Citations

Abstract Background: SARS-CoV-2 mRNA vaccines have been demonstrated to have robust and durable humoral immune response in healthy individuals. However, their effectiveness in immunocompromised patients, particularly cancer patients, remains less known. Newer data suggests that cancer patients may not mount adequate protective immune response after vaccination. Methods: A retrospective study of patients ≥ 18 years old who had SARS-CoV-2 spike antibody (anti-S Ab) testing after 2 doses of SARS-CoV-2 mRNA vaccines between 12-90 days at Mayo Clinic between January 1, 2021 and May 10, 2021 was performed. The Elecsys Anti-SARS-CoV-2 S electrochemiluminescence immunoassay (Roche Diagnostics, Switzerland) was used to measure the antibody response. Patients with prior COVID-19 infection and patients on immunosuppressive therapy for an indication other than cancer were excluded. Categorical variables were summarized as frequencies (percentages) and continuous variables were reported as median with range. Wilcoxon signed rank test was used to compare continuous variables between groups and Chi-squared or Fisher’s exact test was used to compare categorical variables. All tests were two-sided with p value < 0.05 considered statistically significant. The analysis was done using R program version 3.6.2. Results: Among 201 patients, 79 had breast cancer, 91 had a hematologic malignancy, 6 had other solid malignancies, and 25 had no history of cancer. All breast cancer patients on endocrine therapy or trastuzumab ± pertuzumab without chemotherapy (n=35) had anti-S Ab titer ≥ 500 U/mL. Patients on cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) appeared to have low level of anti-S Ab with 28.6% (n=4/14) had anti-S Ab titer ≤ 500 U/mL. Patients on chemotherapy also had low levels of anti-S Ab with 47% (n=14/30) having anti-S Ab titers ≤ 500 U/mL. When combining breast cancer patients on endocrine therapy alone or anti-HER2 therapy with patients without history of cancer as an immunocompetent group, there was significantly greater proportion of immunocompetent patients (97%) who had anti-S Ab titer ≥ 500 U/mL compared with only 8% of patients with hematologic malignancy and 55% of patients with solid malignancy on chemotherapy or CDK4/6i (p < 0.001). Using multivariate logistic regression analysis adjusted for age, gender, and vaccine type, patients with solid malignancies and treatment-related cytopenia, including chemotherapy and CDK4/6i, (OR 35.51 [95%CI 8.38-255.25, p < 0.001]) were more likely than immunocompetent patients to have a suboptimal anti-S Ab results ≤ 500 U/mL.Conclusion: A significant number of breast cancer patients on chemotherapies and CDK4/6i had poor humoral responses after SARS-CoV-2 mRNA vaccination. While CDK4/6i is not commonly considered as immunosuppressive therapy, breast cancer patients on CDK4/6i appeared to have suboptimal response to SARS-CoV-2 mRNA vaccine. Our study also highlights the significance of assessing antibody response after COVID-19 vaccines in these vulnerable patients. Citation Format: Saranya Chumsri, Pooja P. Advani, Tanmayi S Pai, Zhou Li, Marites Acampora, Gina A Reynolds, Alvaro Moreno-Aspitia, Christopher P Marquez, Keith L. Knutson. Antibody responses after SARS-CoV-2 mRNA vaccination in breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-23-01.

Despite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9–responsive cell repertoire is still not well defined. Here, we found that IL-9 mediates proallergic activities in the lungs by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c + and CD11c − interstitial macrophage populations. Interstitial macrophages were required for IL-9–dependent allergic responses. Mechanistically, IL-9 affected the function of lung macrophages by inducing Arg1 activity. Compared with Arg1-deficient lung macrophages, Arg1-expressing macrophages expressed greater amounts of CCL5. Adoptive transfer of Arg1 + lung macrophages but not Arg1 − lung macrophages promoted allergic inflammation that Il9r −/− mice were protected against. In parallel, the elevated expression of IL-9, IL-9R, Arg1, and CCL5 was correlated with disease in patients with asthma. Thus, our study uncovers an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation.

Abstract Alveolar macrophages (AMs) are major lung tissue-resident macrophages capable of proliferating and self-renewal in situ. AMs are vital in pulmonary antimicrobial immunity and surfactant clearance. The mechanisms regulating AM compartment formation and maintenance remain to be fully elucidated currently. In this study, we have explored the roles of mitochondrial transcription factor A (TFAM)–mediated mitochondrial fitness and metabolism in regulating AM formation and function. We found that TFAM deficiency in mice resulted in significantly reduced AM numbers and impaired AM maturation in vivo. TFAM deficiency was not required for the generation of AM precursors nor the differentiation of AM precursors into AMs, but was critical for the maintenance of AM compartment. Mechanistically, TFAM deficiency diminished gene programs associated with AM proliferation and self-renewal and promoted the expression of inflammatory genes in AMs. We further showed that TFAM-mediated AM compartment impairment resulted in defective clearance of cellular debris and surfactant in the lung and increased the host susceptibility to severe influenza virus infection. Finally, we found that influenza virus infection in AMs led to impaired TFAM expression and diminished mitochondrial fitness and metabolism. Thus, our data have established the critical function of TFAM-mediated mitochondrial metabolism in AM maintenance and function.

