Relapse Rate Research Articles

Somatic mutational profiling and clinical impact of driver genes in Latin-Iberian medulloblastomas: Towards precision medicine.

Medulloblastoma (MB) is the most prevalent malignant brain tumor in children, known for its heterogeneity and treatment-associated toxicity, and there is a critical need for new therapeutic targets. We analyzed the somatic mutation profile of 15 driver genes in 69 Latin-Iberian molecularly characterized medulloblastomas using the Illumina TruSight Tumor 15 panel. We classified the variants based on their clinical impact and oncogenicity. Among the patients, 66.7% were MBSHH, 13.0% MBWNT, 7.3% MBGrp3, and 13.0% MBGrp4. Among the 63 variants found, 54% were classified as Tier I/II and 31.7% as oncogenic/likely oncogenic. We observed 33.3% of cases harboring at least one mutation. TP53 (23.2%, 16/69) was the most mutated gene, followed by PIK3CA (5.8%, 4/69), KIT (4.3%, 3/69), PDGFRA (2.9%, 2/69), EGFR (1.4%, 1/69), ERBB2 (1.4%, 1/69), and NRAS (1.4%, 1/69). Approximately 41% of MBSHH tumors exhibited mutations, TP53 (32.6%) being the most frequently mutated gene. Tier I/II and oncogenic/likely oncogenic TP53 variants were associated with relapse, progression, and lower survival rates. Potentially actionable variants in the PIK3CA and KIT genes were identified. Latin-Iberian medulloblastomas, particularly the MBSHH, exhibit higher mutation frequencies than other populations. We corroborate the TP53 mutation status as an important prognostic factor, while PIK3CA and KIT are potential therapeutic targets.

Cefiderocol in Difficult-to-Treat Nf-GNB in ICU Settings

BackgroundThe efficacy and safety of cefiderocol in ICU patients with difficult-to-treat resistance (DTR) non-fermenting Gram-negative bacteria (Nf-GNB) are not as well-established. Consequently, we conducted a cohort study to compare Cefiderocol with the Best Available Therapy (BAT) in ICU patients.MethodsWe included adult patients from 9 different ICUs, including a burn ICU unit, from 2019 to 2023 treated with Cefiderocol for DTR Nf-GNB isolated from the blood or lungs. We matched each patient at a 1:2 ratio based on the same DTR Nf-GBN isolated pathogen, and when possible, within the same type of ICU (burn unit or not). The primary endpoint of the study was the clinical cure at 15 days, with secondary endpoints including clinical cure at 30 days, relapse, and in-ICU mortality. For each outcome, adjusted odds ratios were estimated using bidirectional stepwise regression in a final model, which included 13 preselected confounders.ResultsWe included 27 patients with cefiderocol, matched with 54 patients receiving the BAT. Four patients were not exactly matched on the type of ICU unit. Characteristics were comparable between groups, mostly male with a Charlson Comorbidity Index of 3 [1–5], and 28% had immunosuppression. Cefiderocol patients were most likely to have higher number of antibiotic lines. The main DTR Nf-GNB identified was Pseudomonas aeruginosa (81.5%), followed by Acinetobater baumanii (14.8%) and Stenotrophomonas maltophilia (3.7%). Pneumonia was the identified infection in 21 (78.8%) patients in the Cefiderocol group and in 51 (94.4%) patients in the BAT group (p = 0.054). Clinical cure at 15 and 30-day and the in-ICU mortality was comparable between groups, however relapse was higher in the cefiderocol group (8-29.6% vs. 4-7.4%;aOR 10.06[1.96;51.53])ConclusionCefiderocol did not show an improvement in clinical cure or mortality rates compared to BAT in the treatment of DTR Nf-GNB, but it was associated with a higher relapse rate.

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.

Distinct roles of excitatory and inhibitory neurons in the medial prefrontal cortex in the expression and reconsolidation of methamphetamine-associated memory in male mice.

