Evaluation of an emergency department lean process improvement program to reduce length of stay.

STUDY OBJECTIVE: In recent years, lean principles have been applied to improve wait times in the emergency department (ED). In 2009, an ED process improvement program based on lean methods was introduced in Ontario as part of a broad strategy to reduce ED length of stay and improve patient flow. This study seeks to determine the effect of this program on ED wait times and quality of care. METHODS: We conducted a retrospective cohort study of all ED visits at program and control sites during 3 program waves from April 1, 2007, to June 30, 2011, in Ontario, Canada. Time series analyses of outcomes before and after the program and difference-in-differences analyses comparing changes in program sites with control sites were conducted. RESULTS: In before-after models among program sites alone, 90th percentile ED length of stay did not change in wave 1 (-14 minutes [95% confidence interval {CI} -47 to 20]) but decreased after wave 2 (-87 [95% CI -108 to -66]) and wave 3 (-33 [95% CI -50 to -17]); median ED length of stay decreased after wave 1 (-18 [95% CI -24 to -12]), wave 2 (-23 [95% CI -27 to -19]), and wave 3 (-15 [95% CI -18 to -12]). In all waves, decreases were observed in time to physician assessment, left-without-being-seen rates, and 72-hour ED revisit rates. In the difference-in-difference models, in which changes in program sites were compared with controls, the program was associated with no change in 90th percentile ED length of stay in wave 2 (17 [95% CI -0.2 to 33]) and increases in wave 1 (23 [95% CI 0.9 to 45]) and wave 3 (31 [95% CI 10 to 51]), modest reductions in median ED length of stay in waves 2 and 3 alone, and a decrease in time to physician assessment in wave 3 alone. CONCLUSION: Although the program reduced ED waiting times, it appeared that its benefits were diminished or disappeared when compared with that of control sites, which were exposed to system-wide initiatives such as public reporting and pay for performance. This study suggests that further evaluation of the effectiveness of lean methods in the ED is warranted before widespread implementation.

Phase 2 study of preoperative image-guided intensity-modulated radiation therapy to reduce wound and combined modality morbidities in lower extremity soft tissue sarcoma.

BACKGROUND: This study sought to determine if preoperative image-guided intensity-modulated radiotherapy (IG-IMRT) can reduce morbidity, including wound complications, by minimizing dose to uninvolved tissues in adults with lower extremity soft tissue sarcoma. METHODS: The primary endpoint was the development of an acute wound complication (WC). IG-IMRT was used to conform volumes to avoid normal tissues (skin flaps for wound closure, bone, or other uninvolved soft tissues). From July 2005 to June 2009, 70 adults were enrolled; 59 were evaluable for the primary endpoint. Median tumor size was 9.5 cm; 55 tumors (93%) were high-grade and 58 (98%) were deep to fascia. RESULTS: Eighteen (30.5%) patients developed WCs. This was not statistically significantly different from the result of the National Cancer Institute of Canada SR2 trial (P = .2); however, primary closure technique was possible more often (55 of 59 patients [93.2%] versus 50 of 70 patients [71.4%]; P = .002), and secondary operations for WCs were somewhat reduced (6 of 18 patients [33%] versus 13 of 30 patients [43%]; P = .55). Moderate edema, skin, subcutaneous, and joint toxicity was present in 6 (11.1%), 1 (1.9%), 5 (9.3%), and 3 (5.6%) patients, respectively, but there were no bone fractures. Four local recurrences (6.8%, none near the flaps) occurred with median follow-up of 49 months. CONCLUSIONS: The 30.5% incidence of WCs was numerically lower than the 43% risk derived from the National Cancer Institute of Canada SR2 trial, but did not reach statistical significance. Preoperative IG-IMRT significantly diminished the need for tissue transfer. RT chronic morbidities and the need for subsequent secondary operations for WCs were lowered, although not significantly, whereas good limb function was maintained.

A mutant PTH/PTHrP type I receptor in enchondromatosis.