Background Chronic fatigue syndrome (CFS) is a complex and often disabling chronic condition emerging worldwide, with no curative or definitive therapy yet identified. Ginseng has been widely used to treat fatigue in other patient groups and conditions; however, a systematic review focusing solely on the impact of ginseng on fatigue in patients with CFS has not been performed. Objective This study aimed to assess the current state of evidence regarding ginseng for CFS. Methods Multiple databases were searched from inception to October 2020. All data was extracted independently and in duplicates. Outcomes of interest included the effectiveness and safety of ginseng in patients with CFS. Results 2 studies enrolling 68 patients were deemed eligible, including one randomized clinical trial and one prospective observational study. The certainty of evidence in the effectiveness outcome was low and moderate from both studies, while the safety evidence was very low as reported from one study. Conclusion Study findings highlight a potential benefit of ginseng therapy in the treatment of CFS. However, we are not able to draw firm conclusions due to limited clinical studies. The paucity of data warrants limited confidence. There is a need for future rigorous studies to provide further evidence.

AbstractIntroductionMultiple positron emission tomography (PET) tracers are available for amyloid imaging, posing a significant challenge to consensus interpretation and quantitative analysis. We accordingly developed and validated a deep learning model as a harmonization strategy.MethodA Residual Inception Encoder‐Decoder Neural Network was developed to harmonize images between amyloid PET image pairs made with Pittsburgh Compound‐B and florbetapir tracers. The model was trained using a dataset with 92 subjects with 10‐fold cross validation and its generalizability was further examined using an independent external dataset of 46 subjects.ResultsSignificantly stronger between‐tracer correlations (P < .001) were observed after harmonization for both global amyloid burden indices and voxel‐wise measurements in the training cohort and the external testing cohort.DiscussionWe proposed and validated a novel encoder‐decoder based deep model to harmonize amyloid PET imaging data from different tracers. Further investigation is ongoing to improve the model and apply to additional tracers.

Abstract Background the Xiangya Hospital circuit training (X-CircuiT), was developed to reverse pre-frailty in Chinese older adults and determine potential mechanisms through which pre-frailty is reversed. Methods this randomised controlled trial was performed at Xiangya Hospital, Changsha, China from September 2020 to May 2021. Forty-eight pre-frail older adults were enrolled. Participants were randomly assigned (1:1) to X-CircuiT (46 min/session, three supervised sessions/week for 3 months at a community health centre) or control (1-time advice on physical activity without supervised exercise). The primary outcome was the proportion of participants with pre-frailty after 3-month intervention. The secondary outcomes included absolute risk reduction (ARR), number needed to treat (NNT), and the changes in senior fitness, body composition and clinical measures. Results among 48 participants (mean age, 72 years; women [65%]), 22 participants in the X-CircuiT (92%) and 21 participants in the control (88%) completed the study. After 3 months, the proportion of pre-frailty was significantly lower in the X-CircuiT group than the control (14% versus 95%, P &lt; 0.001). The ARR and NNT were 82% [95% CI, 65–99] and 1 [1–2], respectively. X-CircuiT was associated with significant improvements in senior fitness indicators and body composition. No significant difference in blood chemistry, carotid ultrasound and echocardiography parameters was found between groups. No significant interaction was detected between sex, BMI, baseline peak oxygen consumption and study groups. Conclusion this study demonstrates that X-CircuiT could significantly reverse pre-frailty in Chinese older adults. The underlying mechanisms may involve X-CircuiT-induced improvements in body composition and senior fitness. The trial is registered at Chictr.org.cn. Number: ChiCTR2100048125.

