Citations

Background: Oscillation and pulmonary expansion (OPE) therapy can decrease postoperative pulmonary complications in a general surgical population, but its effect after cardiac surgery has not been reported, to our knowledge. We hypothesized that using an OPE device after cardiac surgery before extubation would decrease pulmonary complications. Methods: This retrospective cohort study included adults undergoing elective open cardiac surgery at our institution from January 2018 through January 2019, who had an American Society of Anesthesiologists score of 3 or greater. For mechanically ventilated patients after cardiac surgery, a new OPE protocol was adopted, comprising an initial 10-min OPE treatment administered in-line with the ventilator circuit, then continued treatments for 48 h after extubation. The primary outcome measure was the occurrence of severe postoperative respiratory complications, including the need for antibiotics, increased use of supplemental oxygen, and prolonged hospital length of stay (LOS). Demographic, clinical, and outcome data were compared between patients receiving usual care (involving post-extubation hyperinflation) and those treated under the new OPE protocol. The primary outcome measure was the occurrence of severe postoperative respiratory complications, including the need for antibiotics, increased use of supplemental oxygen, and prolonged hospital length of stay (LOS). Demographic, clinical, and outcome data were compared between patients receiving usual care (involving post-extubation hyperinflation) and those treated under the new OPE protocol. Results: Of 104 patients, 54 patients received usual care, and 50 received OPE. Usual-care recipients had more men (74% vs. 62%; p = 0.19) and were older (median, 70 vs. 67 years; p = 0.009) than OPE recipients. The OPE group had a significantly shorter hospital LOS than the usual-care group (mean, 6.2 vs. 7.4 days; p = 0.04). Other measures improved with OPE but did not reach significance: shorter ventilator duration (mean, 0.6 vs. 1.1 days with usual care; p = 0.06) and shorter LOS in the intensive care unit (mean, 2.7 vs. 3.4 days; p = 0.06). On multivariate analysis, intensive care unit LOS was significantly shorter for the OPE group (mean difference, −0.85 days; 95% CI, −1.65 to −0.06; p = 0.04). The OPE group had a lower percentage of postoperative complications (10% vs. 20%). Conclusions: OPE therapy after cardiac surgery is associated with decreased intensive care unit (ICU) and hospital LOS.

PURPOSE A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). MATERIALS AND METHODS We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment. RESULTS A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years. CONCLUSION In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

Abstract Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with deficient DNA mismatch repair (d-MMR) cancers, yet less than half of patients with metastatic colorectal cancer (mCRC) receive clinical benefit. We analyzed heterogeneity within d-MMR tumors using a multi-omics approach inclusive of percent unstable microsatellite loci (MS). Methods: We studied consecutive patients with d-MMR mCRC with available primary tumors (N=32) that were treated with an anti-PD-1 antibody at Mayo Clinic (2015-2022). Tumors were profiled using a whole exome and transcriptome platform (ImmunoID NeXT®). MSIsensor was used to calculate percent unstable microsatellite loci from whole exome sequencing data. CIBERSORT and ssGSEA were used to analyze immune gene expression in relationship to percent unstable microsatellite loci. An immune checkpoint gene expression signature was calculated as the mean expression of CD274, CTLA-4, HAVCR2, LAG-3, PDCD1, PDCD1LG2, TIGIT. Aforementioned variables were analyzed in relationship to objective tumor response (RECIST version 1.1). A Cox proportional hazards model was fit to predict progression-free survival (PFS). Results: Among 32 patients with d-MMR mCRC treated with PD-1 blockade, 16 (50%) received first-line anti-PD-1 therapy; others had &gt; 1 prior chemotherapy regimen. Eighteen (56.3%) tumors harbored BRAFV600E, 4 (12.5%) had mutant KRAS, and median PFS was 24.6 months (95% CI: 8.4, NR) with 18 events. Neither tumor mutation burden (TMB) nor PD-L1 mRNA expression predicted PFS. Median percent unstable MS loci was 14.38 (IQR: 2.6-23.2). Patients whose tumors had higher percent unstable MS loci had significantly better PFS (Q2-4 vs Q1; HR: 0.22, 95%CI: 0.06, 0.62; P=0.003), and were associated with increased objective response (P=0.049). Tumors with higher unstable loci also had higher neoantigen clonality (R= 0.64; P= 0.0003) and increased M0 (resting) macrophages (P=0.02). Nonresponders (vs responders) to PD-1 blockade had an increased immune checkpoint expression signature (P= 0.005). Conclusion: A higher percentage of unstable microsatellite loci, associated with higher neoantigen clonality and resting macrophages, was predictive of anti-PD-1 efficacy. Furthermore, an immune checkpoint gene expression signature was associated with objective response. Citation Format: Bahar Saberzadeh-Ardestani, Oluwadunni E. Emiloju, Rondell P. Graham, Jason T. Lewis, Charles W. Abbott, Sean M. Boyle, Frank A. Sinicrope. Prediction of PD-1 treatment outcome in mismatch repair deficient metastatic colorectal cancer using a multi-omic approach [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 578.

