Adjustment For Multiple Comparisons Research Articles

Effect of common medications on immune checkpoint inhibitor efficacy.

e14710 Background: Previous studies have suggested that certain common medications could impact immune checkpoint inhibitor (ICI) efficacy and survival. These studies lacked non-ICI control groups, raising the possibility that survival differences could be explained by confounding. Methods: We developed a pan-cancer cohort of 27,998 patients who received ICIs in the national Veterans Health Administration (VHA) from 2010 to 2023. ICI patients were matched to 66,488 historical control patients treated with chemotherapy or targeted therapy before initial ICI regulatory approval in each cancer. We ascertained baseline use of drugs from 15 common medication classes within 1 year before therapy start and performed propensity-weighted Cox regression analyses to assess the impact of each medication class on overall survival (OS) and time to next treatment (TTNT). Interaction tests measured whether the impact of each medication class was significantly different in ICI versus historical control patients. Results: In the ICI cohort, the most common cancer types were NSCLC (46%) and melanoma (10%). After adjustment for multiple comparisons, only statins (adjusted hazard ratio [aHR] 0.93), PPIs (aHR 1.06), and loop diuretics (aHR 1.19) were associated with overall survival differences among ICI patients; nearly identical associations were observed in historical control patients (interaction p-values > 0.4 for all; Table). Similar results were seen for TTNT and in sensitivity analyses limiting to more recent medication users. Conclusions: Common medications do not appear to impact ICI efficacy. Previously described survival effects are likely the result of confounding. [Table: see text]

The companion dog as a model for inflammaging: a cross-sectional pilot study.

Inflammaging, the chronic, progressive proinflammatory state associated with aging, has been associated with multiple negative health outcomes in humans. The pathophysiology of inflammaging is complex; however, it is often characterized by high serum concentrations of inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and C-reactive protein (CRP). Few studies have evaluated the effects of age on inflammatory cytokines in companion dogs, and most of these studies included dogs of a single breed. In this cross-sectional study, we measured multiple circulating inflammatory markers and hematological parameters in banked serum samples from 47 healthy companion dogs of various breeds enrolled in the Dog Aging Project. Using univariate linear models, we investigated the association of each of these markers with age, sex, body weight, and body condition score (BCS), a measure of obesity in the dog. Serum IL-6, IL-8, and TNF-α concentrations were all positively associated with age. Lymphocyte count was negatively associated with age. Platelet count had a negative association with body weight. IL-2, albumin, cholesterol, triglyceride, bilirubin, S100A12, and NMH concentrations were not associated with age, weight, BCS, or sex after adjustment for multiple comparisons. Our findings replicate previous findings in humans, including increases in IL-6 and TNF-α with age, giving more evidence to the strength of the companion dog as a model for human aging.

Impact of commonly prescribed medications on immune-related adverse events.

e14704 Background: Commonly used medications may have immune modulating properties that affect the risk of immune-related adverse events (irAEs) after immune checkpoint inhibitor (ICI) therapy. Methods: We identified 27,998 patients who received ICI from 2010 to 2023 in the national Veterans Affairs system, matched to 66,488 historical control patients treated with non-ICI systemic therapies. We extracted medication usage in the year before therapy start. We used propensity-weighted Cox regression analysis to assess the effect of each medication on severe irAE (treatment with prolonged course of high-dose steroids, adrenal insufficiency, or new insulin-dependent diabetes). To identify medication effects specific to ICI vs. other therapies, we report the adjusted hazard ratio (aHR) for each medication stratified by cohort (ICI vs. historical control) and the p-value for the interaction between each medication class and cohort. Results: Among ICI patients, 52% of patients were treated in the first line, 72% received ICI monotherapy, and 95% received PD-1/PD-L1 inhibitors alone. The most common cancer types were NSCLC (46%), melanoma (10%), and liver cancer (8%). Among 15 medication classes, metformin, loop diuretics, and PPIs were associated with small, marginally statistically significant differences in toxicity among ICI patients, but similar associations were observed in historical control patients (p for interaction >0.18; Table). After adjustment for multiple comparisons, no medication classes were associated with increased risk of severe irAE in ICI patients. Conclusions: Commonly prescribed medication classes have no significant effects on toxicity specific to ICI therapy. [Table: see text]

Facilitating adaptive coping with fear of recurrence among breast cancer survivors: Feasibility and acceptability outcomes from a three-arm randomized controlled trial.

