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Distal tibial tumor ablation results in combined soft tissue and bone defect that involves the ankle joint. This area is unique and problematic because it combines low caliber limb size, relatively soft tissue deficiency, suboptimal bone and soft tissue healing ability, and the need to sustain increased mechanical loads. The management is difficult, controversial, and traditionally was treated by primary amputation. We present our experience with a limb sparing surgery using biological reconstruction.Between 2004 and 2007, 5 patients with malignant bone tumors of the distal tibia underwent tumor resection and reconstruction with free vascularized osteoseptocutaneous fibula flap. The average age was 33.2 years (range, 11-62 years). In all cases, a skin island was harvested and used for wound closure. Arthrodesis of the ankle joint was preformed in all patients. Double fixation system was used to provide stability and avoid flap rotation.All flaps survived. There were no major complications. One patient had partial loss of the skin paddle that was treated conservatively. Callous formation was documented after an average time of 4 months, partial weight bearing after an average time of 4 months, and full weight bearing after an average time of 11.5 months. All patients regained almost normal ambulation within a year.

Objective: Chondrosarcomas (CS) represent a heterogeneous group of rare sarcomas, poorly responsive to chemotherapy or radiotherapy. When local therapies in recurrent or metastatic disease are exhausted, chemotherapy plays a marginal role. Different molecular pathways have been shown to be activated in CS. In this retrospective study, we summarize our experience in treating a cohort of patients with recurrent unresectable CS with a combination of sirolimus (SIR) and cyclophosphamide (CTX)., Patients and Methods: Ten consecutive patients with unresectable CS were offered off-label treatment with SIR and CTX between 2007 and 2012. Tumor response, progression-free survival (PFS), adverse events, and other relevant clinical data were analyzed., Results: The median patients' age was 49 (range 28-68). Median disease-free interval since the primary diagnosis was 22.5 months. Median time from the disease recurrence to initiation of SIR and CTX treatment was 21.7 months due to additional local surgical treatments, excision of metastases, or slow asymptomatic progression. One (10 %) objective response was observed, and six (60 %) patients had stabilization of disease for at least 6 months. Three patients had progressive disease. Median PFS was 13.4 months (range 3-30.3). No significant adverse events were observed., Conclusions: Although advanced CS remains an incurable disease, our experience suggests that a combination of SIR and CTX is well tolerated and may have meaningful clinical activity with disease control rate of 70 %. Further prospective studies are warranted.

Heparanase is an endoglycosidase that specifically cleaves heparan sulphate side chains of heparan sulphate proteoglycans, activity that is strongly implicated in cell migration and invasion associated with tumour metastasis, angiogenesis and inflammation. Heparanase up-regulation was documented in an increasing number of human carcinomas, correlating with reduced post-operative survival rate and enhanced tumour angiogenesis. Expression and significance of heparanase in human sarcomas has not been so far reported. Here, we applied the Ewing's sarcoma cell line TC71 and demonstrated a potent inhibition of cell invasion in vitro and tumour xenograft growth in vivo upon treatment with a specific inhibitor of heparanase enzymatic activity (compound SST0001, non-anticoagulant N-acetylated, glycol split heparin). Next, we examined heparanase expression and cellular localization by immunostaining of a cohort of 69 patients diagnosed with Ewing's sarcoma. Heparanase staining was noted in all patients. Notably, heparanase staining intensity correlated with increased tumour size (P = 0.04) and with patients' age (P = 0.03), two prognostic factors associated with a worse outcome. Our study indicates that heparanase expression is induced in Ewing's sarcoma and associates with poor prognosis. Moreover, it encourages the inclusion of heparanase inhibitors (i.e. SST0001) in newly developed therapeutic modalities directed against Ewing's sarcoma and likely other malignancies., (© 2011 The Authors Journal compilation © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Purpose: To examine the association between communication self-efficacy, working environment perceptions and burnout in an Israeli sample of oncology nurses., Methods: A non-randomized convenience sample of nurses (n=39) was recruited from six oncology units in a major tertiary medical center in Israel. Measurements included a socio-demographic survey, the Maslach Burnout Inventory, a communication skills self-efficacy inventory and the Working Environment Scale., Findings: Frequent experiences of emotional exhaustion were reported by >60% of participants, cynicism by 28%, and self-actualization by >80%. Several statistically significant associations were demonstrated between communication skills self-efficacy and burnout, as well as between cynicism and reported positive characteristics of the working environment., Conclusions: In our study, emotional exhaustion and self-actualization were found to be separate and distinct experiences that can occur simultaneously. Communication self-efficacy and a positive perception of the working environment appear to buffer the occurrence of emotional exhaustion and promote self-actualization., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

This review describes the kinds of skeletal bone defects in bones which develop through enchondral ossification. It focuses on the biological reconstruction of those defects according to the two main subtypes, intercalary and osteoarticular. We list the causes of bone defects and outline the different types and configurations that result from them. We then review the currently available reconstructive options according to the patient's age and describe the theoretical options as well. Finally, the history, surgical anatomy and clinical use of the free fibula flap will be reviewed. From our own clinical experience and review of the literature, we conclude that biological reconstruction is, in many ways, superior to alloplastic materials, especially in children, adolescents and young adults.

