Small Patient Size Research Articles

A-120 Analytical and Clinical Verification of the Elecsys® Alzheimer’s Disease Cerebrospinal Fluid Biomarkers pTau/Abeta42 and Total-Tau/Abeta42

Abstract Background Alzheimer’s disease (AD) is the most common form of dementia characterized by amyloid beta (Abeta) plaques and neurofibrillary tau tangles in the brain. Cerebrospinal fluid (CSF) biomarkers Abeta42, total tau (tTau), and phosphorylated tau (pTau181) offer a high degree of sensitivity and specificity in the diagnosis of AD and have utility in monitoring disease progression. AD biomarker ratios, pTau181/Abeta42 and tTau/Abeta42, correlate with amyloid positron emission tomography (PET) imaging, and several assays have received FDA clearance. This study was designed to evaluate the analytical performance and clinical utility of AD-related Abeta and tau biomarkers on the Roche cobas e601. Methods Precision studies were performed using Roche PreciControl kits. Intra- and inter-precision samples were tested ten times in a single day or twice a day for ten days, respectively. Five levels of Roche Calcheck material were measured in triplicate for linearity. Method comparison was carried out using 39 samples from the Elecsys CSF Correlation Sample Panel from Roche. Qualitative comparisons to amyloid PET Centiloid scores were performed using 35 CSF samples (n=11 PET negative, n=24 PET positive). CSF samples and PET interpretation were obtained from the Cleveland Clinic Institutional Review Board approved Cleveland Alzheimer's Disease Research Center (CADRC) and Cleveland Clinic Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease Biobank (LRCBH-Biobank). Results Conclusions Evaluation of AD biomarkers on the Roche cobas e601 revealed reliable precision and analytical accuracy. The pTau181/Abeta42 and tTau/Abeta42 ratios demonstrated excellent positive agreement when compared to amyloid PET, but poor negative agreement. This may be due to the small sample size of PET-negative patients. Alternatively, as amyloid PET detects neuritic plaque accumulation, the CSF biomarker-positive/PET-negative patients may have early non-neuritic amyloid plaque pathology not detectable by imaging. Overall, this assay is suitable for use and may serve as a valuable tool in AD diagnosis.

Needle arthroscopy in the surgical management of septic arthritis of the shoulder joint in neonates and infants

Septic arthritis in neonates and infants is a life-threatening condition which should be treated promptly to reduce morbidity and mortality. The chondrolytic effect of bacteria and proteolytic enzymes is well documented. Surgical management consists of repeated needle aspirations in one sitting, arthroscopic washout or arthrotomy for open washout. In very small children, it is difficult to perform arthroscopy using conventional endoscopes. Arthrotomies carry significant risks including iatrogenic injury to the key structures given the small size of patients. It can also leave unsightly scars and the approach to the joint can be challenging. We present two cases of shoulder septic arthritis managed successfully using needle arthroscopy. This technique involves a 1.9 mm Arthrex ‘NanoNeedle Scope’ (Naples, Fl, USA) in a 2.3 mm cannula. A second portal can be used for joint sampling, debridement and irrigation outflow. Both children recovered with no repeated washouts necessary and excellent clinical results at an average follow-up of one year.

O-216 The impact of maternal age on cumulative life birth rates after single euploid embryo transfer: differences between autologous and donor oocyte cycles

Abstract Study question How much of an impact has the maternal age on cumulative life births after euploid Single Embryo Transfer (SET) in autologous and donor oocyte cycles? Summary answer A maternal age ≥ 42 years old affects negatively the cumulative Life Birth Rates (cLBRs) even after euploid SET, but only in the autologous cycles. What is known already Despite the improvements in assisted reproduction technologies (ART) in the last decades, the LBRs remain suboptimal, especially when advanced maternal age is considered. Although several factors could explain these outcomes (i.e. infertility history; uterine pathologies/surgery; advanced paternal age), maternal age-related aneuploidies remain the most limiting factor for a favorable clinical outcome. Thus, the Genetic Testing for Aneuploidies (PGT-A) has been integrated into ART as a strategy to evaluate chromosomal status before transfer. Interestingly, recent studies show that, even after the transfer of euploid blastocyst, the maternal age negatively influences the LBRs. Study design, size, duration This study, carried out in Villa Mafalda Reproductive Medicine Department (Italy), included 568 euploid SET: 542 from autologous cycles (divided in four subgroups according to maternal age: ≤ 34 y.o. (n = 207); 35-38 y.o. (n = 193); 39-41 y.o. (n = 106); ≥ 42 y.o. (n = 36)) and 26 from oocyte donation (OD) cycles (average recipient age is 44.2). All cycles were performed from May 2020 to February 2023. PGT for Monogenic disorders (PGT-M) cycles were excluded. Participants/materials, setting, methods All blastocysts included in this study were analyzed by Next Generation Sequencing (NGS) after a day 5/6 trophectoderm biopsy. For each subgroup was annotated the embryo morphology- divided into good (AA-AB-BA); average (BB-BC-CB) and poor (CC) according to Gardner/Schoolcraft blastocyst grading system- and the day of expanded blastocyst formation (grade 4 of Gardner/Schoolcraft blastocyst grading system). Primary analysis included the cumulative LBRs. Secondarily, blastocyst morphology and blastocyst expansion were examined for all embryo categories considered. Main results and the role of chance The pairwise comparison between groups was performed by Chi-square analysis and p < 0.05 was considered statistically significant. The cLBRs for each subgroup were respectively: ≤ 34 (63.09%); 35-38 (58.47%); 39-41 (56.84%); ≥ 42 (48.57%); OD (69.23%). Data showed that cLBRs decreased with the increase of maternal age, although statistical significance was observed only among women ≤ 34 y.o. and ≥ 42 y.o. (P=0.029). Notably, there was no statistical significance in cLBRs comparing women ≤ 34 y.o. and OD patients (P=0.086). The good-quality blastocyst rate was respectively: ≤ 34 y.o. (54.58%); 35-38 y.o. (47.66%); 39-41 y.o. (60.37%); ≥ 42 y.o. (50%); OD (59.37%). The pairwise comparison showed no significant difference between groups. Furthermore, there was not found significant difference about the day of expanded blastocyst formation: ≤ 34 y.o. (D5: 78.92%; D6 21.07%); 35-38 y.o. (D5: 78.49%; D6: 21.50%); 39-41 y.o. (D5:75.70%;D6: 24.29%); ≥ 42 y.o. (D5:69.44%; D6: 30.55%); OD (D5: 87.5%; D6: 12.5%). Data showed that maternal age ≥ 42 y.o. affects negatively cLBRs even after euploid SET, suggesting that other factors age-related, rather than aneuploidies, influence implantation. Interestingly, these factors do not affect OD recipients, with advanced maternal age, who, instead, reach successful LBRs like patients ≤ 34. Limitations, reasons for caution These results should be evaluated carefully because of the small sample size of the OD patients. A greater number of OD cycles are needed to verify the results obtained. Wider implications of the findings Our findings suggest that embryonic age-related factors - changes in gene expression, metabolism or epigenetics - could influence the embryo capability to, successfully, support implantation other than the ploidy status. This thesis was supported by the OD recipient’s behavior, who had cLBRs comparable to young autologous patients. Trial registration number Not Applicable

