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Vol 15, No 1 (2023)

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Clinical use of bone morphogenetic proteins BMP-2 and BMP-7: analysis of current clinical trials

Mukhametov U.F., Lyulin S.V., Borzunov D.Y., Gareev I.F.


Bone morphogenetic proteins have been used in clinical practice in orthopedics, spine surgery, and maxillofacial surgery for nearly a decade. According to research findings, in most cases the frequency of coalescence when using bone morphogenetic proteins is comparable to or higer that the corresponding indicator when using an autograft. To date, BMP-2 and BMP-7 are commercially available for clinical use and have shown efficacy equal to that of autograft in bone defect replacement.

This study analyzes existing clinical trials registered on the website for the therapeutic use of BMP-2 and BMP-7 in pathologies of the musculoskeletal system.

The search strategy was to use the material from the website, which focuses on key terms such as bonemorphogenetic protein 2 or BMP-2, bone morphogenetic protein 7 or BMP-7, recombinant bone morphogenetic protein 2 or rhBMP-2”, “recombinant bone morphogenetic protein 7 or rhBMP-7”, “InductOs”, “Op1”, “bone” and “diseases of the musculoskeletal system”. The inclusion and exclusion criteria were divided into two stages.

By October 2022, about 85 clinical trials had been registered using BMP-2 and about 12 using BMP-7. Most of the studies are in Phase 2, Phase 2–3, or Phase 4. Most of them focus on areas such as tibial trauma therapy and spinal surgery. However, only 12 clinical trials using BMP-2 provide meaningful results. All the clinical trials have similar preparation methods, and 12 clinical trials have provided positive results without serious side effects.

There is a wide potential for clinical use of BMP-2. Many preclinical and clinical studies on the use of BMP-2 and BMP-7 are currently underway; their future results will further explore their therapeutic potential in treating musculoskeletal diseases.

HERALD of North-Western State Medical University named after I.I. Mechnikov. 2023;15(1):5-20
pages 5-20 views

Complex treatment options of hip osteoarthritis

Urazovskaya I.L., Saiganov S.A., Mazurov V.I., Khaidarov V.M., Mansurov D.S., Balgley A.G., Tkachenko A.N.


Osteoarthritis has the highest prevalence among the musculoskeletal diseases in all economically developed countries. Despite the improvement of diagnostic and treatment methods, the number of patients with osteoarthritis is increasing. The number of cases of newly diagnosed osteoarthritis, cases of disease progression and subsequent disability are also growing. There are many guidelines for treatment of osteoarthritis, however, specialists have no consensus, especially regarding the amount and duration of conservative therapy.

The aim of the study was to analyze publications providing complex treatment options of hip osteoarthritis.

A systematic literature review has been conducted by means of the open acccess Pub-Med/MEDLINE database and eLibrary search for the period until January 2022. The search depth was 20 years and was performed by keywords and phrases: “hip joint osteoarthritis”, “conservative treatment”, “minimally invasive surgery”, “total hip arthroplasty”.

Unfortunately, the screening criteria for patients with osteoarthritis for total hip arthroplasty are not developed. The review analyzes the options of conservative therapy and minimally invasive surgical treatment for patients with osteoarthritis as the opportunity to avoid or delay the total hip replacement. The hip arthroplasty is not considered the “gold” standard; joint decision on surgery based on a comprehensive approach is made only when all the possibilities of conservative therapy are exhausted.

It is widely believed that complex treatment using modern conservative and organ-preserving methods is the most common strategy for managing osteoarthritis of the hip joint. This approach improves clinical and functional condition of patients and slows down the progression of the disease.

HERALD of North-Western State Medical University named after I.I. Mechnikov. 2023;15(1):21-32
pages 21-32 views

Original research

Evaluation of the quality of life dynamics in comorbid patients with hip and knee joint arthroplasty

Aliev B.G., Spichko A.A., Saiganov S.A., Mazurov V.I., Korneenkov A.A., Mansurov D.S., Khaydarov V.M., Urazovskaya I.L., Tkachenko A.N.


