Role for cementoplasty in intra-articular distal radius fractures: Cadaver study and application to arthroscopy.

BACKGROUND: Die-punch intra-articular fractures of the distal radius raise surgical challenges. The residual articular step-off must be less than 1mm to prevent the development of radio-carpal osteoarthritis. The objectives of this cadaver study were to evaluate whether cementoplasty was effective in reducing die-punch fractures and to determine whether this technique was feasible as an arthroscopic procedure. HYPOTHESIS: Cementoplasty performed as an arthroscopic procedure is effective in treating die-punch fractures. MATERIAL AND METHODS: Eleven cadaver forearms collected at a laboratory were studied. In each, a depressed fracture of the lunate fossa of the radial articular surface was created using a Tinius Olsen H25K-S compression test machine. A Kyphon XPander® balloon (Medtronic) was used to lift the depressed area, and calcium-phosphate cement was then injected to stabilise the reduction. Cementoplasty under arthroscopic guidance was performed on an additional forearm. RESULTS: Computed tomography of the wrists after fracture induction showed a mean depression of 4.66mm (range, 4.01-5.25mm). Arthroscopic cementoplasty proved feasible with the arthroscope inserted through the 3-4 radio-carpal portal. Positioning the balloon under the depressed area ensured satisfactory reduction and allowed the injection of cement. DISCUSSION: Cementoplasty may be useful for the treatment of die-punch fractures. Additional indications may be other types of distal radius fractures with articular surface depression. LEVEL OF EVIDENCE: IV, cadaver study.

Outcomes and mutational analysis of patients with lower-risk non-del5q myelodysplastic syndrome treated with antithymocyte globulin with or without ciclosporine A.

Immunosuppressive treatment is a disease-modifying therapy for lower-risk myelodysplastic syndromes (MDS). However, IST is relatively rarely used and long-term outcomes of patients are seldom reported. We retrospectively studied outcomes of 20 patients with lower-risk non del 5q MDS with transfusion dependency, with horse or rabbit antithymocyte globulin ±â€¯ciclosporine A, and frontline eltrombopag in two of them. IPSS-R was low, intermediate and high in 30%, 55% and 10% of the patients, respectively. Fifty-five percent of the patients had hypocellular bone marrow (BM). Baseline mutations were detected in 31.5% of the patients and were more frequent in patients with normo/hypercellular MDS than in patients with hypocellular MDS. Transfusion independence rate for both red blood cells (RBC) and platelets was achieved in 45% of patients. RBC transfusion duration ≤6 months, B-cell counts >0.2 G/L and, marginally, BM blasts ≤2% were associated with higher transfusion independence rate. Age and cellularity did not influence the response rate. Median transfusion independence duration was 53 months. Cumulative incidence of progression to a more aggressive myeloid disease was 0 in patients without baseline mutations and 33% in patients with baseline mutations (P = .008). Median progression-free and overall survival after treatment onset and median overall survival after loss of transfusion independence were 45.5 months, 68 months and not reached, respectively. In conclusion, antithymocyte globulin ±â€¯ciclosporine A results in durable responses in MDS, irrespective of age, in patients with lower-risk disease without B-cell lymphopenia and treated early in the course of the disease.

Distinctive features of Drosophila alternative splicing factor RS domain: implication for specific phosphorylation, shuttling, and splicing activation.

The human splicing factor 2, also called human alternative splicing factor (hASF), is the prototype of the highly conserved SR protein family involved in constitutive and regulated splicing of metazoan mRNA precursors. Here we report that the Drosophila homologue of hASF (dASF) lacks eight repeating arginine-serine dipeptides at its carboxyl-terminal region (RS domain), previously shown to be important for both localization and splicing activity of hASF. While this difference has no effect on dASF localization, it impedes its capacity to shuttle between the nucleus and cytoplasm and abolishes its phosphorylation by SR protein kinase 1 (SRPK1). dASF also has an altered splicing activity. While being competent for the regulation of 5' alternative splice site choice and activation of specific splicing enhancers, dASF fails to complement S100-cytoplasmic splicing-deficient extracts. Moreover, targeted overexpression of dASF in transgenic flies leads to higher deleterious developmental defects than hASF overexpression, supporting the notion that the distinctive structural features at the RS domain between the two proteins are likely to be functionally relevant in vivo.

Characterization of SRp46, a novel human SR splicing factor encoded by a PR264/SC35 retropseudogene.

