Frequent Relapses Research Articles

Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9-dependent AML.

The mainstay of acute myeloid leukemia (AML) treatment still relies on traditional chemotherapy, with a survival rate of approximately 30% for patients under 65 years of age and as low as 5% for those beyond. This unfavorable prognosis primarily stems from frequent relapses, resistance to chemotherapy, and limited approved targeted therapies for specific AML subtypes. Around 70% of all AML cases show overexpression of the transcription factor HOXA9, which is associated with a poor prognosis, increased chemoresistance, and higher relapse rates. However, direct targeting of HOXA9 in a clinical setting has not been achieved yet. The dysregulation caused by the leukemic HOXA9 transcription factor primarily results from its binding activity to DNA, leading to differentiation blockade. Our previous investigations have identified two HOXA9/DNA binding competitors, namely DB1055 and DB818. We assessed their antileukemic effects in comparison to HOXA9 knockdown or cytarabine treatment. Using human AML cell models, DB1055 and DB818 induced in vitro cell growth reduction, death, differentiation, and common transcriptomic deregulation but did not impact human CD34+ bone marrow cells. Furthermore, DB1055 and DB818 exhibited potent antileukemic activities in a human THP-1 AML in vivo model, leading to the differentiation of monocytes into macrophages. In vitro assays also demonstrated the efficacy of DB1055 and DB818 against AML blasts from patients, with DB1055 successfully reducing leukemia burden in patient-derived xenografts in NSG immunodeficient mice. Our findings indicate that inhibiting HOXA9/DNA interaction using DNA ligands may offer a novel differentiation therapy for the future treatment of AML patients dependent on HOXA9.

Myeloperoxidase-specific antineutrophil cytoplasmic antibody-associated vasculitis.

Myeloperoxidase (MPO)-specific antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-ANCA-associated vasculitis) is one of two major ANCA-associated vasculitis variants characterised by systemic necrotising vasculitis with few or no immune deposits. MPO-ANCA-associated vasculitis predominantly affects small blood vessels and, in contrast to its counterpart proteinase 3-ANCA-associated vasculitis, is generally not associated with granulomatous inflammation. The kidneys and lungs are the most commonly affected organs. The pathogenesis of MPO-ANCA-associated vasculitis is characterised by loss of tolerance to the neutrophil enzyme MPO. This loss of tolerance leads to a chronic immunopathological response where neutrophils become both the target and effector of autoimmunity. MPO-ANCA drives neutrophil activation, leading in turn to tissue and organ damage. Clinical trials have improved the therapeutic approach to MPO-ANCA-associated vasculitis. However, there remains substantial unmet need regarding relapse frequency, toxicity of current treatment, and long-term morbidity. In this Series paper, we present the current state of research regarding pathogenesis, diagnosis, and treatment of MPO-ANCA-associated vasculitis.

Predictors of expressed emotion among the caregivers of patients with severe mental illnesses attending a tertiary health facility in Kano

Background: Expressed Emotion (EE) measures the emotional climate between caregivers and patients with major mental disorders. High EE could trigger relapses in schizophrenia and other conditions. However, the factors influencing high EE were poorly understood, especially in Africa. This study explored the socio-demographic, personality, and patient-related predictors of high EE among caregivers in Kano. Objectives: The study aimed to estimate the prevalence of high EE and its associations with socio-demographic factors, personality traits, and patients’ illness characteristics. Methods: The study utilized a descriptive cross-sectional design, encompassing 270 patients diagnosed with schizophrenia or bipolar disorder, each accompanied by their corresponding caregiver, totalling 270 caregivers. All participants attended the psychiatric clinic at Aminu Kano Teaching Hospital. The data collection process involved questionnaires and interviews, addressing socio-demographics, illness characteristics, personality traits, and expressed emotion (EE). Results: We analyzed the socio-demographic factors and EE of 250 patients and their corresponding 250 caregivers. High EE was prevalent (42.8%) due to critical comments and emotional over-involvement. Caregivers scored high on all personality traits, but only neuroticism correlated positively with EE (r = 0.130, p < 0.05). EE was lower for bipolar disorder than for schizophrenia (r = -.126, p < .05). EE also increased with patient symptoms, caregiver burden, and relapse frequency. Conclusion: Caregivers of patients with schizophrenia and bipolar disorder in Kano showed high expressed emotion (EE). However, none of the analyzed factors, including socio-demographic and personality traits, emerged as significant predictors of EE. Further research is needed to improve interventions and support strategies for caregivers of individuals with severe mental illnesses.