Methamphetamine, a commonly abused drug, is known for its high relapse rate. The persistence of addictive memories associated with methamphetamine poses a significant challenge in preventing relapse. Memory retrieval and subsequent reconsolidation provide an opportunity to disrupt addictive memories. However, the key node in the brain network involved in methamphetamine-associated memory retrieval has not been clearly defined. In this study, using the conditioned place preference in male mice, whole brain c-FOS mapping and functional connectivity analysis, together with chemogenetic manipulations of neural circuits, we identified the medial prefrontal cortex (mPFC) as a critical hub that integrates inputs from the retrosplenial cortex and the ventral tegmental area to support both the expression and reconsolidation of methamphetamine-associated memory during its retrieval. Surprisingly, with further cell-type specific analysis and manipulation, we also observed that methamphetamine-associated memory retrieval activated inhibitory neurons in the mPFC to facilitate memory reconsolidation, while suppressing excitatory neurons to aid memory expression. These findings provide novel insights into the neural circuits and cellular mechanisms involved in the retrieval process of addictive memories. They suggest that targeting the balance between excitation and inhibition in the mPFC during memory retrieval could be a promising treatment strategy to prevent relapse in methamphetamine addiction.

Comparison of clinical characteristics and outcomes in primary neuroendocrine breast carcinoma versus invasive ductal carcinoma

BackgroundNeuroendocrine breast carcinoma (NECB) is a rare, special histologic type of breast cancer. There are some small sample studies on the clinical outcomes of NECB patients, which are worthy of further discussion.MethodsWe conducted a retrospective case-control study of clinical characteristics and outcomes among patients with primary NECB versus invasive carcinoma of no special type (NST) between November 2004 and November 2017 in the Peking Union Medical College Hospital, Beijing. NST patients were strictly matched 1:4 during the same period based on the TNM stage. Statistical comparisons were performed to determine the differences in survival between NST and NECB patients and to identify clinical factors that correlate with prognosis.ResultsA total of 121 participants affected by primary NECB were included in our analysis from November 2004 to November 2017. Elderly persons (>60 years of age) were more likely to have primary NECB than young persons (p=0.001). In addition, primary NECB patients had significantly higher odds of having tumors 2-5 cm (36.5%) and >5 cm (6.1%) in size than NST patients. Despite a significant difference in tumor size, the proportion of patients with lymph node metastases showed no difference between the two groups (p=0.021). In addition, the rate of patients with ER-negative tumors in the NECB group (4.2%) was significantly lower than that in the primary NST group (29.8%). Significant differences were noted in the PR-negative (13.3% versus 36.6%, P<0.001) and HER2-negative (90.5% versus 76.4%, P=0.001) expression statuses among these patients. Of 121 primary NECB patients, 11 (9.1%) experienced relapses during the follow-up period. We found that tumor size was an independent risk factor for relapse. For hormone receptors on tumor cells, ER-positive breast cancer patients had significantly lower odds of relapse than receptor-negative patients.ConclusionsOur data demonstrate no significant difference in mortality and relapse between the primary NECB and NST groups. The tumor size in the primary NECB group was significantly larger than that in the NST group. In addition, the absence of ER independently increased the relapse rate for breast carcinoma patients.

Substance Addiction Rehabilitation Drugs

The relapse rate of substance abusers is high, and addiction rehabilitation adjunct drugs need to be developed urgently. There have been numerous reports on blocking the formation of substance addiction, but studies on drugs that can alleviate withdrawal symptoms are very limited. Both the dopamine transporter (DAT) hypothesis and D3 dopamine receptor (D3R) hypothesis are proposed. DAT activators reduce the extracellular dopamine level, and D3R antagonists reduce the neuron’s sensitivity to dopamine, both of which may exacerbate the withdrawal symptoms subsequently. The D3R partial agonist SK608 has biased signaling properties via the G-protein-dependent pathway but did not induce D3R desensitization and, thus, may be a promising drug for the withdrawal symptoms. Drugs for serotoninergic neurons or GABAergic neurons and anti-inflammatory drugs may have auxiliary effects to addiction treatments. Drugs that promote structural synaptic plasticity are also discussed.

