Cerebral aspergillosis in the era of new antifungals: The CEREALS national cohort study Nationwide CEREbral Aspergillosis Lesional study (CEREALS).

BACKGROUND: Cerebral aspergillosis (CA) is a life-threatening disease for which diagnosis and management remain challenging. Detailed analyses from large cohorts are lacking. METHODS: We included 119 cases of proven (n = 54) or probable (n = 65) CA diagnosed between 2006 and 2018 at 20 French hospitals. Data were collected at baseline and during follow-up. Cerebral imaging was reviewed centrally by two neuroradiologists. RESULTS: The most frequent underlying conditions were hematological malignancy (40%) and solid organ transplantation (29%). Galactomannan was detected in the serum of 64% of patients. In 75% of cases, at least one of galactomannan, Aspergillus PCR, and ß-d-glucan was positive in the cerebrospinal fluid. Six-week mortality was 45%. Two distinct patterns of disease were identified according to presumed route of dissemination. Presumed haematogenous dissemination (n = 88) was associated with a higher frequency of impaired consciousness (64%), shorter time to diagnosis, the presence of multiple abscesses (70%), microangiopathy (52%), detection of serum galactomannan (69%) and Aspergillus PCR (68%), and higher six-week mortality (54%). By contrast, contiguous dissemination from the paranasal sinuses (n = 31) was associated with a higher frequency of cranial nerve palsy (65%), evidence of meningitis on cerebral imaging (83%), macrovascular lesions (61%), delayed diagnosis, and lower six-week mortality (30%). In multivariate analysis and in a risk prediction model, haematogenous dissemination, hematological malignancy and the detection of serum galactomannan were associated with higher six-week mortality. CONCLUSION: Distinguishing between hematogenous and contiguous dissemination patterns appears to be critical in the workup for CA, as they are associated with significant differences in clinical presentation and outcome.

Home-based exercise in autoimmune myasthenia gravis: A randomized controlled trial.

The tolerance of exercise and its effects on quality of life in myasthenia gravis are not currently backed up by strong evidence. The aim of this study was to determine whether exercise as an adjunct therapy is well tolerated and can improve health-related quality of life (HRQoL) in stabilized, generalized autoimmune myasthenia gravis (gMG). We conducted a parallel-group, multi-center prospective RCT using computer-generated block randomization. Adults with stabilized, gMG, and no contra-indication to exercise, were eligible. Participants received usual care alone or usual care and exercise. The exercise intervention consisted of 3-weekly 40 min sessions of an unsupervised, moderate-intensity home rowing program over 3 months. The primary endpoint was the change in HRQoL from randomization to post-intervention. Assessor-blinded secondary endpoints were exercise tolerance and effects on clinical, psychological and immunological status. Of 138 patients screened between October 2014 and July 2017, 45 were randomly assigned to exercise (n = 23) or usual care (n = 20). Although exercise was well tolerated, the intention-to-treat analysis revealed no evidence of improved HRQoL compared to usual care (MGQOL-15-F; mean adjusted between-groups difference of -0.8 points, 95%CI -5.4 to 3.7). Two patients hospitalized for MG exacerbation were from the usual care group.

Mismatch negativity to predict subsequent awakening in deeply sedated critically ill patients.

BACKGROUND: Mismatch negativity (MMN) is the neurophysiological correlate of cognitive integration of novel stimuli. Although MMN is a well-established predictor of awakening in non-sedated comatose patients, its prognostic value in deeply sedated critically ill patients remains unknown. The aim of this prospective, observational pilot study was to investigate the prognostic value of MMN for subsequent awakening in deeply sedated critically ill patients. METHODS: MMN was recorded in 43 deeply sedated critically ill patients on Day 3 of ICU admission using a classical 'odd-ball' paradigm that delivers rare deviant sounds in a train of frequent standard sounds. Individual visual analyses and a group level analysis of recordings were performed. MMN amplitudes were then analysed according to the neurological status (awake vs not awake) at Day 28. RESULTS: Median (inter-quartile range) Richmond Assessment Sedation Scale (RASS) at the time of recording was -5 (range, from -5 to -4.5). Visual detection of MMN revealed a poor inter-rater agreement [kappa=0.17, 95% confidence interval (0.07-0.26)]. On Day 28, 30 (70%) patients had regained consciousness while 13 (30%) had not. Quantitative group level analysis revealed a significantly greater MMN amplitude for patients who awakened compared with those who had not [mean (standard deviation) = -0.65 (1.4) vs 0.08 (0.17) µV, respectively; P=0.003). CONCLUSIONS: MMN can be observed in deeply sedated critically ill patients and could help predict subsequent awakening. However, visual analysis alone is unreliable and should be systematically completed with individual level statistics.