Association of Mismatch Profiles and Clinical Outcome from Endovascular Therapy in Large Infarct: A Post-Hoc Analysis of the ANGEL-ASPECT Trial.

We investigated whether patients with large infarct and the presence or absence of perfusion mismatch are associated with endovascular treatment benefit. This is a post-hoc analysis of the Endovascular Therapy in Anterior Circulation Large Vessel Occlusion with a Large Infarct (ANGEL-ASPECT) randomized trial, which enrolled patients within 24 hours of onset with ASPECTS 3 to 5 or ASPECTS 0 to 2 with an infarct core 70 to 100 ml. Mismatch ratio was defined as time-to-maximum (Tmax) >6 s cerebral volume/ischemic core volume, and mismatch volume was defined as Tmax >6 s volume minus ischemic core volume. We divided patients into mismatch ratio ≥1.2 and mismatch volume ≥10 ml, and mismatch ratio ≥1.8 and mismatch volume ≥15 ml groups. The primary outcome was the 90-day modified Rankin Scale score ordinal distribution. Safety outcomes were symptomatic intracranial hemorrhage and 90-day mortality. There were 425 patients included. In both the mismatch ratio ≥1.2 and mismatch volume ≥10 ml (mismatch+, n = 395; mismatch-, n = 31) and mismatch ratio ≥1.8 and mismatch volume ≥15 ml groups (mismatch+, n = 346; mismatch-, n = 80), better 90-day modified Rankin Scale outcomes were found in the endovascular treatment group compared with the MM group (4 [2-5] vs 4 [3-5], common odds ratio [cOR], 1.9, 95% confidence interval [CI] 1.3-2.7, p = 0.001; 4 [2-5] vs 4 [3-5], cOR, 1.9, 95% CI 1.3-2.8, p = 0.001, respectively), but not in patients without mismatch ratio ≥1.2 and mismatch volume ≥10 ml (5 [3-6] vs 5 [4-6], cOR, 1.2, 95% CI 0.3-4.1, p = 0.83), and mismatch ratio ≥1.8 and mismatch volume ≥15 ml (4 [3-6] vs 5 [3-6], cOR, 1.2, 95% CI 0.6-2.7, p = 0.60). However, no interaction effect was found in both subgroups (p interaction >0.10). Endovascular treatment was more efficacious than MM in patients with mismatch profiles, but no treatment effect or interaction was noted in the no mismatch profile patients. However, the small sample size of patients with no mismatch may have underpowered our analysis. A pooled analysis of large core trials stratified by mismatch is warranted. ANN NEUROL 2024.

A prospective double-blind clinical study: Effect of probiotics and thalidomide on radiation enteritis in patients with pelvic cancer undergoing concurrent chemoradiotherapy.

e23013 Background: Radiation induced diarrhea (RID) is one of the commonest and most distressing side effects during and after radiotherapy predominantly in patients whose irradiation region is pelvis. Thalidomide reduces severity as well as the frequency indicated in RID but mechanism of action is not elucidated. Probiotics are beneficial microorganisms that may regulate flora of intestines to increase immunity and have a protective effect on RID. This pilot study was designed to ascertain effects of thalidomide and probiotics on RID in patients being subjected to pelvic irradiation. Methods: A double-blind, single-center, randomized pilot study was conducted. Patients were classified into two groups as thalidomide plus probiotics (Lactobacillus rhamnosus + Probio-M9, ) group (TP group) or plus placebo group (P group).Incidence of grade 3/4 diarrhea, was a primary endpoint of the study. Other secondary endpoints analyzed were rates and severity of diarrhea, antibiotics use, body weight, albumin, and lymphocyte changes. 31 patients undergoing pelvic radiotherapy with or without concurrent chemotherapy were randomly selected from government tertiary general hospital. Results: The incidence of grade 3/4 diarrhea was 9.5% (95% CI: 0 to 24.5%) in TP, which was significantly different from historical data of 30% to 60%. The incidence of grade 3/4 diarrhea in group P was 19.8% (95% CI: 0~41.3%). The frequency and severity of diarrhea in group TP were little less than in group P. There is no significant difference between them. Basically, the time for antibiotic use in groups P and TP was the same, with a slightly longer time from first antibiotic exposure in group TP as compared to group P. The moment of first antibiotics have been prescribed in our study patients, this was better than that of a clinical routine treatment experience and other research data according to the literature. The changes in body weight, albumin level, and lymphocyte at different stages before and after radiotherapy in group TP were not statistically significant, and the level of body weight and albumin in group P was slightly reduced compared with before radiotherapy but increased compared with group TP after radiotherapy. Furthermore, there were no severe adverse effects regarding thalidomide as well as probiotics reported among patients who participated in this study. Conclusions: The combined treatment with thalidomide and probiotics is beneficial to ameliorate RID in patients receiving pelvic radiotherapy, yet this study can't represent whole conclusion due to small size of patients. We will also need larger, multicenter double-blind placebo-controlled trials to confirm exact efficacy and safety of this combined treatment. Clinical trial information: NCT05059613 .

