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Multidisciplinary team meetings are a current international practice in cancer care, but to date, few data exist on the specificity of its practice in hematology. In this manuscript, we present the result of the first national study, realized with quantitative and qualitative methods in France, which brings new insights in order to improve the collegial decision-making process. To improve the effectiveness of MDTMs, the needs to focus on complex cases, to enhance patient centeredness and teamwork are relevant aspects, and a specific focus on hematological particularities is warranted to truly improve process. Background Understanding the Multidisciplinary team meetings (MDTMs) process in different medical specialties facilitates the identification of core factors supporting effective MDTM work. Our mixed-methods study explores the participants' perceptions of hematology MDTMs. Design Online questionnaires collected data concerning the decision-making process, benefits and inconveniences of MDTMs for both patients and professionals. Semi-directive phone interviews were conducted and analyzed, thereby supplying qualitative data. Results A total of 205 professionals responded to the questionnaire and 22 participated in the qualitative interviews. The data indicate the unique characteristics of hematology, including a specific definition of collegiality, the frequent solicitation of expert advice and the anticipation of treatment even prior to the occurrence of MDTMs. Additional information concerning patients' wishes and psychosocial conditions are also needed. Participants emphasize the subjective aspects and the impact of the climate of MDTMs on medical decisions. Conclusion Although MDTMs are recognized to be a valuable tool, organizational and relational issues may interfere with their efficiency. To improve the effectiveness of MDTMs, the needs to focus on complex cases, to enhance patient centeredness and teamwork are relevant aspects. A specific focus on hematological particularities might be warranted to truly improve the collegial decision-making process in the context of hematology. [ABSTRACT FROM AUTHOR]

The article offers information on the ethical measures of clinical research to improve medical care including creation of evidence based medicine, continual adaptation of scientific knowledge and biomedical sciences. Topics include progress in the quality of care, medical ethics and care in hematology.

Résumé: L'intégrité scientifique est un ensemble de règles qui gouvernent la pratique de la recherche et qui ont pour but de faire adopter par chaque chercheur une conduite intègre et honnête. Les manquements à l'intégrité scientifique ont des retentissements et un impact sociétal plus ou moins grands : certains sont pénalement condamnés, d'autres ne font que pénaliser la communauté scientifique. Voilà plus de 10 ans que le sujet de l'intégrité scientifique à grande échelle émerge au travers d'articles spécialisés, d'affaires retentissantes ou de changements institutionnels. À l'heure de la mise en place du plan S en France comme en Europe – peu connu et qui va pourtant dynamiter le monde de l'édition scientifique traditionnel – nous proposons une revue pédagogique de la littérature sur l'intégrité scientifique et plus particulièrement dans le contexte français. [ABSTRACT FROM AUTHOR]

Abstract: Monitoring of human herpesvirus-6 (HHV-6) reactivation is important, especially in immunocompromised patients such as transplant recipients. Reverse transcription PCR (RT-PCR) is a useful method to distinguish between latent and active infection. Here, a RT-nested PCR coupled with a colorimetric plate hybridization assay was established to detect HHV-6 types A and B U79/80 mRNAs. After confirming the reliability of the assay on HHV-6 cultures, it was applied to the detection of HHV-6 reactivation after renal (27 patients), bone marrow (14 patients) or heart (7 patients) transplantation. A total of 206 blood samples were tested from renal (137), bone marrow (58) and heart (11) transplant recipients. U79/80 mRNAs were found in 32 samples that were considered as indicative of HHV-6 reactivation: 15, 13 and 5 from kidney, bone marrow and heart transplant recipients, respectively. Finally, U79/80 mRNA detection was correlated with clinical manifestations including leucopenia, skin rash, graft rejection or dysfunction and diarrhoea. [Copyright &y& Elsevier]

Abstract: The ability of prostaglandin E2 (PGE2) to regulate the immune system is well documented. PGE2 effects are mediated through interactions with four distinct membrane EP receptors (EP1–4). We investigated, for the first time, the functionality of EP receptors on immature forms of blast cells of acute myeloid leukemic (AML) and acute lymphoid leukemic (ALL) patients. RT-PCR experiments documented the presence of the four EP receptor subtype transcripts in leukemic blasts of AML M0, AML M1, AML M2 and ALL patients. Western blot analysis only documented the presence of the EP2 receptor. Functional assays (cAMP production, calcium flux) confirmed Western blot results, i.e., the presence of functional EP2 receptors. Results of the present study suggest that the mechanism used by PGE2 to influence blast physiology is mediated through the EP2 receptor subtype, and subsequently through a cAMP-elevating effect. Results obtained with M0–2 subtypes have to be necessarily extended to more differentiated phenotype. [Copyright &y& Elsevier]

Introduction La transfusion plaquettaire (plq) ABO incompatible (plq non ABO) des patients (pts) est en augmentation en situation d’allogreffe (G). La HAS (niveau preuve 2) incite à éviter ces incompatibilités. Nous déterminons l’incidence du signalement d’effets indésirables (EIR) dans cette situation. Méthodes Les pts allogreffés à Limoges (couple D/R O/O) transfusés en plq non ABO (pré et/ou post G) sont inclus de façon rétrospective, à partir du logiciel Traceline (Mak-system). L’étude est descriptive (test statistique de comparaison χ 2 ). Résultats Entre 2005 et 2016, 47 G ont été réalisées pour 46 pts (34 H, 12 F) et un âge médian de 54 ans. Il y a plus de O+/O+ ( n = 35). Trente et un G (65,9 %) ont reçues des plq non ABO en pré-/post- G, une majorité de CPA A (pré G : n = 63, post G : n = 50). En moyenne, 61,6 PSL ont été transfusés dans le groupe plq non ABO et 20 PSL pour l’autre groupe. Un ratio de 12/47 G (25,5 %) ont une EIR (grade 1) : 3 anti-HLA (3 anti-RH3 dont un avec un anti-RH 1), 1 anti-JK2 (G sans plq non ABO), 2 allergies, 2 RFNH et 1 hyperthermie avant CSH. Un ratio de 11/12 EIR (91,7 %) concernent des G avec plq non ABO, dont 7/11 en pré-G. Il existe significativement plus d’EIR avec les plq non ABO, p = 0,002, sans différence significative entre CPA et MCP. Conclusion Les EIR sont surtout des immunisations anti-érythrocytaires. Leur origine principale est la transfusion de plq (CGR phénotypés RH-KELL), et nécessitent des CGR phénotypés et compatibilisés avec un risque d’impasse transfusionnelle. Le nombre de PSL transfusés est significatif, à corréler avec le contexte de G. Une étude prospective est nécessaire, la transfusion plq en incompatibilité ABO est plus à risque d’EIR. [ABSTRACT FROM AUTHOR]