Allogeneic haematopoietic stem cell transplant in patients with lower risk myelodysplastic syndrome: a retrospective analysis on behalf of the Chronic Malignancy Working Party of the EBMT.

This corrects the article DOI: 10.1038/bmt.2016.266.

Clinical benefit, price and approval characteristics of FDA-approved new drugs for treating advanced solid cancer, 2000-2015.

Background: Prices of anti-cancer drugs are skyrocking. We aimed to assess the clinical benefit of new drugs for treating advanced solid tumors at the time of their approval by the US Food and Drug Administration (FDA) and to search for a relation between price and clinical benefit of drugs. Materials and methods: We included all new molecular entities and new biologics for treating advanced solid cancer that were approved by the FDA between 2000 and 2015. The clinical benefit of drugs was graded based on FDA medical review of pivotal clinical trials using the 2016-updated of the American Society of Clinical Oncology Value Framework (ASCO-VF) and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Characteristics of drugs and approvals were obtained from publicly available FDA documents and price was evaluated according to US Medicare, US Veterans Health Administration and United Kingdom market systems. Results: The FDA approved 51 new drugs for advanced solid cancer from 2000 to 2015; we could evaluate the value of 37 drugs (73%). By the ESMO-MCBS, five drugs (14%) were grade one (the lowest), nine (24%) grade two, 10 (27%) grade three, 11 (30%) grade four and two (5%) grade five (the highest). Thus, 13 drugs (35%) showed a meaningful clinical benefit (scale levels 4 and 5). By the ASCO-VF which had a range of 3.4-67, the median drug value was 37 (interquartile range 20-52). We found no relationship between clinical benefit and drug price (P = 0.9). No characteristic of drugs and of approval was significantly associated with clinical benefit. Conclusion: Many recently FDA-approved new cancer drugs did not have high clinical benefit as measured by current scales. We found no relation between the price of drugs and benefit to society and patients.

Magnetic resonance imaging for abnormally invasive placenta: the added value of intravenous gadolinium injection.

OBJECTIVES: To assess the added value of intravenous gadolinium injection to magnetic resonance imaging (MRI) -based diagnosis of abnormally invasive placenta (AIP) and to examine this in relation to the radiologist's experience. DESIGN: Retrospective study. SETTING: Between March 2009 and October 2012, 31 pregnant women who had previous caesarean delivery together with a placenta praevia and suspected placenta accreta on ultrasound in the third trimester of pregnancy. POPULATION: All were offered MRI examination, and made aware of the limited (but so far reassuring) data regarding fetal safety of gadolinium. Twenty pregnant women agreed to undergo prenatal MRI (1.5 T), with and without gadolinium injection. METHODS: Two sets of MRI examinations without and with gadolinium were reviewed independently 2 months apart by two senior and two junior radiologists; all were blinded to the outcome (known in all cases). Histopathological findings and clinical signs of AIP were considered as the defining criteria of diagnosis. MAIN OUTCOME MEASURE: accuracy of MRI with and without gadolinium was assessed. RESULTS: Eight of the 20 women had confirmed abnormal placental invasion. The overall performance of both sets of readers in detecting AIP increased with gadolinium-sensitivity and specificity of 75.0% (42.0-100%) and 47.9% (19.9-75.9%) increasing to 87.5% (57.1-100%) and 60.4% (33.9-86.9%), respectively (P = 0.04). The added value of gadolinium remained irrespective of radiologist's experience, although senior radiologists performed better overall (sensitivity and specificity of 87.5% and 62.5% versus 62.5% and 33.3%, respectively, increasing with injection to 93.8% and 70.8% versus 81.3% and 50%, respectively; P < 10-4 ). CONCLUSION: There was an association between gadolinium use and improvement in MRI-based diagnostic accuracy for the diagnosis of AIP, for both junior and senior radiologists. TWEETABLE ABSTRACT: Gadolinium injection improves MRI performance of radiologists for the diagnosis of placenta accreta.

