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"abstract": "To determine the safety, tolerability, and efficacy of fluoxetine for proven or presumptive enterovirus (EV) D68-associated acute flaccid myelitis (AFM).\n\n\n\nA multicenter cohort study of US patients with AFM in 2015-2016 compared serious adverse events (SAEs), adverse effects, and outcomes between fluoxetine-treated patients and untreated controls. Fluoxetine was administered at the discretion of treating providers with data gathered retrospectively. The primary outcome was change in summative limb strength score (SLSS; sum of Medical Research Council strength in all 4 limbs, ranging from 20 [normal strength] to 0 [complete quadriparesis]) between initial examination and latest follow-up, with increased SLSS reflecting improvement and decreased SLSS reflecting worsened strength.\n\n\n\nFifty-six patients with AFM from 12 centers met study criteria. Among 30 patients exposed to fluoxetine, no SAEs were reported and adverse effect rates were similar to unexposed patients (47% vs 65%, p = 0.16). The 28 patients treated with >1 dose of fluoxetine were more likely to have EV-D68 identified (57.1% vs 14.3%, p < 0.001). Their SLSS was similar at initial examination (mean SLSS 12.9 vs 14.3, p = 0.31) but lower at nadir (mean SLSS 9.25 vs 12.82, p = 0.02) and latest follow-up (mean SLSS 12.5 vs 16.4, p = 0.005) compared with the 28 patients receiving 1 (n = 2) or no (n = 26) doses. In propensity-adjusted analysis, SLSS from initial examination to latest follow-up decreased by 0.2 (95% confidence interval [CI] -1.8 to +1.4) in fluoxetine-treated patients and increased by 2.5 (95% CI +0.7 to +4.4) in untreated patients (p = 0.015).\n\n\n\nFluoxetine was well-tolerated. Fluoxetine was preferentially given to patients with AFM with EV-D68 identified and more severe paralysis at nadir, who ultimately had poorer long-term outcomes.\n\n\n\nThis study provides Class IV evidence that for patients with EV-D68-associated AFM, fluoxetine is well-tolerated and not associated with improved neurologic outcomes.",
"affiliations": "From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC. kevin.messacar@childrenscolorado.org.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.;From the Departments of Pediatrics (K.M., J.A.M., T.S., M.J.A., S.R.D.) and Neurology (K.M., S.S., J.A.M., T.S., K.L.T.), University of Colorado School of Medicine; Children's Hospital Colorado (K.M., A.L.H., J.A.M., T.S., M.J.A., S.R.D.), Aurora; Children's Hospital of Philadelphia (S.E.H.), PA; Seattle Children's Hospital (C.O.), University of Washington; Boston Children's Hospital (M.W.-M., L.A.B., M.P.G.), MA; Children's Hospital of Los Angeles (B.W., J.D.), CA; Stanford University (J.D.S., K.V.H.), Palo Alto, CA; University of California San Diego (A.T., A.H.T.); Phoenix Children's Hospital (H.K.B., M.C.K.), AZ; Boston Medical Center (A.T.), MA; Naval Medical Center of San Diego (L.Z.), CA; Departments of Pediatrics (J.R.G., N.M.) and Neurology (N.M.), Yale School of Medicine, New Haven, CT; and Children's National Medical Center (R.L.D.), Washington, DC.",
"authors": "Messacar|Kevin|K|;Sillau|Stefan|S|;Hopkins|Sarah E|SE|;Otten|Catherine|C|;Wilson-Murphy|Molly|M|;Wong|Brian|B|;Santoro|Jonathan D|JD|;Treister|Andrew|A|;Bains|Harlori K|HK|;Torres|Alcy|A|;Zabrocki|Luke|L|;Glanternik|Julia R|JR|;Hurst|Amanda L|AL|;Martin|Jan A|JA|;Schreiner|Teri|T|;Makhani|Naila|N|;DeBiasi|Roberta L|RL|;Kruer|Michael C|MC|;Tremoulet|Adriana H|AH|;Van Haren|Keith|K|;Desai|Jay|J|;Benson|Leslie A|LA|;Gorman|Mark P|MP|;Abzug|Mark J|MJ|;Tyler|Kenneth L|KL|;Dominguez|Samuel R|SR|",
"chemical_list": "D000998:Antiviral Agents; D005473:Fluoxetine",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000006670",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "92(18)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000998:Antiviral Agents; D020805:Central Nervous System Viral Diseases; D002648:Child; D002675:Child, Preschool; D005260:Female; D005473:Fluoxetine; D006801:Humans; D008297:Male; D009187:Myelitis; D009468:Neuromuscular Diseases; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "e2118-e2126",
"pmc": null,
"pmid": "30413631",
"pubdate": "2019-04-30",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural",
"references": "27318332;27422805;27640319;24453152;23335743;28968718;25775436;29386095;27063860;12454556;28615421;11986128;26149998;25638662;8369643;17879907;25299607;26369972;15886723;26720027;20928945;29482893",
"title": "Safety, tolerability, and efficacy of fluoxetine as an antiviral for acute flaccid myelitis.",
"title_normalized": "safety tolerability and efficacy of fluoxetine as an antiviral for acute flaccid myelitis"
} | [
{
"companynumb": "US-ALLERGAN-1855028US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
"drugadditional": "4... |
{
"abstract": "BACKGROUND\nThe prevalence of neonatal hypertension in neonatal intensive care units (NICU) ranges between 3 and 9%. However, there is no current data on Latin America.\n\n\nOBJECTIVE\nTo estimate the prevalence of neonatal hypertension and to assess its association with causes previously related to this condi tion.\n\n\nMETHODS\ncross-sectional study. All patients admitted to the NICU during one year were included, excluding those transferred to the cardiovascular NICU. The following maternal and neonatal variables were registered: maternal arterial hypertension, type of delivery, gestational age, age, sex, birth weight, Apgar score, history of pulmonary maturation with corticosteroids, and umbilical vessel catheterization as well as the reason for admission to the NICU, medications, and complications during hospitalization. Blood pressure was measured with an automated oscillometric device, defining neonatal hypertension according to standards in gestational age. Prevalence was ex pressed as percentage (confidence interval 95%, CI95%). Descriptive data were reported as median (range) and frequency of presentation (percentage). Finally, we used the Wilcoxon, Chi2 o Fisher exact test to identify factors related to NH as applicable (p < 0.05).\n\n\nRESULTS\n169 patients were in cluded (60% males). Gestational age was 38 weeks (range 26-42 weeks), 38% were preterm. Birth weight was 3000 g (range 545-4950 g) and 32% presented low birth weight. Eight patients presented hypertension during hospitalization (4.7% prevalence, CI95% 2.4-9). The presence of hypertension was associated with prematurity (p = 0.0003), low birth weight (p = 0.01), prenatal corticosteroid treatment (p = 0.002), umbilical catheterization (p = 0.03), administration of ὅ 2 nephrotoxic drugs (p = 0.02), caffeine treatment (p = 0.0001), acute kidney injury (p = 0.02), and intracranial hyper tension (p = 0.04). Only one patient required antihypertensive pharmacologic treatment and in all cases, hypertension was resolved during follow-up.\n\n\nCONCLUSIONS\nPrevalence of neonatal hypertension in our NICU was 4.7% and in all cases occurred in preterm newborns with previously recognized factors associated with this condition.",
"affiliations": "Hospital General de Niños Pedro de Elizalde, Ciudad Autónoma de Buenos Aires, Argentina.;Hospital General de Niños Pedro de Elizalde, Ciudad Autónoma de Buenos Aires, Argentina.;Hospital General de Niños Pedro de Elizalde, Ciudad Autónoma de Buenos Aires, Argentina.;Hospital General de Niños Pedro de Elizalde, Ciudad Autónoma de Buenos Aires, Argentina.",
"authors": "Balestracci|Alejandro|A|;Capone|Marina Andrea|MA|;Toledo|Ismael|I|;Sticotti|Sebastián|S|",
"chemical_list": null,
"country": "Chile",
"delete": false,
"doi": "10.32641/rchped.vi91i6.26974",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0370-4106",
"issue": "91(6)",
"journal": "Revista chilena de pediatria",
"keywords": null,
"medline_ta": "Rev Chil Pediatr",
"mesh_terms": "D001724:Birth Weight; D003430:Cross-Sectional Studies; D005260:Female; D005500:Follow-Up Studies; D005865:Gestational Age; D006760:Hospitalization; D006801:Humans; D006973:Hypertension; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D008297:Male; D015995:Prevalence; D012307:Risk Factors",
"nlm_unique_id": "0404261",
"other_id": null,
"pages": "891-898",
"pmc": null,
"pmid": "33861825",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prevalence of Arterial Hypertension in a neonatal intensive care unit.",
"title_normalized": "prevalence of arterial hypertension in a neonatal intensive care unit"
} | [
{
"companynumb": "AR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-285728",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAFFEINE"
},
"drugad... |
{
"abstract": "Autologous hematopoietic stem cell transplantation (AHSCT) is thought to be effective therapeutic approach in patients with poor prognosis systemic sclerosis; however, the toxicity remains a challenge. Between years 2003 and 2016, we enrolled 18 patients with systemic sclerosis at median age at transplant of 52 years (range 24-68). The median duration of disease before AHSCT was 14 months (range 2-85). Peripheral blood stem cells were mobilized with cyclophosphamide (CY) and granulocyte colony-stimulating factor. Conditioning regimen included CY (200 mg/kg) and alemtuzumab (median dose, 60 mg) [n = 11], melphalan (MEL; 140 mg/m2) and alemtuzumab [n = 2], CY and rabbit anti-thymocyte globulin (rATG; 7.5 mg/kg) [n = 4], and CY alone (n = 1). Four deaths occurred early after transplant. There were three males and one female at median age at death of 51 years (range 24-68). The AHSCT-related deaths have been observed on days + 1, + 4, + 9, and + 15 after procedure. The causes of death included bilateral pneumonia followed by multi-organ failure in three patients and myocardial infarction in one. Three patients expired late during post-transplant follow-up, after 5, 21, and 42 months. The causes of death were disease progression in two patients and sudden heart attack in one. Eleven patients are alive after median follow-up after AHSCT of 42.0 months (range 0-95). Before proceeding to AHSCT in systemic sclerosis, there is a strong need to optimize patient selection to reduce toxicity. The administration of alemtuzumab should be avoided due to high risk of life-threatening infectious complications.",
"affiliations": "School of Medicine in Katowice, Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland. ghelbig@o2.pl.;School of Medicine in Katowice, Department of Rheumatology, Medical University of Silesia, Katowice, Poland.;School of Medicine in Katowice, Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland.;School of Medicine in Katowice, Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland.;Students' Research Group, School of Medicine in Katowice, Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland.;Students' Research Group, School of Medicine in Katowice, Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland.;Students' Research Group, School of Medicine in Katowice, Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland.;Students' Research Group, School of Medicine in Katowice, Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland.;School of Medicine in Katowice, Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland.;School of Medicine in Katowice, Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland.;School of Medicine in Katowice, Department of Rheumatology, Medical University of Silesia, Katowice, Poland.;School of Medicine in Katowice, Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Dąbrowski street 25, 40-032, Katowice, Poland.",
"authors": "Helbig|Grzegorz|G|http://orcid.org/0000-0003-3703-1268;Widuchowska|Małgorzata|M|;Koclęga|Anna|A|;Kopińska|Anna|A|;Kopeć-Mędrek|Magdalena|M|;Gaweł|Władysław B|WB|;Spałek|Adrianna|A|;Żak|Jakub|J|;Grygoruk-Wiśniowska|Iwona|I|;Liwoch|Robert|R|;Kucharz|Eugeniusz|E|;Markiewicz|Mirosław|M|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-017-3954-5",
"fulltext": "\n==== Front\nClin RheumatolClin. RheumatolClinical Rheumatology0770-31981434-9949Springer London London 395410.1007/s10067-017-3954-5Brief ReportSafety profile of autologous hematopoietic stem cell mobilization and transplantation in patients with systemic sclerosis http://orcid.org/0000-0003-3703-1268Helbig Grzegorz 0048322591310ghelbig@o2.pl 1Widuchowska Małgorzata 2Koclęga Anna 1Kopińska Anna 1Kopeć-Mędrek Magdalena 3Gaweł Władysław B. 3Spałek Adrianna 3Żak Jakub 3Grygoruk-Wiśniowska Iwona 1Liwoch Robert 1Kucharz Eugeniusz 2Markiewicz Mirosław 11 0000 0001 2198 0923grid.411728.9School of Medicine in Katowice, Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Dąbrowski street 25, 40-032 Katowice, Poland 2 0000 0001 2198 0923grid.411728.9School of Medicine in Katowice, Department of Rheumatology, Medical University of Silesia, Katowice, Poland 3 0000 0001 2198 0923grid.411728.9Students’ Research Group, School of Medicine in Katowice, Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland 18 12 2017 18 12 2017 2018 37 6 1709 1714 23 10 2017 15 11 2017 12 12 2017 © The Author(s) 2017\nOpen Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Autologous hematopoietic stem cell transplantation (AHSCT) is thought to be effective therapeutic approach in patients with poor prognosis systemic sclerosis; however, the toxicity remains a challenge. Between years 2003 and 2016, we enrolled 18 patients with systemic sclerosis at median age at transplant of 52 years (range 24–68). The median duration of disease before AHSCT was 14 months (range 2–85). Peripheral blood stem cells were mobilized with cyclophosphamide (CY) and granulocyte colony-stimulating factor. Conditioning regimen included CY (200 mg/kg) and alemtuzumab (median dose, 60 mg) [n = 11], melphalan (MEL; 140 mg/m2) and alemtuzumab [n = 2], CY and rabbit anti-thymocyte globulin (rATG; 7.5 mg/kg) [n = 4], and CY alone (n = 1). Four deaths occurred early after transplant. There were three males and one female at median age at death of 51 years (range 24–68). The AHSCT-related deaths have been observed on days + 1, + 4, + 9, and + 15 after procedure. The causes of death included bilateral pneumonia followed by multi-organ failure in three patients and myocardial infarction in one. Three patients expired late during post-transplant follow-up, after 5, 21, and 42 months. The causes of death were disease progression in two patients and sudden heart attack in one. Eleven patients are alive after median follow-up after AHSCT of 42.0 months (range 0–95). Before proceeding to AHSCT in systemic sclerosis, there is a strong need to optimize patient selection to reduce toxicity. The administration of alemtuzumab should be avoided due to high risk of life-threatening infectious complications.\n\nKeywords\nAutologous hematopoietic stem cell transplantationComplicationsMobilizationSystemic sclerosisToxicityissue-copyright-statement© International League of Associations for Rheumatology (ILAR) 2018\n==== Body\nIntroduction\nSystemic sclerosis is a chronic, multisystem autoimmune disease which heterogeneous manifestation results from inflammation, vasculopathy, and fibrosis. Disease outcome is variable; however, patients with diffuse cutaneous and visceral organ involvement have the worst prognosis with a significantly reduced life-span [1, 2]. It was demonstrated that rapid skin thickness progression in systemic sclerosis was associated with early renal involvement and predicted shorter survival [3]. Similarly, diffuse cutaneous involvement with any organ damage (especially lung) was found to have poor outcome [4]. Treatment approach for patients with systemic sclerosis is complex and takes into account disease stage and organ complications. Immunosuppressants remain a cornerstone of treatment, although the supportive care plays a significant role [5]. Autologous hematopoietic stem cell transplantation (AHSCT) is thought to reset the patient’s abnormal immune system and this procedure was demonstrated to be more effective if compared with intravenous pulses of cyclophosphamide in patients with poor prognosis disease. Nevertheless, the safety of AHSCT remains a challenge [6].\n\nThe aim of our study was to assess the toxicity of mobilization and transplantation in 18 patients with poor prognosis systemic sclerosis.\n\nMaterial and methods\nBetween years 2003 and 2016, 18 patients were enrolled in the study at the Department of Hematology and Bone Marrow Transplantation in Katowice, Poland. They were recruited after a detailed work-up performed in a close cooperation with the Department of Rheumatology in Katowice, Poland. The institutional review board approved the study design and all patients provided an informed consent in accordance with the Declaration of Helsinki.\n\nThe main indication for transplant was progressive systemic sclerosis with poor response to or no response to conventional treatment. Patients were eligible for study participation if they met the following criteria: (1) a Karnofsky score of 80 or more, (2) 70 years of age or less, (3) disease duration of < 10 years with no severe co-morbidities, (4) diffuse systemic sclerosis with the modified Rodnan skin score (mRss) ≥ 15 or less, but coexistent pulmonary involvement, and (5) early pulmonary involvement with forced vital capacity (FVC) or hemoglobin-adjusted diffusion capacity of the lung for carbon monoxide (DLCO) between 80–40% predicted or decline in FVC > 10% or DLCO > 15% on serial testing. Pulmonary arterial hypertension, renal and cardiac insufficiency, and FVC/hemoglobin-adjusted DLCO < 40% predicted were the main exclusion criteria.\n\nThe following evaluations must be performed before study entry: a detailed medical history, physical examination, complete blood count with differential, biochemistry, autoantibody assessments, mRss measurements, pulmonary function tests including the measurement of forced vital capacity (FVC), and diffusion capacity of the lung for carbon monoxide (DLCO), electrocardiogram, and echocardiogram for left ventricular ejection fraction (LVEF).\n\nThe median duration of disease before AHSCT was 14 months (range 2–85). Except skin, the most common clinical involvements included lungs (77%) and heart (44%). Eighty-three percent of study patients had positive anti-nuclear antibodies. Cyclophosphamide was the most frequent agent administered for systemic sclerosis before transplant (61%).\n\nPeripheral blood stem cells were mobilized with cyclophosphamide (CY; 2.0 g/m2 IV on days 1–2) followed by granulocyte colony-stimulating factor (G-CSF; 10 μg/kg) from day +5 after CY administration until apheresis. The CD34-positive cells were mobilized using Optia Spectra cell separator (Caridian BCT, Lakewood, CO, USA) and cryopreserved in liquid nitrogen at − 170 C. The minimum number of stem cells required for AHSCT was 2.0 × 106 CD34+ per kg of body weight (b.w.). Conditioning regimen included CY (200 mg/kg) and alemtuzumab (median dose, 60 mg) [n = 11], melphalan (MEL; 140 mg/m2) and alemtuzumab [n = 2], CY and rabbit anti-thymocyte globulin (rATG; 7.5 mg/kg) [n = 4], and CY alone (n = 1). Supportive care after transplant included co-trimoxazole and fluconazole. Thirteen patients required post-transplant G-CSF support. Blood products were irradiated and leukocyte-depleted. Patient characteristics at diagnosis are described in Table 1.Table 1 Patients characteristics at study entry\n\nCharacteristic\t\nN = 18\t\nAge at diagnosis: years (median; range)\t50 (23–67)\t\nAge at transplant: years (median; range)\t51.5 (24–68)\t\nSex: male/female\t10/8\t\nWBC count (× 109/L); median, range\t9.75 (4.1–17.2)\t\nPLT count (× 109/L); median, range\t323 (174–740)\t\nHGB concentration (g/dL); median, range\t12.2 (9.7–15.2)\t\n\nSerum autoantibodies, n (%)\t\nAnti-nuclear (ANA)\t18 (100)\t\nAnti-Scl70\t17 (94)\t\nAnti-RNA polymerase (ARA)\t1 (6)\t\nGFR; median, range\t125.4 (53.2–225.3)\t\nFVC (%), median, range\t81.7 (62–109)\t\nDLCO (%), median, range\t64 (40–98)\t\nLVEF (%), median, range\t55 (45–65)\t\nBMI, median, range\t22.5 (17–30.5)\t\nmRss, median, range\t21.5 (8–39)\t\nThe summed Medsger severity score (mean ± SD)\t7.39 (± 3.58)\t\n\nClinical manifestation; n (%)\t\nRaynaud phenomenon\t16 (89)\t\nPulmonary fibrosis\t9 (50)\t\nPulmonary hypertension\t2 (11)\t\nAbnormal electrocardiogram\t8 (44)\t\nGastroesophageal reflux\t4 (22)\t\nProteinuria\t1 (6)\t\n\nPrior treatment; n (%)\t\nCyclophosphamide\t11 (61)\t\nCorticosteroids\t9 (50)\t\nMethotrexate\t5 (28)\t\nAzathioprine\t1 (6)\t\nMycophenolate mofetil\t1 (6)\t\n\nd-Penicillamine\t1 (6)\t\n\nBMI body mass index, DLCO diffusing capacity of lung for carbon monoxide, GFR glomerular filtration rate, FVC forced vital capacity, HGB hemoglobin, LVEF left ventricular ejection fraction, mRss the modified Rodnan skin score, PLT platelets, WBC white blood cell\n\n\n\n\nResults\nMobilization data\nWe enrolled 18 patients with systemic sclerosis (ten male and eight female) with median age at transplant of 52 years (range 24–68). Median number of two apheresis (range 1–5) was needed to harvest a sufficient number of CD34-positive cells for transplant. The median number of mobilized CD34+ cells/kg b.w. was 3.9 × 106/kg (range 2.1–13.9). There have been no life-threatening complications during mobilization and stem cell collection. One patient developed fever of unknown origin and one patient suffered from mild infection of upper respiratory tract. Median hospital stay was 14 days (range 6–24). No blood support was needed.\n\nTransplant data\nNeutrophil recovery (absolute neutrophil count > 0.5 × 109/L for three consecutive days) was achieved after median of 10 days (range 0–17). The platelet engraftment (platelet count > 20 × 109/L for three consecutive days without transfusions) was achieved after median of 5 days (range 0–16). Thirteen and nine patients received post-transplant red blood cells (RBCs) and platelet (PLT) support, respectively. Median number of RBCs and PLT transfusions was 2 (range 2–5) and 12 (range 2–30), respectively. Median hospital stay was 23 days (range 12–49). Transplant data were shown in Table 2.Table 2 Stem cells mobilization and transplant data\n\nStem cells mobilization and transplant data\t\nCY dose (mg); median (range)\t3000 (2000–7200)\t\nG-CSF total dose (μg); median (range)\t4880 (2800–12,480)\t\nTotal number of apheresis; median (range)\t2 (1–5)\t\nCD34+ cells in apheresis (%); median (range)\t0.62 (0.14–1.45)\t\nCD34+ cells in apheresis (× 106); median (range)\t3.9 (2.1–13.9)\t\nTotal nucleated cell count in apheresis (108/kg); median (range)\t8.61 (4.14–17.08)\t\nStem cells transplant data\t\n\nConditioning\n\t\nCY; n\n\t16\t\nCY dose in mg; median (range)\t12,300 (5600–18,800)\t\nAlemtuzumab; n\n\t13\t\nAlemtuzumab dose in mg; median (range)\t60 (30–60)\t\nrATG; n\n\t4\t\nrATG dose in mg; median (range)\t300 (225–375)\t\nMEL; n\n\t2\t\nMEL dose in mg\t200\t\n\nEngraftment and supportive care\n\t\nANC > 0.5 × 109/L; day, median (range)\t10 (0–17)\t\nPLT count > 20 × 109/L; day, median (range)\t5 (0–16)\t\nRBC support; units, median (range)\t2 (2–5)\t\nPLT support; units, median (range)\t12 (2–30)\t\nIVIG (g); median (range)\t10 (6–24)\t\nG-CSF (μg); median (range)\t2400 (300–3600)\t\n\nFollow-up\n\t\nMedian hospital stay; (days); median, range\t23 (12–47)\t\nFollow-up duration after transplant (months), median (range)\t42 (0–95)\t\nPatients alive; n (%)\t11 (61)\t\nAHSCT-related death; n (%)\t4 (22)\t\nLate post-AHSCT deaths; n (%)\t3 (16)\t\nPost-AHSCT disease progression; n (%)\t5 (45)\t\n\nAHSCT autologous hematopoietic stem cell transplantation, ANC absolute neutrophil count, rATG rabbit anti-thymocyte globulin, CY cyclophosphamide, G-CSF granulocyte colony-stimulating factor, IVIG immunoglobulin, MEL melphalan, PLT platelet\n\n\n\n\nFour deaths occurred early after transplant. There have been three males and one female at median age at death of 51 years (range 24–68). The AHSCT-related deaths have been observed on days + 1, + 4, + 9, and + 15 after procedure. The causes of death included bilateral pneumonia followed by multi-organ failure in three patients and myocardial infarction in one. The time from diagnosis to AHSCT was 1 year in all expired patients (details were presented in Table 3).Table 3 Summary of early deaths after transplant\n\nAge (years)\tSex\tCo-morbidities\tTime from diagnosis to AHSCT (mo)\tLVEF (%)\tConditioning\tTime from AHSCT to death (days)\tCause of death\t\n68\tF\tHypertension; arrhythmia; diabetes; hypothyroidism\t12\t55\tCY and alemtuzumab\t4\tBilateral pneumonia\t\n53\tM\tHypertension\t12\t55\tCY and rATG\t9\tBilateral pneumonia\t\n46\tM\tNA\t11\t55\tCY\t1\tBilateral pneumonia probably Candida-related\t\n24\tM\tLBBB\t12\t55\tMEL and alemtuzumab\t15\tMyocardial infarction\t\n\nAHSCT autologous hematopoietic stem cell transplantation, CY cyclophosphamide, LBBB left bundle branch block, LVEF left ventricular ejection fraction, MEL melphalan, NA not applicable, rATG rabbit anti-thymocyte globulin\n\n\n\n\nThe other early side effects of transplantation included fever of unknown origin (n = 8), transient cardiac arrhythmia (n = 6), mucositis grade 1/2 (n = 4), urinary tract infection (n = 1), and anxiety attacks (n = 1). All blood and urine cultures were negative. Candida species was demonstrated in throat culture in two patients and Enterobacter cloacae in one. One sputum culture was positive for Candida glabrata.\n\nLate safety data\nThree patients expired during post-AHSCT follow-up, after 5, 21, and 42 months. The causes of death resulted from disease progression in two patients and sudden heart attack in one.\n\nFollow-up\nEleven patients are alive after median follow-up after AHSCT of 42.0 months (range 0–95). Among those patients, we have found a significant reduction in mRss at 12 months after transplant compared to baseline assessment. There was no significant change in lung function. Five out 11 living patients had disease progression and required the introduction of immunosuppressive treatment.\n\nDiscussion\nStem cell transplantation remains an effective therapeutic approach for patients with severe systemic sclerosis; however, one should bear in mind its toxicity mainly affecting the cardiopulmonary system [6]. Several study groups have shown that AHSCT in systemic sclerosis resulted in long-term improvements in skin thickness and pulmonary function, but its efficacy may be tempered by relatively high treatment-related mortality and morbidity. The up-to-date largest randomized clinical trial (ASTIS) compared the safety of AHSCT vs 12 successive monthly intravenous cyclophosphamide in 156 patients randomly assigned to receive AHSCT (n = 79) and CY (n = 77). It was demonstrated that AHSCT was associated with increased treatment-related mortality in first year after procedure; however, its use outperformed CY pulses in long-term event-free survival. In total, eight deaths were deemed to be treatment-related in AHSCT cohort (10%) vs none in CY group. Viral infections were also commonly seen in AHSCT group (28%) which was probably due to ATG use. Importantly, two patients developed EBV-driven post-transplant lymphoproliferative disease. Of note is that two patients expired during mobilization/consolidation period (respiratory failure in both). Three of eight deaths were found to be cardiac-related. More than 60% of transplanted patients developed grade 3 or 4 adverse events, which mainly affected the respiratory and cardiovascular system [7]. These findings were in contrast with data reported by Burt et al. [8] in the first published randomized trial of AHSCT vs CY in patients with systemic sclerosis (ASSIST). The authors enrolled only 19 patients, ten of them were allocated to receive AHSCT. Of note is that no patient died during the study nor developed serious adverse events. This favorable toxicity profile was probably due to small number of included patients and short-term follow-up (2 years). The center experience may also play a role.\n\nWhatever the preparative regimen is selected for transplantation in systemic sclerosis, it is obvious that this procedure carries a substantial risk of morbidity and mortality. Many factors may have an impact on the outcome of transplant procedure and they are as follows: regimen intensity, age of patient, disease duration, the Karnofsky index, and co-morbidities. A special attention should be directed at those co-morbidities which are thought to be sclerosis-related, e.g., decreased LVEF or pulmonary arterial hypertension (PAH) [9]. The use of CY in stem cell harvesting is a commonly accepted practice; however, the preparative regimens differ between centers. Regarding the latter issue, the compromise between efficacy and toxicity should be achieved. Based on the results of ASTIS protocol, the administration of CY at 200 mg/kg of b.w. with rATG 7.5 mg/kg b.w. seems to be a reasonable choice [7]. This protocol was recently implemented in our center, but past regimens were different with relatively wide use of anti-CD52 antibody—alemtuzumab. Due to heterogeneity of regimens used in our center, it is difficult to conclude on their impact on post-transplant mortality. However, five deaths occurred in patients who received alemtuzumab (three of five patients died due to fast-progressing pneumonia). Among our eight expired patients (five in the first year after transplant), CY combined with alemtuzumab was administered in 3/11 (27%), MEL with alemtuzumab in 2/2 (100%), CY in one (100%), and CY with rATG in 1/4 (25%). Two patients from our cohort died from cardiac failure as a consequence of myocardial infarction. Both patients received alemtuzumab in their conditioning. One of them, a 24-year-old male, was found to have left bundle branch block in electrocardiogram before transplant, the second, a 55-year-old male, had no prior history towards cardiac disease. Left ventricular function was normal throughout the study period as measured by LVEF. There was also no evidence of left ventricular dysfunction in electrocardiogram. Unfortunately, cardiac autopsy was not performed as deaths occurred in local hospitals. We did not observe viral reactivations in our patients and febrile neutropenia with negative cultures was the commonest side effect.\n\nBased on the results presented by the North American Group [10], it is reasonable to avoid total body irradiation (TBI) as preparative regimen for transplant. Treatment-related death was 24% in this study and that was the reason of protocol amendment. The other groups have shown much better results with treatment-related mortality fluctuated between 6 and 17% [8, 10, 12]. We must admit that our results with mortality rate of 27% in first year after transplant were at least discouraging, but the avoidance of alemtuzumab and better patients’ selection in terms of cardiopulmonary co-morbidities resulted in significant safety improvements in the following years.\n\nA proper patients’ selection to transplant as well as center experience may play a role in decreasing mortality. The key point is to identify patients at risk of the development of post-transplant life-threatening complications. The screening of cardiac function using only electrocardiogram and echocardiography remains insufficient in the light of our prior experience in this patient population. The clinical utility of right and left heart catheterization as well as cardiac magnetic resonance imaging has been demonstrated in recently published studies, as these tests may identify patients with occult heart disease [11, 12]. Of note is that despite such careful heart examination, four patients died from sudden cardiac arrests during mobilization and transplantation [11]. The updated recommendations regarding cardiopulmonary assessment in patients with systemic sclerosis proceeding to AHSCT have recently been published [13]. Of note is that all patients from our cohort were negatively screened towards PAH.\n\nInterestingly, the post-transplant outcome of non-smokers was far better if compared with ever smokers in up-to-date largest study [7]. In our study group, we identified only three smokers (16%), one of them died from disease progression late after transplant.\n\nOne should also keep in mind other factors that may have an impact on post-transplant outcome. Our suggestions include the tight control of fluid status, monitoring of electrolytes, steroids before ATG, and prophylactic use of acyclovir and co-trimoxazole. The prophylactic administration of angiotensin-converting enzyme (ACE) inhibitors seems to be controversial since the cases of sclerosis-related renal crisis were reported [14].\n\nBy offering patients a transplant, we must be aware of late consequence of this procedure, especially the development of secondary autoimmune disorders or malignancies [15].\n\nConclusions\nAHSCT may remain an interesting therapeutic option for poor-risk patients with systemic sclerosis; however, there is a strong need to optimize patient selection to reduce toxicity and identify those who could benefit most from this procedure. It seems reasonable to propose a pre-transplant work-up which would be focused on cardiopulmonary screening to mitigate toxic effects of AHSCT. The administration of alemtuzumab should be avoided due to high risk of developing life-threatening infectious complications.\n\nCompliance with ethical standards\nDisclosures\nNone.\n==== Refs\nReferences\n1. Gabrielli A Avvedimento E Krieg T Mechanisms of disease: scleroderma N Engl J Med 2009 360 19 1989 2003 10.1056/NEJMra0806188 19420368 \n2. Mayes MD Lacey JVJ Beebe-Dimmer J Gillespie GW Cooper B Laing TJ Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population Arthritis Rheum 2003 48 8 2246 2255 10.1002/art.11073 12905479 \n3. Domsic RT Rodriguez-Reyna T Lucas M Fertig N Medsger TA Jr Skin thickness progression rate: a predictor of mortality and early internal organ involvement in diffuse scleroderma Ann Rheum Dis 2011 70 1 104 109 10.1136/ard.2009.127621 20679474 \n4. Nihtyanova SI Schreiber BE Ong VH Rosenberg D Moinzadeh P Coghlan JG Wells AU Denton CP Prediction of pulmonary complications and long-term survival in systemic sclerosis Arthritis Rheumatol 2014 66 6 1625 1635 10.1002/art.38390 24591477 \n5. Nihtyanova SI Ong VH Denton CP Current management strategies for systemic sclerosis Clin Exp Rheumatol 2014 32 2 Suppl 81 156 164 24742450 \n6. Van Laar JM Sullivan K Stem cell transplantation in systemic sclerosis Curr Opin Rheumatol 2013 25 6 719 725 10.1097/01.bor.0000434669.32150.ac 24047607 \n7. Van Laar JM Farge D Sont JK Naraghi K Marjanovic Z Larghero J Autologous hematopoietic stem cell transplantation vs intravenous cyclophosphamide in diffuse cutaneous systemic sclerosis JAMA 2014 24 2490 2498 10.1001/jama.2014.6368 \n8. Burt RK Shah SJ Dill K Grant T Gheorghiade M Schroeder J Craig R Hirano I Marshall K Ruderman E Jovanovic B Milanetti F Jain S Boyce K Morgan A Carr J Barr W Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomized phase 2 trial Lancet 2011 378 9790 498 506 10.1016/S0140-6736(11)60982-3 21777972 \n9. Binks M Passweg JR Furst D McSweeney P Sullivan K Besenthal C Finke J Peter HH van Laar J Breedveld FC Fibbe WE Farge D Gluckman E Locatelli F Martini A van den Hoogen F van de Putte L Schattenberg AV Arnold R Bacon PA Emery P Espigado I Hertenstein B Hiepe F Kashyap A Kötter I Marmont A Martinez A Pascual MJ Gratwohl A Prentice HG Black C Tyndall A Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease Ann Rheum Dis 2001 60 6 577 584 10.1136/ard.60.6.577 11350846 \n10. Nash RA McSweeney PA Crofford LJ Abidi M Chen CS Godwin JD Gooley TA Holmberg L Henstorf G LeMaistre CF Mayes MD McDonagh KT McLaughlin B Molitor JA Nelson JL Shulman H Storb R Viganego F Wener MH Seibold JR Sullivan KM Furst d High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study Blood 2007 110 4 1388 1396 10.1182/blood-2007-02-072389 17452515 \n11. Burt RK Oliveira MC Shah SJ Moraes DA Simoeas B Gheorghiade M Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis Lancet 2013 381 9872 1116 1124 10.1016/S0140-6736(12)62114-X 23363664 \n12. Fox BD Shimony A Langleben D Hirsch A Rudski L Schlesinger E High prevalence of occult left heart disease in scleroderma pulmonary hypertension Eur Respir J 2013 42 4 1083 1091 10.1183/09031936.00091212 23258775 \n13. Farge D Burt RK Oliveira MC Mousseaux E Rovira M Marjanovic Z de Vries-Bouwstra J del Papa N Saccardi R Shah SJ Lee DC Denton C Alexander T Kiely DG Snowden JA Cardiopulmonary assessment of patients with systemic sclerosis for hematopoietic stem cell transplantation: recommendations from the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party and collaborating partners Bone Marrow Transplant 2017 52 2017 1495 1503 10.1038/bmt.2017.56 28530671 \n14. Hudson M Baron M Tatibouet S Furst DE Khanna D Exposure to ACE inhibitors prior to the onset of scleroderma renal crisis- results from the International Scleroderma Renal Crisis Survey Semin Arthritis Rheum 2014 43 5 666 672 10.1016/j.semarthrit.2013.09.008 24176729 \n15. Daikeler Y Labopin M Di Gioia M Abinun M Miniati I Gualandi F Secondary autoimmune diseases occurring after HSCT for an autoimmune disease: a retrospective study of EBMT Autoimmune Disease Working Party Blood 2011 118 6 1693 1698 10.1182/blood-2011-02-336156 21596847\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0770-3198",
"issue": "37(6)",
"journal": "Clinical rheumatology",
"keywords": "Autologous hematopoietic stem cell transplantation; Complications; Mobilization; Systemic sclerosis; Toxicity",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "1709-1714",
"pmc": null,
"pmid": "29256111",
"pubdate": "2018-06",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "24047607;24591477;28530671;11350846;20679474;23258775;24742450;24176729;12905479;17452515;19420368;25058083;21777972;23363664;21596847",
"title": "Safety profile of autologous hematopoietic stem cell mobilization and transplantation in patients with systemic sclerosis.",
"title_normalized": "safety profile of autologous hematopoietic stem cell mobilization and transplantation in patients with systemic sclerosis"
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"companynumb": "PL-SA-2017SA268889",
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"abstract": "The SCN1A gene with 1274 point mutations in the coding regions or genomic rearrangements is the most clinically relevant epilepsy gene. Recent studies have demonstrated that variations in the noncoding regions are potentially associated with epilepsies, but no distinct mutation has been reported. We sequenced the 5' upstream region of SCN1A in 166 patients with epilepsy and febrile seizures who were negative for point mutations in the coding regions or genomic rearrangements. A heterozygous mutation h1u-1962 T > G was identified in a patient with partial epilepsy and febrile seizures, which was aggravated by oxcarbazepine. This mutation was transmitted from the patient's asymptomatic mother and not found in the 110 normal controls. h1u-1962 T > G was located upstream the most frequently used noncoding exon and within the promoter sequences. Further experiments showed that this mutation decreased the promoter activity by 42.1 % compared with that of the paired haplotype (P < 0.001). In contrast to the null expression that results in haploinsufficiency and severe phenotype, this mutation caused relatively less impairment, explaining the mild epilepsy with incomplete penetrance. The antiepileptic drug-induced seizure aggravation in this patient suggests clinical attention for mutations or variations in noncoding regions that may affect SCN1A expression.",
"affiliations": "Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.;Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.;Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.;Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.;Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.;Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.;Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.;Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.;Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.;Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China.;Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China. wpliao@163.net.;Institute of Neuroscience and the Second Affiliated Hospital, Guangzhou Medical University, Changgang-dong Road 250, Guangzhou, 510260, China. stoneyiwu@163.com.",
"authors": "Gao|Qu-Wen|QW|;Hua|Li-Dong|LD|;Wang|Jie|J|;Fan|Cui-Xia|CX|;Deng|Wei-Yi|WY|;Li|Bin|B|;Bian|Wen-Jun|WJ|;Shao|Chuan-Xing|CX|;He|Na|N|;Zhou|Peng|P|;Liao|Wei-Ping|WP|;Shi|Yi-Wu|YW|",
"chemical_list": "D000927:Anticonvulsants; D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human",
"country": "United States",
"delete": false,
"doi": "10.1007/s12035-016-9800-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0893-7648",
"issue": "54(4)",
"journal": "Molecular neurobiology",
"keywords": "Mutation; Noncoding regions; Partial epilepsy with febrile seizures plus; Promoter; SCN1A",
"medline_ta": "Mol Neurobiol",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D001483:Base Sequence; D005260:Female; D015894:Genome, Human; D006579:Heterozygote; D006801:Humans; D008297:Male; D062550:NAV1.1 Voltage-Gated Sodium Channel; D010375:Pedigree; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D012640:Seizures",
"nlm_unique_id": "8900963",
"other_id": null,
"pages": "2428-2434",
"pmc": null,
"pmid": "26969601",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15229516;24014518;20506560;16921370;17544618;11359211;16835263;16075041;11254444;12083760;18655196;9894880;20550552;15508915;10198179;10742094;25087078;25754450;9126059;24464349;22151702;15207799;25363779;24436055",
"title": "A Point Mutation in SCN1A 5' Genomic Region Decreases the Promoter Activity and Is Associated with Mild Epilepsy and Seizure Aggravation Induced by Antiepileptic Drug.",
"title_normalized": "a point mutation in scn1a 5 genomic region decreases the promoter activity and is associated with mild epilepsy and seizure aggravation induced by antiepileptic drug"
} | [
{
"companynumb": "PHHY2017CN067666",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXCARBAZEPINE"
},
"drugadditional": "1",
"dr... |
{
"abstract": "Non-Hodgkin lymphomas (NHLs) in paranasal sinus are uncommon, accounting for 0.17-2% of all NHL cases; it is especially rare in the sphenoid sinus. In this report, we describe a case of NHL in the sphenoid sinus.\nA 66-year-old man presented with a sudden left eye movement disorder. His head computed tomography and gadolinium-enhanced magnetic resonance imaging (Gd-MRI) showed a mass lesion extending around the left sphenoid sinus. However, the tumor regrowth about twice was observed during 2 weeks, partial removal of tumor was performed by the endoscopic trans-nasal transsphenoidal surgery, then histologically proved it to be diffuse large B-cell lymphoma (DLBCL). After R-THP-COP regimen (rituximab 375 mg/m2,cyclophosphamide 750 mg/m2, epirubicin 50 mg/m2, vincristine 2 mg/day, and prednisolone 100 mg/day) and two courses of intrathecal methotrexate therapy for DLBCL, the symptoms and the lesion of enhanced Gd-MRI and fluorodeoxyglucose-positron emission tomography were completely disappeared.\nNHLs in the sphenoid sinus is very rare disease, however, it is important to be diagnosed pathologically as soon as possible for being in remission state by the chemotherapy.",
"affiliations": "Department of Neurosurgery, Nara Medical University, Shijo-Cho, Kashihara, Nara, Japan.;Department of Neurosurgery, Nara Medical University, Shijo-Cho, Kashihara, Nara, Japan.;Department of Neurosurgery, Nara Medical University, Shijo-Cho, Kashihara, Nara, Japan.",
"authors": "Wajima|Daisuke|D|;Nishimura|Fumihiko|F|;Masui|Katsuya|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.25259/SNI_280_2020",
