Pathogenetic Effects of Bacteria of the Genus <i>Desulfovibrio</i>. Experimental Study. Part One: Iron Metabolism

The aim of the work was to study specific systemic effect of sulfate-reducing bacteria of the genus Desulfovibrio on organism systems through creating an experimental model of intragastric bacterial invasion against the background of dysbiotic conditions of rodent gastrointestinal tract. Materials and methods. The experimental study was conducted on Wistar rats. Intestinal dysbiosis was modeled with the help of antibiotics, amoxicillin and metronidazole. Typical strain Desulfovibrio desulfuricans subsp. desulfuricans VKM B-1799T was used as an infectious agent. Results and discussion. As a result of the experiment performed, during the period of acute infection (on day 15 of the experiment), a direct correlation between the concentration of the injected D. desulfuricans VKM B-1799T bacteria suspension and the serum iron level was observed: the higher the infectious agent dose, the lower the serum iron concentration. During the phase of remote effects (day 38 of the experiment), the inverse correlation between the concentrations of D. desulfuricans VKM B-1799T in the intestines of rodents was revealed: when the concentration of the infecting agent increased from 103 CFU/g and higher, the iron level decreased from 43.5 μmol/l to 38.5 μmol/l. When comparing the level of transferrin and unsaturated iron binding capacity (UIBC), an increase in those parameters was observed in all groups of rats both during the period of acute infection and the period of long-term effects, and the percentage of transferrin iron saturation decreased, indicating the occurrence of iron deficiency against the background of exposure to the infectious agent. Intestinal dysbiosis promotes colonization by opportunistic flora, including Desulfovibrio sp. Changes in the iron metabolism markers in experimental animals against the background of D. desulfuricans VKM B-1799T infestation above 103 CFU/g and the ability of this microorganism to bind iron into an unavailable form suggest that the bacteria Desulfovibrio sp. are one of the key etiological factors of iron deficiency anemia

Рекомендации по проведению тримодальной терапии рака мочевого пузыря (Невский консенсус 2021)

The aim of this work was to clarify and extend the existing clinical guidelines on organ-sparing treatment of muscleinvasive bladder cancer. The standard protocol of radical conservative treatment for muscle-invasive bladder cancer includes transurethral resection of the bladder, external beam radiotherapy with simultaneous chemotherapy (radiosensitization), which is usually referred to as trimodal therapy. The implementation of trimodal therapy into routine practice in Russia is limited due to the lack of distinct criteria for each of the stages. The involvement of surgeons, radiation oncologists, and chemotherapists, on the one hand, provides the required multidisciplinary approach to cancer treatment; on the other hand, it might impede the entire algorithm. To address this problem, specialists from the Department of Radiology (project moderators), Department of Cancer Urology, and Department of Chemotherapy of N.N. Petrov National Medical Research Center of Oncology under the auspices of Saint Petersburg Oncological Research Society formed a group of experts, including radiation oncologists, urologists, and chemotherapists from federal and local cancer (educational) institutions of Saint Petersburg who had an experience of treating muscle-invasive bladder cancer. The guideline was developed with the consideration of available guidelines published by leading professional associations of radiotherapy and oncology (urological), research articles, and own experience.         Цель работы – уточнение и дополнение клинических рекомендаций по органосохраняющему лечению мышечноинвазивного рака мочевого пузыря. Стандартный протокол радикального консервативного лечения мышечно-инвазивного рака мочевого пузыря включает трансуретральную резекцию мочевого пузыря, дистанционную лучевую терапию с одновременной химиотерапией (радиосенсибилизацию) и называется тримодальной терапией. Широкое внедрение тримодальной терапии в отечественную практику ограничено отсутствием четких критериев для каждого из этапов. Участие в протоколе хирургов, радиационных онкологов и химиотерапевтов, с одной стороны, обеспечивает необходимый мультидисциплинарный характер лечения онкологического больного, с другой – затрудняет реализацию всего алгоритма. Для осуществления поставленной задачи отделениями радиотерапии (модераторы проекта) и онкоурологии, а также отделением химиотерапии и инновационных технологий НМИЦ онкологии им. Н.Н. Петрова под эгидой Петербургского онкологического научного общества сформирована группа экспертов, включающая радиационных онкологов, онкоурологов и химиотерапевтов федеральных и городских онкологических (образовательных) учреждений (г. Санкт-Петербург), имеющих опыт лечения мышечно-инвазивного рака мочевого пузыря. Разработка рекомендаций велась с учетом имеющихся рекомендаций ведущих профессиональных радиотерапевтических и онкологических (урологических) ассоциаций, опубликованных статей и собственного опыта

