Landmark Study Research Articles

Abstract B017: Single-cell proteogenomic profiling reveals immune cell networks in renal cell carcinoma

Abstract Introduction: Single-cell proteogenomic profiling has enabled the interrogation of complex milieus of cell types and their corresponding states that interact to regulate the antitumor immune response. While several landmark studies employing single-cell RNA sequencing (scRNAseq) have provided a detailed taxonomy of lymphoid and myeloid phenotypic states within the renal cell carcinoma (RCC) microenvironment, these studies have only been performed on small patient cohorts. As such, the ability to infer coordinated interactions between cellular phenotypes remains limited. Here, we leverage single-cell proteogenomic approaches to map immune cell phenotype co-occurrences across a heterogeneous patient cohort. Experimental procedures: We performed 5’ scRNAseq on 75 dissociated tumor samples from 59 patients undergoing partial or radical nephrectomy using the 10X genomics platform. Paired single-cell TCR/BCR sequencing (scTCR/BCRseq) and cytometry by time-of-flight (CyTOF) were additionally performed on 64 and 48 samples, respectively. Results: scRNAseq captured a total of ~350,000 high quality cells of RCC, stromal and immune (myeloid and lymphoid) origin, across a range of histologies (clear cell 69%, papillary 11%, chromophobe 13%, other 8%) and stages (I 53% II 7%, III 31%, IV 9%), with proportions of major cell types being consistent between scRNAseq and CyTOF. Interestingly, paired scTCRseq revealed a subset of patients (~40%) that displayed intratumoral clonally hyperexpanded TCRs (> 100 copies/clone), with CD8+ cells expressing an exhausted phenotype being most dominant. These samples were also co-enriched for CXCL13+ CD8+ T cells as well as proinflammatory CXCL9/10+ macrophages, a relationship we confirmed upon calculating pairwise correlations between all immune cell phenotype proportions across all samples. Notably, RCC cells from these samples expressed an antigen presentation meta-program identified by non-negative matrix factorization and pathway analysis. A “pro-inflammatory” cell network gene signature was derived and employed across the clear cell RCC (KIRC) cohort of TCGA and IMMotion 151 data sets, to reveal pro-inflammatory enriched RCCs displayed worse survival yet improved response to immunotherapy-based regimens, respectively. Conclusions: Our study provides the largest single-cell proteogenomic characterization of RCC to date, detailing co-occurring immune cell phenotypes across heterogenous patient tumor microenvironments. We leveraged this data to characterize a pro-inflammatory immune cell ecotype of RCC with potential prognostic and predictive implications that warrant further validation. Overall, this data should serve as a fundamental resource for future work developing novel therapeutic strategies and biomarkers against RCC. Citation Format: Keith A Lawson, Shirley Hui, Daniel Stueckmann, Xiaoyu Zhang, Jalna Meens, Lisa Martin, Maria Komisarenko, Julia Szusz, Stephane Chevrier, Sujana Sivapatham, Philip Jonsson, Fred Davis, Cristina Penaranda, Ryan Newton, Nicolas Stransky, Piotr Bielecki, Zhihui Liu, Jennifer Pfeil, Sarah Crome, Dominik Deniffel, Masoom Haider, Jason Lee, Neil Fleshner, Nathan Perlis, Robert Hamilton, Girish Kulkarni, Susan Prendeville, Hartland Jackson, Laurie Ailles, Gromoslaw Smolen, Bernd Bodenmiller, Gary Bader, Antonio Finelli. Single-cell proteogenomic profiling reveals immune cell networks in renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B017.

The Roots of Social Trauma: Collective, Cultural Pain and Its Consequences

Since Kai Erikson’s landmark study of the devastation of five communities in West Virginia, sociology has leveraged the concept of trauma to describe certain social phenomena. Collective trauma came to refer to the destruction of social infrastructure and the ensuing negative mental health outcomes, while cultural trauma has come to describe the imposition of historical and ongoing attacks by a dominant group on the culture (broadly defined) of a group of people sharing a collective identity. The following article sketches out a theory of social trauma designed to bring these two types of sociological trauma together, highlight their similarities and differences, and unite them by grounding them in the neuroscience of (social) pain. The term trauma, borrowed from medical and psychological study, implies pain, but the sociological version of trauma is best understood as the collectivization and enculturation of social pain, or the evolved negative affective response to separation, rejection, exclusion, and isolation from cherished social objects including statuses. The article concludes by modeling the process by which an event transforms individual social pain into collective social trauma as well as the pathways through which social trauma becomes enculturated in a collective identity. Implications for the sociology of mental health follow.

