Basic characteristics and safety of donation in related and unrelated haematopoietic progenitor cell donors - first 10 years of prospective donor follow-up of Swiss donors.

Since July 2007 prospective life-long follow-up (FU) for unrelated (URD) and related donors (RD) is mandatory in Switzerland and data on every allogeneic haematopoietic progenitor cell (HPC) donation are collected prospectively. We report the real-world experience of HPC donation during a 10-year study period (01.07.2007-30.06.2017) with basic characteristics and FU data. 1105 donors underwent 1155 HPC donation procedures. Eighty percent of first donations performed by 802 (73%) RDs and 303 (27%) URDs were peripheral blood stem cells (PBSC), 20% bone marrow (BM). Male donors were over-represented as URD (60% male vs 40% female). Main differences between RDs and URDs concerned age and pre-existing health disorders. RDs were significantly older at first donation (median age 48 years) compared to URD (34 years, p < 0.0001) and had more pre-existing health problems: 25% vs 9% in URD (p < 0.0001). No fatal complications occurred, collection related severe adverse events (SAE) after first donation were not significantly different between groups (RD 1.2%, URD 0.99%), incidence rates for neoplastic and autoimmune diseases did not exceed the rates of the general population. RDs are a more heterogeneous and potentially more vulnerable group, but if donor evaluation is performed appropriately, HPC donation is still safe.

Cyclophosphamide dose adjustment based on body weight and albuminemia in elderly patients treated with R-mini-CHOP.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in elderly patients, and R-CHOP chemotherapy is the standard treatment protocol for DLBCL. Elderly patients (often defined as 75 years of age) are treated with anticancer drugs with precaution; however, the pharmacokinetics and pharmacodynamics (PK and PD) of these agents have not been thoroughly investigated in this population. In this study, we investigated the PK of cyclophosphamide (CP) and doxorubicin (DOXO) in elderly patients in order to verify if there is an influence of age on the PK of these anticancer drugs. MATERIALS AND METHODS: This is a prospective multi-center clinical trial investigating the PK of CP and DOXO in elderly and very elderly patients with DLBCL treated by R-mini-CHOP regimen. Dose levels were 25 mg/m2, 0.7-1.4 mg/m2, 750 mg/m2, and 375 mg/m2 for DOXO, Vincristine (VCR), CP, and Rituximab, respectively. For PK analysis, 7 time point samples were collected over 48 h post-administration on cycle 3. CP and VCR plasma concentrations were measured using UPLC-MS/MS validated method. DOX plasma concentrations were measured using UPLC coupled with fluorescence detection-validated method. PK-POP modeling has been performed with a non-linear mixed-effect model program (Monolix). RESULTS: 31 patients (15 males and 16 females), 75 to 96 years old, were treated with R-miniCHOP protocol. Among them, 19 patients were treated with VCR. A one-compartment (1cpt) open model with linear elimination adequately described CP concentration-time courses. The population PK parameters for CP were: CL = 3.58 L/h, Vmale = 32.2 L, and Vfemale = 28.7 L. Body weight (BW), albuminemia, and gender demonstrated a significant impact on CP PK. A 2-compartment (2cpt) open model with linear elimination best described DOXO concentration-time courses. The population PK parameters for DOXO obtained for the structural model were: CL = 51.1 L/h, Q = 49.6 L/h, V1 = 29.4 L, V2 = 1,130 L (clearances: CL, Q, volumes of distribution: V1, V2). The main covariate effects on DOXO PK were related to gender, BW, and VCR administration. VCR increases DOXO V1 from 29.4 L to 57.5 L (p = 0.02). No hematologic and cardiac grade 3 or 4 toxicity were recorded. CONCLUSIONS: Usually, in the absence of specific data, the majority of the physicians empirically reduce anticancer drug dose in the elderly patients (Tourani in J Geriatr Oncol 3(1): 41-48, 2012), or even does not treat these very-old patients. A better knowledge of the pharmacokinetics in very-old patients should allow a better dose adjustment based on the most significant physiological factors that modify the pharmacokinetic parameters. In this study, no serious toxicity was observed in these very elderly patients (84.1 years). This indicates that dose adjustment of chemotherapies should not only be based on age and creatinine clearance, but also, based upon appropriate physiological and biological data. Our findings indicate that, CP dose adjustment should be done according to serum albumin levels and patients BW and gender.