Swallowed topical steroid therapy for eosinophilic oesophagitis in children: practical, evidence-based guidance by the BSPGHAN Eosinophilic Oesophagitis Working Group

ObjectiveTo develop evidence-based guidance for topical steroid use in paediatric eosinophilic oesophagitis (pEoE) in the UK for both induction and maintenance treatment.MethodsA systematic literature review using Cochrane guidance was carried...

ерсонифицированный подход к диагностике и лечению рецидивирующих форм бактериального вагиноза

According to world statistics, bacterial vaginosis (BV) occupies one of the first places among vaginal diseases. The frequency of its distribution in the population ranges from 12% to 80% and depends on the contingent of women examined. BV develops mainly in women of reproductive age: in 80–87% of women with pathological vaginal discharge and 37–40% of pregnant women. Aim. To evaluate the effectiveness of three-stage therapy for recurrent and combined forms of BV based on the characteristics of the microbiome of the genital tract in women of early reproductive age. Materials and methods. We observed 445 women, who were divided into the following clinical groups. The IP group included 174 (39.10±2.31%) women with a confirmed diagnosis of recurrent BV. The IIP group included 153 (34.38±2.25%) women in whom BV was combined with cervicitis of nonspecific etiology. Group IIIP included 85 (19.10±1.86%) patients with a verified diagnosis of recurrent BV in combination with vulvovaginal candidiasis. The comparison group included 33 (7.42±1.24%) women, whose examination results corresponded to the reference values. Verification of the diagnosis in patients was carried out when contacting the antenatal clinic, based on the anamnesis, the nature of the complaints, and the results of clinical and laboratory examination methods. Laboratory examination included: pH – measurement of vaginal fluid using colpotest; bacterioscopic (urethra, cervical canal, vagina, rectum), bacteriological examination and polymerase chain reaction method in real time characterized the vaginal biotope. Patients with recurrent BV were offered three-stage therapy according to a personalized algorithm we developed, taking into account concomitant vaginal pathology. Results. The data obtained indicated an improvement in the quality of life of patients who underwent a course of three-stage therapy. The clinical effect showed that there were no relapses of the disease in patients of the IIIP group in 83% of cases, in the IIP and IP groups – in 90% and 91% of women, respectively. The highest frequency of relapses after therapy after 6 and 12 months was observed in patients of group IIIP, which amounted to 6% and 8% of Clinical cases (p<0.05). Conclusion. Our data indicate that the use of the proposed diagnostic algorithm and three-stage therapy for recurrent and combined forms of BV made it possible to reduce the frequency of reproductive losses in patients in the prospective study groups: spontaneous miscarriages in early and late gestation – in 6.29, ectopic pregnancies – by 5.54 times, premature births by 3.65 times. The frequency of normal term births in women in the prospective study groups after three-stage therapy increased by 1.4 times.

