Citations

Introduction: Teclistamab (TEC) is a bispecific BCMA-CD3 directed T-cell antibody (BsAb), recently approved by EMA and FDA. Approval was based on the MajesTEC-1 study showing high overall response rates (≥PR in 63.0%) in heavily pretreated patients with relapsed multiple myeloma (RRMM). Few reports have described Real-World experience despite that TEC can induce unique side effects including cytokine release syndrome (CRS), neurotoxicity (ICANS) and a high incidence of infection (MajesTEC-1: incidence 76.4%; ≥Gr3: 44.8%). Thus, we performed a Real-World analysis of TEC therapy from 7 International Myeloma Foundation (IMF) associated MM academic centers. Methods: Patients treated with standard-of-care TEC were included. Data was collected until 7/28/2023. Results: 103 pts were included; median age 63 (range 33-91y); 15 pts. (14.5%) >75 yrs; 56.5% were male, 71.8% Caucasian, 11.6% Hispanic, and 12.6% Asian. Pts received a median of 6 PLT (range 1-16); 75% were triple-class-refractory (n=41/52 (79%), 30/85 (35%) had high-risk cytogenetics/FISH and 32/80 (40%) had 1q21 gain. At least 57/76 (75%) of pts would not have been eligible for MajesTEC-1 (mostly from prior BCMA (n=28 CAR-T, n=14 ADC; n=3 BsAb; n=5 CAR-T+ADC). 14 pts had CrCl <30ml/min with 2 on HD. Median number of hospital days was 8 (n= 72) but 31 patients were treated entirely as outpatients (Mayo clinic (MN, AZ, FL)). CRS was seen in 52 (50.4%) (all grade 1: except 6 Gr2, 1 Gr4), generally resolved within 24 hrs and was managed with tocilizumab alone (n= 27) or dex alone (n=9) or dex+toci (n=12). CRS was more common with inpatient (56.9%) vs outpatient (35.4%) TEC Rx. CrCl <30 ml, did not appear to alter the incidence or severity of CRS (50%; 1 Gr4). ICANS was infrequent (n=5; 4.85%), 1 pt with Gr 4-Sz requiring HD-steroids and TEC discontinuation). Infections were common, seen in 54 (52.4%) of patients, the majority were viral URI or CMV reactivation (n=26; 3 pts receiving CMV Rx, 1 pt with CMV organ disease). IVIG was given in 43/67 (64%) pts. The overall response rate for evaluable patients (n=82) was 63%; (sCR/CR 14; VGPR 23; PR 15; MR 2, SD 14; PD 14). In evaluable pts treated with prior BCMA (n=43), the ORR was 53% (sCR/CR 4; VGPR 14; PR 5; 1 MR; SD 10; PD 9). The most common reason for treatment discontinuation was PD (26.2%). 14 pts have died by the time of data cut-off (7/28/23), with the most common cause of death being disease progression. Conclusions: In this Real-World evaluation of TEC, a high ORR was seen, similar to the MajesTEC-1 study. Responses were rapid and are expected to deepen over time (median f/u 5m). CRS rates were similar to MajesTEC-1 and no new toxicity signal was noted. The rates of infection appear low but may be related to short follow-up. Details regarding the incidence and types of infection and the global use of IVIG will be described. With longer follow-up, additional efficacy/toxicity data will be presented.

