Lower Relapse Rate Research Articles

#1681 Efficacy and safety of combined treatment with rituximab and low doses of cyclophosphamide for ANCA associated renal vasculitis

Abstract Background and Aims Current guidelines recommend the use of rituximab (RTX) or cyclophosphamide (CP) as induction treatment for ANCA-associated vasculitis (AAV) with renal involvement. Some authors have described the combination of CP and RTX in the treatment of severe AAV, and recently a regimen of 6 cycles of low-dose CP combined with RTX has been used with good results. The aim our study was to compare the efficacy and safety of combined treatment with even lower doses of intravenous CP (2-3 cycles) and RTX, compared to standard treatment with RTX. Method We conducted a retrospective study that included 14 patients with histologically confirmed AAV, treated with an induction treatment scheme of corticosteroids, RTX and 2-3 cycles of intravenous CP. A case-control analysis was performed with 16 patients who received only corticosteroids and RTX in the same period, matched by propensity score for age, creatinine at presentation and histological parameters (sclerosed glomeruli, epithelial crescents and normal glomeruli). We compared renal and overall survival, and complications from immunosuppression in both groups. Results At presentation, patients treated with the combined regimen had a mean age of 67 ± 12.1 years, a mean glomerular filtration rate estimated by CKD-EPI of 19.8 ± 11.1 ml/min/1.73 m2, proteinuria of 1.6 (0.81- 1.84) g/24 hours and initial BVAS score of 18.5 ± 6.9. 78.6% of the patients were anti-MPO positive and 21.4% were anti-PR3 positive. According to Berden's classification, 85.7% had a mixed variant, 7.1% crescentic and 7.1% sclerotic, in the renal biopsy. The mean dose of CP was 1445 ± 384 mg, and of RTX was 2g. 28.6% required dialysis at presentation, of which 75% recovered kidney function. The duration of steroid treatment was 8 (4.6-16.9) months. Remission rate at 6 months was 71.4%, and after a median follow-up of 20 (15-35) months, 92.9% had remitted. During follow-up, 50% had serious infections; and at the end, 7.1% progressed to end-stage chronic kidney disease (ESKD). 21.4% of the patients included ended up dying. In comparison with the control group, patients who received the combined treatment had a higher remission rate (92.9% vs. 75%), a lower relapse rate (15.4% vs. 35.7%), lower progression to ESKD (7.1% vs. 20%) and lower mortality (21.4% vs 37.5%), with no differences for serious infections. Conclusion The association of low doses of cyclophosphamide to rituximab induction treatment could improve the prognosis in patients with severe ANCA-associated renal vasculitis.

#1782 Clinicopathological study of renal limited pauci-immune vasculitis and its short-term outcome: a single centre observational study

Abstract Background and Aims Pauci immune crescentic glomerulonephritis, is a leading cause of RPGN. The majority of patients with PICGN have glomerular diseases as a part of a systemic small vessel vasculitis, a minority may present as renal-limited vasculitis. In north-east India, there are still no major studies in this group of patients. Therefore, our study involving north-east Indian population constitutes an effort to prospectively study the clinico-pathological feature of patients with PICGN and assess the short-term outcome. Method This single-centre, prospective, observational, study was conducted over 12 months at the Department of Nephrology, Gauhati Medical College. All renal biopsy-proven patients with pauci-immune renal vasculitis were included, excluding those with secondary vasculitis. Baseline characteristics and laboratory data were recorded, and disease activity was assessed using the Birmingham Vasculitis Activity Score. The ANCA tests were performed using a standardised essay for both indirect immunofluorescence assay and antigen-specific ELISA. The renal biopsy specimen obtained was evaluated by light microscopy and direct immunofluorescence. The sample size was calculated based on the prevalence of pauci-immune glomerulonephritis, and data were analysed using SPSS. Results The study involved 24 patients, predominantly females (70.83%), aged 14-65 years, presenting predominantly with pedal oedema and oliguria. Laboratory findings showed varying levels of haemoglobin, total count, platelet count, creatinine, and 24-hour urine protein. 50% of the patients were (MPO) positive, 33.3% were (PR3) positive while 16% were ANCA negative. Renal biopsy analysis showed a majority with mixed class according to the Berden classification. Treatment involved induction with Methylprednisolone and Cyclophosphamide, with dialysis administered to 58.3% of patients. At six months, 36.3% had a stable GFR, and 50% were on maintenance hemodialysis. Factors predicting renal loss included oliguria, dialysis at presentation, and fibrous/fibrocellular crescents. The best predictor of renal outcome was serum creatinine at presentation. Conclusion Pauci-immune CrGN is a severe disease affecting a wide age range. Early diagnosis and treatment initiation are crucial for better outcomes, including lower ESRD risk and relapse rates. Prognostic factors include baseline serum creatinine levels and fibrous crescents. Optimising treatment regimens may improves outcomes.