"fulltext": "\n==== Front\nSurg Neurol Int\nSurg Neurol Int\nSurgical Neurology International\n2229-5097 2152-7806 Scientific Scholar USA \n\nSNI-11-208\n10.25259/SNI_280_2020\nCase Report\nDiffuse large B-cell lymphoma in the sphenoid sinus: A case report and review of literature\nWajima Daisuke wajima@naramed-u.ac.jp Nishimura Fumihiko fnishi@naramed-u.ac.jp Masui Katsuya masui@nsu.co.jp Department of Neurosurgery, Nara Medical University, Shijo-Cho, Kashihara, Nara, Japan.\n* Corresponding author: Daisuke Wajima, Department of Neurosurgery, Nara Medical University, Shijo-Cho, Kashihara, Nara, Japan. wajima@naramed-u.ac.jp\n2020 \n25 7 2020 \n11 20815 5 2020 26 6 2020 Copyright: © 2020 Surgical Neurology International2020This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background: \nNon-Hodgkin lymphomas (NHLs) in paranasal sinus are uncommon, accounting for 0.17–2% of all NHL cases; it is especially rare in the sphenoid sinus. In this report, we describe a case of NHL in the sphenoid sinus.\n\nCase Description: \nA 66-year-old man presented with a sudden left eye movement disorder. His head computed tomography and gadolinium-enhanced magnetic resonance imaging (Gd-MRI) showed a mass lesion extending around the left sphenoid sinus. However, the tumor regrowth about twice was observed during 2 weeks, partial removal of tumor was performed by the endoscopic trans-nasal transsphenoidal surgery, then histologically proved it to be diffuse large B-cell lymphoma (DLBCL). After R-THP-COP regimen (rituximab 375 mg/m2,\n\ncyclophosphamide 750 mg/m2, epirubicin 50 mg/m2, vincristine 2 mg/day, and prednisolone 100 mg/day) and two courses of intrathecal methotrexate therapy for DLBCL, the symptoms and the lesion of enhanced Gd-MRI and fluorodeoxyglucose-positron emission tomography were completely disappeared.\n\nConclusion: \nNHLs in the sphenoid sinus is very rare disease, however, it is important to be diagnosed pathologically as soon as possible for being in remission state by the chemotherapy.\n\nChemotherapyEndoscopic trans-nasal transsphenoidal surgeryNon-Hodgkin lymphomaSphenoid sinus\n==== Body\nINTRODUCTION\nNon-Hodgkin lymphomas (NHLs) in paranasal sinus are uncommon, accounting for 0.17–2% of all NHL cases; it is especially rare in the sphenoid sinus.[3] It is difficult to diagnose them correctly by imaging modalities. In this report, we describe a case of NHL in the sphenoid sinus.\n\nCASE PRESENTATION\nA 66-year-old man was referred to our hospital with a sudden onset of headache, diplopia, and left ptosis. He was suffered from rheumatoid arthritis for several years and had taken methotrexate (MTX) tablets regularly. Neurological examinations revealed left oculomotor and trochlear nerve palsy without other cranial nerve disorders. Head computed tomography (CT) and gadolinium-enhanced brain magnetic resonance image (Gd-MRI) showed the mass lesion around the left sphenoid bone extending both to the left temporal middle fossa and to sphenoid sinus [Figure 1a and b]. Laboratory findings were white blood cell counts 7700/μl, red blood cell counts 516 × 104/μl, platelet counts 52.8 × 104/μl, lactate dehydrogenase 391U/l, soluble interleukin-2 receptor (sIL-2R) 808 U/ml, Epstein–Barr virus-viral capsid antigen antibody, immunoglobulin G (EB- VCA-IgG) over 20 times, EB-VCA-IgM under 10 times, and EB EBV nuclear antigen (EBNA) over 20 times.\n\nFigure 1: Image examinations of the case. Head computed tomography examinations before operation showed the mass lesion around the left sphenoid bone extending to lateral to the left temporal middle fossa and medial to sphenoid sinus (a). The mass lesion was heterogeneously enhanced with the gadolinium-enhanced magnetic resonance image (Gd-MRI) (b). Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed multiple lesions in the left sphenoid bone, nasal cavity, bilateral humeri, and left femur (c). Two weeks after the first presentation to our hospital, the tumor size was increased about the twice size compared as the previous study (d). After the removal of tumor and chemotherapy, his Gd- MRI and FDG-PET showed the disappearance of the lesion (e and f).\n\nWe thought that pathological examination was necessary to rule out malignant tumors. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed multiple lesions in the left sphenoid bone, nasal cavity, bilateral humeri, and left femur [Figure 1c]. He was suspected as MTX-induced nonspecific lymphoproliferative disorder with rheumatoid arthritis or idiopathic lymphoma. Two weeks later, the tumor volume was increased compared as those of the previous study [Figure 1d], so we performed partial removal of tumor by endoscopic trans- nasal transsphenoidal surgery under general anesthesia.\n\nIn spite of the cessation of oral MTX for rheumatoid arthritis for 2 weeks after the removal of tumor, the tumor regrowth was observed on the head CT. The patient was treated with R-THP- COP regimen (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, epirubicin 50 mg/m2, vincristine 2 mg/day, and prednisolone 100 mg/day) and two courses of intrathecal MTX therapy for central nervous system prophylaxis. After the eighth course of R-THP-COP, his Gd-MRI and FDG-PET showed the disappearance of the lesion [Figure 1e and f], and his symptoms completely disappeared. The patient has stayed recurrence free after the start of the treatment at 3-year follow-up.\n\nHistopathological examinations showed that large B cells with nuclei display prominent nucleoli that diffusely infiltrate the brain tissue in hematoxylin-eosin staining [Figure 2a], cluster of differentiation (CD) 3(‒) [Figure 2b], CD5(+) [Figure 2c], CD10(‒) [Figure 2d], multiple myeloma oncogene (MUM)-1(+) [Figure 2e], Bcl-2(+) [Figure 2f], Bcl-6(+) [Figure 2g], and EBER (EBV-encoded small RNA) in situ hybridization (EBER-ISH) (‒) [Figure 2h], thus the diagnosis was confirmed as diffuse large B-cell lymphoma (DLBCL). The tumor is classified as ABC type using the Hans classification based on MUM1, CD10, and Bcl6.\n\nFigure 2: Histopathological examinations including immunohistochemistry and flow cytometry showed that large cells with nuclei display prominent nucleoli that diffusely infiltrate the brain tissue in hematoxylin-eosin staining (a), cluster of differentiation (CD) 3(‒) (b), CD5(+) (c), CD10(‒) (d), multiple myeloma oncogene (MUM)-1(+) (e), Bcl-2(+) (f), Bcl-6(+) (g), and EBER (EBV-encoded small RNA) in situ hybridization (EBER-ISH) (‒) (h), thus the diagnosis was confirmed as diffuse large B-cell lymphoma.\n\nDISCUSSION\nPrimary malignancies of the sphenoid sinus, especially the lymphoma, are rare. As far as we have reviewed, 15 cases of sphenoid lymphoma including this case have been reported with detailed clinical history [Table 1].[1,2,4-8,10-14] Nasal obstruction or discharge appeared only in 5 patients (33.3%), unlike its high occurrence in other paranasal sinus tumors. Eleven patients (73.3%) initially presented with ptosis or diplopia caused by cranial nerve II, III, IV, and VI palsy. Nine patients experienced headache or facial pain (60%). Tumor extension was most common in the cavernous sinus (33.3%).\n\nTable 1: Reported cases of sphenoidal lymphoma.\n\nIn our case, the patient had oral MTX tablets regularly for rheumatoid arthritis. We suspected the MTX-associated lymphoproliferative disorders; however, the regrowth after the cessation of oral MTX was observed. In addition, we diagnosed clinically this case as the DLBCL in the sphenoid sinus. Pathologically, many cases of MTX -associated lymphoproliferative disorders have been positive in EBER immunostaining;[9] however, EBER-ISH was negative in our case. So finally, we diagnosed DLBCL. It was not definitive about the origin of DLBCL in our case, however, we consider the nasal cavity as the origin, because there were some reports about cases, whose origin was nasal cavity, and other parts (humerus and femur) were not. In addition, many cases have been checked no detailed immunostaining study, however, two cases including our case are ABC type in Hans classification.\n\nIn clinical practice, it is known that definite histological diagnosis is required before the initiation of any treatment.[3] It remains controversial whether or not patients with a very strong clinical suspicion of lymphoma should receive aggressive lymphoma treatment to prevent or recover certain complications. Therefore, the establishment of the optimal treatment option for such patients is required.\n\nCONCLUSION\nNHLs in paranasal sinus are very rare, however, this should be considered as a differential diagnosis of paranasal sinus tumors.\n\nHow to cite this article: Wajima D, Nishimura F, Masui K. Diffuse large B-cell lymphoma in the sphenoid sinus: A case report and review of literature. Surg Neurol Int 2020;11:208.\n\nDeclaration of patient consent\nPatient’s consent not required as patients identity is not disclosed or compromised.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Bisdas S Fetscher S Feller AC Baghi M Knecht R Gstoettner W Primary B cell lymphoma of the sphenoid sinus: CT and MRI characteristics with correlation to perfusion and spectroscopic imaging features Eur Arch Otorhinolaryngol 2007 264 1207 13 17479272 \n2 Chennupati SK Govindaraj S Setzen G Chiu AG Adult Burkitt lymphoma originating in the sphenoid sinus: Case report and review of the literature Ear Nose Throat J 2009 88 E07 19623516 \n3 Cleary KR Batsakis JG Sinonasal lymphomas Ann Otol Rhinol Laryngol 1994 103 911 4 7979008 \n4 Deleu D Lagopoulos M Al Moundhry M Katchy K Isolated bilateral abducens nerve palsy in primary sphenoidal sinus non-Hodgkin lymphoma Acta Neurol Belg 2000 100 103 6 10934562 \n5 Lewis WB Perlman PW Ilasi J Pediatric American Burkitt’s lymphoma of the sphenoid sinus Otolaryngol Head Neck Surg 2000 123 642 4 11077358 \n6 Mra Z Roach JC Brook AL Infectious and neoplastic diseases of the sphenoid sinus-a report of 10 cases Rhinology 2000 40 34 40 \n7 Park YM Cho JH Cho JY Huh JS Ahn JY Non-Hodgkin’s lymphoma of the sphenoid sinus presenting as isolated oculomotor nerve palsy World J Surg Oncol 2007 5 86 17683562 \n8 Re M Di Massimo U Romeo R Mallardi V Burkitt-like lymphoma of the sphenoid sinus: Case report Acta Otorhinolaryngol Ital 2004 24 30 2 15270431 \n9 Rizzi R Curci P Delia M Rinaldi E Chiefa A Specchia G Spontaneous remission of methotrexate-associated lymphoproliferative disorders after discontinuation of immunosuppressive treatment for autoimmune disease. Review of the literature Med Oncol 2009 26 1 9 18461290 \n10 Roth DB Siatkowski RM Bilateral blindness as the initial presentation of lymphoma of the sphenoid sinus Am J Ophthalmol 2000 129 256 8 10682985 \n11 Van Prooyen Keyzer S Eloy P Delos M Doyen C Bertrand B Rombaux P Sinonasal lymphomas. Case report Acta Otorhinolaryngol Belg 2000 54 45 51 10719593 \n12 Vedrine PO Thariat J Merrot O Percodani J Dufour X Choussy O Primary cancer of the sphenoid sinus-a GETTEC study Head Neck 2009 31 388 97 18972425 \n13 Weber AL Loewenheim H Lymphoma of the sphenoid sinus presenting as an expansile mass Ann Otol Rhinol Laryngol 1993 102 318 21 8476174 \n14 Yoshihara S Kondo K Ochi A Diffuse large B-cell lymphoma in the sphenoid sinus mimicking fibrous dysplasia in CT and MRI BMJ Case Rep 2014 2014 1 4\n\n",
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"keywords": "Chemotherapy; Endoscopic trans-nasal transsphenoidal surgery; Non-Hodgkin lymphoma; Sphenoid sinus",
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"title": "Diffuse large B-cell lymphoma in the sphenoid sinus: A case report and review of literature.",
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"abstract": "To assess talazoparib activity in germline BRCA1/2 mutation carriers with advanced breast cancer.\n\n\n\nABRAZO (NCT02034916) was a two-cohort, two-stage, phase II study of talazoparib (1 mg/day) in germline BRCA mutation carriers with a response to prior platinum with no progression on or within 8 weeks of the last platinum dose (cohort 1) or ≥3 platinum-free cytotoxic regimens (cohort 2) for advanced breast cancer. Primary endpoint was confirmed objective response rate (ORR) by independent radiological assessment.\n\n\n\nWe enrolled 84 patients (cohort 1, n = 49; cohort 2, n = 35) from May 2014 to February 2016. Median age was 50 (range, 31-75) years. Triple-negative breast cancer (TNBC) incidence was 59% (cohort 1) and 17% (cohort 2). Median number of prior cytotoxic regimens for advanced breast cancer was two and four, respectively. Confirmed ORR was 21% [95% confidence interval (CI), 10-35; cohort 1] and 37% [95% CI, 22-55; cohort 2]. Median duration of response was 5.8 and 3.8 months, respectively. Confirmed ORR was 23% (BRCA1), 33% (BRCA2), 26% (TNBC), and 29% (hormone receptor-positive). The most common all-grade adverse events (AE) included anemia (52%), fatigue (45%), and nausea (42%). Talazoparib-related AEs led to drug discontinuation in 3 (4%) patients. In an exploratory analysis, longer platinum-free interval was associated with higher response rate in cohort 1 (0% ORR with interval <8 weeks; 47% ORR with interval >6 months).\n\n\n\nTalazoparib exhibited promising antitumor activity in patients with advanced breast cancer and germline BRCA mutation.",
"affiliations": "Institute of Cancer Research and The Royal Marsden Hospital, London, United Kingdom. Nicholas.Turner@icr.ac.uk.;Stanford University School of Medicine, Stanford, California.;University of California San Francisco Comprehensive Cancer Center, San Francisco, California.;Centre Oscar Lambret, Lille, France.;Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.;Universitäts Frauenklinik Tubingen, Eberhard Karls University, Tubingen, Germany.;Banner MD Anderson Cancer Center, Gilbert, Arizona.;Hospital Vall d'Hebron, and Vall d'Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain.;University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.;University of California Los Angeles, Los Angeles, California.;The NIHR Manchester Cancer Research UK Clinical Research Facility at The Christie NHS Foundation Trust & Division of Cancer Sciences University of Manchester, Manchester, United Kingdom.;Medivation LLC, San Francisco, California.;Medivation LLC, San Francisco, California.",
"authors": "Turner|Nicholas C|NC|;Telli|Melinda L|ML|;Rugo|Hope S|HS|;Mailliez|Audrey|A|;Ettl|Johannes|J|;Grischke|Eva-Maria|EM|;Mina|Lida A|LA|;Balmaña|Judith|J|;Fasching|Peter A|PA|0000-0003-4885-8471;Hurvitz|Sara A|SA|;Wardley|Andrew M|AM|0000-0002-9639-0888;Chappey|Colombe|C|;Hannah|Alison L|AL|;Robson|Mark E|ME|;|||",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D001943:Breast Neoplasms; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010793:Phthalazines; D010984:Platinum; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011379:Prognosis; D016879:Salvage Therapy",
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"title": "A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO).",
"title_normalized": "a phase ii study of talazoparib after platinum or cytotoxic nonplatinum regimens in patients with advanced breast cancer and germline brca1 2 mutations abrazo"
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"abstract": "BACKGROUND\nTraditional massage seems to be safe but not entirely risk free, though serious adverse events are very rare. This report is aimed at illustrating a rare but fatal presentation of massive pulmonary embolism caused by leg massage and also to encourage both massage providers and pregnant women to be aware of undetected or subtle deep vein thrombosis, which could be a life threatening condition as a consequence of leg massage.\n\n\nMETHODS\nA 25-year-old primigravid Thai woman underwent massage at a traditional massage shop at 25th week of gestation. Shortly after leg and foot massage, she had a sudden onset of dyspnea, followed by consciousness alteration, brief spastic-like convulsion, became unconscious and suffered a cardiac arrest. Basic life support (BLS) at the event scene as well as during transfer and advanced cardiovascular life support (ACLS) at the hospital were provided, resulting in successful resuscitation but persistent coma. Bedside echocardiography showed poor contractility of the dilated right ventricle, and pulmonary embolism was suspected. CT angiography (CTA) revealed multiple concentric intraluminal filling defects within the right and left pulmonary arteries, indicating massive pulmonary embolism. The fetus died in utero and spontaneous labor and vaginal delivery occurred.\n\n\nCONCLUSIONS\nLeg massage in patients with deep vein thrombosis can dislodge thrombi, leading to life threatening pulmonary embolism, and should be contraindicated. Since pregnant women are at a higher risk of undetected or subtle thromboembolism, traditional massage in pregnant women should be contraindicated unless they are proven to have no such risk.",
"affiliations": "Department of Emergency Medicine, Chiang Mai, Thailand.;Department of Emergency Medicine, Chiang Mai, Thailand.;Department of Emergency Medicine, Chiang Mai, Thailand.;Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.;Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand. theera.t@cmu.ac.th.",
"authors": "Sutham|Krongkarn|K|;Na-Nan|Sukumpat|S|;Paiboonsithiwong|Salilthip|S|;Chaksuwat|Pakorn|P|;Tongsong|Theera|T|",
"chemical_list": null,
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"doi": "10.1186/s12884-020-02924-w",
"fulltext": "\n==== Front\nBMC Pregnancy Childbirth\nBMC Pregnancy Childbirth\nBMC Pregnancy and Childbirth\n1471-2393 BioMed Central London \n\n2924\n10.1186/s12884-020-02924-w\nCase Report\nLeg massage during pregnancy with unrecognized deep vein thrombosis could be life threatening: a case report\nSutham Krongkarn krongkarn.s@cmu.ac.th 1 Na-Nan Sukumpat yo_aquarium@hotmail.com 1 Paiboonsithiwong Salilthip lilthip@hotmail.com 1 Chaksuwat Pakorn pkcswmd@hotmail.com 2 Tongsong Theera theera.t@cmu.ac.th 2 1 Department of Emergency Medicine, Chiang Mai, Thailand \n2 grid.7132.70000 0000 9039 7662Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200 Thailand \n22 4 2020 \n22 4 2020 \n2020 \n20 23728 10 2019 3 4 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nTraditional massage seems to be safe but not entirely risk free, though serious adverse events are very rare. This report is aimed at illustrating a rare but fatal presentation of massive pulmonary embolism caused by leg massage and also to encourage both massage providers and pregnant women to be aware of undetected or subtle deep vein thrombosis, which could be a life threatening condition as a consequence of leg massage.\n\nCase presentation\nA 25-year-old primigravid Thai woman underwent massage at a traditional massage shop at 25th week of gestation. Shortly after leg and foot massage, she had a sudden onset of dyspnea, followed by consciousness alteration, brief spastic-like convulsion, became unconscious and suffered a cardiac arrest. Basic life support (BLS) at the event scene as well as during transfer and advanced cardiovascular life support (ACLS) at the hospital were provided, resulting in successful resuscitation but persistent coma. Bedside echocardiography showed poor contractility of the dilated right ventricle, and pulmonary embolism was suspected. CT angiography (CTA) revealed multiple concentric intraluminal filling defects within the right and left pulmonary arteries, indicating massive pulmonary embolism. The fetus died in utero and spontaneous labor and vaginal delivery occurred.\n\nConclusion\nLeg massage in patients with deep vein thrombosis can dislodge thrombi, leading to life threatening pulmonary embolism, and should be contraindicated. Since pregnant women are at a higher risk of undetected or subtle thromboembolism, traditional massage in pregnant women should be contraindicated unless they are proven to have no such risk.\n\nKeywords\nDeep vein thrombosisMassagePregnancyPulmonary embolismChiang Mai University Research FundCMU-2562Tongsong Theera issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nMassage is generally defined as the systematic manipulation of soft tissues of the body for alleviating pain, muscle relaxation or therapeutic purposes as alternative medicine. Presently, traditional massage is widely practiced and has become popular. The massage consists of several techniques of maneuvering, such as stroking and gliding, percussion, and kneading. Traditional massage is becoming increasingly popular as both a relaxation lifestyle and alternative medicine. However, the serious/fatal complications secondary to the methods are of less concern and rarely mentioned elsewhere. In our country (Thailand), traditional massage is a widely used massage technique and is currently accepted by the local Thai Ministry of Public Health. Nevertheless, the effectiveness and safety of this technique are not well known. Though systematic reviews on the effectiveness of massage therapy have demonstrated positive conclusions, adequate risk-benefit evaluations are not feasible, and several case reports indicate that it is not entirely risk free, though serious adverse events are probably rare [1]. Pulmonary embolism is the most serious consequence of massage, which has rarely been reported [2–4]. To the best of our knowledge, this is the first case of traditional massage causing massive pulmonary embolism in a healthy pregnant woman. Therefore, we report this case, following the CARE guidelines, mainly with the aim of describing a very rare but fatal presentation of massive pulmonary embolism secondary to leg massage. Also, we aim to encourage both professional massage providers and pregnant women to be aware of undetected or subtle deep vein thrombosis, which could be a life threatening condition as a consequence of leg massage.\n\nCase presentation\nThe patient’s background is as follows: She was a 25-year-old primigravid Thai woman. Her obstetric data was limited, since she had never attended prenatal clinic before. Most of her obstetric history was obtained from close relatives. She was a low-risk pregnancy, without any known underlying diseases and with no history of significant familial diseases. The pregnancy course before the event was uneventful, but had not been documented. She attended a traditional massage service at a commercial relaxation massage shop at a shopping center in Chiang Mai, Thailand. The traditional Thai massage is a physical form of massage involving yoga-like movement, stretching, and application of direct pressure with the assistance of the massage performer. The client wears loose clothing and lies down on a padded mat on the floor, going through several poses. The performer may use his/her hands, forearms, knees, elbows, or feet to flex the joints and apply direct or rhythmic pressure to the client’s muscles without the use of oil or lotion. Each session usually takes one or 2 hours. Approximately 5–10 min after the leg and foot massage, the woman had a sudden onset of dyspnea, followed by consciousness alteration, brief spastic-like convulsion, became unconscious and suffered a cardiac arrest. First aid and resuscitation were provided by two nurses who were incidentally at the scene. The emergency medical service (EMS) of Maharaj Nakorn Chiang Mai Hospital was emergently called and arrived at the scene of the event within 20 min, while the patient was pulseless. The EMS team performed basic life support (BLS), endotracheal intubation and continuous cardiopulmonary resuscitation (CPR) at the scene and during transfer to the hospital. About 25 min after initiation of CPR, the patient arrived at the hospital. Electrocardiogram (ECG) indicated pulseless electrical activity. Laboratory tests on admission were as follows: Hb: 11.7 g/dL; Hct: 36.0%; WBC: 12,850 cells/cu.mm; neutrophil: 50.0%; lymphocyte: 44.8%; nucleated red blood cell: 0.3/100 WBC; platelets: 159,000 cells/cu.mm. Coagulation tests gave the following results: PT: 10.50 s; INR: 0.95; PTT: 29.70 s; PTT ratio: 0.93; fibrinogen: 100 mg/dl; blood lactate: 3.14 mmol/L. Urinalysis results were within normal limits. Arterial blood gas showed severe metabolic acidosis. At the emergency room, advanced cardiovascular life support (ACLS) was immediately performed by the emergency physician team, and successful resuscitation was achieved, though the patient was still unconscious or comatose and depended on a ventilator. Bedside ultrasound after successful CPR at the emergency room showed no intra-abdominal free fluid, no pericardial/pleural effusion, no visualized aortic flap, normal left ventricular ejection fraction, hyperdynamic heart, right ventricular dilatation with poor systolic function, and interventricular septum shifted to the left, indicating right heart overload (Fig. 1, Video 1). Due to the sudden onset of dyspnea followed by cardiovascular collapse during leg massage and poor right ventricular function, pulmonary embolism was highly suspected. CTA of the chest was emergently requested and revealed multiple concentric intraluminal filling defects within the right and left pulmonary arteries and almost the entire branches that supply both lower lungs. Multiple intraluminal filling defects within segmental branches in the right middle lung and both upper lobes as well as a few broad base wedge-shaped hypoenhancing consolidation of pulmonary infarction in both upper lobes and superior segment of the right lower lung were also noted. The findings indicated massive pulmonary embolism (Fig. 2, Video 2). CT brain scan, performed to exclude neurological disorders, revealed normal results. Compression ultrasonography of both legs indicated deep vein thrombosis. Due to hypoxic encephalopathy, the CVT (Cardio-Vascular-Thoracic surgery) team decided not to perform embolectomy. However, the patient received conservative medications (Rt-PA: recombinant tissue plasminogen activator, Levophed, etc.). About 10 min after the return of spontaneous circulation, obstetric assessment was done. The ultrasound examination on admission revealed a single live fetus (fetal heart rate: ~ 130 bpm) without structural anomaly, consistent with 25 weeks of gestation, normal grade-1 placenta located at the posterior wall and normal amniotic fluid volume. Dexamethasone for fetal lung maturation was given (6 mg IM). However, 2 hours and a half later, fetal distress was observed and intrauterine resuscitation was provided. The risk and benefit of cesarean section due to fetal distress was comprehensively discussed by the care team, and the option of cesarean section was offered, but the relatives decided against operation to minimize the additional risk of the patient from cesarean section. The fetus died in utero within 8 h of fetal distress, and spontaneous labor occurred, leading to vaginal delivery without intrapartum and postpartum complication. At the time of writing this report (2 months after the event), the patient was still unconscious.\nFig. 1 Bedside echocardiography shows poor contractility of the dilated right ventricles during diastole a and systole b\n\nFig. 2 CTA of the chest (cross-section) shows large focal perfusion defects in the right a and right b pulmonary artery, representing bilateral pulmonary emboli\n\n\n\nDiscussion and conclusion\nDue to sudden onset of dyspnea, consciousness alteration and cardiovascular collapse during massage manipulation of the patient’s leg, which was later proven to have pulmonary embolism and deep vein thrombosis, it is reasonable to conclude that the patient had undetected preexisting deep vein thrombosis, which was mechanically dislodged by the massage and travelled massively to both lungs, leading to a life threatening condition. However, differentiation from other causes of sudden dyspnea should be considered, including heart failure, ischemic heart, pericarditis, pneumonia, pneumothorax, exacerbation of chronic lung disease, and musculoskeletal pain [5–8]. For patients suspected of pulmonary embolism, tests including ECG, chest film, brain natriuretic peptide and troponin levels, and arterial blood gases are often helpful in differential diagnosis and management [5–8]. However, a diagnosis of pulmonary embolism should be confirmed by CTA or magnetic resonance pulmonary angiogram. Patients who are highly suspected of having this condition and unstable hemodynamics must be fully resuscitated, given anticoagulation and diagnostic imaging. For cases that remain unstable despite resuscitation, bedside echocardiography and compression ultrasonography with Doppler of the leg veins should be used to make a rapid diagnosis to justify the administration of potential life-saving treatment, including thrombolytic agents [5–8].\n\nThe important clinical learning point gained from this case report is that massage of the lower extremities in cases of deep venous thrombosis is contraindicated as it can dislodge the thrombus and can cause a life-threatening pulmonary embolus. More importantly, pregnant women are in a physiologic hypercoagulable state and are at a higher risk of thromboembolism. Pregnancy can place patients with preexisting undetected or subtle deep vein thrombosis at a higher risk of pulmonary embolism. Therefore, pregnant women should be advised to avoid leg massage unless they are certain that no thromboembolism disorders exist. This case report should encourage professional massage providers to be aware of subtle preexisting deep vein thrombosis, especially in pregnant women. This case also provides an additional learning point by illustrating the role of bedside echocardiography in right ventricular evaluation in massive pulmonary embolism. Though echocardiography is generally not considered a diagnostic tool for pulmonary embolism, in unstable patients with massive pulmonary embolism, echocardiography for right ventricular evaluation can be used as a diagnostic tool. Furthermore, echocardiography is also useful in risk categorization and prognosis in pulmonary embolism. The echocardiographic features suggesting pulmonary embolism are poor contractility of the right ventricle, right ventricular dilatation, tricuspid regurgitation, paradoxical motion of the interventricular septum, pulmonary artery dilatation, elevated pulmonary pressures, empty left heart and, rarely, a right heart thrombus [4].\n\nThe timing of symptom development in relation to trigger activity was a very unique feature. The onset of cardiovascular collapse was shortly after leg massage, highly suggestive of thrombus embolization. Unlike most previous case reports of leg massage, concerning induced pulmonary embolism that occurred in previously known cases of deep vein thrombosis in non-pregnant patients [2–4], the case presented here is the first case report of leg massage leading to thrombi dislodge with the consequence of severe morbidity in a healthy pregnant woman who had undetected preexisting deep vein thrombosis, which was likely aggravated by physiologic changes during pregnancy. Unfortunately, our patient had not attended antenatal clinic before the event. Thus, she had no chance of undergoing thrombotic risk assessment (Caprini score) in early gestation. If the assessment showed high risk of thromboembolism, preventive anticoagulant might have been helpful. It is noteworthy that not only the mother but also the fetus life was threatened following pulmonary embolization. Fetal distress was detected shortly after admission. This is not unexpected since fetal distress is common after catastrophic events leading to hypoxia in the mother. Certainly, some degree of maternal hypoxia can cause a decrease in placental perfusion, resulting in fetal distress and death finally. In spite of maternal improvement after resuscitation, fetal distress may not always subside because of prior prolonged fetal asphyxia. The resuscitation improved hemodynamics in maternal vital organs but did not restore placental circulation. The decision of cesarean section due to fetal distress in this case was challenging. Several concerns were taken into considerations; for examples, the survival rate of the baby at 25 weeks of gestation in our center, which was about 25%, or much lower in cases of fetal distress, together with high morbidity, additional risk to the patient secondary to cesarean section or hemorrhage which could worsen her life-threatening condition. We followed the standards of care and medical ethics, comprehensive counseling was provided by the care team and the decision was based on the principles of autonomy and nonmalefficience.\n\nIn our country, traditional massage is widely practiced without proper guidance by local governmental agencies. Accordingly, several laypersons without adequate training practice traditional massage, and many massage shops are operated without governmental control. Similar to any other medical therapy, traditional massage may be associated with adverse effects, and it is an issue that needs to be studied further. Based on this report and literature review, strict control of our traditional massage by governmental agencies is needed, and the practice needs standardization.\n\nIn conclusion, leg massage in patients with deep vein thrombosis can dislodge thrombi, leading to life threatening pulmonary embolism; therefore, it should be contraindicated. Since pregnant women are at a higher risk of undetected or subtle thromboembolism, traditional leg massage in pregnant women should be contraindicated unless they are proven to have no such risk.\n\nSupplementary information\n\nAdditional file 1: Video 1. Bedside echocardiography shows poor contractility of the dilated right ventricles and paradoxical motion of the interventricular septum\n\n \nAdditional file 2: Video 2. CTA of the chest (cross-section) shows large focal perfusion defects in the right and right pulmonary artery, representing bilateral pulmonary emboli.\n\n \n\n\nAbbreviations\nACLSAdvanced Cardiovascular Life Support\n\nBLSBasic Life Support\n\nBpmbeat per minute\n\nCPRCardiopulmonary resuscitation\n\nCTACT Angiography\n\nCVTCardio-Vascular-Thoracic surgery\n\nEMSEmergency medical services\n\nPEpulmonary embolism\n\nRt-PArecombinant tissue plasminogen activator\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s12884-020-02924-w.\n\nAcknowledgements\nNot applicable\n\nAvailability of data and material\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nAuthors’ contributions\nKS: Emergency management of the patient, editing and approval of the manuscript. SN: Emergency management of the patient, editing and approval of the manuscript. SP: Emergency management of the patient, editing and approval of the manuscript. PC: Obstetric management of the patient, editing and approval of the manuscript. TT: Obstetric supervision, writing the first draft and approval of the manuscript. All authors contributed to the interpretation and writing of the paper and approved the final version.\n\nFunding\nChiang Mai University Research Fund; (The funder had no any role in the design of the study and interpretation of data and in writing the manuscript.)\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s relative for publication of this case report and accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Ernst E The safety of massage therapy Rheumatology (Oxford) 2003 42 1101 1106 10.1093/rheumatology/keg306 12777645 \n2. Behera C Devassy S Mridha AR Chauhan M Gupta SK Leg massage by mother resulting in fatal pulmonary thromboembolism Med Leg J 2018 86 146 150 10.1177/0025817217706645 28441907 \n3. Jabr FI Massive pulmonary emboli after legs massage Am J Phys Med Rehabil 2007 86 691 10.1097/PHM.0b013e31811e2a7a 17667202 \n4. Lim DC, Jayanthi HK, Money-Kyrle A, Ramrakha P. Massaging the outcome: an unusual presentation of pulmonary embolism. BMJ Case Rep. 2009;2009.\n5. Dado CD Levinson AT Bourjeily G Pregnancy and pulmonary embolism Clin Chest Med 2018 39 525 537 10.1016/j.ccm.2018.04.007 30122177 \n6. Wan T Skeith L Karovitch A Rodger M Le Gal G Guidance for the diagnosis of pulmonary embolism during pregnancy: consensus and controversies Thromb Res 2017 157 23 28 10.1016/j.thromres.2017.06.025 28686913 \n7. Bennett A Chunilal S Diagnosis and Management of Deep Vein Thrombosis and Pulmonary Embolism in pregnancy Semin Thromb Hemost 2016 42 760 773 10.1055/s-0036-1587684 27657494 \n8. Thompson A Pulmonary embolism Clin Med (Lond) 2019 19 357 358\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2393",
"issue": "20(1)",
"journal": "BMC pregnancy and childbirth",
"keywords": "Deep vein thrombosis; Massage; Pregnancy; Pulmonary embolism",
"medline_ta": "BMC Pregnancy Childbirth",
"mesh_terms": "D000328:Adult; D000072226:Computed Tomography Angiography; D005260:Female; D006801:Humans; D008405:Massage; D011247:Pregnancy; D011655:Pulmonary Embolism; D020246:Venous Thrombosis",
"nlm_unique_id": "100967799",
"other_id": null,
"pages": "237",
"pmc": null,
"pmid": "32321459",
"pubdate": "2020-04-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12777645;31308127;28441907;21687002;27657494;30122177;28686913;17667202",
"title": "Leg massage during pregnancy with unrecognized deep vein thrombosis could be life threatening: a case report.",
"title_normalized": "leg massage during pregnancy with unrecognized deep vein thrombosis could be life threatening a case report"
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"abstract": "Cardiac epithelioid hemangioendothelioma (EHE) is a very rare tumour of endothelial origin with the lung and liver as the most easily metastatic organs. We describe herein a patient with hemoptysis, severe anaemia, and diffuse pulmonary nodules with halo signs that represented metastasis of cardiac EHE; these radiologic manifestations are relatively uncommon. During the initial workup for the patient's pulmonary nodules, echocardiography missed the cardiac mass. However, positron emission tomography-computed tomography revealed increased fluorodeoxyglucose intake in the right atrial wall, and cardiac magnetic resonance imaging (MRI) revealed an irregular nodule with normal T1-weighted signal intensity and hyperintense T2-weighted signal intensity. Enhanced abdominal computed tomography (CT) revealed micronodular liver metastases. Video-assisted thoracic surgery was performed to make a definitive diagnosis. Immunohistochemistry staining proved the diagnosis of EHE with positive results for cluster of differentiation (CD) 34, CD31, erythroblast transformation-specific-related gene and Ki-67. The patient started chemotherapy with docetaxel (75 mg/m2 ) and gemcitabine (900 mg/m2 ), but this failed to control his disease and he died from an opportunistic infection related to his immunocompromised status 5 months later. For the work out process of bilateral diffuse pulmonary nodules suspicious for cardiac origin, especially with atrial deviation, echocardiography alone is not sufficient to exclude atrial origin. Cardiac CT or MRI might be a better choice.",
"affiliations": "Department of Respiratory Medicine, Shengjing Hospital of China Medical University, Shenyang, PR China.;Department of Respiratory Medicine, Shengjing Hospital of China Medical University, Shenyang, PR China.;Department of Respiratory Medicine, Shengjing Hospital of China Medical University, Shenyang, PR China.;Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, PR China.;Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, PR China.;Department of Respiratory Medicine, Shengjing Hospital of China Medical University, Shenyang, PR China.",
"authors": "Zhou|Xiaoming|X|https://orcid.org/0000-0002-6165-9277;Li|Peng|P|;Gu|Xiu|X|https://orcid.org/0000-0001-5115-0197;Zheng|Fushuang|F|;Zhao|Jungang|J|;Zhao|Li|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/crj.13121",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1752-6981",
"issue": "14(2)",
"journal": "The clinical respiratory journal",
"keywords": "cancer; cardiac epithelioid hemangioendothelioma; cardiac tumour; computed tomography; hemangioendothelioma; magnetic resonance imaging; pulmonary metastasis",
"medline_ta": "Clin Respir J",
"mesh_terms": "D003937:Diagnosis, Differential; D006325:Heart Atria; D006338:Heart Neoplasms; D018323:Hemangioendothelioma, Epithelioid; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000072078:Positron Emission Tomography Computed Tomography; D020775:Thoracic Surgery, Video-Assisted",
"nlm_unique_id": "101315570",
"other_id": null,
"pages": "173-178",
"pmc": null,
"pmid": "31794151",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case report of right atrial epithelioid hemangioendothelioma with multiple pulmonary metastases.",
"title_normalized": "a case report of right atrial epithelioid hemangioendothelioma with multiple pulmonary metastases"
} | [
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"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-231369",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
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"abstract": "Effective treatment for pediatric embryonal brain tumors includes dose-intensive multiagent chemotherapy (DIMAC) followed by high-dose chemotherapy with stem cell rescue (HDCSCR). Use of repeated cycles of DIMAC including high-dose methotrexate (HDMTX) without HDCSCR has not been described.\n\n\n\nWe retrospectively reviewed the responses/toxicities in 13 patients (aged 2-155 months, median 22 months) with central nervous system (CNS) tumors (atypical teratoid rhabdoid tumors, CNS embryonal tumors not otherwise specified, pineoblastoma, embryonal tumor with multilayered rosettes, and CNS sarcoma) treated over a 12-year period with repeated cycles of HDMTX followed by etoposide, cisplatin, cyclophosphamide, and vincristine.\n\n\n\nSix patients (46.2%) had disseminated disease at presentation and five (38.5%) had gross total resection. A total of 64 courses of therapy were administered with a median of five courses per patient. Eight patients (61.5%) received radiation therapy (one at relapse). By completion of therapy, 11 patients (84.6%) achieved a response (six complete, five partial). Six of the 13 patients (46.2%) remain alive with a median follow-up of 48 months (6-146). Acute toxicities included fever/neutropenia (70.3%), bacteremia (15.6%), and grade 3 mucositis (18.8%). Long-term complications included learning disability, seizure disorder, and brain necrosis, without treatment-related deaths.\n\n\n\nDIMAC with HDMTX without HDCSCR may be an effective treatment option for selected patients with embryonal or high-grade CNS tumors.",
"affiliations": "Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, Alabama.;Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.;Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, Alabama.;Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama.;Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.;Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.;Pathology Department, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.;Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.;Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.;Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.;Department of Pathology, Children's of Alabama, Birmingham, Alabama.;Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.;Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.;Department of Neurology, University of California at San Francisco, San Francisco, California.;Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.",
"authors": "Bernstock|Joshua D|JD|;Alva|Elizabeth|E|;Cohen|Joshua L|JL|;Lobbous|Mina|M|;Chagoya|Gustavo|G|;Elsayed|Galal A|GA|0000-0002-0894-9486;Orr|Brent A|BA|;Rozzelle|Curtis|C|;Rocque|Brandon|B|;Blount|Jeffrey|J|;Johnston|James M|JM|;Li|Rong|R|;Fiveash|John B|JB|;Dhall|Girish|G|;Reddy|Alyssa T|AT|;Friedman|Gregory K|GK|0000-0002-6653-7420",
"chemical_list": "D014750:Vincristine; D005047:Etoposide; D003520:Cyclophosphamide; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28119",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(3)",
"journal": "Pediatric blood & cancer",
"keywords": "ATRT; PNET; high-dose chemotherapy; high-dose methotrexate; medulloblastoma; stem cell rescue",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D016543:Central Nervous System Neoplasms; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D005047:Etoposide; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D060787:Neoplasm Grading; D012189:Retrospective Studies; D015996:Survival Rate; D014750:Vincristine",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28119",
"pmc": null,
"pmid": "31850678",
"pubdate": "2020-03",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Treatment of pediatric high-grade central nervous system tumors with high-dose methotrexate in combination with multiagent chemotherapy: A single-institution experience.",
"title_normalized": "treatment of pediatric high grade central nervous system tumors with high dose methotrexate in combination with multiagent chemotherapy a single institution experience"
} | [
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"companynumb": "US-TEVA-2020-US-1228058",
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"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "VINCRISTINE"
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"drugadditional": "3",
... |
{
"abstract": "A 12.6-year-old girl presented with a 2-month history of headache, recurrent vomiting and 5 kg weight loss. She had been receiving recombinant human growth hormone (rhGH) replacement therapy at a dose of 0.035 mg/kg for the past 10 months, due to short stature. Investigations before initiating rhGH, including brain MRI, had been normal. Physical examination revealed a nystagmus and a mildly elevated arterial blood pressure. Brain MRI revealed a lesion in the posterior aspect of the medulla oblongata, adjacent to the foramen of Magendie. rhGH therapy was discontinued, followed by a gradual resolution of the symptoms. At follow-up 3 months later, she was asymptomatic and physical examination was unremarkable. A subsequent repeat brain MRI showed complete resolution of the lesion, supporting the diagnosis of a variant of reversible posterior leucoencephalopathy syndrome. This is the first case report of a reversible brain lesion linked to rhGH replacement therapy.",
"affiliations": "School of Medicine, Larnaca General Hospital, European University Cyprus, Larnaca, Cyprus.;Pediatric, Larnaca General Hospital, Larnaca, Cyprus.;St George's University of London, University of Nicosia, Nicosia, Cyprus.;Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece.",
"authors": "Hadjipanayis|Adamos|A|;Efstathiou|Elisavet|E|;Theophilou|Leda|L|;Chrousos|George|G|",
"chemical_list": "D011994:Recombinant Proteins; D019382:Human Growth Hormone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-221885",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "drugs: endocrine system; paediatrics; radiology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D002648:Child; D003937:Diagnosis, Differential; D005260:Female; D006261:Headache; D019382:Human Growth Hormone; D006801:Humans; D008279:Magnetic Resonance Imaging; D008526:Medulla Oblongata; D054038:Posterior Leukoencephalopathy Syndrome; D011994:Recombinant Proteins; D014839:Vomiting",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29141928",
"pubdate": "2017-11-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24167801;26563978;24950012;18854436;8432773;19542414;18403560;22218437;9467545;18268188;20523020;15711916;21717193;18356474;22307182;26153506;8559202",
"title": "Reversible brain lesion following growth hormone replacement therapy in an adolescent.",
"title_normalized": "reversible brain lesion following growth hormone replacement therapy in an adolescent"
} | [
{
"companynumb": "CY-EMD SERONO-8206415",
"fulfillexpeditecriteria": "1",
"occurcountry": "CY",
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"actiondrug": "1",
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"activesubstancename": "SOMATROPIN"
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"... |
{
