Citations

Abstract Background Cyclin-dependent kinases (CDK) 4/6 inhibitors have significantly improved outcomes for patients with ER+/HER2− breast cancer. Nevertheless, they differ from each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. Methods We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing the prevalence of QTc prolongation as an adverse event in HR+ breast cancer patients treated with CDK4/6i vs those without CDK4/6i. We pooled relative risk (RR) and mean difference (MD) with 95% confidence interval (CI) for the binary endpoint of QT prolongation. Results We included 14 RCTs comprising 16 196 patients, of whom 8576 underwent therapy with CDK4/6i. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR = 2.35, 95% CI = 1.67 to 3.29, P < .001; I2 = 44%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a relative risk of 3.12 (95% CI = 2.09 to 4.65, P < .001; I2 = 12%), whereas the palbociclib subgroup had a relative risk of 1.51 (95% CI = 1.05 to 2.15, P = .025; I2 = 0%). Conclusion Palbociclib was associated with QTc prolongation; however, the relative risk for any grade QTc was quantitively twice with ribociclib. Furthermore, grade 3 QTc prolongations were observed exclusively with ribociclib. These results are important for guiding clinical decision-making and provide reassurance regarding the overall safety profile of this drug class.

AbstractThe challenge of disease relapsed/refractory (R/R) remains a therapeutic hurdle in chimeric antigen receptor (CAR) T‐cell therapy, especially for hematological diseases, with chronic lymphocytic leukemia (CLL) being particularly resistant to CD19 CAR T cells. Currently, there is no approved CAR T‐cell therapy for CLL patients. In this study, we aimed to address this unmet medical need by choosing the B‐cell activating factor receptor (BAFF‐R) as a promising target for CAR design against CLL. BAFF‐R is essential for B‐cell survival and is consistently expressed on CLL tumors. Our research discovered that BAFF‐R CAR T‐cell therapy exerted the cytotoxic effects on both CLL cell lines and primary B cells derived from CLL patients. In addition, the CAR T cells exhibited cytotoxicity against CD19‐knockout CLL cells that are resistant to CD19 CAR T therapy. Furthermore, we were able to generate BAFF‐R CAR T cells from small blood samples collected from CLL patients and then demonstrated the cytotoxic effects of these patient‐derived CAR T cells against autologous tumor cells. Given these promising results, BAFF‐R CAR T‐cell therapy has the potential to meet the long‐standing need for an effective treatment on CLL patients.

Background: Inferior Vena Cava (IVC) filters have become an advantageous treatment modality for patients with venous thromboembolism. As the use of these filters continues to grow, it is imperative for providers to appropriately educate patients in a comprehensive yet understandable manner. Likewise, generative artificial intelligence models are a growing tool in patient education, but there is little understanding of the readability of these tools on IVC filters. Methods: This study aimed to determine the Flesch Reading Ease (FRE), Flesch–Kincaid, and Gunning Fog readability of IVC Filter patient educational materials generated by these artificial intelligence models. Results: The ChatGPT cohort had the highest mean Gunning Fog score at 17.76 ± 1.62 and the lowest at 11.58 ± 1.55 among the Copilot cohort. The difference between groups for Flesch Reading Ease scores (p = 8.70408 × 10−8) was found to be statistically significant albeit with priori power found to be low at 0.392. Conclusions: The results of this study indicate that the answers generated by the Microsoft Copilot cohort offers a greater degree of readability compared to ChatGPT cohort regarding IVC filters. Nevertheless, the mean Flesch–Kincaid readability for both cohorts does not meet the recommended U.S. grade reading levels.

Abstract Background Delirium is a common complication of older people in hospitals, rehabilitation and long-term facilities. Objective To assess the worldwide use of validated delirium assessment tools and the presence of delirium management protocols. Design Secondary analysis of a worldwide one-day point prevalence study on World Delirium Awareness Day, 15 March 2023. Setting Cross-sectional online survey including hospitals, rehabilitation and long-term facilities. Methods Participating clinicians reported data on delirium, the presence of protocols, delirium assessments, delirium-awareness interventions, non-pharmacological and pharmacological interventions, and ward/unit-specific barriers. Results Data from 44 countries, 1664 wards/units and 36 048 patients were analysed. Validated delirium assessments were used in 66.7% (n = 1110) of wards/units, 18.6% (n = 310) used personal judgement or no assessment, and 10% (n = 166) used other assessment methods. A delirium management protocol was reported in 66.8% (n = 1094) of wards/units. The presence of protocols for delirium management varied across continents, ranging from 21.6% (on 21/97 wards/units) in Africa to 90.4% (235/260) in Australia, similar to the use of validated delirium assessments with 29.6% (29/98) in Africa to 93.5% (116/124) in North America. Wards/units with a delirium management protocol [n = 1094/1664, 66.8%] were more likely to use a validated delirium test than those without a protocol [odds ratio 6.97 (95% confidence interval 5.289–9.185)]. The presence of a delirium protocol increased the chances for valid delirium assessment and, likely, evidence-based interventions. Conclusion Wards/units that reported the presence of delirium management protocols had a higher probability of using validated delirium assessments tools to assess for delirium.

