Edwin Choy

Massachusetts General Hospital, Boston, Massachusetts, United States

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Publications (59)290.66 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND Histologic response to chemotherapy has been shown to be an independent prognostic factor in patients with osteosarcoma and Ewing sarcoma. However, in patients with soft tissue sarcoma (STS), the prognostic impact of histologic response to chemotherapy is less clear. In the current study, the authors sought to determine the prognostic significance of treatment-induced pathologic necrosis in patients receiving neoadjuvant chemoradiotherapy for STS.METHODS Between 1989 and 2011, a total of 113 patients with grade 2 or 3 (graded according to the National Cancer Institute grading system using 3 tiers) extremity or truncal STS were identified who received neoadjuvant interdigitated chemoradiotherapy according to protocol followed by surgery. The extent of tumor necrosis in the resected specimens was quantified and correlated with outcome.RESULTSThe median tumor necrosis rate was 90%, and 103 patients (91%) received all 3 cycles of planned neoadjuvant chemotherapy. The likelihood of achieving ≥95% necrosis was not related to the number of preoperative cycles of chemotherapy received but was found to be related to tumor histology (62% for malignant fibrous histiocytoma vs 0% for synovial sarcoma [P<.001]; 56% for myxoid liposarcoma vs 0% for synovial sarcoma [P = .002]). At a median follow-up of 6 years, there were no statistically significant differences noted in the 5-year local control, disease-specific survival, and overall survival rates for patients with ≥95% necrosis (50 patients; 44%) and <95% necrosis (63 patients; 56%), even when stratifying by histology.CONCLUSIONS In a homogeneous population of patients with high-grade extremity and truncal STS who were treated with neoadjuvant chemoradiotherapy, the extent of pathologic tumor necrosis did not correlate with outcome. Cancer 2014. © 2014 American Cancer Society.
    Cancer 07/2014; · 5.20 Impact Factor
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    ABSTRACT: Background:The major limitation to the success of chemotherapy in osteosarcoma is the development of multidrug resistance (MDR). Preventing the emergence of MDR during chemotherapy treatment has been a high priority of clinical and investigational oncology, but it remains an elusive goal. The NSC23925 has recently been identified as a novel and potent MDR reversal agent. However, whether NSC23925 can prevent the development of MDR in cancer is unknown. Therefore, this study aims to evaluate the effects of NSC23925 on prevention of the development of MDR in osteosarcoma.Methods:Human osteosarcoma cell lines U-2OS and Saos were exposed to increasing concentrations of paclitaxel alone or in combination with NSC23925 for 6 months. Cell sublines selected at different time points were evaluated for their drug sensitivity, drug transporter P-glycoprotein (Pgp) expression and activity.Results:We observed that tumour cells selected with increasing concentrations of paclitaxel alone developed MDR with resistance to paclitaxel and other Pgp substrates, whereas cells cultured with paclitaxel-NSC23925 did not develop MDR and cells remained sensitive to chemotherapeutic agents. Paclitaxel-resistant cells showed high expression and activity of the Pgp, whereas paclitaxel-NSC23925-treated cells did not express Pgp. No changes in IC50 and Pgp expression and activity were observed in cells grown with the NSC23925 alone.Conclusions:Our findings suggest that NSC23925 may prevent the development of MDR by specifically preventing the overexpression of Pgp. Given the significant incidence of MDR in osteosarcoma and the lack of effective agents for prevention of MDR, NSC23925 and derivatives hold the potential to improve the outcome of cancer patients with poor prognosis due to drug resistance.British Journal of Cancer advance online publication, 22 May 2014; doi:10.1038/bjc.2014.254 www.bjcancer.com.