Senescent Immune Signature in Frail and Vulnerable Newly Diagnosed Myeloma Patients: A Cohort Analysis from the UK-MRA Myeloma XIV Fitness Study

Introduction Physical frailty is a key factor driving treatment tolerability and outcome in multiple myeloma (MM). There is a close interplay between physiological aging, frailty and immune dysfunction, with the presence of a malignant disease overlay adding an additional dimension to the host response biology. The UKMRA Myeloma XIV FiTNEss study is the first phase 3 randomised clinical trial to explore the utilisation of frailty assessment as a tool to guide and optimise treatment decision making and deliverability. Here we report on the relationship between physical frailty and T cell dysfunction in a cohort of patients within this landmark study. Methods Multiparameter flow cytometry was used to assess the baseline T cell phenotype in the peripheral blood of 49 participants with NDMM receiving treatment within FiTNEss. Patients were assessed for frailty using the IMWG frailty score and additionally assessed for clinical vulnerability using the UKMRA MRP score (Cook et al, Lancet Haematol. 2019). The IMWG frailty score combines activities of daily living assessment and co-morbidity burden with age to generate a validated, prognostic frailty score. The UKMRA MRP is a risk profile which uses routinely collected clinical data including age, WHO performance status, ISS stage and CRP to define prognostic risk categories with the high-risk category encompassing frailer individuals. Normal T cell subsets were assessed based on CD45RA and CD28 phenotype while dysfunctional subsets (exhausted and senescent) were defined using CD28 and KLRG1. Results The median age of participants was 79 (range 68-90) and 55% were male. The distribution by IMWG was fit 18%, unfit 33%, frail 49% and by MRP was low risk 31%, intermediate risk 28%, high risk 38%. Absolute lymphocyte count (ALC) decreased with increasing frailty (p=0.02), with no patients classified as fit by IMWG or low risk by MRP criteria having a lymphocyte count below the lower limit of normal. No relationship was seen between ALC and age. The ratio remained stable across the IMWG cohorts, suggesting a global reduction in lymphocyte subsets. An accumulation of CD8 TEMRA cells was seen in the MRP high risk cohort (p=0.0085). No differences were seen between cohorts based on the IMWG frailty score. The accumulation of CD8 TEMRA cells indicates a loss of T cell differentiation plasticity and is associated with a cytotoxic and pro-inflammatory immune response. CD4 dysfunctional subsets were comparable across the cohorts. CD8 dysfunctional subsets were most marked in the frail and high-risk cohorts. The MRP high-risk cohort had a skewed ratio of exhausted to senescent cells (p=0.02), with a reduction in CD8 exhausted populations compared to the fit and unfit cohorts (p=0.0477) and a trend towards increased senescent cell burden (p=0.07). This was echoed within the IMWG frail cohort where elevated numbers of senescent CD8 cells were identified (p=0.02). No relationship was seen between CD8 senescent burden and age, CRP, ISS or WHO PS when each variable was assessed independently, suggesting that the presence of this immune population is not directly related to disease burden or physiological aging alone, but reflects a more complex interplay between host response biology and disease characteristics. Principal component analysis demonstrated a high degree of immunological heterogeneity within the MRP low and intermediate risks cohorts, while the high-risk cohort had a more uniform immunological profile (Figure 1A). Significant overlap between a proportion of the non-high-risk cohorts and high-risk cohorts was seen and requires further exploration. A multi-variable correlation analysis identified correlations between the CD4:8 ratio and CD8 cell senescent burden, MRP and ISS, highlighting the important interplay between immunological dysfunction, clinical vulnerability and disease burden (Figure 1B). Conclusion The T cell immunological landscape of the most vulnerable patient populations with newly diagnosed MM is characterised by an accumulation of senescent CD8 T cells which cannot be attributed to age or disease burden alone. Immune senescence is known to be associated with a chronic inflammatory state which may drive the acquisition of the physiological changes, such as sarcopenia, which characterise a frailty phenotype. This provides an opportunity for targeted intervention to address the biological drivers of disease related frailty.

A review of CONCEPTT study findings including subanalyses in pregnant women using continuous glucose monitoring with type 1 diabetes and their offspring.

The main objective of this article is to provide a comprehensive review of continuous glucose monitor (CGM) use in pregnant women with type 1 diabetes (T1D) from the CONCEPTT study including subanalyses. Literature search was accessed through MEDLINE (1966-September 2023) using the key terms: CONCEPTT, pregnancy, women, T1D, and CGM with limitations set to distinguish human subjects written in English. A total of 17 publications including one main clinical trial and 15 subanalyses have been published to date regarding the use of CGM in pregnant women with T1D which were conducted by a research group identified as the CONCEPTT Collaborative Group. While advances in maternal care have resulted in safer pregnancy for both the mother and child, women with preexisting T1D and pregnancy still experience higher rates of complications both in the short and long term. The use of CGM in pregnancy has not been studied extensively until more recently. The CONCEPTT clinical trial was a landmark study that involved several subanalyses. The main trial proved that CGM use in T1D pregnancy resulted in less hyperglycemia in the third trimester, reduced large for gestational age (LGA, >90th percentile), reduced neonatal intensive care unit admissions lasting longer than 24 h, and reduced neonatal hypoglycemia. Although subanalyses showed a variety of results including 'inconclusive' due to lack of prespecification, it is believed that CGM in T1D during pregnancy is to be recommended and used for overall improved outcomes.

