Ultrasound and clinical preoperative characteristics for discrimination between ovarian metastatic colorectal cancer and primary ovarian cancer: A case-control study

The aim of this study was to describe the clinical and sonographic features of ovarian metastases originating from colorectal cancer (mCRC), and to discriminate mCRC from primary ovarian cancer (OC). We conducted a multi-institutional, retrospective study of consecutive patients with ovarian mCRC who had undergone ultrasound examination using the International Ovarian Tumor Analysis (IOTA) terminology, with the addition of evaluating signs of necrosis and abdominal staging. A control group included patients with primary OC. Clinical and ultrasound data, subjective assessment (SA), and an assessment of different neoplasias in the adnexa (ADNEX) model were evaluated. Fisher's exact and Student's t-tests, the area under the receiver-operating characteristic curve (AUC), and classification and regression trees (CART) were used to conduct statistical analyses. In total, 162 patients (81 with OC and 81 with ovarian mCRC) were included. None of the patients with OC had undergone chemotherapy for CRC in the past, compared with 40% of patients with ovarian mCRC (p < 0.001). The ovarian mCRC tumors were significantly larger, a necrosis sign was more frequently present, and tumors had an irregular wall or were fixed less frequently; ascites, omental cake, and carcinomatosis were less common in mCRC than in primary OC. In a subgroup of patients with ovarian mCRC who had not undergone treatment for CRC in anamnesis, tumors were larger, and had fewer papillations and more locules compared with primary OC. The highest AUC for the discrimination of ovarian mCRC from primary OC was for CART (0.768), followed by SA (0.735) and ADNEX calculated with CA-125 (0.680). Ovarian mCRC and primary OC can be distinguished based on patient anamnesis, ultrasound pattern recognition, a proposed decision tree model, and an ADNEX model with CA-125 levels

Pathogenetic rationale for the use of cell therapy in lung injury associated with SARS-CoV-2

Acute respiratory disease COVID-19 caused by the SARS-CoV-2 coronavirus demonstrate weak clinical manifestation in most patients. However, pneumonia and acute respiratory distress syndrome in some cases may cause serious problems due to the lack of effective etiotropic and pathogenetic therapy. Presumably, SARS-CoV-2 leads to the delayed type I interferon activation and loss of control over virus replication in the early stages of infection, which is why the adaptive CD8+T-cell response must be controlled to avoid the development of pulmonary pathology. These data should be taken into account when developing strategies for COVID-19 therapy. Mesenchymal stem cells therapy serves as possible treatment opportunity for severe forms of the disease due to their homing, pronounced anti-inflammatory and antifibrotic properties. It was found that in viral infections, including COVID-19, mesenchymal stem cells can synthesize antiviral defense mediators under the influence of interferon causing resistance to viruses. Thus, mesenchymal stem cells are able to provide comprehensive anti-inflammatory protection, which leads to clinical improvement in patients with COVID-19

Клиническая значимость Р16-позитивного статуса и высокой пролиферативной активности у пациентов с орофарингеальной плоскоклеточной карциномой