#2748 Combined rituximab and daratumumab treatment in difficult to treat nephrotic syndrome cases

Abstract Background and Aims Common treatments for multidrug-resistant and multidrug-dependent nephrotic syndrome (NS) are inconsistently effective and burdened by long-term toxicities. Moreover, affected patients are at high risk of progression to end-stage kidney failure. Objective To test the safety/efficacy profile of combined single infusion of rituximab and daratumumab in inducing proteinuria remission in multidrug resistant nephrotic syndrome and maintaining drug free disease remission in patients with multidrug-dependent nephrotic syndrome after removal of oral immunosuppression. Method We here present a Phase 2 Proof-of-Concept single-arm clinical trial, that enrolled consecutive participants at the Nephrology Unit of the IRCCS Giannina Gaslini Children's Hospital in Genoa, Italy, between September 2021 and March 2023. Enrolled patients, aged between 3 and 24 years, were multidrug-dependent or multidrug-resistant nephrotic syndrome for at least 12 months before enrolment. Multidrug-dependency was defined by the need of at least 2 oral immunosuppressive drugs (prednisone and/or calcineurin inhibitors and/or mycophenolate mofetil) and by the occurrence of at least two consecutive relapses on two immunosuppressive drugs. Multidrug-resistance nephrotic syndrome was defined by the lack of antiproteinuric effect of a double immunosuppressive therapy. Exclusion criteria included genetic forms of NS and administration of monoclonal therapies in the last 9 months before enrolment. Interventions: Rituximab and daratumumab were administered as single doses at 375 mg/m2 and 16 mg/kg, respectively, 15 days apart. Main Outcomes and Measures:Proteinuria, serum albumin, Immunoglobulin M and G, B and T lymphocyte subsets, safety, Quality of Life. Results A total of 7 consecutive multidrug-resistant and 16 multidrug-dependent NS, respectively, were enrolled. In multidrug-resistant NS, combined rituximab and daratumumab promoted complete or partial remission in 6 patients (Fig. 1A). Five subjects experienced proteinuria relapse, that was effectively treated with a second course of combined treatment. Decreased of I'm, but not IgG, correlated with improvement of proteinuria (Fig. 1B).These treatment allowed to reduce the chronic immunosuppressive treatment daily administered (Fig. 1C). In multidrug-dependent NS, combined rituximab and daratumumab extended the relapse-free time, allowing us to remove oral immunosuppressant (Fig. 1D). Disease relapse was invariably anticipated by a recovery of circulating IgM:patients with IgM levels below median values measured at 3 mo post-treatment had a significantly lower rate of relapse at 9 mo than patients with higher IgM levels at 3 mo (Fig. 1E). Combined treatment induced significative reduction of CD38+ plasma cells (Fig. 1F) and IgM, but not IgG. Treatment was well tolerated and significantly increased quality of life. Conclusion Combined rituximab and daratumumab was safe and effective in the treatment of complicated forms of NS, offering a new therapeutic option for this severe condition.

Exploration of the mechanism of Traditional Chinese Medicine for anxiety and depression in patients with diarrheal irritable bowel syndrome based on network pharmacology and meta-analysis.

The efficacy of Chinese herbal medicine (CHM) in managing irritable bowel syndrome with diarrhea (IBS-D) accompanied by anxiety and depression remains uncertain. Thus, a systematic review was carried out employing meta-analysis and network pharmacology to ascertain the efficacy and underlying mechanisms of CHM therapy. By conducting a systematic review, including literature search, screening, and data extraction, we identified 25 randomized controlled trials to assess CHM's effectiveness in treating irritable bowel syndrome alongside anxiety and depression. Network pharmacology was utilized to scrutinize the metabolite utility of CHM in addressing this condition. Potential primary mechanisms were synthesized using information sourced from the PubMed database. Twenty-five studies, including 2055 patients, were analyzed, revealing significant treatment efficacy for IBS-D in the trial group compared to controls [OR = 4.01, 95% CI (2.99, 5.36), I2 = 0%] Additionally, treatment for depression [SMD = -1.08, 95% CI (-1.30, -0.86), p < 0.00001, I2 = 68%; SDS: SMD = -1.69, 95% CI (-2.48, -0.90), p < 0.0001, I2 = 96%] and anxiety [HAMA: SMD = -1.29, 95% CI (-1.68, -0.91), p < 0.00001, I2 = 89%; SAS: SMD = -1.75, 95% CI (-2.55, -0.95), p < 0.00001, I2 = 96%] significantly improved in the trial group. Furthermore, the trial group exhibited a significantly lower disease relapse rate [OR = 0.30, 95% CI (0.20, 0.44), p < 0.00001, I2 = 0%]. CHM treatment consistently improved IBS severity (IBS-SSS) and symptom scores. Network pharmacology analysis identified key chemical metabolites in traditional Chinese medicine formulations, including Beta-sitosterol, Stigmasterol, Quercetin, Naringenin, Luteolin, Kaempferol, Nobiletin, Wogonin, Formononetin, and Isorhamnetin. Utilizing the STRING database and Cytoscape v3.9.0 software, a protein-protein interaction (PPI) network revealed the top eight key targets: IL-6, TNF, PPARG, PTGS2, ESR1, NOS3, MAPK8, and AKT1, implicated in anti-inflammatory responses, antioxidant stress modulation, and neurotransmitter homeostasis maintenance. Chinese Herbal Medicine (CHM) offers a promising and safe treatment approach for patients dealing with Diarrheal Irritable Bowel Syndrome (IBS-D) accompanied by anxiety and depression; thus, indicating its potential for practical implementation. The most active metabolites of CHM could simultaneously act on the pathological targets of IBS-D, anxiety, and depression.The diverse scope of CHM's therapeutic role includes various aspects and objectives, underscoring its potential for broad utilization.

