Impact of detectable measurable residual disease on umbilical cord blood transplantation.

The impact of measurable residual disease (MRD) on cord blood transplantation (CBT) outcomes has remained debated. To address this issue, we assessed the impact of measurable MRD at CBT on outcomes in large cohort of patients with acute leukemia. Inclusion criteria included adult patients with acute myeloid (AML) or acute lymphoblastic leukemia (ALL), CBT as first allo-HCT in first or second complete remission (CR) at transplantation, and known MRD status at the time of CBT. Data from 506 patients were included in the analysis. Among them, 317 patients had AML and 189 had ALL. Positive MRD was reported in 169 (33%) patients while the remaining 337 patients were MRD negative at CBT. At 2 years, relapse incidence was 18% in patients with MRD negativity vs 33% in those with MRD positivity at transplantation (P < .001). Two-year leukemia-free survival (LFS) and overall survival (OS) were 57% and 60%, respectively, in MRD negative patients, vs 38% (P < .001) and 48% (P = .004), respectively, in those with MRD positivity. There was no interaction between the impact of MRD on OS and LFS and diagnosis (ie, ALL vs AML), single or double CBT, and reduced-intensity or myeloablative conditioning. On multivariate analysis, MRD positivity was associated with a higher risk of relapse (HR = 1.8, P = .003), comparable non-relapse mortality (P = .44), worse LFS (HR = 1.4, P = .008) and a trend towards worse OS (HR = 1.3, P = .065). In conclusion, these data suggest that novel strategies that are aiming to achieve MRD negativity at CBT are needed for leukemic patients with positive MRD pre-CBT.

Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation.

RATIONALE: Systemic steroids are the standard treatment for bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) despite their poor efficacy and disabling side effects. OBJECTIVES: To evaluate the effectiveness and tolerance of budesonide/formoterol as an alternative treatment for BOS after HSCT. METHODS: In this randomized, double-blind, placebo-controlled study, we randomly assigned 32 HSCT recipients with mild/severe BOS to receive budesonide/formoterol or placebo for 6 months. The primary outcome was the change in the FEV1 after 1 month of treatment (M1) compared with the baseline value. Patients were unblinded at M1 if there was no improvement in the FEV1. Those who had initially received placebo were switched to budesonide/formoterol. Intention-to-treat analysis was performed to assess the primary outcome. Additional analyses took scheduled treatment contamination into account. MEASUREMENTS AND MAIN RESULTS: At M1, the median FEV1 increased by 260 ml in the budesonide/formoterol arm compared with 5 ml in the placebo arm (P = 0.012). The median increases in the FEV1 at M1 relative to the baseline value for the treated and placebo groups were 13 and 0%, respectively (P = 0.019). Twenty-five patients received budesonide/formoterol during the study. The median difference in the FEV1 between the baseline and after 1 month of treatment for these patients was +240 ml (P = 0.0001). The effect of budesonide/formoterol on the FEV1 was maintained in the 13 patients who completed 6 months of treatment. CONCLUSIONS: Budesonide/formoterol administration led to a significant improvement in the FEV1 in patients with mild/severe BOS after allogeneic HSCT. Clinical trial registered with www.clinicaltrials.gov (NCT00624754).

Cost-effectiveness and clinical outcomes of double versus single cord blood transplantation in adults with acute leukemia in France.

Double cord blood transplantation extends the use of cord blood to adults for whom a single unit is not available, but the procedure is limited by its cost. To evaluate outcomes and cost-effectiveness of double compared to single cord blood transplantation, we analyzed 134 transplants in adults with acute leukemia in first remission. Transplants were performed in France with reduced intensity or myeloablative conditioning regimens. Costs were estimated from donor search to 1 year after transplantation. A Markov decision analysis model was used to calculate quality-adjusted life-years and cost-effectiveness ratio within 4 years. The overall survival at 2 years after single and double cord blood transplants was 42% versus 62%, respectively (P=0.03), while the leukemia-free-survival was 33% versus 53%, respectively (P=0.03). The relapse rate was 21% after double transplants and 42% after a single transplant (P=0.006). No difference was observed for non-relapse mortality or chronic graft-versus-host-disease. The estimated costs up to 1 year after reduced intensity conditioning for single and double cord blood transplantation were € 165,253 and €191,827, respectively. The corresponding costs after myeloablative conditioning were € 192,566 and € 213,050, respectively. Compared to single transplants, double cord blood transplantation was associated with supplementary costs of € 21,302 and € 32,420 up to 4 years, but with increases in quality-adjusted life-years of 0.616 and 0.484, respectively, and incremental cost-effectiveness ratios of € 34,581 and €66,983 in the myeloablative and reduced intensity conditioning settings, respectively. Our results showed that for adults with acute leukemia in first complete remission in France, double cord transplantation is more cost-effective than single cord blood transplantation, with better outcomes, including quality-adjusted life-years.

Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study.

BACKGROUND: The results of the addition of gemtuzumab ozogamicin, an anti-CD33 antibody conjugate, to the standard treatment for patients with acute myeloid leukaemia in phase 3 trials were contradictory. We investigated whether the addition of low fractionated-dose gemtuzumab ozogamicin to standard front-line chemotherapy would improve the outcome of patients with this leukaemia without causing excessive toxicity. METHODS: In a phase 3, open-label study, undertaken in 26 haematology centres in France, patients aged 50-70 years with previously untreated de novo acute myeloid leukaemia were randomly assigned with a computer-generated sequence in a 1:1 ratio with block sizes of four to standard treatment (control group) with or without five doses of intravenous gemtuzumab ozogamicin (3 mg/m(2) on days 1, 4, and 7 during induction and day 1 of each of the two consolidation chemotherapy courses). The primary endpoint was event-free survival (EFS). Secondary endpoints were relapse-free (RFS), overall survival (OS), and safety. Analysis was by intention to treat. This study is registered with EudraCT, number 2007-002933-36. FINDINGS: 280 patients were randomly assigned to the control (n=140) and gemtuzumab ozogamicin groups (n=140), and 139 patients were analysed in each group. Complete response with or without incomplete platelet recovery to induction was 104 (75%) in the control group and 113 (81%) in the gemtuzumab ozogamicin group (odds ratio 1·46, 95% CI 0·20-2·59; p=0·25). At 2 years, EFS was estimated as 17·1% (10·8-27·1) in the control group versus 40·8% (32·8-50·8) in the gemtuzumab ozogamicin group (hazard ratio 0·58, 0·43-0·78; p=0·0003), OS 41·9% (33·1-53·1) versus 53·2% (44·6-63·5), respectively (0·69, 0·49-0·98; p=0·0368), and RFS 22·7% (14·5-35·7) versus 50·3% (41·0-61·6), respectively (0·52, 0·36-0·75; p=0·0003). Haematological toxicity, particularly persistent thrombocytopenia, was more common in the gemtuzumab ozogamicin group than in the control group (22 [16%] vs 4 [3%]; p<0·0001), without an increase in the risk of death from toxicity. INTERPRETATION: The use of fractionated lower doses of gemtuzumab ozogamicin allows the safe delivery of higher cumulative doses and substantially improves outcomes in patients with acute myeloid leukaemia. The findings warrant reassessment of gemtuzumab ozogamicin as front-line therapy for acute myeloid leukaemia. FUNDING: Wyeth (Pfizer).

Comparison of high-dose cytarabine and timed-sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study.

To assess the value of administering timed-sequential chemotherapy (TSC; 2 therapeutic sequences separated by a 4-day interval-free chemotherapy) or high-dose cytarabine (HDAraC) cycles in consolidation therapy for acute myeloid leukemia (AML), 459 patients 15 to 50 years of age were enrolled in the prospective randomized Acute Leukemia French Association-9802 trial. Complete remission was achieved in 89%. A total of 237 patients were then randomized to either TSC consolidation (120 patients) or HDAraC consolidation cycles (117 patients). Overall, there was no significant difference between the 2 consolidation arms (5-year event-free survival [EFS]: 41% for HDAraC vs 35% for TSC), or cumulative incidence of relapse, or treatment-related mortality. Cytogenetically normal AML NPM1(+) or CEBPA(+) and FLT3-ITD(-) had the same outcome as those with favorable cytogenetics. When considering favorable and unfavorable risk groups, the trend was in favor of HDAraC. However, the difference became significant when considering intermediate cytogenetics (5-year EFS: 49% vs 29%; P = .02), especially cytogenetically normal AML (5-year EFS: 48% vs 31%; P = .04), which was related to lower relapse rate and less toxicity. This study demonstrates that TSC did not produce any benefit when used as consolidation therapy in younger adults compared with HDAraC. This trial was registered at www.clinicaltrials.gov as #NCT00880243.

Allogeneic stem cell transplantation for chronic myelomonocytic leukemia: a report from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire.