    British journal of cancer. 05/2014;
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    ABSTRACT: Programmed cell death ligand 1 (PDL1, also known as B7H1) is a cell-surface protein that suppresses the cytotoxic CD8(+) T-cell-mediated immune response. PDL1 expression and its clinical relevance in sarcomas are not well understood. Therefore, we sought to measure RNA expression levels for PDL1 in 38 clinically annotated osteosarcoma tumor samples and aimed to determine if PDL1 expression correlates with clinical features and tumor-infiltrating lymphocytes (TIL). Quantitative real-time RT-PCR for PDL1 was optimized in 18 cell lines, of which 5 were osteosarcoma derived. qRT-PCR results were validated via flow cytometry and immunohistochemistry (IHC) in select cell lines. Total RNA was isolated from 38 human osteosarcoma samples for qRT-PCR analysis. Clinical data were sorted, and significance was determined by the Student t test. TILs were examined in patient samples by tissue microarray hematoxylin-eosin staining. We confirmed the constitutive PDL1 mRNA expression in cell lines by qRT-PCR, flow cytometry, and IHC. Across human osteosarcoma samples, PDL1 mRNA gene expression ranged over 4 log (>5,000-fold difference). Relative expression levels were evaluated against clinical factors such as age/gender, metastasis, recurrence, chemotherapy, percentage of necrosis, and survival; no significant associations were identified. The presence of TILs was associated with high PDL1 expression (R(2) = 0.37; P = 0.01). In summary, we developed an RNA-based assay to determine PDL1 expression levels, and we show, for the first time, that high levels of PDL1 are expressed in a subset of osteosarcoma, and PDL1 expression is positively correlated with TILs. Multiple agents targeting PD1/PDL1 are in clinical development, and this may be a novel immunotherapeutic strategy for osteosarcoma clinical trials. Cancer Immunol Res; 2(7); 1-9. ©2014 AACR.
    Cancer immunology research. 04/2014;
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    ABSTRACT: Reliable prognostic biomarkers for chordoma have not yet been established. Recent studies revealed that expression of miRNA-1 (miR-1) is frequently downregulated in several cancer types including chordoma. The goal of this follow-up study is to investigate the expression of miR-1 as a prognostic biomarker and further confirm the functional role of miR-1 in chordoma cell growth and proliferation. We determined the relative expression levels of miR-1 and Met in chordoma tissue samples and correlated those to clinical variables. The results showed that miR-1 was downregulated in 93.7% of chordoma tissues and expression was inversely correlated with Met expression. miR-1 expression levels also correlated with clinical prognosis. To characterize and confirm the functional role of miR-1 in the growth and proliferation of chordoma cells, miR-1 precursors were stably transfected into chordoma cell lines UCH-1 and CH-22. Cell Proliferation Assay and MTT were used to evaluate cell growth and proliferation. Restoring expression of miR-1 precursor decreased cell growth and proliferation in UCH-1 and CH-22 cells. These results indicate that suppressed miR-1 expression in chordoma may in part be a driver for tumor growth, and that miR-1 has potential to serve as prognostic biomarker and therapeutic target for chordoma patients. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
    Journal of Orthopaedic Research 02/2014; · 2.88 Impact Factor
  • Edwin Choy, Ira Allen Jacobs
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    ABSTRACT: Biologics are important treatments for a number of cancers. Patents for several biologics will expire over the next decade, removing a barrier to the development and commercialization of biosimilars. As biologics differ from small-molecule drugs due to their size and complexity, multifaceted manufacturing process, and their potential for immunogenicity, biosimilars cannot be considered "generic versions" of currently approved biologics. In highly regulated markets, biosimilars can be authorized only if they are demonstrated to be highly similar to the original drug from an analytical and clinical perspective. Any differences must be justified and shown to have no clinically meaningful effect on the safety and efficacy of the biosimilar. The European Medicines Agency has approved a number of biosimilars and the recent approval of the biosimilar infliximab monoclonal antibody is another regulatory milestone. This article will provide context regarding key safety issues addressed in biosimilar development, approval, and delivery, as well as inform oncologists on matters of safety to consider when prescribing biosimilars. Pertinent issues about safety from countries or regions where biosimilars are currently in use also will be reviewed.