Pediatric frequent relapsing nephrotic syndrome with multiple cerebral infarctions accompanied by patent foramen ovale and cerebral venous sinus thrombosis: a case report

BackgroundIdiopathic nephrotic syndrome (NS) presents as a hypercoagulable state, of which thromboembolism (TE) is a well-known life-threatening complication. Although TE is more likely to occur in venous vessels than arterial vessels, arterial TE is important because it may cause after-effects, including tissue necrosis and cerebral infarction (CI); therefore, prompt diagnosis and appropriate treatment are required. We report a pediatric NS case with multiple CIs.Case presentationA 14-year-7-month-old Japanese girl was diagnosed with frequent relapsing NS, accompanied by headache and disturbance of consciousness during the second relapse. Brain magnetic resonance imaging (MRI) and four-dimensional computed tomography revealed multiple CIs, vasogenic edema, and cerebral venous sinus thrombosis (CVST). The patient had no underlying thrombophilia other than hypercoagulability due to NS and prednisolone (PSL), and no cardiac arrhythmia; however, a right-to-left shunt through the patent foramen ovale (PFO) was observed with the Valsalva maneuver by echocardiography. Therefore, we assumed that a potential cause of multiple CIs might be an embolic stroke, caused by thrombosis formed from a hypercoagulable state due to NS and PSL treatment and reached through PFO. Antiplatelet and anticoagulant therapies were administered for TE. She was treated with PSL and mycophenolate mofetil (MMF) for NS. Rituximab (RTX) was administered to prevent NS relapse after complete remission (CR). She underwent transcatheter PFO closure at age 14 years and 9 months because we considered that the right-to-left shunt through the PFO would be one of the risks for recurrent cerebral embolism when NS relapses. One year after the onset of CIs, an MRI indicated that the CVST had resolved, leaving no neurological sequelae due to CI; therefore, anticoagulant therapy was discontinued. And then she has been in CR for NS with only MMF therapy.ConclusionsCI is a serious complication in patients with NS. The pathogenesis of multiple CIs is various, including right-to-left shunt through PFO, in addition to the hypercoagulability due to NS. It is important to investigate and manage underlying risks such as PFO, besides preventing the relapses of NS by aggressive treatments using MMF and RTX, in patients with NS.

Schizophrenia and schizoaffective disorder: Length of stay and associated factors.

Patients with schizophrenia and schizoaffective disorder often require longer admissions. To explore length of stay (LOS) and associated factors of patients with schizophrenia and schizoaffective disorder, admitted to a public sector specialised psychiatric hospital, over a 4-year period. The study was conducted at Tara Hospital in Johannesburg. A retrospective record review of 367 adult schizophrenia and schizoaffective disorder patients admitted between 01 January 2015 and 31 December 2018. Average LOS was calculated and the proportion of short-stay (< 30 days), medium-stay (31-90 days) and long-stay (> 90 days) admissions determined. Sociodemographic, clinical and admission outcome data were collected and analysed from a randomly selected subset of patients in each LOS category. Mean LOS was 128 days (median 87, interquartile range [IQR] 49-164, range 0-755 days). A significantly greater proportion had long-stay admissions (p < 0.001). Male gender (p = 0.018), being unmarried (p = 0.006), treatment resistant (p < 0.001) and on clozapine (p = 0.009) were factors found to have a significant association with long-stay admissions. Rates of unemployment (> 80%), comorbid substance use disorders (> 40%), medical illnesses (> 40%), antipsychotic polypharmacy (> 40%) and readmissions (> 80%) were high. Most (> 80%) were discharged. Long-stay admissions were frequently required for patients with schizophrenia and schizoaffective disorder admitted to Tara Hospital. This study highlights factors associated with long-stay admissions in patients with schizophrenia and schizoaffective disorder. More research is needed into whether increased access to community-based services, such as residential and daycare facilities, outpatient substance rehabilitation programmes and dual diagnosis clinics, could translate into shorter admissions, less frequent relapses and improved outcomes in this population.

TOpCLASS Expert Consensus Classification of Perianal Fistulising Crohn's Disease: A Real-world Application in a Serial Fistula MRI Cohort.

