Articoli di riviste: "Methotrexate Testing"

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KARWAKI, TANYA E., THOMAS K. HAZLET e JENNIFER L. WILSON NORTON. "Lessons Learned in Developing and Testing a Methotrexate Case Study for Pharmacy Education". Cambridge Quarterly of Healthcare Ethics 29, n. 2 (11 marzo 2020): 308–16. http://dx.doi.org/10.1017/s0963180119001099.

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AbstractThis article describes the development, implementation, and evaluation of a complex methotrexate ethics case used in teaching a Pharmacy Law and Ethics course. Qualitative analysis of student reflective writings provided useful insight into the students’ experience and comfort level with the final ethics case in the course. These data demonstrate a greater student appreciation of different perspectives, the potential for conflict in communicating about such cases, and the importance of patient autonomy. Faculty lessons learned are also described, facilitating adoption of this methotrexate ethics case by other healthcare profession educators.

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Chernyshov, Pavel. "Testing for HIV prior to methotrexate administration. Is it an obligatory procedure?" International Journal of Dermatology 45, n. 8 (agosto 2006): 998–99. http://dx.doi.org/10.1111/j.1365-4632.2006.02746.x.

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Satz, W., P. Torres e J. W. Ufberg. "Is liver function testing necessary prior to methotrexate treatment for ectopic pregnancy?" Annals of Emergency Medicine 44, n. 4 (ottobre 2004): S17. http://dx.doi.org/10.1016/j.annemergmed.2004.07.057.

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Jang, Ji-Hun, Seung-Hyun Jeong e Yong-Bok Lee. "Enhanced Lymphatic Delivery of Methotrexate Using W/O/W Nanoemulsion: In Vitro Characterization and Pharmacokinetic Study". Pharmaceutics 12, n. 10 (16 ottobre 2020): 978. http://dx.doi.org/10.3390/pharmaceutics12100978.

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Methotrexate, which is widely used in the treatment of cancer and immune-related diseases, has limitations in use because of its low bioavailability, short half-life, and tissue toxicity. Thus, in this study, a nano-sized water-in-oil-in-water (W/O/W) double emulsion containing methotrexate was prepared to enhance its lymphatic delivery and bioavailability. Based on the results from solubility testing and a pseudo-ternary diagram study, olive oil as the oil, Labrasol as a surfactant, and ethanol as a co-surfactant, were selected as the optimal components for the nanoemulsion. The prepared nanoemulsion was evaluated for size, zeta potential, encapsulation efficiency, pH, morphology, and in vitro release profiles. Furthermore, pharmacokinetics and lymphatic targeting efficiency were assessed after oral and intravenous administration of methotrexate-loaded nanoemulsion to rats. Mean droplet size, zeta potential, encapsulation efficiency, and pH of formulated nanoemulsion were 173.77 ± 5.76 nm, −35.63 ± 0.78 mV, 90.37 ± 0.96%, and 4.07 ± 0.03, respectively. In vitro release profile of the formulation indicated a higher dissolution and faster rate of methotrexate than that of free drug. The prepared nanoemulsion showed significant increases in maximum plasma concentration, area under the plasma concentration-time curve, half-life, oral bioavailability, and lymphatic targeting efficiency in both oral and intravenous administration. Therefore, our research proposes a methotrexate-loaded nanoemulsion as a good candidate for enhancing targeted lymphatic delivery of methotrexate.

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Eisenberger, M., S. Krasnow, S. Ellenberg, H. Silva, J. Abrams, V. Sinibaldi, D. Van Echo e J. Aisner. "A comparison of carboplatin plus methotrexate versus methotrexate alone in patients with recurrent and metastatic head and neck cancer." Journal of Clinical Oncology 7, n. 9 (settembre 1989): 1341–45. http://dx.doi.org/10.1200/jco.1989.7.9.1341.

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Patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN) were stratified by performance status, extent of disease, and prior radiotherapy and subsequently randomized to receive carboplatin (CBDCA; Bristol-Myers, Wallingford, CT) administered intravenously (IV) monthly, initially at doses of 400 mg/m2 in combination with methotrexate (MTX) given IV weekly at doses of 40 mg/m2 or MTX alone at the same dose/schedule. Significant dose-limiting myelosuppression required CBDCA dose reductions to 300 mg/m2 and, subsequently, 200 mg/m2. Nonhematological toxicities were not significant. Our study objective was to determine whether CBDCA plus MTX produce a substantial improvement in response rate over single-agent MTX. A response rate of 50% (complete [CR] plus partial response [PR]) for CBDCA plus MTX compared with 25% for MTX was specified as the difference to be detected. We employed a two-stage study design for randomized trials that allowed for early termination of studies involving relatively ineffective treatment regimens. With this design, the study could be closed after the first stage (20 patients entered onto each treatment arm) if the number of responders to CBDCA plus MTX were not superior to MTX. Five of 20 patients responded to treatment in each arm, and we were able to conclude that the addition of CBDCA to MTX is unlikely to result in a twofold increase in response rate compared with MTX alone in this group of patients. This two-stage design represents a simple and efficient method of testing the relative efficacy of new combinations containing at least one active agent against a suitable control arm in this disease. It addresses scientific and ethical issues of continuing testing with relatively ineffective treatments, and at the same time provides a reliable method for identifying very active regimens likely to represent significant therapeutic advances.

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Gunawan, Prastiya Indra, e Darto Saharso. "A case of juvenile dermatomyositis responding to methotrexate and steroid". Bangladesh Journal of Medical Science 17, n. 4 (19 settembre 2018): 675–77. http://dx.doi.org/10.3329/bjms.v17i4.38336.

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A 4-year-old patient presented with skin rash and muscle weakness. She was diagnosed with juvenile dermatomyositis based on Bohan and Peter criteria as well as laboratory testing. She received steroid and combined with methotrexate. The treatment resulted in a good response.Bangladesh Journal of Medical Science Vol.17(4) 2018 p.675-677

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Bennett, James A., Steven M. Parnes e Ronald C. DeConti. "Growth and Chemosensitivity of Human Head and Neck Cancers Implanted under the Kidney Capsule of Cyclosporine-Immunosuppressed Mice". Annals of Otology, Rhinology & Laryngology 98, n. 6 (giugno 1989): 455–60. http://dx.doi.org/10.1177/000348948909800612.

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Thirty-seven of 54 human squamous cell head and neck carcinomas were grown successfully as first transplant generation xenografts under the kidney capsule of conventional mice immunosuppressed by daily treatment with 60 mg/kg of cyclosporine. Eighteen different tumors were evaluated for chemosensitivity to cis-diamminedichloroplatinum (cisplatin), 5-fluorouracil, and methotrexate. Thirty-nine percent of the tumors responded to cisplatin, 19% to 5-fluorouracil, and 33% to methotrexate. This assay response is consistent with the clinical response of human squamous head and neck carcinoma to these drugs used as single agents. It is hoped that this model will become useful for new drug testing and, in certain cases, for selection of chemotherapy for patients with refractory tumors.

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Kavanaugh, Arthur, Ronald F. van Vollenhoven, Roy Fleischmann, Paul Emery, Iain Sainsbury, Stefan Florentinus, Su Chen, Benoît Guérette, Hartmut Kupper e Josef S. Smolen. "Testing treat-to-target outcomes with initial methotrexate monotherapy compared with initial tumour necrosis factor inhibitor (adalimumab) plus methotrexate in early rheumatoid arthritis". Annals of the Rheumatic Diseases 77, n. 2 (16 novembre 2017): 289–92. http://dx.doi.org/10.1136/annrheumdis-2017-211871.

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ObjectivesTo compare responses in patients with early rheumatoid arthritis (RA) initially treated with the tumour necrosis factor inhibitor (TNFi) adalimumab+methotrexate (MTX) versus MTX monotherapy who may have continued receiving MTX or switched to adalimumab rescue therapy after inadequate response to MTX.MethodsOPTIMA enrolled MTX-naive patients with active RA for <1 year. This post hoc analysis determined the proportion of patients, stratified by initial treatment, who achieved 28-joint modified Disease Activity Score based on C reactive protein <3.2, normal function and/or no radiographic progression at weeks 26, 52 and 78.ResultsSignificantly greater proportions of patients initially treated with adalimumab+MTX (n=466) compared with MTX monotherapy (n=460) achieved good clinical (53% vs 30%), functional (45% vs 33%) and radiographic (87% vs 72%) outcomes at week 26. From weeks 26 to 78, adalimumab rescue patients achieved similar clinical and functional outcomes versus patients initially treated with adalimumab+MTX. However, significantly more patients initially treated with adalimumab+MTX had no radiographic progression at weeks 52 and 78 versus patients initially treated with MTX (both timepoints: 86% vs 72%).ConclusionsIn early RA, starting with MTX monotherapy and adding TNFi after 26 weeks yields similar longer term clinical results as starting with TNFi+MTX combination therapy but allows a small but significant accrual of radiographic damage.

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KOCHARLA, LAKSHMI, JANALEE TAYLOR, TRACEY WEILER, TRACY V. TING, MICHAEL LUGGEN e HERMINE I. BRUNNER. "Monitoring Methotrexate Toxicity in Juvenile Idiopathic Arthritis". Journal of Rheumatology 36, n. 12 (16 novembre 2009): 2813–18. http://dx.doi.org/10.3899/jrheum.090482.