    Seminars in Oncology 02/2014; 41 Suppl 1:S3-S14. · 4.33 Impact Factor
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    ABSTRACT: To compare performance of various tumour response criteria (TRCs) in assessment of regorafenib activity in patients with advanced gastrointestinal stromal tumour (GIST) with prior failure of imatinib and sunitinib. Twenty participants in a phase II trial received oral regorafenib (median duration 47weeks; interquartile range (IQR) 24-88) with computed tomography (CT) imaging at baseline and every two months thereafter. Tumour response was prospectively determined on using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, and retrospectively reassessed for comparison per RECIST 1.0, World Health Organization (WHO) and Choi criteria, using the same target lesions. Clinical benefit rate [CBR; complete or partial response (CR or PR) or stable disease (SD)⩾16weeks] and progression-free survival (PFS) were compared between various TRCs using kappa statistics. Performance of TRCs in predicting overall survival (OS) was compared by comparing OS in groups with progression-free intervals less than or greater than 20weeks by each TRC using c-statistics. PR was more frequent by Choi (90%) than RECIST 1.1, RECIST 1.0 and WHO (20% each), however, CBR was similar between various TRCs (overall CBR 85-90%, 95-100% agreement between all TRC pairs). PFS per RECIST 1.0 was similar to RECIST 1.1 (median 44weeks versus 58weeks), and shorter for WHO (median 34weeks) and Choi (median 24weeks). With RECIST 1.1, RECIST 1.0 and WHO, there was moderate concordance between PFS and OS (c-statistics 0.596-0.679). Choi criteria had less favourable concordance (c-statistic 0.506). RECIST 1.1 and WHO performed somewhat better than Choi criteria as TRC for response evaluation in patients with advanced GIST after prior failure on imatinib and sunitinib.
    European journal of cancer (Oxford, England: 1990) 01/2014; · 4.12 Impact Factor
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    ABSTRACT: While liposarcoma is the second most common soft tissue malignant tumor, the molecular pathogenesis in this malignancy is poorly understood. Our goal was therefore to expand the understanding of molecular mechanisms that drive liposarcoma and identify therapeutically-susceptible genetic alterations. We studied a cohort of high-grade liposarcomas and benign lipomas across multiple disease sites, as well as two liposarcoma cell lines, using multiplexed mutational analysis. Nucleic acids extracted from diagnostic patient tissue were simultaneously interrogated for 150 common mutations across 15 essential cancer genes using a clinically-validated platform for cancer genotyping. Western blot analysis was implemented to detect activation of downstream pathways. Liposarcoma cell lines were used to determine the effects of PI3K targeted drug treatment with or without chemotherapy. We identified mutations in the PIK3CA gene in 4 of 18 human liposarcoma patients (22%). No PIK3CA mutations were identified in benign lipomas. Western blot analysis confirmed downstream activation of AKT in both PIK3CA mutant and non-mutant liposarcoma samples. PI-103, a dual PI3K/mTOR inhibitor, effectively inhibited the activation of the PI3K/AKT in liposarcoma cell lines and induced apoptosis. Importantly, combination with PI-103 treatment strongly synergized the growth-inhibitory effects of the chemotherapy drugs doxorubicin and cisplatin in liposarcoma cells. Taken together, these findings suggest that activation of the PI3K/AKT pathway is an important cancer mechanism in liposarcoma. Targeting the PI3K/AKT/pathway with small molecule inhibitors in combination with chemotherapy could be exploited as a novel strategy in the treatment of liposarcoma.
    PLoS ONE 01/2014; 9(4):e93996. · 3.73 Impact Factor
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    ABSTRACT: The molecular mechanisms underlying chordoma pathogenesis are unknown. We therefore sought to identify novel mutations to better understand chordoma biology and to potentially identify therapeutic targets. Given the relatively high costs of whole genome sequencing, we performed a focused genetic analysis using matrix-assisted laser desorption/ionization-time of flight mass spectrometer (Sequenom iPLEX genotyping). We tested 865 hotspot mutations in 111 oncogenes and selected tumor suppressor genes (OncoMap v. 3.0) of 45 human chordoma tumor samples. Of the analyzed samples, seven were identified with at least one mutation. Six of these were from fresh frozen samples, and one was from a paraffin embedded sample. These observations were validated using an independent platform using homogeneous mass extend MALDI-TOF (Sequenom hME Genotyping). These genetic alterations include: ALK (A877S), CTNNB1 (T41A), NRAS (Q61R), PIK3CA (E545K), PTEN (R130), CDKN2A (R58*), and SMARCB1 (R40*). This study reports on the largest comprehensive mutational analysis of chordomas performed to date. To focus on mutations that have the greatest chance of clinical relevance, we tested only oncogenes and tumor suppressor genes that have been previously implicated in the tumorigenesis of more common malignancies. We identified rare genetic changes that may have functional significance to the underlying biology and potential therapeutics for chordomas. Mutations in CDKN2A and PTEN occurred in areas of chromosomal copy loss. When this data is paired with the studies showing 18 of 21 chordoma samples displaying copy loss at the locus for CDKN2A, 17 of 21 chordoma samples displaying copy loss at PTEN, and 3 of 4 chordoma samples displaying deletion at the SMARCB1 locus, we can infer that a loss of heterozygosity at these three loci may play a significant role in chordoma pathogenesis.