Predictors of Good Functional Outcome in Patients with Tandem Occlusion After Revascularization Treatment: Single-Center Experience with 12-Month Follow-Up

The optimal management and procedural strategy for tandem occlusion (TO) in acute ischemic stroke are still unclear, as is the long-term outcome of these patients. The aim of this study was to evaluate predictors of good functional outcome in patients with TO through the analysis of demographics, clinical, and radiological data with a 1-year follow-up. We collected data on 100 patients with TO who underwent revascularization treatments in our comprehensive stroke center. We divided patients into 2 groups: those with good functional outcome, defined as a modified Rankin Scale 0-2, and those with poor functional outcome, defined as a modified Rankin Scale 3-6 at 3, 6, and 12-month follow-up. Moreover, we investigated which variables were able to influence mortality. At multivariate analysis, endovascular treatment with mechanical thrombectomy combined with emergent cervical carotid artery stenting was an independent predictor of good functional outcome at 6 and 12months (adjusted odds ratio [aOR] 4.3, confidence interval [CI] 1.49-12.31, P= 0.007) (aOR 3.5, CI 1.25-9.61, P= 0.017) and was associated with a lower rate of mortality at 3 and 6months follow-up (aOR 0.14, CI 0.04-0.57, P= 0.006 and aOR 0.296, CI 0.97-0.902, P= 0.032, respectively). Furthermore, smoking habit was associated with a better outcome at 3-month follow-up (aOR 10.7, CI 2.2-51.6, P= 0.003) but not at 6- and 12-month. Our research, conducted in a small sample size of patients with acute ischemic stroke due to TO of anterior circulation, found that acute stent placement seems to be safe, improving clinical outcome, and it is associated with low rate of mortality at long-term follow-up.

Intraoperative Normothermic Intraperitoneal Chemotherapy Following Optimal Cytoreduction in Advanced Ca Ovary: A Feasibility Study

Introduction: Extrapolating the results from the studies using HIPEC, EPIC and normothermic intraperitoneal chemotherapy, we proposed that normothermic chemotherapy instilled after optimal cytoreduction will improve survival in patients who underwent optimal cytoreduction. We undertook this feasibility study with the aim of studying the effectiveness of intraoperative normothermic intraperitoneal chemotherapy in patients with advanced-stage epithelial carcinoma ovary. Methods: This was a single institutional feasibility study. The primary objective was progression-free survival (PFS) following the instillation of normothermic chemotherapy following optimal cytoreduction in cases of advanced ovarian cancer after neoadjuvant chemotherapy. The secondary objective was to study tolerability and toxicity. The study received institutional ethical committee clearance. Results: A total of 24 patients were included in the pilot study over two years. The short-term analysis was made by comparing 45 patients who underwent interval cytoreductive surgery (ICS) with CC 0 and 1 during the same period. The most common side effect was prolonged post-operative ileus which was seen in six patients. The median PFS among patients who received IP chemotherapy was significantly better in comparison to patients who received ICS alone (34.0 vs. 13.0 months, p=0.018). Conclusion: Uniform state-of-the-art management of advanced epithelial ovarian cancer may not be accessible to all due to global resource limitations. Although the evidence is weak due to the small sample size and short follow-up of patients, the findings are encouraging. This feasibility study has provided substantial evidence to work further with this approach in our institute and plan an randomised controlled trial to gain more evidence.

An audit of the continuation and review of intensive care unit (ICU)-initiated medications post ICU discharge

Abstract Introduction Medication errors at transitions of care have widely been reported and the transition of a patient from intensive care unit (ICU) to ward level care has additional risk for error due to the complexity of the cohort. The continuation of ICU-initiated medications at ward level has been associated with adverse drug events, and error mitigation strategies need to be implemented at the point of discharge from ICU to facilitate deprescribing and medication optimisation. Pharmacists are in an excellent position to facilitate this medication optimisation at the point of ICU transfer. Aim This study aimed to evaluate the frequency that ICU-initiated medications are continued on discharge from ICU and subsequently reviewed at ward level in a large teaching hospital. Methods An audit was conducted as a prospective observational study over the period of June and July 2023. A pharmacist reviewed kardexes of patients that had been discharged from ICU to determine the prevalence of ICU-initiated medications that were continued post discharge. Medications continued were documented using an Excel spreadsheet on a password-protected computer. A pharmacist followed patients at day 7 post ICU discharge and an audit was conducted to document if these medications had been reviewed by primary teams. A medication was deemed to be reviewed by a primary team if discontinued on the kardex, a dose altered on the kardex or reference made to the medication in the medical notes. All patients discharged from ICU to ward level care were eligible to be included in the study. Results In total, 53 patients were eligible to be included in the study, of which 51 had ICU-initiated medications continued on discharge. No class of medication was found to be reviewed for all patients discharged on that class of medication. Over half of patients (52.9%) had stress ulcer prophylaxis medications continued, 39.2% had opioids continued and 33.3% had anti-delirium medications continued. No surgical patient had anti-delirium medications reviewed at ward level and surgical patients were found to be the largest cohort discharged on opioids but not reviewed at ward level. Conclusion This study has highlighted that not only are ICU-initiated mediations continued on discharge from ICU, but also that a high proportion of these medications are not reviewed at ward level by primary teams. This has further shown the requirement for pharmacist review and verification of kardexes prior to ICU discharge and the implementation of deprescribing protocols. The main limitation of the study was the small sample size of patients discharged from ICU during the study period. Future studies could focus on the impact that a pharmacist-led quality improvement initiative would have on the continuation and review of ICU-initiated medications on discharge from the ICU and the audit repeated over a longer period of time.

