times. These data indicate that NOS inhibitors and, in particular, compound T1059, are able to create new opportunities in the treatment of hypotensive disorders, including the provision of assistance at the prehospital stage of treatment of such pathologies.

Lung cancer is a disease with a unique genetic pattern and is occasionally related to hereditary syndromes such as Lynch, Louis–Bar, and Li–Fraumeni. In some patients, germinal mutations may be discovered in combination with somatic alterations. For instance, Li–Fraumeni syndrome often reveals a mixture of TP53 and EGFR mutations. The development of new target therapies necessitates an extensive search for new pathogenic mutations. In this article, we present a rare case report of lung cancer, requiring a pneumonectomy, in three sibling brothers.

This text is based on the recommendations accepted by the 4th Hungarian Consensus Conference on Breast Cancer, modified on the basis of the international consultation and conference within the frames of the Central-Eastern European Academy of Oncology. The recommendations cover non-operative, intraoperative and postoperative diagnostics, determination of prognostic and predictive markers and the content of cytology and histology reports. Furthermore, they address some specific issues such as the current status of multigene molecular markers, the role of pathologists in clinical trials and prerequisites for their involvement, and some remarks about the future.

Abstract To understand the radiation effects of the atomic bombing of Hiroshima and Nagasaki among the survivors, radiation from neutron-induced radioisotopes in soil should be considered in addition to the initial radiation directly received from the bombs. 56Mn, which emits both β particles and γ-rays, is one of the dominant radioisotopes created in soil by neutrons from the bomb. Thus we investigated the biological effects of internal exposure to 56MnO2 particle in the lung of male Wistar rats comparing to the effects of external 60Co-γ irradiation. Absorbed doses of internal irradiation of lungs were between 25 and 65 mGy in 56MnO2-exposed animals, while the whole body doses were between 41 and 100 mGy. Animals were examined on days 3 and 61 after the exposure. There were no remarkable pathological changes related to 56MnO2 particle exposure. However, mRNA and protein expressions of aquaporin 5 increased significantly in the lung tissue on day 3 postexposure in 56MnO2 groups (by 1.6 and 2.9 times, respectively, in the highest dose group). Smad7 mRNA expression was also significantly elevated by 30% in the highest dose group of 56MnO2. Our data demonstrated that internal exposure to 56MnO2 induced significant biological responses including gene expression changes in the lungs, while external 60Co-γ irradiation of 2 Gy did not show any changes.

This article reports the electrospinning technique for the manufacturing of multilayered scaffolds for bile duct tissue engineering based on an inner layer of polycaprolactone (PCL) and an outer layer either of a copolymer of D,L-lactide and glycolide (PLGA) or a copolymer of L-lactide and ε-caprolactone (PLCL). A study of the degradation properties of separate polymers showed that flat PCL samples exhibited the highest resistance to hydrolysis in comparison with PLGA and PLCL. Irrespective of the liquid-phase nature, no significant mass loss of PCL samples was found in 140 days of incubation. The PLCL- and PLGA-based flat samples were more prone to hydrolysis within the same period of time, which was confirmed by the increased loss of mass and a significant reduction of weight-average molecular mass. The study of the mechanical properties of developed multi-layered tubular scaffolds revealed that their strength in the longitudinal and transverse directions was comparable with the values measured for a decellularized bile duct. The strength of three-layered scaffolds declined significantly because of the active degradation of the outer layer made of PLGA. The strength of scaffolds with the PLCL outer layer deteriorated much less with time, both in the axial (p-value = 0.0016) and radial (p-value = 0.0022) directions. A novel method for assessment of the physiological relevance of synthetic scaffolds was developed and named the phase space approach for assessment of physiological relevance. Two-dimensional phase space (elongation modulus and tensile strength) was used for the assessment and visualization of the physiological relevance of scaffolds for bile duct bioengineering. In conclusion, the design of scaffolds for the creation of physiologically relevant tissue-engineered bile ducts should be based not only on biodegradation properties but also on the biomechanical time-related behavior of various compositions of polymers and copolymers.

