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Aims: Intubated patients with methicillin-resistant Staphylococcus aureus pneumonia, fail optimized treatment with intravenous (IV) vancomycin (serum trough 15-20 μg/mL) in 38-79% of cases. Airway blood flow is diminished compared to alveoli and we hypothesized that vancomycin concentrations achieved in airway secretions are suboptimal and nonbactericidal. Targeted therapy by inhalation may overcome this deficit., Methods: Airway pharmacokinetics of optimized IV and inhaled vancomycin in infected clinically stable prolonged mechanically ventilated patients were measured. First, IV vancomycin was given until optimized concentrations were achieved (15-20 μg/mL), and, at the same time point, sputum vancomycin concentrations were measured. Then, sputum concentrations were re-assessed after 4 treatments of inhaled vancomycin (120 mg/2 mL) via a previously characterized nebulizing system that deposited 18 ± 2 mg in the lungs. Vancomycin post-distribution phase serum peak and trough concentrations were also obtained. Serum albumin was measured to assess binding to vancomycin., Results: Mean serum trough concentration was 18.4 ± 6.5 μg/mL. Sputum concentrations were affected by serum albumin. Only patients with severe hypoalbuminaemia had penetration of drug leading to therapeutic (15.7-17 μg/mL) sputum concentrations. Following inhaled vancomycin, sputum concentrations increased significantly to 199 ± 37.0 μg/mL (P = .002) exceeding minimum inhibitory concentration by 2 orders of magnitude., Conclusion: Despite optimized serum concentrations, patients with albumin near normal had suboptimal concentrations of vancomycin in their sputum. Inhaled therapy may be clinically important for successful treatment of ventilator-associated methicillin-resistant Staphylococcus aureus infection. Further studies of inhaled therapy are needed to define their role as adjunctive therapy in ventilator-associated pneumonia and as single therapy in tracheobronchitis., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Controversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC., Methods: A search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were analyzed using a linear regression model weighted by sample size. The regression coefficient and R 2 with 95% confidence interval were calculated by the bootstrapping approach., Results: Seven randomized clinical trials were identified for a total of 2385 patients. At the patient level, the R 2 of pCR and MPR with 2-year EFS were 0.82 (0.66-0.94) and 0.81 (0.63-0.93), respectively. The OR of 2-year EFS rates by response status was 0.12 (0.07-0.19) and 0.11 (0.05-0.22), respectively. For the 2-year OS, the R 2 of pCR and MPR were 0.55 (0.09-0.98) and 0.52 (0.10-0.96), respectively. At the trial level, the R 2 for the association of OR for response and HR for EFS was 0.58 (0.00-0.97) and 0.61 (0.00-0.97), respectively., Conclusions: Our analyses reveal a robust correlation between pCR and MPR with 2-year EFS but not OS. Trial-level surrogacy was moderate but imprecise. More mature follow-up and data to assess the impact of study crossover are needed., Competing Interests: Disclosure Drs. Hines and Cameron were supported by the National Institute for General Medical Sciences (T32 GM07019). Dr. Bestvina reports receiving institutional research funding from AstraZeneca and Bristol Myers Squibb; and advisory board membership/consulting for Amgen, AstraZeneca, Bristol Myers Squibb, CVS, Daiichi Sankyo, EMD Serono, Gilead, JNJ, Mirati, Novocure, Regeneron, Sanofi, Takeda, and Tempus. Dr. Garassino reports receiving personal financial support from AstraZeneca, Abion, Merck Sharp & DohmeInternational GmbH, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Incyte, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regeneron, Merck, Blueprint, Janssen, Sanofi, AbbVie, BeiGenius, Oncohost, and Medscape; received institutional financial support from Eli Lilly, Merck Sharp & Dohme, Pfizer (MISP), AstraZeneca, Merck Sharp & Dohme International GmbH, Bristol-Myers Squibb, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine, GlaxoSmithKline, and Spectrum pharmaceuticals; received other forms of support from AIRC, AIFA, Italian Moh, and Transcan; and received research funding from Horizon 2020. Dr. Veronesi has received honoraria from Ab Medica Spa, AstraZeneca, Roche, and Merck Sharp & Dohme outside the submitted work. Dr. Cascone reports receiving speaker fees/honoraria from ASCO Post, AstraZeneca, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Mark Foundation for Cancer Research, Medscape, OncLive, PeerView, Physicians’ Education Resource, Roche, and Society for Immunotherapy of Cancer; has advisory role/consulting fees from Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Genentech, Merck & Co., Pfizer, and Regeneron; and received institutional research funding from AstraZeneca and Bristol Myers Squibb. Dr. Taube reports having an advisory role or have received consulting fees from Akoya Biosciences, AstraZeneca, Bristol Myers Squibb, Merck & Co., Genentech, Lunaphore, Compugen, Elephas, and Regeneron; received institutional research funding from Bristol Myers Squibb and Akoya Biosciences; and received reagents and equipment loan and has stock options from Akoya Biosciences. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objective: Implantable hearing devices represent a modern and innovative solution for hearing restoration. Over the years, these high-tech devices have increasingly evolved but their use in clinical practice is not universally agreed in the scientific literature. Congresses, meetings, conferences, and consensus statements to achieve international agreement have been made. This work follows this line and aims to answer unsolved questions regarding examinations, selection criteria and surgery for implantable hearing devices., Materials and Methods: A Consensus Working Group was established by the Italian Society of Otorhinolaryngology. A method group performed a systematic review for each single question to identify the current best evidence on the topic and to guide a multidisciplinary panel in developing the statements., Results: Twenty-nine consensus statements were approved by the Italian Society of Otorhinolaryngology. These were associated with 4 key area subtopics regarding pre-operative tests, otological, audiological and surgical indications., Conclusions: This consensus can be considered a further step forward to establish realistic guidelines on the debated topic of implantable hearing devices., (Copyright © 2024 Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale, Rome, Italy.)