Therapeutic Effects of Intralesional Injection of Vitamin D3 in Treatment of Recalcitrant Warts: An Evaluator-Blinded Clinical Trial

Background: Viral warts are a prevalent infection that affects people all over the world. Unfortunately, there is no proven antiviral treatment for them. Recalcitrant warts are also difficult to resolve and deciding on a strategy for their treatment is challenging. Recently immunotherapy modalities have led to desired treatment outcomes in patients. This study investigated the efficacy of vitamin D injection (as an immunotherapeutic agent) in the treatment of recalcitrant warts. Methods: In this clinical trial study, 40 patients were divided into two groups: the first group (intervention group) received cryotherapy with an intralesional injection of vitamin D3 (0.1 cc of vitamin D3 (300000 IU/1mL) per lesion and a maximum of 0.5 cc per session), and the second group (control group) received just cryotherapy. In each treatment session, patients were evaluated for treatment responses and any side effects. Each patient received four treatment sessions at 2-week intervals. Results: After 4 treatment sessions, the rate of response in the intervention group and the group that received just cryotherapy was 95.33%±5.87 and 76.67%±25.14, respectively, and this difference was significant (P<0.01). Furthermore, 57% (26 out of 45) of the lesions in the intervention group were completely resolved after 4 sessions, and the rest showed a moderate response to this treatment. Moreover, the minimum response rate was 80% in the intervention group and 30% in the control group. Conclusion: In recalcitrant skin warts, intralesional injection of vitamin D3 combined with cryotherapy significantly increased the treatment response and reduced the financial burden imposed on patients. The limitation of this trial was the small sample size of patients without a follow-up plan after completing the treatment sessions. Trial registration: The Iranian Registry of Clinical Trials registered this study (identifier: IRCT20200513047434N1).

Recent advances in the adjunctive management of diabetic foot ulcer: Focus on noninvasive technologies.

Diabetic foot ulcer (DFU)is one of the most costly and serious complications of diabetes. Treatment of DFU is usually challenging and new approaches are required to improve the therapeutic efficiencies. This review aims to update new and upcoming adjunctive therapies with noninvasive characterization for DFU, focusing on bioactive dressings, bioengineered tissues, mesenchymal stem cell (MSC)based therapy, platelet and cytokine-based therapy, topical oxygen therapy, and some repurposed drugs such as hypoglycemic agents, blood pressure medications, phenytoin, vitamins, and magnesium. Although the mentioned therapies may contribute to the improvement of DFU to a certain extent, most of the evidence come from clinical trials with small sample size and inconsistent selections of DFU patients. Further studies with high design quality and adequate sample sizes are necessitated. In addition, no single approach would completely correct the complex pathogenesis of DFU. Reasonable selection and combination of these techniques should be considered.

Sphenoid sinus disease in geriatric patients: an analytical approach

The article presents an analytical approach based on intelligent statistical processing of different medical data to the diagnosis and treatment of sphenoid sinus diseases in elderly patients. With the increasing average lifespan and the widespread use of CT and MRI, the detectability of sphenoid sinus diseases is expected to increase, including among the elderly population. A retrospective analysis was conducted on patients who received treatment for sphenoid sinus diseases at the Otorhinolaryngology Clinic of the I.P. Pavlov St. Petersburg State Medical University. The study analyzed more than 50 patients with sphenoid sinus pathology, with 9.8% classified as elderly individuals aged 60 years or older. The most common symptom in elderly patients was headache, and surgical treatment was required in 80% of cases half due to the ineffectiveness of conservative therapy and another 40% due to the presence of formations in the sinus (mycetomas). The postoperative period continued without complications and the mean hospital stay was 7 days. Successful treatment of sphenoiditis in the elderly requires a comprehensive diagnosis and an individualized treatment plan. Endoscopic endonasal surgery of the sphenoid sinus can be safely performed in elderly patients with low anesthetic risks and a specialized surgical team. However, our research has limitations, including a small sample size of elderly patients with sphenoid sinus pathology. Future studies could explore factors such as comorbidities, hormonal changes, age-related influences, or lifestyle differences. Such an integrated approach will allow us to delve deeper into the intricacies of sphenoid sinus pathology in elderly patients.

Albumin-bilirubin score in non-malignant liver diseases should be properly validated.

The albumin-bilirubin (ALBI) score to assess the risk of decompensation in patients with initially compensated cirrhosis may improve their prognostic evaluation. This letter critically evaluates the research, which utilizes the ALBI score to forecast decompensation in cirrhosis patients over a three-year period. This score was initially developed to assess liver function in hepatocellular carcinoma, its prognostic utility for non-malignant liver diseases has now been explored, recognizing decompensation as a pivotal event that significantly affects patient's survival. Some concerns regarding the methodology of this research may be raised, particularly the exclusive use of radiological diagnosis, potentially including patients without definite cirrhosis and thus skewing the decompensation risk assessment. The reported predominance of variceal bleeding as a decompensating event conflicts with established literature, that often reports ascites as the initial decompensation manifestation. The letter highlights the absence of details on esophageal varices and their management, which could introduce bias in evaluating the ALBI score's predictive power. Furthermore, the letter points out the small sample size of patients with high-risk ALBI grades, potentially compromising the score's validity in this context. We suggest prospective future research to investigate the dynamic changes in the ALBI score over time to reinforce the validity of the ALBI score as a predictor of decompensation in non-malignant liver disease.