1630 Background: Fear of cancer recurrence (FCR) is one of the most prevalent and disruptive problems for breast cancer survivors (BCS). Acceptance and commitment therapy (ACT) and cognitive behavioral therapy (CBT) have shown promising effects for FCR in a recent meta-analysis, yet head-to-head comparisons of these interventions are rare. We present feasibility and acceptability outcomes from a randomized controlled trial comparing ACT to CBT and enhanced usual care (EUC) for BCS with clinically significant FCR. Methods: Eligible women were ≥18 years old, diagnosed with stage I-IIIA breast cancer, within 5 years of completing cancer treatment (ongoing endocrine therapy was allowed), and reported clinical FCR at enrollment. Participants were randomly assigned to group-based ACT, CBT, or EUC, all delivered via videoconference. ACT and CBT consisted of 6 weekly 1.5-hour sessions; EUC was a single 1.5-hour survivorship coaching session. Outcomes included accrual, session attendance and engagement, intervention helpfulness, and retention. Variables were summarized by mean (SD) if numerical or relative frequency if categorical. At significance level α = 0.05, the Kruskal-Wallis test was used to compare overall differences between the three groups, and two-sample T-tests with unequal variances were used for pairwise comparisons between the groups with Bonferroni multiple-comparison adjustment. Results: Of 446 BCS who screened eligible, 390 (87.4%) enrolled. Most participants were white (81.8%), not Hispanic (98.4%), partnered (68.4%), and college-educated (71.3%). Most were within 2 years of completing cancer treatment (55.7%), and mean age was 55.8 (SD = 12.0) years. Among those assigned to a 6-session intervention, participants attended a mean of 5.0 (ACT) and 5.2 (CBT) sessions; 96.1% of EUC participants attended the single session. Mean session engagement (rated per participant per session by interventionists on a 0-10 scale) was significantly different across the three groups (p < .0001), with mean (SD) of 9.3 (0.8) for ACT, 9.5 (1.0) for CBT, and 7.9 (1.3) for EUC. Pairwise comparisons showed higher engagement ratings in ACT (p < .0001) and CBT (p < .0001) over EUC, with no significant difference between ACT and CBT (p = .14). At post-intervention, participants rated mean (SD) helpfulness on a 0-10 scale as 7.2 (2.6) for ACT, 7.9 (2.0) for CBT, and 5.5 (2.7) for EUC. Overall, mean helpfulness was significantly different across the groups (p < .0001) and favored CBT over ACT (p = .0109) and EUC (p < .001) and favored ACT over EUC (p < 0.001). Outcome data retention was 93.8% through the 6-month follow-up. Conclusions: High accrual and attendance rates suggest that BCS are receptive to FCR interventions and may find ACT or CBT more engaging and helpful than a single session of survivorship coaching. Clinical trial information: NCT05364450 .

The effects of wearing textured versus smooth shoe insoles for 4-weeks in people with diabetic peripheral neuropathy: a randomised controlled trial

Purpose To determine whether short-term wear of textured insoles alters balance, gait, foot sensation, physical activity, or patient-reported outcomes, in people with diabetic neuropathy. Materials and Methods 53 adults with diabetic neuropathy were randomised to wear textured or smooth insoles for 4-weeks. At baseline and post-intervention, balance (foam/firm surface; eyes open/closed) and walking were assessed whilst barefoot, wearing shoes only, and two insoles (textured/smooth). The primary outcome was center of pressure (CoP) total sway velocity. Secondary outcomes included other CoP measures, spatiotemporal gait measures, foot sensation, physical activity, and patient-reported outcomes (foot health, falls efficacy). Results Wearing textured insoles led to improvements in CoP measures when standing on foam with eyes open, relative to smooth insoles (p ≤ 0.04). The intervention group demonstrated a 5% reduction in total sway velocity, indicative of greater balance. The intervention group also showed a 9-point improvement in self-perceived vigour (p = 0.03). Adjustments for multiple comparisons were not applied. Conclusions This study provides weak statistical evidence in favour of textured insoles. Wearing textured insoles may alter measures of balance, suggestive of greater stability, in people with diabetic neuropathy. Plantar stimulation, through textured insoles, may have the capacity to modulate the perception of foot pain, leading to improved well-being. IMPLICATIONS FOR REHABILITATION Short-term wear of textured insoles can lead to improvements in centre of pressure sway measures when standing on a compliant supporting surface. Wearing textured insoles may have the capacity to help relieve foot pain leading to enhanced self-perceived vitality in people with diabetic peripheral neuropathy.

Apical Suspension Repair for Vaginal Vault Prolapse: A Randomized Clinical Trial.

The optimal surgical repair of vaginal vault prolapse after hysterectomy remains undetermined. To compare the efficacy and safety of 3 surgical approaches for vaginal vault prolapse after hysterectomy. This was a multisite, 3-arm, superiority and noninferiority randomized clinical trial. Outcomes were assessed biannually up to 60 months, until the last participant reached 36 months of follow-up. Settings included 9 clinical sites in the US National Institute of Child Health and Human Development (NICHD) Pelvic Floor Disorders Network. Between February 2016 and April 2019, women with symptomatic vaginal vault prolapse after hysterectomy who desired surgical correction were randomized. Data were analyzed from November 2022 to January 2023. Mesh-augmented (either abdominally [sacrocolpopexy] or through a vaginal incision [transvaginal mesh]) vs transvaginal native tissue repair. The primary outcome was time until composite treatment failure (including retreatment for prolapse, prolapse beyond the hymen, or prolapse symptoms) evaluated with survival models. Secondary outcomes included patient-reported symptom-specific results, objective measures, and adverse events. Of 376 randomized participants (mean [SD] age, 66.1 [8.7] years), 360 (96%) had surgery, and 296 (82%) completed follow-up. Adjusted 36-month failure incidence was 28% (95% CI, 20%-37%) for sacrocolpopexy, 29% (95% CI, 21%-38%) for transvaginal mesh, and 43% (95% CI, 35%-53%) for native tissue repair. Sacrocolpopexy was found to be superior to native tissue repair (adjusted hazard ratio [aHR], 0.57; 99% CI, 0.33-0.98; P = .01). Transvaginal mesh was not statistically superior to native tissue after adjustment for multiple comparisons (aHR, 0.60; 99% CI, 0.34-1.03; P = .02) but was noninferior to sacrocolpopexy (aHR, 1.05; 97% CI, 0-1.65; P = .01). All 3 surgeries resulted in sustained benefits in subjective outcomes. Mesh exposure rates were low (4 of 120 [3%] for sacrocolpopexy and 6 of 115 [5%] for transvaginal mesh) as were the rates of dyspareunia. Among participants undergoing apical repair for vaginal vault prolapse, sacrocolpopexy and transvaginal mesh resulted in similar composite failure rates at study completion; both had lower failure rates than native tissue repair, although only sacrocolpopexy met a statistically significant difference. Low rates of mesh complications and adverse events corroborated the overall safety of each approach. ClinicalTrials.gov Identifier: NCT02676973.

