Genetic manipulation of adult-born hippocampal neurons rescues memory in a mouse model of Alzheimer's disease.

In adult mammals, neural progenitors located in the dentate gyrus retain their ability to generate neurons and glia throughout lifetime. In rodents, increased production of new granule neurons is associated with improved memory capacities, while decreased hippocampal neurogenesis results in impaired memory performance in several memory tasks. In mouse models of Alzheimer's disease, neurogenesis is impaired and the granule neurons that are generated fail to integrate existing networks. Thus, enhancing neurogenesis should improve functional plasticity in the hippocampus and restore cognitive deficits in these mice. Here, we performed a screen of transcription factors that could potentially enhance adult hippocampal neurogenesis. We identified Neurod1 as a robust neuronal determinant with the capability to direct hippocampal progenitors towards an exclusive granule neuron fate. Importantly, Neurod1 also accelerated neuronal maturation and functional integration of new neurons during the period of their maturation when they contribute to memory processes. When tested in an APPxPS1 mouse model of Alzheimer's disease, directed expression of Neurod1 in cycling hippocampal progenitors conspicuously reduced dendritic spine density deficits on new hippocampal neurons, to the same level as that observed in healthy age-matched control animals. Remarkably, this population of highly connected new neurons was sufficient to restore spatial memory in these diseased mice. Collectively our findings demonstrate that endogenous neural stem cells of the diseased brain can be manipulated to become new neurons that could allow cognitive improvement.

Reproducibility of acute mountain sickness in children and adults: a prospective study.

OBJECTIVE: Although a history of previous acute mountain sickness (AMS) is commonly used for providing advice and recommending its prophylaxis during subsequent exposure, the intraindividual reproducibility of AMS during repeated high-altitude exposure has never been examined in a prospective controlled study.METHODS: In 27 nonacclimatized children and 29 adults, AMS was assessed during the first 48 hours after rapid ascent to 3450 m on 2 consecutive occasions 9 to 12 months apart.RESULTS: During the first exposure, 18 adults (62%) and 6 children (22%) suffered from AMS; during the second exposure, 14 adults (48%) and 4 children (15%) suffered from this problem (adults versus children, P <= .01). Most importantly, the intraindividual reproducibility of AMS was very different (P < .001) between children and adults. None of the 6 children having suffered from AMS during the first exposure suffered from AMS during the second exposure, but 4 children with no AMS during the first exposure did experience this problem during the second exposure. In contrast, 14 of the 18 adults who suffered from AMS on the first occasion also presented with this problem during the second exposure, and no new case developed in those who had not experienced AMS on the first occasion.CONCLUSIONS: In adults, a history of AMS is highly predictable of the disease on subsequent exposure, whereas in children it has no predictive value. A history of AMS should not prompt practitioners to advise against reexposure to high altitude or to prescribe drugs for its prophylaxis in children. Pediatrics 2011;127:e1445-e1448

Incidence and types of illness when traveling to the tropics: a prospective controlled study of children and their parents.

Increasingly, families travel to tropical destinations exposing them to infectious agents and tropical diseases not encountered at home. We studied 157 children (0-16 years) and their adult relatives traveling to the tropics, who attended a pretravel clinic and were generally adherent to prescribed advice. Incidence rates of common illness in children and adults were respectively 16.9 (14.3-19.7) and 15.1 (12.7-17.8) episodes/100 person-weeks. Diarrhea, abdominal pain, and fever were the most frequent complaints. There was no significant difference in the incidence of morbid episodes between children and adults, except for fever (more frequent in children). Most episodes occurred in the first 10 days of travel. The similar incidence of morbidity in children and adults and the episodes' mildness challenge the view that it is unwise to travel with small children.

Prospective study evaluating the predictability of need for retreatment with intravitreal ranibizumab for age-related macular degeneration.

