bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of enzalutamide in patients with metastatic hormone-sensitive and castration-refractory prostate cancer: authors’ experience
Authors: Ustinova T. V. , Bolotina L. V. , Paichadze A. A. , Kachmazov A. A. , Fedenko A. A. , Kaprin A. D.
Published: December 2021

Prostate cancer is one of the most common neoplasms in men. It currently ranks second in Russian Federation amongst male population in overall number of cases after only lung cancer and third in cancer mortality. Prostate cancer is rarely diagnosed in patients younger than 40 years old, with overage age of diagnosis being between 50 and 70 years. A lot of different new treatment options were developed in the last decade for patients with metastatic prostate cancer (mPC). Despite androgen-deprivation remaining the standard of therapy, it has been proven that the addition of cytotoxic and hormonal drugs of new generation improves overall survival of patients with castration-sensitive and castration-resistant metastatic disease. Recently, enzalutamide became the new standard of care not only in castration-resistant mPC, but also in the setting of metastatic castration-sensitive prostate cancer, due to the data acquired in two large randomized trials ARCHES and ENZAMET. This article provides clinical examples demonstrating the effectiveness of enzalutamide in various forms of prostate cancer. In the first clinical case enzalutamide was used in the treatment of castration-sensitive mPC. Currently, patient continues to receive this therapy with progression-free interval exceeding 11  months. In  the  second clinical case, enzalutamide has shown its efficacy in  the  setting of  castration-resistant PC. Stable disease was achieved and as of  right now patient has shown no signs of  progression for 9 months, which is already a significantly better result in comparison with previous lines of treatment.
Metastatic renal cell carcinoma, the possibility of targeted therapy. Case.
Authors: Menshikov K. V. , Izmailov A. A. , Sultanbaev A. V. , Musin Sh. I. , Chalov V. S. , Menshikova I. A. , Sultanbaeva N. I. , Lipatov D. O.
Published: December 2021

Malignant neoplasms of the kidney are quite an urgent problem. In the Russian Federation in 2019, 20758 patients with a newly diagnosed renal cell carcinoma were registered; it should be noted that at the end of 2019, 177 755 patients with this diagnosis were registered. Clear cell carcinoma of the kidney is the most common (75–80%) and most studied subtype of renal cell carcinoma. Because renal cell carcinoma is resistant to chemotherapy, interleukin-2 or interferon alpha has previously been widely used as the first line of treatment for metastatic disease. Sunitinib is an oral tyrosine kinase inhibitor that includes the vascular endothelial growth factor receptor (VEGFR) and the platelet growth factor receptor (PDGFR). Two phase II studies of sunitinib as an anti-angiogenic agent have shown clinical efficacy in patients who progressed on cytokine therapy. Currently, in connection with the development of immuno-oncological drugs, tyrosine kinase inhibitors are fading into the background. It should also be noted that immuno-oncological drugs have their own spectrum of contraindications and immune-mediated toxicity. A clinical case of treatment of a patient with metastatic renal cell carcinoma in the group with a favorable prognosis for IMDC and contraindications to immunotherapy is presented. A history of autoimmune thyroiditis, which was previously treated with levothyroxine sodium, contraindicated treatment with checkpoint inhibitors. The  patient started therapy with the  tyrosine kinase inhibitor sunitinib. Sunitinib therapy made it possible to achieve disease control for  more than 4  years with satisfactory tolerance. The noted adverse events were stopped during therapy and did not lead to a reduction in doses of sunitinib and its cancellation.
Experience of successful use of axitinib in therapy of metastatic renal cell carcinoma after immunotargeted therapy
Authors: Rumyantsev A. A.
Published: December 2021

The therapeutic options for clear cell renal cell carcinoma have changed significantly in recent years. Back in 2018, clinical guidelines indicated that the standard of therapy for newly diagnosed metastatic renal cell cancer, regardless of the prognosis, was monotherapy with sunitinib or pazopanib. Accumulation of scientific data and clinical experience has significantly changed approaches to the treatment of this disease – according to current recommendations, pazopanib and sunitinib are considered as a possible option only for patients with a favorable prognosis, while the priority in the treatment of CCRCC for other prognostic groups has shifted towards PD-1/PD-L1 antagonists in combination with ipilimumab or anti-VEGFR-based drugs. At the same time, selecting the optimal regimen for patients who have already received immunotherapy as part of a previous regimen can be very challenging. This publication describes a clinical case of successful therapy with axitinib in a patient with clear cell renal cell carcinoma with a favorable prognosis according to IMDC, with disease progression after using a combination of lenvatinib and pembrolizumab in first-line therapy. The data are presented and discussed in the context of the available evidence base for the use of axitinib in the treatment of metastatic kidney cancer, including after progression of the disease on the background of immunotherapy.
Dual anti-HER2 blockade in late-line treatment of metastatic HER2-positive breast cancer
Authors: Frolova M. A. , Stenina M. B.
Published: December 2021

