Surgical outcomes of patients with diffuse-type tenosynovial giant-cell tumours: an international, retrospective, cohort study.

BACKGROUND: Diffuse-type tenosynovial giant-cell tumour is a rare, locally aggressive, and difficult-to-treat soft tissue tumour. Clinical and surgical outcomes depend on multiple factors, including preoperative diagnostic assessment, the localisation and extent of disease, and possibly the choice of treatment modalities by orthopaedic surgeons. We did a retrospective cohort study to characterise global surgical treatment protocols, and assess surgical outcomes, complications, and functional results in patients with diffuse-type tenosynovial giant-cell tumours. METHODS: In this international, multicentre, retrospective cohort study, we included consecutive patients treated in 31 sarcoma reference centres between Jan 1, 1990, and Dec 31, 2017. Eligible patients were of any age and had histologically proven diffuse-type tenosynovial giant-cell tumour of large joints. Patient data were retrieved from the local databases of participating centres. Patients with localised-type tenosynovial giant-cell tumour were excluded. In the analysis, we only included patients with complete core criteria data regarding admission status, date of treatment, type of treatment at participating centre, and first local recurrence after treatment. We used a non-parametric method to estimate recurrence-free survival at 3, 5, and 10 years after initial surgical resection in a tertiary centre. We used a multivariate Cox regression model to estimate the effect of risk factors. We also present subgroup analyses of disease status at presentation (primary vs recurrent disease) and recurrence-free survival by surgery type (open surgery vs arthroscopic synovectomy), and prespecified risk factors were tested in a univariate and multivariable analyses, with an endpoint of first local recurrence after treatment in a tertiary centre. FINDINGS: Data collection for these analyses occurred between January, 2016, and May, 2018. We received the records of 1192 patients, of which 966 (81%) were surgically treated and had complete information on core criteria. 445 patients were admitted with therapy-naive disease of the knee and were primarily treated in a tertiary centre. Since patients with wait and see treatment do not have a starting date of treatment, these patients were excluded in the calculation of median follow-up time for all patients. For this calculation we used time of surgery as a starting date. 758 (64%) of 1192 patients had knee involvement and 628 (54%) of 1163 patients with complete data on type of surgery had one-staged open synovectomy. At a median follow-up of 54 months (IQR 27-97), recurrent disease developed in 425 (44%) of all 966 surgically treated cases, and recurrence-free survival was 62% (95% CI 59-65) at 3 years, 55% (51-58) at 5 years, and 40% (35-45) at 10 years. Surgical complications were reported in 105 (12%) of 906 patients who had complete data on surgical complications. Pain improved after surgical treatment in 255 (59%) of 434 patients and swelling improved in 328 (72%) of 453 patients who had complete data. INTERPRETATION: This study of patients with diffuse-type tenosynovial giant-cell tumour provides a comprehensive and up-to-date disease overview, assessing the clinical profile and management of the disease in multiple specialised referral centres. Surgical treatment of diffuse-type tenosynovial giant cell tumours is not a definitive treatment for every patient because it involves a high risk for local recurrent disease and a relatively high risk for postoperative complications. After surgical treatment in treatment-naive patients, risk factors for recurrent disease in individual patients were not identified in what we believe is the largest cohort to date. FUNDING: Daiichi Sankyo.

Tenosynovial Giant Cell Tumors in Children: A Similar Entity Compared With Adults.