No clear evidence supports the advantage of fixed (up to two years (2yICI)) or continuous treatment (more than two years (prolonged ICI)) in cancer patients achieving stable disease or response on immune checkpoint inhibitors (ICIs). We performed a systematic review and meta-analysis of randomized controlled trials reporting the duration of ICIs (alone or in combination with standard of care (SoC)) across various solid tumors. Overall, we identified 28,417 records through database searching. Based on the eligibility criteria, 57 studies were identified for the quantitative synthesis, including 22,977 patients receiving ICIs (with or without SoC). Prolonged ICI correlated with better overall survival (OS) than 2yICI in patients with melanoma (HR:1.55; 95%CI: 1.22,1.98), while 2yICI-SoC led to better OS than prolonged ICI-SoC in patients with NSCLC (HR: 0.84; 95%CI: 0.68,0.89). Prospective randomized trials are needed to assess the most appropriate duration of ICIs. OBJECTIVE: No clear evidence supports the advantage of fixed (up to two years (2yICI)) or continuous treatment (more than two years (prolonged ICI)) in cancer patients achieving stable disease or response on immune checkpoint inhibitors (ICIs). Here, we assessed the optimal treatment duration for ICIs in solid tumors. CONCLUSIONS: Prolonged ICIs administration does not seem to improve the outcomes of patients with NSCLC an RCC., Competing Interests: Declaration of Competing Interest The authors indicate no financial relationship., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cefiderocol is a novel cephalosporin recently approved by the FDA to aid clinicians in the fight against multidrug-resistant (including carbapenem-resistant) gram-negative organisms. The primary objective of this study is to evaluate the 14- and 28-day mortality associated with cefiderocol. We performed a retrospective chart review of all adult patients admitted at Stony Brook University Hospital between October 2020 and December 2021 and received cefiderocol for at least 3 days. Patients were excluded if they received more than one course of cefiderocol therapy or remained hospitalized at the time of this study. A total of 22 patients met the inclusion criteria. The all-cause mortality on day 28 for all patients was 13.6%, whereas this rate for patients with BSI was 0%, with cUTI was 0% and with LRTI was 16.7%. The all-cause mortality on day 28 for patients who received the dual antibiotics (in conjunction with cefiderocol) was 0%, compared to 25% for patients who only received cefiderocol ( p = 0.25). We noted treatment failure in two patients (9.1%). Our findings suggest that cefiderocol could possibly be associated with lower all-cause mortality than previously thought. In our study, we did not find any significant difference between cefiderocol's use in combination with another antibacterial agent and its use as a monotherapy.

Objectives: The purpose of this study is to evaluate clinical outcomes in patients with critical COVID-19 pneumonia requiring invasive mechanical ventilation who were treated with tocilizumab DESIGN: Single-center retrospective cohort study SETTING: Stony Brook University Hospital, a 600-bed academic tertiary medical center in Suffolk County, New York PARTICIPANTS: Consecutive patients with COVID-19 confirmed by nasopharyngeal polymerase chain reaction (PCR) who were admitted to Stony Brook University Hospital between March 10 and April 2 2020 and required mechanical ventilation in any intensive care unit during their hospitalization EXPOSURE: Treatment with tocilizumab while intubated MAIN OUTCOME: Overall mortality 30 days from the date of intubation RESULTS: Forty-five patients received tocilizumab compared to seventy controls. Baseline demographic characteristics, inflammatory markers, treatment with corticosteroids, and sequential organ failure assessment (SOFA) scores were similar between the two cohorts. Patients who received tocilizumab had significantly lower Charlson co-morbidity index (2.0 vs 3.0,P = 0.01) than controls. There was a trend towards younger mean age in the tocilizumab exposed group (56.2 vs 60.6; P = 0.09). In logistic regression analysis there was no reduction in mortality associated with receipt of tocilizumab (odds ratio (OR) 1.04; 95% CI, 0.27-3.75). There was no observed increased risk of secondary infection in patients given tocilizumab (28.9 vs 25.7; OR 1.17; 95% CI, 0.51-2.71)., Conclusion: When controlling for age, severity of illness, and co-morbidities, tocilizumab was not associated with reduction in mortality in this retrospective cohort study of mechanically ventilated patients with COVID-19 pneumonia. Further studies are needed to determine the role of tocilizumab in the treatment of COVID-19., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Few prospective studies have assessed the role of bevacizumab and included a control arm with