In recent years, there has been a wide range of treatment options for patients with metastatic HER2-positive breast cancer, resulting in  the  highest life expectancy for  these patients among all subtypes. The  addition of  pertuzumab to trastuzumab and docetaxel has been shown to increase overall survival and is therefore recognized as the standard first-line treatment. The most optimal second-line treatment option is trastuzumab emtansine. In  addition, various combinations of  cytostatics and anti HER2 targeting agents can be used. The choice of treatment options in heavily pretreated patients is of great interest. If they have not previously received pertuzumab, is it worth to use it and which combination is the best? One possible option is the combination of eribulin with the dual anti-HER2 blockade with trastuzumab and pertuzumab. Eribulin is an anti-microtubule agent that irreversibly blocks mitosis. In addition, it has non-mitotic effects – in vivo and in vitro experiments demonstrated its ability to restore normal tumor vascularization, reduce the area of hypoxia and, as a consequence, decrease tumor cells migration and invasion. This article represents a clinical case of the use of eribulin with double anti-HER2 blockade in the 6th line of treatment in a patient with metastatic HER2-positive breast cancer. Long-term control of the disease (within 2 years) with a satisfactory quality of life has been demonstrated.
Clinical case of the treatment of metastatic luminal breast cancer
Authors: Nasretdinov A. F. , Sultanbaev A. V. , Menshikov K. V. , Musin Sh. I. , Sultanbaeva N. I. , Izmailov A. A. , Ayupov R. T.
Published: December 2021

Hormone therapy currently open up the prospect of long-term, comfortable and relatively low-toxic treatment for patients with hormone receptor – positive advanced breast cancer. For a long time, the presence of visceral metastases prompted oncologists to abandon hormone therapy in favor of cytostatic agents. Now days, even in the presence of visceral metastases, clinical guidelines allow use of modern hormonal therapy in the absence of a visceral crisis. In particular, the so-called CDK 4/6 inhibitors, presented on the Russian market by drugs: palbociclib, ribociclib and abemacyclib, became the drugs that significantly improved the  results of  hormone therapy. Each of  them has demonstrated its effectiveness in  clinical trials; moreover, there are lots of clinical cases demonstrating the benefits of this therapy in real clinical practice. The article presents a clinical case of treatment of advanced hormone receptor-positive breast cancer. The effectiveness of treatment with CDK 4/6 inhibitors has been demonstrated, a comparatively analysed with the data obtained in the course of clinical trials. The analysis of the tactics of treatment of cytomegalovirus infection of the cornea during therapy with ribociclib was carried out.
Prevention and correction of radiation dermatitis with basic skin care: doctor and patient consensus
Authors: Khlanta D. A. , Romanov D. S.
Published: December 2021

External beam radiation therapy is widely used by doctors around the world as one of the most common form of cancer treatment. The radiotherapy can help reduce the treatment aggression as compared with the surgical intervention in a large number of clinical situations, which ensures that the patient's quality of life will be decreased to a lesser extent in the after-treatment period. However, like the vast majority of anticancer treatments, the radiation therapy has a number of side effects, which are classified into acute radiation reactions and post-radiation injuries. Among them is radiation dermatitis, which is one of the most common adverse reactions to the radiotherapy. This complication manifests as erythema, as well as hyperpigmentation, dry and itchy skin, hair loss. In addition to the obvious negative impact on the patient's quality of life, some of the above factors can result in the development of a secondary skin infection. As one of the most frequent post-radiation complications, radiation dermatitis places radiotherapists before a challenge to reduce the incidence rates of this side effect, as well as to decrease the intensity of its clinical manifestations if it occurs. This challenge suggests the search for targeted drugs aimed to prevent and treat clinical symptoms. To date, dermatocosmetic products that are used to relieve skin manifestations of radiation treatment complications is an alternate option of the effective solution to the problem of radiation dermatitis. In the described clinical case, we assess the experience of using some of the dermatocosmetic products in a patient with a florid form of radiation dermatitis.
Comparative pharmacoeconomic analysis of the use of erythropoiesis-stimulating drugs for the treatment of anemia in cancer patients
Authors: Krysanov I. S. , Makarova E. V. , Ermakova V. Yu.
Published: December 2021

Introduction. Currently, a number of pharmacoeconomic studies describing use of erythropoietin stimulating agent (ESA) in cancer patients with anemia have been published, however, most of the publications on this topic are foreign. At the same time, there are practically no studies comparing the economic efficiency of various ESA preparations with each other. Some of works by foreign colleagues reflect that the clinical efficacy of using ESA namely the degree of increase in Hb, significantly depends on the patient’s body weight: the higher the weight, the greater the dose of EPO is required for a single administration and a course of therapy.

Aim. Сomparative pharmacoeconomic analysis of epoetin alfa usage for the treatment of anemia in adult cancer patients with weight 80 kg.

Materials and methods. The following drugs were selected for comparative analysis: epoetin alfa, epoetin beta, darbepoetin. Clinical efficacy was assessed in terms of the rate of in Hb level increase. Pharmacoeconomic analysis was carried out using the cost-effectiveness method (CEA).

Results. Тhe usage of epoetin alfa 12,000 IU for 8 weeks therapy course in cancer patients weighting over 80 kg had a better cost-effectiveness ratio compared to epoetin alfa (10,000 IU, 30,000 IU, 40,000 IU) and darbepoetin, giving way in price only to the cheapest epoetin beta which can be administered 4 injections simultaneously. Its the infringement of patients rights to avoid additional pain. Its the infringement of patients rights to avoid additional pain. At the 16th week of therapy, the usage of epoetin alfa 12,000 IU had an advantage over all ESA.

Conclusions. Тhe usage of russian epoetin alfa 12,000 IU for the treatment of anemia in adult cancer patients weighing over 80 kg approximately in real clinical practice in Russian Federation is an economically justified approach to the medical care organization.
Results of combined nivolumab and ipilimumab therapy in patients with cancer
Authors: Lyadova M. A. , Lyadov V. K. , Pardabekova O. A. , Pokataev I. A. , Ivannikov M. E. , Koroleva Ya. V. , Chernysheva E. S. , Lyadov K. V.
Published: December 2021

Introduction. The discovery of immune checkpoints and immune checkpoint inhibitors (ICI) became a breakthrough in medical oncology. Currently a search for most effective and safe schemes of ICI therapy for different cancers is ongoing.