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Objective.To determine the frequency of laboratory abnormalities with methotrexate (MTX) use in patients with juvenile idiopathic arthritis (JIA); to identify potential risk factors for MTX toxicity requiring medical interventions; and to compare the frequency of liver function abnormalities in patients treated with MTX to those not treated with MTX.Methods.Results of MTX surveillance laboratory testing (SLT) available in clinical databases were reviewed for 588 children with JIA. Information on demographics, JIA features, and factors previously associated with increased frequency of SLT abnormalities was obtained.Results.Results of SLT performed in at least 4-month intervals were available for 138 JIA patients whose JIA was not treated with MTX, and for 198 JIA patients treated with MTX plus folic acid. On SLT of the MTX-treated patients, there were 44 of 2650 (1.7%) AST tests and 90 of 2647 (3.4%) ALT tests that exceeded 2 times the upper limit of normal (> 2 ULN) in 30 children (15%). AST or ALT tests at > 2 ULN occurred more often with systemic JIA (p = 0.04), macrophage activation syndrome, during infections, in systemic antibiotic use, and after intensifying JIA drug regimens. AST or ALT results at > 2 ULN were as frequent among MTX-treated children as those not treated with MTX. Renal and hematological abnormalities with MTX were uncommon.Conclusion.Liver enzyme abnormalities > 2 ULN are rare in JIA, irrespective of MTX exposure. These data suggest that the adult standard of SLT every 4–8 weeks may not be necessary in children treated with MTX, especially if certain risk factors are absent.

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Hilal, Talal, Alanna Maguire, Heidi E. Kosiorek, Lisa M. Rimsza e Allison C. Rosenthal. "Clinical Features and Cell of Origin Subtyping Using Gene Expression Profiling in HIV-Negative Patients with Primary Central Nervous System Lymphoma". Blood 132, Supplement 1 (29 novembre 2018): 2977. http://dx.doi.org/10.1182/blood-2018-99-110660.

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Abstract Objectives: Primary central nervous system lymphoma (PCNSL) is a rare aggressive B-cell lymphoma, particularly in HIV-negative individuals, that represents a clinical challenge due to its location and lack of comprehensive molecular and biologic description. Histopathologic features are that of diffuse large B-cell lymphoma with expression of pan-B-cell markers as well as cell of origin (COO) germinal center B cell (GCB) and post-germinal center B cell (non-GCB) markers. Previous studies using immunohistochemistry (IHC) suggest that the majority of PCNSL cases are non-GCB. However, gene expression profiling has revealed non-GCB to be comprised of two distinct subtypes, namely activated B-cell (ABC) and unclassified (UNC) subtypes that are indistinguishable by IHC. To date COO testing using the highly accurate Lymph2Cx gene expression profiling assay has not been reported in PCNSL. Methods: IRB approval was obtained and HIV negative patients diagnosed with PCNSL, who had given informed consent and for whom archived tumor tissue was available for testing were identified. COO testing was performed using the Lymph2Cx NanoString assay on RNA extracted from formalin-fixed, paraffin embed tissues using our established laboratory protocols. Clinical data including patient demographics, lines of treatment and survival outcomes were collected and correlated with each other and Lymph2Cx COO results. Results: Thirty-two HIV-negative patients diagnosed between January 2005 and June 2015 were included. Median age was 61 years (30-82) and 53% were male. Radiographic information was available for 18/32 patients. Eleven (61%) had a single brain lesion at diagnosis, while 7 (39%) had >1 brain lesion. Lines of systemic therapy were 1 (91%) and 2 (9%). All patients received methotrexate-based induction therapy (44% received methotrexate, rituximab and temozolomide, 16% received single-agent methotrexate, 31% received methotrexate and rituximab, and 9% received the modified Bonn regimen; methotrexate and cytarabine-based induction). A total of 10 patients (31%) received high-dose chemotherapy and autologous stem cell transplant (ASCT) for consolidation. Of the 10 patients that underwent consolidation therapy, 9 underwent ASCT after first line induction, and 1 underwent ASCT after second line therapy. None of the patients received whole-brain radiation therapy. At a median follow-up of 29 months (range of 2-107) median event-free survival (EFS) was 16.3 months (95% CI, 8.8-45.7), and median overall survival (OS) was 41.2 months (95% CI, 28.5-NE). COO testing using the Lymph2Cx assay revealed that 91% (29/32) were ABC, 9% (3/32) were GCB, and none were UNC. Histopathology reports described COO using the Hans algorithm in 11 of the 32 cases. Of the 3 determined to be GCB on Lymph2Cx, 1 was denoted GCB by the Hans algorithm and 2 were not stained to determine COO. Of the 29 determined to be ABC by Lymph2Cx, 9 were denoted non-GCB and 1 was denoted GCB by the Hans algorithm, and 19 were not stained to determine COO. Conclusions: This series of HIV-negative patients with PCNSL showed median survival consistent with previous studies. In this first series using the Lymph2Cx assay, we confirmed that over 90% of PCNSLs are of ABC subtype, which concurs with previous reports that PCNSL tumors are predominately non-GCB by the Hans algorithm. These findings provide biological rationale forthat pharmacologic interventions targeting B-cell receptor signaling to be explored in clinical trials in the majority of patients with PCNSL. Figure. Figure. Disclosures Rimsza: NanoString: Other: Inventor on the patent for the Lymph2Cx assay.

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Kishor, Dr Kriti, Dr Debashish Mishra, Dr Siddharth Jain, Dr Nusrat Shafiq, Dr Varun Dhir, Dr Sanjay Jain e Dr Shefali K. Sharma. "Prevalence Of Tuberculin Skin Test Positivity In Patients Of Early Rheumatoid Arthritis- Study from a tertiary care centre in North India." International Journal of Medical Research & Review 9, n. 2 (25 marzo 2021): 120–26. http://dx.doi.org/10.17511/ijmrr.2021.i02.12.

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Objective: To assess the prevalence of tuberculin skin test (TST) positivity in early rheumatoidarthritis patients (< 6months disease duration) using Tuberculin sensitivity testing in a TB endemiccountry. Method: Included in this cross-sectional study were 200 patients of early rheumatoidarthritis divided into three groups- treatment naïve, patients on methotrexate only andmethotrexate plus low dose corticosteroids. 1TU (0.1ml) of PPD RT-23 with tween 80 was injectedintradermally over the left forearm and the induration measured after 72 hours. For interpretation,Induration >10mm was taken as positive, < 5mm as negative and 5-10mm as indeterminate.Healthy controls were taken for comparison. Results: 200 early RA patients and 60 healthy controlswere included in this study. The median age of the study population was 43 years (IQR 33-51) witha mean disease duration of 3.4 ± 2.1 months. 54 patients (27%) with early RA and 22 healthycontrol (36.7%) had TST positive (p=0.1). The mean TST positivity inpatient cohort was7.25±6.53(mm) and in the control population(mm) was 7.06±6.07.TST was positive in 26 (22.6%)treatment naïve patients (n= 115);22 (37.9%) patients on methotrexate(n=58) and 6 (22.2%)patients on methotrexate and low dose corticosteroids(n=27) (p=0.08). Prior BCG vaccinationstatus, disease activity, a dose of methotrexate and rheumatoid factor seropositivity had nosignificant effect on TST positivity. Conclusion: Tuberculin positivity is low among patients withearly RA as compared to the general population. The use of low dose steroids or methotrexatedoesn’t affect the tuberculin anergy. Further larger studies with augmented tuberculin doses arerequired to assess the factors affecting TST positivity in RA patients.

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Priest, Virginia L., Evan J. Begg, Sharon J. Gardiner, Christopher M. A. Frampton, Richard B. Gearry, Murray L. Barclay, David W. J. Clark e Paul Hansen. "Pharmacoeconomic Analyses of Azathioprine, Methotrexate and Prospective Pharmacogenetic Testing for the Management of Inflammatory Bowel Disease". PharmacoEconomics 24, n. 8 (2006): 767–81. http://dx.doi.org/10.2165/00019053-200624080-00004.

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Mecoli, Christopher A., Nikolay G. Delev e Clifton O. Bingham. "Measuring transaminases in patients with rheumatoid arthritis on weekly methotrexate: does timing of blood testing matter?" Clinical Rheumatology 35, n. 12 (29 luglio 2016): 3053–56. http://dx.doi.org/10.1007/s10067-016-3361-3.

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Tseng, Li-Hui, Ming-Tseh Lin, John A. Hansen, Ted Gooley, Ji Pei, Anajane G. Smith, Emily G. Martin, Effie W. Petersdorf e Paul J. Martin. "Correlation Between Disparity for the Minor Histocompatibility Antigen HA-1 and the Development of Acute Graft-Versus-Host Disease After Allogeneic Marrow Transplantation". Blood 94, n. 8 (15 ottobre 1999): 2911–14. http://dx.doi.org/10.1182/blood.v94.8.2911.420k21_2911_2914.

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Results of a previous study suggested that recipient mismatching for the minor histocompatibility antigen HA-1 is associated with acute graft-versus-host disease (GVHD) after allogeneic marrow transplantation. In that study, most patients received either cyclosporine or methotrexate for GVHD prophylaxis, and a cytotoxic T-cell clone was used to test for HA-1 disparity. To facilitate large-scale testing, we developed a method that uses genomic DNA to identify HA-1 alleles. A retrospective study was conducted to correlate HA-1 disparity and the occurrence of acute GVHD in 237 HLA-A2–positive white patients who had received a marrow or peripheral blood stem cell transplant from an HLA-identical sibling. All patients received both methotrexate and cyclosporine for GVHD prophylaxis. The presence of HLA-A*0201 was confirmed in 34 of the 36 HA-1 disparate pairs by sequencing the HLA-A locus. Grades II-IV GVHD occurred in 22 (64.7%) of these 34 patients, compared with 86 (42.8%) of the 201 patients without HA-1 disparity (odds ratio, 2.45; 95% confidence interval [CI], 1.15 to 5.23; P = .02). Recipient HA-1 disparity showed a trend for association with acute GVHD (odds ratio, 2.1; 95% CI, 0.91 to 4.68; P = .08) when a multivariable logistic regression model was used to include additional risk factors. These data are consistent with results of the previous study, suggesting an association between HA-1 disparity and risk of acute GVHD, but the strength of this association may be lower in patients who received both methotrexate and cyclosporine than in those who received methotrexate or cyclosporine alone.