Predictors of cocaine use disorder treatment outcomes: a systematic review

BackgroundPsychosocial approaches are the first-line treatments for cocaine dependence, although they still present high dropout and relapse rates. Thus, there is a pressing need to understand which variables influence treatment outcomes to improve current treatments and prevent dropout and relapse rates. The aim of this study is to explore predictors of treatment retention and abstinence in CUD.MethodsThis systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched three databases—PubMed, PsychINFO and Web of Science—for randomized clinical trials (RCTs) published in English and Spanish from database inception through April 1, 2023. We selected all studies that met the inclusion criteria (adults aged ≥ 18, outpatient treatment, CUD as main addiction, and no severe mental illness) to obtain data for the narrative synthesis addressing cocaine abstinence and treatment retention as main outcome variables. After data extraction was completed, risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials (RoB-2).ResultsA total of 566 studies were screened, and, of those, 32 RCTs were included in the synthesis. Younger age, more years of cocaine use, and craving levels were significant predictors of relapse and treatment dropout. Fewer withdrawal symptoms, greater baseline abstinence, greater treatment engagement, and more self-efficacy were all predictors of longer duration of abstinence. The role of impulsivity as a predictor of CUD is unclear due to conflicting data, although the evidence generally suggests that higher impulsivity scores can predict more severe addiction and withdrawal symptoms, and earlier discontinuation of treatment.ConclusionCurrent evidence indicates which variables have a direct influence on treatment outcomes, including well-studied cocaine use-related variables. However, additional variables, such as genetic markers, appear to have a high impact on treatment outcomes and need further study.Systematic review registrationThis systematic review is registered at PROSPERO (ID: CRD42021271847). This study was funded by the Spanish Ministry of Science, Innovation and Universities, Instituto Carlos III (ISCIII) (FIS PI20/00929) and FEDER funds and Fundació Privada Hospital de la Santa Creu i Sant Pau (Pla d’acció social 2020).

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.

Recent Advances in Cognitive-Behavioural Therapy for Eating Disorders (CBT-ED).

Eating disorders require more effective therapies than are currently available. While cognitive behavioural therapy for eating disorders (CBT-ED) has the most evidence to support its effectiveness, it requires substantial improvement in order to enhance its reach and outcomes, and to reduce relapse rates. Recent years have seen a number of noteworthy developments in CBT-ED, which are summarised in this paper. The key advances identified here include: improvements in the efficiency and availability of CBT-ED; expansion of applicability to younger cases across durations of eating disorder; and new methodologies. There have been important recent advances in the field of CBT-ED. However, it is important to stress that there remain gaps in our evidence base and clinical skills, and suggestions are made for future research and clinical directions.

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.

Alemtuzumab treatment for multiple sclerosis in Austria: An observational long-term outcome study.

Observational real-world study to analyze the clinical effects of alemtuzumab (ALEM) and subsequent disease-modifying therapy (DMT) usage in multiple sclerosis (MS). Data retrieved from the Austrian MS treatment registry (AMSTR) included baseline (BL) characteristics (at ALEM start), annualized relapse rate (ARR), 6-month confirmed progression independent of relapse activity (PIRA; ≥ 0.5-point Expanded Disability Status Scale (EDSS) score increase), 6-month confirmed disability improvement (CDI; ≥ 0.5-point EDSS decrease), and safety outcomes until initiation of a subsequent DMT. The EDSS was re-baselined at 30 days from ALEM start (BL EDSS). Eighty-seven ALEM-treated patients (median age: 32 years, 72% female, 14% treatment-naïve) were followed for a median of 55 (interquartile range 31-68) months. We found significant reductions in the ARR from 1.16 before ALEM to 0.15 throughout Years 1-9 (p < 0.001). Subsequent DMTs were initiated in 19 patients (22%, 74% anti-CD20 monoclonal antibodies). At Year 5 (n = 53), more patients achieved CDI (58%, 95% confidence interval (CI) 45%-71%) than had experienced PIRA (14%, CI 7.5%-24%), and 58% remained relapse-free. Shorter MS duration (p < 0.001, hazard ratio (HR) 0.86 (CI 0.80-0.93)) and no previous high-efficacy treatment (p < 0.001, HR 5.16 (CI 2.66-10.0)) were the best predictors of CDI, while PIRA was associated with a higher number of previous DMTs (p = 0.04, HR 3.06, CI 1.05-8.89). We found no new safety signals. ALEM had long-lasting beneficial effects on the ARR and disability improvement, especially when initiated early in the course of the disease. Only a subset of patients received subsequent DMTs.

Ocrelizumab and ofatumumab comparison: an Italian real-world propensity score matched study.

