Observation Arm Research Articles

The Supraglottic Index: An indicator of response to laryngopharyngeal reflux therapy in asthma

BackgroundLaryngopharyngeal reflux (LPR) is associated with gastroesophageal reflux and is known to cause poor asthma control. Moreover, LPR and asthma frequently coexist in the same individual. Controlling LPR could be associated with improved asthma control. The Supraglottic Index (SGI) is a clinically applied visual scale, which correlates with the presence of LPR. The role of SGI in monitoring LPR therapy in individuals with asthma is not known. ObjectiveTo determine whether the SGI can be used over time to assess the presence of LPR in patients with asthma, and whether the SGI improves with LPR treatment. MethodsThis is a pilot study in 15 participants with asthma. Those without evidence of LPR by SGI measurement were assigned to the observation arm. Those with LPR were assigned to the treatment arm and were treated with either standard-of-care LPR treatment (antacids and behavioral management) or a novel therapy (upper esophageal assist device). ResultsThe SGI remained stable in individuals with asthma who underwent observation over 8 weeks. The SGI improved in participants with asthma treated for LPR (P = .024). ConclusionThe SGI is a readily available clinical tool to assess the presence of LPR and monitor its therapy in asthma.

The Safety and Outcomes of Elective Endovascular Aneurysm Repair in the Elderly: A Systemic Review and Meta-Analysis.

Prevalence of abdominal aortic aneurysms (AAAs) increases with age. Previous trials confirm that elective endovascular aneurysm repair (EVAR) is an effective intervention for AAA. However, few elderly patients were recruited into randomized trials, whereas in contemporary clinical practice, elective repair is commonly performed on octogenarians. We evaluated the safety and outcome of elective EVAR in elderly patients to inform clinical practice and vascular service provision. A systematic review and meta-analysis of studies reporting risk of complications and death in patients undergoing elective EVAR was performed (PROSPERO CRD: 42022308423). Observational studies and interventional arms of randomized trials were included if the outcome rates or raw data were provided. Primary outcome was 30-day mortality. Secondary outcomes were longer-term mortality, 30-day major adverse events, and aneurysm-related mortality. Primary and secondary outcomes were compared between octogenarians and non-octogenarians. Exclusion criteria were emergency procedures, non-infrarenal aneurysms, and lack of octogenarian data. A total of 41 studies were eligible from 10 099 citations, including 10 national and 5 international registries, 26 retrospective studies, and our own prospective cohort. The analysis included 208 997 non-octogenarians (mean age=70.19 [SD=0.62]) and 106 188 octogenarians (mean age=83.75 [SD=0.35]). The 30-day mortality post-elective EVAR was higher in octogenarians (1.08% in non-octogenarians, 2.31% in octogenarians, odds ratio [OR]=2.27 [2.08-2.47], p<0.0001). Linear regression demonstrated a 0.83% increase in 30-day mortality for every 10-year age increase above 60 years old. Mortality for octogenarians increased significantly during follow-up: 11.35% (OR=1.87 [1.65-2.13], p<0.001), 22.80% (OR=1.89 [1.52-2.35], p<0.001), 32.00% (OR=1.98 [1.66-2.37], p<0.001), 47.53%, and 51.08% (OR=2.40 [1.90-3.03], p<0.001) at 1-through-5-year follow-up, respectively. The 30-day major adverse events after elective EVAR were higher in octogenarians (OR=1.75-2.83, p<0.001). Octogenarians experience higher but acceptable peri-operative morbidity and mortality compared with younger patients. However, 3-year to 5-year survival is very low among octogenarians. Our findings challenge the notion of routine intervention in elderly patients and support very careful selection for elective EVAR. Many octogenarians with peri-threshold (<6 cm) AAAs may derive no benefit from EVAR due to limited 3-year to 5-year overall survival and low risk of aneurysm rupture with conservative management. An adjusted threshold for intervention in octogenarians may be warranted. Octogenarians with infra-renal AAA are increasingly managed with elective EVAR. Previous studies have demonstrated that EVAR is safer than open repair for octogenarians, with lower peri-operative mortality and major adverse events. However, randomised trials, on which much of contemporary evidence is based, recruited a relatively younger population of participants. This systematic review and meta-analysis provides a contemporary synthesis of the literature comparing outcomes in octogenarians to younger patients. The results of this analysis, together with low rupture rates amongst octogenarians in existing literature, question the benefit of routine elective intervention for peri-threshold aneurysms and an adjusted threshold for intervention in octogenarians may be warranted.

Patterns and predictors of COVID-19 vaccination among young adults at 44 US sites: Secondary analysis of a randomized, controlled, open-label trial, March – December 2021

Background: The introduction of vaccines during the COVID-19 pandemic provided an opportunity to slow transmission of SARS-CoV-2, but initial uptake of COVID-19 vaccination was slow. We analyzed data from a randomized clinical trial of the mRNA-1273 vaccine (NCT04811664) to describe the patterns of uptake of COVID-19 vaccines among young adults.Methods: The CoVPN 3006 trial randomized adults ages 18–29 from 44 sites in the United States to receive 1) immediate mRNA-1273 vaccination from the study site, or 2) standard of care, including the option to seek vaccination at any time in the future. Randomization occurred between March and November 2021, and an observational arm of adults who declined vaccination was enrolled beginning June 2021. Among participants in the standard of care (SoC) or Vaccine Declined arms, we estimated demographic, behavioral, and health history correlates of vaccination, and the four-month cumulative incidence of COVID-19 vaccination using inverse probability weighted Kaplan-Meier estimators.Results: Among 728 SoC and 470 Vaccine Declined participants, 79% and 16% received COVID-19 vaccination, respectively. SoC and Vaccine Declined participants were more likely to seek and receive vaccination if they reported COVID-19 preventive behaviors, including wearing masks, physically distancing, and avoiding large gatherings. We identified strong predictors of vaccination in the Vaccine Declined arm, including attending class in person (adjusted risk ratio [aRR]: 0.47, 95% confidence interval [CI] 0.21, 1.03), having a COVID-19 relevant medical condition (aRR: 1.95, 95% CI: 0.89, 4.26), and avoiding large gatherings (aRR: 2.24, 95% CI: 1.18, 4.25), though low vaccination rates in this arm led to imprecise estimates.Conclusions: Individuals who initially decline vaccination can be convinced to vaccinate, particularly if they are already practicing other forms of COVID-19 prevention. Continued outreach and education from the scientific community can combat low vaccine confidence.