Perianal fistuliing Crohn's disease [PFCD] is an aggressive phenotype of Crohn's disease defined by frequent relapses and disabling symptoms. A novel consensus classification system was recently outlined by the TOpCLASS consortium, which seeks to unify disease severity with patient-centred goals but has not yet been validated. We aimed to apply this to a real-world cohort and to identify factors that predict transition between classes over time. We identified all patients with PFCD and at least one baseline and one follow-up pelvic MRI [pMRI]. TOpCLASS classification, disease characteristics, and imaging indices were collected retrospectively at time periods corresponding with respective MRIs. We identified 100 patients with PFCD, of whom 96 were assigned TOpCLASS Classes 1-2c at baseline. Most patients [78.1%] started in Class 2b, but changes in classification were observed in 52.1% of all patients. Male sex [72.0%, 46.6%, 40.0%, p = 0.03] and prior perianal surgery [52.0% vs 44.6% vs 40.0%, p = 0.02] were more frequently observed in those with improved class compared to unchanged and worsened class. Baseline pMRI indices were not associated with changes in classification; however, greater improvements in mVAI, MODIFI-CD, and PEMPAC were seen among those who improved. Linear mixed effect modelling identified only male sex [-0.31, 95% CI -0.60 to -0.02] with improvement in class. The TOpCLASS classification highlights the dynamic nature of PFCD over time. However, our ability to predict transitions between classes remains limited and requires prospective assessment. Improvement in MRI index scores over time was associated with a transition to lower TOpCLASS classification.

White matter lesion load and location in relation to cognitive impairment in relapsing–remitting multiple sclerosis

Abstract Background In relapsing–remitting multiple sclerosis (RRMS) the connection between cognitive impairment (CI) and white matter lesion load (WM-LL) and location is still unclear. This study aimed to identify the relationship between CI in RRMS patients and WM-LL and locations using a fully automated platform. CI and WM-LL were evaluated in 90 patients with RRMS using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and Automated MRI volumetric measures of WM-LL and lesion distribution. Regression analysis of BICAMS as a dependent variable with different clinical and radiological parameters was performed. Results Data were obtained from 90 patients with RRMS who had a mean age of 32.74 ± 8.43 years and a female-to-male ratio of 3:1. The mean (± SD) cognitive rating scores for the BICAMS subtests were 28.07 ± 11.78 for the Symbol Digit Modalities Test (SDMT), 42.32 ± 12.46 for the California Verbal Learning Test-II (CVLT-II), and 16.13 ± 8.17 for the Brief Visuospatial Memory Test-Revised (BVMT-R). According to the BICAMS criteria, 29 cases (32.2%) had CI. BICAMS scores were significantly correlated with age, education level, relapse frequency, disease duration, and time to start disease-modifying therapies. Whole WM-LL and periventricular lesion load were significantly associated with CI. After controlling for age, sex, and education, logistic regression analysis revealed that total WM-LL was the best predictor for CI together with duration of illness and years of education. The cut-off value of 12.85 cc for total WM-LL predicted CI. Conclusions Whole WM-LL and periventricular lesion load are the best anatomical predictors for CI probably due to the effect on the anterior commissural fibers while years of education and duration of disease are the best demographic predictors for CI.

Comparative Effectiveness of Natalizumab, Fingolimod, and Injectable Therapies in Pediatric-Onset Multiple Sclerosis: A Registry-Based Study.

Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; p = 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31; p < 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00; p = 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies. This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.

CD4+ CAR T-cell exhaustion associated with early relapse of multiple myeloma after BCMA CAR T-cell therapy

