Long-term morbidity and mortality in 2-year hepatoblastoma survivors treated with SIOPEL risk-adapted strategies.

BACKGROUND AND AIMS: Prognosis of hepatoblastoma patients has increased with cisplatin-based chemotherapy and high-quality resection including liver transplant. Consequently current risk-adapted therapeutic strategy aims to reduce long-term side effects in patients with standard risk disease. METHODS: We report long-term mortality and morbidity data concerning 151 2-year hepatoblastoma survivors treated with SIOPEL risk-adapted strategies (sex-ratio M/F = 1.6, median age at diagnosis = 2.6 years [range 0-17.7], median year at diagnosis = 2008 [1994-2017]). Fifty-three patients had loco-regional risk factors VPEFR, 12 were PRETEXT-IV and 30 were metastatic. All received cisplatin and 84 anthracyclines. Twelve had liver transplant. To assess hearing, renal and cardiac functions, audiograms were performed in 116/151 patients (76.8%), glomerular filtration rate in 113/151 (74.8%) and cardiac ultrasound in 65/84 (77.4%) anthracycline-exposed patients. RESULTS: With a median follow-up of 9.4 years (range 2.1-25.8), four late relapses, one second malignancy (Acute Myeloid Leukemia AML-M5) and two deaths (one from hepatoblastoma, one from AML) occurred. The 10-years event free survival and overall survival probabilities were 95.5% (95% CI 91.9-99.1) and 98.7% (95% CI 96.8-100), respectively. Sixty-eight non-oncologic health-events included 57 cases of hearing loss (including 25 Brock 3-4), three liver cirrhosis, three pre-operative portal cavernoma, two focal nodular hyperplasia, two grade-1 chronic kidney diseases and one asymptomatic cardiac dysfunction were reported. Ototoxicity was significantly associated with cisplatin cumulative dose (OR = 2.07, 95% CI 1.32-3.24, p = 0.001) and carboplatin exposure (OR = 3.14, 95% CI 1.30-7.58, p = 0.01) in multivariable analysis adjusted for sex and age at diagnosis. CONCLUSIONS: With current risk-adapted strategies, hepatoblastoma is a highly curable disease, with very rare relapses, and few late effects except hearing loss which remains a serious condition in these very young patients.

CNS-3 status remains an independent adverse prognosis factor in children with acute lymphoblastic leukemia (ALL) treated without cranial irradiation: Results of EORTC Children Leukemia Group study 58951.

AIM: To evaluate the prognostic significance of initial central nervous system (CNS) involvement of children with acute lymphoblastic leukemia (ALL) enrolled in the EORTC 58951 trial. PATIENTS AND METHODS: From 1998 to 2008, 1930 ALL patients were included in the randomized EORTC 58951 trial. Overall treatment intensity was adjusted according to known prognostic factors including the level of minimal residual disease after induction treatment. CNS-directed therapy comprised four to 11 courses of i.v. methotrexate (5g/m2), and 10 to 19 intrathecal chemotherapy injections, depending on risk group and CNS status. Cranial irradiation was omitted for all patients. RESULTS: The overall 8-year event-free survival (EFS) and overall survival (OS) rates were 81.3% and 88.1%, respectively. In the CNS-1, TPL+, CNS-2, and CNS-3 groups, the 8-year EFS rates were 82.1%, 77.1%, 78.3%, and 57.4%, respectively. Multivariable analysis indicated that initial CNS-3 status, but not CNS-2 or TLP+, was an independent adverse predictor of outcome. The 8-year incidence of isolated CNS relapse was 1.7% and of isolated or combined CNS relapse it was 3.7%. NCI high-risk group, male sex, CNS-2 and CNS-3 status were independent predictors for a higher incidence of any CNS relapse. CONCLUSIONS: CNS-3 status remains associated with poor prognosis and requires intensification of both systemic and CNS-directed therapy. This trial was registered at https://clinicaltrials.gov/under/NCT00003728.

A MALDI-TOF MS database for fast identification of Vibrio spp. potentially pathogenic to marine mollusks.

