To explore the role of methotrexate (MTX) in regulating the number of regulatory T cells (Treg) and the mRNA expression of transcription factor Foxp3.
 Methods: 1) We analyzed the number of Treg and the mRNA expression of Foxp3 by flow cytometry (FCM) and quantitative real-time PCR (qRT-PCR) respectively in patients with psoriasis vulgaris, patients with psoriasis vulgaris after the 8-week treatment of MTX, and healthy people. 2) BALB/c female mice were smeared with imiquimod (IMQ) cream for 6 days. We recorded the change of the lesion in mice every day. The morphological changes of lesion in mice were evaluated by the psoriasis area and severity index (PASI) and HE staining. 3) The mouse model was randomly divided into a control group and an MTX group. The MTX group was treated with different doses of MTX (38.5 and 77.0 nmol/L) on the third day of this experiment. The morphological changes of lesion in mice were evaluated by PASI and HE staining. We tested the number of Treg and the expression level of Foxp3 mRNA in splenic lymphocytes.
 Results: 1) The number of Treg and the expression level of Foxp3 mRNA were lower in psoriasis vulgaris patients than those in the healthy control group (P<0.05). After 8-week treatment of MTX, the number of Treg was increased (P<0.05) and Foxp3 mRNA level was up-regulated (P<0.01). 2) Typical psoriasis-like skin lesions, such as red scaly skin plaque were found after topical application of IMQ. Both the number of Treg in the splenic lymphocytes of mice and the Foxp3 mRNA level of Treg were reduced by IMQ (P<0.01 and P<0.05). 3) Different doses of MTX for mice showed the ability to improve skin lesion, increase the number of Treg in the spleen of mice and Foxp3 mRNA level in psoriatic dermatitis of mice (P<0.05).
 Conclusion: MTX is able to regulate the number of Treg and Foxp3 mRNA expression in psoriasis.
Adjuvants, Immunologic ; pharmacology ; Aminoquinolines ; pharmacology ; Animals ; Case-Control Studies ; Female ; Forkhead Transcription Factors ; metabolism ; Humans ; Imiquimod ; Immunosuppressive Agents ; administration & dosage ; pharmacology ; Lymphocyte Count ; Methotrexate ; administration & dosage ; pharmacology ; Mice ; Mice, Inbred BALB C ; Psoriasis ; drug therapy ; immunology ; metabolism ; pathology ; RNA, Messenger ; metabolism ; Random Allocation ; Spleen ; cytology ; T-Lymphocytes, Regulatory ; cytology ; drug effects ; metabolism

PURPOSE: Intravenous immunoglobulin (IVIG) is the standard treatment for Kawasaki disease (KD). However, there is still no standard treatment for IVIG-resistant KD. This study aimed to evaluate the efficacy of low-dose methotrexate (MTX) as a treatment for IVIG-resistant KD. MATERIALS AND METHODS: We retrospectively analyzed 10-year data for patients with IVIG-resistant KD who were administered MTX at Severance Children's Hospital. RESULTS: The subjects included 75 patients with KD aged 5 months to 9.2 years who had been administered MTX. Their maximum body temperatures decreased significantly within 24 h of therapy. The patients' C-reactive protein levels were significantly lower 1 week after administering the first dose of MTX than those before treatment. No adverse effect for MTX was observed. CONCLUSION: MTX treatment of IVIG-resistant KD resulted in rapid defervescence, improvement of clinical symptoms, and normalization of acute-phase reactants in all patients. Thus, MTX could be a candidate treatment for IVIG-resistant KD.
C-Reactive Protein/analysis ; Child ; Child, Preschool ; Coronary Vessels/pathology ; Demography ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Humans ; Immunoglobulins, Intravenous/therapeutic use ; Infant ; Male ; Methotrexate/administration & dosage ; Methotrexate/therapeutic use ; Mucocutaneous Lymph Node Syndrome/blood ; Mucocutaneous Lymph Node Syndrome/drug therapy ; Retrospective Studies ; Steroids/therapeutic use ; Treatment Outcome

BACKGROUNDHigh-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is "gold standard" therapy for osteosarcoma. Plasma concentrations of methotrexate (MTX) are closely related to its efficacy and toxicity. Delayed excretion of MTX can lead to serious adverse reactions that may result in treatment cessation, irreversible organ damage, and death. This study focused on the incidence of delayed excretion of MTX in Chinese osteosarcoma patients.