Эффективность и безопасность комбинации ленватиниба и эверолимуса у больных диссеминированным раком почки, прогрессирующим на фоне антиангиогенной т аргетной терапии: результаты российского многоцентрового наблюдательного исследования ROSLERCM

Objective: an assessment of efficacy and safety of lenvatinib in combination with everolimus in unselected patients with metastatic renal cell carcinoma (mRCC) progressed during or following ≥1 line of antiangiogenic targeted therapy.Material. Russian multicenter observational study ROSLERCM included 73 consecutive patients with morphologically verified mRCC progressed during or following ≥1 line of antiangiogenic targeted therapy, treated with lenvatinib (18 mg/d) and everolimus (5 mg/d) in 20 Russian centers. Median age of the patients was 59 (23–73) years, a male-to-female ratio – 3:1. Most common histological type of kidney cancer was clear-cell RCC (71 (95.8 %)). More than 2 lines of previous therapy were administered in 45 (61.6 %) cases. Most patients were diagnosed with multiple metastases (71 (97.3 %)) in &gt;1 site (61 (83.6 %)). Nephrectomy was performed in 87.7 % (64/73) of cases. At the combined therapy start ECOG PS 2–4 was registered in 16 (20.5 %), poor prognosis according to IMDC score – in 33 (45.2 %) patients. Median follow-up was 9.7 (1–26) months.Results. Median progression-free survival achieved 16.9 (95 % confidence intervals (CI) 12.1–20.6), overall survival – 20.8 (95 % CI 15.7–25.9) months. Objective response rate was 11 % (8/73); tumor control was reached in 93.2 % (68/73) of cases. Median objective response duration was 10.5 (4.3–16.8) months, tumor control duration – 10.0 (2.5–17.5) months. Any adverse events developed in 83.6 % (61/73), adverse events grade III–V – in 23.3 % (17/73) of cases. Most frequent AE grade III–IV were diarrhea (10 (13.6 %)) and arterial hypertension (6 (8.2 %)). Unacceptable toxicity demanded treatment cancellation in 4.2 % (3/73), therapy interruption – in 30.1 % (22/73) and dose reduction – in 32.9 % (24/73) of patients.Conclusion. Unselected mRCC patients administered with combined targeted therapy in the real world practice were registered with similar survival, lower objective response rate, and better tolerability comparing with population assigned for lenvatinib plus everolimus in the randomized phase II trial.Цель – оценка эффективности и безопасности комбинации ленватиниба и эверолимуса в российской популяции неотобранных больных распространенным раком почки, прогрессирующим на фоне или после не менее 1 линии антиангиогенной таргетной терапии.Методы. В российское многоцентровое наблюдательное исследование ROSLERCM последовательно включены 73 больных верифицированным диссеминированным раком почки, прогрессирующим на фоне или после ≥1 линии антиангиогенной терапии, получавших ленватиниб (18 мг / сут) с эверолимусом (5 мг / сут) в 20 клинических центрах России. Медиана возраста – 59 лет (23– 73 года), соотношение мужчин и женщин – 3:1. Доминирующим гистологическим типом опухоли был светлоклеточный вариант (71 (95,8 %)). Более 2 линий терапии ранее получали 45 (61,6 %) больных. На момент старта комбинированной таргетной терапии соматический статус ECOG PS 2–4 имел место у 16 (20,5 %), к группе плохого прогноза IMDC относились 33 (45,2 %)больных. В большинстве случаев метастазы были множественными (71 (97,3 %)) и локализовались более чем в 1 органе 61 (83,6 %). Первичная опухоль была удалена у большинства (64 (87,7 %)) пациентов. Медиана наблюдения – 9,7 мес (1–26) мес.Результаты. Медиана беспрогрессивной выживаемости достигла 16,9 (95 % доверительный интервал 12,1–20,6), ОВ – 20,8 (95 % ДИ 15,7–25,9) мес. Частота объективных ответов на лечение составила 11 % (8/73), (медиана длительности – 10,5 (4,3–16,8) мес), контроля над опухолью – 93,2 % (68/73) (медиана длительности – 10,0 (2,5–17,5) месяца). Нежелательные явления развились у 83,6 % (61 / 73) пациентов и достигли III–V степеней тяжести в 23,3 % (17 / 73) случаев. Наиболее частыми нежелательными явлениями III–IV степеней тяжести были диарея (10 (13,6 %)) и артериальная гипертензия (6 (8,2 %)). Непереносимая токсичность послужила поводом для отмены комбинированной таргетной терапии в 4,2 % (3 / 73), перерыва в лечении – в 30,1 % (22 / 73) и редукции дозы ленватиниба – в 32,9 % (24 / 73) случаев.Заключение. У неотобранных больных, получающих лечение в широкой клинической практике, зарегистрирована сопоставимая выживаемость, более низкая частота объективных ответов и лучшая переносимость терапии ленватинибом с эверолимусом по сравнению с результатами регистрационного исследования