Orbital hemangiopericytomas (HPCs) are rare mesenchymal tumors with a high tendency to recur. Treatment options are quite limited in case of a relapse, but re-irradiation can be useful. Most of the available data limit the possibility of re-irradiation, while novel techniques (e.g., pencil beam proton therapy [PT]) open new approaches for the safe repeating of treatment. To the best of our knowledge, this is the first well-documented case of multi-times (>3) irradiation of tumors located intracranially. The case reported here describes orbital HPCs with proton irradiation performed two times since 1999 in a 30-year-old woman with a medical history as well as surgery followed by conventional radiotherapy (RT) and chemotherapy, and two times stereotactic RT (in 2009 and 2013).In 2016 the patient came to our hospital with the 3rd relapse of the tumor, located in the left orbit, with an intracranial part, involving cavernous sinus, which was close to the temporal lobe. The 4th course of irradiation was done in May to June 2016 by pencil beam PT. Radiation necrosis occurred after 2 years and was treated with bevacizumab (BVZ). Three years later, another relapse was treated with PT and BVZ. The 9-month follow-up showed complete tumor response without signs of brain toxicity. The patient died due to a brain abscess 1 year after the 5th irradiation. This case shows a possibility of irradiation, applied 5 times to the same location, with promising results and manageable toxicity.

Elucidation of the mechanisms for the response of cancer stem cells (CSCs) to radiation exposure is of considerable interest for further improvement of radio- and chemoradiotherapy of cervical cancer (CC). The aim of this work is to evaluate the effects of fractionated radiation exposure on the expression of vimentin, which is one of the end-stage markers of epithelial-mesenchymal transition (EMT), and analyze its association with CSC radiation response and short-term prognosis of CC patients. The level of vimentin expression was determined in HeLa, SiHa cell lines, and scrapings from the cervix of 46 CC patients before treatment and after irradiation at a total dose of 10 Gy using real-time polymerase chain reaction (PCR) assay, flow cytometry, and fluorescence microscopy. The number of CSCs was assessed using flow cytometry. Significant correlations were shown between vimentin expression and postradiation changes in CSC numbers in both cell lines (R = 0.88, p = 0.04 for HeLa and R = 0.91, p = 0.01 for SiHa) and cervical scrapings (R = 0.45, p = 0.008). Associations were found at the level of tendency between postradiation increase in vimentin expression and unfavorable clinical outcome 3–6 months after treatment. The results clarify some of the relationships between EMT, CSCs, and therapeutic resistance that are needed to develop new strategies for cancer treatment.

Insufficient vascular growth in the area of artificial-material implantation contributes to ischemia, fibrosis, the development of bacterial infections, and tissue necrosis around the graft. The purpose of this study was to evaluate angiogenesis after implantation of polycaprolactone microfiber scaffolds modified by a pCMV-VEGF165-plasmid in rats. Influence of vascularization on scaffold degradation was also examined. We investigated flat microfibrous scaffolds obtained by electrospinning polycaprolactone with incorporation of the pCMV-VEGF-165 plasmid into the microfibers at concentrations of 0.005 ng of plasmid per 1 mg of polycaprolactone (0.005 ng/mg) (LCGroup) and 0.05 ng/mg (HCGroup). The samples were subcutaneously implanted in the interscapular area of rats. On days 7, 16, 33, 46, and 64, the scaffolds were removed, and a histological study with a morphometric evaluation of the density and diameter of the vessels and microfiber diameter was performed. The number of vessels was increased in all groups, as well as the resorption of the scaffold. On day 33, the vascular density in the HCGroup was 42% higher compared to the control group (p = 0.0344). The dose-dependent effect of the pCMV-VEGF165-plasmid was confirmed by enhanced angiogenesis in the HCGroup compared to the LCGroup on day 33 (p-value = 0.0259). We did not find a statistically significant correlation between scaffold degradation rate and vessel growth (the Pearson correlation coefficient was ρ = 0.20, p-value = 0.6134). Functionalization of polycaprolactone by incorporation of the pCMV-VEGF165 plasmid provided improved vascularization within 33 days after implantation, however, vessel growth did not seem to correlate with scaffold degradation rate.