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Westhovens, René, William F. C. Rigby, Désirée van der Heijde, Daniel W. T. Ching, William Stohl, Jonathan Kay, Arvind Chopra et al. "Filgotinib in combination with methotrexate or as monotherapy versus methotrexate monotherapy in patients with active rheumatoid arthritis and limited or no prior exposure to methotrexate: the phase 3, randomised controlled FINCH 3 trial". Annals of the Rheumatic Diseases 80, n. 6 (15 gennaio 2021): 727–38. http://dx.doi.org/10.1136/annrheumdis-2020-219213.

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Objectives To investigate efficacy and safety of the Janus kinase-1 inhibitor filgotinib in patients with active rheumatoid arthritis (RA) with limited or no prior methotrexate (MTX) exposure. Methods This 52-week, phase 3, multicentre, double-blind clinical trial (NCT02886728) evaluated once-daily oral filgotinib in 1252 patients with RA randomised 2:1:1:2 to filgotinib 200 mg with MTX (FIL200 +MTX), filgotinib 100 mg with MTX (FIL100 +MTX), filgotinib 200 mg monotherapy (FIL200), or MTX. The primary endpoint was proportion achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 24. Results The primary endpoint was achieved by 81% of patients receiving FIL200+ MTX versus 71% receiving MTX (p<0.001). A significantly greater proportion treated with FIL100+ MTX compared with MTX achieved an ACR20 response (80%, p=0.017) at week 24. Significant improvement in Health Assessment Questionnaire-Disability Index was seen at week 24; least-squares mean change from baseline was −1.0 and −0.94 with FIL200+MTX and FIL100+MTX, respectively, versus −0.81 with MTX (p<0.001, p=0.008, respectively). Significantly higher proportions receiving FIL200+MTX (54%) and FIL100+MTX (43%) achieved DAS28(CRP) <2.6 versus MTX (29%) (p<0.001 for both) at week 24. Hierarchical testing stopped for comparison of ACR20 for FIL200 monotherapy (78%) versus MTX (71%) at week 24 (p=0.058). Adverse event rates through week 52 were comparable between all treatments. Conclusions FIL200+MTX and FIL100+MTX both significantly improved signs and symptoms and physical function in patients with active RA and limited or no prior MTX exposure; FIL200 monotherapy did not have a superior ACR20 response rate versus MTX. Filgotinib was well tolerated, with acceptable safety compared with MTX.

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Sode, Jacob, Sophine B. Krintel, Anting Liu Carlsen, Merete L. Hetland, Julia S. Johansen, Kim Hørslev-Petersen, Kristian Stengaard-Pedersen et al. "Plasma MicroRNA Profiles in Patients with Early Rheumatoid Arthritis Responding to Adalimumab plus Methotrexate vs Methotrexate Alone: A Placebo-controlled Clinical Trial". Journal of Rheumatology 45, n. 1 (15 novembre 2017): 53–61. http://dx.doi.org/10.3899/jrheum.170266.

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Objective.The aim was to identify plasma (i.e., cell-free) microRNA (miRNA) predicting antitumor necrosis and/or methotrexate (MTX) treatment response in patients enrolled in an investigator-initiated, prospective, double-blinded, placebo-controlled trial (The OPERA study,NCT00660647).Methods.We included 180 disease-modifying antirheumatic drug–naive patients with early rheumatoid arthritis (RA) randomized to adalimumab (ADA; n = 89) or placebo (n = 91) in combination with MTX. Plasma samples before and 3 months after treatment initiation were analyzed for 91 specific miRNA by quantitative reverse transcriptase-polymerase chain reaction on microfluidic dynamic arrays. A linear mixed-effects model was used to test for associations between pretreatment miRNA and changes in miRNA expression and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean (28 joints) remission at 3 and 12 months, applying false discovery rate correction for multiple testing. Using leave-one-out cross validation, we built predictive multivariate miRNA models and estimated classification performances using receiver-operating characteristics (ROC) curves.Results.In the ADA group, a higher pretreatment level of miR-27a-3p was significantly associated with remission at 12 months. The level decreased in remitting patients between pretreatment and 3 months, and increased in nonremitting patients. No associations were found in the placebo group receiving only MTX. Two multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months, with 63% and 82% area under the ROC curves, respectively.Conclusion.We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination with MTX. We conclude that pretreatment plasma-miRNA profiles may be of predictive value, but the results need confirmation in independent cohorts.

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Surguladze, David, Erik Corcoran, James Tonra e Yiwen Li. "Synergistic Anti-Leukemic Effect of Combination Therapy with Anti-FLT3 Antibody IMC-EB10 and Methotrexate". Blood 112, n. 11 (16 novembre 2008): 3964. http://dx.doi.org/10.1182/blood.v112.11.3964.3964.

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Abstract FLT3 is a class III receptor tyrosine kinase overexpressed by blast cells in approximately 90% of acute myeloid leukemia and acute lymphoid leukemia (ALL) patients. Recent findings testing a small molecule FLT3 inhibitor (PKC412) in combination with eight conventional antileukemic agents, reported that methotrexate in particular did not combine well with PKC412 against leukemia cells (Furukawa, Y. et al., Leukemia 2007, 21: 1005–1014). IMC-EB10 is a fully human neutralizing antibody that binds FLT3 with high affinity (Kd 158 pM) and blocks FLT3 ligand binding to FLT3 (IC50 ~10 nM), leading to inhibition of MAPK, STAT5, and PI3K/Akt signaling in leukemia cells. Here we test for benefits of adding methotrexate to IMC-EB10. In an SEMK2 model of ALL we evaluated survival effects of treatments administered intraperitoneally, beginning 1 day after after intravenous injection of 5 × 10e5 cells/mouse. In this model the maximum tolerated dose (MTD) of methotrexate administered once per week for 3 weeks, was determined to be 100 mg/kg. At this MTD, Methotrexate increased median survival to 44 days, compared to 30 days in the control group (p<0.0001 versus control by Log Rank Test). IMC-EB10 at its maximally efficacious dose (10 mg/kg, ip, 2×/week) increased survival in the SEMK2 model to 60 days (p<0.0001 versus control). When these two regimens were combined, survival significantly increased to 83 days (p<0.0001 versus all other treatment groups). Furthermore, 4 of 12 combination treated mice survived to 168 days after SEMK2 cell injection, but none of the mice in the other groups survived to this point. In this regard these agents were able to achieve an effect in combination that they could not achieve as monotherapies. These data support the significant therapeutic potential of this combination strategy in the treatment of leukemia.

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Krull, Kevin R., Yin Ting Cheung, Wei Liu, Slim Fellah, Wilburn E. Reddick, Tara M. Brinkman, Cara Kimberg et al. "Chemotherapy Pharmacodynamics and Neuroimaging and Neurocognitive Outcomes in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia". Journal of Clinical Oncology 34, n. 22 (1 agosto 2016): 2644–53. http://dx.doi.org/10.1200/jco.2015.65.4574.

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Purpose To examine associations among methotrexate pharmacodynamics, neuroimaging, and neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia treated on a contemporary chemotherapy-only protocol. Patients and Methods This longitudinal study linked pharmacokinetic assays collected during therapy to neurocognitive and brain imaging outcomes during long-term follow-up. A total of 218 (72.2%) of 302 eligible long-term survivors were recruited for outcome studies when they were more than 5 years post-diagnosis and older than 8 years of age. At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis, and 51% were male. Neurocognitive testing, functional magnetic resonance imaging (MRI) during an executive function task, and structural MRI with diffusion tensor imaging were conducted. Generalized linear models were developed to identify predictors, and models were adjusted for age at diagnosis, sex, and parent education. Results Intelligence was within normal limits (mean, 98; standard deviation, 14) compared with population expectations (mean, 100; standard deviation, 15), though measures of executive function, processing speed, and memory were less than population means (all P < .02 after correction for false discovery rates). Higher plasma concentration of methotrexate was associated with a poorer executive function score (P < .02). Higher plasma methotrexate was also associated with higher functional MRI activity, with thicker cortices in dorsolateral prefrontal brain regions, and with white matter microstructure in the frontostriatal tact. Neurocognitive impairment was associated with these imaging findings as well. Associations did not change after adjustment for age or dose of leucovorin rescue. Conclusion Survivors of childhood acute lymphoblastic leukemia treated on contemporary chemotherapy-only protocols demonstrate executive dysfunction. A higher plasma concentration of methotrexate was associated with executive dysfunction as well as with a thicker cortex and higher activity in frontal brain regions, regions often associated with executive function.

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Thurmond, Robin L., Andrew Greenspan, Waldemar Radziszewski, Xie L. Xu, Ye Miao, Bin Chen, TingTing Ge et al. "Toreforant, A Histamine H4 Receptor Antagonist, in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy: Results of 2 Phase II Studies". Journal of Rheumatology 43, n. 9 (15 luglio 2016): 1637–42. http://dx.doi.org/10.3899/jrheum.160164.

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Objective.To assess toreforant (selective histamine H4 receptor antagonist) in active rheumatoid arthritis (RA).Methods.In a phase IIa, double-blind, placebo-controlled test, 86 patients were randomized (2:1) to once-daily toreforant 100 mg or placebo for 12 weeks. In phase IIb, double-blind, placebo-controlled, dose-range–finding evaluations, 272 patients were randomized (1:1:1:1) to once-daily placebo or toreforant 3/10/30 mg. Primary efficacy endpoints for both studies were Week 12 changes in 28-joint Disease Activity Score–C-reactive protein (DAS28-CRP).Results.Phase IIa testing was terminated prematurely (patient fatality; secondary hemophagocytic lymphohistiocytosis). Posthoc analyses indicated toreforant 100 mg/day reduced RA signs/symptoms through Week 12. Phase IIb testing, however, showed no significant Week 12 improvement in DAS28-CRP with toreforant.Conclusion.Toreforant was not effective in phase IIb testing.