The management of Multiple Sclerosis (MS) has undergone transformative evolution with the introduction of high-efficacy disease-modifying therapies (DMTs), specifically anti-CD20 monoclonal antibodies, such as ocrelizumab (OCR) and ofatumumab (OFA). This is an independent retrospective cohort study in Relapsing MS (RMS) patients followed at eight Italian MS centers who initiated treatment with OCR or OFA in the participating centers and with at least 12months on therapy. A generalized linear regression model inverse probability of treatment weight (IPTW) PS-adjusted was performed to evaluate the relationship between annualized relapse rate (ARR) and treatment groups. No evidence of disease activity-NEDA-3 at 12-month score was also collected. Safety profile of the investigated DMTs was recorded. A total cohort of 396 RMS patients fulfilled the required criteria and were enrolled in the study. Out of them, 216 had a prescription of OCR and 180 of OFA. The mean follow-up was 13.2 ± 1.9months. The estimated means for ARR did not show differences between the two groups, 0.059 for patients on OCR and 0.038 for patients on OFA (p = 0.185). The generalized regression model IPTW PS-adjusted did not reveal differences between patients on OCR and OFA (ExpBOFA 0.974, 95%CI 934-1.015, p = 0.207). NEDA-3 at 12months was experienced by 199(92.1%) patients on OCR and 170(94.4%) patients on OFA (p = 0.368). Generally, both therapies exhibit good tolerability. The treatment with OCR and OFA resulted in comparable control of disease activity with good safety profile. Our results need further validation in larger multicentre studies with long-term follow-up.

Comparative effects of progestin-based combination therapy for endometrial cancer or atypical endometrial hyperplasia: a systematic review and network meta-analysis

ObjectivesThe objective of this network meta-analysis is to systematically compare the efficacy of diverse progestin-based combination regimens in treating patients diagnosed with endometrial cancer or atypical endometrial hyperplasia. The primary goal is to discern the optimal combination treatment regimen through a comprehensive examination of their respective effectiveness.MethodsWe systematically searched four prominent databases: PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials, for randomized controlled trials addressing the efficacy of progestins or progestin combinations in the treatment of patients with endometrial cancer or atypical endometrial hyperplasia. The search spanned from the inception of these databases to December 2023. Key outcome indicators encompassed survival indices, criteria for assessing efficacy, as well as pregnancy and relapse rate. This study was registered in PROSPERO (CRD42024496311).ResultsFrom the 1,558 articles initially retrieved, we included 27 studies involving a total of 5,323 subjects in our analysis. The results of the network meta-analysis revealed that the mTOR inhibitor+megestrol acetate (MA)+tamoxifen regimen secured the top rank in maintaining stable disease (SD) (SUCRA=73.4%) and extending progression-free survival (PFS) (SUCRA=72.4%). Additionally, the progestin combined with tamoxifen regimen claimed the leading position in enhancing the partial response (PR) (SUCRA=75.2%) and prolonging overall survival (OS) (SUCRA=80%). The LNG-IUS-based dual progestin regimen emerged as the frontrunner in improving the complete response (CR) (SUCRA=98.7%), objective response rate (ORR) (SUCRA=99.1%), pregnancy rate (SUCRA=83.7%), and mitigating progression (SUCRA=8.0%) and relapse rate (SUCRA=47.4%). In terms of safety, The LNG-IUS-based dual progestin regimen had the lowest likelihood of adverse events (SUCRA=4.2%), while the mTOR inhibitor regimen (SUCRA=89.2%) and mTOR inbitor+MA+tamoxifen regimen (SUCRA=88.4%) had the highest likelihood of adverse events.ConclusionsPatients diagnosed with endometrial cancer or atypical endometrial hyperplasia exhibited the most favorable prognosis when undergoing progestin combination therapy that included tamoxifen, mTOR inhibitor, or LNG-IUS. Notably, among these options, the LNG-IUS-based dual progestin regimen emerged as particularly promising for potential application.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO, identifier CRD42024496311.

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

BackgroundWhen 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.MethodsThe 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.ResultsThe 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.ConclusionThe 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.

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.