Enchondromas are common benign cartilage tumors of bone. They can occur as solitary lesions or as multiple lesions in enchondromatosis (Ollier and Maffucci diseases). Clinical problems caused by enchondromas include skeletal deformity and the potential for malignant change to chondrosarcoma. The extent of skeletal involvement is variable in enchondromatosis and may include dysplasia that is not directly attributable to enchondromas. Enchondromatosis is rare, obvious inheritance of the condition is unusual and no candidate loci have been identified. Enchondromas are usually in close proximity to, or in continuity with, growth-plate cartilage. Consequently, they may result from abnormal regulation of proliferation and terminal differentiation of chondrocytes in the adjoining growth plate. In normal growth plates, differentiation of proliferative chondrocytes to post-mitotic hypertrophic chondrocytes is regulated in part by a tightly coupled signaling relay involving parathyroid hormone related protein (PTHrP) and Indian hedgehog (IHH). PTHrP delays the hypertrophic differentiation of proliferating chondrocytes, whereas IHH promotes chondrocyte proliferation. We identified a mutant PTH/PTHrP type I receptor (PTHR1) in human enchondromatosis that signals abnormally in vitro and causes enchondroma-like lesions in transgenic mice. The mutant receptor constitutively activates Hedgehog signaling, and excessive Hedgehog signaling is sufficient to cause formation of enchondroma-like lesions.

Long-term outcome of the treatment of high-risk tenosynovial giant cell tumor/pigmented villonodular synovitis with radiotherapy and surgery.

BACKGROUND: The treatment of diffuse tenosynovial giant cell tumor (TGCT) requires extensive surgical resection of the hypertrophic synovium and multiple soft tissue masses yet still may result in high rates of local failure. The authors of this report examined their experience in treating patients with advanced/multiply recurrent TGCT with a combination of surgery and external-beam radiotherapy. METHODS: Fifty patients who were treated for TGCT with radiotherapy and surgery from 1972 to 2006 were identified. Patient demographics, radiotherapy treatment parameters, surgical treatment, and oncologic and functional outcomes were evaluated. All patients had pathologic review at presentation and required at least 1 year follow-up. RESULTS: Forty-nine patients had diffuse TGCT with both intra-articular and extra-articular disease (1 had malignant TGCT). Twenty-eight patients (56%) were referred after at least 1 local recurrence. Thirty patients (60%) underwent at least 2 operations before radiotherapy. The mean dose of radiation delivered was 39.8 gray. At a mean follow-up of 94 months (range, 19-330 months), 47 patients (94%) had not developed a recurrence or had stable disease/signal characteristics on serial cross-sectional imaging (for those patients who had gross residual disease at the time of radiotherapy). Two patients required subsequent total hip arthroplasty because of progressive osteoarthritis, and there were 4 cases of avascular necrosis (only 1 post-treatment). Forty-one patients had good/excellent function. CONCLUSIONS: For patients with extensive or multiple local relapses or when surgery alone would result in a large burden of residual disease or major functional loss, the addition of moderate-dose adjuvant radiotherapy provided excellent local control while maintaining good function with low treatment-related morbidity.

Financing Models for Virtual Care.

Principles for determining physician compensation in the provision of virtual care are discussed along with analysis of the virtual care components included in the 2022 Ontario Physician Services Agreement (SEAMO 2022). Ministries and medical associations should continue to discuss appropriate payment for virtual advice for patients who do not have a primary care provider. They should also determine methods for payment for physician engagement in apps designed to optimize treatment of chronic diseases.

High-risk extracranial chondrosarcoma: long-term results of surgery and radiation therapy.