Aim. To evaluate the efficacy and tolerability of a combination of nivolumab and ipilimumab in cancer patients in real-life clinical practice.

Materials and methods. The study included 30 patients: 13 patients with melanoma, 10 patients with renal cell carcinoma (RCC) and 7 patients with colorectal cancer (CRC). All patients underwent 4 courses of combined immune therapy (melanoma - nivolumab 1 mg/kg + ipilimumab 3 mg/kg; RCC, CRC – nivolumab 3 mg/kg + ipilimumab 1 mg/kg once per 21 days). Nivolumab monotherapy was continued after the achievement of disease control. Objective tumor response was registered in cases of partial or complete tumor regression. Treatment response was determined using iRECIST criteria.

Results. Treatment effect assessment was performed in 91 patients. Complete response (CR) was registered in 1 (5%) patient, partial response (PR) – in 3 (16%) patients, disease stabilization – in 8 (42%) patients, unconfirmed progression – in 7 (37%) patients. No cases of disease progression were registered. Thus, objective response rate was 21%; disease control was achieved in 63% of patients. The most significant immune-mediated adverse effects (imAEs) were gastric toxicity (20%), 1–2 grade fatigue (13%) and 2–3 grade hepatotoxicity (10%).

Conclusions. Combined nivolumab and ipilimumab therapy in patients with melanoma, CRC and RCC is associated with a high rate of disease control with acceptable toxicity profile.
Role of pre-metastatic niche in organ specificity of breast cancer metastasis. Influence on metastatic potential as a basis for CDK4/6-inhibition efficacy in early therapy of disseminated hormone-receptor-positive disease
Authors: Stukan A. I. , Goryainova A. Yu. , Lymar E. V. , Sharov S. V. , Andreev D. V. , Antipova V. V.
Published: December 2021

Influencing the pre-metastatic niche is a very perspective cancer treatment strategy in order of preventing metastases formation. It was found that bone marrow progenitor cells and tumor cells secreting biological compounds are key components in the formation of the pre-metastatic niche. Myeloid suppressor cells (MSCs) are the main type of bone marrow cells in pre-metastatic niches. At the same time, tumor-associated chronic inflammation induces the expression of proinflammatory cytokines triggering myeloid cells differentiation into myeloid suppressor cells. When circulating tumor cells enter the circulatory channel, their interaction with immune cells is observed, which additionally influences the pre-metastatic site preparation. Studies have shown that the entire spectrum of immune cells is capable of influencing the metastasis formation by circulating tumor cells. The epithelialmesenchymal transition with the tumor cell transporting form appearence was found to be related to the function of the ZEB1 protein. Its activity is regulated by numerous signaling mechanisms at the transcriptional level, including TGFβ, Wnt and Notch. This initiates epithelial-mesenchymal transition of breast cancer cells. Zhang Z.et al. proved that CDK4/6 blocking leads ZEB1 protein stability decreasing, preventing metastasis in breast cancer in vitro and in vivo. Moreover, USP51 deubiquitinase has been identified as a target of cyclin-dependent 4/6 kinases. At the molecular level, CDK4/6 phosphorylate and activates USP51, which then influences ZEB1  deubiquitination and stabilization. A  positive correlation was demonstrated between the  expression of p-RB (an indicator of CDK4/6 activity), p-USP51 and ZEB1 in breast cancer samples. Thus, the CDK4/6-USP51-ZEB1 axis may play a key role in the metastasis of breast cancer. In breast cancer cells, inhibition of CDK4/6 was shown to increase the expression of  E-cadherin  but decrease the  expression of  mesenchymal markers, reducing the  migratory ability and invasiveness of  breast cancer cell lines. This biological effect may also explain  the  clinical efficacy of  the  CDK4/6  inhibitor Abemaciclib in early-line therapy of metastatic breast cancer as well as in adjuvant combination hormone therapy for the prevention of metastatic lesions in patients at high risk of recurrence and progression in the MONARCH E study. Besides, there were no response predictors evaluated in trials investigating CDK4/6 in breast cancer treatment and it is unknown if there any differences in treatment response according to the metastatic site. The clinical cases demonstrate abemaciclib clinical efficacy in metastatic breast cancer treatment regardless of metastatic site.
Eribulin-trastuzumab combination in HER2-positive metastatic breast cancer: updated results from a Russian observational study
Authors: Kovalenko E. I. , Artamonova E. V. , Bolotina L. V. , Zhiliaeva L. A. , Ponomarenko D. M. , Karabina E. V. , Mukhametshina G. Z. , Khasanova A. I. , Ratner E. Yu. , Safarova A. R. , Manikhas A. G. , Popova N. O. , Evstigneeva I. V. , Vladimirova L. Yu. , Kramskaya L. V. , Karandeeva T. V. , Suslova I. R. , Romanchuk O. V. , Shikina V. E. , Povyshev A. Yu. , Osipov M. A. , Cherniakova E. M. , Dergunov A. S. , Volkonskiy M. V. , Chernov I. S. , Shumskaya I. E. , Fael M. M. , Garifullina V. I. , Gudkova I. E.
Published: December 2021

Introduction. The standard of 1st line treatment of HER2+ metastatic breast cancer (mBC) is double blockade with trastuzumab and pertuzumab + taxane, 2nd line – Trastuzumab-emtazine. There are no standards for further treatment, as well as the optimal drug sequence. Expansion of the arsenal of therapeutic possibilities and the use of new combinations will certainly improve the results of treatment of this category of patients and increase their life expectancy.