"abstract": "BACKGROUND\nCOVID-19 is characterized by fast deterioration in the mechanism of cytokine storm. Therefore, treatment with immunomodulating agents should be initiated as soon as hyperinflammation is established. Evidence for the use of tocilizumab (TCZ) in COVID-19 is emerging, but the drug in this setting is used \"off label\" with limited data on both effectiveness and safety. Therefore, Hospital for Infectious Diseases in Warsaw established a Standard Operating Procedure (SOP) for the use of TCZ in severe COVID-19 cases.\n\n\nMETHODS\nHere, we present a case of 27-year-old, otherwise healthy man, who was successfully treated with chloroquine, azithromycin, tocilizumab and a standard of care. Initially the magnitude of lung devastation, clinical deterioration and the need for mechanical ventilation suggested unfavorable prognosis. However, we observed complete regression in radiological changes and rapid clinical improvement. Irrespective of this, patient's serum interleukin 6 and aminotransferases remained elevated even after a month from treatment.\n\n\nCONCLUSIONS\nAn overlapping effect of hyperinflammation, hypoxic organ injury and drug-related toxicity warrants a long-term follow-up for COVID-19 survivors. In addition, residual IL-6 receptors blockage may mask new infections. A standardized approach to follow-up for COVID-19 survivors is urgently needed. Current and future research should also investigate the impact of experimental therapies on lung tissue healing and regeneration, as well as long-term treatment toxicities.",
"affiliations": "IV-th Department, Hospital for Infectious Diseases, Warsaw, Poland.;Department of Adults' Infectious Diseases, Medical University of Warsaw, Warsaw, Poland. jdkowalska@gmail.com.;Intensive Care Unit, Hospital for Infectious Diseases in Warsaw, Warsaw, Poland.;Department of Diagnostic Imaging, Hospital for Infectious Diseases in Warsaw, Warsaw, Poland.;IV-th Department, Hospital for Infectious Diseases, Warsaw, Poland.;Molecular Diagnostics Laboratory, Hospital for Infectious Diseases in Warsaw, Warsaw, Poland.;Central Analytical Laboratory, Hospital for Infectious Diseases in Warsaw, Warsaw, Poland.;Department of Adults' Infectious Diseases, Medical University of Warsaw, Warsaw, Poland.",
"authors": "Podlasin|Regina B|RB|;Kowalska|Justyna D|JD|http://orcid.org/0000-0003-1166-4462;Pihowicz|Andrzej|A|;Wojtycha-Kwaśnica|Beata|B|;Thompson|Magdalena|M|;Dyda|Tomasz|T|;Czeszko-Paprocka|Hanna|H|;Horban|Andrzej|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D017963:Azithromycin; D002738:Chloroquine; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1186/s40001-020-00438-x",
"fulltext": "\n==== Front\nEur J Med Res\nEur. J. Med. Res\nEuropean Journal of Medical Research\n0949-2321\n2047-783X\nBioMed Central London\n\n32854774\n438\n10.1186/s40001-020-00438-x\nCase Report\nHow to follow-up a patient who received tocilizumab in severe COVID-19: a case report\nPodlasin Regina B. 1\nhttp://orcid.org/0000-0003-1166-4462\nKowalska Justyna D. jdkowalska@gmail.com\n\n2\nPihowicz Andrzej 3\nWojtycha-Kwaśnica Beata 4\nThompson Magdalena 1\nDyda Tomasz 5\nCzeszko-Paprocka Hanna 6\nHorban Andrzej 2\n1 IV-th Department, Hospital for Infectious Diseases, Warsaw, Poland\n2 grid.13339.3b 0000000113287408 Department of Adults’ Infectious Diseases, Medical University of Warsaw, Warsaw, Poland\n3 Intensive Care Unit, Hospital for Infectious Diseases in Warsaw, Warsaw, Poland\n4 Department of Diagnostic Imaging, Hospital for Infectious Diseases in Warsaw, Warsaw, Poland\n5 Molecular Diagnostics Laboratory, Hospital for Infectious Diseases in Warsaw, Warsaw, Poland\n6 Central Analytical Laboratory, Hospital for Infectious Diseases in Warsaw, Warsaw, Poland\n27 8 2020\n27 8 2020\n2020\n25 3723 5 2020\n19 8 2020\n© The Author(s) 2020\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nCOVID-19 is characterized by fast deterioration in the mechanism of cytokine storm. Therefore, treatment with immunomodulating agents should be initiated as soon as hyperinflammation is established. Evidence for the use of tocilizumab (TCZ) in COVID-19 is emerging, but the drug in this setting is used “off label” with limited data on both effectiveness and safety. Therefore, Hospital for Infectious Diseases in Warsaw established a Standard Operating Procedure (SOP) for the use of TCZ in severe COVID-19 cases.\n\nCase presentation\n\nHere, we present a case of 27-year-old, otherwise healthy man, who was successfully treated with chloroquine, azithromycin, tocilizumab and a standard of care. Initially the magnitude of lung devastation, clinical deterioration and the need for mechanical ventilation suggested unfavorable prognosis. However, we observed complete regression in radiological changes and rapid clinical improvement. Irrespective of this, patient’s serum interleukin 6 and aminotransferases remained elevated even after a month from treatment.\n\nConclusions\n\nAn overlapping effect of hyperinflammation, hypoxic organ injury and drug-related toxicity warrants a long-term follow-up for COVID-19 survivors. In addition, residual IL-6 receptors blockage may mask new infections. A standardized approach to follow-up for COVID-19 survivors is urgently needed. Current and future research should also investigate the impact of experimental therapies on lung tissue healing and regeneration, as well as long-term treatment toxicities.\n\nKeywords\n\nSARS-CoV-2\nCOVID-19\nTocilizumab\nChloroquine\nARDS\nCytokine storm\nissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\n\nIn the course of SARS-CoV-2, most infections are mild or asymptomatic, but up to 25% of hospitalized patients would experience severe complications and progress to critical condition characterized by acute respiratory distress syndrome (ARDS), requiring mechanical ventilation [1]. In the course of Coronavirus Disease 2019 (COVID-19) pathogenic T cells and inflammatory monocytes may enter the pulmonary circulation and initiate the inflammatory storm leading to lung injury and immune disorder in severe COVID-19 patients [2]. Zhang et al. discussed that the sIL-6R (soluble receptor) and mIL-6R (membrane receptor) blockage with tocilizumab used in COVID-19-related cytokine release syndrome may reduce the mortality [3]. This has been confirmed by several retrospective cohort studies and case series from China and Europe [4–10]. The Polish Association of Epidemiologists and Infectiologists recommendations include TCZ as an option for COVID-19 treatment [11]. Therefore, the Hospital for Infectious Diseases in Warsaw established a Standard Operating Procedure (SOP) for its use in this specific indication. Patients were qualified for TCZ if having PCR-confirmed SARS-CoV-2 infection with evidence of COVID-19 pneumonia on chest X-ray, increased IL-6 level and peripheral oxygen saturation (SpO2) ≤ 93% or PAO2/FiO2 ratio < 200 mmHg. For each patient fulfilling inclusion criteria risk–benefit ratio was verified by a committee of three physicians including patient’s physician, intensive care specialist and SOP coordinating physician. This process included verification of any evidence of severe infection other than SARS-CoV-2, as well as review of exclusion criteria. The recommended dosing was 8 mg/kg with a maximum dose of 800 mg per infusion and a second dose of TZC allowed after 8–12 h. The SOP was approved by Bioethical Committee of Medical University of Warsaw (nr KB68/2020).\n\nCase presentation\n\nA 27-year-old, otherwise healthy man with no health risks, was admitted to infectious disease ward with a week history of weakness, fever and sore throat. Due to these conditions he was treated with amoxicillin and clarithromycin with no clinical improvement. On admission the patient reported fever, cough and dyspnea. He had no concomitant chronic conditions and did not take any prescribed medication. On examination he was overweight (body mass 86 kg, BMI 27.8 kg/m2), body temperature of 39.9 °C degrees, blood pressure 138/83 mm Hg, HR 122/min. and respiratory rate 20/min. His peripheral oxygen saturation (SpO2) was 88% and improved to 95% on 6 l/min. oxygen supplementation.\n\nA nasal swab was obtained on admission and reverse transcriptase-polymerase chain reaction (RT-PCR) assay confirmed SARS-CoV-2 infection. On baseline the patient was anti-HIV, anti-HCV and HBsAg negative. Monitoring of ferritin, C-reactive protein (CRP), fibrinogen, D-dimers and interleukin 6 (IL-6) was performed (Table 1). The patient received 500 mg of chloroquine twice daily and 500 mg of azithromycin once daily, according to earlier approved local standard of care. Due to initial suspicion of the lung abscess formation seen on the first chest X-ray, vancomycin was added (Fig. 1a). His computer tomography revealed bilateral changes typical for COVID-19 pneumonia and did not confirm changes characteristic for bacterial infection (Fig. 2a). In addition, low molecular weight heparin in prophylactic doses was started.Table 1 Body weight and laboratory values measured over time in reported patient\n\n\tDay 1 On admission\tDay 2 Before 1st TCZ dose\tDay 3 Before 2nd TCZ dose\tDay 3 After 2nd TCZ dose\tDay 5\tDay 7\tDay 9\tDay 12\tDay 16\tDay 35\t\nBody weight (kg)\t86\t–\t–\t–\t–\t–\t–\t–\t77\t79\t\nSARS-CoV-2 RT-PCRa nasopharyngeal swab\tPositive\t–\t–\t–\t–\tNegative\tNegative\t–\t–\tNegative\t\nSARS-CoV-2 antibodiesb (AU/ml)\t–\t–\t–\t–\t–\tIgM 3.89\n\nIgG 129\n\n\t–\t–\t–\tIgM 2.05\n\nIgG 63.77\n\n\t\nIL-6 (pg/ml)\t177\t298.9\t1836\t1479\t–\t98.2\t86.2\t42\t28.3\t37.1\t\nCRP (mg/l)\t262\t374\t363\t251\t67\t19\t13\t7\t< 5\t< 5\t\nFerritin (ng/ml)\t–\t1615\t5076.3\t–\t–\t1454.3\t1680.5\t860.9\t–\t199.4\t\nD-dimers (ng/ml)\t2007.15\t2208.97\t2336.06\t2363.43\t2821.55\t2440.13\t1587.5\t564.19\t249.43\t110.14\t\nFibrinogen (g/l)\t8.26\t\t7.37\t\t\t4.54\t\t4.15\t\t\t\nProcalcitonin (ng/ml)\t1.12\t1.00\t1.56\t1.39\t1.12\t< 0.05\t < 0.05\t< 0.05\t< 0.05\t< 0.05\t\nLeukocyte count (× 103/mm3)\t4.3\t5.7\t3.9\t3.7\t3.3\t5.4\t6.1\t5.4\t3.7\t4.6\t\nNeutrophile count (× 103/mm3)\t3.76\t3.35\t3.03\t2.71\t1.83\t3.38\t3.99\t2.57\t1.24\t1.94\t\nPlatelet count (× 103/mm3)\t127\t146\t169\t162\t317\t429\t502\t479\t320\t178\t\nHemoglobin (g/dl)\t13.7\t12.1\t11.8\t12.2\t13.6\t13.5\t12.8\t13.4\t13.2\t12.9\t\nALT (U/l)\t74\t61\t–\t50\t–\t304\t236\t209\t180\t124\t\nAST (U/l)\t91\t74\t–\t61\t–\t168\t125\t74\t45\t45\t\nGGTP (U/l)\t137\t165\t–\t141\t–\t547\t514\t336\t214\t96\t\nSerum creatinine (mmol/l)\t83\t81\t53\t42\t110.9\t134\t125\t81\t114\t86\t\na SARS-CoV-2 Genesing Real-Time PCR Assay. Test Vitassay b quantitative chemiluminescence test (CLIA) on Maglumi analyzer by SNIBE (China). Distributed by CORMAY S.A\n\nFig. 1 The evolution of pulmonary infiltrates in X-ray\n\nFig. 2 The evolution of pulmonary infiltrates in computer tomography\n\nWithin several hours from admission and irrespective of oxygen supplementation of 15 l/min, his SpO2 dropped to 90%. He was diagnosed with ARDS, intubated and admitted to intensive care unit. There he was qualified to receive TCZ according to SOP (two doses of 800 mg). The patient was ventilated with P/SIMV (FiO2 1,0-0,9-1,0, f 20, Pi20, PEEP 12) and received standard empiric antibiotic therapy (meropenem and continuation of vancomycin). Patient’s state did not change substantially over the next 4 days, however his body temperature normalized and CRP dropped. At the same time, his pulmonary infiltrates intensified on the control X-ray (Fig. 1b). However, his SpO2 steadily improved as presented in Table 1. After TCZ infusion IL-6 levels increased over ten times, but decreased within the next 3 days (Table 1). In terms of adverse effects the patient had transaminases and GGTP flair, as well as kidney function deterioration on day 7, i.e., 4 days after TCZ infusion (Table 1). On the fifth day the patient’s state improved significantly and he was extubated. After moving back to infectious disease department, the patient continued to improve with normalization of inflammatory markers. The patient was discharged from the hospital on day 21 after confirming significant improvement in his CT scan and two negative SARS-CoV-2 RT-PCR from nasopharyngeal swabs (Fig. 2, Table 1).\n\nA follow-up hospitalization on day 35 revealed no radiological changes on chest X-ray, negative SASR-CoV-2 RT-PCR from nasopharyngeal swab. However, the level of IL-6 and alanine aminotransferase activity were increased. The patient reported improving tolerance for physical activity, but he was unable to perform his previous activities with the same strength, e.g., singing.\n\nDiscussion and conclusions\n\nData on COVID-19 treatment effectiveness and long-term safety are currently sparse. Post-hospitalization follow-up is neither recommended nor their outcomes available in the current publications. Most work in the post-hospitalization area focuses on epidemiological considerations and psychological well-being [12]. In such events, case studies remain an important area of knowledge sharing and could support building expertise in the field where evidence-based approach is not yet available. Here, we present a case of severe COVID-19 in a 27-year-old, otherwise healthy patient. Although we observed full recovery in clinical, radiological and viral terms, some important adverse effects were present during hospitalization and afterwards. In terms of kidney and hepatic injury in the presented patient, it is uncertain whether this was an effect of prescribed treatment (chloroquine, antibiotics and TCZ), hyperinflammation or post-hypoxic organ injury [13–15].\n\nGuaraldi et al. showed that TCZ treatment was associated with a 40% reduction in the risk of invasive mechanical ventilation or death, but at the same time 13% of patients treated with TCZ were diagnosed with new infections, as compared to only 4% of patients treated with standard of care alone [16]. It clearly shows that the risk–benefit ratio for this approach is uncertain and needs to be further evaluated by randomized controlled trials, which are currently ongoing [17, 18]. In our patient, elevated IL-6 was observed even on day 35, which suggests a residual IL-R6 receptor blockage. As TCZ is anti-inflammatory agent a delay in the diagnosis of infection due to reduced fever and inflammation markers is likely [19]. These overlapping factors warrants careful long-term follow-up of COVID-19 patients in terms of adverse effects of medical interventions.\n\nAs reported by Phua et al. in a systematic review, 30% of patients survive ARDS and 70% of survivors will live with significant disability [20]. It remains uncertain to what extent this applies to COVID-19 survivors. Although our case report shows that young patients with no concomitant diseases can present full ‘radiological’ recovery, we were not able to perform any functional lung tests, such as spirometry or plethysmography, due to epidemiological restrictions. Data on a longer term pulmonological assessment and follow-up of COVID-19 survivors are sparse. In addition, it remains on research peripheries and outside recommendation area. Therefore, we introduced to our local practice two planned follow-up visits: 6 weeks after discharge from the hospital to verify immediate complications and after another 6 weeks to check on patients full recovery or any disabilities.\n\nAnother area lacking precision in most guidelines is when to introduce anti-inflammatory treatment and how to monitor its effectiveness and safety. Only few studies investigated an IL-6 level in which TCZ could be indicated in COVID-19 context. Herold et al. proposed a range of 40–80 pg/ml, but most clinical trials do not provide IL-6 threshold guided treatment and follow-up [17, 21].\n\nAs for the effectiveness and safety although ferritin, CRP, fibrinogen and D-dimers levels may be indicative of hyperinflammation these markers are highly nonspecific. IL-6 monitoring seems to be more accurate as a marker of immune system activation, but its levels are highly dependent on age, concomitant diseases (e.g., cancers) and host genetics [22]. Therefore, all these markers need to be monitored frequently to capture the dynamic and predict incoming cytokine storm, but should not mitigate the clinical symptoms progression. As presented also in our case report, IL-6 levels indicate the effectiveness of receptor blockage after TCZ infusion. They have been also proposed as a good prognostic marker after TCZ infusion [6, 7]. Herold et al. presented maximal level of IL-6 followed by CRP level as highly predictive of the need for mechanical ventilation [21]. Therefore, in our experience, all inflammatory markers in symptomatic COVID-19 patients should be monitored at least daily. A decision on TCZ treatment should be made by a multidisciplinary group and individualized for a given patient taking into account the evolution of clinical presentation, dynamic in inflammatory markers and the risk related to concomitant diseases or infections. Currently most interventions are used in COVID-19 experimentally and/or “off label”, therefore careful risk to benefit assessment needs to be performed for each patient individually in order to ascertain minimum harm with maximal benefit.\n\nA standardized approach to follow-up for COVID-19 survivors is urgently needed. Current and future research should also investigate the impact of experimental therapies on lung tissue healing and regeneration, as well as long-term treatment toxicities.\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nAll co-authors contributed equally to this work. All authors read and approved the final manuscript.\n\nFunding\n\nNo funding was received for this work.\n\nAvailability of data and materials\n\nNot applicable.\n\nEthics approval and consent to participate\n\nEthics approval and consent to participate were obtained.\n\nConsent for publication\n\nAll co-authors consent for this publication.\n\nCompeting interests\n\nAll co-authors declare no conflict of interest.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Huang C Wang Y Li X Ren L Zhao J Hu Y Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 2020 395 497 506 10.1016/S0140-6736(20)30183-5 31986264\n2. Fu B Xu X Wei H Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med 2020 18 164 10.1186/s12967-020-02339-3 32290839\n3. Zhang C Wu Z Li JW Zhao H Wang GQ Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality Int J Antimicrob Agents 2020 55 105954 10.1016/j.ijantimicag.2020.105954 32234467\n4. Eimer J Vesterbacka J Svensson AK Stojanovic B Wagrell C Sonnerborg A Tocilizumab shortens time on mechanical ventilation and length of hospital stay in patients with severe COVID-19: a retrospective cohort study J Intern Med 2020 10.1111/joim.13162 32744399\n5. Tomasiewicz K Piekarska A Stempkowska-Rejek J Serafinska S Gawkowska A Parczewski M Tocilizumab for patients with severe COVID-19: a retrospective, multi-center study Expert Rev Anti Infect Ther 2020 10.1080/14787210.2020.1800453 32693650\n6. Luo P Liu Y Qiu L Liu X Liu D Li J Tocilizumab treatment in COVID-19: a single center experience J Med Virol 2020 92 814 818 10.1002/jmv.25801 32253759\n7. Xu X Han M Li T Sun W Wang D Fu B Effective treatment of severe COVID-19 patients with tocilizumab Proc Natl Acad Sci USA 2020 117 10970 10975 10.1073/pnas.2005615117 32350134\n8. Michot JM Albiges L Chaput N Saada V Pommeret F Griscelli F Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report Ann Oncol 2020 31 961 964 10.1016/j.annonc.2020.03.300 32247642\n9. Kewan T Covut F Al-Jaghbeer MJ Rose L Gopalakrishna KV Akbik B Tocilizumab for treatment of patients with severe COVID-19: a retrospective cohort study EClinicalMedicine 2020 24 100418 10.1016/j.eclinm.2020.100418 32766537\n10. Capra R De Rossi N Mattioli F Romanelli G Scarpazza C Sormani MP Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia Eur J Intern Med 2020 76 31 35 10.1016/j.ejim.2020.05.009 32405160\n11. Flisiak R Horban A Jaroszewicz J Kozielewicz D Pawlowska M Parczewski M Recommendations of management in SARS-CoV-2 infection of the Polish Association of Epidemiologists and Infectiologists Pol Arch Intern Med 2020 130 352 357 32231173\n12. Zheng Z Yao Z Wu K Zheng J Patient follow-up after discharge after COVID-19 pneumonia: considerations for infectious control J Med Virol 2020 10.1002/jmv.25994 32779744\n13. Waseem N Chen PH Hypoxic hepatitis: a review and clinical update J Clin Transl Hepatol 2016 4 263 268 27777895\n14. Shu S Wang Y Zheng M Liu Z Cai J Tang C Hypoxia and hypoxia-inducible factors in kidney injury and repair Cells 2019 8 207 10.3390/cells8030207\n15. Emery P Keystone E Tony HP Cantagrel A van Vollenhoven R Sanchez A IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial Ann Rheum Dis 2008 67 1516 1523 10.1136/ard.2008.092932 18625622\n16. Guaraldi G Meschiari M Cozzi-Lepri A Tocilizumab in patients with severe COVID-19: a retrospective cohort study Lancet Rheumatol 2020 2 8 e474 e484 10.1016/S2665-9913(20)30173-9 32835257\n17. Atal S Fatima Z IL-6 inhibitors in the treatment of serious COVID-19: a promising therapy? Pharm Med 2020 34 223 231 10.1007/s40290-020-00342-z\n18. Coomes EA, Haghbayan H. Interleukin-6 in COVID-19: a systematic review and meta-analysis. https://www.medrxiv.org/content/10.1101/2020.03.30.20048058v1. Accessed 9 Aug 2020.\n19. Schiff MH Kremer JM Jahreis A Vernon E Isaacs JD van Vollenhoven RF Integrated safety in tocilizumab clinical trials Arthritis Res Ther 2011 13 R141 10.1186/ar3455 21884601\n20. Phua J Badia JR Adhikari NK Friedrich JO Fowler RA Singh JM Has mortality from acute respiratory distress syndrome decreased over time?: a systematic review Am J Respir Crit Care Med 2009 179 220 227 10.1164/rccm.200805-722OC 19011152\n21. Herold T Jurinovic V Arnreich C Lipworth BJ Hellmuth JC von Bergwelt-Baildon M Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19 J Allergy Clin Immunol 2020 146 128 136.e124 10.1016/j.jaci.2020.05.008 32425269\n22. Flynn MG Markofski MM Carrillo AE Elevated inflammatory status and increased risk of chronic disease in chronological aging: inflamm-aging or inflamm-inactivity? Aging Dis 2019 10 147 156 10.14336/AD.2018.0326 30705775\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0949-2321",
"issue": "25(1)",
"journal": "European journal of medical research",
"keywords": "ARDS; COVID-19; Chloroquine; Cytokine storm; SARS-CoV-2; Tocilizumab",
"medline_ta": "Eur J Med Res",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D017963:Azithromycin; D000073640:Betacoronavirus; D000086382:COVID-19; D002738:Chloroquine; D018352:Coronavirus Infections; D016207:Cytokines; D006801:Humans; D007249:Inflammation; D008297:Male; D056687:Off-Label Use; D058873:Pandemics; D011024:Pneumonia, Viral; D011044:Poland; D000086402:SARS-CoV-2; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9517857",
"other_id": null,
"pages": "37",
"pmc": null,
"pmid": "32854774",
"pubdate": "2020-08-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32693650;30823476;32253759;18625622;30705775;32835257;32766537;32383776;32405160;32425269;32350134;32231173;19011152;32290839;32845568;32535732;32234467;21884601;27777895;32247642;32744399;31986264",
"title": "How to follow-up a patient who received tocilizumab in severe COVID-19: a case report.",
"title_normalized": "how to follow up a patient who received tocilizumab in severe covid 19 a case report"
} | [
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"companynumb": "PL-TEVA-2020-PL-1837384",
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"activesubstancename": "AZITHROMYCIN ANHYDROUS"
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"abstract": "OBJECTIVE\nTo report a novel case of fungal keratitis caused by Biatriospora mackinnonii (Pyrenochaeta mackinnonii), a dematiaceous fungus (black fungus) that rarely causes dermatological infection, in a patient treated for ocular cicatricial pemphigoid.\n\n\nMETHODS\nAn 81-year-old patient with ocular cicatricial pemphigoid was referred to our hospital because of persistent corneal epithelial defects in his left eye. On examination, a slightly elevated dark lesion in the middle of the erosion and hypopyon was observed in that eye, with smear examination of the obtained specimen revealed a filamentous fungal-like material. Initially, treatment included miconazole and fluconazole ophthalmic solution eye drops, natamycin ophthalmic ointment, and systemic voriconazole, followed surgical scraping of the mass, an anterior chamber lavage, and a subconjunctival injection of miconazole. However, the focus had resistance to the treatment and finally led to corneal perforation; hence, therapeutic penetrating keratoplasty (PKP) was subsequently performed.\n\n\nRESULTS\nMycological testing revealed that the lesions were Candida parapsiliosis and black fungus, with the black fungus classified as B. mackinnonii via DNA sequencing of the internal transcribed spacer and the D1/D2 domains of the 28S rRNA gene. Fungal keratitis caused by B. mackinnonii was resistant to the antifungal drugs, yet was ameliorated by PKP, with no recurrence of fungal keratitis for more than 2 years postoperative.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the first reported case of fungal keratitis caused by B. mackinnonii; however, in this case, PKP surgery resulted in a favorable outcome.",
"affiliations": "Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.",
"authors": "Aoki|Takanori|T|;Fukuoka|Hideki|H|;Inatomi|Tsutomu|T|;Horiuchi|Noriko|N|;Kamei|Katsuhiko|K|;Sotozono|Chie|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000002676",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "40(10)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": null,
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "1344-1347",
"pmc": null,
"pmid": "33528226",
"pubdate": "2021-10-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Case of Black Fungal Keratitis Caused by Biatriospora mackinnonii.",
"title_normalized": "a case of black fungal keratitis caused by biatriospora mackinnonii"
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"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2022-00225",
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"activesubstancename": "GATIFLOXACIN"
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"abstract": "To evaluate endocrine activity in terms of ovarian function suppression (OFS) of degarelix (a gonadotropin-releasing hormone [GnRH] antagonist) versus triptorelin (a GnRH agonist) in premenopausal patients receiving letrozole as neoadjuvant endocrine therapy for breast cancer.\n\n\n\nPremenopausal women with stage cT2 to 4b, any N, M0; estrogen receptor and progesterone receptor greater than 50%; human epidermal growth factor receptor 2-negative breast cancer were randomly assigned to triptorelin 3.75 mg administered intramuscularly on day 1 of every cycle or degarelix 240 mg administered subcutaneously (SC) on day 1 of cycle 1 then 80 mg SC on day 1 of cycles 2 through 6, both with letrozole 2.5 mg/day for six 28-day cycles. Surgery was performed 2 to 3 weeks after the last injection. Serum was collected at baseline, after 24 and 72 hours, at 7 and 14 days, and then before injections on cycles 2 through 6. The primary end point was time to optimal OFS (time from the first injection to first assessment of centrally assessed estradiol level ≤ 2.72 pg/mL [≤ 10 pmol/L] during neoadjuvant therapy). The trial had 90% power to detect a difference using a log-rank test with a two-sided α of .05. Secondary end points included response, tolerability, and patient-reported endocrine symptoms.\n\n\n\nBetween February 2014 and January 2017, 51 patients were enrolled (n = 26 received triptorelin plus letrozole; n = 25 received degarelix plus letrozole). Time to optimal OFS was three times faster for patients assigned to degarelix and letrozole than to triptorelin and letrozole (median, 3 v 14 days; hazard ratio, 3.05; 95% CI, 1.65 to 5.65; P < .001). Furthermore, OFS was maintained during subsequent cycles for all patients assigned to receive degarelix and letrozole, whereas 15.4% of patients assigned to receive triptorelin and letrozole had suboptimal OFS after cycle 1 (six events during 127 measurements). Adverse events as a result of both degarelix plus letrozole and triptorelin plus letrozole were as expected.\n\n\n\nIn premenopausal women receiving letrozole for neoadjuvant endocrine therapy, OFS was achieved more quickly and maintained more effectively with degarelix than with triptorelin.",
"affiliations": "1 IEO, European Institute of Oncology Istituto di Recovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.;2 Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA.;1 IEO, European Institute of Oncology Istituto di Recovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.;3 S Orsola Hospital, Bologna, Italy.;4 Ospedale Infermi di Rimini, Azienda Unita Sanitaria (AUSL) della Romagna, Italy.;1 IEO, European Institute of Oncology Istituto di Recovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.;1 IEO, European Institute of Oncology Istituto di Recovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.;5 International Breast Cancer Study Group Coordinating Center, Bern, Switzerland.;5 International Breast Cancer Study Group Coordinating Center, Bern, Switzerland.;5 International Breast Cancer Study Group Coordinating Center, Bern, Switzerland.;5 International Breast Cancer Study Group Coordinating Center, Bern, Switzerland.;5 International Breast Cancer Study Group Coordinating Center, Bern, Switzerland.;5 International Breast Cancer Study Group Coordinating Center, Bern, Switzerland.;6 Hospital of Prato-AUSL Toscana Centro, Prato, Italy.;7 International Breast Cancer Study Group and University of Sydney, Sydney, Australia.;8 Frontier Science and Technology Research Foundation and Harvard Medical School, Boston, MA.;9 International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.;1 IEO, European Institute of Oncology Istituto di Recovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.;1 IEO, European Institute of Oncology Istituto di Recovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.",
"authors": "Dellapasqua|Silvia|S|;Gray|Kathryn P|KP|;Munzone|Elisabetta|E|;Rubino|Daniela|D|;Gianni|Lorenzo|L|;Johansson|Harriet|H|;Viale|Giuseppe|G|;Ribi|Karin|K|;Bernhard|Jürg|J|;Kammler|Roswitha|R|;Maibach|Rudolf|R|;Rabaglio-Poretti|Manuela|M|;Ruepp|Barbara|B|;Di Leo|Angelo|A|;Coates|Alan S|AS|;Gelber|Richard D|RD|;Regan|Meredith M|MM|;Goldhirsch|Aron|A|;Colleoni|Marco|M|;|||",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D009842:Oligopeptides; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D000077289:Letrozole",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.18.00296",
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"issn_linking": "0732-183X",
"issue": "37(5)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D018931:Antineoplastic Agents, Hormonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D004958:Estradiol; D005260:Female; D007987:Gonadotropin-Releasing Hormone; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent; D009842:Oligopeptides; D010053:Ovary; D017697:Premenopause; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D017329:Triptorelin Pamoate",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "386-395",
"pmc": null,
"pmid": "30589600",
"pubdate": "2019-02-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Neoadjuvant Degarelix Versus Triptorelin in Premenopausal Patients Who Receive Letrozole for Locally Advanced Endocrine-Responsive Breast Cancer: A Randomized Phase II Trial.",
"title_normalized": "neoadjuvant degarelix versus triptorelin in premenopausal patients who receive letrozole for locally advanced endocrine responsive breast cancer a randomized phase ii trial"
} | [
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"companynumb": "IT-MYLANLABS-2019M1085985",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRIPTORELIN"
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... |
{
"abstract": "BACKGROUND\nIn the era of genome-guided personalized cancer treatment, we must understand chemotherapy-induced genomic changes in tumors. This study evaluated whether adjuvant FOLFOX chemotherapy modifies the mutational profile of recurrent colorectal cancer (CRC).\n\n\nMETHODS\nWhole exome sequencing was performed on samples from primary CRC tumors, untreated metastatic tumors, and recurrent tumors following adjuvant FOLFOX chemotherapy. The samples were resected from four patients.\n\n\nRESULTS\nThe number of mutations or the mutation spectrum in individual patients was nearly identical. Copy number variants persisted regardless of FOLFOX therapy administration. The genomic signature of oxaliplatin exposure (G > T/C > A, T > A/A > T) was not enriched after FOLFOX chemotherapy. Overlapping single nucleotide variants (SNVs) and indels remained in 26-65% of the patient-matched tumor samples. One patient harbored an AKT1 E17K mutation in the recurrent tumor, whereas PIK3CA E542K and E88Q mutations were detected in the primary and untreated metastatic tumor samples. Genes related to intracellular Ca2+ homeostasis were enriched among the genes uniquely mutated after FOLFOX chemotherapy.\n\n\nCONCLUSIONS\nWe found that the mutation rates, mutation spectrum, and copy number variants were nearly identical regardless of the administration of FOLFOX therapy in the four CRC cases. The mutational discordance between the patient-matched tumor samples is likely caused by tumor heterogeneity and chemotherapy-induced clonal selection. These findings might be useful as pilot data for larger studies to clarify the changes in the mutational landscape induced by adjuvant FOLFOX chemotherapy.",
"affiliations": "Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.;Biobank Translational Research Support Section, Translational Research Management Division, Clinical Research Support Office, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. wokamoto@east.ncc.go.jp.;Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.;Department of Drug Therapy, Aichi Cancer Center, 1-1 Kanokoden, chikusa-ku, Nagoya, Aichi, 464-8681, Japan.;Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.;Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.;Hokkaido University Hospital Cancer Center, Kita 14, Nishi 5, Kita-ku, Sapporo, Hokkaido, 060-8648, Japan.;National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.;Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.",
"authors": "Harada|Kazuaki|K|;Okamoto|Wataru|W|;Mimaki|Sachiyo|S|;Kawamoto|Yasuyuki|Y|;Bando|Hideaki|H|;Yamashita|Riu|R|;Yuki|Satoshi|S|;Yoshino|Takayuki|T|;Komatsu|Yoshito|Y|;Ohtsu|Atsushi|A|;Sakamoto|Naoya|N|;Tsuchihara|Katsuya|K|",
"chemical_list": "D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-019-5479-6",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 547910.1186/s12885-019-5479-6Research ArticleComparative sequence analysis of patient-matched primary colorectal cancer, metastatic, and recurrent metastatic tumors after adjuvant FOLFOX chemotherapy Harada Kazuaki haraharaccho0605@yahoo.co.jp 1Okamoto Wataru +81-4-7133-1111wokamoto@east.ncc.go.jp 2Mimaki Sachiyo smimaki@east.ncc.go.jp 3Kawamoto Yasuyuki y-kawamoto0716@hotmail.co.jp 14Bando Hideaki hbando@aichi-cc.jp 5Yamashita Riu riuyamas@east.ncc.go.jp 3Yuki Satoshi satoshi-yuuki175@joy.ocn.ne.jp 1Yoshino Takayuki tyoshino@east.ncc.go.jp 6Komatsu Yoshito ykomatsu@ac.cyberhome.ne.jp 4Ohtsu Atsushi aohtsu@east.ncc.go.jp 7Sakamoto Naoya sakamoto@med.hokudai.ac.jp 1Tsuchihara Katsuya ktsuchih@east.ncc.go.jp 31 0000 0001 2173 7691grid.39158.36Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-8638 Japan 2 grid.497282.2Biobank Translational Research Support Section, Translational Research Management Division, Clinical Research Support Office, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577 Japan 3 0000 0001 2168 5385grid.272242.3Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577 Japan 4 0000 0004 0378 6088grid.412167.7Hokkaido University Hospital Cancer Center, Kita 14, Nishi 5, Kita-ku, Sapporo, Hokkaido 060-8648 Japan 5 0000 0001 0722 8444grid.410800.dDepartment of Drug Therapy, Aichi Cancer Center, 1-1 Kanokoden, chikusa-ku, Nagoya, Aichi 464-8681 Japan 6 grid.497282.2Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577 Japan 7 grid.497282.2National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577 Japan 21 3 2019 21 3 2019 2019 19 25520 12 2017 14 3 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nIn the era of genome-guided personalized cancer treatment, we must understand chemotherapy-induced genomic changes in tumors. This study evaluated whether adjuvant FOLFOX chemotherapy modifies the mutational profile of recurrent colorectal cancer (CRC).\n\nMethods\nWhole exome sequencing was performed on samples from primary CRC tumors, untreated metastatic tumors, and recurrent tumors following adjuvant FOLFOX chemotherapy. The samples were resected from four patients.\n\nResults\nThe number of mutations or the mutation spectrum in individual patients was nearly identical. Copy number variants persisted regardless of FOLFOX therapy administration. The genomic signature of oxaliplatin exposure (G > T/C > A, T > A/A > T) was not enriched after FOLFOX chemotherapy. Overlapping single nucleotide variants (SNVs) and indels remained in 26–65% of the patient-matched tumor samples. One patient harbored an AKT1 E17K mutation in the recurrent tumor, whereas PIK3CA E542K and E88Q mutations were detected in the primary and untreated metastatic tumor samples. Genes related to intracellular Ca2+ homeostasis were enriched among the genes uniquely mutated after FOLFOX chemotherapy.\n\nConclusions\nWe found that the mutation rates, mutation spectrum, and copy number variants were nearly identical regardless of the administration of FOLFOX therapy in the four CRC cases. The mutational discordance between the patient-matched tumor samples is likely caused by tumor heterogeneity and chemotherapy-induced clonal selection. These findings might be useful as pilot data for larger studies to clarify the changes in the mutational landscape induced by adjuvant FOLFOX chemotherapy.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12885-019-5479-6) contains supplementary material, which is available to authorized users.\n\nKeywords\nColorectal cancerWhole exome sequencingMutagenicityAdjuvant chemotherapyChemo-resistanceNational Cancer Center Research and Development Fund 25A-6issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nColorectal cancer (CRC) is the third most common type of cancer and the fourth leading cause of cancer death worldwide [1]. Combination chemotherapy with cytotoxic and molecular targeting agents has prolonged the survival time of patients with metastatic CRC. In the era of genome-based personalized cancer treatment, an assessment of the molecular profile of individual tumors is necessary to guide the selection of appropriate therapy methods. For example, activating KRAS and NRAS mutations are negative predictive markers for the effectiveness of the anti-epidermal growth factor receptor (EGFR) antibodies panitumumab and cetuximab [2, 3]. Intensive chemotherapy is recommended for patients with the BRAF V600E mutation because this mutation is a strong prognostic factor for poor survival [4, 5]. Moreover, several genetic alterations that are potential prognostic and predictive biomarkers or therapeutic targets have been explored. Extensive data sets of the mutational profiles of CRC have been generated [6], and large collaborations have created gene expression-based classifications that predict patient outcomes [7].\n\nHowever, systemic chemotherapies could alter the mutational landscape of several cancers [8, 9]. A previous exome sequencing study revealed that mutagenic chemotherapy regimens, such as adjuvant chemotherapy with the DNA-alkylating-like agent temozolomide to treat glioma, can induce new mutations and cause the malignant progression of recurrent tumors [9].\n\nFOLFOX is a combination chemotherapy regimen that consists of leucovorin-modulated 5-fluorouracil (5-FU) and oxaliplatin (L-OHP), which are commonly used worldwide as standard adjuvant chemotherapies for curatively resected stage III and IV CRCs [10]. L-OHP is a third-generation platinum (Pt)-containing antitumor compound that induces DNA damage associated with intra- and inter-strand cross-links (Pt-GG adducts) [11–13]. Previously, in vitro studies have demonstrated the mutagenic activity of L-OHP [14]. Therefore, adjuvant FOLFOX chemotherapy has the potential to alter the mutational profiles of recurrent cancers so that they differ from those of primary CRC tumors. Our previous report showed that the mutational status of predictive biomarker genes for the effectiveness of anti-EGFR-antibodies was not altered by FOLFOX therapy [15]. However, the influence of FOLFOX therapy on exome-wide mutational profiles has not been reported previously.\n\nThis study used whole exome sequencing to compare gene alteration profiles of recurrent cancers after adjuvant FOLFOX chemotherapy in patient-matched primary CRC and metastatic tumor samples prior to chemotherapy.\n\nMethods\nPatient selection\nWe reviewed the clinical records of patients with CRC who had been treated with adjuvant FOLFOX chemotherapy after curative resection at the National Cancer Center Hospital East (Kashiwa, Japan). From January 2006 to December 2009, 156 patients were treated with adjuvant FOLFOX at our institution, and 66 patients developed recurrent tumors during or after adjuvant FOLFOX chemotherapy. Of these patients, 26 underwent curative resection of recurrent tumors. We selected four CRC patients for whom tumor specimens from primary tumors, metastases resected prior to FOLFOX chemotherapy (pre-FOLFOX metastasis), and recurrent metastatic tumors in the same organ after adjuvant FOLFOX (post-FOLFOX metastasis) were available. Informed consent to use tissue specimens for this study was obtained from all patients, and the tissue samples were provided by the National Cancer Center Biobank, Japan. The institutional review board at the National Cancer Center approved the study protocol. This study was performed according to the Epidemiological Study Guidelines of the Ministry of Health, Labor, and Welfare of Japan. We disclosed the study design on the National Cancer Center website and gave the relatives of deceased patients the opportunity to decline participation.\n\nDNA samples\nWe obtained matched primary CRC, pre-FOLFOX metastasis, post-FOLFOX metastasis, and normal colorectal tissue samples from four patients. The normal colorectal tissues were collected from surgical specimens of the primary tumors. All tissue samples were formalin-fixed, paraffin-embedded (FFPE) specimens. DNA samples were obtained from macroscopically dissected FFPE specimens cut into 10-μm-thick sections. Genomic DNA was extracted using EZ1 Advanced XL and EZ1 DNA Tissue Kits (Qiagen, Hilden, Germany) according to the manufacturer’s instructions [16]. Nucleic acid yields were determined using a NanoDrop 2000 (Thermo Fisher Scientific, Waltham, MA, USA), and the quality of genomic DNA was examined using a Quant-iT picoGreen dsDNA (Life Technologies, Carlsbad, CA, USA) assay kit.\n\nWhole exome sequencing and variant calling\nUsing genomic DNA from tumors and matched normal samples, we performed exome capture sequencing. Using an Agilent SureSelect Human All Exome V5 + UTRs kit (Agilent Technologies, Santa Clara, CA, USA), whole exome sequencing was performed using an Illumina HiSeq 2000 system (Illumina, San Diego, CA, USA) to generate 100-bp paired-end sequencing reads according to the manufacturer’s instructions. Burrows-Wheeler Aligner (BWA, http://bio-bwa.sourceforge.net/) [17] was used to align the sequencing reads to the human reference genome (hg19). The Genome Analysis ToolKit version 1.6 (GATK, http://www.broadinstitute.org/gatk/) was used for the local realignment and score recalibration of the sequencing reads [18]. We employed Picard (http://broadinstitute.github.io/picard/) for the basic processing and management of the sequencing data. To reduce the false-positive rate, the following filtering criteria were applied: (i) GATK confidence score [18] ≥ 50; (ii) number of forward and reverse reads ≥1; and (iii) variants present in at least 10% of the reads. All mutations detected in the paired non-tumor colon tissues were excluded from our analysis. We also excluded alterations present in dbSNP151, the 1000 Genomes Project, and in-house Japanese exomes derived from 299 normal tissues in our previous studies, with the aim of identifying tumor-specific variants. We also performed a visual inspection to filter out false-positive variants.\n\nAll mutations with clinical inference were annotated using ANNOVAR [19].\n\nGene ontology analysis\nA Gene Ontology (GO) analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID, http://david.abcc.ncifcrf.gov) [20]. Adjusted P-values less than 0.05 were considered significant. The GO analysis was performed for nonsense mutations, small insertions/deletions (indels), and missense mutations that were predicted as “probably damaging” and “possibly damaging” by PolyPhen2 (http://genetics.bwh.harvard.edu/pph2/) [21].\n\nCopy number variant analysis\nThe log ratio of the depth of coverage between the tumor and normal colorectal tissues was calculated using the GATK-depth of coverage tool. Then, copy number variant (CNV) segments were identified from the log ratio of the depth of coverage using the Exome CNV R package [22]. Log ratios of the depth of coverage that were greater than two were considered indicative of significant copy number amplification.\n\nStatistical analysis\nThe Wilcoxon signed-rank test was used to evaluate the difference in the number of genetic alterations between primary, pre-FOLFOX metastatic, and post-FOLFOX metastatic tumors. Increases in specific mutation types among the post-FOLFOX unique mutations were also assessed using this method. Microsoft Office Excel 2013 (Microsoft Corporation, Redmond, WA, USA) was used to perform all the statistical analyses.