Lessons Learned from Landmark Studies in Glaucoma

Background: Glaucoma is a disease characterized by progressive optic neuropathy that can be caused by a variety of etiologies, including both primary and secondary mechanisms, with the main modifiable risk factor being high intraocular pressure (IOP). Visual field defects, along with structural and functional changes, are typically seen. It is one of the leading causes of blindness worldwide, and as the proportion of those over age 40 increases, so will the prevalence of glaucoma.Purpose: This article aims to provide a brief review of the important early glaucoma studies with abundant evidence and thus guide us in our management decisions.Methods: We reviewed diagnostic criteria used by landmark glaucoma clinical trials, which were prospective, multicenter, masked, randomized control trials. We included trials that were concerned mainly with open-angle glaucoma.Result and conclusion: Landmark studies have demonstrated that lowering IOP is of benefit in preventing the onset of glaucoma in ocular hypertension and in reducing disease progression in eyes with primary open-angle glaucoma (POAG) but do not suggest that the degree of protection is related to the degree of IOP reduction.

Adjudicated Adolescents Located on a State Sex Offender Registry Website as Adults: Common Denominators

ABSTRACT This is a landmark study, the first to use a listing on a state sex offender registry website as a predictive variable for tracking adult recidivism of male adolescents adjudicated for sex offenses, and the longest to follow a cohort of these youth after discharge from a secure residential treatment program. Upon admission, the sample (N = 145) were assessed by JSORRAT-II and MEGA ♪ , two contemporary standardized, validated risk assessment tools for assessing youth who have engaged in sexually abusive behavior. They were then followed once discharged for 17.08 years into adulthood (mean follow-up = 14.0 years, SD = 1.71). Recidivism rate was 6.2% (defined as a listing for the subject on the California Megan’s Law Sex Offender Registry Website). The study offers a baseline for future studies that use a state sex offender registry website as a predictive variable for recidivism. Shared common denominators of recidivists and non-recidivists were risk level (i.e. most were High Risk or Very High Risk on MEGA ♪ ); and having a history of adverse childhood experiences other than sexual abuse (i.e. child neglect/emotional abuse and exposure to domestic violence). A history of sexual abuse, experienced by twice as many non-recidivists as recidivists, differentiated the sample. Recidivists also had fewer protective factors than non-recidivists, as assessed by the MEGA ♪ upon admission to the facility. The mean age of recidivists was younger than non-recidivists, suggesting they may have been removed from their home at an early age, and/or had an early onset of persistent coarse sexual improprieties and/or sexually abusive behaviors that persisted into adulthood. The results highlight the importance of integrating trauma-informed interventions in treatment programs for those individuals who are sexually abusive that have a history of multiple adverse childhood experiences.

Use of direct oral anticoagulants in hematologic malignancies

Thrombosis is a common and serious event in cancer patients. While risk factors are well established in solid tumors and have lead to guidance regarding prophylaxis, similar data and recommendations are lacking for patients with hematologic malignancies. Likewise treatment for established venous thrombosis in cancer patients has shifted from low molecular weight heparin to direct oral anticoagulants (DOACs) based on favorable outcomes with the latter drugs in most tumor types while hematologic malignancies remain understudied and the appropriateness of DOAC use in these patients is less certain. Reasons for the knowledge gaps that have developed regarding management of thrombosis in hematologic malignancies include their relative rarity compared to solid organ cancer making large scale trials difficult to complete, and the particular nature of blood cancers and their treatment giving rise frequently to severe thrombocytopenia which is typically regarded as an exclusion from clinical trials.In this review we discuss landmark studies and other available literature regarding management of thromboembolism in hematologic malignancies and highlight unique features of these diseases and their treatment in this context.