Summary: Treatment with azacitidine (AZA) has been suggested to be of benefit for higher‐risk myelodysplastic syndrome (HR‐MDS) patients with chromosome 7 abnormalities (Abn 7). This retrospective study of 235 HR‐MDS patients with Abn 7 treated with AZA (n = 115) versus best supportive care (BSC; n = 120), assessed AZA treatment as a time‐varying variable in multivariable analysis. A Cox Regression model with time‐interaction terms of overall survival (OS) at different time points confirmed that, while chromosome 7 cytogenetic categories (complex karyotype [CK] versus non‐CK) and International Prognostic Scoring System risk (high versus intermediate‐2) retained poor prognosis over time, AZA treatment had a favourable impact on OS during the first 3 years of treatment compared to BSC (Hazard ratio [HR] 0·5 P < 0·001 at 1 year, 0·7 P = 0·019 at 2 years; 0·73 P = 0·029 at 3 years). This benefit was present in all chromosome 7 categories, but tended to be greater in patients with CK (risk reduction of 82%, 68% and 53% at 1, 3 and 6 months in CK patients; 79% at 1 month in non‐CK patients, P < 0·05 for all). AZA also significantly improved progression‐free survival (P < 0·01). This study confirms a time‐dependent benefit of AZA on outcome in patients with HR‐MDS and cytogenetic abnormalities involving chromosome 7, especially for those with CK. [ABSTRACT FROM AUTHOR]

At home injectable chemotherapy for patients receiving treatment for hematological diseases is still in debate. Given the expense of new innovative medicines, at home treatment has been proposed as a suitable option for improving patient quality of life and decreasing treatment costs. We decided to assess the cost of bortezomib administration in France among multiple myeloma patients from an economic standpoint. Patients in this study were treated within a regional hematological network combining outpatient hospital care and Hospital care at Home administration. To make the cost comparison, our team simulated outpatient hospital care expenses. Fifty-four consecutive multiple myeloma patients who received at least one injection of bortezomib in Hospital care at Home from January 2009 to December 2011 were included in the study. The median number of injections was 12 (range 1-44) at home and 6 (range 0-30) in the outpatient care unit. When compared with the cost simulation of outpatient hospital care alone, bortezomib administration with combined care was significantly less expensive for the National Health Insurance (NHI) budget. The mean total cost per patient and per injection was 954.20 € for combined outpatient and Hospital care at Home vs 1143.42 € for outpatient hospital care alone. This resulted in an estimated 16.5 % cost saving (Wilcoxon signed-rank test, p < 0.0001). The greatest savings were observed in administration costs (37.5 % less) and transportation costs (68.1 % less). This study reflects results for a regionally implemented program for multiple myeloma patients treated with bortezomib in routine practice in a large rural area. [ABSTRACT FROM AUTHOR]

The article focuses on diagnosing myelodysplastic syndrome according to the World Health Organization (WHO), which included a refractory cytopenia with unilineage dysplasia (RCUD) category in 2008. Topics discussed include findings of the rare occurrence of WHO 2008 refractory neutropenia (RN) and refractory thrombocytopenia (RT) diagnoses, diagnosis of single cytopenia after 2008, and AML progression in IN and IT.

Background: If the law called ‘‘Leonetti’’ enacted in 2005 allows patients to prepare and submit their advance directives (AD), its ownership in hospital services is still very punctual, even in clinical hematology services where illnesses are severe and can be life-threatening. The objective of our study was to evaluate the impact of a dual approach: caregiver training and information to patients on AD. The secondary objectives are to analyze the obstacles to their appropriation by caregivers and better understanding of the meaning patients give to the AD. Method: Establishment of a proactive approach in a clinical hematology service to encourage discussions about AD and proxy (PC). This multi-professional approach and multi-step was done from 2008 to 2016 targeting both caregiver training and information for patients and their families. The indicator chosen was a joint analysis of both quantitative number of PC and AD traced and collected in the medical records of all patients with malignancies of 2 consecutive periods in 2010 and 2012. A qualitative analysis was conducted among caregivers on the brakes to their ownership and content of DA collected within the service to determine the use of DA by patients. Results: Of the samples, respectively 80 and 197 patients, the percentage of patients who designate a PC is equivalent (from 63 % to 64.5 %) however AD increased from 0 % to 6.1 %. Despite the modest features of these results, they are well above the 2.5 % reported by INED. Qualitative analysis of 6 AD brings up two main themes: the patient’s wishes for his care (therapeutic limitation and management of pain) associated or not with personal messages. The qualitative interviews with carers highlighted five obstacles to their ownership: ignorance of the law of general public, the barrier of writing, the lack of anticipation, the fear of death and difficulties to discuss end of life issues. Conclusion: The law that would register at the societal level strengthening patient self-determination rights is not an easy application because it is not fully known. Our questioning concerns the meaning that patients give to AD, which does not only correspond to the proportionality of care and end of life. An authentic appropriation of AD is possible but requires time, support and better social distribution upstream. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates whether acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) blasts express phospholipase A2 receptors (PLA2-R). It shows the results of real-time polymerase chain reaction (PCR) analysis. Using Western blotting, it analyzes the presence of PLA2-R protein.