Treatment of chronic scapholunate dissociation with tenodesis: A systematic review.

Scapholunate (SL) instability is the most common dissociative carpal instability condition. It is the most frequent cause of wrist osteoarthritis, defined as scapholunate advanced collapse or SLAC wrist. Familiarity with the SL ligament complex is required to understand the various features of SL instability. Damage to the SL interosseous ligament is the main prerequisite for SL instability; however the extrinsic, palmar and dorsal ligaments of the carpus also come into play. When more than 6 weeks has passed since the initial injury event, SL instability is considered chronic because ligament healing is no longer possible. Before osteoarthritis sets in and when the SL instability is still reducible (scaphoid can be reverticalized), ligament reconstruction surgery is indicated. Since the end of the 1970s, various ligament reconstruction or tenodesis techniques have been described. These techniques are used in cases of chronic, dynamic or static reducible SL instability, when no repairable ligament stump and no chondral lesions are present. The aim is to correct the SL instability using a free or pedicled tendon graft to reduce pain while limiting the loss of mobility and protecting against osteoarthritis-related collapse in the long-term. We will perform a systematic review of the various tenodesis techniques available in the literature.

Intracarpal shortening osteotomy for Kienböck's disease: A retrospective study of 28 cases.

INTRODUCTION: Kienböck's disease is rare in patients with a neutral or positive ulnar variance. In these situations, treatment is challenging and controversial. Various intracarpal shortening osteotomy (ICSO) procedures have been proposed. OBJECTIVE: Study the effect of the type of ICSO (isolated capitate osteotomy or combined with hamate osteotomy) on the clinical and radiological outcomes in a retrospective series. METHODS: Patients with Kienböck's disease were treated with ICSO. A dorsal approach centered over the capitate was used. The transverse osteotomy was located 5mm below the capitate's proximal chondral boundary. The osteotomy cut was 2mm thick. In some patients, a hamate osteotomy was done at the same level as that of the capitate. The osteotomy site was fixed with staples. Cases were classified as with or without a vascularized bone graft was added to the ICSO. RESULTS: There were 28 cases and the average follow-up was 43 months. Three patients required surgical revision. Pain relief at rest was achieved in all patients. The flexion/extension range of motion was 84°. Strength was 75% of the opposite side. The mean QuickDASH was 32.5 and the PRWE (Patient Related Wrist Evaluation) was 30.2. Isolated capitate osteotomy resulted in better satisfaction and improved ulnar/radial deviation and flexion range of motion. There was no difference in terms of pain, strength and functional scores. However, it triggered a significant increase in the radioscaphoid angle. Adding a vascularized bone graft did not impact the outcomes. DISCUSSION: Isolated capitate osteotomy provides better outcomes than combined capitate/hamate osteotomy (satisfaction and wrist range of motion) and should be done as the primary procedure. However, since it increases the radioscaphoid angle more than combined capitate/hamate osteotomy, the latter procedure should be used when a large radioscaphoid angle exists preoperatively. We found no benefit of using a vascularized graft. LEVEL OF EVIDENCE: IV.

[Treatment of distal radius extra-articular malunion in young active patients]. / Traitements des cals vicieux extra-articulaires de l'extrémité distale du radius du sujet jeune actif.

Malunion is a common complication of distal radius fractures despite new fixation devices. The authors discuss the surgical indications, preoperative management and the various surgical techniques used to treat distal radius extra-articular malunion, specifically in active young subjects. The treatment goals in this population group are anatomical restoration of the distal radius and distal radioulnar joint, short immobilization period, quick functional recovery and stable results over time, consistent with high functional demands.

Contaminated wounds: Effectiveness of debridement for reducing bacterial load.