Purpose: Most children today with bone sarcomas undergo limb-sparing surgery. When treating children younger than 12 years of age, the result is significant limb length discrepancy (LLD). One of the solutions is the use of an expandable endoprosthesis., Methods: A retrospective analysis of 38 skeletally immature patients with bone sarcoma of the lower limb in whom different types of expandable endoprostheses were used from January 1988 to December 2005 were included. All patients were under the age of 14 years. There were 26 osteosarcoma and 12 Ewing's sarcomas. The data collected included the tumor characteristics, the surgical and other treatment modalities, complications and their treatment, and the final LLD and functional results., Results: Fifty-five percent of the patients survived and had a mean follow-up of 113 months. All survivors reached skeletal maturity at the time of last follow-up. Seventy-one percent of the survivors had satisfactory function and 29% had a poor result. There were three secondary amputations due to local recurrence. Complications were documented in 58% of patients; the most common was infection that was diagnosed 56 times (primary 16% and secondary 84%). A significant correlation was found between function and final LLD (greater than 5 cm = inferior function), the number of complications, and the number of surgical procedures performed other than prosthesis elongation. The younger the patient was at definitive surgery, the shorter the time it took for the prosthesis to fail., Conclusion: In order to improve results, the number of operations must be reduced. This can be achieved by the use of novel non-invasive expandable endoprostheses or biological reconstruction.

Radiotherapy (RT) is our preferred modality for local palliation of metastatic soft tissue sarcoma (STS). A short and intense course of RT is usually needed for rapid palliation and local control of metastatic disease. Seventeen patients at a median age of 61 had symptomatic metastatic sarcoma and required rapid palliation. The symptoms related to the metastases were either pain or discomfort. All patients were treated by a short and intensive course of administration: 39 Gy were given in 13 fractions of 3 Gy/day, 5 times a week. Median follow-up period was 25 weeks. The treatment was well tolerated. Acute side effects included grade one skin toxicity. No wound complications were noted among those undergoing surgery. Late side effects included skin pigmentation and induration of irradiated soft tissues. Durable pain control was achieved in 12 out 15 cases treated for gross metastases. Tumor progression was seen in the 3 other cases within a period of two to nine months. Among 5 lesions which were irradiated as an adjunctive treatment following resection, no local recurrence was observed. The results of this series, although limited in size, point to the safety and feasibility of hypofractionated RT for palliation of musculoskeletal metastases from sarcoma.

Background: Ewing sarcoma (ES) is the second most common solid bone and soft tissue malignancy in children and young adults with low cure rates indicating the need to identify further prognostic markers. The importance of methylation in the inactivation of key tumor suppressor genes including RASSF1A has begun to be appreciated in context of cancer development, prognosis and therapy. However there is lack of similar broad based studies in ES. The objective of this study was to analyze RASSF1A methylation and assess its clinical significance in ES., Procedure: The methylation of RASSF1A was determined 31 ES tumor samples and 4 ES cell lines. ES cell lines were also treated with demethylating agent 5-aza-2'-deoxycytidine to ascertain its effect on methylation. RASSF1A expression was studied in 12 ES tumors. The association between RASSF1A methylation, clinical parameters and outcome was also analyzed., Results: Methylation of RASSF1A was observed in 21/31 (68%) tumors and in 3/4 ES cell lines. A significant correlation of methylation to reduced expression of RASSF1A was observed in 12 ES tumors analyzed (P = 0.0013) and in all cell lines. ES patients with methylated RASSF1A had worse prognosis compared to the unmethylated group (P = 0.049). Treatment with 5-aza-2'-deoxycytidine resulted in the re-expression of the unmethylated form of RASSF1A in two ES cell lines., Conclusion: RASSF1A is frequently methylated in ES.

Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma. Epidermal growth factor receptor (EGFR) may play a putative role in its pathogenesis, and be targeted for therapeutic purposes. The study was aimed at investigating the expression and prognostic influence of EGFR in MPNST. Primary and metastatic MPNSTs were immunostained with antibodies to EGFR. The total EGFR expression (membranous and cytoplasmic) was analyzed by morphometry, grade of positivity and the intensity (score 0-3). An EGFR composite score (range 0-300) was calculated by multiplying the intensity by the grade. A composite score >10 was considered as EGFR overexpression. Score was correlated with clinical behavior. Forty-three percentage of 46 patients with MPNST overexpressed EGFR in the primary tumor, and had a higher prevalence of advanced-stage tumors (>or=IIc, 46% vs. 80%, P = 0.011). Patients without overexpression had a higher prevalence of tumors with a low mitotic rate (31% vs. 0%, P = 0.049). Neurofibromatosis was more prevalent in patients with EGFR overexpression (75% vs. 42%, P = 0.007). Five year disease free survival (mean 30.1 vs. 17.4 months, P = 0.048), time to progression (mean 9.2 vs. 5.2 months, P = 0.005) and 5 year survival (52% vs. 25%, P = 0.041, mean 54 vs. 43 months) were significantly higher among patients without overexpression. EGFR appeared to play a role in MPNST progression. EGFR overexpression was correlated with worse prognostic variables and course. Clinical trials of targeting EGFR in MPNST are warranted.

Background: The incidence of breast cancer (BC) and soft tissue sarcoma (STS) in the Israeli general population is 97/10 women and 1.5/10 persons. It is expected that 1.5/10 x 49/10 of the women in the general population will have both BC and STS., Methods: A retrospective search of 1350 adult STS patient files that were recorded between 1995 and 2005., Results: One hundred thirty-four patients with STS had multiple primary malignancies. BC was observed in 27/64 patients (42%) before/after the STS: BC-first in 19/27, BC-later in 8/27. Of 19 with BC-first the STS was related to radiotherapy in 2, and to lymphedema in 1. Of 8 STS-first, only 1 got chemotherapy before BC. Median interval between first to second malignancies was 6.9 years for BC-first, and 3.8 for BC-later. The incidence of BC among all patients with STS-first followed by a second malignancy is 8/58 (14%), or 27/890 (3%) of all women STS-patients in the registry. The incidence of STS among the BC patients was low, and most of our cases were therapy unrelated. Median survival for BC-first was 305 months, versus 213 for STS-first., Conclusions: BC and STS may naturally occur in the same individual. The etiology for this phenomenon is unclear. Practically, BC screening in patients with STS is warranted.

