Small Study Research Articles

Cox proportional hazards regression in small studies of predictive biomarkers

Predictive biomarkers are essential for personalized medicine since they select the best treatment for a specific patient. However, of all biomarkers that are evaluated, only few are eventually used in clinical practice. Many promising biomarkers may be erroneously abandoned because they are investigated in small studies using standard statistical techniques which can cause small sample bias or lack of power. The standard technique for failure time endpoints is Cox proportional hazards regression with a multiplicative interaction term between binary variables of biomarker and treatment. Properties of this model in small studies have not been evaluated so far, therefore we performed a simulation study to understand its small sample behavior. As a remedy, we applied a Firth correction to the score function of the Cox model and obtained confidence intervals (CI) using a profile likelihood (PL) approach. These methods are generally recommended for small studies of different design. Our results show that a Cox model estimates the biomarker-treatment interaction term and the treatment effect in one of the biomarker subgroups with bias, and overestimates their standard errors. Bias is however reduced and power is increased with Firth correction and PL CIs. Hence, the modified Cox model and PL CI should be used instead of a standard Cox model with Wald based CI in small studies of predictive biomarkers.

Post-Excision Soft X-Ray Radiotherapy for Keloids: Experience in a Tertiary Referral Center.

Keloid is an abnormal proliferation of scar tissue that grows beyond the original margins of the injury. Even after complete resection, recurrences are common and pose a poorly understood challenge in dermatology. There is lack of large prospective clinical trials; thus, treatment recommendations are based on retrospective analyses and small cohort studies. Superficial radiotherapy is recommended in recurrent keloids; however, the successful treatment rates vary greatly. The aim of this study was to evaluate the keloid recurrence rate after post-excision soft X-ray radiotherapy and the associated factors. We reviewed retrospective data of all patients, treated with adjuvant post-excision soft X-ray radiotherapy with 12 Gy in 6 sessions at the tertiary referral center, Department of Dermatology, University Hospital Zurich, Switzerland, between 2005 and 2018. We analyzed individual keloids as separate cases. Successful treatment was defined as no sign of recurrence within 2 years. Of the 200 identified patients, 90 met the inclusion criteria and were included in the final analysis. In 90 patients, 104 cases of treated keloids were analyzed. Keloids were mainly located on the trunk (49%) and were mostly caused by previous surgery (52.2%). 50% of the keloids did not relapse within 2 years after therapy. A significant factor leading to recurrence was the presence of previous therapy, with prior topical therapies, such as steroid injections or 5-fluorouracil, leading to most relapses. 69.2% of keloid cases who relapsed were pretreated. Soft X-ray radiotherapy was well tolerated, with posttreatment hyperpigmentation noted in 34% of patients, particularly in patients with non-Caucasian origin (61.3%). Treatment of refractory keloids is difficult. Post-excision radiotherapy is an established adjuvant treatment option; nevertheless, recurrence rates are high, especially in pretreated keloids. Prospective studies determining the exact dosage and fraction of post-excisional radiotherapy are needed to determine the optimal radiation parameters.