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Schuh, Michael J., e Sheena Crosby. "Methotrexate Central Nervous System Toxicity Identified in a Pharmacogenomics Pharmacist Consult Patient". Senior Care Pharmacist 34, n. 9 (1 ottobre 2019): 595–99. http://dx.doi.org/10.4140/tcp.n.2019.595.

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OBJECTIVE: To report a possible pharmacogenomics (PGx)-related, cognitive dysfunction, adverse drug reaction from methotrexate (MTX) that may be multifactorial in origin. SUMMARY: The patient subject is a 76-year-old Caucasian female of Russian ancestry suffering from rheumatoid arthritis and treated with MTX who presented to the diagnostic and consultative physician service in a medical clinic with advancing cognitive dysfunction, manifesting as memory loss, dizziness, and confusion. Components of this possible adverse drug reaction (ADR) may include ancestry, pharmacogenomics (PGx) characteristics of the patient, and a change in route of administration, among others. The case demonstrates how patients referred to a pharmacist consult service for a suspected ADR with possible PGx implications may uncover other contributory factors to the ADR. CONCLUSION: PGx testing may increase clinical pharmacist referrals to identify a PGx etiology to an ADR. However, they may also identify other non-PGx contributory factors to an ADR.

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Owen, S. A., M. Lunt, S. L. Hider, I. N. Bruce, A. Barton e W. Thomson. "Testing pharmacogenetic indices to predict efficacy and toxicity of methotrexate monotherapy in a rheumatoid arthritis patient cohort". Arthritis & Rheumatism 62, n. 12 (30 novembre 2010): 3827–29. http://dx.doi.org/10.1002/art.27754.

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Bauer, Bruce, Po-Huang Chyou, Erik J. Stratman e Clayton Green. "Noninvasive Testing for Nonalcoholic Steatohepatitis and Hepatic Fibrosis in Patients With Psoriasis Receiving Long-term Methotrexate Sodium Therapy". JAMA Dermatology 153, n. 10 (1 ottobre 2017): 977. http://dx.doi.org/10.1001/jamadermatol.2017.2083.

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23

Mitxelena-Iribarren, Oihane, Sara Lizarbe-Sancha, Jay Campisi, Sergio Arana e Maite Mujika. "Different Microfluidic Environments for In Vitro Testing of Lipid Nanoparticles against Osteosarcoma". Bioengineering 8, n. 6 (4 giugno 2021): 77. http://dx.doi.org/10.3390/bioengineering8060077.

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The use of lipid nanoparticles as biodegradable shells for controlled drug delivery shows promise as a more effective and targeted tumor treatment than traditional treatment methods. Although the combination of target therapy with nanotechnology created new hope for cancer treatment, methodological issues during in vitro validation of nanovehicles slowed their application. In the current work, the effect of methotrexate (MTX) encapsulated in different matrices was evaluated in a dynamic microfluidic platform. Effects on the viability of osteosarcoma cells in the presence of recirculation of cell media, free MTX and two types of blank and drug-containing nanoparticles were successfully assessed in different tumor-mimicking microenvironments. Encapsulated MTX was more effective than the equal dose free drug treatment, as cell death significantly increased under the recirculation of both types of drug-loaded nanoparticles in all concentrations. In fact, MTX-nanoparticles reduced cell population 50 times more than the free drug when 150-µM drug dose was recirculated. Moreover, when compared to the equivalent free drug dose recirculation, cell number was reduced 60 and 100 points more under recirculation of each nanoparticle with a 15-µM drug concentration. Thus, the results obtained with the microfluidic model present MTX-lipid nanoparticles as a promising and more effective therapy for pediatric osteosarcoma treatment than current treatment options.

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Mazewski, Claire, Guolian Kang, Stewart Kellie, Jeffrey Gossett, Sarah Leary, Bryan Li, Paul Aridgides et al. "MBCL-34. EFFICACY OF METHOTREXATE (MTX) ACCORDING TO MOLECULAR SUB-TYPE IN YOUNG CHILDREN WITH MEDULLOBLASTOMA (MB): A REPORT FROM CHILDREN’S ONCOLOGY GROUP PHASE III TRIAL ACNS0334". Neuro-Oncology 22, Supplement_3 (1 dicembre 2020): iii396. http://dx.doi.org/10.1093/neuonc/noaa222.510.

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Abstract ACNS0334, a Phase 3 trial, compared outcomes of children <36 months treated with intensive chemotherapy +/-high-dose methotrexate. Nodular-desmoplastic M0-stage MB were excluded. Treatment included 3 induction cycles (cyclophosphamide/etoposide/vincristine/cisplatin+/-mtx) and 3 consolidation cycles (carboplatin/thiotepa with stem cell rescue). Radiation (RT) was at physician discretion. Molecular sub-typing was by DNA-methylation. Log-rank testing was used to compare survival differences. Molecular sub-typing of 38 MB identified 11 Sonic Hedgehog (SHH), 25 Group 3 (GP3), 2 Group 4 (GP4). Five-year survival (OS) was 100% for 5 SHH with MTX and 4 SHH without MTX; 80% for 10 GP3 with MTX, 40% for 15 GP3 without MTX (p=0.025). Only 6/14 survivors received RT: 4 for residual following therapy (1 SHH and 3 GP3) and 2 GP3 salvaged after progression. Two GP3 deaths were associated with toxicity; all others were due to disease. Histology among SHH was nodular-desmoplastic (8) or classic (3); GP3 histology was classic (17) or anaplastic (7). Whole-exome sequencing identified 6 somatic PTCH1 and 1 germline SUFU alteration(s) among 9 SHH. Among GP3, no p53 mutations were found; copy-number analysis identified 5/25 with myc-amplification, 5/25 iso17q, 11/25 with 8 loss, 14/25 with loss of 11. Among GP3, 14/19 had no significant germline mutation. ACNS0334 achieved 100% survival for metastatic SHH. Benefit of methotrexate was observed in GP3 MB supporting incorporation of methotrexate into standard therapy for GP3. Upfront central pathology review and molecular sub-typing are critical for future clinical trial risk stratification of young children with embryonal tumors.

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Sundbaum, Johanna Karlsson, Eva Baecklund, Niclas Eriksson, Pär Hallberg, Hugo Kohnke e Mia Wadelius. "MTHFR, TYMS and SLCO1B1 polymorphisms and adverse liver effects of methotrexate in rheumatoid arthritis". Pharmacogenomics 21, n. 5 (aprile 2020): 337–46. http://dx.doi.org/10.2217/pgs-2019-0186.

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Aims: To investigate whether variants of MTHFR, TYMS and SLCO1B1 are associated with ALT elevation in rheumatoid arthritis patients starting methotrexate (MTX). Patients & methods: Clinical and laboratory data were collected from the start of MTX treatment. Genotyping of MTHFR, TYMS and SLCO1B1 was performed. Univariate and multiple logistic regression were used for statistical analysis. Results: 34 out of 369 patients experienced ALT >1.5 × ULN less than 6 months from start. MTHFR A1298C (rs1801131) was nominally associated with an ALT >1.5 × ULN within 6 months after the start of MTX (OR = 1.7 [95% CI: 1.04–2.9]; p = 0.03), but did not pass correction for multiple testing. A multiple model containing MTHFR 1298C and clinical factors predicted the outcome (C-statistic 0.735). TYMS and SLCO1B1 were not associated with the outcome. Conclusions: A model containing MTHFR 1298C and clinical factors might predict risk of early ALT elevation.

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Kapetanovic, M. C., T. Saxne, J. A. Nilsson e P. Geborek. "Influenza vaccination as model for testing immune modulation induced by anti-TNF and methotrexate therapy in rheumatoid arthritis patients". Rheumatology 46, n. 4 (13 ottobre 2006): 608–11. http://dx.doi.org/10.1093/rheumatology/kel366.

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Stiebitz, Sebastian, Tasslem von Streng e Moritz Strickler. "Delayed diagnosis of rheumatoid arthritis in an elderly patient presenting with weakness and desolation". BMJ Case Reports 14, n. 2 (febbraio 2021): e237251. http://dx.doi.org/10.1136/bcr-2020-237251.

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We describe the case of an 81-year-old man who presented with unspecific symptoms of desolation and general weakness, which led to a delayed diagnosis of rheumatoid arthritis (RA). The patient had not received any previous treatment as he had not been in contact with medical services for several years prior to hospital admission. This enabled advanced disease manifestations to develop, including peripheral neuropathy with distal paraparesis, lethargy and weight loss. These signs and symptoms were later recognised as extra-articular manifestations of RA and classical features of RA were less pronounced. Following extensive diagnostic testing ruling out other possible causes for the presenting symptoms, an anti-inflammatory therapy with oral glucocorticoids and methotrexate was started.

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Haddad, Anis, Olfa Zoukar, Houda Mhabrich, Awatef Hajjeji e Raja Faleh. "Postpartum Treatment of a Herniation of the Anterior Uterine Wall due to Remains of Placenta Increta". Case Reports in Obstetrics and Gynecology 2018 (30 ottobre 2018): 1–6. http://dx.doi.org/10.1155/2018/5921495.

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In recent years, the incidence of placenta accreta and associated complications has increased significantly. The authors report the case of a pregnant woman in the 5th month of pregnancy for premature rupture of the membranes. The placenta was inserted low. The evolution was marked spontaneous work followed by the expulsion of the fetus. The delivery of the placenta was haemorrhagic and incomplete. Ultrasonic testing showed a placental fragment integrated in the thickness of the myometrium. Conservative treatment with methotrexate was published a few days later and MRI showed that the anterior uterine sac was filled with blood clots associated with pelvic effusion. A laparotomy was then performed to resect the pouch and the one-piece fragment. The follow-up was uneventful.