Omission of Radiotherapy in Primary Mediastinal B-Cell Lymphoma: IELSG37 Trial Results.

The role of consolidation radiotherapy in primary mediastinal B-cell lymphoma (PMBCL) patients is controversial. The IELSG37 trial, a randomized non-inferiority study, aimed to assess whether irradiation can be omitted in PMBCL patients with complete metabolic response (CMR) after induction immunochemotherapy. Primary endpoint was progression-free survival (PFS) at 30 months post-randomization. Patients with CMR were randomly assigned to observation or consolidation radiotherapy (30 Gy). With a non-inferiority margin of 10% (assuming a 30-month PFS of 85% in both arms), a sample size of 540 patients was planned with 376 expected to be randomized. The observed events were considerably lower than expected, therefore, primary endpoint analysis was conducted when ≥95% of patients were followed for ≥30 months. Of 545 patients enrolled, 268 were in CMR after induction and were randomized to observation (n=132) or radiotherapy (n=136). The 30-month PFS was 96.2% in the observation arm and 98.5% in the radiotherapy arm, with a stratified hazard ratio of 1.47 (95%CI, 0.34 to 6.28) and absolute risk difference of 0.68% (95%CI, -0.97% to 7.46%). The 5-year overall survival was 99% in both arms.Non-randomized patients were managed according to local policies. Radiotherapy was the only treatment in 86% of those with Deauville score (DS) 4 and in 57% of those with DS 5. The 5-year PFS and OS of patients with DS 4 (95.8% and 97.5%, respectively) were not significantly different from those of randomized patients. Patients with DS5 had significantly poorer 5-year PFS and OS (60.3% and 74.6%, respectively). This study, the largest randomized trial of radiotherapy in PMBCL, demonstrated favorable outcomes in patients achieving CMR with no survival impairment for those omitting irradiation.

Trial Protocol of a Phase II Study of mFOLFOXIRI after Metastasectomy in Patients with Oligometastatic Colorectal Cancer (FANTASTIC Study).

The survival benefit of adjuvant chemotherapy after surgical resection of oligometastases from colorectal cancer (CRC) remains unclear. The prognostic role of circulating-tumor DNA (ctDNA) was reported recently and a risk stratification strategy based on monitoring minimal/molecular residual disease (MRD) has been proposed, however, which drug regimen is most effective for ctDNA-positive patients is unknown. Oligometastatic CRC patients planning to undergo surgery were registered in this study. After metastasectomy, the registered patients were enrolled in the treatment arm, in which 8 courses of modified-FOLFOXIRI (mFOLFOXIRI; irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, l-leucovorin (l-LV) 200 mg/m2, and 46-h continuous infusion of 5-fluorouracil (5-FU) 2400 mg/m2 every 2 weeks) followed by 4 courses of 5-FU/l-LV are administered. The patients who did not meet the eligibility criteria for the treatment arm or did not consent to mFOLFOXIRI enrolled in the observation arm in which standard of care treatment is provided. Prospective blood collections for retrospective ctDNA analysis are scheduled pre-surgery, and at 28 days, 4 and 7 months after surgery. The primary endpoint is treatment compliance at 8 courses of mFOLFOXIRI and the key secondary endpoints are the ctDNA-positivity rate and survival outcomes in ctDNA-positive and -negative groups. A total of 85 patients will be enrolled from 11 institutions. First patient-in was on July 2020. Accrual completed in February 2024. This study will potentially identify a better treatment strategy for patients with resectable oligometastatic CRC having postsurgical ctDNA positivity, compared to the current standard of care approaches.

Left Frontoparietal Control Network Connectivity Moderates the Effect of Amyloid on Cognitive Decline in Preclinical Alzheimer’s Disease: The A4 Study

BackgroundStronger resting-state functional connectivity of the default mode and frontoparietal control networks has been associated with cognitive resilience to Alzheimer’s disease related pathology and neurodegeneration in smaller cohort studies.ObjectivesWe investigated whether these networks are associated with longitudinal CR to AD biomarkers of beta-amyloid (Aβ).DesignLongitudinal mixed.SettingThe Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study and its natural history observation arm, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study.ParticipantsA sample of 1,021 cognitively unimpaired older adults (mean age = 71.2 years [SD = 4.7 years], 61% women, 42% APOEε4 carriers, 52% Aβ positive).MeasurementsGlobal cognitive performance (Preclinical Alzheimer’s Cognitive Composite) was assessed over an average 5.4 year follow-up period (SD = 2 years). Cortical Aβ and functional connectivity (left and right frontoparietal control and default mode networks) were estimated from fMRI and PET, respectively, at baseline. Covariates included baseline age, APOEε4 carrier status, years of education, adjusted gray matter volume, head motion, study group, cumulative treatment exposure, and cognitive test version.ResultsMixed effects models revealed that functional connectivity of the left frontoparietal control network moderated the negative effect of Aβ on cognitive change (p =.025) such that stronger connectivity was associated with reduced Aβ-related cognitive decline.ConclusionsOur results demonstrate a potential protective effect of functional connectivity in preclinical AD, such that stronger connectivity in this network is associated with slower Aβ-related cognitive decline.

