Prior Clinical Experience Research Articles

Analytical performance of a point-of-care CBC hematology analyzer, including a 5-part differential: A prospective study to evaluate a microfluidic flow cytometry–based analyzer in waived settings

Abstract Objectives A microfluidic flow cytometer–based point-of-care (POC) analyzer was validated against an in-laboratory hematology analyzer (Sysmex XN Automated Hematology System). Concordance on a full complete blood cell count (CBC) with 5-part differential, as performed by operators with no prior clinical laboratory experience, was evaluated. Methods We prospectively collected 376 venous blood specimens (376) from individuals with self-reported medical conditions and from apparently healthy individuals. Forty-six additional remnant specimens were acquired to ensure coverage of analytic measuring ranges. Parallel testing was performed, with up to 7 hours between testing on the POC and Sysmex XN analyzers. Results Regression analysis resulted in r values of 0.998 to 0.932 for all parameters of a 5-part differential CBC other than basophils (0.709). The mean percentage bias from the reference method, inclusive of the upper and lower reporting limits, was less than 2% for parameters other than lymphocytes (–6.4%), monocytes (25.9%), eosinophils (12.2%), and basophils (–15%). Overall agreement on abnormal flagging was 93.3%. Conclusions The Cito CBC microflow cytometer (CytoChip Inc) provides a CBC with a 5-part differential with accuracy, precision, and abnormal flagging equivalent to a moderate-complexity hematology analyzer. It has the key features required of a POC device that can be operated in a waived setting: minimum space requirements, rapid results, single-action measurement (no sample processing or dilution), ease of use, and minimal blood volume.

A hybrid meta-heuristic framework with ensemble deep learning for multi-functional simultaneous optimized automatic intensity-modulated radiotherapy planning

Intensity-modulated radiotherapy (IMRT) is one of the main treatments for patients with cancer, and its treatment planning holds significant importance. Compared to manual treatment planning, automatic treatment planning (ATP) is expected to improve plan quality and efficiency, which is of great clinical importance. However, treatment planning is an intractable “black art” that calls for intuition and heuristics from medical dosimetrists. There are two main issues with the current ATP methods: (i) they rely strongly on prior clinical experience and are not sufficiently scalable, and (ii) they use a single-functional optimization concept that ignores delivery accuracy information, which lowers the delivery accuracy of the generated ATP plans. To address these issues, this paper presents a novel multi-functional simultaneous optimized automatic treatment planning (MFSO-ATP) method. First, to address the issues of high reliance and insufficient scalability, an evolutionary strategy (ES) and simulated annealing (SA)-based hybrid meta-heuristic trial-and-error (ESSA-HMTE) framework is designed to automatically adjust optimization parameters without human intervention. Second, to address the issue of delivery accuracy deterioration, an ensemble deep learning-based gamma passing rate (GPR) prediction (EnDL-GPR) framework was constructed and trained to predict the plan delivery accuracy a priori. The ESSA-HMTE framework effectively fuses dosimetric quality information and delivery accuracy a priori information to simultaneously optimize the two, ensuring delivery accuracy while achieving automatic planning. We tested the MFSO-ATP method using multiple diseases with high inter-tumor heterogeneity. The results showed that the proposed method can improve the quality and delivery accuracy of IMRT plans, reduce the percentage of quality assurance failures, is highly scalable, and has good clinical application prospects.

Empowering Medical Students to Practice High-Value Care

Over the last decade, initiatives like the Choosing Wisely campaign have promoted the practice of evidence-based, cost-conscious care. However, education surrounding value in medicine has been largely restricted to graduate-level medical education or post-clerkship undergraduate medical education. Here, we present a mixed-methods study evaluating pre-clerkship medical student engagement with and response to new value-based curricular initiatives to assess whether high-value care (HVC) can be introduced successfully earlier in training. Initiatives were introduced into the pre-clerkship clinical curriculum without major alterations to the established curricular structure. These comprised an annual event devoted to self-reflecting on HVC observed in prior and current clinical experiences and subsequent small-group facilitated discussion. Engagement with and response to these initiatives were analyzed for two whole-class cohorts using an abductive, progressive focusing approach complementing quantitative survey data. Baseline familiarity with HVC and post-event response to the annual event was higher and more positive, respectively, among responders from the Class of 2025 compared with those from the Class of 2024. Analysis of reflection essays revealed the emergence of five primary themes differentiating the two class years: (1) understanding HVC, (2) addressing barriers to HVC, (3) medical waste and underserved communities, (4) patient–physician relationship and value, and (5) self-reflection. Evaluation of thematic patterns in light of survey response data suggests that early clinical exposure combined with intentional self-reflection could promote engagement with HVC topics in a way that shapes students’ foundational understanding of the practice of medicine.

