Rapid and sustained decline in CXCL-10 (IP-10) annotates clinical outcomes following TNFα-antagonist therapy in hospitalized patients with severe and critical COVID-19 respiratory failure.

BACKGROUND: A feedforward pathological signaling loop generated by TNFα and IFN-γ synergy in the inflamed lung, driving CXCL-10 (IP-10) and CXCL-9 chemokine-mediated activated T-cell and monocyte/macrophage tissue recruitment, may define the inflammatory biology of lethal COVID-19 respiratory failure. METHODS: To assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5 mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥50 compared to baseline and sustained for 48 h. Secondary endpoints included 28-day mortality, dynamic cytokine profiles, secondary infections, duration of supplemental oxygen support, and hospitalization. FINDINGS: Patients were predominantly in critical respiratory failure (15/18, 83%), male (14/18, 78%), above 60 years (median 63 years, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953 ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days; 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Three deaths were attributed to secondary lung infection. Mean plasma IP-10 levels declined sharply from 9183 to 483 pg/ml at Day 3 and 146 pg/ml at Day 14/discharge. Significant Day 3 declines in IFN-, TNFα, IL-27, CRP, and ferritin occurred. IP-10 and CXCL-9 declines were strongly correlated among patients with lymphopenia reversal (Day 3, Pearson r: 0.98, P-value 0.0006). INTERPRETATION: Infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19.

Rapid and sustained decline in CXCL-10 (IP-10) annotates clinical outcomes following TNF-α antagonist therapy in hospitalized patients with severe and critical COVID-19 respiratory failure.

BACKGROUND: A feed-forward pathological signaling loop generated by TNFα and IFN-γ in inflamed lung tissue, driving CXCL-10 (IP-10) and CXCL-9 chemokine-mediated activated T-cell and monocyte/macrophage tissue recruitment, may define, sustain and amplify the inflammatory biology of lethal COVID-19 respiratory failure. METHODS: To assess TNFα-antagonist therapy, 18 hospitalized adults with hypoxic respiratory failure and COVID-19 pneumonia received single-dose infliximab-abda therapy 5mg/kg intravenously between April and December 2020. The primary endpoint was time to increase in oxygen saturation to fraction of inspired oxygen ratio (SpO2/FiO2) by ≥ 50 compared to baseline and sustained for 48 hours. Secondary endpoints included 28-day mortality, dynamic cytokine profiles (Human Cytokine 48-Plex Discovery Assay, Eve Technologies), secondary infections, duration of supplemental oxygen support and hospitalization. FINDINGS: Patients were predominantly in critical respiratory failure (15/18, 83%), male (14/18, 78%), above 60 years (median 63 yrs, range 31-80), race-ethnic minorities (13/18, 72%), lymphopenic (13/18, 72%), steroid-treated (17/18, 94%), with a median ferritin of 1953ng/ml. Sixteen patients (89%) met the primary endpoint within a median of 4 days, 15/18 (83%) recovered from respiratory failure, and 14/18 (78%) were discharged in a median of 8 days and were alive at 28-day follow-up. Deaths among three patients ≥ 65yrs age with pre-existing lung disease or multiple comorbidities were attributed to secondary lung infection. Mean plasma IP-10 levels declined sharply from 9183 pg/ml to 483 pg/ml at Day 3 and further to 146 pg/ml at Day 14/discharge. Significant declines in IFN- γ , TNFα, IL-27, CRP and ferritin were specifically observed at Day 3 whereas other cytokines were unmodified. IL-6 levels declined sharply among patients with baseline levels >10 pg/ml. Among 13 lymphopenic patients, six (46%) had resolution of lymphopenia by day 3, and 11 by day 14. CXCR3-ligand (IP-10 and CXCL-9) declines were strongly correlated among patients with lymphopenia reversal (Day 3, Pearson r: 0.98, p-value: 0.0006). INTERPRETATION: Consistent with a pathophysiological role of TNFα, the clinical and cytokine data indicate that infliximab-abda may rapidly abrogate pathological inflammatory signaling to facilitate clinical recovery in severe and critical COVID-19. Randomized studies are required to formally assess mortality outcomes. Funding: National Center for Advancing Translational Sciences.

Treatment interruption and discontinuation of hormonal therapy in hormone receptor-positive breast cancer patients.

