Longer Remission Research Articles

Analysis of remissions in patients with combined addiction to psychostimulants and other psychoactive substances and comorbid psychiatric pathology after rehabilitation

Despite the annual increase in the number of patients with psychostimulant addiction and the presence of comorbid psychiatric pathology, the question of finding effective therapies for these disorders remains open. When developing therapeutic remission, specialists often do not take into account the peculiarities of its duration and quality in these patients. The purpose of the study is to assess the duration and quality of therapeutic remissions in patients with addiction to psychostimulants, combined use of other psychoactive substances, and comorbid psychiatric pathology. Materials and methods. 325 patients with psychostimulant addiction, who underwent a course of medical and social rehabilitation in the Moscow Research and Practical Centre for Narcology of the Moscow Healthcare Department, were examined. Methods: clinical-psychopathological, psychometric ("Addiction Severity Index: Treatnet Version"), anamnestic, catamnestic, and statistical. The results of the study. It was found that the longest remissions were noted in patients only with psychostimulant addiction. Patients with combined addiction to psychostimulants and the presence of comorbid psychiatric pathology are characterized by short remissions. Patients only with psychostimulant addiction have the best dynamics of remission quality. Conclusion. The revealed clinical features of patients, together with quantitative and qualitative features of remissions, will help to increase the effectiveness of care for these patients.

#1622 Minimal changes disease and myasthenia gravis: a logical association

Abstract Background and Aims Minimal changes disease (MCD) is responsible for 10-25% of nephrotic syndrome cases in adults. It can have a primary or secondary aetiology, being associated with diseases like infections, atopy or even haematological malignancies. There is a described association between MCD and myasthenia gravis (MG) in the literature, which we will explore in this case report. Clinical Case An autonomous 67 years old female, healthy except for overweight develops diplopia and dysphagia, being diagnosed with anti-musk MG (antibodies titters 2,2002 nmol/L). Thymoma presence was excluded by CT scan. She starts oral treatment with pyridostigmine without response. Two months later she develops generalized oedema. Analytically she had normal kidney function (Cr 0.7 mg/dL; BUN 28.5 mg/dL), hypoalbuminemia (2.09 g/dL), dyslipidaemia and nephrotic proteinuria of PCR 8g/g creat, without leucoeritrocyturia. Reno-vesical echography was normal. No alterations in immunological study except for a low IgG 396 mg/dL. Anti-PLA2R was negative. Kidney biopsy was performed, having 4 glomerulus that looked normal in optical microscopy. In our centre we do not have electronic microscopy available, so the biopsy was interpreted as MCD. She started prednisolone (PDN) 1 mg/kg/day with clinical improvement and resolution of the symptoms and proteinuria (0.062 g/g creat). In November 2022, while she was tapering the PDN, she had a myasthenic crisis, with MCD recurrency. She did 5 plasmapheresis sessions, the PDN dose was increased to 1 mg/kg/day and two rituximab administrations (1000 mg each) were done. There was an improvement in MG symptoms during 3 weeks and then she aggravated again. The proteinuria slowly decreased during 6 weeks until RPC 1.3 g/g creat and then started to aggravate when the corticosteroids were tapered. It was decided to initiate mycophenolate mofetil (MMF), there was improvement and both diseases are controlled until today, the patient is asymptomatic under 7.5 mg/day of prednisolone, with a PCR 0.2 g/g creat. Discussion The production of a circulating permeability factor by abnormal T cells, that causes the podocytes damage, is one of the possible explanations for MCD. There are reports of improvements with plasmapheresis (PF) by permeability factor remotion from circulation. MG is also caused by T cells antibodies attack, but the attack occurs against channels essential for the neuromuscular membrane function. The similarities of the mechanisms make the existence of a common branch in the t cells dysregulation seem plausible. Anti musk MG is very responsive to PF but it has a limited effect in time. Rituximab depletes B cells responsible for promoting the impaired T cells responses. It has been associated with longer remissions in cortico-sensitive MCD with relapsing disease. The exact same mechanism occurs when rituximab is used in MG. In this case the patient did not have a satisfactory response to rituximab as the patient kept dependent of high PDN doses, so we decided to initiate MMF with a complete remission of both pathologies and allowing the use of lower PDN doses. Take Home Message The association between MCD and myasthenia gravis is rare, especially in patients without thymoma. When we analyse the diseases physiopathology, we find common mechanisms that can justify the association. The identification of this relation can be advantageous making possible early rituximab use, that has been showing good results in both pathologies. In this particular clinical case, there was a recurrence with rituximab when we tapered the PDN, so the patient started MMF with good response and allowing lower PDN doses.

