High Frequency Of Relapse Research Articles

Tobacco, respiratory diseases, cardiovascular risk, and cancer: Classical approaches and new alternatives

Smoking tobacco is the main preventable aetiological factor of mortality worldwide, with a significant impact on respiratory and cardiovascular diseases and cancer. Smoking cessation and prevention must be prioritized in health care and legislative initiatives to reduce mortality and associated complications. To date, pharmacological treatments and behavioural therapies, along with community strategies, have been shown to be the most effective methods, especially when used in combination with a coordinated approach. However, their efficacy remains suboptimal and diminishes over time due to the high frequency of relapse. Data from the survey on alcohol and other drugs in Spain (EDADES) of the Spanish National Health System showed that the percentage of smokers has hardly decreased in recent decades and that many smokers do not intend to give up smoking, even those who have already suffered from some complications. In this context, the development of new products such as electronic cigarettes and heated tobacco may have some application in the population. The FDA recognition of risk-modifying products, the British Health System reports on electronic cigarettes, and the recommendations of the American College of Cardiology expert consensus on smoking cessation, among others, indicates the need to consider updating the multifactorial and multidisciplinary approach of smoking and its consequences.

Malignant melanotic nerve sheath tumor

Malignant melanotic nerve sheath tumor, previously known as melanotic schwannoma, is a rare variant of peripheral nerve sheath tumor composed of melanin-producing Schwann cells and clinically misdiagnosed as melanoma. Malignant melanotic nerve sheath tumor is a rare tumor with uncertain biological behavior and variable treatment recommendations. Despite the histological features that seem benign, with a low proliferation index, the clinical course of this tumor often becomes malignant, with a high frequency of local relapses and the presence of tumor metastasis signs. Distinctive features of malignant melanotic tumor of the nerve sheath are a relatively young age of patients, the presence of the Carney complex signs and psammomatous bodies in the tumor. The article presents a case of malignant melanotic tumor of the nerve sheath localized in the neck with a recurrent course. In the described clinical observation, the patient underwent surgical treatment twice. Microscopic and immunohistochemical analysis of postoperative materials gave a positive result for melanoma markers and showed the absence of psammoma bodies and low mitotic activity. The clinical course of the disease was malignant, with the appearance of a relapse in the postoperative scar. Diagnosis of malignant melanotic tumor of the nerve sheath is a complex task, both from the radiological and pathological points of view. Communication between the surgeon, radiologist and pathologist, understanding the anatomical relationships of the lesion and careful attention to the histological findings are critical to making the correct diagnosis.

Features of the course of the disease, quality of life and cytokine profile in patients with psoriasis vulgaris in the stationary stage and comorbid depression

Aim. To study the characteristics of the course of the disease, quality of life and cytokine profile in patients with psoriasis vulgaris in the stationary stage and depression.Material and methods. A prospective, cross-sectional comparative study involved 154 patients with vulgar psoriasis in the stationary stage; Of these, two groups were formed: 83 patients with comorbid depression and 71 without comorbid depression. The Hamilton scale was used to determine depressive symptoms and severity.Result. Patients with psoriasis vulgaris in the stationary stage and depression were characterized by a younger age (p=0.007), a more severe course of the disease according to the PASI index (p<0.001), visual analogue scale (p=0.014), and a higher frequency of relapses (p=0.012) and a lower level of quality of life according to the DLQI questionnaire (p<0.001), as well as higher values of IL-6 and IL-17 in the blood serum (p=0.011; p=0.001, respectively). An inverse correlation was established between the average total value on the Hamilton scale and the age of the patients (r= –0.61; p=0.002), a direct one – with the average total values on the PASI index (r=0.72; p=0.001), visually analogue scale (r=0.63; p<0.001), DLQI (r=0.69; p=0.001) and IL-17 (r=0.62; p=0.012).Conclusion. In patients with depression, psoriasis vulgaris in the stationary stage is more severe, accompanied by an increase in systemic proinflammatory changes and a more significant decrease in quality of life than in patients without depression. The results obtained must be taken into account when choosing a therapeutic strategy for psoriasis vulgaris, which will personalize treatment and increase its effectiveness.

