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PDF file, 227K, SFT xenotransplanted in SCID mice pathologic evaluation before and after treatment. A and B Pre-treatment samples: high-grade sarcoma aspects mixed with cartilaginous (A) and osseous component (B). C and D Post-sunitinib, post-bevacizumab and post-pazopanib samples. 120 days after the end of treatment with sunitinib (C), bevacizumab (D) xenografts were sacrificed. The tumor samples were all made of hypercellular viable, mainly spindle tumor cells, intermingled with osteoid matrix. Pazopanib (E) xenograft was instead sacrificed soon after treatment end, Even in this case tumor sample appeared to be completely vital.

Purpose: To explore the value of triazines in solitary fibrous tumor (SFT).Experimental Design: We retrospectively reviewed 8 cases of patients with SFT treated with dacarbazine (1,200 mg/m2 every 3 weeks) as from January 2012. Then, we studied a dedifferentiated-SFT subcutaneously xenotransplanted into severe combined immunodeficient (SCID) mice. Dacarbazine, temozolomide, sunitinib, bevacizumab, and pazopanib were administered at their reported optimal doses for the mouse model when mean tumor volume (TV) was about 80 mm3; each experimental groups included 6 mice. Drug activity was assessed as tumor volume inhibition percentage (TVI%). Dacarbazine was tested according to two different schedules of administration. One hunded twenty days after treatment interruption, mouse tumor samples were analyzed.Results: Among the eight patients treated with dacarbazine, best response evaluation criteria in solid tumors responses (RECIST) were three partial responses, 4 stable disease, 1 progression. Two responsive patients had paraneoplastic hypoglycemia that disappeared after 10 days from starting dacarbazine. In the dedifferentiated-SFT xenograft model, dacarbazine and temozolomide showed the highest antitumor activity (about 95% TVI), confirmed pathologically. Sunitinib and pazopanib were only marginally active (52% and 41% TVI, respectively), whereas bevacizumab caused a 78% TVI. No tumor regrowth was observed up to 100 days from end of treatment with temozolomide and dacarbazine, whereas secondary progression followed sunitinib, pazopanib, and bevacizumab interruption.Conclusions: Dacarbazine as single agent has antitumor activity in SFT. Our preclinical results suggest a cytotoxic effect of temozolomide and dacarbazine, as compared with a cytostatic role for sunitinib, pazopanib, and bevacizumab. A phase II study on dacarbazine in advanced SFT is planned. Clin Cancer Res; 19(18); 5192–201. ©2013 AACR.

PDF file, 256K, A Human primary tumor: morphology (i.e., patternless growth, collagen deposition, moderate cellularity, mitotic index (>4X10 High Power Field (HPF), as shown in panel 1) and immunophenotype (i.e., diffuse positivity for CD34, as shown in panel 1/a) were consistent with a malignant SFT. Immunohistochemistry was positive for PDGFRB expression (panel 1/b). B Human relapsed tumor: morphology was consistent with a dedifferentiated SFT (DSFT), being marked by the abrupt transition from areas with MSFT aspects similar to what observed in the primary tumor (panel 2) to areas with high-grade sarcoma features (panel 3). High-grade areas showed hypercellularity (panel 3/a), chondroid (panel 3/b) and osteoid differentiation (panel 3/c). C Xenograft tumor: morphology was consistent with a high-grade DSFT (panel 4), superimposable to what observed in panel B, 3a/3b/3c, again with presence of mineralized trabeculaes and osteoid (panel 4/a). Immunohistochemistry was positive for PDGFRB expression (panel 4/b). Phospho receptor tyrosine kinase (pRTK) array (ARY001 Proteome ProfilerTM Array, R&D Systems) showed similar profiles for human relapsed tumor (panel B, 3/d) and xenograft (panel C, 4/c) with the activation of PDGFRA (green boxes), PDGFRB (red boxes) and VEGFR1 (yellow boxes). White boxes are the proteome profiler negative controls.

PDF file, 110K, The xenografts were sacrificed five days after starting sunitinib, bevacizumab and pazopanib. One sample was obtained also 4 weeks after the end of treatment with pazopanib. PDGFRB and VEGFR2 activation was analyzed trough immunoprecipitation (IP) and western blotting (WB). PDGFRB activation was reduced by sunitinib and pazopanib, while VEGFR2 activation was decreased by bevacizumab and pazopanib. A re-activation of both PDGFRB and VEGFR2 was detected after 4 weeks of treatment with pazopanib.