Effects of Total Body Irradiation on Hematopoietic Cell Transplantation Outcomes in Pediatric Acute Myeloid Leukemia with Prior Central Nervous System Involvement

The implications of previous central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT) remain inadequately understood. Patients with CNS disease require more upfront CNS-directed intrathecal therapy, but little is known about whether transplant conditioning regimens should be intensified or if previous CNS involvement impacts post-HCT outcomes. While total body irradiation (TBI) remains standard for pediatric acute lymphoblastic leukemia myeloablative conditioning, it has been largely replaced with chemotherapy-only myeloablation in pediatric AML, primarily due to toxicity and late effects associated with TBI. In the setting of previous CNS involvement, it has been suggested that TBI-based myeloablation may have advantages due to superior CNS tissue penetration and thus decreased rates of AML relapse post-HCT. We analyzed a publicly available dataset derived from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry to characterize the impact of TBI in HCT preparative regimens in pediatric AML patients with a history of CNS involvement. The study dataset was obtained from the CIBMTR data repository. The study cohort included patients aged ≤21 years who underwent initial allogeneic HCT with myeloablative conditioning for de novo AML in the first or second complete remission (CR) between 2008 and 2016, who provided consent for research. Patients with mismatched related donor transplants and noncalcineurin inhibitor graft-versus-host disease (GVHD) prophylaxis were excluded. The dataset was further modified by excluding patients with missing disease site data or those with non-CNS extramedullary disease. Patients were categorized as CNS-positive or -negative AML (AML-CNS(+) and AML-CNS(-), respectively) based on the disease status at diagnosis. The Cox regression model and Fine-Grey methods were employed to delineate the effects of TBI and CNS disease on key HCT outcomes. The study cohort comprised 550 pediatric AML patients, of which 25% (n = 136) were AML-CNS(+). CNS involvement was more prevalent in patients aged 0 to 3 years, patients who were in the second CR, and those with a mismatched unrelated donor or umbilical cord blood. AML-CNS(+) patients demonstrated a lower relapse rate (hazard ratio: 0.50, 95% confidence interval: 0.33 to 0.76) compared to AML-CNS(-) patients, with comparable disease-free survival (DFS) and overall survival (OS) (P = .10 and 0.20, respectively) in the two cohorts. The entire TBI-treated cohort showed an association with increased risks of grade 2 to 4 acute GVHD, bloodstream infections, and endocrine dysfunction. TBI use within the AML-CNS(+) cohort was associated with a lower relapse rate but increased risks of nonrelapse mortality and a trend of higher grade 3 to 4 acute GVHD. In this population-based analysis of pediatric patients with de novo AML undergoing HCT, TBI-based conditioning regimens did not confer an advantage in DFS or OS compared to non-TBI regimens, irrespective of CNS disease status. However, TBI use was associated with increased risks of short- and long-term comorbidities. These findings underscore the need for careful consideration of TBI in pediatric AML.