Background: Diffuse large B-cell lymphoma (DLBCL) is a fatal malignancy that needs to identify new targets for additional therapeutic options. This study aimed to clarify the clinical and biological significance of endogenous neurotrophin (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) in DLBCL biopsy samples and cell lines.Methods: We analysed expression of NGF, BDNF, and their receptors (Trk, p75(NTR)) in 51 biopsies and cell lines by immunohistochemistry, immunofluorescence, and western blotting. To investigate the biological role of BDNF/TrkB/p75(NTR) axis, effects of neurotrophin signalling inhibition were determined on tumour cell survival and vascular endothelial growth factor (VEGF) secretion. The pharmacological pan-Trk inhibitor K252a was used for in vitro and in vivo studies.Results: A BDNF/TrkB axis was expressed in all biopsies, which was independent of the germinal centre B-cell (GCB)/non-GCB profile. p75(NTR), TrkB, and BDNF tumour scores were significantly correlated and high NGF expression was significantly associated with MUM1/IRF4, and the non-GCB subtype. Diffuse large B-cell lymphoma cell lines co-expressed neurotrophins and their receptors. The full-length TrkB receptor was found in all cell lines, which was also phosphorylated at Tyr-817. p75(NTR) was associated to Trk and not to its cell death co-receptor sortilin. In vitro, inhibition of neurotrophin signalling induced cell apoptosis. K252a caused cell apoptosis, decreased VEGF secretion, and potentiated rituximab effect, notably in less rituximab-sensitive cells. In vivo, K252a significantly reduced tumour growth and potentiated the effects of rituximab in a GCB-DLBCL xenograft model.Conclusions: This work argues for a pro-survival role of endogenous neurotrophins in DLBCLs and inhibition of Trk signalling might be a potential treatment strategy for rituximab resistant subgroups. [ABSTRACT FROM AUTHOR]

The present study describes the current clinical practice and hospital management of adults with immune thrombocytopenia (ITP) between 2009 and 2012 in France, based on the national discharge hospital database. Adult ITP patients were managed almost exclusively in public hospitals. A relatively stable number of patients, around 3200 per year, were hospitalized for ITP annually over the 4-year period, about two-thirds of whom were newly-diagnosed ITP. Re-hospitalizations tended to decrease over the study period. Intravenous immunoglobulin administration, concerning half of ITP hospitalized patients, and rituximab administration were stable over time, whereas a slight decrease of splenectomies was observed. [ABSTRACT FROM AUTHOR]

BACKGROUND: Reports of patients with secondary acute promyelocytic leukemia (APL) have increased in recent years, particularly for those who received treatment with mitoxantrone, and retrospective studies have suggested that their characteristics and outcomes were similar to those of patients with de novo APL. METHODS: The authors investigated patients with de novo and secondary APL who were included in the ongoing APL-2006 trial. Patients with secondary APL who were included in that trial also were compared with a previous retrospective cohort of patients with secondary APL. RESULTS: In the APL-2006 trial, 42 of 280 patients (15%) had secondary APL. Compared with the retrospective cohort, patients with secondary APL in the APL-2006 trial had a lower incidence of prior breast carcinoma (35.7% vs 57%; P = .03) and a higher incidence of prior prostate carcinoma (26.2% vs 4.7%; P < .001). Treatment of the primary tumor in the APL-2006 trial less frequently included combined radiochemotherapy (28.6% vs 47.2%; P = .044) and no mitoxantrone (0% vs 46.7%; P = .016) but more frequently included anthracyclines (53.3% vs 38.3%; P = .015). In the APL-2006 trial, patients who had secondary APL, compared with those who had de novo APL, were older (mean, 60.2 years vs 48.7 years, respectively; P < .0001) but had a similar complete response rate (97.6% vs 90.3%, respectively), cumulative incidence of relapse (0% vs 1.8%, respectively), and overall survival (92.3% vs 90.9%, respectively) at 18 months. CONCLUSIONS: Although the incidence of secondary APL appears to be stable over time, evolving strategies for the treatment of primary cancers have reduced its occurrence among breast cancer patients but have increased its incidence among patients with prostate cancer. The current results confirm prospectively that patients with secondary APL have characteristics and outcomes similar to those of patients with de novo APL. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) is a pro-angiogenic cytokine activated by tissue-type plasminogen activator (tPA) that might play a role in the progression of multiple myeloma (MM). Preliminary studies indicated that serum HGF levels were higher in patients with AL amyloidosis (AL) compared to those with MM. The aim of the present study was to determine whether HGF is a relevant marker of diagnosis and prognosis in AL. HGF serum levels were measured at diagnosis in patients with monoclonal gammopathy (MG) without AL (76 controls), or with biopsy-proven systemic AL (69 patients). HGF serum levels were significantly higher in patients with AL compared to controls, respectively, 11.2 ng/mL [min: 0.95-max: 200.4] versus 1.4 ng/mL [min: 0.82-max: 6.2] ( p < 0.0001). The threshold value of 2.2 ng/mL conferred optimal sensitivity (88%) and specificity (95%) to differentiate AL and monoclonal gammopathy of undetermined significance (MGUS) patients. Serum HGF concentrations were correlated positively with the severity of cardiac involvement and the serum level of monoclonal light chains. These data suggest that HGF measurement could be used in patients with MG to detect AL or to reinforce a clinical suspicion of AL and to guide indications for diagnostic tissue biopsies. [ABSTRACT FROM AUTHOR]

The treatment of chronic myeloid leukemia (CML) has seen several major advances over the past 30 years, notably with the introduction of interferon followed by Bcr-Abl tyrosine kinase inhibitors. We analyzed trends in the incidence of CML and patient survival in France. All cases recorded in five population-based registries between 1980 and 2009 were included. European (ESR) and world (WSR) standardized incidence rates as well as relative survival (RS) rates were estimated. We analyzed data for 781 patients (9863/3: 13.6%; 9875/3: 82.2%; 9876/3: 4.2%). ESR was 1.02 [95% confidence interval (CI) = 0.93-1.11] and WSR was 0.81 [95% CI = 0.72-0.90]. The five RS rates among patients with Philadelphia chromosome positive (Ph+) CML were 43.7% [30.9-61.9] when diagnosed in 1980-1986, 63.8% [56.9-71.5] in 1987-1999 and 88.7% [84.5-93.0] in 2000-2009. The 8-year RS rate of patients with Ph+ CML diagnosed in 2000-2009 was 83.3% [77.5-89.4]. Therapeutic innovations have thus led to a significant increase in long-term survival in the general CML patient-population. [ABSTRACT FROM AUTHOR]

