Baseline Response Rates Research Articles

Efficacy, safety and differential outcomes of immune-chemotherapy with gemcitabine, cisplatin and durvalumab in patients with biliary tract cancers: A multicenter real world cohort.

Combined Immuno-chemotherapy consisting of gemcitabine, cisplatin and the programmed death-ligand one inhibitor durvalumab (GCD) is the new standard of care for patients with biliary tract cancers (BTC) based on positive results of the TOPAZ-1 study. We here evaluated the efficacy and safety of GCD for BTC in a German multicenter real-world patient cohort. Patients with BTC treated with GCD from 9 German centers were included. Clinicopathological baseline parameters, overall survival (OS), response rate and adverse events (AEs) were retrospectively analyzed. The prognostic impact was determined by Kaplan-Meier analyses and Cox regression models. A total of 165 patients treated with GCD between 2021 and 2024 were included in the study. Median OS and median progression-free survival were 14 months (95% CI 10.3-17.7) and 8months (95% CI 6.8-9.2), respectively. The best overall response rate was 28.5% and disease control rate was 65.5%. While extrahepatic and intrahepatic BTC showed similar outcomes, mOS was significantly shorter in patients with gall bladder cancer (GB-CA) with 9months (95% CI 5.5-12.4; p=0.02). In univariate analyses age ≥70years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥1, status post cholecystectomy, GB-CA and high baseline CRP values were significantly associated with OS. ECOG PS≥1 and GB-CA remained independent prognostic factors for OS in multivariable cox regression analysis. AEs have been reported in 130 patients (78.8%), including 149 grade 3-4 AEs (25.5%). One patient died of severe infectious pneumonia. Immune-related (ir)AEs occurred in 17 patients (10.3%), including 9 grade 3-4 irAEs (2.2%), which led to treatment interruption in 4 patients. Immuno-chemotherapy in patients with BTC was feasible, effective and safe in a real-life scenario. Our results were comparable to the phase 3 clinical trial results (TOPAZ-1). Reduced efficacy was noted in patients with GB-CA and/or a reduced performance status that warrants further investigation.

Outcomes for Patients with Metastatic Castration-Resistant Prostate Cancer and Liver Metastasis Receiving [177Lu]Lu-PSMA-617.

It is well known that patients with liver metastasis from metastatic castration-resistant prostate cancer have poor or only transient responses to many forms of systemic therapy. Data on outcomes after treatment with [177Lu]Lu-PSMA-617 (LuPSMA) are scarce. The VISION trial reports a hazard ratio for overall survival (OS) in the subgroup of patients with liver metastasis without disclosing the absolute duration of survival. Using real-world clinical data, we examined this important subgroup of patients, describing prostate-specific antigen (PSA) response and OS. Methods: A single-institution database was assembled to include all patients receiving LuPSMA at Mayo Clinic in Rochester, Minnesota, for whom treatment was initiated between March 2022 and March 2023. Baseline clinicopathologic and imaging characteristics were abstracted. Patients were then categorized by presence or absence of liver metastasis on pretreatment prostate-specific membrane antigen (PSMA) PET. PSA response and OS for the 2 groups (liver metastasis vs. no liver metastasis) were compared using χ2 testing and the Kaplan-Meier method, respectively. A multivariate Cox regression analysis was performed, including established prognostic factors. Finally, those with pretreatment circulating tumor DNA as determined in an 83-gene panel were assessed for the presence of pathogenic and likely pathogenic alterations. These findings were summarized using descriptive statistics and compared between the 2 cohorts using the Fisher exact test. Results: The overall cohort consisted of 273 patients, including 43 (15.75%) with liver metastasis on pretreatment PSMA PET/CT. The median number of cycles received was 3 (range, 1-6) for patients with liver metastasis and 5 (range, 1-6) for those without hepatic involvement. The 50% or greater reduction in PSA from baseline response rate was lower for those with liver metastasis than for those without (30.23% [13/43] vs 49.77% [106/213], P = 0.019). At a median follow-up of 10 mo (interquartile range, 9-13 mo), there was a significant difference in median OS (8.35 mo vs. not reached, P < 0.001). On multivariate analysis, the presence of liver metastasis was independently associated with shorter survival (hazard ratio, 4.06; P < 0.001). Conclusion: Our data suggest that the presence of liver metastasis predicts poorer outcomes in patients receiving LuPSMA treatment. Alternative and combination approaches should be explored to maximize the antitumor activity of radiopharmaceutical therapy in the liver.

Resistance to change as a function of response speed

This study examined the effects of different response-speed requirements on resistance to change. Undergraduates were exposed to a simulated scenario aiming to destroy pollution sources by clicking on moving targets. During baseline, a multiple variable interval (VI) 15 s VI 15 s was in effect. Points (100) served as reinforcers. In the Low-Speed Component, the response button moved across the computer screen at a speed of 30 % of the screen length per second. In the High-Speed Component, the response button moved across the computer screen at a speed of 60 % of the screen length per second. A VI 10 s of point loss (-95) disrupted responding during the test. Behavioral resistance was calculated as proportional changes from baseline response rates to test response rates. When the point-loss disrupted responding, greater resistance was observed in the Low-Speed Component, corroborating previous studies with other dimensions of physical requirements.