AbstractThe fibrotic tumor microenvironment is a pivotal therapeutic target. Nintedanib, a clinically approved multikinase antifibrotic inhibitor, is effective against lung adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). Previous studies have implicated the secretome of tumor‐associated fibroblasts (TAFs) in the selective effects of nintedanib in ADC, but the driving factor(s) remained unidentified. Here we examined the role of tissue inhibitor of metalloproteinase‐1 (TIMP‐1), a tumor‐promoting cytokine overproduced in ADC‐TAFs. To this aim, we combined genetic approaches with in vitro and in vivo preclinical models based on patient‐derived TAFs. Nintedanib reduced TIMP‐1 production more efficiently in ADC‐TAFs than SCC‐TAFs through a SMAD3‐dependent mechanism. Cell culture experiments indicated that silencing TIMP1 in ADC‐TAFs abolished the therapeutic effects of nintedanib on cancer cell growth and invasion, which were otherwise enhanced by the TAF secretome. Consistently, co‐injecting ADC cells with TIMP1‐knockdown ADC‐TAFs into immunocompromised mice elicited a less effective reduction of tumor growth and invasion under nintedanib treatment compared to tumors bearing unmodified fibroblasts. Our results unveil a key mechanism underlying the selective mode of action of nintedanib in ADC based on the excessive production of TIMP‐1 in ADC‐TAFs. We further pinpoint reduced SMAD3 expression and consequent limited TIMP‐1 production in SCC‐TAFs as key for the resistance of SCC to nintedanib. These observations strongly support the emerging role of TIMP‐1 as a critical regulator of therapy response in solid tumors.

Background Women show increased prevalence and severity of migraine compared to men. Whether small molecule calcitonin gene-related peptide receptor (CGRP-R) antagonists (i.e., gepants) and monoclonal antibodies targeting either the CGRP-R or the CGRP peptide might show sexually dimorphic outcomes for acute and preventive therapy has not been established. Methods We conducted a subpopulation analysis of available published data from FDA reviews to evaluate potential sex differences in the response rates of ubrogepant, rimegepant and zavegepant for acute migraine therapy. Available data from FDA reviews of erenumab, fremanezumab, galcanezumab and eptinezumab, approved CGRP-R and CGRP monoclonal antibodies and of atogepant were examined for prevention outcomes based on patient sex. Preventive outcomes were analyzed separately for patients with episodic migraine and chronic migraine. Results In women, the three approved gepants produced statistically significant drug effects regardless of dose tested on the FDA mandated co-primary endpoints, the proportion of patients achieving two-hour pain-freedom and the proportion of patients free of their most bothersome symptom at two hours post-dose. In women, the average placebo-subtracted two-hour pain-freedom proportion was 9.5% (CI: 7.4 to 11.6) and the average numbers needed to treat was 11. The free from most bothersome symptom at two hours outcomes were also significant in women. The gepant drugs did not reach statistically significant effects on the two-hour pain-freedom endpoint in the men, with an average drug effect of 2.8% (CI: −2.5 to 8.2) and an average number needed to treat of 36. For freedom from most bothersome symptom at two hours post-dose endpoint, differences were not significant in male patients. The treatment effect in each of the gepant studies was always numerically greater in women than in men. In evaluation of prevention outcomes with the antibodies or atogepant using the change from the specified primary endpoint (e.g., monthly migraine days), the observed treatment effect for episodic migraine patients almost always favored drug over placebo in both women and men. For chronic migraine patients the treatment effects of antibodies were similar in men and women and always favored the drug treated group. Conclusion/Interpretation: Small molecule CGRP-R antagonists are effective in acute migraine therapy in women but available data do not demonstrate effectiveness in men. CGRP-targeting therapies are effective for migraine prevention in both male and female episodic migraine patients but possible sex differences remain uncertain. In male and female chronic migraine patients, CGRP/CGRP-R antibodies were similarly effective. The data highlight possible differential effects of CGRP targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women.

