Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals

National Trends and Factors Associated with Hospital Costs Following Thyroid Surgery.

BackgroundMedical costs in the United States have been increasing disproportionally to gross domestic product, raising concerns about the sustainability of U.S. healthcare expenditures. Care of patients with thyroid disease has been identified as an area of medicine where cost increases have been pronounced.ObjectivesThe goals of this study were to identify potential drivers of the cost of hospitalization following thyroid surgery, and to understand which of these factors may be contributing to observed increases in cost from 2003 to 2011.MethodsA retrospective cross-sectional analysis of discharge data from the Nationwide Inpatient Sample (NIS) database for all admissions following thyroid lobectomy or total thyroidectomy in the years 2003, 2007, and 2011 was performed. Multiple regression analysis via a weighted generalized linear model was used to identify factors that were independently associated with high cost of hospitalization. Trend as well as subgroup analyses were then performed to identify which of these factors could be contributing to increasing costs.ResultsThere were 47,854 hospital admissions following total thyroidectomy or thyroid lobectomy identified in the years 2003, 2007, and 2011. The aggregate national cost of hospitalization increased from $198 million in 2003 to$373 million in 2011 in inflation-adjusted 2011 dollars. The weighted mean cost of hospitalization following thyroid surgery increased from $6154 to$8982 from 2003 to 2011 in inflation-adjusted 2011 dollars. Higher comorbidity score, total thyroidectomy, lymphadenectomy, western region, rural region, and certain postoperative complications were the factors most highly associated with increased hospital costs. Of these, an increasing proportion of patients with higher severity of illness score and an increasing proportion of patients undergoing total thyroidectomy and lymphadenectomy were implicated as the most likely contributors to the cost increases. The rate of total thyroidectomy and lymphadenectomy was found to be increasing for patients with both benign and malignant thyroid disease.ConclusionsAccording to the NIS data set, costs associated with hospitalization after thyroid surgery increased markedly from 2003 to 2011. This increase could be in part due to a growing proportion of sicker patients undergoing more extensive surgery, but a number of confounders in this study limit the conclusions. Further analysis of factors that could be associated with the rising costs of inpatient thyroid surgery should be undertaken

National Trends and Factors Associated with Hospital Costs Following Thyroid Surgery

Background: Medical costs in the United States have been increasing disproportionally to gross domestic product, raising concerns about the sustainability of U.S. healthcare expenditures. Care of patients with thyroid disease has been identified as an area of medicine where cost increases have been pronounced. Objectives: The goals of this study were to identify potential drivers of the cost of hospitalization following thyroid surgery, and to understand which of these factors may be contributing to observed increases in cost from 2003 to 2011. Methods: A retrospective cross-sectional analysis of discharge data from the Nationwide Inpatient Sample (NIS) database for all admissions following thyroid lobectomy or total thyroidectomy in the years 2003, 2007, and 2011 was performed. Multiple regression analysis via a weighted generalized linear model was used to identify factors that were independently associated with high cost of hospitalization. Trend as well as subgroup analyses were then performed to identify which of these factors could be contributing to increasing costs. Results: There were 47,854 hospital admissions following total thyroidectomy or thyroid lobectomy identified in the years 2003, 2007, and 2011. The aggregate national cost of hospitalization increased from $198 million in 2003 to$373 million in 2011 in inflation-adjusted 2011 dollars. The weighted mean cost of hospitalization following thyroid surgery increased from $6154 to$8982 from 2003 to 2011 in inflation-adjusted 2011 dollars. Higher comorbidity score, total thyroidectomy, lymphadenectomy, western region, rural region, and certain postoperative complications were the factors most highly associated with increased hospital costs. Of these, an increasing proportion of patients with higher severity of illness score and an increasing proportion of patients undergoing total thyroidectomy and lymphadenectomy were implicated as the most likely contributors to the cost increases. The rate of total thyroidectomy and lymphadenectomy was found to be increasing for patients with both benign and malignant thyroid disease. Conclusions: According to the NIS data set, costs associated with hospitalization after thyroid surgery increased markedly from 2003 to 2011. This increase could be in part due to a growing proportion of sicker patients undergoing more extensive surgery, but a number of confounders in this study limit the conclusions. Further analysis of factors that could be associated with the rising costs of inpatient thyroid surgery should be undertaken