Efficacy and Safety of KRASG12C Inhibitor IBI351 Monotherapy in Patients With Advanced NSCLC: Results From a Phase 2 Pivotal Study

IntroductionKRAS glycine-to-cysteine substitution at codon 12 (G12C) mutation is a well-recognized and increasingly promising therapeutic target with huge unmet clinical needs in NSCLC patients. IBI351 is a potent covalent and irreversible inhibitor of KRAS G12C. Here, we present the efficacy and safety of IBI351 from an open-label, single-arm, phase 2 pivotal study. MethodsEligible patients with NSCLC with KRAS G12C who failed standard therapy were enrolled. IBI351 was orally administered at a dose of 600 mg twice daily. The primary endpoint was confirmed objective response rate assessed by an independent radiological review committee (IRRC) as per Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints were safety, IRRC-confirmed disease control rate, duration of response, progression-free survival (PFS), and overall survival. ResultsAs of December 13, 2023, 116 patients were enrolled (Eastern Cooperative Oncology Group Performance Status 1: 91.4%; brain metastasis: 30.2%; prior treatments with both anti-PD-1 or anti-PD-L1 inhibitors and platinum-based chemotherapy: 84.5%). As per the IRRC assessment, the confirmed objective response rate was 49.1% (95% confidence interval [CI]: 39.7–58.6), and the disease control rate was 90.5% (95% CI: 83.7–95.2). The median duration of response was not reached whereas disease progression or death events occurred in 22 patients (38.6%), and the median PFS was 9.7 months (95% CI: 5.6–11.0). overall survival data was immature. Treatment-related adverse events (TRAEs) occurred in 107 patients (92.2%) whereas 48 patients (41.4%) had equal to or higher than grade three TRAEs. Common TRAEs were anemia (44.8%), increased alanine aminotransferase (28.4%), increased aspartate aminotransferase (27.6%), asthenia (26.7%) and presence of protein in urine (25.0%). TRAEs leading to treatment discontinuation occurred in nine patients (7.8%). In biomarker evaluable patients (n = 95), all patients had positive KRAS G12C in tissue whereas 72 patients were blood-positive and 23 were blood-negative for KRAS G12C. Patients with KRAS G12C in both blood and tissue had higher tumor burden at baseline (p < 0.05) and worse PFS (p < 0.05). Tumor mutation profiling identified tumor protein p53 (45.3%), serine/threonine kinase 11 (STK11) (30.5%), and kelch-like ECH-associated protein 1 (21.1%) as the most common genes co-mutated with KRAS G12C. Among 13 genes with mutation frequency equal to or higher than 5%, mutations of six genes (STK11, kelch-like ECH-associated protein 1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, DNA polymerase epsilon, SMAD family member 4, and BMP/retinoic acid-inducible neural-specific protein 3) were significantly associated with worse PFS (p < 0.05). Mutation in STK11 was also found to have a significant association with higher tumor burden at baseline and lower response rate (p < 0.05). ConclusionsIBI351 monotherapy demonstrated promising and sustained efficacy with manageable safety, supporting its potential as a new treatment option for KRAS G12C-mutant NSCLC.

A blind retrospective analysis of a novel predictive marker to ICB response in NSCLC, calculated directly from histopathological slides.

2665 Background: Immune checkpoint blockers (ICB), and primarily PD-1/PD-L1 inhibitors, are in the forefront of contemporary clinical oncology and have become an integral part of treatment of many malignancies, including non-small cell lung cancer (NSCLC). Nevertheless, tumor response to ICB varies widely. Predictive markers commonly used to distinguish patients likely to respond to ICB, such as PD-L1 expression and tumor mutational burden (TMB) have limited predictive value, which calls for the development of practical and more accurate tests. We present results of a blind retrospective analysis of a novel predictive marker of ICB response in NSCLC, relying solely on histopathological slides. Methods: We obtained high resolution Hematoxylin and Eosin (H&amp;E) slides from tumor-tissue samples of 50 cases of metastatic NSCLC patients treated with first-line PD-1 inhibitors. We retrospectively applied our ENLIGHT-DeepPT (ENLIGHT-DP for short) pipeline to generate, in a blinded manner, an individual response score to PD-1 inhibition for each slide. ENLIGHT-DP is composed of two main steps: (i) predict mRNA expression directly from an H&amp;E slide using DeepPT, our digital-pathology based algorithm; and (ii) use these values as input to ENLIGHT, our transcriptome-based precision oncology platform, which generates a score that predicts response to targeted therapies and ICB (based on a 10-gene signature in this case). We then unblinded the clinical outcome (RECIST1.1), and evaluated ENLIGHT-DP’s performance vs. standard markers. Results: ENLIGHT-DP’s score is predictive of response in this cohort, which had an overall response rate of 68% (34 of 50), with ROC AUC = 0.69 (p = 0.01, one-sided permutation test). Using a predefined threshold for binary classification of response derived from independent data, all 15 patients that were predicted to respond by ENLIGHT-DP indeed responded (100% PPV, 44% sensitivity). In comparison, predicting response according to PD-L1 &gt; 1% achieves 68% PPV and 62% sensitivity, while PD-L1 &gt; 50% achieves 65% PPV and 38% sensitivity, i.e, both thresholds exhibit no predictive power (PPV &lt;= baseline response rate). Patients with high TMB (&gt;10) had 82% PPV and 26% sensitivity, showing lower predictive benefit than ENLIGHT-DP. ENLIGHT-DP was particularly good at stratifying patients with PD-L1 &lt; 1% (18 patients, ROC AUC = 0.8, p = 0.03). Conclusions: ENLIGHT-DP demonstrates high predictive power for response to ICB in NSCLC relying solely on accessible H&amp;E slides, outperforming the commonly used PD-L1 and TMB markers. ENLIGHT-DP is also able to identify responders within patients with PD-L1 &lt; 1%, for whom ICB is usually considered ineffective. Importantly, our approach does not require training on prior treatment outcomes, and can therefore be generalized to drugs for which such data is unavailable or scarce.