Allogeneic haematopoietic stem cell transplant in patients with lower risk myelodysplastic syndrome: a retrospective analysis on behalf of the Chronic Malignancy Working Party of the EBMT.

We report a retrospective analysis of 246 myelodysplastic syndrome (MDS) patients in the EBMT (The European Society for Blood and Marrow Transplantation) database who were transplanted for International Prognostic Scoring System (IPSS) low or intermediate-1 disease. The majority of these patients (76%) were reclassified as intermediate or higher risk according to R-IPSS. The 3-year overall survival (OS) and PFS were 58% and 54%, respectively. In a multivariate analysis, adverse risk factors for PFS were marrow blast percentage (hazard ratio (HR): 1.77, P=0.037), donor/recipient CMV serostatus (donor-/recipient+: HR: 2.02, P=0.011) and source of stem cells (marrow and non-CR: HR: 5.72, P<0.0001, marrow and CR: HR: 3.17, P=0.027). Independent risk factors for OS were disease status at time of transplant and the use of in vivo T-cell depletion (TCD). Patients who did not receive TCD and were transplanted from an unrelated donor had worse OS (HR: 4.08, P<0.0001). In conclusion, 'lower' risk MDS patients have better outcome than those with 'higher risk' after haematopoietic stem cell transplant (HSCT). Selecting the right source of stem cells, a CMV-positive donor for CMV-positive patients and using in vivo TCD results in the best outcome in these patients. More studies are needed to evaluate the role of HSCT in these patients as compared with conventional treatment.

Prevalence, risk factors, and impact on clinical outcome of extended-spectrum beta-lactamase-producing Escherichia coli bacteraemia: a five-year study.

BACKGROUND: The impact of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (ESBL-EC) bacteraemia on outcome remains controversial. METHODS: A retrospective analysis of the prevalence, risk factors, clinical features, and outcomes of all ESBL-EC bacteraemia in one French hospital over a 5-year period was performed. A case-control study was undertaken: cases had at least one ESBL-EC bacteraemia and controls a positive non-ESBL-EC bacteraemia. RESULTS: The prevalence of ESBL-EC bacteraemia increased from 5.2% of all positive E. coli blood cultures in 2005 to 13.5% in 2009 (p<0.003). CTX-M represented 70% of ESBL-EC bacteraemia strains, and strains were not clonally related. On adjusted analysis, the only significant risk factor for ESBL-EC bacteraemia was a previous ESBL-EC colonization (odds ratio 11.3, 95% confidence interval 1.2-107; p=0.003). Initial antimicrobial therapy was less frequently adequate in the ESBL-EC group (48% vs. 85%; p=0.003). The presence of ESBL-EC bacteraemia was not associated with a longer hospital stay (p=0.088). Day 30 mortality was high, but not significantly different in the two groups (30% vs. 27%; p=0. 82). CONCLUSION: The prevalence of ESBL-EC bacteraemia has been increasing dramatically. Previous colonization with ESBL-EC was a strong risk factor for ESBL-EC bacteraemia. More inadequate initial antimicrobial therapy was noted in the ESBL-EC group, but mortality and length of hospital stay were not significantly different from those of patients with non-ESBL-EC bacteraemia.

HLA-matched allogeneic stem cell transplantation improves outcome of higher risk myelodysplastic syndrome A prospective study on behalf of SFGM-TC and GFM.

Allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only a curative treatment in patients with higher risk myelodysplastic syndrome (MDS), although demethylating agents (DMA) have been reported to improve survival. The advantage of HSCT over other treatment comes from retrospective studies and the aim of the current study was to prospectively test this hypothesis, analyzing in particular patients from the pre-transplant period to avoid the selection bias of performing transplantation. This study was conducted to compare overall survival in MDS patients candidates to transplantation according to donor availability. The majority of patients (76%) received a treatment with DMA after registration, 69% had a human leukocyte antigen (HLA)-identical donor, 70% of whom were transplanted. Baseline patient and disease characteristics were similar according to donor availability. Four-year overall survival was significantly better in patients with an HLA matched donor (37%) compared to patients without donor (15%). There was also evidence that this overall survival advantage was because of transplantation. Mortality risk was decreased after transplantation but it became significant only after the second year post transplant, because of early transplant-related mortality. Our results appear to justify, in higher risk MDS, a transplantation approach in all potential candidates who have an HLA identical donor.

Influence of ultrasound determination of fetal head position on mode of delivery: a pragmatic randomized trial.

OBJECTIVE: To evaluate the influence of ultrasound determination of fetal head position on mode of delivery. METHODS: This was a pragmatic open-label randomized controlled trial that included women with a singleton pregnancy in the vertex presentation at ≥ 37 weeks' gestation, cervical dilation ≥ 8 cm and who received epidural anesthesia. Women were assigned randomly to undergo either digital vaginal examination (VE group) or both digital vaginal and ultrasound examinations (VE+US group) to determine fetal head position. When the ultrasound and digital vaginal findings were inconsistent in the VE+US group, the ultrasound result was used for clinical management. The primary outcome assessed was operative delivery (Cesarean or instrumental vaginal delivery), and maternal and fetal morbidity were also assessed. RESULTS: The VE and VE+US groups included 959 and 944 women, respectively. The overall rate of operative delivery was significantly higher in the VE+US group than in the VE group: 33.7% vs 27.1%, respectively (relative risk (RR), 1.24 (95% CI, 1.08-1.43)), as was the rate of Cesarean delivery: 7.8% vs 4.9%, respectively (RR, 1.60 (95% CI, 1.12-2.28)). The rate of instrumental vaginal delivery was also higher, albeit not significantly: 25.8% in the VE+US group vs 22.2% in the VE group (RR, 1.16 (95% CI, 0.99-1.37)). Neonatal outcomes did not differ between the two groups. When analysis was restricted to instrumental vaginal deliveries only, maternal and neonatal morbidity outcomes were similar in both groups. CONCLUSION: Correction of fetal occiput position, determined initially by digital vaginal examination, using systematic ultrasound examination did not improve management of labor and increased the rate of operative delivery without decreasing maternal and neonatal morbidity.

Equivalent outcomes using reduced intensity or conventional myeloablative conditioning transplantation for patients aged 35 years and over with AML.

Allogeneic hematopoietic stem cell transplantation provides the best chance of long-term survival for patients with AML, but is associated with an unpredictable risk of treatment-related mortality. From January 2000 to December 2010, we compared the outcomes for patients with AML aged 35 and over using reduced-intensity conditioning (RIC, N=60) or conventional myeloablative conditioning (MAC) regimen (N=72) transplantation. The median follow-up was 47 months (10-134). The 4-year cumulative incidence of non-relapse mortality was 21%. After adjusting for cytogenetic risk, gender donor/recipient mismatch and CD34+ cells, non-relapse mortality was significantly lower with the RIC regimen (P=0.027). The 4-year cumulative incidence of relapse was 38% and no difference was observed in the adjusted relapse rate between the two groups. The 4-year OS rate was 46%. Using both Cox regression and inverse probability-of-treatment weighted (IPTW) method, a similar OS rate was found with both regimens (adjusted hazard ratios for conventional vs reduced of 1.14 (95% CI 0.67-1.93, P=0.64) with Cox regression, and 1.14 (95% CI 0.55-2.34, P=0.73) with IPTW). Until prospective trials are completed, this study supports the use of a reduced-intensity regimen prior to transplantation for patients with AML aged 35 and over.