The goal of this study was to determine the activity in vitro and in vivo of avarol, a sesquiterpene hydroquinone originating from the Dysidea avara sponge from the south Adriatic Sea, against different cancer cell lines and two types of mouse carcinoma. To investigate the in vitro cytotoxicity, a human cervix adenocarcinoma cell line (HeLa), human colon adenocarcinoma (LS174), human non-small-cell lung carcinoma (A549), and a normal human fetal lung fibroblast cell line (MRC-5) were used. The in vivo antitumor activity was investigated against two transplantable mouse tumors, the Ehrlich carcinoma (EC) and cervical cancer (CC-5). The effect of avarol on cancer cell survival, which was determined by the microculture tetrazolium test, confirmed a significant in vitro potency of avarol against the investigated cell lines, without selectivity towards MRC-5. The highest cytotoxicity was exhibited against HeLa cancer cells (10.22 ± 0.28 μg/mL). Moreover, potent antitumor activity against two tumor models was determined, as the intraperitoneal administration of avarol at a dose of 50 mg/kg resulted in a significant inhibition of tumor growth in mice. After three administrations of avarol, a 29% inhibition of the EC growth was achieved, while in the case of CC-5, a 36% inhibition of the tumor growth was achieved after the second administration of avarol. Therefore, the results indicate that this marine sesquiterpenoid hydroquinone could be a promising bioactive compound in the development of new anticancer medicine.

We study the impact of radiation LET on manifestation of HRS/IRR response in Chinese hamster cells ovary cells exposed to radiations used in radiotherapy. Earlier we have investigated this response to carbon ions (455 MeV/amu) in the pristine Bragg curve plateau and behind the Bragg peak, 60Co γ-rays, and 14.5 MeV neutrons. Now we present results of cytogenetic metaphase analysis in plateau-phase CHO-K1 cells irradiated with scanning beam protons (83 MeV) at doses < 1 Gy and additional data for 14.5 MeV neutrons. Dose curves for frequency of total chromosome aberrations (CA, protons), paired fragments (protons, neutrons), aberrant cells (neutrons) had typical HRS/IRR structure: HRS region (up to 0.1 and 0.15 Gy), IRR region (0.1–0.6 Gy and 0.15–0.35 Gy) for protons and neutrons, respectively, and regular dose dependence. Taken together with previous results, the data show that LET increase shifts the HRS upper border (from 0.08–0.1 Gy for γ-rays, protons and plateau carbons to 0.12–0.15 Gy for “tail” carbons and neutrons). The IRR regions shortens (0.52–0.4 γ-rays and protons, 0.25 plateau carbons, 0.2 Gy “tail” carbons and neutrons). CA level of IRR increases by 1.5–2.5 times for carbons as compared to γ-rays and protons. Outside HRS/IRR the yield of CA also enhanced with LET increase. The results obtained for different LET radiations suggest that CHO-K1 cells with G1-like CA manifested the general feature of the HRS/IRR phenomena.

The radioprotective effects of a new 1-isobutanoil-2-isopropylisothiourea derivative named T1082 are presented. Research methods included toxic characteristics, radioprotective activity (Till–McCulloch’s test and 30-day survival test) in γ-ray total-body-irradiated mice, and a clinical and histological study of the effect of T1082 on acute radiation skin reactions (RSR) in rats after a single or fractionated β-ray local irradiation. T1082 is more effective than its analogue, the NOS inhibitor T1023, at low concentrations and doses (1/12–1/8 LD10), both parenterally and intragastrically. In this case, its therapeutic index (LD50/ED50) reaches 30, and the optimal radioprotective doses (ED84–98—141–224 mg/kg) are an order less than the maximum tolerated doses—1/16–1/10 LD10. These properties allowed T1082, at a low intragastrical dose (160 mg/kg; 1/14 LD10), to significantly limit the severity of acute RSR after single (40 Gy) and fractionated (78 Gy) β-ray irradiation. The results confirm T1082 as one of the safest emergency radioprotectors and indicate the prospects for its further development as a pharmacological agent for the prevention of RT complications.