BACKGROUND: Tenosynovial giant cell tumor (TGCT) is a rare, benign, monoarticular entity. Many case-series in adults are described, whereas TGCT is only incidentally reported in children. Therefore, its incidence rate and natural history in children are unknown. QUESTIONS/PURPOSES: (1) How many cases have been reported of this condition, and what were their characteristics? (2) What is the standardized pediatric incidence rate for TGCT? (3) Is there a clinical difference in TGCT between children and adults? (4) What is the risk of recurrence after open resection in children compared with adults? METHODS: Data were derived from three sources: (1) a systematic review on TGCT in children, seeking sources published between 1990 and 2016, included 17 heterogeneous, small case-series; (2) the nationwide TGCT incidence study: the Dutch pediatric incidence rate was extracted from this nationwide study by including patients younger than 18 years of age. This registry-based study, in which eligible patients with TGCT were clinically verified, calculated Dutch incidence rates for localized and diffuse-type TGCT in a 5-year timeframe. Standardized pediatric incidence rates were obtained by using the direct method; (3) from our nationwide bone and soft tissue tumor data registry, a clinical data set was derived. Fifty-seven children with histologically proven TGCT of large joints, diagnosed and treated between 1995 and 2015, in all four tertiary sarcoma centers in The Netherlands, were included. These clinically collected data were compared with a retrospective database of 423 adults with TGCT. Chi-square test and independent t-test were used to compare children and adults for TGCT type, sex, localization, symptoms before diagnosis, first treatment, recurrent disease, followup status, duration of symptoms, and time to followup. The Kaplan-Meier method was used to evaluate recurrence-free survival at 2.5 years. RESULTS: TGCT is seldom reported because only 76 pediatric patients (39 female), 29 localized, 38 diffuse, and nine unknown type, were identified from our systematic review. The standardized pediatric TGCT incidence rate of large joints was 2.42 and 1.09 per million person-years in localized and diffuse types, respectively. From our clinical data set, symptoms both in children and adults were swelling, pain, and limited ROM with a median time before diagnosis of 12 months (range, 1-72 months). With the numbers available, we did not observe differences in presentation between children and adults in terms of sex, symptoms before diagnosis, first treatment, recurrent disease, followup status, or median time to followup. The 2.5-year recurrence-free TGCT survival rate after open resection was not different with the numbers available between children and adults: 85% (95% confidence interval [CI], 67%-100%) versus 89% (95% CI, 83%-96%) in localized, respectively (p = 0.527) and 53% (95% CI, 35%-79%) versus 56% (95% CI, 49%-64%) in diffuse type, respectively (p = 0.691). CONCLUSIONS: Although the incidence of pediatric TGCT is low, it should be considered in the differential diagnosis in children with chronic monoarticular joint effusions. Recurrent disease after surgical treatment of this orphan disease seems comparable between children and adults. With targeted therapies being developed, future research should define the most effective treatment strategies for this heterogeneous disease. LEVEL OF EVIDENCE: Level III, therapeutic study.

What Are the Long-term Results of MUTARS® Modular Endoprostheses for Reconstruction of Tumor Resection of the Distal Femur and Proximal Tibia?

