Specific effects of bortezomib against experimental malignant pleural effusion: a preclinical study

BACKGROUND: We have previously shown that nuclear factor (NF)-κB activation of mouse Lewis lung carcinoma (LLC) specifically promotes the induction of malignant pleural effusions (MPE) by these cells. In the present studies we hypothesized that treatment of immunocompetent mice with bortezomib tailored to inhibit cancer cell NF-κB activation and not proliferation specifically inhibits MPE formation by LLC cells. RESULTS: Treatment of LLC cells with low concentrations of bortezomib (100 ng/ml) inhibited NF-κB activation and NF-κB-dependent transcription, but not cellular proliferation. Bortezomib treatment of immunocompetent C57BL/6 mice bearing LLC-induced subcutaneous tumors and MPEs significantly blocked tumor-specific NF-κB activation. However, bortezomib treatment did not impair subcutaneous LLC tumor growth, but was effective in limiting LLC-induced MPE. This specific effect was evidenced by significant reductions in effusion accumulation and the associated mortality and was observed with both preventive (beginning before MPE formation) and therapeutic (beginning after MPE establishment) bortezomib treatment. The favorable impact of bortezomib on MPE was associated with suppression of cardinal MPE-associated phenomena, such as inflammation, vascular hyperpermeability, and angiogenesis. In this regard, therapeutic bortezomib treatment had identical favorable results on MPE compared with preventive treatment, indicating that the drug specifically counteracts effusion formation. CONCLUSIONS: These studies indicate that proteasome inhibition tailored to block NF-κB activation of lung adenocarcinoma specifically targets the effusion-inducing phenotype of this tumor. Although the drug has limited activity against advanced solid lung cancer, it may prove beneficial for patients with MPE

Predictors of high flow oxygen therapy failure in COVID-19-related severe hypoxemic respiratory failure

Background: During COVID-19 pandemic, people who developed pneumonia and needed supplemental oxygen, where treated with low-flow oxygen therapy systems and non-invasive methods, including oxygen therapy using high flow nasal cannula (HFNC) and the application of bi-level or continuous positive airway pressure (BiPAP or CPAP). We aimed to investigate the outcomes of critical COVID-19 patients treated with HFNC and unveil predictors of HFNC failure. // Methods: We retrospectively enrolled patients admitted to COVID-19 wards and treated with HFNC for COVID-19-related severe hypoxemic respiratory failure. The primary outcome of this study was treatment failure, such as the composite of intubation or death during hospital stay. The association between treatment failure and clinical features was evaluated using logistic regression models. // Results: One hundred thirty-two patients with a median (IQR) PaO2/FiO2 ratio 96 (63–173) mmHg at HFNC initiation were studied. Overall, 45.4% of the patients were intubated. Hospital mortality was 31.8%. Treatment failure (intubation or death) occurred in 50.75% and after adjustment for age, gender, Charlson Comorbidity index (CCI) score and National Early Warning Score 2 (NEWS2) score on admission and PaO2/FiO2 ratio and acute respiratory distress syndrome (ARDS) severity at the time of HFNO initiation, it was significantly associated with the presence of dyspnea [adjusted OR 2.48 (95% CI: 1.01–6.12)], and higher Urea serum levels [adjusted OR 1.25 (95% CI: 1.03–1.51) mg/dL]. // Conclusions: HFNC treatment was successful in almost half of the patients with severe COVID-19- related acute hypoxemic respiratory failure (AHRF). The presence of dyspnea and high serum Urea levels on admission are closely related to HFNC failure

Increased Indoleamine-2,3-Dioxygenase Activity Is Associated With Poor Clinical Outcome in Adults Hospitalized With Influenza in the INSIGHT FLU003Plus Study