Introduction. In accordance with uICC and AJCC 8th edition TNM classifications, there is a strong evidence for division of oropharyngeal squamous cell carcinoma (OPSCC) into 2 molecular subtypes by HPV-status with distinct prognosis depending on biological differences. Such a division leads to differences in staging OPSCC and in future it will lead to implementation of preventive measures and new therapeutic strategies against HPV-positive cancer.Aim of the study: to assess the clinical and prognostic significance of the combination of P16, a surrogate marker for HPV-positivity, and high proliferative activity in patients with oropharyngeal carcinoma.Material and Methods. Immunohistochemical (ICH) analysis with monoclonal antibodies specific for P16 and Ki67 proteins was used to detect expression patterns in the formalin-fixed, paraffin-embedded tumor samples obtained from 104 patients with squamous cell carcinoma of the tongue and oropharynx, treated at Oncological Dispencery № 1 in Krasnodar from 2011 to 2016. HPV-positive status was determined if more than 70 % of tumor cells had moderate or strong nuclear and cytoplasmic P16-staining. High index of proliferative activity (PA) was detected if more than 50 % tumor cells expressed Ki67 nuclear antigen.Results. P16-positivie status was associated with tonsillar cancer (р=0.002), female gender (р=0.015), age <60 years (р<0.001), non - keratinizing morphology (р=0.022), and high index of PA (p=0.01).The combination of P16>70 % with high PA demonstrated correlation with tonsillar cancer (р<0.001), female gander (р=0.015), age under 60 years (р<0.001) and non - keratinizing morphology (р=0.012). HPV-positive patients and patients with a combination of P16>70 % and high index of PA at N1-2 had an overall survival benefit (p=0.021).Conclusion. The correlation between IHC-complex for P16>70 %/Ki67>50 % and clinicopathologicl parameters and overall survival confirms the biological features of HPV-associated cancer. The evaluation of this IHC-complex can increase the diagnostic accuracy of IHC-analysis of HPV-status and predict the prognosis of patients with OPSCC.Введение. По классификации TNM UICC/AJCC 8-го пересмотра предлагается разделить орофарингеальную плоскоклеточную карциному на 2 молекулярных подтипа по ВПЧ-статусу с различными клиническими и прогностическими характеристиками ввиду биологических особенностей. Так, имеются отличия в подходах к стадированию орофарингеального рака, и в будущем это приведет к реализации профилактических мероприятий и внедрению новых терапевтических стратегий в отношении ВПЧ-позитивного рака.Цель исследования - оценить клинико-прогностическую значимость комбинации суррогатного маркера ВПЧ-позитивного статуса P16 с высокой пролиферативной активностью при орофарингеальном раке.Материал и методы. Иммуногистохимический анализ выполнен с моноклональными антителами к P16 и Ki67 на срезах с парафиновых гистоблоков опухолевых образцов 104 больных плоскоклеточным раком языка и ротоглотки, проходивших лечение в ГБУЗ КОД № 1 г Краснодара в 2011-16 гг Р16-положительный статус определяли при умеренном или сильном ядерном и цитоплазматическом окрашивании более 70 % опухолевых клеток. Высокий индекс пролиферативной активности устанавливался, если более 50 % опухолевых клеток имели ядерное окрашивание антигена Ki67.Результаты. Р16-позитивный статус был связан с раком нёбных миндалин (р=0,002), характерен для женщин (р=0,015), ассоциирован с возрастом моложе 60 лет (р<0,001), морфологией без ороговения (р=0,022), высокой пролиферацией (р=0,01). Сочетание Р16-позитивного статуса с высокой пролиферацией продемонстрировало корреляцию с раком нёбных миндалин (р<0,001), женским полом (р=0,015), возрастом моложе 60 лет (р<0,001) и морфологией без ороговения (р=0,012). ВПЧ-позитивные больные и пациенты с комбинацией Р16-позитивного статуса и высокого индекса пролиферативной активности с метастазами лимфатических узлов (N1-2) имели более высокие показатели 3-летней общей выживаемости (p=0,021).Вывод. Корреляция ИГХкомплекса Р16-позитивности и высокой пролиферативной активности с клинико-морфологическими особенностями и общей выживаемостью подтверждает особенности биологии ВПЧ-ассоциированного рака. Исследование комбинации индекса пролиферативной активности в дополнение к суррогатному маркеру ВПЧ-статуса приведет к повышению диагностической точности ИГХ-анализа ВПЧ-статуса и позволит определять прогноз пациентов с плоскоклеточным раком головы и шеи

Influence of solvent quality on polymer solutions: a Monte Carlo study of bulk and interfacial properties

The effect of solvent quality on dilute and semi-dilute regimes of polymers in solution is studied by means of Monte Carlo simulations. The equation of state, adsorptions near a hard wall, wall-polymer surface tension and effective depletion potentials are all calculated as a function of concentration and solvent quality. We find important differences between polymers in good and theta solvents. In the dilute regime, the physical properties for polymers in a theta solvent closely resemble those of ideal polymers. In the semi-dilute regime, however, significant differences are found.Comment: 10 pages, 13 figure

Equation of State for Macromolecules of Variable Flexibility in Good Solvents: A Comparison of Techniques for Monte Carlo Simulations of Lattice Models