Aim. We sought to describe treatment patterns of  eribulin  and clinical outcomes of  metastatic HER2-positive breast cancer treated with eribulin  plus trastuzumab combination in  academic institutions and community oncology practices across the Russian Federation.

Materials and methods. Patients treated with eribulin anytime between Jan, 2014 and Sep, 2019 with a diagnosis of MBC were identified by 23 providers from Russia. Providers retrospectively reviewed the health records and abstracted selected data points into an electronic case report form for each eligible patient.

Results. 100 HER2-positive pts received eribulin in combination with trastuzumab. Median age was 55 (31–80) yrs and ECOG status 0–3. 67% pts had visceral metastases. Eribulin was administered as 1st and 2nd line to 23 (23%) pts, 3rd line to 31 (31%) pts, 4th line and later to 46 (46%). Median number of cycles was 5 (2–27). ORR was 12%, SD – 72%, SD > 6 months – 23%, PD – 16%. Clinical efficacy rate achieved in 35%. Median PFS was 5.07 months (95% CI 4.021–6.119). According to the ER-status the response to eribulin and trastuzumab was different. ORR was 18.8%, SD 72.9% in pts with ER-positive MBC (n = 48) and 5.8% and 71.2% respectively in ER-negative MBC (n = 52). Median PFS was 6.97 months (95% CI 3.924–10.016) in pts with ER-positive MBC and 4.67 months (95% CI 3.841–5.499) in ER-negative MBC (р = 0.3). The combination was well tolerated: dose reductions were required in 12% pts, withdrawal due to toxicity in 4% pts. The most common type of toxicity was hematological with neutropenia Gr III-IV in 14 (14%) pts. Peripheral neuropathy Gr III was observed in 5 (5%) pts. No cardiotoxicity was detected.

Conclusions. This is the real-life data of clinical outcomes for patients receiving eribulin plus trastuzumab for HER2-positive MBC throughout the Russian Federation. Our experience with eribulin plus trastuzumab demonstrates that this combination may be a potential effective treatment option for HER-2 positive MBC patients.
Optimal solutions in the third line therapy for refractory metastatic colorectal cancer. CORRECTness and CONCURency
Authors: Ayupov R. T. , Izmailov A. A. , Menshikov K. V. , Sultanbaev A. V. , Nasretdinov A. F. , Rakhimov R. R. , Musin Sh. I. , Sultanbaeva N. I.
Published: December 2021

Colon cancer therapy currently includes at least 3 cytostatic agents and 6 targeted drugs, combinations of which constitute many different treatment regimens. Nevertheless, as shown by various clinical studies, the use of oxaliplatin, irinotecan and fluoropyrimidine regimens in conjunction with monoclonal targeted drugs remains the main one. After progression on the main lines of therapy and registration of refractory disease, there are not many standard options for treatment in the 3rd line that have statistical confidence in terms of improving survival rates. There have been attempts to search for genetic aberrations for targeted therapy, predictors of the effectiveness of immunotherapy, the use of re-introduction regimens (re-application of a regimen that the patient stopped taking due to intolerance phenomena) and re-challenge (use of previous regimens, with response at first time, and then developed progression), and the abundance of solutions could only be limited by the imagination of the researcher. However, with the advent of the new multi-kinase inhibitor regorafenib, recommendations for the treatment of colorectal cancer have changed. The  drug has received indications for  use in  the  third line of  therapy for  refractory colorectal cancer. A review of the existing options for targeted therapy and an analysis of studies of different regimens in the 3rd line of therapy in  comparison with regorafenib was carried out. It has been established that regorafenib is currently the  optimal option for the treatment of metastatic colorectal cancer in the third line of therapy, regardless of previous lines of therapy and mutational status, and has a satisfactory spectrum of side effects, many of which may be predictors of therapy efficacy.
Molecular features evaluation of metastatic foci as the basis for metastatic breast cancer treatment personalization. Is there a place of CDK4/6-inhibitors in late-line therapy after chemotherapeutic regimens?
Authors: Stukan A. I. , Goryainova A. Y. , Lymar E. V. , Sharov S. V. , Antipova V. V.
Published: December 2021

The problem of metastatic breast cancer treatment is linked with clonal selection both in the process of tumor evolution and under the  influence of  previous treatment. The  analysis of  metastatic niche microenvironment and the  molecular genetic features become essential for treatment individualization. Studies demonstrate hormonal expression and epidermal growth factor receptor (HER2neu) discordance between the primary tumor and the metastatic focus. The advantages of combined hormone therapy (CНT) with CDK4/6 inhibitors were revealed in comparison with hormone therapy (НT) with survival rates benefits in the 1st and 2nd lines of НT, as well as after the 1st line of chemotherapy in clinical trials. However, there are lack of data on patients with multiple lines of chemotherapy. In the present retrospective study, more than half of the patients were treated palliative chemotherapy before administration of CDK4/6 inhibitors. Main metastatic foci represented luminal types after biopsy, however, loss of progesterone receptor expression was noted with the initial luminal A-subtype. At the time of the data cut-off, most patients have a longterm clinical effect, improvement conditions and reduction of pain, including the cases of late line CHT setting after chemotherapeutic regimens. Taking into account the heterogeneity of metastatic breast cancer, clonal selection and phenotype discordance there is the crucial need for molecular and genetic characteristics of the metastatic process. At the same time it is possible to consider the  appointment of  combined hormone therapy with CDK4/6  inhibitors as additional option for  late-line treatment of the disseminated process. Prospective studies on combined hormonal therapy with CDK4/6 inhibitors in metastatic breast cancer in late lines of therapy with proven HR+HER2neu-negative receptor status of the metastatic focus are strongly recommended.
Efficacy of lorlatinib in the treatment of ALK-positive non-small cell lung cancer patients with progression on crizotinib: personal experience
Authors: Laktionov K. K. , Reutova E. V. , Kruteleva S. Yu. , Antonova E. Yu.
Published: December 2021