Impact of nutritional risk factors on the development of multiple sclerosis

The literature review considers the data on the assessment of the influence of alimentary factors on the development of a severe neurological disease - multiple sclerosis (MS). MS is a polyetiologic disease, the risk of development of which is influenced by both infectious (Epstein-Barr virus, herpes simplex virus, influenza virus, etc.) and noninfectious factors (genetic predisposition, smoking, geographic region of residence, etc.). MS is a progressive demyelinating disease of the central nervous system (CNS), which leads to neurodegeneration accompanied by a variety of clinical manifestations. The pathogenesis of MS is characterized by immune-mediated damage to the myelin sheaths of nerve fibers, which is manifested by inflammation, neurosynaptic damage, and destruction of white matter, axons, and blood vessels. Rapid non-evolutionary dietary and lifestyle changes, which are driven by urbanization, industrialization and globalization of the food market, are leading to an increase in most chronic non-communicable diseases, including MS. The effects induced by alimentary factors are due to changes in the microbial composition of the gastrointestinal tract (GIT), immune cell function, enzyme systems functioning, etc. The aim of the work is to study the influence of micro/macronutrients, as well as the nature of the diet on the risk of MS development, to assess the role of nutrition in the primary prevention of MS. It has been shown that a diet characterized by a high content of animal fats and trans-isomers of fatty acids (TFA), increased consumption of meat products, but low content of vegetables, fruits and whole-grain products is associated with a higher risk of MS development. Regular inclusion in the diet of sources of polyunsaturated fatty acids (PUFAs) (vegetable oils, seeds, nuts, marine fish) and vitamin D (fatty fish, caviar, butter, egg yolk) leads to lower relapse rates and less new brain lesions among MS patients. The literature review was conducted using open sources posted in electronic databases: PubMed, Medline, Scopus, Google Scholar, World Bank publications, WHO, eLibrary, Cyberleninka, Web of Science.

Effectiveness and safety of granulocyte colony-stimulating factor priming regimen for acute myeloid leukemia: A systematic review and meta-analysis of the Clinical Practice Guideline for the use of G-CSF 2022 from the Japan Society of Clinical Oncology.

The outcomes of relapsed or refractory acute myeloid leukemia (AML) remain poor. Although the concomitant use of granulocyte colony-stimulating factor (G-CSF) and anti-chemotherapeutic agents has been investigated to improve the antileukemic effect on AML, its usefulness remains controversial. This study aimed to investigate the effects of G-CSF priming as a remission induction therapy or salvage chemotherapy. We performed a thorough literature search for studies related to the priming effect of G-CSF using PubMed, Ichushi-Web, and the Cochrane Library. A qualitative analysis of the pooled data was performed, and risk ratios (RRs) with confidence intervals (CIs) were calculated and summarized. Two reviewers independently extracted and accessed the 278 records identified during the initial screening, and 62 full-text articles were assessed for eligibility in second screening. Eleven studies were included in the qualitative analysis and 10 in the meta-analysis. A systematic review revealed that priming with G-CSF did not correlate with an improvement in response rate and overall survival (OS). The result of the meta-analysis revealed the tendency for lower relapse rate in the G-CSF priming groups without inter-study heterogeneity [RR, 0.91 (95% CI 0.82-1.01), p=0.08; I2=4%, p=0.35]. In specific populations, including patients with intermediate cytogenetic risk and those receiving high-dose cytarabine, the G-CSF priming regimen prolonged OS. G-CSF priming in combination with intensive remission induction treatment is not universally effective in patients with AML. Further studies are required to identify the patient cohort for which G-CSF priming is recommended.

Comprehensive analysis of the efficacy and safety of CAR T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia: a systematic review and meta-analysis

Background Relapse/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL) represents paediatric cancer with a challenging prognosis. CAR T-cell treatment, considered an advanced treatment, remains controversial due to high relapse rates and adverse events. This study assessed the efficacy and safety of CAR T-cell therapy for r/r B-ALL. Methods The literature search was performed on four databases. Efficacy parameters included minimal residual disease negative complete remission (MRD-CR) and relapse rate (RR). Safety parameters constituted cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results Anti-CD22 showed superior efficacy with the highest MRD-CR event rate and lowest RR, compared to anti-CD19. Combining CAR T-cell therapy with haploidentical stem cell transplantation improved RR. Safety-wise, bispecific anti-CD19/22 had the lowest CRS rate, and anti-CD22 showed the fewest ICANS. Analysis of the costimulatory receptors showed that adding CD28ζ to anti-CD19 CAR T-cell demonstrated superior efficacy in reducing relapses with favorable safety profiles. Conclusion Choosing a more efficacious and safer CAR T-cell treatment is crucial for improving overall survival in acute leukaemia. Beyond the promising anti-CD22 CAR T-cell, exploring costimulatory domains and new CD targets could enhance treatment effectiveness for r/r B-ALL.