ObjectiveOur objective was to evaluate the effect of glucocorticoid regimens on renal response, infections, and mortality among patients with lupus nephritis (LN).MethodsWe performed a systematic review and meta‐analysis of the control arms of randomized clinical trials (RCTs). We included RCTs of biopsy‐proven LN that used a protocolized regimen of glucocorticoids in combination with mycophenolic acid analogs or cyclophosphamide and reported the outcomes of complete response (CR), serious infections, and death. The starting dosage of glucocorticoids, tapering method, and administration of glucocorticoid pulses were abstracted. Meta‐analysis of proportions, meta‐regression, and subgroup meta‐analysis were performed at 6 and 12 months for all outcomes.ResultsFifty RCT arms (3,231 patients with LN) were included. The predicted rates of CR, serious infections, and death when starting on oral prednisone at 25 mg/day without pulses were 19.5% (95% confidence interval [CI] 7.3–31.5), 3.2% (95% CI 2.4–4.0), and 0.2% (95% CI 0.0–0.4), respectively. Starting on prednisone at 60 mg/day (without pulses) increased the rates to 34.6% (95% CI 16.9–52.3), 12.1% (95% CI 9.3–14.9), and 2.7% (95% CI 0.0–5.3), respectively. Adding glucocorticoid pulses increased the rates of CR and death but not serious infections. We observed a dose–response gradient between the initial glucocorticoid dosage and all the outcomes at six months after accounting for the administration of glucocorticoid pulses, underlying immunosuppressant, and baseline proteinuria.ConclusionA higher exposure to glucocorticoids during the initial therapy of LN was associated with better renal outcomes at the cost of increased infections and death.

Abstract Context Low vitamin D status is common and is associated with various common medical conditions. Objective To support the development of the Endocrine Society's Clinical Practice Guideline on Vitamin D for the Prevention of Disease. Methods We searched multiple databases for studies that addressed 14 clinical questions prioritized by the guideline panel. Of the 14 questions, 10 clinical questions assessed the effect of vitamin D vs no vitamin D in the general population throughout the lifespan, during pregnancy, and in adults with prediabetes; 1 question assessed dosing; and 3 questions addressed screening with serum 25-hydroxyvitamin D (25[OH]D). The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess certainty of evidence. Results Electronic searches yielded 37 007 citations, from which we included 151 studies. In children and adolescents, low-certainty evidence suggested reduction in respiratory tract infections with empiric vitamin D. There was no significant effect on select outcomes in healthy adults aged 19 to 74 years with variable certainty of evidence. There was a very small reduction in mortality among adults older than 75 years with high certainty of evidence. In pregnant women, low-certainty evidence suggested possible benefit on various maternal, fetal, and neonatal outcomes. In adults with prediabetes, moderate certainty of evidence suggested reduction in the rate of progression to diabetes. Administration of high-dose intermittent vitamin D may increase falls, compared to lower-dose daily dosing. We did not identify trials on the benefits and harms of screening with serum 25(OH)D. Conclusion The evidence summarized in this systematic review addresses the benefits and harms of vitamin D for the prevention of disease. The guideline panel considered additional information about individuals’ and providers’ values and preferences and other important decisional and contextual factors to develop clinical recommendations.

