Langerhans cells histiocytosis is a variant of malignant histiocytosis. The course and symptoms vary. patients with localized forms have a better prognosis, because local therapy is effective. patients with multifocal forms of histiocytosis receive systemic drug therapy, which cures some of the patients. This review provides up-to-date data about typical presentation of the organ involvement, diagnosis, course and therapy of various forms of Langerhans cells histiocytosis.

Background. Idiopathic thrombocytopenic purpura (ITp) is an autoimmune disease characterized by antibody-mediated platelets destruction and impairment of their production, which manifests itself as: isolated thrombocytopenia, risk of spontaneous hemorrhage and bleeding of varying severity. ITp is a hematological, orphan disease with an incidence of 1–4 cases per 100,000 population. In modern literature, primary and secondary immune thrombocytopenias are distinguished. primary immune thrombocytopenia is a diagnosis of exclusion. To verify it, a certain diagnostic search is required.
Aim. To evaluate clinical characteristics and treatment efficacy in patients with a confirmed primary immune thrombocytopenia in the Moscow region.
Materials and methods. This article presents the results of an analysis of more than 2,400 outpatient records of patients diagnosed with thrombocytopenia (for the period from 2010 to 2022). Of these, about 400 confirmed clinical cases of various ITp forms were included in the ITp registry of the Moscow Region. All patients live in the Moscow region, receive treatment and are observed at the Center for Orphan diseases of the M.f. vladimirskiy Moscow Regional Research Clinical Institute.
Results. There are 415 patients with a verified diagnosis of ITp in the register of the Moscow Region Center for Orphan diseases of the M.f. vladimirskiy Moscow Regional Research Clinical Institute (71 % (n = 294) are female). In 69.8 % (n = 290) of patients at the time of disease manifestation, hemorrhagic syndrome was recorded. As a first-line therapy, 92.8 % (n = 385) of patients received corticosteroids (prednisolone, methylprednisolone, dexamethasone), in the second-line therapy, 82 % (n = 340) of patients were recommended therapy with thrombopoietin receptor agonists (romiplostim, eltrombopag). The options for third-line therapy in patients with ITp are rituximab monotherapy, splenectomy, and intravenous immunoglobulin. Splenectomy was performed in 3.37 % (n = 14) of patients.
Conclusion. when evaluating this register, the highest efficiency of thrombopoietin receptor agonists (romiplostim, eltrombopag) is observed – 84.1 % of the objective response.

Understanding the molecular biological basis of chronic lymphocytic leukemia (CLL) pathogenesis and stratification of patients into risk groups has now led to significant advances in treatment. New targeted drugs with different mechanisms of action (bruton’s tyrosine kinase inhibitors, bCL-2 inhibitors, pI3K inhibitors) have significantly improved the prognosis of high-risk CLL patients. In some CLL cases the nodular tumor component can change to a more aggressive subtype of lymphoma (often diffuse large b-cell) with preservation of the small-cell leukemic component with the CLL phenotype (Richter’s syndrome), usually characterized by rapid progression and poor prognosis. The issue of treatment efficacy in patients with Richter’s syndrome still remains unresolved. The results of new drugs clinical trials are often contradictory and cannot yet be recommended for routine use in clinical practice. The low incidence of Richter’s syndrome, the lack of a unified view of the pathogenesis and therapy approaches make the search for effective drugs an urgent task, so each clinical observation is of undoubted interest.
A clinical case of CLL patient with unfavorable molecular cytogenetic risk and transformation into diffuse large b-cell lymphoma (Richter’s syndrome) is presented. The combined use of bCL-2 inhibitors (venetoclax) and pI3K (duvelisib) led to the achievement of partial remission followed by a gradual increase in the positive antitumor effect.

Kikuchi–Fujimoto disease, or necrotizing histiocytic lymphadenitis, is one of the rare causes of benign lymphadeno-pathy. The diagnosis is based on histological and immunohistochemical analysis of the lymph node biopsy. The article presents four clinical cases of Kikuchi–Fujimoto disease. According to the results of the primary analysis of lymph node tissue three patients were misdiagnosed with lymphoma. due to the unusual for lymphoid malignancy course the primary material was reviewed. The diagnosis of Kikuchi–Fujimoto disease was put. In three patients the disease has a re-current course. during the observation period, the course of the disease in all the presented patients is benign with normal quality of life.