Abstract Background: Much has been published about barriers to research participation for under-represented minority (URM) yet we know little about the experiences, motivations, and decision-making of the URM patients who were successfully treated on clinical trial (CT). The purpose of this study is to draw on the experiences of URM patients as insiders of practical knowledge of CT through photo elicitation to comprehensively understand the current state of recruitment and treatment of URM patients on interventional cancer CTs across the Mayo Clinic enterprise with a short-term goal of informing mechanisms to enrich CT participation and a long-term goal of building a patient-centered cancer practice and clinical trial patient population that is reflective of the diverse communities served by Mayo Clinic. Method: An Appreciative inquiry approach was adapted for this study which acknowledges that existing strengths and everyday experiences of URM patients has the potential to allow a more nuanced view as it pertains to our cancer populations. A total of 138 URM were invited to participate. Using photo elicitation technique, patients were asked to take photographs to portray factors that motivated them and/or facilitated their enrollment, barriers to enrollment and recommendations to improve the process for CT recruitment for other URM. Participant-generated photographs (59) and accompanying 13 interview narratives were analyzed using layered analysis. Results: A total of 13 patients (female =9) participated in the photo interviews. URM detailed their overall experiences around CT participation, motivations for participating in clinical trials; facilitators to clinical trial participation; and opportunities and considerations for increasing minority patients CT participation. Photo analyses provided symbolic representation of patients’ general experiences around CT including celebrating their “new identity”, finding peace in moments of nostalgia, their journey through the trial, lost times and finances and yet finding a new purpose to live through CT participation. Importantly patients described decision making in CT participation as a relational approach. Patients suggested opportunities and considerations for increasing minority patients trial participation, which included minimizing logistical barriers, decentralizing cancer clinical trials, increasing awareness via patient narratives, diversifying research staff, minimizing cost, and being clear on purpose and benefit of the trial. Conclusion: Our study highlights the potential to utilize visual data and narratives from URM in CT recruitment and education programming. It provided valuable insights from the URM community for the URM community on key issues on motivations of CT participation and decision-making in CT participation. Citation Format: Gladys B. Asiedu, Rahma Warsame, Mary O’Shea, Yong-hun Kim, Sara A. Ellingson, Katharine A. Price. Trial participation in pictures: Using photo elicitation to explore minority patients’ experiences on therapeutic cancer clinical trials [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A076.

The scarcity of liver grafts has prompted developments in living donor liver transplantations (LDLT), with previous literature illustrating similar outcomes in recipients compared to deceased donor transplants. However, significant concerns regarding living donor morbidity and mortality have yet to be examined comprehensively. This study aims to provide estimates of the incidence of various outcomes in living liver donors. In this meta-analysis, Medline and Embase were searched from inception to July 2022 for articles assessing the incidence of outcomes in LDLT donors. Complications in the included studies were classified into respective organ systems. Analysis of incidence was conducted using a generalized linear mixed model with Clopper-Pearson intervals. Eighty-seven articles involving 60,829 living liver donors were included. The overall pooled incidence of complications in LDLT donors was 24.7% (CI: 21.6%–28.1%). The incidence of minor complications was 17.3% (CI: 14.7%–20.3%), while the incidence of major complications was lower at 5.5% (CI: 4.5%–6.7%). The overall incidence of donor mortality was 0.06% (CI: 0.0%–0.1%) in 49,027 individuals. Psychological complications (7.6%, CI: 4.9%–11.5%) were the most common among LDLT donors, followed by wound-related (5.2%, CI: 4.4%–6.2%) and respiratory complications (4.9%, CI: 3.8%–6.3%). Conversely, cardiovascular complications had the lowest incidence among the subgroups at 0.8% (CI: 0.4%–1.3%). This study presents the incidence of post-LDLT outcomes in living liver donors, illustrating significant psychological, wound-related, and respiratory complications. While significant advancements in recent decades have contributed towards decreased morbidity in living donors, our findings call for targeted measures and continued efforts to ensure the safety and quality of life of liver donors post-LDLT.

Pontocerebellar hypoplasia (PCH) is a group of rare neurodevelopmental disorders with limited diagnostic and therapeutic options. Mutations in WDR11, a subunit of the FAM91A1 complex, have been found in patients with PCH-like symptoms; however, definitive evidence that the mutations are causal is still lacking. Here, we show that depletion of FAM91A1 results in developmental defects in zebrafish similar to that of TBC1D23, an established PCH gene. FAM91A1 and TBC1D23 directly interact with each other and cooperate to regulate endosome-to-Golgi trafficking of KIAA0319L, a protein known to regulate axonal growth. Crystal structure of the FAM91A1–TBC1D23 complex reveals that TBC1D23 binds to a conserved surface on FAM91A1 by assuming a Z-shaped conformation. More importantly, the interaction between FAM91A1 and TBC1D23 can be used to predict the risk of certain TBC1D23-associated mutations to PCH. Collectively, our study provides a molecular basis for the interaction between TBC1D23 and FAM91A1 and suggests that disrupted endosomal trafficking underlies multiple PCH subtypes.