Taper versus discontinuation of tocilizumab in patients with giant cell arteritis: Real-world experience from a tertiary center

IntroductionFollowing the approval of tocilizumab (TCZ) for giant cell arteritis (GCA), recent studies have shown a high relapse frequency after abrupt discontinuation of TCZ. However, a thorough exploration of TCZ tapering compared to abrupt discontinuation has never been undertaken. Likewise, adverse events have only been scarcely investigated in routine care. This study aimed to compare the incidence of relapses in GCA patients undergoing TCZ tapering compared to abrupt discontinuation. MethodsWe performed a single-center retrospective cohort study from 2012 to 2022. Data from GCA patients treated with TCZ was obtained from the Electronic Patients Record. Relapse-free survival is reported in Kaplan-Meier plots and tapering versus abrupt discontinuation were compared using a Wilcoxon-Brewlos-Gehan test. ResultsWe included 155 patients receiving TCZ treatment for GCA, of which 104 discontinued TCZ. Among the 104 patients discontinuing TCZ, 42 (40 %) experienced a relapse within the first year. A total of 57 patients underwent taper with 6/38 (16 %) and 2/19 (11 %) relapsing while receiving TCZ every second or third week, respectively. In comparison, 59 patients underwent abrupt discontinuation with 27 (46 %) relapsing during follow-up. The patients undergoing abrupt TCZ discontinuation demonstrated a significantly shorter time to relapse compared to all tapered patients (p = 0.02) as well as patients tapered from weekly TCZ treatment to every second week (p < 0.01). Furthermore, 15 % of patients discontinued TCZ due to adverse events. ConclusionThis is the first study indicating that TCZ taper induced longer relapse-free survival than abrupt discontinuation, implying that taper may be favored over discontinuation in patients with GCA.

MDB-26. GENE REGULATORY NETWORK LANDSCAPE OF GROUP 3/4 MEDULLOBLASTOMA

Abstract Intra-tumor heterogeneity in brain cancers contributes to therapy resistance and relapse through positive selection of resistant tumor cell populations. Resolving the molecular mechanisms driving intra-tumor heterogeneity will uncover tumor-specific vulnerabilities and advance effective treatment strategies. Group 3/4 medulloblastomas, the most common embryonal cerebellar tumor subgroup, are highly heterogeneous tumors with high frequency of relapse which are almost certainly fatal. Here, we generated and analyzed a comprehensive single-cell multi-omic Group 3/4 medulloblastoma atlas, comprising 355,295 cells from 38 tumor patients representing eight Group 3/4 molecular subtypes. We identified transcription factor gene regulatory networks driving intra- and inter-tumor heterogeneity in Group 3/4 medulloblastoma, and determined the common regulatory framework that drives this heterogeneity. We show that Group 3/4 tumor diversity stems from differential enrichment of cell-states along four molecular identity axes: photoreceptor, MYC, precursor, and unipolar brush cell-like. Further, we show that intermediate subtype I/VII tumors exhibit a unique biology where a tumor exhibits dual Group 3 and Group 4-like tumor cell-states in a single tumor, and for a subset of these tumors, we identified a potential role of PAX6 in driving the observed dual trajectory. Altogether, our study demonstrates how oncogenic events together with key lineage determinants hijack normal developmental programs and drive Group 3/4 tumor identity away from the normal cerebellar unipolar brush cell-lineage.

Novel psychoplastogen DM506 reduces cue-induced heroin-seeking and inhibits tonic GABA currents in the Prelimbic Cortex

Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior following heroin self-administration. At a single systemic dose of 40 mg/kg, DM506 significantly decreased cue-induced seeking in both male and female rats at abstinence day 1 (AD1) following heroin self-administration. Upon re-testing for cue-induced seeking at AD14, we found that males receiving DM506 continued to show decreased cue-induced seeking, an effect not observed in females. Since there is evidence of psychedelics influencing tonic GABA currents, and opioid and psychoplastogen-mediated neuroadaptations in the medial prefrontal cortex (PrL) underlying its functional effects, we performed patch-clamp recordings on PrL slices of drug-naïve rats with an acute application or chronic incubation with DM506. Tonic GABA current was decreased in slices incubated with DM506 for 2 h. qPCR analysis did not reveal any differences in the mRNA levels of GABAA receptor α and δ subunits at AD14 in heroin and saline self-administered animals that received vehicle or DM506 at AD1. Overall, our data indicate that DM506 attenuates cue-induced heroin seeking and inhibits tonic GABA current in the prelimbic cortex.

