[Show abstract][Hide abstract] ABSTRACT: Creating spontaneous yet genetically tractable human tumors from normal cells presents a fundamental challenge. Here we combined retroviral and transposon insertional mutagenesis to enable cancer gene discovery starting with human primary cells. We used lentiviruses to seed gain- and loss-of-function gene disruption elements, which were further deployed by Sleeping Beauty transposons throughout the genome of human bone explant mesenchymal cells. De novo tumors generated rapidly in this context were high-grade myxofibrosarcomas. Tumor insertion sites were enriched in recurrent somatic copy-number aberration regions from multiple cancer types and could be used to pinpoint new driver genes that sustain somatic alterations in patients. We identified HDLBP, which encodes the RNA-binding protein vigilin, as a candidate tumor suppressor deleted at 2q37.3 in greater than one out of ten tumors across multiple tissues of origin. Hybrid viral-transposon systems may accelerate the functional annotation of cancer genomes by enabling insertional mutagenesis screens in higher eukaryotes that are not amenable to germline transgenesis.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have mapped risk alleles for at least ten distinct cancers to a small region of 63,000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (ASSET) across six distinct cancers in 34,248 cases and 45,036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single nucleotide polymorphisms (SNPs): five in the TERT gene (region 1: rs7726159, P=2.10x10-39; region 3: rs2853677, P=3.30x10-36 and PConditional=2.36x10-8; region 4: rs2736098, P=3.87x10-12 and PConditional=5.19x10-6, region 5: rs13172201, P=0.041 and PConditional=2.04x10-6; and region 6: rs10069690, P=7.49x10-15 and PConditional=5.35x10-7) and one in the neighboring CLPTM1L gene (region 2: rs451360; P=1.90x10-18 and PConditional=7.06x10-16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele specific effects on DNA methylation were seen for a subset of risk loci indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
Human Molecular Genetics 07/2014; · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Complex anatomy of the forearm may impact on local control and survivals of soft tissue sarcoma. Little is known about characteristics and oncologic outcomes following surgical treatment.
Journal of Surgical Oncology 06/2014; · 2.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objectives of this study were to evaluate the risk of local recurrence and survival after soft tissue sarcoma (STS) resection with positive margins and to evaluate the safety of sparing adjacent critical structures.
[Show abstract][Hide abstract] ABSTRACT: Hedgehog (Hh) pathway inhibition in cancer has been evaluated in both the ligand-independent and ligand-dependent settings, where Hh signaling occurs either directly within the cancer cells, or within the non-malignant cells of the tumor microenvironment. Chondrosarcoma is a malignant tumor of cartilage in which there is ligand-dependent activation of Hh signaling. IPI-926 is a potent, orally delivered small molecule that inhibits Hh pathway signaling by binding to Smoothened (SMO). Here, the impact of Hh pathway inhibition on primary chondrosarcoma xenografts was assessed. Mice bearing primary human chondrosarcoma xenografts were treated with IPI 926. The expression levels of known Hh pathway genes, in both the tumor and stroma, and endpoint tumor volumes were measured. Gene expression profiling of tumors from IPI-926-treated mice was conducted to identify potential novel Hh target genes. Hh target genes were studied to determine their contribution to the chondrosarcoma neoplastic phenotype. IPI-926 administration results in down-modulation of the Hh pathway in primary chondrosarcoma xenografts, as demonstrated by evaluation of the Hh target genes GLI1 and PTCH1, as well as inhibition of tumor growth. Chondrosarcomas exhibited autocrine and paracrine Hh signaling and both were affected by IPI-926. Decreased tumor growth is accompanied by histopathological changes, including calcification and loss of tumor cells. Gene profiling studies identified genes differentially expressed in chondrosarcomas following IPI-926 treatment, one of which, ADAMTSL1, regulates chondrosarcoma cell proliferation. These studies provide further insight into the role of the Hh pathway in chondrosarcoma and provide a scientific rationale for targeting the Hh pathway in chondrosarcoma.