OBJECTIVES AND METHODS: Chronic myelomonocytic leukemia (CMML) is a severe disease for which allogeneic stem cell transplantation (allo-SCT) remains the only potentially curative treatment. We describe a retrospective study determining prognostic factors for outcome after allo-SCT in consecutive 73 patients with CMML reported to the SFGM-TC registry between 1992 and 2009. RESULTS: At diagnosis, median age was 53 yrs, and 36% patients had palpable splenomegaly (SPM). 48, 13, and 9 patients had good, intermediate, and poor risk karyotype, respectively, according to IPSS, 61% patients had CMML-1, and 39% had CMML-2. 41/31/1 cases had an HLA-identical sibling, an unrelated and haploidentical donor, respectively. 43 patients received reduced-intensity conditioning. With a median follow-up of 23 month, acute grade 2-4 and chronic GVHD developed in 21 and 25 patients, respectively. The 3-year OS, NRM (non-relapse mortality),EFS, and CIR (cumulative incidence of relapse) were 32%, 36%, 29% and 35%, respectively. OS was not influenced by the CR status, marrow blasts% at allo-SCT, prior treatments, and cGVHD. Using multivariate analysis, year of transplant < 2004 (YOT) (P = 0.005) was associated with higher NRM, YOT <2004 (P = 0.04) and SPM at allo-SCT (P = 0.02) with lower EFS, and YOT < 2004 (P = 0.03) and SPM at allo-SCT (P = 0.04) with poorer OS. CONCLUSIONS: Allogeneic stem cell transplantation is a valid treatment option for patients with CMML, and its outcome has improved with YOT > 2004. Splenomegaly seems to be a negative factor of OS and EFS in this series.

Peripherally inserted central catheter placement in cancer patients with profound thrombocytopaenia: a prospective analysis.

OBJECTIVE: No studies have specifically evaluated the safety of peripherally inserted central catheter (PICC) placement in patients with profound thrombocytopaenia. We prospectively determined the frequency of haemorrhagic complications of PICC placement in cancer patients with uncorrected profound thrombocytopaenia. METHODS: Profound thrombocytopaenia was defined as a platelet count <50 × 10(9)/l. No patients received transfusions before or after the procedure. Three types of adverse effects were analysed: minor oozing, mild haematoma and major haemorrhage. RESULTS: One hundred and forty-three PICC implantations in 101 cancer patients were prospectively included in the study: seven patients (7 %) had a solid tumour and 94 (93 %) a haematological malignancy. Among these 143 procedures in thrombocytopaenic patients, 93 (65 %) were performed with a platelet count 20-50 × 10(9)/l and 50 (35 %) had lower than 20 × 10(9)/l. No major haemorrhage was observed. Minor oozing was observed in six implantations (4 %) and mild haematoma in two (1.5 %), for a total of eight minor haemorrhagic adverse events (5.5 %). In patients with a platelet count <20 × 10(9)/l, 1/50 (2 %) had minor oozing and none had minor haematoma. CONCLUSIONS: In cancer patients with uncorrected profound thrombocytopaenia, the incidence of adverse events after PICC implantation was low, and was limited to minor haemorrhagic adverse events. KEY POINTS: • PICC placement has high technical success in profound thrombocytopaenic cancer patients. • Few adverse events are encountered after PICC placement, limited to minor haemorrhage. • PICC placement does not routinely require platelet transfusion in patients with thrombocytopaenia. • Such PICC placement still seems safe when the platelet count is <20 × 10 (9) /l.

Effectiveness and safe use of modified FOLFOX-6 for metastatic gastric cancer with signet ring cell components complicated by disseminated intravascular coagulation and diffuse bone marrow carcinomatosis.

We report the case of a 62-year-old woman with a metastatic gastric cancer complicated by diffuse bone marrow carcinomatosis, disseminated intravascular coagulation (DIC) and microangiopathic hemolytic anemia (MHA) treated by modified FOLFOX-6 as front-line chemotherapy regimen. This chemotherapy showed clinical, morphological and biological efficiency and safety in this rare and severe hematological complication at initial diagnosis. Furthermore, this is the first case of diffuse bone carcinomatosis from a gastric cancer to be monitored by positron emission tomography integrated computed tomography (PET-CT) scan using 18-fluorodeoxyglucose (18-FDG).

[Primary granulocytic sarcoma of the peritoneum: a case report and literature review]. / Sarcome granulocytaire à localisation péritonéale primitive : à propos d'un cas et revue de la littérature.