BACKGROUND: In recent years, in traumatology and orthopedics, statistical methods of survival analysis have been used to assess long-term treatment results, which make it possible to take into account censored clinical observations. This method of statistical analysis allows to take into account both cases of attrition from care and cases of incomplete follow-ups. There is no concurrent point of view on the dependence of the long-term results of hip and knee arthroplasty on the comorbidity of a patient. This circumstance fosters a special study using survival analysis.

AIM: To study the long-term results of total hip and knee arthroplasty in the patients with osteoarthritis. To determine the patients’ quality of life depending on the presence of pronounced concomitant pathology.

MATERIALS AND METHODS: The groups of patients with comorbidity and without significant concomitant pathology have been compared. The first group included 806 patients aged 19 to 88 years who underwent primary total hip replacement in the Clinic of Traumatology and Orthopedics of the North-Western State Medical University named after I.I. Mechnikov from 2014 to 2018 in connection with osteoarthritis. The second group consisted of 376 patients aged 43 to 85 years who underwent primary total KR due to osteoarthritis in the V.A. Baranov Republican Hospital (Petrozavodsk) in 2016–2019. Statistical data processing and graph design have been carried out with R programming language with open access via The probability of maintaining a satisfactory assessment of the quality of life by a certain observation point t (year of observation) has been assessed using the Kaplan–Mayer method. The logrank test has been used in order to compare the probability of maintaining a satisfactory assessment of quality of life during the entire follow-up period in the groups of patients with and without polymorbidity.

RESULTS: At the end of the 5th year of follow-up, the probability of maintaining excellent and good quality of life after hip replacement with a 95% confidence interval was 0.88 (0.81; 0.94) in the patients without comorbidity, 0.84 (0.79; 0.88) in the patients with severe concomitant pathology. Test statistics (Z = 0.93) and p = 0.31 indicate statistically insignificant differences in survival curves between the groups of patients with varying degrees of comorbidity.

When analyzing the five-year results of the knee replacement, the quality of life among patients with high and low comorbidity did not differ significantly. The probability of excellent and good quality of life at the 5th year of follow-up in practically healthy patients and in cases of mild therapeutic disease was 0.78 (0.67; 0.88); with a high degree of comorbidity — 0.74 (0.65; 0.81).

CONCLUSIONS: By the end of the 5th year of follow-up of the patients who have undergone hip or knee replacement due to osteoarthritis, an excellent and good quality of life can be expected on average in 80% of the patients. Satisfactory and unsatisfactory — in 20% of the patients. Excellent and good quality of life 5 years after hip or knee arthroplasty in the patients with severe comorbidity does not significantly differ from that in the practically healthy patients without comorbidity (p > 0,05).

HERALD of North-Western State Medical University named after I.I. Mechnikov. 2023;15(1):33-42
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Evaluation of the nephroprotective strategy effectiveness in the late stages of chronic kidney disease

Sadovskaya D.S., Vishnevsky K.A., Konakova I.N., Golubeva O.R., Bakulina N.V.


Background. Classical nephroprotection reduces its effectiveness at the late CKD stages; the search for effective algorithms is hampered by accelerating decline in GFR, therefore there are no generally accepted ways to evaluate the effectiveness.

Aim: to build a model for predicting the GFR decline rate in order to assess the effectiveness of the intensive follow-up.

Methods. A representative group of regular follow-up (N=540) was allocated from the city database (N=7696) to built-up the polynomial model that predicts GFR annual decline. We used the model to evaluate the intensive monitoring effectiveness (N=100) by the difference between predicted and actual rates of GFR decline. We also selected well matched subgroup of 200 patients for direct comparison of hard and surrogate outcomes.