Randomized Trial of Postoperative Radiation Therapy After Wide Excision of Neurotropic Melanoma of the Head and Neck (RTN2 Trial 01.09)

BackgroundCutaneous neurotropic melanoma (NM) of the head and neck (H&N) is prone to local relapse, possibly due to difficulties widely excising the tumor. This trial assessed radiation therapy (RT) to the primary site after local excision.MethodsParticipants from 15 international centers were randomized to observation or RT. The participants were required to have microscopically negative excision margins 5 mm wide or wider and no evidence of disease elsewhere. The primary outcome was time to local relapse. The secondary outcomes included time to any recurrence, overall survival (OS), and toxicity.ResultsThe trial ceased prematurely due to slow recruitment and the COVID-19 pandemic. During 2009–2020, 50 participants were randomized: 23 to observation and 27 to RT. The most common NM subsites were scalp (32%), midface (22%), and lip (20%). The median depth of invasion was 5 mm, and desmoplasia observed in 69%. The median duration from randomization to last contact was 4.8 years. Four participants (8%) experienced local relapse as a first recurrence during the study period: 3 in the observation arm and 1 in the RT arm (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.03–2.76; p = 0.279). No statistically significant difference in time to any relapse or OS was observed. More than 6 months after randomization, grade 3 or greater toxicity was experienced by 10% of the participants in the observation arm and 12.5% of the participants in the RT arm of the study.ConclusionDue to low accrual, the role of adjuvant RT for cutaneous NM of the H&N excised with microscopically negative margins 5 mm wide or wider remains undefined. Its routine use cannot be recommended. Local relapse might be less common than previously anticipated based on retrospective reports.

Abstract PO4-19-05: OptimICE-pCR: De-escalation of therapy in early-stage TNBC patients who achieve pCR after neoadjuvant chemotherapy with checkpoint inhibitor therapy (Alliance A012103)

Abstract Background: For patients with stage II-III triple-negative breast cancer (TNBC), standard of care systemic therapy consists of neoadjuvant pembrolizumab with chemotherapy, followed by 27 weeks of adjuvant pembrolizumab based on the results of the phase III KEYNOTE-522 trial. This trial demonstrated that pathologic complete response (pCR) rates and event-free survival (EFS) were significantly better among patients who received neoadjuvant followed by adjuvant pembrolizumab in addition to chemotherapy compared to chemotherapy alone. An exploratory analysis from this study demonstrated better EFS among patients who experienced a pathologic complete response (pCR) to neoadjuvant therapy compared to those with residual disease. Additionally, other studies, including GeparNuevo, which did not include adjuvant checkpoint inhibition, demonstrated EFS benefit from the addition of preoperative checkpoint inhibitor therapy to chemotherapy. It is therefore unclear if adjuvant pembrolizumab improves outcomes for patients with early-stage TNBC who achieve a pCR after neoadjuvant pembrolizumab plus chemotherapy. OptimICE-pCR trial utilizes response to preoperative therapy to tailor adjuvant therapy, and the goal is to determine whether patients who achieve pCR to pembrolizumab plus chemotherapy can achieve a similar recurrence-free survival (RFS) with observation compared to adjuvant pembrolizumab monotherapy Methods: OptimICE-pCR is an open-label, multicenter, randomized phase III trial that is enrolling patients with stage T1cN1-2 or T2-4N0-2 TNBC. To be eligible, patients must have experienced a pCR after the completion of neoadjuvant therapy containing a minimum of six cycles of chemotherapy in combination with pembrolizumab. Participants are randomized 1:1 to receive either 27 weeks of adjuvant pembrolizumab or to observation. Participants on the pembrolizumab arm receive pembrolizumab 200 mg IV on day 1 of each 21-day cycle for 9 cycles, or 400 mg IV on day 1 of each 42-day cycle for 4 cycles, followed by one dose of 200 mg IV every 21 days. The primary objective is to evaluate whether observation results in non-inferior RFS compared to adjuvant pembrolizumab. Non-inferiority is defined as an estimated 3-year RFS of 91% or higher in the observation arm compared to 94% in the pembrolizumab arm. The total sample size will be 1,295 patients, which will provide 80% power at one-sided significance level of 0.05 to detect this difference, which corresponds to a non-inferiority hazard ratio of 1.52. Key secondary endpoints include overall survival, locoregional recurrence, quality of life, financial toxicity, work productivity impairment, cost-effectiveness, and safety and tolerability. Key correlative objectives include detection of ctDNA at baseline and association with RFS and association of key biomarkers (TILs, PDL1, immune gene expression) from the primary tumor with RFS. The trial is currently open and enrolling patients. Support: U10CA180821, U10CA180882; U24 CA196171; U10CA180820 (ECOG-ACRIN); U10CA180863 (CCTG); https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT05812807 Citation Format: Sara Tolaney, Karla Ballman, Charles M Perou, David Cescon, Margaret Gatti-Mays, Victoria Blinder, Shoshana Rosenberg, Elizabeth Mittendorf, Anna Weiss, Hope Rugo, Alice Ho, Dana Casey, Baljit Singh, Fabrice Smieliauskas, Yara Abdou, Vijay Damarla, Jane Meisel, Lisa Carey, Ann Partridge. OptimICE-pCR: De-escalation of therapy in early-stage TNBC patients who achieve pCR after neoadjuvant chemotherapy with checkpoint inhibitor therapy (Alliance A012103) [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 PO4-19-05.