Urinary Proteomic Biomarkers of Trabecular Bone Volume Change during Army Basic Combat Training.

Optimize a dMS-based urinary proteomic technique and evaluate the relationship between urinary proteome content and adaptive changes in bone microarchitecture during BCT. Urinary proteomes were analyzed with an optimized dMS technique in two groups of 13 recruits (n = 26) at the beginning (Pre) and end (Post) of BCT. Matched by age (21 ± 4 yr), sex (16 W), and baseline tibial trabecular bone volume fractions (Tb.BV/TV), these groups were distinguished by the most substantial (High) and minimal (Low) improvements in Tb.BV/TV. Differential protein expression was analyzed with mixed permutation ANOVA and false discovery proportion-based adjustment for multiple comparisons. Tibial Tb.BV/TV increased from pre- to post-BCT in High (3.30 ± 1.64%, p < 0.0001) but not Low (-0.35 ± 1.25%, p = 0.4707). The optimized dMS technique identified 10,431 peptides from 1,368 protein groups that represented 165 integrative biological processes. 74 urinary proteins changed from pre- to post-BCT (p = 0.0019) and neutrophil mediated immunity was the most prominent ontology. Two proteins (Immunoglobulin heavy constant gamma 4 and C-type lectin domain family 4 member G) differed from pre- to post-BCT in High and Low (p = 0.0006). The dMS technique can identify more than 1000 urinary proteins. At least 74 proteins are responsive to BCT, and other principally immune system-related proteins show differential expression patterns that coincide with adaptive bone formation.

Assessing the causality of interferon‐γ and its receptor 1/2 with systemic lupus erythematosus risk using genetic data

AbstractBackgroundThe interferon‐γ (IFN‐γ) signaling pathway is activated in systemic lupus erythematosus (SLE). This study aimed to assess the causal association between IFN‐γ, IFN‐γ receptor 1 (IFN‐γR1), and IFN‐γR2 and SLE using a bidirectional Mendelian randomization (MR) design.MethodsGenetic instruments for exposure to IFN‐γ, IFN‐γR1, and IFN‐γR2 were derived from a large genome‐wide association study (GWAS) that included a sample size of 3301 participants. Instrumental variables for SLE were selected from another independent GWAS analysis comprising 5201 cases and 6099 controls with European ancestry. Bidirectional two‐sample MR was performed using inverse variance weighting, MR‐Egger regression, and weighted median methods. A series of sensitivity analyses were conducted to assess the robustness of the results.ResultsThe inverse variance weighting showed that IFN‐γ had a positive causal association with the risk of SLE (odd ratio [OR] = 1.24, 95% confidence interval [CI]: 1.03–1.47, p = 0.018). IFN‐γR2 levels were not associated with SLE risk after adjustment for multiple comparisons (OR = 0.85, 95% CI: 0.73–0.99, p = 0.034). No genetic association was also detected between IFN‐γR1 and SLE (OR = 0.97, 95% CI: 0.79–1.19, p = 0.768). Evidence from bidirectional MR did not support reverse causality. The weighted median regression also showed directionally similar estimates.ConclusionHigher levels of IFN‐γ are significantly associated with an increased risk of SLE, providing insights into the pathogenesis of SLE.

Acupuncture for Chronic Radiation-Induced Xerostomia in Head and Neck Cancer

Patients with head and neck cancer who undergo radiotherapy can develop chronic radiation-induced xerostomia. Prior acupuncture studies were single center and rated as having high risk of bias, making it difficult to know the benefits of acupuncture for treating radiation-induced xerostomia. To compare true acupuncture (TA), sham acupuncture (SA), and standard oral hygiene (SOH) for treating radiation-induced xerostomia. A randomized, blinded, 3-arm, placebo-controlled trial was conducted between July 29, 2013, and June 9, 2021. Data analysis was performed from March 9, 2022, through May 17, 2023. Patients reporting grade 2 or 3 radiation-induced xerostomia 12 months or more postradiotherapy for head and neck cancer were recruited from community-based cancer centers across the US that were part of the Wake Forest National Cancer Institute Community Oncology Research Program Research Base. Participants had received bilateral radiotherapy with no history of xerostomia. Participants received SOH and were randomized to TA, SA, or SOH only. Participants in the TA and SA cohorts were treated 2 times per week for 4 weeks. Those experiencing a minor response received another 4 weeks of treatment. Patient-reported outcomes for xerostomia (Xerostomia Questionnaire, primary outcome) and quality of life (Functional Assessment of Cancer Therapy-General) were collected at baseline, 4 (primary time point), 8, 12, and 26 weeks. All analyses were intention to treat. A total of 258 patients (201 men [77.9%]; mean [SD] age, 65.0 [9.16] years), participated from 33 sites across 13 states. Overall, 86 patients were assigned to each study arm. Mean (SD) years from diagnosis was 4.21 (3.74) years, 67.1% (n = 173) had stage IV disease. At week 4, Xerostomia Questionnaire scores revealed significant between-group differences, with lower Xerostomia Questionnaire scores with TA vs SOH (TA: 50.6; SOH: 57.3; difference, -6.67; 95% CI, -11.08 to -2.27; P = .003), and differences between TA and SA (TA: 50.6; SA: 55.0; difference, -4.41; 95% CI, -8.62 to -0.19; P = .04) yet did not reach statistical significance after adjustment for multiple comparisons. There was no significant difference between SA and SOH. Group differences in Functional Assessment of Cancer Therapy-General scores revealed statistically significant group differences at week 4, with higher scores with TA vs SOH (TA: 101.6; SOH: 97.7; difference, 3.91; 95% CI, 1.43-6.38; P = .002) and at week 12, with higher scores with TA vs SA (TA: 102.1; SA: 98.4; difference, 3.64; 95% CI, 1.10-6.18; P = .005) and TA vs SOH (TA: 102.1; SOH: 97.4; difference, 4.61; 95% CI, 1.99-7.23; P = .001). The findings of this trial suggest that TA was more effective in treating chronic radiation-induced xerostomia 1 or more years after the end of radiotherapy than SA or SOH. ClinicalTrials.gov Identifier: NCT02589938.