\n\nResults\nPatient characteristics and clinical courses\nTable 1 shows the patient characteristics. There were two male and two female participants with a median age of 68 years. The primary tumor sites were the colon in one patient and the rectum in three patients. After curative resection of their primary and metastatic tumors, all patients were treated with a modified FOLFOX6 (mFOLFOX6) regimen including an L-OHP dose of 85 mg/m2 administered every 14 days; 12 treatment cycles were planned [23]. Post-FOLFOX metastasis developed during (cases 1 and 2) or after (cases 3 and 4) adjuvant chemotherapy. Histopathological analyses diagnosed the primary CRC tumors as well-differentiated adenocarcinoma (cases 2 and 4) and moderately differentiated adenocarcinoma (cases 1 and 3). All metastatic tumors exhibited histology concordant with the corresponding primary colorectal adenocarcinoma.Table 1 Patient characteristics\n\nCase\tAge range\tSex\tPrimary site\tHistopathological type\tMetastatic site (Pre−/Post-FOLFOX)\tFOLFOX cycles\tDFS (days)\tDays from end of FOLFOX until recurrence\t\n1\t65–69\tMale\tS\tMode\tLiver\t4\t97\t−16a\t\n2\t65–69\tMale\tRs-S\tWell\tLiver\t9\t109\t−88a\t\n3\t60–64\tFemale\tRs\tMode\tLiver\t11\t328\t120\t\n4\t65–69\tFemale\tRb\tWell\tLung\t12\t556\t264\t\nS sigmoid colon, Rs rectosigmoid, Rb rectum below the peritoneal reflection\n\nMode Moderately differentiated adenocarcinoma, Well Well-differentiated adenocarcinoma\n\nDFS Disease-free survival\n\naFOLFOX administered after recurrence\n\n\n\nAdditional file 1 Figure S1 summarizes the clinical courses of these four patients. In case 1, adjuvant mFOLFOX6 was initiated after the colectomy for primary sigmoid colon cancer and hepatic resection was performed for the synchronous colorectal metastases. After three cycles of mFOLFOX6, recurrence in the remnant liver was examined by computed tomography (CT) imaging. In case 2, the patient underwent high anterior resection and liver metastasectomy. Early recurrence in the liver was identified by CT imaging after three cycles of adjuvant mFOLFOX6, which was continued according to the clinician’s discretion. In total, the patient received nine cycles of mFOLFOX6 before resection of the liver recurrence. In case 3, the patient was diagnosed with stage IIA rectal adenocarcinoma, received lower anterior resection without chemoradiotherapy, and was followed without adjuvant chemotherapy. Liver metastasis was diagnosed 14 months after the first operation. Adjuvant mFOLFOX6 was administered following liver metastasectomy, and adjuvant therapy was discontinued at 11 cycles as a result of intolerable peripheral sensory neuropathy. Liver recurrence was identified four months after the end of adjuvant chemotherapy. In case 4, the patient underwent lower anterior resection and lung metastasectomy for metastatic diseases. Nine months after completing the planned adjuvant chemotherapy, lung recurrence was identified by CT imaging.\n\nA median of 10 mFOLFOX6 cycles was reported in this study (range, 4–12 cycles), and the median disease-free survival was 218.5 days (range, 97–556 days).\n\nComparison of the mutation rates and analysis of the mutation spectrum\nWhole exome sequencing was performed to investigate the profile of somatic alterations in all tumor samples. The tumors were sequenced to an average 124-fold coverage (range, 90–155), enabling the sensitive detection of single nucleotide variants (SNVs) and indels to a 10% variant frequency. To identify germline mutations, we sequenced the paired non-tumor colon tissues in addition to the tumor tissues from each patient. Additional file 2: Table S1 shows a summary of the coverage details.\n\nThe mutation rate of the somatic SNVs and indels in each tumor sample ranged from 0.90 to 3.26/Mb, with a median of 1.66/Mb. The rates were consistent with those of non-hypermutated CRC cases reported by The Cancer Genome Atlas (TCGA) [6]. Although the mutation rates increased slightly after FOLFOX administration, there were no significant differences between the matched primary CRC, pre-FOLFOX metastatic, and post-FOLFOX metastatic samples (P > 0.05, Fig. 1a).Fig. 1 a Comparison of mutation rates: Box-and-whisker plot showing the range, median, and 25th and 75th percentile levels of the number of mutations in all primary, pre-FOLFOX metastatic, and post-FOLFOX metastatic tumor samples. The difference in the number of mutations was not significant among the primary, pre-FOLFOX metastatic, and post-FOLFOX metastatic tumor samples across all cases (P > 0.05, Wilcoxon signed-rank test) b Comparison of mutation spectra: Stacked bar plot showing the proportion of mutations accounted for by each of the six mutation types in all primary, pre-FOLFOX metastatic, and post-FOLFOX metastatic tumor samples for each case\n\n\n\nNext, the mutation spectrum of each tumor was investigated. All tumor samples harbored a predominance of C > T/G > A transitions (range, 45–70%), which is reported as a mutational signature of CRC [6, 24] (Fig. 1b). C > A/G > T and T > A/A > T transversions were reported previously as the most common mutations produced by L-OHP in cultured cells [14]. In addition, C > A mutations were particularly prominent in a CpC context (equivalently, G > T in a GpG context) as a result of intrastrand cross-links induced by cisplatin, which is a Pt-containing antitumor compound similar to L-OHP [25]. Therefore, we evaluated whether these platinum exposure signature mutations were enriched among the post-FOLFOX unique mutations. Figure 2 shows the mutation spectra of the primary CRC, pre-FOLFOX, and post-FOLFOX unique mutations. There was no significant increase in C > A/G > T (primary vs post-FOLFOX metastasis, P = 0.27; pre- vs post-FOLFOX metastasis, P = 1.00) or T > A/A > T (primary vs post-FOLFOX metastasis, P = 1.00; pre- vs post-FOLFOX metastasis, P = 0.14) transversions among the post-FOLFOX unique mutations. The incidence of C > A mutations in a CpC context was not increased in post-FOLFOX metastasis (primary vs post-FOLFOX metastasis, P = 0.18; pre- vs post-FOLFOX metastasis, P = 0.18). In addition, there were no significant differences in other mutation fractions (Additional file 3: Figure S2).Fig. 2 Comparison of the mutation spectrum among unique mutations: The relative frequencies of 96 trinucleotides are shown for unique mutations in the primary, pre-FOLFOX metastatic, and post-FOLFOX metastatic tumor samples. The presented number of mutations is the sum of the data recorded for the four patients. For specific mutation types, a Wilcoxon signed-rank test was used, and significant enrichment in the platinum exposure signature, C > A in a CpC context (equivalently, G > T in a GpG context), was not observed\n\n\n\nAnalysis of CNVs\nTo evaluate whether the CNV was affected by FOLFOX treatment, the CNVs in post-FOLFOX metastatic tumors were compared to those in primary tumors and pre-FOLFOX metastatic tumors. Our comparative analysis revealed that CNVs persisted regardless of the administration of FOLFOX therapy in any tumor sample in cases 1, 2, and 4 (Fig. 3). In case 3, we observed focal amplification of the 7q21, 10q22, and 10q23 chromosomal regions, which persisted regardless of FOLFOX therapy administration. However, the amplification of some genes, such as SEMA3E, SEMA3A, PCLO, AK055932, and BX647900, was observed only in pre- and post-FOLFOX metastasis and not in the primary tumor in case 3 (Additional file 4: Table S2).Fig. 3 Comparison of copy number alterations: The CNV patterns were similar among primary (blue), pre-FOLFOX metastatic (purple), and post-FOLFOX metastatic (red) tumor samples in all cases. The x-axis coordinates represent positions along the genome; the vertical bars indicate the borders between chromosomes. The y-axis represents the chromosomal copy number in the tumor compared to normal tissues. A log ratio greater than two was considered significant copy number amplification\n\n\n\nOverlap of SNVs and indels between patient-matched tumor samples\nThe overlap of the detected mutations between the primary, pre-FOLFOX metastatic, and post-FOLFOX metastatic tumor samples in the individual cases was investigated. Additional file 5: Table S3 lists the details of all detected gene mutations. Of the gene mutations detected in each post-FOLFOX metastatic sample, 112 (82%) in case 1, 114 (46%) in case 2, 71 (73%) in case 3, and 125 (86%) in case 4 were shared in the matched tumor samples, indicating that 14–54% of the mutations were post-FOLFOX unique mutations (Fig. 4a).Fig. 4 a Overlap of SNVs and indels: All somatic mutations and indels were classified into three categories: mutations present in all tumor regions (common, blue), mutations shared in more than two but not all regions (shared, green), and mutations in one tumor region (unique, yellow) in each case. The distributions of all somatic mutations in each tumor sample are shown in a stacked bar plot. The number of analyzed mutations is displayed on the right side of each bar. b Comparison of Mut-driver gene mutations: Mutations in 14 Mut-driver genes were detected in all tumor samples, and eight of these were classified as common mutations. A discordant mutation in the PI3K pathway before and after FOLFOX administration was observed in case 2\n\n\n\nNext, we focused on Mut-driver genes, as advocated by Vogelstein et al. [26]; these genes include tumor suppressor genes for which at least 20% of the mutations caused truncation of the gene product and oncogenes for which at least 20% of the missense mutations occurred at a single position along the polypeptide chain. High mutational concordance of these genes, including frequent mutation in CRC genes such as APC, KRAS, FBXW7, TP53, and PIK3CA, was observed between the matched tumor samples in the individual cases (Fig. 4b). However, in case 2, a lack of PIK3CA mutations was found in the post-FOLFOX metastatic samples, although the PIK3CA E542K and E88Q mutations were detected in both the primary tumor and pre-FOLFOX metastatic samples. By contrast, AKT1 E17K (C > T) mutations were found only in the post-FOLFOX metastasis samples in case 2.\n\nAfter FOLFOX administration, we also identified the gain or loss of some mutations that were predicted as functionally important variants by Polyphen2 [21]. Additional file 6: Table S4 lists the details of these mutations.\n\nGene ontology analysis of post-FOLFOX unique mutations\nPost-FOLFOX unique mutations in recurrent tumors may reflect the mechanism of chemo-resistance because recurrent tumors are thought to develop through chemotherapy-induced selective pressure. A GO analysis was performed to identify the molecular functions enriched in post-FOLFOX metastatic samples. For this analysis, we selected gene mutations that predict a possible impact of an amino acid substitution on the structure and function of a human protein (the analyzed gene lists are shown in Additional file 7: Table S5). Although no identical gene mutations were detected in more than two cases, four significant functional clusters were identified (Table 2). The genes annotated to the GO term “calcium ion binding” were detected in all cases, and genes annotated to “calcium ion transport” were detected in three cases. These GO terms were not enriched among the pre-FOLFOX unique gene mutations or among common mutations (Additional file 8: Table S6).Table 2 Significant functional clusters among post-FOLFOX unique mutations\n\nGene Ontology term\tGene symbol\tAdjusted P value\t\nCase 1\tCase 2\tCase 3\tCase 4\t\nGO:0007155~cell adhesion\t\n–\n\t\nCDH9\n\n\nTRPM7\n\n\nCOL22A1\n\n\nNLGN4X\n\n\nPCDH17\n\t\nPCDHA9\n\n\nPDZD2\n\t\n–\n\t0.033\t\nGO:0030695~GTPase regulator activity\t\n–\n\t\nDOCK1\n\n\nTBC1D9\n\n\nRICTOR\n\n\nIQSEC1\n\t\n–\n\t\nTBC1D12\n\t0.037\t\nGO:0006816~calcium ion transport\t\nCACNA1E\n\t\nTRPM7\n\n\nTRPV5\n\n\nSLC24A6\n\t\n–\n\t\nJPH3\n\t0.0014\t\nGO:0005509~calcium ion binding\t\nCACNA1E\n\t\nCDH9\n\n\nTRPM7\n\n\nTBC1D9\n\n\nTRPV5\n\n\nSLC24A6\n\n\nPCDH17\n\t\nPDCHA9\n\n\nPLCB3\n\t\nDOC2A\n\n\nRUNX1\n\t0.00044\t\n\n\nDiscussion\nIn this study, we performed whole exome sequencing on primary colorectal, metastatic, and recurrent tumor samples after adjuvant FOLFOX therapy to evaluate the influence of this cytotoxic chemotherapy regimen on the mutational profile of recurrent CRC. Recently, a wide range of genomic alterations have displayed associations with cancer behavior, and most of these alterations are typically found in coding regions [27]. Therefore, whole exome sequencing is a reasonable strategy for identifying clinically actionable alterations induced by adjuvant FOLFOX chemotherapy in recurrent CRC. Furthermore, one of the most important aims of this study was to evaluate whether adjuvant FOLFOX chemotherapy produces genetic alterations in recurrent CRC. Thus, we excluded variants that could possibly be regarded as germline alterations from our analysis by using the sequencing results from patient-matched normal tissues and previous SNP databases.\n\nOur data showed that the mutation rates and mutation spectrum were nearly identical between the primary CRC, pre-FOLFOX metastatic, and post-FOLFOX metastatic samples. Although the mutagenic activity of L-OHP was demonstrated in cultured cells [14], an enrichment in the L-OHP signature was not observed in post-FOLFOX metastatic tumors. Differences between the results of that study and our results may be due to differences in the drug concentration used in that in vitro study and the concentration used in clinical practice. A significant dose-dependent increase in mutation frequency was observed when CHO-K1 cells were exposed to 10–40 μM L-OHP [14]. However, the Cmax of L-OHP has been reported as approximately 3.6 μM in the clinical dose setting with mFOLFOX6 therapy (85 mg/m2) [28], which might explain the differences between the in vitro findings and those of the present study. A recent study revealed that some recurrent gliomas were hypermutated and harbored driver mutations in the RB and Akt-mTOR pathways that bore the signature of temozolomide-induced mutagenesis after adjuvant temozolomide chemotherapy. Recurrent gliomas that showed evidence of temozolomide-induced hypermutation underwent malignant progression to high-grade tumors with a poorer prognosis [9]. By contrast, our study suggests that FOLFOX is a safe regimen that lacks the potential risk of inducing new driver mutations and malignant progression, unlike adjuvant chemotherapy involving temozolomide to treat glioma.\n\nThe patterns of CNVs were nearly identical before and after FOLFOX chemotherapy in all the cases. The focal amplification of the 7q21, 10q22, and 10q23 chromosomal regions in the post-FOLFOX metastasis samples was also detected in the primary or pre-FOLFOX metastasis samples in case 3. However, we revealed that some gene amplifications were observed only in the pre- and post-FOLFOX metastasis samples and not in the primary tumor samples in case 3. Among these genes, we focused on SEMA3E, which has an expression level reported to be positively correlated with increased metastasis in ovarian, melanoma, and colon cancers [29]. Our results suggest that the acquisition of SEMA3E gene amplification might relate to the metastatic potential in CRC and that CNVs can change during the process of tumor progression.\n\nOne of the limitations of our study is its small sample size due to the strict patient selection criteria. Several studies have reported that differences in mutational profiles depend on the metastatic site [30–32]. Therefore, it was necessary to analyze patient- and organ-matched pre-FOLFOX metastasis and post-FOLFOX metastasis samples. However, such samples are rarely found in daily clinical practice. Our analysis used valuable samples from four CRC cases and accurately assessed the influence of adjuvant FOLFOX chemotherapy on the mutational profile of CRC. The other limitation is the possibility that our cases may have had primary resistance to FOLFOX therapy. This resistance may have been why we failed to observe a chemotherapy-induced signature in the recurrent tumor samples. Our findings should be further validated in a large cohort that includes multiple patients with various backgrounds, such as variations in the duration of FOLFOX chemotherapy or the timing of recurrence.\n\nIt is also possible that there was simply not enough time to observe a chemotherapy-induced signature in the recurrent tumor samples that we used. Twelve-cycle FOLFOX chemotherapy was planned as the full adjuvant chemotherapy course, but it was often discontinued due to tumor relapse or intolerable adverse events. Our data reflect a correlation between adjuvant FOLFOX chemotherapy and the mutation profile of CRC in clinical practice, but further investigation is necessary regarding whether long-term treatment with FOLFOX chemotherapy, such as chemotherapy for unresectable CRC, can induce additional mutations. A previous study suggested that a circulating tumor DNA analysis could be used to reliably monitor tumor dynamics in subjects with cancer who were undergoing surgery or chemotherapy for CRC [33]. This non-invasive approach may be a more suitable way to test residual tumor cells and analyze temporal changes in mutation profiles.\n\nPrevious comparative genomic studies have reported varying degrees of divergence in the genomic profiles of primary CRC and matched metastases. Substantial mutational divergence between paired primary tumor and metastasis samples was reported in a whole exome sequencing analysis with a low sequencing depth [34] and in shallow-targeted sequencing analysis variants with a variant allele frequency greater than 20% [35]. By contrast, a recent deep-targeted sequencing analysis [36, 37] and whole exome sequencing study with an average sequencing depth of > 100-fold [38] showed a high degree of mutational concordance, generally 50–80%, between primary CRC and metastases. These studies also suggest an exceedingly high level of concordance between primary CRC and metastases in genetic alterations that occur early in colorectal carcinogenesis, such as alterations in APC, KRAS, NRAS, and BRAF. In our study, we achieved an average coverage depth of 124-fold, enabling the sensitive detection of SNVs and indels to a 10% variant frequency. Our results are comparable to the results of previous high-resolution sequencing analyses. Therefore, it is more accurate to state that the majority of mutations are shared between primary CRC and metastatic tumors in at least some cases. Furthermore, our finding confirms our previous results [15] showing that both primary tumors and their subsequent metastases could be valid sources of DNA for patient selection before commencing anti-EGFR therapy.\n\nBrannon et al. demonstrated that some of the mutational discordance could be explained by spatial heterogeneity in the patient tumors. They also suggest chemotherapy-derived clonal selection based on the finding that pre-treated tumors were less likely to have unique mutations than chemo-naive tumors in patients with concurrently resected tumors [36]. The increase in unique mutations after FOLFOX chemotherapy in our cases is also likely explained by intra-tumor heterogeneity and clonal selection rather than by the mutagenicity of L-OHP. According to the Big Bang model of human colorectal tumor growth [39], numerous heterogeneous subclones predominantly expand through tumor evolution. After treatment-derived clonal selection via methods such as surgery and cytotoxic chemotherapy, clones acquiring a fitness advantage in the environment become dominant in residual tumors. Our findings raise the possibility that surgery and adjuvant FOLFOX chemotherapy change the clonal composition, resulting in differences in genetic alterations before and after FOLFOX administration. This hypothesis may explain the mutational discordance in case 2. The AKT1 E17K mutation can activate the PI3K/AKT/mTOR pathway in a similar manner as PIK3CA alterations and promotes carcinogenesis through increasing cell proliferation or survival [40] via the PI3K pathway. AKT1 mutant clones, which were found in the minority of primary tumor samples, might sufficiently increase via clonal selection to detectable levels following surgery and adjuvant chemotherapy. The high rate of unique mutations in post-FOLFOX metastatic samples (54% in case 2) also indicates that there are differences in the clonal composition of these tumors compared to those of primary tumor and pre-FOLFOX metastatic samples. However, because of the very limited number of cases and the heterogeneity of the tumors, further validation is necessary. Furthermore, in a recent report, Angelova M et al. demonstrated that the immune system also influences tumor clonal composition and tumor evolution during the metastatic process [41]. In future studies, we must focus on clonal selection induced by not only chemotherapeutic agents but also by the immune system.\n\nIn addition, we reported that some genes that might be related to drug resistance were gained or lost during chemotherapy. Previous studies have indicated that CIAPIN1 is involved in the development of multiple drug resistance (MDR) [42]. PTPRJ is expressed in CRC cells, and it is reported that the sustained inhibition of PTPRJ increased cell resistance to 5-fluorouracil (5-FU)-induced apoptosis [43]. Wang et al. indicated that the TopBP1 expression level was related to the prognosis of non-small cell lung cancer patients treated with platinum-based chemotherapy [44]. The CIAPIN1 R132W and PTPRJ L738 V mutations were identified among the post-FOLFOX unique mutations in case 2. Conversely, in case 2, the TOPBP1 S630 L mutation was identified in primary and pre-FOLFOX metastasis but not in post-FOLFOX metastasis. These mutations were non-synonymous and were predicted as functionally important variants by ANNOVAR [19] in addition to Polyphen2 [21]. Thus, these mutations may affect the function of proteins related to drug resistance. However, the true function of these mutations is unclear, and further investigation is necessary.\n\nThe results of the GO analysis showed an enrichment of genes that are annotated as “calcium ion transport” among genes uniquely mutated after FOLFOX. For example, TRPM7 encodes a calcium-permeant ion channel that is notable for its inherent serine/threonine kinase activity [45]. The product of CACNA1E is the alpha 1E subunit of R-type voltage-dependent calcium channels [46]. The calcium-selective channel encoded by TRPV5 is activated by a low internal calcium level [47]. SLC24A6 encodes a family of potassium-dependent sodium/calcium exchangers that maintain cellular calcium homeostasis [48]. Previous in vitro studies have indicated that there is a relationship between intracellular Ca2+ homeostasis and the P-glycoprotein-dependent MDR phenotype [49], which is considered one of the mechanisms underlying resistance to L-OHP [50]. Although further investigation of the true function of these mutations is necessary in a larger cohort, alterations in genes involved in intracellular Ca2+ homeostasis may be related to resistance to FOLFOX therapy with the development of MDR.\n\nConclusions\nIn conclusion, our data showed that the mutation rates, mutation spectra, or CNVs were nearly identical between the primary tumor, pre-FOLFOX metastatic, and post-FOLFOX metastatic samples in four CRC cases. We found that some gene mutations that might be related to FOLFOX resistance were gained or lost during chemotherapy, and the inter-tumor discordance of the mutational profiles suggests the existence of intra-tumor heterogeneity and the induction of clonal selection as a result of response to the FOLFOX chemotherapy. Our findings might be useful as pilot data for a larger study to clarify the changes in the mutational landscape induced by adjuvant FOLFOX chemotherapy.\n\nAdditional files\n\nAdditional file 1: Figure S1. Clinical courses of the four cases. The blue arrows indicate the day of surgery, and the red arrows indicate the day on which the recurrent tumors were diagnosed during or after adjuvant FOLFOX therapy. The arrowheads (light blue) indicate the number of FOLFOX treatments. Disease-free survival (DFS) is calculated from the time of the final operation until post-FOLFOX recurrence (TIF 259 kb)\n\n \nAdditional file 2: Table S1. Coverage details. Summary of the sequencing coverage depth in each sample. (XLSX 10 kb)\n\n \nAdditional file 3: Figure S2. Comparison of the mutation spectrum among unique mutations. Relative mutation frequencies are shown for unique mutations in primary, pre-FOLFOX metastatic, and post-FOLFOX metastatic tumor samples. The presented number of mutations is the sum of data recorded in the four patients. There were no significant differences in all mutation fractions (Wilcoxon signed-rank test). (TIF 119 kb)\n\n \nAdditional file 4: Table S2. Focal amplification in case 3. Summary of the gene amplification in case 3. (XLSX 10 kb)\n\n \nAdditional file 5: Table S3. Detailed information for all detected gene mutations. List of all gene mutations detected in our analysis. (XLSX 86 kb)\n\n \nAdditional file 6: Table S4. The gain or loss of the mutations that were predicted as functionally important. (XLSX 13 kb)\n\n \nAdditional file 7: Table S5. Post-FOLFOX unique gene mutations used for the GO analysis. List of selected gene mutations for the GO analysis. (XLSX 16 kb)\n\n \nAdditional file 8: Table S6. Significant functional clusters in each mutation category. List of the Gene Ontology terms enriched among unique gene mutations before FOLFOX administration or among common mutations. (XLSX 10 kb)\n\n \n\n\nAbbreviations\n5-FU5-fluorouracil\n\nBWABurrows-Wheeler Aligner\n\nCNVCopy number variant\n\nCRCColorectal cancer\n\nCTComputed tomography\n\nDAVIDDatabase for Annotation, Visualization, and Integrated Discovery\n\nEGFREpidermal growth factor receptor\n\nFFPEFormalin-fixed, paraffin-embedded\n\nGATKGenome Analysis ToolKit\n\nGOGene Ontology\n\nIndelsSmall insertions/deletions\n\nL-OHPOxaliplatin\n\nMDRMulti-drug resistance\n\nPtPlatinum\n\nSNVSingle nucleotide variant\n\nThe National Cancer Center Biobank is supported by the National Cancer Center Research and Development Fund, Japan.\n\nFunding\nThis study was supported by research funding from the National Cancer Center. The funding body helped in material collection and data analyses.\n\nAvailability of data and materials\nThe datasets supporting the conclusions of this article are included within the article and its additional files.\n\nAuthors’ contributions\nKT and WO conceived the study with advice from SM and TY. KH, WO, SM, and RY performed the data analysis. YK (Kawamoto), HB, TY, and AO provided clinical data and helped collect the tumor tissues. KH and WO wrote the manuscript with advice from SM, YK (Kawamoto), HB, RY, SY, TY, YK (Komatsu), AO, NS, and KT. All authors have read and approved the manuscript.\n\nEthics approval and consent to participate\nThe study protocol was approved by the Institutional Review Board of the National Cancer Center. Samples of the four patients admitted before June 2011 and whose written informed consents could not be obtained were used with the approval of the Institutional Review Board, which privileged the opt-out for the patients, according to the Ethical Guidelines for Epidemiological Research issued by Ministry of Education, Culture, Sports, Science and Technology, and Ministry of Health, Labour and Welfare of Japan.\n\nConsent for publication\nInformed consent to publish identifying patient details was obtained from all participants included in this study.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. DeSantis CE Lin CC Mariotto AB Siegel RL Stein KD Kramer JL Cancer treatment and survivorship statistics, 2014 CA Cancer J Clin 2014 64 252 271 10.3322/caac.21235 24890451 \n2. Douillard JY Oliner KS Siena S Tabernero J Burkes R Barugel M Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer N Engl J Med 2013 369 1023 1034 10.1056/NEJMoa1305275 24024839 \n3. Van Cutsem E Lenz HJ Kohne CH Heinemann V Tejpar S Melezinek I Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer J Clin Oncol 2015 33 692 700 10.1200/JCO.2014.59.4812 25605843 \n4. Loupakis F Cremolini C Masi G Lonardi S Zagonel V Salvatore L Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer N Engl J Med 2014 371 1609 1618 10.1056/NEJMoa1403108 25337750 \n5. Yuan ZX Wang XY Qin QY Chen DF Zhong QH Wang L The prognostic role of BRAF mutation in metastatic colorectal cancer receiving anti-EGFR monoclonal antibodies: a meta-analysis PLoS One 2013 8 e65995 10.1371/journal.pone.0065995 23776587 \n6. The Cancer Genome Atlas Network Comprehensive molecular characterization of human colon and rectal cancer Nature. 2012 487 330 337 10.1038/nature11252 22810696 \n7. Guinney J Dienstmann R Wang X de Reynies A Schlicker A Soneson C The consensus molecular subtypes of colorectal cancer Nat Med 2015 21 1350 1356 10.1038/nm.3967 26457759 \n8. Ding L Ley TJ Larson DE Miller CA Koboldt DC Welch JS Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing Nature. 2012 481 506 510 10.1038/nature10738 22237025 \n9. Johnson BE Mazor T Hong C Barnes M Aihara K McLean CY Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma Science. 2014 343 189 193 10.1126/science.1239947 24336570 \n10. Benson AB 3rd Venook AP Bekaii-Saab T Chan E Chen YJ Cooper HS Colon cancer, version 3.2014 J Natl Compr Cancer Netw 2014 12 1028 1059 10.6004/jnccn.2014.0099 \n11. Woynarowski JM Faivre S Herzig MC Arnett B Chapman WG Trevino AV Oxaliplatin-induced damage of cellular DNA Mol Pharmacol 2000 58 920 927 10.1124/mol.58.5.920 11040038 \n12. Hah SS Sumbad RA de Vere White RW Turteltaub KW Henderson PT Characterization of oxaliplatin-DNA adduct formation in DNA and differentiation of cancer cell drug sensitivity at microdose concentrations Chem Res Toxicol 2007 20 1745 1751 10.1021/tx700376a 18001055 \n13. Sharma S Gong P Temple B Bhattacharyya D Dokholyan NV Chaney SG Molecular dynamic simulations of cisplatin- and oxaliplatin-d (GG) intrastand cross-links reveal differences in their conformational dynamics J Mol Biol 2007 373 1123 1140 10.1016/j.jmb.2007.07.079 17900616 \n14. Silva MJ Costa P Dias A Valente M Louro H Boavida MG Comparative analysis of the mutagenic activity of oxaliplatin and cisplatin in the Hprt gene of CHO cells Environ Mo Mutagen 2005 46 104 115 10.1002/em.20138 \n15. Kawamoto Y Tsuchihara K Yoshino T Ogasawara N Kojima M Takahashi M KRAS mutations in primary tumours and post-FOLFOX metastatic lesions in cases of colorectal cancer Br J Cancer 2012 107 340 344 10.1038/bjc.2012.218 22617127 \n16. Bando H Yoshino T Tsuchihara K Ogasawara N Fuse N Kojima T KRAS mutations detected by the amplification refractory mutation system-scorpion assays strongly correlate with therapeutic effect of cetuximab Br J Cancer 2011 105 403 406 10.1038/bjc.2011.247 21730978 \n17. Li H Durbin R Fast and accurate short read alignment with burrows-wheeler transform Bioinformatics. 2009 25 1754 1760 10.1093/bioinformatics/btp324 19451168 \n18. DePristo MA Banks E Poplin R Garimella KV Maguire JR Hartl C A framework for variation discovery and genotyping using next-generation DNA sequencing data Nat Genet 2011 43 491 498 10.1038/ng.806 21478889 \n19. Wang K Li M Hakonarson H ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data Nucleic Acids Res 2010 38 e164 10.1093/nar/gkq603 20601685 \n20. Huang d W Sherman BT Lempicki RA Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources Nat Protoc 2009 4 44 57 10.1038/nprot.2008.211 19131956 \n21. Adzhubei IA Schmidt S Peshkin L Ramensky VE Gerasimova A Bork P A method and server for predicting damaging missense mutations Nat Methods 2010 7 248 249 10.1038/nmeth0410-248 20354512 \n22. Sathirapongsasuti JF Lee H Horst BA Brunner G Cochran AJ Binder S Exome sequencing-based copy-number variation and loss of heterozygosity detection: ExomeCNV Bioinformatics. 2011 27 2648 2654 10.1093/bioinformatics/btr462 21828086 \n23. Allegra CJ Yothers G O'Connell MJ Sharif S Colangelo LH Lopa SH Initial safety report of NSABP C-08: a randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer J Clin Oncol 2009 27 3385 3390 10.1200/JCO.2009.21.9220 19414665 \n24. Wood LD Parsons DW Jones S Lin J Sjoblom T Leary RJ The genomic landscapes of human breast and colorectal cancers Science. 2007 318 1108 1113 10.1126/science.1145720 17932254 \n25. Meier B Cooke SL Weiss J Bailly AP Alexandrov LB Marshall J C. Elegans whole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency Genome Res 2014 24 1624 1636 10.1101/gr.175547.114 25030888 \n26. Vogelstein B Papadopoulos N Velculescu VE Zhou S Diaz LA Jr Kinzler KW Cancer genome landscapes Science. 2013 339 1546 1558 10.1126/science.1235122 23539594 \n27. Choi M Scholl UI Ji W Liu T Tikhonova IR Zumbo P Genetic diagnosis by whole exome capture and massively parallel DNA sequencing Proc Natl Acad Sci U S A 2009 106 19096 19101 10.1073/pnas.0910672106 19861545 \n28. Ehrsson H Wallin I Yachnin J Pharmacokinetics of oxaliplatin in humans Med Oncol 2002 19 261 265 10.1385/MO:19:4:261 12512920 \n29. Casazza A Finisguerra V Capparuccia L Camperi A Swiercz JM Rizzolio S Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice J Clin Invest 2010 120 2684 2698 10.1172/JCI42118 20664171 \n30. Kim MJ Lee HS Kim JH Kim YJ Kwon JH Lee JO Different metastatic pattern according to the KRAS mutational status and site-specific discordance of KRAS status in patients with colorectal cancer BMC Cancer 2012 12 347 10.1186/1471-2407-12-347 22876814 \n31. Baas JM Krens LL Guchelaar HJ Morreau H Gelderblom H Concordance of predictive markers for EGFR inhibitors in primary tumors and metastases in colorectal cancer: a review Oncologist. 2011 16 1239 1249 10.1634/theoncologist.2011-0024 21742964 \n32. Kopetz S Overman MJ Chen K Lucio-Eterovic AK Fogelman BKKDR Dasari A Mutation and copy number discordance in primary versus metastatic colorectal cancer (mCRC) J Clin Oncol 2014 32 Suppl 5s 3509 10.1200/jco.2014.32.15_suppl.3509 \n33. Diehl F Schmidt K Choti MA Romans K Goodman S Li M Circulating mutant DNA to assess tumor dynamics Nat Med 2008 14 985 990 10.1038/nm.1789 18670422 \n34. Lee SY Haq F Kim D Jun C Jo HJ Ahn SM Comparative genomic analysis of primary and synchronous metastatic colorectal cancers PLoS One 2014 9 e90459 10.1371/journal.pone.0090459 24599305 \n35. Vermaat JS Nijman IJ Koudijs MJ Gerritse FL Scherer SJ Mokry M Primary colorectal cancers and their subsequent hepatic metastases are genetically different: implications for selection of patients for targeted treatment Clin Cancer Res 2012 18 688 699 10.1158/1078-0432.CCR-11-1965 22173549 \n36. Brannon AR Vakiani E Sylvester BE Scott SN McDermott G Shah RH Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions Genome Biol 2014 15 454 457 10.1186/s13059-014-0454-7 25164765 \n37. Tan IB Malik S Ramnarayanan K McPherson JR Ho DL Suzuki Y High-depth sequencing of over 750 genes supports linear progression of primary tumors and metastases in most patients with liver-limited metastatic colorectal cancer Genome Biol 2015 16 32 10.1186/s13059-015-0589-1 25808843 \n38. Lim B Mun J Kim JH Kim CW Roh SA Cho DH Genome-wide mutation profiles of colorectal tumors and associated liver metastases at the exome and transcriptome levels Oncotarget. 2015 6 22179 22190 26109429 \n39. Sottoriva A Kang H Ma Z Graham TA A big bang model of human colorectal tumor growth Nat Genet 2015 47 209 216 10.1038/ng.3214 25665006 \n40. Cully M You H Levine AJ Mak TW Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis Nat Rev Cancer 2006 6 184 192 10.1038/nrc1819 16453012 \n41. Angelova M Mlecnik B Vasaturo A Bindea G Fredriksen T Lafontaine L Buttard B Morgand E Bruni D Jouret-Mourin A Hubert C Kartheuser A Humblet Y Ceccarelli M Syed N Marincola FM Bedognetti D Van den Eynde M Galon J Evolution of metastases in space and time under immune selection Cell. 2018 18 751 765 10.1016/j.cell.2018.09.018 \n42. Zhang YF Li XH Shi YQ Wu YY Li N He Q CIAPIN1 confers multidrug resistance through up-regulation of MDR-1 and Bcl-L in LoVo/Adr cells and is independent of p53 Oncol Rep 2011 25 1091 1098 21240465 \n43. Yan CM Zhao YL Cai HY Miao GY Ma W Blockage of PTPRJ promotes cell growth and resistance to 5-FU through activation of JAK1/STAT3 in the cervical carcinoma cell line C33A Oncol Rep 2015 33 1737 1744 10.3892/or.2015.3769 25634668 \n44. Wang LR He LJ Wang Y Li YY Lou Y Zhang GB Li Y Chen. Correlation between BRCA1 and TopBP1 protein expression and clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy J Cancer Chemother Pharmacol 2015 76 163 170 10.1007/s00280-015-2773-0 \n45. Runnels LW Yue L Clapham DE TRP-PLIK, a bifunctional protein with kinase and ion channel activities Science. 2001 291 1043 1047 10.1126/science.1058519 11161216 \n46. Vajna R Schramm M Pereverzev A Arnhold S Grabsch H Klockner U New isoform of the neuronal Ca2+ channel alpha1E subunit in islets of Langerhans and kidney--distribution of voltage-gated Ca2+ channel alpha1 subunits in cell lines and tissues Eur J Biochem 1998 257 274 285 10.1046/j.1432-1327.1998.2570274.x 9799129 \n47. Hoenderop JG van der Kemp AW Hartog A van de Graaf SF van Os CH Willems PH Molecular identification of the apical Ca2+ channel in 1, 25-dihydroxyvitamin D3-responsive epithelia J Biol Chem 1999 274 8375 8378 10.1074/jbc.274.13.8375 10085067 \n48. Cai X Lytton J The cation/ca(2+) exchanger superfamily: phylogenetic analysis and structural implications Mol Biol Evol 2004 21 1692 1703 10.1093/molbev/msh177 15163769 \n49. Sulova Z, Seres M, Barancik M, Gibalova L, Uhrik B, Polekova L, et al. Does any relationship exist between P-glycoprotein-mediated multidrug resistance and intracellular calcium homeostasis. Gen Physiol Biophys 2009;28 Spec No Focus:F89–F95.\n50. Martinez-Balibrea E Martinez-Cardus A Gines A Ruiz de Porras V Moutinho C Layos L Tumor related molecular mechanisms of Oxaliplatin resistance Mol Cancer Ther 2015 14 1767 1776 10.1158/1535-7163.MCT-14-0636 26184483\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "19(1)",
"journal": "BMC cancer",
"keywords": "Adjuvant chemotherapy; Chemo-resistance; Colorectal cancer; Mutagenicity; Whole exome sequencing",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D017024:Chemotherapy, Adjuvant; D060965:Clonal Evolution; D003082:Colectomy; D015179:Colorectal Neoplasms; D056915:DNA Copy Number Variations; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D009944:Organoplatinum Compounds; D010865:Pilot Projects; D057285:Precision Medicine; D000078542:Proctectomy; D000073359:Whole Exome Sequencing",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "255",
"pmc": null,
"pmid": "30898102",
"pubdate": "2019-03-21",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "10085067;11040038;11161216;12512920;15163769;15887215;16453012;17900616;17932254;18001055;18670422;19131956;19414665;19451168;19861545;20093732;20354512;20601685;20664171;21240465;21478889;21730978;21742964;21828086;22173549;22237025;22617127;22810696;22876814;23539594;23776587;24024839;24336570;24599305;24890451;24994923;25030888;25164765;25337750;25605843;25634668;25665006;25808843;26003539;26109429;26184483;26457759;30318143;9799129",
"title": "Comparative sequence analysis of patient-matched primary colorectal cancer, metastatic, and recurrent metastatic tumors after adjuvant FOLFOX chemotherapy.",
"title_normalized": "comparative sequence analysis of patient matched primary colorectal cancer metastatic and recurrent metastatic tumors after adjuvant folfox chemotherapy"
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"abstract": "Antiviral therapy improves hepatic outcomes in hepatitis C virus (HCV)-infected cancer patients. However, such patients are not treated simultaneously with antivirals and chemotherapy, owing to overlapping toxicities with previous standard of care treatment of pegylated interferon and ribavirin.\n\n\n\nTo examine the safety and clinically-significant drug-drug interactions observed in patients who received simultaneous treatment with direct-acting antivirals (DAAs) and chemotherapy.\n\n\n\nSafety was determined by the presence of adverse events which were graded according to the division of AIDS Table (version 2.0). Adverse events were monitored throughout antiviral treatment and up to 3 months after its completion. Drug-drug interactions were assessed using current online databases. Sustained virological response (SVR) was defined as absence of serum HCV RNA 12 weeks after end of DAA treatment. Cirrhosis was diagnosed via imaging, biopsy or with the use of non-invasive fibrosis markers.\n\n\n\nTwenty-one patients received concomitant treatment with DAAs and chemotherapy between January 2013 and September 2016. Concomitant treatment was started either for virological (14; 67%) or oncologic (7; 33%) reasons. DAAs used were sofosbuvir, ledipasvir, simeprevir, daclatasvir ± ribavirin. The adverse events observed were mainly constitutional (12; 57%), hematological and gastrointestinal (7; 33% each). Physicians changed the DAA regimens in two patients (10%) in anticipation of drug-drug interactions with daclatasvir and dexamethasone. The overall SVR rate was 95% (20/21).\n\n\n\nHepatitis C virus-targeted antiviral therapy can be used concomitantly with selected anti-neoplastic agents under close monitoring for drug-drug interactions. This therapeutic intervention may prevent delay in the administration of chemotherapy in HCV-infected cancer patients.",
"affiliations": "Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Pharmacy Clinical Programs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Economides|M P|MP|;Mahale|P|P|;Kyvernitakis|A|A|;Turturro|F|F|;Kantarjian|H|H|;Naing|A|A|;Hosry|J|J|;Shigle|T L|TL|;Kaseb|A|A|;Torres|H A|HA|",
"chemical_list": "D000970:Antineoplastic Agents; D000998:Antiviral Agents; D012367:RNA, Viral",
"country": "England",
"delete": false,
"doi": "10.1111/apt.13825",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "44(11-12)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D008297:Male; D009369:Neoplasms; D012367:RNA, Viral",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "1235-1241",
"pmc": null,
"pmid": "27730654",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
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"title": "Concomitant use of direct-acting antivirals and chemotherapy in hepatitis C virus-infected patients with cancer.",
"title_normalized": "concomitant use of direct acting antivirals and chemotherapy in hepatitis c virus infected patients with cancer"
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"abstract": "Patients with cancer frequently use herbal supplements and concomitant medications along with antineoplastic agents. These patients are at high risk of herb-drug interactions (HDIs) and drug-drug interactions (DDIs). We aimed to determine clinically relevant DDIs and HDIs leading to pharmaceutical intervention.\n\n\n\nPatients starting a new anticancer therapy were asked to complete a questionnaire to identify concomitant use of any over-the-counter drug or herbal supplement. Potential DDIs and HDIs were identified using two different databases. If a potentially clinically relevant DDI was recognized by the clinical pharmacist, a notification was sent to the prescribing oncologist, who decided whether to carry out a suggested intervention. Regression analyses were performed to identify variables associated with clinically relevant DDIs.\n\n\n\nA total of 149 patients were included in this study, with 36 potentially clinically relevant DDIs identified in 26 patients (17.4%; 95% CI, 11.3% to 23.5%), all of them leading to therapy modifications. In total, four patients (2.7%; 95% CI, 0.1% to 5.3%) had experienced clinical consequences from DDIs at the time of pharmacist notification. Additionally, 84 patients (56.4%; 95% CI, 48.4% to 64.4%) reported using concurrent herbal supplements, and 122 possible HDIs were detected. Concomitant use of two or more drugs was independently associated with high risk of a clinically significant DDI (odds ratio, 2.53; 95% CI, 1.08 to 5.91; P = .03).\n\n\n\nPotentially clinically relevant DDIs and possible HDIs were frequently detected in this prospective study. A multidisciplinary approach is required to identify and avoid potentially harmful combinations with anticancer therapy.",
"affiliations": "Hospital San Juan de Dios; and University of Costa Rica, San José, Costa Rica.;Hospital San Juan de Dios; and University of Costa Rica, San José, Costa Rica.;Hospital San Juan de Dios; and University of Costa Rica, San José, Costa Rica.",
"authors": "Ramos-Esquivel|Allan|A|;Víquez-Jaikel|Álvaro|Á|;Fernández|Cristina|C|",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D019587:Dietary Supplements; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D054539:Medication Therapy Management; D008875:Middle Aged; D009369:Neoplasms; D004366:Nonprescription Drugs; D010595:Pharmacists; D011795:Surveys and Questionnaires",
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"title": "Potential Drug-Drug and Herb-Drug Interactions in Patients With Cancer: A Prospective Study of Medication Surveillance.",
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"abstract": "Gingival overgrowth is well documented side effect associated with three major classes of drugs viz, anticonvulsants, calcium channel blockers, and immunosuppressants. Despite our greater understanding of pathogenesis of Drug induced Gingival Overgrowth (DIGO), its treatment still remains a challenge for the periodontists and treatment is still largely limited to maintenance of improved level of oral hygiene and surgical removal of overgrown tissue. Dental Surgeons need to discuss this issue with their medical colleagues and to practice care while prescribing the drugs associated with gingival overgrowth. The aim of present article is to report a rare case where even after extraction of all teeth; the enlargement did not subsided for one month.",
"affiliations": "Assistant Professor, Department of Periodontics, RUHS College of Dental Sciences , Jaipur, India .;Assistant Professor, Department of Conservativ Dentistry & Endodontics, RUHS College of Dental Sciences , Jaipur, India .;Senior Professor and Head, Department of Dentistry, S. P. Medical College & Hospital , Bikaner, India .;Senior Lecturer, Department of Oral Pathology, Rajasthan Dental College & Hospital, , Jaipur, India .;Professor, Department of Pathology, M.G. Medical College & Hospital , Jaipur, India .",
"authors": "Mathur|Setu|S|;Khatri|Rohit Kumar|RK|;Mathur|Ranjan|R|;Srivastava|Rashi|R|;Nag|B P|BP|",