Finding new prognostic factors to identify patients with Hodgkin lymphoma (HL) at risk of treatment resistance or relapse remains challenging in daily practice. We evaluated the relationship between CD68 expression, interim positron emission tomography (iPET) results and outcome in 158 patients with HL diagnosed from February 1995 to July 2011. Immunohistochemistry (anti-CD68) gave two groups: low with ≤ 25% positive cells (121 patients) and high with > 25% (37 patients). Five-year overall survival was higher in the low group (88.4% vs. 63.2%, p = 0.0151), as was progression-free survival (74.5% vs. 40.7%, p = 0.0003). In 68 patients evaluable, iPET correlated with CD68: 13/52 patients (25%) in the low group had positive iPET as compared to 11/16 patients (68%) in the high group ( p = 0.0016). This study confirms the prognostic value of CD68 in HL. We found a correlation between CD68 and iPET suggesting potential for a better stratification. [ABSTRACT FROM AUTHOR]

Background During the last few decades, patients' rights have been reinforced in many countries by acts of law. Measures now include health care proxies to uphold the doctor-patient relationship and advance directives for end-of-life patients. These could be relevant tools as early as the initial diagnosis of haematological malignancies because of the uncertain disease course. The aim of this research was to assess the factors associated with the designation of a proxy and writing advance directives by patients in a haematology department in France. Methods After a specific programme to encourage discussions about end-of-life preferences, we conducted a mixed-methods study comprising retrospective analysis of a random sample of 200 patients' medical records, crossed with a qualitative analysis of the content of advance directives. Statistical analysis was performed by the RKward V 0.6.1 software with 0.05 denoting significance. The study was performed and presented in accordance with the STROBE guidelines. A thematic analysis of the advance directives was performed by two researchers. Results A total of 197 medical records were evaluable. The mean age of the patients was 66 years (range: 18-91). Nearly 2/3 of them (64.5%) designated a proxy, 6.1% wrote advance directives, and 8.1% and 4.6% expressed a wish to meet a religious representative or a volunteer, respectively. The 2-year survival rate was 78.4% [95%CI: 68.2-90.2]. Patients who wrote advance directives were statistically older (p<0.00025). Patients who wrote an advance directive were more likely to have expressed a wish to meet a religious representative (p<0.001) or a volunteer (p=0.003). Marital status was a significant factor in appointing a proxy (p=0.04). Conclusions To the best of our knowledge, this is the first paper to identify influencing factors for proxies and advance directives in a homogenous population of patients with haematological malignancies. Most patients chose a proxy. However, despite several training programmes for the carers and a care planning programme, few patients wrote advance directives. Our findings suggest that influencing factors are advanced age and a wish to see a religious representative. This study highlights the importance of oral communication about end-of-life issues between carers, patients and their relatives. [ABSTRACT FROM AUTHOR]

We evaluated the safety and efficacy of standard-dose yttrium-90 (Y 90 ) ibritumomab tiuxetan combined with high-dose BEAM (carmustine, etoposide, cytarabine, and melphalan) after first-line induction treatment in young patients with poor prognoses diffuse large B cell lymphoma (DLBCL) (clinicaltrials.gov: NCT00689169 ). Seventy-five high-risk (≥2 International Prognostic Index [IPI] factors) consecutive DLBCL patients (≤65 years old) in complete remission (CR) or partial remission (PR) after rituximab chemotherapy were treated with Y 90 ibritumomab tiuxetan and BEAM regimen followed by autologous stem cell transplantation (ASCT). The median follow-up was 34 months. Of the 75 patients, 71 underwent ASCT and were eligible for analysis. Median time to reach a neutrophil count of >500/μL and platelet count of >20,000/μL was 11 days. Mucositis ≥3 (51%) occurred in most patients. Other adverse events were similar to those seen with BEAM alone. The overall response rate was 86%; 59 patients (83%) achieved a CR or unconfirmed CR. The 2-year event-free survival (EFS), overall survival (OS), and disease-free survival were 79%, 83%, and 91%, respectively. Disease status (CR/PR) and positron emission tomography (PET) findings before transplantation did not predict treatment failure. The IPI (2 versus >2) and maximum tumor diameter of ≥10 cm at diagnosis appeared to be prognosis factors for OS but not for EFS. Adding Y 90 ibritumomab tiuxetan to BEAM is safe and does not increase transplantation-related toxicity. First-line consolidation with Y 90 ibritumomab tiuxetan and high-dose chemotherapy induced high rates of EFS and OS in poor-prognosis patients with DLBCL, regardless of PET status after induction treatment and warrants a randomized study. [ABSTRACT FROM AUTHOR]

In acquired thrombotic thrombocytopenic purpura (TTP), the persistence of severe ADAMTS13 deficiency (<10%) during remission is associated with more relapse. Preemptive (ie, after remission) administration of rituximab in these patients to prevent relapses remains controversial. We performed a cross-sectional analysis of 12-year follow-up data to compare the relapse incidence with or without preemptive rituximab infusion. Among 48 patients who experienced at least one episode of acquired TTP followed by severe ADAMTS13 deficiency during remission, 30 received preemptive rituximab (group 1); the other 18 did not (group 2). After a median of 17 months (interquartile range [IQR], 11 -29) following rituximab, the relapse incidence decreased from 0.57 episodes/year (IQR, 0.46-0.7) to 0 episodes/year (IQR, 0-0.81) (P< .01) in group 1. ADAMTS13 activity 3 months after the first rituximab infusion increased to 46% (IQR, 30%-68%). Nine patients required additional courses of rituximab. In 5 patients, ADAMTS13 activity failed to increase durably. Four patients experienced manageable adverse effects. In group 2, the relapse incidence was higher (0.5 relapses/year; IQR, 0.12-0.5; P< .01). Relapse-free survival was longer in group 1 (P = .049). A persistent severe ADAMTS13 deficiency during TTP remission should prompt consideration of preemptive rituximab to prevent relapses. [ABSTRACT FROM AUTHOR]