Improved Outcome of Allogeneic Transplantation in Older Patients Treated for Myeloid Malignancies Using Post-Transplantation Cyclophosphamide and Reduced Duration of Immune Suppression

BackgroundAllogeneic stem cell transplantation (alloSCT) offers curative potential for older patients with myeloid malignancies. We evaluated the efficacy and safety of alloSCT using post-transplantation cyclophosphamide (PTCy) in combination with a very short duration of immune suppression (IS) in this population. MethodsWe retrospectively analyzed 92 consecutive patients aged 65 years and older who underwent an alloSCT for myeloid malignancies between February 2018 and December 2022 at our institution. Data on patient characteristics, treatment modalities, and outcomes were collected. ResultsNinety-two patients received an alloSCT with PTCy-based GVHD prophylaxis. The majority had minimal comorbidities and were diagnosed with acute myeloid leukemia (AML). Patients mostly received conditioning regimens with low to intermediate TCI scores. In 43% of patients, IS could be permanently stopped at day +90, resulting in a median time of IS of 2.93 months in high-risk patients. At a median follow-up of 21.3 months, the 1- and 2-year overall survival rates were 89% and 87%, respectively. Relapse-free survival rates were 88% and 84% at 1 and 2 years, respectively. The 1- and 2-year cumulative incidences of relapse were 8% and 13%, while transplant-related mortality (TRM) estimates were 9% at both time points. Acute GVHD grade 3-4 occurred in 7% within the first 180 days and severe chronic GVHD in 6% of patients. This all resulted in a 1- and 2-year graft versus host and relapse free survival (GRFS) of 74% and 70%, respectively. ConclusionAlloSCT using PTCy in combination with a short duration of IS in older patients with myeloid malignancies demonstrates favorable survival outcomes due to low relapse rates and a low TRM. The low incidence of relapse and acceptable rates of graft-versus-host disease suggest the efficacy and safety of this approach. Further studies are warranted to validate these findings and optimize transplant strategies for older patients with myeloid malignancies.

Gradually tapering off antipsychotics: lessons for practice from case studies and neurobiological principles.

There has been an increasing focus on deprescribing in psychiatry recently, particularly of antipsychotic medication, with recognition that not all patients with psychotic disorders require lifelong medication. We summarize some empirical and theoretical papers, and examine case studies to provide instruction on this topic. Recent studies have found that slower tapering (over months or longer) of antipsychotics is associated with a lower relapse rate than quicker tapering (weeks). Case studies presented suggest that the process of reduction is associated with the precipitation or exacerbation of psychotic symptoms and that a slower process of reduction may minimize this effect. This may be because faster reductions cause greater disruption of homeostatic equilibria, provoking psychotic symptoms either as direct withdrawal symptoms or consequences of nonpsychotic withdrawal symptoms (e.g. insomnia) - although not all patients will experience withdrawal symptoms. This suggests that smaller dose reductions, especially at lower doses, made very gradually, may minimize the risk of psychotic symptoms. Slower tapering of antipsychotics may provide time for adaptations made to the presence of the medications to resolve, thus reducing the disruption to homeostatic equilibrium caused by dose reduction, potentially reducing the risk of relapse. Exacerbation of psychotic symptoms on antipsychotic reduction may not represent evidence of the need for a higher dose of antipsychotic on a long-term basis but may indicate the need for more gradual reduction. Gradual reduction of antipsychotics, especially after long-term use in clinical practice is prudent.

Vacancy-Driven High-Performance Metabolic Assay for Diagnosis and Therapeutic Evaluation of Depression.

Depression is one of the most common mental illnesses and is a well-known risk factor for suicide, characterized by low overall efficacy (<50%) and high relapse rate (40%). A rapid and objective approach for screening and prognosis of depression is highly desirable but still awaits further development. Herein, a high-performance metabolite-based assay to aid the diagnosis and therapeutic evaluation of depression by developing a vacancy-engineered cobalt oxide (Vo-Co3O4) assisted laser desorption/ionization mass spectrometer platform is presented. The easy-prepared nanoparticles with optimal vacancy achieve a considerable signal enhancement, characterized by favorable charge transfer and increased photothermal conversion. The optimized Vo-Co3O4 allows for a direct and robust record of plasma metabolic fingerprints (PMFs). Through machine learning of PMFs, high-performance depression diagnosis is achieved, with the areas under the curve (AUC) of 0.941-0.980 and an accuracy of over 92%. Furthermore, a simplified diagnostic panel for depression is established, with a desirable AUC value of 0.933. Finally, proline levels are quantified in a follow-up cohort of depressive patients, highlighting the potential of metabolite quantification in the therapeutic evaluation of depression. This work promotes the progression of advanced matrixes and brings insights into the management of depression.

Kinetics of BCR::ABL1 transcript levels and molecular relapse after tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia patients: preliminary results from the DES-CML study.

