Cell therapy for posttraumatic shoulder osteonecrosis.

PURPOSE: This study compared the clinical and radiological results of bone marrow mesenchymal stem cell implantation with traditional simple core decompression (CD) using a matched pair case-control design for osteonecrosis of the humeral head (ONHH) after fracture of the proximal humerus. PATIENTS: We retrospectively reviewed 64 patients who had surgery for ONHH. Thirty patients had been treated with cell therapy between 2010 and October 2015, with 18 patients at pre-collapse stage (8 stages-I, 10 stages-II), and 12 patients at post-collapse stages (7 stages-III and 5 stages-IV). Using a matched pair case-control design, these 30 study patients were compared to 34 other patients who were treated with simple core decompression (CD) without cells (control group). METHODS: The cell therapy group was treated with percutaneous mesenchymal cell (MSCs) injection obtained from bone marrow (BM) concentration. During a mean follow-up duration of 7years (5 to 10years), radiographs performed each year were used to evaluate the radiological results; the Constant score and visual analogue scale were chosen to assess the clinical results. We assessed stage progression, collapse and arthroplasty conversion rate. Survivor rate analysis was performed using these parameters as the primary endpoints. RESULTS: Among the 30 shoulders included in the cell therapy group, three (10%) humeral heads had collapsed at the most recent follow-up, versus 25 (74%) in 34 shoulders after simple core decompression (P<0.0001). As consequence, we observed statistically significant difference (P=0.0001) in the humeral head survival (absence of arthroplasty conversion) rate at the end time point between the cell therapy group (93% survival) and simple core decompression (26% survival). Better results were obtained for early stages (stages I and II) osteonecrosis without collapse at baseline. CONCLUSION: Core decompression with cell therapy was a safe and effective procedure for treatment in the pre-collapse stages of posttraumatic shoulder osteonecrosis and improved the outcome of the disease as compared with simple core decompression without cells.

Psychometric validation of an Assessment Questionnaire on the Perception of and Adaptation to Visual Handicap in Adults (QUEPAHVA).

PURPOSE: Handicap evaluation in adults with acquired or progressive congenital visual loss allows for identification of the individual's specific needs and targeted therapy (medical, technical, rehabilitative and psychological). Currently, the subjective dimension of the handicap remains poorly explored in the field of visual loss. Our questionnaire aims to understand the whole of these subjective impacts. It differs from existing quality of life scales in ophthalmology in its approach centered on the process of adaptation, individual resources (technical, cognitive, psychic and environmental), and investigation of the perception of the handicap. The goal of the present study is to validate this questionnaire, which could be used in any adult with a visual handicap, regardless of the extent of the visual loss, its etiology, or the type of treatment or compensatory mechanisms. MATERIALS AND METHODS: The Assessment Questionnaire on the Perception of and Adaptation to Visual Handicap in Adults (QUEPAHVA) is composed of 28 items relating to perception of the visual impairment, its impact, and adaptive resources. They are divided into 3 sub-categories: Perception of daily life and relationships (10 items), Perception of visual status and compensatory mechanisms (8 items), and Psychological impact of the visual handicap (10 items). The responses are graded on a Likert scale. Factor analysis and verification of psychometric qualities were performed based on the responses of 446 subjects. The discriminatory validity of the NEI-VFQ 25 was proven with 99 subjects. Reliability over time (mean interval between T1 and T2=49.43 days) was measured in 31 subjects. Sensitivity to change between pre- and post-management (mean interval between T1 and T2=410 days) was tested in 123 subjects. RESULTS: Internal consistency was very good for the global scale (α=.90) as well as for the 3 sub-dimensions (α=.86; α=.79; α=.80). The discriminatory validity was satisfactory (r=.70). This result had to be interpreted as a function of the qualitative specificity of the questionnaire. The questionnaire enjoyed good reproducibility over time with regard to its total score and relatively satisfactory reproducibility with regard to its sub-dimensions. Sensitivity to change was very high and accounted for adaptations to the disability over time. CONCLUSION: The QUEPAHVA displays good psychometric qualities. It constitutes a new means of evaluation. Its potential applications are many. It permits evaluation of the needs of the individual and adaptation of the protocol of care. Its use in institutions may support a step forward in the science of evaluation and continued improvement in quality of care.