Molecular Cancer Therapeutics 03/2014; · 5.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the effect of flap reconstruction on perineal complications in locally advanced rectal cancers (LARC) and locally recurrent rectal cancers (LRRC). Prior studies have suggested that flap reconstruction may decrease wound complications after ablative surgery for rectal cancer but are limited by small sample sizes, heterogeneity of pathologies, and lack of comparison groups.
A retrospective cohort study (1999-2010) was performed on consecutive patients undergoing abdominoperineal resection (APR) or pelvic exenteration for locally advanced/locally recurrent rectal cancers. Differences in perineal complications between patients treated with and without perineal flap reconstruction were analyzed by using univariable, multivariable, and propensity score regression analyses.
Flap reconstruction was performed in 52 of 177 patients (29 %). Patients receiving flap reconstruction had multiple risk factors for perineal morbidity, including longer operative times and more complex procedures. In our final multivariable analyses that were stratified by type of ablative procedure, we found a trend toward lower odds of perineal complications in patients receiving flaps (p = 0.065) compared with primary closure after pelvic exenteration. Although operative time and sacrectomy were significant determinants of perineal morbidity for pelvic exenteration patients, no significant predictors of perineal outcomes were identified for patients undergoing APR.
This study suggests that flap reconstruction may provide some protective effect against perineal complications in patients undergoing pelvic exenteration, although this was not observed for APR. The most important determinants of perineal complications after pelvic exenteration were operative time and sacral resection, but no predictive factors for post-APR perineal outcomes were identified.
Annals of Surgical Oncology 02/2014; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite the importance of Hedgehog signaling in bone development, the relationship between Hedgehog pathway expression and osteosarcoma clinical characteristics and outcome has not been investigated. In this study of 43 high-grade human osteosarcoma samples, we detected high expression levels of the Hedgehog ligand gene, IHH, and target genes, PTCH1 and GLI1, in most samples. Further analysis in tumors of patients with localized disease at diagnosis identified coexpression of IHH and PTCH1 exclusively in large tumors. Higher levels of IHH were observed more frequently in males and patients with higher levels of GLI1 were more responsive to chemotherapy. Subgroup analysis by tumor size and IHH expression indicated that the well-known association between survival and tumor size was further refined when IHH levels were taken into consideration.
[Show abstract][Hide abstract] ABSTRACT: The operative treatment of soft tissue sarcomas (STS) requires extensive planning involving a multidisciplinary approach. The diagnosis is established through imaging and subsequent biopsy, which must be performed without contaminating surrounding tissues in ways that might complicate the definitive resection. Many factors related to both the patient and the sarcoma must be carefully evaluated to determine the most appropriate form of adjuvant treatment and the feasibility of limb salvage. Finally, patients should be counseled preoperatively regarding functional expectations. This chapter discusses the techniques and considerations that are essential to optimizing both oncologic outcome and patient satisfaction in the management of STS.
[Show abstract][Hide abstract] ABSTRACT: Context.-Histologic grade is one of the best predictors of outcome in adult soft tissue sarcomas. Current grading systems were validated on resection specimens; however, there has been a trend toward the use of biopsies to diagnosis these tumors. Objectives.-To determine whether the grade of an extremity soft tissue sarcoma determined on tissue obtained by either core needle biopsy or incisional biopsy is predictive of metastasis- or disease-free survival, and whether either sampling modality is superior. Design.-One hundred three core needle biopsies and 107 incisional biopsies of nonmetastatic spindle cell sarcomas of the extremities were retrieved from the archives. All cases had a minimum 2-year follow-up. Patient data and outcome and tumor characteristics were recorded. Tumors were reviewed and evaluated using the French Federation of Cancer Centers Sarcoma Group grading system. Kaplan-Meier survival curves were generated to correlate tumor grade with metastasis- and disease-free survival for both groups. Results.-Patient and tumor characteristics were similar between groups except that more tumors were grade 3 and superficial in the incisional biopsy group. Grade determined on core needle biopsy was not predictive of either metastasis-free survival (P = .59) or disease-free survival (P = .50). In contrast, grade determined on incisional biopsy was predictive of both metastasis-free survival (P < .001) and disease-free survival (P = .001). Conclusions.-Biopsy, particularly core needle biopsy, represents a convenient diagnostic tool, particularly in the context of neoadjuvant therapy. However, based on these results incisional biopsy is recommended if grading is to be used to predict prognosis in spindle cell soft tissue sarcomas of the extremities.