BACKGROUND: Modular endoprostheses are commonly used to reconstruct defects of the distal femur and proximal tibia after bone tumor resection. Because limb salvage surgery for bone sarcomas is relatively new, becoming more frequently used since the 1980s, studies focusing on the long-term results of such prostheses in treatment of primary tumors are scarce. QUESTIONS/PURPOSES: (1) What proportion of patients experience a mechanical complication with the MUTARS® modular endoprosthesis when used for tumor reconstruction around the knee, and what factors may be associated with mechanical failure? (2) What are the nonmechanical complications? (3) What are the implant failure rates at 5, 10, and 15 years? (4) How often is limb salvage achieved using this prosthesis? METHODS: Between 1995 and 2010, endoprostheses were the preferred method of reconstruction after resection of the knee in adolescents and adults in our centers. During that period, we performed 114 MUTARS® knee replacements in 105 patients; no other endoprosthetic systems were used. Four patients (four of 105 [4%]) were lost to followup, leaving 110 reconstructions in 101 patients for review. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 8.9 years (95% confidence interval [CI], 8.0-9.7). Mean age at surgery was 36 years (range, 13-82 years). Predominant diagnoses were osteosarcoma (n = 56 [55%]), leiomyosarcoma of bone (n = 10 [10%]), and chondrosarcoma (n = 9 [9%]). In the early period of our study, we routinely used uncemented uncoated implants for primary reconstructions. Later, hydroxyapatite (HA)-coated implants were the standard. Eighty-nine reconstructions (89 of 110 [81%]) were distal femoral replacements (78 uncemented [78 of 89 {88%}, 42 of which were HA-coated [42 of 78 {54%}]) and 21 (21 of 110 [19%]) were proximal tibial replacements. In 26 reconstructions (26 of 110 [24%]), the reconstruction was performed for a failed previous reconstruction. We used a competing risk model to estimate the cumulative incidence of implant failure. RESULTS: Complications of soft tissue or instability occurred in seven reconstructions (seven of 110 [6%]). With the numbers we had, for uncemented distal femoral replacements, we could not detect a difference in loosening between revision (five of 17 [29%]) and primary reconstructions (eight of 61 [13%]) (hazard ratio [HR], 1.72; 95% CI, 0.55-5.38; p = 0.354). Hydroxyapatite-coated uncemented implants had a lower risk of loosening (two of 42 [5%]) than uncoated uncemented implants (11 of 36 [31%]) (HR, 0.23; 95% CI, 0.05-1.06; p = 0.060). Structural complications occurred in 15 reconstructions (15 of 110 [14%]). Infections occurred in 14 reconstructions (14 of 110 [13%]). Ten patients had a local recurrence (10 of 101 [10%]). With failure for mechanical reasons as the endpoint, the cumulative incidences of implant failure at 5, 10, and 15 years were 16.9% (95% CI, 9.6-24.2), 20.7% (95% CI, 12.5-28.8%), and 37.9% (95% CI, 16.1-59.7), respectively. We were able to salvage some of the failures so that at followup, 90 patients (90 of 101 [89%]) had a MUTARS® in situ. CONCLUSIONS: Although no system has yet proved ideal to restore normal function and demonstrate long-term retention of the implant, MUTARS® modular endoprostheses represent a reliable long-term option for knee replacement after tumor resection, which seems to be comparable to other modular implants available to surgeons. Although the number of patients is relatively small, we could demonstrate that with this prosthesis, an uncemented HA-coated implant is useful in achieving durable fixation. LEVEL OF EVIDENCE: Level IV, therapeutic study.

A prospective study on quality of life and functional outcome in children and adolescents after malignant bone tumor surgery.

BACKGROUND: Few longitudinal data are available concerning quality of life (QoL) and functioning of young patients undergoing surgical procedures for malignant bone tumors around the knee joint. Aim of the present study was to evaluate patients' quality of life, functional ability, and physical activity during a 2-year postoperative period. METHODS: This prospective study included patients who underwent surgery for a malignant bone tumor around the knee joint between 2004 and 2008. Assessments were done at 3, 6, 9, 12, 18, and 24 months after surgery. QoL was measured with the TNO-AZL Children's or Adult's Quality of Life Questionnaires (TACQOL and TAAQOL), the Short Form-36 (SF-36) and Bone tumor (Bt)-DUX; functional ability with the Toronto Extremity Salvage Scale (TESS), the 6-minute walk test (6 MWT) and four functional performance tests; and physical activity with the Baecke questionnaire and the ActiLog® activity monitor. Statistical analysis included linear mixed model analysis. RESULTS: Forty-four patients (27 males, 17 females, mean age 14.9 (SD 4.8) years) were included, 27 (61%) underwent limb-salvage and 17 (39%) ablative surgery. Twenty patients were lost during the 2 years follow-up as a consequence of oncological complications. Over the first year, survivors showed significant improvement of QoL, functional ability and physical activity, except for the mental dimension of the SF-36 and the activity monitor results. Over the second year, these improvements were less pronounced. CONCLUSIONS: In the first 2 years after bone tumor surgery, survivors improved significantly with respect to QoL, functional ability, and physical activity levels.

Functional ability and physical activity in children and young adults after limb-salvage or ablative surgery for lower extremity bone tumors.