The highly conserved SR family contains a growing number of phosphoproteins acting as both essential and alternative splicing factors. In this study, we have cloned human genomic and cDNA sequences encoding a novel SR protein designated SRp46. Nucleotide sequence analyses have revealed that the SRp46 gene corresponds to an expressed PR264/SC35 retropseudogene. As a result of mutations and amplifications, the SRp46 protein significantly differs from the PR264/SC35 factor, mainly at the level of its RS domain. Northern and Western blot analyses have established that SRp46 sequences are expressed at different levels in several human cell lines and normal tissues, as well as in simian cells. In contrast, sequences homologous to SRp46 are not present in mice. In vitro splicing studies indicate that the human SRp46 recombinant protein functions as an essential splicing factor in complementing a HeLa cell S100 extract deficient in SR proteins. In addition, complementation analyses performed with beta-globin or adenovirus E1A transcripts and different splicing-deficient extracts have revealed that SRp46 does not display the same activity as PR264/SC35. These results demonstrate, for the first time, that an SR splicing factor, which represents a novel member of the SR family, is encoded by a functional retropseudogene.

Specific inhibition of serine- and arginine-rich splicing factors phosphorylation, spliceosome assembly, and splicing by the antitumor drug NB-506.

Specific phosphorylation of serine- and arginine-rich pre-mRNA splicing factors (SR proteins) is one of the key determinants regulating splicing events. Several kinases involved in SR protein phosphorylation have been identified and characterized, among which human DNA topoisomerase I is known to have DNA-relaxing activity. In this study, we have investigated the mechanism of splicing inhibition by a glycosylated indolocarbazole derivative (NB-506), a potent inhibitor of both kinase and relaxing activities of topoisomerase I. NB-506 completely inhibits the capacity of topoisomerase I to phosphorylate, in vitro, the human splicing factor 2/alternative splicing factor (SF2/ASF). This inhibition is specific, because NB-506 does not demonstrate activity against other kinases known to phosphorylate SF2/ASF such as SR protein kinase 1 and cdc2 kinase. Importantly, HeLa nuclear extracts competent in splicing but not splicing-deficient cytoplasmic S100 extracts treated with the drug fail to phosphorylate SF2/ASF and to support splicing of pre-mRNA substrates containing SF2/ASF-target sequences. Native gel analysis of splicing complexes revealed that the drug affects the formation of the spliceosome, a dynamic ribonucleoprotein structure where splicing takes place. In the presence of the drug, neither pre-spliceosome nor spliceosome is formed, demonstrating that splicing inhibition occurs at early steps of spliceosome assembly. Splicing inhibition can be relieved by adding phosphorylated SF2/ASF, showing that extracts treated with NB-506 lack a phosphorylating activity required for splicing. Moreover, NB-506 has a cytotoxic effect on murine P388 leukemia cells but not on P388CPT5 camptothecin-resistant cells that carry two point mutations in conserved regions of topoisomerase I gene (Gly361Val and Asp709Tyr). After drug treatment, P388 cells accumulated hypophosphorylated forms of SR proteins and polyadenylated RNA in the nucleus. In contrast, neither SR protein phosphorylation nor polyadenylated mRNA distribution was affected in P388 CPT5-treated cells. Consistently, NB506 treatment altered the mRNA levels and/or splicing pattern of several tested genes (Bcl-X, CD 44, SC35, and Sty) in P388 cells but not in P388 CPT5 cells. The study shows for the first time that indolocarbazole drugs targeting topoisomerase I can affect gene expression by modulating pre-mRNA splicing through inhibition of SR proteins phosphorylation.

Transforming potential of truncated v-myb and stimulation of replication by gag-myb fusion products.

We have previously reported that truncated forms of the v-myb oncogene of avian myeloblastosis virus (AMV) are expressed in transformed chicken embryo fibroblasts (CEF). In this paper, we show that deletion mutants encoding v-myb products altered in either the DNA-binding or the negative regulatory domains are able to induce CEF transformation. In addition, we report that recombinant plasmids expressing gag-myb fusion proteins are maintained as extrachromosomal forms in transfected cells. This observation provides an important clue for a possible role of myb in the DNA replication processes.

C-myb proto-oncogene: evidence for intermolecular recombination of coding sequences.