Аcupuncture as a means of rehabilitation for people with bronchial asthma

The article considers the possibility of using acupuncture as a means of acupuncture in the rehabilitation of adolescents with bronchial asthma. It is noted that bronchial asthma remains one of the dangerous diseases that cause significant mortality among children and adults. The purpose of the study was to study the effect of acupuncture on the state of the function of external breathing during respiratory rehabilitation among people with bronchial asthma in remission. Research methods: analysis of scientific and methodical literature; analysis of outpatient charts of patients, surveys, traditional and calculation methods of determining the main indicators of the external respiratory system, methods of mathematical statistics. It has been shown that adolescents with bronchial asthma have a decrease in external respiratory function indicators. In adolescents with bronchial asthma, there is a decrease in the indicators of the function of external breathing. The deviation of the actual indicators from the appropriate ones was: LVEF – 27%, FLVEF – 38%, FEV1 – 44%, Ntype – 33%, respectively; Tiffno index – 79%, Tweed – 23 p. The expansion of the motor regime and the use of acupuncture reflexology during the remission period contributed to the increase in the indicators of the function of external breathing in the main group compared to the control group: LVEF by 10.47% and 2.36%, LVEF – 13.32% and 1.96%, FEV1 – 19 ,24% and 7.14%, Ntype – 13.72% and 5.34%, IT – 3.7% and 0.17%, Tweed – 11.58% and 5.89%, respectively.
 The use of needle reflexology as a means of acupuncture in respiratory rehabilitation and timely correction of the motor regime will improve bronchial patency, improve the functioning of the respiratory system of the body, increase the work capacity of the younger generation, will contribute to reducing the severity of the disease, limiting the use of drug therapy, and longer remission.

Analysis of SLC6A4 (5 ‑HTTLPR) gene polymorphism depending on clinical features and efficacy of therapeutic and rehabilitation measures in patients with psychostimulant addiction

The annual increase in the number of patients with psychostimulant addiction and the low duration of remissions as a result of treatment of such disorders prompt researchers to search for new approaches to therapy. It seems relevant to search for and introduce into practice new clinical and genetic markers that increase the effectiveness of psychostimulant addiction therapy within the framework of a personalized approach. The purpose of the study is to determine the impact of a number of clinical characteristics and SLC6A4 (5‑HTTLPR) gene polymorphism on the efficacy of treatment and rehabilitation program in patients with psychostimulant addiction. Materials and methods. The study included 325 patients diagnosed with «mental and behavioral disorders due to use of psychostimulants» (F14.2, F15.2, F19.2 according to ICD-10); men and women aged 18 to 50 years, ethnically Russian, signed informed consent to participate in the study. Methods: clinical-psychopathological, anamnestic, molecular-genetic, psychometric (Montgomery — Åsberg Depression Rating Scale (MADRS)), and statistical methods. Results. All patients were divided into groups depending on the psychoactive substances used and comorbid psychiatric pathology. It was found that SSRI monotherapy (Escitalopram) for the relief of affective disorders in the post-withdrawal period was most effective in the patients who used only psychostimulants (p<0.005). Combined psychopharmacotherapy was more efficient in other groups (p<0.001). The patients with SS and SL genotypes of the SLC6A4 (5‑HTTLPR) gene tolerated Escitalopram monotherapy worse; a statistical difference was achieved for the patients with LL and SL/SS genotypes of group 2 (p<0.036). There were more patients who passed the rehabilitation program and with the longest remissions among those with the SL and SS genotypes of the SLC6A4 (5‑HTTLPR) gene in all groups. Conclusion. After analyzing the results, the conclusions about the association between a number of clinical and genetic characteristics of patients with psychostimulant addiction and the effectiveness of treatment and rehabilitation measures were drawn.

High-multiplex single-cell imaging analysis reveals tumor immune contexture associated with clinical outcomes after CAR T cell therapy

Chimeric antigen receptor (CAR) T-cell therapy has made great progress in treating lymphoma, yet patient outcomes still vary greatly. The lymphoma microenvironment may be an important factor in the efficacy of CAR T therapy. In this study, we designed a highly multiplexed imaging mass cytometry (IMC) panel to simultaneously quantify 31 biomarkers from 13 patients with relapsed/refractory DLBCL who received CAR19/22 T-cell therapy. A total of twenty sections were sampled before CAR T-cell infusion or after infusion when relapse occurred. 35 cell clusters were identified, annotated and subsequently redefined into 10 metaclusters. The CD4+ T-cell fraction was positively associated with remission duration. Significantly higher Ki67, CD57, and TIM3 levels and lower CD69 levels on T cells, especially the CD8+/CD4+ Tem and Te cell subsets, were seen in patients with poor outcomes. Cellular neighborhood containing more immune cells was associated with longer remission. Fibroblasts and vascular endothelial cells resided much closer to tumor cells in patients with poor response and short remission after CAR T therapy. Our work comprehensively and systematically dissects the relationship between cell composition, state, and spatial arrangement in the DLBCL microenvironment and the outcomes of CAR T-cell therapy, which is beneficial to predict CAR T therapy efficacy.

Comparative pharmacogenetic study of disulfiram or cyanamide efficacy for alcohol dependence: the key role of dopamine neurotransmission gene polymorphisms