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"title": "Drug induced gingival overgrowth: a rare case report.",
"title_normalized": "drug induced gingival overgrowth a rare case report"
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"abstract": "Angelman syndrome is a genetically inherited syndrome with severe retardation of psychomotor development and speech disturbances, usually accompanied by epilepsy, typical dysmorphic features, and some skeletal symptoms. The aim of the current report is to present new skeletal symptoms which may occur in the course of AS, based on a case report of an 8-year-old girl with confirmed 15q11;12 microdeletion and recurrent low-trauma bone fractures. According to our knowledge it is the first report of such skeletal symptoms in patient with a diagnosis of AS.",
"affiliations": "Department of Paediatric Propedeutics and Metabolic Bone Diseases, Medical University of Lodz, Poland. agnieszka.rusinska@wp.pl",
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"references": null,
"title": "Recurrent fractures as a new skeletal problem in the course of Angelman syndrome.",
"title_normalized": "recurrent fractures as a new skeletal problem in the course of angelman syndrome"
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"abstract": "Plasmablastic lymphoma (PBL) is a rare and aggressive form of B-cell non-Hodgkin lymphoma. This subtype of lymphoma has a post-germinal center cell-of-origin called the plasmablast, and the immunophenotype is more consistent with that of a plasma cell than a lymphocyte. Because of these unique features, PBL is notoriously difficult to treat. Case reports and small reviews have evaluated the addition of agents directed against plasma cell disorders in combination with traditional lymphoma-directed regimens. We describe the largest case series to date, with the longest follow-up, evaluating bortezomib in combination with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (V-EPOCH) for the treatment of PBL. Our results show that this is a safe and effective regimen with an overall and complete response rate of 100% and 2-year overall survival of 50%.",
"affiliations": "a Division of Hematology and Oncology Medicine , University of North Carolina at Chapel Hill , Chapel Hill , NC , USA.;b Division of Hematology and Oncology Medicine , University of North Carolina at Chapel Hill , Chapel Hill , NC , USA.;c Division of Pathology and Cytopathology , Louisiana State University , Shreveport , LA , USA.;d Lineberger Comprehensive Cancer Center , University of North Carolina at Chapel Hill , Chapel Hill , NC , USA.;e Levine Cancer Institute, Carolinas Healthcare System , Charlotte , NC , USA.",
"authors": "Dittus|Christopher|C|0000-0002-9794-7908;Grover|Natalie|N|;Ellsworth|Steven|S|;Tan|Xianming|X|;Park|Steven I|SI|",
"chemical_list": "D014750:Vincristine; D000069286:Bortezomib; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
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"issue": "59(9)",
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"keywords": "Lymphoma and Hodgkin disease; chemotherapeutic approaches; immunotherapy",
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"mesh_terms": "D000328:Adult; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003520:Cyclophosphamide; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D000069293:Plasmablastic Lymphoma; D011241:Prednisone; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "9007422",
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"pages": "2121-2127",
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"pubdate": "2018-09",
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"title": "Bortezomib in combination with dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) induces long-term survival in patients with plasmablastic lymphoma: a retrospective analysis.",
"title_normalized": "bortezomib in combination with dose adjusted epoch etoposide prednisone vincristine cyclophosphamide and doxorubicin induces long term survival in patients with plasmablastic lymphoma a retrospective analysis"
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"abstract": "Bronchiolitis obliterans (BO) and paraneoplastic pemphigus are rare and ominous complications of Castleman disease. Collectively, these processes have been reported as part of paraneoplastic autoimmune multiorgan syndrome (PAMS), and they can occur in the setting of various hematologic malignant tumors, carcinoid tumors, and melanoma. Irrespective of the underlying malignancy driving PAMS, the clinical outcomes are uniformly poor, and there are no standard treatment regimens, given the clinical rarity of the syndrome. We describe 2 patients with unicentric Castleman disease complicated by paraneoplastic pemphigus and bronchiolitis obliterans. In addition to primary surgical resection for Castleman disease, we also used therapy from a treatment protocol used for bronchiolitis obliterans resulting from hematopoietic stem cell transplant (HSCT). We were able to treat the patients using intravenous immunoglobulin; rituximab; fluticasone, azithromycin, and montelukast (FAM); and rosuvastatin therapy. One patient demonstrated a favorable response, while the other demonstrated minimal response to this therapy.",
"affiliations": "Division of Pulmonary Medicine, Mayo Clinic Hospital, Phoenix, AZ, USA.;Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ, USA.;Division of Hematology and Medical Oncology, Mayo Clinic Hospital, Phoenix, AZ, USA.;Department of Dermatology, Mayo Clinic, Scottsdale, AZ, USA.;Division of Pulmonary Medicine, Mayo Clinic Hospital, Phoenix, AZ, USA.;Division of Cardiothoracic Radiology, Mayo Clinic, Scottsdale, AZ, USA.;Division of Pulmonary Medicine, Mayo Clinic Hospital, Phoenix, AZ, USA.",
"authors": "Raza|Hassan A|HA|;Nokes|Brandon T|BT|;Rosenthal|Allison C|AC|;Mangold|Aaron R|AR|;Kelemen|Katalin|K|;Jokerst|Clinton E|CE|;Cartin-Ceba|Rodrigo|R|",
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"doi": "10.1016/j.rmcr.2018.08.002",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(18)30114-X10.1016/j.rmcr.2018.08.002Case ReportUnicentric castleman disease complicated by paraneoplastic bronchiolitis obliterans and pemphigus Raza Hassan A. MD.aNokes Brandon T. MD.cRosenthal Allison C. DO.bMangold Aaron R. MD.dKelemen Katalin MD.aJokerst Clinton E. MD.eCartin-Ceba Rodrigo MD.,MSc.cartinceba.rodrigo@mayo.eduaf∗a Division of Pulmonary Medicine, Mayo Clinic Hospital, Phoenix, AZ, USAb Division of Hematology and Medical Oncology, Mayo Clinic Hospital, Phoenix, AZ, USAc Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ, USAd Department of Dermatology, Mayo Clinic, Scottsdale, AZ, USAe Division of Cardiothoracic Radiology, Mayo Clinic, Scottsdale, AZ, USAf Division of Pulmonary Medicine, Mayo Clinic, Scottsdale, AZ, USA∗ Corresponding author. Division of Pulmonary Medicine, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA. cartinceba.rodrigo@mayo.edu10 8 2018 2018 10 8 2018 25 129 132 26 4 2018 3 8 2018 4 8 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Bronchiolitis obliterans (BO) and paraneoplastic pemphigus are rare and ominous complications of Castleman disease. Collectively, these processes have been reported as part of paraneoplastic autoimmune multiorgan syndrome (PAMS), and they can occur in the setting of various hematologic malignant tumors, carcinoid tumors, and melanoma. Irrespective of the underlying malignancy driving PAMS, the clinical outcomes are uniformly poor, and there are no standard treatment regimens, given the clinical rarity of the syndrome. We describe 2 patients with unicentric Castleman disease complicated by paraneoplastic pemphigus and bronchiolitis obliterans. In addition to primary surgical resection for Castleman disease, we also used therapy from a treatment protocol used for bronchiolitis obliterans resulting from hematopoietic stem cell transplant (HSCT). We were able to treat the patients using intravenous immunoglobulin; rituximab; fluticasone, azithromycin, and montelukast (FAM); and rosuvastatin therapy. One patient demonstrated a favorable response, while the other demonstrated minimal response to this therapy.\n\nKeywords\nBronchiolitisChest imagingLeukotriene receptor antagonistMultisystemic syndromeSmall airway disease\n==== Body\nAbbreviations\nCTcomputed tomography\n\nIVIgintravenous immunoglobulin\n\nFEV1forced expiratory volume in the first second of expiration\n\nFVCforced vital capacity\n\nHSCThematopoietic stem cell transplant\n\nPAMSparaneoplastic autoimmune multiorgan syndrome\n\nPFTpulmonary function test\n\nPNPparaneoplastic pemphigus\n\n1 Introduction\nBronchiolitis obliterans and paraneoplastic pemphigus (PNP) are rare, ominous complications of Castleman disease [1], and they have been reported as part of paraneoplastic autoimmune multiorgan syndrome (PAMS) [2]. Irrespective of the underlying malignancy driving PAMS, the clinical outcomes are uniformly poor because of secondary respiratory failure and no standard treatment regimen, given the clinical rarity of the syndrome. We describe 2 patients with PAMS secondary to Castleman disease. In conjunction with treatment for Castleman disease, the patients also received therapy based on a transplant protocol for bronchiolitis obliterans and standard therapy for pemphigus [[3], [4], [5]] (intravenous immunoglobulin [IVIg], rituximab, and rosuvastatin; and fluticasone, azithromycin, and montelukast [FAM therapy]) [[3], [4], [5]].\n\n1.1 Case reports\nA 39-year-old woman without a smoking history was evaluated for dyspnea on exertion. She had a history of recurrent unicentric Castleman disease complicated by PNP (Fig. 1). Her initial pulmonary function tests (PFTs) in August 2017 showed a forced vital capacity (FVC) of 63% and a forced expiratory volume in the first second of expiration (FEV1) of 37% (FEV1/FVC ratio, 59%). Computed tomography (CT) showed mild, diffuse bronchial wall thickening and multiple patchy areas of air-trapping consistent with small airway disease (Fig. 2). After initiation of the above treatment regimen, the patient's respiratory symptoms began to improve (Fig. 3). However, shortly thereafter, she discontinued azithromycin and rosuvastatin because of muscle aches, which she said were intolerable. Repeat PFTs in December 2017 showed progressive respiratory failure (FVC, 55%; FEV1, 23%; FEV1/FVC ratio, 43%). Currently, she is undergoing extracorporeal photopheresis, which has been used to treat patients with bronchiolitis obliterans after hematopoietic stem cell transplant (HSCT).Fig. 1 Axial Image From Contrast-Enhanced Computed Tomography (CT). A, Homogeneously enhancing mass in the left hemipelvis (*) was consistent with an enlarged lymph node. The degree of enhancement suggested hypervascularity, a characteristic finding in Castleman disease. B, The lesion was fluorodeoxyglucose-avid on subsequent positron emission tomography–CT.\n\nFig. 1Fig. 2 High Resolution Axial Computed Tomography Scan. A, Inspiratory phase. B, Expiratory phase. There is persistent hypoattenuation of the pulmonary parenchyma in the expiratory phase, consistent with diffuse air-trapping. The posterior membrane of the bronchi has collapsed (arrow), confirming the expiratory technique. There is mild, diffuse bronchial wall thickening (circles). These findings are consistent with bronchiolitis obliterans.\n\nFig. 2Fig. 3 Axial Computed Tomography 3 Months Before Patient Admission. A, Normal-appearing airways (arrow). B, Airway at the time of diagnosis. Bronchial wall thickening developed in the interval between scans (arrowhead). C, Another axial image at diagnosis with narrow window display settings showing diffuse air-trapping with a few scattered normal areas of lung (*).\n\nFig. 3\n\nA 40-year-old man without a smoking history was evaluated for dyspnea on exertion. He also had a history of unicentric Castleman disease complicated by PNP (Fig. 4). Initial pulmonary function tests (PFTs) in November 2016 showed a forced vital capacity (FVC) of 69% and a forced expiratory volume in the first second of expiration (FEV1) of 41% (FEV1/FVC ratio, 58%). Computed tomography (CT) showed mild, diffuse bronchial wall thickening and multiple patchy areas of air-trapping consistent with small airway disease. After initiation of the above treatment regimen, the patient's respiratory symptoms began to improve (Fig. 5). He remained therapy compliant, and repeat PFTs in October 2017 showed a relatively stable condition (FVC, 88%; FEV1, 60%; FEV1/FVC ratio, 68%). On most recent follow-up in April 2018, his chest CT showed stability of his respiratory disease (Fig. 6).Fig. 4 Axial Image From Contrast-Enhanced Computed Tomography. A, Hypervascular mass in the precaval region (*), consistent with an enlarged lymph node related to Castleman disease. B, This node was fluorodeoxyglucose-avid on subsequent positron emission tomography–computed tomography.\n\nFig. 4Fig. 5 Axial Images From Computed Tomography. A, Inspiratory phase. B, Expiratory phase. Mild, diffuse bronchial wall thickening (arrows) and patchy areas of air-trapping (*) were consistent with bronchiolitis obliterans.\n\nFig. 5Fig. 6 Axial images from a CT scan performed at time of presentation (A) and several months later (B) demonstrate interval resolution of lingular ground glass opacity (arrow) consistent with improvement.\n\nFig. 6\n\n2 Discussion\nAmong patients with Castleman disease who succumb to PAMS, the most common cause of mortality is progressive respiratory failure due to bronchiolitis obliterans, for which there are no agreed upon therapeutic options. The mechanism for this respiratory failure, initially proposed by Nousari et al., [6] is related to the unique autoantibodies in PNP. Unlike pemphigus vulgaris, which has autoantibodies to desmogleins 1 and 3 that do not cross-react with respiratory epithelia, various autoantibodies of PNP do react (desmoplakin I, bullous pemphigoid antigen I, desmoplakin II, envoplakin, periplakin, plectin, a previously unidentified 170 kD protein, and α-2-macroglobulin-like-1) [[6], [7], [8]]. Rat bladder antibody testing by immunofluorescence is often used as a surrogate for antibodies to envoplakin, periplakin, and desmoplakins, although desmogleins 1 and 3 (the autoantibody targets in non-PNP) are not present [8].\n\nThe mainstay of therapy for paraneoplastic manifestations of Castleman disease is definitive treatment of the neoplasm. However, autoimmune features can persist, especially in recurrent disease [9]. IVIg and rituximab were effective in resolving our patients’ mucocutaneous lesions after surgery for Castleman disease recurrences. FAM therapy and rosuvastatin are given to patients for bronchiolitis obliterans after HSCT and for chronic lung rejection because of their anti-inflammatory effects: orally inhaled fluticasone (topical anti-inflammatory effects), azithromycin (impaired interleukin-8 production), and montelukast (blockade of leukotriene production). Our first patient initially improved but then had progressive respiratory decline, which may have resulted from noncompliance to therapy or the natural course of her disease. The paraneoplastic respiratory manifestations in our second patient have all but resolved, however, as demonstrated by improvement in symptoms, PFTs, and chest imaging. Further study is needed to further characterize the context in which this treatment regimen may be most beneficial. We believe the therapy regimen we used for our patients may be valuable for treating this rare clinical condition.\n\nConflicts of interest\nAaron R. Mangold, MD: Scientific advisory board for Genentech, specifically for rituximab.\n\nNone of the other authors have any conflicts of interest to disclose.\n\nAppendix A Supplementary data\nThe following is the supplementary data related to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgments\nEditing, proofreading, and reference verification were provided by Scientific Publications, Mayo Clinic.\n\nAppendix A Supplementary data related to this article can be found at https://doi.org/10.1016/j.rmcr.2018.08.002.\n==== Refs\nReferences\n1 Maldonado F. Pittelkow M.R. Ryu J.H. Constrictive bronchiolitis associated with paraneoplastic autoimmune multi-organ syndrome Respirology 14 1 2009 129 133 19144057 \n2 Wieczorek M. Czernik A. Paraneoplastic pemphigus: a short review Clin. Cosmet. Invest. Dermatol. 9 2016 291 295 \n3 Filipovich A.H. Weisdorf D. Pavletic S. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report Biol. Blood Marrow Transplant. 11 12 2005 945 956 16338616 \n4 Williams K.M. How I treat bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation Blood 129 4 2017 448 455 27856461 \n5 Reid D.W. Walters E.H. Johns D.P. Bronchial hyperresponsiveness and the bronchiolitis obliterans syndrome after lung transplantation J. Heart Lung Transplant. 24 4 2005 489 492 15797754 \n6 Nousari H.C. Deterding R. Wojtczack H. The mechanism of respiratory failure in paraneoplastic pemphigus N. Engl. J. Med. 340 18 1999 1406 1410 10228191 \n7 Yong A.A. Tey H.L. Paraneoplastic pemphigus Australas. J. Dermatol. 54 4 2013 241 250 22759072 \n8 Poot A.M. Diercks G.F. Kramer D. Laboratory diagnosis of paraneoplastic pemphigus Br. J. Dermatol. 169 5 2013 1016 1024 23796242 \n9 Nikolskaia O.V. Nousari C.H. Anhalt G.J. Paraneoplastic pemphigus in association with Castleman's disease Br. J. Dermatol. 149 6 2003 1143 1151 14674890\n\n",
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"issue": "25()",
"journal": "Respiratory medicine case reports",
"keywords": "Bronchiolitis; Chest imaging; Leukotriene receptor antagonist; Multisystemic syndrome; Small airway disease",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "129-132",
"pmc": null,
"pmid": "30128272",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "15797754;27729809;22759072;19144057;14674890;23796242;16338616;10228191;27856461",
"title": "Unicentric castleman disease complicated by paraneoplastic bronchiolitis obliterans and pemphigus.",
"title_normalized": "unicentric castleman disease complicated by paraneoplastic bronchiolitis obliterans and pemphigus"
} | [
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"activesubstancename": "ROSUVASTATIN"
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{
"abstract": "BACKGROUND\nBaclofen is commonly used in both pediatric and adult patients to treat spasticity secondary to spinal cord and cerebral pathology. A broad range of symptoms and severity of baclofen toxicity have been described. However, to our knowledge, there are no reports to date of baclofen toxicity mimicking brain death in pediatric patients.\n\n\nOBJECTIVE\nWe reviewed the presentation, clinical course, diagnostic studies including imaging and electroencephalography, and outcome of a patient with transient coma and loss of brainstem reflexes mimicking brain death secondary to baclofen toxicity.\n\n\nMETHODS\nDuring a baclofen pump refill, a 12-year-old boy with cerebral palsy had inadvertent injection of 12,000 μg of baclofen into the pocket around his pump. Within an hour, he presented with acute altered mental status that rapidly progressed to a comatose state with absent brainstem reflexes.\n\n\nRESULTS\nAfter appropriate management, the patient returned to his neurological baseline by hospital day 3.\n\n\nCONCLUSIONS\nWe reviewed the literature for varying presentations of baclofen toxicity and associated electroencephalography findings, mechanism of overdose, and different management options. In this case, the mechanism of baclofen toxicity was suspected to be secondary to extravasation from the pump pocket and subsequent systemic absorption.\n\n\nCONCLUSIONS\nPatients with baclofen toxicity may have a dramatic presentation and an initial examination mimicking brain death. Given its rarity, this clinical entity may not be readily recognized, and there is potential for misinterpretation of diagnosis and prognosis. It is important for physicians to be familiar with this clinical scenario to avoid false declaration of brain death.",
"affiliations": "From the Department of Neurology.;From the Department of Neurology.;Department of Neurosurgery, University of California, Irvine.",
"authors": "Pearson|Rachel P|RP|;Hoang|LeAnn K|LK|;Roufail|John|J|;Muhonen|Michael G|MG|;Galion|Anjalee W|AW|",
"chemical_list": "D009125:Muscle Relaxants, Central; D001418:Baclofen",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000002361",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "37(3)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000328:Adult; D001418:Baclofen; D001926:Brain Death; D002648:Child; D006801:Humans; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D008297:Male; D009125:Muscle Relaxants, Central; D009128:Muscle Spasticity",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "e141-e146",
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"pmid": "33651765",
"pubdate": "2021-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Baclofen Toxicity Mimicking Brain Death: A Case Report of a Pediatric Patient.",
"title_normalized": "baclofen toxicity mimicking brain death a case report of a pediatric patient"
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"companynumb": "US-UNICHEM PHARMACEUTICALS (USA) INC-UCM202103-000294",
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"activesubstancename": "BACLOFEN"
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"abstract": "A 41-year-old Caucasian woman with a history of infertility dating from 2011 was identified as wild-type (no mutations) for methylenetetrahydrofolate reductase single nucleotide polymorphisms (MTHFR-SNPs). Previous treatment included three failed in vitro fertilization/intracytoplasmic sperm injection cycles as well as one failed cycle of in vitro fertilization/intracytoplasmic sperm injection with donated oocytes. Counseling for a further oocyte donation cycle included advice to take high doses of folic acid (5 mG per day). Prior to initiation of this cycle, in October 2017 she attended our unit for general gynecological assessment and was found to have a slightly increased level of homocysteine, 12.2 µmol/L. A further test in February 2018 showed an increase to 17.2 µmol/L. Folic acid was stopped, and she was treated with 5-MTHF (500 µG daily), which supports the one-carbon cycle. After 5 days of treatment, her homocysteine level dropped to a baseline level of 8.2 µmol/L. As previously described in mice, high doses of folic acid can induce a \"pseudo MTHFR\" syndrome in wild-type patients, leading to an elevated unmetabolized folic acid syndrome which results in increased serum levels of homocysteine.",
"affiliations": "Clinique de La Muette, Paris, France.;Laboratoire Clement, Paris, France.;Laboratoire Clement, Paris, France.;Laboratoire Clement, Paris, France.",
"authors": "Cornet|Dominique|D|;Clement|Arthur|A|;Clement|Patrice|P|;Menezo|Yves|Y|https://orcid.org/0000-0001-6861-8905",
"chemical_list": null,
"country": "England",
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"doi": "10.1177/2050313X19850435",
"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1985043510.1177_2050313X19850435Case ReportHigh doses of folic acid induce a pseudo-methylenetetrahydrofolate\nsyndrome Cornet Dominique 1Clement Arthur 2Clement Patrice 2https://orcid.org/0000-0001-6861-8905Menezo Yves 231 Clinique de La Muette, Paris,\nFrance2 Laboratoire Clement, Paris, France3 London Fertility Associates, London,\nUKYves Menezo, Laboratoire Clement, avenue\nD’Eylau, 75016 Paris, France. Email:\nyves.menezo@gmail.com17 5 2019 2019 7 2050313X1985043528 1 2019 23 4 2019 © The Author(s) 20192019SAGE PublicationsThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which\npermits non-commercial use, reproduction and distribution of the work\nwithout further permission provided the original work is attributed as\nspecified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).A 41-year-old Caucasian woman with a history of infertility dating from 2011 was\nidentified as wild-type (no mutations) for methylenetetrahydrofolate reductase\nsingle nucleotide polymorphisms (MTHFR-SNPs). Previous treatment included three\nfailed in vitro fertilization/intracytoplasmic sperm injection cycles as well as\none failed cycle of in vitro fertilization/intracytoplasmic sperm injection with\ndonated oocytes. Counseling for a further oocyte donation cycle included advice\nto take high doses of folic acid (5 mG per day). Prior to initiation of this\ncycle, in October 2017 she attended our unit for general gynecological\nassessment and was found to have a slightly increased level of homocysteine,\n12.2 µmol/L. A further test in February 2018 showed an increase to 17.2 µmol/L.\nFolic acid was stopped, and she was treated with 5-MTHF (500 µG daily), which\nsupports the one-carbon cycle. After 5 days of treatment, her homocysteine level\ndropped to a baseline level of 8.2 µmol/L. As previously described in mice, high\ndoses of folic acid can induce a “pseudo MTHFR” syndrome in wild-type patients,\nleading to an elevated unmetabolized folic acid syndrome which results in\nincreased serum levels of homocysteine.\n\nFolic acidpseudo-MTHFRhomocysteine5-MTHF (methyltetrahydrofolate)UMFA (unmetabolized folic acid)cover-dateJanuary-December 2019\n==== Body\nIntroduction\nFolic acid (FA, Pteroyl glutamic acid) supplementation has for many years been\nconsidered a dogma, based on the fact that FA intake during the periconception\nperiod decreases the risk of neural tube defects (NTDs) in the babies conceived.1 FA is a synthetic compound that must undergo a 2-step transformation by\ndihydrofolate reductase (DHFR) before it can enter the FA cycle (Figure 1). The folate cycle is\nan obligatory component of all methylation processes that are ubiquitous and of\nmajor importance in cell physiology. The FA cycle is linked to the one-carbon cycle\n(1-CC), which recycles homocysteine (Hcy) to methionine (Met). Hcy is a toxic\ninhibitor of methylation,2 competes with Met for the same amino acid transporter, and is known to induce\nnumerous pathologies.3 During reproduction, methylation processes are involved in oogenesis and\nspermatogenesis: methylation of DNA and histones regulates epigenesis and\nimprinting. Anomalies of methylation, especially those linked to polymorphism of\nenzymes involved in the 1-CC will also affect early embryo trophoblast growth and implantation.4 Methylenetetrahydrofolate reductase (MTHFR) is the most common single\nnucleotide polymorphism (SNP), affecting up to 50% of the population in some\ngeographical areas.5 Women who carry MTHFR have up to 75% reduction in the capacity to form active\nfolate (5-MTHF: 5-methyltetrahydrofolate). Liver DHFR activity is slow and weak, so\nthat the capacity for synthetic FA to enter the FA cycle is reduced.6 High doses of FA (5 mG/day) are usually recommended prior to conception\nbecause the neural tube closes at around 28 days post fertilization. FA at these\ndoses can decrease circulating Hcy to some extent, during advancing in pregnancy,\nbut has no effect on Lipoprotein(a) in pregnant patients, irrespective of their\ngenetic MTHFR SNP background.7 However, at this time, the placenta has also a regulatory role in Hcy\nmetabolism, depending upon the paternal genetic background.8 Poor FA metabolism may lead to its accumulation in high concentrations, an\nunmetabolized FA (UMFA) syndrome (Figure 1).9,10 Non-metabolized FA competes with natural folate (5-MTHF) for\nbinding and transport into the cells, leading to a pseudo-MTHFR deficiency11 with altered lipid metabolism: this can lead to fetal losses and other\nharmful effects. UMFA is strongly suspected to be involved in the flare-up of some\ntumors (colorectal and prostate).10 This case report describes a wild-type (WT) patient who developed a\npseudo-MTHFR syndrome with continuous elevation of Hcy after taking high doses of FA\nprior to an oocyte donation cycle.\n\nFigure 1. The one-carbon cycle (1-CC) and the folic acid (FA) cycle: The poor capacity\nto metabolize high doses of FA by the liver (6) induces an accumulation of\nhomocysteine and unmetabolized FA and may induce a reversal of the 1-CC.\n\nSAM: S-adenosyl methionine; SAH: S-adenosyl\nhomocysteine; DHFR: dihydrofolate reductase; MTHFR,\nmethylenetetrahydrofolate reductase; THF: tetrahydrofolate; MTHF:\nmethyltetrahydrofolate.\n\nCase report\nA 41-year-old French Caucasian woman presented with infertility dating from 2011. Her\nhusband (53 years old) had oligoasthenospermia (3.8 million sperm/mL, 1% motility).\nThe couple had experienced 3 failed assisted reproductive technology\n(ART)/intracytoplasmic sperm injection (ICSI) cycles, with 10 metaphase II oocytes\ninjected, 5 oocytes fertilized, and a total of 3 embryos transferred. A subsequent\noocyte donation cycle (carried out in Spain due to restrictive laws in France) also\nfailed to achieve a pregnancy. At the beginning of October 2017, the Spanish center\nprescribed a dose of 5 mG/day FA prior to starting a second oocyte donation cycle.\nShe attended our center for full gynecological assessment, and as per our routine\nwas tested for MTHFR SNPs C677T and A1298C, and for serum Hcy levels. She was found\nto be WT for both SNPs; her Hcy was 12.2 µmol/L on 26 October. This level is higher\nthan the expected baseline (7.8 µmol/L) usually observed in WT patients. The oocyte\ndonation cycle was delayed for unknown reasons, and she returned on 13 February 2018\nfor further assessment. Her Hcy level was 17.2 µmol/L, which is greater than the\nlevel we observe in C677T patients (14.2 µmol/L). Our policy is to treat patients\nwith elevated Hcy levels with a supplement containing 5-MTHF, 500 µG daily, which\nsupports the 1-CC. (Tetrafolic®, Nurilia, France, or Impryl®,\nParthenogen CH). 5-MTHF is known to reduce circulating Hcy,12,13 without\ncontributing to UMFA syndrome. It bypasses most of the mutations that may affect the\nFA cycle and is directly metabolized by Met synthase. Pre-conceptional support of\nthe 1-CC has a positive effect in hypofertile patients.14–17 This patient stopped FA and\nstarted Tetrafolic® on 17 February. Monitoring on 21 February revealed\nthat her Hcy level had fallen to 8.2 µmol/L, an appropriate baseline level for WT\npatients.\n\nDiscussion\nGeneral nutritional supplementation, especially in the United States and Canada, has\nled to the disturbing observation that UMFA can be found in a large number of\npatients. Of even greater concern is the fact that high levels of UMFA, at least\nfive times greater than is generally considered safe, are found in the blood and the\numbilical cord of pregnant patients9 who have been prescribed very high doses of FA.10 In men, high doses of FA induce sperm DNA methylation anomalies that are\nknown to affect sperm fertility and methylation patterns/epigenesis in\nparticular.18,19 This case report demonstrates that high doses of FA can reverse\nthe FA cycle in WT patients, resulting in increased circulating Hcy, a situation\nthat is observed in patients who carry MTHFR SNPs. This can be explained in two\nways: (1) circulating UMFA competes with the “natural” folate 5-MTHF and may\nincrease “folate deficiency” and the ability to recycle Hcy and (2) accumulated UMFA\ncan lead to “excess-substrate inhibition,” a common deviation from Michaelis–Menten\nenzyme kinetics: this inhibits DHFR activity, which is already slow and variable.6 DHFR activity is required to allow synthetic FA to enter the folate cycle\n(see Figure 1).\n\nA second similar case also attended our clinic: a female patient awaiting oocyte\ndonation was found to have elevated circulating Hcy, up to 15.2 µmol/L. Interrupting\nFA treatment and prescribing 5-MTHF allowed the Hcy level to rapidly return to\nbaseline, confirming that 5-MTHF is bio-available as a substrate for Met synthase.\nIn our experience with MTHFR SNP carriers, return to a correct physiological level\nof around 10 µmol/L is observed after 10 days of treatment. The slow and low level\nof liver DHFR activity results in a weak ability to provide the correct input to the\n1-CC: this should to be taken into account when FA is prescribed, especially in\nconsideration of the fact that MTHF minimizes the risk of birth defects.20 Although nutritional supplementation with FA has reduced the incidence of\nNTDs by 20%–30% in the United States,21 the policy is now due for re-evaluation.\n\nConclusion\nAlthough the prevalence of MTHFR SNPs is high, and these patients have a higher risk\nof Hcy elevation, the majority of pregnant patients are not tested for MTHFR SNPs.\nIt is now clear that the practice of prescribing high doses of synthetic FA should\nbe at least a matter for debate. 5-MTHF, the “active” folate that is immediately\navailable for conversion of Hcy to Met, should be proposed instead of FA for\npericonceptional support and even for nutritional supplementation in general.\n\nThe authors want to thank Dr Kay Elder, MD, PhD for her help in the translation\ncorrections.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases\nor case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized\ninformation to be published in this article. In France, by law, the consent for\nthe testing is mandatory. It has to be signed by the doctor, the laboratory\nmaking the tests, and the patients. Specific form has to be filled and signed.\nThe consent for anonymous publication is oral, not written. During consultation,\nthe doctor cannot propose a form for written consent for anonymous publication.\nAs soon as the patient agrees for the test, the test can be used anonymously,\nfor publication or for statistics.\n\nORCID iD: Yves Menezo \nhttps://orcid.org/0000-0001-6861-8905\n==== Refs\nReferences\n1 \nHibbard BM Hibbard E Jeffcoate TN. \nFolic acid and reproduction . Acta Obstet\nGynecol Scand \n1965 ; 44 :\n375 –400 .5863074 \n2 \nMenezo Y Khatchadourian C Gharib A et al \nRegulation of S-adenosyl methionine synthesis in\nthe mouse embryo . Life Sci \n1989 ; 44 (21 ):\n1601 –1609 .2733543 \n3 \nSkovierova H Vidomanová E Mahmood S et al \nThe molecular and cellular effect of\nhomocysteine metabolism imbalance on human health .\nInt J Mol Sci \n2016 ; 17 (10 ):\nE173 .26861304 \n4 \nEnciso M Sarasa J Xanthopoulou L et al \nPolymorphisms in the MTHFR gene influence embryo\nviability and the incidence of aneuploidy . Hum\nGenet \n2016 ; 135 (5 ):\n555 –568 .27068821 \n5 \nZappacosta B Graziano M Persichilli S et al \n5,10-Methylenetetrahydrofolate reductase (MTHFR)\nC677T and A1298C polymorphisms: genotype frequency and association with\nhomocysteine and folate levels in middle-southern Italian\nadults . Cell Biochem Funct \n2014 ; 32 (1 ):\n1 –4 .24277487 \n6 \nBailey SW Ayling JE. \nThe extremely slow and variable activity of dihydrofolate\nreductase in human liver and its implications for high folic acid\nintake . Proc Natl Acad Sci U S A \n2009 ; 106 (36 ):\n15424 –15429 .19706381 \n7 \nHekmati Azar Mehrabani Z Ghorbanihaghjo A Sayyah Melli M et al \nEffects of folic acid supplementation on serum\nhomocysteine and lipoprotein (a) levels during pregnancy .\nBioimpacts \n2015 ; 5 (4 ):\n177 –182 .26929921 \n8 \nMohanraj PS Rahat B Mahajan A et al \nTemporal expression of genes involved in folate\nmetabolism and transport during placental development, preeclampsia and\nneural tube defects . Mol Biol Rep . Epub\nahead of print 2 \n4 \n2019 DOI: 10.1007/s11033-019-04776-w. \n9 \nPlumptre L Masih SP Ly A et al \nHigh concentrations of folate and unmetabolized\nfolic acid in a cohort of pregnant Canadian women and umbilical cord\nblood . Am J Clin Nutr \n2015 ; 102 (4 ):\n848 –857 .26269367 \n10 \nCrider KS Bailey LB Berry RJ. \nFolic acid food fortification—its history, effect, concerns, and\nfuture directions . Nutrients \n2011 ; 3 (3 ):\n370 –384 .22254102 \n11 \nChristensen KE Mikael LG Leung KY et al \nHigh folic acid consumption leads to\npseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in\nmice . Am J Clin Nutr \n2015 ; 101 (3 ):\n646 –658 .25733650 \n12 \nVenn BJ Green TJ Moser R et al \nComparison of the effect of low-dose\nsupplementation with L-5-methyltetrahydrofolate or folic acid on plasma\nhomocysteine: a randomized placebo-controlled study .\nAm J Clin Nutr \n2003 ; 77 :\n658 –662 .12600857 \n13 \nLamers Y Prinz-Langenohl R Moser R et al \nSupplementation with\n[6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total\nhomocysteine concentrations in healthy women . Am J\nClin Nutr \n2004 ; 79 (3 ):\n473 –478 .14985224 \n14 \nServy EJ Jacquesson-Fournols L Cohen M et al \nMTHFR isoform carriers. 5-MTHF (5-methyl\ntetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case\nseries . J Assist Reprod Genet \n2018 ; 35 (8 ):\n1431 –1435 .29882091 \n15 \nGoyco Ortiz LE Servy EJ Menezo YJR. \nA successful treatment with 5 methyltetrahydrofolate of a 677 TT\nMTHFR woman suffering premature ovarian insufficiency post a NHL\n(non-Hodgkin’s lymphoma) and RPL (repeat pregnancy losses) .\nJ Assist Reprod Genet \n2019 ; 36 :\n65 –67 .30406447 \n16 \nDattilo M D’Amato G Caroppo E et al \nImprovement of gamete quality by stimulating and\nfeeding the endogenous antioxidant system: mechanisms, clinical results,\ninsights on gene-environment interactions and the role of\ndiet . J Assist Reprod Genet \n2016 ; 33 :\n1633 –1648 .27423667 \n17 \nCornet D Amar E Cohen M et al \nClinical evidence for the importance of 1-carbon\ncycle support in subfertile couples . Austin J Reprod\nMed Infertil \n2015 ; 2 : 1011 .\n18 \nAarabi M SanGabriel MC Chan D et al \nHigh-dose folic acid supplementation alters the\nhuman sperm methylome and is influenced by the MTHFR C677T\npolymorphism . Hum Mol Genet \n2015 ; 24 (22 ):\n6301 –6313 .26307085 \n19 \nAarabi M Christensen KE Chan D et al \nTesticular MTHFR deficiency may explain sperm\nDNA hypomethylation associated with high dose folic acid\nsupplementation . Hum Mol Genet \n2018 ; 27 (7 ):\n1123 –1135 .29360980 \n20 \nBailey SW Ayling JE. \nThe pharmacokinetic advantage of 5-methyltetrahydrofolate for\nminimization of the risk for birth defects . Sci\nRep \n2018 ; 8 (1 ):\n4096 .29511242 \n21 \nHonein MA Paulozzi LJ Mathews TJ et al \nImpact of folic acid fortification of the US\nfood supply on the occurrence of neural tube defects .\nJAMA \n2001 ; 285 (23 ):\n2981 –2986 .11410096\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-313X",
"issue": "7()",
"journal": "SAGE open medical case reports",
"keywords": "5-MTHF (methyltetrahydrofolate); Folic acid; UMFA (unmetabolized folic acid); homocysteine; pseudo-MTHFR",
"medline_ta": "SAGE Open Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101638686",
"other_id": null,
"pages": "2050313X19850435",
"pmc": null,
"pmid": "31205715",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "11410096;12600857;14985224;19706381;22254102;24277487;25733650;26269367;26307085;26929921;27068821;2733543;27423667;27775595;29360980;29511242;29882091;30406447;30941645;5863074",
"title": "High doses of folic acid induce a pseudo-methylenetetrahydrofolate syndrome.",
"title_normalized": "high doses of folic acid induce a pseudo methylenetetrahydrofolate syndrome"
} | [
{
"companynumb": "FR-LEADING PHARMA, LLC-2072680",
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"occurcountry": "FR",
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"activesubstance": {
"activesubstancename": "FOLIC ACID"
},
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... |
{
"abstract": "A 51-year-old man underwent abdominoperineal resection for advanced rectal cancer at a hospital. He attended our outpatient clinic 58 months later with pain in the external genitalia, and was diagnosed with local pelvic recurrence and metastasis to the para-aortic lymph node and both adrenal glands. He received a total of 30 Gy of radiation for analgesia; subsequently, chemotherapy(mFOLFOX6 plus bevacizumab)was initiated. However, extreme left buttock and left femoral pain developed after the 6 courses of chemotherapy. Abdominal CT revealed Fournier's gangrene caused by small intestinal perforation. Emergency drainage under spinal anesthesia was immediately performed. Two additional drainage procedures were required thereafter and an ileostomy was constructed. The patient was discharged 100 days after the initial drainage. This is an extremely rare example of a bevacizumab-related small intestinal perforation that developed into Fournier's gan- grene.",
"affiliations": "Dept. of Surgery, Saiseikai Utsunomiya Hospital.",
"authors": "Ishida|Takashi|T|;Shinozaki|Hiroharu|H|;Ozawa|Hiroki|H|;Kobayashi|Toshimichi|T|;Kato|Subaru|S|;Wakabayashi|Taiga|T|;Matsumoto|Kenji|K|;Sasakura|Yuuichi|Y|;Shimizu|Tetsuichiro|T|;Terauchi|Toshiaki|T|;Kimata|Masaru|M|;Furukawa|Junji|J|;Kobayashi|Kenji|K|;Ogata|Yoshiro|Y|",
"chemical_list": "D009944:Organoplatinum Compounds; D000068258:Bevacizumab; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
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"issn_linking": "0385-0684",
"issue": "43(7)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D059248:Chemoradiotherapy; D004322:Drainage; D017809:Fatal Outcome; D005472:Fluorouracil; D018934:Fournier Gangrene; D006801:Humans; D007416:Intestinal Perforation; D007421:Intestine, Small; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D012004:Rectal Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "909-11",
"pmc": null,
"pmid": "27431640",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Fournier's Gangrene Caused by Small Intestinal Perforation during Bevacizumab Combination Chemotherapy.",
"title_normalized": "a case of fournier s gangrene caused by small intestinal perforation during bevacizumab combination chemotherapy"
} | [
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"activesubstancename": "BEVACIZUMAB"
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{
"abstract": "A case of acute kidney injury (AKI) strongly suspected to be drug-induced (oxaliplatin and non-steroidal anti-inflammatory drug) is discussed regarding the mechanism of a reduced glomerular filtration rate responsible for the development of AKI. Urinary biochemical tests are useful for the differential diagnosis of pre- renal (functional) AKI and intrinsic (structural) AKI(so-called acute tubular necrosis). In this case, although a comprehensive differential diagnosis using these parameters supported intrinsic AKI, only one pa- rameter, fractional excretion of urea (FEurea), indicated the existence of prerenal AKI. As a result of treatment with the appropriate management of body fluid in addition to avoiding nephrotoxic medications, AKI rapidly improved. FEurea revealed the underlying mechanism of AKI. [Review].",
"affiliations": null,
"authors": "Iwazu|Yoshitaka|Y|;Kotani|Kazuhiko|K|;Yamada|Toshiyuki|T|",
"chemical_list": "D015415:Biomarkers; D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0047-1860",
"issue": "64(5)",
"journal": "Rinsho byori. The Japanese journal of clinical pathology",
"keywords": null,
"medline_ta": "Rinsho Byori",
"mesh_terms": "D058186:Acute Kidney Injury; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D003967:Diarrhea; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D012004:Rectal Neoplasms; D014839:Vomiting",
"nlm_unique_id": "2984781R",
"other_id": null,
"pages": "595-600",
"pmc": null,
"pmid": "30695374",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Acute Kidney Injury in a Patient with Diarrhea and Vomiting Undergoing Chemotherapy for Colorectal Cancer.",
"title_normalized": "acute kidney injury in a patient with diarrhea and vomiting undergoing chemotherapy for colorectal cancer"
} | [
{
"companynumb": "JP-TEVA-2019-JP-1061092",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LOXOPROFEN"
},
"drugadditional": "1",
... |
{
"abstract": "The cingulum bundle (CB) is a major white matter fiber tract of the limbic system that underlies cingulate cortex, passing longitudinally over the corpus callosum. The connectivity of this white matter fiber tract plays a major role in emotional expression, attention, motivation, and working memory, all of which are affected in schizophrenia. Myelin related CB abnormalities have also been implicated in schizophrenia. The purpose of this study is to determine whether or not CB abnormalities are evident in individuals at clinical high risk (CHR) for psychosis, and whether or not cognitive deficits in the domains subserved by CB are related to its structural abnormalities.\n\n\n\nDiffusion Tensor Imaging (DTI) was performed on a 3 T magnet. DT tractography was used to evaluate CB in 20 individuals meeting CHR criteria (13 males/7 females) and 23 healthy controls (12 males/11 females) group matched on age, gender, parental socioeconomic status, education, and handedness. Fractional anisotropy (FA), a measure of white matter coherence and integrity, radial diffusivity (RD), thought to reflect myelin integrity, trace, a possible marker of atrophy, and axial diffusivity (AD), thought to reflect axonal integrity, were averaged over the entire tract and used to investigate CB abnormalities in individuals at CHR for psychosis compared with healthy controls.\n\n\n\nSignificant group differences were found between individuals at CHR for psychosis and controls for FA (p = 0.028), RD (p = 0.03) and trace (p = 0.031), but not for AD (p = 0.09). We did not find any significant correlations between DTI measures and clinical symptoms.\n\n\n\nThese findings suggest abnormalities (possibly myelin related) in the CB in individuals at CHR for psychosis.",
