Identification of Novel Candidate Oncogenes in Chromosome Region 17p11.2-p12 in Human Osteosarcoma

Osteosarcoma is the most common primary malignancy of bone. The tumours are characterized by high genomic instability, including the occurrence of multiple regions of amplifications and deletions. Chromosome region 17p11.2–p12 is amplified in about 25% of cases. In previous studies, COPS3 and PMP22 have been identified as candidate oncogenes in this region. Considering the complexity and variation of the amplification profiles for this segment, the involvement of additional causative oncogenes is to be expected. The aim of the present investigation is to identify novel candidate oncogenes in 17p11.2–p12. We selected 26 of in total 85 osteosarcoma samples (31%) with amplification events in 17p11.2–p12, using quantitative PCR for 8 marker genes. These were subjected to high-resolution SNP array analysis and subsequent GISTIC analysis to identify the most significantly amplified regions. Two major amplification peaks were found in the 17p11.2–p12 region. Overexpression as a consequence of gene amplification is a major mechanism for oncogene activation in tumours. Therefore, to identify the causative oncogenes, we next determined expression levels of all genes within the two segments using expression array data that could be generated for 20 of the selected samples. We identified 11 genes that were overexpressed through amplification in at least 50% of cases. Nine of these, c17orf39, RICH2, c17orf45, TOP3A, COPS3, SHMT1, PRPSAP2, PMP22, and RASD1, demonstrated a significant association between copy number and expression level. We conclude that these genes, including COPS3 and PMP22, are candidate oncogenes in 17p11.2–p12 of importance in osteosarcoma tumourigenesis

Less Anterior Knee Pain with a Mobile-bearing Prosthesis Compared with a Fixed-bearing Prosthesis

Anterior knee pain is one of the major short-term complaints after TKA. Since the introduction of the mobile-bearing TKA, numerous studies have attempted to confirm the theoretical advantages of a mobile-bearing TKA over a fixed-bearing TKA but most show little or no actual benefits. The concept of self-alignment for the mobile bearing suggests the posterior-stabilized mobile-bearing TKA would provide a lower incidence of anterior knee pain compared with a fixed-bearing TKA. We therefore asked whether the posterior-stabilized mobile-bearing knee would in fact reduce anterior knee pain. We randomized 103 patients scheduled for cemented three-component TKA for osteoarthrosis in a prospective, double-blind clinical trial. With a 1-year followup, more patients experienced persistent anterior knee pain in the posterior-stabilized fixed-bearing group (10 of 53, 18.9%) than in the posterior-stabilized mobile-bearing group (two of 47, 4.3%). No differences were observed for range of motion, visual analog scale for pain, Oxford 12-item questionnaire, SF-36, or the American Knee Society score. The posterior-stabilized mobile-bearing knee therefore seems to provide a short-term advantage compared with the posterior-stabilized fixed-bearing knee

A conditionally replicating adenovirus with strict selectivity in killing cells expressing epidermal growth factor receptor

AbstractVirotherapy of cancer using oncolytic adenoviruses has shown promise in both preclinical and clinical settings. One important challenge to reach the full therapeutic potential of oncolytic adenoviruses is accomplishing efficient infection of cancer cells and avoiding uptake by normal tissue through tropism modification. Towards this goal, we constructed and characterized an oncolytic adenovirus, carrying mutated capsid proteins to abolish the promiscuous adenovirus native tropism and encoding a bispecific adapter molecule to target the virus to the epidermal growth factor receptor (EGFR). The new virus displayed a highly selective targeting profile, with reduced infection of EGFR-negative cells and efficient killing of EGFR-positive cancer cells including primary EGFR-positive osteosarcoma cells that are refractory to infection by conventional adenoviruses. Our method to modify adenovirus tropism might thus be useful to design new oncolytic adenoviruses for more effective treatment of cancer

Long-Term Neurodevelopmental Outcome of Monochorionic and Matched Dichorionic Twins

Contains fulltext : 79941.pdf (publisher's version ) (Open Access)BACKGROUND: Monochorionic (MC) twins are at increased risk for perinatal mortality and serious morbidity due to the presence of placental vascular anastomoses. Cerebral injury can be secondary to haemodynamic and hematological disorders during pregnancy (especially twin-to-twin transfusion syndrome (TTTS) or intrauterine co-twin death) or from postnatal injury associated with prematurity and low birth weight, common complications in twin pregnancies. We investigated neurodevelopmental outcome in MC and dichorionic (DC) twins at the age of two years. METHODS: This was a prospective cohort study. Cerebral palsy (CP) was studied in 182 MC infants and 189 DC infants matched for weight and age at delivery, gender, ethnicity of the mother and study center. After losses to follow-up, 282 of the 366 infants without CP were available to be tested with the Griffiths Mental Developmental Scales at 22 months corrected age, all born between January 2005 and January 2006 in nine perinatal centers in The Netherlands. Due to phenotypic (un)alikeness in mono-or dizygosity, the principal investigator was not blinded to chorionic status; perinatal outcome, with exception of co-twin death, was not known to the examiner. FINDINGS: Four out of 182 MC infants had CP (2.2%) - two of the four CP-cases were due to complications specific to MC twin pregnancies (TTTS and co-twin death) and the other two cases of CP were the result of cystic PVL after preterm birth - compared to one sibling of a DC twin (0.5%; OR 4.2, 95% CI 0.5-38.2) of unknown origin. Follow-up rate of neurodevelopmental outcome by Griffith's test was 76%. The majority of 2-year-old twins had normal developmental status. There were no significant differences between MC and DC twins. One MC infant (0.7%) had a developmental delay compared to 6 DC infants (4.2%; OR 0.2, 95% 0.0-1.4). Birth weight discordancy did not influence long-term outcome, though the smaller twin had slightly lower developmental scores than its larger co-twin. CONCLUSIONS: There were no significant differences in occurrence of cerebral palsy as well as neurodevelopmental outcome between MC and DC twins. Outcome of MC twins seems favourable in the absence of TTTS or co-twin death