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of patients with chronic myeloid leukemia. Patients who achieve sustained deep molecular response are eligible for treatment discontinuation. DES-CML is an ongoing, phase 2 multicentric discontinuation trial. Adult patients with CML in chronic phase with typical BCR::ABL1 transcripts, stable deep molecular response (MR4.5 IS) for two years, and no previous resistance were eligible. Patients underwent a phase of TKI dose de-escalation for six months before discontinuation. TKI was reintroduced at the previous dose if the patient lost major molecular response (MMR) at any time. This study aimed to assess the impact of BCR-ABL transcript kinetics during TKI de-escalation and discontinuation phases on treatment-free survival. So far, the study recruited 41 patients, and 38 patients discontinued therapy (4 were in the second discontinuation attempt). Eleven patients lost MMR, one during the de-escalation phase and ten after discontinuation. 24-month treatment-free survival was 66% (95% CI: 48-84%) in a median follow-up of 7 (1-30) months. No patient lost hematological response or had disease progression. A higher rate of molecular relapses occurred in patients with fluctuating BCR::ABL1 levels after the discontinuation phase (with loss of MR4.5, but no loss of MMR) (P=0.04, HR-4.86 (1.03-22.9) but not confirmed in the multivariate analysis. The longer duration of TKI treatment (P=0.03, HR-1.02, 95%CI - 1.00-1.04) and MMR (P=0.004, HR-0.95, 95%CI - 0.92-098) were independent factors of a lower relapse rate.

Long-term remission and relapse of anxiety and depression in older adults after Cognitive Behavioural Therapy (CBT): A 10-year follow-up of a randomised controlled trial

BackgroundThis study examined the long-term durability of cognitive behaviour therapy (CBT) for older adults with comorbid anxiety and depression 10 years after treatment, in comparison to an active control group. MethodParticipants from a randomised controlled trial for older adults with comorbid anxiety and depression (Wuthrich et al., 2016) were re-contacted. Participants had received either group CBT or an active control treatment (Discussion Group). The final sample (N = 54; Aged 70–84, Mage = 76.07, SD = 3.83; 59 % of the eligible original sample) completed a diagnostic interview, cognitive assessment and self-report measures of symptoms and quality of life. ResultsCBT was associated with significantly improved long-term (10-year) efficacy for reducing anxiety and depression in older adults compared to the Discussion group. Effects included higher rates of remission (58 % remission of all diagnoses vs 27 %, 88 % of all depressive diagnoses vs 54 %, 63 % of all anxiety diagnoses vs 35 %, 67 % of primary diagnosis vs 42 %), lower rates of relapse (25–31 % vs 50–78 %) and lower rates of chronic treatment-resistance (8 % primary disorder vs 39 %, 21 % any disorder vs 58 %). Participants who showed an acute treatment response at post-treatment were 7–9 times more likely to be in remission after 10 years than those with residual symptoms. LimitationsResults may not generalise to those who do not complete CBT, and the time trajectory of symptom change is unclear. ConclusionsLong-term improvements in symptoms are specific to CBT. Results provide compelling evidence for CBT as an effective and durable treatment for late-life anxiety and depression.

Comparable outcomes for TBI-based versus treosulfan based conditioning prior to allogeneic hematopoietic stem cell transplantation in AML and MDS patients

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a standard treatment for patients with AML and MDS. The combination of fractionated total body irradiation(8GyTBI/Flu) with fludarabine is an established conditioning regimen, but fludarabine/treosulfan(Flu/Treo) constitutes an alternative in older/comorbid patients. We conducted a retrospective analysis of 215 AML(in CR) and 96 MDS patients undergoing their first allo-HCT between 2011 and 2022, identifying 53 matched Flu/Treo and 8GyTBI/Flu patients through propensity score matching. Median follow-up of survivors was 3.3 years and 4.1 years. For the Flu/Treo group, 1-year non-relapse mortality (2% vs. 10%, p = 0.03) was lower, while 1-year relapse incidence (16% vs. 13%, p = 0.81) was similar. Three-year outcomes, including relapse-free survival and graft-versus-host disease incidence, were comparable (OS: 81% vs. 74%, p = 0.70; RFS: 78% vs. 66%, p = 0.28; chronic GvHD: 34% vs. 36%, p = 0.97; acute GvHD (100 days): 11% vs. 23%, p = 0.11). Multivariable analysis, considering age, ECOG, HCT-CI, and MRD status, revealed no associations with main outcomes. Dose-reduced conditioning with Flu/Treo or 8GyTBI/Flu demonstrated favorable and comparable survival rates exceeding 70% at 3 years with 1-year NRM rates below 10% and low relapse rates in the matched cohort. These data underline the need for further evaluation of TBI and Treo-based conditionings in prospective trials.

A new approach to urinalysis: effectiveness of a contingency management program among adolescent offenders in Spain.