Background Infectious events have been reported as major environmental triggers of thrombotic thrombocytopenic purpura ( TTP). We detail here the potential association between infections and TTP. Study Design and Methods We recruited randomly and prospectively a cohort of 280 consecutive TTP patients during a 9-year period. Features of infection were systematically recorded. Results Features consistent with an infectious event were observed in 114 patients (41%) at time of TTP diagnosis. Infectious agents were documented in 34 cases and were mainly Gram-negative bacilli. At time of diagnosis infected patients more frequently had fever (p < 0.001). Infections at diagnosis did not impact prognosis and outcome. Thirty-six percent of patients experienced an infectious event during hospitalization, which resulted in more exacerbation of TTP (p = 0.02). Infections were not overrepresented during treatment in patients who received steroids and/or rituximab. Further genetic analysis of toll-like receptor ( TLR)-9 functionally relevant polymorphisms revealed that TLR-9 +2848 G and TLR-9 +1174 A genotypes were more frequent in TTP patients than in controls (p = 0.04 and p = 0.026, respectively) and more particularly in patients negative for the Class II human leukocyte antigen system susceptibility allele DRB1*11 (p = 0.001 and p = 0.002, respectively). Haplotypes estimation showed that 1174 A-2848 G haplotype was significantly more frequent in TTP (p = 0.004), suggesting a primary role for this haplotype variation in conferring a predisposition for acquired TTP. Conclusion Infections should be considered as an aggravating factor during the course of TTP. Particular polymorphisms in TLR-9 gene may represent risk factors for TTP. [ABSTRACT FROM AUTHOR]

Admission of patients with hematological malignancies to intensive care unit (ICU) raises recurrent ethical issues for both hematological and intensivist teams. The decision of transfer to ICU has major consequences for end of life care for patients and their relatives. It also impacts organizational human and economic aspects for the ICU and global health policy. In light of the recent advances in hematology and critical care medicine, a wide multidisciplinary debate has been conducted resulting in guidelines approved by consensus by both disciplines. The main aspects developed were (i) clarification of the clinical situations that could lead to a transfer to ICU taking into account the severity criteria of both hematological malignancy and clinical distress, (ii) understanding the process of decision-making in a context of regular interdisciplinary concertation involving the patient and his relatives, (iii) organization of a collegial concertation at the time of the initial decision of transfer to ICU and throughout and beyond the stay in ICU. The aim of this work is to propose suggestions to strengthen the collaboration between the different teams involved, to facilitate the daily decision-making process, and to allow improvement of clinical practice. [ABSTRACT FROM AUTHOR]

IPH2101 is an anti-killer inhibitory receptor (anti-KIR) mAb that can block KIRmediated inhibition of natural killer (NK) cells to enhance cytotoxicity against acute myeloid leukemia blasts. We have conducted a phase 1 study of IPH2101 in elderly patients with acute myeloid leukemia in first complete remission. Patients received escalating doses (0.0003-3 mgI kg) of IPH2101 following a 3 + 3 design. Safety, toxicity (primary end points), pharmacokinetics, outcome, and immunologic correlates were evaluated. Twenlythree patients (median age, 71 years), were enrolled. Adverse events were mild and transient, consisting mainly of infusion syndrome and erythema. The maximum tolerated dose was not reached, although full KIR saturation (> 90%) was sustained for more than 2 weeks at 1 and 3 mg/kg. There was a clear correlation between mAb exposure and KIR occupancy. Neither hematologic toxicity nor significant changes in the numbers and distribution of lymphocyte subsets, NK cell receptor expression, or in vitro cytotoxicity were seen. At the highest dose levels (0.3, 1, and 3 mg/kg), transient increases in TNF-α and MIP-1β serum concentrations and NK cell CD69 expression were observed. Overall and relapsefree survival in the present study compared favorably to reports in comparable patient populations. We conclude that IPH2101 administration is safe and can block KIR for prolonged periods of time with limited side effects. [ABSTRACT FROM AUTHOR]

Marrow cells from patients with higher-risk myelodysplastic syndrome ( MDS) exhibit constitutive nuclear factor ( NF)-κB activation. The proteasome inhibitor, bortezomib, has limited efficacy as a single agent in acute myeloid leukaemia. Its activity on leukaemic cell lines is potentiated by chemotherapy. We treated 43 higher-risk MDS patients with bortezomib (1·5 mg/m2, days 1, 4, 8 and 11) and low dose cytarabine arabinoside ( LDAC; 10 mg/m2, then 20 mg/m2 from days 1-14), every 28 d for four cycles. Median follow-up was 29·7 months. Responses were seen in 12 of the 43 patients (28%), including complete response ( CR, n = 1), marrow- CR ( n = 3), partial response ( PR, n = 5) and haematological improvement ( HI, n = 3). Responses were seen in 12 (36%) of the 33 previously untreated patients (11% CR, 13% PR, 2·5% HI), compared to none in the 12 previously treated patients ( P < 0·01). Responders had better overall survival (median 18·2 vs. 10 months). One CR and 3 marrow- CRs were seen in patients with complex karyotypes. Main toxicity was haematological, responsible for infection in six patients and bleeding in 3. Three patients with Grade 1-2 pre-treatment haematotoxicity developed Grade 3-4 toxicity. Neuropathy was seen in 12% of patients. The addition of bortezomib to LDAC in higher-risk MDS may improve results obtained with LDAC alone, especially in patients with unfavourable karyotypes. [ABSTRACT FROM AUTHOR]

The article discusses the assessment of the effectiveness and safeness of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange at the French Thrombotic Microangiopathies Reference Center. Adults having severe thrombocytopenic purpura who displayed poor response to therapeutic plasma exchange and were treated with rituximab had shorter overall treatment time and decreased one-year relapses than historical controls.

Background: Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. Immunochemotherapy, a combination of rituximab to standard chemotherapy, has resulted in improved survival. However a substantial proportion of patients still fail to reach sustained remission. We have previously demonstrated that autocrine brain-derived neurotrophic factor (BDNF) production plays a function in human B cell survival, at least partly via sortilin expression. As neurotrophin receptor (Trks) signaling involved activation of survival pathways that are inhibited by rituximab, we speculated that neurotrophins may provide additional support for tumour cell survival and therapeutic resistance in DLBCL. Methodology/Principal Findings: In the present study, we used two DLBCL cell lines, SUDHL4 and SUDHL6, known to be respectively less and more sensitive to rituximab. We found by RT-PCR, western blotting, cytometry and confocal microscopy that both cell lines expressed, in normal culture conditions, BDNF and to a lesser extent NGF, as well as truncated TrkB and p75NTR/sortilin death neurotrophin receptors. Furthermore, BDNF secretion was detected in cell supernatants. NGF and BDNF production and Trk receptor expression, including TrkA, are regulated by apoptotic conditions (serum deprivation or rituximab exposure). Indeed, we show for the first time that rituximab exposure of DLBCL cell lines induces NGF secretion and that differences in rituximab sensitivity are associated with differential expression patterns of neurotrophins and their receptors (TrkA). Finally, these cells are sensitive to the Trk-inhibitor, K252a, as shown by the induction of apoptosis. Furthermore, K252a exhibits additive cytotoxic effects with rituximab. Conclusions/Significance: Collectively, these data strongly suggest that a neurotrophin axis, such NGF/TrkA pathway, may contribute to malignant cell survival and rituximab resistance in DLBCL. [ABSTRACT FROM AUTHOR]

