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.

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.

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.

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.

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.

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.

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.

Prediction of high risk Ewing's sarcoma by gene expression profiling.

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.

Limb sparing approach: adjuvant radiation therapy in adults with intermediate or high-grade limb soft tissue sarcoma.

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.

A single-team experience of limb sparing approach in adults with high-grade malignant fibrous histiocytoma.

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.

Radiotherapy for spinal cord compression in patients with soft-tissue sarcoma.

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.

A possible role for IVIg in the treatment of soft tissue sarcoma: a clinical case and an experimental model.

A patient with a malignant peripheral nerve sheath tumor (MPNST) was treated with IVIg for multiple sclerosis. Her MPNST course was remarkably longer and more indolent than expected; she achieved a disease-free interval (DFI) of 30 months. Seven other patients, who were not treated by IVIg, had a relatively aggressive course (median DFI 3 months). These results led us to examine the effect of IVIg on the growth of sarcoma in vitro and in vivo in an experimental model of MCA-bearing mice. When added to MCA-105 sarcoma cell cultures, IVIg produced a dose-dependent inhibitory effect on [(3)H]-thymidine incorporation. The maximal inhibitory effect was at a concentration of 50 mg/ml IVIg. Cell cycle analysis revealed a hypodiploid peak at the lower fluorescence values which appeared in the samples treated with IVIg. These results demonstrate that the anti-proliferative activity results from an apoptotic effect of IVIg on the tumor cells. In a second set of experiments, we evaluated the capability of IVIg, when administered orally or subcutaneously, to inhibit the growth of MCA-105 sarcoma lung metastases. A decrease in the mean lung weight was observed in the mice that were treated by s.c. or oral administration, the latter being more effective. A possible role for IVIg in the treatment of MPNST and other soft tissue sarcomas is suggested.

Expression of p53 gene product and cell proliferation marker Ki-67 in Ewing's sarcoma: correlation with clinical outcome.

Overexpression of tumor suppressor gene p53, cell proliferation nuclear antigen Ki-67, and proto-oncogene HER-2/neu are associated with poor prognosis in some tumors. We studied p53, Ki-67, and HER-2/neu immunohistochemical expression in archival biopsies of 37 patients with Ewing's sarcoma (ES). Patients with ES were treated at four Israeli hospitals between 1982 and 2000. Formalin-fixed paraffin-embedded tissue sections were stained by immunohistochemistry for p53, Ki-67, and HER-2/neu. More than 300 cells were counted on each slide, and the percentage of positively stained nuclei was computed. p53 overexpression was defined as nuclear staining of >2.3% of cells, Ki-67 overexpression as nuclear staining of >8.3% malignant cells. HER-2/neu staining was scored semiquantitatively on a scale of 0 to 4+. Twenty-two of 37 patients are alive and well, with mean follow-up time of 38 months. There was overexpression of p53 in 16 patients (43%) and of Ki-67 in 21 patients (57%). The correlation between p53 and Ki-67 overexpressions was 0.61. We found no overexpression of HER-2/neu. Median relapse-free survival (RFS) was statistically significantly shorter for patients with p53 overexpression (25 months) than for patients with negative staining (>92 months). The prognostic value of p53 overexpression was also significant after adjusting for tumor location and age. Median RFS was shorter for patients with positive Ki-67 staining (40 months) than for patients with negative staining (80 months) but did not reach statistical significance. Our study suggests that p53 is a predictor of RFS in patients with ES. More patients must be studied to assess the validity of this observation.

Presacral tumors: a practical classification and treatment of a unique and heterogeneous group of diseases.

BACKGROUND: Presacral tumors are a rare and diverse group of diseases that originate from the different tissues that comprise the potential presacral space. Because of their relative rarity, confusion exists regarding their clinical presentation, natural history, and treatment. The aim of this study is to describe a single institution's experience with the management of presacral tumors and to suggest a practical method of classification. METHODS: Records of all patients who underwent operation for presacral tumors from the years 1991 to 2001 were reviewed. Clinical, pathologic, treatment, and outcome variables were evaluated. RESULTS: Forty-two patients were included in the study and were divided into 4 groups according to lesion pathology: benign congenital (n = 12), malignant congenital (n = 9), benign acquired (n = 9), and malignant acquired (n = 12). Symptoms were nonspecific, and 26% of the cases were completely asymptomatic. Diagnosis was made with rectal examination and confirmed with pelvic computerized tomographic scan. Surgical approach varied among the different groups, with the posterior approach used mainly for congenital tumors and the anterior approach for acquired. Complete surgical resection of the tumor was obtained in all cases of benign tumors and in 76% of malignant tumors. No postoperative mortality was seen, and complications occurred in 36% (15/42); most were reversible. None of the patients with benign tumors had recurrences, and all are alive at this time. The survival rate of patients with malignant tumors was significantly improved when complete resection was possible. CONCLUSION: Classification of presacral tumors into congenital versus acquired and benign versus malignant is simple and efficient. Treatment is complete surgical resection, which can be performed safely with low morbidity and no mortality.

High frequency of genomic instability in Ewing family of tumors.

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.

Limb-sparing resections of the shoulder girdle.