BACKGROUND: A study was undertaken to evaluate results of surgery and radiotherapy (RT) for high-risk extracranial chondrosarcomas. METHODS: Between 1986 and 2006, 60 patients underwent surgery and RT for extracranial high-risk chondrosarcoma. Preoperative RT (median, 50 gray [Gy]) and postoperative RT (median, 60 Gy) were used in 40% and 60% patients, respectively. Sites included pelvis/lower extremity (48%), chest wall (22%), spine/paraspinal (17%), and head and neck (13%). Overall, median tumor size was 7 cm (range, 1-22 cm), and tumor grade was I, II, and III in 22%, 64%, and 14% of cases, respectively. RESULTS: Pathologically clear surgical margins (R0) were present in 50%, microscopic positive margins (R1) in 28%, and gross positive margins (R2) in 13%, half of whom had clinically detectable residual disease; surgical margin was unknown in 8%. Median follow-up was 75 months (range, 5-230 months). The crude local control rate was 90%. Patients with R0, R1, and R2 resections had local control of 100%, 94%, and 42%, respectively. Of the 8 cases that had R2 resection, 3 experienced uncontrolled progression, but 5 patients had stable disease with long-term follow-up. The 10-year overall survival, progression-free survival, and cause-specific survival were 86%, 80.5%, and 89.4%, respectively. Younger age and grade III tumors were associated with worse progression-free survival (P = .03 and .0003, respectively). CONCLUSIONS: Although surgery with complete resection is paramount in management of chondrosarcoma, RT is a useful adjuvant treatment and appears to offer excellent and durable local control where wide surgical resection is difficult to accomplish.

Patient-oriented functional results of total femoral endoprosthetic reconstruction following oncologic resection.

BACKGROUND AND OBJECTIVES: Functional outcomes following oncologic total femoral endoprosthetic reconstruction (TFR) are lacking. We compared patient-oriented functional results of TFRs to proximal femur and distal femur reconstructions (PFR and DFR). We also compared function and complications with regard to knee and hip componentry. METHODS: Fifty-four TFR patients were identified from three institutional prospective databases. Forty-one had fixed- and 13 had rotating-hinge knees, 37 hemiarthroplasty and 17 total hip arthroplasty componentry. Toronto Extremity Salvage Scores (TESS) for n = 27 were compared between groups and to cohorts of PFR (n = 31) and DFR (n = 85) patients using the Mann-Whitney U-test. RESULTS: Follow-up averaged 4 years. Mechanical complications included five hip dislocations and one femoral malrotation. Four dislocations were in fixed-hinge implants, all in those lacking abductor reattachment. TESS averaged 69.3 ± 17.8, statistically decreased from DFR (P = 0.002) and PFR patients (P = 0.036). No significant differences were detected between patients in the fixed-hinge (n = 18) and rotating-hinge (n = 9) groups (P = 0.944), or total hip (n = 8) and hemiarthroplasty (n = 19) groups (P = 0.633). CONCLUSIONS: TFR is reserved for extreme cases of limb salvage, portending a poor prognosis overall. Function reflects additive impairments from PFR and DFR. TFR outcomes differ little with rotating- or fixed-hinge, total hip or hemiarthroplasty implants.

A biomechanical evaluation of press-fit stem constructs for tumor endoprosthetic reconstruction of the distal femur.

This study was designed to assess the biomechanical parameters of the older Kotz Modular Femur Tibia Reconstruction (Stryker Inc, Mahwah, NJ) stem and the newer Restoration and the unfluted Global Modular Replacement System (Stryker Inc, Mahwah, NJ) uncemented stems for use with tumor endoprostheses as well as to assess the optimal reaming technique for insertion of these stems. Fresh-frozen adult femora or composite distal femora were implanted with the uncemented stems. Separate experiments were performed to compare reaming technique and bone resection level. All constructs were mechanically tested for axial compression, lateral bending, and torsional stiffness and torque to failure. Results showed that the biomechanical performance of all the stems were similar with respect to each parameter. Cylindrical reaming was associated with a significantly higher torque to failure than flexible reaming in the diaphysis (P = .006). Newer uncemented stems provide adequate initial biomechanical stability for implantation in the distal femur.

Complete femoral nerve resection with soft tissue sarcoma: functional outcomes.