"affiliations": "Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America; Psychiatry Neuroimaging Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America. Electronic address: jfitzsimmons@bwh.harvard.edu.;Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America; Laboratory of Psychiatric Neuroimaging (LIM-21), Department & Institute of Psychiatry, Faculty of Medicine, Center of Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil; Psychiatry Neuroimaging Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.;Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America; Psychiatry Neuroimaging Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.;Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America; Psychiatry Neuroimaging Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.;Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States of America; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States of America; Psychiatry Neuroimaging Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.;Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States of America.;Beth Israel Deaconess Medical Center-Massachusetts Mental Health Center, Public Psychiatry Division, Harvard Medical School, Boston, MA, United States of America.;Beth Israel Deaconess Medical Center-Massachusetts Mental Health Center, Public Psychiatry Division, Harvard Medical School, Boston, MA, United States of America.;Beth Israel Deaconess Medical Center-Massachusetts Mental Health Center, Public Psychiatry Division, Harvard Medical School, Boston, MA, United States of America.;Department of Psychiatry, VA Boston Healthcare System, Harvard Medical School, Boston, MA, United States of America.;Beth Israel Deaconess Medical Center-Massachusetts Mental Health Center, Public Psychiatry Division, Harvard Medical School, Boston, MA, United States of America; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America.;Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America; Research and Development, VA Boston Healthcare System, Boston, MA, United States of America; Psychiatry Neuroimaging Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.;Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America; Psychiatry Neuroimaging Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.",
"authors": "Fitzsimmons|Jennifer|J|;Rosa|Pedro|P|;Sydnor|Valerie J|VJ|;Reid|Benjamin E|BE|;Makris|Nikos|N|;Goldstein|Jill M|JM|;Mesholam-Gately|Raquelle I|RI|;Woodberry|Kristen|K|;Wojcik|Joanne|J|;McCarley|Robert W|RW|;Seidman|Larry J|LJ|;Shenton|Martha E|ME|;Kubicki|Marek|M|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.schres.2019.08.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-9964",
"issue": "215()",
"journal": "Schizophrenia research",
"keywords": "Cingulum bundle; Diffusion Tensor Imaging; Fractional anisotropy; High risk psychosis; Limbic system; Myelination",
"medline_ta": "Schizophr Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D060825:Cognitive Dysfunction; D056324:Diffusion Tensor Imaging; D005260:Female; D006801:Humans; D008032:Limbic System; D008297:Male; D009186:Myelin Sheath; D009434:Neural Pathways; D011618:Psychotic Disorders; D012306:Risk; D012559:Schizophrenia; D066127:White Matter; D055815:Young Adult",
"nlm_unique_id": "8804207",
"other_id": null,
"pages": "385-391",
"pmc": null,
"pmid": "31477373",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Cingulum bundle abnormalities and risk for schizophrenia.",
"title_normalized": "cingulum bundle abnormalities and risk for schizophrenia"
} | [
{
"companynumb": "US-OTSUKA-2020_006203",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Interstitial lung disease (ILD) is a rare, but potentially serious, side effect associated with crizotinib, a tyrosine kinase inhibitor for anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer. Our objective was to determine the incidence and nature of ILD associated with crizotinib in 4 PROFILE trials (ClinicalTrials.gov identifiers, NCT00585195, NCT00932451, NCT00932893, and NCT01154140).\n\n\n\nGrade ≥ 3 respiratory adverse events (AEs) and serious AEs (SAEs) and any grade AEs/SAEs reported as pneumonitis, ILD, or radiation pneumonitis in trials PROFILE 1001, PROFILE 1005, PROFILE 1007, and PROFILE 1014 were evaluated by an expert independent review committee that included a pulmonologist, medical oncologist, and radiologist. Events were designated as disease progression, de novo ILD possibly or probably related to crizotinib, exacerbation or recurrence of pre-existing ILD, concurrent illness, other toxicity not thought to be related to ILD, or inconclusive.\n\n\n\nThe independent review committee evaluated 446 events (in 368 of 1669 patients who had received crizotinib therapy). They classified these events as follows: progressive disease, 77; de novo ILD, 20; pre-existing ILD, 3; concurrent illness, 9; other toxicities, 310; and inconclusive, 27. The incidence of de novo ILD was 1.2% overall, 1.3% in whites, and 1.2% overall in Asians, but greater at 3.7% in Japanese patients. The median onset of ILD from the initiation of crizotinib therapy was 23 days (range, 3-763 days). The mortality rate due to ILD was 50%. Survival was improved if crizotinib was discontinued on presentation of ILD (9 of 14 patients) compared with discontinued later or continued (1 of 6 patients).\n\n\n\nILD associated with crizotinib, although rare, can occur at any time and requires close monitoring.",
"affiliations": "Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of California, Davis, Sacramento, CA. Electronic address: kyyoneda@ucdavis.edu.;Pfizer Oncology, Groton, CT.;Bioclinica, Princeton, NJ.;Pfizer Oncology, La Jolla, CA.;Pfizer Oncology, Groton, CT.;Pfizer Oncology, La Jolla, CA.;Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of California, Davis, Sacramento, CA.",
"authors": "Yoneda|Ken Y|KY|;Scranton|Judith R|JR|;Cadogan|Michael A|MA|;Tassell|Vanessa|V|;Nadanaciva|Sashi|S|;Wilner|Keith D|KD|;Stollenwerk|Nicholas S|NS|",
"chemical_list": "D000970:Antineoplastic Agents; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cllc.2017.03.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-7304",
"issue": "18(5)",
"journal": "Clinical lung cancer",
"keywords": "Adverse event; Anaplastic lymphoma kinase; Independent review; Pneumonitis; Tyrosine kinase inhibitor",
"medline_ta": "Clin Lung Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D044466:Asians; D002289:Carcinoma, Non-Small-Cell Lung; D000077547:Crizotinib; D005260:Female; D006801:Humans; D015994:Incidence; D007564:Japan; D017563:Lung Diseases, Interstitial; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles; D011725:Pyridines; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D044465:Whites; D055815:Young Adult",
"nlm_unique_id": "100893225",
"other_id": null,
"pages": "472-479",
"pmc": null,
"pmid": "28373069",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Interstitial Lung Disease Associated With Crizotinib in Patients With Advanced Non-Small Cell Lung Cancer: Independent Review of Four PROFILE Trials.",
"title_normalized": "interstitial lung disease associated with crizotinib in patients with advanced non small cell lung cancer independent review of four profile trials"
} | [
{
"companynumb": "JP-PFIZER INC-2011221910",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LOXOPROFEN"
},
"drugadditional": null,
... |
{
"abstract": "The purpose of this study is to characterize adverse events (AEs) of clinical interest reported with ceftolozane-tazobactam and ceftazidime-avibactam, as an aid in monitoring patients affected by severe multidrug-resistant Gram-negative infections. We queried the worldwide FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis, selecting only designated medical events (DMEs) where ceftolozane-tazobactam and ceftazidime-avibactam were reported as suspect. Serious neurological AEs were further investigated. The reporting odds ratios were calculated, deemed significant by the lower limit of the 95% confidence interval (LL95% CI) > 1. All other drugs/events recorded in FAERS and cephalosporins showing clinical evidence of neurological AEs were respectively selected as comparator for analysis of DMEs and neurotoxicity. Qualitative analysis including case-by-case assessment and deduplication was also performed. Overall, 654 and 506 reports mentioning respectively ceftolozane-tazobactam and ceftazidime-avibactam were found, with DMEs accounting respectively for 13.1% and 10.9% of cases. Agranulocytosis (N = 12; LL95% CI = 12.40) and pancytopenia (14; 6.18) emerged as unexpected AEs with ceftolozane-tazobactam, while acute pancreatitis (7; 8.63) was an over-reported unexpected DME with ceftazidime-avibactam. After deduplication, four unequivocally different cases of agranulocytosis with ceftolozane-tazobactam were retained, occurring on average after 8.8 days. Causality was probable and possible respectively in three and one case. Among neurological AEs exhibiting significant disproportionality, encephalopathy with both antibiotics and mental status changes with ceftazidime-avibactam were retained in at least three cases after deduplication. Although rare, clinicians should monitor high-risk patients (i.e. individuals affected by haematological malignances, HIV infection, or treated with concomitant myelotoxic agents) for early unexpected occurrence of agranulocytosis with ceftolozane-tazobactam.",
"affiliations": "Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. milo.gatti2@unibo.it.;Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.;Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.",
"authors": "Gatti|Milo|M|http://orcid.org/0000-0003-3018-3779;Raschi|Emanuel|E|https://orcid.org/0000-0003-0487-7996;De Ponti|Fabrizio|F|https://orcid.org/0000-0002-0367-9595",
"chemical_list": "D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D002511:Cephalosporins; D004338:Drug Combinations; D007769:Lactams; C000595613:avibactam, ceftazidime drug combination; D065093:beta-Lactamase Inhibitors; C000594038:ceftolozane, tazobactam drug combination; D002442:Ceftazidime; D000078142:Tazobactam",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10096-020-04149-3",
"fulltext": "\n==== Front\nEur J Clin Microbiol Infect Dis\nEur J Clin Microbiol Infect Dis\nEuropean Journal of Clinical Microbiology & Infectious Diseases\n0934-9723\n1435-4373\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n33415492\n4149\n10.1007/s10096-020-04149-3\nOriginal Article\nSerious adverse events with novel beta-lactam/beta-lactamase inhibitor combinations: a large-scale pharmacovigilance analysis\nhttp://orcid.org/0000-0003-3018-3779\nGatti Milo milo.gatti2@unibo.it\n\nhttps://orcid.org/0000-0003-0487-7996\nRaschi Emanuel\nhttps://orcid.org/0000-0002-0367-9595\nDe Ponti Fabrizio\ngrid.6292.f 0000 0004 1757 1758 Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy\n7 1 2021\n7 1 2021\n2021\n40 6 11691176\n23 10 2020\n28 12 2020\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nThe purpose of this study is to characterize adverse events (AEs) of clinical interest reported with ceftolozane-tazobactam and ceftazidime-avibactam, as an aid in monitoring patients affected by severe multidrug-resistant Gram-negative infections. We queried the worldwide FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis, selecting only designated medical events (DMEs) where ceftolozane-tazobactam and ceftazidime-avibactam were reported as suspect. Serious neurological AEs were further investigated. The reporting odds ratios were calculated, deemed significant by the lower limit of the 95% confidence interval (LL95% CI) > 1. All other drugs/events recorded in FAERS and cephalosporins showing clinical evidence of neurological AEs were respectively selected as comparator for analysis of DMEs and neurotoxicity. Qualitative analysis including case-by-case assessment and deduplication was also performed. Overall, 654 and 506 reports mentioning respectively ceftolozane-tazobactam and ceftazidime-avibactam were found, with DMEs accounting respectively for 13.1% and 10.9% of cases. Agranulocytosis (N = 12; LL95% CI = 12.40) and pancytopenia (14; 6.18) emerged as unexpected AEs with ceftolozane-tazobactam, while acute pancreatitis (7; 8.63) was an over-reported unexpected DME with ceftazidime-avibactam. After deduplication, four unequivocally different cases of agranulocytosis with ceftolozane-tazobactam were retained, occurring on average after 8.8 days. Causality was probable and possible respectively in three and one case. Among neurological AEs exhibiting significant disproportionality, encephalopathy with both antibiotics and mental status changes with ceftazidime-avibactam were retained in at least three cases after deduplication. Although rare, clinicians should monitor high-risk patients (i.e. individuals affected by haematological malignances, HIV infection, or treated with concomitant myelotoxic agents) for early unexpected occurrence of agranulocytosis with ceftolozane-tazobactam.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1007/s10096-020-04149-3.\n\nKeywords\n\nCeftolozane-tazobactam\nCeftazidime-avibactam\nSafety profile\nAgranulocytosis\nNeurotoxicity\nAlma Mater Studiorum - Università di BolognaOpen Access funding provided by Alma Mater Studiorum - Università di Bologna\n\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2021\n==== Body\nIntroduction\n\nCeftolozane-tazobactam (C/T) and ceftazidime-avibactam (C/A) are novel beta-lactam/beta-lactamase inhibitors (BL/BLIs), respectively approved by the Food and Drug Administration (FDA) in 2014 and in 2015, and by the European Medicines Agency (EMA) in 2015 and in 2016, characterized by activity against multidrug-resistant (MDR) Gram-negative pathogens, including extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) and carbapenemase producing Enterobacteriaceae (CPE) [1].\n\nAlthough the risk-benefit ratio is generally favourable in severe MDR infections, the safety profile of these antibiotics still requires thorough investigation. Specifically, no differences were found in serious adverse events (AEs) between novel BL/BLIs and controlled treatments in pivotal trials [2], being tolerability predictable and comparable to those seen with other beta-lactams, while real-world evidence is limited to the description of AEs reported with C/A [3]. However, given their expanding use at higher dosage in challenging scenarios, including patients affected by severe renal impairment [4], characterization of potential unexpected AEs with novel BL/BLIs becomes necessary.\n\nThe FDA Adverse Event Reporting System (FAERS) has attracted considerable interest among clinicians for accurate and timely characterization of drug-related risks occurring in real-world patients, also including the assessment of antimicrobials in challenging settings [5–7]. These post-marketing studies are particularly suited to early detect rare, unexpected and delayed AEs, which cannot be fully appreciated in pivotal trials, and are recommended for real-time safety assessment of recently marketed drugs.\n\nWe queried the FAERS database to characterize AEs of clinical interest reported with novel BL/BLIs, as an aid in prioritizing monitoring in patients affected by severe MDR Gram-negative infections.\n\nMethods\n\nAn observational, retrospective disproportionality analysis was performed to highlight and characterize AEs of clinical interest with higher-than-expected reporting. The FAERS database (public dashboard), the US repository of AEs and medication errors comprising more than 20 million reports gathered worldwide, was queried to retrieve C/T and C/A reports recorded between the first quarter (Q1) of 2015 and Q2 of 2020.\n\nIn order to assign a clinical priority to emerging safety issues, the public list developed by the EMA including 62 different reactions was used to select designated medical events (DMEs), namely rare, serious AEs with a recognized drug-attributable risk, which may constitute a safety issue under certain circumstances (e.g. plausible causality with exclusion of alternative causes) [8].\n\nFurthermore, given the non-negligible risk of neurotoxicity reported with cephalosporins [9], we searched clinical signs/symptoms, known as preferred terms (PTs) according to the Medical Dictionary for Regulatory Activities, in the following High Level Group Terms: “Seizures” (comprising 77 PTs), “Deliria” and “Hallucinations” (12 PTs each). Specific PTs concerning neurotoxicity (namely “encephalopathy”, “tremor”, “agitation”, “anxiety”, “cognitive disorder”, “mental impairment”, “altered state of consciousness”, “mental disorder”, “mental status changes”, “myoclonus”, “neurotoxicity”) were also analysed.\n\nThe reporting odds ratio (ROR) with relevant 95% confidence interval (CI) was calculated as a measure of disproportionality. All other drugs/events recorded in FAERS and cephalosporins showing clinical evidence of neurological AEs (namely cefazolin, ceftriaxone, cefixime, cefotiam, ceftazidime and cefepime according to the review of Sutter et al. [10]) were respectively selected as comparator for analysis of DMEs and neurotoxicity. Specifically, a case‑non-case approach was applied: Cases were defined by reports of the event of interest for C/T or C/A in which the drug was suspiciously recorded, while non-cases were represented by AE reports recorded for comparators. The ROR is the odds of exposure to C/T or C/A among the cases divided by the odds of exposure to C/T or C/A among the non-cases. If the proportion of the event of interest is greater in patients exposed to C/T or C/A (cases) than in patients exposed to all other drugs reported in FAERS, or for the selected cephalosporins (non-cases), a disproportionality signal emerges. Cases counted as many-fold as the number of DMEs or “neurological” events recorded in a given report. Traditional criteria for signal detections were used, i.e. lower limit of the 95% CI of the ROR > 1 with at least three cases of interest reported [11].\n\nDMEs or neurological AEs emerging from disproportionality analysis were further scrutinized to better describe relevant clinical features: demographic information, reported indication, proportion of death, proportion of septic shock and/or multi-organ dysfunction syndrome and concomitant risk factors and/or drugs implicated in the events of interest (i.e. proportion of renal impairment or underlying nervous abnormalities for neurological events).\n\nDMEs with disproportionality signal were also classified into three broad categories, according to the predictability of the reaction: (1) expected AEs, anticipated from pre-marketing pivotal trials; (2) disease-related AEs, for which underlying sepsis/septic shock represents per se a risk factor; and (3) unexpected AEs, on the basis of pharmacodynamic properties.\n\nUnexpected DMEs and neurological AEs were further scrutinized to detect potential duplicates, based on overlapping data in six key fields, as previously performed [6]: event date, age, sex, reporter’s country, concomitant reactions and concomitant drugs. Records with at least five out of six overlaps were considered duplicates and excluded by case assessment.\n\nFinally, unexpected DMEs with at least 3 unduplicated cases, a widely accepted signalling criterion [11], were further characterized by accessing original narratives submitted by the reporter through a Freedom of Information Act requested to the FDA: Information on medical history, laboratory findings, dechallenge/rechallenge, medical management and latency were used to assess causality according to the WHO system [12].\n\nResults\n\nOverall, 654 and 506 reports mentioning respectively C/T and C/A as suspect were found, of which 65.4% and 87.2% were serious. Subjects aged > 50 years old were the most represented, with slight male preponderance for both C/T and C/A (Supplementary Table 1).\n\nDMEs were respectively reported in 86 (13.1%) and 55 cases (10.9%) with C/T and C/A; 12 and 13 DMEs were reported at least once, respectively. Disproportionality analysis was performed for 4 and 6 DMEs respectively with C/T and C/A (eight and seven AEs were reported in less than three cases; Supplementary Table 2). Increased reporting was found for acute kidney injury (N = 24; ROR 5.50; 95% CI 3.66–8.27), agranulocytosis (12; 21.96; 12.40–38.87), pancytopenia (14; 10.50; 6.18–17.82) and renal failure (27; 7.88; 5.36–11.58) with C/T. Acute kidney injury (16; 4.71; 2.86–7.76), anaphylactic shock (3; 6.85; 2.20–21.33), haemolytic anaemia (3; 11.56; 3.72–35.98), hepatic failure (4; 5.74; 2.15–15.36), acute pancreatitis (7; 18.19; 8.63–38.36) and renal failure (13; 4.82; 2.78–8.37) emerged as over-reported DMEs with C/A (Table 1).Table 1 Designated medical events (DMEs) and selected neurological adverse events (AEs) reported with ceftolozane-tazobactam and ceftazidime-avibactam showing statistically significant disproportionality. Main clinical features after deduplication are also showed\n\nDMEs or neurological AEs\tNo. of cases\tROR (95% CI)\tPredictability\tNo. of cases after deduplication\tProportion of potential confounders*\t\nCeftolozane-tazobactam – DMEs\t\n Acute kidney injury\t24\t5.50 (3.66–8.27)\tExpected\n\nDisease-related\n\n\t10\t5 (50.0%)\t\n Agranulocytosis\t12\t21.96 (12.40–38.87)\tUnexpected\t4\t1 (25.0%)\t\n Pancytopenia\t14\t10.50 (6.18–17.82)\tUnexpected\t2\t1 (50.0%)\t\n Renal failure\t27\t7.88 (5.36–11.58)\tExpected\n\nDisease-related\n\n\t12\t6 (50.0%)\t\nCeftazidime-avibactam – DMEs\t\n Acute kidney injury\t16\t4.71 (2.86–7.76)\tExpected\n\nDisease-related\n\n\t9\t4 (44.4%)\t\n Anaphylactic shock\t3\t6.85 (2.20–21.33)\tExpected\t2\t0 (0.0%)\t\n Haemolytic anaemia\t3\t11.56 (3.72–35.98)\tExpected\t3\t0 (0.0%)\t\n Hepatic failure\t4\t5.74 (2.15–15.36)\tDisease-related\t3\t0 (0.0%)\t\n Pancreatitis acute\t7\t18.19 (8.63–38.36)\tUnexpected\t2\t2 (100.0%)\t\n Renal failure\t13\t4.82 (2.78–8.37)\tExpected\n\nDisease-related\n\n\t8\t6 (75.0%)\t\nCeftolozane-tazobactam – selected neurological AEs\t\n Encephalopathy\t19\t2.63 (1.66–4.19)\tExpected\t3\t1 (33.3%)\t\n Epilepsy\t11\t3.61 (1.96–6.65)\tExpected\t1\t0 (0.0%)\t\n Generalized tonic-clonic seizure\t10\t6.60 (3.43–12.70)\tExpected\t2\t0 (0.0%)\t\n Status epilepticus\t10\t1.93 (1.03–3.65)\tExpected\t1\t0 (0.0%)\t\nCeftazidime-avibactam – selected neurological AEs\t\n Encephalopathy\t18\t3.25 (2.01–5.24)\tExpected\t10\t3 (30.0%)\t\n Mental status changes\t8\t4.04 (1.98–8.26)\tExpected\t7\t3 (42.9%)\t\n Tonic convulsion\t4\t14.42 (4.99–41.71)\tExpected\t1\t0 (0.0%)\t\nAEs adverse events; DMEs designated medical events; ROR reporting odds ratio; CI confidence interval\n\n*Concomitant drugs or underlying conditions potentially implicated in the specific adverse event\n\nAgranulocytosis and pancytopenia with C/T and pancreatitis acute with C/A emerged as unexpected AEs. Overall, concomitant drugs or underlying conditions potentially confounding were retrieved in 45.5% of cases (Supplementary Table 3).\n\nAfter deduplication, only two cases of pancytopenia with C/T and two cases of pancreatitis acute with C/A were found as unequivocally different. Narratives were requested for the four confirmed cases of agranulocytosis with C/T (Table 2). Patients were ≥ 70 years old with female preponderance (75.0%). Agranulocytosis occurred after an average of 8.8 days (range 4–17 days) following the beginning of C/T treatment. In two cases, potential confounders related to underlying conditions (i.e. HIV infection, acute leukaemia, lymphoma) or concomitant therapies (i.e. rituximab, allopurinol, trimethoprim-sulfamethoxazole, metimazole) were recorded. In three cases, C/T was withdrawn, and in two patients, the administration of granulocyte colony-stimulating factor was required. All events were serious, leading to prolonged hospitalization. Recovery and increased in neutrophil count occurred in all cases after approximately 5–10 days. Causality was probable in three cases and possible in one case.Table 2 Narrative review of cases of agranulocytosis reported with ceftolozane-tazobactam and submitted to FAERS\n\nCase ID\tAge/sex\tReporter country\tDose/route of administration\tTime onset (days)*\tMedical history\tConcomitant therapies\tAcute medical condition\tLaboratory and imaging findings\tSpecific treatment\tDechallenge/rechallenge\tOutcome\tCausality assessment\t\n13844290\t87/M\tSpain\t1 g q8h IV\t17\tHigh blood pressure, congestive heart failure, atrial fibrillation, chronic obstructive pulmonary disease (COPD) with oxygen therapy, insomnia, loss of personal independence in daily activities, arthralgia\tAmiodarone\n\n200 mg/day\n\nFurosemide\n\n40 mg q12h\n\nTrazodone\n\n100 mg/day\n\nTramadol\n\n50 mg q8h\n\n\tCOPD decompensation due to LRTI caused by PA XDR\tNeutrophil count:\n\n2.96 × 109/L before treatment with C/T\n\n1.33 × 109/L at the moment of C/T withdrawn\n\n5.45 × 109/L at recovering\n\n\tC/T withdrawn 1 day after the occurrence of agranulocytosis\n\nProgressive increase in leucocyte count after C/T withdrawn\n\n\tYes/No\tProlonged hospitalization\n\nRecovered after 6 days\n\n\tProbable\n\n(reasonable time relationship with drug intake; unlikely role of other diseases/drugs; positive dechallenge)\n\n\t\n14034547\t79/F\tFrance\tLD 1 g IV\n\nMD 250 mg q8h IV\n\nUndergoing haemodialysis\n\n\t8\tAtrial fibrillation, pulmonary embolism\tAmiodarone\n\nFluindione\n\n\tcUTI with bacteraemia caused by PA MDR\tBefore treatment with C/T\n\nNeutrophil count:\n\n1.76 G/L\n\nWhite cell count:\n\n2.84 G/L\n\nDuring C/T treatment\n\nNeutrophil count:\n\n0.13 G/L\n\nWhite cell count:\n\n2.61 G/L\n\nOsteomedullar biopsy:\n\ndecrease of the granulocytic density at 10%, no impairment of other cell lines. Suspected toxic cause.\n\nAt recovering\n\nNeutrophil count:\n\n6.13 G/L\n\nWhite cell count:\n\n8.29 G/L\n\n\tC/T withdrawn 1 day after occurrence of agranulocytosis\n\nSwitch to ceftazidime-avibactam and administration of filgrastim\n\nProgressive increase in leucocytes and neutrophil count after C/T withdrawn\n\n\tYes/No\tProlonged hospitalization\n\nRecovered\n\n\tProbable\n\n(osteomedullar biopsy suggestive for toxic cause; reasonable time relationship with drug intake; unlikely role of other diseases/drugs; positive dechallenge)\n\n\t\n15505937\t71/F\tPortugal\t3 g q8h IV\t4\tNHL with medullar invasion\n\nMature B cell type acute leukaemia undergoing induction chemotherapy\n\nControlled HIV infection\n\n\tFluconazole\n\n200 mg/day\n\nTigecycline\n\n100 mg q12h\n\nMetamizole**\n\nRituximab**\n\nTMP-SMX**\n\nAllopurinol**\n\n\tPneumonia caused by XDR PA\tRepeated myelogram: no presence of lymphoblast\tC/T continuation\n\nAdministration of growth factors with no benefit\n\n\tNo/No\tProlonged hospitalization\n\nAbsolute neutropenia for 10 days with refractoriness to growth factors. Haemoglobin and platelet recovery was maintained.\n\nRecovered\n\n\tPossible\n\n(concomitant drugs/diseases potentially explaining the event; dechallenge not performed)\n\n\t\n15659483\t70/F\tPortugal\t1.5 g q8h IV\t6\tHIV infection\n\nDepressive symptom\n\nLymphoma\n\nVertigo\n\n\tAbacavir/Lamivudine\n\n600/300 mg/day\n\nTigecycline\n\n100 mg/day\n\nNevirapine\n\n400 mg/day\n\nAllopurinol***\n\n300 mg/day\n\nTMP-SMX*** 800/160 mg q8h\n\n\tSepsis\tNA\tC/T withdrawn 5 days after the occurrence of agranulocytosis\tYes/No\tProlonged hospitalization\n\nLife-threatening\n\nRecovered/resolved\n\n\tProbable\n\n(reasonable time relationship with drug intake; unlikely role of other diseases/drugs: no worsening of HIV infection; no ongoing treatment for lymphoma; allopurinol and TMP-SMX prescribed 45 days before the event; positive dechallenge)\n\n\t\nCOPD chronic obstructive pulmonary disease; LRTI lower tract respiratory infection; PA Pseudomonas aeruginosa; XDR extensively drug-resistant; MDR multidrug-resistant; C/T ceftolozane-tazobactam; cUTI complicated urinary tract infection; NHL non-Hodgkin’s lymphoma; TMP-SMX cotrimoxazole; NA not available\n\n*After ceftolozane-tazobactam administration\n\n**The indicated drugs were previously administered to the patient before admission without experience of agranulocytosis\n\n***Prescribed 45 days before occurrence of agranulocytosis\n\nOverall, 78 (11.9%) and 71 (14.0%) neurological AEs were respectively found with C/T and C/A. Disproportionality analysis was performed for six and seven AEs respectively with C/T and C/A. Compared to selected cephalosporins, encephalopathy (19; 2.63; 1.66–4.19), epilepsy (10; 6.60; 3.43–12.70), generalized tonic-clonic seizure (11; 3.61; 1.96–6.65) and status epilepticus (10; 1.93; 1.03–3.65) reported with C/T exhibited significant ROR. Increased reporting was found for encephalopathy (18; 3.25; 2.01–5.24), mental status changes (8; 4.04; 1.98–8.26) and tonic convulsion (4; 14.42; 4.99–41.71) with C/A (Table 1; Supplementary Table 4).\n\nAfter deduplication, only encephalopathy with both BL and BLIs and mental status changes with C/A were confirmed in at least three cases. Overall, concomitant renal impairment was found in 28.0% of cases, while no underlying nervous abnormalities were recognized (Supplementary Table 5).\n\nDiscussion\n\nTo the best of our knowledge, this is the first large-scale study reporting serious AEs with novel BL/BLIs. Haematological reactions emerged as unexpected life-threatening AEs for C/T, while C/A exhibited a predictable safety profile according to anticipated common AEs found in pivotal trials (i.e. anaphylactic shock, haemolytic anaemia) and expected clinical complications of severe infections caused by CPE (i.e. septic shock with hepatic/renal failure). Furthermore, an over-reporting of different serious neurological AEs (namely encephalopathy and mental status changes) compared to other cephalosporins [10] in patients receiving C/T or C/A was found.\n\nNotably, signals of unexpected pancytopenia and agranulocytosis with C/T, detected by disproportionality, were refuted by our qualitative analysis, including concomitant use of different agents (namely linezolid, ganciclovir, valacyclovir and trimethoprim-sulfamethoxazole) known to cause myelotoxicity. Therefore, possible confounders responsible for synergic toxicity may be implicated in the occurrence of pancytopenia. Conversely, in the four retained cases of agranulocytosis with C/T, the limited presence of concomitant risk factors together with causality assessment suggests a true safety issue. Although currently no case reports or preclinical evidence of ceftolozane-induced agranulocytosis exist, the immune-mediated hypothesis may reasonably explain the occurrence of this unexpected AE with C/T, as reported for other agents, including beta-lactams [13, 14]. However, a dose-dependent direct toxic effect on granulocytopoiesis cannot be excluded [15]. Additionally, elderly and female gender are recognized risk factors for drug-induced agranulocytosis [13]. Notably, mean age of our cases was approximately 77 years with female preponderance (75.0%). Furthermore, the mean onset time of our cases (8.8 days) overlaps with agranulocytosis reported in 12 patients with piperacillin-tazobactam (17.6 days) and in 62 subjects treated with different beta-lactams (16 days) [14, 15], consistently with the immune-mediated hypothesis. Although in two of our cases potential confounders (underlying diseases and/or concomitant myelotoxic drugs) were found, all these agents were previously administered for several cycles without occurrence of agranulocytosis, nor was any previous event of neutropenia noted in patients affected by leukaemia or lymphoma. Notably, in three cases, a probable causal association was detected, and none was classified as unlikely. Given the non-negligible proportion of XDR-PA infections in haematological patients [16], C/T may assume a leading role in this scenario. Consequently, the over-reporting of agranulocytosis calls for clinical monitoring in patients treated with C/T. Particularly, assessment of host-dependent risk factors (i.e. elderly, haematological malignances, HIV infection, concomitant myelotoxic agents) coupled with intensive blood cell count monitoring (every 24 h during the entire treatment with C/T) should be implemented (Fig. 1).Fig. 1 Suggested clinical monitoring for designated medical events (DMEs) and neurological adverse events (AEs) reported with ceftolozane-tazobactam and ceftazidime-avibactam and emerged as significant. TDM: therapeutic drug monitoring; MIC: minimum inhibitory concentration; TMP-SMX: cotrimoxazole\n\nThe two unduplicated cases of acute pancreatitis with C/A deserve attention for the following reasons: In the literature, no case of definite or probable association was found for ceftazidime [17]; in our reports, concomitant use of tigecycline, known to cause pancreatitis [18], was noted. Although C/A could not be considered the only primary suspect, considering its wide use in combination with tigecycline in complicated intraabdominal infections caused by CPE [19], clinicians should evaluate the risk of pancreatitis on a case-by-case basis in critically ill patients treated with drug combination, possibly implementing additional laboratory (i.e. serum amylase/lipase) or imaging monitoring (Fig. 1).\n\nOur analysis found an over-reporting of different serious neurological AEs with novel BL/BLIs compared to selected cephalosporins. Although neurotoxicity is a well-known safety concern in susceptible patients with risk factors (i.e. elderly, renal impairment, underlying nervous abnormalities) [9, 10], the higher reporting with novel BL/BLIs, rather than reflecting an intrinsically higher risk related to these agents per se, may be the result of a channelling bias favoured by their well-established use at standard/higher dosage to improve efficacy in severe MDR infections in critical settings [4]. To this regard, although C/A includes a maximum dose of ceftazidime (namely 6 g/day) for subject with normal renal function, novel BL/BLIs are commonly used in real-world scenarios at higher than recommended dosage also in patients with severe renal impairment or requiring continuous renal replacement therapy (CRRT), in order to overcome pharmacokinetic issues usually observed in critically ill subjects (e.g. wide increase in volume of distribution, high intensity CRRT, prompt recovery of renal function in the first 48–72 h), and achieve aggressive PK/PD targets directly associated with better clinical outcome and prevention of resistance development [4, 20–22]. However, in this scenario, it could be possible that toxic serum concentrations are more likely achieved, thus leading to a greater risk of neurological AEs. Adaptive therapeutic drug monitoring of novel BL/BLIs could be useful, retaining steady-state concentrations below tenfold the minimum inhibitory concentration (Fig. 1) [23].\n\nNotwithstanding the well-known limitations of our approach (e.g. potential reporting biases, including under-reporting phenomenon, lack of exposure data and clinical details, inability in establishing firm causality between drug exposure and occurrence of AEs, possible remaining duplicates), agranulocytosis emerged as an early and unexpected, albeit rare, AEs with C/T, thus calling for both stringent clinical monitoring in high-risk patients (namely those affected by haematological malignancies, HIV infection, acute or chronic kidney injury, or treated with concomitant myelotoxic or nephrotoxic agents) affected by severe MDR Gram-negative infections, and further observational studies to better characterize this safety aspect.\n\nSupplementary information\n\nESM 1 (DOCX 57 kb).\n\nESM 2 (XLSX 120 kb).\n\nESM 3 (XLSX 95 kb).\n\nAuthor’s contributions\n\nMG made substantial contributions to the conception and design of the study. MG made substantial contributions to the acquisition and analysis of data. MG, ER and FDP made substantial contributions in the interpretation of data. MG was involved in drafting the manuscript. ER and FDP made substantial contributions in revising the manuscript critically for important intellectual content. All authors approved the final version of the manuscript.\n\nFunding\n\nOpen Access funding provided by Alma Mater Studiorum - Università di Bologna. This study was supported by the Institutional Funds of the University of Bologna granted to ER and FDP. This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.\n\nData availability\n\nData supporting the findings of this study were derived from the following resource available in the public domain: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard.\n\nCompliance with ethical standards\n\nConflict of interest\n\nThe authors declare that they have no conflict of interest.\n\nEthics approval\n\nUnder current legislation, institutional review board approval is not required when performing analysis of the publicly available FAERS database, because it contains anonymized data that cannot allow patients’ identification.\n\nConsent to participate\n\nNot applicable.\n\nConsent for publication\n\nNot applicable.\n\nCode availability\n\nNot applicable.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Koulenti D Song A Ellingboe A Abdul-Aziz MH Harris P Gavey E Lipman J Infections by multidrug-resistant Gram-negative Bacteria: what’s new in our arsenal and what’s in the pipeline? Int J Antimicrob Agents. 2019 53 3 211 224 10.1016/j.ijantimicag.2018.10.011 30394301\n2. Chen M Zhang M Huang P Lin Q Sun C Zeng H Deng Y Novel β-lactam/β-lactamase inhibitors versus alternative antibiotics for the treatment of complicated intra-abdominal infection and complicated urinary tract infection: a meta-analysis of randomized controlled trials Expert Rev Anti Infect Ther. 2018 16 2 111 120 10.1080/14787210.2018.1429912 29343141\n3. Gatti M, Raschi E, De Ponti F (2019) Relationship between adverse drug reactions to antibacterial agents and the Klebsiella pneumoniae carbapenemase-producing (KPC) Klebsiella pneumoniae outbreak: insight from a pharmacovigilance study. BMC Pharmacol Toxicol. 20, 65(1)\n4. Giannella M Bartoletti M Gatti M Viale P Advances in the therapy of bacterial bloodstream infections Clin Microbiol Infect. 2020 26 2 158 167 10.1016/j.cmi.2019.11.001 31733377\n5. Gatti M, Raschi E, De Ponti F (2020) Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-pharmacokinetic/pharmacodynamic analysis. Eur J Clin Pharmacol. 10.1007/s00228-020-02990-1\n6. Poluzzi E Raschi E Motola D Moretti U De Ponti F Antimicrobials and the risk of torsades de pointes: the contribution from data mining of the US FDA Adverse Event Reporting System Drug Saf. 2010 33 4 303 314 10.2165/11531850-000000000-00000 20297862\n7. Patek TM Teng C Kennedy KE Alvarez CA Frei CR Comparing acute kidney injury reports among antibiotics: a pharmacovigilance study of the FDA Adverse Event Reporting System (FAERS) Drug Saf. 2020 43 1 17 22 10.1007/s40264-019-00873-8 31691256\n8. European Medicines Agency. Designated Medical Event (DME) list. 2020. https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/signal-management#designated-medical-events-section. Accessed August 17, 2020\n9. Deshayes S Coquerel A Verdon R Neurological adverse effects attributable to β-lactam antibiotics: a literature review Drug Saf. 2017 40 12 1171 1198 10.1007/s40264-017-0578-2 28755095\n10. Sutter R Rüegg S Tschudin-Sutter S Seizures as adverse events of antibiotic drugs: a systematic review Neurology. 2015 85 15 1332 1341 10.1212/WNL.0000000000002023 26400582\n11. Raschi E Poluzzi E Salvo F Pharmacovigilance of sodium-glucose co-transporter-2 inhibitors: what a clinician should know on disproportionality analysis of spontaneous reporting systems Nutr Metab Cardiovasc Dis. 2018 28 6 533 542 10.1016/j.numecd.2018.02.014 29625780\n12. The Uppsala Monitoring Center. The use of the WHO-UMC system for standardized case causality assessment. Available at: https://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessment.pdf. [Accessed 06 September 2020]\n13. Lorenzo-Villalba N Alonso-Ortiz MB Maouche Y Zulfiqar AA Andrès E Idiosyncratic drug-induced neutropenia and agranulocytosis in elderly patients J Clin Med. 2020 9 6 1808 10.3390/jcm9061808\n14. Wang Q, He Z, Wu X, Wei Y, Huang J (2020) Hematologic adverse effects induced by piperacillin-tazobactam: a systematic review of case reports. Int J Clin Pharm. 10.1007/s11096-020-01071-8\n15. Vial T Bailly H Perault-Pochat MC Default A Boulay C Chouchana L Kassai B French Network of Pharmacovigilance Centres. Beta-lactam-induced severe neutropaenia: a descriptive study Fundam Clin Pharmacol. 2019 33 2 225 231 10.1111/fcp.12419 30289173\n16. Willmann M Bezdan D Zapata L Susak H Vogel W Schröppel K Liese J Weidenmaier C Autenrieth IB Ossowski S Peter S Analysis of a long-term outbreak of XDR Pseudomonas aeruginosa: a molecular epidemiological study J Antimicrob Chemother. 2015 70 5 1322 1330 10.1093/jac/dku546 25583750\n17. Nitsche C Maertin S Scheiber J Ritter CA Lerch MM Mayerle J Drug-induced pancreatitis Curr Gastroenterol Rep. 2012 14 2 131 138 10.1007/s11894-012-0245-9 22314811\n18. McGovern PC Wible M Korth-Bradley JM Quintana A Pancreatitis in tigecycline Phase 3 and 4 clinical studies J Antimicrob Chemother. 2014 69 3 773 778 10.1093/jac/dkt427 24216769\n19. Rodríguez-Baño J Gutiérrez-Gutiérrez B Machuca I Pascual A Treatment of infections caused by extended-spectrum-beta-lactamase-, AmpC-, and carbapenemase-producing Enterobacteriaceae Clin Microbiol Rev. 2018 31 2 e00079 e00017 10.1128/CMR.00079-17 29444952\n20. Crass RL Rodvold KA Mueller BA Pai MP Renal dosing of antibiotics: are we jumping the gun? Clin Infect Dis. 2019 68 9 1596 1602 10.1093/cid/ciy790 30219824\n21. Gatti M Giannella M Raschi E Viale P De Ponti F Ceftolozane/tazobactam exposure in critically ill patients undergoing continuous renal replacement therapy: a PK/PD approach to tailor dosing J Antimicrob Chemother. 2021 76 1 199 205 10.1093/jac/dkaa416 33057628\n22. Sumi CD Heffernan AJ Lipman J Roberts JA Sime FB What antibiotic exposures are required to suppress the emergence of resistance for Gram-negative bacteria? A Systematic Review Clin Pharmacokinet. 2019 58 11 1407 1443 10.1007/s40262-019-00791-z 31325141\n23. Abdul-Aziz MH Alffenaar JC Bassetti M Bracht H Dimopoulos G Marriott D Neely MN Paiva JA Pea F Sjovall F Timsit JF Udy AA Wicha SG Zeitlinger M De Waele JJ Roberts JA Infection Section of European Society of Intensive Care Medicine (ESICM); Pharmacokinetic/pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID); Infectious Diseases Group of International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT); Infections in the ICU and Sepsis Working Group of International Society of Antimicrobial Chemotherapy (ISAC). Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper Intensive Care Med. 2020 46 6 1127 1153 10.1007/s00134-020-06050-1 32383061\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0934-9723",
"issue": "40(6)",
"journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology",
"keywords": "Agranulocytosis; Ceftazidime-avibactam; Ceftolozane-tazobactam; Neurotoxicity; Safety profile",
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000380:Agranulocytosis; D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D002442:Ceftazidime; D002511:Cephalosporins; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D007769:Lactams; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010198:Pancytopenia; D060735:Pharmacovigilance; D012189:Retrospective Studies; D000078142:Tazobactam; D065093:beta-Lactamase Inhibitors",
"nlm_unique_id": "8804297",
"other_id": null,
"pages": "1169-1176",
"pmc": null,
"pmid": "33415492",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "31325141;22314811;33057628;30394301;25583750;32383061;24216769;32901348;30219824;29343141;20297862;31691256;30289173;29444952;29625780;31733377;32500262;32531979;26400582;31718688;28755095",
"title": "Serious adverse events with novel beta-lactam/beta-lactamase inhibitor combinations: a large-scale pharmacovigilance analysis.",
"title_normalized": "serious adverse events with novel beta lactam beta lactamase inhibitor combinations a large scale pharmacovigilance analysis"
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{
"abstract": "While the thrombotic complications of COVID-19 have been well described, there are limited data on clinically significant bleeding complications including hemorrhagic stroke. The clinical characteristics, underlying stroke mechanism, and outcomes in this particular subset of patients are especially salient as therapeutic anticoagulation becomes increasingly common in the treatment and prevention of thrombotic complications of COVID-19.\n\n\n\nWe conducted a retrospective cohort study of patients with hemorrhagic stroke (both non-traumatic intracerebral hemorrhage and spontaneous non-aneurysmal subarachnoid hemorrhage) who were hospitalized between March 1, 2020, and May 15, 2020, within a major healthcare system in New York, during the coronavirus pandemic. Patients with hemorrhagic stroke on admission and who developed hemorrhage during hospitalization were both included. We compared the clinical characteristics of patients with hemorrhagic stroke and COVID-19 to those without COVID-19 admitted to our hospital system between March 1, 2020, and May 15, 2020 (contemporary controls), and March 1, 2019, and May 15, 2019 (historical controls). Demographic variables and clinical characteristics between the individual groups were compared using Fischer's exact test for categorical variables and nonparametric test for continuous variables. We adjusted for multiple comparisons using the Bonferroni method.\n\n\n\nDuring the study period in 2020, out of 4071 patients who were hospitalized with COVID-19, we identified 19 (0.5%) with hemorrhagic stroke. Of all COVID-19 with hemorrhagic stroke, only three had isolated non-aneurysmal SAH with no associated intraparenchymal hemorrhage. Among hemorrhagic stroke in patients with COVID-19, coagulopathy was the most common etiology (73.7%); empiric anticoagulation was started in 89.5% of these patients versus 4.2% in contemporary controls (p ≤ .001) and 10.0% in historical controls (p ≤ .001). Compared to contemporary and historical controls, patients with COVID-19 had higher initial NIHSS scores, INR, PTT, and fibrinogen levels. Patients with COVID-19 also had higher rates of in-hospital mortality (84.6% vs. 4.6%, p ≤ 0.001). Sensitivity analyses excluding patients with strictly subarachnoid hemorrhage yielded similar results.\n\n\n\nWe observed an overall low rate of imaging-confirmed hemorrhagic stroke among patients hospitalized with COVID-19. Most hemorrhages in patients with COVID-19 infection occurred in the setting of therapeutic anticoagulation and were associated with increased mortality. Further studies are needed to evaluate the safety and efficacy of therapeutic anticoagulation in patients with COVID-19.",