Abstract: Isolated 20q deletion is common in MDS and considered of good prognosis, but no large series have been reported. We compared characteristics of 62 MDS patients with isolated del 20q, 36 patients with del 20q and other cytogenetic abnormalities, and 1335 MDS patients without del20q. Significant differences between MDS with isolated del 20q and patients without del 20q were lower platelet count (mean 144 vs. 196 G/l, p =0.005), lower marrow blast count (mean 3.9% vs. 5.6%, p =0.0008), and higher reticulocyte count (mean 72.5 vs. 51.7 G/l, p =0.04). Ten (16%) patients with isolated del 20q had Hb>12g/dl and platelets <100 G/l, compared to 7.3% of patients without del 20q (p =0.025). Review of marrow slides of those 10 patients showed that could be readily identified as MDS prior to cytogenetics. Fourteen percent of patients with isolated del 20q progressed to AML compared to 11% with one and 24% with several additional abnormalities. Median survival was 54 months in patients with isolated del 20q, not reached and 12 months for del 20q with one and several additional abnormalities, respectively (p =0.035) confirming the favorable prognosis of del 20q without complex abnormalities. [Copyright &y& Elsevier]

Summary: Background: Diffuse large B-cell lymphoma is a common cancer in elderly patients. Although treatment has been standardised in younger patients, no prospective study has been done in patients over 80 years old. We aimed to investigate the efficacy and safety of a decreased dose of CHOP (doxorubicin, cyclophosphamide, vincristine, and prednisone) chemotherapy with a conventional dose of rituximab in elderly patients with diffuse large B-cell lymphoma. Methods: We did a prospective, multicentre, single-arm, phase 2 study of patients aged over 80 years who had diffuse large B-cell lymphoma. Patients were included from 38 centres in France and Belgium. All patients received six cycles of rituximab combined with low-dose CHOP (R-miniCHOP) at 3-week intervals. Patients received 375 mg/m2 rituximab, 400 mg/m2 cyclophosphamide, 25 mg/m2 doxorubicin, and 1 mg vincristine on day 1 of each cycle, and 40 mg/m2 prednisone on days 1–5. The primary endpoint was overall survival, both unadjusted and adjusted for treatment and baseline prognostic factors. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT01087424. Findings: 150 patients were enrolled between Jan 9, 2006, and Jan 23, 2009 and 149 were included in the intention-to-treat analyses. Median age was 83 years (range 80–95). After a median follow-up of 20 months (range 0–45), the median overall survival was 29 months (95% CI 21 to upper limit not reached); 2-year overall survival was 59% (49–67%). In multivariate analyses, overall survival was only affected by a serum albumin concentration of 35 g/L or less (hazard ratio 3·2, 95% CI 1·4–7·1; p=0·0053). Median progression-free survival was 21 months (95% CI 13 to upper limit not reached), with a 2-year progression free survival of 47% (38–56). 58 deaths were reported, 33 of which were secondary to lymphoma progression. 12 deaths were attributed to toxicity of the treatment. The most frequent side-effect was haematological toxicity (grade ≥3 neutropenia in 59 patients; febrile neutropenia in 11 patients). Interpretation: R-miniCHOP offers a good compromise between efficacy and safety in patients aged over 80 years old. R-miniCHOP should be considered as the new standard treatment in this subgroup of patients. Funding: Groupe d''Etude des Lymphomes de l''Adulte (GELA). [Copyright &y& Elsevier]

Introduction. FibroScan, a non-invasive tool for measuring liver stiffness (LS), is not specific to liver fibrosis. Other extra-hepatic conditions may modify the LS value. Objectives. Our aim was to examine whether amyloid deposition in the liver may modify LS. Methods. LS was measured prospectively in 41 patients with systemic AL amyloidosis (AL) in the French AL Reference Center, comprising: 5 patients with liver involvement (LI) and no cardiac involvement (CI), 11 with CI and no LI, 12 with both LI and CI and 13 with neither (2005 consensus criteria); 26 negative controls, 50 patients infected with Hepatitis C virus (HCV)-infected and 18 AL-free patients with right-sided heart disease (''cardiac controls'') were also examined. Results. Median LS was significantly higher in patients with AL with liver involvement [[27.4 (10.3--75) kPa]] than in negative controls [[4.8 (2.8--11.9) kPa]] ( p < 0.0001), and patients infected with HCV [[(6.8 (2.9--69.1) kPa]] ( p == 0.001), and tended to be higher than in the ''cardiac controls'' [[11 (4.1--75) kPa]] ( p == 0.08). A cut-off value of 17.3 kPa, prioritising specificity, is proposed for routine diagnosis of significant AL liver infiltration. Conclusion. LS > 17.3 kPa is suggestive of AL hepatic disease in patients with non-fibrotic liver changes, and may have diagnostic value in patients with known AL. [ABSTRACT FROM AUTHOR]

Severe ADAMTS13 deficiency occurs in 13% to 75% of thrombotic microangiopathies (TMA). In this context, the early identification of a severe, antibody-mediated, ADAMTS13 deficiency may allow to start targeted therapies such as Blymphocytes- depleting monoclonal antibodies. To date, assays exploring ADAMTS13 activity require skill and are limited to only some specialized reference laboratories, given the very low incidence of the disease. To identify clinical features which may allow to predict rapidly an acquired ADAMTS13 deficiency, we performed a cross-sectional analysis of our national registry from 2000 to 2007. The clinical presentation of 160 patients with TMA and acquired ADAMTS13 deficiency was compared with that of 54 patients with detectable ADAMTS13 activity. ADAMTS13 deficiency was associated with more relapses during treatment and with a good renal prognosis. Patients with acquired ADAMTS13 deficiency had platelet count <306109/L (adjusted odds ratio [OR] 9.1, 95% confidence interval [CI] 3.4-24.2, P<.001), serum creatinine level≤200 mmol/L (OR 23.4, 95% CI 8.8-62.5, P<.001), and detectable antinuclear antibodies (OR 2.8, 95% CI 1.0-8.0, P<.05). When at least 1 criteria was met, patients with a severe acquired ADAMTS13 deficiency were identified with positive predictive value of 85%, negative predictive value of 93.3%, sensitivity of 98.8%, and specificity of 48.1%. Our criteria should be useful to identify rapidly newly diagnosed patients with an acquired ADAMTS13 deficiency to better tailor treatment for different pathophysiological groups. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to a study on DBA.44(CD76) expression as being restricted to tumor cells infiltrating the red pulp of the spleen with a diffuse architectural pattern.