In mollusk aquaculture, a large number of Vibrio species are considered major pathogens. Conventional methods based on DNA amplification and sequencing used to accurately identify Vibrio species are unsuitable for monitoring programs because they are time-consuming and expensive. The aim of this study was, therefore, to develop the MALDI-TOF MS method in order to establish a rapid identification technique for a large panel of Vibrio species. We created the EnviBase containing 120 main spectra projections (MSP) of the Vibrio species that are potentially responsible for mollusk diseases, comprising 25 species: V. aestuarianus, V. cortegadensis, V. tapetis and species belonging to the Coralliilyticus, Harveyi, Mediterranei, and Orientalis clades. Each MSP was constructed by the merger of raw spectra obtained from three different media and generated by three collaborating laboratories to increase the diversity of the conditions and thus obtain a good technique robustness. Perfect discrimination was obtained with all of the MSP created for the Vibrio species and even for very closely related species as V. europaeus and V. bivalvicida. The new EnviBase library was validated through a blind test on 100 Vibrio strains performed by our three collaborators who used the direct transfer and protein extraction methods. The majority of the Vibrio strains were successfully identified with the newly created EnviBase by the three laboratories for both protocol methods. This study documents the first development of a freely accessible database exclusively devoted to Vibrio found in marine environments, taking into account the high diversity of this genus. KEY POINTS: • Development of a MALDI-TOF MS database to quickly affiliate Vibrio species. • Increase of the reactivity when faced with Vibrio associated with mollusk diseases. • Validation of MALDI-TOF MS as routine diagnostic tool.

External pH modulation during the growth of Vibrio tapetis, the aetiological agent of brown ring disease.

AIMS: Brown ring disease (BRD) is an infection of the Manila clam Ruditapes philippinarum due to the pathogen Vibrio tapetis. During BRD, clams are facing immunodepression and shell biomineralization alteration. In this paper, we studied the role of pH on the growth of the pathogen and formulated hypothesis on the establishment of BRD by V. tapetis. METHODS AND RESULTS: In this study, we monitored the evolution of pH during the growth of V. tapetis in a range of pH and temperatures. We also measured the pH of Manila clam haemolymph and extrapallial fluids (EPFs) during infection by V. tapetis. We highlighted that V. tapetis modulates the external pH during its growth, to a value of 7·70. During the development of BRD, V. tapetis also influences EPFs and haemolymph pH in vitro in the first hours of exposure and in vivo after 3 days of infection. CONCLUSIONS: Our experiments have shown a close interaction between V. tapetis CECT4600, a pathogen of Manila clam that induces BRD, and the pH of different compartments of the animals during infection. These results indicate that the bacterium, through a direct mechanism or as a consequence of physiological changes encountered in the animal during infection, is able to interfere with the pH of Manila clam fluids. This pH modification might promote the infection process or at least create an imbalance within the animal that would favour its persistence. This last hypothesis should be tested in future experiment. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first observation of pH modifications in the context of BRD and might orient future research on the fine mechanisms of pH modulation associated with BRD.

A proteomic study of resistance to Brown Ring disease in the Manila clam, Ruditapes philippinarum.

Marine mollusk aquaculture has more than doubled over the past twenty years, accounting for over 15% of total aquaculture production in 2016. Infectious disease is one of the main limiting factors to the development of mollusk aquaculture, and the difficulties inherent to combating pathogens through antibiotic therapies or disinfection have led to extensive research on host defense mechanisms and host-pathogen relationships. It has become increasingly clear that characterizing the functional profiles of response to a disease is an essential step in understanding resistance mechanisms and moving towards more effective disease control. The Manila clam, Ruditapes philippinarum, is a main cultured bivalve species of economic importance which is affected by Brown Ring disease (BRD), an infection induced by the bacterium Vibrio tapetis. In this study, juvenile Manila clams were subjected to a 28-day controlled challenge with Vibrio tapetis, and visual and molecular diagnoses were carried out to distinguish two extreme phenotypes within the experimental clams: uninfected ("RES", resistant) and infected ("DIS", diseased) post-challenge. Total protein extractions were carried out for resistant and diseased clams, and proteins were identified using LC-MS/MS. Protein sequences were matched against a reference transcriptome of the Manila clam, and protein intensities based on label-free quantification were compared to reveal 49 significantly accumulated proteins in resistant and diseased clams. Proteins with known roles in pathogen recognition, lysosome trafficking, and various aspects of the energy metabolism were more abundant in diseased clams, whereas those with roles in redox homeostasis and protein recycling were more abundant in resistant clams. Overall, the comparison of the proteomic profiles of resistant and diseased clams after a month-long controlled challenge to induce the onset of Brown Ring disease suggests that redox homeostasis and maintenance of protein structure by chaperone proteins may play important and interrelated roles in resistance to infection by Vibrio tapetis in the Manila clam.

