Treatment of chronic-phase chronic myeloid leukemia in patients randomized to dasatinib or imatinib after suboptimal responses to three months of imatinib therapy: final 5-year results from DASCERN.

Early molecular response (EMR) at 3 months is predictive of improved overall survival (OS) and progression-free survival (PFS) in patients with chronic myeloid leukemia in the chronic phase (CML-CP). Although about one-third of patients treated with first-line imatinib do not achieve EMR, long-term OS and PFS are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved EMR after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib versus imatinib (77% vs. 44%, P.

Treatment-free remission after dasatinib in patients with chronic myeloid leukaemia in chronic phase with deep molecular response: Final 5-year analysis of DASFREE.

Patients with chronic myeloid leukaemia in chronic phase (CML-CP) who have a sustained deep molecular response (DMR) are eligible to discontinue treatment and attempt treatment-free remission (TFR). In the DASFREE study (ClinicalTrials.gov; NCT01850004), the 2-year TFR rate after dasatinib discontinuation was 46%; here we present the 5-year update. Patients with a stable DMR after ≥2 years of dasatinib therapy discontinued treatment and were followed for 5 years. At a minimum follow-up of 60 months, in 84 patients discontinuing dasatinib, the 5-year TFR rate was 44% (n = 37). No relapses occurred after month 39 and all evaluable patients who relapsed and restarted dasatinib (n = 46) regained a major molecular response in a median of 1.9 months. The most common adverse event during the off-treatment period was arthralgia (18%, 15/84); a total of 15 withdrawal events were reported in nine patients (11%). At the 5-year final follow-up, almost half of the patients who discontinued dasatinib after a sustained DMR maintained TFR. All evaluable patients who experienced a relapse quickly regained a DMR after restarting dasatinib, demonstrating that dasatinib discontinuation is a viable and potentially long-term option in patients with CML-CP. The safety profile is consistent with the previous report.

Event studies in international finance research.

Event studies are widely used in finance research to investigate the implications of announcements of corporate initiatives, regulatory changes, or macroeconomic shocks on stock prices. These studies are often used in a single-country setting (usually the U.S.), but little work has yet been conducted in an international context, perhaps due to the complexities inherent in implementing cross-country studies. This paper explores the methodological challenges of conducting event studies in international finance research. We emphasize how scholars should choose an event, select the study period (short vs. long term), estimate abnormal returns, infer statistically whether the event under consideration produces a reliable price reaction, and explore the role of formal and informal institutions in explaining cross-country differences in price reactions. We also provide an extension of event studies to an important but less studied asset class in an international setting - the fixed-income market. We conclude by offering practical recommendations for researchers conducting cross-country finance event studies and identifying opportunities for future research. Given the increasing number of global events, such as the COVID-19 pandemic, Brexit, and the Paris and Trans-Pacific Partnership agreements, we believe our paper is especially timely.

Les études d'événements sont largement utilisées dans la recherche financière pour étudier les implications des annonces d'initiatives d'entreprises, de changements réglementaires ou de chocs macroéconomiques sur les prix des actions. Ces études sont souvent utilisées dans le cadre d'un seul pays (généralement les États-Unis), mais peu de travaux ont encore été menés dans un contexte international, probablement en raison des complexités inhérentes à la mise en oeuvre d'études transnationales. Cet article explore les défis méthodologiques de la conduite d'études d'événements dans la recherche en finance internationale. Nous mettons l'accent sur la manière dont les chercheurs doivent choisir un événement, sélectionner la période d'étude (court ou long terme), estimer les rendements anormaux, déduire statistiquement si l'événement considéré produit une réaction fiable des prix, et explorer le rôle des institutions formelles et informelles dans l'explication des réactions des prix à travers les réactions des prix. Nous proposons également une extension des études d'événements à une classe d'actifs importante mais moins étudiée dans un contexte international - le marché des titres à revenu fixe. Nous concluons en offrant des recommandations pratiques aux chercheurs qui mènent des études d'événements financiers transnationaux et en identifiant les possibilités de recherches futures. Compte tenu du nombre croissant d'événements mondiaux, tels que la pandémie de COVID-19, le Brexit et les accords de Paris et de partenariat transpacifique, nous pensons que notre article est particulièrement opportun.