(115) SEXUAL SELF-ESTEEM IN TWO SAMPLES OF ADOLESCENT AND YOUNG ADULT CANCER SURVIVORS: A QUALITATIVE INVESTIGATION

Abstract Introduction As rates of survival from cancer continue to increase in adolescents and young adults, long term physical and psychological impacts are likely to rise. For those diagnosed with cancer during childhood or adolescence, one such late effect may be delayed sexual development. Delayed sexual development may manifest as issues of sexual functioning (i.e., the ability to successfully complete the sexual response cycle) as well as issues of sexual self-concept (i.e., how one navigates the world as a sexual being). These issues may, in turn, impact survivors’ self-esteem. These concerns are likely to be exponentially exacerbated when survivors identify as a member of a sexual and/or gender minority (SGM) group. Objective Based on empirical research and two studies from our team, we examine variables that impact the sexual self-esteem of AYA cancer survivors, particularly those that identify as members of an SGM group. Methods In our small pilot project, we conducted cognitive interviews to assess whether a novel model, adapted from sexual health frameworks established by Woods (1995) and Evan et al. (2006), applied to AYA cancer survivors. Following analysis of these interviews, we refined our model, and received funding for a larger qualitative study (n = 30) tailored to AYA cancer survivors who identify as members of an SGM group. Results Four cisgender female cancer survivors participated in this small qualitative study, which provided preliminary validation that variables such as body image, amount of sexual education, quality of interpersonal relationships, and sexual functioning, were all tied into one’s perception of their sexual self-esteem. Several additional potential variables were identified from these interviews, including amount of sexual equity (how much participants felt that their sexual activity was balanced between them and a partner), religiosity, negative self-evaluative emotions (e.g., guilt and shame), and SGM identity, that could influence sexual self-esteem. Preliminary analyses of our SGM-focused qualitative study have revealed high levels of asexuality and mental health comorbidities that may be affecting sexual self-esteem. Recruitment and analysis for this study is ongoing. Conclusions Results from these two studies will provide some of the first empirical research on sexual self-esteem in a population for which sexual health is vastly under researched. We anticipate that this work will lay the foundation for novel measurements and interventions for these individuals. By providing a voice to those who are underrepresented in research, we hope that this research may have high-impact in informing future interventions to become more holistic and culturally-informed to allow for studies to ensure they are reflecting all identities of cancer survivors. Finally, we anticipate that this research may be of significant benefit to oncology providers and clinicians to overhaul and adapt sexual education for patients in treatment, as well as inform areas of concern and assessment for these providers and clinicians, particularly among their SGM patients and survivors. Disclosure No.

Intravascular Lithotripsy for Treatment of Severely Calcified Common Femoral Artery Disease: Results From the Disrupt PAD III Observational Study.

Surgical endarterectomy is currently considered the front-line therapy for the treatment of calcified lesions in the common femoral artery (CFA). Endovascular interventions have evolved, and their use is increasing in frequency. Intravascular lithotripsy (IVL) has shown promising safety and effectiveness in calcified CFA lesions in a small pilot study, but "real-world" evidence from a larger cohort is lacking. The Disrupt PAD III Observational Study (NCT02923193) was a prospective, multicenter registry designed to assess the acute safety and effectiveness of IVL treatment for calcified peripheral arterial disease. Any concomitant treatment with other calcium-modifying technologies as well as definitive treatment strategies was at the discretion of the operators. Patients with CFA lesions were evaluated for acute angiographic safety and effectiveness outcomes following IVL treatment as determined by an independent angiographic core lab. Common femoral artery treatment was indicated in 177 patients (n=163 could be analyzed based on core-laboratory data) enrolled at 23 sites. Characteristics for 164 treated lesions included moderate-severe calcification 95.1%, diameter stenosis 74.8±17.7%, and lesion length 53.6±53.1 mm. Concomitant calcium-modifying therapy was used in 32.3% of lesions. Final therapy included drug-coated balloons in 68.9% and stenting in 16.5% of lesions. Post-IVL and final residual stenoses were 29.2±16.5%and 23.6±11.5%, respectively. No vascular complications (flow-limiting dissections, perforations, embolization, slow or no reflow, or abrupt closure) were present at the end of the procedure by core-laboratory assessment, with 1 (0.8%) flow-limiting dissection initially occurring immediately following IVL treatment. This study represents the largest real-world experience of IVL treatment in heavily calcified CFA lesions. Intravascular lithotripsy treatment showed significant stenosis reduction and favorable periprocedural safety in this challenging patient population. In this study we show that calcified common femoral artery disease can be safely and effectively treated with shockwave balloon angioplasty with high procedural success and low complication rates and in clinical practice can now be offered as an alternative to surgical treatment in those patients reluctant to or high risk for vascular surgery. This opens another option for clinicians to treat calcified common femoral artery disease without the risk of dissection, perforation or distal embolization that are associated with atherectomy. This study shows that shockwave lithoplasty offers an innovative plaque modification technology to tackle calcified disease in the common femoral artery.

Scoping review: Mobility aids for people with sight loss across the ICF domains of functions, activities, and participation.

There is little literature linking mobility aids for people with sight loss to the functions, activities, and participation domains of the International Classification of Functioning, Disability and Health (ICF). Future studies on this relationship should be funded and pursued to better understand ways to maximize the benefit of mobility aids. The ICF domains of functions, activities, and participation are potentially health-supporting aspects of daily living that may be impeded for people with sight loss. Although mobility aids facilitate safely navigating obstacles to optimize independence, it is not clear if they have any effect on functions, activities, or participation. This review explores the current literature to establish the associations between mobility aids and ICF domains. An established scoping review methodological framework was used to systematically search, select, and synthesize the existing literature. Of 116 unique retrieved articles, three observational studies were eligible for inclusion with a total of 124 participants. A small experimental study found that blind adults had slower Timed Up and Go times than sighted and better performance with a long cane than without. One observational study found that physical activity was strongly related to level of visual acuity but with no independent impact of mobility aids. A single mixed-methods study explored travel frequency for blind people with assistance dogs and considered constraints to participation. Despite the included studies involving some aspect of mobility aid use by people with sight loss, to date, no study has focused exclusively on mobility aid intervention for people with sight loss within the physical function, physical activity, and participation domains of the ICF. There is no reliable evidence on the associations between mobility aids and physical function, physical activity, and participation. This is an important knowledge gap for determining the most suitable aids, as well as their use, to best facilitate health-supporting activities.