Results. During last year before need in dialysis, the rate of GFR decline in intensive group was 5.98±1.69 vs. the predicted 9.06±0.59ml/min/1.73 m²/year. We used that assessment of the intervention effectiveness as dependent variable in regression and categorical analysis. The significant components of the nephroprotection: phosphatemia decrease (0.25 mmol/l), hemoglobin increase (1 g/dl), effective administration of RAAS blockers (to reduce proteinuria by 0.1 g/l), systolic blood pressure decrease (5 mmHg), calcemia deviations decrease from the target (0.1 mmol/l), acidosis correction (2 mmol/l), inflammation reduction and albumin increase (1.5 g/l) -were associated with the smaller GFR decrease rate by 15%. In intensive group, the dialysis risk was 2.2 times lower, the death risk was 4 times. The only planned dialysis start was ensured in intensive group, 67% chose peritoneal dialysis.

Conclusions. The prediction of GFR decline rate calculated by nonlinear model in comparison with the actual one can evaluate the nephroprotection effectiveness; it differs significantly from the classical ones at the CKD late stages.

HERALD of North-Western State Medical University named after I.I. Mechnikov. 2023;15(1):43-62
pages 43-62 views

The amount of surgery in patients with early breast cancer and complete clinical response to neoadjuvant systemic therapy

Amirov N.S., Krivorotko P.V., Mortada V.V., Donskikh R.V., Pesotskiy R.S., Emelyanov A.S., Tabagua T.T., Gigolaeva L.P., Yerechshenko S.S., Komyakhov A.V., Nikolaev K.S., Zernov K.Y., Zhiltsova E.K., Bondarchuk Y.I., Enaldieva D.A., Bessonov A.A., Artemyeva A.S., Novikov S.N., Busko E.A., Semiglazova T.Y., Semiglazov V.F., Belyaev A.M.


BACKGROUND: Neoadjuvant systemic therapy for triple-negative and HER2-positive breast cancer can achieve a complete pathologic response in approximately 60% of patients. Pathological complete response to neoadjuvant systemic therapy is a predictive factor consistent with a positive prognosis which can be accurately determined by percutaneous vacuum aspiration biopsy.

AIM: To evaluate the amount of surgery in the group of patients with triple-negative and HER2-positive early breast cancer whose complete pathologic response was confirmed by vacuum aspiration biopsy and who did not undergo standard surgery.

MATERIALS AND METHODS: The following single-centre study has been conducted in the Russian Federation. Women aged 18 years old and older with unicentric (cT1-2N0-1M0 by classification TNM) triple-negative or HER2-positive breast cancer with complete clinical response after neoadjuvant systemic therapy according to imaging diagnostic methods. The patients underwent vacuum aspiration biopsy on the mammary gland under ultrusound control with standard amount of surgical intervention on the axillary region. In case when no invasive or in situ disease was detected, no further breast surgery was performed and the patients underwent standard radiation therapy. The survival with no tumor relapse in the ipsilateral mammary gland was assessed as the primary endpoint. The study is registered on с, NCT04293796.

RESULTS: Between June 2020 and May 2022, twenty-seven (84.4%) patients (all women; mean age 47.5 (32–68) years) were enrolled in the study and underwent visually controlled vacuum aspiration biopsy. The average initial tumor size was 20.5 (7–35) mm. 7 (25.9%) patients initially had metastases in the axillary lymph nodes confirmed by puncture biopsy; 15 (55.6%) patients had HER2-positive breast cancer, and 12 (44.4%) had triple-negative breast cancer. A study of vacuum aspiration biopsy samples showed that 6 (22.2%) patients had a residual tumor, and 21 (77.8%) patients achieved complete pathologic response (95% confidence interval 53.2 to 81.4). At a median follow-up of 12.4 months, there were no tumor relapses in the ipsilateral mammary gland in 21 patients with complete pathologic response confirmed by vacuum aspiration biopsy after neoadjuvant systemic therapy, as well as other relapses or progression of the disease.

CONCLUSIONS: The patients with a complete pathologic response, which is confirmed by the vacuum aspiration biopsy method, who refused to perform surgery on the mammary gland do not demonstrate worse results with a short period of observation. However, additional prospective clinical studies are needed.