Cohort assessment of medical and pharmacy student interprofessional attitudes at an academic medical centre from baseline to programme completion

Background: Interprofessional interactions between pharmacy and medical students have been emphasised by accreditation standards. This study aimed to document medical and pharmacy student cohorts’ baseline and longitudinal interprofessional attitudes across four years of pre-licensure education. Methods: Student cohorts shared two structured interprofessional learning experiences within the first two years, then unstructured/variable learning experiences during the final two years. The 27-item Interprofessional Attitudes Scale comprising five subscales was administered upon programme entry, then towards the end of each programme year. Results: Baseline response rates were 73.5% and 90% for 136 medicine and 57 pharmacy students, respectively; pharmacy student responses were significantly higher for teamwork, roles, and responsibilities and significantly lower for interprofessional biases subscales. Longitudinal medical and pharmacy student responses only showed a significant increase in interprofessional biases, while medical student responses showed significant decreases in teamwork, roles, responsibilities, and community-centredness. Conclusion: Compared to pharmacy students, baseline responses from medical students confirm significantly lower scores for teamwork, roles, and responsibilities on programme entry, which may further decrease by the end of the first pre-clinical year. Though significant subscale changes mirrored the completion of structured pre-clinical interprofessional curricula and/or clinical education for both student cohorts, further research is needed secondary to study limitations.

Factors associated with dental students' mental health during the COVID-19 pandemic: a longitudinal study.

The aim of the present study was to examine the relationships between gender, sense of coherence (SOC), social support, perception of academic environment and mental health of dental students during the coronavirus disease 2019 (COVID-19) pandemic. A longitudinal study involving 65 undergraduates enrolled from the first to sixth semesters in the bachelor dental course of Universidade Federal Fluminense, Brazil, was conducted. Baseline data (2018) included age, gender, SOC, social support, stress control and perception of education environment. Depression, anxiety and stress were assessed at baseline (response rate: 93%) and two-year follow-up (2020; response rate: 37%). Structural Equation Modelling was used to test the relationships between independent variables and depression, anxiety and stress during COVID-19 pandemic. Lower social support (β = -0.15), lower stress control (β = -0.20) and lower SOC (β = -0.39) were directly linked to higher depression (β = 0.22). Female gender (β = 0.22), worse perception of educational environment (β = -0.24) and lower SOC (β = -0.57) directly predicted higher anxiety. Female gender (β = 0.18), lower stress control (β = -0.21), and lower SOC (β = -0.46) directly predicted higher stress. The link between gender and both depression and stress, was mediated by stress control. Social support was indirectly linked to depression and stress via SOC. Perception of educational environment mediated the link between SOC and anxiety. Mental health of dental students during COVID-19 pandemic was influenced by demographic characteristics, perception of educational environment, social support and SOC through both direct and indirect pathways.

Measuring Patient-Reported Use and Outcomes From Complementary and Integrative Health Therapies: Development of the Complementary and Integrative Health Therapy Patient Experience Survey.

Assessing the use and effectiveness of complementary and integrative health (CIH) therapies via survey can be complicated given CIH therapies are used in various locations and formats, the dosing required to have an effect is unclear, the potential health and well-being outcomes are many, and describing CIH therapies can be challenging. Few surveys assessing CIH therapy use and effectiveness exist, and none sufficiently reflect these complexities. In a large-scale Veterans Health Administration (VA) quality improvement effort, we developed the "Complementary and Integrative Health Therapy Patient Experience Survey", a longitudinal, electronic patient self-administered survey to comprehensively assess CIH therapy use and outcomes. We obtained guidance from the literature, subject matter experts, and Veteran patients who used CIH therapies in designing the survey. As a validity check, we completed cognitive testing and interviews with those patients. We conducted the survey (March 2021-April 2023), inviting 15,608 Veterans with chronic musculoskeletal pain with a recent CIH appointment or referral identified in VA electronic medical records (EMR) to participate. As a second validity check, we compared VA EMR data and patient self-reports of CIH therapy utilization a month after survey initiation and again at survey conclusion. The 64-item, electronic survey assesses CIH dosing (amount and timing), delivery format and location, provider location, and payor. It also assesses 7 patient-reported outcomes (pain, global mental health, global physical health, depression, quality of life, stress, and meaning/purpose in life), and 3 potential mediators (perceived health competency, healthcare engagement, and self-efficacy for managing diseases). The survey took 17minutes on average to complete and had a baseline response rate of 45.3%. We found high degrees of concordance between self-reported and EMR data for all therapies except meditation. Validly assessing patient-reported CIH therapy use and outcomes is complex, but possible.