BACKGROUND: The functional consequences of resecting the femoral nerve in conjunction with soft tissue sarcoma management are not well described. In comparison, sciatic nerve involvement by sarcoma was once considered an indication for amputation, but sciatic resection is now commonly performed as part of a limb-salvage approach. We compared functional outcomes following resection of either the femoral or sciatic nerve in patients with soft tissue sarcoma. We also compared both groups with patients with large thigh sarcomas without nerve involvement. METHODS: The prospectively collected database from a tertiary referral center for sarcomas was retrospectively reviewed to identify all patients with resection of the femoral nerve performed during wide excision of a soft tissue sarcoma. Patient demographics, treatment, complications, and functional outcomes in the form of the Musculoskeletal Tumor Society (MSTS) 1987 score, MSTS 1993 score, and Toronto Extremity Salvage Score (TESS) were collected. Control groups of sarcoma patients with sciatic nerve resection in the thigh as well as similarly sized tumors in the quadriceps requiring no nerve resections were also analyzed. RESULTS: Ten patients with femoral nerve resections were identified, all women, aged 47-78 years, with large soft tissue sarcomas of varied subtypes. All patients received adjuvant radiotherapy, most preoperatively. Six patients developed fractures during long-term follow-up, four in nonirradiated portions of the skeleton but directly from falls related to absent active knee extensors, and two at least partially attributable to sequelae of radiation. MSTS 1987 hip scores demonstrated one excellent, four good, and five fair results. MSTS 1993 hip scores averaged 71.4 +/- 17.2% and TESS averaged 61.7 +/- 21.8. There were no significant differences between the functional scores for patients with femoral or sciatic nerve resections (P = 1.0). CONCLUSIONS: Femoral nerve resection appears more morbid than anticipated. The falls to which patients were prone, even years after surgery, subject them to ongoing long-term risks for fractures and other injuries. These nerve-specific functional implications should be considered when counseling patients in preparation for possible resection of the femoral nerve when it is directly involved by a soft tissue sarcoma.

Clinical and functional outcomes of patients with a pathologic fracture in high-grade osteosarcoma.

BACKGROUND AND OBJECTIVES: There have been variable reports of outcomes of patients with osteosarcoma and pathologic fractures. The purpose of this study was to document outcomes after management of this clinical entity at a single large oncology center. METHODS: A retrospective review was undertaken of our database between 1989 and 2006. We compared oncologic and functional outcomes of 201 patients with high-grade osteosarcoma without pathologic fractures to 31 patients with pathologic fractures. RESULTS: The rate of amputation in the group with pathologic fracture was significantly higher than the group without fracture (39% vs. 14%, P = 0.001). There was no difference in the rate of local recurrence between groups. The 5-year survival was superior in the group without pathologic fracture (60% vs. 41%, P = 0.0015). For patients with localized disease, 5-year survival was higher in patients without fracture (68% vs. 52%, P = 0.006). Disability as measured by the Toronto Extremity Salvage Score was no different between the groups. Impairment as measured by the Musculoskeletal Tumor Society scores was lower in the group without fracture. CONCLUSIONS: Presentation with a pathologic fracture in osteosarcoma did not preclude limb salvage surgery in a majority of patients, did not increase the risk of local recurrence, but was associated with poorer overall survival.

Oncologic and functional outcome of scapular chondrosarcoma.