Surgical management of contaminated hand wounds may seem anecdotal, but such injuries actually account for an appreciable amount of the activity in emergency hand centers, and recommendations put forward by scientific societies differ. Dealing effectively with this public health issue calls for clarifying the usefulness of the various available treatments. Our study's objective was to determine the effectiveness of surgical debridement. In this prospective study, 92 patients with contaminated hand wounds underwent surgical debridement. Selection criteria included the length of time between injury and treatment, and the mechanism of injury. Patients with infected wounds, those treated by antibiotics, who were immunosuppressed or had osteoarthritis were excluded. Skin samples were collected both before and after debridement. In 62% of cases, the wounds were contaminated before debridement. Following the procedure, 87% of the bacterial smears were negative. The comparison between debridement and smear results was statistically significant (Student's t test, P<0.001). Surgical debridement, with appropriate irrigation, can effectively eradicate bacterial flora due to contamination.

Radiological and clinical analysis of Madelung's deformity in children.

INTRODUCTION: Madelung's deformity is a bone dysplasia that occurs predominantly in adolescent females, characterized by early epiphyseal growth arrest in the medial part of the distal radius. This leads to an upward and medial displacement of the radial joint surface, restricting range of motion. OBJECTIVES: The objective of this study was to determine whether there was a link between clinical and radiological data in children with Madelung's deformity and to test the hypothesis of a relation between the deformity and a genetic mutation. METHODS: A retrospective study recruited 13 patients with Madelung's deformity, with a mean age of 13.2 years (range, 8-18 years). Assessment comprised level of pain, range of motion and grip force, with standard AP and lateral wrist X-rays. Every patient except one underwent molecular genetic screening, adhering to current recommendations. RESULTS: Pronation-supination, radial inclination and grip force were significantly impaired compared to normal results. All X-ray measurements were significantly abnormal, except for the lunate-covering ratio. Genetic mutation (SHOX) was systematic in the 12 patients screened. DISCUSSION: Radiological deformity did not correlate with functional disturbance or pain. Non-acquired Madelung's deformity requires molecular screening for SHOX or XO mutation, which definitively diagnoses Léri-Weill dyschondrosteosis or Turner syndrome. CONCLUSION: A larger series is necessary to confirm these preliminary results, which nevertheless suggest that non-acquired Madelung's deformity is not isolated but syndromic. Early detection of Léri-Weill or Turner syndrome is essential, due to their therapeutic specificities. LEVEL: IV.

[Analytic study of dot blotting for the detection of anti-Jo-1, anti-M2, anti-ribosomes and anti-LKM]. / Etude analytique d'un dot blot pour la détection des auto-anticorps anti-Jo-1, anti-M2, anti-ribosomes et anti-LKM1.

The Cyto-Dot 4 HM043 kit commercialised by BMD, has replaced the Cyto-Dot HM010 kit that allowed three auto-antibodies detection (anti-Jo-1, anti-M2 and anti-ribosomal protein). Detection of anti-LKM1 auto-antibody was added. These four auto-antibodies have in common only the intracytoplasmic localisation of their respective antigen. The aim of our study was to evaluate this new kit using 104 sera and to compare our results with reference techniques (indirect immunofluorescence IF for anti-M2, anti-ribosomal protein and anti-LKM1, double immunodiffusion ID for anti-Jo-1 and anti-LKM1, western blotting WB for anti-M2) and with Cyto-Dot HM010. The one hundred and four sera were divided into five groups: Group I (n = 12) with anti-Jo-1 detected by ID; Group II (n = 28) with 26 anti-M2 positive by IF and WB, 2 anti-M2 positive only by WB; Group III (n = 10) with anti-ribosomal protein detected by IF 5 of which precipitated by ID; Group IV (n = 32) with anti-LKM1 by IF and ID divided into 18 AIH2 and 14 HCV; Group V (n = 22) consisting of 14 healthy individuals and 8 patients with hypergammaglobulinemia. Results of this study are similar to those of Cyto-Dot HM010 for the three auto-antibodies already in use. Cyto-Dot 4 is a very good anti-LKM1 confirmation method as it is ID.

Multidrug resistance-associated protein MRP1 expression in human gliomas: chemosensitization to vincristine and etoposide by indomethacin in human glioma cell lines overexpressing MRP1.