PURPOSE: To investigate the rhythm and predictability of the need for retreatment with intravitreal injections of ranibizumab for neovascular age-related macular degeneration (nAMD). METHODS: This prospective study enrolled 39 patients with treatment-naïve nAMD. After three loading doses of intravitreal ranibizumab, patients underwent an intensified follow-up for 12 months (initially weekly, then with stepwise increases to every 2 weeks and to monthly after each injection). Patients were retreated on an as-needed basis if any fluid or increased central retinal thickness (CRT) (>50 μm) was found on spectral domain optical coherence tomography (OCT). Statistical analysis included patients who received at least two retreatments (five injections). RESULTS: A mean of 7.5 injections (range 0-12) were given between months 3 and 15. The mean visual acuity increased by 13.1 and 12.6 ETDRS letters at months 12 and 15 respectively. Two or more injection-retreatment intervals were found in 31 patients. The variability of their intra-individual intervals up to 14 weeks was small (SD 0-2.13 weeks), revealing a high regularity of the retreatment rhythm. The SD was correlated with the mean interval duration (r = 0.89, p < 0.001). The first interval was a good predictor of the following intervals (regression coefficient =0.81). One retreatment criterion was stable in 97 % of patients (cysts or subretinal fluid). CONCLUSION: The results of this study demonstrate a high intra-individual predictability of retreatment need with ranibizumab injections for nAMD. These findings may be helpful for developing individualized treatment plans for maintained suppression of disease activity with a minimum of injections and visits.

Monitoring de l'immunosuppression par les thiopurines dans les maladies inflammatoires chroniques de l'intestin par le suivi de la macrocytose

Background¦Erythrocyte MCV might be used as an inexpensive marker to predict and¦optimize the efficacy and tolerability of thiopurine therapy in IBD patients.¦Aim and methods¦This retrospective observational study aimed to assess the monitoring¦performances of MCV in patients under 3 months or more thiopurine treatment followed up¦in the Swiss IBD Cohort Study. All available MCV, white blood cells (WBC) and 6¦thioguanine nucleotide (6TGN) measurements, among others, were recorded. An IBD¦"flare" was defined as a composite outcome encompassing treatment change,¦colonoscopy, histology, CT scan or MRI reports showing active IBD lesions, occurrence of¦intestinal surgery and IBD-related hospitalisations. Whether MCV measurements predicted¦efficacy of thiopurine treatment was investigated by assessing the statistical association¦between the occurrence of IBD "flares", and the current or recent MCV values, taking into¦account the patient clustering and longitudinal aspect of data.¦Results¦140 patients (77 women), mean age 38 years (17-74), 104 diagnosed with¦Crohn's disease, 36 with ulcerative colitis, mean disease duration 8 years (0.25-36),¦receiving either azathioprine (n=125) or 6-mercaptopurine (n=15) were included, most of¦them over 3-year follow up.¦Thiopurines increased mean patient MCV by an average 5.8±5.2 fL, while¦patientsfluctuated by ±4.3 fL around their individual mean (p<0.001). They decreased¦WBC by an average of 2.4+/- 2.6 G/L (p<0.001).¦Significant associations were observed between the probability of flare occurrence and low¦current MVC (p=0.017) or high current WBC (p=0.009) and, with a relative risk of 3.7% for¦every fL of MCV decrease or 8% for every G/L of WBC increase. Both markers revealed¦some memory effect.¦Despite this, the performance of MCV and WBC to predict IBD "flare" remained rather¦limited, as it is less accurate than the 6-TGN-level , although only determined in a¦subgroup of patients in this study.¦Conclusion¦MCV and WBC deserve to be observed to check and monitor therapeutic¦exposure to thiopurine agents in IBD patients. Unfortunately, their predictive performance¦precludes their privileged use for optimization of therapy. Further prospective studies¦should suitably include the systematic measurement of metabolite concentration.

Overuse of upper gastrointestinal endoscopy in a country with open-access endoscopy: a prospective study in primary care.

BACKGROUND: This prospective observational study was aimed at evaluating the appropriateness of use of upper gastrointestinal endoscopy (UGE) in primary care in a country with open access to and high availability of the procedure. METHODS: Outpatients were consecutively included in two clinical settings: Setting A (20 primary care physicians during 4 weeks) and B (university-based outpatient clinic during 3 weeks). In patients undergoing UGE, appropriateness of referral was judged by explicit Swiss criteria developed by the RAND/UCLA panel method. RESULTS: Patient visits (8135) were assessed. Six hundred eleven patients complained of upper gastrointestinal symptoms. Physicians decided to perform UGE in 63 of these patients. Twenty-five (40%) of the endoscopies were rated appropriate, 7 (11%) equivocal, and 31 (49%) inappropriate. Overuse of UGE occurred in 5.1% (setting A: 4.7%; setting B:6.5%; p = 0.39) of the patients who presented with upper gastrointestinal symptoms. The decision to perform UGE in previously untreated dyspeptic patients was the most common clinical situation resulting in overuse. CONCLUSIONS: Inappropriate use of UGE is high in Switzerland. However, to better reflect primary care decision making, overuse should be related not only to patients referred for a medical test, but also to the number of patients who complain of the symptoms that would be investigated by the procedure.