Methods of Evaluating EEG Reactivity in Adult Intensive Care Units: A Review.

EEG reactivity (EEG-R) has become widely used in intensive care units for diagnosing and prognosticating patients with disorders of consciousness. Despite efforts toward standardization, including the establishment of terminology for critical care EEG in 2012, the processes of testing and interpreting EEG-R remain inconsistent. A review was conducted on PubMed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria consisted of articles published between January 2012, and November 2022, testing EEG-R on adult intensive care unit patients. Exclusion criteria included articles focused on highly specialized stimulation equipment or animal, basic science, or small case report studies. The Quality In Prognostic Studies tool was used to assess risk of bias. One hundred and five articles were identified, with 26 variables collected for each. EEG-R testing varied greatly, including the number of stimuli (range: 1-8; 26 total described), stimulus length (range: 2-30 seconds), length between stimuli (range: 10 seconds-5 minutes), frequency of stimulus application (range: 1-9), frequency of EEG-R testing (range: 1-3 times daily), EEG electrodes (range: 4-64), personnel testing EEG-R (range: neurophysiologists to nonexperts), and sedation protocols (range: discontinuing all sedation to no attempt). EEG-R interpretation widely varied, including EEG-R definitions and grading scales, personnel interpreting EEG-R (range: EEG specialists to nonneurologists), use of quantitative methods, EEG filters, and time to detect EEG-R poststimulation (range: 1-30 seconds). This study demonstrates the persistent heterogeneity of testing and interpreting EEG-R over the past decade, and contributing components were identified. Further many institutional efforts must be made toward standardization, focusing on the reproducibility and unification of these methods, and detailed documentation in the published literature.

A thorough analysis of data on the correlation between COL9A1 polymorphisms and the susceptibility to congenital talipes equinovarus: a meta-analysis

BackgroundCongenital talipes equinovarus (CTEV) is a prevalent pediatric deformity with a multifactorial etiology. The objective of this meta-analysis was to explore the association between genetic variations in COL9A1 and the susceptibility to CTEV.MethodsA comprehensive analysis of pertinent literature released before November 15, 2023, in electronic bibliographic databases was carried out. The importance of the connection was clarified through odds ratios (ORs) with 95% confidence intervals (CIs), utilizing random or fixed-effects models depending on study heterogeneity. Statistical analysis was executed using Comprehensive Meta-Analysis software (Version 4.0).ResultsA total of eight case-control studies involving 833 CTEV patients and 1280 healthy individuals were included in the analysis. Among these, four studies investigated the rs1135056 variant, encompassing 432 CTEV cases and 603 controls; two studies examined the rs35470562 variant, with 189 CTEV cases and 378 controls; and two studies explored the rs592121 variant, including 212 CTEV cases and 299 controls. The results revealed a significant association between the rs1135056 and rs35470562 polymorphisms in the COL9A1 gene, suggesting an increased risk of CTEV in the overall population. Conversely, no such association was found for the rs592121 variant.ConclusionOur findings reveal a substantial association between the genetic variants COL9A1 rs1135056 and rs35470562 and susceptibility to CTEV. Conversely, the variant rs592121 did not exhibit any corresponding link. However, the limitations imposed by the small study population have compromised the statistical reliability and generalizability of the results.

Does Improving Depression Symptoms in Young Adults With Inflammatory Bowel Disease Alter Their Microbiome?