The 190 kDa multidrug resistance protein MRP1 is likely to be involved in the multidrug resistance phenotype of human gliomas. MRP1 expression was evaluated in surgical tumor samples from 17 patients with gliomas. In addition, the impact of the MRP's inhibitor, indomethacin, on the chemosensitivity to etoposide (VP16) and vincristine (VCR) of two glioblastoma cell lines expressing MRP1 (GL15 and 8MG) was investigated. When evaluated in tumor samples, MRP1 expression was observed in all of them with more than 90% of stained tumor cells in 14/15 high-grade gliomas. MRP1 was also strongly expressed at the membrane of the vascular endothelial cells in the same 14 tumor samples, suggesting that the permeability to anticancer drugs could be also limited across brain tumor vessels. At concentrations comprised between 5 and 50 microM, indomethacin significantly increased the cytotoxic effect of etoposide in both cell lines but it was more efficient in increasing the cytotoxicity of VCR on GL15 cells, as compared with 8MG cells. These results suggest that the association of indomethacin to VCR or etoposide could be of interest in the clinical management of gliomas.

Molecular heterogeneity of oligodendrogliomas suggests alternative pathways in tumor progression.

OBJECTIVE: To identify different genetic molecular profiles in oligodendrogliomas and to evaluate their prognostic significance. METHODS: The main genetic alterations reported in glial tumors were investigated in 26 oligodendrogliomas (10 World Health Organization grade II and 16 World Health Organization grade III). Correlation between identified molecular changes and pathologic grade or clinical course was subsequently analyzed using univariate and multivariate statistical analyses. RESULTS: Loss of heterozygosity (LOH) on chromosome 1p, 19q, and 10; P16/CDKN2A homozygous deletion; EGFR (epidermal growth factor receptor) amplification; and TP53 and PTEN mutations were observed in 14 (54%), 15 (58%), 9 (35%), 7 (27%), 5 (19%), 1 (4%), and 0 cases. LOH 1p and 19q were tightly associated (p < 0.0001). A mutual exclusion was found between LOH 1p/19q and EGFR amplification (p = 0.01), P16/CDKN2A deletions (p = 0.001), or LOH on 10q (p = 0.03), suggesting the existence of distinct genetic subsets in oligodendrogliomas. On univariate analysis, age <50 years (p = 0.002) and LOH 1p (p = 0.01) were associated with a longer progression-free survival (PFS) whereas LOH 10q (p = 0.03) and EGFR amplification (p = 0.007) were associated with a worse PFS. In multivariate analyses, age <50 years (p = 0.001) and LOH 1p (p = 0.006) remained independent predictive factors for PFS. CONCLUSION: These results provide evidence for two alternative molecular pathways of progression in oligodendrogliomas. The first one is associated with loss of 1p and 19q and the second one with P16/CDKN2A deletion, 10q loss, and EGFR amplification. The findings confirm the value of loss of 1p as predictor of longer progression-free survival; in addition, the study demonstrates the unfavorable impact of 10q loss and EGFR amplification on the prognosis.

Glioblastomas with an oligodendroglial component: a pathological and molecular study.

Glioblastoma (GBM) is considered by the WHO classification to represent the most malignant grade of the astrocytic tumors. However, a subset of GBM includes recognizable areas with oligodendroglial features, suggesting that some GBM may also have an oligodendroglial origin. The aim of this study was to analyze the molecular profile of GBM associated with an oligodendroglial component (GBMO). We analyzed a series of 25 GBMO. Loss of heterozygosity (LOH) on 1p and 19q, known as common markers of oligodendroglial tumors, were observed in 40% and 60% of cases, respectively; 72% of the tumors displayed one or both of these markers. All but 4 tumors (84%) showed alterations known to be preferentially involved in the progression of astrocytic tumors to GBM, such as EGFR amplification (44%), P16 deletion (48%), LOH on 10q (64%), PTEN (20%), and TP53 (24%) mutations. Therefore, GBMO displayed all the genetic aberrations found in "standard" GBM with a comparable incidence, but differed from GBM by having a higher rate of LOH on 1p and 19q. These results suggest that GBMO might represent a subgroup of tumors of oligodendroglial origin that is distinct from the "standard" GBM in terms of tumorigenesis pathway.