AbstractMultiple myeloma is characterized by frequent clinical relapses after conventional therapy. Recently, chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA) has been established as a treatment option for patients with relapsed or refractory disease. However, although >70% of patients initially respond to this treatment, clinical relapse and disease progression occur in most cases. Recent studies showed persistent expression of BCMA at the time of relapse, indicating that immune-intrinsic mechanisms may contribute to this resistance. Although there were no preexisting T-cell features associated with clinical outcomes, we found that patients with a durable response to CAR T-cell treatment had greater persistence of their CAR T cells than patients with transient clinical responses. They also possessed a significantly higher proportion of CD8+ T-effector memory cells. In contrast, patients with short-lived responses to treatment have increased frequencies of cytotoxic CD4+ CAR T cells. These cells expand in vivo early after infusion but express exhaustion markers (hepatitis A virus cellular receptor 2 [HAVCR2] and T-cell immunoglobulin and mucin domain-containing-3 [TIGIT]) and remain polyclonal. Finally, we demonstrate that nonclassical monocytes are enriched in the myeloma niche and may induce CAR T-cell dysfunction through mechanisms that include transforming growth factor β. These findings shed new light on the role of cytotoxic CD4+ T cells in disease progression after CAR T-cell therapy.

Comparative analysis of resection boundaries depending on the defect elimination method in oral mucosal cancer

Introduction. Surgical intervention remains the main method for treatment of the oral mucosa cancer. The generally accepted standard of the resection boundary that provides optimal local control is 5 mm. Adequate boundaries of indentation and choice of the reconstruction method are important issues facing specialists in head and neck tumors. Aim. To evaluate parameters of the resection edge in the surgical treatment of malignant neoplasms of the oral mucosa depending on the method of eliminating of the post-resection defect and its effect on the frequency of local relapse. Materials and methods. A retrospective analysis included 168 primary patients (50 % men and 50 % women) who received surgical treatment in the head and neck tumor department of the Republican Clinical Oncology Dispensary of the ministry of Health of the Republic of Bashkortostan (ufa) from 2019 to 2023. The median age of patients was 63 years (interquartile range (IQR) 55–69 years). most often, the primary tumor was located in the tongue – in 59.5 % (100/168) of cases. According to the method of post-resection defect removal, the patients were divided into 3 groups. In group 1, reconstruction was performed with local tissues (n = 71), in group 2 – with pedicle flaps (n = 41), and in group 3 – with revascularized flaps (n = 56). The median follow-up period was 18 months (IQR 8–28 months). Results. Resection boundaries in group 1 were 7.0 mm (IQR 5.0–12.5 mm), in group 2 – 6.5 mm (IQR 5–13 mm), and in group 3 – 12.5 mm (IQR 7.5–15.0 mm). The overall frequency of near/positive resection boundaries was 14.8 % (25/168). In group 1, it was 15.5 % (11/71), in group 2 – 19.5 % (8/41), in group 3 – 10.7 % (6/56). According to the analysis, relapse of the disease after radical treatment was noted in 32 % (55/168) of patients, of which 14.8 % (25/168) had a local relapse, 12.5 % (21/168) had a regional relapse, and 5.4 % (9/168) developed distant metastases. The frequency of local relapse in group 1 was 18.3 % (13/71), in group 2 – 23.8 % (10/41), in group 3 – 5.5 % (3/56). According to the analysis data, statistically significant differences in the boundary of indentation in the groups were revealed depending on the reconstruction method (p = 0.005). Conclusion. Based on the results of the present retrospective analysis, the choice of reconstruction method affects the resection boundary in real clinical practice. Limitations in the surgical indentation that surgeon faces when choosing a method for eliminating a post-resection defect are demonstrated.

Abstract CT158: A dose escalation and cohort expansion study of the CDK9 inhibitor KB-0742 in relapsed, refractory and transcriptionally addicted solid tumors