OTUB2 silencing promotes ovarian cancer via mitochondrial metabolic reprogramming and can be synthetically targeted by CA9 inhibition

Ovarian cancer is an aggressive gynecological tumor characterized by a high relapse rate and chemoresistance. Ovarian cancer exhibits the cancer hallmark of elevated glycolysis, yet effective strategies targeting cancer cell metabolic reprogramming to overcome therapeutic resistance in ovarian cancer remain elusive. Here, we revealed that epigenetic silencing of Otubain 2 (OTUB2) is a driving force for mitochondrial metabolic reprogramming in ovarian cancer, which promotes tumorigenesis and chemoresistance. Mechanistically, OTUB2 silencing destabilizes sorting nexin 29 pseudogene 2 (SNX29P2), which subsequently prevents hypoxia-inducible factor-1 alpha (HIF-1α) from von Hippel-Lindau tumor suppressor-mediated degradation. Elevated HIF-1α activates the transcription of carbonic anhydrase 9 (CA9) and drives ovarian cancer progression and chemoresistance by promoting glycolysis. Importantly, pharmacological inhibition of CA9 substantially suppressed tumor growth and synergized with carboplatin in the treatment of OTUB2-silenced ovarian cancer. Thus, our study highlights the pivotal role of OTUB2/SNX29P2 in suppressing ovarian cancer development and proposes that targeting CA9-mediated glycolysis is an encouraging strategy for the treatment of ovarian cancer.

Abstract PO1-22-08: Ductal Lavage versus Oral Corticosteroids in Patients with Idiopathic Granulomatous Mastitis: A Multicenter, Open-label, Randomized, Controlled, Non-inferiority Study

Abstract Background: Idiopathic granulomatous mastitis (IGM) is an inflammatory breast disease characterized by the presence of mass, erythema and fistula. Various treatments have been proposed, including steroids, surgery, immunosuppressants, and observation alone. However, most of the reported studies are single-center, retrospective, single-arm with limited sample sizes, leaving the optimal treatment strategy unknown. In a previous single-arm study, we reported the efficacy and safety of ductal lavage as a novel treatment. This presentation presents the results of a multicenter, open-label, randomized controlled, non-inferiority trial that compares the efficacy and safety of ductal lavage with oral corticosteroids as the first-line treatment for IGM patients. Methods: Eligible IGM patients were randomized 1:1 to receive either ductal lavage or oral corticosteroids, stratified by M-score status. The M-score quantitatively evaluates IGM symptom severity as reported in our previous studies. Ductal lavage involved the intraductal infusion of lidocaine, triamcinolone acetonide, and ceftriaxone with saline, a total 5 times within 2 weeks. Oral corticosteroids were administered using prednisone or methylprednisolone at an initial dose of 20-40mg per day, decreased by 5mg every 2 weeks, and then maintained at 20mg per day for at least 1 month. The primary outcome was the rate of complete Clinical Response (cCR), which was defined as achieving M-score≤1 during any follow-up visit. Secondary outcomes included median time to first cCR, treatment failure, relapse, adverse events, and protocol compliance rate. If the lower limit of 95%CI of the absolute difference between ductal lavage and oral corticosteroids was greater than -15%, the non-inferiority was met. This trial was approved by the ethical committee of Sun Yat-sen Memorial Hospital and registered with ClinicalTrials.gov (NCT03724903). Results: Recruitment for this trial began in March 2019 and follow-up ended in May 2023 at 3 hospitals in China. In the intention-to-treat set (N=140), 69 patients were randomly assigned to the ductal lavage group and 71 patients to the oral corticosteroids group. The cCR rates after treatment were 85.51% (95% CI 77.20 ~ 93.81%) and 87.32% (95% CI 79.59 ~ 95.06%) in the ductal lavage and oral corticosteroids groups, respectively. The rate difference was -1.82% (95% CI -13.17 ~ 9.54%), not exceeding the non-inferiority margin (Non-inferiority P=0.011). In the per-protocol set (N=111), the cCR rate difference was -5.32%(ductal lavage: 92.86% vs. oral corticosteroids: 98.18%),with a 95%CI of -12.94% to 2.29%,also not exceeding the non-inferiority margin(Non-inferiority P=0.006).No significant differences were observed between groups in median time to first cCR (34.0 vs. 32.5 days, P= 0.878), treatment failure rate (14.49% vs. 11.27%, P=0.569), or relapse rate (10.14% vs. 4.23%, P=0.302).In the safety analysis set (N=129), the most frequently reported adverse events ( &amp;gt;15%) in the ductal lavage group were irregular menstruation (46.27%), while in the oral corticosteroids group, they were Cushingoid (79.03%), epigastric pain (17.74%), and arthralgia (16.13%). Conclusions: Ductal lavage demonstrates non-inferiority to oral corticosteroids in terms of efficacy as a first-line treatment for IGM patients. Furthermore, ductal lavage exhibits a significantly favorable adverse events profile. Primary endpoint in ITT and PP set *P value for non-inferiority comparison. Secondary endpoint in PP set §P value calculated by chi-square test. Adverse event in safety set No adverse event exceeding Grade3 have been recorded. Citation Format: Kai Chen, Xiaolin Chen, Shunrong Li, Liling Zhu, Jian Zhang, Tingting Hu, Hui Huang, Heng Huang, Lili Chen, Qiaozhen Xiao, Linhong Su. Ductal Lavage versus Oral Corticosteroids in Patients with Idiopathic Granulomatous Mastitis: A Multicenter, Open-label, Randomized, Controlled, Non-inferiority Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-22-08.