[Genes implicated in glial tumors]. / Gènes impliqués dans les tumeurs gliales.

Because of the absence of specific marker, the histological classification of gliomas remain controversial. Identifying the genetic alterations involved in gliomas makes it possible to define specific molecular pathway of tumoral progression and to define markers of prognostic and diagnostic relevance. For example, p53 mutations are frequent in low grade astrocytoma, anaplastic astrocytoma and secondary glioblastoma suggesting that it takes place at an early stage of development of astrocytic tumors, whereas inactivation of PTEN arises mainly in glioblastomas and EGFR amplification is preferentially associated with "de novo" glioblastoma. Loss of chromosomes 1p and 19q characterizes oligodendroglial tumors. However the putative tumor suppressor genes located on 1p and 19q and specifically inactivated are not known yet. Emerging technologies, like microarrays and microdissection, will allow to refine molecular data and provide a molecular classification of gliomas mechanism involved in the repair of the respiratory epithelium.

Frequent loss of 1p32 region but no mutation of the p18 tumor suppressor gene in meningiomas.

After chromosome 22 and NF2 inactivation, the loss of chromosome 1p is one of the most frequent abnormalities encountered in meningiomas. However the putative tumor suppressor gene located on 1p inactivated in meningiomas has still to be identified. We screened 68 meningiomas for LOH on chromosome 22 and 1. We found 34 LOH on the NF2 region on chromosome 22 (50%) and 19 LOH on 1p (28%), 16 being associated with loss of chromosome 22. Partial deletions delimited a candidate region located between D1S234 and D1S2797. The p18INK4C tumor suppressor gene, a member of the genes family coding for inhibitors of cyclin-dependent kinases, is located in this region. To determine whether p18 is involved in development of meningiomas, we performed a mutation analysis of the p18 gene and a search for homozygous deletion in the 19 meningiomas with 1p loss. Sequencing analysis of the p18 gene revealed one polymorphism, but no somatic mutations and no homozygous deletions were found. These results confirm that the loss of chromosome 1p32 is a frequent feature in meningiomas, however the p18 tumor suppressor gene which is located in this region, does not seem to be involved.

European brown hare syndrome virus: molecular cloning and sequencing of the genome.

The genome of the European brown hare syndrome virus (EBHSV), a calicivirus related to rabbit haemorrhagic disease virus (RHDV), was fully sequenced. It was 7442 bases long and contained two ORFs. In RHDV, the 5' large ORF (ORF1) is predicted to encode a polyprotein precursor to the non-structural and capsid proteins. The small ORF (ORF2) encodes a predicted protein of 12 kDa. Alignment of sequences of EBHSV and RHDV showed 71% nucleotide identity; the changes were uniformly scattered over the whole genome. Minor differences could be detected when comparing two EBHSV sequences, indicating that EBHSV could vary to the same extent as RHDV. Four cleavage sites previously identified on the RHDV polyprotein were conserved in EBHSV. These sequencing data clearly show that EBHSV and RHDV share a similar genomic organization and confirm that EBHSV and RHDV are two distinct members within the family Caliciviridae.

Sequence and genomic organization of a rabbit hemorrhagic disease virus isolated from a wild rabbit.

Rabbit hemorrhagic disease virus (RHDV) is a member of the caliciviridae family. The nucleotidic sequence of a full-length cDNA of one RHDV isolate (RHDV-SD) is reported. The genome is 7437 bases long and includes two ORFs, ORF1 (7034 b) and ORF2 (353 b), coding for the polyprotein and the Vp12, respectively. The coding sequence for the second structural protein (the capsid protein, Vp60) is located at the 3' end of ORF1. Comparison of RHDV-SD with the German RHDV isolated revealed 470 nucleotide substitutions (96% homology). The deduced amino acid sequences of the two isolates are closely related (98% identity), and no hypervariable region could be identified either in the structural or nonstructural proteins.