The osmotic equation of state for the athermal bond fluctuation model on the simple cubic lattice is obtained from extensive Monte Carlo simulations. For short macromolecules (chain length N=20) we study the influence of various choices for the chain stiffness on the equation of state. Three techniques are applied and compared in order to critically assess their efficiency and accuracy: the repulsive wall method, the thermodynamic integration method (which rests on the feasibility of simulations in the grand canonical ensemble), and the recently advocated sedimentation equilibrium method, which records the density profile in an external (e.g. gravitation-like) field and infers, via a local density approximation, the equation of state from the hydrostatic equilibrium condition. We confirm the conclusion that the latter technique is far more efficient than the repulsive wall method, but we find that the thermodynamic integration method is similarly efficient as the sedimentation equilibrium method. For very stiff chains the onset of nematic order enforces the formation of isotropic-nematic interface in the sedimentation equilibrium method leading to strong rounding effects and deviations from the true equation of state in the transition regime.Comment: 32 pages, 18 figures, submitted to Phys.Rev.E; one paragraph added to conclusions sectio

Induction of ovarian steroidogenesis as an additional potential risk factor for progression in premenopausal patients with hormone-receptor-positive breast cancer receiving tamoxifen as adjuvant therapy

Introduction. Patients with hormone-receptor-positive (HR+) breast cancer (BC) over 40 years old who take tamoxifen are not subject to mandatory castration. However this cohort of patients is not homogeneous.Aim. The present study is aimed at studying the features of ovarian steroidogenesis in perimenopausal breast cancer patients receiving adjuvant hormone therapy (HT) with tamoxifen.Materialy and methods. The study included 82 patients aged 42 to 53 years with GH+BC who received HT with tamoxifen 20 mg daily. Within 9 months from the start of HT in patients, the levels of estradiol and follicle-stimulating hormone in the peripheral blood were studied every 3 months.Results. In 66.7% of patients who received chemotherapy (CT), the development of amenorrhea was noted. Half of the patients in the HT-only group demonstrated amenorrhea. Oligomenorrhea was observed in 20.8% and 16.7% in each group, respectively. The incidence of amenorrhea in women treated with chemotherapy was higher (OR 2.02; 95% CI: 0.73-5.67), but the differences were not statistically significant (p = 0.1766). In the general cohort, in 15.7-16.8% of patients, the level of estradiol exceeded 251 pg / ml - the upper limit of the norm of the follicular phase of the menstrual cycle. Differences between groups in the incidence of estradiol levels > 251 pg/ml were statistically significant (p = 0.0293). 3.4-5.6% of patients in the total cohort (depending on the period of observation) had an estradiol level > 649 pg / ml, which corresponded to the highest ovulatory value.Conclusions. Against the background of HT with tamoxifen in some perimenopausal patients hyperestrogenism is observed which indicates the implementation of the effect of induction of ovarian steroidogenesis and can be considered as an additional potential risk factor for the progression of HR+BC. Amenorrhea after CT is not a reliable marker of ovarian suppression

Evolution of the CDK4/6 inhibitor abemaciclib: from palliative to adjuvant therapy. Clinical experience with abemaciclib in patients with hormone-receptor-positive, HER2-negative breast cancer

Introduction. Cyclin-dependent kinase 4/6 inhibitors are indicated in endocrine therapy for the treatment of hormone receptorpositive, HER2-negative, advanced, or metastatic breast cancer. In the recent past, abemaciclib made its debut as a combinatorial partner for adjuvant therapy in hormone-dependent breast cancer. This article demonstrates the analysis of our own experience of introducing abemaciclib into clinical practice.Aim. The aim of the study was to evaluate the preliminary results of treatment of patients with hormone receptor-positive HER2-negative metastatic breast cancer using abemaciclib outside the framework of clinical trials, in the real clinical practice of an oncological dispensary.Materials and methods. A retrospective analysis of the results of treatment was carried out in 27 patients who were prescribed abe-maciclib in various regimens and lines from April 2021 to January 2022 in the conditions of routine practice in the Krasnodar region.Results and discussion. Analysis of the total population of 27 patients at a median follow-up of 8 months showed that the median PFS was not reached. The one-year PFS was 68.8%. Treatment outcomes were independent of prescribing abemaciclib to treat baseline metastatic disease or breast cancer progression after previous radical treatment (p = 0.60). The PFS did not depend on the expression of progesterone receptors in the tumor tissue (p = 0.326) and the proliferative activity index Ki-67 (p = 0.618). Patients who received no more than 2 lines of previous drug treatment for a history of metastatic breast cancer had the greatest benefit from abemaciclib therapy (p = 0.001).Conclusions. Despite a relatively difficult group of patients (96% of patients with visceral metastases), abemaciclib has demonstrated efficacy and safety. The effectiveness did not depend on the analyzed factors: Ki-67, the level of expression of progesterone receptors, the type of metastatic disease (de novo metastatic or progressive breast cancer). In view of the best results, it is advisable to prescribe abemaciclib in the early lines of therapy