Abstract Abstract Title: Real-world analysis comparing Black and White patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 Background: KEYNOTE-522 was a randomized, double-blind, placebo-controlled phase 3 trial which resulted in the FDA approval of pembrolizumab with neoadjuvant chemotherapy for patients with newly diagnosed, high-risk, early-stage triple-negative breast cancer (TNBC). Despite the significant improvement in pathological complete response (pCR) and event-free survival rates across all patients, the landmark trial included only 4.5% Black patients. It is essential to assess outcomes in representative treatment populations. We assessed real-world toxicity and treatment outcomes across Black and White patients who received standard-of-care treatment per KEYNOTE-522. Methods: In this retrospective, multicenter study, we examined patients with early-stage TNBC who received planned treatment per KEYNOTE-522 as standard-of-care (SOC) therapy. 16 sites were included in the analysis. IRB approval was obtained from each participating site. Number and length of treatment delays, treatment-related toxicities (both chemotherapy and immune-related) of all grades, and pCR rate were collected from the electronic medical record of each participating site, and deidentified data were shared for central analysis. Results: Of the 577 patients who initiated treatment with chemotherapy and immunotherapy, 534 patients were included in this analysis with 105 patients who self-identified as Black (19.7%) and 429 who self-identified as White (80.3%). There were no statistically significant differences in clinical and pathological characteristics between the two groups. White women were more likely to have grade 3+ immune-related adverse events (irAEs) compared to Black women (33.8% vs 20.9%, P=0.011). There was no significant difference across Black and White patients with respect to grade 3+ chemotherapy-related adverse events. Out of the 444 patients who have completed surgery, no difference in pCR rate was observed between Black and White women (45/86 52.3% vs 200/358 55.9%) (p = 0.6). The authors also saw no difference in the rates of hospitalizations between Black and White women (39% vs 36% p = 0.5), and rates of acute care utilization (38% vs 38% p = 0.9). Conclusions: We report safety and efficacy across Black and White women in a real-world analysis of patients who received treatment per KEYNOTE-522. Notably, White patients had a significantly higher frequency of grade 3+ irAEs, although the reason for this finding is unclear based on this analysis. Black patients had similar pCR rates and rates of treatment-related hospitalizations compared to White patients. Assessment of outcomes and toxicity by race in clinical trials and real-world analyses are critical in drug development. Citation Format: Mara Hofherr, Andrew Davis, Spenser January, Emily Owen, Farah Raheem, Lida A. Mina, Suganya Arunachalam Karikalan, Lauren Lyons, Meredith Watson Rose, Katherine Madden, Jerline Hsin, Aimee Keegan, Wai Yu, Shawna Kraft, Allison Schepers, Emily Armgardt, Douglas Mazewski, Alison Svoboda, Kayla Harwood, Jodi Taraba, Yonatan Resnick, Shelly Hummert, Lisa Grate, Sidney Keisner, Jacob Hobbs, Todd Davis, Kristin Bastian, Dawn Minikel, Wiliam Adler, Traci White, Avneek Singh Sandu, Fouad Boulbol, Kelsey Finch, Katherine Clifton. Real-world analysis comparing Black and White patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 [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 PS14-02.

Abstract Title: Real-world analysis of adverse events in patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 Background: KEYNOTE-522 was a randomized, double-blind, placebo-controlled phase 3 trial which resulted in the FDA approval of pembrolizumab with neoadjuvant chemotherapy for patients (pts) with newly diagnosed, high-risk, early-stage triple-negative breast cancer (TNBC). Given the improvement in pathological complete response (pCR) and event-free survival rates, this regimen has emerged as standard-of-care (SOC) therapy. To date, real world outcome analyses are limited. Methods: In this retrospective, multicenter study, we examined pts with early-stage TNBC who received planned treatment per KEYNOTE-522 as SOC. 16 sites were included in the analysis. IRB approval was obtained from each participating site. Number and length of treatment delays, treatment related toxicities (both chemotherapy and immune-related) of all grades, and pCR rate were collected from the electronic medical record of each participating site, and deidentified data were shared for central analysis. Results: 577 pts were included in this analysis. The median age of the cohort was 52 [range 27-77]. 457 pts had T1-2 disease and 139 had T3-4 disease. 316 pts had N0 disease and 261 had N1-3 disease. 506 pts had baseline ECOG 0, 62 had ECOG 1, and 9 had ECOG 2-3. Of the 482 patients who had surgery at the time of this analysis, 219 patients had pCR (54.5%) and 192 pts were still receiving treatment. 217 patients (37%) had an adverse drug event (ADE) causing dose reductions and 228 patients (39.5%) had to discontinue treatment early. There were 360 unplanned care visits, with 91 patients having 2+ visits. 66 patients had hospitalizations due to the regimen with 102 total hospitalizations. 179 (31%) of patients had grade 3+ immune related adverse events (irAEs), including many that are rare and potentially serious. 317 (54%) had an immune related adverse effect (see Table 1). There was no significant difference in the frequency of grade 3+ irAE based on age or body mass index. We observed no difference in residual disease between patients who discontinued treatment early and those who did not. However, if patients had an ADR causing a dose reduction, pts were significantly more likely to have residual disease (P=0.039) Conclusions: In a multicenter real-world analysis, the KEYNOTE-522 regimen was associated with a high frequency of dose reductions, early treatment discontinuations, ER visits, and hospitalizations. This may have accounted for a lower pCR rate than observed in the landmark clinical trial. Most grade 3+ irAEs occurred at greater frequency in our real-world analysis. Providers should carefully monitor for toxicity to ensure optimal patient outcomes. Table 1 Citation Format: Mara Hofherr, Katherine Clifton, Spenser January, Emily Owen, Farah Raheem, Lida A. Mina, Suganya Arunachalam Karikalan, Lauren Lyons, Meredith Watson Rose, Katherine Madden, Jerline Hsin, Aimee Keegan, Wai Yu, Shawna Kraft, Allison Schepers, Emily Armgardt, Douglas Mazewski, Alison Svoboda, Kayla Harwood, Jodi Taraba, Yonatan Resnick, Shelly Hummert, Lisa Grate, Sidney Keisner, Jacob Hobbs, Todd Davis, Kristin Bastian, Dawn Minikel, Traci White, William Adler, Avneek Singh Sandu, Fouad Boulbol, Kelsey Finch, Andrew Davis. Real-World Analysis of Adverse Events in Patients with Triple Negative Breast Cancer Receiving Therapy per KEYNOTE-522 [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 PS14-06.