METHODSA total of 1277 osteosarcoma patients were treated with HD-MTX chemotherapy (4291 cycles) from 2010 to 2015. Factors that could influence delayed excretion of MTX (gender, age, number of chemotherapy cycles, and serum concentration of MTX) were analyzed.

RESULTSThe incidence of delayed excretion of MTX (serum concentrations at 24 h [C24 h] >5 μmol/L) and severe delayed excretion of MTX (C24 h >20 μmol/L) were 6.19% and 0.86% per patient, and 2.31% and 0.26% per cycle of treatment, respectively. The incidence of severe delayed excretion of MTX was associated with gender, age, and C24 h.

CONCLUSIONSPrecaution of delayed excretion of MTX is needed during osteosarcoma treatment using HD-MTX. An optimal individualized rescue strategy can be created with consideration of gender, age, and C24 h.

Adolescent ; Adult ; Age Factors ; Child ; Drug Administration Schedule ; Female ; Humans ; Infusions, Intravenous ; Male ; Methotrexate ; administration & dosage ; pharmacokinetics ; therapeutic use ; Osteosarcoma ; blood ; drug therapy ; Retrospective Studies ; Sex Factors ; Treatment Outcome ; Young Adult

OBJECTIVETo characterize the clinical features of desmoid tumor, assess the efficacy of conservative chemotherapy for inoperable desmoid tumor and analyze the prognostic factors.

METHODSFrom August 2009 to December 2013, 52 patients with inoperable desmoid tumor were treated in our department and received chemotherapy with vinorelbine combined with low-dose methotrexate. The clinical data of the patients were analyzed retrospectively.

RESULTSThe patients studied included 22 male and 30 female patients with the age of disease onset ranging from 2 to 46 years (mean 18.7 years). The lesions occurred most frequently in the lower limbs (36.5%, 19/52) and the tumor size ranged from 2.7 to 37 cm (mean 9.5 cm). The patients were followed up for a median of 29 months (7 to 64 months). The chemotherapy lasted for 4 to 30 months (median 12 months). After completion of the chemotherapy, 1 patient had a complete response (CR), 18 showed partial responses (PR), 27 cases had stable disease (SD), and 6 had progressive disease (PD), with an overall response rate (ORR) of 88.5%. The progression-free survival (PFS) time of the patients ranged from 4 to 63 months (median 26.5 months) with a 2-year PFS rate of 76.7% and 5-year PFS rate of 41.9%. A longer chemotherapy duration (over 12 months) was associated with a more favorable prognosis. No significant differences in PFS were found between the patients stratified by gender, age of disease onset, age when receiving chemotherapy, tumor site, or tumor size.

CONCLUSIONFor recurrent, inoperable and progressive desmoid tumor, long enough cycles of vinorelbine combined with low-dose methotrexate can be an effective and safe option for tumor control.

Adolescent ; Adult ; Antineoplastic Combined Chemotherapy Protocols ; Child ; Child, Preschool ; Disease-Free Survival ; Female ; Fibromatosis, Aggressive ; drug therapy ; Humans ; Male ; Methotrexate ; administration & dosage ; therapeutic use ; Middle Aged ; Prognosis ; Retrospective Studies ; Vinblastine ; administration & dosage ; analogs & derivatives ; therapeutic use ; Young Adult

INTRODUCTIONAtopic dermatitis is a common, chronic pruritic condition affecting both children and adults, which has a negative impact on the quality of life. These guidelines were developed by an expert workgroup appointed by the Dermatological Society of Singapore, to provide doctors with information to assist in the management of their patients with atopic dermatitis. The workgroup members are experienced dermatologists with interest and expertise in eczemas.