Microvascular dysfunction associated with reduced nailfold capillary density in patients with ischemia with no obstructive coronary artery disease

Abstract Funding Acknowledgements None. Introduction The impairment of microvascular function present in coronary microcirculation with chronic angina without obstructive coronary arteries. There are insufficient data in the literature regarding possible generalized microangiopathy in this population. Aim The aim of this study is to demonstrate whether patients with Angina with No Obstructive Coronary Artery Disease (ANOCA) compared to individuals without coronary microvascular dysfunction (CMD) are characterized by a different level of nailfold capillaroscopy abnormalities. Methods We examined 18 participants without CMD - non-CMD group [9 female, 50%, mean age: 54.4±8.1 years) and 26 patients with ANOCA - CMD group (22 female, 84,6%, mean age : 53.2±10.7 years). Functional coronary angiography was performed for the assessment of coronary microcirculation in all patients. Coronary flow reserve (CFR) and index of microvascular resistance (IMR) were measured in the left anterior descending coronary artery using a temperature/pressure sensor-tipped guidewire. In addition, the assessment of skin microcirculation was performed by capillaroscopy, a non-invasive technique to evaluate small vessels of the microcirculation in the nailfold, using stereomicroscope in all patients. Results In CMD group, mean CFR and IMR were 1.34±0.6 and 44.8±28, respectively. Out of the 26 MVD patients with abnormal CFR, 7 of them (27%) had a normal value of IMR, indicating functional microvascular dysfunction. On the other hand, 18 patients (69%) had an abnormal IMR, indicating structural microvascular dysfunction. Capillary density in patients with MVD was significantly decreased compared to the control group (7.6±2.2 vs 10.9±1.8 vessels/mm, p=0.04). The difference in capillary density between the two groups was statistically significant after adjustment for multiple comparisons (p&amp;lt;0.05). No significant difference was found in body mass index, renal function, medical history of dyslipidemia, diabetes mellitus and smoking status between the two groups (p&amp;lt;0.05). Conclusion Nailfold capillary density was reduced in ANOCA patients compared to control group. These data may provide new insights regarding possible generalized microangiopathy in CMD patients. These results suggest that there is an association between microcirculatory impairment at both heart and peripheral vascular bed level.

265 Effect of L-glutamine and enzyme supplementation of liquid creep feed from d 8 to 28 of age on pre-weaning growth and health of pigs

Abstract The provision of liquid creep feed has been shown to increase dry matter intake (DMI) compared with dry creep feeding. The greater DMI associated with liquid feeding means that it could be used as an effective route for feed additive supplementation of suckling pigs to optimize growth and health at weaning. The objective of this study was to assess the effect of L-glutamine or enzyme supplementation of liquid creep feed on growth and medication usage in suckling pigs. Sows (n = 60) were blocked on parity, previous number of piglets weaned and body weight (BW) at d 107 of gestation, and randomly assigned to one of 3 dietary treatments from d 8 of age to weaning at d 28: 1) liquid starter (control); 2) control supplemented with 10 kg of L-glutamine per tonne of starter diet (glutamine); and 3) control supplemented with a cocktail of enzymes (lipase, protease and α-amylase included at 200 g, 50 g and 112.5 g, respectively per tonne of starter diet; enzymes). Individual piglets were weighed on d 8, 14, 21 and 27 of age. Litter dry matter intake, the volume of antibiotics and anti-inflammatories administered per pig and per sow were recorded for the pre-weaning period. Data were analyzed using the mixed models procedure in SAS (version 9.4; SAS Institute Inc.) with treatment as a fixed effect, and day post-partum as the repeated measure. Block was included as a random effect and the number of pigs/litter at d 8 and the average pig BW at d 8 were included as co-variates when significant in the model. Means separation was by Tukey’s adjustment for multiple comparisons. The piglet nested within sow was the experimental unit. The DMI of creep feed did not differ between treatments (P &amp;gt; 0.05). From d 14 to 21, glutamine decreased average daily gain (ADG) by 7% compared with the control (P &amp;lt; 0.05). However, ADG did not differ between treatment groups from d 8 to 14 or from d 21 to 27. Body weight was not affected by treatment at d 8 or 14 (P &amp;gt; 0.05). However, at d 21, glutamine tended to reduce BW by 2% compared with the control (P = 0.09) and at d 27, it tended to reduce BW by 2% compared with the control and enzymes (P = 0.08). The volume of antibiotics or anti-inflammatories administered to piglets or sows was not affected by treatment. However, glutamine tended to increase diarrhea incidence by 12% between d 8 and 27 compared with the control (P = 0.09). In conclusion, supplementing liquid creep feed with 10 kg of glutamine/tonne of feed reduced pre-weaning growth and tended to increase diarrhea incidence in piglets. In addition, supplementing liquid creep feed with enzymes had no effect on pre-weaning growth and medication usage in piglets.