    PLoS ONE 01/2014; 9(7):e101283. · 3.73 Impact Factor
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    ABSTRACT: Local recurrence (LR) following limb-sparing surgery and radiation therapy (RT) for extremity soft tissue sarcoma (STS) is rare. The current study investigates the utility of surveillance nuclear magnetic resonance imaging (MRI) for detection of asymptomatic LRs. The study cohort consisted of 168 adult patients with extremity STS treated with limb-sparing surgery and RT with curative intent between October 2001 and January 2011. Follow-up surveillance MRIs and history and physical examinations were performed per the NCCN guidelines with additional MRIs as clinically indicated. The method of LR detection and MRI number and indication were determined. After a median follow-up of 4.7 years (range: 0.6-10.5) 11 (6.5%; 11/168) patients developed LRs. Five hundred two MRIs were obtained, 429 (85.5%; 429/502) for surveillance and 73 (14.5%; 73/502) as clinically indicated. One hundred fourteen patients underwent ≥1 surveillance MRI. The median surveillance MRI interval was 6.4 months (range 1.4-68.9). Surveillance MRI detected an asymptomatic LR in 1 (0.9%; 1/114) patient with a complex reconstruction. Surveillance MRI infrequently detects asymptomatic LRs following limb-sparing surgery and RT for extremity STS and should be limited to patients whose primary tumor sites are not easily assessed by history and physical examination. J. Surg. Oncol. © 2013 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 12/2013; · 2.64 Impact Factor
  • Gregory M Cote, Edwin Choy
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    ABSTRACT: The improvement in outcome for patients with localized and metastatic Ewing sarcoma since the development of cytotoxic chemotherapy remains one of the most profound advances in oncology and one of the proudest achievements of sarcoma researchers. Identification of molecular targets for new treatments has become an intense area within Ewing sarcoma research. The development of improved preclinical Ewing sarcoma models and advanced molecular techniques will build on knowledge of EWS/FLI1 function, EWS/FLI1 transcription targets, and the other critical driver events in these tumors.
    Hematology/oncology clinics of North America 10/2013; 27(5):1007-1019. · 2.05 Impact Factor
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    ABSTRACT: Liposarcoma is the second most common soft tissue sarcoma in adults, but treatment options have been quite limited thus far. In this study, we investigated the functional and therapeutic relevance of cyclin-dependent kinase 11 (CDK11) as a putative target in liposarcoma. CDK11 knockdown by synthetic siRNA or lentiviral shRNA decreased cell proliferation, and induced apoptosis in liposarcoma cells. Moreover, CDK11 knockdown enhances the cytotoxic effect of doxorubicin to inhibit cell growth in liposarcoma cells. These findings suggest that CDK11 is critical for the growth and proliferation of liposarcoma cells. CDK11 may be a promising therapeutic target for the treatment of liposarcoma patients.
    Cancer letters 09/2013; · 4.86 Impact Factor
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    ABSTRACT: Mutations in the gene-encoding β-catenin, CTNNB1, are highly prevalent in sporadic desmoid tumors and may predict the risk for recurrence. We sought to determine the prevalence of CTNNB1 mutations in a large cohort of sporadic desmoid tumors and to determine whether CTNNB1 mutation status correlates with disease outcome. Single-base extension genotyping of the CTNNB1 gene was performed on 145 sporadic, paraffin-embedded desmoid tumor specimens. Correlation of mutation status with outcome was performed on a subset of 115 patients who underwent macroscopically complete surgical resection. CTNNB1 mutations were detected in 106 of 145 (73%) tumor specimens and in 86 of 115 (75%) specimens from patients who underwent curative-intent surgical resection, including discrete mutations in the following codons of CTNNB1 exon 3: T41A (46%), S45F (25%), S45P (1.7%), and S45C (0.9%). Desmoid tumors of the superficial trunk were significantly less likely to harbor CTNNB1 mutations than tumors located elsewhere, but none of the other examined clinicopathologic factors were found to be associated with CTNNB1 mutation status. At a median follow-up of 31 months, 5-year recurrence-free survival was slightly, although not statistically significantly, worse for patients with β-catenin-mutated tumors than for those with wild-type tumors (58% vs. 74%, respectively). The specific CTNNB1 codon mutation did not correlate with the risk for recurrence. CTNNB1 mutations are indeed common in sporadic desmoid tumors. However, our study did not detect a statistically significant difference in recurrence risk according to either the CTNNB1 mutation status or the specific CTNNB1 mutation.