BACKGROUND: The scapula is a common site for chondrosarcoma to occur. There has been disagreement between recent studies documenting the oncologic outcomes in patients with chondrosarcoma of the scapula. The purpose of this study was to investigate both the oncologic and functional outcomes of patients presenting to a large oncology center with primary chondrosarcoma of the scapula. METHODS: A review of our prospectively collected database was carried out. All patients in the years 1989 to 2004 undergoing surgical resection of primary chondrosarcoma of the scapula were included. We documented patient demographics, whether the patient underwent partial or total scapulectomy, oncologic outcomes including local and systemic recurrence, and functional outcome using the Musculoskeletal Tumor Society (MSTS) 87, MSTS 93, and Toronto Extremity Salvage Score (TESS) rating systems. RESULTS: Twenty-four patients (16 males, 8 females), with a mean age of 44 years (range 18-74 years), met the inclusion criteria. There were no local recurrences. Two patients died of metastatic disease at 23 and 103 months postoperatively. No other patients have developed systemic disease. Sixteen patients underwent partial scapulectomy while eight underwent total scapulectomy. Functional outcome was better in the group undergoing partial scapulectomy with significantly higher MSTS 87 (30.8 versus 16.6), MSTS 93 (89.6 versus 68.3), and TESS (92.6 versus 74.9) scores than the total scapulectomy group. CONCLUSION: Patients with primary chondrosarcoma of the scapula have an excellent oncologic prognosis with a very low local recurrence and metastatic rate. Functional outcomes are better for patients undergoing partial rather than total scapulectomy.

"So, are you back to work yet?" Re-conceptualizing 'work' and 'return to work' in the context of primary bone cancer.

People with primary bone cancer typically are young (usual age-at-onset 16-35 years old) and undergo arduous treatments. The current standard of care (tumour resection and limb reconstruction with or without chemotherapy) results in survival rates in excess of 60%, but also results in significant disability at a time when patients are choosing career paths, establishing their independence and embarking on new roles. To date, the nature of the relationship between experiences of osteosarcoma illness and experiences of vocation has remained unclear. This study sought to examine this relationship using qualitative narrative methodology. In-depth audiotaped interviews were conducted with 14 osteosarcoma survivors (8 men, 6 women) who were being treated at Mount Sinai Hospital, Toronto, Canada. Interview transcripts were analyzed for story typology and thematic content via constant comparison. Respondents reported engaging in three types of 'work': 'illness work', 'identity work' and 'vocational work'. Osteosarcoma illness represented a crisis for respondents, one which necessitated considerable illness work. Illness work was portrayed as all-consuming, whereby respondents were forced to stop vocational work for considerable periods. The illness crisis also precipitated 'identity work'. Respondents recounted a transformative process, of 'becoming other' to whom they had been prior to illness. As a result, respondents told of re-entering the vocational sphere with a different sense of themselves from when they left it. When patients return for surgical follow up, clinicians routinely ask, "So, are you back to work yet?" expecting simple 'yes/no' answers. This study suggests that the answer is instead highly complex, and that patients could be seen as having been 'working' all along. This study offers a re-conceptualization of 'work' and 'return to work' in the context of osteosarcoma, with implications for clinical and return-to-work practices.

Creating sustained improvements in patient access and flow: experiences from three Ontario healthcare institutions.

Ensuring that patients receive timely, high-quality healthcare is the highest priority of Ontario's hospitals, physicians and nurses. Given that the emergency department (ED) is often the "front door" to our healthcare system, developing approaches to improve access and flow in the ED is important - made more challenging by rising patient demand and acuity. Long-standing efforts to improve the ED system have outlined promising approaches and pushed access and flow up the priority list. Recently, in partnership with the Ministry of Health and Long-Term Care (MOHLTC), several Ontario hospitals participated in an intensive and sustained effort to improve access and flow, with promising results. Participants in these efforts described the initiatives as transformational, and the results have been promising and sustained. This article chronicles the efforts of three hospitals to enable other hospitals, physicians and nurses to learn from these experiences and gain confidence that a similar impact can be achieved in their facilities. Specifically, it discusses the following: The three pillars of sustainable transformation. Hospital case studies. St. Joseph's Health Centre (SJHC), Toronto. London Health Sciences Centre (LHSC) - University Hospital. University Health Network (UHN) - Toronto General and Toronto Western. Advice for other hospitals

Radiation planning comparison for superficial tissue avoidance in radiotherapy for soft tissue sarcoma of the lower extremity.