Granulocytic sarcoma is a rare tumor composed of immature granulocytic cells. Prognosis is poor. The periosteum is preferentially involved. A peritoneum localization is unusual. We report the case of a 20 years old man without particular previous pathologies, which brutally presented an ascitic syndrome in a context of health impairment state. The laparoscopy showes many white nodules on all the peritoneum. The histologic examination of one of these nodules showed granulocytic sarcoma. The blood and bone marrow cell count are without any anomaly. The treatment consisted of a standard acute myeloid leukaemia's chemotherapy with very good evolution. The rarity of peritoneal chloroma causes a diagnostic problem, especially in the absence of hematologic abnormalities. It must be mentioned in the presence of peritoneal nodules even if the blood count and bone marrow are normal.

Hematopoietic Recovery using Multi-Cytokine Therapy in 8 Patients Presenting Radiation-Induced Myelosuppression after Radiological Accidents.

Treatment of accidental radiation-induced myelosuppression is primarily based on supportive care and requires specific treatment based on hematopoietic growth factors injection or hematopoietic cell transplantation for the most severe cases. The cytokines used consisted of pegylated erythropoietin (darbepoetin alfa) 500 IU once per week, pegylated G-CSF (pegfilgrastim) 6 mg × 2 once, stem cell factor 20 µg.kg-1 for five days, and romiplostim (TPO analog) 10 µg.kg -1 once per week, with different combinations depending on the accidents. As the stem cell factor did not have regulatory approval for clinical use in France, the French regulatory authorities (ANSM, formerly, AFSSAPS) approved their compassionate use as an investigational drug "on a case-by-case basis". According to the evolution and clinical characteristics, each patient's treatment was adopted on an individual basis. Daily blood count allows initiating G-CSF and SCF delivery when granulocyte <1,000/mm3, TPO delivery when platelets <50,000/mm3, and EPO when Hb<80 g/L. The length of each treatment was based on blood cell recovery criteria. The concept of "stimulation strategy" is linked to each patient's residual hematopoiesis, which varies among them, depending on the radiation exposure's characteristics and heterogeneity. This paper reports the medical management of 8 overexposed patients to ionizing radiation. The recovery of bone marrow function after myelosuppression was accelerated using growth factors, optimized by multiple-line combinations. Particularly in the event of prolonged exposure to ionizing radiation in dose ranges inducing severe myelosuppression (in the order of 5 to 8 Gy), with no indication of hematopoietic stem cell transplantation.

Low nonrelapse mortality and prolonged long-term survival after reduced-intensity allogeneic stem cell transplantation for relapsed or refractory diffuse large B cell lymphoma: report of the Société Française de Greffe de Moelle et de Thérapie Cellulaire.

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have a very poor prognosis. However, they may achieve long-term survival by undergoing allogeneic stem cell transplantation (SCT). The purpose of this study was to assess the outcome of all adult patients with DLBCL whose treatment included a reduced-intensity conditioning (RIC) regimen for allogeneic SCT and whose data were reported in the French Society of Marrow Transplantation and Cellular Therapy registry. Sixty-eight patients (median age: 48 years) were transplanted from October 1998 to January 2007. They had received a median of 2 regimens of therapy prior to allogeneic SCT, and 54 (79%) had already undergone SCT. Prior to transplantation, 32 patients (47%) were in complete remission (CR). For all patients but 1, conditioning regimens were based on fludarabine (Flu), which was combined with other chemotherapy drugs in 50 cases (74%) and with total body irradiation (TBI) in 17 (25%). For 56 patients (82%), the donor was an HLA-matched sibling, and peripheral blood was the most widely used source of stem cells (57 patients, 84%). With a median follow-up of 49 months, estimated 2-year overall survival (OS), progression-free survival (PFS), and the cumulative incidence of relapse were 49%, 44%, and 41%, respectively. The 1-year cumulative incidence of nonrelapse mortality (NRM) was 23%. According to multivariate analysis, the patients in CR before transplantation had a significantly longer PFS and a lower CI of relapse than patients transplanted during partial remission or stable or progressive disease. These results suggest that reduced-intensity allergenic transplantation is an attractive therapeutic option for patients with high-risk DLBCL.

Emerging therapy for improving wound repair of severe radiation burns using local bone marrow-derived stem cell administrations.