MATERIALS AND METHODSWorkgroup members arrived at a consensus on the topics to be included. Relevant studies from the literature were assessed for best evidence, supplemented by the collective experience of the workgroup.

RESULTSFor mild atopic dermatitis, emollients, mild potency topical steroids and topical calcineurin inhibitors are recommended. For moderate-to-severe atopic dermatitis, the use of emollients, moderate-to-potent topical steroids, topical calcineurin inhibitors, wet dressings, antimicrobials for secondary skin infection, phototherapy, and systemic therapy (e.g. prednisolone, cyclosporine, azathioprine or methotrexate) may be warranted. Patients with moderate-to-severe atopic dermatitis should be managed in conjunction with a dermatologist.

CONCLUSIONGood outcomes can be achieved with an individualised therapeutic approach combined with adequate patient and parental education.

Administration, Cutaneous ; Adrenal Cortex Hormones ; therapeutic use ; Anti-Bacterial Agents ; therapeutic use ; Azathioprine ; therapeutic use ; Calcineurin Inhibitors ; therapeutic use ; Coinfection ; complications ; drug therapy ; Cyclosporine ; therapeutic use ; Dermatitis, Atopic ; complications ; immunology ; therapy ; Dermatology ; Disease Management ; Emollients ; therapeutic use ; Food Hypersensitivity ; immunology ; Humans ; Immunosuppressive Agents ; therapeutic use ; Methotrexate ; therapeutic use ; Patient Education as Topic ; Phototherapy ; Practice Guidelines as Topic ; Referral and Consultation ; Severity of Illness Index ; Singapore

BACKGROUNDHigh-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is the gold standard therapy in the treatment of osteosarcoma. The plasma concentration of MTX is closely related to efficacy and toxicity. There are large individual differences. Many authors have described the pharmacokinetic (PK) profile of MTX regarding osteosarcoma under a variety of circumstances. However, no data concerning Chinese osteosarcoma patient PKs using the nonlinear mixed effects models (NONMEM) have been previously reported. The goals of this study were to establish the population pharmacokinetics (PPK) of HD-MTX treatment in Chinese osteosarcoma patients, and to explore the influence of patient covariates and between-occasion variability on drug disposition.

METHODSAn intravenous HD-MTX solution (10 g/m 2 ) was given 274 times to 148 osteosarcoma patients. MTX plasma concentrations were measured at 0, 6, 12, 24, 48 and 72 h after commencement of the infusion, and the fluorescence polarization immunoassay was used to determine MTX plasma concentrations. The PPK model and parameters were estimated using NONMEM software. The effects of fixed-effect factors were evaluated, and the final regression model was obtained.

RESULTSThe following population parameters were obtained using a two-compartment model: CL1 (clearance of central compartment): (CL1 ) = CL1TV × [1 - θ CL1- MTXNUM × MTXNUM] × [1 - θ CL1- CrCl1 × (CrCl1 - 1.89)] × e ηCL1i (L/h). V1 (central volume): (V1)i = V1TV × e ηV1i (L). CL2 (clearance of peripheral compartment): (CL2)i = CL2TV × [1 - θCL2 - BODY AREA × (body area - 1.62)] × e ηCL2i (L/h). V2 (peripheral compartment): (V2 )i = V2TV × [1 - θ V2-bodyarea × (bodyarea-1.62)] × e ηV2i (L). The PPK parameters (RSD%) were CL1, V1, CL2 and V2 with values of 6.20 L/h (8.48%), 19.6 L (extremely small), 0.0172 L/h (50.9%) and 0.515 L (39.1%), respectively. Creatinine clearance and the number of methotrexate chemotherapy cycles before MTX infusion had a significant effect on the CL1, and body surface area had a significant effect on the CL2 and the V2 (P < 0. 01).