    The Oncologist 08/2013; · 4.10 Impact Factor
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    ABSTRACT: Giant cell tumour of bone (GCTB) is a very rare, aggressive, and progressive osteolytic tumour for which no standard medicinal treatment or chemotherapy exists. We report interim safety and efficacy results from a phase 2 study of denosumab in patients with GCTB. We did an international, open-label, parallel-group, phase 2 trial of patients with histologically confirmed GCTB and radiographically measurable active disease. Eligible patients were adults or skeletally mature adolescents with radiographic evidence of at least one mature long bone who were at least 12 years old and weighed at least 45 kg. We divided patients into three cohorts-those with surgically unsalvageable GCTB (cohort 1), those with salvageable GCTB whose surgery was associated with severe morbidity (cohort 2), and those who transferred from a previous study of denosumab for GCTB (cohort 3). Patients in cohorts 1 and 2 received 120 mg of subcutaneous denosumab every 4 weeks with loading doses on days 8 and 15 of the first cycle; those in cohort 3 continued the regimen from the previous study. Investigator-determined disease status and clinical benefit were assessed every 4 weeks. Our primary endpoint was the safety profile of denosumab in terms of adverse events and laboratory abnormalities. Prespecified secondary endpoints were time to disease progression in cohort 1 and the proportion of patients without any surgery at 6 months in cohort 2. Safety analyses included all patients who received at least one dose of denosumab. Efficacy analyses included all eligible patients who received at least one dose of denosumab. This study is registered with ClinicalTrials.gov, identifier NCT00680992. 282 patients, including ten adolescents, were included between Sept 9, 2008, and March 25, 2011. Of the 281 patients analysable for safety, three (1%) had osteonecrosis of the jaw and 15 (5%) hypocalcaemia. The most common grade 3-4 adverse events were hypophosphataemia, which occurred in nine (3%) patients, and anaemia, back pain, and pain in extremities, each of which occurred in three patients (1%). Serious adverse events were reported in 25 (9%) patients. No treatment-related deaths were reported. On the basis of investigators' assessment of disease status, 163 of 169 (96%) analysable patients in cohort 1 had no disease progression after median follow-up of 13 months (IQR 5·8-21·0). In cohort 2, 74 of 100 (74%) analysable patients had no surgery and 16 of 26 (62%) patients who had surgery underwent a less morbid procedure than planned. Median follow-up in cohort 2 was 9·2 months (IQR 4·2-12·9). Adverse events were consistent with the known safety profile of denosumab. Denosumab was associated with tumour responses and reduced the need for morbid surgery in patients with GCTB. Denosumab represents a new treatment option for patients with GCTB. Amgen.
    The Lancet Oncology 07/2013; · 25.12 Impact Factor
  • Gregory M Cote, Edwin Choy
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    ABSTRACT: OPINION STATEMENT: Sarcoma is a disease that includes many different subtypes that can present with a wide range of differing clinical findings, prognosis, and treatment options. For certain subsets (e.g., Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, gastrointestinal stromal tumor [GIST]), extensive clinical trials have delineated effective treatment regimens often involving combination therapy, including surgery, radiation, systemic chemotherapy, and small molecular inhibitors of tyrosine kinases (as in the case of GIST). For nearly all patients with sarcoma who have relapsed or developed metastasis, the therapeutic benefit of chemotherapy has reached a plateau and as such new treatment approaches are needed to move this field forward. We recommend that all patients have the opportunity to participate in clinical trials where available. Recently, in our clinic we have started to increase our use of molecular testing and DNA sequencing studies to help identify potential treatment options for patients. One area of evolving basic and clinical research in sarcomas is the field of epigenetic therapeutics. The enclosed article reviews the basics of epigenetics and highlights some completed and ongoing clinical trials of epigenetic treatments in sarcoma. We anticipate in the future that diagnostic platforms will be developed to help clinicians determine if an epigenetic therapy could be effective for an individual patient with sarcoma.