Patients with inflammatory bowel diseases (IBDs) are more likely to have depression and anxiety symptoms compared with healthy individuals and those with other chronic illnesses. Previous studies have shown a link between the microbiome composition and depression symptoms; however, many antidepressant medications have antibacterial activity confounding cross-sectional studies of these populations. Therefore, we aimed to determine whether we could detect longitudinal changes in the microbiome of a subset of patients who participated in a previously published mindfulness-based cognitive therapy (MBCT) study to improve depression symptoms in adolescents and young adults with IBD. Stool samples were collected at baseline and 8 weeks (n = 24 participants, 37 total samples, 13 paired samples). During this time, some participants achieved a 50% reduction in their depression symptoms either through MBCT or treatment as usual with their mental health team (responders). The microbiome composition and function of responders were compared with participants who did not improve their depression scores (nonresponders). Depression scores were determined using the depression, anxiety, and stress score (DASS-21), and metagenomic sequencing of stool samples was performed. No difference in alpha diversity was found between responders and nonresponders. Beta diversity measures were similarly unchanged. Clinical features including fecal calprotectin, C-reactive protein, and serum IL-6 levels were unchanged. In this small longitudinal study, we were not able to detect longitudinal changes in the microbiome associated with improvement in depression scores. Follow-up studies that are sufficiently powered to detect changes in the microbiome are required to confirm our results.

Extracellular vesicles as novel uro-oncology biomarkers: insights toward clinical applications.

We discussed the challenges associated with the clinical application of extracellular vesicles and summarized their potential impact on oncological clinical practice in urology. Despite extensive research on extracellular vesicles, their clinical applications remain limited; this is likely to be because of small study cohorts, a lack of large-scale analyses, and the impact of variable extraction and storage methods on analysis outcomes. However, promising results have emerged from clinical trials targeting urinary extracellular vesicles in prostate cancer using ExoDx Prostate Test. The ExoDx Prostate Test has demonstrated its efficacy in diagnosing prostate cancer in previous studies and is the only FDA-approved kit for this purpose. Moreover, recent trials have investigated the use of the ExoDx Prostate Test to determine the optimal timing for biopsies in prostate cancer patients undergoing active surveillance. We summarized recent studies on the potential of extracellular vesicles in the management of urological cancers. Particularly, the diagnosis of prostate cancer using the ExoDx Prostate Test has yielded positive results in several clinical trials. Additionally, while there are other studies suggesting its efficacy, most of these are based on retrospective analyses. These findings warrant further large-scale studies to optimize extracellular vesicle-based diagnostic and monitoring strategies. Although further research is required, extracellular vesicles would be attractive for early detection and surveillance.

Long-term Outcomes of Cryoballoon-based Empirical Superior Vena Cava Isolation in Addition to Pulmonary Vein Isolation in Persistent Atrial Fibrillation.

Superior vena cava (SVC) is atrial fibrillation (AF)'s most common non-pulmonary vein (PV) foci. Studies reported conflictory results when SVC isolation (SVCi) was combined with PVi and long-term outcomes were lacking. Therefore, we aimed to evaluate the long-term efficacy and safety of empirical SVCi as an adjunct to cryoballoon-based PV isolation (PVi) in persistent AF ablation. A total of 40 consecutive persistent AF patients (60.6 ± 8.2 years, 52.5% females) who underwent SVCi in addition to PVi compared with a propensity score matched cohort of 40 persistent AF patients (58.6 ± 8.7 years, 50% female) in whom PVi-only was performed. Second-generation cryoballoon (CB2) was used in all procedures. Atrial tachyarrhythmia (ATa) recurrence was defined as the detection of AF, atrial flutter, or atrial tachycardia (≥30 s) after a 3-month blanking period. Pulmonary veins and SVC were successfully isolated in all patients. At a mean of 46.7 ± 7.8 months follow-up, 22 (55%) patients in the PVi-only group, and 27 (67.5%) patients in the PVi + SVCi group were free of ATa after the index procedure (P =.359). Phrenic nerve injury (PNI) was detected in 2 (5%) patients in the PVi-only group (during right PVi) and 2 (5%) patients in the PVi + SVCi group (during SVCi) (P = 1.00). Cox regression analysis revealed that early recurrence was the only predictor of recurrence (hazard ratio 4.88, 95% confidence interval 1.59-14.96; P =.005). Long-term results of our small sample-sized study revealed that CB-based PVi + SVCi was associated with outcomes similar to the PVi-only strategy in patients with persistent AF. Although complication rates were similar between the groups, close follow-up of diaphragmatic movement is crucial to prevent PNI during SVCi.