Abstract PO5-25-11: Appropriate use of interventional cohort studies with threshold-crossing designs for de-escalation trials in breast cancer

Abstract For some populations of patients with early breast cancer (BC), clinical outcomes have improved such that the focus has shifted to identifying aspects of therapy that can be reduced or omitted to spare patients toxicity without compromising outcomes. For example, in patients with HER2+ disease, introduction of HER2-targetted therapy significantly reduced event rates but at increased exposure to toxicity. For those with a pathological complete response (pCR) to neo-adjuvant anti-HER2 therapy, the absolute gain from continued adjuvant therapy is likely to be small and the event rate sufficiently low such that any deviation from the expected prognosis would be sufficient to infer failure of a reduced treatment strategy. Previous studies would usually adopt a non-inferiority (NI) trial randomising patients between standard of care (SOC) and reduced therapy. The reduced therapy would be declared non-inferior if the difference between the groups does not exceed a pre-agreed NI margin. Some populations, such as those described, have a very low rate of recurrence and thus large sample sizes are required to gain sufficient power resulting in several issues. In these situations, threshold-crossing designs, also known as interventional cohort studies (ICS), provide an alternative to traditional NI trials. In ICS, a single cohort is recruited and receives the reduced therapy. The event rate is compared to a pre-defined fixed threshold, above which recurrence rates would be considered unacceptable. When conducted appropriately, such studies are statistically and logistically efficient, and should be considered definitive. ICS can be used when 1. A stable background of SOC exists with robust data from which an appropriate crossing-boundary can be defined. Critically, the historical control population used to define the boundary must closely reflect the study population and those seen in clinical practice. 2. The event rate is sufficiently low and consequently has low variability, so a concurrent control group is not required because an accurate estimate of the event rate with SOC already exists. 3. The primary endpoint of interest is reliable, sensitive to treatment and timely to allow early stopping if interim analyses indicate an issue. The well-defined excellent prognosis of patients with HER2+ BC who have a pCR to contemporary neo-adjuvant therapy, coupled with the pattern of relapse rates dropping off rapidly after 3 years, makes this an appropriate setting for implementing such designs. Three recently initiated studies testing reduced therapy in this patient population, HER2-RADiCAL (NIHR131362), CompassHER2 (NCT04266249) and DECRESCENDO (NCT04675827), all have an ICS design. An ICS approach is also valid for trials testing avoidance of radiotherapy in very low-risk populations, where the absolute benefit is likely low and occurrence of late local events is salvageable so as not to impact on overall survival, such as in PRIMETIME (ISRCTN 41579286). In contrast, there are several settings where these designs should not be used. For example, in the assessment of systemic therapy in ER+ HER2- BC the recurrence rate is constant beyond 3 years meaning events cannot be picked up in a timely manner and a fixed threshold defined at 3/5 years would not allow preclusion of a later drop-off in efficacy. It would also be premature to use ICS in TNBC following immunotherapy as outcome data is not yet sufficiently mature to accurately define a suitable threshold. Finally, if relapse rates are not sufficiently low, natural variation in control group incidence rates would prevent setting a suitable fixed threshold. We will discuss the key requirements and design features for using ICS to efficiently evaluate avoidance of treatment in BC and highlight the importance of patient involvement in the development of such trials. Citation Format: Holly Tovey, Laura Finneran, Lucy Kilburn, Iain Macpherson, Andrew Wardley, Hilary Stobart, Lesley Turner, Mairead MacKenzie, Charlotte Coles, Cliona Kirwan, Judith Bliss. Appropriate use of interventional cohort studies with threshold-crossing designs for de-escalation trials in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-25-11.