"With Great Responsibility Comes Great Uncertainty".

Uncertainty is inherent in medicine, and trainees are particularly exposed to the adverse effects of uncertainty. Previous work suggested that junior residents seek to leverage the support of supervisors to regulate the uncertainty encountered in clinical placements. However, a broader conceptual framework addressing uncertainty experience, from the sources of uncertainty to residents' responses, is still needed. To capture the spectrum of uncertainty experiences in medical residents, providing an integrative framework that considers the influence of specialties and training stages on their experience with clinical uncertainty. We used Hillen's uncertainty tolerance framework to conduct a thematic template analysis of individual and focus group interviews, identifying themes and subthemes reflecting residents' experience of clinical uncertainty. Medical residents from diverse medical specialty training programs, across five French medical schools. Qualitative study driven by an interpretivist research paradigm. Twenty residents from all years of medical residency and diverse medical specialties were interviewed during three focus groups and five individual interviews. They described managing treatments, making ethical decisions, and communicating uncertainty, as their major sources of uncertainty. We identified residents' delayed response to uncertainty as a key theme, fostering the development of experiential learnings. Prior clinical experience was a key determinant of uncertainty tolerance in medical residents. Entrusting residents with responsibilities in patient management promoted their perception of self-efficacy, although situations of loneliness resulted in stress and anxiety. Residents face significant uncertainty in managing treatments, ethical decisions, and communication due to limited clinical experience and growing responsibilities. Scaffolding their responsibilities and clearly defining their roles can improve their comfort with uncertainty. To that extent, effective supervision and debriefing are crucial for managing emotional impacts and fostering reflection to learn from their uncertain experiences.

Emotion regulation in emotionally focused therapists working with high-conflict couples.

Guided by the Person-of-the Therapist Training (POTT) Model, the current qualitative study explores emotional experiences and emotion regulation strategies of emotionally focused trained therapists who work with high-conflict couples in Turkey. Twenty-one therapists who completed at least the externship in emotionally focused couple therapy (EFCT) and had prior or current clinical experience working with high-conflict couple(s) were recruited through various social media platforms and professional organizations' listservs. Semistructured individual interviews were conducted, audio-recorded, and transcribed verbatim. Thematic analysis of the qualitative data revealed five main themes: (1) Different Compelling Emotional Experiences of the Therapists, (2) Sun After Storm, (3) Triggers of Therapists' Emotions, (4) Perceived Adaptive Emotion Regulation Strategies, and (5) Positive Impact of the Therapist's Regulation Strategies on the Therapy Process. Overall, the findings supported the three phases of the POTT model: namely, knowledge of self, access to self, and use of self. Our study demonstrates the need for integrating self-of-the-therapist work into the clinical practice, training, and supervision of therapists working with distressed couples.

Ocular manifestations of mpox.

To highlight the clinical features of mpox with an emphasis on ocular manifestations and to review treatment options for this re-emerging infectious disease. Ocular involvement of mpox varies by clade. The most recent 2022 outbreak appears to be associated with fewer conjunctivitis cases compared to previous outbreaks. However, the ocular findings occurring during this newly emerging clade can be visually threatening and include cases of keratitis, rapidly progressing scleritis, and necrotizing periorbital rashes. Ocular mpox is an important clinical feature of systemic mpox virus (MPXV) infection. Heightened clinical suspicion allows for a timely diagnosis and the initiation of antiviral treatment, when appropriate. Randomized clinical trials for mpox systemic and ocular treatment efficacy are lacking. Prior clinical experience with smallpox and in-vitro mpox data support the use of systemic antivirals such as tecovirimat, cidofovir, brincidofovir and topical use of trifluridine in ocular mpox management, though treatment-resistant infection can occur and portend a poor prognosis.

A first-in-human phase 1 trial of T cell membrane-anchored tumor targeted IL12 (ATTIL12) -T cell therapy in advanced/metastatic soft tissue and bone sarcoma.