Los estudios de eventos son ampliamente usados en la investigación financiera para indagar las implicaciones de los anuncios de iniciativas empresariales, cambios regulatorios o choques macroeconómicos en los precios de las acciones. Estos estudios se utilizan a menudo en el marco de un solo país (normalmente EE.UU.), pero todavía se han realizado pocos trabajos en un contexto internacional, quizá debido a las complejidades inherentes a la realización de estudios transfronterizos. Este artículo explora los retos metodológicos de llevar a cabo estudios de eventos en la investigación financiera internacional. Enfatizamos cómo los académicos deben elegir un evento, seleccionar el período de estudio (corto frente a largo plazo), estimar los rendimientos anormales, inferir estadísticamente si el evento en cuestión produce una reacción fiable de los precios, y explorar el papel de las instituciones formales e informales para explicar las diferencias entre países en las reacciones de los precios. También ofrecemos una extensión de los estudios de eventos a una clase de activos importante pero menos estudiada en un entorno internacional: el mercado de renta fija. Concluimos ofreciendo recomendaciones prácticas para los investigadores que realizan estudios de eventos financieros entre países e identificando oportunidades para futuras investigaciones. Dado el creciente número de eventos mundiales, como la pandemia del COVID-19, el Brexit y el Acuerdo de París y el Acuerdo de Asociación Transpacífico, creemos que nuestro artículo es especialmente oportuno.

Estudos de eventos são amplamente utilizados em pesquisas sobre finanças para investigar as implicações de anúncios de iniciativas corporativas, mudanças regulatórias ou choques macroeconômicos nos preços das ações. Esses estudos são frequentemente usados em um único país (geralmente os EUA), mas pouco trabalho foi realizado em um contexto internacional, talvez devido às complexidades inerentes à implementação de estudos entre países. Este artigo explora os desafios metodológicos na condução de estudos de eventos na pesquisa de finanças internacionais. Enfatizamos como acadêmicos devem escolher um evento, selecionar o período de estudo (curto prazo versus longo prazo), estimar retornos anormais, inferir estatisticamente se o evento em análise produz uma reação de preço confiável e explorar o papel de instituições formais e informais na explicação de diferenças entre países nas reações de preços. Também fornecemos uma extensão dos estudos de eventos para uma classe de ativos importante, mas menos estudada em um cenário internacional ­ o mercado de renda fixa. Concluímos oferecendo recomendações práticas para pesquisadores que realizam estudos de eventos em finanças entre países e identificando oportunidades para pesquisas futuras. Dado o número crescente de eventos globais, como a pandemia de COVID-19, Brexit e os acordos de Paris e parceria Trans-Pacific, acreditamos que nosso artigo é especialmente oportuno.

Consecutive Severe Orofacial Complications in Intensive Care Unit Patients: Quincke's Disease and Macroglossia due to Prolonged Prone Positioning for Management of Acute Respiratory Distress Syndrome.

Critically ill patients admitted into the intensive care units are susceptible to a wide array of complications that can be life-threatening, or lead to long-term complications. Some complications are inherent to the patient's condition and others are related to therapeutics or care procedure. The prolonged prone positioning and mechanical ventilation devices are the first risk factors for orofacial complications. We report the case of a 47-year-old male patient, with a history of sleep apnoea syndrome, morbid obesity (body mass index of 43 kg/m2), and gastroesophageal reflux disease, presented to the emergency department with recent otorhinolaryngological symptoms of dysphonia and exertional dyspnoea lasting two days, and complicated with Quincke's disease. First-line treatment consisted of a compilation of intravenous antihistamines and corticosteroids. The patient's condition worsened. He developed an acute respiratory distress syndrome secondary to ventilator-acquired pneumonia with prone positioning ventilation, complicated by severe macroglossia. Soaked gauze dressings were placed around his tongue. Progressively, the size of his tongue reduced. LEARNING POINTS: Intensive care unit (ICU) patients are susceptible to a wide array of life-threatening complications that can be linked.Oral severe acquired Quincke's disease is an isolated form of angioneurotic oedema that is induced by several factors including gastroesophageal reflux disease, sleep apnoea, inhalation exposure, or drug reactions. Macroglossia is rare life-threatening complication due to prolonged prone positioning of unknown pathogenesis. An experienced critical care staff with standardised protocol is needed to prevent such a complication.Because of possible consecutive severe orofacial complications, prolonged prone positioning for management of acute respiratory distress syndrome (ARDS) is not recommended in patients with inaugural oral angioedema.