26 Effects of increasing net energy or standardized ileal digestible lysine in soybean meal-based diets on early and late finishing pig performance

Abstract A total of 2,265 finishing pigs [337×1050, PIC; initial body weight (BW) = 50.2 kg) were used in two 28-d trials to determine the effect of increasing net energy (NE) or standardized ileal digestible Lys in soybean meal (SBM) based diets on early and late finishing pig performance. There were 27 pigs/pen and 21 pens/treatment. Soybean meal NE value used in diet formulation was either 78% (2,087 kcal/kg) or 100% (2,672 kcal/kg) of corn NE. Four treatment diets were assigned to pens in a completely randomized design and consisted of: 1) high level of SBM estimated at 100% NE of corn (High SBM); 2) low level of SBM estimated at 100% NE of corn with added feed-grade AA (Low SBM); 3) low level of SBM estimated at 78% NE of corn with added fat (Low SBM w/fat) to equal the NE in diets 1 and 2; and 4) low level of SBM estimated at 100% NE of corn with increased feed-grade AA and increased Lys:NE (Low SBM w/AA). Following the early finishing 28-d growth trial (initial BW = 50.2 kg), pigs were fed a common diet for 30-d and pens were randomly reallotted to 1 of the same 4 treatments for the late finishing trial (initial BW 114.1 kg). In early finishing, there were no differences (P &amp;gt; 0.10) in average daily gain (ADG), but pigs fed Low SBM w/AA had increased (P &amp;lt; 0.05) average daily feed intake (ADFI) compared with pigs fed High SBM (Table). The increased ADFI without increased ADG resulted in decreased (P &amp;lt; 0.05) gain to feed ratio (G:F) in pigs fed Low SBM w/AA compared with pigs fed Low SBM w/fat. Pigs fed Low SBM w/fat had improved (P &amp;lt; 0.05) caloric efficiency (CE) compared with pigs fed Low SBM w/AA. In late finishing, there was a tendency (P = 0.099) for a treatment effect on G:F where pigs fed High SBM had the greatest G:F, but there was not a significant difference (P &amp;gt; 0.05) between any two treatments when using a Tukey multiple comparison adjustment. There was no evidence (P &amp;gt; 0.10) for a difference between treatments on ADG, ADFI, or CE. Based on the performance of pigs fed the Low SBM w/AA diet, the decreased growth performance of low SBM diets is not due to a low Lys:Calorie ratio that results when NE is underestimated. Using caloric efficiency, an estimate of the NE of SBM was calculated by adjusting NE of SBM used in formulation until CE for the High SBM and Low SBM treatments were equal. These results showed SBM was estimated to contain 94% the NE of corn in the early finishing period and 125% the NE of corn in the late finishing period.

Abstract PO4-12-11: Patient (pt) time burden with IV vs subcutaneous (SC) administration of trastuzumab/pertuzumab (HP): A time and motion (T+M) substudy of a single arm phase II trial of adjuvant endocrine therapy plus HP for stage I HER2+ breast cancer

Abstract Background: The time required for in-clinic drug administration may have a substantial detrimental impact on breast cancer patients’ quality of life. SC drug administration, as opposed to IV, may reduce this time commitment. The purpose of this study was to estimate the relative difference in time and logistical burden between IV and SC administration of HP. Methods: We prospectively enrolled a pre-specified sub-cohort of pts participating on the ADEPT trial (NCT04569747) to this T+M substudy. The ADEPT trial is an ongoing single arm prospective phase II trial of adjuvant SC HP (for 1 yr) plus endocrine therapy for pts with hormone receptor-positive (HR+) and HER2+ stage I (pT1N0 or pT1N1mi) breast cancer. Pts eligible for ADEPT have completed primary breast surgery and are systemic therapy-naïve. Pts who received cycle 1 of loading SC HP at Dana-Farber Cancer Institute and tolerated SC drug administration were eligible and enrolled consecutively to the T+M substudy until the T+M accrual goal; accrual to the T+M substudy was mandatory for eligible pts. The T+M substudy was a single arm crossover design in which pts received 2 cycles of IV HP, followed by 2 cycles of maintenance dose SC HP. During those 4 treatment (tx) cycles, timepoints in the drug preparation and administration process were captured from the electronic medical record or flowsheets filled out by infusion nurses. The primary endpoint of the T+M substudy was total pt chair time in the infusion area (measured from start of first drug administration to end of final post-drug observation period). Exploratory endpoints included total drug preparation time and total pt tx experience time. A sample size of 22 pts was estimated to provide 86% power with 2-sided alpha 0.05 to detect a difference of 70 mins in the primary endpoint by tx arm (IV vs SC). For all endpoints, the average time across both tx cycles was calculated for each pt, and the overall mean across pts for each of IV and SC administration was computed (with standard deviation). Average times for IV vs SC administration were compared via paired Wilcoxon signed rank tests. Adjustments for multiple comparisons were not included. Results: 22 pts participated on the T+M substudy, and each had timepoints captured during 4 tx cycles (2 IV and 2 SC cycles), for a total of 88 patient-cycles analyzed overall. Pts had median age 58 yrs (range 42-83), and were 96% female, 82% White, 9% Black, 9% Asian; and 100% non-Hispanic. Comparison of time intervals for IV vs SC drug administration is shown in the Table. Mean total pt infusion chair time was 84.3 mins with IV HP, vs 22.5 mins with SC HP, for a difference of 61.8 mins shorter pt time commitment in favor of SC administration (p&amp;lt; 0.0001). The mean total drug preparation time was significantly decreased in favor of SC administration (by 78.2 mins; p&amp;lt; 0.0001); and the total pt tx experience time was significantly decreased in favor of SC administration (by 81.8 mins; p&amp;lt; 0.0001). Conclusions: This prospective T+M study demonstrated that pt infusion chair time is significantly decreased with SC as compared to IV administration of HP, shortening this pt time burden by approximately one hour. SC drug administration is an approach that may help to improve and shorten the pt breast cancer therapy experience and decrease pharmacy burden. Table. SD, standard deviation Citation Format: Adrienne Waks, Noah Graham, Emily Chen, Anna Mae Frey, Victoria Attaya, Ibrahim Abbass, Anita Fung, Jesse Sussell, Patricia Cortazar, Caroline Harvey, Kenneth Almeida, Denise Leth, Wendy Chen, Jose Leone, Susan Schumer, Nabihah Tayob, Sara Tolaney. Patient (pt) time burden with IV vs subcutaneous (SC) administration of trastuzumab/pertuzumab (HP): A time and motion (T+M) substudy of a single arm phase II trial of adjuvant endocrine therapy plus HP for stage I HER2+ breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-11.

