[Show abstract][Hide abstract] ABSTRACT: Background An important objective on diagnosis of patients with Langerhans cell histiocytosis (LCH) is to determine the extent of disease. However, whether systematic extrathoracic investigation is needed in adult patients with clinically isolated pulmonary LCH (PLCH) has not been evaluated. Methods In this prospective, multicentre study, 54 consecutive patients with newly diagnosed clinically isolated PLCH were systematically evaluated at inclusion by bone imaging and blood laboratory testing to search for subclinical extrapulmonary LCH involvement. The patients were followed over a 2-year period. At each visit, they were asked about the presence of extrapulmonary manifestations of LCH. Results In the absence of bone symptoms, the skeletal X-ray survey results were normal for all but two patients who had a localised bone lesion consistent with possible LCH involvement, that remained unchanged over 2 years of follow-up. Whole-body bone scintigraphy did not add information to the plain radiography findings for the detection of asymptomatic bone involvement in isolated PLCH. Conversely, it showed nonspecific focal bone uptake in 18 % of the patients, mainly corresponding to post-traumatic or degenerative abnormalities unrelated to LCH. Mild leucocytosis due to neutrophilia was observed in 22 % of the patients and was not related to their smoking habits. Three patients had mild isolated lymphocytosis without haematological disease, whereas two patients had mild lymphopaenia. A mild inflammatory biological syndrome was observed in a minority of patients without infection or constitutional symptoms and was not associated with progressive disease. A substantial proportion (24.5 %) of the patients had abnormal biological liver test results, including elevated liver enzymes and/or cholestasis, which were not linked to LCH involvement in this cohort. Conclusions Obtaining a thorough history and performing comprehensive physical examination are essential for staging patients diagnosed with PLCH. In the absence of symptoms or signs suggestive of extrapulmonary LCH involvement, the systematic performing of recommended bone imaging does not appear informative. Although the observed blood laboratory abnormalities were not specifically related to LCH, performing these tests in the diagnostic workup for PLCH is useful because some of these alterations may impact patient management. Trial registration ClinicalTrials.gov: No. NCT01225601; URL: www. clinicaltrials. gov
Preview · Article · Dec 2016 · Orphanet Journal of Rare Diseases
[Show abstract][Hide abstract] ABSTRACT: Acute myeloid leukemia with high white blood cell count (WBC) is a medical emergency. A reduction of tumor burden with hydroxyurea may prevent life-threatening complications induced by straight chemotherapy. To evaluate this strategy, we reviewed medical charts of adult patients admitted to our institution from 1997 to 2011 with non-promyelocytic AML and WBC over 50 G/L. One hundred and sixty patients were included with a median WBC of 120 G/L (range 50-450), 107 patients received hydroxyurea prior to chemotherapy, and 53 received emergency induction chemotherapy (CT). Hospital mortality was lower for patients treated with hydroxyurea (34% versus 19%, p = 0.047) even after adjusting for age (p < 0.01) and initial WBC count (p = 0.02). No evidence of any difference between treatment groups in terms of WBC decline kinetics and disease free survival (p = 0.87) was found. Oral hydroxyurea prior to chemotherapy seems a safe and efficient strategy to reduce early death of hyperleukocytic AML patients.
No preview · Article · Feb 2016 · Leukemia & lymphoma
[Show abstract][Hide abstract] ABSTRACT: Non-del(5q) transfusion-dependent low/int-1 MDS patients achieve an erythroid response with lenalidomide in 25-30% of cases. Addition of erythropoiesis-stimulating agent could improve the erythroid response rate. The impact of recurrent somatic mutations identified in the diseased clone on response to lenalidomide and the drug effects on clonal evolution remain unknown. We investigated recurrent mutations by next generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo2008 clinical trial to lenalidomide or lenalidomide + EPO. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases, and re-analyzed at later time points in 18 cases. The fate of clonal architecture of single CD34(+)CD38(-) hematopoietic stem cells was also determined in 5 cases. Four genes had a mutation frequency over 10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%) and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15/20 responders compared to 10/22 non-responders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in non-responders (P<0.001). Genotyping of single CD34(+)CD38(-) cell-derived colonies showed that the decrease in the size of the dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient and disease escape was associated with the re-emergence of the initially dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. The trial is registered to www.clinicaltrials.gov as NCT01718379.