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Alten, R. E., C. Zerbini, S. Jeka, F. Irazoque, F. Khatib, P. Emery, A. Bertasso, M. Rabbia e J. P. Caulfield. "Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy". Annals of the Rheumatic Diseases 69, n. 2 (8 aprile 2009): 364–67. http://dx.doi.org/10.1136/ard.2008.104802.

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Objective:To determine the efficacy and safety of pamapimod in adult patients with active rheumatoid arthritis (RA) who had an inadequate clinical response to methotrexate (MTX).Methods:Patients receiving stable doses of MTX were randomised to one of six dose groups and received 12 weeks of double-blind pamapimod (up to 300 mg once daily) or matching placebo. The primary efficacy measure was the proportion of patients with ⩾20% improvement in RA based on the American College of Rheumatology criteria (ACR20) at 12 weeks. Secondary measures were ACR50, Disease Activity Score (DAS)/European League Against Rheumatism (EULAR) responses and the individual ACR core set of parameters. Safety measures included adverse events (AEs), laboratory testing and immunology assessments.Results:On a background of MTX, the percentage of patients with an ACR20 response at week 12 in the pamapimod groups (31% to 43%) was not significantly different from placebo (34%). Secondary efficacy end points showed a similar pattern. AEs were typically mild and included infections, gastrointestinal disturbances, dizziness and rashes; AEs resulting in discontinuation of study drug were primarily attributed to infections.Conclusion:In patients with active RA receiving stable doses of MTX, pamapimod showed non-significant improvement in efficacy outcomes compared to placebo.

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Cheung, Yin Ting, Raja B. Khan, Wei Liu, Tara M. Brinkman, Michelle N. Edelmann, Wilburn E. Reddick, Deqing Pei et al. "Biomarkers of brain injury and neurologic outcomes in children treated with chemotherapy for acute lymphoblastic leukemia (ALL)." Journal of Clinical Oncology 35, n. 15_suppl (20 maggio 2017): 10521. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.10521.

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10521 Background: Little is known about neurotoxic mechanisms associated with chemotherapy in children with ALL. Cerebrospinal fluid (CSF) biomarkers of brain injury may provide insight into this process. Methods: 235 patients (51% male; mean [SD] age diagnosed 6.8 [4.7] years) treated on a chemotherapy only protocol provided CSF samples following diagnosis and through consolidation. CSF was assayed for biomarkers of myelin degradation (myelin basic protein [MBP]), neuronal damage (nerve growth factor [NGF], total-Tau [T-Tau]) and astrogliosis (glial fibrillary acidic protein [GFAP]). Leukoencephalopathy was evaluated by brain MRI’s during therapy. At ≥5 years post-diagnosis, 138 (70%) of the 198 still eligible survivors (without relapse and unrelated neurologic injury) completed neurocognitive testing and brain diffusion tensor imaging of white matter integrity at age 13.6 [4.6] years. Log-binomial and general linear models were used to examine whether biomarker changes from baseline through consolidation were related to serum methotrexate exposure, acute leukoencephalopathy, and long-term brain outcomes. Results: NGF and T-Tau increased from baseline to consolidation ( P's < 0.001), while MBP and GFAP were elevated at baseline and remained so through consolidation. The number of intrathecal injections (methotrexate, hydrocortisone, cytarabine) was positively correlated with NGF increase at consolidation ( P= 0.005). Increases in GFAP (RR 1.2; 95% CI [1.0 – 1.4]), MBP (RR 1.1 [1.0 – 1.1]) and T-Tau (RR 1.8 [1.1 – 2.8]) were related to higher risk for acute leukoencephalopathy, and higher diffusivity in frontal lobe white matter at ≥5 years post-diagnosis ( P’s < 0.05). Increase in T-Tau at consolidation was associated with worse long-term sustained attention ( P= 0.03), and visual- ( P= 0.04) and visual-motor ( P= 0.02) processing speed. Conclusions: Glial injury, which is evident at diagnosis, may be related to leukemia and methotrexate exposure. Neuronal injury is associated with intrathecal chemotherapy and long-term neurocognitive and brain imaging outcomes. Monitoring CSF biomarkers may be useful in identifying individuals at risk for poor neurological outcomes.

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Guillermo Prieto Eibl, Pilar, Appaji Rayi, Iyad Alnahhas, Pierre Giglio e Narendranath Epperla. "NCMP-12. RAPIDLY PROGRESSIVE NEUROPATHIES AS THE SOLE PRESENTATION OF NEUROLYMPHOMATOSIS". Neuro-Oncology 22, Supplement_2 (novembre 2020): ii125. http://dx.doi.org/10.1093/neuonc/noaa215.523.

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Abstract Neurolymphomatosis (NL) is a rare and challenging entity characterized by hematological neoplastic infiltration of the peripheral nervous system. Only 40% of the cases have malignant cells on CSF sampling. We present a 52-year-old Caucasian male with primary refractory diffuse large B-cell lymphoma (DLBCL) who relapsed within 3 months of achieving complete remission to R-CHOP. First, he experienced right tongue numbness and lumbar pain. Initial MRI of the face, brain and entire spine, and CSF analysis were unremarkable. Three weeks later, he noticed left facial numbness, dysphonia, and left leg weakness. Neuraxis MRI revealed enhancement of left CN V3 and several cervical, thoracic, and lumbar nerve roots. PET/CT showed increased uptake at L4 nerve root. EMG/NGS showed left L5 denervation. After one week, he further developed new right CN VI palsy, left-sided ptosis, anisocoria, and right arm weakness. Repeat MRI showed worsening enhancement and thickening of multiple cranial nerves, cervical and lumbosacral plexus. Extensive testing for infectious, inflammatory, and paraneoplastic processes was negative. Patient underwent plasmapheresis with no response. Biopsy of nerve root was deferred due to potential permanent deficits that would impair his quality of life. Repeat CSF testing was negative for malignancy and PET/CT showed SUV of 23.8 at L4-5 with multiple new hypermetabolic foci in muscle and ribs. He received R-HD-methotrexate with clinical and radiographic (PET/CT) improvement following 2 cycles. He completed 4 cycles of R-HD methotrexate-based chemotherapy followed by autologous hematopoietic stem cell transplantation. Most of his symptoms resolved and he remained stable for about a year when PET/CT showed disease progression. He subsequently received CAR-T cell therapy with adequate tolerance and remains clinically stable. Even with negative initial imaging and CSF studies, a careful exam and attention to uncommon presentations along with serial advanced imaging (MRI, PET/CT) surveillance are key to early detection and timely treatment.

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Mititelu, Roxana, Larry W. Cheung e Denis Sasseville. "Cutaneous polyarteritis nodosa and concurrent pseudoxanthoma elasticum–like phenotype: A case report". SAGE Open Medical Case Reports 8 (gennaio 2020): 2050313X2095311. http://dx.doi.org/10.1177/2050313x20953110.

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We report a unique case of a patient presenting with histologically confirmed pseudoxanthoma elasticum–like phenotype and cutaneous polyarteritis nodosa. Cardiac, gastroenterological, and ophthalmologic evaluations were within normal limits. Genetic evaluation was pertinent for absent ABCC6, ENPP1, and GGCX mutations and a normal array comparative genomic hybridization. Extensive workup revealed skin-limited cutaneous polyarteritis nodosa, and further genetic testing for ADA2 deficiency was negative. The cutaneous polyarteritis nodosa lesions had an excellent response to hydroxychloroquine and methotrexate. Pseudoxanthoma elasticum and polyarteritis nodosa are relatively uncommon, and our patient is among the first reported cases presenting with both pseudoxanthoma elasticum–like and polyarteritis nodosa. Furthermore, this case emphasizes the importance of a thorough cutaneous exam, as the patient had the lesions consistent with pseudoxanthoma elasticum–like since childhood and had previously gone undiagnosed.

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Berkowitz, Eran, Ella Arnon, Alona Yaakobi, Yuval Cohen e Beatrice Tiosano. "IgG4-Related Disease Presenting as Isolated Scleritis". Case Reports in Ophthalmological Medicine 2017 (2017): 1–4. http://dx.doi.org/10.1155/2017/4876587.

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A rare case of IgG4-related disease (IgG4-RD) manifesting as nodular scleritis is presented in a 20-year-old female. Patient complained of left eye pain and redness for one week. Ocular examination together with ancillary testing led to the diagnosis of nodular scleritis. Since the patient did not show apparent improvement after one week of systemic steroidal treatment, she underwent a biopsy of the affected area revealing histopathological characteristics of IgG4-RD. Long-term treatment with corticosteroids and a steroid-sparing agent (methotrexate) led to significant improvement in signs and symptoms. This case highlights the significance of IgG4-RD in the differential diagnosis of scleritis and raises the question as to whether various organs affected by IgG4-RD may have different underlying pathophysiological mechanisms in which pathogenic T cells play a role.

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Waber, Deborah P., Jennifer Turek, Lori Catania, Kristen Stevenson, Philippe Robaey, Ivonne Romero, Heather Adams et al. "Neuropsychological Outcomes From a Randomized Trial of Triple Intrathecal Chemotherapy Compared With 18 Gy Cranial Radiation As CNS Treatment in Acute Lymphoblastic Leukemia: Findings From Dana-Farber Cancer Institute ALL Consortium Protocol 95-01". Journal of Clinical Oncology 25, n. 31 (1 novembre 2007): 4914–21. http://dx.doi.org/10.1200/jco.2007.10.8464.