Impact of Prior Bendamustine Exposure on Bispecific Antibody Treatment Outcomes for Patients with B-Cell Lymphoma

Introduction: Bispecific antibodies (BsAbs) were recently approved for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) and follicular lymphoma (FL) based on phase I-II clinical trials. These T-cell engaging agents achieve 40-50% of complete responses, but information regarding prognostic factors is scarce. Given the deleterious effect of previous bendamustine (benda) reported for patients receiving chimeric antigen receptor (CAR) T-cell therapy, we aimed to assess if prior benda exposure had an impact on BsAb outcomes. Methods: We conducted a retrospective, multicenter study including patients with LBCL or FL treated at 5 centers with BsAbs from November 2017 to March 2023. We analyzed baseline characteristics, response rates and survival outcomes according to prior benda exposure. Then, we carried out subgroup analyses according to histology (LBCL and FL) and treatment partner (monotherapy and combination regimens), assessing the impact of benda in each of these cohorts. Finally, we examined the impact of benda dose and washout before BsAb start on efficacy outcomes. Results: We included 143 patients (104 LBCL, 39 FL) who received BsAb therapy, 43 (30%) of which had been previously exposed to benda at a median of 653 days (range 31-2369 days). The BsAb targeted CD20/CD3, either in monotherapy (60%) or in combination with other agents (40%). Median follow-up for the full data set was 21.8 months (CI 95% 18.1 - 25.1 months). In terms of baseline characteristics (table) median age was 66 years and most patients had an advanced stage of disease (86%), increased LDH (65%) and at least 1 prior line of therapy (90%, median 2 [range 0-9]); CAR T-cell therapy was a prior line for 15% of patients. The benda-exposed cohort had an increased rate of transformed indolent lymphoma (47% vs 25%, p=0.01) and more prior lines of therapy (&amp;gt;2, 53% vs 26%, p&amp;lt;0.01) in comparison with benda-naïve patients. First, we analyzed the impact of previous benda on several parameters. Patients with prior exposure to benda had lower median CD3+ cells (543 vs 930/mm3, p=0.01) than benda-naïve patients. In terms of toxicity, there were no differences in the incidence or severity of cytokine release syndrome and neurotoxicity. Regarding efficacy, overall and complete response rates (ORR [CRR]) were comparable between benda-exposed and naïve patients (75% [60%] vs 72% [56%], respectively [p=0.73]). Median PFS and OS for the full cohort were 16.0 months and 43.4 months, respectively, without significant differences for the benda-exposed and naïve cohorts (16.8 vs 15.3 months [p=0.88] and NR vs 43.4 months [p=0.99]). In the univariate analysis for PFS, primary refractory and bulky disease, increased LDH and &amp;gt;2 previous lines were associated with a shorter survival. The same factors carried a negative impact for OS, with the addition of previous CAR T-cell therapy and ECOG &amp;gt;0. Then, we carried out subgroup analyses according to underlying histology. In the LBCL cohort (n=104), overall and complete response rates were similar between benda-exposed and naïve patients (74% [52%] vs 71% [55%], p=0.81), as were PFS (p=0.78) and OS (p=0.76). In the FL cohort (n=39), overall and complete response rates were also comparable (77% [71%] vs 78% [61%], p=0.94) as were PFS (p=0.96) and OS (p=0.96). We focused next on the presence of a treatment partner with the BsAb. Overall (complete) response rates were significantly increased in the combination cohort (mainly with immunotherapy [70%] or chemotherapy [30%]), compared to monotherapy (90% [75%] vs 62% [46%], p&amp;lt;0.01), as were 12-month PFS (77% vs 36%, p&amp;lt;0.01) and 12-month OS (88% vs 55%, p&amp;lt;0.01). Inside both of these cohorts, we did not identify any differences in response rate or survival between the benda-exposed and naïve patients. Given the wide range in washout from last benda dose, we analyzed the impact of this interval on efficacy outcomes. We did not identify any difference according to time between last benda dose and BsAb start. Noteworthy, only 7 patients had a washout shorter than 6 months. In terms of the benda dose, median number of cycles was 6 (range 1-10). We did not identify an impact of benda cycles on response rate or survival. Conclusions: Bendamustine-containing regimens do not seem to confer a negative prognostic impact before BsAb therapy, in contrast to what has been reported in the CAR T-cell setting. Longer follow-up and larger cohorts are warranted to confirm these results.