[Show abstract][Hide abstract] ABSTRACT: Background
Cancer patients are at high risk for acute kidney injury (AKI), which is associated with high morbidity and mortality. We sought to appraise the incidence, risk factors, and outcome of AKI in a large multicentre cohort study of critically ill patients with haematological malignancies.
We used a retrospective analysis of a prospectively collected database. The study was carried out in 17 university or university-affiliated centres in France and Belgium between 2010 and 2012. AKI was defined according to the Acute Kidney Injury Network (AKIN) definition.
Of the 1011 patients admitted into the intensive care unit (ICU) during the study period, 1009 were included in this study. According to the AKIN definition, 671 patients (66.5%) developed an AKI during their ICU stay, of which 258 patients (38.4%) were AKI stage 1, 75 patients (11.2%) AKI stage 2 and 338 patients (50.4%) AKI stage 3. After adjustment for confounders, main adverse risk factors of AKI were older age, severity [non-renal Sequential Organ Failure Assessment (SOFA)], history of hypertension, tumour lysis syndrome, exposure to nephrotoxic agents and myeloma. Hospital mortality was 44.3% in patients with AKI and 25.4% in patients without AKI (P < 0.0001). After adjustment for confounders, AKI was independently associated with hospital mortality [OR 1.65 (95% CI 1.19–2.29)]. Overall, 271 patients required renal replacement therapy (RRT), of whom 57.2% died during their hospital stay as compared with 31.2% (P < 0.0001) in those not requiring RRT.
Two-thirds of critically ill patients with haematological malignancies developed AKI. Hospital mortality in this population of patients developing AKI or requiring RRT is close to that in general ICU population.
Full-text · Article · Dec 2015 · Nephrology Dialysis Transplantation
[Show abstract][Hide abstract] ABSTRACT: In patients with hematological malignancies and acute respiratory failure (ARF), noninvasive ventilation was associated with a decreased mortality in older studies. However, mortality of intubated patients decreased in the last years. In this study, we assess outcomes in those patients according to the initial ventilation strategy.
We performed a post hoc analysis of a prospective multicentre study of critically ill hematology patients, in 17 intensive care units in France and Belgium. Patients with hematological malignancies admitted for ARF in 2010 and 2011 and who were not intubated at admission were included in the study. A propensity score-based approach was used to assess the impact of NIV compared to oxygen only on hospital mortality.
Among 1011 patients admitted to ICU during the study period, 380 met inclusion criteria. Underlying diseases included lymphoid (n = 162, 42.6 %) or myeloid (n = 141, 37.1 %) diseases. ARF etiologies were pulmonary infections (n = 161, 43 %), malignant infiltration (n = 65, 17 %) or cardiac pulmonary edema (n = 40, 10 %). Mechanical ventilation was ultimately needed in 94 (24.7 %) patients, within 3 [2–5] days of ICU admission. Hospital mortality was 32 % (123 deaths). At ICU admission, 142 patients received first-line noninvasive ventilation (NIV), whereas 238 received oxygen only. Fifty-five patients in each group (NIV or oxygen only) were matched according the propensity score. NIV was not associated with decreased hospital mortality [OR 1.5 (0.62–3.65)].
In hematology patients with acute respiratory failure, initial treatment with NIV did not improve survival compared to oxygen only.
Clinical trial.gov number NCT 01172132
Full-text · Article · Dec 2015 · Annals of Intensive Care
[Show abstract][Hide abstract] ABSTRACT: After failure of erythropoiesis-stimulating agents (ESA), Lenalidomide (LEN) yields red blood cells (RBC) transfusion independence (TI) in 20-30% of lower risk non-del5q MDS. Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement 6 RBC units/8weeks) lower risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg/day, 21 days/4 weeks (L arm) or LEN (same schedule)+erythropoietin (EPO) beta, 60 000 U/week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after 4 treatment cycles (primary endpoint) was 23.1% (95% CI: 13.5-35.2) in the L arm and 39.4% (95%CI: 27.6-52.2) in the LE arm (P=0.044), while RBC transfusion independence (TI) was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the 2 arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower risk non-del5q MDS patients with anemia resistant to ESA.Leukemia accepted article preview online, 26 October 2015. doi:10.1038/leu.2015.296.