The actual direction of increasing the efficacy of alcohol dependence (AD) treatment is the search for opportunities for individualization of therapy using pharmacogenetic markers to stratify patients in order to select the most optimal therapeutic tactics.Aims. To test an associations of possible pharmacogenetic markers with indicators of the efficacy of disulfiram and cyanamide to stabilize remission in patients with AD.Materials and methods. A pharmacogenetic study was conducted on the basis of a double-blind, randomized, comparative, placebo-controlled clinical study of the efficacy and tolerability of disulfiram and cyanamide in the treatment of alcohol dependence syndrome. The main outcome: the duration of retention of patients in the treatment program (in remission), and withdrawal from the treatment program for any reason was considered a negative outcome. Secondary outcomes: time to relapse to alcohol use and time to recurrence to AD. 150 patients with AD (ICD-10 criteria) (av. age - 40.65±1.09 y.o., 19.3% females) were randomly assigned to one of three treatment groups (50 subjects in each): Disulfiram, Cyanamid and Placebo. All patients had weekly (12 weeks) visits to research clinic for brief counselling session. The genetic panel of the study consisted of 15 polymorphic loci in 9 genes: dopamine receptors 2 (DRD2) and 4 (DRD4) types, transmembrane dopamine transporter (DAT), enzymes dopamine-beta-hydroxylase (DBH) and catechol-ortho-methyl-transferase, as well as a two polymorphisms in the genes of the endogenous opioid system and the aldehyde dehydrogenase enzyme gene cluster.Results. For disulfiram, the DBH rs1108580 is associated with a longer remission (p=0.053, trend), and DRD4 VNTR 48 bp is associated with a shorter remission (p=0.006). For cyanamide, DAT VNTR 40 bp was associated with shorter remission (p=0.006) and rapid recurrence to AD (p=0.045). DAT rs27072 has an effect simultaneously in two treatment groups, while the direction of the effect is opposite. For cyanamide, the marker is slightly associated with a longer remission (p = 0.082, trend), a longer time to relapse (p = 0.063, trend) and a longer time to recurrence to AD (p = 0.083, trend). For placebo, DAT rs27072, on the contrary, is associated with a shorter time to to recurrence to AD (p = 0.066, trend). For placebo, DRD2 rs1799732 was associated with a shorter remission (p = 0.001), a shorter time to relapse (p = 0.018), and a shorter time to recurrence to AD (p = 0.001).Conclusion. Preliminary pharmacogenetic markers of the efficacy of alcohol dependence treatment have been identified in genes that control dopaminergic neurotransmission. After independent validation, the obtained genetic markers may be used for pharmacogenetic stratification of patients in order to select the optimal treatment options for alcohol dependence.

Modern aspects of diagnosis and treatment of chronic inflammatory demyelinating polyneuropathy in children

Analysis of demographic, clinical, laboratory, electrophysiological and neuroimaging data and pathogenetic therapy of pediatric patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Patients (n=30) were observed in a separate structural unit of the Russian Children's Clinical Hospital of the Russian National Research Medical University named after. N.I. Pirogova Ministry of Health of the Russian Federation in the period from 2006 to 2023. The examination was carried out in accordance with the recommendations of the Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society on the Management of CIDP (2021). All patients received immunotherapy, including intravenous immunoglobulin (IVIG) (n=1), IVIG and glucocorticosteroids (GCS) (n=17, 56.7%), IVIG+GCS+plasmapheresis (n=12, 40.0%). Alternative therapy included cyclophosphamide (n=1), cyclophosphamide followed by mycophenolate mofetil (n=1), rituximab (n=2, 6.6%), azathioprine (n=3), mycophenolate mofetil (n=2, 6.6%). In all patients, there was a significant difference between scores on the MRCss and INCAT functional scales before and after treatment. At the moment, 11/30 (36.6%) patients are in clinical remission and are not receiving pathogenetic therapy. The median duration of remission is 48 months (30-84). The longest remission (84 months) was observed in a patient with the onset of CIDP at the age of 1 year 7 months. Early diagnosis of CIDP is important, since the disease is potentially curable; early administration of pathogenetic therapy provides a long-term favorable prognosis.

RHINOPHYMA — FROM THE GENETICS OF THE DISEASE TO A NEW THERAPEUTIC PROTOCOL

Background. Rhinophyma is a chronic and progressive condition, considered a form of severe rosacea, which classically affects the tip of the nose. Some people have rhinophyma without having rosacea. The disease also carries a risk of 3-10% of malignant transformation. Different therapeutic methods have been described over time, with different grades of efficiency, and each of them with its associated risks. At present, the gold standard treatment for the "established" rhinophyma is the ablative laser Aim. To propose a new therapeutic protocol, combining ablative and non-ablative lasers, with an early approach, that results in a better cosmetic outcome and a longer free disease interval. Materials and Methods. The four stages of the new proposed protocol involve early treatment of rosacea with vascular lasers (PDL, NdYAG), then the use of an ablative laser (CO2) and further revision of the post-ablative result (CO2, ErYAG, PDL/NdYAG). Results. The results of the treatment are presented with "before" and "after" photos of the patients. Conclusions. The proposed approach, combining ablative and non-ablative lasers, leads to a better cosmetic result and a longer remission.

Prognostic impact of HLA‐I neoantigen‐specific CD8+ T cells in limited‐stage follicular lymphoma