TPS11586 Background: Interleukin-12 (IL12) is a cytokine that induces antitumor immune response and immune memory by activation of NK cells, induction of IFNg, and maturation of DC cells in the tumor microenvironment (TME). However, prior clinical experience with IL12 has been limited by toxicities including cytokine release syndrome (CRS) and hepatotoxicity. We developed a novel tumor-targeted IL12 gene (ttIL12) that encodes the p35 and p40 VNTANST fusion subunits that targets cell surface vimentin (CSV). Vimentin is expressed intracellularly in many normal and neoplastic mesenchymal cells but our group discovered that intracellular vimentin is often flipped to the cell surface (referred to as CSV) across multiple tumor types.2 Preclinical studies demonstrated efficacy and induction of long-term memory of ttIL12 against metastatic osteosarcoma with reduced toxicity in immune competent models.3 However, ttIL12 had limited efficacy in treating large volume tumors and did not completely eliminate toxic peripheral cytokines. To address this, our team generated a membrane anchored ttIL12 to arm T cells known as attIL12-T cell therapy. We hypothesize attIL12 will minimize toxic cytokines in peripheral tissues but promote induction of INFg/TNFa in the TME to decrease the toxicity and boost efficacy. Methods: This is a phase 1 trial of attIL12-T cells in patients (pts) with locally advanced or metastatic soft tissue or bone sarcomas to assess safety, maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pts in part A (dose finding) will be enrolled using a Bayesian optimal interval (BOIN) design in up to 6 dose levels. Part B (dose expansion) will evaluate preliminary efficacy in 10 additional pts with osteosarcoma treated at the RP2D. Treatment:Pts will undergo leukapheresis to collect peripheral blood mononuclear cells (PBMCs) for generation of attIl12-T cells. Bridging therapy is permitted but not required. Pts will receive cyclophosphamide (Cy) IV prior to planned T cell administration. attIL12 T cells will be administered at the specified dose level IV in a single infusion (dose level 1 and 2) or 2 serial doses (dose level 3-6) on day 0 and day 14. Pts will be monitored for toxicity and response evaluation. Pts will also undergo pre-treatment/on-treatment tumor biopsies for translational and correlative analysis. Eligibility:Pts must be ≥ 12 years of age, have a confirmed diagnosis of locally advanced or metastatic sarcoma, evaluable disease, received at least 1 prior line of standard systemic therapy, ECOG PS 0-1, and adequate organ function to tolerate immune-effector cell therapy. Pts with known sensitivity to Cy, active/prior autoimmune disease, uncontrolled CNS disease, or other uncontrolled comorbidities that pose potential safety risk will be excluded. Enrollment to cohort 1 began in Dec 2023. Clinical trial information: NCT05621668 .

Teaching foundational language equity concepts in the pre-clinical curriculum

BackgroundDespite the prevalence of non-English languages in the US population, existing medical training to teach communication with linguistically diverse communities is limited to electives or solely focuses on medical interpreting. Language-appropriate communication skills are seldom comprehensively integrated in medical education. This study describes the development and evaluation of an intervention to teach foundational language equity concepts.MethodsThe authors implemented a pre-clinical language equity course at three medical school campuses between August 2020 and March 2022. Sessions focused on the impact of language in health, physician language proficiency standards, and working with medical interpreters. The study sought to (1) understand students’ language skills and prior clinical experiences with patients with non-English language preference and (2) evaluate the curriculum’s impact. Students self-reported their language skills and experiences as part of a voluntary pre-questionnaire. Pre and post-questionnaires evaluated knowledge, attitudes, and intent to apply language equity concepts. Descriptive statistics and chi-squared tests were used to examine trends; themes were identified from free-text responses.ResultsOverall, 301 students completed the course, 252 (83%) completed at least one questionnaire; for each session, between 35% and 46% of learners completed both pre and post-questionnaires. Three quarters (189/252) reported non-English languages. Over half (138/252) reported previous non-English language patient care, and 28% (62/224) had served as ad hoc (untrained) interpreters. Only two students (< 1%) had ever been assessed for medical language abilities. Students demonstrated improved post-course language equity knowledge, strategies for interpreter-mediated encounters, and likelihood to report a plan for language skills assessment (all p < .001). Most plans were multifaceted (61%, 38/62), involving goals like completing a language course, taking a proficiency exam, openly discussing skills and uncertainties with team members, and increasing professional interpreter utilization.ConclusionsA longitudinal language equity curriculum can be feasibly integrated in pre-clinical education, highlight the linguistic diversity of the student body, and serve as a first step in ensuring that all students have a strong language equity foundation prior to clinical rotations. Future steps include evaluating the intervention’s potential long-term effects on professional interpreter utilization, student clinical performance, and institutional culture that promotes multilingualism.