[Psychometric validation of an Assessment Questionnaire on the Perception of and Adaptation to Visual Handicap in Adults (QUEPAHVA). French translation of the article]. / Validation psychométrique d'un Questionnaire d'Évaluation de la Perception et de l'Adaptation au Handicap Visuel chez l'Adulte (QUEPAHVA).

PURPOSE: Handicap evaluation in adults with acquired or progressive congenital visual loss allows for identification of the individual's specific needs and targeted therapy (medical, technical, rehabilitative and psychological). Currently, the subjective dimension of the handicap remains poorly explored in the field of visual loss. Our questionnaire aims to understand the whole of these subjective impacts. It differs from existing quality of life scales in ophthalmology in its approach centered on the process of adaptation, individual resources (technical, cognitive, psychic and environmental), and investigation of the perception of the handicap. The goal of the present study is to validate this questionnaire, which could be used in any adult with a visual handicap, regardless of the extent of the visual loss, its etiology, or the type of treatment or compensatory mechanisms. MATERIALS AND METHODS: The Assessment Questionnaire on the Perception of and Adaptation to Visual Handicap in Adults (QUEPAHVA) is composed of 28 items relating to perception of the visual impairment, its impact, and adaptive resources. They are divided into 3 sub-categories: perception of daily life and relationships (10 items), Perception of visual status and compensatory mechanisms (8 items), and Psychological impact of the visual handicap (10 items). The responses are graded on a Likert scale. Factor analysis and verification of psychometric qualities were performed based on the responses of 446 subjects. The discriminatory validity of the NEI-VFQ 25 was proven with 99 subjects. Reliability over time (mean interval between T1 and T2=49.43 days) was measured in 31 subjects. Sensitivity to change between pre- and post-management (mean interval between T1 and T2=410 days) was tested in 123 subjects. RESULTS: Internal consistency was very good for the global scale (α=.90) as well as for the 3 sub-dimensions (α=.86; α=.79; α=.80). The discriminatory validity was satisfactory (r=.70). This result had to be interpreted as a function of the qualitative specificity of the questionnaire. The questionnaire enjoyed good reproducibility over time with regard to its total score and relatively satisfactory reproducibility with regard to its sub-dimensions. Sensitivity to change was very high and accounted for adaptations to the disability over time. CONCLUSION: The QUEPAHVA displays good psychometric qualities. It constitutes a new means of evaluation. Its potential applications are many. It permits evaluation of the needs of the individual and adaptation of the protocol of care. Its use in institutions may support a step forward in the science of evaluation and continued improvement in quality of care.

Return to sports and quality of life after high tibial osteotomy in patients under 60 years of age.

INTRODUCTION: Since knee osteoarthritis is unicompartmental in most cases, a knee osteotomy is the most logical solution to limit degeneration of the arthritic compartment, thereby delaying knee arthroplasty. Younger patients have high functional demands. The purpose of this study was to evaluate the return to sports and quality of life after high tibial osteotomy (HTO) in athletic patients less than 60 years of age. The hypothesis was that patients can return to sports within 1 year of HTO. MATERIALS AND METHODS: A single-centre, retrospective study was performed of 30 patients under 60 years of age with medial tibiofemoral osteoarthritis and no history of surgery or trauma who underwent HTO between January 2014 and August 2015. The primary endpoint was the return to sport at 1 year based on the Tegner score. Secondary endpoints were the subjective IKDC score, Lysholm score and SF-36. RESULTS: The mean follow-up was 1.3 years [1-1.5] and no patients were lost to follow-up. All the patients had returned to sports at 1 year: 73.3% at their pre-surgery level (before the pain started) and 23.3% at a higher level. Their quality of life was significantly improved according to the SF-36 questionnaire: 65.3% pre-operatively compared with 72.5% postoperatively (P=0.01). The preoperative and 1-year postoperative scores were comparable for the Tegner (P=0.167), IKDC (P=0.093) and Lysholm (P=0.061). CONCLUSION: HTO allows patients to resume their sports activities within 1 year of surgery and significantly improves their quality of life. LEVEL OF EVIDENCE: Level IV - Retrospective cohort study.