Blood pressure and cerebral oxygenation with physiologically-based cord clamping: sub-study of the BabyDUCC trial

BackgroundCord-clamping strategies may modify blood pressure (BP) and cerebral tissue oxygen saturation (rStO2) immediately after birth.MethodsWe conducted a sub-study nested within the Baby-Directed Umbilical Cord-Clamping trial. Infants ≥32+0 weeks’ gestation assessed as requiring resuscitation were randomly allocated to either physiologically-based cord clamping (PBCC), where resuscitation commenced prior to umbilical cord clamping, or standard care where cord clamping occurred early (ECC). In this single-site sub-study, we obtained additional measurements of pre-ductal BP and rStO2. In a separate observational arm, non-randomised vigorous infants received 2 min of deferred cord clamping (DCC) and contributed data for reference percentiles.ResultsAmong 161 included infants, n = 55 were randomly allocated to PBCC (n = 30) or ECC (n = 25). The mean (SD) BP at 3–4 min after birth (primary outcome) in the PBCC group was 64 (10) mmHg compared to 62 (10) mmHg in the ECC group, mean difference 2 mmHg (95% confidence interval −3–8 mmHg, p = 0.42). BP and rStO2 were similar across both randomised arms and the observational arm (n = 106).ConclusionWe found no difference in BP or rStO2 with the different cord clamping strategies. We report reference ranges for BP and rStO2 for late-preterm and full-term infants receiving DCC.ImpactAmong late-preterm and full-term infants receiving varying levels of resuscitation, blood pressure (BP, at 3–4 minutes and 6 min) and cerebral tissue oxygen saturation (rStO2) are not influenced by timing of cord clamping in relation to establishment of ventilation.Infants in this study did not require advanced resuscitation, where cord clamping strategies may yet influence BP and rStO2.The reference ranges for BP and rStO2 represent the first, to our knowledge, for vigorous late-preterm and full-term infants receiving deferred cord clamping.rStO2 > 90% (~90th percentile) may be used to define cerebral hyperoxia, for instance when studying oxygen supplementation after birth.

Abstract 2409: Circulating differential methylation allele fraction (DMAF) strongly correlates with circulating tumor DNA (ctDNA) variant allele fraction (VAF)

Abstract Measurement of ctDNA has been established as a prognostic biomarker of cancer disease burden. Emerging evidence has demonstrated that differential methylation patterns can serve as an accurate biomarker both for cancer detection and for predicting the tissue of origin. While it is important to distinguish cancer-positive from cancer-negative patients, clinical decision making increasingly depends on the exact level of the measured biomarker. To that end, we report on the correlation between ctDNA VAF and DMAF across patients with colorectal cancer (CRC). Pre-surgical plasma samples from patients with CRC (N=70) were sourced from the prospective GALAXY, observational arm of ongoing CIRCULATE-Japan study trial (UMIN000039205). Samples classified as ctDNA-positive by a tumor-informed ctDNA assay (SignateraTM) were included in this analysis and ctDNA VAF (%) was calculated. We performed deep methylation sequencing (Illumina Novaseq) across multiple target regions using two independent target sets. DMAF was calculated computationally, which estimates the fraction of differential methylation alleles for circulating cell-free DNA across target regions. Among 70 CRC patients, 68 had positive ctDNA results. Median age at testing was 64.0 years and male individuals represented 55.9% (n=38) of the cohort. Among them, 9 (13.2%) were stage I, 24 (35.3%) were stage II, 22 (32.3%) were stage III, 8 (11.7%) were stage IV, and 5 (7.3%) had unknown staging. The correlation of DMAF with ctDNA VAF was 0.894 (Spearman’s Rank Correlation Coefficient) and was independent of disease stage, histology, age, and sex. Among MSS (micro-satellite stable; n=58) and MSI-H (micro-satellite unstable n=10) patients, the DMAF correlation was 0.9 and 0.915, respectively. The correlation between two target sets evaluating DMAF with differing numbers of targeted regions was high (0.89). These data demonstrate that abundance of differential methylation in CRC patients correlates with VAF regardless of clinicopathologic features of patients with CRC. Methylation-based assays are a promising tool for cancer detection and quantifying the disease burden. Citation Format: Preethi Srinivasan, Tzu-Chun Chen, Ehsan Haghshenas, Misagh Kordi, Ilker Tunc, Wenching Chan, Omid Shams Solari, Joshua Babiarz, Yoshiaki Nakamura, Takayuki Yoshino, Alexey Aleshin, Trupti Kawli, Johannes G. Reiter. Circulating differential methylation allele fraction (DMAF) strongly correlates with circulating tumor DNA (ctDNA) variant allele fraction (VAF) [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 2409.

Evaluation of the Prognostic Impact of SP263-Evaluated PD-L1 Expression in Patients with Stage III Non-Small Cell Lung Cancer (NSLC) Treated with Radio-Chemotherapy.

The PACIFIC study showed that after radio-chemotherapy, patients with NSCLC derived a benefit in PFS and OS when treated with durvalumab. This effect was limited to patients with a PD-L1 expression of >1%, partly because the outcome in the observational control arm was surprisingly favorable. Thus, it could be speculated that a lack of PD-L1 expression confers a favorable outcome for patients with stage III NSCLC. Clinical data, PD-L1 expression, predictive blood markers, and the outcomes of 99 homogeneously treated patients with stage III NSCLC were retrospectively captured. Statistical analyses using the log rank test were performed. The median OS of patients with an expression of PD-L1 < 1% was 20 months (CI 10.5-29.5) and the median OS of patients with an expression of PD-L1 ≥ 1% was 28 months (CI 16.5-39.2) (p = 0.734). The median PFS of patients with an expression of PD-L1 < 1% was 9 months (CI 6.3-11.6) and the median PFS of patients with an expression of PD-L1 ≥ 1% was 12 months (CI 9.8-14.2) (p = 0.112). The assumption that the lack of PD-L1 expression represents a favorable prognostic factor after radio-chemotherapy vs. PD-L1 expression > 1% was not confirmed.

Role of adjuvant chemotherapy in patients with stage II-III ampullary cancer.