"affiliations": "Department of Neurology, NYU Langone Medical Center, New York, NY, 10016, USA. Alexandra.Kvernland@nyulangone.org.;Department of Neurology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Radiology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurosurgery, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Radiology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurosurgery, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Radiology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurosurgery, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurosurgery, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Radiology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Radiology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.;Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, 84132, USA.;Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, 02903, USA.;Department of Neurology, NYU Langone Medical Center, New York, NY, 10016, USA.;Department of Neurology, NYU Langone Medical Center, New York, NY, 10016, USA.",
"authors": "Kvernland|Alexandra|A|http://orcid.org/0000-0002-5273-8897;Kumar|Arooshi|A|;Yaghi|Shadi|S|;Raz|Eytan|E|;Frontera|Jennifer|J|;Lewis|Ariane|A|;Czeisler|Barry|B|;Kahn|D Ethan|DE|;Zhou|Ting|T|;Ishida|Koto|K|;Torres|Jose|J|;Riina|Howard A|HA|;Shapiro|Maksim|M|;Nossek|Erez|E|;Nelson|Peter K|PK|;Tanweer|Omar|O|;Gordon|David|D|;Jain|Rajan|R|;Dehkharghani|Seena|S|;Henninger|Nils|N|;de Havenon|Adam|A|;Grory|Brian Mac|BM|;Lord|Aaron|A|;Melmed|Kara|K|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1007/s12028-020-01077-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1541-6933",
"issue": "34(3)",
"journal": "Neurocritical care",
"keywords": "COVID-19; Coagulopathy; Coronavirus; Hemorrhagic stroke; Intracerebral hemorrhage; Pandemic; Subarachnoid hemorrhage",
"medline_ta": "Neurocrit Care",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D000086382:COVID-19; D005260:Female; D000083302:Hemorrhagic Stroke; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D009519:New York City; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate",
"nlm_unique_id": "101156086",
"other_id": null,
"pages": "748-759",
"pmc": null,
"pmid": "32839867",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "32396456;32614385;33031830;32526372;32338605",
"title": "Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System.",
"title_normalized": "anticoagulation use and hemorrhagic stroke in sars cov 2 patients treated at a new york healthcare system"
} | [
{
"companynumb": "US-CIPLA LTD.-2021US08010",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nAdult Fontan patients are at increased risk for thrombosis and thromboembolic complications leading to increased morbidity and mortality. Most are prescribed antiplatelet or anticoagulant therapy for thromboprophylaxis; novel oral anticoagulants (NOACs) are uncommonly used given lack of data on their use in this population and generalized concerns regarding Fontan patients' abnormal coagulation. We report the largest single-center experience with the use of NOACs for treatment and prophylaxis of thrombosis and thromboembolism in adult Fontan patients.\n\n\nRESULTS\nA retrospective chart review identified 21 patients (11 female, 10 male), median age 33 years (18-50) at first initiation, who were prescribed a NOAC on 27 different occasions. The main indications for anticoagulation were arrhythmia (N = 12), thrombosis (N = 8), and persistent right to left shunts (N = 2); one patient was initially on anticoagulation for arrhythmia but restarted for thrombosis. The most common indications for initiation of a NOAC over warfarin were patient/provider preference (N = 11), labile international normalized ratio (INR) (N = 5), initiation of therapy elsewhere (N = 3), and history of poor clinical follow-up (N = 2). Over a cumulative 316 months of patient therapy, one new thrombotic event was noted. No major or nonmajor bleeding events occurred, and 10 patients experienced minor bleeding that did not require the cessation of therapy. One patient died from multiorgan system failure following an unwitnessed, out of hospital arrest. At present, 10 patients remain on NOAC therapy in the setting of ongoing arrhythmia (N = 4), history of stroke (N = 2), history of pulmonary embolism (N = 2), history of deep vein thrombosis (N = 1), and history of right ventricle thrombus (N = 1).\n\n\nCONCLUSIONS\nWhile our study is limited by size, our results suggest that NOACs may be a non-inferior alternative to traditional anticoagulation and that further study is warranted.",
"affiliations": "Division of Pediatric Cardiology, Cohen Children's Medical Center/Northwell Health, New Hyde Park, New York, USA.;Department of Internal Medicine/Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.;Section of Pediatric Cardiology, Texas Children's Hospital/Baylor College of Medicine, Houston, Texas, USA.;Division of Adult Congenital Cardiology, Texas Children's Hospital/Baylor College of Medicine, Houston, Texas, USA.;Division of Adult Congenital Cardiology, Texas Children's Hospital/Baylor College of Medicine, Houston, Texas, USA.;Division of Adult Congenital Cardiology, Texas Children's Hospital/Baylor College of Medicine, Houston, Texas, USA.;Division of Adult Congenital Cardiology, Texas Children's Hospital/Baylor College of Medicine, Houston, Texas, USA.",
"authors": "Georgekutty|Justin|J|;Kazerouninia|Amir|A|http://orcid.org/0000-0003-1240-2499;Wang|YunFei|Y|;Ermis|Peter R|PR|;Parekh|Dhaval R|DR|;Franklin|Wayne J|WJ|;Lam|Wilson W|WW|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1111/chd.12603",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1747-079X",
"issue": "13(4)",
"journal": "Congenital heart disease",
"keywords": "Fontan; arrhythmia; novel oral anticoagulant; thrombosis",
"medline_ta": "Congenit Heart Dis",
"mesh_terms": "D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000925:Anticoagulants; D005260:Female; D006330:Heart Defects, Congenital; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D013923:Thromboembolism; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "101256510",
"other_id": null,
"pages": "541-547",
"pmc": null,
"pmid": "29575675",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Novel oral anticoagulant use in adult Fontan patients: A single center experience.",
"title_normalized": "novel oral anticoagulant use in adult fontan patients a single center experience"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-046017",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "BACKGROUND\nHigh-dose intravenous methylprednisolone is the most common therapeutic modality to treat acute exacerbations in multiple sclerosis (MS). Various cardiac arrhythmias have been reported during corticosteroid pulse therapy. This study was conducted to detect cardiac rhythm changes in patients with MS while receiving high dose methylprednisolone.\n\n\nMETHODS\nWe enrolled 52 consecutive MS patients with acute relapse to perform cardiac monitoring 4h before, during and 18 h after infusion of 1000 mg intravenous (IV) methylprednisolone.\n\n\nRESULTS\nSinus tachycardia was the most common change in cardiac rhythms before, during, and after corticosteroid pulse therapy. Up to 41.9% of the patients, developed sinus bradycardia after pulse infusion. Sinus arrest and sinus exit block were observed in 12 patients. Atrial fibrillation and ventricular tachycardia were observed in three patients and one patient, respectively. The most important cardiac arrhythmias including ventricular tachycardia, sinus arrest, and sinus exit block, were correlated with smoking and more commonly observed during 12h post infusion. Sinus bradycardia and atrial fibrillation were detected more commonly in patients with history of urinary dysfunction.\n\n\nCONCLUSIONS\nHigh dose intravenous prednisolone might cause different types of arrhythmias in MS patients. Cigarette smokers and patients with autonomic disturbances like sphincter and bowel problems have more chance to develop arrhythmias while receiving high dose steroids.",
"affiliations": "Department of Cardiology, Sina Hospital, Tehran University of Medical Sciences, Hassan Abad Square, Tehran, Iran.",
"authors": "Vasheghani-Farahani|Ali|A|;Sahraian|Mohammad Ali|MA|;Darabi|Leila|L|;Aghsaie|Aida|A|;Minagar|Alireza|A|",
"chemical_list": "D008775:Methylprednisolone",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jns.2011.07.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-510X",
"issue": "309(1-2)",
"journal": "Journal of the neurological sciences",
"keywords": null,
"medline_ta": "J Neurol Sci",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001145:Arrhythmias, Cardiac; D005260:Female; D006329:Heart Conduction System; D006801:Humans; D015994:Incidence; D007262:Infusions, Intravenous; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D009103:Multiple Sclerosis; D020551:Pulse Therapy, Drug; D012907:Smoking; D055815:Young Adult",
"nlm_unique_id": "0375403",
"other_id": null,
"pages": "75-8",
"pmc": null,
"pmid": "21831398",
"pubdate": "2011-10-15",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Incidence of various cardiac arrhythmias and conduction disturbances due to high dose intravenous methylprednisolone in patients with multiple sclerosis.",
"title_normalized": "incidence of various cardiac arrhythmias and conduction disturbances due to high dose intravenous methylprednisolone in patients with multiple sclerosis"
} | [
{
"companynumb": "IR-PFIZER INC-2019190504",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "Multiple myeloma (MM) is the second most common haematological malignancy in the USA. MM has been linked to various autoimmune disorders in many studies; one systemic review even suggested an increased risk of MM among patients with autoimmune disorders. MM is associated with many haematological, rheumatologic and neurological conditions. A few case reports suggest that MM can be associated with immune thrombocytopenic purpura (ITP), although this is rare. We present a case of MM with concurrent ITP which was refractory of steroids and intravenous immunoglobulin but had a response with anti-neoplastic therapy for MM. We also review all the cases of ITP with MM described in the literature. If conventional treatment for ITP associated with MM fails to improve platelet count, anti-neoplastic therapy for MM should be considered.",
"affiliations": "Department of Internal Medicine, Houston Methodist, Houston, TX 77030, USA.;Houston Methodist Cancer Center/Weill Cornell Medicine, Houston, TX 77030, USA.;Department of Pathology, Houston Methodist, Houston, TX 77030, USA.;Houston Methodist Cancer Center/Weill Cornell Medicine, Houston, TX 77030, USA.",
"authors": "Sarfraz|Humaira|H|;Anand|Kartik|K|;Liu|Shujuan|S|;Shah|Shilpan|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3332/ecancer.2020.1012",
"fulltext": "\n==== Front\nEcancermedicalscience\nEcancermedicalscience\necancermedicalscience\necancermedicalscience\n1754-6605 Cancer Intelligence \n\n10.3332/ecancer.2020.1012\ncan-14-1012\nCase Report\nMultiple myeloma with concurrent immune thrombocytopenic purpura\nSarfraz Humaira 1* Anand Kartik 2* Liu Shujuan 3 Shah Shilpan 2 \n1 Department of Internal Medicine, Houston Methodist, Houston, TX 77030, USA\n\n2 Houston Methodist Cancer Center/Weill Cornell Medicine, Houston, TX 77030, USA\n\n3 Department of Pathology, Houston Methodist, Houston, TX 77030, USA\n\n* Equal contribution\nCorrespondence to: Shilpan Shah sshah2@houstonmethodist.org\n2020 \n20 2 2020 \n14 101207 9 2019 © the authors; licensee ecancermedicalscience.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Multiple myeloma (MM) is the second most common haematological malignancy in the USA. MM has been linked to various autoimmune disorders in many studies; one systemic review even suggested an increased risk of MM among patients with autoimmune disorders. MM is associated with many haematological, rheumatologic and neurological conditions. A few case reports suggest that MM can be associated with immune thrombocytopenic purpura (ITP), although this is rare. We present a case of MM with concurrent ITP which was refractory of steroids and intravenous immunoglobulin but had a response with anti-neoplastic therapy for MM. We also review all the cases of ITP with MM described in the literature. If conventional treatment for ITP associated with MM fails to improve platelet count, anti-neoplastic therapy for MM should be considered.\n\nmultiple myelomaITPthrombocytopeniaauto immune disorderimmunoglobulin\n==== Body\nIntroduction\nMultiple myeloma (MM) is a plasma cell disorder characterised by clonal proliferation of malignant cells in the bone marrow with monoclonal protein in the serum and/or urine and is associated with end-organ damage including anaemia, hypercalcemia, renal dysfunction and bone disease [1]. MM is the second most common haematological malignancy with an incidence of 6.2/100,000 [2]. MM at presentation can be symptomatic or asymptomatic; for diagnosis, at least >10% clonal bone marrow plasma cells plus ≥1 multiple myeloma defining events are required [3]. Aetiology of MM remains unknown; some of the risk factors are advanced age, family history, male gender and environmental factors [4]. Several studies suggest a link between autoimmune disorders and MM, one systemic review suggested patients with autoimmune disease are at high risk for development of MM [5]. MM is associated with many haematological, rheumatologic and neurological conditions [6]. A few case reports suggest that rarely MM can be associated with immune thrombocytopenic purpura (ITP) [7]. The likely mechanisms, which may explain the correlation between MM and ITP, include that autoimmune conditions may lead to chronic B cell activation and development of MM. However, MM itself is also associated with the development of autoimmune phenomena. Third, thrombocytopenia may occur as a result of certain drugs used for treatment of MM. Most cases of ITP associated with MM respond to steroids and intravenous immunoglobulins (IVIg) [7]. Here, we present a case of MM with concurrent ITP which was refractory to corticosteroids and IVIg and had response to anti-neoplastic therapy for MM.\n\nCase presentation\nA 60-year-old male with a past medical history of bipolar disorder and schizophrenia on olanzapine presented to the hospital with generalised weakness and weight loss for the past 2 months. His physical exam was unremarkable for any petechiae, bleeding, bruises, hepatosplenomegaly or evidence of lymphadenopathy. Laboratory examination showed haemoglobin of 5.9 g/dL, WBC 2.88 k/μL with normal differential, platelet count of 1 k/μL, creatinine 1.1 mg/dL, calcium 8.6 mg/dL, albumin 2.7 g/dL and total protein 7.6 g/dL. Prothrombin was within normal limits (WNL), and activated partial thromboplastin time (PTT) was elevated at 42.3 seconds. Further work regarding the elevation of PTT revealed the presence of lupus anticoagulant. The D-dimer level was elevated at 2.9 μg/mL, and fibrinogen was elevated as well at 463 mg/dL. Haptoglobin was WNL at 189 mg/dL, LDH was elevated at 506 U/L and reticulocyte index was low at 2 with no spherocytosis or schistocytes on peripheral smear exam which ruled out haemolysis. Immunoglobin quantification showed increased IgG at 2,157 mg/dL, IgA WNL at 338 mg/dL and decreased IgM at <25 mg/dL. Serum and urine protein electrophoresis with immunofixation showed the presence of IgG lambda paraproteinemia at a concentration of 0.8 and 0.6 g/dL, respectively. ESR was found to be elevated at 55 mm/1st hour and beta-2 microglobulin was elevated at 4.1 mg/L. The patient was transfused packed red blood cells with an appropriate rise in haemoglobin, but there was no rise in platelet count checked 1 hour after platelet transfusion indicating peripheral destruction. Bone marrow biopsy was performed which showed normocellular marrow with 30% lambda restricted plasma cells (Figure 1A–C) and focal megakaryocytic hyperplasia, staining positive by CD61 (Figure 1D–E). Congo red staining for amyloid was negative. Skeletal survey showed no lytic lesions. Work up done to rule out secondary causes of thrombocytopenia, including HIV, hepatitis C virus, rheumatological workup with anti-nuclear antibody and imaging to detect splenomegaly, was unremarkable. Hence, with all the work described earlier, a diagnosis of concurrent ITP and MM was established. This patient satisfied the criteria for MM due to the presence of >10% clonal plasma cells in the bone marrow along with anaemia [3]. An initial trial for ITP treatment with IVIg 1 g/kg for 2 days and dexamethasone 40 mg daily for 4 days did not lead to an increase in platelet count. Given his refractory thrombocytopenia and concurrent multiple myeloma, he was subsequently started on cyclophosphamide, bortezomib, dexamethasone (CyBorD). On day 6 of cycle 1, a rise in platelet count to 29 k/μL was noted. Subsequent days thereafter, the platelet count continued to increase and peaked at 171 k/μL before the start of his next cycle of chemotherapy. From a multiple myeloma standpoint, there was a decrease in paraprotein load from 0.8 to 0.3 g/dL. He recently received his cycle 2 of induction chemotherapy with a future plan to repeat a bone marrow biopsy and move on to high dose chemotherapy followed by stem cell rescue.\n\nDiscussion\nHere, we describe a case of concurrent immune thrombocytopenic purpura with multiple myeloma which was refractory to treatment with pulse dexamethasone and IVIg but responded to treatment with chemotherapy for Multiple Myeloma with CyBorD. While thrombocytopenia may be seen with multiple myeloma commonly, ITP has rarely been encountered as an association with multiple myeloma. In most cases, thrombocytopenia results from chemotherapy during multiple myeloma treatment or marrow infiltration by the plasma cells. In our case, the absence of an increase in platelet count with platelet transfusion indicated a destructive aetiology for thrombocytopenia. Moreover, the absence of secondary causes and megakaryocytes noted on bone marrow exam confirmed diagnosis of ITP. To date, 11 cases of ITP associated with MM have been reported (Table 1), comprising of 7 males and 4 women. M proteins in all patients were of IgG type. Four cases (1, 6, 9, 10) were diagnosed with ITP after receiving chemotherapy for MM, while three cases of ITP (4, 5, 11) were diagnosed before MM. As per the literature review, there are only three cases (3, 7, 8) of Multiple Myeloma and ITP being diagnosed concurrently (2, 4, 5). The age spectrum of the previous cases described range from 49 to 78 years. In the case series by Gupta et al ], their patient with concurrent ITP and MM, thrombocytopenia responded to treatment with IVIg and was subsequently started on chemotherapy with VAD for MM treatment. In the case report by Tabata et al [9], initially, the patient was diagnosed with MM with mild thrombocytopenia noted with increased megakaryocytes in the bone marrow. He was treated for MM with melphalan and prednisone but could not receive subsequent rounds of chemotherapy due to severe neutropenic infections. It was observed that with the progression of MM, platelet count continued to decrease while the megakaryocyte concentration was preserved indicating that there could potentially be an association between MM severity and thrombocytopenia which was demonstrated by the rise in platelet associated antibody. The platelet count in that case responded to cepharanthine (natural alkaloid) most likely associated with decreased cytokine production. In the case described by Yao et al, immunosuppression for ITP was linked to MM. For cases in which MM was diagnosed before ITP (1, 6, 9, 10), it is likely that MM led to certain autoimmune sequelae resulting ITP. In such cases, medication induced effects would also need to be considered. On the other hand, when MM follows ITP diagnosis (4, 5, 11), most likely mechanism implicated is chronic B-cell activation. While these cases may allude to the cause of an association between MM and ITP, it is still difficult to ascertain the exact mechanism given paucity of evidence and heterogeneity of disease.\n\nIn our case, there was a lack of response to IVIg and dexamethasone to ITP but there was a remarkable response of thrombocytopenia to treatment with CyBorD. While bortezomib has been found to have a good response in MM, bortezomib itself is implicated in causing thrombocytopenia in some cases too. The rise in platelets seen in our patient with concurrent ITP raises the possibility that manifestation of ITP is perhaps caused by MM itself and the treatment of MM reciprocally leads to its resolution [10, 11].\n\nThe pathogenesis of ITP with MM is poorly understood. It has been hypothesised that immune alterations promote the generation of autoimmune platelet antibodies [8]. This case presentation describes a rare autoimmune manifestation of MM (ITP) and highlights that the treatment of MM with combination chemotherapy can lead to resolution of ITP refractory to IVIg and corticosteroids treatment.\n\nConclusion\nIn conclusion, we discuss a rare case of MM complicated by concurrent ITP. In contrast to most common associations of ITP and MM which usually respond to IVIg, steroids or splenectomy, ours was a unique case where administration of chemotherapy (CyBorD) resulted in normalisation of platelet count. This response suggests the implication of abnormal immune mechanisms in ITP associated with MM.\n\nConflicts of interest\nNone.\n\nFunding\nThe authors received no specific funding for this work.\n\nFigur and Table\nFigure 1. Clustering of lambda-light chain restricted plasma cells on Bone marrow biopsy section (A–C). A. HE × 200; B. Lambda light chain ISH x100; C. Lambda light chain ISH x100. D. Focal loose clustering of megakaryocytes. A HE ×200; E CD61 immunohistochemical stain ×200.\nTable 1. Cases of ITP with MM described in the literature till date excluding the current case.\nCase\tReference\tAge/Gender\tM protein type at diagnosis\tM protein conc (g/dL)\tPlatelet 109/L\tITP \nDiagnosis timing\tITP\nManagement\tAlive/Cause of death\t\n1\tVerdirame et al [12]\t67 y/F\tIgG/lambda\t2.4\t10\tAfter MM Tx\tPrednisone, splenectomy\tAlive\t\n2\tVerdirame et al [12]\t55 y/M\tIgG/kappa\t3.4\t48\tDuring MM Tx\tPrednisone, splenectomy\tAlive\t\n3\tGupta et al [8]\t49 y/M\tIgG/lambda\t4.0\t21\tAt MM Dx\tIVIg, VAD\tSepsis\t\n4\tGupta et al [8]\t36 y/M\tIgG/kappa\t11.9\t5\tBefore MM Dx\tPrednisone, IVIg, splenectomy, VAD\tSepsis\t\n5\tGupta et al [8]\t45 y/M\tIgG/lambda\t6.1\t20\tBefore MM Dx\tSteroid, IVIg, splenectomy\tAlive\t\n6\tFalco et al [13]\t45 y/M\tIgG/kappa\t1.8\t<10\tAfter MM Tx\tPrednisone, IVIg\tN/A\t\n7\tSiniscalchi et al [14]\t67 y/F\tIgG/kappa\t2.6\t3\tAt MM Dx\tPrednisone, IVIg, Rituximab\tAlive\t\n8\tTabata et al [9]\t78 y/M\tIgG/kappa\t4.18\t17\tAt MM Dx\tMelphalan, Prednisone, \nCepharanthine\tUnknown cause of death\t\n9\tFaller et al [7]\t66 y/M\tIgG/kappa\t1.00\t<10\tAfter MM Tx\tIVIg\tAlive\t\n10\tFaller et al [7]\t41 y/F\tIgA/kappa\tN/A\t<10\tAfter MM Tx\tIVIg, Dexamethasone\tGI bleed\t\n11\tYao et al [15]\t61 y/M\tIgG/kappa\tN/A\t27\tBefore MM Dx\tRefractory ITP; Prednisone, IVIg, Danazol, IFN, AZT\tAlive\n==== Refs\nReferences\n1. Palumbo A Anderson K Multiple myeloma N Engl J Med 2011 364 11 1046 1060 10.1056/NEJMra1011442 21410373 \n2. Siegel RL Miller KD Jemal A Cancer statistics CA Cancer J Clin 2016 66 1 7 30 10.3322/caac.21332 26742998 \n3. Rajkumar SV Dimopoulos MA Palumbo A International myeloma working group updated criteria for the diagnosis of multiple myeloma Lancet Oncol 2014 15 12 e538 e548 10.1016/S1470-2045(14)70442-5 25439696 \n4. Alexander DD Mink PJ Adami HO Multiple myeloma: a review of the epidemiologic literature Int J Cancer 2007 120 12 40 61 10.1002/ijc.22718 17405120 \n5. McShane CM Murray LJ Landgren O Prior autoimmune disease and risk of monoclonal gammopathy of undetermined significance and multiple myeloma: a systematic review Cancer Epidemiol Biomarkers Prev 2014 23 2 332 342 10.1158/1055-9965.EPI-13-0695 24451437 \n6. Shimanovsky A Alvarez Argote J Murali S Autoimmune manifestations in patients with multiple myeloma and monoclonal gammopathy of undetermined significance BBA Clin 2016 6 12 18 10.1016/j.bbacli.2016.05.004 27331023 \n7. Faller E Chapman L Enright H Immune thrombocytopenia purpura associated with multiple myeloma Ann Hematol 2016 95 8 1371 1372 10.1007/s00277-016-2694-y 27178045 \n8. Gupta V Hegde UM Parameswaran R Multiple myeloma and immune thrombocytopenia Clin Lab Haematol 2000 22 4 239 242 10.1046/j.1365-2257.2000.00125.x 11012639 \n9. Tabata R Tabata C Tazoh A Low dose cepharanthine ameliorates immune thrombocytopenic purpura associated with multiple myeloma Int Immunopharmacol 2012 13 3 242 244 10.1016/j.intimp.2012.04.015 22561120 \n10. Richardson PG Sonneveld P Schuster MW Bortezomib or high-dose dexamethasone for relapsed multiple myeloma N Engl J Med 2005 352 24 2487 2498 10.1056/NEJMoa043445 15958804 \n11. Lonial S Waller EK Richardson PG Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma Blood 2005 106 12 3777 3784 10.1182/blood-2005-03-1173 16099887 \n12. Verdirame JD Feagler JR Commers JR Multiple myeloma associated with immune thrombocytopenic purpura Cancer 1985 56 5 1199 1200 4040420 \n13. Falco P Bertola A Bringhen S Successful management of immune thrombocytopenic purpura with thalidomide in a patient with multiple myeloma Hematol J 2004 5 5 456 457 10.1038/sj.thj.6200404 15448677 \n14. Siniscalchi A Stasi R Fratoni S Management of immune thrombocytopoenia in a patient with newly-diagnosed smouldering myeloma and colorectal cancer BMJ Case Rep 2009 2009 bcr0320091715 \n15. Yao H Zhang X Liu J Multiple myeloma developing during long-term clinical course of refractory immune thrombocytopenic purpura: a case report and review of literature Int J Clin Exp Pathol 2015 8 11 15429 15432 26823908\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1754-6605",
"issue": "14()",
"journal": "Ecancermedicalscience",
"keywords": "ITP; auto immune disorder; immunoglobulin; multiple myeloma; thrombocytopenia",
"medline_ta": "Ecancermedicalscience",
"mesh_terms": null,
"nlm_unique_id": "101392236",
"other_id": null,
"pages": "1012",
"pmc": null,
"pmid": "32256695",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "15958804;4040420;17405120;15448677;27331023;22561120;21410373;16099887;26823908;24451437;27178045;25439696;21686970;11012639;26742998",
"title": "Multiple myeloma with concurrent immune thrombocytopenic purpura.",
"title_normalized": "multiple myeloma with concurrent immune thrombocytopenic purpura"
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2022SP002567",
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"activesubstancename": "DEXAMETHASONE"
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"abstract": "Immune checkpoint inhibitors are being commonly used as anticancer therapies to treat malignancies. Immune checkpoint inhibitors have been associated with numerous immune-related adverse events (irAEs). IrAEs are well documented; however, rheumatic irAEs are infrequently reported in published literature. The objective of this single-center retrospective chart review study was to evaluate the incidence of arthralgias with immune checkpoint inhibitor therapy as well as the management of these immune-related events. Patients were included if they received one or more doses of nivolumab, pembrolizumab, atezolizumab, ipilimumab, or a combination of agents within the last year. Exclusion criteria included documented history of autoimmune disease, off-label use of immune checkpoint inhibitor, and non-FDA-approved weight-based dosing. This study included 98 patients for review and identified 11 patients that developed arthralgias with immune checkpoint inhibitor therapy. Median time to event was 63 days. Seven patients were treated with corticosteroids. Immune checkpoint inhibitor therapy was held in six patients with arthralgias. Inflammatory markers were collected for six patients and elevated in four of these cases. One patient was referred to rheumatology. The three patients who had grading of arthralgias were not managed optimally according to guideline recommendations. These findings show that 11% of patients treated with immune checkpoint inhibitors had documented arthralgias, consistent with previous reports in the literature. Also, the report shows that management and treatment of these events at our institution was not consistent between providers. Lastly, collaboration with rheumatology may be essential in managing arthralgias and other rheumatologic irAEs.",
"affiliations": "Department of Pharmacy, Medical University of South Carolina, Charleston, SC, USA.;Department of Pharmacy, Medical University of South Carolina, Charleston, SC, USA.;Department of Pharmacy, Medical University of South Carolina, Charleston, SC, USA.",
"authors": "Lee|Jenessa|J|https://orcid.org/0000-0002-8026-9178;Graham|Anastasia|A|;Sion|Amy|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000074324:Ipilimumab; D000077594:Nivolumab; C000594389:atezolizumab; C582435:pembrolizumab",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218822707",
"fulltext": null,
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"issue": "25(8)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Arthralgia immune-related adverse event; immune checkpoint inhibitor; immune-mediated adverse event; rheumatic immune-related adverse event; rheumatologic immune mediated",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D018771:Arthralgia; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D000077594:Nivolumab; D012189:Retrospective Studies",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1867-1872",
"pmc": null,
"pmid": "30651028",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of arthralgias in adult oncology patients receiving immune checkpoint inhibitors.",
"title_normalized": "evaluation of arthralgias in adult oncology patients receiving immune checkpoint inhibitors"
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"activesubstancename": "PEMBROLIZUMAB"
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{
"abstract": "Traumatic carotid cavernous fistula may occur as a complication of endovascular treatment of acute stroke. We report 3 cases of such lesions. All patients were initially managed conservatively. Two patients have remained asymptomatic. One patient became symptomatic with right eye proptosis, chemosis, and right lateral gaze diplopia 3 weeks post thrombectomy. He underwent endovascular embolization via transfemoral transvenous approach via the inferior ophthalmic vein.",
"affiliations": "Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. Electronic address: alann@upmc.edu.;Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.;Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.;Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.;Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.;Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.",
"authors": "Alan|Nima|N|;Nwachuku|Enyinna|E|;Jovin|Tudor J|TJ|;Jankowitz|Brian T|BT|;Jadhav|Ashutosh P|AP|;Ducruet|Andrew F|AF|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.wneu.2017.01.112",
"fulltext": null,
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"issn_linking": "1878-8750",
"issue": "100()",
"journal": "World neurosurgery",
"keywords": "Carotid-cavernous fistula; Cerebral angiography; Complications; Endovascular; Stroke",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000368:Aged; D020216:Carotid-Cavernous Sinus Fistula; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D007049:Iatrogenic Disease; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D020521:Stroke",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "710.e15-710.e20",
"pmc": null,
"pmid": "28185973",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of Iatrogenic Direct Carotid Cavernous Fistula Occurring During Endovascular Treatment of Stroke.",
"title_normalized": "management of iatrogenic direct carotid cavernous fistula occurring during endovascular treatment of stroke"
} | [
{
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{
"abstract": "Nocardia takedensis was first isolated in 2005, from soil in Japan. We report here two cases of lymphangitis in France (2012-2017) caused by N. takedensis both occurring after skin injury while gardening, which enabled its inoculation. The two patients were immunocompromised and successfully treated by an antimicrobial agent active on the isolated strain, trimethoprim-sulfamethoxazole and amoxicillin-clavulanic acid for patient one and patient two, respectively. Our study along with previous ones supports the idea of a newly recognized cutaneous opportunistic pathogen and reinforces the recommendation of using gloves during soil exposure for immunocompromised patients. Lastly, according to data found in the literature, we would recommend trimethoprim-sulfamethoxazole as an efficient empirical antibiotic therapy in case of cutaneous infection caused by N. takedensis.",
"affiliations": "Department of Bacteriology, Nice Academic Hospital, Nice, France. lotte.r@chu-nice.fr.;Department of Bacteriology, Nice Academic Hospital, Nice, France.;Research Group On Bacterial Opportunistic Pathogens and Environment UMR5557 Écologie Microbienne, French Observatory of Nocardiosis, Institute of Infectious Agents, Hospices Civils de Lyon, Université de Lyon 1, CNRS, VetAgro Sup, Lyon, France.;Department of Bacteriology, Nice Academic Hospital, Nice, France.;Department of Bacteriology, Nice Academic Hospital, Nice, France.;Université Côte D'Azur, CHU de Nice, Nice, France.;Université Côte D'Azur, Inserm, C3M, Nice, France.;Research Group On Bacterial Opportunistic Pathogens and Environment UMR5557 Écologie Microbienne, French Observatory of Nocardiosis, Institute of Infectious Agents, Hospices Civils de Lyon, Université de Lyon 1, CNRS, VetAgro Sup, Lyon, France.;Department of Dermatology and Infectious Diseases, Centre Hospitalier Intercommunal, Fréjus-Saint-Raphaël, Fréjus, France.;Department of Bacteriology, Nice Academic Hospital, Nice, France.",
"authors": "Lotte|Romain|R|;Chevalier|Alicia|A|;Dantas|Sabine|S|;Degand|Nicolas|N|;Gaudart|Alice|A|;Rörhlich|Pierre-Simon|PS|;Boyer|Laurent|L|;Rodriguez-Nava|Veronica|V|;Del Giudice|Pascal|P|;Ruimy|Raymond|R|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s12941-020-00379-7",
"fulltext": "\n==== Front\nAnn Clin Microbiol Antimicrob\nAnn. Clin. Microbiol. Antimicrob\nAnnals of Clinical Microbiology and Antimicrobials\n1476-0711 BioMed Central London \n\n379\n10.1186/s12941-020-00379-7\nShort Report\nNocardia takedensis: a newly recognized pathogen responsible for skin and soft tissue infections\nLotte Romain lotte.r@chu-nice.fr 123 Chevalier Alicia 1 Dantas Sabine 4 Degand Nicolas 1 Gaudart Alice 1 Rörhlich Pierre-Simon 25 Boyer Laurent 3 Rodriguez-Nava Veronica 4 Del Giudice Pascal 6 Ruimy Raymond 123 1 Department of Bacteriology, Nice Academic Hospital, Nice, France \n2 grid.410528.a0000 0001 2322 4179Université Côte D’Azur, CHU de Nice, Nice, France \n3 Université Côte D’Azur, Inserm, C3M, Nice, France \n4 grid.413852.90000 0001 2163 3825Research Group On Bacterial Opportunistic Pathogens and Environment UMR5557 Écologie Microbienne, French Observatory of Nocardiosis, Institute of Infectious Agents, Hospices Civils de Lyon, Université de Lyon 1, CNRS, VetAgro Sup, Lyon, France \n5 Department of Pediatric Hematology, Nice Academic Hospital, Nice, France \n6 grid.418062.90000 0004 1795 3510Department of Dermatology and Infectious Diseases, Centre Hospitalier Intercommunal, Fréjus-Saint-Raphaël, Fréjus, France \n20 8 2020 \n20 8 2020 \n2020 \n19 3817 10 2019 9 8 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Nocardia takedensis was first isolated in 2005, from soil in Japan. We report here two cases of lymphangitis in France (2012–2017) caused by N. takedensis both occurring after skin injury while gardening, which enabled its inoculation. The two patients were immunocompromised and successfully treated by an antimicrobial agent active on the isolated strain, trimethoprim-sulfamethoxazole and amoxicillin-clavulanic acid for patient one and patient two, respectively. Our study along with previous ones supports the idea of a newly recognized cutaneous opportunistic pathogen and reinforces the recommendation of using gloves during soil exposure for immunocompromised patients. Lastly, according to data found in the literature, we would recommend trimethoprim-sulfamethoxazole as an efficient empirical antibiotic therapy in case of cutaneous infection caused by N. takedensis.\n\nissue-copyright-statement© The Author(s) 2020\n==== Body\nNocardia takedensis was first isolated from soil in 2005 [1]. The first isolation in human was reported in 2006 in Japan [2]. Since then, five cases of cutaneous Nocardiosis caused by N. takedensis have been described during a seven-year period (2010–2017): one in the US [3], one in Mexico [4], two in Asia [5, 6] and one in France [7] (Table 1). We report two cases of lymphangitis caused by N. takedensis both occurring after skin injury while gardening. The patients were both immunocompromised and living in Southeast France. We discuss the source of contamination, the global dissemination of this Nocardia species, and the measures to prevent infection.Table 1 Main features of reported cases of human infections caused by N. takedensis\n\nAuthors\tSex/age (years)\tUnderlying conditions(s)\tImmunosuppression (risk factors)\tType of infection\tTreatment\tInoculation\tGeographical origin of the strain\tMethods of identification\tEvolution\t\nWatanabe et al. [2]\tM/75\tT-lymphoma\tYes (T-lymphoma)\tNA\tNA\tNA\tJapan\tSequencing 16S rRNA gene\tNA\t\nBetran et al. [13]\tF/41\tDiabetes\n\nEosinophilic granuloma\n\n\tYes (corticosteroid, diabetes)\tLung colonization\tNA\tNA\tSpain\tSequencing 16S rRNA gene\tNA\t\nTan et al. [5]\tF/68\tDiabetes\n\nChronic kidney disease\n\n\tYes (diabetes, chronic kidney disease)\tFoot cellulitis\tTrimethoprim-Sulfamethoxazole\tUnknown\tTaiwan\tSequencing 16S rRNA gene\tRecovery\t\nKresch-Tronik et al. [4]\tM/33\tNA\tNA\tThoracic mycetoma\tTrimethoprim-Sulfamethoxazole (800/160 mg/b.i.d) and Dapsone (100 mg/day)—14 months\tLocal traumatic injury\tMexico\tSequencing 16S rRNA gene\tRecovery\t\nChung et al. [3]\tF/68\tFollicular lymphoma\n\nMyelodysplastic syndrome\n\n\tYes (corticosteroid, immunosuppressive treatment with sirolimus)\tLymphangitis of the left forearm\tCefuroxime (500 mg/b.i.d)—7 days\n\nAmoxicillin-clavulanate (875 mg/b.i.d)—14 days\n\nTrimethoprim-Sulfamethoxazole (800/160 mg/b.i.d)—7 days\n\n\tAbrasion on the left dorsal hand\tUSA\tSequencing 16S rRNA gene\tRecovery\t\nCoussement et al. [15]\tNA\tSolid organ transplant\tYes (solid organ transplant)\tNA\tNA\tNA\tFrance\tSequencing 16S rRNA and hsp65 genes\tNA\t\nGeun Lee et al. [6]\tF/87\tArterial hypertension\tNo\tErythematous and swollen plaque on her left forearm\n\nPustules, abscesses, ulcers\n\n\tTrimethoprim-Sulfamethoxazole (400/80 mg/b.i.d)—40 days\tAbrasion on the left forearm\tKorea\tSequencing 16S rRNA gene\tRecovery\t\nBenzaquen et al. [7]\tM/76\tMarginal zone lymphoma\n\nDiabetes\n\nArterial hypertension\n\n\tYes (corticosteroid, immunosuppressive treatment with chloraminophene and rituximab, diabetes)\tChronic ulcerative suppurative and painful nodules on the right forearm\tRifampicin (600 mg/day)—3 months\n\nClarithromycin (500 mg/b.i.d)—6 months\n\nEthambutol (800 mg/day)—6 months\n\n\tSkin trauma\tFrance\tSequencing 16S rRNA gene\tRecovery\t\nLebeaux et al. [14]\tNA\tNA\tNA\tNA\tNA\tNA\tFrance\tSequencing 16S rRNA gene\tNA\t\nPatient 1, 2012 (our study)\tM/49\tMyeloma\tYes (corticosteroid, immunosuppressive treatment with tacrolimus and lenalidomid)\tSkin abscess and ulcerated nodular lymphangitis on the left forearm\tTrimethoprim-Sulfamethoxazole—1 month\tSkin trauma when gardening\tFrance\tSequencing 16S rRNA gene\tRecovery\t\nPatient 2, 2017 (our study)\tM/82\tMyasthenia\n\nDiabetes\n\nChronic kidney disease\n\nArterial hypertension\n\n\tYes (corticosteroid, immunosuppressive treatment with azathioprin, diabetes, chronic kidney disease)\tSkin abscess and nodular lymphangitis on the right forearm\tAmoxicillin-clavulanic acid (1 g/t.id)—6 days\tHand skin wound when gardening\tFrance\tSequencing 16S rRNA gene\tRecovery\t\nNA not available\n\n\n\nStudy\nOur study was performed in Nice Teaching Hospital, in Southeast France, during 1999–2019. A total of 50 isolates of Nocardia species were collected from 36 patients. The major types of infections were cutaneous infections (58%), pulmonary infections (33%) and bacteremia (9%). During the study period, all the isolates were identified to the species level using 16S rDNA gene sequencing as previously described [8].\n\nFor the two N. takedensis strains isolated from patient 1 and patient 2, blast analysis of the 1435 nucleotides amplicon both showed 99.6% identity to the 16S rDNA sequence of N. takedensis CIP108681T. Phylogenetic positions of the two clinical strains within the genus Nocardia are shown in Fig. 1. The tree was obtained by neighbor-joining method using MEGA X software as previously described [9]. The two isolates and N. takedensis CIP108681T were compared using a random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR) with a coliphage M13 single stranded primer (5′-GAGGGTGGCGGCTCT-3). M13-PCR has been previously described by Guinebretière et al. for molecular typing of Bacillus cereus [10]. In the present work, this method was used to obtain and compare the RAPD-PCR profiles of N. takedensis isolates. Antibiotic susceptibility testing was performed using E-Test strips (bioMérieux) and CLSI interpretative standards for Nocardia spp.[11]. The two strains were sent to a French reference laboratory dedicated to Nocardia (French Observatory for Nocardiosis) to confirm AST results.Fig. 1 Phylogenetic tree based on the 16S rDNA sequence of Nocardia strains isolated from patients 1 and 2. Phylogenetic positions of the Nocardia strains isolated from patient 1 and patient 2 within the genus Nocardia based on the 16S rDNA sequences. The tree was obtained by Neighbor-joining method using MEGA X software [9]. Scale bar (= 0.01) indicates accumulated changes per nucleotide. The numbers next to the branches are the percentages determined in bootstrap analysis greater than 70% (1,000 replicates). The number in parentheses are the accession numbers of species in GenBank. T type strain,*species not yet validly published\n\n\n\nThe first N. takedensis strain was isolated on November 19, 2012, from a 49 years-old male (patient 1) followed for a myeloma diagnosed in 2005. The patient had received allogeneic hematopoietic cell transplantation in 2008. In November 2012, he pricked his finger with a rose thorn while gardening at home without gloves in Fréjus (65 km from Nice). The patient attended the dermatology ward two weeks later, as a painful lesion had developed and spread from his hand to his left forearm. Physical examination by a dermatologist showed three inflammatory and painful ulcers distributed in a linear fashion, which suggested an ulcerated nodular lymphangitis with no regional adenopathy (Fig. 2). The body temperature was normal. The patient had an immunosuppressive therapy due to chronic GVHD (Graft-versus-host Disease) including prednisone 20 mg/day and tacrolimus, and for relapse of myeloma he received lenalidomid 15 mg/day and dexamethasone 40 mg/week. A bacterial (pyogenic bacteria, atypical mycobacteria, Nocardia) or fungal infection was suspected. Whole-body computed tomography (CT) scan was performed and a systemic invasive infection was ruled out. Biopsy samples of the lesions were sent for analysis and a presumptive antibiotic treatment by levofloxacin was initiated. Microscopic histological examination showed specific infection markers. Both Gram and Ziehl–Neelsen staining were negative. Chlorazol black fungal staining did not retrieve any mycelial filament. After 72 h, cultures on blood agar plates at 35 °C under 5% CO2 remained negative. The antibiotic treatment by levofloxacin was stopped after 3 days because of suspicion of Quinolone-induced Achilles tendinopathy. The dermatologist then switched the treatment to trimethoprim-sulfamethoxazole as he suspected a cutaneous Nocardiosis based on the first microbiological results (negativity of standard cultures after 72 h). Coletsos medium (Bio-Rad™, Marnes-la-Coquette, France) seeded for detection of atypical mycobacteria, grew N. takedensis under aerobic conditions at 30 °C in 4 days. The patient showed a rapid reduction of pain and cutaneous lesions within a week after the introduction of cotrimoxazole. He was considered cured after 1 month of treatment. Clinical and paraclinical long-term follow-up (every 2 weeks for multiple myeloma) excluded a late relapse of the nocardial infection.Fig. 2 Ulcerated nodular lymphangitis of the left arm and forearm of patient 1. a Painful linear ulcerated nodules of the left arm and forearm (arrowhead) (on the first day of antibiotic treatment). b Healed lesions three weeks later\n\n\n\nThe second N. takedensis strain was isolated on November 24, 2017, from an 82-years-old immunocompromised male patient (patient 2) treated with prednisone 15 mg/day and azathioprine 150 mg/day for myasthenia since 2016. He was hospitalized in November 2017 to manage an acute ocular myasthenia with altered general conditions. Physical examination revealed a painless and non-itchy cutaneous abscess measuring 6 mm in diameter on the palmar face of his right hand with serous and hematic fluid, as well as a nodular lymphangitis on his right forearm. The body temperature was normal. A thorough interview of the patient revealed that this lesion had developed a few days before his admission, following a minimal hand skin wound when gardening at home without gloves in Menton (30 km from Nice). Laboratory investigations revealed an elevated C-reactive protein (CRP) at 55 mg/L. Whole-body CT scan excluded a systemic infection. Before starting the antibiotic treatment, a sterile swab was used to collect pus from the abscess. Gram staining did not show any microorganism. Swab cultures grew N. takedensis after 72 h of incubation both on blood agar plate (Oxoid, Dardilly, France) under aerobic atmosphere and on chocolate agar plate under 5% CO2. The patient was discharged with a prescription of amoxicillin-clavulanic acid 1 g t-i-d for 7 days. The wound completely healed 10 days after the beginning of this treatment. Long term hospital follow-up of this myasthenic patient (every two months) excluded a late relapse of the cutaneous Nocardiosis.