Increased Perceived Confidence in Professional Role Skills among Undergraduate Dietetic Students Following Simulation-Based Learning Experiences

Simulation-based learning experiences (SBLEs) are effective for teaching healthcare students clinical and communication skills. The current study assessed self-perceived clinical and communication confidence among dietetics students completing a series of four SBLEs (3 group, 1 individual) across nine months. Dietetics students were recruited in February 2023 prior to their first SBLE. Simultaneously through the academic year, students completed clinical and communication courses. Students were invited to complete an online, anonymous self-reported survey regarding confidence with nutrition care and communication prior to their first SBLE (Time 1), prior to their third SBLE (Time 2), and following their final SBLE (Time 3). The survey measured healthcare work experience and self-perceived confidence. Student confidence increased among 30 of the 38 indicators (p &lt; 0.05). At Time 2 (following two group SBLEs), those with healthcare experience had higher confidence among 12 of the 39 items (p &lt; 0.05). At Time 3 (following four simulation experiences) those with healthcare experience had higher confidence among just four of the 39 total items (p &lt; 0.05). Cohort increases in confidence suggest that SBLEs, along with dietetics coursework, were critical in increasing confidence and students’ perceived ability to carry-out entry-level tasks of a dietitian. While student confidence increased across the cohort, SBLEs were particularly beneficial in leveling confidence between those with prior clinical experience and those without.

Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis

BackgroundIvacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF. MethodsIn this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements. ResultsSeven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (−40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed. ConclusionsIn this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.

Maternity healthcare professionals’ experiences of supporting women in decision-making for labour and birth: a qualitative study

ObjectivesTo explore and characterise maternity healthcare professionals’ (MHCPs) experience and practice of shared decision-making (SDM), to inform policy, research and practice development.DesignQualitative focus group study.SettingLarge Maternity Unit in the Southwest...

Abstract 1932: Overcoming acquired resistance to KRAS(G12D) inhibition using a KRAS-HSP90 hetero-bifunctional small molecule therapeutic agent

Abstract KRAS mutations are highly prevalent across many different cancer types. Recent advancements in KRAS-targeted drugs, such as the FDA-approved KRAS(G12C) inhibitors sotorasib and adagrasib for NSCLC patients, have shown great promise in the clinic. Nonetheless, these new agents fail to address other mutations, such as KRAS(G12D), which overall is the most common KRAS mutation in cancers, being found in 37% of pancreatic ductal adenocarcinomas, 12.5% of colorectal cancers and 4.9% of lung adenocarcinomas. Recently, MRTX1133 has been described as a selective, non-covalent inhibitor of KRAS(G12D) that shows promising preclinical efficacy and is undergoing clinical testing. However, based on prior clinical experience with sotorasib and adagrasib, acquired resistance to MRTX1133 may reasonably be anticipated. In fact, we find that KRAS(G12D)-mutated cell lines and a patient-derived organoid model exhibit varying degrees of inherent resistance to MRTX1133. To examine the consequences of blocking KRAS signaling, we employed a KRAS(G12D)-specific PROTAC, which simulated the effects of KRAS deletion. This demonstrated that receptor tyrosine kinase (RTK) activation could compensate for loss of KRAS signaling and was a key de novo resistance mechanism. This suggests that combination therapies may need to be individually tailored to treat patients resistant to KRAS(G12D)-targeted therapies. Additionally, we developed MRTX1133 resistant cells by culturing sensitive AsPC-1 pancreatic cancer cells in gradually increasing concentrations of the inhibitor. The resulting resistant cells displayed a complex RTK activation profile compared to parental cells. To counteract this, we employed KRAS(G12D)-CHAMP RNK08179, a hetero-bifunctional small molecule agent that simultaneously targets both KRAS(G12D) and HSP90, an RTK-regulating chaperone protein. RNK08179 effectively suppressed both KRAS signaling and RTK activation in MRTX1133-resistant cancer models, overcoming the compensatory resistance mechanisms observed with MRTX1133 alone. These findings highlight the potential of KRAS-CHAMPs as a novel, effective treatment strategy for KRAS-driven cancers, particularly those resistant to KRAS(G12D) inhibitors. Citation Format: Ines Pulido Endrino, Laura gunder, Qiyue Luan, Chenghao Ying, Zimo Yang, Jinhua Li, Yaya Wang, Yuetong Sun, Chuhe Liu, Yan Dai, Haoxin Zhou, Malek Massad, Ian Papautsky, Thomas L. Prince, Guoqiang Wang, Kevin P. Foley, Weiwen Ying. Overcoming acquired resistance to KRAS(G12D) inhibition using a KRAS-HSP90 hetero-bifunctional small molecule therapeutic agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1932.