A ‘STRONG REGIME’ FOR SAFE ANKLES: A PROSPECTIVE STUDY TO VALIDATE AN EARLY MOBILIZATION PROGRAMME AFTER A LATERAL ANKLE LIGAMENT REPAIR WITH SUTURE TAPE AUGMENTATION

ObjectiveTo evaluate early mobilization with the ‘STRONG regime’ is safe after lateral ankle ligament repair with suture tape augmentation.BackgroundThe ESSKA-AFAS ankle instability group presented in 2016 evidence-based guidelines for rehabilitation and return to activity after lateral ankle ligament repair. Early mobilization is considered an important element of postoperative rehabilitation. Patients have to be immobilized for approximately six weeks to protect the delicate repair. Lateral ankle ligament repair with suture tape augmentation results in greater strength compared with standard repairs and early mobilization proved to be successful in small sample size studies. Augmented surgery technique is getting increasingly popular. However, it is unknown which rehabilitation regimes are used. It is essential to establish a clear evidence-based guideline for rehabilitation after surgery.MethodsA systematic literature search was performed to obtain the best evidence research regarding this surgery. In cooperation between the orthopaedic- and physical therapy department a post-operative rehabilitation protocol with early mobilization was established. This STRONG protocol (figure 1) is based on milestones and three stages.ResultsIn February 2016 the first patients were selected for the early mobilization regime. In total 102 patients with a lateral ankle ligament repair were treated with the STRONG protocol. No re-ruptures were observed with a follow up of a year. In a subgroup of athletes hop tests showed a symmetry index of 100,5% for triple hop, 98,6 for side hop and 103,6 for figure of 8 hop. First return to sport was achieved between 9–12 weeks, with full return to competition after a mean of 4 months.ConclusionsAn early postoperative mobilization regime based on supervised exercises seems to be a safe intervention after a lateral ankle ligament reconstruction.Clinical implicationsAugmented ankle ligament surgery with early mobilization could be an important advancement in treating patients with chronic ankle injuries.For any figures or tables, please contact authors directly.

Location of Shoulder Glenoid Labral Tears: A Study of 1763 Consecutive Patients

Background: Anterior shoulder labral tearing has historically been considered the most common location of shoulder labral pathology. Recently, smaller studies have reported that posterior labral involvement may be more common than previously recognized. Purpose: To examine the location of surgically repaired labral tears by a single surgeon over a consecutive 23-year period. Study Design: Case series; Level of evidence, 4. Methods: A total of 1763 consecutive patients who underwent arthroscopic or open shoulder labral repair by a single seniorsports medicine fellowship–trained orthopaedic surgeon between April 2000 and April 2023 were retrospectively reviewed. Current Procedural Terminology codes were used to identify patients, which included 29806, 29807, 29822, and 29823. Exclusion criteria included isolated shoulder manipulation or glenohumeral joint or labral debridement that did not include repair. Intraoperative glenoid labral tears observed were categorized into 7 broad categories: (1) anterior labral tears, (2) posterior labral tears, (3) superior labral anterior posterior (SLAP) type II tears (A, B, or C), (4) SLAP type V tears, (5) SLAP type VIII tears, or (6) circumferential labral tears (combined SLAP, anterior, and posterior labral tear). Shoulders diagnosed with multiple tear patterns (ie, anterior and posterior) were also noted. Results: During the 23-year period, 1763 patients underwent arthroscopic or open labral repair; they included 1295 male and 468 female patients, ranging in age from 12 to 70 years, with a mean age of 23.2 years and median age of 19 years. Overall, 28.4% of tears involved the anterior labrum, 64.9% involved the posterior labrum, and 59.6% involved the superior labrum. Regarding isolated tears, 9.3% were isolated anterior labral tears, 19.7% were isolated posterior labral tears, 11.5% involved the anterior and posterior labrum, 22.2% were isolated superior (SLAP type II-IV) tears, 3.63% were isolated SLAP type V tears, 29.8% were isolated SLAP type VIII tears, and 4.1% were circumferential tears. Conclusion: Posterior shoulder labral tearing was more common than anterior tearing in a large consecutive series of 1763 patients who underwent surgical repair. This highlights the importance of posterior labral pathology, which sometimes may be overlooked because of more vague complaints, with pain and loss of function being the most common.

A pharmacovigilance study of drug-reduced male semen quality based on the Food and Drug Administration adverse event reporting system database.