Temporal trends in characteristics and outcomes in patients undergoing percutaneous mitral valve repair for secondary mitral regurgitation

Abstract Background and purpose Several studies have investigated the procedural and clinical outcomes of patients with secondary mitral regurgitation (MR) who underwent percutaneous mitral valve repair. However, temporal trend of patients’ characteristics and outcomes has not been studied in comparison with landmark studies. Thus, this systematic review investigated the temporal trend in patient characteristics and outcomes from observational studies over years in comparison with landmark studies in secondary MR. Methods The identified observational studies were grouped into two 5-year periods. The first 5-year period included 36 studies that started recruiting patients at any year between 2008 and 2012, whereas 25 studies in the second 5-year period started recruitment between 2012 and 2018. Pooled data of two every 5-year period were compared with the landmark studies. Multicenter studies with potential overlap in term of recruitment periods were excluded. Variables from observational studies were compared with those of landmark trials using a random-effects model for each variable. R software was used for non-comparative pooling of variables, and the RevMan software was used for the comparative meta-analysis. Results EVEREST versus observational studies: In first 5-year period, patients in EVERST program were more likely to have non-ischemic MR aetiology and less likely to be symptomatic at presentation (i.e., NYHA III/IV) or getting implanted cardiac device. They were less likely to have MR grade ≤2+ (OR 0.58, 95% CI:0.44-0.78) post procedure but maintained NYHA class I/II at 12-month follow-up (OR 1.74, 95% CI: 1.38-2.19) with no difference in mortality. In the subsequent 5-year period, there was no change from the former comparisons. COAPT versus observational studies: In the first period, COAPT patients were more likely to have renal insufficiency and receive beta-blockers and implanted device. They were less likely to present with severe heart failure symptoms or severe MR. There was no difference in post procedure outcomes, but they were more likely to maintain MR grade ≤2+ at follow-up (OR 3.98, 95% CI: 2.15-7.37). In the following period, COAPT patients were more likely to present with MR grade 3+ without a difference in procedural or clinical outcomes except for more chance to maintain procedural success at 12-mont follow-up (i.e., MR grade ≤2+; OR 2.41, 95% CI: 1.27-4.58). MITRA-FR versus observational studies: In the first period, MITRA-FR patients were less likely to have atrial fibrillation, renal insufficiency, or NYHA class III/IV. They were more likely receive beta-blockers and implanted device. However, there was no difference in post procedure and clinical outcomes. In the second period, there was no major change from the previous comparisons. Conclusion Although patients from landmark studies, namely COAPT and MITRA-FR, may have favourable characteristics, this did not translate into better outcome over time.

Left ventricular stroke volume index outperforms ejection fraction in predicting 1-year mortality in patients with acute heart failure - data from the SwissHeart Failure Network (SHFN)

Abstract Background Left ventricular ejection fraction (LVEF) has prevailed as the gold standard for quantifying LV function in acute heart failure (AHF) for both clinical trials and routine clinical practice. Most landmark studies in AHF stratify patients according to LVEF-based cut-offs. AHF is a clinical syndrome resulting from insufficient cardiac output, defined as LV stroke volume (LVSV) x heart rate. Thus, LVSV and its derived value LVSV index (LVSVI = LVSV/body surface area) may be better suited than LVEF for assessing LV function and heart failure severity, as well as predicting outcome in AHF. Purpose This study compared the predictive power for 1-year all-cause mortality of readily available echocardiographic parameters related to LV function (LVEF, LVSV and LVSVI) in patients with AHF. Methods Automatic data extraction was performed in 966 patients fulfilling criteria for AHF, retrospectively included between 2015-19 in 4 tertiary centres in Switzerland constituting the SwissHeart Failure Network (SHFN). Patients were selected if they had a standardised TTE study performed upon diagnosis of AHF, wherein all necessary values were reported. Cut-off values were chosen in consideration of the cohort’s median values. Patient follow-up was censored at 365d. Values are displayed as medians and interquartile ranges. Hazard ratios (HR) for 1-year all-cause mortality were computed with univariate Cox Proportional Hazards models. Kaplan-Meier curves were derived along with log-rank p-values. Results Median values for the evaluated parameter were as follows: LVEF (%): 38 (28–54); LVSV (mL): 45 (35–58); LVSVI (ml/m2): 24 (19–31). 1-year all-cause mortality was 33.7% (326/966 patients). The highest predictive capacity for 1-year all-cause mortality was observed for LVSVI<25ml/m2 (HR = 1.57 [1.26–1.97], p<0.001), followed by LVSV<45ml (HR = 1.57 [1.26–1.96], p<0.001). The lowest predictive capacity was seen for LVEF<40% (HR = 1.35 [1.08–1.68], p = 0.007, Figure 1). Applying the rounded medians as cut-off values, Kaplan-Meier curves showed greater divergence for higher vs. lower LVSVI (log-rank p<0.001) than for higher vs. lower LVEF (log-rank p = 0.007, Figures 2A and 2B). For patients with higher LVSVI, mortality rates did not change irrespective of higher or lower LVEF (Figure 2C, blue vs. green curves: log-rank p = 0.885). Patients with lower LVEF showed significantly higher mortality when they also had lower LVSVI (green vs. orange curves: log-rank p= 0.001). Conclusions In patients with AHF, LVSV and its derived value LVSVI are superior in predicting 1-year all-cause mortality compared to LVEF. Requiring the same echocardiographic measurements and thus being as readily available as the currently prevailing LVEF, the assessment of LVSV and LVSVI deserves intensified attention, both for future studies and clinical routine.Figure 1:Hazard RatiosFigure 2:Kaplan-Meier Analyses