Atrial Septal Defect Device Closure in Patients with Metabolic or Genetic Diseases

Background: The coexistence of a metabolic or genetic disease can complicate the course of an atrial septal defect device closure. Methods: The database of our hospital was searched for patients who had undergone atrial septal defect (ASD) device closure and had concurrent metabolic and genetic diseases. Out of 188 such patients, 11 were identified. Results: This cohort study included 11 patients with type 1 diabetes mellitus, insulin resistance, mitochondrial diseases, rickets, Seckel syndrome, Alagille syndrome, cystic fibrosis, Down syndrome, and Crigler-Najjar syndrome type II. The patients were followed for a median of 4 years. Two patients experienced thromboembolic events. One procedure failed as the device was embolized. Large devices with a waist circumference greater than 1.5 times the body weight were used in 3 patients. One patient died 19 days after the procedure due to multi-organ failure, which was not related to device closure. Conclusions: In patients with metabolic or genetic diseases, this procedure may be complicated by factors such as small patient size, hypercoagulation, organ failure (cardiac, renal, or hepatic), vascular abnormalities, and issues with anesthesia or transesophageal echocardiography. It is recommended that careful attention be given to the specific challenges associated with each disease. The utilization of large devices can be considered safe, particularly in patients beyond 4 years of age.

Sequential Chemotherapy and Blinatumomab to Improve Minimal Residual Disease in Adult Ph- B-Lineage Acute Lymphoblastic Leukemia. Final Results of the Phase II Gimema LAL2317 Trial

Introduction. The outcome of adult patients with acute lymphoblastic leukemia (ALL) has markedly improved following the introduction of a pediatric inspired chemotherapy backbone coupled with minimal residual disease (MRD) monitoring at well-defined timepoints (TP), translating into a rational patients' stratification for allogeneic transplantation (Tx). Immunotherapy, in particular blinatumomab, represents a further advancement in the management of ALL. We designed a phase II trial (GIMEMA LAL2317) for adult Ph- CD19+ B-lineage ALL (Ph- B-ALL) consisting of a pediatric chemotherapy backbone - with dose adjustment in patients >55 years - to which 2 cycles of blinatumomab were added, the first after early consolidation cycle 3 (high-dose methotrexate and Ara-C) and the second after late consolidation cycle 6. Tx allocation was based on MRD assessment, carried out in most cases by RQ-PCR and by flow cytometry when a sensitive molecular marker was not identified. The primary objective of the trial was to assess the impact of blinatumomab in increasing the rate of early MRD negativity at end of week 14 (TP3). Patients and methods. The protocol was designed for adults up to the age of 65 years with newly diagnosed Ph- B-ALL; 149 patients were enrolled. Median age was 41 years (18-65), with 28 patients (19%) being older than 55. Eighty-one patients were males, and the median white blood count (WBC) was 4.5x10 9/l (1-474); 12 cases harbored the KMT2A rearrangement, 5 the TCF3:: PBX1 transcript and 31 were classified as Ph-like according to the BCR/ABL1-like predictor . The median follow-up is 37.5 months (0.55-62.8) Results. At the end of induction (TP1, after cycles 1 and 2), 131 patients (88%) were in complete remission (CR), with a significant difference according to age: 94%, 92% and 64% in the 18-40, 40.55 and >55 years cohorts, respectively (p<0.001). All patients with KMT2A and TCF3::PBX1 rearrangements achieved a CR, while 5 Ph-like patients did not. At TP2, i.e. after early consolidation, 85 patients (70%) became MRD-negative (MRD neg). TP3, after the 1 st blinatumomab cycle, 102 patients were MRD neg; the rate of MRD negativity increased to 93% (p<0.001). Imposable results were obtained considering only paired MRD samples. Eight patients remained MRD pos, including 4 with a KMT2A rearrangement and 1 with a E2A::PBX1 rearrangement. OS and DFS at 36 months are 71% and 66% on the whole cohort. OS was significantly different (p=0.00013) according to age cohorts: 76%, 74% and 49% for patients aged 18-40, 40-55 and >55 years, respectively. Likewise, DFS was 71%, 62% and 42% for the same age cohorts, without reaching statistical significance. When patients were stratified for TP2 MRD, OS and DFS were significantly better for MRD neg vs MRD pos cases (p=0.0006 and p<0.0001, respectively). At variance, at TP3, with the caveat of the small sample size of MRD pos patients, the differences between MRD neg and MRD pos patients at TP3 were abolished: indeed, OS and DFS were 82% and 68% for MRD neg, 80% and 70% for MRD pos and 88% and 72% for those lacking MRD evaluation (Figure). Finally, 30 relapses have so far occurred, including 10 Ph-like, 1 KMT2A and 3 TCF3::PBX1 rearranged cases. The overall cumulative incidence of relapse (CIR) was 27.5%; of note, within TP3 MRD neg patients CIR was 42.5% in Ph-like cases vs 17.5% in the remaining patients. By univariate analysis, significant factors for OS were age (p<0.001), CR achievement (p<0.001) and TP2 MRD (p=0.002); TP2 MRD retained significance in multivariate analysis (p=0.001). Univariate analysis for DFS showed as significant the Ph-like signature (p=0.026) and TP2 MRD (p<0.001); both retained statistical significance in multivariate analysis (p=0.021 and <0.001, respectively). Toxicity details will be provided. Conclusions. This phase II trial shows the benefit of adding blinatumomab for the management of Ph- B-ALL, with the primary objective being achieved with 93% of patients being MRD neg after the 1 st cycle of blinatumomab. With a median follow-up of 37.5 months, OS and DFS are 71% and 66%, respectively, better than in historical results, particularly in patients up to the age of 55. Importantly, at TP3 the MRD status no longer impacted, highlighting the therapeutic role of blinatumomab, as observed in Ph+ ALL. Finally, the Ph-like signature retains its negative prognostic impact, suggesting that a combination strategy, similar to that in place for Ph+ ALL, is required.