Background: Postoperative pain in patients with bone and soft tissue cancer is different from that of other surgical patients due to the severity of the pain generated during surgery and because many of them have already been in pain preoperatively. The search for optimal intravenous pharmacologic management for this population is an ongoing one. We conducted a 10-month prospective, randomised, double blind study to compare the effects of a standard morphine dose to a 35%-lower dose plus a subanaesthetic dose of ketamine for postoperative pain control in patients undergoing bone and soft tissue cancer surgery under standardised general anaesthesia., Methods: After extubation, when objectively awake (>or=5/10 on a 0-10 visual analogue scale (VAS)) and complaining of pain (>or=5/10 VAS), patients were connected to an intravenous patient-controlled analgesia (IV-PCA) device that delivered 1.5 mg morphine/bolus (MO group) or 1 mg morphine+5mg ketamine/bolus (MK group), with a 7 min lockout time. Rescue intramuscular diclofenac 75 mg was available Q4/day. Follow-up lasted 96 h., Results: Fifty-seven patients (24 males, aged 18-74 years) completed the study. Pain scores were lower in the MK group compared to the MO patients, although MO patients (n=29) used 32.9+/-24.9 mg/patient morphine during the first 24 postoperative h compared to 14.6+/-11.4 mg/patient (P<0.05) for the MK patients (n=28). At that time point, 11 MO versus 4 MK patients still required IV-PCA (P<0.05). Diclofenac was also used more in the MO group. All vital signs were similar between the groups. The physiotherapy score was 35% higher for the MK patients (P<0.05). No patient had hallucinations. Postoperative nausea and vomiting rates were higher in the MO group., Conclusions: The use of subanaesthetic ketamine plus 2/3 the standard dose of morphine following bone and tissue resections results in 1) lower and more stable pain score, 2) approximately 60% morphine sparing effect, 3) a shorter period of postoperative IV-PCA dependence. Such therapy is also associated with better early physical performance.

Despite comprehensive management of pediatric sarcomas, only 60% to 70% of children become long-term survivors. This study was undertaken to evaluate whether regular follow-up improves overall survival of children with recurrent sarcomas. The medical charts of 107 children diagnosed with soft tissue and bone sarcomas were reviewed, of whom 29 relapsed. They were divided into 2 groups according to the way of relapse diagnosis: due to complaints/physical examination (14) or on routine imaging studies (15). All were followed by regular physical examination and imaging studies (chest computed tomography, magnetic resonance imaging, and bone scan/positron emission tomography-computed tomography scan with fluorodeoxyglucose) at regular intervals. Analysis of the results showed that (1) regular imaging studies do not facilitate earlier recognition of relapse in children with sarcomas; (2) regular follow-up with imaging studies does not influence overall survival of children with sarcomas; (3) other diagnostic and treatment approaches are needed to improve the survival of children with recurrent sarcomas.

Background: Simple resection of diffuse pigmented villonodular synovitis of the ankle joint is associated with local recurrence rates as high as 50%. Thus, adjuvant treatment modalities, such as radiation or intra-articular isotope injection, are sometimes used after tumor resection. Our initial and highly satisfactory experience with the injection of radioactive yttrium 90 to treat pigmented villonodular synovitis of the ankle joint eroded with time so much so that we discontinued its use in the ankle and believe that it is important to alert our colleagues to the complications that we observed., Methods: Between 1989 and 2006, we treated seven patients who had diffuse pigmented villonodular synovitis of the ankle joint with subtotal synovectomy followed by intra-articular injection of 15 mCi of yttrium 90., Results: Two of the study patients had full-thickness skin necrosis develop around the injection site, necessitating free muscle flap transfer within three months of treatment, and a third patient had development of a draining sinus that was associated with chronic severe pain. The other four patients reported pain after the injection that was reasonably controlled by the use of nonsteroidal anti-inflammatory drugs. At the most recent follow-up evaluation, no study patient had recurrent disease., Conclusions: Because of the unacceptably high rate of serious complications associated with the injection of yttrium 90 into the ankle joint following subtotal synovectomy, we discontinued its use as a local adjuvant in the management of diffuse pigmented villonodular synovitis of the ankle.

Objective: The incidence of musculoskeletal tumors during pregnancy is very low. The aim of this study was to summarize our experience in treating a large cohort of pregnant patients diagnosed with these rare tumors., Methods: Women diagnosed with musculoskeletal tumors during pregnancy or immediately after delivery were identified retrospectively in our database between 1996 and 2006. Relevant maternal and neonatal data were collected., Results: Twenty patients, 8 with bone sarcomas (BS) and 12 with soft tissue sarcomas (STS) were identified. Two women were treated by wide excision of mass during pregnancy. In all other cases oncological treatment was delayed until delivery or termination of pregnancy. Vaginal delivery was possible in 9 patients, cesarean section was performed in 7, spontaneous abortion occurred in 1, and 3 underwent termination of pregnancy. Three newborns were premature, but normal growth and development were observed. Different techniques of fertility preservation were used in our patients. Five patients with BS and 5 patients with STS received preoperative chemotherapy, with different grades of toxicity. The degree of tumor necrosis tended to correlate with dose-intensity of chemotherapy. Seven patients with BS received adjuvant chemotherapy. Two patients with STS received adjuvant chemotherapy, two - radiotherapy, and four - both modalities. Median disease-free survival was 15.1 months, median overall survival - 25.4 months., Conclusions: Musculoskeletal tumors diagnosed during pregnancy, or after delivery, do not appear to have a significant impact on the prognosis. A multidisciplinary team should tailor the oncological approach individually., ((c) 2008 S. Karger AG, Basel.)

Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma likely results from abnormal proliferation and differentiation during skeletal myogenesis. Multiple genetic alterations are associated with the three RMS histopathological subtypes, embryonal, alveolar, and pleomorphic adult variant. Recently, we reported the novel amplification of the FGFR1 gene in a RMS tumor. The involvement of FGFR1 in RMS was now further studied in primary tumors and RMS cell lines by mutation screening, quantitative RNA expression, and methylation analyses. No mutation was found by DHPLC and sequencing of the entire FGFR1 coding sequence and exon-intron boundaries. However, FGFR1 over-expression was detected in all primary RMS tumors and cell lines tested. A hypomethylation of a CpG island upstream to FGFR1 exon 1 was identified in the primary RMS tumors, using sodium bisulfite modification method, suggesting a molecular mechanism to FGFR1 over-expression. Expression analysis of additional genes, AKT1, NOG and its antagonist BMP4, which interact downstream to FGFR1, demonstrated expression differences between primary RMS tumors and normal skeletal muscles. Our data suggest an important role for FGFR1 and FGFR1-downstream genes in RMS tumorigenesis and a possible association with the deregulation of proliferation and differentiation of skeletal myoblasts in RMS., (Copyright (c) 2007 Wiley-Liss, Inc.)

Purpose: Despite advances in therapy, >50% of patients with Ewing sarcoma will relapse. The current prognostic factors are not optimal for risk prediction. Studies have shown that telomere length could predict outcome in different malignancies. Our aim was to evaluate whether telomere length could be a better prognostic factor in Ewing sarcoma and correlate the results with clinical variables, outcome, and chromosomal instability., Experimental Design: Telomere length was determined in the primary tumor and peripheral blood of 32 patients with Ewing sarcoma. Chromosomal instability was evaluated by combining classical cytogenetics, comparative genomic hybridization and random aneuploidy. Telomere length was correlated to clinical variables, chromosomal instability, and outcome., Results: In 75% of the tumors, changes in telomere length, when compared with the corresponding peripheral blood lymphocytes, were noted. The majority of changes consisted of a reduction in telomere length. Patients harboring shorter telomeres had a significantly adverse outcome (P = 0.015). Chromosomal instability was identified in 65% of tumors, significantly correlating with short telomeres (P = 0.0094). Using multivariate analysis, telomere length remained the only significant prognostic variable (P = 0.034). Patients with short telomeres had a 5.3-fold risk of relapse as compared to those with unchanged or longer telomeres., Conclusion: We have shown that tumors with telomere length reduction result in genomic instability. In addition, telomere length reduction was the only significant predictor of outcome. We suggest that reduction of telomere length in tumor cells at diagnosis could serve as a prognostic marker in Ewing sarcoma.

Between December 1995 and March 2003, 38 adult patients with intermediate or high-grade liposarcoma in a limb were treated by limb-sparing surgery and post-operative radiotherapy. The ten-year local recurrence-free survival was 83%, the ten-year metastasis-free survival 61%, the ten-year disease-free survival 51% and the ten-year overall survival 67%. Analysis of failure and success showed no association with the age of the patients, gender, the location of the primary tumour, the type of liposarcoma and the quality of resection. Our results indicate that liposarcoma may recur even ten years after the end of definitive therapy and may spread to unexpected sites as for soft-tissue sarcoma.

Rhabdomyosarcoma, the most common pediatric soft tissue sarcoma, likely results from deregulation of the skeletal myogenesis program. Although associations between PAX3, PAX7, FOXO1A, and RMS tumorigenesis are well recognized, the entire spectrum of genetic factors underlying RMS development and progression is unclear. Using a combined approach of spectral karyotyping, array-based comparative genomic hybridization (CGH), and expression analysis, we examined 10 primary RMS tumors, including embryonal, alveolar, and the rare adult pleomorphic variant, to explore the involvement of different genes and genetic pathways in RMS tumorigenesis. A complete karyotype established for each tumor revealed a high aneuploidy level, mostly tetraploidy, with double minutes and additional structural aberrations. Quantitative expression analysis detected the overexpression of the AURKA gene in all tumors tested, suggesting a role for this mitotic regulator in the aneuploidy and chromosomal instability observed in RMS. Array-based CGH analysis in primary RMS tumors detected copy number changes of genes involved in multiple genetic pathways, including transcription factors such as MYC-related gene from lung cancer and the cytoskeleton and cell adhesion-encoding genes laminin gamma-2 and p21-activated kinase-1. Our data suggest the involvement of genes encoding cell adhesion, cytoskeletal signaling, and transcriptional and cell cycle components in RMS tumorigenesis.

