Clinical activity of mTOR inhibition in combination with cyclophosphamide in the treatment of recurrent unresectable chondrosarcomas.

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.

Communication skills, working environment and burnout among oncology nurses.

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.

Pre-clinical and clinical significance of heparanase in Ewing's sarcoma.

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.

Biological reconstruction of bone defects: the role of the free fibula flap.

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.

Radiation therapy for palliation of sarcoma metastases: a unique and uniform hypofractionation experience.

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.

Expandable endoprosthesis for limb-sparing surgery in children: long-term results.

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.

Aberrant methylation and reduced expression of RASSF1A in Ewing 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.

Expression and significance of EGFR in malignant peripheral nerve sheath tumor.

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.

The co-occurrence of breast cancer and soft tissue sarcoma in a single cohort series.

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.

Subanaesthetic ketamine spares postoperative morphine and controls pain better than standard morphine does alone in orthopaedic-oncological patients.

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.

Unacceptable complications following intra-articular injection of yttrium 90 in the ankle joint for diffuse pigmented villonodular synovitis.

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.

The complexity of management of pregnancy-associated malignant soft tissue and bone tumors.

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.

Short telomeres: a novel potential predictor of relapse in Ewing sarcoma.

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.

FGFR1 over-expression in primary rhabdomyosarcoma tumors is associated with hypomethylation of a 5' CpG island and abnormal expression of the AKT1, NOG, and BMP4 genes.

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.

Large tumors of the axilla: limb-sparing resection versus amputation in 27 patients.

Tumors of the axilla are rare and pose a surgical challenge because they are usually large at presentation and in close proximity to the major neurovascular bundle of the upper extremity. The use of detailed preoperative evaluation studies and extensile surgical exposure for these tumors enabled us to determine tumor resectability and proceed with a safe resection or perform an amputation when required. We retrospectively reviewed 27 patients who underwent resection of an axillary tumor from 1989 to 2004 and analyzed their presenting symptoms, results of preoperative studies, type of surgery, and functional outcome. Tumors were exposed using a utilitarian shoulder approach that revealed no tumor invasion of the neurovascular bundle in 19 patients and invasion in eight. The former group was treated with tumor resection and the latter with forequarter amputation. Neurologic deficit, limb edema, and angiographic observation of arterial narrowing were associated with amputation. Good function was achieved in 15 of 19, shoulder range of motion was preserved in 14 of 19, and local tumor control was maintained in 16 of 19 patients who underwent a limb-sparing resection.

Knee stability after resection of the proximal fibula.

Managing tumors of the proximal fibula may require en bloc resection of the fibular head with the attachment site for the lateral collateral ligament. These resections of the proximal fibula cause unavoidable knee instability. We describe a reconstructive technique intended to minimize that instability. We retrospectively reviewed 24 patients who had proximal fibular resections from 1987 to 2004 and analyzes their knee stability and functional outcome. Resections were less (Type I) or more (Type II) radical depending upon the tumor type. Reconstruction included stapling the lateral collateral ligament to the lateral tibial metaphysis, cast immobilization, and protected weightbearing for 3 weeks. MSTS function scores were available for 19 of the 24 patients. At their most recent followup, 20 patients had a stable knee, three had 1 to 5 mm lateral joint space opening, and one had 6 to 10 mm lateral joint space opening. Patients with Type I resection had a better stability and function than those with a Type II resection. Stapling the lateral collateral ligament was a reliable technique for reconstructing the lateral collateral ligament after resecting the proximal fibula.

Free fibula flap elbow-joint hemiarthroplasty reconstruction for chronic osteomyelitis of the distal humerus.

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.

Novel genes implicated in embryonal, alveolar, and pleomorphic rhabdomyosarcoma: a cytogenetic and molecular analysis of primary tumors.

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.

Vacuum-assisted wound closure after resection of musculoskeletal tumors.

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.