An artificial intelligence-assisted clinical framework to facilitate diagnostics and translational discovery in hematologic neoplasia

The increasing volume and intricacy of sequencing data, along with other clinical and diagnostic data, like drug responses and measurable residual disease, creates challenges for efficient clinical comprehension and interpretation. Using paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) as a use case, we present an artificial intelligence (AI)-assisted clinical framework clinALL that integrates genomic and clinical data into a user-friendly interface to support routine diagnostics and reveal translational insights for hematologic neoplasia. We performed targeted RNA sequencing in 1365 cases with haematological neoplasms, primarily paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) from the AIEOP-BFM ALL study. We carried out fluorescence in situ hybridization (FISH), karyotyping and arrayCGH as part of the routine diagnostics. The analysis results of these assays as well as additional clinical information were integrated into an interactive web interface using Bokeh, where the main graph is based on Uniform Manifold Approximation and Projection (UMAP) analysis of the gene expression data. At the backend of the clinALL, we built both shallow machine learning models and a deep neural network using Scikit-learn and PyTorch respectively. By applying clinALL, 78% of undetermined patients under the current diagnostic protocol were stratified, and ambiguous cases were investigated. Translational insights were discovered, including IKZF1plus status dependent subpopulations of BCR::ABL1 positive patients, and a subpopulation within ETV6::RUNX1 positive patients that has a high relapse frequency. Our best machine learning models, LDA and PASNET-like neural network models, achieve F1 scores above 97% in predicting patients' subgroups. An AI-assisted clinical framework that integrates both genomic and clinical data can take full advantage of the available data, improve point-of-care decision-making and reveal clinically relevant insights promptly. Such a lightweight and easily transferable framework works for both whole transcriptome data as well as the cost-effective targeted RNA-seq, enabling efficient and equitable delivery of personalized medicine in small clinics in developing countries. German Ministry of Education and Research (BMBF), German Research Foundation (DFG) and Foundation for Polish Science.

Specifics of regional recurrences in lateral tissue of the neck after surgical treatment of highly differentiated thyroid cancer

Introduction: Despite the fact that highly differentiated thyroid cancer is included in the group of malignant neoplasms with a favorable prognosis, data on the high frequency and recurrence of relapses are reported. The presence of metastatic lymph nodes in HDTC increases the risk of regional relapse by up to 27 %. According to the literature, the factors that increase the risk of recurrence are: histological type, stage, depth of extrathyroid invasion, the presence of metastatic lymph nodes, age, and the volume of primary surgical intervention. Lateral neck dissection should be performed in patients with morphologically verified metastatic thyroid cancer, but there is still no clear consensus on the volume of dissection. Aim: Assessment of factors affecting the risk of regional recurrence in the lateral neck tissue and the localization of recurrence. Materials and methods: The study included 56 patients with HDTC, in whom metastatic lateral neck nodes were identified and verified. All patients previously underwent unilateral or bilateral neck lymph node dissection in various institutions. During the period of dynamic follow-up, these patients revealed regional recurrences in the lateral tissue of the neck. The patients were observed and treated for recurrence at the N. N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia. Results: Age over 55 years is a prognostically significant factor affecting the frequency of regional relapse in the lateral neck tissue (p = 0.002). The presence of metastatic nodes in the lateral tissue of the neck at the initial treatment is a prognostically significant factor that increases the risk of regional recurrence in the lateral tissue of the neck (p = 0.017). According to the results of a single-factor analysis, a statistically significant effect of the stage on the risk of regional relapses in the lateral neck tissue was noted (p = 0.014). In 35.7 % of cases, recurrent nodes were localized in the level V. Conclusion: Main risk factors for relapse are clinico-morphological, such as age, aggressive type of HDTC, stage of the disease, N1b status after primary surgery, as well as technical defects during primary surgical treatment.

The Course of Schizophrenia Spectrum Disorders With Episodes of Catatonic Depressions