Introduction. Lorlatinib is a  third generation ALK tyrosine kinase inhibitor. Back in  2018, the  drug underwent accelerated FDA approval and was recommended for the treatment of patients with ALK-positive non-small cell lung cancer after progression on crizotinib and another ALK inhibitor. For a long time, the use of the drug in Russia was possible only in clinical trials or expanded access program. However, now this drug is becoming available in our country.

Purpose. To analyze the overall and intracranial response during lorlatinib therapy, as well as the tolerability of lorlatinib therapy in patients with ALK-positive non-small cell lung cancer who previously received crizotinib and one or more lines of cytostatic therapy.

Materials and methods. The  study included 39  patients aged 28  to 76  years, diagnosed with non-small cell lung cancer. In 36 cases, a translocation in the ALK gene was detected, in three, a ROS1 translocation. All patients received targeted therapy with crizotinib and one or more lines of chemotherapy before starting lorlatinib therapy. All patients received 100 mg lorlatinib therapy until disease progression or intolerable toxicity.

Results. During the observation period for the moment of September 2021, an objective response was achieved in 28 patients (71.7%), in 10 patients (25.6%) – stabilization of the disease, in one patient (2.6%) – progression. The median duration of the drug was just over 40 months. The drug intake was characterized by a predictable and manageable toxicity profile.

Conclusions. These data indicate a high direct efficacy of lorlatinib in patients with ALK/ROS1 translocations. The data obtained do not contradict the  results obtained in  the  course of  clinical trials. The  drug lorlatinib has currently received registration in Russia for the treatment of non-small cell lung cancer in cases of the development of progression while taking secondgeneration ALK inhibitors or several lines of therapy with ALK inhibitors.
Role of Post-Neoadjuvant therapy with trastuzumab emtansine in HER2-positive breast cancer
Authors: Lubennikova E. V. , Vishnevskaya Ya. V.
Published: December 2021

The widespread introduction of anti-HER2 agents has changed the natural course of Her2-positive breast cancer. The use of trastuzumab, and later dual anti-HER2 blockade with pertuzumab, in neoadjuvant regimens significantly increased the chances of complete cure. However, among patients with early and locally advanced forms of Her2-positive cancer, there is a cohort with an extremely unfavorable prognosis – tumors that have not achieved complete pathomorphological regression after neoadjuvant chemotherapy.

The presence of a residual tumor in Her2-positive breast cancer has long been only a prognostically unfavorable factor without the potential to influence disease outcome. The results of the international phase III study KATHERINE, which demonstrated the high efficacy of post-adjuvant therapy with trastuzumab emtansine (T-DM1) in this patient cohort, have established a new standard of care. Due to T-DM1 adjuvant therapy, the possibility to significantly improve long-term results determined the predictive characteristics of the morphological response to the choice of treatment tactics, which became an important argument in favor of neoadjuvant therapy in patients with not only locally advanced but also primarily resectable Her2-positive breast cancer, followed by personalization of therapy.

This article presents our own experience with post-neoadjuvant therapy with trastuzumab emtansine in a young patient with a residual tumor. The data of the main studies in early Her2-positive breast cancer are summarized.
Target therapy of luminal HER2-negative advanced breast cancer with PIK3CA mutation: combination of alpelisib plus fulvestrant in real clinical practice
Authors: Filonenko D. A. , Ibragimova T. M. , Polshina N. I. , Belogurova A. V. , Khatkova E. I. , Arutiunian E. A. , Volkova E. I. , Zhukova L. G.
Published: December 2021

Introduction. Сombination of alpelisib plus fulvestrant is approved in patients with hormone receptor positive, HER2-negative, PIK3CA-mutated advanced breast cancer (ABC) after progression on hormonotherapy. Efficacy data of alpelisib in heavily pretreated patients with HR+/HER-2-, PIK3CA-mutated advanced breast cancer are limited, only results from phase I trial are available. Here we report our results of alpelisib efficacy in 19 heavily pretreated patients.

Object: to evaluate efficacy and safety of combination alpelisib plus fulvestrant in patients with HR+/HER2-, PIK3CA-mutated advanced breast cancer in initial and later lines of therapy in real clinical practice.

Materials and methods. Combination of  alpelisib plus fulvestrant was investigated in  19  patients with HR+/HER2-, PIK3CAmutated ABC, alpelisib at a dose of 300 mg per day plus fulvestrant at a dose of 500 mg i.m. every 28 days and once on day 15. Treatment continued until disease progression or unacceptable toxicity.

Results. From February 2021 19 patients with HR+/HER2-, PIK3CA-mutated advanced breast cancer were treated with alpelisib plus fulvestrant. The data cut off is October 2021. Median lines of treatment in advanced disease was five, including 19 (100%) patients received CDK4/6, 14 (74%) – fulvestrant and/or everolimus and 15 (79%) – chemotherapy. 4 (21%) received alpelisib in a second line, 15 (79%) – in subsequent lines. Median progression-free survival was 7 months. The response was evaluated in 18 patients: partial response was achieved in 5 (28%) patients, stable disease – in 9 (50%), disease progression – 4 (22%). The most frequent adverse events were hyperglycemia – 74% (grade 3 – 22%), creatinine increased – 42% and rash – 37% (grade 3 – 22%). Only one patient has discontinued the treatment due to Quincke`s edema.