Safe and Effective Escalation of Evidence-Based Chemotherapy for Mature B Cell Non-Hodgkin's Lymphoma in a Low Resource Setting

BACKGROUND Although high intensity chemotherapy regimens result in &amp;gt;90% long term survival of children with Mature B-cell Non-Hodgkin Lymphoma (MB-NHL), low intensity chemotherapy regimens are used in most Sub-Sahara African (SSA) setting resulting in decades of less than 20% long term survival. This is in part because dose-intense chemotherapy strategies that are standard of care in high income countries (HIC) have not been widely or effectively implemented in low- and middle income countries (LMIC). We investigated the toxicity and outcomes of children with MB-NHL who were treated with a treatment regimen that includes 1g/M2 of methotrexate per dose (mini COPADM) at Mulago National Referral Hospital in Uganda. The objective of this study was to evaluate the safety and effectiveness of an incremental chemotherapy escalation strategy to control treatment-related toxicities and increase response and survival of children treated for MB-NHL at a pediatric oncology center in the SSA setting. METHODS We prospectively collected clinical outcomes on children under 18 years with MB-NHL at Mulago National Referral Hospital (MNRH) in Uganda between January 2020 and July 2023. Overall (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method. Events in the EFS analysis were: 1) Death; 2) Relapse; or 3) Persistent or progressive disease at the end of Cycle 3. Patients were censored at the earlier of two years from presentation or their last day of follow-up. Descriptive statistics were presented. Toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5. RESULTS We identified 77 patients, among whom 16 (21%) died prior to commencement of the first cycle of chemotherapy and 6 (8%) treated with alternative therapies. The 55 patients who were treated with mini COPADM with 1g/M 2 of methotrexate and are included in this analysis had similar demographics and clinical phenotypes to the 22 that were excluded. The median age was 9.6 years (interquartile range ((IQR) 6.6 - 11.7 years) with 38 (69%) males. Patients were Stage III (53%, 29/55), stage IV (38%, 21/55); and 55%, (30/55) were high-risk. The most common presentations were abdominal mass 43 (78%) and jaw mass 14 (25%). With a median follow-up time of 9 months (IQR 6 - 24 months), the 1-year overall survival (OS) and event free survival (EFS) were 56%; 95% CI (41 - 76) and 41%; 95%CI (27 - 61) respectively. For children with high-risk disease, 1-year OS was 44%; 95%CI (28 - 72) and EFS 25%; 95% CI (12 - 51). Toxicities included febrile neutropenia (83%) and CTCAE grade ≥3 mucositis (44%). For the 12 patients whose cause of mortality was recorded, 1 case (8.3%) was treatment-related and 11 (91.7%) were due to cancer. CONCLUSION: This study establishes baseline response rates, survival, and toxicity for patients with pediatric MB-NHL in Uganda treated with 1g/M2 of methotrexate. Toxicities were consistent with treatment received, perhaps exacerbated by synergy of anthracycline (50 mg/m2) along with intermediate dose MTX. These findings suggest that mini-COPADM with 1g/M 2 of methotrexate can be safely supported with the current clinical resources at MNRH and this low dose regimen accounts for the poor survival of children with MB-NHL in our center. We plan to escalate our therapy to mini-COAPDM with 3g/M2 and addition of Rituximab, with contingent intensification of supportive care to curb treatment-related toxicities.

A Multifaceted Intervention to Improve Teamwork on an Inpatient Pediatric Neurosurgery Service

Increased safety reports related to interprofessional teamwork on an acute care unit at a quaternary children's hospital prompted a teamwork-focused improvement effort on the pediatric neurosurgery service. An interprofessional workgroup was formed and met twice monthly throughout the project. A survey using modified validated items was disseminated to pediatric neurosurgery nurses, advanced practice providers (APPs), and physicians in March 2021 to identify opportunities for improvement. Structured debriefs on survey results promoted discourse on teamwork. The researchers implemented two interventions: (1) nursing-centered interprofessional education and (2) a rounding checklist before redistributing the survey in December 2021. Baseline and follow-up survey response rates were 84.1% (58/69) and 71.4% (50/70), respectively. Nurses at baseline perceived lower teamwork scores for 12 items compared to physicians and APPs (p < 0.05). Nurse perceptions improved after interventions in: "using 'we' rather than 'they'" (21.3% vs. 51.2% agree, p = 0.003), "I am confident that this team works effectively" (46.8% vs. 80.5%, p = 0.001), "shared understanding of each other's role on the team" (48.9% vs. 73.2% agree, p = 0.02), and "getting others on the team to listen" (46.8% vs. 75.6%, p = 0.004). Mean teamwork effectiveness improved from 4.12 to 5.25 (out of 7; p < 0.0001). Nurses ranked three interventions as most effective: interprofessional training (35/41, 85.4%), educational clinical pearls (14/41, 34.1%), and structured opportunities to discuss teamwork (10/41, 24.4%). Interprofessional training, a teamwork survey, and structured debriefing improved nurse perceptions of teamwork. Interventions targeting social components of change can improve teamwork even without process changes.