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Purpose We evaluated late neuropsychological toxicity in children treated for standard-risk acute lymphoblastic leukemia (ALL) who were randomly assigned to receive either cranial radiation therapy (CRT) with double intrathecal (IT) chemotherapy or intensive triple IT chemotherapy (no CRT) as CNS-directed therapy. Patients and Methods Between 1996 and 2000, 164 children with standard-risk ALL treated on Dana-Farber Cancer Institute Consortium Protocol 95-01 were randomly assigned to receive either 18 Gy CRT delivered in twice daily fractions (0.9 Gy) with double IT therapy (methotrexate and cytarabine) or intensive triple IT drug (methotrexate, cytarabine and hydrocortisone) without CRT. Neuropsychological testing was completed at a median 6 years postdiagnosis for 79 children (CRT, n = 39; triple IT, n = 40), all of whom were in continuous complete remission. Results Cognitive function for both groups was solidly in the average range, with no consistent group differences in basic cognitive skills. Children treated on the CRT plus double IT arm did, however, exhibit less fluent output and were less effective at modulating their behavior by parent report. Conclusion This randomized trial revealed only subtle differences 6 years after diagnosis between children who received CNS therapy as CRT plus double IT drug or as intensive triple IT drug. In most situations where comparable therapeutic efficacy can be achieved without CRT, it is preferable to do so. Where therapeutically necessary, however, CRT at lower doses may not add risk for significant neurotoxicity.

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Shu, Jenny, Vivian P. Bykerk, Gilles Boire, Boulos Haraoui, Carol Hitchon, J. Carter Thorne, Diane Tin, Edward C. Keystone e Janet E. Pope. "Missing Anticitrullinated Protein Antibody Does Not Affect Short-term Outcomes in Early Inflammatory Arthritis: From the Canadian Early Arthritis Cohort". Journal of Rheumatology 42, n. 11 (1 settembre 2015): 2023–28. http://dx.doi.org/10.3899/jrheum.150260.

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Objective.Anticitrullinated protein antibody (ACPA) is as sensitive as, but more specific than, rheumatoid factor (RF) and is detected earlier in rheumatoid arthritis (RA). Although part of the RA classification criteria, ACPA testing is not routinely paid for/accessible in all jurisdictions. The effect of missing ACPA testing was studied to determine whether failure to perform ACPA testing could cause a care gap in early inflammatory arthritis.Methods.Nearly 2000 patients (n = 1998) recruited to an early inflammatory arthritis cohort were allocated into 3 groups: (1) seropositive (either RF+ or ACPA+), (2) seronegative (RF− and ACPA−), and (3) missing ACPA and RF−. Analyses were adjusted for age, sex, symptom duration, and smoking status if p < 0.1. Disease Activity Score at 28 joints (DAS28) at 3 months was studied, because beyond then, disease activity is expected to determine ongoing treatment.Results.More seropositive patients fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism RA criteria than seronegative patients. Group 3 was slightly older and had a smaller percentage of females, as well as shorter symptom duration and less smoking. At 3 months, group 3 was treated with fewer disease-modifying antirheumatic drugs and methotrexate (p < 0.00002) than groups 1 and 2, but there were no significant differences in DAS28, Health Assessment Questionnaire-Disability Index (HAQ-DI), proportion receiving corticosteroids, or physician’s/patient’s global assessments.Conclusion.There was no care gap in the RF-negative, unknown ACPA group because there were no significant differences in the DAS28, 3-month change in DAS28, or HAQ-DI, despite less treatment. Cost-effectiveness of ensuring ACPA testing availability in suspected RA is unknown because early outcomes did not differ, whether or not ACPA was available.

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Mazewski, Claire, Guolian Kang, Stewart Kellie, Jeffrey Gossett, Sarah Leary, Bryan Li, Paul Aridgides et al. "ETMR-20. IMPACT OF HIGH DOSE CHEMOTHERAPY WITH AND WITHOUT METHOTREXATE (MTX) ON OUTCOME OF PATIENTS WITH EMBRYONAL TUMORS WITH MULTI-LAYERED ROSETTES (ETMRs): A REPORT FROM CHILDREN’S ONCOLOGY GROUP PHASE III TRIAL ACNS0334". Neuro-Oncology 22, Supplement_3 (1 dicembre 2020): iii327. http://dx.doi.org/10.1093/neuonc/noaa222.223.

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Abstract Infant embryonal brain tumors comprise a spectrum of histologic and molecular entities including medulloblastoma (MB) and tumors collectively called CNS PNET’s, including supratentorial PNET (sPNET), pineoblastoma and other less common histologic entities. Non-MB embryonal tumors, historically considered high risk disease, were included in ACNS0334, A Children’s Oncology Group prospective phase III trial which compared efficacy of an induction regimen with and without methotrexate combined with high dose chemotherapy and stem cell rescue; no radiation was mandated. Molecular testing performed after ACNS0334 closure identified 14 patients with embryonal tumors with multi-layered rosettes (ETMRs), a new molecular entity previously classified under various diagnostic categories. ETMR patients made up 20% of the molecularly analyzed ACNS0334 cohort and were predominantly females. Tumors were largely non-metastatic (10/14 M0, 1 M1, 3 M2/M3) and originated in the cerebrum (8), cerebellum (3) and pineal gland (3). Gross total tumor resection was achieved in 5/11 patients with M0/M1 disease; 9/14 patients completed full treatment with 5 randomized to MTX induction and 9 to no-MTX. Five of 14 patients progressed on treatment, one had a toxic death. Disease progression was primarily local (88 %). No difference by methotrexate randomization was observed. Four patients are alive without progression 5–10+ years off therapy, none received radiation. No patients received radiation prior to progression. Four were irradiated after progression and died from disease within 3 to 13 months. Our study, a first report on ETMRs prospectively treated on a clinical trial, suggests high dose chemotherapy benefits a portion of ETMR patients.

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Triano, Matthew J., William D. Haberstroh, Abhishek Lenka e Sean A. Whelton. "Relapsed granulomatosis with polyangiitis with panhypopituitarism". BMJ Case Reports 14, n. 1 (gennaio 2021): e237774. http://dx.doi.org/10.1136/bcr-2020-237774.

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A man in his early 60s with a medical history of granulomatosis with polyangiitis (GPA) in remission for two decades without maintenance therapy presented with non-specific complaints of profound fatigue and 40-pound weight loss. He was seronegative for antinuclear antibodies and cytoplasmic antineutrophilic antibodies, but erythrocyte sedimentation rate and C reactive protein levels were elevated. Endocrinological testing revealed adrenal insufficiency, hypogonadism, hypothyroidism and diabetes insipidus. An MRI of the head revealed extensive sinonasal inflammation eroding through the floor of the sella turcica and into the pituitary gland and stalk. Biopsy of the sinonasal tissues was inconclusive. On review of his case, a multidisciplinary team diagnosed him with panhypopituitarism secondary to a recurrence of GPA. He responded well to glucocorticoids and methotrexate with marked reduction of pituitary enhancement on imaging and resolution of diabetes insipidus. He will require lifelong testosterone, levothyroxine and glucocorticoids for hormone replacement therapy.

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Giri, Bhupendra Raj, Jung Suk Kim, Jong Hyuck Park, Sung Giu Jin, Kyeong Soo Kim, Fakhar ud Din, Han Gon Choi e Dong Wuk Kim. "Improved Bioavailability and High Photostability of Methotrexate by Spray-Dried Surface-Attached Solid Dispersion with an Aqueous Medium". Pharmaceutics 13, n. 1 (16 gennaio 2021): 111. http://dx.doi.org/10.3390/pharmaceutics13010111.

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Low aqueous solubility and poor bioavailability are major concerns in the development of oral solid-dosage drug forms. In this study, we fabricated surface-attached solid dispersion (SASD) to enhance the solubility, bioavailability, and photostability of methotrexate (MTX), a highly lipophilic and photo-unstable drug. Several MTX-loaded SASD formulations were developed for spray-drying using water as the solvent, and were investigated for their aqueous solubility and dissolution kinetics. An optimized ternary SASD formulation composed of MTX/ sodium carboxymethyl cellulose (Na-CMC)/sodium lauryl sulfate (SLS) at 3/0.5/0.5 (w/w) had 31.78-fold and 1.88-fold higher solubility and dissolution, respectively, than MTX powder. For SASD, the in vivo pharmacokinetic parameters AUC and Cmax were 2.90- and 3.41-fold higher, respectively, than for the MTX powder. Solid-state characterizations by differential scanning calorimetry and X-ray diffraction revealed that MTX exists in its crystalline state within the spray-dried SASD. The MTX-loaded SASD formulation showed few physical changes with photostability testing. Overall, the results indicate that the spray-dried MTX-loaded SASD formulation without organic solvents enhances the solubility and oral bioavailability of MTX without a significant deterioration of its photochemical stability.

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Taylor, S. G., E. Applebaum, J. L. Showel, M. Norusis, L. D. Holinger, J. C. Hutchinson, A. K. Murthy e D. D. Caldarelli. "A randomized trial of adjuvant chemotherapy in head and neck cancer." Journal of Clinical Oncology 3, n. 5 (maggio 1985): 672–79. http://dx.doi.org/10.1200/jco.1985.3.5.672.