Abstract Background MYC transcriptional deregulation is a hallmark of cancer and is associated with poor clinical outcomes. MYC deregulated solid tumors including non-small cell (NSCLC), small cell lung cancer (SCLC), triple negative breast cancer (TNBC), and ovarian cancer are known for their aggressiveness and frequent relapse. Analysis of a real-world solid tumor cohort including NSCLC (n= 20,470), SCLC (n=1,517), TNBC (n=2,576) and ovarian cancer (n=1,667) demonstrated MYC family overexpression and/or genomic amplification in 47% to 87% of patients. Although MYC remains difficult to drug, targeting of its cofactors has emerged as an attractive strategy to inhibit MYC oncogenic activity. Cyclin-dependent kinase 9 (CDK9), a MYC cofactor, is a critical regulator of oncogenic MYC expression and activity. KB-0742 is a potent, selective, and orally bioavailable inhibitor of CDK9 with a long plasma half-life. KB-0742 is being evaluated in an ongoing Phase 1/2 study in advanced solid tumors (NCT04718675). Methods The Phase 1/2 study is being conducted in two parts: dose escalation and dose expansion. Part 1 dose escalation comprises patients with relapsed or refractory solid tumors. Part 2 dose expansion comprises patients with solid tumors that have a high prevalence of MYC overexpression including ovarian cancer, NSCLC, TNBC and SCLC. KB-0742 is dosed orally once daily for 3 consecutive days followed by 4 days off on a weekly basis in 28-day cycles until unacceptable toxicity or disease progression. Eligibility criteria include age &amp;gt; 18 years acceptable organ function and ECOG PS &amp;lt; 2. Up to 170 patients are planned to be enrolled in the study. Primary objectives include evaluation of pharmacokinetics (PK), pharmacodynamics (PD), safety, tolerability, and preliminary anti-tumor activity with the goal of identifying a maximum tolerated dose (MTD). Plasma PK measurements include Cmax, tmax, AUC0-last, accumulation ratio (Racc) and t1/2. Safety data will be evaluated per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. RP2D is informed by PD in peripheral blood mononuclear cells using assays to evaluate phosphorylation of the CDK9 substrate serine 2 on the RNA Polymerase II C-terminal domain (pSER2) and CDK9-responsive gene expression. Radiographic tumor response is assessed using RECIST 1.1 criteria. Exploratory objectives include assessment of KB-0742 PD in tumor tissue and profiling of treatment-related genomic, transcriptomic, and proteomic changes. The study is continuing as planned; the next data analysis will occur in 2024. Citation Format: Miguel Villalona Calero, Mark Agulnik, Monica Mita, Alain Mita, Noah Federman, Drew Rasco, David Spigel, Jia Luo, Glenn Hanna, Gregory Cote, Mohamad A. Salkeni, Rashmi Chugh, Natraj R. Ammakkanavar, Satish A. Shah, Amol Rao, Kamalesh Kumar Sankhala, Richard E. Cutler, Tressa Hood, Luis Carvajal, Crystal MacKenzie, Charles Lin, Jorge DiMartino, Elizabeth A. Olek, Brian Van Tine. A dose escalation and cohort expansion study of the CDK9 inhibitor KB-0742 in relapsed, refractory and transcriptionally addicted solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT158.

The use of derma-fat grafts to eliminate defects during operations on the parotid glands

Introduction. The effectiveness of surgical treatment of parotid gland tumors is determined by the frequency of local relapse and functional and aesthetic results, which are determined not only by the anatomical and functional safety of the facial nerve. It is also very important to level aesthetic deformities of the parotid region and reduce the severity of frey’s syndrome. Aim. To retrospectively analyze the use of dermal fat grafts to correct defects during operations on the parotid glands. Materials and methods. Our study included 7 patients (2 men and 5 women) who were treated at the Leningrad Regional Clinical Oncology Dispensary named after L. D. Roman from 2021 to 2022. The average age of the patients was 49.7 years (42–64 years), the average follow-up period was 20.4 months (19–22 months). All patients underwent total / subtotal resection of the parotid gland; we used an abdominal dermal fat graft to close the defect. Histological examination of the surgical material revealed a pleomorphic adenoma of the parotid gland in 5 cases; in 2 cases, a ma-lignant tumor (adenocystic carcinoma and basal cell carcinoma of the salivary glands), which required adjuvant radiation therapy in radical doses. To assess aesthetic and functional results in the recipient and donor areas, we developed and used a questionnaire. Results. 6–8 months after the end of treatment, 5 patients completed questionnaires. 4 people indicated complete symmetry of the face, one patient indicated an average depression. 3 patients did not note any pain in the parotid area, 2 patients had minor discomfort that did not cause any problems. Only one respondent noted redness of the face when eating, which did not cause him any problems; the rest of the survey participants did not find these changes. None of the survey participants noted the appearance of sweat on their face when eating. Conclusion. The use of dermal fat grafts can improve the aesthetic and functional results of treatment in patients undergoing operations on the parotid glands. This technique is quite easy to use and does not significantly increase the time of surgical intervention. A derma-fat graft does not make it difficult to monitor disease relapses.