Pediatric Polytrauma Fire Victim Simulation.

Pediatric trauma has long been one of the primary contributors to pediatric mortality. There are multiple cases in the literature involving cyanide (CN) toxicity, carbon monoxide (CO) toxicity, and smoke inhalation with thermal injury, but none in combination with mechanical trauma. In this 45-minute simulation case, emergency medicine residents and fellows were asked to manage a pediatric patient with multiple life-threatening traumatic and metabolic concerns after being extracted from a van accident with a resulting fire. Providers were expected to identify and manage the patient's airway, burns, hemoperitoneum, and CO and CN toxicities. Forty learners participated in this simulation, the majority of whom had little prior clinical experience managing the concepts highlighted in it. All agreed or strongly agreed that the case was relevant to their work. After participation, learner confidence in the ability to manage each of the learning objectives was high. One hundred percent of learners felt confident or very confident in managing CO toxicity and completing primary and secondary surveys, while 97% were similarly confident in identifying smoke inhalation injury, preparing for a difficult airway, and managing CN toxicity. This case was a well-received teaching tool for the management of pediatric trauma and metabolic derangements related to fire injuries. While this specific case represents a rare clinical experience, it is within the scope of expected knowledge for emergency medicine providers and offers the opportunity to practice managing multisystem trauma.

Immigrant Mothers' Perspectives on Pediatric Primary Care: Challenges and Solutions to Improve Medical Home Use

Abstract: Children in immigrant families (CIF) constitute 25% of all children in the United States. Known barriers to accessing and navigating the health care system for immigrants (i.e., poverty, fear, limited English proficiency, lack of insurance) lead to decreased medical home establishment among CIF, although the ways in which these obstacles affect medical home access are less studied. With a focus on Congolese, Afghan, Syrian/Iraqi, and Central American immigrants, key informant interviews and focus groups were conducted to identify mothers' perceptions of and experiences with pediatric primary health care. Five common themes emerged: mothers' critical role in children's health, uniqueness of the U.S. health care system, logistical challenges, influence of prior clinical experiences, and importance of culturally appropriate communication. Few, but distinct, differences among the groups revealed specific obstacles for individual populations. Improving rates of medical home use among CIF requires targeted, immigrant-informed approaches that involve population outreach as well as systems-level changes.