The vascularized fibula flap has become a major tool in upper limb reconstruction. Free fibula flap reconstructions of the humeral part of the shoulder and the radial part of the wrist joints are well-documented, but reports of elbow joint reconstruction are rare. The authors report a 53-year-old patient with chronic osteomyelitis of the distal humerus that was unsuccessfully treated by many local surgical debridements and long-term systemic antibiotics. The patient underwent a wide debridement of the distal two-thirds of the humerus, and a spacer was inserted to fill the bony humeral gap. At a second stage, the distal humerus was reconstructed with a free fibula flap that included the proximal fibular head. The fibular shaft was used to bridge the bony gap and the fibular head created an elbow joint with the olecranon process. At an 18-month follow-up after surgery, the patient has stable and sufficient function of his elbow joint with no signs of infection. The free fibula flap has an important role for distal humerus reconstruction, both for bridging the bony gap with a vascularized bone, and for restoring elbow joint function.

Background: Limb soft tissue sarcomas (STS) are currently treated with limb sparing surgery (LSS) followed by radiation therapy (RT)., Patients and Methods: Between October 1994 and October 2002, 133 adult patients with intermediate or high-grade limb STS were approached by LSS+RT., Results: RT related toxicity was manageable, with a low rate of severe effects. At 4-year median follow-up, there were 48 recurrences of any type, 23 of isolated local failure, and 35 of systemic spread w/o local failure. DFS and OS were influenced by disease stage II vs I, primary site in the upper limb vs lower limb, MPNST vs other types, induction therapy vs no induction, adequate resection vs marginal resection or involved margins, and good response to induction therapy vs bad response. DFS and OS were Patient's age and sex, tumor depth, acute or late toxicity of RT, or the interval of time between the date of definitive surgery and the start of RT did not affect DFS and or OS., Conclusions: The RT protocol is applicable in the era of complicated, expensive and time-consuming 3D therapy. Our results of LSS+RT in adults with limb HG STS are satisfactory.

Unlabelled: Resection of musculoskeletal tumors may result in large soft tissue defects that cannot be closed primarily and require prolonged dressing changes and complex surgical interventions for wound coverage. We retrospectively reviewed 23 patients with such defects treated with a vacuum-assisted wound closure system and compared the outcome of these patients with a control group. The study group included 15 women and eight men who had their wounds located at the back (two), pelvic girdle (11), thigh (eight), and leg (two). Treatment included sealed wound coverage with polyurethane foam and overlying tape connected to a vacuum pump. This system was disconnected and changed every 48 hours for 7 to 19 days, after which all defects were reduced in size by an average of 25% and covered with a viable granulation tissue. This allowed primary closure in seven patients, primary closure with skin grafting in 14 patients, and healing by secondary intention in two patients. Compared with the control group, patients in the study group had shorter hospital stays and number of surgical interventions and greater rates of primary wound closure. The use of vacuum-assisted wound closure facilitates wound healing and primary wound closure in patients who have a large soft tissue defect after resection of a musculoskeletal tumor., Level of Evidence: Therapeutic study, Level III (retrospective comparative study). See the Guidelines for Authors for a complete description of levels of evidence.

Malignant fibrous histiocytoma (MFH) is the most common subtype of soft-tissue sarcoma (STS). When located in a limb, MFH, is currently treated with limb sparing surgery (LSS) followed by radiation therapy (RT). During 8 years, 42 adult patients with high-grade limb MFH were approached by LSS and RT. Our results reflect a single-team experience and point to several important conclusions. High grade MFH, treated by conservative approach, lead to a 10-year relapse-free survival of 62% and a 10-year overall survival rate of 80%. Recurrences of MFH tend to occur during the first 2 years. Relapse-free survival was affected mainly by location in the lower limb vs. the upper limb, irrespective of the tumor size. Patients who had their diagnostic biopsies in another medical center had a greater tendency to local and systemic relapse. It seems that the most important clues for disease-free survival are the team experience and cooperation. All other factors are tumor-biology dependent, and thus far are beyond our control.

Unlabelled: Metastatic bone disease of the humerus may require surgery for treatment of an impending or existing pathologic fracture or for alleviating disabling pain. Prompt restoration of function is a main goal of surgery, although published results do not reveal if that goal is being met. We retrospectively reviewed range of motion and function of 59 patients operated on from 1986-2003 for those indications. After resection, tumors around the humeral head and condyles (n = 20) were reconstructed with a prosthesis, and tumors at the humeral diaphysis (n = 39) were reconstructed with cemented nailing. Each patient's range of motion was recorded, and functional outcome was evaluated according to the American Musculoskeletal Tumor Society system. Patients who had cemented nailing had better shoulder motion, hand positioning, lifting ability, and emotional acceptance than patients who had endoprosthetic reconstruction. Pain alleviation and dexterity were comparable in both groups. All patients had a stable extremity, and the overall function of 56 patients (95%) was greater than 68% of normal upper extremity function. An aggressive surgical approach in patients with humeral metastases who met the criteria for surgical intervention was associated with good function., Level of Evidence: Therapeutic study, Level IV (case series--no, or historical control group). See the Guidelines for Authors for a complete description of levels of evidence.

Background: Associations between physical health and depression are consistent across cultures among adults up to 65 years of age. In later life, the impact of physical health on depression is much more substantial and may depend on sociocultural factors., Aims: To examine cross-national differences in the association between physical health and depressive symptoms in elderly people across western Europe., Method: Fourteen community-based studies on depression in later life in nine western European countries contributed to a total study sample of 22 570 respondents aged 65 years and older. Measures were harmonized for depressive symptoms (EURO-D scale), functional limitations and chronic physical conditions., Results: In the majority of the participating samples, the association of depressive symptoms with functional disability was stronger than with chronic physical conditions. Associations were slightly more pronounced in the UK and Ireland., Conclusions: The association between physical health and depressive symptoms in later life is consistent across western Europe.