Donor site morbidity following radial forearm free flap reconstruction with split thickness skin grafts using negative pressure wound therapy

Abstract Background Donor site complications secondary to radial forearm free flap (RFFF) reconstruction can limit recovery. Optimizing hand and wrist function in the post-operative period may allow more efficient self-care and return to activities of daily living. Negative pressure wound dressings (NPD) may increase blood flow and perfusion as compared to static pressure dressings (SPD) designed to minimize shear forces during the healing period. This study aims to compare subjective and objective hand and wrist functional outcomes following RFFF reconstruction with split thickness skin grafts (STSG) in patients treated with NPD and SPD. Methods Adult patients undergoing RFFF with STSG were identified preoperatively and randomized to receive NPD or SPD following their RFFF reconstruction. NPD involved a single-use, portable device capable of applying 80 mmHg of negative pressure to the forearm donor site. SPD involved a volar splint. Dressings were left in place for seven days with subjective and objective function assessed at seven days, one month and three months postoperatively. The primary outcome was self-reported hand function as measured with the function subscale of the Michigan Hand Questionnaire (MHQ). Secondary outcomes included hand and wrist strength, range of motion, sensation, scar aesthetics, and skin graft complications. Results Twenty-four patients undergoing RFFF were randomized to NPD or SPD. Patients treated with NPD had improved MHQ self-reported functional scores as compared to those treated with SPD at seven days postoperatively (P = 0.016). Flexion at seven days was improved in NPD group (P = 0.031); however, all other strength and range of motion outcomes were similar between groups. There were no differences in rates of graft complications, scar aesthetics, or sensation. Conclusions In the immediate post-operative period, NPD was associated with improved patient-reported hand and wrist function. Wound care to optimize hand and wrist function could allow for improved patient outcomes in the immediate postoperative period

Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with rates of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) dramatically increasing. The overexpression of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for the trimethylation at lysine 27 of histone 3 (H3K27me3), is associated with a poor clinical prognosis and aggressive HPV-positive phenotypes. Methods We utilized three EZH2 pathway inhibitors, GSK-343, DZNeP, and EPZ-5687, and tested their efficacy in two HPV-positive and two HPV-negative OPSCC cell lines. Results Treatment with GSK-343 decreased H3K27me3 in all cell lines and treatment with DZNeP decreased H3K27me3 in only HPV-negative cell lines as determined by Western blot. Cells treated with EPZ-5687 displayed no appreciable change in H3K27me3. Epigenetic effect on gene expression was measured via ddPCR utilizing 11 target probes. Cells treated with DZNeP showed the most dramatic expressional changes, with decreased EGFR in HPV-positive cell lines and an overall increase in proliferation markers in HPV-negative cell lines. GSK-343-treated cells displayed moderate expressional changes, with CCND1 increased in HPV-positive cell lines and decreased TP53 in HPV-negative SCC-1. EPZ-5687-treated cell lines displayed few expressional changes overall. Only DZNeP-treated cells displayed anti-proliferative characteristics shown in wound-healing assays. Conclusions Our findings suggest that EZH2 inhibitors are a viable therapeutic option for the role of epigenetic effect, potentially sensitizing tumors to current chemotherapies or limiting cell differentiation

Brief electrical stimulation and synkinesis after facial nerve crush injury: a randomized prospective animal study

Abstract Background Recent studies have examined the effects of brief electrical stimulation (BES) on nerve regeneration, with some suggesting that BES accelerates facial nerve recovery. However, the facial nerve outcome measurement in these studies has not been precise or accurate. Furthermore, no previous studies have been able to demonstrate the effect of BES on synkinesis. The objective of this study is to examine the effect of brief electrical stimulation (BES) on facial nerve function and synkinesis in a rat model. Methods Four groups of six rats underwent a facial nerve injury procedure. Group 1 and 2 underwent a crush injury at the main trunk of the nerve, with group 2 additionally receiving BES for 1 h. Group 3 and 4 underwent a transection injury at the main trunk, with group 4 additionally receiving BES for 1 h. A laser curtain model was used to measure amplitude of whisking at 2, 4, and 6 weeks. Fluorogold and fluororuby neurotracers were additionally injected into each facial nerve to measure synkinesis. Buccal and marginal mandibular branches of the facial nerve were each injected with different neurotracers at 3 months following injury. Based on facial nucleus motoneuron labelling of untreated rats, comparison was made to post-treatment animals to deduce whether synkinesis had taken place. All animals underwent trans-cardiac perfusion with subsequent neural tissue sectioning. Results At week two, the amplitude observed for group 1 and 2 was 14.4 and 24.0 degrees, respectively (p = 0.0004). Group 4 also demonstrated improved whisking compared to group 3. Fluorescent neuroimaging labelling appear to confirm improved pathway specific regeneration with BES following facial nerve injury. Conclusions This is the first study to use an implantable stimulator for serial BES following a crush injury in a validated animal model. Results suggest performing BES after facial nerve injury is associated with accelerated facial nerve function and improved facial nerve specific pathway regeneration in a rat model