Abstract Multiple myeloma (MM) therapeutics have evolved tremendously in recent years, with significant improvement in patient outcomes. As newer treatment options are developed, stem cell transplant (SCT) remains an important modality that provides excellent disease control and delays the progression of disease. Over the years, SCT use has increased overall in the U.S., but two distinct gaps remain, including suboptimal use overall, and racial-ethnic disparities. We evaluated the National Cancer Database (NCDB) to study what sociodemographic factors might play a role within a given racial-ethnic group leading to disparate SCT utilization, such that targeted approaches can be developed to optimize SCT use for all. In nearly 112,000 cases belonging to mutually exclusive categories of non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB), Hispanics, non-Hispanic Asians (NHA), and others, we found certain factors including age, comorbidity index, payor type, facility type (academic vs. community) and facility volume to be uniformly associated with SCT use for all the racial-ethnic groups, while gender was not significant for any of the groups. There were several other factors which had a differential impact on SCT utilization among the various race-ethnicity groups studied, including year of diagnosis (significant for NHW, NHB and Hispanics), income level (significant for NHW and Hispanics), literacy level (significant for NHW and NHB), and geographic location of the treatment facility (significant for NHW and NHA). The suboptimal SCT utilization overall in the U.S., suggests that there may be room for improvement for all, even including the majority NHW, while we continue to work on factors that lead to disparities for the traditionally underserved populations. This study helps identify sociodemographic factors that may play a role specifically in each group and paves the way to devise targeted solutions such that resource utilization and impact can be maximized.

AbstractBackgroundBreast cancer patients experienced heightened anxiety during the pandemic. Also, modifications to clinical trial activities allowing for virtual platforms, local assessments, and greater flexibility were introduced to facilitate participation. We sought to evaluate the association between pandemic‐related anxiety and willingness to participate in trials and how pandemic‐era modifications to trial activities affect the decision to participate.MethodsWe conducted an online survey from August to September, 2021 of patients with breast cancer assessing pandemic‐related anxiety; clinical trials knowledge and attitudes; willingness to participate during and before the pandemic; and how each modification affects the decision to participate. Fisher's exact tests evaluated differences in proportions and two‐sample t‐tests evaluated differences in means. The association of pandemic‐related anxiety with a decline in willingness to participate during compared to prior to the pandemic was modeled using logistic regression.ResultsAmong 385 respondents who completed the survey, 81% reported moderate–severe pandemic‐related anxiety. Mean willingness to participate in a trial was lower during the pandemic than prior [2.97 (SD 1.17) vs. 3.10 (SD 1.09), (p < 0.001)]. Severe anxiety was associated with higher odds of diminished willingness to participate during the pandemic compared to prior (OR 5.07). Each of the modifications, with the exception of opting out of research‐only blood tests, were endorsed by >50% of respondents as strategies that would increase their likelihood of deciding to participate.ConclusionsWhile pandemic‐related anxiety was associated with diminished willingness to participate in trials, the leading reasons for reluctance to consider trial participation were unrelated to the pandemic but included worries about not getting the best treatment, side effects, and delaying care. Patients view trial modifications favorably, supporting continuation of these modifications, as endorsed by the National Cancer Institute and others.

Abstract Objectives Patients with systemic sclerosis (SSc) are at increased risk for osteoporosis (OP) and associated fragility fractures. This study aimed to identify underlying risk factors for these conditions in patients with SSc. Methods This cross-sectional study was based on a large prospective cohort of patients with SSc using retrospectively collected bone health data. OP was defined as the presence of a T-score below -2.5 at the femoral neck or lumbar spine, a previous major osteoporotic fracture, or the prescription of anti-osteoporotic therapy. Results A total of 485 patients fulfilling the ACR/EULAR 2013 diagnostic criteria for SSc, followed in the Lille University Hospital, were included in the study. The prevalence of OP was 23%; fragility fractures occurred in 18% of patients. OP was associated with higher age, diffuse cutaneous subset, interstitial lung disease (ILD), anti-topoisomerase I positivity, treatment with glucocorticoids (GC) and DMARDs in univariable analysis. Multivariable analysis indicated that higher age (OR 1.06 [95%CI 1.04–1.08]), anti-topoisomerase I antibody positivity (OR 2.22 [1.18–4.16]) and treatment with GC (OR 4.48 [2.42–8.26]) were significantly and independently associated with OP. Conclusion Our study shows that OP risk in patients with SSc is determined by age, disease-related factors such as diffuse cutaneous subset, ILD and anti-topoisomerase I antibody positivity, but also treatment with GC independently of other factors.

Background Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce. Methods In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT). Results Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58–74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7–3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4–3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS. Conclusions Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.