Full-text · Article · Oct 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: Purpose
Over the last two decades, noninvasive ventilation (NIV) has been proposed in various causes of acute respiratory failure (ARF) but some indications are debated. Current trends in NIV use are unknown.
Comparison of three multicenter prospective audits including all patients receiving mechanical ventilation and conducted in 1997, 2002, and 2011 in francophone countries.
Among the 4132 patients enrolled, 2094 (51 %) required ventilatory support for ARF and 2038 (49 %) for non-respiratory conditions. Overall NIV use was markedly increased in 2010/11 compared to 1997 and 2002 (37 % of mechanically ventilated patients vs. 16 % and 28 %, P < 0.05). In 2010/11, the use of first-line NIV for ARF had reached a plateau (24 % vs. 16 % and 23 %, P < 0.05) whereas pre-ICU and post-extubation NIV had substantially increased (11 % vs. 4 % and 11 % vs. 7 %, respectively, P < 0.05). First-line NIV remained stable in acute-on-chronic RF, continued to increase in cardiogenic pulmonary edema, but decreased in de novo ARF (16 % in 2010/11 vs. 23 % in 2002, P < 0.05). The NIV success rate increased from 56 % in 2002 to 70 % in 2010/11 and remained the lowest in de novo ARF. NIV failure in de novo ARF was associated with increased mortality in 2002 but not in 2010/11. Mortality decreased over time, and overall, NIV use was associated with a lower mortality.
Increases in NIV use and success rate, an overall decrease in mortality, and a decrease of the adverse impact NIV failure has in de novo ARF suggest better patient selection and greater proficiency of staff in administering NIV.
Clinicaltrials.gov Identifier NCT01449331.
Full-text · Article · Oct 2015 · Intensive Care Medicine
[Show abstract][Hide abstract] ABSTRACT: Importance
Noninvasive ventilation has been recommended to decrease mortality among immunocompromised patients with hypoxemic acute respiratory failure. However, its effectiveness for this indication remains unclear.Objective
To determine whether early noninvasive ventilation improved survival in immunocompromised patients with nonhypercapnic acute hypoxemic respiratory failure.Design, Setting, and Participants
Multicenter randomized trial conducted among 374 critically ill immunocompromised patients, of whom 317 (84.7%) were receiving treatment for hematologic malignancies or solid tumors, at 28 intensive care units (ICUs) in France and Belgium between August 12, 2013, and January 2, 2015.Interventions
Patients were randomly assigned to early noninvasive ventilation (n = 191) or oxygen therapy alone (n = 183).Main Outcomes and Measures
The primary outcome was day-28 mortality. Secondary outcomes were intubation, Sequential Organ Failure Assessment score on day 3, ICU-acquired infections, duration of mechanical ventilation, and ICU length of stay.Results
At randomization, median oxygen flow was 9 L/min (interquartile range, 5-15) in the noninvasive ventilation group and 9 L/min (interquartile range, 6-15) in the oxygen group. All patients in the noninvasive ventilation group received the first noninvasive ventilation session immediately after randomization. On day 28 after randomization, 46 deaths (24.1%) had occurred in the noninvasive ventilation group vs 50 (27.3%) in the oxygen group (absolute difference, −3.2 [95% CI, −12.1 to 5.6]; P = .47). Oxygenation failure occurred in 155 patients overall (41.4%), 73 (38.2%) in the noninvasive ventilation group and 82 (44.8%) in the oxygen group (absolute difference, −6.6 [95% CI, −16.6 to 3.4]; P = .20). There were no significant differences in ICU-acquired infections, duration of mechanical ventilation, or lengths of ICU or hospital stays.Conclusions and Relevance
Among immunocompromised patients admitted to the ICU with hypoxemic acute respiratory failure, early noninvasive ventilation compared with oxygen therapy alone did not reduce 28-day mortality. However, study power was limited.Trial Registration
Full-text · Article · Oct 2015 · JAMA The Journal of the American Medical Association