Conclusions. Combination of alpelisib with fulvestrant is an effective option both in initial and later lines of therapy in patients with HR+/HER2-, PIK3CA-mutated advanced breast cancer including fulvestrant, CDK4/6 inhibitors and/or everolimus – pretreated patients.
Efficacy of the immune checkpoint inhibitor nivolumab in the treatment of advanced hepatocellular carcinoma with the exhausted possibilities of therapy with tyrosine kinase inhibitors
Authors: Goryainova A. Yu. , Stukan A. I. , Murashko R. A. , Sharov S. V. , Kirsanova O. I. , Lymar E. V.
Published: December 2021

Hepatocellular carcinoma is one of the most formidable and deadly cancers. The limited possibilities of surgical methods of treatment as well as the formation of multiple drug resistance caused by the biological characteristics of both the liver tissue itself and tumor cells with their microenvironment determine the unsatisfactory indicators of relapse free survival and overall survival of patients. In addition, therapy with tyrosine kinase inhibitors, which has become the “gold” standard, has limited possibilities: a large number of side effects significantly reduce the quality of life and adherence to treatment in patients with hepatocellular cancer. The search for molecular biological targets, as well as new therapeutic agents that block these targets, does not always lead to positive results. Immunotherapy in this sense is a priority, having good tolerance, a low number of side effects, no need for additional testing of the patient’s biological material before starting treatment, high efficiency and a long response time. However, there are many unresolved questions about the duration of therapy, predicting its efficacy, the optimal combination of drugs or the use of monotherapy, the formation of priority subgroups of patients. Understanding the mechanisms of immune evasion, an ability that hepatocellular carcinoma possesses, – is the key to successful use of immunotherapeutic agents alone, in combination with tyrosine kinase inhibitors, antiangiogenic drugs or among themselves. This article provides an overview of data from clinical studies of modern drugs for the treatment of hepatocellular carcinoma and describes the mechanism of liver immunological tolerance as a possible predictive marker of sensitivity to immunotherapy. It seems promising to study the role of cells in the microenvironment of hepatocellular carcinoma for predicting the effectiveness of immunotherapy. The clinical example is used to demonstrate the successful experience of using the immunotherapeutic drug nivolumab in the treatment of hepatocellular carcinoma resistance to tyrosine kinase inhibitors. This is a classic example of duration of response to therapy, lack of reactivation of chronic viral hepatitis and controlled toxicity. All these indicators enable the clinician to consider immunotherapy as a priority option for the treatment of inoperable hepatocellular carcinoma.
Prognostic value of the proportion of the sclerosing component in fibrolamellar liver carcinoma
Authors: Antonova E. Yu. , Moroz E. A. , Podluzhny D. V. , Kudashkin N. E. , Dzhanyan I. A. , Volkov A. Yu. , Laktionov K. K. , Breder V. V.
Published: December 2021

Introduction. Fibrolamellar hepatocellular carcinoma (FLC), which develops most often in the younger population. In FLC, variable histoarchitectonics are noted, possibly the presence of a sclerosing component, foci of necrosis and dystrophy of tumor cells.

Objective. Assessment of the influence of the proportion of the sclerosing component in fibrolamellar carcinoma (FLC) of the liver on the course and prognosis of the disease. Determination of the relationship between the proportion of the sclerosing component in the tumor and the frequency of microvascular invasion.

Materials and methods. A retrospective study included 34 patients with a diagnosis of FLC, who underwent radical surgical treatment at the first stage. A histological assessment of the proportion (%) of the sclerosing component in FLC was made. The effect of  the  proportion of  the  sclerosing component on overall (OS) and relapse-free (DFS) survival was assessed. The  analysis of the relationship between the proportion of the sclerosing component in the tumor and the frequency of microvascular invasion was carried out.

Results. Significantly worse RFS was achieved in the groups of patients with a sclerosing component in FLC > 5% than in the group of patients with a sclerosing component in FLC ≤ 5% (p = 0.0010; p = 0.024; log – rank test). Median DDS in group 1 is 107 (95% CI, 22–192) months; at 2 – 11 (95% CI, 8–14) months; in 3 – 21 (95% CI, 8–33). The frequency of histologically confirmed microvascular invasion in the compared groups was 29, 74, 87.5%, respectively. OS was significantly worse in 2 groups (27 patients in total) with a sclerosing component in FLC > 5% than in the group of patients with a sclerosing component in FLC ≤ 5%. Median OS in group 1 120 (95% CI, 60–180) months; at 2 – 41 (95% CI, 15–92) months; in 3 – 69 (95% CI, 35–103). A direct relationship was found between an increase in the proportion of the sclerosing component in a tumor and an increase in the frequency of microvascular invasion.