Archives of pathology & laboratory medicine 12/2013; 137(12):1774-1779. · 2.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE
The aim of this study was to assess the utility of MRI in identifying the presence of residual disease in incompletely excised soft tissue sarcomas.
METHOD AND MATERIALS
Following IRB approval, 315 consecutive cases of incomplete excision of soft tissue sarcoma were identified from a surgical database. 237 patients with a positive margin at initial surgery who underwent MRI prior to re-excision were included. Two MSK radiologists, blinded to the final pathological finding at re-operation reviewed all MRIs in consensus. Pulse sequences varied but included axial and longitudinal T1 and fat suppressed fluid sensitive images in all cases. Post-gadolinium T1 fat-suppressed images were available in some. Imaging features evaluated included lesion morphology, location, fascial penetration, signal characteristics and enhancement. An overall consensus prediction was made regarding the presence of residual disease. The individual findings and the overall prediction were compared to the final pathology.
There were 98 females and 139 males with an average age of 55 years (range 17-89). The pathological diagnosis was malignant fibrous histocytoma (n=67), leiomyosarcoma (n=47) and liposarcoma (28). The remaining 96 patients had undifferentiated sarcomas or rare subtypes. 120 patients had residual disease, 48 with microscopic foci and 72 with macroscopic foci greater than 10 mm in diameter. 117 patients had no residual disease on pathology. MRI had a sensitivity of 60%, specificity of 91%, PPV of 87% and NPV of 69%. When a mass was present on pathology, MRI had a high sensitivity (88%) and specificity (88%) and a high NPV (94%). There was a poor sensitivity (19%) in detection of microscopic residual disease. 82 lesions had nodular, 40 plaque and 115 reticular morphology. The presence of a nodule had a high specificity (89%) and PPV (84%) but a low sensitivity (58%). Plaque and reticular morphology had low sensitivities and predictive values.
MRI performs poorly in identifying those with microscopic disease but has a better performance in the presence of macroscopic disease. The presence of a nodule is the most specific morphologic predictor of residual disease.
Many soft tissue sarcomas have positive margins at initial surgery. MRI is the modality of choice for re-evaluation. Further investigation of its utility in predicting disease is of value.
Radiological Society of North America 2013 Scientific Assembly and Annual Meeting; 12/2013
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to evaluate the early results of a custom non-fluted diaphyseal press-fit stem for use with the global modular replacement system (GMRS) tumour prosthesis and the early complications associated with this implant.
A total of 53 patients (54 implants) were identified from a prospective database where a custom non-fluted diaphyseal press-fit stem was used as part of the reconstruction of the limb. All patients had a minimum of 22 months of follow-up.
The rates of stem revision for any reason were calculated. The median follow-up was 36 months (range 22-85 months). Aseptic loosening was not observed in any patient.
At early term follow-up, an uncemented non-fluted stem used with the GMRS tumour endoprosthesis provides a stable bone-prosthesis interface with no evidence of aseptic loosening.
International Orthopaedics 09/2013; · 2.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated the clinical outcome of internal fixation for pathological fracture of the femur after primary excision of a soft-tissue sarcoma that had been treated with adjuvant radiotherapy. A review of our database identified 22 radiation-induced fractures of the femur in 22 patients (seven men, 15 women). We noted the mechanism of injury, fracture pattern and any complications after internal fixation, including nonunion, hardware failure, secondary fracture or deep infection. The mean age of the patients at primary excision of the tumour was 58.3 years (39 to 86). The mean time from primary excision to fracture was 73.2 months (2 to 195). The mean follow-up after fracture fixation was 65.9 months (12 to 205). Complications occurred in 19 patients (86%). Nonunion developed in 18 patients (82%), of whom 11 had a radiological nonunion at 12 months, five a nonunion and hardware failure and two an infected nonunion. One patient developed a second radiation-associated fracture of the femur after internal fixation and union of the initial fracture. A total of 13 patients (59%) underwent 24 revision operations. Internal fixation of a pathological fracture of the femur after radiotherapy for a soft-tissue sarcoma has an extremely high rate of complication and requires specialist attention. Cite this article: Bone Joint J 2013;95-B:1144-8.