Poststroke fatigue following minor infarcts: a prospective study.

OBJECTIVE: To explore the potential relationship between fatigue following strokes and poststroke mood, cognitive dysfunction, disability, and infarct site and to determine the predictive factors in the development of poststroke fatigue (PSF) following minor infarcts. METHODS: Ninety-nine functionally active patients aged less than 70 years with a first, nondisabling stroke (NIH Stroke Scale score ≤6 in acute phase and ≤3 after 6 months, modified Rankin Scale score ≤1 at 6 months) were assessed during the acute phase and then at 6 (T1) and 12 months (T2) after their stroke. Scores in the Fatigue Assessment Inventory were described and correlated to age, gender, neurologic and functional impairment, lesion site, mood scores, neuropsychological data, laboratory data, and quality of life at T1 and T2 using a multivariate logistic regression analysis in order to determine which variables recorded at T1 best predicted fatigue at T2. RESULT: As many as 30.5% of the patients at T1 and 34.7% at T2 (11.6% new cases between T1 and T2) reported fatigue. At both 6 and 12 months, there was a significant association between fatigue and a reduction in professional activity. Attentional-executive impairment, depression, and anxiety levels remained associated with PSF throughout this time period, underlining the critical role of these variables in the genesis of PSF. There was no significant association between the lesion site and PSF. CONCLUSION: This study suggests that attentional and executive impairment, as well as depression and anxiety, may play a critical role in the development of PSF.

Voluntary Explicit versus Involuntary Conceptual Memory Are Associated with Dissociable fMRI Responses in Hippocampus, Amygdala, and Parietal Cortex for Emotional and Neutral Word Pairs.

Although functional neuroimaging studies have supported the distinction between explicit and implicit forms of memory, few have matched explicit and implicit tests closely, and most of these tested perceptual rather than conceptual implicit memory. We compared event-related fMRI responses during an intentional test, in which a group of participants used a cue word to recall its associate from a prior study phase, with those in an incidental test, in which a different group of participants used the same cue to produce the first associate that came to mind. Both semantic relative to phonemic processing at study, and emotional relative to neutral word pairs, increased target completions in the intentional test, but not in the incidental test, suggesting that behavioral performance in the incidental test was not contaminated by voluntary explicit retrieval. We isolated the neural correlates of successful retrieval by contrasting fMRI responses to studied versus unstudied cues for which the equivalent "target" associate was produced. By comparing the difference in this repetition-related contrast across the intentional and incidental tests, we could identify the correlates of voluntary explicit retrieval. This contrast revealed increased bilateral hippocampal responses in the intentional test, but decreased hippocampal responses in the incidental test. A similar pattern in the bilateral amygdale was further modulated by the emotionality of the word pairs, although surprisingly only in the incidental test. Parietal regions, however, showed increased repetition-related responses in both tests. These results suggest that the neural correlates of successful voluntary explicit memory differ in directionality, even if not in location, from the neural correlates of successful involuntary implicit (or explicit) memory, even when the incidental test taps conceptual processes.

10-year follow-up of a prospective randomized trial comparing bare-metal stenting with internal mammary artery grafting for proximal, isolated de novo left anterior coronary artery stenosis the SIMA (Stenting versus Internal Mammary Artery grafting) trial

OBJECTIVES: This study was designed to compare the long-term clinical outcome of coronary artery bypass grafting (CABG) with intracoronary stenting of patients with isolated proximal left anterior descending coronary artery. BACKGROUND: Although numerous trials have compared coronary angioplasty with bypass surgery, none assessed the clinical evaluation in the long term. METHODS: We evaluated the 10-year clinical outcome in the SIMA (Stent versus Internal Mammary Artery grafting) trial. Patients were randomly assigned to stent implantation versus CABG. RESULTS: Of 123 randomized patients, 59 underwent CABG and 62 received a stent (2 patients were excluded). Follow-up after 10 years was obtained for 98% of the randomized patients. Twenty-six patients (42%) in the percutaneous coronary intervention group and 10 patients (17%) in the CABG group reached an end point (p < 0.001). This difference was due to a higher need for additional revascularization. The incidences of death and myocardial infarction were identical at 10%. Progression of the disease requiring additional revascularization was rare (5%) and was similar for the 2 groups. Stent thrombosis occurred in 2 patients (3%). Angina functional class showed no significant differences between the 2 groups. CONCLUSIONS: Both stent implantation and CABG are safe and highly effective in relieving symptoms in patients with isolated, proximal left anterior descending coronary artery stenosis. Stenting with bare-metal stents is associated with a higher need for repeat interventions. The long-term prognosis for these patients is excellent with either mode of revascularization.