508 Background: Survival benefits for patients (pts) with ampullary cancer (AC) on adjuvant chemotherapy (ACT) remain unknown. Some studies support post-operative treatment, while others state the opposite. Also, there are no clear evidence indicating that histopathological types (pancreaticobiliary (PB-type) and intestinal (IN-type)) can be used to guide the adjuvant setting. The aim of this study is to assess the ACT efficacy in different histopathological types of ampullary adenocarcinoma (pathological stages II-III). Methods: 81 pts were enrolled in the study in total, 45.7% were males, median age was 66.0 (range 43.9-83.8) years. 36.9% were IN-type, 50.8% – PB-type, and 12.3% – mixed. Almost all (97.5%) pts underwent Whipple procedure. 50 pts (61.7%) received ACT: 78.0% – 5-FU-based regimen and 22.0% – gemcitabine-based. Results: There was no clinical benefit in pts administered with ACT in terms of overall survival (OS): median OS was 55.5 months versus 43.6 month in observation arm; p=0.93. The ACT (FU-based or gemcitabine-based) did not correlate to improve OS in patients with IN-type: 38.0 months in patients who received ACT versus 30.5 months in those who did not; p=0.75. The ACT has shown better survival benefit in patients with PB-type compared to observation, however there was no statistical difference: 21.1 and 43.6 months, respectively; p=0.52. 5-FU-based ACT did not show any benefits compared to gemcitabine-based therapy in this subgroup. Conclusions: The use of adjuvant chemotherapy (FU-based or gemcitabine-based) in patients with II-III stage ampullary cancer was not associated with improved overall survival in our trial. There was no clinical benefit from addition of ACT either despite the heterogeneity of the tumor tissue origin (IN-type or PB-type).

Predicting recurrence using a tumor-uninformed ctDNA assay detecting MRD in patients with resected stage II or III colorectal cancer: Subset analysis from the GALAXY study in CIRCULATE-Japan.

21 Background: The presence of circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who are at risk of recurrence and aid with postsurgical risk stratification. ~80% of stage II and only 50% of stage III colorectal cancer (CRC) patients are cured by surgery alone. A tumor-uninformed plasma-only approach for MRD assessment accelerates the turnaround time, enabling rapid adjuvant chemotherapy (ACT) treatment decision making, optimizing the impact on patient outcomes. Methods: A subset of samples from GALAXY, an observational arm of the CIRCULATE-Japan study (UMIN000039205), were analyzed for postsurgical ctDNA detection at a landmark time point (LMT) defined as 4 weeks after curative surgery in pathological stage II or III CRC patients. In a prospective lead-in to clinical validation, 80 patients meeting pre-specified eligibility criteria were randomly selected with enrichment for recurrence to 50% while maintaining the stage II:III recurrent (R)/nonrecurrent (NR) ratio to that observed in GALAXY. Residual plasma samples were analyzed with the Tempus xM assay (xM), a tumor-uninformed ctDNA MRD assay that integrates methylation and genomic variant MRD classifiers to deliver a binary MRD call. All calls were blinded to clinical outcomes. The methylation-based classifier detects fragments with CRC methylation signatures in differentially methylated regions trained by sequencing CRC and presumed-healthy samples on a 6Mbp panel. The variant-based MRD classifier detects highly prevalent CRC variants. Artifacts, CHIP, and germline variant filtering algorithms were also applied. Results: Of the 80 patients (pts), 70 [Stage II n= 29 (41%), Stage III n= 41 (59%)] were evaluable (36 R and 34 NR). At the LMT and with at least 1-year follow-up, 18/36 R pts had detectable ctDNA (xM MRD+) and 30/34 NR pts had undetectable ctDNA (xM MRD-), providing a sensitivity of 50% and specificity of 88%. Additionally, xM MRD+/- status strongly correlated with disease-free survival (DFS) with a hazard ratio (HR) of 5.09, adjusted to account for a 24% recurrence rate in GALAXY. In an updated, ongoing longitudinal analysis of the 4 false positive pts, 2 were Stage III, MRD+ from both the methylation and genomic classifiers, received ACT, and have likely cleared their ctDNA without any sign of clinical recurrence. An adjusted sensitivity and specificity analysis resulted in xM clinical performance of 53% (20/38 R) and 94% (30/32 NR), respectively. Conclusions: xM is a novel tumor-uninformed assay that demonstrated remarkable performance to detect clinical recurrence at a LMT, and a clinically meaningful correlation with DFS. A larger clinical validation study including longitudinal analysis, correlation with ACT, and outcomes from the GALAXY study is currently underway.

AMPLIFY-7P: Phase 1 and randomized phase 2 study of amphiphile immunotherapy ELI-002 7P as adjuvant treatment for subjects with G12D, G12R, G12V, G12C, G12A, G12S and G13D Kirsten rat sarcoma (KRAS)-mutated pancreatic ductal adenocarcinoma.