Introduction Mood symptoms, especially depressive ones, occur in the majority of patients with schizophrenia spectrum disorders (SSD). Therefore, depression is often identified as one of the symptomatological dimensions of schizophrenia. Catatonia is also considered by some researchers as one of the dimensions of schizophrenia, or as an independent transnosological formation. Catatonia in SSD may be associated with affective dysregulation and is often accompanied by depression. Although the clinical course of SSD has been well studied previously, its relationship with psychopathological structure of episodes of SSD remains not entirely clear.ObjectivesTo determine the impact of episodes of catatonic depression on the course and prognosis of SSD.MethodsA sample of 60 patients with episodic course of SSD who met the criteria for catatonia according to the Bush-Francis Catatonia Screening Instrument (BFCSI) and for depression according to the Calgary depression schizophrenia scale (CDSS) was analyzed. An analysis of the clinical course of SSD was carried out on the basis of the medical history of all patients in the study sample and follow-up observation of 42 patients for 5 years. Global Assessment of Functioning Scale (GAF) was used to assess the prognosis of SSD.ResultsPatients were divided into two groups depending on the period of manifestation of catatonia in the clinical course of SSD: during the first episode or during subsequent episodes. The sample of patients with the first episode (n=43, 71.7 %) was divided into three subgroups. A relatively favorable course of SSD was observed only in 13 patients (30.2 %; 21.7 % of SSD sample). The course of disorder was characterized by similar episodes with a high proportion of affective symptoms, long-term remissions and minimally expressed negative symptoms (GAF score=75.2±5.82). A relatively unfavorable course of SSD was observed in 15 patients (34.9 %; 25.0 % of SSD sample). It was characterized by moderate negative and chronic subdepressive symptoms with low frequency of catatonic and psychotic relapses (GAF score=62.3). An unfavorable course of SSD was also observed in 15 patients (34.9 %; 25.0 % of SSD sample). It was characterized by a high frequency of relapses with a tendency to form a chronic conditions with residual catatonic signs and psychotic symptoms (GAF score=50.1). In the sample of patients with manifestation of catatonia in the second or subsequent episodes (n=17; 28.3 %), the clinical course of SSD was unfavorable. It was characterized by a rapid augmenting of negative symptoms with the formation of psychomotor poverty syndrome with residual catatonic symptoms (GAF score=52.7).ConclusionsOur study shows that the occurrence of catatonic depressive episodes in the clinical course of SSD in most cases is an unfavorable prognostic factor.Disclosure of InterestNone Declared

Abstract B020: Pan-RAS inhibitors to treat luminal B beast cancer

Abstract The RAS oncoprotein has not traditionally been considered as an important driver of breast cancer due to the paucity of RAS mutations in this disease. However, RAS signaling pathways are frequently hyper-activated in breast cancers and genetic/epigenetic inactivation of RAS negative regulators (GAPs) is common. This is particularly true for Luminal B breast cancer. Luminal breast cancer makes up the majority of Breast Cancers, ~ 65% of cases. About 2/3 of these are classed as Luminal A and about 1/3 being the Luminal B class. Although current therapeutic options for luminal A (surgery, endocrine therapy) can be reasonably effective, Luminal B tumors are much more dangerous. These tumors are less sensitive to therapy in the first place and have a high frequency of relapse. Moreover, Luminal B tumors tend to occur more frequently in younger women and have a higher incidence of metastasis. One recent analysis has shown that Luminal B cancers have little better overall survival rates than the notorious triple negative breast cancers. Therefore, better therapies for Luminal B breast cancer are urgently required. One approach may be to target the hyper-active wild-type RAS oncoprotein that drives many of these Luminal B tumors. We have used in silico library screening followed by Medicinal Chemistry optimization to develop a series of novel small molecules that bind to all three main wild type RAS proteins and inhibit RAS function. We have validated the agents by using Microscale Thermophoresis binding procedures to quantify recombinant protein interaction. We used 3D growth inhibition and protein-based RAS signaling assays to quantify the biological action of the agents. Finally, we validated one of the more effective agents in vivo against a Luminal B cell line xenograft. This may be the first example of an effective anti-RAS therapy in breast cancer. It serves as proof of principal for the use of ant-RAS drugs in Luminal B disease. As basal breast cancers often exhibit loss of function of the RAS GAP called NF1, this strategy may have applications beyond Luminal B disease. Citation Format: Geoff Clark, Raphael Jigo, Howard Donninger, Joe Burlison, Mike Sabo, tariq Arshad, John Trent. Pan-RAS inhibitors to treat luminal B beast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B020.