We have previously demonstrated a high antitumor potential of NOS inhibitor T1023 (1-isobutanoyl-2-isopropylisothiourea hydrobromide): antitumor antiangiogenic activity in several animal tumor models and its ability to synergistically enhance the antitumor effects of bevacizumab, cyclophosphamide and γ-radiation. At the same time, rather rapid adaptation of experimental neoplasias to T1023 treatment was often observed. We attempted to enhance the antitumor activity of this NOS inhibitor by supplementing its molecular structure with a PDK-inhibiting fragment, dichloroacetate (DCA), which is capable of hypoxia-oriented toxic effects. We synthesized compound T1084 (1-isobutanoyl-2-isopropylisothiourea dichloroacetate). Its toxic properties, NOS-inhibiting and PDK-inhibiting activity in vivo, and antitumor activity on the mouse Ehrlich carcinoma model (SEC) were investigated in compare with T1023 and Na-DCA. We found that the change of the salt-forming acid from HBr to DCA does not increase the toxicity of 1-isobutanoyl-2-isopropylisothiourea salts, but significantly expands the biochemical and anti-tumor activity. New compound T1084 realizes in vivo NOS-inhibiting and PDK-inhibiting activity, quantitatively, at the level of the previous compounds, T1023 and Na-DCA. In two independent experiments on SEC model, a pronounced synergistic antitumor effect of T1084 was observed in compare with T1023 and Na-DCA at equimolar doses. There were no signs of SEC adaptation to T1084 treatment, while experimental neoplasia rapidly desensitized to the separate treatment of both T1023 and Na-DCA. The totality of the data obtained indicates that the combination of antiangiogenic and hypoxia-oriented toxic effects (in this case, within the molecular structure of the active substance) can increase the antitumor effect and suppress the development of hypoxic resistance of neoplasias. In general, the proposed approach can be used for the design of new anticancer agents.

Background: The possible involvement of p53 signaling, FGFR3 expression, and FGFR3 mutation rates in the prediction of the NMIBC anti-PD-L1 treatment response needs to be clarified. The main aim of our study was to explore predictive value of p53 expression, FGFR3 expression, and its gene mutation status for the therapeutic success of anti-PD-L1 treatment in the patient-derived murine model of recurrent high-PD-L1(+) GATA3(−)/CR5/6(−) high-grade and low-grade NMIBC. Methods: twenty lines of patient-derived xenografts (PDXs) of relapsed high-PD-L1(+) double-negative NMIBC were developed, of which 10 lines represented high-grade tumors and the other ones—low-grade bladder cancer. Acceptors of each grade-related branch received specific anti-PD-L1 antibodies. Animals’ survival, tumor-doubling time, and remote metastasis were followed during the post-interventional period. PD-L1, GATA3, CR5/6, and p53 protein expressions in engrafted tumors were assessed by immunohistochemistry. The FGFR3 expression and FGFR3 mutations in codons 248 and 249 were detected by real-time polymerase chain reaction. Results: The expression of p53 protein is an independent factor affecting the animals’ survival time [HR = 0.036, p = 0.031] of anti-PD-L1-treated mice with low-grade high-PD-L1(+) double-negative NMIBC PDX. The FGFR3 expression and FGFR3 mutation rate have no impact on the anti-PD-L1 treatment response in the interventional groups. Conclusions: p53 expression may be considered as a prognostic factor for the anti-PD-L1 treatment efficacy of low-grade high-PD-L1-positive GATA3(−)/CR5/6(−)-relapsed noninvasive bladder cancer.

Previously, we showed that a nitric oxide synthase (NOS) inhibitor, compound T1023, induces transient hypoxia and prevents acute radiation syndrome (ARS) in mice. Significant efficacy (according to various tests, dose modifying factor (DMF)—1.6–1.9 against H-ARS/G-ARS) and safety in radioprotective doses (1/5–1/4 LD10) became the reason for testing its ability to prevent complications of tumor radiation therapy (RT). Research methods included studying T1023 effects on skin acute radiation reactions (RSR) in rats and mice without tumors and in tumor-bearing animals. The effects were evaluated using clinical, morphological and histological techniques as well as RTOG classification. T1023 administration prior to irradiation significantly limited the severity of acute RSR. This was due to a decrease in radiation alteration of the skin and underlying tissues, and the preservation of the functional activity of cell populations that are critical in the pathogenesis of radiation burn. The DMF values for T1023 for skin protection were 1.4–1.7. Moreover, its radioprotective effect was fully selective to normal tissues in RT models of solid tumors—T1023 reduced the severity of acute RSR and did not modify the antitumor effects of γ-radiation. The results indicate that T1023 can selectively protect the non-malignant tissues against γ-radiation due to hypoxic mechanism of action and potentiate opportunities of NOS inhibitors in RT complications prevention.