Safety and efficacy of fedratinib, a selective oral inhibitor of Janus kinase-2 (JAK2), in patients with myelofibrosis and low pretreatment platelet counts.

Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, is approved for patients with myelofibrosis (MF) and platelet counts ≥50 × 109 /l, based on outcomes from the phase 3, placebo-controlled JAKARTA trial in JAK-inhibitor-naïve MF, and the phase 2, single-arm JAKARTA2 trial in patients previously treated with ruxolitinib. We evaluated the efficacy and safety of fedratinib 400 mg/day in patients with baseline platelet counts 50 to <100 × 109 /l ("Low-Platelets" cohorts), including 14/96 patients (15%) in JAKARTA and 33/97 (34%) in JAKARTA2. At 24 weeks, spleen response rates were not significantly different between the Low-Platelets cohort and patients with baseline platelet counts ≥100 × 109 /l ("High-Platelets" cohort), in JAKARTA (36% vs. 49%, respectively; p = 0.37) or JAKARTA2 (36% vs. 28%; p = 0.41). Symptom response rates were also not statistically different between the Low- and High-Platelets cohorts. Fedratinib was generally well-tolerated in both platelet-count cohorts. New or worsening thrombocytopaenia was more frequent in the Low-Platelets (44%) versus the High-Platelets (9%) cohort, but no serious thrombocytopaenia events occurred. Thrombocytopaenia was typically managed with dose modifications; only 3/48 Low-Platelets patients discontinued fedratinib due to thrombocytopaenia. These data indicate that fedratinib 400 mg/day is safe and effective in patients with MF and low pretreatment platelet counts, and no initial fedratinib dose adjustment is required for these patients.

Association of high SARS-CoV-2 RNAemia with diabetes and mortality in critically ill COVID-19 patients.

It has been suggested that during the period of respiratory worsening of severe COVID-19 patients, viral replication plays a less important role than inflammation. Using the droplet-based digital PCR (ddPCR) for precise quantification of plasma SARS-CoV-2 viral load (SARS-CoV-2 RNAemia), we investigated the relationship between plasma viral load, comorbidities, and mortality of 122 critically ill COVID-19 patients. SARS-CoV-2 RNAemia was detected by ddPCR in 90 (74%) patients, ranging from 70 to 213,152 copies per mL. A high (>1 000 copies/ml) or very high (>10,000 copies/ml) SARS-Cov-2 RNAemia was observed in 46 patients (38%), of which 26 were diabetic. Diabetes was independently associated with a higher SARS-CoV-2 RNAemia. In multivariable logistic regression models, SARS-CoV-2 RNAemia was strongly and independently associated with day-60 mortality. Early initiation of antiviral therapies might be considered in COVID-19 critically ill patients with high RNAemia.

Perception and adaptation of pastoralists to climate variability and change in Morocco's arid rangelands.

Since the late 1970s, extensive livestock production in the high plateaus of Eastern Morocco, particularly of small ruminants, has been seriously threatened by climate change (CC). Negative impacts include reduction in rangeland forage production and water availability, increased poverty and inequality, and increased degradation of rangelands. Different categories of pastoralists have adopted different combinations of adaptation strategies, but the factors influencing adoption have not to date been investigated. This paper aims to identify the perceptions of pastoralists on CC, to analyze the adaptive responses of different wealth categories, and to determine the factors affecting the adoption of adaptation measures. The Mann-Kendall, Pettitt and Buishand tests and the standardized precipitation index were used to analyze the climate data. Data on adaptation were examined using the chi-square homogeneity test, Kruskal-Wallis test and binary logistic regression. The observed climate trends perfectly corroborated pastoralists' perceptions of significant changes in their local climate since the 1970s: a considerable decrease in annual rainfall and an increase in temperature and frequency of droughts and high winds. There were significant differences (Chi square = 7.603, p = 0.022, df = 2) between small, medium and large pastoralists in the frequency adoption of adaptation strategies, especially between small and large pastoralists (U statistic = 16.000, p = 0.009). The distribution of most adaptation actions also differed significantly between these two groups. Wealthier pastoralists have adopted a greater range of strategies, while poorer pastoralists have less diverse adaptation portfolios, and are more likely to adopt less advantageous strategies such as casual labor. The adoption of adaptation practices was significantly influenced by equipment, educational level, household size, herd size, training received, CC perceptions and agroecological setting. Public interventions to improve the adaptive capacity of pastoralists in Morocco's arid rangelands should be geared towards addressing these determinants and should prioritise small-scale pastoralists.

