Association of p53 gene alterations with the expression of antiapoptotic survivin splice variants in breast cancer.

Survivin, a member of the inhibitory apoptosis protein family, gives rise, by an alternative splicing, to four variants with different functions. Many experimental studies indicate that p53 can regulate the expression of survivin and some of its splice variants. Although both the expression of survivin splice variants and the p53 gene were frequently altered in human cancers, nothing is known about their interactions in in vivo tumour samples. Here, we report that, in 162 breast carcinomas, p53 mutations are significantly associated with an increased expression of survivin and, in particular, its antiapoptotic splice variants (survivin-DeltaEx3 and survivin-3B). The upregulation of these variant expressions is particularly related to p53 mutations occurring in the residues belonging to the tetramerization domain. The loss of heterozygosity in the p53 gene is also associated with an increased expression of the survivin-DeltaEx3 variant. The expression of the proapoptotic variants (survivin-2B and survivin-2alpha) is not affected by any of these alterations. Our results provide for the first time in vivo evidence that, in human breast cancer, the survivin expression as well as its splicing depends on the p53 status. The results also suggest that the upregulation of antiapoptotic survivin variant expression by the mutant p53 may increase breast cancer cells survival and resistance to therapy.

[Spontaneous pneumomediastinum in a 4-month-old boy]. / Pneumomédiastin spontané chez un nourrisson de 4 mois.

Spontaneous pneumomediastinum is a rare entity in children, especially in young infants. We report the case of a 4-month-old infant with a massive spontaneous pneumomediastinum caused by acute viral bronchiolitis. Treatment including bed rest, codeine for its antitussive action, and nitrogen washout resolved the pneumomediastinum within 3 days. In the literature, cases of pneumomediastinum in very young infants are exceptional. To our knowledge, codeine has never been used in this situation. Nitrogen washout is also rarely used because of poorly demonstrated efficacy.

Surveillance of carbapenemase-producing Enterobacteriaceae in the Indian Ocean Region between January 2010 and December 2015.

BACKGROUND: The aim of this study was to trace the emergence of carbapenemase-producing Enterobacteriaceae (CPE) on Reunion Island, a French overseas territory well suited for the surveillance of CPE emergence in patients from the entire Indian Ocean Region. METHODS: This retrospective multicenter study was conducted on Reunion Island between 2010 and 2015. RESULTS: A total of 43 CPEs were isolated during the course of the study, in 36 patients (50% in the last year alone). Among these patients, 21 had a link with a foreign country (58%), mainly Mauritius (47.6%). Over the same period, CPEs were isolated from 13 of 1735 (0.7%) repatriated patients to Reunion Island from another country of the Indian Ocean Region. The incidence of isolation of CPEs in the repatriated patients treated in Mauritius was higher (9.2%) than in patients treated in Madagascar or the Comoros Islands (<1%, P<0.001). The most commonly isolated microorganism was Klebsiella pneumoniae (39.5%). The most frequently identified carbapenemase was NDM-1 (81.4%); 100% and 56% of the NDM-1 strains were susceptible to tigecycline and colistin, respectively. In-hospital mortality rate was higher in patients presenting with CPE infection than in patients without CPE infection (75% vs. 25%, P=0.04). CONCLUSION: As elsewhere in the world, the number of CPE cases on Reunion Island is on the rise. Most cases involve patients from Mauritius, which justifies screening and isolating CPE in patients from that country.

Prevalence and risk factors of iron overload after hematopoietic stem cell transplantation for childhood acute leukemia: a LEA study.

Data on post-transplant iron overload (IO) are scarce in pediatrics. We conducted a prospective multicenter cohort study (Leucémie de l'Enfant et de l'Adolescent cohort) to determine the prevalence and risk factors of IO in 384 acute leukemia survivors transplanted during childhood. Prevalence of IO (ferritin level ⩾350 ng/mL) was 42.2% (95%CI 37.2-47.2%). Factors significantly associated with IO were: 1) in univariate analysis: older age at transplant (P<0.001), allogeneic versus autologous transplantation (P<0.001), radiation-based preparative regimen (P=0.035) and recent period of transplantation (P<0.001); 2) in multivariate analysis: older age at transplant in quartiles (Odds Ratio (OR)=7.64, 95% CI: 3.73-15.64 for age >12.7 years and OR=5.36, 95% CI: 2.63-10.95 for age from 8.2 to 12.7 years compared to age < 4.7 years), acute myeloid leukemia (OR=3.23, 95% CI: 1.47-7.13), allogeneic graft (OR=4.34, 95% CI: 2.07-9.12 for alternative donors and OR=2.53, 95% CI: 1.2-5.33 for siblings, compared to autologous graft) and radiation-based conditioning regimen (OR=2.45, 95% CI: 1.09-5.53). Graft-versus-host disease was an additional risk factor for allogeneic graft recipients. In conclusion, IO is a frequent complication in pediatric long-term survivors after transplantation for acute leukemia, more frequently observed in older children, those transplanted from alternative donors or with graft-versus-host disease.