A Prospective Multicenter SPOG 2003 FN Study of Microbiologically Defined Infections in Pediatric Cancer Patients with Fever and Neutropenia.

BACKGROUND: Fever and neutropenia (FN) often complicate anticancer treatment and can be caused by potentially fatal infections. Knowledge of pathogen distribution is paramount for optimal patient management. METHODS: Microbiologically defined infections (MDI) in pediatric cancer patients presenting with FN by nonmyeloablative chemotherapy enrolled in a prospective multi-center study were analyzed. Effectiveness of empiric antibiotic therapy in FN episodes with bacteremia was assessed taking into consideration recently published treatment guidelines for pediatric patients with FN. RESULTS: MDI were identified in a minority (22%) of pediatric cancer patients with FN. In patients with, compared to without MDI, fever (median, 5 [IQR 3-8] vs. 2 [IQR1-3] days, p < 0.001) and hospitalization (10 [6-14] vs. 5 [3-8] days, p < 0.001) lasted longer, transfer to the intensive care unit was more likely (13 of 95 [14%] vs. 7 of 346 [2.0%], p < 0.001), and antibiotics were given longer (10 [7-14] vs. 5 [4-7], p < 0.001). Empiric antibiotic therapy in FN episodes with bacteremia was highly effective if not only intrinsic and reported antimicrobial susceptibilities were considered but the purposeful omission of coverage for coagulase negative staphylococci and enterococci was also taken into account (81% [95%CI 68 - 90] vs. 96.6% [95%CI 87 - 99.4], p = 0.004) CONCLUSIONS: MDI were identified in a minority of FN episodes but they significantly affected management and the clinical course of pediatric cancer patients. Compliance with published guidelines was associated with effectiveness of empiric antibiotic therapy in FN episodes with bacteremia.

Existential values transformation in all organ transplantation : a qualitative prospective study

The aim of this qualitative study was to analyze psychological concerns in wait-listed patients T1 and six months after transplantation T2. Semi-structured interviews were conducted and qualitative analysis performed. T1 Kidney patients maintained apparent normality, building emotional protection, and a fatalist attitude. Liver patients set physical limits, reevaluation of life values was reported. Lung patients developed physical and psychological self-protection. Modified life values, fatalism and spirituality were mentioned. Heart patients husbanded ressources and self-protection. Modified life values, fatalist attitude were reported. T2 Kidney patients described new life perspectives and increase of empathy. Liver patients underlined positive identity and life values modifications. Lack of respect of life values generated anger. Heart and lung patients set their existential priorities and underlined increase in spirituality, greater openness and more closeness to significant ones. Lack of respect of human values induced negative feelings. TX comes with physical benefits, but also with positive existential values transformations and a humanistic, altruistic attitude.

Integrated Analysis of High-Resolution Gene Expression and Copy Number Profiling Identified Biallelic Deletion of CDKN2A/2B Tumor Suppressor Locus As the Most Frequent and Unique Genomic Abnormality in Diffuse Large B-Cell Lymphoma (DLBCL) with Strong Prognostic Value in Both GCB and ABC Subtypes and Not Overcome by a Dose-Intensive Immunochemotherapy Regimen Plus Rituximab. Results of a Prospective GELA Clinical Trial Program