    Current Treatment Options in Oncology 06/2013; · 2.42 Impact Factor
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    ABSTRACT: Brachyury is a marker for notochord-derived tissues and neoplasms, such as chordoma. However, the prognostic relevance of brachyury expression in chordoma is still unknown. The improvement of tissue microarray technology has provided the opportunity to perform analyses of tumor tissues on a large scale in a uniform and consistent manner. This study was designed with the use of tissue microarray to determine the expression of brachyury. Brachyury expression in chordoma tissues from 78 chordoma patients was analyzed by immunohistochemical staining of tissue microarray. The clinicopathologic parameters, including gender, age, location of tumor and metastatic status were evaluated. Fifty-nine of 78 (75.64%) tumors showed nuclear staining for brachyury, and among them, 29 tumors (49.15%) showed 1+ (<30% positive cells) staining, 15 tumors (25.42%) had 2+ (31% to 60% positive cells) staining, and 15 tumors (25.42%) demonstrated 3+ (61% to 100% positive cells) staining. Brachyury nuclear staining was detected more frequently in sacral chordomas than in chordomas of the mobile spine. However, there was no significant relationship between brachyury expression and other clinical variables. By Kaplan-Meier analysis, brachyury expression failed to produce any significant relationship with the overall survival rate. In conclusion, brachyury expression is not a prognostic indicator in chordoma.
    PLoS ONE 01/2013; 8(9):e75851. · 3.73 Impact Factor
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    ABSTRACT: BACKGROUND: Patients with large, high-grade extremity and truncal soft tissue sarcomas (STS) are at considerable risk for recurrence. A regimen of pre-operative chemotherapy consisting of mesna, adriamycin, ifosfamide and dacarbazine (MAID), interdigitated with radiotherapy (RT), followed by resection and post-operative chemotherapy with or without RT, has demonstrated high rates of local and distant control. The goal of this study is to assess outcomes in a recent cohort of patients treated on this regimen. METHODS: We retrospectively reviewed records of 66 consecutive patients with STS of the extremity or trunk who were treated with the aforementioned regimen from May 2000 to April 2011. Clinicopathologic characteristics and patient outcomes were analysed. RESULTS: Sixty-six patients were analysed and were equally divided between grade 2 and 3 tumours. Margins were negative in 57 (89%) patients and positive in seven (11%) patients. At a median follow-up of 46months, there were six (9%) locoregional and 20 (30%) distant recurrences. The locoregional and distant 5-year recurrence-free survival (RFS) rates were 91% and 64%, respectively. The 5-year overall (OS) and disease-specific survival rates were 86% and 89%, respectively. There were no treatment-related deaths or secondary myelodysplasias. Thirty-four (52%) patients had grade 3 or 4 acute haematologic chemotherapy-related toxicity. There were no statistically significant predictors of OS or RFS. CONCLUSIONS: For a contemporary cohort of patients with high-risk extremity and truncal STS, a regimen of neoadjuvant chemoradiotherapy and surgery continues to result in high rates of survival with tolerable short- and long-term toxicity.
    European journal of cancer (Oxford, England: 1990) 10/2012; · 4.12 Impact Factor
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    ABSTRACT: Osteosarcoma is the most common primary malignant tumor of bone. Patients with localized osteosarcoma are routinely treated with chemotherapy and surgery. However, many of these patients eventually relapse after these treatments. In such cases, there are limited treatment options for these patients and most will eventually die with metastatic disease. Therefore, it is imperative to identify better therapeutic strategies. Hedgehog-GLI is responsible for the development of vertebrate embryonic and tumorigenesis. Specifically, the transcription factor, GLI-2, plays a key role in development of normal prostate. Aberrant activation of GLI-2 is correlated with various malignancies. We observe that GLI-2 is highly expressed in osteosarcoma cell lines, and this correlates with poor clinical outcomes in patients. Knockdown of GLI-2 by siRNA decreases osteosarcoma cell proliferation and viability, which eventually induces cell death as revealed in both in 2D and 3D cultures. In addition, we notice that administration of GLI-2 siRNA can increase the sensitivity of osteosarcoma cells to chemotherapeutic drugs. These findings suggest GLI-2 is required for osteosarcoma cell proliferation and survival. GLI-2 may be exploited as a therapeutic target for the treatment of osteosarcoma patients. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
    Journal of Orthopaedic Research 09/2012; · 2.88 Impact Factor
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    ABSTRACT: BACKGROUND: Desmoid tumors are rare and exhibit a highly unpredictable natural history. We sought to analyze prognostic factors associated with recurrence in a large single-institution study of patients with desmoid tumors. METHODS: We performed a retrospective review of 177 patients with desmoid tumor who underwent macroscopically complete surgical resection, with or without the addition of radiotherapy (RT) or systemic therapy, from 1970 to 2009. We examined patterns of presentation, all known risk factors for recurrence, and their association with recurrence-free survival (RFS). RESULTS: Twenty-two patients (12 %) had intra-abdominal desmoid tumors, and 155 (88 %) had extra-abdominal tumors. Patterns of presentation included primary (n = 133, 75 %) and locally recurrent (n = 44, 25 %) disease. Treatment was surgery alone in 125 patients (71 %), surgery and RT in 36 (20 %), and surgery and systemic therapy with or without RT in 20 (11 %). Median follow-up was 40 months. Overall, the local relapse rate was 29 %, and 10-year RFS was 60 %. R0 resection status was the only predictor of freedom from local recurrence on multivariate analysis (odds ratio 0.32; 95 % confidence interval 0.15-0.66; P = 0.002). The selective use of adjuvant RT appeared to improve local control in patients with positive margins. CONCLUSIONS: For patients with desmoid tumors undergoing surgery, wide excision with negative margins should be the goal, but not at the expense of function, as fewer than half of patients with positive margins will experience recurrence.