Prospective observational study to evaluate treatment satisfaction and effectiveness in patients with relapsing multiple sclerosis starting cladribine tablets (CLADREAL) in Italy.

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) reduce relapse frequency, magnetic resonance imaging (MRI) activity, and slow disability progression. Numerous DMTs are approved for relapsing forms of MS although real-world data on patient-reported outcomes (PROs) and quality of life (QoL) are needed to inform treatment choice. Immune reconstitution therapy with cladribine tablets is a highly effective treatment for relapsing MS (RMS). We present the protocol for an observational study to prospectively assess the effectiveness of cladribine tablets on clinical and MRI parameters as well as on PROs, including treatment satisfaction, QoL, sleep quality, self-perceived health, fatigue, and physical function. Enrolled patients at study sites in Italy will be adults with RMS (including relapsing-remitting and active secondary progressive MS) who are either treatment naïve or have received at least one first-line disease modifying DMT or no more than one second-line DMT. The primary objective will be change in global treatment satisfaction measured with the Treatment Satisfaction Questionnaire for Medication Version 1.4 approximately 24 months after initiating cladribine tablets in patients switching from previous DMTs. Secondary objectives will include global treatment satisfaction at earlier timepoints, will comprise treatment naïve patients, and will quantify treatment effectiveness and tolerability. We will also assess relapses, disability progression, MRI activity, and other PROs at approximately 12 and 24 months. The findings will provide insight from daily clinical practice into the patient's experience to complement data from controlled trials and inform treatment choice. EU PAS Registration Number EUPAS49334 filed 17/10/2022.

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

Effectiveness and infectious complications of BCMA T-cell engagers in treating multiple myeloma: Real-world evidence from Sweden.

Multiple myeloma (MM), an incurable disease characterized by frequent relapses and a need for multiple treatments, often progresses to a relapse/refractory status resistant to all available drugs and drug classes. Bispecific antibodies, specifically BCMA T-cell engagers, have emerged as effective treatments for MM, demonstrating impressive efficacy. However, these treatments can adversely affect the immune system, increasing vulnerability to infections. This study evaluated the efficacy and safety of BCMA T-cell engagers in 58 Swedish patients with poor MM prognosis. The patients exhibited a 69% overall response rate, with 69% survival and 60% progression-free survival at 15 months. Despite the risk of infectious complications, the prognosis of MM patients can be significantly improved with vigilant monitoring and proactive management of infections. This real-world data highlight the potential of BCMA T-cell engagers in treating MM, emphasizing the need for careful patient monitoring to mitigate infection risks.