HERALD of North-Western State Medical University named after I.I. Mechnikov. 2023;15(1):63-71
pages 63-71 views

Features of autonomic regulation of heart rate in patients with takotsubo syndrome

Evdokimov D.S., Boldueva S.A., Feoktistova V.S., Ermolov S.Y.


BACKGROUND: The pathophysiological mechanisms underlying takotsubo syndrome are still being actively investigated, but it is generally accepted that sympathetic nervous system hyperactivity is of key importance. The method for assessing heart rate variability allows to study the vegetative status of a patient, however, there are few scientific works on this topic at present, and the results obtained are ambiguous.

AIM: To study heart rate variability in patients with takotsubo syndrome in acute and late periods of the disease at rest, when performing vegetative tests (the deep-breath test, active orthostatic test), as well as before and after mental stress tests and to compare the data obtained with the results of the examination of the control group.

MATERIALS AND METHODS: The study included patients with takotsubo syndrome (n = 48), including 43 (89.6%) women; the average age of the patients was 63.3 ± 13.5 years, and healthy volunteers of the same sex and age (control group, n = 40). All the subjects with takotsubo syndrome in the acute (first 7–14 days from the onset of the disease) and in the long-term periods of the disease (after 1 year and 2 years) and the ones in the control group underwent cardiorhythmography at rest to assess the heart rate variability after mental stress tests and against the background of vegetative tests.

RESULTS: According to the cardiorhythmography at rest, in 47 (97.9%) patients with takotsubo syndrome, the influence of sympathetic nervous system on the heart rate prevailed, which persisted in the long-term period of the disease. The vegetative tests revealed a paradoxical reaction of the sympathetic nervous system and reduced activity of the parasympathetic nervous system in the acute and late periods of takotsubo syndrome, compared with the control group. In the acute and long-term periods in the patients with takotsubo syndrome after mental stress tests, in comparison with control group, there was no increase in parasympathetic nervous system activity.

CONCLUSIONS: According to the study findings, the patients with takotsubo syndrome revealed autonomic dysfunction in the form of an excessive increase in the activity of the sympathetic nervous system both before the onset of the disease, and in the acute and long-term periods as well as a decrease in vagal tone, which was reflected in the suppressed response of the parasympathetic nervous system to the deep-breath test and mental stress tests.

HERALD of North-Western State Medical University named after I.I. Mechnikov. 2023;15(1):73-86
pages 73-86 views

Control of resection margins after neoadjuvant systemic therapy in breast-conserving surgery in breast cancer patients

Krivorotko P.V., Bondarchuk Y.I., Donskih R.V., Zhiltsova E.K., Amirov N.S., Bagnenko S.S., Chernaya A.V., Pesotskiy R.S., Emelyanov A.S., Mortada V.V., Tabagua T.T., Gigolaeva L.P., Yerechshenko S.S., Komyakhov A.V., Nikolaev K.S., Zernov K.Y., Enaldieva D.A., Bessonov A.A., Artemyeva A.S., Busko E.A., Semiglazov V.V., Semiglazova T.Y., Semiglazov V.F., Belyaev A.M.


BACKGROUND: Surgical treatment of breast cancer plays a major role in the combined and complex treatment of patients. The “purity” of the examined edges of the resected breast tissue is the main indicator of the reliability of the breast-conserving surgery and one of the main factors in the development of local recurrence. Neoadjuvant (preoperative) systemic therapy allows evaluating the effectiveness of therapy in vivo and reducing the size of the initial formation, both in locally advanced and resectable forms of breast cancer. The main advantage of this treatment is the ability for surgeons to perform breast-conserving surgery to improve patients quality of life and aesthetic outcomes without compromising disease-free and overall survival.

AIM: To study the clinical and pathological characteristics and analyze of the breast-conserving surgery in patients with breast cancer after neoadjuvant chemotherapy.