Treatment Complications of Venous Thromboembolism in Patients with Central Nervous System Tumors

Introduction: In the last decade, landmark studies have been conducted in patients with cancer-associated venous thromboembolism (CA-VTE), helping to guide treatment decisions of anticoagulant therapy. Although these trials outlined new treatment opportunities, they either completely excluded or included only a small number of patients with primary brain tumors or central nervous system (CNS) metastasis. Additionally, there are very limited data on complication rates of anticoagulants in patients with spinal metastasis. Consequently, there is an ongoing knowledge gap for safe and effective anticoagulation options for patients with acute VTE in this high-risk patient population. Methods: We conducted a single institution IRB-approved retrospective study evaluating the rates of hemorrhage and recurrent thromboses in patients with CA-VTE and a diagnosis of a primary brain tumor or brain and/or spinal metastases. Our investigation was conducted at The Preston Robert Tisch Brain Tumor Center and the Center for Brain and Spine Metastasis at Duke between 2017 and 2021. The cohort was built through identifying patients by ICD-10 codes searched within the electronic medical records. Inclusion criteria consisted of patients ≥ 18 years of age, a history of confirmed primary brain tumor or brain and/or spinal metastases prior to VTE, treatment with anticoagulation or an inferior vena cava (IVC) filter, and followed up at least once since starting treatment beyond 1 month of VTE diagnosis . We compared complication event rates and the anticoagulant selected for treatment. Data obtained included patient demographic information, medical and social histories, cancer-related history, VTE history and treatment, recurrent thrombotic and hemorrhagic events, and patient mortality. Results: We identified 3584 total patients during the study timeframe. Eight hundred and twenty-five patients were included and 2759 were excluded for not meeting our inclusion criteria. Of the 825 included patients, 766 were treated with either apixaban (348/766; 45%), rivaroxaban (178/766; 23%), or enoxaparin (240/766; 31%) for their initial CA-VTE (Table 1). The other 59 patients were treated with another anticoagulant or received an IVC filter without anticoagulation. The median age for our cohort of 766 patients was 61.0 (20.0 - 87.0). There was no significant statistical association between relevant past medical histories of obesity or hypertension among the 3 anticoagulant groups. There was no significant statistical association between the 3 anticoagulant cohorts and primary brain tumors, or brain and/or spinal metastases ( p= 0.06). Although it trended towards significance, there was no statistically significant difference in the proportion of patients receiving anti-VEGF inhibitors at time of initial VTE among the 3 anticoagulant cohorts ( p = 0.052). When looking at our primary outcomes of recurrent thrombosis, major hemorrhage, or clinically relevant non-major bleeding, 171 individual patients experienced a total of 188 unique events that occurred during treatment with apixaban, rivaroxaban, or enoxaparin (Table 2). Of the 171 unique patients, enoxaparin use was the most common (80/171; 47%), followed by apixaban (61/171; 36%), rivaroxaban (28/171; 16%), and a small percentage (2/171; 1%) were treated with a combination of apixaban, rivaroxaban, or enoxaparin during their unique event. When excluding the 2 patients with multiple anticoagulant treatments, there was no statistical difference among anticoagulant rates and any event of recurrent thrombosis, major hemorrhage, clinically relevant non-major bleeding, or any multiple events ( p = 0.07). Conclusions: We present the largest unique data set comparing anticoagulant use in a known high-risk patient population of primary brain tumors, brain and/or spinal metastases. Our data demonstrate up to 22% of patients with CA-VTE and primary brain tumors, brain and/or spinal metastases have a subsequent hemorrhagic or recurrent thrombotic complication during treatment with apixaban, rivaroxaban, or enoxaparin for their initial event. However, our data did not demonstrate a statistically significant difference in complication rates between these 3 anticoagulants. These findings indicate a need for future large-scale prospective investigations to determine optimal treatment in this high-risk patient population.