Outcome after failure of allogeneic hematopoietic stem cell transplantation in children with acute leukemia: a study by the société Francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in the case of post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent 10-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted of chemotherapy alone (n=108), chemotherapy followed by second SCT (n=70), supportive/palliative care (n=67), combination of chemotherapy and donor lymphocyte infusion (DLI; n=30), or isolated reinfusion of donor lymphocytes (DLI; n=13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy=385 days, second allograft=391 days, chemotherapy=174 days, DLI alone=140 days, palliative care=43 days. A second SCT or a combination of chemotherapy and DLI yielded similar outcome (hazard ratio (HR)=0.85, P=0.53) unlike chemotherapy alone (HR=1.43 P=0.04), palliative care (HR=4.24, P<0.0001) or isolated DLI (HR=1,94, P<0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML.

Strain and Magnetic Field Induced Spin-Structure Transitions in Multiferroic BiFeO3.

The magnetic-field-dependent spin ordering of strained BiFeO3 films is determined using nuclear resonant scattering and Raman spectroscopy. The critical field required to destroy the cycloidal modulation of the Fe spins is found to be significantly lower than in the bulk, with appealing implications for field-controlled spintronic and magnonic devices.

[Hodgkin disease revealed by a nephrotic syndrome: A case report]. / Lymphome de Hodgkin révélé par un syndrome néphrotique : à propos d'un cas.

Pediatric nephrotic syndrome (NS) is most often idiopathic or primary but in rare cases, it can be secondary to neoplasia. We report on a case of steroid-resistant NS revealing as a paraneoplastic syndrome of Hodgkin disease (HD) in a 12-year-old boy. The onset of the NS can be earlier, later, or simultaneous to the HD. Treatment of the lymphoma allows the disappearance of the NS. In the case we observed, the diagnosis of HD was delayed because HD presented with an isolated, hilar adenopathy in the absence of retroperitoneal or peripheral locations. In children aged 10 years or more presenting with NS, steroid-resistant or otherwise, a possible paraneoplastic origin such as Hodgkin lymphoma should always be taken into consideration and eventually eliminated.

Hematopoietic stem cell transplantation in relapsed ALK+ anaplastic large cell lymphoma in children and adolescents: a study on behalf of the SFCE and SFGM-TC.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a treatment option for relapsed anaplastic large cell lymphoma (ALCL) in children, but reports on its efficacy in this disease are still limited. We analyzed data concerning 34 patients under 18 years of age prospectively registered in the French SFGM-TC database, who had undergone an allo-SCT for the treatment of ALK+ ALCL between 1993 and 2011. At transplant, 28 patients (82.4%) were in CR, whereas 6 exhibited detectable disease. Conditioning regimens were mostly myelo-ablative (n=31). With a median follow-up of 6 years, 5-year overall and event-free survival rates were 70% (SE=8%) and 58% (SE=9%), respectively. The 5-year cumulative incidence of relapse and treatment-related mortality was 18% (SE=7%) and 24% (SE=8%), respectively. Six patients had relapsed (median time, 141 days (35-235)). A durable CR had been obtained in 4/6 patients after injection of donor lymphocytes (n=1) or vinblastine-corticosteroid therapy (n=3). Ten patients had died, eight due to transplant toxicity and two due to progressive disease. Allo-SCT is an efficient treatment for pediatric patients with high-risk relapsed ALK+ ALCL. However, the overall morbidity of allo-SCT raises questions about its place, given the efficacy of targeted agents currently under development in this disease.

Childhood acute lymphoblastic leukaemia and indicators of early immune stimulation: the Estelle study (SFCE).

BACKGROUND: Factors related to early stimulation of the immune system (breastfeeding, proxies for exposure to infectious agents, normal delivery, and exposure to animals in early life) have been suggested to decrease the risk of childhood acute lymphoblastic leukaemia (ALL). METHODS: The national registry-based case-control study, ESTELLE, was carried out in France in 2010-2011. Population controls were frequency matched with cases on age and gender. The participation rates were 93% for cases and 86% for controls. Data were obtained from structured telephone questionnaires administered to mothers. Odds ratios (OR) were estimated using unconditional regression models adjusted for age, gender, and potential confounders. RESULTS: In all, 617 ALL and 1225 controls aged ⩾1 year were included. Inverse associations between ALL and early common infections (OR=0.8, 95% confidence interval (CI): 0.6, 1.0), non-first born (⩾3 vs 1; OR=0.7, 95% CI: 0.5, 1.0), attendance of a day-care centre before age 1 year (OR=0.7, 95% CI: 0.5, 1.0), breastfeeding (OR=0.8, 95% CI: 0.7, 1.0), and regular contact with pets (OR=0.8, 95% CI: 0.7, 1.0) in infancy were observed. CONCLUSIONS: The results support the hypothesis that conditions promoting the maturation of the immune system in infancy have a protective role with respect to ALL.