Outcome of total claviculectomy in six cases

Total claviculectomy is a rare surgical procedure that has been performed for more than 90 years for a variety of indications, such as malignancy, trauma, and infection. What are the results for the pain score, and what is the influence of a total claviculectomy on the range of motion of the shoulder? We could not find the answers in the literature and analyzed 6 cases of total claviculectomy. The pain scores are good in a chronic osteitis case and in the two malignancy cases. In the 3 posttraumatic cases, the indication was pain, and all 3 had poor results because of persistent pain. All 6 patients had full range of motion. A resection of the entire clavicle did not disturb the motion of the shoulder. A tendency but no final conclusions can be drawn because of too few patients and heterogeneous indication

Region of interest and pixel-by-pixel analysis of dynamic contrast enhanced magnetic resonance imaging parameters and time-intensity curve shapes: a comparison in chondroid tumors

Dynamic contrast enhanced (DCE) MRI is widely acknowledged to be a helpful tool in the diagnosis and differentiation of tumors. In common clinical settings, the dynamic changes described by the time-intensity curves (TICs) are evaluated to find patterns of atypical tissue behavior, i.e., areas characterized by rapid contrast wash-in and wash-out. Despite the ease of this approach, there is no consensus about the specificity of the TIC shapes in discriminating tumor grades. We explore a new way of looking at TICs, where these are not averaged over a selected region of interest (ROI), but rendered pixel-by-pixel. In this way, the characteristic of the tissue is not given as a single TIC classification but as a distribution of the different TIC patterns. We applied this method in a group of patients with chondroid tumors and compared its outcome with the outcome of the standard ROI-based averaged TIC analysis. Furthermore, we focused on the problem of ROI selection in these tumors and how this affects the outcome of the TIC analysis. Finally, we investigated what relationship exists between the "standard" DCE-MRI parameter maximum enhancement (ME) and the TIC shape. CONCLUSIONS: We demonstrate that, where the ROI approach fails to show the presence of areas of rapid contrast wash-in and wash-out, the pixel-by-pixel approach reveals the coexistence of a heterogeneous pattern of TIC shapes. Secondly, we point out the differences in the DCE MRI parameters and tumor volume that can result when selecting the tumor based on DCE parameter maps or post-contrast T1-weighted images. Finally, we show that ME maps and TIC shape maps highlight different tissue areas and, therefore, the use of the ME maps is not appropriate for the correct identification of areas of atypical TIC

Two-incision minimally invasive total hip arthroplasty - results and complications

The purpose of this study was to determine the complication rate and functional result after two-incision minimally invasive total hip arthroplasty in a retrospective consecutive case series of the first 45 patients treated by a single surgeon. The mean follow up period was 2.1 years. There were 4 early major complications (2 peri-operative fractures and 2 re-interventions) and 28 early minor complications (1 superficial infection and 27 patients with a loss of sensation of the lateral aspect of the thigh). One stem loosening required revision within two years. The mean modified Harris Hip Score at final follow-up was 91,5. Our experience shows a relatively high complication risk after two-incision minimally invasive total hip arthroplasty, and we have since abandoned this techniqu

Focal chromosomal copy number aberrations identify CMTM8 and GPR177 as new candidate driver genes in osteosarcoma

Osteosarcoma is an aggressive bone tumor that preferentially develops in adolescents. The tumor is characterized by an abundance of genomic aberrations, which hampers the identification of the driver genes involved in osteosarcoma tumorigenesis. Our study aims to identify these genes by the investigation of focal copy number aberrations (CNAs, <3 Mb). For this purpose, we subjected 26 primary tumors of osteosarcoma patients to high-resolution single nucleotide polymorphism array analyses and identified 139 somatic focal CNAs. Of these, 72 had at least one gene located within or overlapping the focal CNA, with a total of 94 genes. For 84 of these genes, the expression status in 31 osteosarcoma samples was determined by expression microarray analysis. This enabled us to identify the genes of which the over- or underexpression was in more than 35% of cases in accordance to their copy number status (gain or loss). These candidate genes were subsequently validated in an independent set and furthermore corroborated as driver genes by verifying their role in other tumor types. We identified CMTM8 as a new candidate tumor suppressor gene and GPR177 as a new candidate oncogene in osteosarcoma. In osteosarcoma, CMTM8 has been shown to suppress EGFR signaling. In other tumor types, CMTM8 is known to suppress the activity of the oncogenic protein c-Met and GPR177 is known as an overexpressed upstream regulator of the Wnt-pathway. Further studies are needed to determine whether these proteins also exert the latter functions in osteosarcoma tumorigenesi