Associations between disability and depression have been shown to be consistent across cultures among middle-aged adults. In later life the association between disability and depression is much more substantial and may be amenable to influences by health care facilities as well as economic and sociocultural factors. Fourteen community-based studies on depression in later life in 11 western European countries contribute to a total study sample of 22,570 respondents aged 65 years or older. Measures are harmonised for depressive symptoms (EURO-D scale) and disability. Using multilevel modelling to control for the stratified data structure we examined whether the association between disability and depressive symptoms is modified by national health care and mental health care availability, national economic circumstances, demographic characteristics and religious tradition. The association between depressive symptoms and disability is attenuated by health care expenditure and availability of mental health care and also by gross domestic product; it was more pronounced in countries with high levels of orthodox religious beliefs. Higher levels of depressive symptoms are found in countries with a larger gross domestic product (per capita) and higher health care expenses but are interpreted with care because of measurement differences between the centres. The findings from this contextual perspective indicate that general and mental health care should be geared to one another wherever possible.

Ewing's sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. Currently accepted clinical prognostic factors fail to classify ES patients' risk to relapse at diagnosis. We aimed to find a new strategy to distinguish between poor and good prognosis ES patients already at diagnosis. We analysed the gene expression profiles of 14 primary tumor specimens and six metastases from ES patients, using oligonucleotide microarray analysis. The over-expression of two genes was validated by quantitative PCR using the LightCycler system. We identified two distinct gene expression signatures distinguishing high-risk ES patients that are likely to progress from low-risk ES patients with a favorable prognosis of long-term progression-free survival. The microarray-based classification was superior to currently used prognostic parameters. Over-expressed genes in the poor prognosis patients included genes regulating the cell cycle and genes associated with invasion and metastasis, while among the downregulated genes were tumor suppressor genes and inducers of apoptosis. Our results indicate the existence of a specific gene expression signature of outcome in ES already at diagnosis, and provide a strategy to select patients who would benefit from risk-adapted improved therapy.

We report our experience with a new technique for cryosurgical ablation of bone tumours which allows accurate determination of the temperature and freezing time within a cavity of any geometrical shape. Between 1997 and 2000, 58 patients diagnosed with 13 malignant and 45 aggressive benign bone tumours underwent argon-based cryoablation. This technique includes removal of the tumour by curettage and filling the cavity with a gel medium into which metal probes are inserted. Argon gas is delivered through the metal probes and both time and temperature are computer-controlled. After formal reconstruction, all patients were followed for more than two years. None had skin necrosis, infection, neurapraxia or thromboembolic complication. Fractures occurred in two patients (3.4%) and the tumour recurred in two patients (3.4%).

The fibula free flap became popular in orthopedic oncology for limb-sparing long bone tumor resection. It is particularly suitable for intercalary or resection arthrodesis options. In the present series, a surgical reconstruction algorithm was used, enabling each patient to receive a personalized technique. During the years 1998 to 2002, 30 patients underwent limb-sparing surgery for long bone sarcoma. There were 18 males and 12 females. Their mean age was 23 years (range, 9 to 70 years). The diagnoses were Ewing's sarcoma (11 patients), osteogenic sarcoma (eight patients), chondrosarcoma (five patients), giant cell tumor of bone (three patients), high-grade soft-tissue sarcoma (two patients), and leiomyosarcoma of bone (one patient). The majority of tumors where located in the lower extremity (23 patients), mostly in the femur (15 patients with four tumors in the proximal femoral shaft, five tumors in the distal femoral shaft, five tumors in the whole femoral shaft, and one tumor in the proximal femoral head). In seven patients, the upper extremity was involved; in six patients, the radius was involved; and in one patient, the humerus was involved. The free fibula flap was used in three types of approaches: vascularized fibula as an osseous flap only (18 patients), a combination of a vascularized fibula flap in conjunction with an allograft (Capanna's technique; 10 patients), and a free double-barreled fibula (two patients). All flaps survived. Postoperatively, all patients were monitored clinically, radiologically, and by radioisotope bone scan studies. Callus formation and union were shown 2.6 to 8 months postoperatively. Patients who underwent lower extremity reconstruction were nonweightbearing for 3 to 9 months, with a transition period in which they used a brace and gradually increased weightbearing until full weightbearing was achieved. Eight patients had 11 recipient-site complications. Two patients (6.7 percent) had hematomas, and three patients (10 percent) had infection and dehiscence of the surgical wound with bone exposure in one patient; all complications resolved with conservative treatment only. Failure of the hardware fixation system occurred in two patients, mandating surgical correction. No fibula donor-site complications were recorded. In intercalary resections, the use of the vascularized fibula flap as an isolated osseous flap might be insufficient. Different body sites have different stress loads to carry, depending on the age of the patient and on his individual physical status. To achieve initial strength in the early period, the authors combined the free fibula flap with an allograft (Capanna's method) or augmented it as a double-barreled fibula. They propose a surgical algorithm to assist the surgeon with the preferred method for reconstruction of various long bone defects in different body locations at childhood or adulthood. Long bone reconstruction using a vascularized fibula flap, alone or in combination with an allograft, autogenous bone graft, or double-barreled fibula for limb-sparing surgery, is a safe and reliable method with a predictable bony union, good functional outcome, and a low complication rate.