CONCLUSIONSA good fit was derived for the PPK. The model could be used to provide guidance for MTX treatment and reduce adverse effects.

Adolescent ; Adult ; Child ; Female ; Humans ; Infusions, Intravenous ; Leucovorin ; administration & dosage ; therapeutic use ; Male ; Methotrexate ; administration & dosage ; therapeutic use ; Models, Molecular ; Osteosarcoma ; drug therapy ; Young Adult

OBJECTIVETo survey effective treatment strategies for cesarean scar pregnancy (CSP).

METHODSThe clinical data of 78 patients diagnosed with CSP from January 2010 to December 2013 were reviewed.

RESULTSAmong these patients, 17 patients were first treated at our hospital; of them, 2 were misdiagnosed. The other 61 patients were referred from other hospitals; of them, 21 were initially misdiagnosed. There were 9 patients who were treated with laparotomy, 50 patients with curettage after uterine artery embolization (UAE) with or without local methotrexate (MTX) infusion, 10 patients with dilatation and curettage, 6 patients with transvaginal sonographic guided local intragestational MTX injection, and 3 patients with systemic MTX injection. All patients finally recovered. Patients with excessive vaginal hemorrhage underwent either emergency UAE treatment or laparotomy. These two treatments had similar success rates (81.82% vs. 100%, χ2 =0.289, P>0.05).

CONCLUSIONSThe accurate diagnosis of CSP is important. Curettage after UAE with or without local MTX infusion is a safe and effective method.

Adult ; Cesarean Section ; Cicatrix ; complications ; Curettage ; Female ; Humans ; Methotrexate ; administration & dosage ; Pregnancy ; Pregnancy, Ectopic ; diagnosis ; etiology ; therapy ; Retrospective Studies ; Uterine Artery Embolization

Treatment of Leptomeningeal carcinomatosis (LMC) from solid cancers has not advanced noticeably since the introduction of intra-cerebrospinal fluid (CSF) chemotherapy in the 1970's. The marginal survival benefit and difficulty of intrathecal chemotherapy injection has hindered its wide spread use. Even after the introduction of intraventricular chemotherapy with Ommaya reservoir, frequent development of CSF flow disturbance, manifested as increased intracranial pressure (ICP), made injected drug to be distributed unevenly and thus, the therapy became ineffective. Systemic chemotherapy for LMC has been limited as effective CSF concentration can hardly be achieved except high dose methotrexate (MTX) intravenous administration. However, the introduction of small molecular weight target inhibitors for primary cancer treatment has changed the old concept of 'blood-brain barrier' as the ultimate barrier to systemically administered drugs. Conventional oral administration achieves an effective concentration at the nanomolar level. Furthermore, many studies report that a combined treatment of target inhibitor and intra-CSF chemotherapy significantly prolongs patient survival. Ventriculolumbar perfusion (VLP) chemotherapy has sought to increase drug delivery to the subarachnoid CSF space even in patients with disturbed CSF flow. Recently authors performed phase 1 and 2 clinical trial of VLP chemotherapy with MTX, and 3/4th of patients with increased ICP got controlled ICP and the survival was prolonged. Further trials are required with newly available drugs for CSF chemotherapy. Additionally, new LMC biologic/pharmacodynamic markers for early diagnosis and monitoring of the treatment response are to be identified with the help of advanced molecular biology techniques.
Administration, Intravenous ; Administration, Oral ; Cerebrospinal Fluid ; Drug Therapy ; Early Diagnosis ; Humans ; Intracranial Pressure ; Meningeal Carcinomatosis* ; Methotrexate ; Molecular Biology ; Molecular Weight ; Perfusion