Attitudes and Perception of the REFLECT Communication Curriculum for Clinical Oncology Graduate Medical Education

Communication and interpersonal skills are essential components of oncology patient care. The REFLECT (Respect, Empathy, Facilitate Effective Communication, Listen, Elicit Information, Compassion, and Teach Others) curriculum is a novel framework to improve and refine physician/patient interactions for oncology graduate medical trainees. We seek to evaluate the attitudes and perceptions of the REFLECT communication curriculum among oncology trainees. Seven-question and 8-question Likert scale surveys (1 = not beneficial and 5 = beneficial) were distributed to resident/fellow participants and faculty mentors, respectively. Questions asked trainees and faculty about their perceptions of improvement in communication, handling of stressful situations, the value of the curriculum, and overall impression of the curriculum. Descriptive statistics determined the survey’s baseline characteristics and response rates. Kruskal–Wallis rank sum tests were used to compare the distribution of continuous variables. Thirteen resident/fellow participants completed the participant survey. Six (43.6%) Radiation Oncology trainees and 7 (58.3%) Hematology/Oncology fellows completed the trainee survey. Eight (88.9%) Radiation Oncologists and 1 (11.1%) Medical Oncologist completed the observer survey. Faculty and trainees generally felt that the curriculum increased communication skills. Faculty responded more favorably to the program’s impact on communication skills (median 5.0 vs. 4.0, p = 0.008). Faculty were more assertive about the curriculum’s capabilities to improve a learner’s ability to handle stressful situations (median 5.0 vs. 4.0, p = 0.003). Additionally, faculty had a more favorable overall impression of the REFLECT curriculum than the residents/fellows (median 5.0 vs. 4.0, p < 0.001). Radiation Oncology residents felt more strongly that the curriculum enhanced their ability to handle stressful topics, compared to Heme/Onc fellows (median 4.5 vs. 3.0, range 1–5, p = 0.379). Radiation Oncology trainees felt more consistently that the workshops improved their communication skills, compared to Heme/Onc fellows (median 4.5 vs. 3.5, range 1–5, p = 0.410). The overall impression between Rad Onc resident and Heme/Onc fellows was similar (median 4.0, p = 0.586). Conclusions: Overall, the REFLECT curriculum enhanced communication skills of trainees. Oncology trainees and faculty physicians feel that the curriculum was beneficial. As interactive skills and communication is critical to build positive interactions, further work is needed to improve the REFLECT curriculum.

Feasibility of CAR-T in very old patients with relapsed/refractory diffuse large B-cell lymphoma.

e19521 Background: Chimeric antigen receptor T-cell therapy (CAR-T) has shown great efficacy in older relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) patients (pts). Pivotal trials have shown similar progression free survival (PFS) and overall survival (OS) between older and younger pts, and no difference in the incidence of cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), or grade 3-4 hematologic and non-hematologic toxicities. Nevertheless, there are limited reports in the literature concerning very old pts (≥75 years) receiving CAR-T for R/R DLBCL, and especially real world data in correlation with co-morbidities. Methods: We conducted a retrospective, single center analysis, including R/R DLBCL pts who underwent apheresis for CAR-T at 75 and older. We assessed co-morbidities by Cumulative Illness Rating Scale (CIRS-G) tool which set a score of 0-4 on all organ systems according to severity, and polypharmacy at time of apheresis, defined as ≥5 medications per day. We analyzed baseline characteristics, response rates, toxicity, and survival outcomes (PFS and OS). Results: A total of 47 pts were referred for CAR-T treatment. Median age at apheresis was 76.6 (75-86) years. Most of these pts received first-line treatment with full or attenuated dose R-CHOP (89%). However, 20 pts (42.5%) had refractory disease, and those achieving PR/CR had a median time to relapse of 13 months. Thirty-two pts (68%) were referred for CAR-T with refractory disease. Six pts died before receiving the CAR-T infusion due to PD. Characteristics of 41 pts receiving CAR-T infusion divided into subgroups of pts with CIRS-G categories 3-4 and pts with polypharmacy are shown in the table. Conclusions: CAR-T in very old (≥ 75 years) R/R DLBCL is feasible with no increased toxicity. While efficacy is important, the preliminary survival analysis seems suboptimal. At 1-year follow-up only a third of pts are alive. Severe co-morbidities or polypharmacy did not impact response or survival. Most deaths were due to disease progression, these outcomes might be attributed to the high rate of refractory disease. [Table: see text]

Prediction of cancer treatment response from histopathology images through imputed transcriptomics.

1551 Background: In recent years, the use of tumour molecular profiling within the clinic has allowed for more accurate cancer diagnostics, as well as the delivery of precision oncology. Rapid advances in digital histopathology have allowed the extraction of clinically relevant information embedded in tumor slides by applying machine learning methods, capitalizing on recent advancements in image analysis via deep learning. However, as in many supervised learning approaches, predicting response to therapy using whole slide images (WSI) of tissue stained with hematoxylin and eosin (H&amp;E) requires large datasets comprising matched imaging and response data, severely restricting the applicability of this approach. Methods: To overcome this critical challenge, we introduce here for the first time a generic methodology for generating WSI-based predictors of patients’ response for a broad range of cancer types and therapies, which does not require matched WSI and response data for training. The approach, termed ENLIGHT-DeepPT, consists of: (1) DeepPT, a new deep-learning framework that predicts exome-wide tumor mRNA expression from slides, and (2) ENLIGHT, a recently published response prediction algorithm, applied here to predict response based on the DeepPT predicted expression values, instead of measured values. Results: First, we study the ability to predict tumor expression, showing that DeepPT successfully predicts transcriptomics in all 16 TCGA cohorts tested and generalizes well to two independent datasets. Second, aligned with our key aim, we analyze six independent clinical trial datasets of patients with different cancer types that were treated with various targeted and immune therapies, on which DeepPT was never trained. We show that ENLIGHT, without any adaptation, can successfully predict the true responders from the expression values imputed by DeepPT, using only H&amp;E images: ENLIGHT-DeepPT successfully predicts true responders in these cohorts with an overall odds ratio of 2.19, increasing the baseline response rate by 38.8% on average among predicted responders. Conclusions: ENLIGHT-DeepPT is the first approach to successfully predict response to multiple targeted and immune cancer therapies directly from H&amp;E slides, without requiring any drug-specific training data. ENLIGHT-DeepPT can provide rapid treatment recommendations without requiring tumor sequencing, bringing precision oncology to low-income countries and other situations where NGS is prohibitive.