Aam assessment instrument for disease activity in Aamavata: Scope and challenges

Development and validation of instruments based on concepts and clinical features described in Ayurveda is a constructive step towards translational research in Ayurveda. The clinical decisions in traditional medical practices often depend on clinical features. Such attempts from Ayurveda experts also contribute to strengthen an endeavour of integrative medicine. A recently published article in J-AIM on development and validation of Aam Assessment Instrument (AAI) to assess the disease activity in amavata is a landmark study. This study is undertaken in patients with rheumatoid arthritis (RA), a prototype of inflammatory arthritis.We suggest that the specificity and reliability of AAI in RA and amavata would increase if complemented with joint count as described in Ayurveda texts. These joint counts can be further sub-classified for different types of inflammatory arthritides. Similarly, this AAI can also be validated and used for constitutional features in other ama-dominant non-rheumatic systemic diseases. This may need development of more comprehensive ama-specific features. We also need to consider the limitations of patient-reported outcome measures (PROMs) during further development and validation of AAI. Collective, multicentric, organized efforts by Ayurveda clinicians will lead to the development of reliable, sensitive, specific, and reproducible instruments for clinical assessments in various diseases.

Effective sequencing of chimeric antigen receptor T-cell therapy in the treatment of LBCL in 2023

Over the last decade, CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has profoundly changed the management of relapsed/refractory large-B-cell lymphoma (LBCL). At present, there are three FDA-approved anti-CD19 CAR T-cell products for LBCL: axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel). Two of these (axi-cel & liso-cel) are approved for use in the second-line setting under certain conditions. As CAR T-cell therapy continues to define a new role in the treatment armamentarium for LBCL, questions remain regarding which product to use and how to sequence CAR T-cell therapy with other therapeutic options. Here we will briefly review the key features of each FDA-approved anti-CD19 CAR T-cell product and the data that led to regulatory approval for each. Next, we will focus on the recent landmark studies that have established the use of CAR T-cell therapy as second-line treatment. While no direct prospective head-to-head comparisons exist of the 3 constructs, we will review some retrospective studies that suggest some emerging differences between the products. Lastly, we will turn our attention to the horizon as we explore some of the ongoing questions of how to best leverage the curative potential of CAR T-cell therapy for the most effective management of LBCL. These areas include the consideration of CAR T-cell therapy in the frontline setting, the optimal timing for CAR T-cell referral, the optimal bridging approach, and how to continue advancing novel CAR T-cell approaches in the context of the current treatment landscape.

Current Strengths and Weaknesses of ChatGPT as a Resource for Radiation Oncology Patients and Providers

Purpose: ChatGPT, an artificial intelligence (AI) program that uses natural language processing to generate conversational-style responses to questions or inputs, is increasingly being used by both patients and healthcare professionals. This study aims to evaluate the accuracy and comprehensiveness of ChatGPT in radiation oncology-related domains, including answering common patient questions, summarizing landmark clinical research studies, and providing literature reviews with specific references supporting current standard of care clinical practice in radiation oncology. Methods: We assessed the performance of ChatGPT version 3.5 (ChatGPT3.5) in three areas. We evaluated ChatGPT3.5’s ability to answer 28 templated patient-centered questions applied across 9 cancer types. We then tested ChatGPT3.5’s ability to summarize specific portions of 10 landmark studies in radiation oncology. Next, we used ChatGPT3.5 to identify scientific studies supporting current standard of care practice in clinical radiation oncology for five different cancer types. Each response was graded independently by two reviewers, with discordant grades resolved by a third reviewer. Results: ChatGPT3.5 frequently generated inaccurate or incomplete responses. Only 39.7% of responses to patient-centered questions were considered correct and comprehensive. When summarizing landmark studies in radiation oncology, 35.0% of ChatGPT3.5′s responses were accurate and comprehensive, improving to 43.3% when provided the full text of the study. ChatGPT3.5′s ability to present a list of studies related to standard of care clinical practices was also unsatisfactory, with 50.6% of the provided studies fabricated. Conclusion: ChatGPT should not be considered a reliable radiation oncology resource for patients or providers at this time, as it frequently generates inaccurate or incomplete responses. However, natural language programming-based AI programs are rapidly evolving, and future versions of ChatGPT or similar programs may demonstrate improved performance in this domain.

The ISCHEMIA trial revisited: setting the record straight on the benefits of coronary bypass surgery and the misinterpretation of a landmark trial.

The ISCHEMIA trial is a landmark study that has been the subject of heated debate within the cardiovascular community. In this analysis of the ISCHEMIA trial, we aim to set the record straight on the benefits of coronary artery bypass grafting (CABG) and the misinterpretation of this landmark trial. We sought to clarify and reorient this misinterpretation. We herein analyse the ISCHEMIA trial in detail and describe how its misinterpretation has led to an erroneous guideline recommendation downgrading for prognosis-altering surgical therapy in these at-risk patients. The interim ISCHEMIA trial findings align with previous evidence where CABG reduces the long-term risks of myocardial infarction and mortality in advanced coronary artery disease. The trial outcomes of a significantly lower rate of cardiovascular mortality and a higher rate of non-cardiovascular mortality with the invasive strategy are explained according to landmark evidence. The ISCHEMIA trial findings are aligned with previous evidence and should not be used to downgrade recommendations in recent guidelines for the indisputable benefits of CABG.