Molecular and genetic profile of head and neck squamous cell carcinoma

To determine the molecular pathways of head and neck squamous cell carcinoma (HNSCC) tumorogenesis there are held a great amount of investigations. New therapeutic models for HNSCC are discussed considering genetic and biochemical specifications and taking in account significant scientific strategies. Dividing HNSCC into 2 large groups in accordance to human papilloma virus (HPV) association with different survival rates is a great achievement of the last decades in carcinogenesis researching and treatment of HNSCC. It is well known that chemical carcinogens are the main cause of HPV-negative tumors development. HPV-positive HNSCC is associated with E6 and E7 HPV proteins. The results of whole exome sequencing of HNSCC are of the great interest. Molecular expression profile of Rb-E2F/p53 were diff erent in HPV-positive and HPV-negative tumors. The phosphorylated pRb and p16 proteins analysis showed low pRb and high p16 levels in HPV-positive tumors in contrast to HPV-negative samples due to the HPV E7 ability to degrade Rb. P16 expression was higher in HPV-positive tumors, so it is immunohystochemical marker of HPV-positive status. The p53 expression pattern is determined also to identify its mechanism of degradation in HPV-positive tumors. Due to carcinogenic HPV ability by inactivation of cell cycle regulators р53 and pRb with the help of E6 and E7 oncoproteins, mutations of TP 53 shouldn’t play leading role in HPV-induced tomorogenity. Nevertheless, there are controversial data concerning HPV-positive tumors that part of them gain p53-mutations at the same time having integrated HPV-genome. The p53 expression in HPV-positive samples was the same as if in the absence of HPV

Liquid biopsy: the current state of the issue

Background Liquid biopsy is a promising method of diagnosing malignant tumors. It allows determining the level of free circulating tumor cells – micrometastases, tumor DNA, microRNA and exosomes in blood plasma, as well as detecting various genetic changes. This work included a literature review of current scientific publications on liquid biopsy techniques indexed in PubMed.Objective The aim of the study was to evaluate the efficacy and peculiarities of this technique in comparison with standard methods of morphological verification of oncological diseases, as well as the feasibility of its use in clinical practice. Compared to tissue biopsy LB has the following advantages: simplicity and speed of examination, easy repeatability and low invasiveness, possibility of dynamic monitoring of tumor progression – general clonal transformation as well as the appearance of resistance to treatment. The disadvantages of this method include low sensitivity, difficulty in proper interpretation of biomarkers and determination of their specificity, high risk of false positive and false negative results due to the presence of dormant tumor cells.Conclusion Currently, liquid biopsy analysis in clinical practice requires standardization and continuous validation

Значение герминальной BRCA-мутации при формировании опухолевого микроокружения Эффективность PARP-ингибирования в поздней линии терапии метастатического кастрационно-резистентного рака предстательной железы