The bone & joint journal. 08/2013; 95-B(8):1144-1148.
[Show abstract][Hide abstract] ABSTRACT: Neoadjuvant radiotherapy followed by surgical resection and soft tissue reconstruction provides the best possibility of achieving superior limb function in soft tissue sarcomas. The aim of this study was to report our experience of free flap microsurgical reconstruction of recently irradiated soft tissue sarcoma defects.
A retrospective study of microsurgical outcome in consecutively treated extremity and trunk sarcoma patients undergoing free tissue transfer between 2007 and 2012 was conducted from a prospectively collected database. Outcomes in pre-operatively irradiated patients were compared with non-irradiated patients. Demographic data, operative details, limb salvage rate, post-operative including microsurgical complications, and long-term limb function (Toronto Extremity Salvage score, TESS; Musculoskeletal Tumour Society Rating Scale, MSTS) were recorded and analysed for differences between the two study groups.
Forty-six patients underwent 46 free flaps (pre-irradiated n = 32, non-irradiated n = 14) over the study period. Microvascular complications (intra-operative revision, flap re-exploration, flap loss) were uncommon and similar between the two groups (4/32 and 2/14 respectively, p > 0.05). Recipient site wound healing complications (i.e. not flap related) occurred more frequently in pre-irradiated patients (16 events) compared with the control group (2 events, p = 0.03). There was no significant difference in limb salvage rate, or TESS/MSTS functional outcome scores between the two patient groups.
Free tissue transfer is safe and effective in patients undergoing surgical resection and reconstruction following neoadjuvant radiotherapy.
Journal of Plastic Reconstructive & Aesthetic Surgery 07/2013; · 1.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10(-9)) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10(-8) and 2.9 × 10(-7), respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To evaluate MRI imaging appearances of nodular fasciitis in a pathologic-proven series of 29 patients. MATERIALS AND METHODS: Review of the orthopedic oncology and pathology databases yielded 51 cases of histologically proven nodular fasciitis. MR imaging was available in 29 patients. Three musculoskeletal radiologists retrospectively reviewed all cases in consensus. Imaging features evaluated included location in the body, size, compartmental localization, relationship to fascia, signal characteristics, enhancement pattern, transcompartmental extension, and osseous and intra-articular involvement. RESULTS: There were 15 male and 14 female patients. Mean age was 33 years (range, 16-59 years). Lesions ranged in size from 1.6 to 9 cm with 84 % of lesions measuring less than 4 cm. Twenty-three lesions were located in the upper arm or shoulder girdle. Nine lesions were subcutaneous in location, nine were intra-muscular, and 11 were inter-muscular. Lesions were consistently ovoid in shape with broad fascial contact. They exhibited internal homogenous low T1 and heterogeneous intermediate T2 signal with surrounding edema and slightly inhomogeneous enhancement. Twelve lesions exhibited central non-enhancing areas. Trans-compartmental spread was demonstrated in nine lesions. Osseous changes were seen in five cases and included extrinsic cortical saucerization, medullary edema, and transcortical osseous invasion. Two lesions demonstrated intra-articular extension. CONCLUSIONS: MR imaging features of nodular fasciitis are generally non-specific and can be mistaken for a soft tissue sarcoma. This series, the largest MRI series of musculoskeletal cases in the literature, confirms the predilection of nodular fasciitis for the upper extremity in young adults but also demonstrates that aggressive imaging features such as transcompartmental spread, and osseous and intra-articular involvement may be seen in association with this benign soft tissue lesion.