Highlights on the link between vitamin D and lipid panel in Egyptian multiple sclerosis patients

Abstract Background Diversity of risk factors, namely, vitamin D and lipid panel abnormalities, are connected to multiple sclerosis (MS) etiology and may possess an influential role on disease course. In a cross-sectional study, we correlated the demographic, clinical and radiological characteristics of 111 relapsing–remitting MS (RRMS) patients with their serum levels of vitamin D and lipid profile to evaluate the consequences of their abnormalities on disease activity and/or its progression. Results In the study group, the mean serum level of vitamin D was 18.93 ± 9.85 ng/mL, over 80% had insufficient level ( &lt; 30 ng/mL) and significantly lower in females (P = 0.011). Insufficient vitamin D significantly associated with high relapse frequency (P = 0.005). Measurement the direction of this association showed that each 1 ng/mL increase in vitamin D was correlated with both decrease in annualized relapse rate (ARR) of 0.02 relapse/year (P = 0.017) and with decrease in number of relapses during last 2 years of 0.02 relapse (P = 0.045). Analysis of serum lipid panel showed a direct link between higher levels of TC and LDL to increased total number of relapses (P &lt; 0.001 and 0.003, respectively) and EDSS (P = 0.001 and 0.022), also between higher TG and EDSS (P = 0.001). This link became indirect between HDL and both total number of relapse and EDSS (P = 0.001 and 0.001). Radiologically, positively linked confluent brain lesion to elevated TC and TG levels (P = 0.001 and 0.002, respectively) and cord lesions to elevated TC (P = 0.007). Longer disease duration positively associated with all lipids-related variables. As a direct effect on lipid metabolism, each 1 ng/mL increase in vitamin D was associated with reduction in serum TC of 1.48 mg/dL (P = 0.002) and rise in HDL of 0.35 mg/dL (P = 0.028). Conclusions Management of vitamin D insufficiency may decrease risk of higher ARR and the same for dyslipidemia in reduction of disability and confluent brain T2 lesion. Increasing vitamin D was positively correlated with HDL but negatively with TC.

New approaches to the diagnosis and tactics of surgical treatment of intestinal intussusception in children

Intestinal intussusception (IR) is an urgent problem of pediatric surgery. The relevance is high due to the incidence of the disease, which ranges from 1.5 to 4 per 1000 children and tends to increase cases over the past 10 years, as well as diagnostic difficulties and a high frequency of relapses of the disease. The frequency of diagnostic mistakes reaches 75-85%, and the mortality rate for intussusception ranges from 0.5 to 1%, reaching from 6 to 14.5% in complicated forms. The aim of the study is to improve the results of treatment of intestinal intussusception in children by optimizing approaches to diagnosis and tactics of surgical treatment. Materials and methods. Over the past 20 years, 237 children aged 3 months to 12 years were hospitalized in the Department of Emergency Surgery, Specialized Pediatric Surgical Clinic of Samarkand State Medical University, with a diagnosis of intestinal intussusception, of which 116 were confirmed during a clinical examination. Depending on the applied therapeutic and tactical approaches, all examined patients with intestinal intussusception are divided into 2 groups. Group 1 (comparison group) consisted of 43 patients treated in the period from 2000 to 2013. In this group, the diagnosis was based on plain radiography and pneumoirrigoscopy. Group 2 (main group) consisted of 73 patients treated for the period from 2014 to the present. In this group, diagnosis and conservative treatment was based on the method of hydroechocolonographic disinvagination under ultrasound control.

Modern understanding of the problem of bisphosphonate osteonecrosis of the jaws

The article is devoted to the concept of osteonecrosis formation in oncological patients with bone metastases taking bisphosphonate preparations. The significance of the problem of bisphosphonate osteonecrosis of the jaws is associated with an increase in the number of such patients over the past few decades, a high frequency of complications and relapses, and a negative prognosis of the disease. The number of inflammatory lesions of the jaws when using bisphosphonate preparations can reach 25% of the total number of patients, the number of abscesses and phlegmon reaches 45%. The article considers risk factors, the frequency of inflammatory lesions of the jaw bones, known approaches to the diagnosis and treatment of drug-associated osteonecrosis of the jaws.

Long-term efficacy of tailored prolonged immunosuppressive therapy in biopsy-proven virus- negative myocarditis: a single center propensity weighted study