Background and aim of the study: Genomic gains and losses play a crucial role in the development and progression of DLBCL and are closely related to gene expression profiles (GEP), including the germinal center B-cell like (GCB) and activated B-cell like (ABC) cell of origin (COO) molecular signatures. To identify new oncogenes or tumor suppressor genes (TSG) involved in DLBCL pathogenesis and to determine their prognostic values, an integrated analysis of high-resolution gene expression and copy number profiling was performed. Patients and methods: Two hundred and eight adult patients with de novo CD20+ DLBCL enrolled in the prospective multicentric randomized LNH-03 GELA trials (LNH03-1B, -2B, -3B, 39B, -5B, -6B, -7B) with available frozen tumour samples, centralized reviewing and adequate DNA/RNA quality were selected. 116 patients were treated by Rituximab(R)-CHOP/R-miniCHOP and 92 patients were treated by the high dose (R)-ACVBP regimen dedicated to patients younger than 60 years (y) in frontline. Tumour samples were simultaneously analysed by high resolution comparative genomic hybridization (CGH, Agilent, 144K) and gene expression arrays (Affymetrix, U133+2). Minimal common regions (MCR), as defined by segments that affect the same chromosomal region in different cases, were delineated. Gene expression and MCR data sets were merged using Gene expression and dosage integrator algorithm (GEDI, Lenz et al. PNAS 2008) to identify new potential driver genes. Results: A total of 1363 recurrent (defined by a penetrance > 5%) MCRs within the DLBCL data set, ranging in size from 386 bp, affecting a single gene, to more than 24 Mb were identified by CGH. Of these MCRs, 756 (55%) showed a significant association with gene expression: 396 (59%) gains, 354 (52%) single-copy deletions, and 6 (67%) homozygous deletions. By this integrated approach, in addition to previously reported genes (CDKN2A/2B, PTEN, DLEU2, TNFAIP3, B2M, CD58, TNFRSF14, FOXP1, REL...), several genes targeted by gene copy abnormalities with a dosage effect and potential physiopathological impact were identified, including genes with TSG activity involved in cell cycle (HACE1, CDKN2C) immune response (CD68, CD177, CD70, TNFSF9, IRAK2), DNA integrity (XRCC2, BRCA1, NCOR1, NF1, FHIT) or oncogenic functions (CD79b, PTPRT, MALT1, AUTS2, MCL1, PTTG1...) with distinct distribution according to COO signature. The CDKN2A/2B tumor suppressor locus (9p21) was deleted homozygously in 27% of cases and hemizygously in 9% of cases. Biallelic loss was observed in 49% of ABC DLBCL and in 10% of GCB DLBCL. This deletion was strongly correlated to age and associated to a limited number of additional genetic abnormalities including trisomy 3, 18 and short gains/losses of Chr. 1, 2, 19 regions (FDR < 0.01), allowing to identify genes that may have synergistic effects with CDKN2A/2B inactivation. With a median follow-up of 42.9 months, only CDKN2A/2B biallelic deletion strongly correlates (FDR p.value < 0.01) to a poor outcome in the entire cohort (4y PFS = 44% [32-61] respectively vs. 74% [66-82] for patients in germline configuration; 4y OS = 53% [39-72] vs 83% [76-90]). In a Cox proportional hazard prediction of the PFS, CDKN2A/2B deletion remains predictive (HR = 1.9 [1.1-3.2], p = 0.02) when combined with IPI (HR = 2.4 [1.4-4.1], p = 0.001) and GCB status (HR = 1.3 [0.8-2.3], p = 0.31). This difference remains predictive in the subgroup of patients treated by R-CHOP (4y PFS = 43% [29-63] vs. 66% [55-78], p=0.02), in patients treated by R-ACVBP (4y PFS = 49% [28-84] vs. 83% [74-92], p=0.003), and in GCB (4y PFS = 50% [27-93] vs. 81% [73-90], p=0.02), or ABC/unclassified (5y PFS = 42% [28-61] vs. 67% [55-82] p = 0.009) molecular subtypes (Figure 1). Conclusion: We report for the first time an integrated genetic analysis of a large cohort of DLBCL patients included in a prospective multicentric clinical trial program allowing identifying new potential driver genes with pathogenic impact. However CDKN2A/2B deletion constitutes the strongest and unique prognostic factor of chemoresistance to R-CHOP, regardless the COO signature, which is not overcome by a more intensified immunochemotherapy. Patients displaying this frequent genomic abnormality warrant new and dedicated therapeutic approaches.