MATERIALS AND METHODS: 156 performed breast-conserving surgery after neoadjuvant chemotherapy were analyzed. Breast-conserving resection implied radical removal of the residual tumor node within healthy breast tissues with the achievement of negative resection margins. If pathologists detected stained invasive cells/cancer in situ in a formalin-fixed preparation, a second surgical intervention was performed.

RESULTS: Of the 156 studied anatomical preparations after breast-conserving surgery, a positive margin was found in 4 (2.56%) cases. In 4 patients, positive margin was represented by ductal carcinoma in situ. According to the results of trephine biopsy, no intraductal component was found before neoadjuvant chemotherapy. The greatest length of the ductal carcinoma in situ section is 2.2 mm. In 3 cases, the distance to the stained resection margin of the micropreparation was 1 mm. As a result of repeated pathomorphological examination of pre-cut margins after surgical intervention, cancer in situ was not found.

CONCLUSIONS: The ongoing neoadjuvant systemic therapy for breast cancer with a partial or complete response of the tumor increases the percentage of breast-conserving surgery performed in patients who initially belong to the group of radical mastectomy, but who want to save breast tissue.

HERALD of North-Western State Medical University named after I.I. Mechnikov. 2023;15(1):87-95
pages 87-95 views

Optimization of treatment of patients of older age groups with osteoporosis and fractures of the proximal femur

Kucheev I.O., Kabanov M.Y., Linnik S.A., Sementsov K.V., Kashanskii Y.B., Polikarpov A.V., Romashov P.P., Kondratev I.P., Tsololo Y.B., Radysh V.G.


BACKGROUND: Osteoporosis is mainly found in elderly people, often leading to fractures of the proximal part of the femur, and can worsen the patient’s quality of life. The article describes approaches to the choice of tactics and techniques of medical assistance to patients of older age groups (elderly, senile age, and centenarians according to World Health Organization criteria) with fractures of the proximal femur (S72.0, S72.1, S72.2. according to International Classification of Diseases 10th Revision) and with concomitant osteoporosis.

AIM: To improve the treatment results of patients of older age groups with fractures of the proximal femur by modernizing and developing new methods for implant fixation.

MATERIALS AND METHODS: 322 patients with fractures of the proximal femur with the presence of II and III degree of osteoporosis, who were treated at the Hospital for War Veterans in Saint Petersburg from 2017 to 2020 were included for the analysis. All the patients were divided into two groups depending on the methods of the treatment used. The first group consisted of 145 patients treated with the proposed method. The patients of the 2nd group (177 people) were treated using the traditional method. To assess the immediate results, the anatomical and functional result and possible complications (false joint, delayed consolidation of fragments, shortening of the damaged lower limb, dislocation of the endoprosthesis, migration of metal structures, osteomyelitis) were studied. The results were evaluated according to Leken’s functional index, and the quality of life was assessed according to the World Health Organization scale.

RESULTS: In 52.5% of the paients from the first group, good outcomes were obtained after 6 months according to the Leken’s scale, while in group 2 such results were demonstrated only in 21.6% of the patients, and a year later, in 53.7% and 19.1%, respectively. In the first group, 13 patients (12.0%) had unsatisfactory outcomes after a year, 12 (13.5%) — after 3 years, while in the second group 36 patients (31.3%) had unsatisfactory outcomes after a year, and 38 (35.8%) — after 3 years.

CONCLUSIONS: As a result, the use of the proposed method for providing care to patients with fractures of the proximal femur ensures significant improve (p < 0.01) of the treatment outcomes for this category of patients.

HERALD of North-Western State Medical University named after I.I. Mechnikov. 2023;15(1):97-106
pages 97-106 views

Treatment of patients with knee osteoarthritis with hyaluronate sodium (Revisk) in clinical practice

Shostak M.S., Leineman I.A., Trofimov E.A., Mazurov V.I.