[Allogeneic stem cell transplantation from an HLA-haploidentical related donor: SFGM-TC recommendations (part 2)]. / Greffes de cellules souches hématopoïétiques à partir d'un donneur haploidentique : recommandations de la SFGM-TC (deuxième partie).

Haploidentical allogeneic stem cell transplantation (CST) has globally taken off in the past decade. It appears to be a valid alternative to other sources of stem cells; however, further research is necessary to validate the use of this approach in standard patient care. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. This is part two of the recommendations regarding allogeneic stem cell transplantation from an HLA-haploidentical related donor.

[SFGM-TC recommendation on indications for allogeneic stem cell transplantation in children with congenital neutropenia]. / Indications d'allogreffe dans les neutropénies constitutionnelles : recommandation de la SFGM-TC.

In this report, we address the issue of allogeneic stem cell transplantation in children with congenital neutropenia. Constitutional disorders with neutropenia are exceptional. Treatment and prevention of severe infections are a major concern in the management of chronic neutropenia. These disorders, especially Kostmann's disease and Shwachman-Bodian-Diamond syndrome, are associated with an increased risk of leukemia. The role of allogeneic stem cell transplantation in these patients is still unclear. In an effort to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille.

[Allogeneic stem cell transplantation from an HLA-haploidentical related donor: SFGM-TC recommendations (Part 1)]. / Greffes de cellules souches hématopoïétiques à partir d'un donneur haplo-identique : recommandations de la SFGM-TC (première partie).

Haploidentical allogeneic stem cell transplantation (CST) has globally taken off in the past decade. It appears to be a valid alternative to other sources of stem cells; however, further research is necessary to validate the use of this approach in standard patient care. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. This is part one of the recommendations regarding allogeneic stem cell transplantation from an HLA-haploidentical related donor.

Impact of uncontrolled freezing and long-term storage of peripheral blood stem cells at - 80 °C on haematopoietic recovery after autologous transplantation. Report from two centres.

Controlled-rate freezing and storage in vapour phase nitrogen are used by most transplantation teams for the cryopreservation and storage of peripheral blood haematopoietic stem cells (PBSC). In this study, we analysed 666 autologous PBSC transplants after uncontrolled freezing and storage of PBSC at -80 °C. Statistical analysis showed that neutrophil recovery was associated with both the infused CD34(+) cell dose (P=0.01) and the post transplantation use of growth factors (P<0.001) and that platelet recovery was associated with the infused CD34(+) cell dose (P<0.001) and with the diagnosis (P=0.02). We analysed three groups according to the duration of the cryopreservation period (less than 6 months, between 6 and 12 months or more than 1 year). Haematopoietic recovery was not found to be adversely affected by longer storage at -80 °C. The haematopoietic recoveries of 50 pairs of sequential transplantations from the same PBSC mobilization were analysed. Despite prolonged cryopreservation, there were no statistically significant differences in neutrophil (P=0.09) or platelet (P=0.22) recovery in the second compared with the first transplant. In conclusion, the long-term storage of PBSC at -80 °C after uncontrolled-rate freezing is an easy and comparatively inexpensive cryopreservation method that leads to successful haematopoietic recovery even after prolonged storage.

Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment.

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-SCT) may provide donor cytotoxic T cell-/NK cell-mediated disease control in patients with rhabdomyosarcoma (RMS). However, little is known about the prevalence of graft-vs-RMS effects and only a few case experiences have been reported. METHODS: We evaluated allo-SCT outcomes of 30 European Group for Blood and Marrow Transplantation (EBMT)-registered patients with advanced RMS regarding toxicity, progression-free survival (PFS) and overall survival (OS) after allo-SCT. Twenty patients were conditioned with reduced intensity and ten with high-dose chemotherapy. Twenty-three patients were transplanted with HLA-matched and seven with HLA-mismatched grafts. Three patients additionally received donor lymphocyte infusions (DLIs). Median follow-up was 9 months. RESULTS: Three-year OS was 20% (s.e.±8%) with a median survival time of 12 months. Cumulative risk of progression was 67% (s.e.±10%) and 11% (s.e.±6%) for death of complications. Thirteen patients developed acute graft-vs-host disease (GvHD) and five developed chronic GvHD. Eighteen patients died of disease and four of complications. Eight patients survived in complete remission (CR) (median: 44 months). No patients with residual disease before allo-SCT were converted to CR. CONCLUSION: The use of allo-SCT in patients with advanced RMS is currently experimental. In a subset of patients, it may constitute a valuable approach for consolidating CR, but this needs to be validated in prospective trials.