Abstract PO3-19-02: White Button Mushroom and Biomarkers of Immune Cell and Inflammatory Responses in Obese Postmenopausal Women at High Risk of Breast Cancer

Abstract Background: White Button Mushroom (WBM), Agaricus bisporus, has anti-tumor and anti-inflammatory effects. Oral WBM mitigated the effects of a high fat diet on hepatic steatosis and insulin resistance in ovariectomized mice. A Phase I trial of WBM in men with prostate cancer demonstrated decreased myeloid derived suppressor cells (MDSC) in those with decreased PSA; MDSC have been linked to different cancers, including breast, and conditions of chronic inflammation. Design: This is a preliminary evidence trail in postmenopausal, obese women at high risk of breast cancer with a single intervention arm of 14g of WBM taken as 28 tablets daily for 3 months to assess effects on inflammation. Participants undergo a physical exam, measuring height, weight, and waist circumference, an optional fine needle aspiration (FNA) of breast tissue, a blood draw, a food frequency questionnaire and a 24-hour food recall at baseline and final visits. Participants are contacted monthly for tolerance and adherence. Blood samples and FNA adipose are used for metabolic measurements and processed for biomarkers of inflammation and immune response. Peripheral blood mononuclear cells (PBMC) will be used for RNA single-cell analysis to assess for immune cell profiles and expression with an interest in evaluating MDSC. Red blood cells will be assessed for fatty acid profiles. Eligibility: Postmenopausal, obese (BMI ≥30, Asian ≥25) women with high risk for breast cancer who can swallow pills are eligible. Patients are high risk if their relative risk of breast cancer is ≥2 times that of the general population; this includes women with a strong family history, a genetic mutation associated with hereditary breast cancer, a high-risk breast histology, Gail model 5-year risk &amp;gt;1.67, or a previous history of stage I-II breast cancer. Participants are excluded for an active malignancy within 5 years, ongoing active or preventative cancer treatment, or lab abnormalities of serum creatinine and total bilirubin &amp;gt;1.5 the upper limit of normal, hemoglobin of &amp;lt; 9.0 g/dL, platelets of &amp;lt; 100,000/mm3, or a total white blood cell count of &amp;lt; 3,500/mm3. Participants cannot be taking mushroom supplements, immunosuppressants, or non-steroidal anti-inflammatories. Specific Aims: This study aims to evaluate the effects of WBM on regulating immune response and inflammation in obese women at high risk for breast cancer. Our primary objective is the assessment of PBMC, specifically MDSC immune profiles before and after treatment. Our secondary objective is to evaluate changes in biomarkers of inflammation, immune cell profiles in breast adipose tissue, BMI, waist circumference, and metabolic biomarkers. Additionally, the study aims to assess tolerability of the WBM dose and effects on diet quality. Statistical Methods: 26 patients will provide 80% power to detect a change in %MDSC of -0.67, assuming a standard deviation of 1.15, and a 2-sided type I error of 5%. We will have similar power to evaluate changes in other immune subsets, inflammatory markers, metabolic markers, anthropometric measurements, and diet quality. FNA adipose tissue analysis will be used as a safety signal to evaluate the potential for unwanted inflammation with taking WBM. 13 patients with FNA will provide 80% power to detect a change of 85% of the standard deviation of the difference in the measure of biomarkers such as Interleukin-6 with a 2-sided type I error of 5%. As a safety signal, the signal will be reported without adjustment for multiple comparisons. Any conclusions based on such secondary endpoints will make note of the multiple comparison issue. Accrual: The accrual target is 26 evaluable patients with an estimated need to enroll 31. The study has enrolled 27 patients, 14 completed the study and 5 are currently on treatment. 8 participants were removed; 3 never started treatment, 1 was diagnosed with breast cancer, and 4 had other medical issues preventing continuation. Contact: Jessica Dzubnar, MD: jdzubnar@coh.org Citation Format: Jessica Dzubnar, Lisa Yee, Shiuan Chen. White Button Mushroom and Biomarkers of Immune Cell and Inflammatory Responses in Obese Postmenopausal Women at High Risk of Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-02.