We have characterized a novel chicken c-myb exon whose sequences are specifically expressed in thymic cells. In situ hybridization experiments indicate that this thymus-specific coding exon is localized on a small chromosome, distinct from the large acrocentric chromosome 3 on which we recently mapped the bulk of 15 exons, common to the c-myb mRNA species expressed in hematopoietic cells of both B and T lineages. These observations indicate that intermolecular recombination is required for the tissue-specific expression of the c-myb proto-oncogene. We also show that these thymus-specific sequences are conserved in human DNA and lie on chromosome 17q25, whereas the human c-myb locus is localized on chromosome 6q22-23. Sequencing data obtained from genomic DNA and PCR analyses performed with c-myb mRNA species expressed in chicken thymic cells strongly suggest that a repeated decameric sequence plays a key role in the recombination process.

Organization of 5'-proximal c-myb exons in chicken DNA. Implications for c-myb tissue-specific transcription.

The organization of 5'-proximal c-myb exons in chicken DNA has been established by restriction enzyme mapping and nucleotide sequencing. Hybridization studies performed with cDNA probes revealed that yolk sac and thymic c-myb RNAs differ in their 5'-termini. A comparison of the genomic c-myb sequence with that of cDNAs isolated from normal thymic and lymphoma avian cells suggests that different promoter regions are used to initiate c-myb transcription in hematopoietic cells of different origins.

Expression of a truncated v-myb product in transformed chicken embryo fibroblasts.

Transformed cells have been isolated after transfection of chicken embryo fibroblasts (CEF) with the DNA of a recombinant clone (KXA 3457) in which the v-myb sequences are flanked by the two AMV-LTRs. Abnormal myb-specific RNA species and myb-related polypeptides were found to be expressed in these cells, suggesting that transformation of CEF by v-myb might require alterations of the oncogene product.

Chromosomal reallocation of the chicken c-myb locus and organization of 3'-proximal coding exons.

In the course of our studies concerning the tissue-specific expression of the c-myb proto-oncogene, we have established the nucleotide sequence of the chicken c-myb 3'-proximal coding exons. In situ hybridization performed with different genomic DNA probes corresponding to nearly all the c-myb gene allowed us to localize the corresponding locus on the large acrocentric chromosome 3 in chicken. Our sequencing data also indicate that the 3'-proximal noncoding sequences represented in c-myb mRNA species are derived from non-contiguous exons.

Transforming potential of the v-myb oncogene from avian myeloblastosis virus: alterations in the oncogene product may reveal a new target specificity.

Transfection of brown leghorn chicken embryo fibroblasts by DNA containing v-myb sequences cloned either in a complete AMV proviral DNA or in a retroviral derived vector has led to the isolation of two kinds of transformed cells. A characterization of the proviral sequences retained and expressed in these transformed cells revealed that they contained either new or altered v-myb-related RNA species. The experiments presented in this paper also show that both types of transformants expressed truncated myb-related polypeptides, suggesting that alterations of the v-myb product may result in a new target specificity, leading to the transformation of chicken embryo fibroblasts.

The usefulness of prostate-specific antigen and prostatic acid phosphatase in clinical practice.

A comparative study was performed on the usefulness of prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) in control subjects (69), benign prostatic hypertrophy (BPH) patients (150), and patients with prostatic carcinoma (113) in a urology department. We establish, as others, the greater clinical sensitivity of PSA and its effectiveness as a prognostic tool in the evaluation of prostatic cancer therapy and in the early detection of residual tumor following radical prostatectomy. However, patients are admitted to our department with more severe and complicated benign prostatic pathology and urinary dysfunctions, which decreases the specificity of the PSA test to 30% (N = 2.7 ng/ml). A cutoff threshold of 50 ng/ml becomes necessary to maintain a 90% positive predictive value. The combination of PSA sensitivity (96%) and PAP specificity (95%) enabled a better definition of the high-risk subpopulation among noncancer patients and, in addition, was a help for differential diagnosis, confirmation of advanced stages of prostatic cancer, and selection of low-stage prostatic cancer candidates undergoing radical prostatectomy. Routine serum PSA measurements in the population of patients consulting a urology department will no doubt bring about a new approach to the management of prostate cancer.

[Prostatic carcinoma: histoprognosis, prognostic value of Gleason's index]. / Carcinomes prostatiques: histopronostic, valeur pronostique de l'index de Gleason.

This paper recalls the definition of the Gleason index and describes the five architectural types that enable a calculation of the index. The conditions of the practical application of the index are defined, with a discussion of reproducibility of results based on current literature and the author's experience. The index allows appreciation of the developmental potential of prostatic cancer and distinguishes between patients with a high risk of metastases and death from the cancer and those with low potential development. While the Gleason index cannot predict the course of the tumour in any given patient, it can be considered a useful element among the clinical and biological factors assessed in the prognosis of prostatic carcinoma.