Transesophageal echocardiography for cardiovascular risk estimation in patients with sepsis and new-onset atrial fibrillation: a multicenter prospective pilot study.

BACKGROUND: Echocardiographic parameters have been poorly investigated for estimating cardiovascular risk in patients with sepsis and new-onset atrial fibrillation. We aim to assess the prevalence of transesophageal echocardiographic abnormalities and their relationship with cardiovascular events in mechanically ventilated patients with sepsis and new-onset atrial fibrillation. METHODS: In this prospective multicenter pilot study, left atrial/left atrial appendage (LA/LAA) dysfunction, severe aortic atheroma, and left ventricular systolic dysfunction were assessed using an initial transesophageal echocardiographic study, which was repeated after 48-72 h to detect LA/LAA thrombus formation. The study outcome was a composite of cardiovascular events at day 28, including arterial thromboembolic events (ischemic stroke, non-cerebrovascular arterial thromboembolism, LA/LAA thrombus), major bleeding, and all-cause death. RESULTS: The study population comprised 94 patients (septic shock 63%; 35% women; median age 69 years). LA/LAA dysfunction, severe aortic atheroma, and left ventricular systolic dysfunction were detected in 17 (19%), 22 (24%), and 27 (29%) patients, respectively. At day 28, the incidence of cardiovascular events was 46% (95% confidence interval [CI]: 35 to 56). Arterial thromboembolic events and major bleeding occurred in 7 (7%) patients (5 ischemic strokes, 1 non-cerebrovascular arterial thromboembolism, 2 left atrial appendage thrombi) and 18 (19%) patients, respectively. At day 28, 27 patients (29%) died. Septic shock (hazard ratio [HR]: 2.36; 95% CI 1.06 to 5.29) and left ventricular systolic dysfunction (HR: 2.06; 95% CI 1.05 to 4.05) were independently associated with cardiovascular events. CONCLUSIONS: Transesophageal echocardiographic abnormalities are common in mechanically ventilated patients with sepsis and new-onset atrial fibrillation, but only left ventricular systolic dysfunction was associated with cardiovascular events at day 28.

Sustained low-efficiency dialysis with regional citrate anticoagulation for patients with liver impairment in intensive care unit: A single-center experience.

Regional citrate anticoagulation (RCA) is a recommended method for extracorporeal circuit anticoagulation during renal replacement therapy (RRT). Increased risk of citrate accumulation by default of hepatic metabolism limits its use in liver failure patients. A Catot /Caion ratio ≥2.5 is established as an indirect control of plasma citrate poisoning. To investigate the safety of RCA in patients with liver impairment during sustained low-efficiency dialysis (SLED), we conducted a retrospective study of 41 patients with acute or chronic hepatocellular failure requiring RRT between January 2014 and June 2015 in the intensive care unit of the Groupe Hospitalier Sud Ile de France. Sixty-seven SLED sessions were performed. At admission, 32 (78%) patients had acute liver dysfunction and nine (22%) patients had cirrhosis with a median MELD score of 27 (IQR: 18.8, 42.0). Despite a majority of poor prognosis patients (SAPS-II (Simplified Acute Physiology Score II) score 71 [IQR: 58; 87]), with acute liver impairment as a part of multi-organ failure, no dosage of Catot /Caion ratio after SLED sessions exceeded the critical threshold of 2.5. Of the 63 complete sessions, neither dyscalcemia nor major dysnatremia, nor extracorporeal circuit thrombosis were noticed. Observed acid-base disturbances (16.4%) were not significantly correlated with the Catot /Caion ratio (P = .2155). In this retrospective study using RCA during intermittent RRT in ICU patients with severe liver dysfunction, we did not observe any citrate accumulation but monitoring of acid-base status and electrolytes remains necessary to ensure technique safety.

Automated vs. conventional ventilation in the ICU: a randomized controlled crossover trial comparing blood oxygen saturation during daily nursing procedures (I-NURSING).