Is Less Chemotherapy Detrimental in Adults with Philadelphia Chromosome (Ph)-Positive Acute Lymphoblastic Leukemia (ALL) Treated with High-Dose Imatinib? Results of the Prospective Randomized Graaph-2005 Study

Aim: To compare a less intensive regimen based on high-dose imatinib (IM) to an intensive IM/HyperCVAD regimen in adults with Ph+ ALL, in terms of early response and outcome after stem cell transplantation (SCT). Methods: Patients aged 18-60 years with previously untreated Ph+ ALL not evolving from chronic myeloid leukemia were eligible if no contra-indication to chemotherapy and SCT (ClinicalTrials.gov ID, NCT00327678). After a steroid prephase allowing Ph and/or BCR-ABL diagnosis, cycle 1 differed between randomization arms. In arm A (IM-based), IM was given at 800 mg on day 1-28, combined with vincristine (2 mg, day 1, 8, 15, 22) and dexamethasone (40 mg, day 1-2, 8-9, 15-16, and 22-23) only. In arm B (IM/HyperCVAD), IM was given at 800 mg on day 1-14, combined with adriamycin (50 mg/m2, day 4), cyclophosphamide (300 mg/m2/12h, day 1, 2, 3), vincristine (2 mg, day 4 and 11), and dexamethasone (40 mg, day 1-4 and 11-14). All patients received a cycle 2 combining high-dose methotrexate (1 g/m2, day 1) and AraC (3 g/m2/12h, day 2 and 3) with IM at 800 mg on day 1-14, whatever their response. Four intrathecal infusions were given during this induction/consolidation period. Minimal residual disease (MRD) was centrally evaluated by quantitative RQ-PCR after cycle 1 (MRD1) and cycle 2 (MRD2). Major MRD response was defined as BCR-ABL/ABL ratio <0.1%. Then, all patients were to receive allogeneic SCT using related or unrelated matched donor stem cells or autologous SCT if no donor and a major MRD2 response. IM/chemotherapy maintenance was planned after autologous SCT. In the absence of SCT, patients received alternating cycles 1 (as in arm B) and cycles 2 followed by maintenance, like in the published IM/HyperCVAD regimen. The primary objective was non-inferiority of arm A in term of major MRD2 response. Secondary objectives were CR rate, SCT rate, treatment- and transplant-related mortality, relapse-free (RFS), event-free (EFS) and overall (OS) survival. Results: Among the 270 patients randomized between May 2006 and August 2011, 265 patients were evaluable for this analysis (133 arm A, 132 arm B; median age, 47 years; median follow-up, 40 months). Main patient characteristics were well-balanced between both arms. Due to higher induction mortality in arm B (9 versus 1 deaths; P=0.01), CR rate was higher in the less intensive arm A (98% versus 89% after cycle 1 and 98% versus 91% after cycle 2; P= 0.003 and 0.006, respectively). A total of 213 and 205 patients were evaluated for bone marrow MRD1 and MRD2. The rates of patients reaching major MRD response and undetectable MRD were 45% (44% arm A, 46% arm B; P=0.79) and 10% (in both arms) at MRD1 and 66% (68% arm A, 63.5% arm B; P=0.56) and 25% (28% arm A, 22% arm B; P=0.33) at MRD2, respectively. The non-inferiority primary endpoint was thus demonstrated (P= 0.002). Overall, EFS was estimated at 42% (95% CI, 35-49) and OS at 51% (95% CI, 44-57) at 3 years, with no difference between arm A and B (46% versus 38% and 53% versus 49%; P=0.25 and 0.61, respectively). Of the 251 CR patients, 157 (80 arm A, 77 arm B) and 34 (17 in both arms) received allogeneic and autologous SCT in first CR, respectively. Allogeneic transplant-related mortality was similar in both arms (31.5% versus 22% at 3 years; P=0.51). Of the 157 allografted patients, 133 had MRD2 evaluation and 89 had MRD2 <0.1%. In these patients, MRD2 did not significantly influence post-transplant RFS and OS, either when tested with the 0.1% cutoff or as a continuous log covariate. Of the 34 autografted patients, 31 had MRD2 evaluation and, according to the protocol, 28 had MRD2 <0.1%. When restricting the comparison to patients achieving major MRD2 response and with the current follow-up, a trend for better results was observed after autologous as compared to allogeneic SCT (RFS, 63% versus 49.5% and OS, 69% versus 58% at 3 years; P=0.35 and P=0.08, respectively). Conclusions: In adults, the use of TK inhibitors (TKI) has markedly improved the results of Ph+ ALL therapy, now close to those observed in Ph-negative ALL. We demonstrated here that chemotherapy intensity may be safely reduced when associated with high-dose IM. We will further explore this TKI-based strategy using nilotinib prior to SCT in our next GRAAPH-2013 trial. The trend towards a better outcome after autologous compared to allogeneic SCT observed in MRD responders validates MRD as an important early surrogate endpoint for treatment stratification and new drug investigation in this disease.