Abstract Background The efficacy of immunosuppressive therapy (IT) in biopsy-proven (BP) myocarditis was proved by small trials in lymphocytic myocarditis with heart failure (HF) presentation. Aim To evaluate the efficacy of IT in a single center cohort of BP myocarditis patients, irrespective of histological type and clinical presentation. Methods Consecutive BP myocarditis patients were included and, in the absence of contraindications, were treated with IT according to current guidelines on top of standard care. IT patients were compared with a propensity score-weighted control group of non-IT patients, considering age, gender, ejection fraction (EF), NYHA class and histological type (Fig. 1A). The primary outcome was a composite of death or heart transplant (HTx), and the secondary outcome a composite of variation of biventricular function, NYHA class and myocarditis relapse. Results 87 IT patients were compared with 265 without IT. IT patients were older (44 vs 39 years, p=0.035), and more frequently had a systemic immune-mediated disease (34% vs 10%, p&amp;lt;0.001), and HF (59% vs 46%, p=0.048) or fulminant presentation (9% vs 2 %, p=0.002). IT patients had lower baseline left ventricular (LV) EF both on echocardiography (35±15% vs 43±15%, p=0.001) and cardiac magnetic resonance (26±16 % vs 45.5±15 %, p=0.0013), lower right ventricular (RV) fractional area change (FAC: 34±11 % vs 41±11 %, p&amp;lt;0.001) and higher frequency of lymphocytic, eosinophilic and giant cell myocarditis (71% vs 58%, 11% vs 1 %, and 7% vs 2%, p&amp;lt;0.001 respectively) compared to non IT patients. IT was indicated because of unremitting HF (62%) and recurrent chest pain (14%), and mainly involved prednisone (PDN) and azathioprine as first-line (61%) and PDN and mycophenolate mofetil as second-line therapy (62%). IT lasted on average 24 months. No difference was observed in the primary outcome between the two groups (5 years survival 88% in IT vs 91% in non-IT patients, p=0.8, Fig. 1B), while relapse incidence was higher in IT patients (p&amp;lt;0.001, Fig.2B). At long-term follow up (54 months, IQR 21.4-96.45), LVEF and RV FAC were within the normal range in both groups, and propensity score weighting analysis showed that IT patients presented LVEF values of only 3% lower than non-IT (p=0.013, Fig. 2). In addition, IT patients had a similar probability of presenting the same NYHA class as non-IT patients at last follow up (p=0.46). Conclusions Our study shows for the first time the efficacy of prolonged tailored IT in BP lymphocytic and non lymphocytic autoimmune myocarditis, with or without HF and with or without RV dysfunction. IT patients, despite having lower biventricular function and a higher risk profile at baseline as well as a higher frequency of relapses, at long-term follow up showed normalized biventricular function and a similar survival compared to their propensity-score weighted controls. Thus, autoimmune myocarditis responds to IT, even when the disease relapses.Figure 1.Figure 2.

Idasanutlin and Navitoclax Induce a Synergistic p53-Dependent Apoptotic Cell Death in T-Cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with a five-year event-free survival rate that declines with age. Existing therapies for T-ALL, particularly in adults, are intensive and poorly tolerated, with high rates of of treatment-related morbidity and mortality and a high frequency of relapse. In T-ALL, activating Notch pathway mutations are common and thought to induce transformation in part through activation of c-Myc. Typically, increased expression of c-Myc induces apoptosis through the p19(ARF)-Mdm2-p53 tumor suppressor pathway. Unsurprisingly, over 70% of T-ALL cases have inactivating mutations in CDKN2A (p19Arf). However, greater than 95% of primary and 75% of relapsed T-ALL cases maintain wild type p53. We hypothesized that MDM2 inhibition would lead to T-ALL cell apoptosis by bypassing the loss of ARF. We reported in a previous ASH abstract initial studies evaluating the MDM2 inhibitor idasanutlin in the context of T-ALL. We observed that T-ALL patient-derived xenograft (PDX) lines treated in vitro showed modest induction of apoptosis. Additionally, we observed upregulation of pro-apoptotic p53 target genes including Bax and Puma1, leading us to hypothesize that inhibition of pro-survival BH3 domain proteins Bcl-2, Bcl-xL, and Bcl-W by navitoclax (ABT-263) would synergize to enhance apoptosis. In vitro treatment of a panel of PDX lines with combined therapy led to robust cell death with strong induction of pro-apoptotic p53 targets in all lines. In vivo, we assessed the response of four T-ALL xenografts to dual treatment. All showed a significant reduction of tumor burden compared to the most efficacious single therapy and evidence of synergy in all tested lines, as evaluated by a modified Bliss Independence test analyzing average daily change in tumor burden. Overall survival was significantly increased in the combination treatment group. We report here further mechanistic characterization of idasanutlin and navitoclax dual therapy in the context of T-ALL, as well as several therapeutically-oriented comparisons. While our initial studies used navitoclax due to prior work showing that T-ALL frequently expresses and is dependent on Bcl-xL ( Chonghaile et al., 2014), navitoclax can cause a dose-limiting thrombocytopenia due to on-target Bcl-xL inhibition in circulating platelets. Therefore, we treated our PDX panel with a dose matrix of idasanutlin with navitoclax or venetoclax, which lacks Bcl-xL activity. We observed that the navitoclax combination showed strong evidence of synergic activity, as measured by zero interaction potency (ZIP) score ( Yadav et al., 2015). Idasanutlin and navitoclax combination therapy had global ZIP scores suggesting an additive effect in 1 line and strongly synergic activity in the remaining 4 lines. Venetoclax showed an additive benefit in 3 lines, but was only synergistic in 1 of 5 lines tested. These results underscore the importance of Bcl-xL targeting in T-ALL and support further investigation of whether combination treatment with idasanutlin permits a more tolerable navitoclax dosing regimen. We also evaluated ruxolitinib in combination with idasanutlin, as recent work has shown overlapping responses to inhibitors of Jak/Stat or Bcl-2 ( Yuan et al. 2022). While we observed moderate activity of ruxolitinib monotherapy, combination with idasanutlin was additive against one and synergistic in none of the tested lines. To confirm the p53-dependence of idasanutlin dual therapy, we engineered p53 knockout T-ALL cell lines and observed strong induction of apoptosis and p53 target genes in wildtype cells, which was entirely abrogated in p53 LOF lines. Additionally, we performed RNA-seq on PDX cells treated with single or dual therapy to mechanistically characterize transcriptional responses to the drug combination. We observed minimal changes in navitoclax-only treated cells at the RNA level, consistent with its on-target post-transcriptional regulation of apoptotic induction. Idasanutlin and combination therapy samples clustered closely in PCA analysis, with p53 response a strongly-induced pathway, as expected. Our data suggest that the rational combination of idasanutlin and navitoclax is highly active against T-ALL, with greater synergic opportunity compared to other available idasanutlin combination treatments, through induction of a p53-dependent apoptotic cell death.