PURPOSE: Three types of preoperative radiotherapy (RT) plans for extremity soft tissue sarcoma were compared to determine the amount of dose reduction possible to the planned surgical skin flaps required for tumor resection and wound closure, without compromising target coverage. METHODS AND MATERIALS: Twenty-four untreated patients with large, deep, lower extremity STS treated with preoperative RT and limb salvage surgery had their original conventional treatment plans re-created. The same clinical target volume was used for all three plans. The future surgical skin flaps were created virtually through contouring by the treating surgeon and regarded as an organ at risk. The original, conformal, and intensity-modulated RT (IMRT) plans were created to deliver 50 Gy in 25 fractions to the clinical target volume. Clinical target volume and organ-at-risk dose-volume histograms were calculated and the plans compared for conformality, target coverage, and dose sparing. RESULTS: The mean dose to the planned skin flaps was 42.62 Gy (range, 30.24-48.65 Gy) for the original plans compared with 40.12 Gy (range, 24.24-47.26 Gy) for the conformal plans and 26.71 Gy (range, 22.31-31.91 Gy) for the IMRT plans (p = 0.0008). An average of 86.4% (range, 53.2-97.4%) of the planned skin flaps received >or=30 Gy in the original plans compared with 83.4% (range, 36.2-96.2%) in the conformal plans and only 34.0% (range, 22.5-53.3%) in the IMRT plans (p = 0.0001). IMRT improved target conformality compared with the original and conformal plans (1.27, 2.34, and 1.76, respectively, p = 0.0001). CONCLUSION: In a retrospective review, preoperative IMRT substantially lowered the dose to the future surgical skin flaps, sparing a greater percentage of this structure's volume without compromising target (tumor) coverage.

Studies of the in vivo radiosensitivity of human skin fibroblasts.

BACKGROUND AND PURPOSE: To examine the radiosensitivity of skin cells obtained directly from the irradiated skin of patients undergoing fractionated radiation treatment prior to surgery for treatment of soft tissue sarcoma (STS) and to determine if there was a relationship with the development of wound healing complications associated with the surgery post-radiotherapy. METHODS: Micronucleus (MN) formation was measured in cells (primarily dermal fibroblasts) obtained from human skin at their first division after being removed from STS patients during post-radiotherapy surgery (2-9 weeks after the end of the radiotherapy). At the time of radiotherapy (planned tumor dose - 50Gy in 25 daily fractions) measurements were made of surface skin dose at predetermined marked sites. Skin from these sites was obtained at surgery and cell suspensions were prepared directly for the cytokinesis-blocked MN assay. Cultured strains of the fibroblasts were also established from skin nominally outside the edge of the radiation beam and DNA damage (MN formation) was examined following irradiation in vitro for comparison with the results from the in situ irradiations. RESULTS: Extensive DNA damage (MN) was detectable in fibroblasts from human skin at extended periods after irradiation (2-9 weeks after the end of the 5-week fractionated radiotherapy). Analysis of skin receiving a range of doses demonstrated that the level of damage observed was dose dependent. There was no clear correlation between the level of damage observed after irradiation in situ and irradiation of cell strains in culture. Similarly, there was no correlation between the extent of MN formation following in situ irradiation and the propensity for the patient to develop wound healing complications post-surgery. CONCLUSIONS: Despite the presence of DNA damage in dermal fibroblasts weeks after the end of the radiation treatment, there was no relationship between this damage and wound healing complications following surgery post-irradiation. These results suggest that factors other than the radiosensitivity of the skin fibroblasts likely also play a role in wound healing in deep wound sites associated with surgery for STS following radiation therapy.

TP53 mutations and outcome in osteosarcoma: a prospective, multicenter study.