[Diagnosis and treatment of CMV and EBV Reactivation as well as Post-transplant Lymphoproliferative Disorders following Allogeneic Stem Cell Transplantation: An SFGM-TC report]. / Prise en charge d'une réactivation/infection à CMV chez l'allogreffé et prise en charge de la réactivation EBV/syndrome lymphoproflifératif à EBV chez l'allogreffé de cellules souches hématopoïétiques.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here the SFGM-TC addressed the issue of post-transplant CMV and EBV reactivation, and EBV-related Lymphoproliferative Disorders.

Reduced-intensity conditioning followed by allogeneic transplantation in pediatric malignancies: a report from the Société Française des Cancers de l'Enfant and the Société Française de Greffe de Moelle et de Thérapie Cellulaire.

We report French prospective experience with reduced-intensity conditioning-allo-SCT in 46 patients (median age: 15.5 years, 4.8-20.2) presenting high-risk AL (n=11), Hodgkin's lymphoma (n=15) or solid tumors (n=20). Graft sources were BM (n=21), PBSC (n=20) and cord blood (CB; n=5) from related (n=20) or unrelated (n=26) donors. For CB grafts, only one patient out of five achieved sustained engraftment. For PBSC/BM grafts, engraftment rate was 95%, hematopoietic recovery times were not significantly different between BM, PBSC, sibling or unrelated grafts, day+100. Full donor chimerism was achieved in 94% of patients, and incidences of primary acute GVHD and chronic GVHD were 49% and 14%, respectively. Underlying disease was fatal in 39% of patients. TRM was 6.9%. Three-year OS was 49.15%. OS and EFS were not significantly different between patients transplanted with different grafts and with or without primary GVHD. Patients with solid tumor or measurable disease at transplant had poorer outcomes. Three-year EFS: 33.3% for ALL, 75.0% for AML, 51.8% for Hodgkin's lymphoma, 28.6% for neuroblastoma and 22.2% for sarcoma patients. This multicentre study concluded that Bu/fludarabine/anti-thymocyte globulin conditioning with PB or BM, related or unrelated grafts in patients with various malignancies at high-risk for transplantation toxicity results in high engraftment rates, low TRM and acceptable survival.

Long-term red blood cell exchange in children with sickle cell disease: manual or automatic?

Little information is available on erythrocytapheresis in children with sickle cell disease, and no comparison has ever been made with manual exchanges in a long-term blood exchange program. We matched a historical cohort of five patients who received 60 erythrocytapheresis procedures with five who received 124 manual exchanges. Long-term erythrocytapheresis was feasible and well-tolerated even in children of low weight. In a long-term approach, automated exchanges were more efficient in maintaining a low HbS level, and exchanges could be spaced out. This approach appears especially useful in the cases where the HbS level must be maintained below 30%.

[Megakaryoblastic acute leukemia: bone and joint manifestations in a 7-month-old child]. / Présentation ostéo-articulaire d'une leucémie aiguë mégacaryoblastique chez une enfant de 7 mois.

Acute megakaryoblastic leukemia accounts for approximately 3-10% of acute myeloid leukemia in children. Its diagnosis may be difficult because of associated myelofibrosis. We report the case of a 7-month-old child who presented hepatomegaly with bicytopenia. She also developed bone and joint pain with recurrent aseptic arthritis. We suggested the diagnosis of megakaryoblastic leukemia early but multiple bone marrow investigations had been processed without positive results because of sampling problems and lack of abnormal cells in the morphological, phenotypic, and cytogenetic examinations. We had a variety of indirect evidence for our assumption: the x-ray showing periosteal new bone, lytic lesions and metaphyseal bands, bone marrow aspirate smears with micromegakaryocytes, and bone marrow biopsy suggesting myelofibrosis. This was very suggestive of leukemia but we could not prove it and we finally found megakaryoblasts on bone marrow aspirate smears after more than 2 months of investigation and initiated a course of corticosteroids.