Cytogenetics and outcome of allogeneic transplantation in first remission of acute myeloid leukemia: the French pediatric experience.

We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post-transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved.

Metabolic syndrome in adults who received hematopoietic stem cell transplantation for acute childhood leukemia: an LEA study.

We evaluated prospectively the incidence and risk factors of the metabolic syndrome (MS) and its components in 170 adult patients (mean age at evaluation: 24.8±5.4 years) who received an hematopoietic stem cell transplantation for childhood ALL, n=119, or AML, n=51. TBI was carried out in 124 cases; a busulfan-based conditioning was done in 30 patients. Twenty-nine patients developed a MS (17.1%, 95% confidence intervals: 11.7-23.6). The cumulative incidence was 13.4% at 25 years of age and 35.5% at 35 years of age. A higher body mass index (BMI) before transplantation and a growth hormone deficiency were associated with increased MS risk (P=0.002 and 0.01, respectively). MS risk was similar for patients who received TBI or busulfan-based conditioning. The TBI use increased the hyperglycemia risk (odds ratio (OR): 4.7, P=0.02). Women were at the risk of developing increased waist circumference (OR: 7.18, P=0.003) and low levels of high-density lipoprotein cholesterol (OR: 2.72, P=0.007). The steroid dose was not a risk factor. The MS occurs frequently among transplanted survivors of childhood leukemia. Its incidence increases with age. Both intrinsic (BMI, gender) and extrinsic factors (TBI, alkylating agents) contribute to its etiopathogenesis.

Risk factors of Ganciclovir-related neutropenia after allogeneic stem cell transplantation: a retrospective monocentre study on 547 patients.

Cytomegalovirus (CMV) infection is a serious complication that may occur in the weeks or months following bone marrow transplantation. However, both Ganciclovir and the CMV infection itself can cause marrow toxicity, notably neutropenia, that may consequently expose these immunosuppressed patients to life-threatening bacterial and/or fungal infections. The aim of this retrospective study was to identify factors associated with the occurrence of grade III-IV neutropenia among patients receiving pre-emptive Ganciclovir therapy after allogeneic stem cell transplantation at our Institution. We identified 547 consecutive patients transplanted from January 2005 to June 2011 at our Institution. In all, 190 patients (35%) presented with CMV reactivation of whom 30 patients (5%) were excluded from the analysis because they already had neutropenia at the time of reactivation. Finally, 160 (29%) patients were analysed. According to multivariate analysis, at the time of treatment initiation, the risk factors significantly associated with a grade III-IV Ganciclovir-related neutropenia included a high viral load (hazard ratio (HR) = 2.68, 95% CI 1.25-5.737, p 0.01); an absolute neutrophil count >3000 was a protective factor (HR = 0.26, 95% CI 0.125-0.545, p <0001) whereas serum creatinine >2 mg/dL was associated with higher Ganciclovir-related neutropenia (HR = 2.4, 95% CI 1.11-5.17, p 0.002). This large analysis revealed three risk factors for Ganciclovir-related neutropenia among patients with CMV reactivation after allogeneic stem cell transplantation; prompt identification of patients at risk when antiviral therapy is started may allow clinicians to adopt adequate preventive measures, so reducing the morbidity and mortality associated with CMV reactivation.

Tandem autologous-allo-SCT is feasible in patients with high-risk relapsed non-Hodgkin's lymphoma.