Introduction: Follicular lymphoma (FL) is the most common indolent NHL. Recently, we demonstrated in limited and advanced stage FL (LSFL, ASFL), that patients with longer remissions had raised clonally expanded intratumoral CD8+ T cells (Tobin, JCO 2019). Durable remissions occur in ∼50% of LSFL patients whereas ASFL is incurable. However, little is known regarding the immunological features associated with this difference. We hypothesized HLA-I neoantigen (neoAg)-specific CD8+ T cells may play a role. Methods: The discovery cohort comprised 101 patients with diagnostic paraffin embedded tissue from the TROG99.03 LSFL clinical trial (MacManus, JCO 2018), in which stage I/II patients were randomized to involved field radiation (IFRT) only or combined modality therapy between 2000 and 2012 (PET from 2006). Contemporaneous validation cohorts were (a) AusLSFL: 60 PET staged, stage I FL patients from Australia (treatment miscellaneous), and (b) CanLSFL: 60 PET staged, stage I FL patients drawn principally from Canada (IFRT only). Digital gene expression (NanoString), targeted sequencing (330 genes), and germline HLA-typing was performed. Mutations observed by sequencing were used to predict neoAgs in TROG99.03 tissues using 8 algorithms (PVACseq) and filtered according to strong binding affinity to HLA-I over wild-type (TESLA consortium guidelines; Wells, Cell 2020). Results: CD8A gene expression was tested for prognostic significance. In TROG99.03, elevated intratumoral CD8A (by MaxStat) was associated with ∼2-fold improvement in PFS for all patients: HR 0.45 (CI: 0.77–0.26, p = 0.0053) and stage I only patients: HR 2.4 (CI: 1.2–4.6, p = 0.036). In keeping with a relationship between CD8+ T cell infiltration and tumor antigen presentation, raised expression of NLRC5 (a transcriptional HLA-I activator) was also associated with superior PFS: HR 0.48 (CI: 0.99–0.24, p = 0.024). CD8A significance was confirmed in both validation cohorts (whereas NLRC5 was validated in AusLSFL only). In keeping with recent IHC CD8 protein data (Los-de Vries, Bld Adv 2022), CD8A gene expression was raised in stage I LSFL vs. 68 ASFL patients treated with immunochemotherapy (p = 0.02). Mutational profiling was concordant with published LSFL data, with CREBBP and KMT2DA most frequent. NeoAg calling methods including functional assays for neoAg peptide binding were confirmed in a separate cohort of fresh FL tissues. 59% of TROG99.03 tissues had ≥1 neoantigens detected. Importantly, unsupervised hierarchical clustering showed 2-fold enrichment of samples with neoantigens among those with high vs. low HLA-I. Conclusions: Raised CD8A is associated with favorable prognosis in LSFL. Our data suggests disease control involves populations of expanded HLA-I neoAg-specific T cells. These findings have implications for novel immunotherapeutic strategies designed to increase the rate of durable remissions. The research was funded by: National Health and Medical Research Council, Australia; Leukaemia Foundation; Mater Foundation Keywords: Diagnostic and Prognostic Biomarkers, Indolent non-Hodgkin lymphoma, Microenvironment Conflicts of interests pertinent to the abstract. C. Keane Honoraria: Takeda, Roche, AZ, MSD, Beigene C. Cheah Consultant or advisory role: Roche, Janssen, Gilead, AstraZenecca, Lilly, TG therapeutics, Beigene, Novartis, Menarini, Daizai, Abbvie, Genmab. BMS Honoraria: BMS, Roche, Abbvie; MSD, Lilly R. Kridel Research funding: Abbvie Educational grants: Eisai M. K. Gandhi Research funding: Beigene, Janssen

Cytomegalovirus reactivation in ulcerative colitis patients: Early indicators.

The association of. ytomegalovirus (CMV) infection with ulcerative colitis (UC) still remains a controversial topic for the clinicians. Aim: In this study, we aimed to elucidate the CMV infection related parameters in the exacerbation of UC. In this study, 812 UC patients who have admitted to our institution between June 2008 and November 2020 were analyzed retrospectively. CMV infection was diagnosed by the detection of CMV DNA with polymerase chain reaction (PCR) in tissue biopsies with presence of clinical colitis symptoms. CMV negative UC patient group was defined as UC activation group with negative PCR results. A total of 153 patients met the inclusion criteria during the study period, with a median age of 41.8 years. CMV PCR positivity had been detected in tissue biopsy in 43 (28.1%) UC patients. CMV-positive patients had a statistically significant higher frequency of steroid resistance, treatment with azathioprine, longer disease duration, longer remission, and hospitalization day. The mean C-reactive protein (CRP) level, platelet to lymphocyte ratio (PLR) were higher, and mean albumin level was lower in CMV positive patients, with statistically significance. Also, colectomy and anti-tumor necrosis factor-α (TNF-α) therapy were more frequent in CMV-reactivated group in long-term follow-up. In a multivariable model, steroid resistance, treatment with azathioprine, long disease duration, low albumin value was independently associated with colonic CMV infection. Steroid resistance, treatment with azathioprine, long disease duration, low albumin levels were significant risk factors for CMV colitis, among patients with UC activation.

Maintenance regimen of GM-CSF with rituximab and lenalidomide improves survival in high-risk B-cell lymphoma by modulating natural killer cells.

The treatment of high-risk B-cell lymphoma (BCL) remains a challenge, especially in the elderly. A total of 83 patients (median age 65 years), who have achieved a complete response after induction therapy, were divided into two groups: R2 + GM-CSF regimen (lenalidomide, rituximab, granulocyte-macrophage colony-stimulating factor [GM-CSF]) as maintenance therapy (n = 39) and observation (n = 44). The efficacy of the R2 + GM-CSF regimen as maintenance in patient with high-risk BCL was analyzed and compared with observation. The number of natural killer cells in patients increased after R2 + GM-CSF regimen administration (0.131 × 109 /L vs. 0.061 × 109 /L, p = 0.0244). Patients receiving the R2 + GM-CSF regimen as maintenance therapy had longer remission (duration of response: 18.9 vs. 11.3 months, p = 0.001), and longer progression-free survival (not reached (NR) vs. 31.7 months, p = 0.037), and overall survival (OS) (NR vs. NR, p = 0.015). The R2 + GM-CSF regimen was safe and well tolerated. High international prognostic index score (p = 0.012), and high tumor burden (p = 0.005) appeared to be independent prognostic factors for worse PFS. The maintenance therapy of R2 + GM-CSF regimen may improve survival in high-risk BCL patients, which might be modulated by amplification of natural killer cells. The efficacy of the R2 + GM-CSF maintenance regimen has to be further validated in prospective random clinical trials.