Background. Multiple myeloma complicated by extramedullary plasmacytoma is an unfavorable variant of the disease. It remains unknown what triggers tumor transformation. The review presents literature data on the pathogenesis of extramedullary disease, as well as a clinical example of a comprehensive study of the tumor substrate.

Aim. To study the molecular and biological characteristics of the tumor substrate of the bone marrow and extramedullary plasmacytoma using various research methods.

Materials and methods. A 55-year-old patient was admitted to National Medical Research Center for Hematology with a diagnosis of multiple myeloma occurring with extramedullary plasmacytoma of the retroperitoneal space. dNA was isolated from samples of different localization (blood plasma, Cd138+ bone marrow cells, plasmacytoma and buccal epithelial cells). The profile of short tandem dNA repeats (STR) from the obtained samples was studied by multiplex polymerase chain reaction followed by fragment analysis. fluorescent in situ hybridization (fISH) of bone marrow Cd138+ cells was performed using various dNA probes. Comparative genomic hybridization on a microarray (arrayCGH) plasmacytoma dNA was also performed. The mutation profile of the KRAS, NRAS, BRAF genes was studied by Sanger sequencing in tumor samples of various localizations.

Results. The induction therapy (vCd (bortezomib + cyclophosphamide + dexamethasone), vRd (bortezomib + lenalidomide + dexamethasone), daratumumab therapy) was ineffective, death occurred 4 months after the first clinical manifestations appeared. Comparison of STR markers of circulating cell-free tumor dNA (cfdNA), Cd138+ bone marrow cells, and plasmacytoma revealed the largest number of involved loci exactly in plasmacytoma’ dNA. A mutation in the NRAS gene was found only in plasmacytoma’ dNA. This indicates the presence of another clone of tumor cells in the extra-medullary plasmacytoma. Molecular karyotyping of plasmacytoma using the arrayCGH method revealed rearrangements of many chromosomes. 1p32.3 bi-allelic deletion, amplification of 1q21, 8q24/MyC rearrangements and del17p13 were confirmed by arrayCGH molecular karyotyping and fISH studies in bone marrow and plasmacytoma.

Conclusion. A comprehensive molecular genetic study of the extramedullary plasmacytoma’ substrate is necessary to understand the pathogenesis mechanisms and, on this basis, to develop differentiated therapeutic approaches.

A complex clinical case of acute myelomonocytic leukemia with extramedullary lesion of the testis is presented. patient yu., born in 1968, applied to the National Medical Research Centre for Oncology (Rostov-on-don) after an injury to the inguinal region. ultrasound was performed: in the right testicle in the middle third, a mass of 30 × 23 × 16 mm was revealed. A biopsy was performed: the morphological picture is characteristic of a typical seminoma. Orchofuniculectomy was performed on the right. Histopathological conclusion: the morphological picture is more characteristic of a typical seminoma, but does not allow excluding lymphoma. In order to differentiate between a germ cell tumor and a lymphoproliferative disease, an immunohistochemical study of the tumor tissue, a morphological and immunophenotypic study of the bone marrow were performed. According to the immunohistochemical data, the morphological picture and immunophenotype of tumor cells are characteristic of extranodal NK/T-cell lymphoma of the testis with Cd4 co-expression. However, according to the myelogram data, 20 % of morphologically heterogeneous blast cells were found: with round or bean-shaped nuclei, delicate mesh structure of chromatin, 1–2 nucleoli and a monocytoid form of nuclei with indistinct nucleoli. The cytoplasm of varying basophilia degrees, vacuolized, with delicate azurophilic granularity. The content of the monocytoid population was increased (19 %), represented mainly by promonocytes, which corresponds to acute myelomonocytic leukemia. According to flow cytometry, the immunophenotype of blast cells corresponds to acute myeloid leukemia with Cd56 co-expression. In connection with the new data obtained, the histological preparation was revised again with the expansion of the immunohistochemical study. Result: morphological picture and immunophenotype of tumor cells are characteristic of acute myelomonocytic leukemia with extramedullary lesions of the right testicular tissue. final diagnosis: acute myelomonocytic leukemia with extramedullary lesion of the right testicle, with Cd56 co-expression. The presented clinical case showed the need to use a wide range of diagnostic techniques to determine the nature of the disease. The results of morphological and cytometric studies of the bone marrow were decisive in establishing the diagnosis of M4 acute myeloid leukemia with extramedullary lesions of the right testicle in this patient.