Metastatic castration-resistant prostate cancer is a difficult problem for a clinical oncologist. In addition, mutations in genes of homologous DNA recombination, including BRCA1/2, suggest an aggressive behavior and therapy resistance. Treatment options for such patients were significantly limited until new drugs - PARP inhibitors have been registered. Nevertheless, there is evidence that BRCA1/2 gene mutations are associated with increased mutational load, neoepitopes formation, increased number of tumor-infiltrating lymphocytes and a response to the immune response checkpoints blockade. Studies have shown that BRCA2-mutated prostate cancer demonstrates high level of immune cells infiltration compared to tumors without mutation, in particular with respect to CD4+, CD8+ and FOXP3+ T-lymphocytes. It should be noted that studies have shown a tendency of CD8+ T-lymphocytes/FOXP3+ T-cells ratio decreasing in BRCA2-mutated tumors. Thus, the mutational status of BRCA2 presumably forms the immune phenotype of prostate cancer with an increase of intratumoral immune cells, but with immunosuppressive properties. At the same time, the use of immune checkpoint blockers in advanced prostate cancer has been unsuccessful in terms of overall survival. Despite the fact that immune checkpoint blocker's efficacy is often associated with a high intracellular CD4+ and CD8+ T lymphocytes, their presence is clearly insufficient for response. Studies showed that PARP inhibitors effect tumor microenvironment significantly. Anti-PD-1/PD-L1 combination with PARP inhibitors is being actively studied due to their properties of modulating the tumor microenvironment. Thus, future immunooncological strategies for primary prostate cancer therapy may include not only an increase in mutational load, but also an impact on the immunosuppressive microenvironment. The article presents clinical cases of 3 brothers, carriers of the germinal BRCA2 c.9371A>T mutation, suffering from prostate cancer with a burdened family history. The disease development under standard therapies was studied and markers of the tumor microenvironment were immunohistochemically evaluated. PARP inhibitor Olaparib efficacy in prostate cancer of older brother in late-line therapy for metastatic castration-resistant disease was analyzed.Метастатический кастрационно-резистентный рак предстательной железы является сложной проблемой для клинического онколога. Кроме этого, наличие мутации в генах гомологичной рекомбинации ДНК, в том числе BRCA1/2, предполагает агрессивное течение и резистентность к проводимой терапии. До регистрации новой группы препаратов - PARP-ингибиторов - опции лечения таких больных были существенно ограниченны. Тем не менее есть данные о том, что мутации генов BRCA1/2 связаны с повышенной мутационной нагрузкой, образованием неоэпитопов, увеличением количества инфильтрирующих опухоль лимфоцитов и ответом на блокаду контрольных точек иммунного ответа. В исследованиях показано, что BRCA2-мутированный рак предстательной железы обладает высоким уровнем инфильтрации иммунными клетками по сравнению с опухолями без мутации, в частности в отношении Т-лимфоцитов, экспрессирующих CD4, CD8 и FOXP3. Следует отметить, что в исследованиях наблюдалась тенденция к снижению отношения CD8+-Т-лимфоцитов к FOXP3+-Т-клеткам в BRCA2-мутированных опухолях. Таким образом, мутационный статус BRCA2 предположительно формирует иммунный фенотип рака предстательной железы с увеличением количества интратуморальных иммунных клеток, но с иммуносупрессивными свойствами. При этом использование блокаторов контрольных точек иммунитета при распространенном раке предстательной железы до сих пор было в значительной степени безуспешным в отношении показателей общей выживаемости пациентов. Несмотря на то что эффективность блокаторов контрольных точек иммунитета зачастую связана с высоким содержанием внутриопухолевых CD4+- и CD8+-Т-лимфоцитов, их присутствия явно недостаточно для ответа. Как показано в исследованиях, ингибиторы PARP способны оказывать существенное влияние на микроокружение опухоли. Активно изучается комбинация анти-PD-VPD-Lt с ингибиторами PARP за счет их свойств модулирования микроокружения опухоли. Таким образом, будущие онкоиммунологические стратегии первичной терапии рака предстательной железы могут включать не только повышение мутационной нагрузки, но и воздействие на иммуносупрессивное микроокружение. В статье представлены случаи развития рака предстательной железы у 3 братьев, носителей герминальной мутации гена BRCA2 c.9371A>T с отягощенным семейным анамнезом. Изучено клиническое течение заболевания при применении стандартных методов терапии, иммуногистохимически оценены маркеры микроокружения опухоли. Проанализирована эффективность использования PARP-ингибитора олапариба у одного из братьев в поздней линии терапии при метастатическом кастрационно-резистентном заболевании