Эффективность и безопасность комбинации ленватиниба и эверолимуса у больных диссеминированным раком почки, прогрессирующим на фоне антиангиогенной таргетной терапии: второй анализ данных российского многоцентрового наблюдательного исследования

Objective. The primary endpoint was progression-free survival; secondary endpoints included overall survival, objective response rate and duration, tumor control rate and duration, as well as safety profile of lenvatinib with everolimus in consecutive patients with advanced renal cell carcinoma who had disease progression after targeted antiangiogenic therapy.Materials and methods. This observational study included 129 consecutive patients with metastatic renal cell carcinoma resistant to targeted antiangiogenic therapy. The median age was 60 years; a male to female ratio was 3.1:1. Twenty-seven patients (20.9 %) had ECOG performance status of 2—4. The majority of study participants (n = 127; 98.4 %) had multiple metastases. Tumor lesions were located in &gt;1 organ in 104 cases (80.6 %). The primary tumor was removed in 110 (85.3 %), including 39 (30.2 %) patients undergone cytoreductive surgery. Seventy patients (54.2 %) had earlier received more than one line of therapy. Upon enrollment, there were 13 IMDC favourable-risk patients (10.1 %), 86 IMDC intermediate-risk patients (66.6 %), and 29 IMDC poor-risk patients (22.5 %). In one patient (0.8 %), the IMDC risk was not estimated. All patients received lenvatinib at a dose of 18 mg/day and everolimus at a dose of 5 mg/day. The median follow-up was 10.5 (1—30) months.Results. Median progression-free survival was 14.9 (11.9—17.9) months; overall survival was 19.9 (15.2—24.6) months. The objective response rate was 17.0 % (median duration 9.7 (2.8—16.5) months); tumor control rate was 72.9 % (median duration 10.0 (2.5—17.5) months). Adverse events were observed in 112patients (86.8 %) with grade III—IVadverse events registered in 27participants (20.9 %). Five participants (3.9 %) needed inpatient treatment of adverse events; one patient (0.8 %) died due to adverse events. Adverse events required treatment discontinuation in 4 patients (3.1 %), treatment interruption in 35 patients (27.1 %), and dose reduction in 33 patients (25.6 %).Conclusion. The results of the secondary analysis in the ROSLERCM observational study confirmed the results obtained earlier on the efficacy and safety of the lenvatinib plus everolimus combination in the second- and subsequent-line therapy for advanced renal cell carcinoma resistant to targeted antiangiogenic therapy in consecutive Russian patients.Цель. Первичной конечной точкой являлась беспрогрессивная выживаемость, вторичными — общая выживаемость, частота и длительность ответа на лечение и контроля над опухолью, а также профиль безопасности комбинации ленватиниба и эверолимуса у неотобранных пациентов с распространенным почечно-клеточным раком, прогрессирующим после антиангиогенной таргетной терапии.