Time-Dependent Analysis of Plasmalogens in the Hippocampus of an Alzheimer’s Disease Mouse Model: A Role of Ethanolamine Plasmalogen

Plasmalogens are alkenyl-acyl glycerophospholipids and decreased in post-mortem Alzheimer’s disease (AD) brains. The aim of this study is to investigate the time-dependent changes of plasmalogens in the hippocampus of an AD model mouse (J20). Plasmalogen levels at 3, 6, 9, 12 and 15 months were analyzed by liquid-chromatography-targeted-multiplexed-selected-reaction-monitoring-tandem-mass-spectrometry (LC-SRM/MS). Reactive oxygen species (ROS) levels were evaluated using dichlorofluorescein diacetate (DCF-DA). Plasmalogen synthesizing enzyme glycerone-phosphate O-acyltransferase (GNPAT) and late endosome marker Rab7 levels were quantified by Western blotting. GNPAT localization, changes of neuronal and glial cell numbers were evaluated by immunostaining. Compared to wild-type mice (WT), total plasmalogen-ethanolamine, but not plasmalogen-choline levels, were increased at 9 months and subsequently decreased at 15 months in J20 mice. A principal component analysis of plasmalogen-ethanolamine species could separate WT and J20 mice both at 9 and 15 months. Both GNPAT and Rab7 protein were increased in J20 mice at 9 months, whereas GNPAT was decreased at 15 months. ROS levels were increased in J20 mice except for 9 months. Our results suggest that increased plasmalogen-ethanolamine could counteract ROS levels and contribute to the phagocytosis process in J20 mice at 9 months. Such results might indicate a transient protective response of plasmalogen-ethanolamine in AD conditions.

Improvement Diagnosis and Treatment of Mantle Cell Lymphoma in a Middle-Income Country: A Time-Dependent Analysis in Mexico

Introduction: Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma representing 4-9% of all lymphomas. The disease prognosis remains adverse. However, diagnosis and treatment of MCL have undergone a significant improvement in the last years. The World Bank considers Mexico as a Middle-Income Country (MIC). Therefore, MICs experience a delay in accomplishing diagnosis and prognosis strategies and low access to treatment innovation for hematologic malignancies. In Mexico, there is scarce information on the clinical features and treatment patterns of MCL over time. Mainly, the prognosis impact of these strategies is unknown. Methods: We retrospectively evaluated all consecutive patients with a pathological diagnosis of MCL in three referral centers for the uninsured population in Mexico from 2008 to 2020. We followed patients to June 2021 until lost follow-up or death. We made a Time-Dependent-Analysis (TDA) to evaluate the effect of the diagnosis and treatment improvements over time. We divided the population into two groups, from 2008 to 2014 (Group A) and from 2015 to 2020 (Group B). Hematopathologists reviewed all cases at their respective centers. We excluded patients that do not receive treatment and patients without pathological confirmation. Clinical, pathological, and treatment data were collected. Responses were assessed per the Lugano criteria. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method, differences between the groups were evaluated with a log-rank test. Multivariate analysis of factors associated with mortality was assessed with a Cox regression model with a Confidence Interval(CI) of 95%. Results: A total of 139 patients were included in the analysis; 67 patients from Group A; and 72 patients from Group B. The median age was 64 years, 42% were younger than 65 years, 76% were male, 22% had ECOG 2-4, 81% had extra nodal involvement, 28.1% had bulky disease, 94% had stage III/IV disease, 58% had bone marrow involvement, 40.7% had high risk simplified MIPI. Regarding diagnosis approaches between the two groups, only 23% in Group A had an immunohistochemical evaluation of Ki67 compared with an 84% of Group B (p<0.001). The rest of the differences between the groups are in Table 1. In terms of treatment, 84% received an anthracycline-based treatment, 3% bendamustine-based treatment, and 12% a low-intensity treatment, with no difference between the groups. In addition to base treatment, 30% received High-dose Cytarabine (HiDAC), been more frequent in Group B (p<0.001), 59% received rituximab during induction, 37% in Group A, and 80% in Group B, (p<0.001). The main reason to avoid the use of rituximab was the cost and only 20.3% used rituximab maintenance, being more frequent in Group B (p=0.018). The 13.7% received an autologous stem cell transplant, been more frequent in Group B (p= 0.002). Only two patients (1.4%) received treatment in a Clinical Trial setting. In terms of response, in Group A, 58% achieved Complete Response (CR) against 34% of Group B (p=0.006). Median OS on Group A was 38 months (95% CI 25.6 -50.3) against Not Reached in Group B (Log Rank p = 0.037). On the other hand, the median EFS on Group A was 17 months (95% CI 11.6-22.39) against 29 months (95% CI17.6-40.3) in Group B (Log Rank p = 0.005) Figure 2. A multivariate analysis of factors associated with higher mortality found a high-risk MIPI score with an HR of 2.54 (CI 95% 1.5-4.0, p <0.001). Factors associated with lower mortality were the addition of HiDAC in induction HR 0.39 (CI 95% 0.20- 0.75, p= 0.005) and rituximab maintenance HR 0.48 (CI 95% 0.24-0.94, p=0.035) Conclusion: This is the first real-world report of MCL in Mexico. Characteristics of the disease resemble the ones reported by other countries. Despite the limitations of a retrospective analysis, the TDA makes evident the prognosis improvement over time. With progress in EFS of 12 months and an OS impact. Even though the prognosis improvement, to the date, there is a 20% of patients with no rituximab access. Transplant access is low beside that 42% of patients were younger than 65 years, and Clinical Trial access is almost null. Novel therapies for MIC are under development with encouraging results in the first-line and relapsed/refractory setting. However, the high costs of these therapies will limit the access in MIC and would expand the gap of MCL prognosis if a health care strategy that allow access to them is not implemented. Figure 1 Figure 1. Disclosures Rangel-Patiño: Abbvie: Speakers Bureau; Bristol: Consultancy. Agreda: Roche: Speakers Bureau; Astrofarma: Speakers Bureau; Janssen: Speakers Bureau. Gomez-Almaguer: Bristol-Myers-Squibb: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau. Ramirez-Ibarguen: Takeda: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Astra Zeneca: Speakers Bureau; Abbvie: Speakers Bureau; MSD: Consultancy; Asofarma: Consultancy.