Utilizing CLL-1 Positive Leukemia Stem Cells As a Marker of Early Treatment Response in Acute Myeloid Leukemia

Background: Current methods to evaluate therapeutic response in Acute Myeloid leukemia (AML) rely primarily on morphological evaluation of leukemia blasts in bone marrow at end of treatment cycles, with complete remission (CR) defined as less than 5% bone marrow blast counts without leukemic phenotype. Measurable residual disease (MRD) has been shown highly prognostic for outcome. MRD by molecular methods is limited to subgroup of patients with defined genetic mutations. MRD detection by Multicolor Flow Cytometry (MFC) is still being standardized. Leukemia stem cells (LSC) has been established as source of treatment resistance and disease recurrence in AML. In this study, we aim to analyze change in LSC during treatment using immunophenotypically defined markers and examine whether information gained from LSC analysis could provide additional insights into disease course and assist management of AML under routine clinical practice setting. Methods: We analyzed flow cytometry data from bone marrow aspirate (BMA) and/or peripheral blood (PB) in patients with AML (excluding acute promyelocytic leukemia) before and after treatment. "Leukemic blasts” were identified by morphology and Leukemia-associated Immunophenotype by MFC. Hematopoietic stem cells (HSCs) gating was based on CD45dim/SSC and CD34+CD38low/- expression. Leukemic stem cells (LSC) fractional change was analyzed using CD371 (CLL-1), CD366 (TIM3), and CD45RA percent of positive over HSCs. A chart review was conducted to determine correlation between LSC fractional change and clinical outcome. Statistical analysis was performed using GraphPad Prism version 9. Results: Fifty AML cases with both pre- and post-treatment data from a single institution in the past 3 years were included in this study. Consistent with published literature, patients with significant reduction in LSC subsets was associated with longer remission, while patients with no significant decrease in the LSC subsets demonstrated no or only a temporary remission. Intriguingly, several patients with drastic reduction in LSC after induction chemotherapy achieved complete remission, despite initial post-treatment bone marrow showing persistence of ">5% leukemia blasts” indicating possibly failed induction therapy. In contrast, in patients with persistently high or increased LSC fraction post-treatment, overt clinical relapse occurred quickly despite "absence” or <1% of leukemia blast differential counts in initial bone marrow. In a series of patients who received allogeneic stem cell transplant (Allo-SCT), rise of LSC fraction post Allo-SCT was associated with early AML relapse (within 6 months), while the decrease of LSC fraction was associated with prolonged remission (Representative patient cases shown in Figure 1). Lastly, among the three LSC-specific markers analyzed, the changes in LSC characterized by CLL-1 expression showed the best correlation with clinical course. In addition, the LSC fraction measured by CLL-1 in the peripheral blood is highly correlated with that of the bone marrow (R2=0.93, P<0.0001). Conclusion: This retrospective study explored the value and applicability of LSC detection in routine clinical practice. Importantly, conventional methods relying on evaluating leukemic blast counts in post-treatment bone marrow can sometimes over- or under- estimate the benefit of certain treatment regimen, leading to inappropriate continuation of the same treatment or switch of a potentially effective treatment regimen. In those groups of patients, the change in LSC fraction provides additional information for early treatment response evaluation, refines outcome prediction, and helps with treatment regimen selection. Trending LSC fractional change identifies impending relapse in post Allo-SCT. LSC fractional change determined by CLL-1 showed the best clinical correlation and should be incorporated into routine evaluation for AML patient in clinical practice, and possibly for those participating in investigational trials. Future studies will focus on collecting more data to validate above findings, determining the thresholds of LSC fractional change which constitute potential treatment response vs failure and testing the feasibility of tracking LSC subsets non-invasively in peripheral blood during treatment to predict therapeutic outcome and potentially guide treatment decisions. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