Chronic myeloid leukemia is a ph-positive myeloproliferative disease, which is usually manifested by hyperleukocytosis and massive splenomegaly. Chronic myeloid leukemia is rare in childhood and adolescence, it accounts for 2 to 3 % of all leukemias cases. priapism is a rare manifestation of chronic myeloid leukemia and is an urgent urological condition that requires timely treatment to prevent long-term complications, in particular, erectile dysfunction.
This review presents the literature information about priapism as the first sign of chronic myeloid leukemia, as well as the first description in the Russian literature of a clinical case of priapism in a 9-year-old patient with chronic myeloid leukemia.

Background. For many years the primary aim of treatment strategy for ph-negative myeloproliferative neoplasms has been to restrain disease progression, with lasting relief and management of symptoms to improve patients’ quality of life. Generally, this did not lead to a significant increase in life expectancy with primary myelofibrosis and didn’t decrease the risk of fibrosis in patients with polycythemia vera and essential thrombocythemia. To date a new class of targeted drugs has been developed, it is JAK2 inhibitors with pathogenetic effects. The results of clinical trials showed the high efficacy of the first registered drug of this its kind – ruxolitinib – that includes a faster reduction in the symptoms of tumor intoxication and in symptoms associated with the development of splenomegaly and increase in the overall survival rates. It is known that the data obtained during clinical trials of medicines may differ from the results obtained in routine clinical practice. In actual practice drugs are used in a much wider heterogeneous population of patients, less limited first of all by age and comorbid characteristics. It is possible to analyze cohorts of patients including a larger number of clinical cases with a longer follow-up period. In this regard of great interest is the actual clinical experience of long-term use of ruxolitinib in patients whose set is limited only by clinical contraindications for prescribing the drug.
Aim. To present our own actual experience of targeted therapy of myelofibrosis and compare the results obtained with the data of clinical trials.
Materials and methods. Our analysis includes data from 141 patients (67 (47.5 %) men and 74 (52.5 %) women) in a chronic phase myelofibrosis. All patients received ruxolitinib. Of these, 109 (69 %) patients had primary myelofibrosis, 26 (16 %) – postpolycythemia myelofibrosis, 6 (4 %) – postessential thrombocythemia myelofibrosis. The median age at the start of therapy was 62 (18–84) years. The median disease duration before ruxolitinib was prescribed – 79 (1–401) months. According to the dIpSS (dynamic International prognostic Scoring System) criteria, 13 % of patients were assigned to the low risk group, 38 % – to the intermediate-1, 36 % – to the intermediate-2, 13 % – to the high risk group. Most patients (52 %) had grade 3 bone marrow fibrosis.
Results. The median duration of treatment was 18 (range from 1 to 115) months. Symptoms of intoxication were relieved 74 (81 %) of 91 patients, the spleen size decreased in 81 % of patients (the spleen size returned to normal in 25 % of patients). The increase in the median hemoglobin level was 15 %. The proportion of patients requiring blood transfusion decreased by 4 times (from 39 to 9 %). Mean platelet levels normalized in most patients with baseline high and low platelet levels. A complete clinical and hematological response was achieved in 16 % (n = 23) of cases, a partial response – in 26 % (n = 37) of cases, clinical improvement – in 21 % (n = 30), disease stabilization – in 33 % (n = 46) of cases. No response was received in 1 (1 %) patient and in 3 (3 %) cases there was progression of the disease. At the time of analysis, 81 (57 %) of 141 patients were continuing the ruxolitinib treatment. The fatal outcome in 33 (22 %) patients was associated with concomitant diseases, among which 20 (14 %) died from proven COvId-19 infection. Overall survival: 1-year 81 %, 2-year 73 %, 5-year 50 %. Overall survival excluding deaths due to COvId-19: 1-year 92 %, 2-year 85 %, 5-year 70 %. Massive splenomegaly and a high degree of fibrosis were unfavorable predictors of prognosis of overall survival.
Conclusion. Target therapy with Janus kinase inhibitor ruxolitinib has demonstrated high efficacy in patients with myelofibrosis in routine clinical practice. The most rapid effect ruxolitinib had on the spleen size and the symptoms of intoxication. Tolerability of ruxolitinib therapy was generally satisfactory. The overall and progression-free survival rates in patients with myelofibrosis, receiving ruxolitinib in the clinical setting was consistent with the results of international multicenter clinical trials.