The therapeutic management of severe radiation burns remains a challenging issue today. Conventional surgical treatment including excision, skin autograft, or flap often fails to prevent unpredictable and uncontrolled extension of the radiation-induced necrotic process. In a recent very severe accidental radiation burn, we demonstrated the efficiency of a new therapeutic approach combining surgery and local cellular therapy using autologous mesenchymal stem cells (MSC), and we confirmed the crucial place of the dose assessment in this medical management. The patient presented a very significant radiation lesion located on the arm, which was first treated by several surgical procedures: iterative excisions, skin graft, latissimus muscle dorsi flap, and forearm radial flap. This conventional surgical therapy was unfortunately inefficient, leading to the use of an innovative cell therapy strategy. Autologous MSC were obtained from three bone marrow collections and were expanded according to a clinical-grade protocol using platelet-derived growth factors. A total of five local MSC administrations were performed in combination with skin autograft. After iterative local MSC administrations, the clinical evolution was favorable and no recurrence of radiation inflammatory waves occurred during the patient's 8-month follow-up. The benefit of this local cell therapy could be linked to the "drug cell" activity of MSC by modulating the radiation inflammatory processes, as suggested by the decrease in the C-reactive protein level observed after each MSC administration. The success of this combined treatment leads to new prospects in the medical management of severe radiation burns and more widely in the improvement of wound repair.

IL-24 induces apoptosis of chronic lymphocytic leukemia B cells engaged into the cell cycle through dephosphorylation of STAT3 and stabilization of p53 expression.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of long-lived monoclonal B cells mostly arrested at the G(0)/G(1) phase of the cell cycle. CLL cells strongly express intracellular melanoma differentiation-associated gene-7 (MDA7)/IL-24. However, adenovirus-delivered MDA7 was reported to be cytotoxic in several tumor cell lines. We report herein that rIL-24 alone had no effect; however, sequential incubation with rIL-2 and rIL-24 reduced thymidine incorporation by 50% and induced apoptosis of CLL cells in S and G(2)/M phases of the cell cycle, but not of normal adult blood or tonsil B cells. IL-24 stimulated STAT3 phosphorylation in IL-24R1-transfected cells but not in normal or CLL B cells. In contrast, IL-24 reversed the IL-2-induced phosphorylation of STAT3 in CLL, and this effect was neutralized by anti-IL-24 Ab. Phospho- (P)STAT3 inhibition induced by IL-24 was reversed by pervanadate, an inhibitor of tyrosine phosphatases. The addition of rIL-24 to IL-2-activated CLL B cells resulted in increases of transcription, protein synthesis. and phosphorylation of p53. The biological effects of IL-24 were reversed by the p53 inhibitor pifithrin-alpha and partly by the caspase inhibitor zvad. Troglitazone (a protein tyrosine phosphatase, PTP1B activator) phosphatase inhibited PSTAT3 and augmented p53 expression. PSTAT3 is a transcriptional repressor of p53, and therefore IL-24 induction of p53 secondary to PSTAT3 dephosphorylation may be sensed as a stress signal and promote apoptosis in cycling cells. This model explains why IL-24 can protect some resting/differentiated cells and be deleterious to proliferating cells.

Risk factors and decision criteria for intensive chemotherapy in older patients with acute myeloid leukemia.

BACKGROUND: There is a need for standardization of treatment decisions in older patients with acute myeloid leukemia. The aim of the present study was to analyze the decisional value of poor risk factors in 416 elderly patients treated in the ALFA-9803 trial in order to derive a decisional index. DESIGN AND METHODS: Standard multivariate analysis was used to identify risk factors for overall survival. Risk factors were then considered as good decision tools if associated with a frequency >10% and a false positive rate <10% in predicting overall survival as poor as observed after low-dose cytarabine therapy (25% survival or less at 12 months). RESULTS: Among six independent risk factors (age, performance status, white blood cell count, hematopoietic cell transplantation comorbidity index, infection at baseline, and cytogenetics), cytogenetics was the only potent, independent decision tool. High hematopoietic cell transplantation comorbidity index scores or infections were found too rarely to guide further decisions. The three other factors (age, performance status, and white cell count) needed to be combined to provide a good specificity. The proposed decisional index, therefore, included high-risk cytogenetics and/or the presence of at least two of the following criteria: age > or =75 years, performance status > or =2, and white cell count > or =50 x 10(9)/L. This simple two-class decisional index, which was validated in an independent patient set, enabled us to discriminate 100 patients (24%) who had an estimated overall survival of only 19% at 12 months, with a good 9% false positive rate. CONCLUSIONS: We propose waiting for cytogenetic information before making treatment decisions in elderly patients with acute myeloid leukemia. Those patients with unfavorable cytogenetics, as well as patients with at least two of the following features, age > or =75 years, performance status > or =2, and white cell count > or =50 x 10(9)/L, should not be considered for standard intensive chemotherapy (ClinicalTrials.gov identifier: NCT00363025).