La depleción de triptófano (TRP) mediada por indolamina-2,3-dioxigenasa (IDO) tiene efectos antimicrobianos e inmunorreguladores. El aumento de las proporciones de quinurenina (KYN) a TRP (KT), que refleja una mayor actividad de IDO, se ha asociado con peores resultados de varias infecciones. Métodos: Realizamos un análisis de casos y controles (1: 2; emparejados por edad y sexo) de adultos hospitalizados con influenza A (H1N1) pdm09 con progresión de la enfermedad definida por el protocolo (fallecidos / transferidos a UCI / ventilación mecánica) después de la inscripción (casos) o sobrevivió sin progresión (controles) durante 60 días de seguimiento. Se utilizó la regresión logística condicional para analizar la relación entre el cociente KT basal y otros metabolitos y la progresión de la enfermedad. Resultados: se incluyeron 32 casos y 64 controles con una mediana de edad de 52 años; El 41% eran mujeres y la mediana de duración de los síntomas de la influenza antes de la hospitalización fue de 8 y 6 días para los casos y los controles, respectivamente ( p = 0,04). Las razones medianas de KT al inicio fueron 2 veces más altas en los casos (0.24 mM / M; IQR, 0.13-0.40) que en los controles (0.12; IQR, 0.09-0.17; P ≤ .001). Cuando se dividió en terciles, el 59% de los casos frente al 20% de los controles tenían proporciones KT en el tercil más alto (0,21-0,84 mM / M). Cuando se ajustó por la duración de los síntomas, la razón de probabilidades para la progresión de la enfermedad para aquellos en los terciles más altos frente a los más bajos de la razón KT fue 9,94 (IC del 95%, 2,25-43,90). Conclusiones: Un índice alto de KT se asoció con un resultado desfavorable en adultos hospitalizados con influenza A (H1N1) pdm09. La utilidad clínica de este biomarcador en este entorno merece una mayor exploración.Background. Indoleamine-2,3-dioxygenase (IDO) mediated tryptophan (TRP) depletion has antimicrobial and immuno-regulatory effects. Increased kynurenine (KYN)-to-TRP (KT) ratios, reflecting increased IDO activity, have been associated with poorer outcomes from several infections. Methods. We performed a case-control (1:2; age and sex matched) analysis of adults hospitalized with influenza A(H1N1) pdm09 with protocol-defined disease progression (died/transferred to ICU/mechanical ventilation) after enrollment (cases) or survived without progression (controls) over 60 days of follow-up. Conditional logistic regression was used to analyze the relationship between baseline KT ratio and other metabolites and disease progression. Results. We included 32 cases and 64 controls with a median age of 52 years; 41% were female, and the median durations of influenza symptoms prior to hospitalization were 8 and 6 days for cases and controls, respectively (P = .04). Median baseline KT ratios were 2-fold higher in cases (0.24 mM/M; IQR, 0.13–0.40) than controls (0.12; IQR, 0.09–0.17; P ≤ .001). When divided into tertiles, 59% of cases vs 20% of controls had KT ratios in the highest tertile (0.21–0.84 mM/M). When adjusted for symptom duration, the odds ratio for disease progression for those in the highest vs lowest tertiles of KT ratio was 9.94 (95% CI, 2.25–43.90). Conclusions. High KT ratio was associated with poor outcome in adults hospitalized with influenza A(H1N1)pdm09. The clinical utility of this biomarker in this setting merits further exploration

Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial

BACKGROUND: Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. METHODS: In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. FINDINGS: From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). INTERPRETATION: When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. FUNDING: US National Institutes of Health

Octreotide and chylothorax

Purpose of review This article reviews the current literature concerning the role of somatostatin and its synthetic analogue, octreotide, in the treatment of chylothorax. Record findings Management of chylothorax includes evacuation of the pleural cavity through a chest tube to alleviate dyspnoea, and dietary fat restriction aimed at reducing lymph flow. When these measures fail to control lymph flow, surgical interventions are employed to achieve definite closure of the thoracic duct leak. Several case reports and series have shown that octreotide is safe and probably effective in both children and adults with chylothorax of different origins. The property of somatostatin and octreotide to induce leak closure is attributed to a decelerating effect on lymph flow, although their exact mechanism of action is not well defined. In successful cases, a substantial reduction of lymph drainage through the chest tube is evident within the first few days of commencing the drug, and treatment. lasts for 1-2 weeks. Treatment failure has been also reported, however. Summary Accumulating evidence suggests that octreotide is a putative novel therapeutic intervention for chylothorax. It, is imperative that randomized controlled studies are conducted in order to fully elucidate the efficacy and safety of this treatment

Drug resistance in patients with tuberculous pleural effusions

Purpose of review To summarize data regarding categories, detection methods, prevalence and patterns of drug resistance among patients with tuberculous pleural effusion (TPE) and to comment on the management of suspected drug-resistant TPE. Recent findings Pleural and pulmonary tuberculosis (TB) present similar patterns of drug resistance. Approximately 10% and 6-10% of pleural Mycobacterium tuberculosis isolates are resistant to at least one first-line anti-TB drug or at least isoniazid, respectively. The prevalence of multidrug-resistant-pleural and extensively drug-resistant-pleural TB is 1-3% and 0-1%, respectively. Summary Although guidelines suggest the empirical standard anti-TB regimen (i.e. 2 months of isoniazid, rifampicin, pyrazinamide and ethambutol followed by 4 months of isoniazid and rifampicin) for TPE treatment, the data regarding drug resistance among TPE patients are limited. The few studies examining the issue report a notable drug resistance. In suspected drug-resistant TPE, every effort is warranted to isolate M. tuberculosis to perform drug susceptibility testing and provide guided therapy. For this purpose, the use of cultures or molecular methods with pleural biopsies is superior to their use in pleural fluid. If still M. tuberculosis cannot be detected, prolonged administration of ethambutol with isoniazid and rifampicin during the continuation phase of treatment might be considered

Can pharmacologic agents speed the rate of resorption of pleural fluid?

Purpose of review Pleural effusion is a common clinical problem resulting from a wide range of diseases. Treatment options include targeting the primary cause or, in persistent cases, invasive removal of the excess fluid from the pleural cavity. In this review, we summarize the experimental data concerning pharmacological agents that influence pleural fluid resorption and examine their potential as a novel noninvasive treatment strategy. Recent findings Recently published evidence indicates that adrenergic agents and corticosteroids can increase pleural fluid clearance from the cavity. On the contrary, paracetamol and certain nonsteroid anti-inflammatory drugs can impede fluid outflow. These concepts are based on data extracted by in-vivo studies using provoked hydrothoraces in rabbits and mice, as well as by ex-vivo electrophysiological experiments using sheep and human pleural tissue. Summary In conclusion, the available experimental data indicate that certain pharmacological agents may impact fluid resorption, thus affecting pleural fluid accumulation and the rate of pleural effusion resolution