Gut Microbiota and Pulmonary Tuberculosis (Literature Review)

The review analyzes 69 publications, of which 45 are devoted to studying gut microbiota in tuberculosis patients. The review presents data on the effect of gut microbiota disorders on the development of tuberculosis, severity and relapse rate. It covers the issues of changes in gut microbiota composition during anti-tuberculosis therapy and the effect of their management with probiotics on the tolerability of anti-tuberculosis therapy and effectiveness of treatment, including children.

Abstract PO3-17-09: Outcome after the introduction of personalized treatment for axilla in patients with clinically node-negative early breast cancer

Abstract Background : After the results of ACOSOG Z0011 and AMAROS trials were reported, axillary treatment has been promoted to de-escalation. For clinically negative cases of axillary lymph node metastasis (cN0), axillary dissection (Ax) has been the standard treatment when sentinel lymph node (SN) metastasis is positive. In our hospital, for patients with cN0, if SN macro metastasis is positive, Ax or irradiation (RT) is selected after sufficient explanation to the patients. Five years have passed since the introduction of treatment selection for the axilla, we examined treatment outcomes retrospectively. Methods : The subjects were 1376 patients who underwent SN biopsy for primary breast cancer with cN0 at our hospital from October 2004 to December 2018 (median observation period 79 months). Cases who underwent preoperative chemotherapy were excluded. We have introduced the treatment choice system since December 2015, and compared prognosis (local recurrence, distant recurrence and breast cancer specific death) before and after introduction using the log-rank test. Results : There were 947 cases before introduction of treatment choice system (pre group) and 429 cases after introduction (post group). The median observation period for each group was 91 months and 41 months. The maximum observation period post group was 67 months, then we compared the number of events in patients with observation period less than 67 months in pre group. There was no significant difference between two groups (Pre/Post) in terms of age (p=0.52), menopausal status (p=0.90), invasion of primary lesion (p=0.19), biology and SN metastasis status (p=0.41). There were 54 patients (12.6%) in pre group and 135 (14.3%) patients in post group had positive sentinel lymph nodes. In post group, 33 patient (61.1%) were macrometastasis of SN, 28 of whom underwent Ax and 5 underwent RT. Local recurrence was 4 cases (1.7%) in pre group, 9 cases (2.1%) in post group (p=0.84), distant recurrence was 13 cases (5.6%) and 5 cases (1.2%) (p=0.0002), and breast cancer specific death was 8 cases (0.8%) and 1 case (0.2%) (p=0.0003), respectively. Discussion : There was no significant difference in local recurrence rate within 67 months, but were poor prognosis in pre introduction group for distant metastasis and breast cancer specific survival. In the results of this study, there was no significant difference in local recurrence, but the prognosis for distant recurrence and breast cancer-specific death was poor in the before introduction group. The median observation period in the post introduction group was 47 months, and late recurrence of ER-positive breast cancer occurs later. It is necessary to continue the study by extending period and accumulation cases. Conclusion : For cN0 cases, if the case is suitable, we introduced the treatment choice system that allows omitting Ax by performing radiotherapy in SN macrometastasis positive patients. After introduction, there was no increase in the relapse rate after introduction in the short term. Appropriate case selection allowed the safety introduction of individualizes treatment for axilla. Citation Format: Mai Tomiguchi, Kaori Hidaka, Lisa Goto-Yamaguchi, Ayako Kajiwara, Kanako Nishikido, Toko Inao, Yutaka Yamamoto. Outcome after the introduction of personalized treatment for axilla in patients with clinically node-negative early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-17-09.