TPS720 Background: KRAS mutations occur in 25% of human tumors, frequently in pancreatic where over 85% relapse after locoregional treatment. ELI-002 7P is a lymph node targeted immunotherapy comprised of Amphiphile (Amph)-modified G12D, G12R, G12V, G12C, G12A, G12S and G13D mutant KRAS peptides together with an Amph-modified CpG oligonucleotide adjuvant. In the first in human AMPLIFY-201 study, a two peptide G12D/G12R formulation increased KRAS-specific T cells in 87% of patients, and T cell responses 13-fold or higher over baseline correlated with outcomes including reduction in risk of relapse or death. The AMPLIFY-7P study hypothesizes that adjuvant administration of ELI-002 7P will be safe and will delay relapse compared to observation in patients with KRAS mutated pancreatic cancers who have completed curative intent locoregional treatment. Methods: This open-label, phase 1 and randomized phase 2 study is evaluating ELI-002 7P in patients with KRAS mutated pancreatic adenocarcinoma following standard of care chemotherapy and surgery. In phase 2, patients are randomized 2:1 to ELI-002 7P versus observation with crossover of the observation arm permitted at the time of confirmed radiographic relapse via iRECIST. Eligible patients must be within 6 months of completion of locoregional treatment for up-front resectable pathologically confirmed pancreatic cancer (Stage I-III) with radiographic NED (no evidence of disease). Phase 2 patients are included regardless of biomarker evidence of recurrent disease, however, those who have not recovered absolute lymphocytes to the normal range following cytotoxic therapy are excluded. The primary phase 2 objective is to compare the efficacy of ELI-002 7P versus observation, with primary endpoint disease-free survival per investigator. Secondary objectives compare biomarker response (reduction or clearance of ctDNA or if ctDNA was not detectable, serum tumor antigen CA19-9) in the subset with positive baseline values, OS, safety, and iRECIST response rate in the crossover subset. Exploratory endpoints include immunogenicity, the association of immunogenicity with high resolution HLA typing, and evaluation of tumor-infiltrating T cells and the tumor microenvironment in the event biopsy tissue is available. An Independent Data Monitoring Committee reviewed phase 1 data and recommended opening phase 2. Subsequent patients will receive up to 10 doses of Amph-peptides 7P 700 mcg each (4.9 mg total), together with Amph-CpG-7909 (10.0 mg) administered over a five-month treatment period. In Phase 2, approximately 135 patients will be enrolled in the United States. An interim analysis is planned using group sequential design for control of overall alpha 0.10. Clinical trial information: NCT05726864 .

Quantitative ultrasound radiomics guided adaptive neoadjuvant chemotherapy in breast cancer: early results from a randomized feasibility study.

In patients with locally advanced breast cancer (LABC) receiving neoadjuvant chemotherapy (NAC), quantitative ultrasound (QUS) radiomics can predict final responses early within 4 of 16-18 weeks of treatment. The current study was planned to study the feasibility of a QUS-radiomics model-guided adaptive chemotherapy. The phase 2 open-label randomized controlled trial included patients with LABC planned for NAC. Patients were randomly allocated in 1:1 ratio to a standard arm or experimental arm stratified by hormonal receptor status. All patients were planned for standard anthracycline and taxane-based NAC as decided by their medical oncologist. Patients underwent QUS imaging using a clinical ultrasound device before the initiation of NAC and after the 1st and 4th weeks of treatment. A support vector machine-based radiomics model developed from an earlier cohort of patients was used to predict treatment response at the 4th week of NAC. In the standard arm, patients continued to receive planned chemotherapy with the treating oncologists blinded to results. In the experimental arm, the QUS-based prediction was conveyed to the responsible oncologist, and any changes to the planned chemotherapy for predicted non-responders were made by the responsible oncologist. All patients underwent surgery following NAC, and the final response was evaluated based on histopathological examination. Between June 2018 and July 2021, 60 patients were accrued in the study arm, with 28 patients in each arm available for final analysis. In patients without a change in chemotherapy regimen (53 of 56 patients total), the QUS-radiomics model at week 4 of NAC that was used demonstrated an accuracy of 97%, respectively, in predicting the final treatment response. Seven patients were predicted to be non-responders (observational arm (n=2), experimental arm (n=5)). Three of 5 non-responders in the experimental arm had chemotherapy regimens adapted with an early initiation of taxane therapy or chemotherapy intensification, or early surgery and ended up as responders on final evaluation. The study demonstrates the feasibility of QUS-radiomics adapted guided NAC for patients with breast cancer. The ability of a QUS-based model in the early prediction of treatment response was prospectively validated in the current study. clinicaltrials.gov, ID NCT04050228.

Mixed-methods randomised study exploring the feasibility and acceptability of eye-movement desensitisation and reprocessing for improving the mental health of traumatised survivors of intensive care following hospital discharge: protocol

IntroductionPost-traumatic symptoms are common among patients discharged from intensive care units (ICUs), adversely affecting well-being, increasing healthcare utilisation and delaying return to work. Non-pharmacological approaches (eg, music, therapeutic touch and...

Functional connectivity of the frontoparietal control network is positively associated with cognition, independent of amyloid and tau burden, in the A4 study

AbstractBackgroundThe Anti‐Amyloid in Asymptomatic Alzheimer’s Disease (A4) study is the first secondary prevention trial of an anti‐amyloid therapy, solanezumab, in cognitively unimpaired older adults with elevated amyloid‐beta (Ab)‐PET burden. The inclusion of resting‐state functional connectivity MRI (fcMRI) as a secondary outcome measure is a novelty for clinical trials. Despite promising longitudinal findings, there is mixed evidence for cross‐sectional associations between functional connectivity in the default mode (DMN) and frontoparietal control (FPCN) networks, with Ab, tau, and cognition. Here, in a large cross‐sectional sample, we investigate these associations and assess whether fcMRI accounts for variability in cognition that is not attributable to Ab or tau.Method1,641 participants from A4 and the LEARN observational arm with fcMRI passed quality control and had complete data for sociodemographics, cognition, and Ab (Florbetapir)‐PET (Table 1). A subset had tau (Flortaucipir)‐PET (n = 420). Within‐network connectivity estimates of the default mode (DMN) and left and right frontoparietal control networks (FPCN) were obtained using template‐based rotation (Fig. 1).Using hierarchical regressions, we examined the independent associations of functional connectivity with Ab burden (mean cortical standardized uptake value [SUVr]), tau burden (mean of inferior temporal and entorhinal SUVrs), and cognition (Preclinical Alzheimer’s Cognitive Composite), independent of covariates (age, sex, education level, head motion, scanner and, where applicable, Ab and/or tau burden).ResultAb and tau burden were not independently associated with DMN or right FPCN connectivity. Higher tau was associated with reduced left FPCN connectivity, independent of Ab. Stronger left and right FPCN connectivity were associated with better cognition, independent of Ab and tau (Table 2). This association was stronger for the left FPCN.ConclusionFPCN functional connectivity is associated with better cognition, independent of Ab and tau burden. This association was strongest in the left FPCN and supports evidence that implicates FPCN connectivity in cognitive reserve and resilience. While this association is robust, weak effect sizes suggest that functional connectivity explains a limited amount of variability in cognition after accounting for covariates and AD pathology. Future release of the A4 study longitudinal data will enable quantification of the added value of fcMRI in AD clinical trials.