When addressing antisocial behaviour among adolescents, programs based on the paradigm of positive psychology through enhancing self-efficacy have demonstrated their effectiveness in furthering the positive development of young people with a history of antisocial behaviour. Nevertheless, there has been little research into the effectiveness of these type of programs in mitigating substance abuse among juvenile offenders. The aim of this paper is to analyse the effectiveness of a contingency management program in reducing the prevalence of relapses into drug consumption among adolescents who have committed serious crimes. The study consisted of a sample of 91 male adolescents, between 15 and 19 years, in juvenile detention, who were divided into two treatment groups. For both groups, biological testing was used to detect drug consumption upon their re-turn from leave permits from the Centre. The quasi-experimental group had significantly lower rates of relapse than the quasi-control group. Furthermore, being part of the quasi-experimental group was a significant predictor of reduced rates of relapses. The results suggest that the incorporation of treatment strategies which reinforce feelings of self-efficacy and adequate orientation towards the future, as a complement to disciplinary sanctions, are effective in reducing relapses in drug use among adolescent offenders.

Survival Outcomes in Patients with Monobloc-Resected Stage IIC (pT4bN0) Colon Cancer: A Retrospective Observational Cohort Study

BackgroundStage II colon cancer (CC) exhibits considerable prognostic heterogeneous. Our objective was to assess survival but also the prognosis impact of microsatellite instability (MSI) in patients with stage IIC (T4bN0M0) CC. Patients and MethodsWe conducted a retrospective observational study including all patients who had primary stage IIC CC resection between 2010 and 2020 in 2 expert centers. The primary endpoint was overall survival (OS) and disease-free survival (DFS) and time-to-relapse (TTR) were secondary endpoints. ResultsSixty-six patients, median age of 74 years [30-95], were included, with 37.9% presenting MSI (n = 25). Organ invasion involved the last ileal loop (n = 17), another colonic segment (n = 15), omentum (n = 13), visceral peritoneum (n = 13), and the bladder (n = 4). Surgical quality criteria showed complete monobloc resection in all patients and 93.9% R0 resection. After a median follow-up of 5 years [3.5-6.6], the entire population showed a 5-year OS of 65.2% [53.0-80.3] and 5-year DFS of 53.5% [41.1-69.6], with 18.9% [6.8-29.4] experiencing relapses at 5 years. The MSI phenotype correlated with improved 5-year OS (75.5% [56.5-100] vs. 59.5% [44.9-79.0], HR 0.41 [0.17-0.99]; P = .04), but DFS and TTR did not differ. Adjuvant chemotherapy was administered to 34.9% of patients. Univariate analysis identified age > 65 years, MSI status, and the number of nodes as factors associated with OS. ConclusionThese data underline, in relation to a low rate of relapse, the lack of consensus regarding the appropriate indication for adjuvant chemotherapy in this high-risk stage II population.

Switching from natalizumab to an anti-CD20 monoclonal antibody in relapsing remitting multiple sclerosis: A systematic review

BackgroundUse of natalizumab (NTZ) is precluded in many Multiple Sclerosis (MS) patients by the risk of progressive multifocal leukoencephalopathy (PML). Regardless, some patients may commence natalizumab for short term disease control in spite of being seropositive, and others may seroconvert whilst on treatment. In these circumstances, discontinuation of NTZ should not occur until a clear exit strategy is established to prevent post-NTZ disease reactivation, which often exceeds the severity of disease activity prior to NTZ treatment. The objective of this systematic review was to summarise the available evidence for CD20-monoclonal antibodies (CD20mAb) as a suitable NTZ exit strategy, and to identify whether a superior switch protocol can be established. MethodsIn accordance with PRISMA guidelines, a total of 2393 references were extracted from a search of three online databases (PubMed, Scopus, MEDLINE). Following the application of inclusion/exclusion criteria, a total of 5 studies representing 331 patients were included. ResultsThe overall incidence of clinical relapse during washout periods ranging from 4.4–10.7 weeks was 0 %. The incidence of clinical relapse during two-year follow-up ranged from 1.8 % to 10 % for switches to all types of CD20 monoclonal antibody. The weighted mean for clinical relapse at 12 months was 8.8 %. Three studies reported an annualised relapse rate (ARR) ranging from 0.02–0.12 with a weighted mean ARR of 0.07. The overall incidence of PML during washout was 0 % and the overall incidence of PML within 6 months follow-up was 0.6 %. ConclusionsThis systematic review provides the first attempt at identifying a superior switch protocol in patients at risk of PML transitioning from NTZ to a CD20mAb. Our results indicate that CD20mAb's are a suitable transitional option for patients who discontinue NTZ, with our cohort demonstrating very low rates of carryover PML and low rates of clinical relapse. The most appropriate washout period is unclear due to confounding factors but is likely between 4 and 12 weeks.

Transforming the Niche: The Emerging Role of Extracellular Vesicles in Acute Myeloid Leukaemia Progression.