Abstract Background Health-related quality of life (HRQOL) is reduced in patients (pts) with ulcerative colitis (UC). We report on the HRQOL benefits of maintenance treatment with upadacitinib (UPA), a selective and reversible Janus kinase inhibitor, in pts with moderately to severely active UC in the Phase, 3 multicentre, randomised, double-blind U-ACHIEVE maintenance study (NCT02819635). Methods This study included a primary analysis of, 451 pts who achieved clinical response following treatment with UPA, 45 mg once daily (QD) in two replicate, 8-week induction studies, U-ACHIEVE induction, and U-ACCOMPLISH (NCT03653026). In U-ACHIEVE maintenance, pts from both induction studies were re-randomised, 1:1:1 to receive QD UPA, 15 mg, UPA, 30 mg, or PBO. HRQOL outcomes evaluated included the percent of pts reporting a clinically meaningful within-person change (MWPC) from induction baseline to Week, 0 (maintenance baseline) and Week, 52 (end of maintenance) in a broad range of HRQOL measures, including Inflammatory Bowel Disease Questionnaire (IBDQ), Work Productivity and Impairment Questionnaire (WPAI), Short Form, 36 (SF-36), European Quality of Life-5 Dimensions, 5 Levels (EQ-5D-5L), and Ulcerative Colitis Symptoms Questionnaire (UC-SQ). Results A total of, 149, 148, and, 154 pts received PBO, UPA, 15 mg, and UPA, 30 mg QD, respectively, during maintenance. At Week, 0 of the maintenance study, there were no significant differences between UPA and PBO treatment groups in the percentage of pts reporting MWPC relative to induction baseline for most pt-reported outcomes (PROs) as all pts enrolled in maintenance were UPA clinical responders during IP. For IBDQ, a significantly greater proportion of pts achieved MWPC criteria (p&lt;0.001) with UPA, 15 mg (68.9%) and UPA, 30 mg (78.6%) vs, 39.6% for PBO at Week, 52 (Figure, 1). Also, a significantly greater proportion of pts treated with either, 15 mg or, 30 mg UPA dosage vs PBO over, 52 weeks achieved MWPC for the WPAI domains (p≤0.01) of overall work improvement, presenteeism, and activity impairment (Figure, 2), in both physical and mental component summaries of SF-36 (p&lt;0.001, Figure, 3), in EQ-5D-5L (p&lt;0.001, Figure, 4), and in UC-SQ (p&lt;0.001). A numerically greater proportion of pts receiving UPA, 30 mg vs, 15 mg achieved MWPC in most PROs at Week 52. Conclusion A significantly higher percentage of pts with moderately to severely active UC who responded to UPA induction therapy maintained clinically meaningful improvements with UPA, 15 mg of, 30 mg compared to PBO consistently across a broad range of HRQOL outcomes after, 52 weeks of maintenance treatment. These HRQOL aspects include IBD symptoms (IBDQ, UC-SQ), work productivity (WPAI), physical and mental functioning (SF-36), and general well-being (IBDQ, EQ-5D).

Abstract Background Upadacitinib (UPA), a selective and reversible Janus kinase inhibitor, has been shown to be safe and effective when administered at a dose of 45 mg once daily (QD) as 8-week induction therapy in moderate-to-severe Ulcerative Colitis (UC). This analysis evaluated outcomes following extended induction (45 mg QD for 16 weeks) followed by maintenance (15 or 30 mg QD) treatment with UPA in patients with UC who did not achieve a clinical response after 8 weeks’ induction. Methods Patients with moderate-to-severe UC who failed to achieve a clinical response (Adapted Mayo score decrease of ≥2 points and ≥30% from baseline, plus ≥1-point decrease in rectal bleeding score [RBS] or absolute RBS ≤1) to 8 weeks’ induction treatment with UPA 45 mg QD in the U-ACHIEVE Induction (NCT02819635) or U-ACCOMPLISH (NCT03653026) studies, continued to receive UPA 45 mg QD in an 8-week open-label extension. Responders at the end of the open-label extension entered the U-ACHIEVE Maintenance study and were randomised 1:1 to UPA 15 mg or 30 mg QD for 52 weeks. The efficacy endpoints were evaluated at Week 16 for the induction studies and at Week 52 for the maintenance study. Results In total, 125 patients who failed to achieve a clinical response after 8 weeks’ induction treatment received open-label UPA 45 mg for a further 8 weeks. Of these patients, 48.3% achieved a clinical response at Week 16 and were re-randomised to UPA 15 or 30 mg in U-ACHIEVE Maintenance. Among 16-week responders who entered the maintenance study, clinical remission, maintenance of clinical response, and endoscopic improvement, respectively, at Week 52 were achieved in 33.3% versus 19.0%, 66.7% versus 35.7%, and 37.5% versus 23.8% of those who received UPA 30 versus UPA 15 mg QD as maintenance treatment (Table 1). Adverse events of special interest were reported infrequently in the two maintenance treatment groups (Table 2). Conclusion In this analysis, prolonged induction treatment for a total of 16 weeks was beneficial in almost half of UC patients who failed to achieve a clinical response after 8 weeks’ induction with UPA 45 mg. The benefit of maintenance therapy in these delayed responders was further demonstrated, with UPA 30 mg providing greater benefit than UPA 15 mg QD.