Purpose: Spinal metastases of soft-tissue sarcoma (STS) occur rarely and pose a therapeutic problem. Although wide resection is warranted for best local control, it is rarely feasible. A radiotherapy (RT) dose of 70 Gy is usually needed to treat limb STS, but only 45 Gy can be given to the spine. In the present series, we report our experience using RT to treat spinal cord compression (SpCC) associated with STS., Methods and Materials: The medical files of 19 adult patients with STS and SpCC were reviewed. RT was considered in all the cases, together with steroids and analgesics. The prescribed dose was 30 Gy in 10 fractions within 12 days. The effect of treatment was evaluated on a clinical basis., Results: Twenty-three events of SpCC were found. The prevailing symptom was pain. The Karnofsky performance status was 40-70% at presentation. RT was given in all but 1 patient and surgical decompression in 3. Small, but important, improvements in signs and Karnofsky performance status were noted in 14 of 23 cases of SpCC, expressed mainly by pain alleviation and restoration of independence. The median survival after the diagnosis of SpCC was 5 months., Conclusion: Radiotherapy is an important tool in palliating SpCC in patients with STS.

Competence of the extensor mechanism is the major determinant of functional outcome of patients after proximal tibia resection. A method of secondary reconstruction of the extensor mechanism using the middle third of the quadriceps tendon and the patellar retinaculum augmented with Gore-Tex strips and gastrocnemius flap is described. Between 1981 and 1997, 7 patients with extension lag greater than 20 degrees at least 1 year after the initial surgery underwent secondary reconstruction of the extensor mechanism. All patients were followed up for a minimum of 2 years. Full extension to an extension lag of 10 degrees was achieved in three patients, and an extension lag between 10 degrees and 20 degrees was achieved in 4 patients. All patients had good to excellent functional outcomes and reported no limitations in daily life activities.

We tested Ewing sarcoma tumors for microsatellite instability (MSI) and loss of heterozygosity (LOH) to investigate the role of genomic instability (GI) in this sarcoma. We detected a high frequency of GI (57%), mostly on 1p and 11p, 35% and 30%, respectively. Patients with GI compared to those with stable genome had a median progression-free survival (PFS) and overall survival (OS) of 24 months and 70 months, compared with 39 and 84 months, respectively. MSI was observed in 48% (11/23) of the tumor samples. Low-MSI (L-MSI) patients (with MSI presented at only one locus) tended to have a better prognosis, 70% PFS, compared with 25% in the high-MSI (H-MSI) group (P=0.13). LOH without MSI did not correlate with progression. H-GI (MSI and/or LOH in > or =30% of tested markers) tended to associate with an adverse prognosis (P=0.28), and correlated significantly with the pelvic site of the primary tumor (P=0.02). The instability of 1p was not associated with progression, while alterations at the 11p locus tended to correlate with a more aggressive disease (P=0.18). Our data suggest that GI may play a role in Ewing sarcoma clinical behavior and outcome.

Background: Tumors in the Ewing family (EFTs) are the second most common bone tumors in children and adolescents. Despite aggressive chemotherapy, one-third of patients with localized tumor still may develop recurrences. This implies that not all tumor cells are eradicated and that the patients may have a level of residual disease. EFTs are characterized by specific chromosomal translocations that result in chimeric transcripts that can be detected with reverse transcriptase-polymerase chain reaction (RT-PCR) analysis., Methods: The authors report the prognostic potential of the positive chimeric transcript (EWS/FLI1) in bone marrow (BM) and/or peripheral blood (PBL) in 26 patients with EFT during a long follow-up period (median, 61 months)., Results: At diagnosis, 43% of patients had positive RT-PCR BM results, with no correlation to tumor progression (P = 0.3). During follow-up, 58% of patients had positive RT-PCR results in their last sample analyzed (BM and/or PBL). A highly significant correlation between the presence of the chimeric transcript and disease progression was detected (P = 0.0028). In a multivariate analysis, the percentage of tumor necrosis (P = 0.007) and RT-PCR results during follow-up (P = 0.02) remained significant prognostic markers. In 10 of 11 patients who developed disease progression, BM and/or PBL samples were positive for the chimeric transcript before evidence of overt clinical recurrence., Conclusions: Occult tumor cells in BM and/or PBL samples during long follow-up are strong predictors of recurrent disease in patients with nonmetastatic EFTs., (Copyright 2004 American Cancer Society.)

Unlabelled: Pain after bone malignancy surgery is intense and requires large amounts of analgesics. The augmented antinociceptive effects of dextromethorphan (DM), a N-methyl-D-aspartate receptor antagonist, were demonstrated previously. We assessed the use of postoperative patient-controlled epidural analgesia (PCEA) or IV patient-controlled analgesia (PCA) in patients undergoing surgery for bone malignancy under standardized combined general and epidural anesthesia with or without DM. Patients (n = 120) were randomly allocated to receive PCEA (ropivacaine 3.2 mg plus fentanyl 8 microg/dose) or IV-PCA (morphine 2 mg/dose) postoperatively, starting at subjective visual analog scale pain intensity >or=4 of 10 for up to 96 h. Placebo or DM 90 mg orally (30 patients/group/set) was given in a double-blinded manner before surgery and for 2 days afterwards. Diclofenac 75 mg IM was available as a rescue drug. DM patients used PCA and rated their pain >50% less than their placebo counterparts in each set, especially during the first 2 postoperative days (P < 0.01). Hourly and overall maximal pain intensity among PCEA patients was approximately 50% less than in the IV-PCA set (P < 0.01). Diclofenac was used 42% less (P < 0.01) by the PCA-DM patients compared with their placebo counterparts. Seven PCEA-DM and 11 IV-PCA-DM individuals reported having side effects compared with 44 in the PCEA-placebo and the IV-PCA-placebo groups (P < 0.01). Time to first ambulation was similar with both analgesia techniques but shorter among the DM-treated patients compared with the placebo recipients (1.5 +/- 0.8 versus 2.1 +/- 1.1 days, P = 0.02). Thus, DM afforded better pain control and reduced the demand for analgesics, augmented the PCEA effect versus IV-PCA, and was associated with minimal untoward effects in each analgesia set. DM patients ambulated earlier than placebo recipients., Implications: Patients undergoing bone-malignancy surgery under combined general and epidural anesthesia received randomly patient-controlled epidural analgesia (PCEA) or IV patient-controlled analgesia (PCA) postoperatively and dextromethorphan (DM) 90 mg or placebo double-blindly for 3 days (n = 30/group/set). The DM effect was recorded with minimal untoward effects: it afforded better pain control and reduced the demand for analgesics compared with the placebo, especially when associated with PCEA. DM patients ambulated earlier than placebo recipients.