Development of approaches to the evaluation of pharmacotherapy effectiveness for chronic hepatitis C

Objective: to analyse the consumption pattern of antiviral therapy (AVT) for chronic hepatitis C on the example of an infectious hospital.Material and methods. The study was based on data from 380 discharge summaries of an infectious diseases hospital for 2011–2019. The criterion of sampling was the established diagnosis of chronic hepatitis C. The first line therapy regimens were analyzed and compared; the calculations were based on direct treatment costs of the study sample. The pharmacoeconomic effectiveness of therapy was assessed by calculating the cost-effectiveness ratio (CER).Results. A retrospective analysis of patients’ sampling allowed to establish a general profile: a 40-year-old man with hepatitis C virus genotype 1 and a mild degree of liver fibrosis. A total of 18 international nonproprietary names (17 trade names) were used for AVT. The pattern of drugs prescribed correlated with the clinical guidelines for the studied period and allowed to distinguish the beginning of the transition from interferonbased regimens to direct-acting antivirals (DAAs). The change in the treatment paradigm was associated not only with increased efficacy in achieving a sustained virologic response, but also with minimization of side effects. The high frequency of prescribing interferon regimens as AVT was accompanied by low rates of achieving virus elimination (63.69%), high frequency of relapses (12.88%), as well as the lack of response to pharmacological correction (21.32%) and premature discontinuation of therapy due to adverse events (2.11%). A total of 142,450,414.91 rubles was spent on the first line pharmacotherapy in the study cohort during the study period. Costs per 1 patient with the diagnosis “chronic hepatitis C” and F0–F3 fibroses according to METAVIR were 372,847.07 rubles with achieving sustained virologic response without relapse in 66% of cases, costs per patient with F4 liver lesion were 398,464.73 rubles (45,16%, respectively).Conclusion. The findings allow us to note the transition from interferon-, nucleoside- and nucleotide-based drugs to DAAs, which can be associated with an increase in therapy effectiveness and proportion of cases with sustained virologic response achieved along with a decrease in the number of adverse events. The results of the study have practical implications for building a strategy for hepatitis C virus elimination in terms of choosing effective pharmacotherapy while reducing the economic burden.

F-18 FDG PET/CT in staging and response assessment of primary cutaneous diffuse large B-cell lymphoma (leg type)

Primary cutaneous Diffuse Large B-Cell Lymphoma-leg type (PCDLBCL-LT) is a rare subtype of cutaneous lymphomas, with high frequency of extra-cutaneous relapse and poor prognosis. We report a case of 70-year-old lady who was diagnosed with PCDLBCL-LT on biopsy and underwent a baseline F-18 FDG PET/CT, followed by interim and post-treatment PET/CTs. With this case report, we highlight the findings of F-18 FDG PET/CT in the staging of this cutaneous lymphoma, and also emphasize on its role in the response assessment.