Acute myeloid leukaemia (AML) management remains a significant challenge in oncology due to its low survival rates and high post-treatment relapse rates, mainly attributed to treatment-resistant leukaemic stem cells (LSCs) residing in bone marrow (BM) niches. This review offers an in-depth analysis of AML progression, highlighting the pivotal role of extracellular vesicles (EVs) in the dynamic remodelling of BM niche intercellular communication. We explore recent advancements elucidating the mechanisms through which EVs facilitate complex crosstalk, effectively promoting AML hallmarks and drug resistance. Adopting a temporal view, we chart the evolving landscape of EV-mediated interactions within the AML niche, underscoring the transformative potential of these insights for therapeutic intervention. Furthermore, the review discusses the emerging understanding of endothelial cell subsets' impact across BM niches in shaping AML disease progression, adding another layer of complexity to the disease progression and treatment resistance. We highlight the potential of cutting-edge methodologies, such as organ-on-chip (OoC) and single-EV analysis technologies, to provide unprecedented insights into AML-niche interactions in a human setting. Leveraging accumulated insights into AML EV signalling to reconfigure BM niches and pioneer novel approaches to decipher the EV signalling networks that fuel AML within the human context could revolutionise the development of niche-targeted therapy for leukaemia eradication.

Antibiotics efficacy in clinical and microbiological cure of uncomplicated urinary tract infection: a systematic review and network meta-analysis.

Fosfomycin has been used more frequently in managing uncomplicated urinary tract infections (UTIs) due to decreased compliance and increased multidrug-resistant bacteria. The aim of this network meta-analysis was to assess the efficacy of Fosfomycin compared to Nitrofurantoin, Trimethoprim-Sulfamethoxazole (TMP-SMX), and Ciprofloxacin in terms of clinical and microbiological cure alongside with other measurements. We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). We included randomized control trials (RCTs) with uncomplicated UTI patients who received Fosfomycin, Nitrofurantoin, TMP-SMX, or Ciprofloxacin and reported the clinical or microbiological cure. We used Cochrane Risk of Bias Assessment Tool to assess the included studies' quality. R-software was used for all statistical analysis. We ranked all antibiotics using the netrank function which yielded P scores. Frequentist network meta-analysis was used to assess the efficacy of all outcomes. We included 13 RCTs with a total number of 3856 patients that showed Fosfomycin ranked the highest among the other antibiotics with respect to clinical cure (P-score = 0.99) and microbiological cure (P-score = 0.99) while Ciprofloxacin ranked the lowest (P-score = 0.11 and 0.02, respectively). Moreover, Ciprofloxacin yielded the highest relapse rate (P-score = 1), whereas TMP-SMX had the lowest relapse rate (P-score = 0.07). As for the adverse events, Ciprofloxacin demonstrated the highest adverse events as opposed to Fosfomycin (P-score = 0.98 and 0.05, respectively). The network meta-analysis demonstrated that Fosfomycin is the most effective antibiotic in treating uncomplicated UTIs with respect to clinical cure, microbiological cure, and adverse events profile.

Long-Term Outcomes of Endoscopic Ultrasound–Guided Ablation Vs Surgery for Pancreatic Cystic Tumors

Endoscopic ultrasound-guided pancreatic cyst ablation (EUS-PCA) is performed as an alternative to surgical resection in selected patients with pancreatic cystic tumors (PCTs). We aimed to directly compare the long-term outcomes between EUS-PCA and surgery for PCTs. We reviewed a PCT database to identify patients with unilocular or oligolocular PCTs who underwent EUS-PCA or surgery between January 2004 and July 2019. We performed 1:1 propensity score matching based on potential confounding factors. The primary outcome was long-term morbidities. Secondary outcomes included early (≤14 days) and late (>14 days) major adverse events (MAEs), development of diabetes mellitus, readmission, length of hospital stay, and therapeutic efficacy. A total of 620 patients (EUS-PCA, n= 310; surgery, n= 310) were selected after propensity score matching. The EUS-PCA group showed a lower 10-year rate of cumulative long-term morbidities (1.6% vs 33.5%; P= .001) as well as lower rates of early MAE (1.0% vs 8.7%; P= .001), late MAE (0.3% vs 5.5%; P= .001), and readmission (1.0% vs 15.2%; P= .001). The EUS-PCA group had a shorter hospital stay (3.5 vs 10.3 d; P= .001) and a lower incidence of diabetes mellitus (2.2% vs 22.8%; P= .001), whereas the surgery group had a higher complete resolution rate (76.5% vs 100%; P= .001) and a lower relapse rate (4.6% vs 0.3%; P= .001). For select patients with PCTs, EUS-PCA showed superior results to surgery in terms of long-term safety profile and preservation of pancreatic function.