Abstract Introduction: First pass effect (FPE), achievement of complete recanalization (mTICI 2c/3) with a single pass, is a significant predictor of favorable outcomes for endovascular treatment (EVT) in large vessel occlusion stroke (LVO). However, data concerning the impact on functional outcomes and predictors of FPE in medium vessel occlusions (MeVO) are scarce. Patients and Methods: We conducted an international retrospective study on MeVO cases. Multivariable logistic modeling was used to establish independent predictors of FPE. Clinical and safety outcomes were compared between the two study groups (FPE vs non-FPE) using logistic regression models. Good outcome was defined as modified Rankin Scale 0–2 at 3 months. Results: Eight hundred thirty-six patients with a final mTICI ⩾ 2b were included in this analysis. FPE was observed in 302 patients (36.1%). In multivariable analysis, hypertension (aOR 1.55, 95% CI 1.10–2.20) and lower baseline NIHSS score (aOR 0.95, 95% CI 0.93–0.97) were independently associated with an FPE. Good outcomes were more common in the FPE versus non-FPE group (72.8% vs 52.8%), and FPE was independently associated with favorable outcome (aOR 2.20, 95% CI 1.59–3.05). 90-day mortality and intracranial hemorrhage (ICH) were significantly lower in the FPE group, 0.43 (95% CI, 0.25–0.72) and 0.55 (95% CI, 0.39–0.77), respectively. Conclusion: Over 2/3 of patients with MeVOs and FPE in our cohort had a favorable outcome at 90 days. FPE is independently associated with favorable outcomes, it may reduce the risk of any intracranial hemorrhage, and 3-month mortality.

Abstract Introduction . Dispersion in an accelerator quantifies the deviation of the proton trajectory when there is a momentum deviation. We present for the first time a safe method of measuring dispersion in the clinic, using a scintillator detector and the momentum deviations within a spill. This is an important accelerator quantity as we found that this is the reason behind the large dose fluctuation in our absolute dosimetry measurement. Methods . Dispersions are measured for nine energies in a Hitachi ProBeat system at three locations (isocenter and at two profile monitors) and at two gantry angles (0 and 90 degrees) by first measuring the spot position and momentum drift within a spill. The spot position drift is measured by the XRV-4000 at the isocenter, and by the two profile monitors located at 0.57 and 2.27 m from the isocenter. The momentum drift is calculated from the intra-spill range drift which is measured using the Ranger accessory. The dispersion at isocenter and its gradient are calculated using the weighted least square regression on the measured dispersions at the three locations. A constraint is formulated on the dispersion and its gradient to ensure minimal intra-spill spot position deviation around the isocenter. Results . The measured intra-spill range and spot positional drift at isocenter are less than 0.25 mm and 0.7 mm respectively. The momentum spread calculated from the range drift are less than 0.08%. The dispersion at the isocenter ranged from 0.50 to 4.30 m and the zero-crossing happens upstream of isocenter for all energies. 2 of the 9 energies (168.0 and 187.5 MeV) violated the constraint and has an intra-spill spot positional deviation greater than 1.0 within 5 cm from the isocenter. Conclusion . This measurement is recommended as part of commissioning and annual quality assurance for accelerator monitoring and to ensure intra-spill spot deviations remain low.

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross‐sectional and prospective association analyses of blood‐derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole‐genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1‐SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04–1.12; P <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P =0.11) or in the reverse direction (β=−0.012; P =0.076). Additional bidirectional Mendelian randomization analyses revealed that low‐density lipoprotein cholesterol had a causal effect on mtDNA CN (β=−0.084; P <0.001), but the reverse direction was not significant ( P =0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low‐density lipoprotein cholesterol level ( P =0.52), whereas there was a strong direct causal effect of higher low‐density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=−0.092; P <0.001). Conclusions Our findings indicate that high low‐density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

PURPOSE CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication. PATIENTS AND METHODS Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti–CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts). RESULTS Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, –1.5 to 4.4; all-pts) and 1.4% (95% CI, –1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup. CONCLUSION In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.