[Show abstract][Hide abstract] ABSTRACT: Background: Response-adaptive randomisation designs have been proposed to improve the efficiency of phase III randomised clinical trials and improve the outcomes of the clinical trial population. In the setting of failure time outcomes, Zhang and Rosenberger (2007) developed a response-adaptive randomisation approach that targets an optimal allocation, based on a fixed sample size. Objectives: The aim of this research is to propose a response-adaptive randomisation procedure for survival trials with an interim monitoring plan, based on the following optimal criterion: for fixed variance of the estimated log hazard ratio, what allocation minimizes the expected hazard of failure? We demonstrate the utility of the design by redesigning a clinical trial on multiple myeloma. Methods: To handle continuous monitoring of data, we propose a Bayesian response-adaptive randomisation procedure, where the log hazard ratio is the effect measure of interest. Combining the prior with the normal likelihood, the mean posterior estimate of the log hazard ratio allows derivation of the optimal target allocation. We perform a simulation study to assess and compare the performance of this proposed Bayesian hybrid adaptive design to those of fixed, sequential or adaptive – either frequentist or fully Bayesian – designs. Non informative normal priors of the log hazard ratio were used, as well as mixture of enthusiastic and skeptical priors. Stopping rules based on the posterior distribution of the log hazard ratio were computed. The method is then illustrated by redesigning a phase III randomised clinical trial of chemotherapy in patients with multiple myeloma, with mixture of normal priors elicited from experts. Results: As expected, there was a reduction in the proportion of observed deaths in the adaptive vs. non-adaptive designs; this reduction was maximized using a Bayes mixture prior, with no clear-cut improvement by using a fully Bayesian procedure. The use of stopping rules allows a slight decrease in the observed proportion of deaths under the alternate hypothesis compared with the adaptive designs with no stopping rules. Conclusions: Such Bayesian hybrid adaptive survival trials may be promising alternatives to traditional designs, reducing the duration of survival trials, as well as optimizing the ethical concerns for patients enrolled in the trial.
No preview · Article · Sep 2015 · Methods of Information in Medicine
[Show abstract][Hide abstract] ABSTRACT: Background and aimsAnal fistula plug (AFP) is a bioabsorbable bioprosthesis used in ano-perineal fistula treatment. We aimed to assess efficacy and safety of AFP in fistulising ano-perineal Crohn's disease (FAP-CD).Methods
In a multicentre, open-label, randomized controlled trial we compared seton removal alone (control group) with AFP insertion (AFP group) in 106 Crohn's disease patients with non or mildly active disease having at least one ano-perineal fistula tract drained for more than one month. Patients with abscess (collection ≥ 3 mm on MRI) or recto-vaginal fistulas were excluded. Randomization was stratified in simple or complex fistulas according to AGA classification. Primary end point was fistula closure at week 12.Results54 patients were randomized to AFP group (control group 52). Median fistula duration was 23 [10-53] months. Median Crohn's Disease Activity Index at baseline was 81 [45-135]. Fistula closure at week 12 was achieved in 31.5% patients in AFP group and in 23.1 % in control group (relative risk stratified on AGA classification, RR: 1.31; 95%CI: 0.59-4.02; p=0.19). No interaction in treatment effect with complexity stratum was found. 33.3% patients with complex fistula and 30.8% patients with simple fistula closed the tracts after AFP, as compared to 15.4% and 25.6% in controls respectively (RR of success=2.17 in complex fistula vs. RR=1.20 in simple fistula; p= 0.45). Concerning safety, at week 12, 17 patients developed at least one adverse event in AFP group vs. 8 in controls (p=0.07).ConclusionAFP is not more effective than seton removal alone to achieve FAP-CD closure.