    Annals of Surgical Oncology 09/2012; · 4.12 Impact Factor
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    ABSTRACT: Identification of new targeted therapies is critical to improving the survival rate of patients with osteosarcoma. The goal of this study is to identify kinase based potential therapeutic target in osteosarcomas. We used a lentiviral-based shRNA kinase library to screen for kinases which play a role in osteosarcoma cell survival. The cell proliferation assay was used to evaluate cell growth and survival. siRNA assays were applied to confirm the observed phenotypic changes resulting from the loss of kinase gene expression. CDK11 (PITSLRE) was identified as essential for the survival of osteosarcoma cells, and its expression was confirmed by Western blot analysis and immunohistochemistry. Overall patient survival was correlated with the CDK11 expression and its prognosis. The role of CDK11 expression in sustaining osteosarcoma growth was further evaluated in an osteosarcoma xenograft model in vivo. Osteosarcoma cells display high levels of CDK11 expression. CDK11 expression knocked down by either lentiviral shRNA or siRNA inhibit cell growth and induce apoptosis in osteosarcoma cells. Immunohistochemical analysis showed that patients with osteosarcoma with high CDK11 tumor expression levels were associated with significantly shorter survival than patients with osteosarcoma with low level of tumor CDK11 expression. Systemic in vivo administration of in vivo ready siRNA of CDK11 reduced the tumor growth in an osteosarcoma subcutaneous xenograft model. We show that CDK11 signaling is essential in osteosarcoma cell growth and survival, further elucidating the regulatory mechanisms controlling the expression of CDK11 and ultimately develop a CDK11 inhibitor that may provide therapeutic benefit against osteosarcoma.
    Clinical Cancer Research 07/2012; 18(17):4580-8. · 7.84 Impact Factor
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    ABSTRACT: Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary end point was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] ≥ 16 weeks). Serial tumor biopsies were obtained from consenting patients whenever possible. From February to December 2010, 34 patients were enrolled at four US centers. As of July 28, 2011, 33 patients had received at least two cycles of regorafenib (range, two to 17 cycles). CBR was 79% (95% CI, 61% to 91%). Four patients achieved PR, and 22 exhibited SD ≥ 16 weeks. Median progression-free survival was 10.0 months. The most common grade 3 toxicities were hypertension and hand-foot-skin reaction. Regorafenib has significant activity in patients with advanced GIST after failure of both imatinib and sunitinib. A phase III trial of regorafenib versus placebo is ongoing to define more fully the safety and efficacy of regorafenib in this setting.
    Journal of Clinical Oncology 05/2012; 30(19):2401-7. · 18.04 Impact Factor

Publication Stats

486 Citations
290.66 Total Impact Points

Institutions

  • 2008–2014
    • Massachusetts General Hospital
      • • Center for Sarcoma and Connective Tissue Oncology
      • • Department of Orthopaedic Surgery
      Boston, Massachusetts, United States
  • 2013
    • Partners HealthCare
      Boston, Massachusetts, United States
  • 2010–2013
    • Harvard Medical School
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
  • 2011–2012
    • Huazhong University of Science and Technology
      Wu-han-shih, Hubei, China