Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

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

Intravascular metastatic melanoma : a difficult diagnosis

Melanoma is a common cancer with the potential for widespread metastasis; however intravascular metastasis is extremely rare. We report an unusual case of a patient with metastatic melanoma in whom 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) demonstrated an intravascular melanoma metastasis in the superior vena cava (SVC), successfully treated with external beam radiotherapy. To our knowledge, this is the first reported case where FDG PET-CT was used to make this diagnosis.3 page(s

Screening for obstructive sleep apnoea in post‐treatment cancer patients

Abstract Background and aims For cancer patients, comorbid obstructive sleep apnea (OSA) poses additional risk to their surgical/anaesthetic outcomes, quality of life, and survival. However, OSA screening is not well‐established in oncology settings. We tested two screening tools (STOP‐Bang questionnaire [SBQ] and the at‐home monitoring device, ApneaLink™Air), for predicting polysomnography (PSG) confirmed OSA in post‐treatment cancer patients. Methods Breast (n = 56), endometrial (n = 37) and melanoma patients (n = 50) were recruited from follow‐up clinics at Westmead Hospital (Sydney, Australia). All underwent overnight PSG, 137 completed SBQ, and 99 completed ApneaLink™Air. Positive (PPV) and negative (NPV) predictive values for PSG‐determined moderate‐to‐severe OSA and severe OSA, were calculated using an SBQ threshold ≥3 au and ApneaLink™Air apnoea‐hypopnea index thresholds of ≥10, ≥15 and ≥30 events/h. Results Both SBQ and ApneaLink™Air had high NPVs (92.7% and 85.2%–95.6% respectively) for severe OSA, but NPVs were lower for moderate‐to‐severe OSA (69.1% and 59.1%–75.5%, respectively). PPV for both tools were relatively low (all <73%). Combining both tools did not improve screening performance. Conclusions These screening tools may help identify cancer patients without severe OSA, but both are limited in identifying those with moderate‐to‐severe or severe OSA. PSG remains optimal for adequately identifying and managing comorbid OSA in cancer patients

Symposium Celebrating Women Surgeons Around the World

Introduction We must thank Dr. Sanziana Roman for organizing this symposium about women in surgery. Powerful testimonials from women surgeons, from Europe to the United States, from Africa to Australia and Asia. Each of them is different, as it reflects the culture of the place where their career took place. However, they all have in common the struggle to establish themselves in the surgical profession, traditionally a male-dominated field. Over the last two decades, the situation has clearly improved. Today in most medical schools about 50% of the students are women, and a similar percentage is present in many surgical residency programs. Twenty-one Departments of Surgery in the United States are led by women, a major change as compared to only 5 years ago. Much more must be done to establish a work environment where women are as welcomed and respected as men; where they are accepted as surgeons, and not as women surgeons, treasuring the contribution they can give. We do hope that..

Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma

Purpose: To evaluate the effects of treatment with the potent mutant BRAF inhibitors GSK2118436 or vemurafenib (PLX4720) on immune responses to metastatic melanoma in tissues taken before and after treatment. Experimental Design: Thirty-seven tumor biopsies were collected from 15 patients with unresectable American Joint Committee on Cancer stage III or IV melanoma immediately before and approximately 7 days after the commencement of BRAF inhibitor treatment and at the time of tumor progression. Immunohistochemical staining was carried out on the biopsies using specific antibodies for CD8, CD4, CD20, CD1a, and Granzyme B. Results: Tumor infiltration by CD4⁺ and CD8⁺ lymphocytes increased markedly following BRAF inhibitor treatment (both ρ = 0.015). There was a correlation between the degree of tumor infiltration by CD8⁺ and Granzyme B-expressing lymphocytes in post-BRAF inhibitor-treated biopsies (r = 0.690 and ρ = 0.013). Increased intratumoral CD8⁺ lymphocyte expression was correlated with a reduction in tumor size and an increase in necrosis in posttreatment biopsies (r = -0.793, ρ = 0.011; and r = 0.761, ρ = 0.004, respectively). Conclusions: The increase in tumor-infiltrating lymphocytes induced by treatment with BRAF inhibitors provides strong support for conducting trials that combine BRAF inhibitors with immunotherapy in the hope of prolonging clinical responses.9 page(s

Effects of BRAF inhibitors on human melanoma tissue before treatment, early during treatment, and on progression

Selective BRAF inhibitors (BRAFi) are a standard of care for the treatment of BRAFV600-mutant metastatic melanoma. We analyzed a unique set of serial triplicate human metastatic melanoma tumor biopsies to identify biomarkers of BRAFi response and resistance. Morphologic features and immunohistochemical biomarkers were analyzed in 37 metastatic melanoma biopsies at pretreatment (PRE), early during treatment (EDT), and on progression (PROG) from 15 patients treated with a BRAFi and correlated with response and outcome. At EDT, proliferative markers decreased regardless of response, whereas markers of cell death increased in responders. High expression of nuclear p27 at baseline was the strongest predictor of a poorer OS and predicted worse response. The results show that BRAFi are universally antiproliferative, regardless of clinical response, whereas markers of cell death increased only in responders. The addition of therapies targeting the cell cycle machinery may improve the response and duration of BRAFi, and investigation of the mechanisms of apoptosis may provide additional therapeutic targets.10 page(s