BACKGROUND: Aim of our study was to compare functional ability and physical activity in children and young adults who underwent surgery for a malignant bone tumor that was located around the knee. METHODS: This cross-sectional study included 82 patients aged 8-25 years with a follow-up of 1-5 years. The functional ability and the amount of physical activity were evaluated by means of questionnaires and objective instruments. RESULTS: Thirty nine patients underwent limb-salvage surgery (24 allograft and 15 endoprosthesis) and 43 underwent ablative surgery (27 amputations and 16 rotationplasty). Patients in the limb-salvage group were significantly older at the time of surgery than patients in the ablative group (mean age 15.2 years vs. 13.2 years, P = 0.03). Apart from significantly better scores for the timed up and down stairs and various walking activities in the limb-salvage group as compared to the ablative surgery group, no significant differences were seen for any of the outcome measures. CONCLUSIONS: One to 5 years after limb-salvage and ablative surgery due to a malignant bone tumor children and young adults do, apart from a few activities involving walking and climbing stairs, not differ with respect to overall functional ability and physical activity.

Juxta-articular myxoma of the knee.

Juxta-articular myxoma is a benign lesion usually presenting as a slow-growing, well-circumscribed mass. Occasionally, however, the lesion grows rapidly and is poorly circumscribed, and it is this clinical presentation that arouses suspicion of malignancy. Furthermore, on histology a myxoma can also be confused with a variety of sarcomas. We present a case of juxta-articular myxoma and discuss the possible diagnostic dilemmas involved.

Quality of life in young patients after bone tumor surgery around the knee joint and comparison with healthy controls.

BACKGROUND: This study aimed to compare the health related quality of life (HRQoL) of children and adolescents after malignant bone tumor surgery of the leg with healthy controls. PROCEDURE: Patients between 8 and 25 years old were cross-sectional recruited. Patients under 16 years of age received the TNO (Netherlands Organization for Applied Scientific Research) and AZL (Leiden University Medical Center) Children's Quality of Life Questionnaire (TACQOL), patients aged 16 years and older received the TNO-AZL Questionnaire for Adult's Quality of Life (TAAQOL) and the Short Form-36 (SF-36). Three age- and sex-matched normative random samples, drawn from large, nationwide studies, were used for the comparison with healthy controls. Patients were interviewed regarding their most important problems related to the disease and its treatment. RESULTS: Eighty-one patients with a mean age of 16.9 years (SD 4.2) were included (41 female). Limb sparing surgery was executed in 38 patients, ablative surgery in 43 patients. In comparison with healthy controls, patients had significantly poorer HRQoL within the domains autonomy and motor function of the TACQOL, gross motor function, cognitive functioning, daily functioning and sexuality of the TAAQOL, and physical functioning, role physical, general health, and the physical and mental component summary scales of the SF-36. Patients reported limitations in physical activities, participation in sports, and cosmetic aspects as the most detrimental consequences of their disease and its treatment. CONCLUSION: In children and adolescents who underwent surgery for a malignant tumor of the leg physical, functioning was significantly impaired as compared to healthy controls.

The Bt-DUX: development of a subjective measure of health-related quality of life in patients who underwent surgery for lower extremity malignant bone tumor.

BACKGROUND: To examine the practical applicability, internal consistency, and validity of the Bt-DUX, a disease-specific Health Related Quality of Life (HRQoL) instrument. The Bt-Dux was developed to examine patients' individual values of their life after a malignant bone tumor of the lower extremity at four domains (cosmetic, social, emotional, and functional). PROCEDURE: Patients were eligible for this cross-sectional, multicenter study if they underwent surgery for a malignant tumor of the leg in a period ranging between 12 and 60 months before the recruitment. Assessments included: Bt-DUX, Toronto Extremity Salvage Score (TESS) Short Form (SF)-36, TNO-AZL Questionnaire for Adult's Quality of Life (TAAQOL), and TNO-AZL Children's Quality of Life Questionnaire (TACQOL). RESULTS: Seventy-two patients (35 male, 37 female), mean age 17 (SD 4) years were included. Limb sparing surgery took place in 32 patients and ablative surgery in 40 patients. The Bt-DUX was completed in less than 5 min and easy to comprehend. The mean Bt-DUX score was 69.8 (SD 15.5), with Cronbach's alpha being 0.92. Domain-total correlations ranged between 0.84 and 0.88 (P < 0.01). Correlations between Bt-DUX Total score and TESS, SF-36 Physical and Mental Component Summary scales and selected TACQOL and TAAQOL scores were statistically significant (P < 0.05), except for the social scale of the TACQOL. The Bt-DUX was able to discriminate between patients with higher and lower TESS scores (P < 0.05). CONCLUSION: The Bt-DUX was found to be a practical and valid instrument. Its added value compared with existing HRQoL measures needs to be further established.