Evaluation of a digital intervention for depression among Lebanese&Syrian refugees in Lebanon

Abstract Background Lebanon is a low-to-middle-income country, hosting more than 1.1 million Syrian refugees, with 90% mental health treatment gap. The National Mental Health Programme (NMHP) in Lebanon along with the World Health Organization (WHO) launched the Step-by-Step (SbS) e-mental health intervention for adults with depression. Step-by-Step is a 5-sessions, self-help, minimally guided digital program for adults with depression. Two Randomized Controlled Trials (RCTs) assessed its effectiveness and cost-effectiveness in the local setting. Methods Participants (n = 569 Syr, n = 680 Leb) were recruited online and randomly allocated to Step-by-Step (n = 283 Syr, n = 331), or Enhanced Care as Usual (n = 286 Syr, n = 349). The ECAU group received one-page psychoeducation and a referral list to services. Online assessments were administered at baseline, post-assessments at eight weeks after enrolment, and follow-up assessments at 20 weeks after enrolment. Primary outcomes were the Patient Health Questionnaire-9 and World Health Organization Disability Assessment Scale 2.0 scores at all post-assessments. Results Intention-to-treat analyses showed significant effects on depression scores (standardized mean differences, SMD: 0.71; 95% CI: 0.45 to 0.97 for Lebanese, and SMD: 0.48; 95% CI: 0.26; 0.70 for Syrians). Significant results were maintained on all secondary outcomes and at follow-up assessments. Conclusions SbS proved effective for depressive and functionality symptoms. Subsequently, it was adopted by MoPH as an official, free-of-charge, and first-line service for depression. A global version of SbS is currently being developed by WHO to be replicated and used in several settings worldwide. Key messages • This landmark study provided unique evidence on the effectiveness of guided-e-mental health interventions for the Lebanese and Syrian refugees affected by adversity in Lebanon. • This study guided the scaled-up of SbS into a widely accessible service among the general population.

BCL-xL Targeting to Induce Apoptosis and to Eliminate Chemotherapy-Induced Senescent Tumor Cells: From Navitoclax to Platelet-Sparing BCL-xL PROTACs.

Restoring apoptotic cell death is a critical goal for cancer therapy. One of the primary mechanisms by which cancer cells evade death and maintain survival in the face of stress signals is by overexpression of prosurvival B-cell lymphoma 2 (BCL2) family members such as BCL2, BCL-xL, and MCL1, which suppress the intrinsic (mitochondrial) pathway of apoptosis through complex protein and membrane interactions. While these antiapoptotic proteins have been validated as potent therapeutic targets, synthesis of their inhibitors remained challenging for decades mainly due to the presence of a difficult to target, highly hydrophobic groove on the surface. The groove serves as a binding site for the BH3 domain of corresponding proapoptotic partners, which leads to their sequestration and prevents apoptosis. In 2008, a Cancer Research article by Tse and colleagues, led by Dr. Steven Elmore from Abbott Laboratories, reported the discovery of the first orally bioavailable BCL2/BCL-xL inhibitor, navitoclax (ABT-263), marking the onset of an era of "BH3 mimetics" in cancer therapeutics and changing the therapeutic landscape especially for leukemia. Here, we reflect on how this landmark study fueled development of small-molecule BH3 mimetics like venetoclax and seek to indicate new strategies and future directions for improving the clinical activity of navitoclax for hematologic malignancies. See related article by Tse and colleagues, Cancer Res 2008;68:3421-3428.

Raring to go? A cross-sectional survey of student paramedics on how well they perceive their UK pre-registration course to be preparing them to manage suspected seizures

BackgroundParamedics convey a high proportion of seizure patients with no clinical need to emergency departments (EDs). In a landmark study, only 27% of UK paramedics reported being “Very…”/ “Extremely confident” making seizure conveyance decisions. Improved pre-registration education on seizures for paramedics is proposed. Clarity is needed on its potential given recent changes to how UK paramedics train (namely, degree, rather than brief vocational course). This study sought to describe UK student paramedics’ perceived readiness to manage seizures and educational needs; compare this to what they report for other presentations; and, explore subgroup differences.MethodsSix hundred thirty-eight students, in year 2 or beyond of their pre-registration programme completed a cross-sectional survey. They rated perceived confidence, knowledge, ability to care for, and educational needs for seizures, breathing problems and, headache. Primary measure was conveyance decision confidence.ResultsFor seizures, 45.3% (95% CI 41.4–49.2) said they were “Very…”/“Extremely confident” to make conveyance decisions. This was similar to breathing problems, but higher than for headache (25.9%, 95% CI 22.6–29.5). Two hundred and thirty-nine participants (37.9%, 95% CI 34.1–41.8) said more seizure education was required – lower than for headache, but higher than for breathing problems. Subgroup differences included students on university-based programmes reporting more confidence for conveyance decisions than those completing degree level apprenticeships.ConclusionsStudent paramedics report relatively high perceived readiness for managing seizures. Magnitude of benefit from enhancements to pre-registration education may be more limited than anticipated. Additional factors need attention if a sizeable reduction to unnecessary conveyances for seizures is to happen.