The data from nine centres in Europe which had used the Geriatric Mental Scale (GMS) AGECAT were analysed to compare prevalence of diagnoses in subjects aged 65 years and over living in the community. Levels of depressive illness were: Iceland 8.8%, Liverpool 10.0%; Zaragoza 10.7%; Dublin 11.9%; Amsterdam 12.0%; Berlin 16.5%; London 17.3%; Verona 18.3% and Munich 23.6%. Taking all levels of depression, five high (Amsterdam, Berlin, Munich, London and Verona) and four low (Dublin, Iceland, Liverpool, Zaragoza) scoring centres were identified. Meta-analysis of all 13,808 subjects yielded a mean level of depression of 12.3% (95% CI 11.8-12.9), 14.1% for women (95% CI 13.5-14.8) and 8.6% for men (95% CI 7.9-9.3). Symptom levels varied between centres: 40% of the total study population in Amsterdam reported depressive mood against only 26% in Zaragoza. To incorporate studies from other centres using other methods for depression identification, the EURO-D scale was developed from 12 items of the GMS and validated against other scales and expert diagnosis. A two factor solution emerged, an 'affective suffering factor' and a 'motivation factor'. The EURO-D scale was applied to 14 population based surveys. Depression score tended to increase with age unlike levels of prevalence of depression. Large between centre differences were evident in levels of depression unexplained by age, gender or marital status. These data show that depressive illness defined as suitable for intervention is common among older people in Europe. Opportunities for effective treatment are almost certainly being lost. Levels of depressive symptoms vary significantly between high and low scoring centres, prompting the next phase of this study, an examination of risk factors in Europe.

We present a case of giant osteofibrous dysplasia (OFB) of the proximal tibia with 15 years of follow-up. The tumor recurred after first biopsy and curettage done at the age of 6 years and, again, 4 years later. Following recurrence, the option of amputation was suggested. Staged treatment of curettage, cryosurgery, bone cement as a temporary spacer with internal fixation at age 12 years, followed by bone grafting at age 14 years, led to complete healing. The staged protocol for treatment is proposed as an alternative to more radical solutions. It is suggested to postpone surgical treatment towards skeletal maturity.

Background: High-dose methotrexate (MTX) is an important component of current protocols for the treatment of osteosarcoma. Although MTX uptake proceeds primarily through the reduced folate carrier (RFC) protein and efflux occurs via multidrug resistance protein 1 (MRP1), RFC protein expression in osteosarcoma remains unexamined., Methods: RFC and MRP1 expression (normalized to beta-actin expression) was examined with Western blot analysis in 11 osteosarcoma specimens obtained at diagnosis and 9 osteosarcoma specimens obtained on recurrence., Results: The average RFC level in specimens obtained on recurrence was significantly higher than the level in specimens obtained at diagnosis (P = 0.0005). Furthermore, in all three matched pairs of diagnosis and recurrence specimens, RFC levels were higher in recurrence specimens than in the corresponding diagnosis specimens. Potential correlations between RFC and MRP1 expression and histologic response to preoperative chemotherapy were examined. Tumors with poor histologic responses (i.e.,

Purpose: Telomerase is considered a molecular marker for malignancy. The aim of this study was to determine telomerase activity (TA) as a prognostic factor at diagnosis and as a marker for minimal residual disease during therapy and follow-up in nonmetastatic Ewing family of tumors (EFT)., Patients and Methods: Primary tumor specimens and 97 peripheral blood (PBL) samples from 31 EFT patients were analyzed for TA by the Telomeric Repeat Amplification Protocol (TRAP assay). The telomerase catalytic subunit (human telomerase reverse transcriptase [hTERT]) gene expression was evaluated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and telomere length was determined by Southern blotting. The presence of the EFT chimeric transcripts was analyzed by RT-PCR. Correlations with progression-free survival were evaluated., Results: At diagnosis, TA in primary tumors did not correlate with outcome. During therapy and follow-up, highly significant correlation was observed between high TA in PBL samples and adverse prognosis (P <.0001). None of the patients harboring low TA progressed, with a long follow-up (median, 60 months) and a progression-free survival (PFS) of 100%. In nine patients, high TA actually could predict relapse, long before overt clinical relapse. The group of patients with high TA and positive RT-PCR had the most adverse outcome; PFS of 20% (P =.0025). TA was found to be a better prognostic factor than RT-PCR and histopathologic response at surgery., Conclusion: The results suggest that TA is a significant prognostic variable, superior to the established clinical prognostic parameters during therapy and tumor surveillance. It could be used in combination with RT-PCR for a new risk classification.