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.

UNLABELLED: 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 TICs.

Bone sarcoma incidence in the Netherlands.

AIMS: Chondrosarcoma, osteosarcoma and Ewing sarcoma form the majority of malignant primary tumours of bone. High-grade bone sarcomas require intensive treatment due to their rapid and invasive growth pattern and metastasising capabilities. This nationwide study covers overall incidence, treatment and survival patterns of bone sarcomas in a 15-year period (2000-2014) in the total population of the Netherlands. PATIENTS AND METHODS: Data for this study were derived from the Netherlands Cancer Registry, which receives primary notification from the national pathology database. Classification and categorisation was based on the ICD-O-3 classification and the WHO classification 2013 applied according to our clinicopathological expertise. Overall incidence over the 15-year-period was calculated as a rate per 100,000 person-years (using the European Standardised Rate, ESR). Survival was analysed with Kaplan-Meier curves and Cox proportional hazards regression. RESULTS: Incidence for high-grade chondrosarcoma (n = 429) was estimated at 0.15 per 100,000 ESR, and 5-year overall survival at 65.9% (95% confidence interval (CI): 61.0%-70.4%). Incidence for high-grade central osteosarcoma (n = 605) was estimated at 0.25 per 100,000 ESR and 5-year survival at 53.9% (95%CI: 49.7%-58.0%). Ewing sarcoma incidence (n = 334) was estimated at 0.15 per 100,000 ESR and 5-year survival at 59.3% (95%CI: 53.5%-64.6%). For high-grade central osteosarcoma, treatment at a bone tumour centre was associated with better survival (HR 0.593). CONCLUSIONS: This study provides comprehensive incidence estimates for all the main primary bone sarcomas over a 15-year time period in a Northern European country with little migration. Centralisation of bone sarcoma care improves the clinical outcome in osteosarcoma.

Less anterior knee pain with a mobile-bearing prosthesis compared with a fixed-bearing prosthesis.

UNLABELLED: 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. LEVEL OF EVIDENCE: Level I, therapeutic study.

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 indications.

Conditionally replicative adenovirus with tropism expanded towards integrins inhibits osteosarcoma tumor growth in vitro and in vivo.

PURPOSE: The clinical course of osteosarcoma (OS) demands the development of new therapeutic options. Conditionally replicative adenoviruses (CRAds) represent promising agents for the treatment of solid tumors, because CRAds have an intrinsic replication capacity that allows in situ amplification and extensive tumor infection through lateral spread. The CRAd AdDelta24 has been developed to replicate selectively in cells with a defective retinoblastoma (Rb) pathway. Because genetic alterations in the Rb pathway are frequently observed in OS, AdDelta24 might be useful in the treatment of this cancer. EXPERIMENTAL DESIGN: Because the lack of Coxsackie adenovirus receptor on OS cells limits the efficacy of CRAd treatment, we explored alternative target molecules on OS. Insertion of an Arg-Gly-Asp (RGD-4C) integrin-targeting motif into the adenovirus fiber knob expanded tropism toward the alpha(nu)beta(3) and alpha(nu)beta(5) integrins. The oncolytic capacity of the CRAd Ad5-Delta24RGD was tested on primary OS cells in vitro and in vivo. RESULTS: The alpha(nu)beta(3)and alpha(nu)beta(5) integrins are abundantly expressed on OS cells. RGD-mediated infection augmented adenovirus infection of primary OS cells by two orders of magnitude. Ad5-Delta24RGD was shown to be highly active in killing human OS cell lines, as well as primary cell cultures. Furthermore, intratumoral injections with Ad5-Delta24RGD into established human OS xenografts that were derived directly from a patient with OS refractory for chemotherapeutic treatment caused a significant tumor-growth delay. Furthermore, adenoviral particles could be detected in tumor cells 25 days posttumor injection. CONCLUSIONS: Targeting adenovirus toward integrins rendered OS cells more sensitive to killing by Ad5-Delta24RGD. These findings suggest that Ad5-Delta24RGD has potential for use in OS treatment.