Prostate cancer is the second most frequent malignancy (after lung cancer). Preoperative staging of PCa is the basis for the selection of adequate treatment tactics. In particular, an urgent problem is the classification of indolent and aggressive forms of PCa in patients with the initial stages of the tumor process. To solve this problem, we propose to use a new binary classification machine-learning method. The proposed method of monotonic functions uses a model in which the disease’s form is determined by the severity of the patient’s condition. It is assumed that the patient’s condition is the easier, the less the deviation of the indicators from the normal values inherent in healthy people. This assumption means that the severity (form) of the disease can be represented by monotonic functions from the values of the deviation of the patient’s indicators beyond the normal range. The method is used to solve the problem of classifying patients with indolent and aggressive forms of prostate cancer according to pretreatment data. The learning algorithm is nonparametric. At the same time, it allows an explanation of the classification results in the form of a logical function. To do this, you should indicate to the algorithm either the threshold value of the probability of successful classification of patients with an indolent form of PCa, or the threshold value of the probability of misclassification of patients with an aggressive form of PCa disease. The examples of logical rules given in the article show that they are quite simple and can be easily interpreted in terms of preoperative indicators of the form of the disease.

Background: Establishment of heterotopic patient-derived xenografts of primary and relapsed non-muscular invasive bladder cancer (NMIBC) to explore the biological property of PD-L1 signaling that may impact bladder tumor growth in humanized animals. Methods: Tumor cells of luminal, basal, and p53 subtypes of primary and relapsed NMIBC were engrafted to irradiated (3.5 Gy) NOG/SCID female mice along with intraperitoneal transplantation of human lymphocytes (5 × 107 cells/mouse); a role of PD-L1 signaling pathway inhibition for bladder cancer growth was assessed in humanized animals that carried PD-L1-expressing main molecular subtypes of bladder carcinoma patient-derived xenografts (PDX) and provided with selective anti-PD-L1 treatment. We used two-tailed Student’s t test to explore differences between main and control subgroups. Significance of intergroup comparison was measured with one-way ANOVA followed by the Tukey’s or Newman−Keul’s criterion. Survival curves were analyzed with the Gehan’s criterion with the Yate’s correction. The Spearman’s correlation was used to assess the link between CD8+ expression and sPD-L1 serum level. Differences were considered statistically significant at p < 0.05. Results: Heterotopic primary and relapsed luminal, basal, and p53 subtypes of NMIBC PDXs were established. More than 25% of counted tumor cells of all PDX specimens expressed PD-L1, so the tumors were ranged as PD-L1 positive. Anti-PD-L1 intervention increased survival of the animals that carried both primary and relapsed luminal noninvasive, muscular invasive, and relapsed luminal bladder cancer xenografts. There was significant retardation of tumor volume duplication time in aforementioned subgroups correlated with PD-L1 expression. Bad response of p53 mutant subtypes of NMIBC on specific anti-PD-L1 treatment may be associated with low CD8+ cells representation into the tumors tissue. Conclusions: Established PD-L1-positive NMIBC PDXs differently replied on anti-PD-L1 treatment due to both NMIBC molecular subtype and tumor T-suppressors population. The results may have major implications for further clinical investigations.

DNA double-strand breaks (DSB) are among the most harmful DNA lesions induced by ionizing radiation (IR). Although the induction and repair of radiation-induced DSB is well studied for acute irradiation, responses to DSB produced by chronic IR exposures are poorly understood, especially in human stem cells. The aim of this study was to examine the formation of DSB markers (γH2AX and phosphorylated kinase ATM, pATM, foci) in human mesenchymal stem cells (MSCs) exposed to chronic gamma-radiation (0.1 mGy/min) in comparison with acute irradiation (30 mGy/min) at cumulative doses of 30, 100, 160, 240 and 300 mGy. A linear dose-dependent increase in the number of both γH2AX and pATM foci, as well as co-localized γH2AX/pATM foci (“true” DSB), were observed after an acute radiation exposure. In contrast, the response of MSCs to a chronic low dose-rate IR exposure deviated from linearity towards a threshold model, for γH2AX, pATM foci and γH2AX/pATM foci, with an indication of a “plateau”. The state of equilibrium between newly formed DSB at a low rate during the protracted exposure time and the elimination of a fraction of DSB is proposed as a mechanistic explanation of the non-linear DSB responses following a low dose-rate irradiation. This notion is supported by the observation of the elimination of a substantial fraction of DSB 6 h after the cessation of the exposures. Our results demonstrate non-linear dose responses for γH2AX and pATM foci in human MSCs exposed to low dose-rate IR and showed the existence of a threshold, which may have implications for radiation protection in humans.