Equine relative preferences regarding selected cool-season grass hays

Horse preferences for cool season grass cultivars under grazing has been described. However, preference for cool-season grass cultivars as hays has not been widely evaluated in horses, particularly the new varieties of Tall Fescue with novel endophytes designed to produce less ergovaline, the compound to which fescue toxicosis is attributed. First cutting hay was harvested in 2019 and 2020 from seven cool season grasses: Tall Fescue v. KY 31; Tall Fescue v. Bronson, endophyte free; Tall Fescue v. Texoma MaxQ, novel/non-toxic endophyte; Meadow Fescue v. Preval; Festulolium v. Spring Green; Perennial Ryegrass v. Elgon; and Orchardgrass v. Crown Royal. First cutting yield was determined on a dry weight basis. Sub-samples were analyzed for forage quality parameters and ergovaline concentrations. The effect of cultivar on mean hay yields was analyzed using a one-way ANOVA, and since the F-Value was significant (< 0.001) the least significant differences were further determined to compare yield differences among the cultivars. All three Tall Fescue cultivars, Meadow Fescue, and Festulolium had significantly greater yields than the Perennial Ryegrass and Orchardgrass (P < 0.05). All samples tested for ergovaline were below the reporting threshold of the laboratory. Subsequently, tillers of the Tall Fescue cultivars were evaluated for endophyte presence. Endophyte was detected in only 3.3 % and 16.7 % of v Bronson and Texoma MaxQ tillers, respectively. No endophyte was detected in v KY 31. To evaluate preference four mature idle horses (6 ± 1.08 yrs) were fasted 30 min prior to being in the test stalls for 30 min. First choice and weight consumed were recorded. Preference testing occurred within harvest year. Equine preference data were analyzed within year using a one-way ANOVA pairwise comparison with the Tukey-Kramer adjustment for multiple comparisons. Both forward and backward stepwise regression modelling were used to investigate proximate analyses values as potential predictors of cultivar consumption by the horses during the preference tests. The best performing model explained 36 % of the variation in cultivar consumption. Based on amounts consumed horses had similar preferences each year; the overall rank of the cultivars was very similar with only the two least preferred cultivars transposed from 2019 to 2020. Horses most preferred the lowest yielding cultivars (Perennial Ryegrass and Orchardgrass). Despite low ergovaline and endophyte content in the Tall Fescue varieties, adult horses preferred hay of other cultivars. Festulolium is an option for hay producers that balances both yield and horse preference.

Pharmacokinetics, pharmacodynamics and antinociceptive effects of buprenorphine following transdermal administration to horses

ObjectiveThis study describes the pharmacokinetics and pharmacodynamics, including antinociceptive effects, of a transdermal buprenorphine solution in horses. It was hypothesized that transdermal application would lead to sustained blood concentrations and antinociceptive effects with fewer adverse effects compared with intravenous (IV) injection. Study designProspective nonrandomized four-part parallel experimental study. AnimalsA group of eight horses (three mares and five geldings) aged 6–12 years. MethodsHorses were administered incremental doses of 15, 30 and 45 μg kg–1 of buprenorphine transdermal solution and a single IV dose of 5 μg kg–1 of buprenorphine with a 2 week washout period between treatments. Concentrations of buprenorphine were determined in plasma using liquid chromatography–tandem mass spectrometry and modeled using a nonlinear mixed effects population pharmacokinetic model to determine pharmacokinetic parameters. Pharmacodynamic effects, including changes in locomotor activity, heart rate, body temperature, gastrointestinal borborygmi, thermal and mechanical nociceptive thresholds were recorded. Mixed effects analysis of variance and post hoc comparisons were performed using a Bonferroni multiple comparison adjustment to assess differences in pharmacodynamic parameters between baseline and each time point within each dose group and between dose groups at the same time point. ResultsTransdermal application of buprenorphine resulted in low systemic concentrations relative to IV injection. Bioavailability after transdermal application was 11%. Thermal nociceptive thresholds were significantly (p < 0.05) increased (4.3–10.7% relative to baseline) for up to 72 hours in the IV dose group, but only sporadically in the transdermal dose groups (2.5–9.9% relative to baseline). Changes in locomotor activity, heart rate and borborygmi varied over time and with dose. Conclusions and clinical relevanceLimited thermal antinociceptive effects were observed at the transdermal doses studied likely owing to limited absorption relative to IV dosing. Future studies may be directed toward investigating antinociceptive effects of higher transdermal doses and different application sites.

Efficacy and Safety of Secukinumab in US Patients with Psoriatic Arthritis: A Subgroup Analysis of the Phase 3 FUTURE Studies.

The aim of this work is to evaluate secukinumab vs. placebo in a challenging-to-treat and smaller US patient subpopulation of the international FUTURE 2-5 studies in patients with psoriatic arthritis (PsA). Data were pooled from US patients enrolled in the phase 3 FUTURE 2-5 studies (NCT01752634, NCT01989468, NCT02294227, and NCT02404350). Patients received secukinumab 300 or 150 mg with subcutaneous loading dose, secukinumab 150 mg without subcutaneous loading dose, or placebo. Categorical efficacy and health-related quality-of-life (QoL) outcomes and safety were evaluated at week 16. Subgroup analyses were performed based on tumor necrosis factor inhibitor (TNFi) status and body mass index (BMI). For hypothesis generation, odds ratios (ORs) for American College of Rheumatology (ACR) 20/50/70 and Psoriasis Area and Severity Index (PASI) 75/90/100 responses by treatment were estimated using logistic regression without adjustment for multiple comparisons. Of 2148 international patients originally randomized, 279 US patients were included in this pooled analysis. Mean BMI was > 30 kg/m2 and 55.2% had prior TNFi treatment. ORs for ACR20/50/70 significantly favored patients receiving secukinumab 300 mg and 150 mg with loading dose vs. placebo (P < 0.05), but not those receiving secukinumab 150 mg without loading dose vs. placebo. For PASI75, ORs favored all secukinumab groups over placebo (P < 0.05); for PASI90 and PASI100, only the secukinumab 300-mg group was significantly favored over placebo (P < 0.05). In this challenging sub-population of US patients with PsA, secukinumab provided rapid improvements in disease activity and QoL. Patients with PsA and active psoriasis might benefit more from secukinumab 300mg than 150mg.