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Abstract (sommario):

Ninety-five patients with squamous cell carcinoma of the head and neck were entered into a randomized study testing a two-week course of induction chemotherapy with methotrexate and leucovorin given prior to regional therapy. In addition, following regional therapy, patients randomized to chemotherapy were to receive similar methotrexate courses every three months for one year. Poor tolerance to this regimen after radiation and surgery led to a change in the chemotherapy following regional therapy to a combination of Adriamycin (Adria Laboratories, Columbus, Ohio) and cisplatin every three weeks for four cycles after the first 35 patients had been entered. Nine cases were ineligible and four lacked any follow-up data, leaving 82 analyzable cases. Using Cox regression analysis, no differences in the percentage of patients achieving disease control, the relapse-free survival, or the overall survival were identified between any treatment group. As has been described in many pilot studies of induction chemotherapy of head and neck cancer, chemotherapy responders had a more favorable disease-free survival than chemotherapy nonresponders in the total group of patients receiving adjuvant chemotherapy. However, correcting for imbalances in the expected three year disease-free survival of these patients, based on their disease site and stage, erased this difference, indicating tumor response to this regimen of chemotherapy is not an independent factor affecting disease outcome. The division of patients into arbitrary prognostic categories based on the expected outcome for each specific tumor site and stage proved to be a useful method for balancing treatment groups, given the multiple site-stage combinations within the upper aerodigestive tract. The defined prognostic categories were the single most sensitive predictors of relapse-free and overall survival.

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Ali, Zain, Joanna Chyu, Mhd Hasan Almekdash e Mohamad M. Al-Rahawan. "ALL-058: Evaluating Urine pH and Specific Gravity: A Single-Center Experience Comparing Different Urine Testing Methods in Children Receiving High-Dose Methotrexate". Clinical Lymphoma Myeloma and Leukemia 21 (settembre 2021): S265—S266. http://dx.doi.org/10.1016/s2152-2650(21)01647-5.

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Bnatig, Fahad, Leen Raddaoui, Talal Hijji e Lina El Kibbi. "Mixed Cryoglobulinemia in a Patient with Juvenile Idiopathic Arthritis". Case Reports in Rheumatology 2019 (6 giugno 2019): 1–2. http://dx.doi.org/10.1155/2019/5858106.

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Cryoglobulinemia is a rare illness of cryoglobulin accumulation in the blood which can typically present with arthralgia, purpura, skin ulcers, glomerulonephritis, and peripheral neuropathy. It is classified as mixed cryoglobulinemia when cryoglobulins contain more than one immune component such as IgM rheumatoid factor and polyclonal IgG. Typically, it presents in the setting of clonal hematologic disease, viral infection, or certain connective tissue diseases. Herein, we report the case of a 24-year-old man diagnosed and treated as mixed cryoglobulinemia in the setting of juvenile idiopathic arthritis (JIA). Investigations for viral etiologies, including HBV, HCV, and HIV, and all serologic tests were negative. Additionally serum protein and urine protein electrophoresis did not reveal monoclonal gammopathy; however, testing for plasma cryoglobulins was positive, and qualitative analysis revealed a faint polyclonal pattern. Thus, he was diagnosed with cryoglobulinemia in the setting of JIA, which has not been reported in the literature before. He dramatically improved upon initiation of rituximab and methotrexate.

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MORI, SHUNSUKE, ISAMU CHO e MINEHARU SUGIMOTO. "A Followup Study of Asymptomatic Carriers ofPneumocystis jiroveciDuring Immunosuppressive Therapy for Rheumatoid Arthritis". Journal of Rheumatology 36, n. 8 (16 giugno 2009): 1600–1605. http://dx.doi.org/10.3899/jrheum.081270.

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Objective.To examine the preventive effects of prophylaxis againstPneumocystis jiroveci-induced pneumonia (PCP) in patients receiving immunosuppressive therapy for rheumatoid arthritis (RA) who are colonized by this organism.Methods.We performed molecular testing by polymerase chain reaction (PCR) forP. jirovecion induced sputum or bronchoalveolar lavage fluids of 82 patients with RA. During primary prophylaxis, asymptomatic carriers of this organism were examined by high-resolution computed tomography and PCR every 2 weeks. RA patients who had developed PCP received PCR tests every week. Once negative results were obtained, PCR testing was scheduled at Months 1, 3, and 6, followed by reexaminations every 6 months.Results.We found 9 cases of asymptomatic carriage ofP. jiroveci.All the carriers had received low doses of methotrexate. Upon introduction of PCP prophylaxis, 5 cases tested negative for PCR within 1 month. Three carriers developed PCP before starting prophylaxis, but these tested negative for PCR after short periods (1–2 weeks) of PCP treatment. OnceP. jiroveciwas eradicated, all cases maintained negative PCR results during followup without prophylactic intervention, even after resuming immunosuppressive therapy. One patient refused PCP prophylaxis, but no PCP developed.Conclusion.RA patients with asymptomatic carriage ofP. jirovecibenefited from short-term prophylaxis against PCP. Positive PCR results appeared to be predictive of future development of PCP in RA patients. Identification ofP. jirovecicarriers will encourage prompt introduction of PCP prophylaxis when rheumatologists consider immunosuppressive therapy for RA.

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Bouri, S., J. Geldof, J. Willsmore, S. Donnelly, S. Gabe e A. Hart. "P583 The prevalence of side effects to immunomodulators and biologics in patients with Crohn’s disease intestinal failure compared with Crohn’s disease without intestinal failure". Journal of Crohn's and Colitis 14, Supplement_1 (gennaio 2020): S488—S489. http://dx.doi.org/10.1093/ecco-jcc/jjz203.711.

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Abstract Background Treatment of Crohn’s disease (CD) involves medications and surgery but experiencing medication side effects (SE) limits medical options. The aim of this study was to compare SE experienced by patients with CD and intestinal failure (CD-IF) vs. CD without IF as this may contribute to a higher surgical requirement. Methods A single tertiary centre retrospective analysis was performed on CD-IF patients on parenteral nutrition due to short-bowel syndrome vs. small bowel CD without IF. Patients with CD without IF were selected from consecutive clinics who lived in the local catchment area. Results 94 CD-IF and 94 CD patients were included. The proportion of female patients was 56.4% (CD-IF) and 46.8% (CD); mean age was 51.2 (CD-IF) and 41.5 years (CD); mean duration of disease 24 years (CD-IF) and 16 years (CD). Most CD-IF patients had multiple resections. In the CD group, 50 patients never had surgery, 22 had 1 resection, and 9 had 2 or more. From the past medication history for these patients, the proportion in whom a medication was stopped due to SE was similar for CD-IF and CD for azathioprine, mercaptopurine and vedolizumab (Table 1). There were no SE to ustekinumab. Patients in the CD-IF group had a preceding history of significantly more SE to anti-TNF therapy and methotrexate were observed in CD-IF group, of which allergies were most frequent. In the CD group, 2 patients previously had an allergic reaction to infliximab whereas, in the CD-IF group 6 patients had a history of anaphylaxis and 5 an allergy to infliximab, 1 had an allergy to adalimumab and 3 to methotrexate (Table 2). Data on drug levels amongst those with allergy events were limited (due to prior availability of testing); of those tested, 1 had positive antibodies and 1 did not. The frequency of non-response and loss of response was similar between the two groups for each medication. Conclusion The frequency of SE to immunomodulators and biologics was similar between CD and CD-IF, except for anti-TNF therapy and methotrexate due to more allergy/anaphylaxis events in CD-IF. The frequency of these reactions may have caused an earlier shift towards surgical treatment. 92/94 CD-IF patients were diagnosed prior to 2014; it would be useful to review the incidence of CD-IF before 2014 (pre-vedolizumab and ustekinumab) vs. the new biological era.

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Ali, Zain, Joanna Chyu, Mhd Hasan Almekdash e Mohamad M. Al-Rahawan. "Poster: ALL-058: Evaluating Urine pH and Specific Gravity: A Single-Center Experience Comparing Different Urine Testing Methods in Children Receiving High-Dose Methotrexate". Clinical Lymphoma Myeloma and Leukemia 21 (settembre 2021): S206. http://dx.doi.org/10.1016/s2152-2650(21)01289-1.

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Claytor, Jennifer, Omar Viramontes, Stephanie Conner, Kwun Wah Wen, Kendall Beck, Timothy J. Henrich, Peter Chin-Hong, Peter Chin-Hong e Michael J. Peluso. "969. TNF-alpha inhibition in the setting of undiagnosed HIV infection: a call for enhanced screening guidelines". Open Forum Infectious Diseases 7, Supplement_1 (1 ottobre 2020): S514. http://dx.doi.org/10.1093/ofid/ofaa439.1155.

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Abstract Background Despite the risks of immunosuppression, recommendations regarding screening for HIV infection prior to initiation of biologic therapies targeting common autoimmune disorders, including inflammatory bowel disease (IBD) and inflammatory arthritides, are limited. Few cases of patients started on biologics while living with undiagnosed HIV have been reported. Methods We report 3 cases of patients initiated on biologics in the absence of recent or concurrent HIV screening who developed refractory disease or unanticipated complications and were later found to have undiagnosed chronic HIV infection. Results In Case 1, a 53-year-old man who has sex with men (MSM) with negative HIV testing 10 years prior presented with presumed rheumatoid arthritis. He did not respond to methotrexate (MTX), so adalimumab (ADA) was started. HIV testing to evaluate persistent symptoms was positive 9 months later; CD4 was 800 cells/uL. Antiretroviral therapy (ART) resulted in resolution of symptoms, which were attributed to HIV-associated arthropathy. In Case 2, a 55-year-old woman with injection drug use in remission and no prior HIV testing presented with Hidradenitis Suppurativa (HS). She was initiated on infliximab (IFX) and MTX with good response. After she developed weight loss and lymphopenia, an HIV test was positive; CD4 was 334 cells/uL. Biologic HS therapy was discontinued, with subsequent poor HS control. In Case 3, a 32-year-old MSM with no prior HIV testing presented with presumed IBD; IFX and steroids were started. Symptoms progressed despite IBD-directed therapy, and he was diagnosed with extensive Kaposi Sarcoma (KS) with visceral and cutaneous involvement likely exacerbated by immunosuppression. HIV testing was positive; CD4 was 250 cells/uL. KS initially worsened due to ART-associated immune reconstitution inflammatory syndrome. He is now improving with systemic chemotherapy and ART. HIV-associated KS is presumed to be hte underlying diagnosis. Conclusion All 3 patients had elevated risk for HIV infection, and 2 had final diagnoses attributed to chronic HIV infection, not warranting therapeutic immunosuppression. Screening for HIV infection prior to initiation of biologic therapy should be incorporated into clinical practice guidelines. Disclosures All Authors: No reported disclosures

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Alrajhi, Saad, Pascale Germain, Myriam Martel, Peter Lakatos, Talat Bessissow, Talal Al-Taweel e Waqqas Afif. "Concordance between tuberculin skin test and interferon-gamma release assay for latent tuberculosis screening in inflammatory bowel disease". Intestinal Research 18, n. 3 (30 luglio 2020): 306–14. http://dx.doi.org/10.5217/ir.2019.00116.