Transformation of an Unclassified Myeloproliferative Neoplasm with a Rare BCR-JAK2 Fusion Transcript Resulting from the Translocation (9;22)(p24;q11).

BCR-ABL1 negative myeloproliferative neoplasms (MPNs) are known to contain alterations of the tyrosine kinase JAK2 (located on 9p24) that result in constitutive activation of the encoded protein. JAK2 fusions are reported in acute and chronic leukemias of myeloid and lymphoid phenotypes. Here, we report an unclassified case of MPN (MPN-U) showing a t(9;22)(p24;q11), which generates a BCR-JAK2 fusion gene by fusing the BCR at intron 13 to JAK2 at intron 17 on the derivative chromosome 22. Most reported JAK2 fusions cases reveal an aggressive clinical course and long-term remissions have only been achieved after allogeneic stem cell transplantation (ASCT). To the best of our knowledge, this is the thirteenth case reported worldwide to describe a BCR-JAK2 fusion transcript in MPN-U. The present report revealed a sustained complete clinical, hematologic, and cytogenetic remission 35 months after diagnosis and ~24 months after ASCT. Regarding BCR-ABL1 negative MPN patients this case report provides strong support for a role of JAK2 activation in the oncogenesis and suggests a possible diagnostic and therapeutic target that should be investigated.

The costimulatory molecule CD70 is regulated by distinct molecular mechanisms and is associated with overall survival in diffuse large B-cell lymphoma.

In diffuse large B-cell lymphomas (DLBCL), a recurrent deletion of the 19p13 region has recently been described. CD70 and TNFSF9 genes are suspected tumor suppressor genes, but previous studies suggest an oncogenic role for CD70. Therefore, we studied the consequences of variation in CD70 copy number and epigenetic modifications on CD70 expression. Copy-number variation was investigated in 144 de novo DLBCL tissues by comparative genomic hybridization array and quantitative multiplex PCR. Gene expression was assessed by quantitative RT-PCR, and CD70 promoter methylation was determined by pyrosequencing. The 19p13.3.2 region was deleted in 21 (14.6%) cases, which allowed the minimal commonly deleted region of 57 Kb that exclusively includes the CD70 gene to be defined. Homozygous deletions were observed in four (2.7%) cases, and acquired single-nucleotide variations of CD70 were detected in nine (6.3%) cases. CD70 was highly expressed in both germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL compared to normal tissue, with distinct molecular mechanisms of mRNA expression regulation. A gene dosage effect was observed in the GCB subtype, whereas promoter methylation was the predominant mechanism of down regulation in the ABC subtype. However, high CD70 expression levels correlated to shorter overall survival in both the GCB (P = 0.0021) and the ABC (P =0.0158) subtypes. In conclusion, CD70 is targeted by recurrent deletions, somatic mutations and promoter hypermethylation, but its high level of expression is related to an unfavorable outcome, indicating that this molecule may constitute a potential therapeutic target in selected DLBCL.

The isotype of the BCR as a surrogate for the GCB and ABC molecular subtypes in diffuse large B-cell lymphoma.