BACKGROUND: Limb-sparing surgeries around the shoulder girdle pose a surgical difficulty, because tumors arising in this location are frequently large at presentation, are juxtaposed to the neurovascular bundle, require en bloc resection of proportionally large amounts of bone and soft tissues, and necessitate complex resection and reconstruction. STUDY DESIGN: Between 1980 and 1997, we treated 134 patients who presented with 110 primary malignant, 12 metastatic, and 12 benign aggressive bone and soft tissue tumors of the shoulder girdle and subsequently underwent a limb-sparing resection. Reconstruction of the bone defect included 92 proximal humerus and 9 scapular prostheses. All patients were followed up for a minimum of 2 years. We summarize the principles of limb-sparing resections of the shoulder girdle, with emphasis on the surgical anatomy of the shoulder girdle, principles of resection and reconstruction, and functional outcomes. RESULTS: Function was estimated to be good or excellent in 101 patients (75.4%), moderate in 23 patients (17.1%), and poor in 10 patients (7.5%). Complications included 13 transient nerve palsies, 2 deep wound infections, and 1 prosthetic loosening. Local tumor recurrence occurred in 5 of 103 (4.9%) patients with primary sarcomas of the shoulder girdle. CONCLUSIONS: Detailed preoperative evaluation and surgical planning are essential for performing a limb-sparing resection around the shoulder girdle. Local tumor control, associated with good functional outcomes, is achieved in the majority of patients.

Induction chemotherapy for bone sarcoma in adults: correlation of results with erbB-4 expression.

Tumor response to preoperative chemotherapy is an important prognostic factor for localized, operable extremity osteosarcoma. Other clinical variables include tumor size and location, age and sex, and serum enzymes. Advances in molecular oncology yielded a second group of factors such as multidrug resistance status, loss of heterozygosity of RB gene, and HER2/erbB-2 expression. The aim of this study was to investigate the expression and the prognostic value of the newly described erbB-4 receptor in specimens from adults with bone sarcomas treated by pre- and postoperative chemotherapy. Thirty-three patients with non-metastatic bone sarcoma have been treated by two doxorubicin-based induction chemotherapy regimen, followed by limb sparing surgery and tailored adjuvant chemotherapy. Pre-chemotherapy tissue specimens were investigated for the expression of erbB-4 receptor and post-induction specimens were assessed for pathological response. The clinical response rates were 32-36%. The degree of induced necrosis was correlated with the disease-free survival (DFS). Patients achieving >/=90% necrosis had an improved DFS over patients with poor histological response. ErbB-4 expression was significantly associated with poor histologic response and shorter DFS. ErbB-4 expression may be used for prognostication of adults with bone sarcomas.

Sarcoma and thyroid disorders: a common etiology?

We have recently observed that many of our sarcoma patients presented also with thyroid disorders. Literature data are almost unavailable on this topic. The relationship between the sarcoma and thyroid disorders is examined. Retrospective analysis of files of patients with sarcoma and clinically overt thyroid disorders was carried out. Of the 375 patients with soft tissue sarcomas (STS) and 235 with bone sarcoma (BS) including small blue round cell tumors (SBRC), 28 patients (4.6%) had an associated significant thyroid disorder. The types of sarcoma were mainly liposarcoma followed by malignant fibrous histiocytoma, leiomyosarcoma and bone sarcoma. The primary sites were mainly limb and trunk. The interval between the diagnosis of the thyroid disorder and the sarcoma varied between -14 years (thyroid first) and +16.5 years (thyroid later) with a median of -0.2 years. Thyroid disorders included goiter, thyroiditis and carcinoma. There are both basic-science and clinical evidence to a possible common pathway that leads to the association between overt thyroid disorders and sarcomas of bone or soft tissues. Oncogene erbA activity is related to thyroid receptors to T3 and to development of sarcoma. Cross talk of the sarcoma oncogene and the erbA might contribute to the development of sarcoma. The thyroid hormone receptor and the highly related viral oncoprotein v-erbA are found exclusively in the nucleus as stable constituents of chromatin. It has been shown that v-erbA can block the spontaneous differentiation in erythroid cells transformed by various retroviral oncogenes. V-erbA can alter the spectrum of neoplasia induced by the v-src oncogene, which causes predominantly sarcomas and erythroblastosis in chicks. The erbA can cooperate with other oncogenes such as v-erbB or with v-fms, v-ras, and c-kit. Cooperation with v-myc may play a role in the development of rhabdomyosarcoma especially in thyroid hormone deficiency state. The possible clinical implications are the need to screen patients with sarcoma to thyroid disorders, and patients with thyroid disorders for malignant diseases.

Dextromethorphan for phantom pain attenuation in cancer amputees: a double-blind crossover trial involving three patients.

BACKGROUND: Phantom limb pain is an intriguing pain syndrome that may result from damage to peripheral nerve tissue but could also involve central amplifying congeners. N-methyl-D-aspartate (NMDA)-receptor antagonists were recently shown to alleviate neuropathic pain in both animal and human models. Dextromethorphan is a noncompetitive NMDA-receptor antagonist. STUDY DESIGN: Oral dextromethorphan (120-180 mg daily) was administered to three selected cancer patients during a 3-week study and an additional 1 month of treatment with the dosage subjectively judged to be best. RESULTS: Oral dextromethorphan effectively reduced postamputation phantom limb pain, bestowing improvement in feeling and minimizing sedation in comparison with the pretreatment or placebo conditions, with no side effects. Pain recurred in one patient 1 month after treatment was stopped. CONCLUSIONS: Further clinical trials are warranted to determine the optimal dosage and identify which patients with phantom pain would benefit the most from this therapeutic approach.

Free fibula long bone reconstruction in orthopedic oncology: a surgical algorithm for reconstructive options.

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.