BackgroundRheumatoid arthritis (RA) patients usually present extra-articular manifestations (1,2), which affect muscle mass and, consequently, physical function (3). Among the various methods to assess muscle mass we tested muscle morphology by ultrasound (MU) to verify the associations of the quadriceps muscle with clinical features, muscle strength, functional capacity and physical function.ObjectivesTo assess the MU of the quadriceps muscle and verify the muscle quality assessed by the pennation angle and its associations with clinical features, muscle strength, functional capacity and physical function in RA patients.MethodsRA women, age ≥18years and who met 2010 American College of Rheumatology (ACR) criteria were included. Morphological parameters in quadriceps muscle consisted of the pennation angle of rectus femoris (RF), vastus intermedius (VI) and vastus lateralis (VL). RA activity was measured by 28-joint disease activity score (DAS28), muscle strength by handgrip and chair stand tests, functional capacity by health assessment questionnaire (HAQ), and physical function by timed-up-and-go (TUG) test and short physical performance battery (SPPB). Pearson’s or Spearman’s correlation coefficients were explored. The significance level was set at p ≤ 0.05 for all analyzes.ResultsEighty-one patients were included (age: 58.64±9.52 years old; DAS28: 3.24±1.34). Smaller pennation angle in rectus femoris (RF) were associated with lower handgrip strength (r= 0.224, p=0.044), chair stand test (r= -0.372, p=0.004), HAQ (r= -0.404, p=0.001), SPPB (r= 0.262, p=0.047), as well as higher disease activity by DAS-28 (r= -0.415, pConclusionThe pennation angles of the quadriceps muscle evaluated by ultrasound (RF, VI and VL muscles) were associated with chair stand test and DAS-28. In addition, the level of disease activity assessed by DAS-28 also appears to be affecting the quadriceps muscle. Finally, MU may be a useful method to evaluate the impact of the disease on skeletal muscle.References[1]Summers GD, Deighton CM, Rennie MJ, Booth AH. Rheumatoid cachexia : a clinical perspective. 2008;(April):1124–31.[2]da Rocha OM, Batista A de AP, Maestá N, Burini RC, Laurindo IMM, Kayser C. Sarcopenia in rheumatoid cachexia: Definition, mechanisms, clinical consequences and potential therapies. Rev Bras Reum. 2009;49, 294–30.[3]de Santana FS, da Cunha Nascimento D, de Freitas JPM, Miranda RF, Muniz LF, Neto LS, et al. Assessment of functional capacity in patients with rheumatoid arthritis: Implications for recommending exercise. Rev Bras Reumatol. 2014;54(5):378–85.Table 1.Associations between the quadriceps muscle morphology by ultrasound (pennation angle) with clinical features, muscle strength, functional capacity and physical function in rheumatoid arthritis patients.VariablesnComponents of the quadriceps muscleRp-valueAge (y)81RF-0.2900.009VINSNSVL-0.2720.014Disease duration (y)81RFNSNSVINSNSVLNSNSDas-28 (CRP)81RF-0.415VI-0.3040.006VL-0.2370.033Handgrip strength test (kg)81RF0.2240.044VINSNSVLNSNSChair stand test (s)58RF-0.3720.004VI-0.2810.033VL-0.2900.027HAQ (score)65RF-0.4040.001VI-0.3020.015VLNSNSTUG test (s)68RFNSNSVINSNSVLNSNSSPPB (score)58RF0.2620.047VINSNSVLNSNSRF: rectus femoris; VI: vastus intermedius; VL: vastus lateralis; n: number; y: years; s: seconds; kg: kilogram; DAS28: Disease Activity Score 28; CRP: C-reactive protein; TUG: Timed-up-and-go; SPPB: Short Physical Performance Battery; NS: Not significant.AcknowledgementsWe thank the Coordination for the Improvement of Higher Level Personnel (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—CAPES) institution, the Foundation for Research Support of the Rio Grande do Sul State (Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul-FAPERGS), the Research and Events Incentive Fund (Fundo de Incentivo à Pesquisa e Eventos-FIPE) of HCPA and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq).Disclosure of InterestsNone declared