PURPOSE: Mutations of the TP53 gene have been associated with resistance to chemotherapy as well as poor prognosis in many different malignancies. This is the first prospective study of the prognostic value of somatic TP53 mutations in patients with newly diagnosed extremity osteosarcoma. PATIENTS AND METHODS: One hundred ninety-six patients with high-grade, nonmetastatic osteosarcoma of the extremities were enrolled from seven tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 44 months). All patients received neoadjuvant or adjuvant chemotherapy and surgery. Tumors were analyzed for the presence of TP53 mutations by polymerase chain reaction single-strand conformation polymorphism analysis and direct DNA sequencing. The association of the status of the TP53 gene with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors. RESULTS: Patient age was the only factor that varied with TP53 gene status (P = .05). No relationship was identified between TP53 status and systemic relapse (relative risk, 1.24; P = .41). Analyses based on missense or nonsense mutations gave similar results (P > .10). In multivariate analysis, large (> 9 cm) tumor size (relative risk, 1.9; P = .006) and poor histologic response (< or = 90% necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome. CONCLUSION: We found no evidence that TP53 mutations predict for development of metastases in patients with high-grade osteosarcoma. Identification of other genes that influence chemotherapy response and clinical outcome in osteosarcoma is needed to facilitate further improvements in patient outcomes.

Wound healing morbidity in STS patients treated with preoperative radiotherapy in relation to in vitro skin fibroblast radiosensitivity, proliferative capacity and TGF-beta activity.

BACKGROUND AND PURPOSE: In a recent study, we demonstrated that the ability of dermal fibroblasts, obtained from soft tissue sarcoma (STS) patients, to undergo initial division in vitro following radiation exposure correlated with the development of wound healing morbidity in the patients following their treatment with preoperative radiotherapy. Transforming growth factor beta (TGF-beta) is thought to play an important role in fibroblast proliferation and radiosensitivity both of which may impact on wound healing. Thus, in this study we examined the interrelationship between TGF-beta activity, radiosensitivity and proliferation of cultured fibroblasts and the wound healing response of STS patients after preoperative radiotherapy to provide a validation cohort for our previous study and to investigate mechanisms. PATIENTS AND METHODS: Skin fibroblasts were established from skin biopsies of 46 STS patients. The treatment group consisted of 28 patients who received preoperative radiotherapy. Eighteen patients constituted a control group who were either irradiated postoperatively or did not receive radiation treatment. Fibroblast cultures were subjected to the colony forming and cytokinesis-blocked binucleation assays (low dose rate: approximately 0.02 Gy/min) and TGF-beta assays (high dose-rate: approximately 1.06 Gy/min) following gamma-irradiation. Fibroblast radiosensitivity and initial proliferative ability were represented by the surviving fraction at 2.4 Gy (SF(2.4)) and binucleation index (BNI), respectively. Active and total TGF-beta levels in fibroblast cultures were determined using a biological assay. Wound healing complication (WHC), defined as the requirement for further surgery or prolonged deep wound packing, was the clinical endpoint examined. RESULTS: Of the 28 patients treated with preoperative radiotherapy, 8 (29%) had wound healing difficulties. Fibroblasts from patients who developed WHC showed a trend to retain a significantly higher initial proliferative ability after irradiation compared with those from individuals in the treatment group with normal wound healing, consistent with the results of our previous study. No link was observed between fibroblast radiosensitivity and WHC. Neither active nor total TGF-beta levels in cultures were significantly affected by irradiation. Fibroblast proliferation in unirradiated and irradiated cultures, as well as radiosensitivity, was not influenced by TGF-beta content. TGF-beta expression in fibroblast cultures did not reflect wound healing morbidity. CONCLUSIONS: These data are consistent with our previous study and combined the results suggest that in vitro fibroblast proliferation after irradiation may be a useful predictor of wound healing morbidity in STS patients treated with preoperative radiotherapy. TGF-beta levels in culture do not predict WHC, suggesting that the role of TGF-beta in wound healing is likely controlled by other in vivo factors.

hCDC4 variation in osteosarcoma.