Breakthrough invasive fungal disease in patients receiving posaconazole primary prophylaxis: a 4-year study.

Posaconazole (PSC) is currently recommended as primary prophylaxis in neutropenic patients with acute myeloid leukaemia (AML) and in allogenic haematopoietic stem cell transplantation (AHSCT) recipients with graft-versus-host disease (GVHD). Studies focusing on breakthrough invasive fungal disease (IFD) upon PSC prophylaxis show disparate results. In order to evaluate the incidence of IFD in patients on PSC prophylaxis and identify IFD risk factors, we carried out a retrospective study of all consecutive patients on PP from January 2007 to December 2010 in our hospital. Breakthrough IFDs were identified from the database of the central pharmacy and the French administrative database (PMSI), registering final medical diagnoses of hospitalized patients. Medical data were reviewed to study proven or probable IFD, according to EORTC/MSG definition. PSC plasma concentrations (PPC) were also retrieved. Poisson models were used for statistical analysis. Two hundred and seventy-nine patients received PSC prophylaxis for a median duration of 1.4 months (range 0.2-17.9). Proven (n=6) or probable (n=3) IFDs were diagnosed in nine cases (3.2%). IFD incidence rate per 100 person-month was 1.65 (95% CI, 0.79-2.97). IFDs were candidaemia (Candida glabrata, n=2), pulmonary invasive aspergillosis (n=3), disseminated fusariosis (n=2) and pulmonary mucormycosis (n=2). Seven deaths were reported, directly related to IFD in three patients (33.3%). First dosage of PPC under 0.3 mg/L was the single significant risk factor for IFD (RR, 7.77; 95% CI, 1.30-46.5; p 0.025). Breakthrough IFD in patients receiving PSC prophylaxis is rare but associated with a poor outcome. Low PSC plasma concentrations are associated with an increased risk of IFD.

Permutation tests for centre effect on survival endpoints with application in an acute myeloid leukaemia multicentre study.

When analysing multicentre data, it may be of interest to test whether the distribution of the endpoint varies among centres. In a mixed-effect model, testing for such a centre effect consists in testing to zero a random centre effect variance component. It has been shown that the usual asymptotic χ(2) distribution of the likelihood ratio and score statistics under the null does not necessarily hold. In the case of censored data, mixed-effects Cox models have been used to account for random effects, but few works have concentrated on testing to zero the variance component of the random effects. We propose a permutation test, using random permutation of the cluster indices, to test for a centre effect in multilevel censored data. Results from a simulation study indicate that the permutation tests have correct type I error rates, contrary to standard likelihood ratio tests, and are more powerful. The proposed tests are illustrated using data of a multicentre clinical trial of induction therapy in acute myeloid leukaemia patients.

Long-term survival of advanced triple-negative breast cancers with a dose-intense cyclophosphamide/anthracycline neoadjuvant regimen.

BACKGROUND: Triple-negative (TN) breast cancers exhibit major initial responses to neoadjuvant chemotherapy, but generally have a poor outcome. Because of the lack of validated drug targets, chemotherapy remains an important therapeutic tool in these cancers. METHODS: We report the survival of two consecutive series of 267 locally advanced breast cancers (LABC) treated with two different neoadjuvant regimens, either a dose-dense and dose-intense cyclophosphamide-anthracycline (AC) association (historically called SIM) or a conventional sequential association of cyclophosphamide and anthracycline, followed by taxanes (EC-T). We compared pathological responses and survival rates of these two groups and studied their association with tumours features. RESULTS: Although the two regimens showed equivalent pathological complete response (pCR) in the whole population (16 and 12%), the SIM regimen yielded a non-statistically higher pCR rate than EC-T (48% vs 24%, P=0.087) in TN tumours. In the SIM protocol, DFS was statistically higher for TN than for non-TN patients (P=0.019), although we showed that the TN status was associated with an increased initial risk of recurrence in both regimens. This effect gradually decreased and after 2 years, TN was associated with a significantly decreased likelihood of relapse in SIM-treated LABC (hazard ratio (HR)=0.25 (95% CI: 0.07-0.86), P=0.028). CONCLUSIONS: AC dose intensification treatment is associated with a very favourable long-term survival rate in TN breast cancers. These observations call for a prospective assessment of such dose-intense AC-based regimens in locally advanced TN tumours.