Currently, therapeutic tactics in patients with myelodysplastic syndrome is based on risk-adapted therapy followed by allogeneic hematopoietic stem cell transplantation, which remains the only radical method of treatment. for patients who cannot undergo transplantation, the problem of finding new methods of treatment remains urgent. Modern knowledge about the pathogenesis of the disease allows us to get an idea of the key pathways associated with oncogenesis and to develop new epigenetic methods of treatment.

Aim. To consider the therapeutic approaches currently used in the treatment of patients with myelodysplastic syndrome of low and high risk groups, as well as to demonstrate the relevance of the search for new methods of targeted and immunotherapy. In this review, we highlight the achievements in the field of targeted therapy, in particular, the study of the biology of the TIM3 molecule and its ligands, new data from clinical trials of anti-TIM3 monoclonal antibodies.

Background. The presence of the FLT3-ITD mutations in patients with AML serves as a marker of poor prognosis, which is included in the ELN 2017 risk stratification guideline. The main criterion for dividing patients into groups according to the predicted outcomes was the allelic ratio (AR) with a cutoff of 0.5: an AR value <0.5 is considered low, and ≥0.5 is considered high. At the same time, if the importance of AR determination is beyond doubt, the value of information about the length of the repeat and localization is still controversial. There are two common approaches for FLT3-ITD screening. The first, more accessible and cheaper method is the method of pCR electrophoresis and the second, more expensive and requiring special equipment, is the fragment analysis method, which allows not only to detect a mutation and determine the repeat length, but also to quantify or calculate AR.
Aim. To compare fragment analysis and pCR electrophoresis in the search for the FLT3-ITD mutations in dNA samples from AML patients.
Materials and methods. for the period of 2020–2022 fragment analysis and pCR electrophoresis were used to analyze blood and/or bone marrow samples taken from 45 patients with a confirmed diagnosis of AML who were treated at the Regional Clinical Hospital (Krasnoyarsk). Confirmation and identification of the FLT3-ITD mutations was performed by means of Sanger sequencing.
Results. both methods revealed the FLT3-ITD mutations in 11 (24.45 %) patients among the 45 patients studied. According to the results of fragment analysis, the median repeat length was 42.70 base pairs (range 26.01–99.84 base pairs), AR was 0.532 (0.027–3.328), and the allelic frequency (Af) was 34.71 (2.67–76.90) %. Three different ITds were identified in one sample. Sanger sequencing identified mutations in 9 of 11 patients.
Conclusion. fragment analysis and pCR electrophoresis showed similar results when analyzing samples with different ITd lengths and with different allelic ratios. but it can be assumed that in the case of a small ITd and low AR and Af values, when using pCR electrophoresis, the mutant allele will not be visualized, which can lead to a false negative result. The disadvantage of using the pCR electrophoresis method is also that without the use of special programs that allow determining the size and intensity of the band corresponding to the mutant allele, it is impossible to determine the AR value, which is important for AML risk stratification. Thus, for detection of the FLT3-ITD we recommend using the fragment analysis method.

Background. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment method of refractory and recurrent forms of acute leukemia in children, while the question of choosing a conditioning regimen in order to achieve the best treatment results remains debatable. Conditioning based on total body irradiation (TbI) was confirmed to be most effective in some trials, but there are still issues of overcoming early and late toxicity, as well   as difficulties in planning and routing patients.
Aim. To share the experience of interdisciplinary patient management during the conditioning period with TbI inclusion in Saint petersburg, to evaluate the feasibility, toxicity and effectiveness of the method.
Materials and methods. patients undergoing allo-HSCT for high risk acute lymphoblastic leukemia conditioned either with TbI (n = 12) or chemotherapy (n = 10) were included. Medical data were retrospectively analyzed with an assessment of the following transplant outcomes: HSCT-associated toxicity, the frequency and severity of infectious complications, graft versus host disease, as well as overall and event-free survival rates. we have evaluated radiotherapy plans in order to assess the compliance of radiation exposure with acceptable values for critical organs.
Results. All patients with acute lymphoblastic leukemia in both groups received appropriate myeloablative conditioning. According to the study results, despite the lack of significance, we obtained differences in HSCT-associated mortality (8.3 and 30 %; p = 0.151), 2-years overall and event-free survival (66 ± 13.6 and 36 ± 16.1 %; p = 0.122) in group with TbI and HdCT respectively. It should be noted that there was a trend towards a decrease of toxic reactions frequency in case of TbI-containing regimens; however we didn’t reveal any significant differences in the number of infectious complications during post-transplant period. The median follow-up was 24.2 months and there were no signs of delayed toxicity.
Conclusion. TbI-based conditioning was well tolerated with a low incidence of early and delayed toxicity, better overall and event-free survival. based on feasibility of TbI in Saint petersburg hospitals it is possible to recommend the method in routine practice, taking into account clinical indications.