“Selection, planning and execution of minimally invasive surgery in adult spinal deformity correction”

Minimally invasive surgery (MIS) for correction of adult spinal deformity was developed to address the high rate of medical and surgical complications rate in open surgical treatment of increasingly aging and frail patient population. In the past decade, MIS group within the International Spine Study Group (ISSG) has been in the forefront of the application of MIS techniques to fulfill the well-established principles of ASD surgery. These efforts have resulted in landmark studies. Here, we review these studies that encompass all aspects of MIS surgical treatment of ASD including patient selection with Minimally Invasive Spinal Deformity Surgery (MISDEF) and MISDEF-2 algorithms, surgical planning with anterior column realignment classification and the Minimally Invasive Interbody Selection Algorithm (MIISA), and surgical execution with Spinal Deformity Complexity Checklist (SDCC). We will highlight that with careful selection, diligent planning and meticulous execution the MIS techniques can treat patients with ASD, abiding to correction principles and radiographic parameters.

THU596 Heteromerization Of The Angiotensin II Type 1 Receptor And The Bradykinin Type 2 Receptor

Abstract Disclosure: E.K. Johnstone: Grant Recipient; Self; Australian Research Council. K.D. Pfleger: Grant Recipient; Self; Australian Research Council. Stock Owner; Self; Dimerix Bioscience Pty Ltd. Background: Receptor heteromerization is the phenomenon whereby two different receptors form a functional complex that attains unique pharmacological properties. Consequently, receptor heteromers can be considered novel drug targets, with the potential to achieve greater therapeutic selectivity and specificity. In a landmark study, the first receptor heteromer to be associated with a disease was the heteromer that forms between the angiotensin II type 1 (AT1) receptor and the bradykinin type 2 (B2) receptor (1). The AT1-B2 heteromer reportedly led to increased angiotensin II signalling, which was implicated in the angiotensin II hypersensitivity involved in pre-eclampsia. However, the validity of this study was questioned by a collaboration of several groups who were unable to find any evidence for a physical or a function interaction between the two receptors (2). As a consequence of these conflicting studies, the existence of the AT1-B2 receptor heteromer has remained controversial. Aim: Investigation of evidence for heteromerization of the AT1 receptor and the B2 receptor. Methods: AT1 receptor and B2 receptor pharmacology and potential heteromerization was investigated in HEK293FT cells using various bioluminescence resonance energy transfer (BRET)-proximity based assays, as well as Dimerix’s Receptor-Heteromer Investigation Technology (Receptor-HIT) (3). Receptor-HIT enables the investigation of receptor heteromers through their specific ligand-induced proximity to interacting proteins. BRET assays, including in the Receptor-HIT configuration, allow real time, live cell monitoring of proximity between biomolecules of interest. Results: Using the Receptor-HIT assay, we confirmed the existence of the AT1-B2 receptor heteromer in HEK293FT cells. We found that the heteromer was able to recruit various GPCR interacting proteins, such as G proteins and arrestin in a bradykinin-dependent manner. Additionally, the heteromer also internalised and trafficked through the cell upon treatment with bradykinin. The close proximity of the two receptors was confirmed using a variation of the Receptor-HIT assay, which monitors receptor-ligand binding rather than protein-protein interactions. Discussion: Our study supports the existence of the AT1-B2 receptor heteromer and identifies various pharmacological properties of the complex. Further studies are required to relate these molecular properties to physiological consequences of heteromerization. (1)AbdAlla et al. Nat Med2001, 7 (9), 1003 1009.(2)Hansen et al. J Biol Chem2009;284(3):1831 1839.(3)Johnstone et al. Biochem Soc T. 2021;49:1555–65. Presentation: Thursday, June 15, 2023

Investigating the Dimensions of Mind Perception

Mind perception is the ability to infer the presence of a mind in other beings or non-living things (e.g., a tree, an animal, a robot) and make judgements about what "kind" of mind that being possesses. Research has shown that there is a dimensionality to the schema of mind perception, though the number of dimensions is debated. The present study aimed to explore the dimensions via a mind perception scale that measures participants’ perceptions of mental capacities (n = 181). The data was highly suited for factor analysis, so principal axis factoring and multiple criteria were used to find the retained factors. Findings suggest a two-dimensional model of mind perception, supporting the field’s landmark study by Gray et al. (2007).