Unlocking the potential: A novel prognostic index signature for acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive malignancy characterized by challenges in treatment, including drug resistance and frequent relapse. Recent research highlights the crucial roles of tumor microenvironment (TME) in assisting tumor cell immune escape and promoting tumor aggressiveness. This study delves into the interplay between AML and TME. Through the exploration of potential driver genes, we constructed an AML prognostic index (AMLPI). Cross-platform data and multi-dimensional internal and external validations confirmed that the AMLPI outperforms existing models in terms of areas under the receiver operating characteristic curves, concordance index values, and net benefits. High AMLPIs in AML patients were indicative of unfavorable prognostic outcomes. Immune analyses revealed that the high-AMLPI samples exhibit higher expression of HLA-family genes and immune checkpoint genes (including PD1 and CTLA4), along with lower T cell infiltration and higher macrophage infiltration. Genetic variation analyses revealed that the high-AMLPI samples associate with adverse variation events, including TP53 mutations, secondary NPM1 co-mutations, and copy number deletions. Biological interpretation indicated that ALDH2 and SPATS2L contribute significantly to AML patient survival, and their abnormal expression correlates with DNA methylation at cg12142865 and cg11912272. Drug response analyses revealed that different AMLPI samples tend to have different clinical selections, with low-AMLPI samples being more likely to benefit from immunotherapy. Finally, to facilitate broader access to our findings, a user-friendly and publicly accessible webserver was established and available at http://bioinfor.imu.edu.cn/amlpi. This server provides tools including TME-related AML driver genes mining, AMLPI construction, multi-dimensional validations, AML patients risk assessment, and figures drawing.

Pursuing dynamics of minimal residual leukemic subclones in relapsed and refractory acute myeloid leukemia during conventional therapy.

Acute myeloid leukemia (AML) is characterized by clonal heterogeneity, leading to frequent relapses and drug resistance despite intensive clinical therapy. Although AML's clonal architecture has been addressed in many studies, practical monitoring of dynamic changes in those subclones during relapse and treatment is still understudied. Fifteen longitudinal bone marrow (BM) samples were collected from three relapsed and refractory (R/R) AML patients. Using droplet digital polymerase chain reaction (ddPCR), the frequencies of patient's leukemic variants were assessed in seven cell populations that were isolated from each BM sample based on cellular phenotypes. By quantifying mutant clones at the diagnosis, remission, and relapse stages, the distribution of AML subclones was sequentially monitored. Minimal residual (MR) leukemic subclones exhibit heterogeneous distribution among BM cell populations, including mature leukocyte populations. During AML progression, these subclones undergo active phenotypic transitions and repopulate into distinct cell population regardless of normal hematopoiesis hierarchic order. Of these, MR subclones in progenitor populations of patient BM predominantly carry MR leukemic properties, leading to more robust expansion and stubborn persistence than those in mature populations. Moreover, a minor subset of MR leukemic subclones could be sustained at an extremely low frequency without clonal expansion during relapse. In this study, we observed treatment persistent MR leukemic subclones and their phenotypic changes during the treatment process of R/R AML patients. This underscores the importance of preemptive inhibition of clonal promiscuity in R/R AML, proposing a practical method for monitoring AML MR subclones.

The Critical Role of Intracellular Bacterial Communities in Uncomplicated Recurrent Urinary Cystitis: A Comprehensive Review of Detection Methods and Diagnostic Potential.

Urinary tract infections (UTIs) are among the most common bacterial infections worldwide and are particularly prevalent in women. Recurrent UTIs significantly diminish quality of life due to their symptoms and frequent relapses. Patients often experience immediate relapse following slightly strenuous activities or intense psychological stress. In this review, we explore why infections persist despite the advent of various treatments and suggest strategies to manage recurrent cystitis by targeting the mechanisms of adhesion and infection. Vitamin D levels and the expression of neutrophil gelatinase-associated lipocalin are linked to the recurrence of UTIs. During a UTI, bacteria employ adhesins to invade the urinary tract, adhere to urothelial cells, and then penetrate these cells, where they rapidly multiply to establish intracellular bacterial communities. Bacteria can also form quiescent intracellular reservoirs that escape immune responses and antibiotic treatments, leading to recurrence under certain conditions. The surface proteins of bacteria and D-mannose are crucial in the adhesion of bacteria to the urothelium. Understanding these processes provides valuable insights into potential therapeutic approaches that focus on preventing bacterial attachment and cluster formation. By disrupting the ability of bacteria to adhere to and form clusters on cells, we can better manage recurrent UTIs and improve patient outcomes.