BACKGROUND: Hypoxia is common during daily nursing procedures (DNPs) routinely performed on mechanically ventilated patients. The impact of automated ventilation on the incidence and severity of blood oxygen desaturation during DNPs remains unknown. METHODS: A prospective randomized controlled crossover trial was carried out in a French intensive care unit to compare blood oxygen pulse saturation (SpO2) during DNPs performed on patients mechanically ventilated in automated and conventional ventilation modes (AV and CV, respectively). All patients with FiO2 ≤ 60% and without prone positioning or neuromuscular blocking agents were included. Patients underwent two DNPs on the same day using AV (INTELLiVENT-ASV®) and CV (volume control, biphasic positive airway pressure, or pressure support ventilation) in a randomized order. The primary outcome was the percentage of time spent with SpO2 in the acceptable range of 90-95% during the DNP. RESULTS: Of the 265 included patients, 93% had been admitted for a medical pathology, the majority for acute respiratory failure (52%). There was no difference between the two periods in terms of DNP duration, sedation requirements, or ventilation parameters, but patients had more spontaneous breaths and lower peak airway pressures during the AV period (p <  0.001). The percentage of time spent with SpO2 in the acceptable range during DNPs was longer in the AV period than in the CV period (48 ± 37 vs. 43 ± 37, percentage of DNP period; p = 0.03). After adjustment, AV was associated with a higher number of DNPs carried out with SpO2 in the acceptable range (odds ratio, 1.82; 95% CI, 1.28 to 2.6; p = 0.001) and a lower incidence of blood oxygen desaturation ≤ 85% (adjusted odds ratio, 0.50; 95% CI, 0.30 to 0.85; p = 0.01). CONCLUSION: AV appears to reduce the incidence and severity of blood oxygen desaturation during daily nursing procedures (DNPs) in comparison to CV. TRIAL REGISTRATION: This study was registered in clinical-trial.gov ( NCT03176329 ) in June 2017.

Duration of prone position sessions: a prospective cohort study.

BACKGROUND: Prone position (PP) is highly recommended in moderate-to-severe ARDS. However, the optimal duration of PP sessions remains unclear. We searched to evaluate the time required to obtain the maximum physiological effect, and to search for parameters related to patient survival in PP. METHODS AND RESULTS: It was a prospective, monocentric, physiological study. We included in the study all prone-positioned patients in our ICU between June 2016 and January 2018. Pulmonary mechanics, data from volumetric capnography and arterial blood gas were recorded before prone positioning, 2 h after proning, before return to a supine position (SP) and 2 h after return to SP. Dynamic parameters were recorded before proning and every 30 min during the session until 24 h. 103 patients (ARDS 95%) were included performing 231 PP sessions with a mean length of 21.5 ± 5 h per session. They presented a significant increase in pH, static compliance and PaO2/FiO2 with a significant decrease in PaCO2, Pplat, phase 3 slope of the volumetric capnography, PetCO2, VD/VT-phy and ΔP. The beneficial physiological effects continued after 16 h of PP and at least up to 24 h in some patients. The evolution of the respiratory parameters during the first session and also during the pooled sessions did not find any predictor of response to PP, whether before, during or 2 h after the return in SP. CONCLUSIONS: PP sessions should be prolonged at least 24 h and be extended in the event that the PaO2/FiO2 ratio at 24 h remains below 150, especially since no criteria can predict which patient will benefit or not from it. Trial registration The trial has been registered on 28 June 2016 in ClinicalTrials.gov (NCT02816190) (https://clinicaltrials.gov/ct2/show/NCT02816190?term=propocap&rank=1).

Dasatinib vs. imatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) who have not achieved an optimal response to 3 months of imatinib therapy: the DASCERN randomized study.

Early molecular response is associated with improved probability of deep molecular response and superior survival in patients with CML-CP. However, ~1 in 3 patients on first-line imatinib do not achieve this threshold. The phase 2b DASCERN trial (NCT01593254) assessed the outcome of early switch to dasatinib in patients with suboptimal response to first-line imatinib. Adult patients with CML-CP were randomized (2:1) to receive 100 mg dasatinib (n = 174) or continue imatinib at ≥400 mg (n = 86). The primary endpoint was the rate of major molecular response (MMR) at 12 months, which was 29% (dasatinib) and 13% (imatinib; P = 0.005). After ≥2 years of follow-up, 45 patients (52%) randomized to continue imatinib had crossed over to dasatinib. Considering treatment crossover, the 2-year cumulative MMR rate was 64% with dasatinib and 41% with imatinib (66% and 67%, respectively by intent-to-treat). Adverse events were consistent with the established safety profiles of both drugs. The results of this first prospective study support early monitoring of patients treated with first-line imatinib, and suggest that switching to dasatinib in cases of suboptimal response may offer clinical benefit. Further follow-up is needed to assess the long-term clinical benefit of early switching.

Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study.

Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is considered a feasible option, especially with the ability of second-generation tyrosine kinase inhibitors to induce higher rates of sustained deep molecular response (DMR). DASFREE is an open-label, single-arm, multicenter phase II trial assessing TFR after dasatinib discontinuation in patients with CML-CP (N = 84). At 2 years, TFR was 46% in all patients. Multivariate analyses revealed statistically significant associations between 2-year TFR and duration of prior dasatinib (≥median; p = .0051), line of therapy (first line; p = .0138), and age (>65 years; p = .0012). No disease transformation occurred, and the most common adverse events experienced off treatment were musculoskeletal (observed in 30 patients); however, dasatinib withdrawal events were reported in nine patients (11%) by the investigator. Overall, these findings support the feasibility of discontinuing dasatinib for patients with CML-CP in sustained DMR in the first line and beyond.

Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial.

BACKGROUND: The randomized phase 3 ELOQUENT-2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab plus lenalidomide and dexamethasone (ELd) versus lenalidomide and dexamethasone (Ld) in relapsed/refractory multiple myeloma (RRMM), and to date, has the longest follow-up of any monoclonal antibody in patients with RRMM. METHODS: In this extended 4-year follow-up of the ELOQUENT-2 trial, the coprimary endpoints of progression-free survival (PFS) and overall response rate as well as the secondary endpoint of overall survival were assessed. In the absence of head-to-head trials comparing Ld-based triplet regimens to guide treatment selection, 4 randomized controlled trials-ELOQUENT-2, ASPIRE, TOURMALINE-MM1, and POLLUX-were indirectly compared to provide insight into the relative efficacy of these regimens in RRMM. RESULTS: Data at 4 years were consistent with 2- and 3-year follow-up data: ELd reduced the risk of disease progression/death by 29% versus Ld (hazard ratio, 0.71) while maintaining safety. The greatest PFS benefit among the assessed subgroups was observed in patients at the median time or further from diagnosis (≥3.5 years) with 1 prior line of therapy, who had a 44% reduction in the risk of progression/death, and in patients in the high-risk category, who had a 36% reduction in favor of ELd. This regimen also showed a relative PFS benefit that was maintained beyond 50 months. CONCLUSIONS: The sustained PFS benefit and long-term safety of ELd at 4 years, similar to those observed at 2 and 3 years, support ELd as a valuable therapeutic option for the long-term treatment of patients with RRMM.

Does metformin exposure before ICU stay have any impact on patients' outcome? A retrospective cohort study of diabetic patients.

BACKGROUND: Impact of metformin exposure before ICU stay remains controversial. Metformin is thought to induce lactic acidosis and haemodynamic instability but may reduce ICU mortality. We evaluated its influence on outcome in diabetic patients admitted in the ICU and then compared two different populations based on the presence of septic shock. METHODS: We conducted a retrospective cohort study in a 24-bed French ICU between October 2010 and December 2013, including all ICU-admitted diabetic patients. RESULTS: Among 635 diabetic patients admitted during the study period, 131 (21%) were admitted with septic shock. Multivariate analysis showed no difference in hospital mortality in all metformin users (OR 0.75 [95% CI 0.44-1.28]; p = 0.29), except in the septic shock subgroup (OR 0.61; 95% CI [0.37-0.99]; p = 0.04) despite higher vasopressor dosages in the first hours after shock onset. Blood lactate level was higher in metformin users than in non-metformin users in all patients (p < 0.001), in septic shock patients (p < 0.001) and in patients without kidney injury (p < 0.001). Metformin users did not have more septic shock from unknown aetiology (p = 0.65) or unknown pathogen (p = 0.99). CONCLUSIONS: Metformin use before admission to ICU did not affect in-hospital mortality. However, for patients with septic shock, mortality was lower, despite worse clinical presentation on admission. Blood lactate levels were always higher with or without septic shock and indifferent of kidney function.

Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease.