Background. The increase in life expectancy of children who survived cancer leads to new tasks for doctors, psychologists and rehabilitation specialists to assessing the consequences of the experienced disease and its treatment. The most common disorders in children who have survived oncological diseases are behavioral disorders, a decrease in mood background, as well as chronic fatigue.
Aim. To identify predictors of behavioral disorders in children who have survived central nervous system oncological diseases.
Materials and methods. The study involved 52 children with central nervous system tumors aged 6 to 17 years. The median time after completion of therapy in this group of patients was 18 (3–117) months.
Results. As a result of the study, it was shown that such treatment parameters as the degree of tumor malignancy and the radiation therapy volume are associated with behavioral disorders in children who have survived cancer. In such children, a reduced mood background was revealed, and the older the child, the higher the probability of a reduced mood background. A reduced mood background is also associated with the use of vincristine preparation. Children who have a residual tumor are more likely to complain of unpleasant sensations in the body. All children, despite the specifics of their treatment, complain of constant fatigue, which affects their daily activity.
Conclusion. Thus, factors that are associated with behavioral disorders in children who have survived oncological diseases in the central nervous system were identified.

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is an aggressive hematological disease. Modern polychemotherapy protocols allow achieving a 5-year overall survival of 60–90 % in different age groups, however, relapses and refractory forms of T-ALL remain incurable. Over the past decades, the pathogenesis of this variant of leukemia has been studied in many trials, and it has been found that various signaling pathways are involved in the multi-step process of leukemogenesis. This opens the way for targeted therapy.
In this review, we provide an update on the pathogenesis of T-ALL, opportunities for introducing targeted therapies, and issues that remain to be addressed.

Background. Nutritional deficiency in malignant hematological diseases is a common condition that contributes to a decrease in functionality, tolerability of anticancer treatment and patient quality of life, and an increase in mortality rates. Often, malnutrition develops even before the start of anticancer treatment or during therapy and often remains unrecognized up to pronounced stages. despite the obvious importance of assessing and correcting the nutritional status in patients with hematological malignancies, this problem remains poorly understood.
Aim. To evaluate the effect of nutritional support on the tolerability and results of treatment in patients with hemoblastoses.
Materials and methods. The study included 40 patients with newly diagnosed hemoblastoses with nutritional deficiency or at risk of its development, who received program chemotherapy. patients were randomized into 2 comparable groups: in the main group (n = 20) patients received 2–3 bottles of Nutridrink compact protein mixture per day for 30 days, in the control group (n = 20) they ate at their own discretion without the use of additional enteral nutrition.
Results. Comparative results of laboratory monitoring showed a significant increase in albumin levels in the main group compared with the control group (p <0.01). In the main group, less severe gastrointestinal toxicity of systemic anticancer therapy was observed: a tendency to a lower incidence of diarrhea and mucositis, a statistically significant reduction in the frequency of constipation, and a significant 2.8-fold decrease in the frequency of taste changes (25 % versus 70 %). Assessment of hematological toxicity showed that pancytopenia persisted in the control group (decrease in leukocytes, erythrocytes, hemoglobin, hematocrit and platelets levels), which was absent in the main group; leukocytes, hemoglobin, hematocrit, platelets and eosinophils were statistically significantly lower compared to the main group.
Conclusion. The use of the Nutridrink compact protein mixture within 30 days from the start of treatment in patients with newly diagnosed hemablastoses contributed to an increase in albumin level, and reduced the incidence of gastrointestinal and hematological toxicity during systemic antitumor therapy.