No preview · Article · Sep 2015 · Journal of Crohn s and Colitis
[Show abstract][Hide abstract] ABSTRACT: Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain, heavy chain, or both along basement membranes. While renal involvement is prominent, treatment strategies, such as the impact of novel anti-myeloma agents, remain poorly defined. Here we retrospectively studied 49 patients with MIDD who received a median of 4.5 cycles of intravenous bortezomib plus dexamethasone. Of these, 25 received no additional treatment, 18 also received cyclophosphamide, while 6 also received thalidomide or lenalidomide. The hematological diagnoses identified 38 patients with monoclonal gammopathy of renal significance, 10 with symptomatic multiple myeloma, and 1 with Waldenstrom macroglobulinemia. The overall hematologic response rate, based on the difference between involved and uninvolved serum-free light chains (dFLCs), was 91%. After median follow-up of 54 months, 5 patients died and 10 had reached end-stage renal disease. Renal response was achieved in 26 patients, with a 35% increase in median eGFR and an 86% decrease in median 24-h proteinuria. Predictive factors were pre-treatment eGFR over 30 ml/min per 1.73 m(2) and post-treatment dFLC under 40 mg/l; the latter was the sole predictive factor of renal response by multivariable analysis. Thus, bortezomib-based therapy is a promising treatment strategy in MIDD, mainly when used early in the disease course. dFLC response is a favorable prognostic factor for renal survival.Kidney International advance online publication, 15 July 2015; doi:10.1038/ki.2015.201.
No preview · Article · Jul 2015 · Kidney International
[Show abstract][Hide abstract] ABSTRACT: Systemic rheumatic diseases (SRD) patients may require ICU management for SRD exacerbation, treatment-related infectious or toxicities.
Observational study in 10 university-affiliated ICUs in France. Consecutive patients with SRD were included. Determinants of ICU mortality were identified through multivariable logistic analysis.
363 patients (65.3 % women, median age 59y (IQR, 42-70)) accounted for 381 admissions. Connective tissue disease (primarily Systemic Lupus Erythematosus) accounted for 66.1% of SRD and systemic vasculitides for 26.2 % (chiefly ANCA-associated vasculitides). SRD was newly diagnosed in 43 (11.3%) cases. Direct admission to ICU occurred in 143 (37.9%) cases. Reasons for ICU admissions were infection (39.9%), SRD exacerbation (34.4%), toxicity (5.8 %) or miscellaneous (19.9%). Respiratory involvement was the leading cause of admission (56.8 %), followed by shock (41.5 %) and acute kidney injury (42.2%). Median SOFA on day-1 was 5 [3-8]. Mechanical ventilation was required in 57% cases, vasopressors in 33.9% and renal replacement therapy in 28.1%. ICU mortality rate was 21.0% (80 deaths). Factors associated with ICU mortality were shock (OR: 3.77 [95%CI, 1.93 -7.36]), SOFA score at day 1 (OR: 1.19 [95%CI, 1.10-1.30]) and direct admission (OR: 0.52, [CI 0.28-0.97]. Neither comorbidities nor SRD characteristics were associated with survival.
In SRD patients, critical care management is mostly needed in patients with previously known SRD; still, diagnosis can be made in the ICU in 12% of the patients. Infection and SRD exacerbation account for more than two-third of the situations, both targeting chiefly the lungs. Direct admission to the ICU might improve outcomes.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to evaluate pre-operative education versus no education and mini-invasive surgery versus standard surgery to reach complete independence.
We conducted a four-arm randomized controlled trial of 209 patients. The primary outcome criterion was the time to reach complete functional independence. Secondary outcomes included the operative time, the estimated total blood loss, the pain level, the dose of morphine, and the time to discharge.
There was no significant effect of either education (HR: 1.1; P = 0.77) or mini-invasive surgery (HR: 1.0; 95 %; P = 0.96) on the time to reach complete independence. The mini-invasive surgery group significantly reduced the total estimated blood loss (P = 0.0035) and decreased the dose of morphine necessary for titration in the recovery (P = 0.035).
Neither pre-operative education nor mini-invasive surgery reduces the time to reach complete functional independence. Mini-invasive surgery significantly reduces blood loss and the need for morphine consumption.
No preview · Article · May 2015 · International Orthopaedics