XEN1101, a Novel Potassium Channel Modulator: Interim Data From an Ongoing, Long-Term, Open-Label Extension of a Phase 2b study (X-TOLE) in Adults with Focal Epilepsy (S44.008)

XEN1101, a Novel Potassium Channel Modulator: Interim Data From an Ongoing, Long-Term, Open-Label Extension of a Phase 2b study (X-TOLE) in Adults with Focal Epilepsy (S44.008)

Abstract 4355: Prediction of cancer treatment response from histopathology images for a broad set of treatments and indications

Abstract Background: Advances in artificial intelligence have paved the way for predicting cancer patients’ survival and response to treatment from hematoxylin and eosin (H&amp;E)-stained tumor slides. Extant approaches do so either via prediction of actionable mutations and gene fusions, or directly from the H&amp;E images by training a task-specific model using large treatment outcome data. Methods: Here we present the first approach for predicting patient response to multiple targeted treatments and immunotherapies directly from H&amp;E slides. It is founded on two conceptual steps: (1) First, we developed DeepPT, a deep-learning framework that trains on formalin-fixed, paraffin-embedded (FFPE) TCGA whole slide images and their corresponding gene expression profiles to predict wide-scale tumor gene expression from the slides. (2) Second, we apply ENLIGHT, a published approach that predicts individual responses to a wide range of targeted and immunotherapies based on the tumor biopsy measured transcriptomics. Here we apply ENLIGHT to predict patient treatment response from the DeepPT predicted expression values instead of those measured directly from the tumor, notably, without any further training or adaptation of ENLIGHT. Results: First, we find that DeepPT generalizes well to predicting gene expression in all 13 TCGA cohorts tested in cross-validation and importantly, in two independent unseen breast and brain cancer datasets. DeepPT outperforms HE2RNA, a state-of-the-art algorithm for the same task. Second, we demonstrate that the combined DeepPT/ENLIGHT pipeline (termed ENLIGHT-DeepPT) successfully predicts true responders using the original ENLIGHT decision threshold with odds ratios of 1.5 - 4.5, increasing the baseline response rates by 15-85% among predicted responders in five independent unseen cohorts of diverse cancer types and treatments. Remarkably, in one dataset where matched data was available, ENLIGHT-DeepPT has similar performance to that obtained by a supervised learning algorithm that was recently published in Nature, trained on the same cohort. Conclusions: We present for the first time a general framework for predicting patient response to a broad array of targeted and checkpoint therapies from histopathological images, without reliance on treatment outcome data, which are yet scarce and challenging to obtain. Importantly, ENLIGHT-DeepPT offers clinicians real-time treatment recommendations when one cannot wait for sequencing results. Also, and due to its very low cost, we very much hope that it will facilitate the advent of precision oncology in developing countries. Citation Format: Danh-Tai Hoang, Gal Dinstag, Leandro C. Hermida, Doreen S. Ben-Zvi, Efrat Elis, Katherine Caley, Sanju Sinha, Neelam Sinha, Christopher H. Dampier, Tuvik Beker, Kenneth Aldape, Ranit Aharonov, Eric A. Stone, Eytan Ruppin. Prediction of cancer treatment response from histopathology images for a broad set of treatments and indications. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4355.

The effect of childhood adversities on the persistence of suicidal ideation and plans among college students: A longitudinal study

BackgroundExposure to childhood adversities (CAs) is known to be associated with the onset of suicidal ideation and plans. However, little is known regarding the contribution of CAs to their persistence. AimsThe study aims to examine the type, number and frequency of CA exposure on the persistence of suicidal ideation and plans at one-year. MethodData were drawn from the French portion of the World Mental Health International College Student survey. At baseline (n = 2661, response rate = 7,58 %), exposure to 12 types of CAs prior to age 18, lifetime mental disorders, lifetime and 12-month suicidal ideation and plans were assessed. At one-year follow-up (n = 1221), 12-month mental disorders, suicidal ideation and plans were assessed. Among those with a prior history of suicidal ideation, logistic regressions were performed to examine the role of CAs on the persistence of ideation and plans at one-year. ResultsAt baseline, frequency and number of CAs were associated with 12-month suicidal ideation and plans. Among lifetime ideators, 49.6 % reported 12-month suicidal ideation at follow-up. Physical abuse was associated with an increased risk of suicidal ideation and plan persistence at one year in univariate analyses. However, CAs were not associated with the persistence of suicidal ideation and plans at one-year in multivariate analyses. LimitationsRetrospective report of CA exposure, and low baseline response rate. ConclusionsUsing a fine-grained operationalization of CA exposure, CAs were not involved in the persistence of suicidal ideation or plans, their deleterious effect more likely to occur early in the course of psychopathology.