OVARIAN ENDOMETRIOSIS: RISK FACTORS OF THE PROCESS PROGRESSION AND RECURRENCE

Ovarian endometriosis is one of the dominant forms in the structure of the external genital endometriosis and affects up to 55% of reproductive age women being one of the main causes of infertility.&#x0D; The aim of the study was to identify prognostic factors and reduce the development and recurrence of ovarian endometriosis among women of reproductive age by elaboration of the program of preventive measures.&#x0D; Materials and methods. The outpatient, in-patient, and questionnaire cards of 440 women were retrospectively analyzed. The first group included 167 patients with first time diagnosed ovarian endometrioid cysts (ОЕC), and the second group included 213 women with the recurrent ОЕC. The control group was formed of 60 healthy women without gynecologic pathology, who have given birth at least twice, and went to the clinic for a preventive examination or surgical sterilization.&#x0D; Results. The risk of OEC recurrence is higher in the women of older age group (OR=1,99; 95% СІ: (1,31-3,01); р&lt;0,05). The size of the cysts ≤ 4 cm increases the odds of recurrence of ovarian endometriosis (OR=3.53; 95% СІ: (2.37-5.26); р&lt;0.05) by three times; their prevalence in seven times (OR=7,01; 95% СІ: (4.35-11.30); р&lt;0.05), combined with the pelvic inflammatory diseases – more than four times (OR=4.76; 95% СІ: (2.91-7.79); р&lt;0.05). The combination of OEC with the endometrioid heterotopias sixteen times increases the odds of OEC recurrence (OR=16.44; 95% СІ: (9.88-27.34); р&lt;0.05). Furthermore, a major impact on OEC recurrence has the hyperproliferative processes of the uterus and endometrium (OR=5,06; 95% СІ: (2,85-8,99); р&lt;0,05), the menstrual disorders – algodysmenorrhea and hyperpolymenorrhea (OR=6,93; 95 % СІ (4,39-10,93); р&lt;0,005), and the lack of anti-recurrence treatment (OR=7,24; 95% СІ: (1,99-26,34), р&lt;0,002). Analysis of CA-125 the level before the surgical treatment showed an increase in 57.8% (108) cases, but 6 months after suppressive hormone therapy optimized with a complex of antibacterial and anti-edematous and anti-inflammatory medications, this indicator showed a statistically significant decrease in the reference limits in two-thirds of observations. The ovarian reserve before the surgical treatment was determined in 47 (25.1%) cases, a decrease in the level of Anti-Müllerian hormone is noted in one-third of observations. The rate of a below-average level after the surgical treatment increased up to 55.6% of patients, especially in the case of a combination of OEC and chronic pelvic inflammatory diseases and small forms of genital endometriosis. Our results indicate that the number of patients with low ovarian reserve or premature ovarian insufficiency increased 1.7 times compared to the data before surgical treatment. The highest percent of recurrence was noticed in cases where after the surgical treatment the anti-recurrence therapy has not been administered – 38.9 %.&#x0D; Conclusions. Canceling hormonal therapy leads to the recurrence of endometriosis regardless of the type of treatment, which requires searching for the new methods of the prolonged treatment program until the decision on pregnancy planning is made. The longest remission was noted in the case of dydrogesterone use, as well as the greatest number of spontaneous pregnancies. There is an advantage of an optimized anti-inflammation program with gestagens during the postsurgical period for the women planning for pregnancy. The recurrence of endometriomas is clearly associated with dienogest use.

The effect of brain neurotrophic factor gene polymorphism on the effectiveness of therapeutic and rehabilitation measures in patients with psychostimulant dependence

Justification. Along with the rising consumption of psychostimulants, the number of patients with dependence on psychostimulants is increasing all over the world and in Russia in particular. At the same time, the number of patients with dependence on drug combinations is increasing, most of which are psychostimulants.&#x0D; Aim. The aim of the work is to develop a personalized approach to the therapy of patients with dependence on psychostimulants, taking into account the polymorphism of the neurotrophic factor gene of the brain.&#x0D; Material and methods. 305 patients with dependence on psychostimulants, men and women from 18 to 50 years old, were studied. Depending on the drug used and their combinations, as well as the presence of comorbid psychiatric pathology, all patients were divided into 6 groups. Research methods: molecular-genetic, clinical-psychopathological, catamnestic, statistical (parametric and nonparametric methods using Statistica 10.0 programs of STAT Soft Inc., USA). The effect of polymorphism of the neurotrophic factor gene of the brain on the effectiveness of therapeutic and rehabilitation measures in patients in different groups was evaluated.&#x0D; Results. It was found that patients who use only psychostimulants and psychostimulants with cannabinoids, having a homozygous (GG) genotype of the neurotrophic factor gene of the brain, are longer in the rehabilitation program and have the longest remissions.&#x0D; Conclusion. Polymorphism of the neurotrophic factor gene of the brain affects the effectiveness of therapeutic and rehabilitation measures in patients with dependence on psychostimulants.

Development of an exosomal gene signature to detect residual disease in dogs with osteosarcoma using a novel xenograft platform and machine learning

AbstractOsteosarcoma has a guarded prognosis. A major hurdle in developing more effective osteosarcoma therapies is the lack of disease-specific biomarkers to predict risk, prognosis, or therapeutic response. Exosomes are secreted extracellular microvesicles emerging as powerful diagnostic tools. However, their clinical application is precluded by challenges in identifying disease-associated cargo from the vastly larger background of normal exosome cargo. We developed a method using canine osteosarcoma in mouse xenografts to distinguish tumor-derived from host-response exosomal messenger RNAs (mRNAs). The model allows for the identification of canine osteosarcoma-specific gene signatures by RNA sequencing and a species-differentiating bioinformatics pipeline. An osteosarcoma-associated signature consisting of five gene transcripts (SKA2, NEU1, PAF1, PSMG2, and NOB1) was validated in dogs with spontaneous osteosarcoma by real-time quantitative reverse transcription PCR (qRT-PCR), while a machine learning model assigned dogs into healthy or disease groups. Serum/plasma exosomes were isolated from 53 dogs in distinct clinical groups (“healthy”, “osteosarcoma”, “other bone tumor”, or “non-neoplastic disease”). Pre-treatment samples from osteosarcoma cases were used as the training set, and a validation set from post-treatment samples was used for testing, classifying as “osteosarcoma detected” or “osteosarcoma-NOT detected”. Dogs in a validation set whose post-treatment samples were classified as “osteosarcoma-NOT detected” had longer remissions, up to 15 months after treatment. In conclusion, we identified a gene signature predictive of molecular remissions with potential applications in the early detection and minimal residual disease settings. These results provide proof of concept for our discovery platform and its utilization in future studies to inform cancer risk, diagnosis, prognosis, and therapeutic response.