111. Duration of Antibiotic Therapy after Debridement and Implant Retention in Patients with Periprosthetic Joint Infections

Background Debridement, antibiotics, and implant retention (DAIR) is appropriate for select acute postoperative and hematogenous periprosthetic joint infections (PJIs). However, the optimal duration of antimicrobial therapy in patients treated with DAIR has not been defined. Therefore, we aimed to identify the ideal duration of parenteral and oral antibiotics after DAIR. Methods We performed a retrospective study of patients >18 years of age with hip or knee PJI managed with DAIR between January 1, 2008, and December 31, 2018, at Mayo Clinic. PJI was defined using criteria adapted from the International Consensus Meeting on PJI. The outcome was defined as either PJI recurrence or unplanned reoperation due to infection. Joint-stratified Cox proportional hazards regression models with time-dependent covariates were used to assess nonlinear effects of antibiotic duration. Hazard ratios were computed based on prespecified time points for comparison, whereas p-values represented the overall effect across the entire range of durations. Results There were 247 unique episodes of PJI in 237 patients during the study period. Parenteral antibiotics were given in 99.2% of cases (n=245). This was followed by chronic oral antibiotic suppression in 92.2% (n=226) with a median duration of 2.2 years (1.0-4.1). DAIR failed in 65 cases over a median follow-up of 4.4 years, with a 5-year cumulative incidence of 28.1%. After adjustment for risk factors, there was no significant association between duration of parenteral antibiotics and treatment failure (p=0.203), with no difference between four versus six weeks (HR 1.11; 95% CI 0.71-1.75) (Figure 1). However, both use and longer duration of oral antibiotic therapy was associated with a lower risk of failure (p=0.006). To account for the possibility that this association was driven by results during early follow-up, conditional analyses at one- and two-year follow-up were performed. Both showed a significantly lower risk for a longer duration of antibiotics (Figure 2). Figure 1. Time-Dependent Analysis of Parenteral Antibiotic Duration Figure 2. Time-Dependent Analysis of Oral Antibiotic Suppression Duration Conclusion After DAIR, efficacy from four weeks of parenteral antibiotics was no different from six weeks when followed by chronic oral antibiotic suppression. Our results could not establish an optimal duration but suggested that continuing suppression portends a lower risk of failure of DAIR. Disclosures Elie Berbari, MD, Uptodate.com (Other Financial or Material Support, Honorary unrelated to this work) Matthew P. Abdel, MD, Stryker and AAOS Board of Directors (Board Member, Other Financial or Material Support, Royalties) Aaron J. Tande, MD, UpToDate.com (Other Financial or Material Support, Honoraria for medical writing)

In-depth time-dependent analysis of the benefit of Allo-HSCT for elderly patients with CR1 AML: a FILO study

The benefit of allogeneic hematopoietic stem cell transplantation (Allo-HSCT) for acute myeloid leukemia (AML) patients over 60 years remains a matter of debate, notably when performed in first complete remission (CR1). In order to clarify this issue, the French Innovative Leukemia Organization (FILO) performed a 10-year real-world time-dependent analysis. The study enrolled patients between 60 and 70 years of age with AML in CR1 after intensive chemotherapy with intermediate (IR) or unfavorable (UR) risk according to the European LeukemiaNet (ELN)-2010. The impact of Allo-HSCT was analyzed through three models, respectively i) time-dependent Cox, ii) multistate for dynamic prediction and iii) super landmark. The study enrolled 369 (73%) IR and 138 (27%) UR AML patients, 203 of whom received an Allo-HSCT. Classical multivariate analysis showed that Allo-HSCT significantly improved relapse-free (RFS; Hazard Ratio/HR [95%CI]: 0.47 [0.35-0.62], p<0.001) and overall (OS; HR [95%CI]: 0.56 [0.42-0.76], p<0.001) survivals, independently of the ELN risk group. With the multistate model, the predicted 5-year probability for IR and UR patients to remain in CR1 without Allo-HSCT was 8% and 1%, respectively. Dynamic predictions confirmed that patients without Allo-HSCT continue to relapse over time. Finally, the super landmark model showed that Allo-HSCT significantly improved RFS (HR [95%CI]: 0.47 [0.36-0.62], p<0.001) and OS (HR [95%CI]: 0.54 [0.40-0.72], p<0.001). Allo-HSCT in CR1 is demonstrated here to significantly improve the outcome of fit older AML patients. Long-term RFS without Allo-HSCT is very low (<10%), supporting Allo-HSCT as being the best curative option for these patients.