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IMPORTANCE Dermatofibrosarcoma protuberans (DFSP) has the potential for local destruction and recurrence, although it carries a low risk of metastasis. Complete surgical resection with negative margins is considered the gold standard for treatment; however, there are cases that are unresectable owing to tumor extension or size or owing to risk of cosmetic and/or functional impairment. Imatinib treatment has been used for locally advanced or metastatic DFSP.OBJECTIVE To evaluate the usefulness of imatinib for treating DFSP. EVIDENCE REVIEWWe conducted a systematic review on the PubMed and Embase databases for articles published from September 2002 through October 2017 using the key words "dermatofibrosarcoma" or "dermatofibrosarcoma protuberans" AND "therapy" AND "imatinib." References within retrieved articles were also reviewed to identify additional studies. Studies of adults with histologically proven DFSP treated with imatinib as monotherapy or as an adjuvant or neoadjuvant therapy to surgery were included. Extracted data were analyzed using descriptive statistics. PRISMA guidelines were followed. All analysis took place October through December 2017.FINDINGS Nine studies met inclusion criteria; 152 patients were included. The calculated mean patient age was 49.3 years (range, 20-73 years). Calculated mean tumor diameter was 9.9 cm (range, 1.2-49.0 cm). When COL1A1-PDGFβ protein translocation (collagen, type 1, alpha 1-platelet-derived growth factor β) was reported, it was present in 90.9% of patients (111 of 122). Complete response was seen in 5.2% of patients (8 of 152), partial response in 55.2% (84 of 152), stable disease in 27.6% (42 of 152), and progression in 9.2% (14 of 152). Four of the 152 patients (2.6%) were excluded from the analysis owing to unknown or unevaluable response. There were no differences in response rate using 400-mg or 800-mg daily doses (67.5% or 27 of 40 patients for 400-mg dose vs 67.1% or 49 of 73 patients for 800-mg dose complete or partial response; P > .99). Adverse events were present in at least 73.5% of cases (78 of 106); severe adverse events were present in 15.1% of cases (20 of 132). CONCLUSIONS AND RELEVANCEImatinib is a useful directed therapy in patients with DFSP who are not surgical candidates owing to disease extension or significant cosmetic or functional impairment. There seems to be no difference between 400-or 800-mg daily doses.
IMPORTANCE Dermatofibrosarcoma protuberans (DFSP) has the potential for local destruction and recurrence, although it carries a low risk of metastasis. Complete surgical resection with negative margins is considered the gold standard for treatment; however, there are cases that are unresectable owing to tumor extension or size or owing to risk of cosmetic and/or functional impairment. Imatinib treatment has been used for locally advanced or metastatic DFSP.OBJECTIVE To evaluate the usefulness of imatinib for treating DFSP. EVIDENCE REVIEWWe conducted a systematic review on the PubMed and Embase databases for articles published from September 2002 through October 2017 using the key words "dermatofibrosarcoma" or "dermatofibrosarcoma protuberans" AND "therapy" AND "imatinib." References within retrieved articles were also reviewed to identify additional studies. Studies of adults with histologically proven DFSP treated with imatinib as monotherapy or as an adjuvant or neoadjuvant therapy to surgery were included. Extracted data were analyzed using descriptive statistics. PRISMA guidelines were followed. All analysis took place October through December 2017.FINDINGS Nine studies met inclusion criteria; 152 patients were included. The calculated mean patient age was 49.3 years (range, 20-73 years). Calculated mean tumor diameter was 9.9 cm (range, 1.2-49.0 cm). When COL1A1-PDGFβ protein translocation (collagen, type 1, alpha 1-platelet-derived growth factor β) was reported, it was present in 90.9% of patients (111 of 122). Complete response was seen in 5.2% of patients (8 of 152), partial response in 55.2% (84 of 152), stable disease in 27.6% (42 of 152), and progression in 9.2% (14 of 152). Four of the 152 patients (2.6%) were excluded from the analysis owing to unknown or unevaluable response. There were no differences in response rate using 400-mg or 800-mg daily doses (67.5% or 27 of 40 patients for 400-mg dose vs 67.1% or 49 of 73 patients for 800-mg dose complete or partial response; P > .99). Adverse events were present in at least 73.5% of cases (78 of 106); severe adverse events were present in 15.1% of cases (20 of 132). CONCLUSIONS AND RELEVANCEImatinib is a useful directed therapy in patients with DFSP who are not surgical candidates owing to disease extension or significant cosmetic or functional impairment. There seems to be no difference between 400-or 800-mg daily doses.