Материалы и методы. В наблюдательное исследование последовательно включены 129 больных диссеминированным почечноклеточным раком, резистентным к антиангиогенной таргетной терапии. Медиана возраста — 60 лет, соотношение мужчин и женщин — 3,1:1. Соматический статус расценен как ECOG 2—4у 27 (20,9 %) больных. У127 (98,4 %) пациентов имелись множественные метастазы. Опухолевые очаги локализовались в &gt;1 органе в 104 (80,6 %) случаях. Первичная опухоль удалена у 110 (85,3 %) больных, в 39 (30,2%) наблюдениях — с циторедуктивной целью. Ранее &gt;1 линии предшествующей терапии получали 70 (54,2 %) больных. На момент включения в исследование к группе благоприятного прогноза по шкале IMDC относились 13 (10,1 %), промежуточного — 86 (66,6 %), неблагоприятного — 29 (22,5 %) больных; группа прогноза не определена у 1 (0,8 %) пациента. Всем больным назначали ленватиниб 18мг/сут с эверолимусом 5мг/сут. Медиана наблюдения за всеми пациентами составила 10,5 (1—30) мес. Результаты. Медиана беспрогрессивной выживаемости достигла 14,9(11,9—17,9) мес, общей выживаемости — 19,9(15,2—24,6) мес. Частота объективного ответа составила 17,0 % (медиана длительности — 9,7(2,8—16,5) мес), частота контроля над опухолью — 72,9 % (медиана длительности — 10,0 (2,5—17,5) мес). Нежелательные явления зарегистрированы у 112 (86,8 %), в том числе, III—IV степеней тяжести — у 27 (20,9 %) больных. Госпитализация для коррекции нежелательных явлений потребовалась в 5 (3,9 %) случаях, 1 (0,8 %) пациент умер из-за нежелательных явлений. Нежелательные явления послужили причиной отмены терапии в 4 (3,1 %), перерыва в лечении — в 35 (27,1 %), редукции дозы — в 33 (25,6 %) случаях.Заключение. Результаты второго анализа наблюдательного исследования ROSLERCM подтвердили ранее полученные результаты применения комбинации ленватиниба с эверолимусом во 2-й и последующих линиях терапии распространенного почечно-клеточного рака, рефрактерного к антиангиогенному лечению, у неотобранных российских больных

NEW ADVANCES IN THE TREATMENT OF BREAST CANCER: THE ROLE EPOTHILONES

The review considers information about the efficacy and safety of Ixabepilone as a monotherapy and as a component of combination therapy for advanced breast cancer. Successful treatment of metastatic breast cancer is often confounded by resistance to chemotherapy, in particular anthracyclines and taxanes. The limited number of effective treatment options for patients with more aggressive biological subtypes, such as triple-negative metastatic breast cancer, is especially important. A therapy clinically proven to be effective in this subtype would be of great value. Ixabepilone, a novel synthetic lactam analog of epothilone B, demonstrated better clinical outcomes in metastatic disease, particularly in triple-negative breast cancer and “intensivelytreated” variant. Most recently, studies have shown the activity of ixabepilone in the neoadjuvant setting, suggesting a role for this drug in primary disease

Efficacy and safety of lenvatinib in combination with everolimus in metastatic renal cell carcinoma resistant to antiangiogenic targeted therapy: Russian multicenter observational study ROSLERCM