Abstract C003: RAMP 205: A phase 1b/2a study of gemcitabine, nab-paclitaxel, avutometinib, and defactinib in untreated metastatic pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) accounts for ~90% of pancreatic cancer. Surgery is the only curative treatment. Unfortunately, most patients are diagnosed with advanced disease and are not candidates for resection. Combination chemotherapy approaches have provided incremental improvements to PDAC outcomes. However, impact on survival for patients with inoperable disease remains modest, with a 2-year survival rate of less than 7%. Activating mutations in the KRAS oncogene are a key initiating event in ~80-90% of PDAC. Permanent activation of KRAS drives tumor cell proliferation and survival, tumor microenvironment modulation, and metabolic alterations in PDAC. Patients with KRAS mutant PDAC have worse outcomes compared to those with KRAS wild-type PDAC. In addition, hyperactivation of focal adhesion kinase (FAK) has been correlated with high stromal density, resulting in therapeutic resistance and poor survival. Avutometinib is a first-in-class oral RAF/MEK clamp that potently inhibits MEK kinase activity while also blocking the compensatory reactivation of MEK by upstream RAF. Defactinib is a selective inhibitor of focal adhesion kinase (FAK), which has been shown to mediate resistance to multiple anticancer agents. Preclinical data have shown that the combination of avutometinib + FAK inhibition (FAKi) + chemotherapy (gemcitabine + paclitaxel as a surrogate for nab-paclitaxel) induced tumor regression in a autochthonous KRAS/TP53 mutant PDAC mouse model. Prior clinical experience of defactinib + pembrolizumab + chemotherapy was safe, showed responses, decreased stromal density, and increased CD8+ T cell infiltration in patients with PDAC (NCT02546531). Methods: RAMP 205 is a multi-center, open-label, single arm Phase 1b/2a study of gemcitabine and nab-paclitaxel in combination with avutometinib and defactinib in patients with previously untreated metastatic PDAC (NCT05669482). The study is being conducted in 2 parts: Parts A (dose evaluation) and Part B (dose expansion). The starting dose is 2.4 mg avutometinib orally (PO) twice weekly + 200 mg defactinib PO twice per day, in combination with standard once weekly gemcitabine/nab-paclitaxel (QW IV). All study drugs are dosed 3 weeks on, 1 week off. Following determination of the Recommended Phase 2 Dose (RP2D) in Part A, Part B will evaluate efficacy of the RP2D via objective response rate (primary endpoint). Mandatory tumor biopsies and blood samples will be collected for correlative studies, including circulating tumor DNA, molecular profiling and pharmacodynamic markers. Eligible patients must have histologic or cytologic evidence of metastatic PDAC and measurable disease according to RECIST v1.1. Patients with prior or concomitant treatment for metastatic PDAC or prior treatment with RAS/MAPK or FAK inhibitors are not eligible. The study will enroll ~35 patients with 6-12 patients in Part A, and 23 patients in Part B. Citation Format: Kian-Haut Lim, Manuel Hidalgo, Mark H. O'Hara, Kristen R. Spencer, Ignacio Garrido-Laguna, David G. DeNardo, Vijeta Bhambhani, Gloria Patrick, Yaofeng Cheng, Silvia Coma, Jonathan A. Pachter, Louis J. Denis. RAMP 205: A phase 1b/2a study of gemcitabine, nab-paclitaxel, avutometinib, and defactinib in untreated metastatic pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C003.

Evaluation of anesthetic skills acquisition in pre-graduate veterinary students with different grades of anesthetic experience using veterinary simulation exercises.

Anesthetic skills are usually learned through continuous supervision by experienced trainers who observe, advise and challenge students. Current educational techniques rely less on live animal training and include the use of simulations and models for teaching and assessment of surgical and anesthetic skills. To evaluate the development of anesthetic skills of veterinary students having different levels of previous experience using simulation. An additional aim was to evaluate the impact of the simulation training on students with no anesthesia experience. Single group periinterventional and postinterventional study. Initial and final anesthesia simulation training recording were obtained from 53 randomly selected veterinary students. Seven faculty members blinded to previous student anesthesia experience reviewed the simulation recording and scored student performance using a rubric, results were recorded and analyzed. All students participating in an anesthesia and surgery course reached higher proficiency levels on fundamental anesthesia skills regardless of their previous amount of experience with anesthesia. Simulation based learning positively influenced the final score in veterinary students having no previous anesthesia training, suggesting that it is possible for veterinary students to achieve a level of competence in anesthesia skills with simulation-based training. Sample size, group simulation, multiple reviewers bias. Students having no experience with clinical anesthesia demonstrated remarkable improvement in their skills, achieving a score that was similar to students having extensive prior clinical anesthesia experience. Despite this clear improvement students having no prior clinical anesthesia experience required more time to complete all anesthesia tasks and may require more training sessions to acquire the speed demonstrated by peers who had significant prior clinical anesthesia experience. Overall, all participants reached a higher proficiency level performing fundamental anesthesia skills at the end of the course.