Background. Acute tumor lysis syndrome (ATLS) complicates the treatment of highly aggressive leukemias and lymphomas in children and leads to death in 21.4 % of severe cases. ATLS is based on the death of tumor cells, so the volume of decay products exceeds the excretory capacity of the kidneys. The ATLS risk group includes patients with acute lymphoblastic leukemia accompanied by hyperleukocytosis (above 100 × 109/L) and non-Hodgkin’s lymphomas with a large tumor mass (stage III–Iv of the disease). The development of acute renal and then multiple organ failure require intensive monitoring of ATLS clinical and biochemical markers and the development of optimal patient management tactics jointly by an intensive care physician and a pediatric oncologist-hematologist.
Aim. To summarize the literature and our own clinical experience in the diagnosis and treatment of ATLS in pediatric oncohematology.
Materials and methods. The literature data on the diagnosis and treatment of ATLS in children with oncohematological diseases were analyzed. Summarized own clinical experience from January 2009 to January 2022.
Results. Of 379 patients with acute lymphoblastic leukemia and non-Hodgkin’s lymphomas, who are at risk for developing ATLS, 350 (93.4 %) patients underwent conservative ATLS therapy, of which in 31 (8.8 %) cases, hemodiafiltration was required to eliminate tumor decay products. The average number of hemodiafiltration procedures is 3 (from 1 to 15). Nevertheless, despite the whole range of therapeutic measures, the addition of infectious and multiple organ complications caused death in 7 (22.6 %) of 31 patients. Most (5 out of 7) fatal cases occurred between 2009 and 2013, and the number of lethal cases because of ATLS from 2014 to 2022 years were only 2. In 24 (77.4 %) patients, the signs of ATLS were successfully managed, the patients continued antitumor treatment. when observing patients for 6 years (from 7 months to 13 years), there were no signs of disease relapse, as well as renal dysfunction.
Conclusion. prevention and treatment of ATLS, including cytoreductive prephase, infusion therapy, allopurinol and rasburicase, and in case of ineffectiveness, hemodiafiltration is the basis of modern intensive therapy for hematological malignancies in children. Additional study of the pathogenetic mechanisms of ATLS development, identification of key targets of drug therapy, and a multidisciplinary approach in the treatment of an extremely unfavorable group of oncohematological patients with advanced stages of the tumor process are possible components for further increasing the effectiveness of ATLS therapy.

Background. Chronic lymphocytic leukemia (CLL) is a b-cell tumor of small b-lymphocytes. In CLL, significant lymphocytosis (5000 monoclonal b-lymphocytes) is observed in the blood, there are no morphological signs of bone marrow involvement. The 2020 Russian Clinical Guidelines “Chronic lymphocytic leukemia/Small lymphocyte lymphoma” approved several main chemotherapy regimens for the treatment of CLL patients.
Aim. To perform a pharmacoeconomic analysis of the feasibility of fixed therapy regimens based on venetoclax in comparison with other targeted drugs registered in Russia, from the class of bruton kinase inhibitors, used until CLL progression or unacceptable toxicity.
Materials and methods. A list of direct costs in the health care system was compiled. To assess the change in the cost structure and budget impact analyze, 4 mathematical models were constructed from a health care system perspective. Model 1 analyzed the direct costs of the health care system over 5 years, without taking into account the addition of new patients to the model. At the beginning of the modeling, the patients were equally divided between the strategies; later, there was a natural withdrawal of patients from the cycle. Models 2–4 analyze the economic impact of increasing the proportion of venetoclax-based fixed regimens.
Results. with venetoclax + rituximab and venetoclax + obinutuzumab combinations used in 65 % of new patients, a cost reduction of 6.97 % would be observed in 2nd year of the budget impact analysis. In the case of an increase in the use of venetoclax in combination with rituximab or obinutuzumab to 80 % for new patients in the 5th year of the budget impact analysis, direct costs will decrease by 31.17 %, to 9,077,299,932 rubles.
Conclusion. Increasing the proportion of fixed-dose venetoclax-based combinations compared to regimens prior to CLL progression or unacceptable toxicity in all models demonstrates cost-effectiveness.