IMPORTANCE Local failure after chemoradiotherapy (CT-RT) significantly contributes to mortality in patients with locally advanced non-small cell lung cancer (LA-NSCLC). One approach to improve local control is through targeted radiosensitization of the tumor. OBJECTIVE To evaluate the dose-limiting toxic effects, maximally tolerated dose, and recommended phase 2 dose of the protease inhibitor nelfinavir mesylate, administered concurrently with CT-RT in patients with LA-NSCLC, and, in the phase 2 portion of the study, to estimate the objective response rate, local and distant failure rates, and overall survival. DESIGN, SETTING, AND PARTICIPANTS This prospective, open-label, single-group, single-institution phase 1/2 trial tested the oral protease inhibitor nelfinavir in combination with concurrent CT-RT in 35 patients aged 18 to 89 years with biopsy-confirmed unresectable stage IIIA/IIIB LA-NSCLC and a minimum Karnofsky performance status from June 29, 2007, to February 22, 2012, with an analysis date of May 9, 2017. Median follow-up for all patients was 6.8 years, with a minimum 5 years of follow-up for all survivors. INTERVENTIONS Oral nelfinavir mesylate, 625 mg, twice daily or 1250 mg, twice daily was administered for 7 to 14 days before and during concurrent CT-RT. MAIN OUTCOMES AND MEASURES Graded toxic effects, overall survival, local failure, distant failure, objective response rate, and progression-free survival as measured by Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS Thirty-five patients (16 women and 19 men; median age, 60 years [range, 39-79 years]) enrolled and met protocol-specified criteria for adherence, with 5 at a dose of 625 mg twice daily and 30 at a dose of 1250 mg twice daily. No dose-limiting toxic effects were observed. No grade 4 or higher nonhematologic toxic effects were observed. Thirty-three of the 35 patients had evaluable posttreatment computed tomographic scans, with an objective response rate of 94% (31 of 33; 95% CI, 86%-100%). The cumulative incidence of local failure was 39% (95% CI, 30.5%-47.5%). Median progression-free survival was 11.7 months (95% CI, 6.2-17.1 months). Median overall survival for all patients was 41.1 months (95% CI, 19.0-63.1 months); the 5-year mean (SE) overall survival rate was 37.1% (8.2%). CONCLUSIONS AND RELEVANCE This study suggests that nelfinavir administered with concurrent CT-RT is associated with acceptable toxic effects and a promising objective response rate, local failure, progression-free survival, and overall survival in unresectable LA-NSCLC. These data suggest that nelfinavir may enhance the efficacy of standard CT-RT in this disease. Additional testing in the randomized phase 3 setting should be conducted to establish the improvement associated with nelfinavir with concurrent CT-RT. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00589056
Cell cycle progression in mammals is strictly controlled by a number of cyclin-dependent kinases (CDKs) and CDK inhibitors (CKIs), the expression of which is often dysregulated in cancer cells. Our previous work revealed that Cullin 4B (CUL4B), a critical component of the Cullin4B-RING E3 ligase complex (CRL4B), is overexpressed in human osteosarcoma cells through an unknown mechanism. Here, we demonstrated that CUL4B forms an E3 ligase with RBX1 (RING-box 1), DDB1 (DNA damage binding protein 1), and DCAF11 (DDB1 and CUL4 associated factor 11) in human osteosarcoma cells. In vitro and in vivo ubiquitination analyses indicated that CRL4BDCAF11 E3 ligase was able to specifically ubiquitinate a CDK inhibitor—p21Cip1 at K16, K154, K161 and K163 but not at K75 and K141. Knocking down any component of the CRL4BDCAF11 complex, including CUL4B, DDB1 or DCAF11, using short hairpin RNAs (shRNAs) attenuated the ubiquitination level of p21Cip1, inhibited osteosarcoma cell proliferation, led to cell cycle arrest at S phase, and decreased colony formation rate. Taken together, our data suggest that the CRL4BDCAF11 complex represents a unique E3 ligase that promotes the ubiquitination of p21Cip1 and regulates cell cycle progression in human osteosarcoma cells.
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