Objective: an assessment of efficacy and safety of lenvatinib in combination with everolimus in unselected patients with metastatic renal cell carcinoma (mRCC) progressed during or following ≥1 line of antiangiogenic targeted therapy.Material. Russian multicenter observational study ROSLERCM included 73 consecutive patients with morphologically verified mRCC progressed during or following ≥1 line of antiangiogenic targeted therapy, treated with lenvatinib (18 mg/d) and everolimus (5 mg/d) in 20 Russian centers. Median age of the patients was 59 (23–73) years, a male-to-female ratio – 3:1. Most common histological type of kidney cancer was clear-cell RCC (71 (95.8 %)). More than 2 lines of previous therapy were administered in 45 (61.6 %) cases. Most patients were diagnosed with multiple metastases (71 (97.3 %)) in &gt;1 site (61 (83.6 %)). Nephrectomy was performed in 87.7 % (64/73) of cases. At the combined therapy start ECOG PS 2–4 was registered in 16 (20.5 %), poor prognosis according to IMDC score – in 33 (45.2 %) patients. Median follow-up was 9.7 (1–26) months.Results. Median progression-free survival achieved 16.9 (95 % confidence intervals (CI) 12.1–20.6), overall survival – 20.8 (95 % CI 15.7–25.9) months. Objective response rate was 11 % (8/73); tumor control was reached in 93.2 % (68/73) of cases. Median objective response duration was 10.5 (4.3–16.8) months, tumor control duration – 10.0 (2.5–17.5) months. Any adverse events developed in 83.6 % (61/73), adverse events grade III–V – in 23.3 % (17/73) of cases. Most frequent AE grade III–IV were diarrhea (10 (13.6 %)) and arterial hypertension (6 (8.2 %)). Unacceptable toxicity demanded treatment cancellation in 4.2 % (3/73), therapy interruption – in 30.1 % (22/73) and dose reduction – in 32.9 % (24/73) of patients.Conclusion. Unselected mRCC patients administered with combined targeted therapy in the real world practice were registered with similar survival, lower objective response rate, and better tolerability comparing with population assigned for lenvatinib plus everolimus in the randomized phase II trial

Syntaxonomy and biogeography of the Irano-Turanian mires and springs

Aims: To develop the first comprehensive syntaxonomic classification for patchy montane mire and spring vegetation across the Irano-Turanian phytogeographical region in Iran, Tajikistan and Kyrgyzstan and to explore the effects of the main environmental and geographic gradients on their distribution. Location: Alborz Mountain range (Iran), Pamir-Alai Mountains (Tajikistan) and Tian Shan Mountains (Kyrgyzstan); total area of about 3,000,000 km2. Methods: A database of 1,015 vegetation relevés including a total of 675 vascular and bryophyte taxa was established, covering the large mountains ranges of the Irano-Turanian regions in Iran, Tajikistan and Kyrgyzstan, at altitude ranging from 1,300 to 4,505 m a.s.l. A semi-supervised k-means analysis was performed. Additional analyses were carried out to show differences among predefined vegetation groups in terms of phytogeographical, climatic and compositional factors. Results: Two large groups of mire communities, referable to mires and springs were identified. Twenty associations, one subassociation and four alliances of these wetlands, belonging to three orders and three classes, were defined. Among them, ten associations, one subassociation and two alliances were formally described as new syntaxa. Moreover, a new order Caricetalia orbicularis, that comprises phytogeographically unique vegetation of the Irano-Turanian mires, is proposed. Conclusions: Based on our results and comparison between the Irano-Turanian and other phytogeographical regions, we propose a first comprehensive syntaxonomic synopsis for the IranoTuranian mires and springs. Despite some identical character species and their vicariant nature, the Irano-Turanian, Euro-Siberian and Mediterranean mires and springs show considerable compositional differences. Irano-Turanian wetlands contain a large and distinct set of endemic plant species, which are mixed with Euro-Siberian species in the west and north, but predominate in the eastern locations. They have patchy pattern and scattered distribution and serve as inland hotspots of wetland vegetation in the vast dry landscape of SW and Central Asia

Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study

Background: Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington's disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability. Methods: PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington's disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington's Disease Rating Scale total motor score [UHDRS-TMS] ≥25 points), and reduced independence (UHDRS independence score ≤90%). Patients were randomly assigned (1:1:1:1:1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67·5, 90, or 112·5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials.gov (NCT02006472). Findings: Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67·5 mg (n=82), 90 mg (n=81), or 112·5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67·5 mg group, 81 in the 90 mg group, and 81 in the 112·5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n=4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112·5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug. Interpretation: Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies. Funding: Teva Pharmaceutical Industries