Real-world big data studies on drug-reduced male semen quality are few and far between, with most studies based on animal trials, small scale retrospective studies, or a limited number of pre-market clinical trials. This study aimed to identify culprit drugs that reduced male semen quality based on the United States Food and Drug Administration adverse event reporting system. The Medical Dictionary for Regulatory Activities preferred terms and standardized Medical Dictionary for Regulatory Activities queries were used to define reduced male semen quality. Adverse events related to drug-reduced male semen quality were then analyzed by disproportionality analysis using the United States Food and Drug Administration adverse event reporting system data between 2004 and 2023. At the preferred term level, 59 drugs with risk signals were detected to be associated with drug-reduced male semen quality, with the three most frequently reported second-level Anatomical Therapeutic Chemical groups being antineoplastic agents (n=16, 27.12%), psychoanaleptics (n=9, 15.25%), and psycholeptics (n=6, 10.17%). At the standardized Medical Dictionary for Regulatory Activities queries level, the five drugs with the greatest number of cases were finasteride (845 cases, IC025=7.72), dutasteride (163 cases, IC025=7.22), tamsulosin (148 cases, IC025=5.99), testosterone (101 cases, IC025=4.08), and valproic acid (54 cases, IC025=2.44). Additionally, clinical information about drug-reduced male semen quality is absent from the Summary of Product Characteristics of 41 drugs in our study. Using the United States Food and Drug Administration adverse event reporting system database, we offer a list of drugs with risk signals for reducing male semen quality. In the future, there is still a need for more studies on drugs whose effects on male semen quality are not fully understood.

Wolverine population density and home range size in Arctic Alaska

AbstractUnderstanding the spatial requirements of exploited wildlife species, including population density and home range size, is important for wildlife management and conservation. Wolverines (Gulo gulo) are hunted and trapped across the Arctic, and are vulnerable to numerous, often interrelated, threats resulting from anthropogenic changes in their environment. Previous population density estimates for wolverines in the Arctic range tenfold, from the lowest to highest available for the species, limiting their utility outside the specific areas and times they were derived. The most recent density estimate in Arctic Alaska, USA, was produced 4 decades ago and was derived from a relatively small study area. We evaluated wolverine population density and home range size across the North Slope of Alaska during 2017–2022 using global positioning system (GPS)‐based collar data and spatial capture‐recapture models. Population density estimates were 2.0 individuals/1,000 km2 (95% credible interval = 1.3–3.5) in 2018 and 2.8 individuals/1,000 km2 (95% credible interval = 1.7–3.5) in 2021. Median home range sizes modeled with autocorrelated kernel density estimators and Ornstein‐Uhlenbeck foraging movement processes were 699 km2 (range = 158–2,895 km2) among 12 females and 2,332 km2 (range = 797–4,699 km2) among 10 males. These population density estimates are nearly 10 times lower than the previous estimate for Arctic Alaska. We recommend incorporating this information into management strategies to ensure sustainable harvest, particularly as the region's remote areas are more efficiently accessed by hunters and are being considered for transportation corridors supporting new industrial development.

Settler teachers’ engagement with first nations content in the Australian curriculum

ABSTRACT Situated in the curriculum space created by the recent enhancements to First Nations content is the opportunity for teachers to better connect with First Nations perspectives. Using constructivist theory methodology and drawing on two studies, a small qualitative school-based study of teachers who teach in the early years of schooling, and a large-scale study of professional development across two Australian states, the paper explores teachers’ preparedness to teach First Nations content. The tenets of critical literacy frame the discussion and are positioned as reflective tools that can be used to support the ‘settler teacher’ in self-reflection. Audio-recorded transcripts of planning sessions, a teacher survey, comments from feedback forms and researcher memos form the data sets. Findings from the study necessitate discursive practices for the development of teacher knowledge, dispositions, and confidence, and highlight the imperative for teacher critical self-reflection.

Evaluation of the study of control arms in randomized clinical trials of cancer.