Allo-SCT is used to exploit GVL effect in high-risk relapsed non-Hodgkin's lymphoma (NHL). Here, we retrospectively analyzed 34 high-risk NHL patients who underwent auto-SCT followed closely by reduced-intensity allo-SCT ('tandem auto-allo') from January 2002 to November 2010. The search for an allogeneic donor was started at the beginning of salvage regimen. Median patients' age was 47 (27-68) years; histotypes were: diffuse large B-cell n=5, follicular n=14, transformed follicular n=4, mantle-cell n=5, plasmocytoid lymphoma n=1, anaplastic large T-cell n=2, peripheral T-cell n=3. Donors were HLA-identical siblings (n=29) or 10/10-matched unrelated individuals (n=5). Median interval between auto-SCT and allo-SCT was 77 days (36-197). At a median follow-up of 46 (8-108) months since allo-SCT, 5-year OS is 77% (61-93) and PFS is 68% (51-85). Disease relapse or progression occurred in six patients, 100-day TRM was 0%, 2-year TRM incidence was 6%. In conclusion, tandem transplantation is feasible in high-risk NHL patients having a HLA-identical donor. This approach could represent a suitable therapeutic option for those patients with high-risk NHL potentially benefitting from further therapy after auto-SCT. Donor searches should be started promptly whenever such an approach is chosen.

Efficacy and safety of micafungin for prophylaxis of invasive fungal infections in patients undergoing haplo-identical hematopoietic SCT.

Invasive fungal infections (IFIs) such as candidiasis and mold infections have caused significant morbidity and mortality among immunocompromised patients in recent years. Micafungin, a new echinocandin, inhibits fungal cell wall ß-glucan synthesis, with potent activity against most species of Candida and Aspergillus. The aim of this observational study was to investigate the efficacy and safety of micafungin in prophylaxis of IFIs in 26 high-risk adult patients with various hematological diseases receiving haplo-identical Allo-SCT. Only two patients had a history of possible aspergillosis before transplant treated by voriconazole. The patients received a median of four lines (2-7) of treatment before Allo-SCT. Thirteen patients (50%) received at least one prior Auto-SCT; and eight patients (31%) received a previous Allo-SCT. Patients received a median of 29 infusions (range, 15-85) of micafungin (50 mg/day i.v. as a 1-h infusion). The treatment was initiated at the beginning of the transplant conditioning regimen until the hospital discharge. None of our patients discontinued the treatment for drug-related adverse events. Micafungin was not associated with any hepatotoxicity. Only one patient (4%) discontinued the treatment because of early disease progression. In all patients no Candida and/or Aspergillus species was documented after 3 and 6 months from transplant. None of our patients presented a positive galactomannan antigenemia >0.5. Nine patients (35%) presented a CMV reactivation. Four patients presented an acute GVHD grade II and two patients presented a chronic GVHD. The median follow-up was 11 months (3-23). At the last follow-up, there were 20 patients (77%) who were alive; four patients (12%) died because of disease progression and two patients because of graft failure. Micafungin has a good safety and tolerability profile, with an efficacy in preventing IFI in this high-risk population. Our data provide support for an efficacy study in a prophylaxis setting, but prospective and comparative clinical trials using micafungin are urgently needed to define the role of this drug in prophylaxis after haplo-identical Allo-SCT.

Vancomycin prescription in neonates and young infants: toward a simplified dosage.

BACKGROUND: There is no consensus on vancomycin dosing in newborns and young infants. OBJECTIVE: The first objective was to assess the efficiency of a simplified dosing regimen with a cohort study. The secondary objective was to examine pharmacokinetic data to determine how this simplified dosing could be improved. METHODS: All neonates admitted to our intensive care unit and treated with vancomycin were included in the pharmacokinetic study (PK group, 83 treatments, 156 measurements). The vancomycin dosing regimen consisted of a loading dose of 7 mg/kg, followed by a constant continuous dose of 30 mg/kg/day. The target serum vancomycin concentration ranged from 10 mg/l to 30 mg/l. Data from patients whose medications followed the scheduled dosing without modifications or prescription errors (actual dosing group: 62 treatments, 108 measurements) were analysed separately. A population pharmacokinetic analysis was performed (PK group) to simulate several vancomycin dosings. RESULTS: Prescription errors were found in 10 of 83 treatments (12%). In the actual dosing group, 89.2% of vancomycin measurements were within the target range. Serum creatinine remained stable throughout treatment. Vancomycin concentrations varied widely. The modified regimen for a target vancomycin concentration of 25 mg/l consisted of a bolus of 20 mg/kg followed by continuous infusion of 30 mg/kg. CONCLUSION: Our pharmacokinetic data and bedside results suggest that a simplified schedule of vancomycin can achieve the targeted drug concentrations in most patients while avoiding secondary renal toxicity. The proposed new dosing scheme should be validated in a drug survey, but due to pharmacokinetic variability, still requires therapeutic drug monitoring.