Rosacea treatments: Current standards and additional options

AbstractBackgroundRosacea, a chronic facial and ocular inflammatory disease, is readily visible with consequential adverse psychosocial impacts. Progress in epidemiology, pathophysiology, treatments, psychosocial and quality of life impact has led to improved outcomes. Additionally, there has been a transition to updated clinical criteria for diagnosis and classification, the phenotype approach, based on rosacea‐associated features.ObjectiveOur objective was to identify current evidence‐based standards of treatment for rosacea highlighting recently approved interventions and including innovative options.MethodsReviews establishing current standards of care published over the past three years and English language clinical studies of rosacea treatment from 2018‐ March 2021 were included. In addition to pivotal trials, the latter were also selected based on innovation and practicality of the intervention.ResultsIn addition to treatments identified in guidelines and systematic reviews, additional options derive from use in other dermatological conditions ‐ such as botulinum toxin, hydroxychloroquine, photodynamic therapy, radiofrequency with or without microneedling ‐ or from other medical conditions, such as artemether and sumatriptan.ConclusionWe provide a template of longitudinal care for rosacea based on features divided into current standards and additional options. The latter may provide the impetus for further research and development to provide options with greater efficacy, longer remissions and/or lower risk of adverse events to improve outcomes in patients with rosacea.

Improved outcome in AML relapse after allogeneic transplant with high-intensity chemotherapy followed by 2nd allogeneic stem cell transplant or donor lymphocyte infusion.

Acute myeloid leukemia (AML) relapse after allogeneic stem cell transplant (alloSCT) remains a major therapeutic challenge. While patients with longer remission after initial alloSCT are recommended to receive cell therapy (CT) such as 2ndalloSCT or donor lymphocyte infusion (DLI), survival for patients who relapse within 6months of alloSCT has been dismal. We evaluated the outcomes of AML relapse after alloSCT to assess the impact of different treatments on long-term survival. One hundred and seventy-two patients with AML underwent alloSCT at the Penn State Cancer Institute from January 2014 to August 2019. Sixty-nine patients relapsed (median age, 60years; range, 10-75). Of these, 4 patients underwent 2ndalloSCT, and 26 received DLI. One-year overall survival (OS) in all cases was 20.3% (95% CI: 11.8-30.4%). Patients with ECOG performance status (PS) 0-2 at relapse showed a better 1-year OS than those with PS 3-4. Median OS for patients who received chemotherapy only or chemotherapy with CT was 74 or 173.5days, respectively (p < 0.001). Relapsed patients receiving conventional re-induction chemotherapy were categorized as the high-intensity chemotherapy (H) group, while those receiving treatments such as hypomethylating agents or targeted agents were categorized as the low-intensity chemotherapy (L) group. The H group showed a better 1-year OS compared with the L group. Patients who received H + CT showed a better 1-year OS of 52.9% than the other 3 groups (p < 0.001). Even for patients with post-alloSCT remission duration of less than 6months, the statistical significance was preserved. Factors including age, donor source at 1stalloSCT, time to relapse, blast counts, PS at relapse, and treatment type after post-alloSCT relapse were used for a multivariate analysis, and matched or mismatched related donor and H + CT after alloSCT were identified as independent factors associated with OS. These findings support the use of H + CT as the treatment option of choice for AML patients who relapse after alloSCT when feasible.

Abstract 671: Development of an exosomal biomarker signature to detect minimal residual disease in dogs with osteosarcoma using a novel xenograft platform and machine learning