[Flow cytometry in cancer of the bladder]. / Cytométrie en flux dans les cancers de la vessie.

We reassessed the use of DNA flow cytometry in bladder cancers on the basis of our research and already published findings. We discuss technical aspects underlying the validity of the results. Currently, the validity of DNA flow cytometry is established by parametric analysis of the DNA content of tumor cells found in the course of multiple biopsies of the tumor. In addition, we examine the results obtained with bladder washings and, in some cases, the results of biopsies of the bladder mucosa which may appear normal under cystoscopy. The complementarity of these examinations appears to be essential. Our experience confirms the results already published, suggesting that the frequency of DNA aneuploidy increases significantly according to the grade and the tumor stage. However, clinical interpretation of DNA flow cytometry results calls for some caution. There is a general consensus not to use these results in the screening of bladder cancers. However, DNA flow cytometry is particularly useful in the follow-up of carcinoma in situ since DNA aneuploidy is almost always present. DNA flow cytometry is also useful in the stratification of superficial grade 2 tumors. Finally, during the follow-up of invasive tumors, the persistence or appearance of DNA aneuploidy may be attributed to therapeutic resistance.

[Standards, Options, and Recommendations for brachytherapy in patients with prostate cancer: efficacy and toxicity]. / Standards, Options et Recommandations pour la curiethérapie des patients atteints de cancer de la prostate: efficacité et toxicité.

CONTEXT: The "Standards, Options and Recommendations" (SOR) collaborative project was initiated in 1993 by the Federation of the French Cancer Centres (FNCLCC), with the 20 French Regional Cancer Centres, several French public university and general hospitals, as well as private clinics and medical specialty societies. Its main objective is the development of serviceable clinical practice guidelines in order to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review, followed by a critical appraisal by a multidisciplinary group of experts. Draft guidelines are produced, then validated by specialists in cancer care delivery. OBJECTIVES: Produce clinical practice guidelines for the brachytherapy of prostate cancer using the methodology developed by the Standards, Options and Recommendations project. METHODS: The FNCLCC and the French Urology Association (AFU) first designated the multidisciplinary group of experts. Available data were collected by a search of Medline and lists selected by experts in the group. A first draft of the guidelines was written, they validated by independent reviewers. RESULTS: The main recommendations are: 1/Brachytherapy with permanent seeds alone is a possible curative treatment for prostate cancer patients with the following prognosis factors: tumour stage T1 or T2a (TNM 1992), Gleason score < or = 6 and PSA < 10 micrograms/L. 2/Combined treatment with brachytherapy and hormonal therapy could be more efficient than brachytherapy alone for prostate cancer patients with Gleason score > 7 and/or PSA > 10.3/Combination of brachytherapy and external beam radiation therapy can be proposed to prostate cancer patients with intermediate prognosis. 4/Before and after seed implantation, risks of infection must be prevented by appropriate antibiotic therapy (recommendation). 5/Brachytherapy must not be performed within 2 months of transurethral prostate resection. 6/The height of the urethra receiving more than 200% of the prescribed dose must be reported. The portion of the rectum receiving 100 and 120% of the prescribed dose must be limited to 10 and 5 mm length, respectively.

[Substitute bladders]. / Les vessies de remplacement.

Following prostato-cystectomy in men or total cystectomy in women the bladder can be replaced by constructing an intestinal pouch to be connected to the urethra. This bladder replacement reservoir should possess the specific qualities of the natural bladder: it should collect and retain the urine at low pressure, protect the upper urinary tract against reflux and distension, control voluntary micturition at a socially acceptable rhythm and avoid the metabolic disorders due to the reabsorption of urine by the intestinal mucosa. Low pressure reservoirs are the ones most commonly used. They are obtained by opening the ileal or ileocaecal graft along its antimesenteric border and rearranging the intestinal tissue to form a pouch connected to the urethra. Detubulated reservoirs have a capacity and a compliance that are close to those of the urinary bladder. Daytime continence is acquired in the immediate postoperative period, and night-time continence is possible in 60 to 70 per cent of the patients. These are the main advantages of bladder replacement by tubular small intestine. The reservoirs thus constructed have few contractions, but they have not yet proved to be capable of full evacuation in the long term. Intermittent bladder catheterization might well be the price to be paid in the future for an immediate improvement in night-time continence.