Sunflower Syndrome: A Survey of Provider Awareness and Management Preferences

BackgroundSunflower syndrome is a rare photosensitive pediatric epilepsy characterized by stereotyped hand-waving in response to bright lights. These stereotyped movements with maintained awareness can be mistaken for a movement disorder. This study assessed neurology providers’ diagnostic reasoning, evaluation, and treatment of Sunflower syndrome. MethodsA 32-question anonymized electronic survey, including a clinical vignette and video of hand-waving in sunlight, was distributed to child neurology providers to assess (1) initial diagnosis and evaluation based on clinical information, (2) updated diagnosis and management after electroencephalography (EEG), and (3) prior experience with Sunflower syndrome. ResultsAmong 277 viewed surveys, 211 respondents provided information about initial diagnosis and evaluation, 200 about updated diagnosis, 191 about management, and 189 about prior clinical experience. Most providers (135, 64%) suspected seizure, whereas fewer suspected movement disorders (29, 14%) or were unsure of the diagnosis (37, 22%). EEG was recommended by 180 (85%). After EEG, 189 (95%) diagnosed epilepsy, 111 of whom specifically diagnosed Sunflower syndrome. The majority (149, 78%) recommended antiseizure medications (ASMs) and sun avoidance (181, 95%). Only 103 (55%) had managed Sunflower syndrome. Epileptologists and those with prior clinical experience were more likely to suspect a seizure, order an EEG, and offer ASMs than those without prior experience. ConclusionsAlthough many providers had not managed Sunflower syndrome, the majority recognized this presentation as concerning for epilepsy. Epilepsy training and prior clinical experience are associated with improved recognition and appropriate treatment. Educational initiatives that increase awareness of Sunflower syndrome may improve patient care.

“Primer shot” fractionation with an early treatment break is theoretically superior to consecutive weekday fractionation schemes for early-stage non-small cell lung cancer

PurposeRadiotherapy is traditionally given in equally spaced weekday fractions. We hypothesize that heterogeneous interfraction intervals can increase radiosensitivity via reoxygenation. Through modeling, we investigate whether this minimizes local failures and toxicity for early-stage non-small cell lung cancer (NSCLC). MethodsPreviously, a tumor dose-response model based on resource competition and cell-cycle-dependent radiosensitivity accurately predicted local failure rates for early-stage NSCLC cohorts. Here, the model mathematically determined non-uniform inter-fraction intervals minimizing local failures at similar normal tissue toxicity risk, i.e., iso-BED3 (iso-NTCP) for fractionation schemes 18Gyx3, 12Gyx4, 10Gyx5, 7.5Gyx8, 5Gyx12, 4Gyx15. Next, we used these optimized schedules to reduce toxicity risk (BED3) while maintaining stable local failures (TCP). ResultsOptimal schedules consistently favored a “primer shot” fraction followed by a 2-week break, allowing tumor reoxygenation. Increasing or decreasing the assumed baseline hypoxia extended or shortened this optimal break by up to one week. Fraction sizes of 7.5 Gy and up required a single primer shot, while smaller fractions needed one or two extra fractions for full reoxygenation. The optimized schedules, versus consecutive weekday fractionation, predicted absolute LF reductions of 4.6%-7.4%, except for the already optimal LF rate seen for 18Gyx3. Primer shot schedules could also reduce BED3 at iso-TCP with the biggest improvements for the shortest schedules (94.6Gy reduction for 18Gyx3). ConclusionA validated simulation model clearly supports non-standard “primer shot” fractionation, reducing the impact of hypoxia-induced radioresistance. A limitation of this study is that primer-shot fractionation is outside prior clinical experience and therefore will require clinical studies for definitive testing.

Phase 1/2 Study of Donor-Derived Anti-CD33 Chimeric Antigen Receptor Expressing T Cells (VCAR33) in Patients with Relapsed or Refractory Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation

Background and Significance: Although allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative therapy for patients with high-risk acute myeloid leukemia (AML), relapse occurs in 30% to 40% of alloHCT recipients and is associated with a 2-year post-relapse survival rate of less than 20%. Chimeric antigen receptor (CAR) T cells targeting tumor-associated antigens have demonstrated efficacy in relapsed/refractory (R/R) acute lymphoblastic leukemia and other hematologic malignancies, but there is limited clinical experience with CAR T cell therapies for AML. Current challenges for autologous AML CAR T cell therapy include the inability to harvest adequate numbers of functional, undifferentiated T cells as CAR T cell starting material. In addition, the potential presence of AML blasts in an autologous cell collection can interfere with T cell proliferation and function during the manufacturing process. To circumvent these impediments in patients with R/R AML after alloHCT, VCAR33 represents a CD33-directed CAR T cell product generated from lymphocytes from each patient's prior allogeneic stem cell donor. CAR T cell manufacture from HLA-matched donors will likely not only eliminate delays and failures in production due to lymphopenia but also improve T cell function by using healthy starting material. CD33 is a preferential target for AML CAR T cell therapy as it is expressed on the majority (&amp;gt;80%) of AML blasts and because prior clinical experience with gemtuzumab ozogamicin (GO; tradename: Mylotarg TM) has demonstrated the safety and efficacy of targeting CD33. Study Design and Methods: Study NCTxxxxxxxx* is a multi-center phase 1/2 study evaluating the safety and preliminary efficacy of VCAR33, donor-derived allogeneic CAR T cells targeting CD33 (Figure 1). The CAR construct used for the manufacture of VCAR33 contains a lintuzumab-derived binding domain and a CD28 co-stimulatory domain. Key inclusion criteria include adult patients with relapsed or measurable residual disease positive (MRD+) AML after undergoing alloHCT with an 8/8 HLA-matched related or unrelated donor. Patients who have undergone alloHCT with trem-cel, a CD33-deleted allogeneic stem cell product intended to facilitate the post-HCT treatment with CD33-directed therapies by reducing on-target off-tumor hematotoxicity, may also participate. Patients will be assigned to one of two study arms based on their AML disease burden: Arm A for morphologic disease with ≥ 5% blasts in the bone marrow, or Arm B for MRD+ defined as &amp;lt; 5% blasts in the bone marrow with ≥ 0.1% CD33+ leukemia cells by flow cytometry. The patient's prior stem cell donor undergoes apheresis for collection of mononuclear cells, which are used as starting material for VCAR33 manufacturing. Patients will receive lymphodepletion on days -5 to -2 with fludarabine (total 120 mg/m 2) and cyclophosphamide (total 1000 mg/m 2) followed by infusion of VCAR33 on Day 0. Each study arm will enroll and escalate independently according to a standard 3+3 trial design, starting at 1 x 10 6 CAR T cells/kg for Dose Level 1. The dose limiting toxicity monitoring period is 28 days, at which time patients will undergo evaluation of disease response. Secondary endpoints include incidence of cytokine release syndrome, graft-vs-host disease, and clinical response. Exploratory endpoints aim to correlate VCAR33 properties with clinical response by characterizing T cell phenotypes within the VCAR33 product and by examining VCAR33 expansion and persistence after infusion. Follow up on trial will continue for up to 2 years after infusion followed by long term monitoring for up to 15 years. Patients may undergo second alloHCT for consolidation of remission or for rescue of prolonged cytopenia due to on-target off-tumor effects of VCAR33. *NCT number pending. Clinical trial information submitted to CT.gov on July 19, 2023.

Development and Validation of a Nomogram to Predict the Risk of Tinnitus Severity in Patients With Unilateral Subjective Tinnitus.

Purpose: To develop and validate a nomogram for predicting the risk of tinnitus severity in patients with unilateral subjective tinnitus. Methods: The objective of this study was to establish and validate a nomogram specifically designed for patients with unilateral subjective tinnitus. We collected data on unilateral subjective tinnitus from the Air Force Medical Center, including 146 participants between January 2021 and June 2022. Risk factors for unilateral subjective tinnitus severity were evaluated by least absolute shrinkage and selection operator (LASSO) and binary logistic regression analysis. Internal verification was used to evaluate the performance of the nomogram. The discriminative ability was measured by the consistency index (C-indices) and the area under the curve (AUC) of the receiver operating characteristic (ROC) curves. Results: All included patients were randomized according to a 7:3 ratio into the training cohort (104 patients) and the validation cohort (42 patients). The LASSO regression model identified sex, tinnitus loudness, and hearing loss as candidate variables. Binary logistic regression analysis showed that gender (OR: 0.76; 95% CI: 0.6-0.95; P = 0.021) and tinnitus loudness (OR: 1.37; 95% CI: 1.09-1.72; P = 0.009) were significant predictors of unilateral subjective tinnitus severity, while age, tinnitus matching frequency, and tinnitus duration were not. The significant predictors were included in the nomogram. Hearing loss was included in the nomogram based on prior clinical experience and previous studies. The training and validation cohorts C-indexes were 0.707 (95% CI: 0.607-0.806) and 0.706 (95% CI: 0.548-0.863), respectively. The training and validation cohort's AUC of the ROC curves were 0.692 and 0.705, respectively. Conclusion: We have developed and validated a nomogram based on gender, hearing loss, and tinnitus loudness, which can effectively predict the risk of tinnitus severity in patients with unilateral subjective tinnitus. The nomogram provides personalized prediction results for patients with unilateral subjective tinnitus, which is beneficial for clinical decision-making and treatment plan development.