Exploration of Language As a Barrier to the Assessment and Management of CAR T-Cell Therapy Associated Toxicities

Introduction: Chimeric antigen receptor T-cell therapy (CAR T) is a novel therapy associated with a unique toxicity profile, namely cytokine release syndrome (CRS) occurring in (37-93%) of patients (pts) and immune effector cell associated neurotoxicity (ICANS) occurring in 23-67% of pts [Zahid, 2020]. Grading and management of these toxicities varies amongst institutions and patient populations. Furthermore, assessment of ICANS utilizes the Immune Effector Cell-Associated Encephalopathy (ICE) scoring system which includes 5-components that are dependent on a patient's English- speaking proficiency [Lee 2019]. We previously reported a higher-grade of neurotoxicity assessed in non-English speaking pts in a cohort of 127 pts at our institution [Melody, 2023]. We sought to confirm our previous findings by analyzing the impact of language spoken on the incidence, severity, and management including resource utilization for CAR T associated toxicities, in a larger multi-institutional cohort. Methods: We compiled retrospective data from 13 academic institutions for pts with aggressive B-cell lymphoma treated with CD-19 directed CAR T between 2015 through 2022. Baseline characteristics, lymphoma treatment, along with incidence, severity and management patterns of CRS and ICANS were compared between non-native English-speaking (NNES) and native-English speaking (ES) pts with Pearson Chi-squared test. OS was estimated via Kaplan-Meier method. Results: In a cohort of 582 pts treated with CAR T, 555 pts were ES and 27 were NNES pts; 17= Spanish, 3= Cantonese, 7= other (including Arabic, Burmese, Polish, Igbo, Japanese, Korean, & Mandarin). Demographic and clinical data for NNES and ES cohorts are included in Table 1. There was no difference in baseline disease characteristics between the two pt populations with the exception of younger pts and a higher proportion of women in the NNES group (p =0.02). Translator services were utilized for 20 (74%) of NNES pts at any point during CAR T-cell treatment. Two-thirds (66.7%) of NNES pts developed CRS (4=grade 0, 6= grade 1, 9= grade 2, 1= grade 3, 2 =grade 4, 5=Missing data) vs 55.5% of ES pts developed CRS (63=grade 0, 131= grade 1, 134= grade 2, 56= grade 3, 1 =grade 4, 1=grade 5, missing= 169), p < 0.001. For CRS management, there was no difference in the use of tocilizumab (48.1% vs 46.0%, p= 0.85) or escalation to ICU care (13.3% vs 10.1%, p= 0.66) for NNES vs ES groups, respectively. Thirty-seven percent of NNES pts developed ICANS (6=grade 0, 4= grade 1, 2= grade 2, 3= grade 3, 1=grade 4, 11=missing) compared with 39.8% of ES pts who developed ICANS (120=grade 0, 75= grade 1, 60= grade 2, 75= grade 3, 8= grade 4, 3= grade 5, missing= 241), p= 0.92. ICE scoring for ICANS assessment was recorded in 48% and 51% of NNES and ES pts, respectively. For management of ICANS, there was no difference in the use of steroids (51.9% vs 43.4%, p= 0.43), lamotrigine (61.5% vs 46.0%, p=0.39), or anakinra (10% vs 11.7%, p= 1.0) between NNES vs ES pts. There was no difference in escalation to ICU care for management of ICANS between groups (15.4% vs 19.1%, p=1.0). Neurology consults were obtained more frequently for NNES vs ES but this difference was not statistically significant (61.5% vs 40.5% respectively, p=0.16). Similarly, neuroimaging was obtained more frequently in NNES vs ES pts though not statistically significant (69.2% vs 53.4% respectively, p= 0.39). There was no difference between re-admission rates within 90 days post CAR T for NNES and ES pts (34.6% vs 26%, p = 0.36). With median follow-up of 35.3 mo (1.4-82.9), there was also no statistical difference in median overall survival of 17.8 mo in NNES pts compared to 28.9 mo in ES pts (p= 0.50; Figure 1). Conclusions: Despite our previous observations of increased severity of CRS and ICANS in NNES pts at our own institution, expansion to a larger multi-institutional cohort did not identify differences in occurrence, assessment, or management of toxicities between NNES and ES pts. Analyses were limited by small sample size of NNES patients and missing data for our patient cohort as a whole. This may be explained by decreased access to tertiary care for CAR T in NNES pts and highlights the lack of standardization in assessment and management of CRS/ICANS more globally. None-the-less, the assessment of language as a barrier to care warrants further exploration as does validation of current ICANS assessment tools in NNES pts.

Safety and efficacy of non-vitamin K antagonist oral anticoagulants compared to warfarin in patients with atrial fibrillation and end stage renal disease: a meta-analysis of randomized trials

Abstract Background Stroke prevention in patients with atrial fibrillation (AF) and end stage renal disease (ESRD) is difficult because of the lacking of high-quality evidence. Although there were few randomized trials comparing NOACs and warfarin in AF patients with ESRD, the small patient size prohibits these studies from making a conclusion. We aimed to perform a meta-analysis to evaluate currently available randomized trials in this special population. Methods We searched the literature for randomized clinical trials comparing NOAC to warfarin in AF patients with ESRD undergoing hemodialysis. Results A total of 3 randomized trials were identified from the literature (one for rivaroxaban [Valkyrie study] and two for apixaban [AXADIA-AFNET 8 and RENAL-AF]). About the principal efficacy outcome, NOACs did not decrease the risk compared to warfarin (relative risk [RR] 0.79, 95%CI 0.45-1.37) while a significant heterogeneity was noted (p = 0.03). In Valkyrie study, rivaroxaban had better efficacy outcome than warfarin (RR 0.57, 95%CI 0.43-0.75). For the safety outcome, the risk was similar between NOACs and warfarin (RR 0.81, 95%CI 0.52-1.27) without significant heterogeneity (p = 0.11)(Figure 1). The pooled event rate of 3 trials disclosed a high risk of all-cause mortality (39.9% for NOACs, 34.6% for warfarin) and cardiovascular mortality (10.1% for NOACs, 8.5% for warfarin) for AF patients with ESRD even on OACs (Figure 2). Conclusions This meta-analysis suggested that NOACs (rivaroxaban or apixaban) was at least as safe and effective as warfarin in AF patients with ESRD. Even on OACs, these patients remain at high risk of cardiovascular events and all-cause mortality. Integrated care and holistic management were important for this high-risk population.