Папилломавирусная инфекция и возможности повышения эффективности терапии рецидивирующих аногенитальных бородавок.

Introduction. In recent years, there has been an increase in the number of cases of anogenital warts, with localization in the urethra, which present significant difficulties in management tactics due to the high frequency of relapses, progression of clinical manifestations and damage to underlying tissues. According to a systematic review including PubMed and EMBASE data, severe anogenital warts may be associated with a decrease in local and systemic immunity, a decrease in the level of vitamin 25(OH)D and zinc in the blood serum. The search for methods to increase the effectiveness of therapy for anogenital warts is a very urgent problem. The aim of the study was to develop a method for increasing the effectiveness of combined therapy for recurrent anogenital warts. Materials and methods. The study included 25 men aged 24 to 50 years, with the diagnosis of recurrent anogenital warts. All patients had laboratory research in human papillomavirus (HPV) in scrapings; in sexually transmitted infections; determination of the level of 25(OH)D, zinc. The complex therapy included treatment with the extract of Solanum tuberosum (Panavir) in the form: Panavir solution, Panavir-gel, Panavir-Intim spray and topical use of imichimod and surgical destruction of genital warts. Results. Monitoring patients for 6 months showed the remission of 23 men, reccurent warts in the distal section of urethra – 2 patients. Conclusions. The study obtained the high efficiency of complex therapy with the inclusion of Solanum tuberosum and surgical treatment.

Advances in Understanding the Links between Metabolism and Autophagy in Acute Myeloid Leukemia: From Biology to Therapeutic Targeting.

Autophagy is a highly conserved cellular degradation process that regulates cellular metabolism and homeostasis under normal and pathophysiological conditions. Autophagy and metabolism are linked in the hematopoietic system, playing a fundamental role in the self-renewal, survival, and differentiation of hematopoietic stem and progenitor cells, and in cell death, particularly affecting the cellular fate of the hematopoietic stem cell pool. In leukemia, autophagy sustains leukemic cell growth, contributes to survival of leukemic stem cells and chemotherapy resistance. The high frequency of disease relapse caused by relapse-initiating leukemic cells resistant to therapy occurs in acute myeloid leukemia (AML), and depends on the AML subtypes and treatments used. Targeting autophagy may represent a promising strategy to overcome therapeutic resistance in AML, for which prognosis remains poor. In this review, we illustrate the role of autophagy and the impact of its deregulation on the metabolism of normal and leukemic hematopoietic cells. We report updates on the contribution of autophagy to AML development and relapse, and the latest evidence indicating autophagy-related genes as potential prognostic predictors and drivers of AML. We review the recent advances in autophagy manipulation, combined with various anti-leukemia therapies, for an effective autophagy-targeted therapy for AML.

Anticonvulsant Role of Adenosine is Blunted During Alcohol Withdrawal Syndrome in an Adult Zebrafish Model.

Alcohol (ethanol) dependence and related disorders are life-threatening conditions and source of suffering for the user, family members and society. Alcohol withdrawal syndrome (AWS) is a little-known dynamic process associated with a high frequency of relapses. A state of hyperglutamatergic neurotransmission and imbalanced GABAergic function is related to an increased susceptibility to seizures during alcohol withdrawal. Adenosine signaling display an important role in endogenous response to decrease seizure and related damages. Here, an intermittent alcohol exposure regimen (1h daily of 0.5% ethanol solution) for 16 days or 8 days of the same ethanol exposure regimen followed by 1 or 8 days of ethanol withdrawal was used to assess adenosine signaling in the context of seizure susceptibility using adult zebrafish. In both abstainer groups, a sub-convulsant dose of pentylenetetrazol (2.5 mM) was able to increase the frequency of animals reaching a clonic seizure-like state, while continuous-treated animals had no seizure, as did control animals. The total brain mRNA expression of A1 adenosine receptor was decreased in animals with 1day of ethanol withdrawal. The agonism of A1 adenosine receptor induced an anticonvulsant effect in animals with 1day of ethanol withdrawal after the injection of the specific agonist (N6-cyclopentyladenosine, 10mg.Kg- 1; i.p.). These findings reinforce A1 adenosine receptor as a key target in acute alcohol withdrawal syndrome and zebrafish as an excellent platform to study biological mechanism of AWS.