Gene-directed enzyme prodrug therapy for osteosarcoma: sensitization to CPT-11 in vitro and in vivo by adenoviral delivery of a gene encoding secreted carboxylesterase-2.

Despite improvement in the treatment of osteosarcoma (OS), there are still many patients who cannot benefit from current treatment modalities. This warrants exploration of new treatment options. To that end, we investigated gene-directed enzyme prodrug therapy (GDEPT) with the use of human liver carboxylesterase-2 (CE2) and the anticancer agent CPT-11. CPT-11 is a clinically approved prodrug that needs to be metabolized into the active drug SN-38 by CEs, which occurs rather inefficiently in humans. GDEPT aims at high production of CE2 at the tumor site, resulting in efficient local conversion of CPT-11 into SN-38. Here, we show that OS cells transduced with an adenoviral vector containing the cDNA encoding a secreted form of CE2 (Ad-sCE2) expressed and efficiently secreted CE2. In vitro, transduction of a panel of OS cell lines with Ad-sCE2 resulted in sensitization up to 2800-fold to CPT-11 treatment. Primary OS short-term cultures, derived from patients suffering from a classic high-grade OS, demonstrated increased CPT-11 sensitivity up to 70-fold after transduction with Ad-sCE2 in vitro. When mice bearing s.c. MG-63 OS xenografts were intratumorally injected with Ad-sCE2 and CPT-11, this resulted in a significant difference in time to reach 2000 mm(3) in tumor volume as compared with animals receiving Ad-sCE2 or CPT-11 treatment (P < 0.05). Taken together, these data suggest that OS cells are sensitive for the combination of Ad-sCE2 and CPT-11.

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 tumorigenesis.

A patient with scapular Ewing sarcoma; 5-year follow-up after extracorporeal irradiation and re-implantation of the scapula, a case report.

In 2007 a 9½-year-old boy was treated with resection, extracorporeal irradiation and re-implantation of the right scapula. He also received chemotherapy. During five year follow-up shoulder function remained largely intact. Subtotal resorption of the scapula occurred, leaving only the glenohumeral joint intact. Sensibility and strength are intact. To date there is no sign of local or metastatic recurrence.

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.

[Clinical problems in multiple osteochondroma]. / Klinische problemen bij multipele osteochondromen.

Multiple osteochondroma, also known as hereditary multiple exostoses, is a relatively rare genetic disorder characterized by the presence of multiple osteochondromas. The disease is frequently painful, with restriction of the activities of daily living, problems with carrying out an occupation and performance at school. In addition, characteristic skeletal deformities and postural abnormalities of the joints very frequently occur in patients with this disorder. Malignant transformation of osteochondroma to chondrosarcoma occurs in 1-5% of the patients with multiple osteochondroma. Treatment of patients with multiple osteochondromas must be tuned to the problems experienced by the patient. Symptomatic osteochondromas are often an indication for excision; knowledge of the natural progression of the abnormality is important in this. Periodical screening is essential: in children to prevent or correct deformity and postural abnormalities and in adults to detect and treat malignant transformation of osteochondroma at an early stage.