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Background/Aims: Latent tuberculosis screening is mandatory prior to initiating anti-tumor necrosis factor (anti-TNF) medications. Guidelines recommend interferon-gamma release assays (IGRA) as first line screening method for the general population. Studies provided conflicting evidence on IGRA and tuberculin skin test (TST) performance in inflammatory bowel disease (IBD) patients. We assessed test concordance and the effects of immunosuppression on their performance in IBD patients.Methods: We searched MEDLINE, Embase and Cochrane databases (2011–2018) for studies testing TST and IGRA in IBD. Primary outcome was TST and IGRA concordance. Secondary outcomes were effects of immunosuppressive therapy on performance. Immunosuppression defined as either steroids, thiopurine, methotrexate or cyclosporine use. We used the pooled random effects model to adjust for heterogeneity analyzed using (I2–Q statistics). We compared the fixed model to exclude smaller study effects.Results: Sixteen studies (2,488 patients) were included. Pooled TST and IGRA concordance was 85% (95% confidence interval [CI], 81%–88%; P=0.01). Effects of immunosuppression were reported in 8 studies (814 patients). The odds ratio of testing positive by IGRA decreased to 0.57 if immunosuppressed (95% CI, 0.31–1.03; P=0.06). The odds ratio of testing positive by TST if immunosuppressed was 1.14 (95% CI, 0.61–2.12; P=0.69). The fixed model yielded similar results, however the negative effect of immunosuppression on IGRA reached statistical significance (P=0.01).Conclusions: While concordance was 85% between TST and IGRA, the performance of IGRA seems to be negatively affected by immunosuppression. Given the importance of detecting latent tuberculosis prior to anti-TNF initiation, further randomized controlled trials comparing the performance of TST and IGRA in IBD patients are needed.

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Kager, Leo, Meyling H. Cheok, Wenjian Yang, Gianluigi Zaza, Ching-Hon Pui, James R. Downing, Mary V. Relling e William E. Evans. "Folate Pathway Gene Expression Differs in Genetic Subtypes of Acute Lymphoblastic Leukemia and Influences Methotrexate Pharmacodynamics." Blood 104, n. 11 (16 novembre 2004): 452. http://dx.doi.org/10.1182/blood.v104.11.452.452.

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Abstract Methotrexate (MTX) is an essential treatment component for acute lymphoblastic leukemia (ALL). The ability of leukemia cells to accumulate MTX in its polyglutamylated form (MTXPG) is recognized as an important determinant of its antileukemic effect. We measured in vivo MTXPG accumulation in leukemia cells from 101 children with ALL, and established that blasts of B-lineage ALL with either the TEL-AML1 (n=24 patients, median 911, range 338 to 5906 pmol/109 blasts) or E2A-PBX1 gene fusion (n=5, median 553, range 364 to 800 pmol/109 blasts) or T-lineage ALL (n=14, median 572, range 284 to 1468 pmol/109 blasts) accumulate significantly lower MTXPG, compared to those of other B-lineage ALL (BNHD, n=39, median 2210, range 186 to 9722 pmol/109 blasts) or hyperdiploid ALL (BHD, n=19, median 4375, range 377 to 9206 pmol/109 blasts) (E2A-PBX1 versus BHD, p=0.008; E2A-PBX1 vs. BNHD, p=0.010; TEL-AML1 vs. BHD, p<0.001; TEL-AML1 vs. BNHD, p=0.004; T-ALL vs. BHD and BNHD, p<0.001; p-values are from pair-wise comparisons using Wilcoxon rank sum test, adjusted for multiple testing using Holm’s method). To elucidate mechanisms underlying these differences in MTXPG accumulation, we used oligonucleotide microarrays (Affymetrix® HG-U133A) to analyze expression of 32 folate pathway genes (53 probe sets) in diagnostic bone marrow blasts from 197 children with ALL. This revealed ALL subtype-specific patterns of folate metabolism gene expression and identified differences in gene expression that discriminated the MTXPG accumulation phenotype in ALL cells. We found significantly lower expression of the reduced folate carrier (SLC19A1, MTX uptake transporter) in E2A-PBX1 ALL; significantly higher expression of breast cancer resistance protein (ABCG2, MTX efflux transporter) in TEL-AML1 ALL; and lower expression of FPGS (catalyzes formation of MTXPG) in T-ALL; consistent with lower MTXPG accumulation in these ALL subtypes. These findings reveal distinct mechanisms of subtype-specific differences in MTXPG accumulation and point to new strategies to overcome this potential cause of treatment failure in childhood ALL.

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DeLuca, Marie, Philip A. Gruppuso e Edward J. Wing. "Successful treatment of Takayasu’s arteritis in a HIV positive adult patient with long term follow up". Case Reports in Internal Medicine 3, n. 4 (16 agosto 2016): 14. http://dx.doi.org/10.5430/crim.v3n4p14.

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Although vasculitides occur in patients with HIV, only 4 previous cases of Takayasu’s arteritis (TA) have been reported in HIVpatients. We describe the first case of TA in an HIV positive patient with successful treatment and long term follow up. A38-year-old woman who was HIV positive for the last 5 years on antiretroviral medications presented with increasing pain in herleft arm. Blood pressure and pulse were unrecordable in that arm. Laboratory testing revealed hemoglobin 7.9 g/dl, CRP 98.8 mg/L, CD4 675 cells/μl and HIV viral load < 48 copies/ml. Both MRA and standard angiography demonstrated occlusion of theleft subclavian artery from its origin to the vertebral artery where it was reconstituted via retrograde flow from the left vertebralartery and left carotid artery branches (subclavian steal). Narrowing of the vertebral artery was also noted. Treatment withprednisone and methotrexate for one year improved her symptoms and stabilized her lesions without infectious complications. Follow up 4 years after stopping therapy revealed mild symptoms and stable lesions on MRA.

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Fernando, Suran L., Therese Boyle, Annika Smith e John D. E. Parratt. "The Successful Use of Infliximab in a Relapsing Case of Susac’s Syndrome". Case Reports in Neurological Medicine 2020 (10 giugno 2020): 1–6. http://dx.doi.org/10.1155/2020/9317232.

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Susac’s syndrome is a rare and debilitating disease characterized by the triad of encephalopathy, branch retinal artery occlusions, and sensorineural hearing loss. All manifestations may not be clinically apparent at presentation resulting in delayed diagnosis. Early recognition of the syndrome may prevent disease sequelae such as permanent cognitive, visual, and hearing loss. We present such a case of Susac’s syndrome that was also refractory to conventionally prescribed combination of immunosuppressive treatments including high-dose potent corticosteroids, intravenous cyclophosphamide, methotrexate, plasma exchange, rituximab, and mycophenolate. His disease was stabilized with infliximab in combination with a tapering course of low-dose prednisone. After 2 years of remission with TNF treatment, consideration is being given to ceasing therapy. He has the sequelae of bilateral sensorineural hearing loss but no visual impairment or cognitive deficits on follow-up with neuropsychometric testing. This is the first case report to our knowledge of the successful use of infliximab for a patient with Susac’s syndrome that was necessary following treatment with cyclophosphamide and then rituximab.

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Jones, S. E., J. C. Dean, L. A. Young e S. E. Salmon. "The human tumor clonogenic assay in human breast cancer." Journal of Clinical Oncology 3, n. 1 (gennaio 1985): 92–97. http://dx.doi.org/10.1200/jco.1985.3.1.92.

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The human tumor clonogenic assay (HTCA) was evaluated in 407 fresh samples of breast cancer from 288 patients. Seventy samples were inadequate for testing. Adequate in vitro growth for drug testing (greater than 30 colonies/plate) was obtained in 91 (27%) of the 337 viable samples, inadequate growth for drug evaluation (5 to 30 colonies/plate) in 17%, and no colony formation (less than 5 colonies/plate) in 56%. Operationally defining a greater than or equal to 50% inhibition of colony formation as in vitro drug sensitivity, the in vitro response rates to 12 anticancer drugs tested against ten to 36 different cancers (arranged in decreasing order according to the number of tests performed) were as follows: doxorubicin (14%), bisantrene (54%), vinblastine (33%), mitomycin (36%), interferon clone A (23%), 5-fluorouracil (20%), methotrexate (17%), leukocyte interferon (33%), mitoxantrone (42%), cyclophosphamide (25%), m-AMSA (16%), and melphalan (10%). Among 25 patients receiving single-agent therapy, there were ten (59%) of 17 with in vitro sensitivity who responded; resistance was correctly predicted in nine patients (100%), P = .01. Among 34 patients treated with combination chemotherapy, seven (50%) of 14 with in vitro sensitivity responded, and resistance was predicted in 13 (65%) of 20 patients. Difficulties in using the HTCA in breast cancer (including small specimen size, difficulties in disaggregation, and inadequacy of growth) will require additional research. Nonetheless, the assay appears to detect in vitro activity as well as resistance of a variety of anticancer agents and appears to predict clinical responsiveness to standard as well as some investigational single agents.

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