Francisella tularensis-infected human neutrophils are trojan horses for infection of macrophages

Francisella tularensis, the causative agent of tularemia, is a Gram-negative bacterium that infects neutrophils (polymorphonuclear leukocytes, PMNs) and macrophages. Previous studies by our group and others demonstrate that F. tularensis inhibits the respiratory burst, escapes the phagosome, replicates in the cytosol, and significantly prolongs human neutrophil lifespan. However, the fate of infected neutrophils and their bacterial cargo are unknown. We now demonstrate that F. tularensis-infected neutrophils (iPMNs) interacted more efficiently with primary human monocyte-derived macrophages (MDMs) than aged, control PMNs despite their viability and paucity of surface phosphatidylserine and identified an important role for serum and C1q in this process. Uptake by this mechanism supported bacterial growth in MDMs, indicating that iPMNs can act as Trojan horses to spread infection. Efferocytosis of apoptotic cells favors repolarization of macrophages from a proinflammatory (M1) phenotype to a pro-resolution (M2) phenotype. In marked contrast, the effects of iPMN were distinct, as these cells elicited an atypical MDM phenotype notable for downregulation of both M1 and M2 surface markers that was accompanied by sustained expression of indoleamine 2,3 dioxygenase and suppressor of cytokine signaling 1 as well as low proinflammatory cytokine secretion. Altogether, our data advance understanding of neutrophil-macrophage interactions and reveal a potential new mechanism for F. tularensis dissemination and immunomodulation within a host

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma Concomitant With Non-IgM Plasma Cell Neoplasm: Report of 5 Cases With Laboratory Evidence of Biclonal B-Cell Neoplasms in Single Individuals

Abstract Introduction Plasma cell neoplasm (PCN) is rarely associated with Waldenstrom macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL), and its clonal relationship to WM/LPL is unclear. Methods We retrospectively analyzed five cases of PCN concomitant with WM/LPL for clinicopathologic features. Results Of five patients, three were female and two were male with a median age of 75 years at diagnosis of concurrent PCN-WM/LPL. Three cases presented with serum paraprotein of IgM type and had a diagnosis of WM/LPL before identifying concurrent PCN, with an interval of 1 to 10 years. In the remaining two cases, PCN and WM/LPL were concurrently diagnosed. All patients demonstrated biclonal M-spikes with distinct heavy chain isotypes but concordant light chain isotype (kappa or lambda) by immunofixation electrophoresis. In all four cases, two neoplastic populations were highlighted with immunohistochemistry, including expression of CD56/cyclin D1 (1), cyclin D1 (2), and IgA (1) in neoplastic plasma cells and negativity of CD56/cyclin D1 in LPL. Of three patients with clinical information available, two were treated with chemotherapy, and the other was treated with autologous stem cell transplant. At follow-up, one patient died of PCN progression at 24 months, one had recurrent WM/LPL at 144 months, and the other was alive with disease 5 months after the diagnosis of concurrent neoplasms. Conclusion Discordant heavy chain isotype restrictions between PCN and WM/LPL suggest biclonal B-cell neoplasms, which is supported by PCN’s phenotypic distinction, such as expression of cyclin D1 and/or CD56, from coexisting WM/LPL. However, our cases had WM/LPL either preceding or concurring with PCN, and all exhibited concordant light chain restrictions, raising a possibility that PCN may be evolved from WM/LPL with class switching. This issue of clonal relationship between the two B-cell neoplasm and underlying pathogenesis remains to be investigated with sequencing analysis on sorted PCN or WM/LPL and comparison of mutation profiles between them. </jats:sec