Using a transdiagnostic approach to examine the associations among internalizing symptoms, emotion regulation, and distress tolerance

Difficulty tolerating distress (e.g., distress tolerance [DT]) and regulating emotions (e.g., emotion regulation [ER]) are implicated as transdiagnostic risk factors for various internalizing disorders. The present study investigated the relationships among six internalizing disorder symptoms, baseline ER, and DT in college students ( N = 137) to identify which internalizing disorders were most closely associated with DT. We expected ER and internalizing symptoms to be associated with DT and that ER would moderate relationships among internalizing symptoms and both trait DT and state distress. Results indicated that ER, Post-traumatic Stress Disorder (PTSD), and social anxiety symptoms influenced trait DT. ER moderated the associations between depression, anxiety, and panic disorder (PD) symptoms, and trait DT at the .05 level. Similarly, ER moderated the association between PD symptoms and anticipatory distress at the .05 level. However, these analyses did not withstand the Bonferroni adjustment ( p = .008) for multiple comparisons. Findings suggest that, when considering transdiagnostic symptoms, certain internalizing symptoms (i.e., social anxiety, PTSD) may have a stronger influence on trait DT. Further, strong ER abilities may buffer the adverse effects of internalizing symptoms on one’s perceived ability to handle distress. These patterns may not translate to individuals’ behavioral capacity to handle distress.

Prevalence of long COVID symptoms in Haryana, India: a cross-sectional follow-up study

Emerging research indicates growing concern over long COVID globally, although there have been limited studies that estimate population burden. We aimed to estimate the burden of long COVID in three districts of Haryana, India, using an opportunity to link a seroprevalence study to follow-up survey of symptoms associated with long COVID. We used a population-based seroprevalence survey for COVID-19 conducted in September 2021 across Haryana, India. Adults from three purposively selected districts (Rohtak, Gurugram, and Jhajjar) were eligible to participate; 2205 of 3213 consented to participate in a survey on health status. Trained investigators administered a structured questionnaire that included demographic characteristics, self-reported symptoms of illness in the last six months before the survey, mental health, and history of COVID-19. Unadjusted regression estimates indicated positive correlations between symptomatic complaints and COVID-19 exposure, suggesting lingering effects of COVID-19 in this population. The overall physical morbidity index was higher among those who tested positive for COVID-19, as was the incidence of new cases. However, both morbidity and incidence became statistically insignificant after adjustment for multiple comparisons. Cough emerged as the only statistically significant individual persistent symptom. Sex-stratified analyses indicated significant estimates only for physical morbidity in women. This study is one of the first from India that uses a large population-based sample to examine longer term repercussions of COVID infections. The burden of long COVID should primarily be addressed in clinical settings, where specialised treatment for individual cases continues to evolve. Our analyses also provide insight into the size and nature of studies required to assess the population-level burden of long COVID. This paper was produced under the auspices of the Lancet COVID 19 Commission India Task Force, which was supported financially by the Reliance Foundation. The Lancet COVID 19 Commission was set up in July 2020 and submitted its final report by October 2022. This report by the India Task Force was prepared during the same period.

Abstract 6130: Association of vitamin D-related genetic variants and prostate cancer risk in Black men

Abstract Background: What we know of the relationship between vitamin D status and prostate cancer has largely been characterized among men of European ancestry, hereafter referred to as “White”. Research among White men indicate positive associations between circulating vitamin D status, as measured by concentrations of 25-hydroxyvitamin D (25(OH)D), with prostate cancer risk, and that genetic scores based on genome-wide associated single nucleotide polymorphisms (SNPs) reflecting high vs. low 25(OHD) is positively associated with aggressive disease. Limited research exists elucidating this relationship among men of African ancestry, hereafter referred to as “Black”. This is despite the fact that Black populations experience chronically lower circulating 25(OH)D, and ancestry-specific differences in genetic variants in some vitamin D-related genes. Given the paucity of research in this area, we examined the role of genetic variants in six commonly studied genes in the vitamin D pathway involved in synthesis (CYP27A1 and CYP27B1), transport (GC), activity (VDR and RXR), and metabolism (CYP24A1) in relation to prostate cancer among Black men. Methods: We assessed a total of 78 candidate SNPs in six vitamin D pathway genes that were either previously associated with circulating 25(OHD) and/or associated with prostate cancer risk in studies of White men. We compared vitamin D gene SNP associations with prostate cancer in Black and White men using summary statistics from a large GWAS of over 10,000 prostate cancer cases and 10,000 controls among Black men and over 85,000 cases and 91,000 controls among White men. A statistical significance threshold of 0.00064 (0.05/78 candidate SNPs) was used to adjust for multiple comparisons. Results: None of the examined SNPs were significantly associated with prostate cancer risk among Black men after adjustment for multiple comparisons. However, four SNPs were nominally significant in Black men, including two in RXR [rs41400444 OR=1.09, 95% CI: 1.01-1.17, P = 0.024 and rs10881574 OR = 0.93, 0.867-0.999, P = 0.04556] and two in VDR [rs2853563 OR = 1.07, 1.012-1.13, P = 0.0173 and rs1156882 OR = 1.06, 1.00-1.12, P = 0.0495]. The latter SNP rs1156882 was also positively associated with prostate cancer risk in White men (OR = 1.035, 1.02-1.06, P = 0.00024), along with VDR SNP rs4516035 (OR = 1.027, 1.012-1.042, P = 0.00055), both after correction for multiple comparisons. Conclusions: We observed non-significant, though suggestive, associations between genetic variants in vitamin D pathway genes previously associated with prostate cancer or vitamin D levels in White populations and prostate cancer risk in Black men. Future research exploring the potential role of vitamin D pathway genes and prostate cancer in Black men – a population at high risk both for low circulating vitamin D and prostate cancer - will need to identify vitamin D-related genetic variants specific to carcinogenesis in Black men. Citation Format: Tracy M. Layne, Joseph H. Rothstein, Xiaoyu Song, Weiva Sieh, Robert J. Klein. Association of vitamin D-related genetic variants and prostate cancer risk in Black men [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 6130.