Methotrexate (MTX) carries a risk of lymphoproliferative disorders (LPDs), but MTX-associated LPDs (MTX-LPDs) can resolve spontaneously after MTX withdrawal. However, the precise clinicopathologic features of MTX-LPD remain unclear. We aimed to investigate the clinicopathologic characteristics, outcomes, and prognostic factors for histologic types of MTX-LPD. Paraffin-embedded tissue samples of 219 patients with MTX-LPD were analyzed. In total, 30,33,106, and 26 had reactive lymphoid hyperplasia (RH), polymorphic-LPD (Poly-LPD), diffuse large B-cell lymphomas (DLBCLs), and classic Hodgkin lymphoma (CHL), respectively. The clinicopathologic features of RH, Poly-LPD, DLBCLs, and CHL were as follows: extranodal involvement: 13.8% (4/29), 36.4% (12/33), 69.5% (73/105), and 15.4% (4/26); Epstein-Barr virus encoded RNA positivity: 55.2% (16/29), 71.9% (23/32), 45.3% (48/106), and 76.9% (20/26); necrosis: 0% (0/29), 51.5% (17/33), 34.3% (36/105), and 12.0% (3/25); and Hodgkin Reed-Sternberg-like cells: 17.2% (5/29), 50% (14/28), and 19.8% (21/106). The median duration from MTX withdrawal to the time of disease regression was 10.4, 3.0, 4.2, and 2.7 months for RH, Poly-LPD, DLBCLs, and CHL. After MTX withdrawal, progression-free survival was the greatest for RH, followed by for Poly-LPD, DLBCL, and CHL (all P<0.05). Overall survival did not differ significantly between the groups. On univariate analysis, the predictive factors for progression-free survival included plasma cell infiltrate for CHL, eosinophil infiltrate, age above 70 years, and extensive necrosis for Poly-LPD, while they were Epstein-Barr virus encoded RNA positivity and International Prognostic Index risk for DLBCL on multivariate analysis. In conclusion, histologic categorization and histology-specific factors could be useful for predicting MTX-LPD progression after MTX withdrawal.
Although recent accumulative data reveal the clinicopathogenesis of regression in methotrexate-induced lymphoproliferative disorders (MTX-LPDs), the precise understanding including this category remains controversial. In this study, we analyzed 62 patients with MTX-LPD. Forty-three patients showed regression (Reg group), with high rates of Hodgkin lymphoma (HL) and LPD (90 and 88%, respectively). Among the 43 patients of the Reg group, 14 patients (33%) relapsed. The median duration before relapse in the Reg group was 10.6 months. Although the difference of OS between the Reg and Non-Reg groups was not significantly different, relapse-free patients in the Reg group had a superior overall survival (OS). MTX duration had a significant impact on Epstein-Barr virus (EBV) infection (p = .00131). Furthermore, EBV infection was significantly related to clinical manifestations, including spleen invasion, in the regression phenomenon. Some human leukocyte antigens (HLA) alleles might affect MTX-LPD development via EBV infection, although A*2402 and DRB1*0405 might be affected as fundamental factors.
Integrin ␣IIb3 plays a critical role in platelet aggregation through its interaction with fibrinogen. Elucidation of the mechanisms of ␣IIb3-fibrinogen interaction is critical to understanding hemostasis and thrombosis. Here we report that mutations of Gly-184, Tyr-189, Tyr-190, Phe-191, and Gly-193 within the predicted turn structure of the third amino-terminal repeat of ␣IIb significantly block binding of ␣IIb3 to soluble fibrinogen. These mutations also block binding of ␣IIb3 to ligandmimetic monoclonal antibodies PAC-1, OP-G2, LJ-CP3, which have an RGD-related RYD sequence in their antigen-binding sites. These mutations do not significantly affect the expression of ␣IIb3, in contrast to most of the natural ␣IIb mutations occurring in Glanzmann's thrombasthenic patients. The data suggest that these residues are critically involved in ␣IIb3-ligand interactions.Integrin ␣IIb3 (glycoprotein IIb-IIIa, CD41/CD61), a platelet receptor for fibrinogen, plays a critical role in primary hemostasis through mediating interactions between platelets and fibrinogen (1). Disruption of fibrinogen-␣IIb3 interaction due to quantitative and/or qualitative defects in platelet ␣IIb3 leads to a hemorrhagic disorder known as Glanzmann's thrombasthenia (2). Also, excessive ␣IIb3-fibrinogen interaction could cause thrombosis. Therefore, elucidation of the mechanisms of ␣IIb3-fibrinogen interaction is critical for understanding hemostasis and thrombosis.␣IIb3-fibrinogen interaction is blocked by synthetic peptides derived from the sequence HHLGGAKQAGDV at the carboxyl terminus of the ␥ chain (3) or from RGD sequences in the ␣ chain (4, 5) of fibrinogen. Peptide cross-linking (6, 7), peptide binding or inhibition (8 -11), mutagenesis (12), and genetic studies (13-15) suggest that several regions in 3 may be involved in ligand binding. A highly conserved EF hand-like sequence near Asp-119 of 3 has been reported to bind divalent cations as well as RGD peptide (16,17). The ␣IIb subunit consists of a large extracellular domain, a single transmembrane domain, and a short cytoplasmic segment (18,19). The amino-terminal portion of the extracellular domain contains seven repeats of homologous sequences of about 80 amino acids. The last four repeats each contain a putative divalent cation binding site consisting of the general sequence DXDX-DGXXD (18,19). Although several other integrin ␣ subunits (e.g. ␣2, ␣L, ␣M) have an I (inserted) domain of about 200 amino acids which is critical for ligand binding (20 -25) between the second and third repeats, ␣IIb has no such domain. The ligand binding site of the non-I domain integrin ␣ subunit has not been well characterized. A recombinant ␣IIb fragment encompassing residues 171-464 has been shown to bind to immobilized fibrinogen (26). The amino-terminal 334 residues of ␣IIb have recently been shown to be required for ligand binding to ␣IIb3 (27). The ␥ chain peptide or RGD-containing peptides chemically cross-link to several regions of ␣IIb, including residues 294 -314, that contain the...
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