Abstract: Several reports have demonstrated an important role of leukotriene B4 (LTB4) in the immune system. We investigated whether leukemic blasts from acute myeloid leukemic (AML) and acute lymphoid leukemic (ALL) patients produced LTB4, 12- and 15-hydroxyeicosatetraenoic acids (12-HETE and 15-HETE) and whether these compounds affected blast proliferation and apoptosis. Leukemic blasts from AML M0-2 and ALL patients expressed 5-LOX, 12-LOX and 15-LOX transcripts. Quantitative polymerase chain reaction indicated that 5-LOX transcripts were far more abundant than 12-LOX and 15-LOX ones. Leukemic blasts expressed 5-LOX activating protein (FLAP) transcripts and produced LTB4 in response to calcium ionophore. In contrast no 15-HETE production was found. Calcium ionophore-stimulated leukemic blasts produced 12-HETE but also released thromboxane A2 suggesting that contaminating platelets accounted for the release of these compounds. No significant effect of LTB4, 12-HETE or 15-HETE could be documented on leukemic blast growth and on their apoptose rate. Results of the present study indicate that immature form of leukemic blasts produce LTB4. However, the three major lipoxygenase metabolites of arachidonic acid; i.e., LTB4, 12-HETE or 15-HETE, had no evident effect on their growth and apoptosis. We may speculate that LTB4-derived blast cells might initiate, augment or prolong tissue inflammation and damages by affecting the marrow and blood cytokine network. [Copyright &y& Elsevier]

Abstract: Platelet-activating factor (PAF) is a phospholipid mediator with potent immunoregulatory activities on mature leukocytes. PAF modulates leukocyte cytosolic Ca2+ concentration ([Ca2+]i) through a Gq mediated pathway. We highlight, for the first time, Gq transcripts, PAF receptor (PAF-R) transcripts and protein in blast cells of acute myeloid (AML) and lymphoid (ALL) leukemia patients. PAF stimulated [Ca2+]i in leukemic blast cells; PAF effects being prevented by a specific PAF-R antagonist. In conclusion, functional PAF-R are present in blast cells of patients with acute leukemia; a result that could be of physiologic importance regarding the important effect of PAF on leukocytes maturation and functions. [Copyright &y& Elsevier]

Abstract: Human cytomegalovirus (HCMV) and human herpesvirus-6 (HHV-6) are two closely related viruses, which belong to the Herpesviridae family. Following primary infection, they are thought to persist for life as latent forms in mononuclear cells. HCMV and HHV-6 can cause considerable morbidity in immunocompromised individuals, such as transplant patients. A sensitive and specific LightCycler multiplex real-time PCR assay based on fluorescence energy transfer (known as FRET) was developed. This assay, by using two sets of hybridization probes specific for HHV-6 (A and B) and HCMV, can differentiate reliably and quantify simultaneously both viruses in order to diagnose reactivation processes. The assay was optimized and the lower limit of detection for both viruses was determined to be 10 viral genome copies per reaction. Both viruses were quantified in 83 peripheral blood mononuclear cells (PBMCs) and 87 polymorphonuclear leukocytes (PMNLs) collected from 32 transplant recipients. This multiplex real-time quantitative PCR was finally compared with two other quantitation and detection assays used daily in laboratory (PCR DIG detection and antigenemia for HCMV, TaqMan Assay for HHV-6). This technique can be useful for the differentiation and quantitation of HCMV and HHV-6 for monitoring transplant patients. [Copyright &y& Elsevier]

Eczema craquele, or asteatotic eczema, has been associated with malignant lymphoma although this is rare. Since 1986, we have observed seven patients, six men and one woman, mean age 71.5 years (range 43–86 years), with systemic lymphoma and concurrent eczema craquele. Five patients had T‐cell lymphoma, one had a B‐cell lymphoma and one had Hodgkin's disease. All patients shared several characteristics: (1) a synchronous onset of eczema craquele and lymphoma, (2) generalized eczema, (3) absence of alternative disease or conditions that could favour the onset of eczema craquele, and (4) eczema refractory to topical corticosteroids and emollients, but which resolved upon lymphoma remission and invariably recurred with the lymphoma relapse. All the patients except one died within 1 year, most with active lymphoma. The finding of recalcitrant generalized eczema craquele should prompt a search for lymphoma, particularly in older men. Lymphoma‐associated eczema craquele has most characteristics of paraneoplastic syndromes and may be a hallmark of aggressive lymphoma. [ABSTRACT FROM AUTHOR]

We report on a randomized trial aimed to determine the impact of a second consolidative high-dose cytarabine-based chemotherapy (HiDAC) in patients with acute myeloid leukaemia prior to an autologous stem cell transplantation (ASCT). Patients aged 18–60 years, in complete remission (CR) received a first consolidation with daunorubicin and cytarabine at reduced dose. Patients not allocated to allogeneic transplantation received one course of HiDAC and then were randomized to receive an ASCT immediately (HiDAC 1 group) or after one more course of HiDAC (HiDAC 2 group). Out of the 437 initial patients, 351 achieved CR (80%), of those 277 (79%) were eligible for first HiDAC, and 128 (36%) were randomized (HiDAC 1: 65, HiDAC 2: 63). Overall survival, leukaemia-free survival and cumulative incidence of relapse and non-relapse deaths were 41% and 53% (P = 0·14), 39% and 48% (P = 0·12), 57% and 47% (P = 0·11), 8% and 8% (P = 0·95) for HiDAC 1 and HiDAC 2 groups, respectively. Further studies are warranted with a larger number of patients to test the place of a second course of HiDAC in this setting. [ABSTRACT FROM AUTHOR]