Functional connectivity of the frontoparietal control network is positively associated with cognition, independent of amyloid and tau burden, in the A4 study

AbstractBackgroundThe Anti‐Amyloid in Asymptomatic Alzheimer’s Disease (A4) study is the first secondary prevention trial of an anti‐amyloid therapy, solanezumab, in cognitively unimpaired older adults with elevated amyloid‐beta (Ab)‐PET burden. The inclusion of resting‐state functional connectivity MRI (fcMRI) as a secondary outcome measure is a novelty for clinical trials. Despite promising longitudinal findings, there is mixed evidence for cross‐sectional associations between functional connectivity in the default mode (DMN) and frontoparietal control (FPCN) networks, with Ab, tau, and cognition. Here, in a large cross‐sectional sample, we investigate these associations and assess whether fcMRI accounts for variability in cognition that is not attributable to Ab or tau.Method1,641 participants from A4 and the LEARN observational arm with fcMRI passed quality control and had complete data for sociodemographics, cognition, and Ab (Florbetapir)‐PET (Table 1). A subset had tau (Flortaucipir)‐PET (n = 420). Within‐network connectivity estimates of the default mode (DMN) and left and right frontoparietal control networks (FPCN) were obtained using template‐based rotation (Fig. 1). Using hierarchical regressions, we examined the independent associations of functional connectivity with Ab burden (mean cortical standardized uptake value [SUVr]), tau burden (mean of inferior temporal and entorhinal SUVrs), and cognition (Preclinical Alzheimer’s Cognitive Composite), independent of covariates (age, sex, education level, head motion, scanner and, where applicable, Ab and/or tau burden).ResultAb and tau burden were not independently associated with DMN or right FPCN connectivity. Higher tau was associated with reduced left FPCN connectivity, independent of Ab. Stronger left and right FPCN connectivity were associated with better cognition, independent of Ab and tau (Table 2). This association was stronger for the left FPCN.ConclusionFPCN functional connectivity is associated with better cognition, independent of Ab and tau burden. This association was strongest in the left FPCN and supports evidence that implicates FPCN connectivity in cognitive reserve and resilience. While this association is robust, weak effect sizes suggest that functional connectivity explains a limited amount of variability in cognition after accounting for covariates and AD pathology. Future release of the A4 study longitudinal data will enable quantification of the added value of fcMRI in AD clinical trials.

Exploratory Study on Impact of Comorbid Sleep Apnea Treatment in Patients with Polycythemia Vera and Essential Thrombocythemia

Background: Systemic inflammation has been implicated in the progression of myeloproliferative neoplasms (MPNs), polycythemia vera (PV) and essential thrombocythemia (ET). Obstructive sleep apnea (OSA) is a highly prevalent disorder that can lead to TNF-driven systemic inflammation. OSA leads to oxidative stress and NF-kB driven inflammatory gene expression through the mechanistic pathways of intermittent hypoxia and autonomic activation. We therefore sought to understand the prevalence of OSA in patients with MPNs and the feasibility of understanding the impact of treating comorbid sleep apnea in patients with PV and ET. Methods: Patients with PV and ET diagnosed using the 2008 or 2016 WHO criteria underwent STOP-BANG questionnaires to evaluate for the likelihood of OSA. Based on the finding of 3 or more positive responses on STOP-BANG questionnaire (PLoS One 2015;10:e0143697), patients underwent further evaluation with polysomnography or home sleep apnea test to diagnose OSA at an American Academy of Sleep Medicine-certified sleep laboratory (Figure 1). Patients with apnea-hypopnea index (AHI) of 5 or more events per hour and Eastern Cooperative Oncology Group scale score of 0-2 underwent continuous positive airway pressure therapy (CPAP). Effects of CPAP therapy on MPN-symptom assessment form total symptom scores (MPN-SAF TSS), JAK2V617F, MPL and CALR allelic burden, and exploratory endpoints of changes in inflammatory and thrombotic markers were ascertained (Figure 1). Comparisons with observational cohorts were planned to ascertain changes in the above endpoints at 0-, 3- and 6-months intervals (Figure 1). Based on a 40% reduction in allele burden (SD of 25%) and correlation of 0.5 between paired measurements, it was estimated that using a paired t-test with 27 evaluable patients will provide a 95% power to detect a 20% change in JAK2V617F burden from 40% to 20%. Similarly, assuming a 50% correlation (SD of 16) between pre- and post-therapy MPN-SAF TSS scores, 27 evaluable patients will provide a 80% power to detect a change of 10 at the two-sided 0.025 significance level. Results: Screening for OSA in patients with ET and PV revealed a high prevalence of OSA risk based on STOP-BANG scores. 26/29 males (mean age 63.6±11.8 years; BMI 29±3.3) and 16/26 females (mean age 61.5±12.8 years; BMI 28.2±6.5) had STOP-BANG scores of 3 or more. 8 patients with PV and ET have so far been enrolled into this study. 6/8 patients (age ranges from 41-74 years; 4 females and 2 males) with OSA (AHI 5-56 events/hr; 4% oxygen desaturation index 4.7-30/hr) underwent CPAP therapy. 1/6 patients in the CPAP arm did not tolerate CPAP and was excluded. 5/6 patients completed study procedures as did 2 additional patients without OSA in the observational study arm. Of 5/6 patients undertaking CPAP, 3/5 had the JAK2V617F mutations whereas 2/5 had the CALR mutation. JAK2V617F allele burdens at baseline in 2/5 patients were 80.7% and 4% at baseline and reduced to 73% and 1% at 6 months respectively whereas the third patient had undetectable JAK2V617F burdens throughout the study. All except one patient experienced improvement in MPN-SAF TSS scores after 6 months of CPAP therapy. While all 5 patients treated with CPAP showed improvements in C-reactive protein levels, analysis of NFkB1, TNF and IL-6 transcript levels showed mixed results. Similar mixed results were found with hypoxia-inducible factor (HIF) target gene expression ( SLC2A1, VEGF-A, EDN1) and markers of iron turnover (% transferrin saturation, transferrin, iron and ferritin levels) despite reduction in erythropoietin values in 4/5 patients with CPAP therapy at 6 months. Conclusions: Given the significant likelihood of OSA in patients with PV and ET (as based on STOP-BANG scores of 3 or more), there is need to evaluate and treat for OSA. Preliminary results show abnormalities in inflammatory markers with reductions in C-reactive protein and erythropoietin levels following CPAP therapy even though mixed results were noted in inflammatory and HIF-target gene transcripts, and markers of iron turnover. Larger studies and longer follow-up are required to understand the impact of OSA on not only the thrombotic and inflammatory milieu in patients with MPNs, but also the benefit of treating on prevention of disease progression and thrombotic manifestations common in MPNs. Funding: Huntsman Interventional Trial Grant CTO #HCI-17-HEM 28.