Gene expression profiling has identified two major molecular subtypes of diffuse large B-cell lymphoma (DLBCL) that are histologically indistinguishable but differ in cure rates. Here, we investigated whether the isotype of the B-cell receptor (BCR) expressed by the tumoral cells correlated with the molecular subtype and survival. Gene expression analysis clustered the 53 patients included in this study into three subgroups, 17 germinal center B-cell-like (GCB) cases, 26 activated B-cell-like (ABC) cases and 10 intermediate cases. The molecular subtype was correlated with the isotype, as 15/17 GCB cases expressed a secondary isotype (immunoglobulin (Ig)G or IgA), whereas 24/26 ABC cases expressed a primary isotype (IgM or IgD) (P<0.0001). There was a trend toward a worse outcome for patients with an ABC DLBCL and a shorter overall survival for patients with IgM+ tumor (P=0.21 and 0.014, respectively). Finally, fluorescence in situ hybridization (FISH) analysis revealed a striking asymmetric pattern, as the IGHM gene is conserved only on the productive IGH allele in most IgM+ tumors. Taken together, these data indicate that the isotype of the BCR is a reliable indicator for the GCB and ABC subtypes in DLBCL, and suggest that the conservation of an IgM is required for ABC DLBCL lymphomagenesis to occur.

Copolymer-in-oil phantom materials for elastography.

Phantoms that mimic mechanical and acoustic properties of soft biological tissues are essential to elasticity imaging investigation and to elastography device characterization. Several materials including agar/gelatin, polyvinyl alcohol and polyacrylamide gels have been used successfully in the past to produce tissue phantoms, as reported in the literature. However, it is difficult to find a phantom material with a wide range of stiffness, good stability over time and high resistance to rupture. We aim at developing and testing a new copolymer-in-oil phantom material for elastography. The phantom is composed of a mixture of copolymer, mineral oil and additives for acoustic scattering. The mechanical properties of phantoms were evaluated with a mechanical test instrument and an ultrasound-based elastography technique. The acoustic properties were investigated using a through-transmission water-substituting method. We showed that copolymer-in-oil phantoms are stable over time. Their mechanical and acoustic properties mimic those of most soft tissues: the Young's modulus ranges from 2.2-150 kPa, the attenuation coefficient from 0.4-4.0 dB.cm(-1) and the ultrasound speed from 1420-1464 m/s. Their density is equal to 0.90 +/- 0.04 g/cm3. The results suggest that copolymer-in-oil phantoms are attractive materials for elastography.

Recurrent genomic aberrations combined with deletions of various tumour suppressor genes may deregulate the G1/S transition in CD4+CD56+ haematodermic neoplasms and contribute to the aggressiveness of the disease.

CD4+CD56+ haematodermic neoplasms (HDN) constitute a rare disease characterized by aggressive clinical behaviour and a poor prognosis. Tumour cells from HDN are leukaemic counterparts of plasmacytoid dendritic cells (pDCs). Despite increased knowledge of the ontogenetic origin of these tumours, the genetic causes and oncogenic signalling events involved in malignant transformation are still unknown. To delineate novel candidate regions and disease-related genes, we studied nine typical CD4+CD56+ HDN cases using genome-wide high-resolution array comparative genomic hybridization (CGH). Genomic imbalances, which were predominantly losses, were frequently detected. Gross genomic losses or gains involving an entire chromosome were observed in eight cases. The most frequent imbalances were deletions of chromosome 9, chromosome 13 and partial losses affecting 17p or 12p. Combinations of deletions of tumour suppressor genes (TSG), namely RB1, CDKN1B (p27), CDKN2A, (p16(ink4a), p14(arf)) or TP53 (p53), were observed in all cases. These results indicate that deletion events altering G1/S regulation are crucial for HDN oncogenesis. Furthermore, in addition to frequent sporadic gene losses, in one case we observed a 8q24 interstitial deletion that brought MYC closer to miR-30b/miR-30d, which may be related to their deregulation. Taken together, these results indicate that in addition to frequent G1/S checkpoint alterations, various genetic events could contribute to the chemoresistance of the tumour.

Genome profiling of acute myelomonocytic leukemia: alteration of the MYB locus in MYST3-linked cases.