Efficacy of Chemo-Free Combination Therapy with BRAF Inhibitor and Rituximab in Classic Hairy Cell Leukemia: Insights from the French Experience

Background: Hairy cell leukemia (HCL) is a rare form of leukemia. The introduction of purine analogs has revolutionized its prognosis, leading to a life expectancy closer to that of the general population. However, patients experience relapses and require other treatment options. The BRAF V600E mutation is present in 80-100% of patients with HCL, which has prompted the use of BRAF inhibitors (vemurafenib or dabrafenib) in this condition. Recently, the combination of vemurafenib with rituximab has shown efficacy with durable responses in relapsed patients. Here, we present, for the first time, real-life data on the combination of a BRAF inhibitor with rituximab through a retrospective study involving 9 French centers. Data collection was completed by July 1, 2023. Results: We collected data from 17 patients with a male-to-female ratio of 13:4; the median age was 69 years (38-90), and 6 patients were aged over 75. The median number of previous treatments was 4 (0-7), and 3 patients were treatment-naive because they were deemed ineligible for purine analogs based on age or performance status. All 14 relapsed patients had previously received purine analogs once or multiple times (1-3). The median progression-free survival (PFS) after purine analogs was 48 months, and the median PFS after the last line of therapy was 24 months. Five patients were exposed to moxetumumab pasudotox, and 3 patients received single-agent vemurafenib previously. The BRAF V600E mutation was tested and positive for 16 patients. In our cohort, 13 patients received a combination of vemurafenib with rituximab (V+R), and 4 patients received a combination of dabrafenib with rituximab (D+R). All patients received the same regimen (Tiacci, NEMJ 2021), which included an induction phase (V+R or D+R for 8 weeks) followed by rituximab consolidation (4 injections every 15 days), except for one patient who received a rituximab sequence followed by vemurafenib. At the time of analysis, 15 out of 17 patients had completed the treatment, and the remaining 2 had completed the induction phase. Fourteen patients initiated treatment at the standard dose (960 mg bid for vemurafenib and 150 mg bid for dabrafenib), and 3 patients at a reduced dose (240-480 mg bid for vemurafenib). Toxicity of any grade was reported in 15 out of 17 patients, with 3 of them experiencing grade 3-4 toxicity. Skin toxicity was the most frequent, recorded in 12 patients (grade 1-2), leading to temporary treatment interruption in 2 patients and dose reduction in 6 patients. Other toxicities included musculoskeletal, hepatic, hematological, and cardiac, with only one patient experiencing a grade 2 infection during treatment. No secondary cancers were reported during or after treatment. Treatment was discontinued due to toxicity in 5 patients, with 4 of them resuming treatment later. Eight patients required a dosage reduction, with a median final vemurafenib dosage of 480 mg bid. At the end of treatment, 14 patients achieved a complete hematological response, and 1 patient achieved a partial response. Among the 9 patients with early response data, the median time for platelet recovery was 15 days, and for neutrophil recovery, it was 14 days. End-of-treatment bone marrow aspiration and/or biopsy was performed for 8 patients, showing a complete response in 7 patients. With a median follow-up of 12 months (4-56), only 2 patients had progressed, and as of the last update, no patients had died, and the 2 relapsed patients achieved a complete response after a new line of therapy. Conclusion: Despite a limited median follow-up of 12 months, the combination of a BRAF inhibitor with rituximab proves to be an effective regimen in heavily treated patients with HCL, achieving a 100% overall response rate. Our study confirms a rapid hematological response and an acceptable toxicity profile, even in elderly patients. The most frequent toxicity observed was cutaneous toxicity, mainly grade 1-2, and it never led to a definitive treatment discontinuation. A comparison of the two BRAF inhibitors in terms of efficacy or toxicity cannot be established due to the small sample size of patients treated with dabrafenib. Lastly, the combination of rituximab with vemurafenib or dabrafenib appears to be an interesting option in frontline treatment for patients ineligible for purine analogs.

THU430 Post Discharge Treatment Practice And Outcomes Following Osteoporotic Hip Fracture - A Tertiary Care Center Experience

Abstract Disclosure: N. Vaghasia: None. Y. Yin: None. F. Hasan: None. Introduction: Osteoporosis remains significantly undertreated. Even after osteoporotic hip fracture most patients remain untreated. Patients who sustain hip fracture have significant morbidity like subsequent fractures, loss of functional independence and high rate of readmission to hospital and also have high rate of mortality in subsequent years compared to controls. The objective of our study is to understand treatment practice and outcomes following hip fracture at a tertiary care hospital. Methods: We did a retrospective study of patients admitted between January 2016 and June 2020 with hip fracture at two tertiary care academic hospital. We included patient above 40 years of age who and previously not treated for osteoporosis. We excluded patients with traumatic fracture, advanced renal disease and active malignancy. We collected demographics like age, sex and race. Other variables like admitting and discharging team, length of hospital stay, readmission and mortality rate, referral to specialty (Endocrinology/Rheumatology) on discharge, specialty follow up after discharge, treatment initiation after discharge, preadmission and postadmission DXA scan and polypharmacy (five or more daily prescription medication) were collected. The primary objective of the study was to see the differences in treatment practice of osteoporosis fracture based on follow up with specialist versus primary care physician. Secondary objective was to see differences in outcomes like readmission and mortality based on treatment initiation and follow up with specialist. Results: Among the 421 patients reviewed, 253 met inclusion criteria. Among them 70.2% (177) were above 70 years age; 70.8% (179) were female; 94.4% (239) were Caucasian; 3.6% (9) were given referral to specialist on discharge; 8% (20) followed with specialist; 69.1% (170) were on polypharmacy; 64.3% (159) had readmission within two years and 23.6% (58) died within two years of hip fracture. Patients followed by specialist had higher chances of being treated with osteoporosis medication (70% vs. 6.9%, p<0.0001) and having post fracture DXA scan (84.2% vs. 13%, p<0.0001). Following specialist had higher chances of being treated within six months of fracture (40% vs. 4.3%, p<0.0001). Among those presented with hip fracture only 22.8% of female ≥ 65 years and 4.2% of male ≥ 70 years had preadmission DXA scan. Patients treated after hip fracture had lower rate of readmission (56.7% vs. 65.4%) and mortality (10% vs. 25.1%) however did not reach statistical significance due to small sample size of overall patients treated. Conclusion: Our study suggest that osteoporotic hip fracture remains significantly untreated. Follow up with specialist increases one’s chance of being treated especially early on after the fracture. Our study also suggest that screening guidelines of getting DXA scan in both female and male is significantly neglected. Presentation: Thursday, June 15, 2023