Conclusions. We can assume that the severity of the sclerosing component in the FLK tumor can serve as an effective morphological marker of a less favorable prognosis for this HCC subtype and correlate with the frequency of microvascular invasion.
Cazaquistão entre as potências
Authors: Curado Pedro Rocha Fleury , Gonçalves Ribeiro Gabriel
Published: December 2021

A presente pesquisa objetiva analisar a política externa do Cazaquistão durante o governo de Nur-Sultan Nazarbaev (1991-2019). Descrita como “multivetorial”, a política externa cazaque buscou multiplicar o número de parceiros estratégicos (vetores) no plano internacional. Valendo-se de conceitos da geografia política, o presente trabalho explora a dupla condição de Estado-tampão e Estado sem litoral para enfatizar os limites da inserção multivetorial cazaque. Para tanto, o texto examina a evolução das relações do país com Rússia, China e países do Ocidente, diferenciando a participação de cada vetor em temas relacionados às esferas militar e econômica.
Normative Political Theory and Global Migration Governance
Authors: Santos Marcelo
Published: December 2021

Based on the main contributions of normative political theory on global justice and migration ethics, this article assesses the global Compacts on refugees and migration, approved by the United Nations General Assembly in December 2018. The set of conclusions indicates that the Compacts constitute an important advance in global moral and political projects and commitments. However, the application of their predicted terms can bring about problems, distortions, and impasses in the sharing of responsibilities.
Covid-19 no Japão
Authors: Uehara Alexandre Ratsuo , Lopes Beatriz
Published: December 2021

Este artigo busca analisar os impactos da pandemia da COVID-19 no Japão, que apresenta uma baixa taxa de contágio e de mortalidade, contrariando os temores que surgiram por ser o país com a sociedade mais envelhecida do mundo. Buscar-se-á mostrar que, apesar dos indicadores serem muito melhores do que dos EUA, do Brasil e de vários países europeus, que tiveram as atitudes das populações e governos criticados, as políticas de enfrentamento implementadas pelo Japão e os comportamentos e reações da sua sociedade também não ocorreram sempre de maneira coerente.
A guerra financeira no século XXI a revolução da “bomba-dólar” e a contrarrevolução (?) do “renminbi digital”
Authors: Silva Fernando , Kosinski Daniel
Published: December 2021

A “bomba-dólar”, produto das respostas dos Estados Unidos aos atentados do 11 de setembro de 2001, é instrumento do seu uso exclusivo que, apoiado nas posições hegemônicas do dólar e das suas finanças no sistema financeiro internacional, lhe permite impor sanções financeiras com grau de sofisticação e poder de destruição nunca antes vistos. Assim, revolucionou a guerra financeira e a ordem internacional no século XXI. Todavia, na China, as autoridades adaptaram as tecnologias das criptomoedas privadas e descentralizadas, como o bitcoin, para criar o renmimbi digital (e-RMB) com objetivos explícitos de construir as bases de um sistema financeiro internacional alternativo, confrontando diretamente a capacidade estadunidense para sancionar. Assim, este artigo objetiva identificar em que medida esse efeito será real. A investigação revelou que autoridades e centros de pesquisa estadunidenses constataram que, de fato, o e-RMB reduzirá significativamente a capacidade dos Estados Unidos para impor sanções. Dessa forma, concluímos que há fortes indícios de que, quando em pleno funcionamento a partir de 2022, o e-RMB neutralizará a bomba-dólar, abrindo um novo capítulo nas guerras financeiras e nos interesses, disputas e conflitos nas relações internacionais.
Guerras brasílicas do século XXI eclipse da soberania nos black spots das grandes metrópoles brasileiras
Authors: de Oliveira Henrique , Franchi Tássio
Published: December 2021

A soberania é um dos pilares dos Estados-nação, no entanto, sua definição é ambígua e controversa. Não obstante à perene contestação de conceitos, este estudo se propõe a estabilizar contingencialmente uma acepção de soberania adequada à realidade brasileira. No maior país sulamericano, os aglomerados subnormais das metrópoles nacionais concentram populosas áreas de baixa governabilidade e com atuação destacada de criminosos, entretanto, a base teórica anglo-saxã, dominante na literatura acadêmica, dispõe de escassos recursos para uma interpretação da fragilidade endêmica de um Estado consolidado e distante dos parâmetros da falência. Assim, a partir de premissas essenciais, como a autoridade, coerção e territorialidade, a investigação aprofunda a compreensão e a caracterização do efeito deletério do crime organizado sobre a soberania estatal brasileira. Oferece, também, um suporte argumentativo que amplia a agenda de pesquisa relacionada ao emprego das Forças Armadas no enfrentamento ao crime organizado. Os resultados obtidos pela combinação entre a elucidação teórica e estudos empíricos indicam que, embora não apresentem uma retórica direta revisionista ou de contestação, as organizações criminosas se sobrepõem ao poder estatal de forma seletiva e progressiva nos black spots das metrópoles nacionais brasileiras.
Submarinos para quê? condicionantes do programa de desenvolvimento dos submarinos brasileiros
Authors: Ronaldo Deywisson , de Oliveira Marcos Aurélio
Published: December 2021

Quais são os fatores indutores do Programa de Desenvolvimento de Submarinos? Este artigo explica que o alto investimento na produção de novos submarinos convencionais e do primeiro submarino de propulsão nuclear do Brasil está condicionado a objetivos em três esferas de interesse: (1) para a defesa da Amazônia Azul, seus recursos naturais e energéticos (sobretudo as reservas de petróleo do pré-sal), e proteção das rotas de comércio exterior; (2) interesses em nível regional, em que o Brasil busca fortalecer o processo de integração como forma de promover a estabilidade regional e consolidar sua liderança na América do Sul; e (3) para fomentar objetivos de nível global, em que o País busca ampliar sua inserção internacional, participar de processos decisórios de maior relevância e adquirir assento permanente no Conselho de Segurança das Nações Unidas (CSNU). A metodologia foi qualitativa, norteada pelas particularidades do caso e operacionalizada pela técnica bibliográfico-documental. Constatou-se que os atributos táticos, diplomáticos e ofensivos dos submarinos são adequados aos interesses brasileiros, pois instrumentalizam sua política externa e de defesa.
China e seus Riscos Geopolíticos pós COVID-19 um exame a partir de cenários prospectivos
Authors: Túlio Marco , Alan Marcos
Published: December 2021