Methotrexate (MTX)-induced leukoencephalopathy is the most often reported leukoencephalopathy following intrathecal or intravenous administration. A 72-year-old woman developed leukoencephalopathy localized to the cerebellum after treatment with oral MTX at a dose of 15 mg/week for 3 years. She complained of subtle imbalance during walking and reported having fallen. Her symptoms improved after discontinuation of MTX, and the leukoencephalopathy resolved. This is therefore a case report of selective cerebellar reversible leukoencephalopathy associated with oral MTX.
Administration, Intravenous ; Aged ; Cerebellum ; Female ; Humans ; Leukoencephalopathies* ; Methotrexate* ; Walking

OBJECTIVETo provide guidance for the high-dose methotrexate (HD-MTX) treatment of pediatric acute lymphoblastic leukemia (ALL), and to understand the impact of SLCO1B1c.521T>C (rs4149056) variant on methotrexate (MTX) pharmacokinetics and clinical outcome in children with ALL.

METHODEighty-two children with ALL in Division of Hematology of Wuhan Children's Hospital from January 2008 to February 2013 were enrolled. All patients were genotyped for rs4149056 single nucleotide polymorphism (SNP) into wild-type group (TT genotype) and variant group (TC/CC genotype). According to the ALL-BFM 2000 protocol, all patients received intravenous infusion of MTX every ten days at 3 to 5 g/m(2). Leucovorin rescue was performed after 36 hours of the MTX administration and its dose was adjusted according to the MTX plasma concentration at 48 hours. The concentrations of MTX and its metabolite at 24, 48 and 72 h were determined by high performance liquid chromatography with solid phase extraction. Population pharmacokinetic parameters were estimated by the NLME software. The pharmacokinetics, toxicity and leucovorin rescue was compared. The relapse rate within 5 years and event-free survival were followed up.

RESULTEighty-two pediatric patients were classified into two groups: variant group including 20 TC genotype carriers and one CC genotype carrier, wild-type group included 61 patients with TT genotype. Compared with wild-type group, plasma concentration of MTX at 48 and 72 h increased significantly [48 h: (1.00±1.41) vs.(0.34±0.17) µmol/L, t=2.131, P=0.046; 72 h: (0.31±0.26) vs.(0.08±0.04) µmol/L; t=3.995, P=0.001]. Area under the concentration time curve (AUC48-∝) of MTX significantly increased in variant group [(23.18±19.91) vs.(5.66±2.01) h·µmol/L] (t=4.025, P=0.001). Time above the MTX safety threshold (TC>0.1 µmol/L) increased significantly in variant group [(95.3±22.0) vs.(67.1±7.5) h, t=5.880, P<0.001]. Rescue dosage of leucovorin in variant group was higher than that in wild-type group [(312.7±287.8) vs.(140.6±27.5) mg/m2, t=2.614, P=0.017]. The children carrying rs4149056 C allele suffered from a higher frequency of serious adverse effect [gastrointestinal toxicity: 33% (7/21) vs. 5% (3/61);hepatic toxicity: 24% (5/21) vs. 2% (1/61)]. The difference was statistically significant (χ2=9.275, 8.289, all P<0.05). Hospital stay of variant group was significantly longer than that of wild-type [(4.95±1.43) vs. (4.05±0.22) d, t=2.881, P=0.009]. The relapse rate within 5 years of variant group and wild-type group were 9% (2/21) and 13% (8/61), respectively. There were no significant differences in the event-free survival between the two groups (χ2=0.001, P=0.971).

CONCLUSIONThe SLCO1B1 c.521T>C variant was an important determinant of MTX pharmacokinetics. An appropriate leucovorin dose raise in variant group was beneficial to reducing the serious toxicity and did not affect the long-term clinical outcome.

Alleles ; Antineoplastic Combined Chemotherapy Protocols ; Asparaginase ; Child ; Daunorubicin ; Disease-Free Survival ; Genotype ; Humans ; Leucovorin ; administration & dosage ; Methotrexate ; administration & dosage ; pharmacokinetics ; Organic Anion Transporters ; genetics ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; genetics ; Prednisone ; Solute Carrier Organic Anion Transporter Family Member 1b1 ; Treatment Outcome ; Vincristine