Practices regarding human Papillomavirus counseling and vaccination in head and neck cancer: a Canadian physician questionnaire

Abstract Background Human papillomavirus (HPV) has recently been implicated as a causative agent in a rapidly growing number of oropharyngeal cancers. Emerging literature supports the hypothesis that HPV vaccination may protect against HPV-related head and neck cancer (HNC) in addition to HPV-related cervical and anogenital disease. While the association between HPV infection and cervical cancer is widely understood, its relation to HNC is less well known. The purpose of this study was to better understand HPV counseling practices for infection and vaccination in relation to HNC of primary care physicians (PCPs), Obstetricians/Gynecologists (OBGYNs), and Otolaryngology - Head and Neck Surgeons (OHNSs) in Canada. Methods A Canada-wide electronic questionnaire regarding counseling practices on HPV infection, transmission, and vaccination was designed and distributed to PCPs, OBGYNs, and OHNSs across Canada through electronic and paper-based methods. Basic Descriptive statistics were used to analyze responses. Results In total, 337 physicians responded (239 family physicians, 51 OHNSs, 30 OBGYNs, and 17 pediatricians). Three out of four PCPs reported routine counseling of their patients regarding HPV infection, transmission, and vaccination. Among this group, 68% reported “never” or “rarely” counseling patients that HPV can cause HNC. The most commonly reported reason that PCPs cited for not counseling was a lack of knowledge. The majority of OHNSs (81%) and OBGYNs (97%) counseled patients regarding HPV infection, transmission, and vaccination. However, very few OHNSs (10%) regularly counseled patients with HPV-related HNC about HPV-related anogenital cancer. Similarly, very few OBGYNs (18%) regularly counseled patients with HPV related cervical/anogenital cancer about HPV related HNC. Conclusions The rate of counseling on HPV infection, transmission, and vaccination in relation to HNC among PCPs is low. The most common reason is a lack of knowledge. Specialists rarely counsel patients with confirmed HPV-related cancer about other HPV-related malignancies. More research is needed on the relationship between different HPV-related cancers in order to better inform counseling practices

EGFR as a biomarker of smoking status and survival in oropharyngeal squamous cell carcinoma

Abstract Background This study aims to investigate EGFR as a prognostic biomarker in oropharyngeal squamous cell carcinoma (OPSCC). Methods OPSCC patients from retrospective (1998–2009) and prospective cohorts (2014–2017) were included. Retrospectively collected tumors were used to construct tissue microarrays (TMAs), which were stained with EGFR, p16, DAPI and Pan-cytokeratin, and digitally quantified. EGFR, CDKN2A and HPV E6/7 levels from prospectively collected OPSCC was measured by droplet digital PCR (ddPCR). Biomarkers were compared to patient covariates, factors and survival outcomes. Results A total of 249 patients were included retrospectively and 64 patients were enrolled prospectively. p16 status (p < 0.001), smoking above 10 pack years (p = 0.04), smoking above 20 pack years (p < 0.001), total EGFR tumor levels (p = 0.016), and high EGFR within high or low Ki67 tumor nuclear staining (p = 0.03) were found to be significant predictors of 5-year disease specific survival (DSS). A Cox proportional hazard model of DSS showed smoking status and eGFR expression to be dependent of each other on predicting 5-year DSS. ddPCR analysis showed a significant association between smoking status and EGFR levels. Conclusions Total EGFR tumor levels are predictive of 5-year DSS. EGFR levels correlate with. smoking and could be an objective marker for this disease etiology