O presente artigo ampara-se na literatura sobre constru- ção de cenários para analisar o contexto geopolítico da República Popular da China face à recente pandemia do COVID-19. Temos como objetivo oferecer um referencial de futuros alternativos que nos permita, nesse caso espe- cífico, analisar riscos geopolíticos. Podemos afirmar que a atual estratégia chinesa se baseia no crescimento econô- mico por meio de investimentos em tecnologia e abertura de mercados, se conjugando com a iniciativa “一带一路” (Cinturão e Rota). Tal estratégia se encontrou ameaçada pela atual crise sanitária mundial, que fechou portos, fronteiras, mercados e causou sérios danos à imagem in- ternacional da China. De modo a realizar tais objetivos, o presente artigo se fundamenta na visão de teóricos vin- culados à análise de cenários prospectivos e de estudos estratégicos. Objetivando avançar a compreensão sobre o tema, criamos três cenários, a dizer: um cenário cautelo- so; um cenário otimista, e um cenário de agressividade intensa. Esperamos, a partir dessa construção, observar as possíveis situações futuras e riscos à estratégia geopo- lítica da China.
Truman Doctrine (1946); Defense Planning Guidance (1991) & The National Security Strategy (2002) the Mackinder & Spykman Dialects revisited
Authors: Varella Luiz
Published: December 2021

The aim of this article is to test the hypothesis that Halford Mackinder and Nicholas Spykman’s geopolitical theories, which sustained the grand strategy of the United States with the implementation of 1946 Truman Doctrine, are still relevant today after their termination. The results indicate that the intellectual matrixes were found in documents of the grand strategy of the United States in two moments. First, in 1992, in the George Herbert Walker Bush’s government’s Defense Planning Guidance document, formulated by the Pentagon, in February 1992. Second, they were found replicated 10 years after in the first term of President George Walker Bush, inaugurated in 2001. In the latter, the theoretical formulations repercussions were depicted in the official documents Quadrennial Defense Review (2001) and the National Security Strategy (2002). The article concluded that the authors’ ideas remain valid to explain and interpret the actions of the United States’ grand strategy in the international scenario.
E-navigation solução safety e sustentável para uma nova era?
Authors: Raysa Laís
Published: December 2021

Numa escala temporal, a partir de mudanças de paradigmas (gerenciais e operacionais), a maneira de execução da atividade ao mar tem evoluído, agregada a ferramentas tecnológicas fundamentais. Apesar da regulamentação da Organização Marítima Internacional (IMO) na busca por soluções safety, security, e sustentáveis, acidentes marítimos continuaram a acontecer – numa abordagem causal simples, devido a “erros humanos”. Sendo incalculáveis os prejuízos decorrentes de tais circunstâncias, verificou-se que a navegação poderia ser aprimorada com o auxílio da tecnologia, a fim de proporcionar um maior controle das ações humanas – conceito e-Navigation – o que caracteriza o início de uma nova era para a navegação. O presente estudo pretende analisar a e-Navigation como solução para os aspectos safety e sustentável do âmbito marítimo, numa aplicação das Ciências Náuticas por método indutivo, associada a uma proposta técnico-científica que apresenta as mudanças de paradigmas da atividade comercial marítima (setor petroleiro) em eras específicas, com análise aplicável a toda a indústria de transporte marítimo. Verificou- se que, numa fase inicial, soluções “inteligentes”, safety e sustentáveis para a navegação comercial podem ser possíveis; mas só até certo limite (ponto de inflexão), quando situações imprevistas, circunstâncias adversas ou falhas humanas, por exemplo, venham a acontecer.
Between Russia and europe the role of national identities in international relations of Estonia, Latvia and Lithuania
Authors: Resende Erica , Dumard Graziela
Published: December 2021

Thirty years after the restauration of their independence, Estonia, Latvia and Lithuania are now members of the European Union and demonstrate little affinity with Russia, heir to the USSR. What is the role identity discourses in their foreign policy choices? We argue that Estonia, Latvia and Lithuania define their national identities – and therefore the thrust of their foreign policies – according to a logic of triangular attraction and repulsion towards Russia and Europe. Based on the Self/Other dichotomy, this article identifies how meanings associated with Baltic national identities were incorporated into their foreign policies after the fall of URSS. More specifically, the article examines the discourses of Russification and/or Sovietisation and Europeanisation, how these discourses differ from one another, and how the Baltic states respond to those influences in constructing their foreign policies.
THE FRANCO-BRAZILIAN NETWORK ON NATURAL PRODUCTS (FB2NP): A NEW NETWORK PROMOTING COOPERATION AND EXCHANGES IN NATURAL PRODUCTS RESEARCH
Authors: Almeida Jackson , Grougnet Raphaël , Quintans Lucindo , Chevalier Sylvie , Feuilloley Marc , Robert Thomas , Bach Stéphane , Oliveira Raimundo , Thiéry Valérie , Bazureau Jean-Pierre , Mongin Florence , Kritsanida Marina , Sol Vincent , Costa Vicente , Bourgougnon Nathalie , Marchand Pascal , Picot Laurent
Published: December 2021

THE FRANCO-BRAZILIAN NETWORK ON NATURAL PRODUCTS (FB2NP): A NEW NETWORK PROMOTING COOPERATION AND EXCHANGES IN NATURAL PRODUCTS RESEARCH