PURPOSE: To investigate predictors of treatment interruption and early discontinuation of adjuvant hormonal therapy (HT) in a retrospective cohort of women with newly diagnosed hormone receptor-positive (HR +) breast cancer. METHODS: Eligible cases were identified from a single institutional tumor registry from 2009 to 2015. Patients were followed from initiation of adjuvant HT for a minimum of one year through December 1, 2016. Predictors of treatment interruption or early discontinuation were analyzed with Cox proportional hazards regression models. RESULTS: With a median follow-up time of 3.0 years (IQR 1.5-4.5), 22 women (10.9%) discontinued HT early and 47 (23.4%) had at least one treatment interruption of > 14 days. Adjusted Cox proportional hazards regression models showed that women with pre-existing affective disorders were more likely to discontinue therapy early (HR 3.15; 95% CI 1.35-7.37), while those with pre-existing chronic pain disorders were at increased risk for treatment interruption (HR 2.24; 95% CI 1.20-4.19). HT-related symptoms were the most commonly reported reason for HT interruption or discontinuation. Women who experienced severe treatment-related symptoms were at increased risk for both HT interruption (HR 2.64; 95% CI 1.07-6.50) and HT discontinuation (HR 3.48; 95% CI 1.20-10.1). CONCLUSIONS: This study showed that HT interruptions and discontinuation were common, often associated with HT-related symptoms. Clinicians caring for breast cancer patients on HT should monitor closely for treatment-emergent symptoms, especially women with pre-existing disorders, and support them to continue therapy through aggressive symptom management and other patient-centered approaches.

Prospective Evaluation of Effect of Metformin on Activation of AMP-activated Protein Kinase (AMPK) and Disease Control in a Sub-group Analysis of Patients with GI Malignancies.

BACKGROUND: Observational studies have demonstrated association of metformin with reduced cancer incidence and mortality in multiple cancer types, including gastrointestinal (GI) malignancies. Anti-neoplastic effects of metformin are believed through many mechanisms including activation of AMP-activated protein kinase, which controls mammalian target of rapamycin (mTOR) growth regulatory pathway. METHODS: In a pilot, delayed-start randomized study, non-diabetic patients with GI cancers were randomized to 2 arms, Stage 1: concurrent metformin (500mg twice daily) plus chemotherapy vs. chemotherapy alone followed by cross over to metformin plus chemotherapy arm in Stage 2, while adverse events (DLT) were assessed by CTCAE v.3.0. As a translational correlate, we used phosphorylation of AMPKα at Thr172 to measure AMPK activation by western blot technique in PBMCs isolated from patients before and after receiving M. These levels were correlated with radiological (RECIST 1.1) and tumor marker outcomes by descriptive analysis. In this study, we present the sub-group analysis of patients with GI cancers. RESULTS: 41 patients with GI cancers (colorectal: 22, pancreatic: 12, gastroesophageal: 4, biliary: 2, others: 1) were treated in this trial. Mean duration of metformin therapy was 85 days (range: 9-443). There was no significant difference in grade 3 or above DLT in metformin plus chemotherapy vs. chemotherapy arm (14% vs. 12% respectively). Gel band density analysis on 19 patients showed that 63% patients had increased phosphorylation of AMPKα after metformin (ratio of phospho-AMPKα after and before metformin > 1) with mean = 1.227 (± 0.134). RECIST 1.1 restaging showed disease control in 55% patients and 45% patients had decline in tumor markers. Of note, 60% of patients with disease control also showed increase in phosphorylation of AMKα. CONCLUSIONS: This group of patients treated with metformin prospectively demonstrates the impact of metformin on AMPKα phosphorylation, and correlates with clinical benefit in patients with GI cancers when metformin was added to systemic chemotherapy of varying types. We aim to perform a dose-escalation of metformin in our next study with additional metabolomics correlates.

Hepatitis B virus reactivation following imatinib therapy: A comparative review of 9 cases.

Patients undergoing cytotoxic or immunosuppressive therapy for cancer have an established predilection for hepatitis B virus reactivation; however, the risk associated with newer molecularly targeted agents has not been well investigated. Imatinib, a small molecule tyrosine kinase inhibitor, induces rapid and sustained clinical benefit by inhibiting a number of signaling pathways, including BCR-ABL and c-KIT. We report the case of a patient who developed hepatitis B virus reactivation while receiving imatinib therapy for gastrointestinal stromal tumor. Furthermore, a structured literature search of the medical databases consisting of MEDLINE and PubMed was performed using the terms "hepatitis B", "reactivation", and "imatinib". The search identified nine case reports only. The data on patients' characteristics, epidemiology, clinical features, comorbid conditions, diagnosis, and management are summarized. Imatinib-associated hepatitis B virus reactivation was reported in seven patients with chronic myeloid leukemia, one with desmoid tumor, and one with gastrointestinal stromal tumor. This review serves to outline our current understanding of the epidemiology, risk factors, and pathophysiology of chronic hepatitis B virus reactivation secondary to imatinib therapy as well as the current approaches to diagnosis and management of this condition. We aim to increase awareness about this possible association and advocate for hepatitis B virus screening prior to imatinib therapy, especially in patients who are at increased risk for chronic hepatitis B virus infection.