Abstract Osteosarcoma, the most common primary bone tumor in humans and dogs, has a guarded prognosis. A major hurdle in developing more effective osteosarcoma therapies is the lack of disease-specific biomarkers to predict risk, prognosis, or therapeutic response. Exosomes are secreted extracellular microvesicles emerging as powerful diagnostic tools. However, the wide clinical use of exosomes is precluded by the challenges in identifying disease-associated cargo from the vastly larger background of normal exosome cargo. We developed a method using canine osteosarcoma xenografts to distinguish tumor-derived exosome mRNAs and host-response mRNAs, allowing for identification of osteosarcoma-specific gene signatures, which were then validated in samples from dogs with osteosarcoma. A canine osteosarcoma-associated gene signature was developed using exosomes from mouse xenograft experiments and a species-aware bioinformatics pipeline. Validation of the gene signature in canine serum exosomes was done by qRT-PCR analysis. Machine learning algorithms assigned dogs into healthy or disease groups based on the qRT-PCR data. Dogs in a validation set of clinical osteosarcoma cases with post-treatment samples were classified as “osteosarcoma -detected” or “osteosarcoma - NOT detected”, and clinical outcome measures were compared. An osteosarcoma-associated signature consisting of five mRNAs (SKA2, NEU1, PAF1, PSMG2, and NOB1) was identified using our canine osteosarcoma xenograft model. Serum exosomes were isolated from 53 dogs in distinct clinical groups, including “healthy”, “osteosarcoma”, “other bone tumor”, or “non-neoplastic disease”. Dogs in a validation set whose post-treatment samples were classified as “osteosarcoma - NOT detected” had longer remissions than dogs classified as “osteosarcoma - detected” for up to 15 months after treatment. In conclusion, we identified a gene signature associated with canine osteosarcoma for the detection of minimal residual disease. This gene signature was validated by qRT-PCR with serum exosomes from canine patients with osteosarcoma, and used to train artificial intelligence. The test results were predictive of molecular remissions in dogs up to 15 months after initiating therapy, suggesting it will have applications in the early detection and minimal residual disease settings. This study combines a bioinformatics approach to biomarker discovery with machine learning to correctly identify osteosarcoma in canine patients. These results set the stage for future discoveries to inform cancer risk, diagnosis, prognosis, and response to therapy. Citation Format: Kelly M. Makielski, Alicia J. Donnelly, Ali Khammanivong, Milcah C. Scott, Hirotaka Tomiyasu, John Garbe, Lauren J. Mills, Gary R. Cutter, Andrea Ortiz, Dana C. Galvan, Kristi Ward, Alexa N. Montoya, Brad A. Bryan, Joelle M. Fenger, William C. Kisseberth, Subbaya Subramanian, Jaime F. Modiano. Development of an exosomal biomarker signature to detect minimal residual disease in dogs with osteosarcoma using a novel xenograft platform and machine learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 671.

Novel systemic therapies in the treatment of fibrolamellar carcinoma.

e16161 Background: Fibrolamellar carcinoma (FLC) is an exceedingly rare liver cancer affecting children and young adults without underlying liver disease. Complete surgical resection is the primary treatment option, but recurrence is common. There are currently no established systemic therapies. We have treated patients in both the neoadjuvant and adjuvant setting with three novel combination therapies: 5-fluorouracil/interferon/nivolumab (“Triple Therapy” or TT), gemcitabine/oxaliplatin/lenvatinib (GOL), and nivolumab/lenvatinib/quercetin (NLQ). The purpose of this study was to evaluate objective responses and tolerability of three multi-agent systemic therapies in the treatment of FLC. Methods: Data from all patients with FLC who received TT, GOL, or NLQ between May 2018 and February 2021 were reviewed. Patients who received a minimum of six cycles of systemic therapy with follow up scans at least two months after initiation were assessed based on objective response, survival, and toxicity. Results: Twenty-nine patients with FLC who were treated with novel multi-agent systemic therapy were evaluable based on the above criteria. Median age at start of treatment was 20 (7-52; 16F, 12M, 1 non-disclosed). Twenty-three patients received one combination therapy (13 TT, 8 GOL, 2 NLQ), five received two different lines (3 TT/NLQ, 2 TT/GOL), and one patient received all three novel combinations. Between our 29 patients, they had relapsed 36 total times, and 11 had already tried 2+ systemic therapies. Best RECIST 1.1 objective response (clinical remission + partial response) and tumor control rate (clinical remission + partial response + stable disease) were 58%/95%, 55%/100%, and 33%/83% for TT, GOL, and NLQ respectively. The median longest Progression Free Survival (PFS) on any novel multi-agent regimen was 9 months (2-29; 9.5 for TT, 7 for GOL, 6.5 for NLQ), with 18 patients still receiving the therapy extending their PFS. Of those with previous relapses, 56% have a PFS longer than their previous longest remission and 69% have a PFS longer than their previous shortest time to relapse. Half of patients with previous relapses are still receiving the treatment responsible for their longest PFS. Fever, chills, and nausea were the most common adverse effects experienced throughout all three regimens. Seven patients experienced 1+ grade 3 adverse event. There were no toxic deaths or organ failure. Two patients died as a result of disease; their longest PFS (1 on GOL, 1 on TT) were nine and 10 months. Conclusions: FLC is a devastating cancer with patients often relapsing even after successful surgical remission. There is a strong need for effective and tolerable systemic therapies for those with unresectable, relapsed, progressive, or metastatic disease. We have had promising results in treating FLC and prolonging survival with minimal toxicities using novel multi-agent regimens.

Additional effect of excimer light therapy in patients with psoriasis under other therapies.

Excimer light is an effective therapy for psoriasis resulting in faster clearance and a longer remission. We studied its additional effect in patients with psoriasis under other therapies. Subjects were composed of 261 patients with psoriasis, all of which were treated with topical application of steroid and vitamin D mixed ointment. Other therapies were composed of apremilast and biologics. PASI 100 rate were evaluated until 12months after the start of its therapy. PASI 100 rate was elevated from 13 patients (5.0%) to 34 patients (13.0%, P<0.01). Twenty-one of 63 patients (33.3%, P<0.01) not reaching PASI 100 reached it after excimer light therapy. The addition of excimer light therapy in each treatment showed no significant difference compared with that before addition. Irradiation amount in patients with guselkumab (822±259mJ) was significantly smaller that with excimer only (1370+731mJ) and that with IL-17 (1747±749mJ). In addition, irradiation amount in patients reached PASI-100 in Guselkumab (717±75mJ) which was significantly smaller that in the excimer only group (1530±450mJ). Additional effect of excimer light therapy in psoriasis, especially in patients with guselkumab, was speculated.