The mutator phenotype caused by defects in the mismatch repair system is observed in a subset of solid neoplasms characterized by widespread microsatellite instability-high (MSl-H). It is known to be very rare in non-Hodgkin lymphomas (NHL), whereas mutator NHL is the most frequent tumor subtype in mismatch repair- deficient mice. By screening a series of 603 human NHL with specific markers of the mutator phenotype, we found here 12 MSI-H cases (12/603, 2%). Of interest we demonstrated that this phenotype was specifically associated with immunodeficiency-related lymphomas (ID-RL), because it was observed in both posttransplant lymphoproliferative disorders (9/111, 8.1%) and HIV infection- related lymphomas (3/128, 2.3%) but not in a large series of NHL arising in the general population (0/364) (P < 0.0001). The M5l pathway is known to lead to the production of hundreds of abnormal protein neoantigens that are generated in MSl-H neoplasms by frameshift mutations of a number of genes containing coding microsatellite sequences. As expected, MSI-H ID-RL were found to harbor such genetic alterations in 12 target genes with a putative role in lymphomagenesis. The observation that the MSl-H phenotype was restricted to HIV infection-related lymphomas and posttransplant lymphoproliferative disorders suggests the existence of the highly immunogenic mutator pathway as a novel oncogenic process in lymphomagenesis whose role is favored when host immunosurveillance is reduced. Because MSl-H-positive cases were found to be either Epstein-Barr virus-positive or -negative, the mutator pathway should act synergistically or not with this other oncogenic factor, playing an important role in ID-RL. [ABSTRACT FROM AUTHOR]

Introduction: A prospective randomised study involving 810 elderly patients was conducted in an attempt to compare alternating chemotherapy with conventional first-line chemotherapy in aggressive non-Hodgkin’s lymphoma in order to improve prognosis with an acceptable toxicity for elderly patients.Patients and methods: Patients included were 55–69 years old and had at least one adverse prognostic factor. Patients were treated either with ACVBP followed by consolidation (n = 396) or with an alternating regimen (n = 414). This regimen was an association of active drugs in NHL relapsing patients, alternating VIMMM with ACVBP for induction and alternation of VIM and ACVM in consolidation. Eight hundred and sixty-six patients were randomised. After histological review, 810 patients met the inclusion criteria: 396 in arm A, 414 in arm B.Results: The complete response rate after induction was superior for conventional first-line therapy (58.5% vs 48%, P = 0.003) but at the end of treatment, the CR rate was not statistically different (52% vs 48%, P = 0.19). Conventional chemotherapy had a better five-year event-free survival than alternating regimen (33% (95% CI: 30–36%) vs 28% (95% CI: 26–30%), P = 0.0289) but overall survival was not statistically different (40% (CI 95% 38–42%) vs 36% (CI 95% 34–38%), P = 0.068). In this elderly high risk population, the toxicity was very high: 19% in arm A and 26% in arm B died during treatment.Conclusion: Alternating regimen did not improve outcome, was less efficient and more toxic.The Hematology Journal (2001) 2, 279–285 [ABSTRACT FROM AUTHOR]

In spite of the recent improvement in the outcome of acute promyelocytic leukaemia (APL) with treatment combining all trans retinoic acid (ATRA) and chemotherapy (CT), some patients with this disease still have a poor outcome. The prognostic significance of chromosomal abnormalities in addition to t(15;17) in APL is uncertain. We examined the prognostic significance of secondary chromosomal changes in 292 patients included in a European trial who were treated with ATRA and CT. The incidence of chromosomal abnormalities in addition to t(15;17) was 26% and trisomy 8 was the most frequent secondary change (46% of the cases with secondary changes). No significant differences were seen with regard to age, sex, initial white blood cell count, % of circulating blasts, platelet count, fibrinogen level and incidence of microgranular variants between patients with or without additional rearrangements. Outcome was also similar between patients with t(15;17) alone and patients with t(15;17) and other clonal abnormalities for complete remission (92% vs. 93% respectively), event-free survival at 2 years (76·1% vs. 78·1% respectively), relapse at 2 years (16·7% vs. 11·6% respectively) and overall survival at 2 years (79·9% vs. 79·5% respectively). Analysis according to the type of induction treatment (ATRA followed by CT or ATRA plus CT) or the type of maintenance treatment (with ATRA, low-dose CT or both) also failed to show any difference between the two groups. Thus, in a large cohort of APL patients treated with ATRA and CT, additional chromosomal abnormalities had no impact on prognosis. [ABSTRACT FROM AUTHOR]

Background: Treatment with interferon prolongs survival in chronic myelogenous leukemia. We conducted a clinical trial to assess the efficacy of treatment with a combination of interferon and cytarabine.Methods: Previously untreated patients with chronic myelogenous leukemia were randomly assigned to receive either hydroxyurea (50 mg per kilogram of body weight per day) and interferon alfa-2b (5 million units per square meter of body-surface area per day), or hydroxyurea and interferon in the same dosages plus monthly courses of cytarabine (20 mg per square meter per day, for 10 days). The end points were overall survival, complete hematologic remission at 6 months, and major cytogenetic response (less than 35 percent Philadelphia chromosome-positive cells in the bone marrow) at 12 months.Results: The trial was stopped when a sequential analysis showed a benefit of interferon and cytarabine. A significant improvement in survival was observed in the interferon-cytarabine group (360 patients) as compared with the interferon group (361 patients) (P=0.02; relative risk of death, 0.64; 95 percent confidence interval, 0.44 to 0.93). After three years, the survival rate was 85.7 percent with interferon and cytarabine and 79.1 percent with interferon alone. The rate of hematologic response was higher in the interferon-cytarabine group than in the interferon group (P=0.003). Major cytogenetic responses were observed 12 months after randomization in 126 of 311 patients treated with interferon and cytarabine (41 percent) and in 75 of 314 patients treated with interferon only (24 percent, P<0.001).Conclusions: The combination of interferon and cytarabine, as compared with interferon alone, increases the rate of major cytogenetic response and prolongs survival in patients with the chronic phase of chronic myelogenous leukemia. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Prognosis of Acquired Hemophilia in Older People."