standard treatments for recurrent glioblastoma. We conducted a noncomparative phase II trial (AVAREG) to examine the efficacy of bevacizumab or fotemustine in this setting., Methods: Eligible patients were randomized 2:1 to receive bevacizumab (10 mg/kg every 2 weeks) or fotemustine (75 mg/m(2) on days 1, 8, and 15, then 100 mg/m(2) every 3 weeks after a 35-day interval). The primary endpoint was 6-month overall survival (OS) rate (OS-6). No formal efficacy comparison was made between the treatment arms., Results: Ninety-one patients were enrolled (bevacizumab n = 59; fotemustine n = 32). Median age was 57 years (range, 28-78 y), and patients had Eastern Cooperative Oncology Group performance status of 0 (n = 42), 1 (n = 35), or 2 (n = 14). OS-6 rate was 62.1% (95% confidence interval [CI], 48.4-74.5) with bevacizumab and 73.3% (95% CI, 54.1-87.7) with fotemustine. OS-6 rates were lower in bevacizumab-treated patients with MGMT promoter methylated tumors than in those with unmethylated tumors (50% and 85%, respectively), but higher in fotemustine-treated patients (87.5% and 50%, respectively). OS rates at 9 months were 37.9% (95% CI, 25.5-51.6) and 46.7% (95% CI, 28.3-65.7) with bevacizumab and fotemustine, respectively, and median OS was 7.3 months (95% CI, 5.8-9.2) and 8.7 months (95% CI, 6.3-15.4), respectively. Toxicity was as expected with the 2 agents., Conclusion: Single-agent bevacizumab may have a role in patients with recurrent glioblastoma., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

High-energy X-ray Bragg coherent diffraction imaging (BCDI) is a well established synchrotron-based technique used to quantitatively reconstruct the three-dimensional morphology and strain distribution in nanocrystals. The BCDI technique has become a powerful analytical tool for quantitative investigations of nanocrystals, nanotubes, nanorods and more recently biological systems. BCDI has however typically failed for fine nanocrystals in sub-100 nm size regimes - a size routinely achievable by chemical synthesis - despite the spatial resolution of the BCDI technique being 20-30 nm. The limitations of this technique arise from the movement of nanocrystals under illumination by the highly coherent beam, which prevents full diffraction data sets from being acquired. A solution is provided here to overcome this problem and extend the size limit of the BCDI technique, through the design of a novel stabilization method by embedding the fine nanocrystals into a silica matrix. Chemically synthesized FePt nanocrystals of maximum dimension 20 nm and AuPd nanocrystals in the size range 60-65 nm were investigated with BCDI measurement at beamline 34-ID-C of the APS, Argonne National Laboratory. Novel experimental methodologies to elucidate the presence of strain in fine nanocrystals are a necessary pre-requisite in order to better understand strain profiles in engineered nanocrystals for novel device development.

The prevalence of coronary artery disease (CAD) is high in hemodialysis (HD) patients. The aim of the study was to assess the diagnostic and prognostic value of dipyridamole stress echocardiography (DSE) in nondiabetic HD patients without signs or symptoms of CAD. In 51 out of 158 evaluated HD patients (21 females, age 67 [33-85] years, HD duration 38 [9-271] months), resting echocardiography and DSE were performed. Exclusion criteria were known CAD, diabetes mellitus, and pulmonary and oncologic pathologies. Logistic regression analysis was carried out to identify predictors of abnormal DSE response, while Cox regression analysis was performed to determine variables associated with total and cardiovascular mortality, after 43.3 (11-60) months of follow-up. Seven patients (14%) showed a positive response to DSE (DSE+). In 5/7, CAD was documented by angiography: All of them underwent coronary revascularization. DSE+ patients had significantly smaller body mass index than patients with a negative response (DSE-): 21.7 ± 1.9 vs. 25.1 ± 3.4 kg/m(2) (p = 0.018). During follow-up, 16 (31%) patients died. Older age hazard ratio [HR = 1.07; confidence interval (CI) = 1.01-1.12; p = 0.02] and higher plasma phosphate levels (HR = 10.41; CI = 2.30-47.17; p < 0.01) were predictors of total mortality. Male gender (HR = 22.7; CI = 1.45-354.4; p = 0.03), older age (HR = 1.24; CI = 1.03-1.50; p = 0.02), longer HD duration (HR = 1.13; CI = 1.01-1.26; p = 0.04), and positive response to DSE (HR = 5.82; CI = 1.04-32.65; p = 0.04) were associated with cardiovascular mortality. Ten percent of asymptomatic HD patients had significant CAD, but timely diagnosis did not seem to improve their prognosis. Total survival was associated with age and higher levels of plasma phosphate, while male gender, older age, longer HD duration, and DSE+ were predictors of cardiovascular mortality., (© 2011 The Authors; Hemodialysis International © 2011 International Society for Hemodialysis.)