[Treatment of radiation burns with surgery and cell therapy. A report of two cases]. / Irradiation aiguü localisée: chirurgie et thérapie cellulaire. A propos de deux cas.

Treatment of severe radiation burns remains a difficult challenge. Conventional surgical treatment (excision, skin grafting, skin or muscle flaps) often fails to prevent unpredictable and uncontrolled extension of the necrotic process. We report two clinical cases in which surgery was combined with mesenchymal stem cell (MSC) therapy. Clinical outcome was good and there was no recurrence of radiation inflammatory waves observed in the first patient after one year. This novel multi-disciplinary therapeutic approach, combining physical techniques, modern plastic surgery and cell therapy should improve the medical management of severe localized radiation burns.

[Efficacy of rituximab in hairy cell leukemia]. / Efficacité du rituximab dans la leucémie à tricholeucocytes.

INTRODUCTION: Rituximab is an alternative treatment for hairy cell leukemia, when the standard treatments are unavailable. CASE: An 82-year-old woman was diagnosed with hairy cell leukemia. The severity of her neutropenia ruled out purine analogs, while heart disease and age both contraindicated use of interferon. Rituximab, in four weekly treatments, was effective from the first treatment and the positive response was sustained thereafter. DISCUSSION: Rituximab may be used to treat hairy cell leukemia, especially for patients refractory to purine analogs or after relapse or in the case of severe neutropenia, when interferon is contraindicated.

Osteogenic Potential of Mesenchymal Stromal Cells Contributes to Primary Myelofibrosis.

Primary myelofibrosis is a myeloproliferative neoplasm that is a precursor to myeloid leukemia. Dysmegakaryopoiesis and extramedullary hematopoiesis characterize primary myelofibrosis, which is also associated with bone marrow stromal alterations marked by fibrosis, neoangiogenesis, and osteomyelosclerosis. In particular, contributions to primary myelofibrosis from mesenchymal stromal cells (MSC) have been suggested by mouse studies, but evidence in humans remains lacking. In this study, we show that bone marrow MSCs from primary myelofibrosis patients exhibit unique molecular and functional abnormalities distinct from other myeloproliferative neoplasms and these abnormalities are maintained stably ex vivo in the absence of leukemic cells. Primary myelofibrosis-MSC overexpressed heparin-binding cytokines, including proinflammatory TGFß1 and osteogenic BMP-2, as well as glycosaminoglycans such as heparan sulfate and chondroitin sulfate. Transcriptome and functional analyses revealed alterations in MSC differentiation characterized by an increased osteogenic potential and a TGFß1 signaling signature. Accordingly, phospho-Smad2 levels were intrinsically increased in primary myelofibrosis-MSC along with enhanced expression of the master bone regulator RUNX2, while inhibition of the endogenous TGFß1 receptor TGFßR1 impaired osteogenic differentiation in these MSCs. Taken together, our results define the source of a critical osteogenic function in primary myelofibrosis that supports its pathophysiology, suggesting that combined targeting of both the hematopoietic and stromal cell compartments in primary myelofibrosis patients may heighten therapeutic efficacy.

EPR retrospective dosimetry with fingernails: report on first application cases.

For localized irradiation to hands, in case of sources accidentally handled, it is very difficult to estimate the dose distribution by calculation. Doses may reach several tens of grays, and the dose distribution is usually very heterogeneous. Until recently, doses in such situations could be estimated only by analysis of bone biopsies using Electron Paramagnetic Resonance (EPR) spectroscopy. This technique was used previously on surgical wastes or after amputation of a finger. In this case, the dose information was available in one or a few locations on the hand only, due to the limited number of biopsy fragments usually collected. The idea to measure free radicals (FRs) induced by radiation in nails to estimate a dose is not new, but up to now, no application cases were reported. As a matter of fact, the EPR analysis of nails is complex due to the presence of intrinsic signals and parasitic signals induced by the mechanical stress (when nails are collected), which overlaps the radio-induced components. In addition, the radio-induced FRs identified up to now are unstable and very sensitive to humidity. In these conditions, it was difficult to foresee any application for dosimetry with fingernails. Recently, stable radio-induced FRs in nails has been identified and an associated protocol for dose assessment developed. This protocol has been applied by the Institut de Radioprotection et de Sûreté Nucléaire on fingernail samples from victims of three different radiological accidents that occurred between 2008 and 2012 in different places.