The t(8;16)(p11;p13) is a rare translocation involved in de novo and therapy-related myelomonocytic and monocytic acute leukemia. It fuses two genes encoding histone acetyltransferases (HATs), MYST3 located at 8p11 to CREBBP located at 16p13. Variant translocations involve other HAT-encoding genes such as EP300, MYST4, NCOA2 or NCOA3. MYST3-linked acute myeloid leukemias (AMLs) share specific clinical and biological features and a poor prognosis. Because of its rarity, the molecular biology of MYST3-linked AMLs remains poorly understood. We have established the genome and gene expression profiles of a multicentric series of 61 M4/M5 AMLs including 18 MYST3-linked AMLs by using array comparative genome hybridization (aCGH) (n=52) and DNA microarrays (n=44), respectively. We show that M4/5 AMLs have a variety of rare genomic alterations. One alteration, a gain of the MYB locus, was found recurrently and only in the MYST3-linked AMLs (7/18 vs 0/34). MYST3-AMLs have also a specific a gene expression profile, which includes overexpression of MYB, CD4 and HOXA genes. These features, reminiscent of T-cell acute lymphoid leukemia (ALL), suggest the targeting of a common T-myeloid progenitor.

The expression of 16 genes related to the cell of origin and immune response predicts survival in elderly patients with diffuse large B-cell lymphoma treated with CHOP and rituximab.

Gene expression profiles have been associated with clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated with anthracycline-containing chemotherapy. Using Affymetrix HU133A microarrays, we analyzed the lymphoma transcriptional profile of 30 patients treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and 23 patients treated with rituximab (R)-CHOP in the Groupe d'Etude des Lymphomes de l'Adulte clinical centers. We used this data set to select transcripts showing an association with progression-free survival in all patients or showing a differential effect in the two treatment groups. We performed real-time quantitative reverse transcription-PCR in the 23 R-CHOP samples of the screening set and an additional 44 R-CHOP samples set to evaluate the prognostic significance of these transcripts. In these 67 patients, the level of expression of 16 genes and the cell-of-origin classification were significantly associated with overall survival, independently of the International Prognostic Index. A multivariate model comprising four genes of the cell-of-origin signature (LMO2, MME, LPP and FOXP1) and two genes related to immune response, identified for their differential effects in R-CHOP patients (APOBEC3G and RAB33A), demonstrated a high predictive efficiency in this set of patients, suggesting that both features affect outcome in DLBCL patients receiving immunochemotherapy.

Acute myeloid leukaemia with 8p11 (MYST3) rearrangement: an integrated cytologic, cytogenetic and molecular study by the groupe francophone de cytogénétique hématologique.

Thirty cases of acute myeloid leukaemia (AML) with MYST histone acetyltransferase 3 (MYST3) rearrangement were collected in a retrospective study from 14 centres in France and Belgium. The mean age at diagnosis was 59.4 years and 67% of the patients were females. Most cases (77%) were secondary to solid cancer (57%), haematological malignancy (35%) or both (8%), and appeared 25 months after the primary disease. Clinically, cutaneous localization and disseminated intravascular coagulation were present in 30 and 40% of the cases, respectively. AMLs were myelomonocytic (7%) or monocytic (93%), with erythrophagocytosis (75%) and cytoplasmic vacuoles (75%). Immunophenotype showed no particularity compared with monocytic leukaemia without MYST3 abnormality. Twenty-eight cases carried t(8;16)(p11;p13) with MYST3-CREBBP fusion, one case carried a variant t(8;22)(p11;q13) and one case carried a t(8;19)(p11;q13). Type I (MYST3 exon 16-CREBBP exon 3) was the most frequent MYST3-CREBBP fusion transcript (65%). MYST3 rearrangement was associated with a poor prognosis, as 50% of patients deceased during the first 10 months. All those particular clinical, cytologic, cytogenetic, molecular and prognostic characteristics of AML with MYST3 rearrangement may have allowed an individualization into the World Health Organization classification.