BACKGROUND: There are no effective treatments or validated clinical response markers in systemic sclerosis (SSc). We assessed imaging biomarkers and performed gene expression profiling in a single-arm open-label clinical trial of tyrosine kinase inhibitor dasatinib in patients with SSc-associated interstitial lung disease (SSc-ILD). METHODS: Primary objectives were safety and pharmacokinetics. Secondary outcomes included clinical assessments, quantitative high-resolution computed tomography (HRCT) of the chest, serum biomarker assays and skin biopsy-based gene expression subset assignments. Clinical response was defined as decrease of >5 or >20% from baseline in the modified Rodnan Skin Score (MRSS). Pulmonary function was assessed at baseline and day 169. RESULTS: Dasatinib was well-tolerated in 31 patients receiving drug for a median of nine months. No significant changes in clinical assessments or serum biomarkers were seen at six months. By quantitative HRCT, 65% of patients showed no progression of lung fibrosis, and 39% showed no progression of total ILD. Among 12 subjects with available baseline and post-treatment skin biopsies, three were improvers and nine were non-improvers. Improvers mapped to the fibroproliferative or normal-like subsets, while seven out of nine non-improvers were in the inflammatory subset (p = 0.0455). Improvers showed stability in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), while both measures showed a decline in non-improvers (p = 0.1289 and p = 0.0195, respectively). Inflammatory gene expression subset was associated with higher baseline HRCT score (p = 0.0556). Non-improvers showed significant increase in lung fibrosis (p = 0.0313). CONCLUSIONS: In patients with SSc-ILD dasatinib treatment was associated with acceptable safety profile but no significant clinical efficacy. Patients in the inflammatory gene expression subset showed increase in skin fibrosis, decreasing pulmonary function and worsening lung fibrosis during the study. These findings suggest that target tissue-specific gene expression analyses can help match patients and therapeutic interventions in heterogeneous diseases such as SSc, and quantitative HRCT is useful for assessing clinical outcomes. TRIAL REGISTRATION: Clinicaltrials.gov NCT00764309.

Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth.

The randomized phase III ELOQUENT-2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab + lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) in relapsed/refractory multiple myeloma. ELd reduced the risk of disease progression/death by 30% versus Ld (hazard ratio [HR] 0·70). Median time from diagnosis was 3·5 years. We present extended 3-year follow-up data. Endpoints included progression-free survival (PFS), overall response rate (ORR) and interim overall survival (OS). Exploratory post-hoc analyses included impact of time from diagnosis and prior lines of therapy on PFS, and serum M-protein dynamic modelling. ORR was 79% (ELd) and 66% (Ld) (P = 0·0002). ELd reduced the risk of disease progression/death by 27% versus Ld (HR 0·73; P = 0·0014). Interim OS demonstrated a trend in favour of ELd (P = 0·0257); 1-, 2- and 3-year rates with ELd versus Ld were: 91% versus 83%, 73% versus 69% and 60% versus 53%. In patients with ≥ median time from diagnosis and one prior therapy, ELd resulted in a 53% reduction in the risk of progression/death versus Ld (HR 0·47). Serum M-protein dynamic modelling showed slower tumour regrowth with ELd. Adverse events were comparable between arms. ELd provided a durable and clinically relevant improvement in efficacy, with minimal incremental toxicity.

Efficiency of goal-directed oxygen delivery in ICU patients.

BACKGROUND: Current clinical practice guidelines promote a goal-directed approach for oxygen delivery with respect to SpO2 objectives. We evaluated the efficiency of a strategy based on goal-directed O2 delivery in the ICU. METHODS: A group of 30 patients (Group 1) with a proven history of chronic obstructive pulmonary disease suffering from acute hypercarbic exacerbation was compared to 2 other groups of patients admitted for acute respiratory failure with no history of pulmonary disease: 30 patients requiring oxygen supply and/or non-invasive ventilation (Group 2) and 30 requiring invasive ventilation (Group 3). The delivery of oxygen was based on SpO2 measurement: 88-94% for Group 1 and 90-96% for others. The time spent with an SpO2 below, within and above the prescribed limits was collected. RESULTS: The mean time spent within the prescribed range was for Groups 1, 2 and 3, respectively as follows: 61.9% [60.5-63.2], 63.7% [62.3-65] and 56.4% [55.3-57.6] (P < 0.001 for each group). A history of chronic obstructive pulmonary disease was not correlated with better results (P = 0.11), while invasive ventilation was related to the time spent out of the prescribed range (P < 0.001; OR 1.3 [1.22-1.28]) especially in hyperoxaemia (40.7% [39.6-41.8] P < 0.001). Efficiency seems unrelated to nursing workload or night team exhaustion (r = -0.09, P = 0.77). CONCLUSIONS: Goal-directed oxygen delivery based on SpO2 objectives in ICU patients ensures that in only approximately 64% of the time, SpO2 stays within the prescribed range.