[Multifocal fibrosclerosis (retroperitoneal, mediastinal, mesenteric and pelvic involvement) associated with vasculitis and revealed by a livedo: clinical, histopathological and ultrastructural study in a case (author's transl)]. / Fibrosclérose multifocale (médiastinale, rétropéritonéale, pelvienne, avec mésentérite rétractile) associée a une vascularite et révélée par un livedo. Etude clinique, histopathologique et ultrastructurale.

A 22-year-old male patient was seen with vasculitis and subcutaneous nodules on arms and legs. Discret thoracic venous dilations were noticed and venography demonstrated obstruction of the superior vena cava. Clinical and biological examination, roentgenograms revealed no sign of immunological disease but led to the diagnosis of mediastinal and retroperitoneal idiopathic fibrosis. No drug could be incriminated. Right hydronephrosis obliged to a surgical bilateral ureterolysis combined with systemic steroid therapy. Histological and ultrastructural examinations on retroperitoneal biopsies showed dense collagenous fibrosis, with vasculitis. Perivascular infiltrate was mainly composed of extravased erythrocytes and lymphocytes. Fibrin deposits were seen around implicated vessels. Direct immunofluorescence investigations were negative. These morphological features seem to be in agreement with the physiopathological hypothesis of sclerosis. No retroperitoneal or mediastinal fibrosis extension occurred three years after surgical procedure, and under corticosteroid therapy. Similar vasculitis with mediastinal and retroperitoneal idiopathic fibrosis have previously been reported in only one case by R. W. Carton and R. Wrong. Multifocal fibrosclerosis is the generic term currently used, since Comings et al. (1967), to describe a group of fibrosing conditions which affect separate organ systems. Findings suggest that retroperitoneal fibrois, mediastinal fibrosis, sclerosing cholangitis, Riedel's thyroiditis and pseudotumors of the orbit may be different manifestations of a single disease whose pathogenesis remains obscure.

[Prognostic value of cytofluorometry in bladder tumors]. / Intérêt pronostique de la cytofluorométrie dans les tumeurs vésicales.

Bladder lavage fluid was examined using flow-cytometry (FCM) in 112 patients with transitional cell carcinoma seen over 30 months. FCM investigates the entire mucosa, furnishes indications as to the possible existence of dysplasia or carcinoma in situ, and thus provides for a more accurate evaluation of the evolutive potential of the "bladder disease". FCM consists in the automated assay of the DNA content of epithelial cells. The test is positive when "tumorous" diploid or aneuploid cells are demonstrated. The diagnostic sensitivity of FCM is comparable to that of cytologic diagnosis on bladder lavage specimens, but FCM has the additional advantage of detecting those patients at high risk for disease progression by measurement of the DNA index. Grade 1 and 2 tumors are diploid in 70% of patients, against only 14% for grade 3 tumors and carcinomas in situ. Follow up of 25 grade 2 patients and determination of the recurrence index clearly establishes the prognostic significance of the degree of tumorous ploidy. Furthermore, the effectiveness of endovesical chemotherapy can be monitored using FCM measurement of the aneuploidy index.

[Spontaneous regression of regressive pulmonary metastases from kidney cancer. Myth or reality? Apropos of 2 cases]. / Régression spontanée de métastases pulmonaires régressives de cancer du rein. Un mythe ou une réalité? A propos de deux cas.

The authors report two cases of regression of lung metastases from renal cell cancer with cytological and histological proof. They present a complete review of the literature and analyse the theories proposed to explain this phenomenon.

[Reproducibility and prognostic value of Gleason's and Gaeta's histological grades in prostatic carcinoma]. / Reproductibilité et valeur pronostique des grades histologiques de Gleason et de Gaeta dans les carcinomes de la prostate.

Two histopathologic grading systems for prostatic adenocarcinomas are reevaluated: the Gleason system and the Gaeta system. Two pathologists reviewed 234 specimens to assess reproducibility. Exact agreement is achieved in 88% with the Gaeta system, in 65% with the Gleason system. Nevertheless, agreement to within one score unit is achieved in 94% with the Gleason grading. One pathologist's autoreproducibility exceed 80% with either system. Actuarial survival curves and mortality index (deaths per patient-year of follow-up) provided evidence of their predictive value. Regardless of the clinical stage these two grading systems select groups of patients sharing a good, intermediate or bad prognosis but none can predict a given patient's accurate survival. The Gleason system would allow a better discrimination between poorly and highly aggressive tumors of intermediate grade.