11023 Background: Randomized clinical trials (RCTs) in cancer typically compare experimental to control arm regimens. The choice of an appropriate control (ctrl) arm can have a major impact on the expected success of an RCT. The frequency with which cancer RCTs use control arms based on established dosing and scheduling protocols has not been described. Methods: The HemOnc knowledgebase (KB) was used to identify systemic anti-cancer therapy (SACT) regimen variants, defined as regimens with identical components that differ in dosing, scheduling, and/or route. Non-cancer, nonrandomized, and non-SACT studies were excluded. Study publication year was used to define standard variants as those evaluated in the experimental arm of a positive phase 3 RCT >1 year prior to publication as a control arm, regardless of cancer type or context of treatment. Study-variant dyads were evaluated to determine whether the variant was standard. Success rates of RCTs with standard vs non-standard control arms were evaluated with Fisher’s exact test. Results: 5221 studies were associated with ≥1 named variant in the HemOnc KB, as of 2024-02-06. After exclusions, there were 3511 study-variant dyads (2386 studies; 1714 variants). The 9 most common regimens are shown in the Table. The median (IQR) number of variants per regimen was 2 (1-3); carboplatin & paclitaxel (CP) had the most variants (n=33). Across all control arm study-variant dyads, 2228/3492 (64%) utilized non-standard variants. For example, 60/97 studies (62%) of docetaxel as control used the 75 mg/m2 q3wk variant after it was established in 2000, whereas n=27 others used 19 non-standard variants. Trials that used a standard control arm had a numerically higher success rate, 45% vs 42% (OR 1.10, 95% CI 0.92-1.32). Conclusions: Non-standard regimen variants are frequently used in cancer RCTs. Reasons for this could include toxicity, patient convenience, or emerging data from smaller studies that establish comparable efficacy or improved toxicity to standard variants. However, the a priori efficacy of non-standard control arms is less rigorously established, and trials with standard control arms might be more successful. Future directions include quantifying the granular differences between standard and non-standard variants and investigating whether certain types of non-standard variation (e.g. fewer cycles, lower doses) associate with trial success rates. [Table: see text]

Temozolomide and nivolumab in patients with refractory metastatic melanoma (MM).

e21521 Background: Immune checkpoint inhibitors (ICI) are the standard treatment for patients (pts) with MM. However, only a subset of pts respond to ICIs. Temozolomide (TEM) is used in refractory settings but with low objective response rates and no clear overall survival benefit. The efficacy of combined ICI + TEM is not well described. Methods: This was a single center, retrospective study of pts with MM who received treatment with nivolumab (NIVO) and TEM or TEM alone between 11/6/2013 and 11/6/2023. Demographic information, disease characteristics, LDH, treatment, toxicity, objective response, and outcomes were collected. Results: 34 patients were included. 16 were treated with NIVO + TEM and 18 were treated with TEM alone. In the NIVO + TEM group, 81% were male (n = 13) with median age of 59.5 years (range 20-79), and in the TEM group, 56% were male with median age 61 (range 35-81). For NIVO + TEM, 31% had partial response (PR; n = 5), 6% had stable disease (SD, n = 1), and 63% had progressive disease (PD; n = 10). For TEM, 11% had PR (n = 2), 22% had SD (n = 4), and 67% had PD (n = 12) (p = 0.37). For NIVO + TEM, 2 PRs were durable, ongoing at 442 and 741 days; 3 PRs were transient (85-179 days); 1 pt had durable SD ongoing at 201 days. For TEM, PR durations were 173 and 504 days, and SD durations between 213-435 days. Five pts with PD treated with NIVO + TEM had mixed responses (31%) compared with 1 pt treated with TEM (6%). Median progression free survival (PFS) was 80 days (range 11-748) for NIVO + TEM and 55.5 days (7-415) for TEM (p = 0.31). Median overall survival (OS) was 160 days (43-363) for NIVO + TEM and 118 days (7-1938) for TEM (p = 0.15). There were 26 adverse events (AEs) for NIVO + TEM (27% grade 1, 42% grade 2, 19% grade 3, and 12% grade 4; thrombocytopenia and pneumonitis), and 25 AEs for TEM (40% grade 1, 40% grade 2, 12% grade 3, and 8% grade 4; thrombocytopenia) [p = 0.64]. Conclusions: NIVO + TEM occasionally produced durable responses, although outcome metrics were not clearly superior to TEM alone in this small study. Further studies should quantify the benefit of ICI + chemotherapy regimens in refractory MM. [Table: see text]

Genome-wide DNA methylation profiles and breast cancer among World Trade Center survivors.