The hCDC4 gene (also known as Fbw7 or Archipelago) encodes an F-box protein that is responsible for targeting cyclin E for Skp1-cullin-F box protein (SCF) ubiquitination and proteosomal degradation. Disruption of this pathway has been associated with chromosomal instability and aneuploidy in several cancer cell lines and primary tumors. This study aimed to examine whether hCDC4 mutations contribute to aneuploidy in osteosarcoma. We analyzed 147 primary high-grade osteosarcoma specimens and 6 osteosarcoma cell lines. The protein truncation test (PTT) and single-strand conformation polymorphism (SSCP) analysis with subsequent sequencing were performed to detect alterations of the hCDC4 gene. All specimens exhibited the same PTT pattern of normal bands with less intense common bands. Two shifts were detected by SSCP, and subsequent DNA analysis identified one in-frame three-base GAG (424-426) deletion and one silent nucleotide substitution (C1261T). We conclude that somatic hCDC4 mutations are infrequent in osteosarcoma, and are unlikely to play an important role in aneuploidy of this tumor.

Histopathologic Features of Prognostic Significance in High-Grade Osteosarcoma.

Context .- In osteosarcoma treated with neoadjuvant chemotherapy the extent of tumor necrosis on resection is considered an indicator of treatment response, and this has been shown to correlate with survival in most but not all studies. Objective .- To identify additional histologic variables of prognostic significance in high-grade osteosarcoma. Design .- Slides of pretreatment biopsy and primary postneoadjuvant chemotherapy resections from 165 patients with high-grade osteosarcoma were reviewed. Univariate (Kaplan-Meier) and multivariate (Cox regression) analyses were performed to identify clinical and histomorphologic attributes associated with overall survival. Results .- Univariate analyses confirmed the prognostic significance of metastatic status on presentation, primary tumor size, anatomic site, and histologic subtype. Additionally, the identification of lymphovascular invasion, 10% or more residual viable tumor, and 10 or more mitoses per 10 high-powered fields assessed in posttreatment resections were associated with poor survival, retaining significance in multivariate analyses. Based on results from multivariate analysis, we developed a prognostic index incorporating primary tumor size and site, and significant histologic features assessed on resection (ie, lymphovascular invasion status, mitotic rate, and extent of viable tumor). This scoring system segregates patients into 3 risk categories with significant differences in overall survival and retained significance in an independent validation set of 42 cases. Conclusions .- The integration of clinical and microscopic features improves prognostication of patients with osteosarcoma.

Histologic assessment of peritumoral edema in soft tissue sarcoma.

PURPOSE: To evaluate whether satellite tumor cells can be identified histologically in the tissues surrounding a soft tissue sarcoma and whether their presence correlates with increased T(2)-weighted signal intensity on MRI. METHODS AND MATERIALS: Fifteen patients with a high-grade extremity or truncal soft tissue sarcoma underwent preoperative MRI. The extent of high T(2)-weighted signal changes in the tissues surrounding tumor, thought to represent peritumoral edema/reactive changes, was determined. Twelve patients received i.v. gadolinium, and contrast enhancement was determined. All patients underwent surgical resection in the absence of preoperative chemotherapy or radiotherapy. The presence of tumor cells in the surrounding tissues was determined histologically in representative paraffin-embedded sections and correlated with the MRI findings. RESULTS: The extent of peritumoral T(2)-weighted MRI signal changes ranged from 0 to 7.1 cm (mean, 2.5 cm); contrast enhancement ranged from 0 to 5.3 cm (mean, 1.1 cm). Sarcoma cells were identified histologically in the tissues beyond the tumor in 10 of 15 cases. In 6 cases, tumor cells were located within 1 cm of the tumor margin, and in 4 cases, malignant cells were found at a distance >1 cm and up to a maximum of 4 cm. The location of tumor cells beyond the margin did not correlate with tumor size nor did it correlate with the location or extent of peritumoral changes. CONCLUSION: The ability to identify tumor cells beyond the margin of a soft tissue sarcoma has important implications in planning appropriate targets for treatment. This could influence the use of new radiotherapy technologies such as intensity-modulated radiotherapy that aim to minimize treatment volumes through conformal planning.