Efficacy and toxicity of Ipilimumab-Nivolumab combination therapy in elderly metastatic melanoma patients.

Immunotherapy has revolutionized metastatic Melanoma therapy. The most active regimen is combination therapy of Ipilimumab-Nivolumab (Ipi-Nivo) with response rates (RR) of ~60% and median overall survival (OS) of ~6 years. Immune-related adverse events (irAE) are common (~60% develop grade 3-4) and pose a challenge when treating frail patients. We sought to examine whether Ipi-Nivo therapy is feasible in elderly metastatic melanoma patients. Electronic records of patients treated at the Ella Lemelbaum Institute with Ipi-Nivo between the years 2017-2021 were screened for age. Elderly patients were defined as age 75 and older (group A) and were matched with records of patients age <75 (group B). Records were analyzed for baseline parameters, immunotherapy regimen, RR, toxicity and progression-free survival (PFS). Twenty-six relevant patients age >75 (median 77) were identified and were matched to 34 younger patients (median age 57). No statistically significant differences were noted in terms of baseline parameters except for BRAF mutation status (group A 15%, group B 47%, p=0.008). Response rate in group A was 38% and is consistent with previously published data. Median PFS was the same for both groups (A = 5.5 months, B= 7.5 months, p=NS). Treatment was similarly tolerated: 35% of group A patients completed 4 cycles of therapy compared to 28% for group B (p=NS). Grade 2-4 irAE were the same (A=58%, B=66%, p=NS) and there was no difference in the need for hospitalization for G3-4 events between the groups. (A=63%, B=69%, p=NS). Further division into 4 age groups (>80 vs 75-79 in group A and 65-74 vs <65 in group B) found no difference in terms of response rate or G3-4 toxicity. Ipilimumab-Nivolumab combination therapy in elderly metastatic Melanoma patients seems to be well tolerated and efficient in selected elderly patients based on performance status and comorbidities, just as in younger patients. This regimen seems to be a feasible treatment option for this age group.

Development, implementation, and evaluation of a simulation-based educational curriculum for pediatric hospitalists.

Minimal published simulation-based educational training exists for practicing pediatric hospitalists. Our aim was to determine specific pediatric hospital medicine (PHM) knowledge, skill, and competency needs aligned with our scope of practice and evaluate the impact of a simulation-based training curriculum. Baseline and post-training surveys were administered to 48 physicians providing self-ratings on a 5-point scale from Novice to Expert on published PHM competencies. Results were used to develop a targeted simulation curriculum. Participants were considered competent in a domain if their mean score was 3 or greater. We categorized participant responses to individual questions into nine domain scores on survey self-assessments. Score analysis was performed using the signed-rank test and McNemar's test. Post-training evaluations solicited curriculum acceptance and perceived clinical value. The baseline response rate was 98%and the post-training response rate was 85%. Areas with the lowest competency on baseline self-assessment included advanced airway management (38%), vascular access and emergency medications (38%), code cart skills (19%), team communication (51%), and medically complex care (49%). Post-training scores improved significantly for five of nine domains, with the largest gains in the "not competent" at baseline group. Percent competent (% with mean score >3) increased significantly in three domains (advanced airway management, code cart skills, and complex care). Participants rated educational sessions favorably (98%) and most (95%) reported using knowledge/skills learned for patient care. Baseline self-assessment results were instrumental in curriculum design. Post-training analysis revealed gains in multiple domains and identified opportunities for future interventions. Most hospitalists reported participation positively impacted patient care with high learner satisfaction.

Increasing Pediatric Morning Report Educational Value Through Quality Improvement.

Morning report (MR) is a common case-based conference in graduate medical education. Recent studies highlight participant dissatisfaction with the educational value of MR, but data are lacking on means for improvement. We aimed to increase MR quality and participant satisfaction at our academic pediatric residency program. Improvement science was used to develop and implement a new standardized pediatric MR process (intervention), with 5 core educational elements and structured resident-faculty mentorship. Educational elements were measured via feedback forms and tracked using a run chart. Residents and faculty were surveyed regarding MR quality and satisfaction at baseline and 6 months postintervention; responses were analyzed using mixed effects logistic regression. The median of educational elements increased from 3 to 5 (5 maximum) during the 6-month study period and 12-months poststudy. Baseline and postintervention survey response rates were 90% (18 of 20) for residents and 66% (51 of 77) for faculty. Residents reporting high quality MR changed from 50% to 72% (P = .20), and faculty from 29% to 85% (P <.001). Satisfaction with MR content increased for both residents (50%-89%, P = .03) and faculty (25%-67%, P <.001). Resident satisfaction with faculty mentorship before MR increased from 28% to 78% (P = .01); satisfaction with faculty feedback after MR increased from 11% to 56% (P = .02). Improvement science can be used to develop a new pediatric graduate medical education process. Requiring core educational elements and providing structured mentorship were associated with improvements in pediatric MR quality and participant satisfaction.