Increased incidence of cancer has been reported among World Trade Center (WTC)-exposed persons. Aberrant DNA methylation is a hallmark of cancer development. To date, only a few small studies have investigated the relationship between WTC exposure and DNA methylation. The main objective of this study was to assess the DNA methylation profiles of WTC-exposed community members who remained cancer free and those who developed breast cancer. WTC-exposed women were selected from the WTC Environmental Health Center clinic, with peripheral blood collected during routine clinical monitoring visits. The reference group was selected from the NYU Women's Health Study, a prospective cohort study with blood samples collected before 9 November 2001. The Infinium MethylationEPIC array was used for global DNA methylation profiling, with adjustments for cell type composition and other confounders. Annotated probes were used for biological pathway and network analysis. A total of 64 WTC-exposed (32 cancer free and 32 with breast cancer) and 32 WTC-unexposed (16 cancer free and 16 with prediagnostic breast cancer) participants were included. Hypermethylated cytosine-phosphate-guanine probe sites (defined as β > 0.8) were more common among WTC-exposed versus unexposed participants (14.3% vs. 4.5%, respectively, among the top 5000 cytosine-phosphate-guanine sites). Cancer-related pathways (e.g., human papillomavirus infection, cGMP-PKG) were overrepresented in WTC-exposed groups (breast cancer patients and cancer-free subjects). Compared to the unexposed breast cancer patients, 47 epigenetically dysregulated genes were identified among WTC-exposed breast cancers. These genes formed a network, including Wnt/β-catenin signaling genes WNT4 and TCF7L2, and dysregulation of these genes contributes to cancer immune evasion. WTC exposure likely impacts DNA methylation and may predispose exposed individuals toward cancer development, possibly through an immune-mediated mechanism.

Presentation, Management, and Child Protective Service Reporting of Children Who Test Positive for Cannabis in an Emergency Room Setting.

Rates of cannabis ingestion among young children are increasing. Small studies have evaluated symptomatology of these children. The literature lacks research regarding factors influencing medical management. Our goal was to 1) understand circumstances leading to exposure over time and 2) gain insight into factors that may influence emergency room management and Child Protective Services reporting over time. Retrospective cross-sectional study on children younger than 10 years with cannabis-positive urine drug screens in the emergency room setting. Single-factor analysis of variance and Fisher exact tests were used to assess for trends. Two-tailed t tests and Fisher exact tests were used to compare management of children presenting to the emergency room with chief complaint (CC) "ingestion" versus those without. Of the 179 children, the mean age was 3.7 years and 48% were boys. We observed a significant increase over time in cannabis-positive children. The most common location of exposure was the primary residence (54%), with parents as the most frequent users (46%). In the emergency department, the most common CC was ingestion followed by altered mental status and fatigue. Children with an "ingestion" CC were managed with less testing than those with other CCs. They received fewer needle sticks (43% vs 91%), less imaging (5% vs 56% computed tomography heads), and fewer procedures (0% vs 8% lumbar punctures). Children with "ingestion" CC were less likely to be reported to Child Protective Services. Pediatric cannabis exposures are increasing and have a wide array of clinical presentations that complicate emergency room management. Parental report of cannabis ingestion seems to impact and reduce potentially unnecessary testing.

Exploring the literature on artificial intelligence use in oncology.

e13642 Background: Artificial Intelligence (AI) allows machines to analyze data in a way that mimics human intelligence. AI has been used in oncology diagnostics such as radiology and pathology. However, the specific processes and tasks that AI can support, especially in oncology, have not been fully explored. Methods: The electronic databases PubMed and MEDLINE were searched from September 1, 2018, to September 1, 2023, for publications related to the use of AI in oncology. Inclusion criteria consisted of English language, article type “study” and keywords Artificial Intelligence, Healthcare, Predictive/Prediction, Fever, Cytokine Release Syndrome, Nursing, Patient Care, Oncology, and Neutropenic Fever applied in a progressive manner to narrow the search. Results: The term Artificial Intelligence yielded over 124,385 studies. This number was reduced to 466 when adding “healthcare, predictive/prediction, and oncology.” Adding “patient care” further reduced the number to 102. Out of the 102, seven studies identified included the term “nursing” and focused on clinician decision support, readmissions, palliative care, and scheduling. One identified study discussed the potential benefits of AI-generated algorithms for risk stratification related to cytokine release syndrome. The keywords “neutropenic fever” did not generate any results. Six studies were identified by adding in the term “fever,” which focused on AI use in specialties outside of oncology. The literature reviewed shows that AI has had limited use in oncology outside of radiology and pathology. Only one study suggested the use of AI would be beneficial in predicting symptoms related to treatment. Small studies were identified showing the value of AI in increasing adherence to schedules, reducing readmissions, and providing precision medicine. Conclusions: AI is a promising tool for the future of oncology. The current availability of AI within oncology practices has been limited. Further studies should be undertaken to identify how AI can reduce provider burnout, care costs, and early identification of symptoms to prevent adverse events.