Influence of migration on characteristics of type 2 diabetes in sub-Saharan Africans.

AIM: This study compared the clinical and biochemical characteristics and microvascular complications found in three groups of type 2 diabetes (T2D) patients: Africans living in Africa; African immigrants living in France; and Caucasians living in France. METHODS: Diagnosed T2D Africans living in Cameroon (n=100) were compared with 98 African migrants diagnosed with T2D after having moved to France, and a group of 199 T2D Caucasian patients living in France. All underwent clinical and biochemical evaluations, and all were assessed for microvascular complications. RESULTS: The median duration of stay of the migrants in France was 15years before being diagnosed with diabetes. Despite similar durations of diagnosis, they were 8.9years younger at the time of diagnosis than Africans living in Cameroon (P<0.001). Caucasians and African immigrants in France had lower HbA1c values than Africans in Cameroon (P<0.001); they were also more aggressively treated for hypertension and dyslipidaemia and, therefore, had significantly lower blood pressure levels and better lipid profiles. Diabetic nephropathy and retinopathy rates were higher in Cameroon than in the two other groups. After adjusting for age, diabetes duration, HbA1c, hypertension and other covariates, only the prevalence of diabetic nephropathy (OR: 5.61, 95% CI: 2.32-13.53; P<0.0001) was higher in Cameroon compared with those living in France. CONCLUSION: Our results suggest that Africans who emigrate to France may develop diabetes earlier than those staying in their home country. However, the latter may be a reflection of late diagnosis of diabetes. Also, the less adequate diabetes and hypertension control in the latter would explain their higher rates of nephropathy. Large-scale cohorts are now warranted to substantiate these observations.

Increased incidence of Campylobacter jejuni-associated Guillain-Barré syndromes in the Greater Paris area.

The role of Campylobacter jejuni as the triggering agent of Guillain-Barré syndrome (GBS) has not been reassessed since the end of the 1990s in France. We report that the number of C. jejuni-related GBS cases increased continuously between 1996 and 2007 in the Paris region (mean annual increment: 7%, P = 0·007).

Repeat measurements of nuchal translucency at 11-14 weeks of gestation: when do we need them?

OBJECTIVE: Previous studies have recommended that several repeat measurements of nuchal translucency (NT) be obtained to optimize sensitivity of the screening process. However, truncation is applied within the risk calculation for small NT measurements; therefore, repeating NT measurements in the lower range may be unnecessary. The aim of this study was to determine the optimal number of NT measurements and whether this is dependent on the initial value obtained. METHODS: We simulated the expected distribution of sets of five repeat NT measurements and their corresponding likelihood ratios (LR) for a variety of crown-rump length (CRL) values at 11-14 weeks' gestation, based on the published mixture model for first-trimester NT measurements and on published data regarding NT measurement variability. The ratio between LR obtained from the highest and the initial measurement in each set were computed, with a ratio of 1 indicating that repeat measurements would have no effect on risk estimation. We calculated NT cut-offs below which a change in estimated LR would occur in fewer than 10% of cases if repeat measurements were obtained, and we tested this approach on a real first-trimester screening dataset. RESULTS: The simulations performed indicated that repeating NT measurements when the first NT obtained ranged between ≤ 0.9 and ≤ 1.6 mm at CRLs of 45 and 84 mm, respectively, is not useful. When applied to a real dataset, our approach allowed avoiding repetition of measurements in 47/165 cases (28%). CONCLUSIONS: Although there is some variability in NT measurements, repeat assessment is not useful to optimize screening performance for the smallest NT measurements due to lower truncation limits that are applied in risk calculation. Our study provides NT cut-off values, in relation to CRL, below which it appears that there is no need to repeat measurements once a good quality image has been obtained.