BACKGROUND: Osteoarthritis is a disease highly associated with a wide range of comorbidities, which leads to significant limitations of the therapeutic possibilities, in particular, the long-term use of non-steroidal anti-inflammatory drugs. Thus, develop algorithms for effective treatment of osteoarthritis aimed at reducing the need for anti-inflammatory therapy is of great importance.

AIM: To evaluate the efficacy and safety of hyaluronic acid for the treatment of osteoarthritis in patients with comorbid pathology.

MATERIALS AND METHODS: 30 patients aged 40 to 65 years with II–III stages of knee osteoarthritis who received treatment with the hyaluronate sodium were examined according to the Kellgren–Lawrence scale. The course of treatment included standard intra-articular injections of Revisk (sterile sodium hyaluronate gel obtained by microbial fermentation) into the knee joints once a week, in a course of 3 injections. During the study non-steroidal anti-inflammatory drugs therapy was allowed at stable standard dosages. The effectiveness of treatment was assessed by changes in the WOMAC index, the Visual Analog scale pain scores for pain on movement, at rest, goniometry data, 30-meters walking test and stair climb test.

RESULTS: A positive effect of treatment on all the parameters has been noted: significant improvement in clinical indicators of pain according to the visual analog scale, functional tests, and the WOMAC index scores. The positive dynamics of the estimated parameters during treatment started from the 7th day of therapy.

CONCLUSIONS: The hyaluronate sodium (Revisk) can be used for treating patients with II–III stages of knee osteoarthritis with moderate dysfunction of joints.

HERALD of North-Western State Medical University named after I.I. Mechnikov. 2023;15(1):107-115
pages 107-115 views

Case report

Evolution of precancerous changes in the gastric mucosa. A case report

Tryapitsin A.V., Malkov V.A., Gasanov E.M., Belyakov I.A.


To present the experience of long-term observation of a patient with atrophic and dysplastic measurements of the gastric mucosa, to try to analyze the correctness of treatment, dynamic observation.

The analysis included the period from 2008 to 2022. 19 esophagogastroduodenoscopies were performed. A histological study was conducted according to the Operative Link for Gastritis Assessment. Neoplastic changes were evaluated according to the World Health Organization classification of gastrointestinal tumors of 2019. The evolution of changes was observed under conditions of limited possibility of eradication of Helicobacter pylori due to intolerance to antibacterial drugs.

During 14 years of follow-up, the endoscopic picture did not demonstrate significant changes. In each study, atrophy of the gastric mucosa was noted; in most cases no intestinal metaplasia and hyperplasia, erosion, ulcers, and neoplasms of the examined segments were detected. According to the histology, atrophy, intestinal metaplasia and hyperplastic changes in the gastric mucosa, Helicobacter pylori were constantly present from 2008 to 2013. Unsuccessful attempts of eradication were made. In 2013 low-grade intraepithelial neoplasia was detected, and in 2014 — local high-grade intraepithelial neoplasia. Due to the small-scale nature of the changes, the observation tactics were continued. In 2015, against the background of persistent intraepithelial neoplasia of an indeterminate nature, an attempt was made to eradicate Helicobacter pylori. In 2016, a regression of neoplastic changes to low-grade intraepithelial neoplasia was recorded. From 2016 to 2022, there was a stabilization of inflammatory and atrophic changes. Intraepiteal neoplasia of the gastric mucosa and Helicobacter pylori did not recur.

The observation is notable for the fact that for 7 years it was impossible to carry out Helicobacter pylori eradication therapy. There was no negative dynamics for 5 years. In the period from 2013 to 2015, high-grade intraepithelial neoplasia of gastric mucosa was formed. The situation changed with the introduction of antibacterial therapy, after which neoplastic changes regressed and a stable picture was observed over the next 6 years. Despite the observations of various specialists, the availability of objective and reliable information, and the decisions made on its basis allowed to prevent the development of stomach cancer.

HERALD of North-Western State Medical University named after I.I. Mechnikov. 2023;15(1):117-128
pages 117-128 views

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