Impact of Lymphopenia on Definitive Treatment of Locally Advanced Cervical Cancer

Pre-treatment lymphopenia prior to initiating treatment has been correlated with reduced survival in a number of different cancers. The purpose of this study is to evaluate the association between lymphopenia and survival in women with locally advanced cervical cancer (LACC) treated with primary chemoradiation (CRT). We retrospectively reviewed patients with LACC treated at a single institution from 2005 - 2021 with available lymphocyte information. Patient and treatment characteristics were recorded including age, tumor size and stage, EBRT dose/fractionation, and brachytherapy dosimetry data. Absolute lymphocyte counts (ALC) were collected prior to initiating CRT and at 3-month intervals following CRT and graded based on severity of lymphopenia using CTCAE v 5.0. Overall survival (OS), progression free survival (PFS), and local control (LC) were calculated from the start of treatment to date of last follow-up. Kaplan-Meier survival analysis was performed to evaluate whether lymphocyte changes were associated with OS, PFS, or LC. A total of 124 patients met study inclusion criteria with stage IB - IV disease (41 stage I, 41 stage II, 36 stage III, 6 stage IV) and a median follow up of 3.6 years (range 0.2-16.5 years). The median age was 49 years (range 26-77). The median EBRT dose was 45 Gy (range: 26-57.5 Gy) and 44.2% of patients received para-aortic (PA) nodal EBRT (28.8% elective and 15.4% with positive PA nodes). 5-year OS, PFS, and LC were 60.3% (95% CI 51.5-70.7), 47.5% (95% CI 39-58), and 75.5% (95% CI 67.3-82.9), respectively. Pre-treatment lymphopenia (ALC <1000 cells/mm3) was present in 11 (9%) patients. When the total cohort was divided into patients with and without pre-treatment lymphopenia, OS was statistically improved in the patients without baseline lymphopenia, with a 5-year OS of 63.2% (95% CI 53.9-73.9) versus 35.3% (95% CI 14.5-86.3) in the lymphopenia group (p = 0.034). LC also trended to being improved in the patients without lymphopenia, though this did not reach statistical significance in our small sample size of lymphopenic patients, with 5-year LC of 76.8% (95% CI 68.4-84.3) versus 67.5% (05% CI 36.6-93.8), p = 0.45. In this single institution experience of LACC treated with definitive CRT, we found that baseline lymphopenia is associated with inferior OS. Patients with higher pre-CRT ALC may represent a population with more robust immune systems, producing more favorable tumor responses to treatment. Additional studies are warranted to investigate the evolving role of combined EBRT and systemic therapy in LACC.

Acute and Late Toxicities in Patients with Collagen Vascular Disease Receiving Curative-Intent Intensity-Modulated Radiotherapy to the Head and Neck Region

Historically, collagen vascular disease (CVD) was considered at least a relative contraindication to radiotherapy (RT). However, more recent meta-analyses suggest that for patients with certain CVDs such as rheumatoid arthritis (RA), there may not be an increased risk for severe toxicities, while for patients with CVDs such as systemic lupus erythematosus (SLE), dermatomyositis (DM) and scleroderma, there may be as high as a 2- to 4-fold risk for severe toxicities compared to patients without CVD. There are also data to suggest that patients with head and neck cancer (HNC) and comorbid CVD are at especially high risk of severe toxicities from RT. This study evaluated the hypothesis that among patients with HNC treated with curative-intent intensity-modulated radiation therapy (IMRT), patients with SLE or DM were more likely to have had late grade ≥3 toxicity rates compared to patients with other CVDs. A total of 23 patients who had HNC with comorbid CVD and received IMRT between 2005-2022 were included. Acute (≤90 days after completion of RT) and late (>90 days) toxicities were retrospectively classified using CTCAE v5.0. Toxicity rates were compared across CVD groups using Chi-squared tests. Median follow-up was 56.3 months. The most common CVDs were RA (9 patients, 39%), SLE (4 patients, 17%), and DM (4 patients, 17%). Median total RT dose was 66 Gy (range: 48-70 Gy), in 1.8-2.4 Gy fractions. Nine (39%) patients received concurrent chemotherapy. 14 (61%) patients had mucosal squamous cell carcinoma (SCC), 3 (13%) had cutaneous SCC, 2 (9%) had nasal cavity/paranasal sinus tumors, 2 (9%) had salivary gland tumors, 1 (4%) had cutaneous melanoma, and 1 (4%) had mucosal melanoma. Eight (35%) patients experienced acute grade ≥3 toxicities, and 3 (13%) patients experienced late grade ≥3 toxicities (Table 1). No patients had grade≥4 toxicities. Patients with SLE or DM did not have significantly higher risk of late grade ≥3 toxicities compared to those with other CVDs (25% vs. 7%, p = 0.21). In this small sample size of patients with HNC and comorbid CVD, definitive or post-operative IMRT was associated with approximately 35% acute and 15% late severe toxicity rates. While SLE/DM were associated with >3-fold late grade ≥3 toxicities, this association needs to be confirmed with larger data sets.