CD16, CD57 and DNAM-1 Positive NK Cells Predict MRD Negativity in Newly Diagnosed Multiple Myeloma Patients Treated with Daratumumab, Bortezomib, Thalidomide and Dexamethasone

Introduction: Daratumumab-based quadruplets are the current standard of care for newly diagnosed transplant-eligible multiple myeloma (MM) patients, because of improved depth of response and survival, compared with triplet regimens without daratumumab. Since one of the primary mechanisms of action of daratumumab is the induction of antibody-dependent cellular cytotoxicity (ADCC) via the Fc-gamma receptor CD16 on natural killer (NK) cells, it is crucial to understand the role of NK cells in combination therapy. We therefore set out to comprehensively profile NK cells by flow cytometry in newly diagnosed MM (NDMM) patients treated with either daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTD) or VTD. Methods: A subset of NDMM patients (n = 152) who were treated in the Cassiopeia trial (EudraCT: 2014-004781-15) was included in this immunomonitoring analysis. In this trial, patients were first randomized to receive either four induction cycles and two consolidation cycles of D-VTD or VTD in conjunction with autologous stem cell transplantation (ASCT). In the second part of this trial, patients who achieved partial response or better at day 100 post-ASCT were randomized to either receive daratumumab maintenance or observation for the duration of two years. Bone marrow (BM) and peripheral blood (PB) samples were collected at study entry (baseline), and for PB at additional time points: cycle 1 day 28, cycle 4 day 28, day 100 (post-ASCT) and week 52 (maintenance). All baseline BM and PB samples and a selection of longitudinal PB samples were profiled by flow cytometry, with a focus on NK cell phenotype (CD56, CD16, CD57, DNAM-1, TIGIT, KLRG1, PD1, TIM3, NKG2A, NKG2C, NKG2D). To identify NK cell profiles associated with minimal residual disease (MRD) negativity, baseline PB and BM data were compared between MM patients based on MRD status after consolidation. Additionally, longitudinal data of PB samples collected during treatment were assessed to understand the impact of D-VTD and VTD on NK cell profiles. Results: In this cohort, 49 patients out of 77 (64%) randomized to the D-VTD arm achieved MRD negativity post-consolidation, while this was the case in 28 out of 75 patients (37%) in the VTD arm (fisher exact-test, p = 0.008). Patients with a higher proportion of BM-residing NK cells expressing the ADCC receptor CD16 (median 86 vs 72%, p = 0.007), the activating receptor DNAM-1 (median 94 vs 89%, p = 0.029), or the maturation marker CD57 (median 58 vs 48 %, p = 0.049) at baseline were more likely to achieve MRD-negativity post-consolidation in the D-VTD arm (Figure 1). Notably, this association was not present in the VTD arm. Although not significant, we found a similar trend for CD16 in PB in the D-VTD arm. During D-VTD treatment, we observed an increase in the proportion of CD56 bright and NKG2A + in PB NK-cells, and a corresponding decline in cells expressing CD16, CD57 and DNAM-1 (linear mixed effect model (LME) p &amp;lt;0.001). During VTD treatment we also observed a decrease in CD16 + NK-cells and an increase in CD56 bright and NKG2A + NK-cells (LME p &amp;lt;0.05), although these changes were more pronounced in the D-VTD arm. In patients who were assigned D-VTD at the first randomization and were subsequently randomized to the observation arm, we observed a restoration of the proportion of CD16 +, CD57 +, and CD56 bright NK cells to baseline values at week 52 after ASCT (Figure 2). As expected, the daratumumab associated NK cell changes persisted in the group that was randomized to the daratumumab maintenance arm. Conclusion: This study highlights the importance of NK cell immunophenotypic profiles in bone marrow as predictive markers for MRD negativity in NDMM patients treated with D-VTD in in conjunction with ASCT. Additionally, our findings illustrate that NK cell changes associated with daratumumab return to baseline levels after treatment cessation, indicating the potential for sequential NK cell-based therapies. In conclusion, this study not only provides valuable insights into the role of NK cells in the treatment of NDMM patients with D-VTD and ASCT, but also indicates that further research to optimize NK cell function in the context of combination therapies is warranted.