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Wrist arthrodesis after resection of a giant cell tumor of the distal radius can be performed using a vascularized free fibular transfer (VFFT) or a nonvascularized structural iliac crest transfer (NICT). The purpose of this study was to compare the union times, functional outcomes, and complications after these procedures. METHODS: We identified 27 patients at 2 centers: 14 underwent VFFT, and 13 NICT. The 2 groups were comparable for age, sex, and tumor grade. We assessed functional outcomes of the wrist with the Toronto Extremity Salvage Score, Musculoskeletal Tumor Society 1987 and 1993 scores, and Disabilities of the Arm, Shoulder, and Hand scores. RESULTS: Two local recurrences occurred in the VFFT group and 1 in the NICT group. The VFFT group had 3 patients who had already undergone or were planning to undergo surgery for improved appearance, hardware removal, or tendon release. In the NICT group, 2 infections required debridement, 1 of which went on to free fibular transfer, but there were no reoperations for nonunion or donor site morbidity. The surgical time was significantly shorter for NICT. Functional scores showed no differences between groups on any of the parameters studied for the upper limb. CONCLUSIONS: Both VFFT and NICT were effective surgical techniques for wrist fusion after distal radial resection for giant cell tumor. Vascularized free fibular transfer should be considered when a major skin defect is anticipated, because it allows the inclusion of a vascularized skin paddle, or when the osseous defect is too long (> 10 cm) for NICT. We were unable to demonstrate a difference in upper limb functional scores between VFFT and NICT. Because the surgical time is significantly shorter and reoperation rate is lower for NICT, we recommend NICT whenever possible. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.
The Journal of hand surgery 02/2013; · 1.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Upper limb preservation after soft tissue sarcoma resection often requires flap reconstruction. The aim of this study was to compare pre- and post-operative upper limb function following shoulder, elbow or wrist/hand sarcoma resection and soft tissue reconstruction with a pedicled or free flap. PATIENTS: Between 1989 and 2008, 113 patients underwent resection of an upper limb soft tissue sarcoma and required flap reconstruction. Perioperative morbidity, mortality and flap loss were studied. Functional outcome was assessed pre and postoperatively using the Toronto Extremity Salvage Score (TESS), a measure of disability, and the Musculoskeletal Tumour Society Rating Scale (MSTS), a measure of impairment. Statistical analyses were performed to evaluate the relationship between flap type and functional outcome scores. RESULTS: Patients underwent soft tissue sarcoma excision in the shoulder (n = 64), elbow (n = 27) or wrist/hand (n = 22) region with soft tissue reconstruction using either a pedicled (n = 76) or free flap (n = 37). Comparison of the post-operative MSTS (n = 88) and TESS (n = 84) revealed no significant differences between the free and pedicled flap groups. A significant pre- to post-operative difference was identified in MSTS 87 scores for patients in both the pedicled (p < 0.02) and free flap groups (p < 0.04). Comparison of the pre- and post-operative MSTS 93 scores also revealed a significant difference (p < 0.01) but this was limited to the free flap group. The most notable post-operative score reductions in these patients were due to major joint, nerve, tendon or muscle group resection. CONCLUSION: Reconstruction of the soft tissue defect following sarcoma resection in the upper limb maintains a similar satisfactory level of upper limb activity with either pedicled or free flap reconstructions. Based on TESS scores, patients rated themselves as having better function compared to impairment measures such as MSTS.
Journal of Plastic Reconstructive & Aesthetic Surgery 02/2013; · 1.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ewing's sarcoma is a relatively rare malignancy, occurring mainly between 4 and 25 years of age. It usually arises from the pelvis, followed by the femur, tibia, and remainder of both the long bones of the extremities and flat bones of the axial skeleton. To the best of our knowledge, Ewing's sarcoma of the patella has never been reported previously. Patellar tumors occur infrequently and represent an uncommon etiology of anterior knee pain. We describe the rare case of a 41-year-old man who presented with a 3-4 month history of escalating right anterior knee pain and swelling. Imaging demonstrated an aggressive patellar tumor with an adjacent soft tissue mass. The diagnosis of Ewing's sarcoma was confirmed by pathology. Physicians should be aware of atypical locations for Ewing's sarcoma and, conversely, of rare tumors arising in the patella and accounting for anterior knee pain. Early recognition of such malignancies allows prompt initiation of treatment, hence improving prognosis.