\n\nBoth N. takedensis isolates displayed the same antimicrobial susceptibility pattern: susceptible to beta-lactams, trimethoprim-sulfamethoxazole, linezolid, amikacin, tobramycin and minocycline but resistant to ciprofloxacin and clarithromycin (Table 2). To date, data concerning N. takedensis susceptibility to antibiotics are scarce. Only 8 isolates have been tested (including our study) and were susceptible to trimethoprim-sulfamethoxazole in vitro and 100% of the patients treated by an antibiotic treatment including trimethoprim-sulfamethoxazole completely recovered [5, 6, 12, 13]. Therefore, we assume that this molecule could be used as an empirical antibiotic therapy in case of cutaneous Nocardiosis due to N. takedensis, before an AST is available.Table 2 Antimicrobial susceptibility testing determined using the E-test method\n\nAntimicrobial agent\tStrain patient 1\tStrain patient 2\t\nMIC (µg/ml)\tClinical categorizationa\tMIC (µg/ml)\tClinical categorizationa\t\nAmikacin\t0.38\tS\t1\tS\t\nAmoxicillin-clavulanic acid\t6\tS\t6\tS\t\nCeftriaxone\t1.5\tS\t0.25\tS\t\nCiprofloxacin\t32\tR\t2\tI\t\nClarithromycin\t3\tR\t4\tR\t\nImipenem\t0.25\tS\t0.125\tS\t\nLinezolid\t1.5\tS\t0.19\tS\t\nMinocycline\t1\tS\t0.125\tS\t\nTrimethoprim-sulfamethoxazole\t0.047\tS\t1\tS\t\nTobramycin\t0.75\tS\t3\tS\t\naInterpretations of MICs in terms of susceptibility for Nocardia according to the criteria of CLSI [11].\n\n\n\nThe M13-PCR typing revealed that the two patients were infected by 2 different strains and excluded a clonal transmission between the 2 patients or a same origin of the strains. The two strains isolated in Southeast France were also different from the type strain N. takedensis CIP108681T isolated in Japan (Fig. 3). N. takedensis was first characterized in 2005 by Yamamura et al. [1]. The two first reference strains of N. takedensis i.e. MS1-3t and AS4-2 were isolated in Japan respectively from a moat sediment and from sludge obtained from a sewage treatment plant. To date, only nine clinical isolates of N. takedensis have been reported in human [2–7, 13–15]. The main clinical and microbiological features of N. takedensis isolates are summarized in the Table 1. Including the two patients of our study, the mean patients’ age was 64 years (33–87 years), with a sex ratio of 1.25. N. takedensis is mostly involved in primary cutaneous Nocardiosis, just as the closely related species N. brasiliensis is [16, 17]. Indeed, seven out of eight infected patients (88%) presented various forms of skin and soft tissue infections such as cellulitis, chronic skin ulceration, lymphangitis, or mycetoma, that occurred several days after a skin lesion allowing bacterial inoculation [3–7, 15, our study]. In one patient N. takedensis was isolated from a respiratory specimen but without any clinical or radiological signs of pulmonary Nocardiosis, therefore corresponding to a transient pulmonary colonization [13]. For the last three clinical isolates reported in the literature, no clear and substantial data referring to the clinical cases were available [2, 14, 15].Fig. 3 Molecular typing using M13-PCR methods, as described by Guinebretière et al. [10]. Nocardia takedensis strains isolated from the two patients and Nocardia takedensis CIP108681T\n\n\n\nCollectively, these cases of primary cutaneous nocardiosis reported in US [3], Mexico [4], Asia [5, 6], and Europe [7, our study], during 2010–2017 support the idea of N. takedensis as a newly recognized pathogen involved in skin infections. An interesting hypothesis is that climatic and soil conditions could have play a role in the environmental spread of this bacterial species. Indeed, in most of the cases published in the literature, N. takedensis strains were isolated in geographical area with favorable climatic conditions (South–East France, Spain, Korea, Japon, Taiwan or Mexico) [2, 4–7, 13, our study]. Moreover, Brown-Elliott et al., have previously suggested that Nocardia brasiliensis, a species that is phylogenetically closely related to N. takedensis, is predominantly isolated in tropical or subtropical region [16]. Recently, Lebeaux et al., showed a higher density of Nocardia isolates in the South of France and overseas territories than in other French areas, suggesting that environmental conditions may also increase the spread of Nocardia sp [14]. To date, data found in the literature concerning the potential impact of the climatic conditions on soil and on N. takedensis spreading are scarce and further studies will be necessary to assess this challenging hypothesis.\n\nConcerning the source of contamination, it is likely possible that the two patients got infected by traumatic inoculation of N. takedensis present in the soil as both of them were gardening without gloves in the days preceding the onset of the symptoms. Furthermore, the two patients had received immunosuppressive drugs and corticosteroids which could have played a role in the infection. Immunosuppressive therapy or known risk factors of immunosuppression were found in all but one patient with N. takedensis infections (Table 1).\n\nConclusions\nWith the spread of 16S rDNA sequencing, new Nocardia species have been recently described and the genus Nocardia currently encompasses more than 50 species involved in human diseases [16–18]. Besides, the rising number of patients receiving immunosuppressive therapies increases the risk of Nocardial infection through environmental exposure. Our study emphasizes the idea of N. takedensis as a newly recognized opportunistic pathogen responsible for skin infections. Infections occur after an inoculation following a cutaneous lesion. As this bacterium is found in the environment especially in soil, physicians should recommend their immunocompromised patients to wear shoes as well as clothing covering the skin when they are working in the soil (https://www.cdc.gov/nocardiosis/prevention/index.html). More, we would strongly recommend to immunocompromised patients to wear gloves when manipulating soil. This recommendation could also be extended to non-immunocompromised patient as primary cutaneous Nocardiosis has been repeatedly reported in this population. Lastly, because of the slow growth of Nocardia sp., prolonged culture conditions are required when a cutaneous Nocardiosis is suspected.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nRomain Lotte and Alicia Chevalier contributed equally to this work\n\nAcknowledgements\nWe thank Carole Besancon, Coralie Blanc, Sandrine Courtial, Sabrina Esposito and Sylvain Carpentier and the entire technician’s team of the laboratory for their technical assistance. We also thank Emmanuelle Bergeron from the French Observatory of Nocardiosis.\n\nAuthors’ contributions\nRL: Wrote the manuscript and contributed to the acquisition of clinical and microbiological data. AC: Helped write the manuscript, drafted the manuscript and also contributed to collect the clinical and microbiological data. SD and VRN: Drafted the manuscript. Contributed to the acquisition of microbiological data. Performed control antimicrobial susceptibility tests on the strains at the French Observatory of Nocardiosis. ND and AG: Drafted the manuscript and performed antimicrobial susceptibility tests on the strains. PDG and PSR: Physicians in charge of patient one and patient two clinical follow-ups. Helped collect the clinical data. Drafted the manuscript. RR: Participated in the sequence alignment of the 16S sequences of the patient’s strain. Designed the study. Drafted the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThe authors received no financial support for this work.\n\nAvailability of data and materials\nAll datasets on which the conclusions of the manuscript rely are presented in the main paper and in the figures and tables.\n\nConsents to participate and ethic approval\nInformed consents to participate were obtained from the two patients that were reported in this article. Consents to publish were obtained from the two patients. For this retrospective observational study, ethics adherence was not required.\n\nCompeting interests\nThe authors declare that this work was not carried out in the presence of any personal, professional or financial relationships that could potentially be construed as a conflict of interest.\n==== Refs\nReferences\n1. Yamamura H Hayakawa M Nakagawa Y Tamura T Kohno T Komatsu F Nocardia takedensis sp. Nov., isolated from moat sediment and scumming activated sludge Int J Syst Evol Microbiol 2005 55 433 436 10.1099/ijs.0.63189-0 15653914 \n2. Watanabe K Shinagawa M Amishima M Iida S Yazawa K Kageyama A First clinical isolates of Nocardia carnea , Nocardia elegans , Nocardia paucivorans , Nocardia puris and Nocardia takedensis in Japan J Med Mycol 2006 47 85 89 10.3314/jjmm.47.85 \n3. Chung E Pulitzer MP Papadopoulos EB Papanicolaou GA Babady NE Marchetti MA Lymphangitic papules caused by Nocardia takedensis JAAD Case Rep 2015 1 126 128 10.1016/j.jdcr.2015.03.001 27051706 \n4. Kresch-Tronik NS Carrillo-Casas EM Arenas R Atoche C Del Río-Ávila C Ochoa-Carrera LA First case of mycetoma associated with Nocardia takedensis J Dermatol 2013 40 135 136 10.1111/1346-8138.12009 23083296 \n5. Tan C-K Lai C-C Lin S-H Liao C-H Chou C-H Hsu H-L Clinical and microbiological characteristics of Nocardiosis including those caused by emerging Nocardia species in Taiwan, 1998–2008 Clin Microbiol Infect 2010 16 966 972 10.1111/j.1469-0691.2009.02950.x 19860823 \n6. Lee TG Jin WJ Jeong WS Moon SH Kwon TG Lee SK Primary cutaneous nocardiosis caused by Nocardia takedensis Ann Dermatol 2017 29 471 475 10.5021/ad.2017.29.4.471 28761296 \n7. Benzaquen M Belenotti P Lebowitz D Drancourt M Serratrice J Primary cutaneous nocardiosis caused by Nocardia takedensis with pulmonary dissemination in an immunosuppressed patient Australas J Dermatol 2017 58 e97 e100 10.1111/ajd.12468 27000389 \n8. Ruimy R Breittmayer V Elbaze P Lafay B Boussemart O Gauthier M Phylogenetic analysis and assessment of the genera Vibrio, Photobacterium, Aeromonas, and Plesiomonas deduced from small-subunit rRNA sequences Int J Syst Bacteriol 1994 44 416 426 10.1099/00207713-44-3-416 7520733 \n9. Kumar S Stecher G Li M Knyaz C Tamura K MEGA X: Molecular Evolutionary Genetics Analysis across computing platforms Mol Biol Evol. 2018 35 6 1547 1549 10.1093/molbev/msy096 29722887 \n10. Guinebretière M-H Nguyen-The C Sources of Bacillus cereus contamination in a pasteurized zucchini purée processing line, differentiated by two PCR-based methods FEMS Microbiol Ecol 2003 43 207 215 19719681 \n11. Clinical and Laboratory Standards Institute. Susceptibility testing of mycobacteria, nocardiae, and other aerobic Actinomycetes; approved standard. CLSI document M24-A2. 2nd ed. Wayne, PA; 2011.\n12. Larruskain J Idigoras P Marimón JM Pérez-Trallero E Antibiotic Susceptibility of 186 Nocardia sp. isolates to 20 antimicrobial agents Antimicrobial Agents Chemother. 2011 55 6 2995 2998 10.1128/AAC.01279-10 \n13. Betrán A Rezusta A Lezcano MA Villuendas MC Revillo MJ Boiron P First Spanish case of nocardiosis caused by Nocardia takedensis J Clin Microbiol 2009 47 1918 1919 10.1128/JCM.00090-09 19386840 \n14. Lebeaux D Bergeron E Berthet J Djadi-Prat J Mouniée D Boiron P Antibiotic susceptibility testing and species identification of Nocardia isolates: a retrospective analysis of data from a French expert laboratory, 2010–2015 Clin Microbiol Infect 2018 25 489 495 10.1016/j.cmi.2018.06.013 29933049 \n15. Coussement J Lebeaux D van Delden C Guillot H Freund R Marbus S Nocardia infection in solid organ transplant recipients: a multicenter European case-control study Clin Infect Dis 2016 63 338 345 10.1093/cid/ciw241 27090987 \n16. Brown-Elliott BA Brown JM Conville PS Wallace RJ Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy Clin Microbiol Rev. 2006 19 259 282 10.1128/CMR.19.2.259-282.2006 16614249 \n17. Conville PS Brown-Elliott BA Smith T Zelazny AM The complexities of Nocardia taxonomy and identification J Clin Microbiol 2017 26 56 \n18. Ruimy R Riegel P Carlotti A Boiron P Bernardin G Monteil H Nocardia pseudobrasiliensis sp. nov., a new species of Nocardia which groups bacterial strains previously identified as Nocardia brasiliensis and associated with invasive diseases Int J Syst Bacteriol. 1996 46 259 264 10.1099/00207713-46-1-259 8573505\n\n",
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"journal": "Annals of clinical microbiology and antimicrobials",
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"title": "Nocardia takedensis: a newly recognized pathogen responsible for skin and soft tissue infections.",
"title_normalized": "nocardia takedensis a newly recognized pathogen responsible for skin and soft tissue infections"
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"abstract": "Chronic histiocytic intervillositis (CHI) is an extremely rare pathological condition but is strongly associated with severe obstetric complications and has a high recurrence rate. The management of this condition has not yet been established. We describe herein the occurrence of CHI in the late second-third trimester in each of three consecutive pregnancies in a single patient with four previous consecutive early miscarriages. In this patient, each of the three complicated pregnancies was managed with one of the following, respectively: low-dose aspirin; heparin plus low-dose aspirin; and prednisolone plus low-dose aspirin. CHI was histologically confirmed in all three pregnancies, but the clinical results and pathology (e.g. extent of histiocytic infiltration) in each pregnancy clearly differed with treatment. Both combination treatments eventuated in a live birth. Immunosuppressive therapy seemed to produce better clinical results by restricting the extent of the affected areas. The elevated alkaline phosphatase associated with the CHI was assumed to have no clinical prognostic value.",
"affiliations": "Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.;Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.;Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.;Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.;Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.;Department of Pathology, Dokkyo Medical University, Koshigaya Hospital, Saitama, Japan.",
"authors": "Ozawa|Nobuaki|N|http://orcid.org/0000-0002-1748-1635;Yamaguchi|Koushi|K|;Shibata|Megumi|M|;Sugibayashi|Rika|R|;Yagi|Hiroya|H|;Sago|Haruhiko|H|;Matsuoka|Kentaro|K|",
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"doi": "10.1111/jog.13404",
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"issue": "43(9)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "anticoagulant; chronic histiocytic intervillositis; fibrin deposition; prednisolone; recurrent pregnancy loss",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D002824:Chorionic Villi; D005260:Female; D015614:Histiocytosis; D006801:Humans; D050498:Live Birth; D010922:Placenta Diseases; D011247:Pregnancy",
"nlm_unique_id": "9612761",
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"pages": "1504-1508",
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"pmid": "28691359",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Chronic histiocytic intervillositis in three consecutive pregnancies in a single patient: Differing clinical results and pathology according to treatment used.",
"title_normalized": "chronic histiocytic intervillositis in three consecutive pregnancies in a single patient differing clinical results and pathology according to treatment used"
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"abstract": "COVID-19 has surfaced as a multi-organ disease predominantly affecting the respiratory system. Detection of the viral RNA through reverse transcriptase-PCR (RT-PCR) from a nasopharyngeal or throat sample is the preferred method of diagnosis. Recent evidence has suggested that COVID-19 patients can shed the SARS-CoV-2 for several weeks. Herein, we report six cases of COVID-19 who had persistently positive SARS-CoV-2 on repeat RT-PCR testing reaching up to 9 weeks. The spectrum of cases described ranges from asymptomatic infection to severe COVID-19 pneumonia. A full understanding of the virus's transmission dynamics needs further research. Prolonged viral shedding currently has unclear implications on the management and isolation decisions-the role of the cycle threshold (Ct) value in guiding therapeutic decisions is yet to be clarified. More data on the relationship between Ct values and viral cultivation are needed, especially in patients with prolonged viral shedding, to understand the virus's viability and infectivity.",
"affiliations": "1Department of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.;2Department of Infectious Diseases, Communicable Disease Center, Hamad Medical Corporation, Doha, Qatar.;1Department of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.;1Department of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.;1Department of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.;1Department of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.;3Department of Virology, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.;2Department of Infectious Diseases, Communicable Disease Center, Hamad Medical Corporation, Doha, Qatar.;1Department of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar.",
"authors": "Alsaud|Arwa E|AE|;Nair|Arun Prabhakaran|AP|;Matarneh|Ahmad S|AS|;Sasi|Sreethish|S|;El Hassan|Rania|R|;Khan|Fahmi|F|;Coyle|Peter|P|;Abu Khattab|Mohamed|M|;Mohamed|Mouhand F H|MFH|",
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"fulltext": "\n==== Front\nAm J Trop Med Hyg\nAm J Trop Med Hyg\ntpmd\ntropmed\nThe American Journal of Tropical Medicine and Hygiene\n0002-9637\n1476-1645\nThe American Society of Tropical Medicine and Hygiene\n\n33626020\ntpmd200933\n10.4269/ajtmh.20-0933\nArticles\nCase Report: Prolonged Viral Shedding in Six COVID-19 Patients\nAlsaud Arwa E. 1\nNair Arun Prabhakaran 2\nMatarneh Ahmad S. 1*\nSasi Sreethish 1\nEl Hassan Rania 1\nKhan Fahmi 1\nCoyle Peter 3\nAbu Khattab Mohamed 2\nMohamed Mouhand F. H. 1\n1 Department of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar;\n2 Department of Infectious Diseases, Communicable Disease Center, Hamad Medical Corporation, Doha, Qatar;\n3 Department of Virology, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar\n* Address correspondence to Ahmad S. Matarneh, Internal Medicine Department, Hamad Medical Corporation, Al Nasser Street, P.O. Box 3050, Doha, Qatar. E-mail: amatarneh@hamad.qa\nDisclosure: We sought local IRB approval for the publication of this case series. All patients provided verbal consent for the publication of this case series.\n\nAuthors’ addresses: Arwa E. Alsaud, Ahmad S. Matarneh, Sreethish Sasi, Rania El Hassan, Fahmi Khan, and Mouhand F. H. Mohamed, Department of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar, E-mails: arwa.alsaud@gmail.com, amatarneh@hamad.qa, sreethishsasi@gmail.com, raniadoc71@hotmail.com, fkhan@hamad.qa, and dr.m.oraiby@hotmail.com. Arun Prabhakaran Nair and Mohamed Abu Khattab, Department of Infectious Diseases, Communicable Disease Center, Hamad Medical Corporation, Doha, Qatar, E-mails: anair9@hamad.qa and mabukhattab@hamad.qa. Peter Coyle, Department of Virology, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar, E-mail: pcoyle@hamad.qa.\n\n4 2021\n24 2 2021\n24 2 2021\n104 4 14721475\n01 8 2020\n15 2 2021\n© The American Society of Tropical Medicine and Hygiene\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ Open Access statement. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and reproduction in any medium for non-commercial purposes, provided the original author and source are credited, a link to the CC License is provided, and changes – if any – are indicated.\n\nABSTRACT\n\nCOVID-19 has surfaced as a multi-organ disease predominantly affecting the respiratory system. Detection of the viral RNA through reverse transcriptase–PCR (RT-PCR) from a nasopharyngeal or throat sample is the preferred method of diagnosis. Recent evidence has suggested that COVID-19 patients can shed the SARS-CoV-2 for several weeks. Herein, we report six cases of COVID-19 who had persistently positive SARS-CoV-2 on repeat RT-PCR testing reaching up to 9 weeks. The spectrum of cases described ranges from asymptomatic infection to severe COVID-19 pneumonia. A full understanding of the virus’s transmission dynamics needs further research. Prolonged viral shedding currently has unclear implications on the management and isolation decisions—the role of the cycle threshold (Ct) value in guiding therapeutic decisions is yet to be clarified. More data on the relationship between Ct values and viral cultivation are needed, especially in patients with prolonged viral shedding, to understand the virus’s viability and infectivity.\n\nNote: Supplemental table appears at www.ajtmh.org.\n==== Body\nINTRODUCTION\n\nAlthough SARS-CoV-2 infection most often presents as asymptomatic or as mild upper respiratory tract infection (URTI), almost 14% of patients develop severe disease requiring hospitalization, including 5% needing intensive care unit (ICU) admission.1 COVID-19 can result in serious injuries, including acute respiratory distress syndrome, sepsis, acute kidney, heart failure, and multi-organ failure. Older age and increasing comorbidities are risks for higher mortality.1,2 Currently, many diagnostic tests are available for COVID-19 with variable sensitivities.3 Nonetheless, viral RNA detection by reverse transcription–PCR remains the preferred method to establish the diagnosis. Serological detection of IgM and IgG antibodies against the virus using ELISA is also used for screening purposes and to identify past infection or immunity. However, its diagnostic value and accuracy are being evaluated.3\n\nRecent studies showed that patients could asymptomatically shed SARS-CoV-2 for weeks.4,5 Herein, we report six cases of COVID-19 who showed persistent positive SARS-CoV-2 on repeated RT-PCR nasopharyngeal swab testing for varying durations, reaching 9 weeks after the initial diagnosis.\n\nCASE PRESENTATION\n\nCase 1.\n\nThe first case is a 74-year-old man known to have asthma, diabetes mellitus (DM), hypertension (HTN), coronary artery disease (CAD), and dyslipidemia (Table 1). He was admitted to a quarantine facility because of an asymptomatic COVID-19 infection identified through screening (RT-PCR). The local guideline at the time warranted two negative PCR swabs before discharge. SARS-CoV-2 was repeatedly positive for 49 days. He showed clinical improvement and was discharged after negative results (Table 1).\n\nTable 1 Summary of baseline characteristics, clinical features, and laboratory test results, diagnoses, treatments, and outcomes of six cases with prolonged viral shedding\n\nCharacteristic\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tPatient 6\t\nDemographics\t\n Age (years)\t74\t19\t46\t53\t35\t65\t\n Gender (M: male)\tM\tM\tM\tM\tM\tM\t\n Comorbid conditions\tDM2, HTN, Coronary artery disease, and BA\tNone\tNone\tDM2, HTN, and end-stage renal disease\tPulmonary tuberculosis\tChronic myeloid leukemia on active immunosuppressive therapy\t\nPresenting symptoms, and clinical and radiological features on admission\t\n Symptoms\tNA\tFever and sore throat\tFever, cough, and SOB\tFever, diarrhea and abdominal pain\tFever, headache, and cough\tFever, cough, and SOB\t\n Symptoms’ duration before admission (days)\tNA\t2–3\t7\t4–5\t10\t5–6\t\n Oxygen saturation (%) on room air\t99\t99\t100\t96\t99\t97\t\n Chest X-ray\tNormal\tNormal\tBilateral consolidations\tBilateral patchy infiltrates\tLeft lung opacity/cavitary lesion\tBilateral lower lobes collapse with effusion\t\nLaboratory tests on admission\t\n White blood cell count (4–10 × 103/µL)\tNA\t9.7\t7.4\t6.3\t8.6\t3.8\t\n Hemoglobin (13–17 gm/dL)\tNA\t17.4\t11.7\t14.8\t11.3\t7.5\t\n Platelet count (150–400 × 103/µL)\tNA\t260\t181\t152\t511\t42\t\n Absolute neutrophil count (2–7 × 103/µL)\tNA\t7.32\t4.9\t4.5\t7\t0.4\t\n Lymphocyte count (1–3 × 103/µL)\tNA\t1.68\t2.2\t1.22\t1\t0.9\t\n C-reactive protein (0–5 mg/L)\tNA\tNA\t49.9\t30\t225\t74.6\t\n Lactate dehydrogenase (135–225 U/L)\tNA\tNA\t282\tNA\tNA\t201\t\n Ferritin (30–490 µg/L)\tNA\tNA\t664\tNA\t3,439\t286\t\n D-dimer (< 0.4 mcg/mL)\tNA\tNA\tNA\tNA\tNA\t3.41\t\n Creatinine (63.6–110.5 µmol/L)\tNA\t81\t86\t1,112\t61\t80\t\n Alanine aminotransferase (0–55 U/L)\tNA\t26.4\t32\t12.6\t42\t10\t\n Aspartate aminotransferase (5–34 U/L)\tNA\t22\t35\t24\t92\t17\t\nDiagnosis\t\n\tAsymptomatic\tUpper respiratory tract infection\tPneumonia\tPneumonia\tPneumonia\tPneumonia\t\nTreatment\t\n Hydroxychloroquine\tNo\tNo\tYes\tYes\tYes\tNo\t\n Antivirals\tNo\tNo\tYes\tYes\tYes\tYes\t\n Antibiotics\tNo\tNo\tYes\tYes\tYes\tYes\t\n Corticosteroid\tNo\tNo\tNo\tNo\tNo\tNo\t\n Tocilizumab\tNo\tNo\tNo\tNo\tNo\tYes\t\nOutcome\t\n Intensive care unit admission\tNo\tNo\tNo\tNo\tNo\tYes\t\n Invasive ventilation\tNo\tNo\tNo\tNo\tNo\tNo\t\n Noninvasive ventilation\tNo\tNo\tNo\tNo\tNo\tYes\t\n Supplemental oxygen\tNo\tNo\tNo\tYes\tNo\tYes\t\n Total symptoms’ duration (days)\tNA\t4\tNA\t15\t20\t35\t\n Time to radiologic recovery (days)\tNA\tNA\tNA\t14\t46\t47\t\nAST = aspartate aminotransferase; BA = bronchial asthma; DM 2 = diabetes mellites type II; HD = hemodialysis; HTN = hypertension; NA = not available; SOB = shortness of breath.\n\nCase 2.\n\nA healthy 19-year-old man presented with a short history of fever and sore throat. The examination was remarkable for low-grade fever and tachycardia, and laboratory investigations and chest X-ray were unremarkable. He was diagnosed as a case of COVID-19 mild URTI and did not require hospital admission but transited through quarantine. His PCR swab remained positive for 48 days.\n\nCase 3.\n\nA previously healthy 46-year-old man presented with a 7-day history of fever, dry cough, and mild dyspnea. On examination, he was febrile, mildly tachypneic, tachycardic, but maintained oxygen saturation on room air. His chest X-ray revealed consolidation involving the left mid and lower zones. SARS-CoV-2 PCR tested positive, and he was started on COVID-19 management for pneumonia following local protocols. The repeated PCR tests were persistently positive for 47 days. The patient was discharged home, asymptomatic after negative PCR.\n\nCase 4.\n\nA 53-year-old man, known to have HTN, DM, and end-stage renal disease (ESRD), presented with fever, abdominal pain, diarrhea, nausea, and vomiting. Physical examination revealed a tired-looking man with mild abdominal tenderness but was otherwise unremarkable. Abdominal computed tomography (CT) scan was performed to rule out causes of acute abdomen. It showed no abdominal pathology but numerous bilateral lungs’ basal patchy consolidations and ground-glass opacities. Subsequently, nasopharyngeal PCR confirmed COVID-19. He received the treatment guided by the local protocol, and he became symptom-free and was discharged home following negative swab PCR after 28 days. Eighteen days later, he again presented with fever, chest pain, and mild dyspnea. The chest X-ray showed bilateral lung infiltrates increasing compared with the previous Images. The initial test for COVID-19 was inconclusive; then, the repeat test was positive 2 days after the second hospital admission. He was restarted on the treatment protocol and continued to improve with an unremarkable hospital stay. The repeated test was negative after 1 week from the second presentation. The patient had 48 days elapsing from the first positive PCR result until the last positive sample.\n\nCase 5.\n\nA 35-year-old man presented with a 10-day history of fever, headache, and dry cough. Physical examination was unremarkable. His baseline blood investigation was remarkable for high inflammatory markers and mild transaminitis. Chest X-ray revealed left mid-zone consolidation with a cavitary lesion. He was found to be positive for SARS-CoV-2 from nasopharyngeal swab PCR. Given the cavitary lesion, tuberculosis (TB) was suspected, and sputum smear acid-fast bacilli confirmed the presence of mycobacterial infection. Thus, the patient was treated as a case of COVID-19 pneumonia and active pulmonary TB. TB culture showed Mycobacterium tuberculosis sensitive for first-line anti-TB drugs. He later developed a rise in liver enzymes suspected to be either secondary to TB drugs versus COVID-19–related hepatitis. Subsequently, he was shifted temporarily to second-line antituberculosis therapy until improvement in his liver enzymes. Re-swabbing was performed as per the protocol, and the patient tested persistently positive for a total of 62 days.\n\nCase 6.\n\nThis is a 65-year-old man known to have chronic myeloid leukemia (CML) on dasatinib. He presented with a short history of fever, productive cough, and dyspnea. The examination revealed low-grade fever, tachycardia, and bilateral rhonchi on chest examination. Chest X-ray showed bilateral lower lobe consolidation with effusion. SARS-CoV-2 PCR was positive, and he was subsequently diagnosed as a severe case of COVID-19 pneumonia and received antibiotics and antiviral drugs. His condition deteriorated further during his stay, requiring noninvasive ventilation and ICU admission for 7 days. He eventually improved and was stepped down to the general medical wards for post-ICU care. He continued to have positive PCR for 54 days from the initial positive test.\n\nDISCUSSION\n\nCoronaviruses have structural proteins, including envelope (E), nucleocapsid (N), and spike (S) proteins. Their replication and transcription are expressed from an open reading frame called ORF1ab, and RNA dependent on the RNA polymerase gene (RdRp). The ORF1ab, E, RdRp, N, and S genes are the targets used for the detection of SARS-CoV-2 by RT-PCR.6\n\nSARS-CoV-2 may be detected via an upper respiratory tract PCR sample a few days before symptom onset. Viral shedding persists for varying periods after symptoms’ onset, with a study reporting a median duration of 11 days.7 Newer evidence suggested the long-term shedding of SARS-CoV-2 in the urine and stool of infected patients even when their nasopharyngeal swabs were negative.8,9 Factors independently associated with prolonged respiratory viral shedding include fever (> 38.5°C), severe disease, old age (> 60), male gender, concomitant HTN, steroid use, invasive ventilation, ICU admission, and lack of antiviral drugs.7,10–13\n\nAlthough some investigators observed a longer duration of viral shedding in symptomatic patients,14 our patients ranged from having an asymptomatic infection (case 1) to severe COVID-19 pneumonia (case 6). All had prolonged viral shedding ranging between 6 and 9 weeks, as depicted by PCR (Figure 1). The periods reported in our series are an underrepresentation of the exact shedding window. The shedding likely exceeded these periods as we calculated only from the first positive test till the last positive test; this excludes shedding before diagnosis and between the last positive and first negative tests. Interestingly, cases 5 and 6 had the most extended shedding window, which may be attributed to their immunosuppressed status (active pulmonary tuberculosis and CML on active chemotherapy, respectively). Two recently reported leukemia and lymphoma cases shed the virus for 70 and 60 days, respectively.15,16 The mechanism by which immunosuppressed status affects SARS-CoV-2 shedding is not well elucidated.16 Nonetheless, derangement of T-cell immune function, which has a strong role in COVID-19 pathophysiology, is likely involved.17 Similarly, impaired immunity and the accompanying increased viral load might have delayed resolution in diabetic patients in cases 1 and 4.18\n\nFigure 1. Schematic presentation of SARS-CoV-2 PCR results. This figure appears in color at www.ajtmh.org.\n\nBullard et al.19 tried to describe the infectiousness through viral cultures and found that viable SARS-CoV-2 was cultured when the RT-PCR cycle threshold (Ct) value was < 24 and within less than 8 days from symptoms onset. Singanayagam et al.20 also found a strong correlation between the Ct value and viral load with a probability of retrieving viable virus, declining to 8% in samples with Ct > 35, and 6% 10 days after symptoms onset. In line with these findings, multiple Ct value cutoffs were used by different guidelines generating bodies to define the infectivity and guide isolation decisions, which has led to differences in reported COVID-19 prevalence. Nonetheless, RT-PCR positivity is a surrogate that does not necessarily indicate that an individual is infectious or is shedding live viruses. Moreover, the optimal Ct value cutoff is unknown. The CDC and the WHO do not recommend using a test-based strategy guided by the Ct value to ascertain infectivity, at least at this stage.21,22 At the time of this series, our local protocol initially mandated two negative PCR results, and it was revised later in the mid of our patient’s observation to a single negative test. The adopted Ct value cutoff was 33 to guide isolation discontinuation decisions in hospitalized patients. Time lines of the nasopharyngeal PCR Ct value in our cases showed that multiple gene loci fall under the infectious range (Supplemental Table 1). Median Ct values at 2 weeks and even above 6 weeks showed a CT value of less than 33, possibly suggesting high viral load. Most patients had persistent shedding despite symptoms’ resolution; this could imply a carrier state and prolonged infectivity possibly exceeding 6 weeks. To review the possibility of reinfection or relapse in case 4, we analyzed his Ct values chronologically and assessed his Ct values using different genes. When this patient was discharged at 28 days, he had two negative results with the Thermo Fisher kit showing a Ct value > 40 on all gene locus (N, Orf, and S). After 18 days, he presented to the hospital again with clinical and radiological worsening with a Ct value of 32 in Roche E-gene. It is not clear whether this represents a relapse with the same virus with prolonged viral shedding or reinfection with a new virus from the community.\n\nCONCLUSION\n\nIn this case series, we observe a persistent viral shedding in patients with immunosuppressive conditions such as DM, leukemia, tuberculosis, and severe COVID-19 pneumonia. SARS-CoV-2 prolonged shedding currently has unclear implications on the management and isolation decisions—the role of the Ct value in guiding infection control decisions is yet to be clarified. More data on the relationship between viral and Ct values are needed, especially in patients with prolonged viral shedding, to assess the virus’s viability and infectivity.\n\nSupplemental table\n\nSupplemental materials\n\nACKNOWLEDGMENTS\n\nWe thank Hamad Medical Corporation for supporting academic research and the medical staff involved in the care of COVID-19 patients. Publication charges for this article were waived due to the ongoing pandemic of COVID-19.\n==== Refs\nREFERENCES\n\n1. Wu Z McGoogan JM , 2020. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese center for disease control and prevention. J Am Med Assoc 323 : 1239–1242.\n2. Cascella M Rajnik M Cuomo A Dulebohn SC Di Napoli R , 2020. Features, Evaluation and Treatment Coronavirus (COVID-19). Napoli, Italy: StatPearls Publishing. Available at: http://www.ncbi.nlm.nih.gov/pubmed/32150360. Accessed December 18, 2020.\n3. Carter LJ 2020. Assay techniques and test development for COVID-19 diagnosis. ACS Cent Sci 6 : 591–605.32382657\n4. Li J Zhang L Liu B Song D , 2020. Case report: viral shedding for 60 days in a woman with COVID-19. Am J Trop Med Hyg 102 : 1210–1213.32342849\n5. Zapor M , 2020. Persistent detection and infectious potential of SARS-CoV-2 virus in clinical specimens from COVID-19 patients. Viruses 12 : 1384.\n6. Khailany RA Safdar M Ozaslan M , 2020. Genomic characterization of a novel SARS-CoV-2. Gene Rep 19 : 100682.32300673\n7. Li TZ 2020. Duration of SARS-CoV-2 RNA shedding and factors associated with prolonged viral shedding in patients with COVID-19. J Med Virol 93 : 506–512.32644223\n8. Baj A Azzi L Dalla Gasperina D Genoni A Tamborini A Gambarini C Carcano G Grossi P Sessa F , 2020. Pilot study: long-term shedding of SARS-CoV-2 in urine: a threat for dispersal in wastewater. Front Public Health 8 : 569209.33330316\n9. Morone G 2020. Incidence and persistence of viral shedding in COVID-19 post-acute patients with negativized pharyngeal swab: a systematic review. Front Med 7 : 562.\n10. Zheng S 2020. Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study. BMJ 369 : m1443.32317267\n11. Fang Z Zhang Y Hang C Ai J Li S Zhang W , 2020. Comparisons of viral shedding time of SARS-CoV-2 of different samples in ICU and non-ICU patients. J Infect 81 : 147–178.\n12. Xu K 2020. Factors associated with prolonged viral RNA shedding in patients with coronavirus disease 2019 (COVID-19). Clin Infect Dis 71 : 799–806.32271376\n13. Yan D Liu XY Zhu YN Huang L Dan BT Zhang GJ Gao YH , 2020. Factors associated with prolonged viral shedding and impact of lopinavir/ritonavir treatment in hospitalised non-critically ill patients with SARS-CoV-2 infection. Eur Respir J 56 : 2000799.32430428\n14. Noh JY Yoon JG Seong H Choi WS Sohn JW Cheong HJ Kim WJ Song JY , 2020. Asymptomatic infection and atypical manifestations of COVID-19: comparison of viral shedding duration. J Infect 81 : 816–846.\n15. Avanzato VA 2020. Case study: prolonged infectious SARS-CoV-2 shedding from an asymptomatic immunocompromised individual with cancer. Cell 183 : 1901–1912.e9.33248470\n16. Nakajima Y Ogai A Furukawa K Arai R Anan R Nakano Y Kurihara Y Shimizu H Misaki T Okabe N , 2020. Prolonged viral shedding of SARS-CoV-2 in an immunocompromised patient. J Infect Chemother 27 : 387–389.33328135\n17. Wise J , 2020. COVID-19: T cell response lasts for at least six months after infection, study shows. BMJ 371 : m4257.33139323\n18. Huang I Lim MA Pranata R , 2020. Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia – a systematic review, meta-analysis, and meta-regression: diabetes and COVID-19. Diabetes Metab Syndr Clin Res Rev 14 : 395–403.\n19. Bullard J 2020. Predicting infectious severe acute respiratory syndrome coronavirus 2 from diagnostic samples. Clin Infect Dis. 10.1093/cid/ciaa638.\n20. Singanayagam A Patel M Charlett A Bernal JL Saliba V Ellis J Ladhani S Zambon M Gopal R , 2020. Duration of infectiousness and correlation with RT-PCR cycle threshold values in cases of COVID-19, England, January to May 2020. Eurosurveillance 25 : 1.\n21. CDC, 2020. Interim Guidelines for Clinical Specimens for COVID-19. Available at: https://www.cdc.gov/coronavirus/2019-nCoV/lab/guidelines-clinical-specimens.html. Accessed December 19, 2020.\n22. WHO, 2020. Criteria for releasing COVID-19 patients from isolation. Available at: https://www.who.int/publications/i/item/criteria-for-releasing-covid-19-patients-from-isolation. Accessed December 19, 2020.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0002-9637",
"issue": null,
"journal": "The American journal of tropical medicine and hygiene",
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"pmid": "33626020",
"pubdate": "2021-02-24",
"publication_types": "D016428:Journal Article",
"references": "32091533;32300673;32663611;32445728;32334395;32271376;33330316;32317267;32442256;32644223;33248470;33328135;32209381;33139323;32430428;32342849;32382657;32984389;32794447;33287245",
"title": "Case Report: Prolonged Viral Shedding in Six COVID-19 Patients.",
"title_normalized": "case report prolonged viral shedding in six covid 19 patients"
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"abstract": "Pulmonary arterial hypertension (PAH) is a rare and progressive disorder. Current treatment in the pediatric population includes phosphodiesterase 5 inhibitors (PDE-5i), endothelin receptor antagonists (ERA), and both inhaled and intravenous prostacyclin pathway agonists. As of December 22, 2015 the first oral prostacyclin pathway agonist, selexipag (Uptravi®), was FDA approved in the US. In this case series, we discuss our single-center experience using selexipag in a pediatric population, composed of both patients with idiopathic PAH, and patients with congenital heart disease and PAH.",
"affiliations": "Department of Pediatric Cardiology, Mattel Children's Hospital UCLA, 200 UCLA Medical Plaza, Suite 224, Los Angeles, CA, 90095, USA.;Department of Pediatric Cardiology, Mattel Children's Hospital UCLA, 200 UCLA Medical Plaza, Suite 224, Los Angeles, CA, 90095, USA.;Department of Pediatric Cardiology, Mattel Children's Hospital UCLA, 200 UCLA Medical Plaza, Suite 224, Los Angeles, CA, 90095, USA.;Department of Pediatric Cardiology, Mattel Children's Hospital UCLA, 200 UCLA Medical Plaza, Suite 224, Los Angeles, CA, 90095, USA. jalejos@mednet.ucla.edu.",
"authors": "Gallotti|Roberto|R|;Drogalis-Kim|Diana E|DE|;Satou|Gary|G|;Alejos|Juan|J|",
"chemical_list": "D000081:Acetamides; D000959:Antihypertensive Agents; D011719:Pyrazines; C523468:selexipag; D011464:Epoprostenol; C427248:treprostinil",
"country": "United States",
"delete": false,
"doi": "10.1007/s00246-017-1677-7",
"fulltext": null,
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"issue": "38(7)",
"journal": "Pediatric cardiology",
"keywords": "Pediatrics; Pulmonary hypertension; Remodulin®; Selexipag; Treprostinil; Uptravi®",
"medline_ta": "Pediatr Cardiol",
"mesh_terms": "D000081:Acetamides; D000293:Adolescent; D000959:Antihypertensive Agents; D002648:Child; D011464:Epoprostenol; D005260:Female; D006330:Heart Defects, Congenital; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D011719:Pyrazines; D016896:Treatment Outcome; D000070857:Walk Test; D055815:Young Adult",
"nlm_unique_id": "8003849",
"other_id": null,
"pages": "1405-1409",
"pmc": null,
"pmid": "28702718",
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"title": "Single-Center Experience Using Selexipag in a Pediatric Population.",
"title_normalized": "single center experience using selexipag in a pediatric population"
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"abstract": "Patients with autism spectrum disorder and developmental delay or encephalopathy rarely demonstrate no or negligible hair and nail growth, suggesting a biotin-responsive clinical disorder.\n\n\n\nA ten-year-old girl presented with features of autism spectrum disorder, isolated headaches, and episodes of headaches and limb shaking. Her medical history revealed that her hair and nails did not grow. Administration of biotin restored her nail and hair growth and improved intellectual ability and school performance. Her episodes of headaches, single limb shaking, and loss of consciousness responded to administration of acetazolamide, and her school performance and social skills further improved.\n\n\n\nA de novo c.1091 C > T, p.T364M pathogenic variant was found in the ATP1A2 gene by whole-exome sequencing, but a genetic etiology in the biotin-responsive metabolic pathways was not identified.\n\n\n\nThe combination of biotin and acetazolamide treatment was successful in restoring normal mental function and school performance. Poor or no clinical nail and hair growth in any child with a developmental delay-autism spectrum disorder presentation should be considered as evidence for a biotin-responsive genetic disorder even when exome testing is negative.",
"affiliations": "Genetics Division, Joe DiMaggio Children's Hospital, and Charles E. Schmidt College of Medicine, Hollywood, Florida. Electronic address: pbenke@mhs.net.;Neurology Division, Nicklaus Children's Hospital, Miami, Florida.;GeneDx, Gaithersburg, Maryland.",
"authors": "Benke|Paul J|PJ|;Duchowny|Michael|M|;McKnight|Dianalee|D|",
"chemical_list": "D000927:Anticonvulsants; D014803:Vitamin B Complex; D001710:Biotin; C498531:ATP1A2 protein, human; D000254:Sodium-Potassium-Exchanging ATPase; D000086:Acetazolamide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.pediatrneurol.2017.10.013",
"fulltext": null,
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"issn_linking": "0887-8994",
"issue": "79()",
"journal": "Pediatric neurology",
"keywords": "ATP1A2 gene; Autism spectrum disorder; biotin; hemiplegic migraine",
"medline_ta": "Pediatr Neurol",
"mesh_terms": "D000086:Acetazolamide; D000927:Anticonvulsants; D000067877:Autism Spectrum Disorder; D001710:Biotin; D002648:Child; D005260:Female; D006201:Hair Diseases; D006801:Humans; D008881:Migraine Disorders; D009260:Nail Diseases; D000254:Sodium-Potassium-Exchanging ATPase; D014803:Vitamin B Complex",
"nlm_unique_id": "8508183",
"other_id": null,
"pages": "61-64",
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"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Biotin and Acetazolamide for Treatment of an Unusual Child With Autism Plus Lack of Nail and Hair Growth.",
"title_normalized": "biotin and acetazolamide for treatment of an unusual child with autism plus lack of nail and hair growth"
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2018SP010760",
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"abstract": "To describe the response to vagus nerve stimulator (VNS) in otherwise neurotypical children with medically intractable primary generalized epilepsy.\n\n\n\nRetrospective chart review of patients who underwent vagus nerve stimulator surgery between January 2011 and December 2015.\n\n\n\nEleven patients were identified. Median follow-up duration was 2.5 years (1.2-8.4 years). Prior to vagus nerve stimulator surgery, all patients had at least 1 seizure per week, and 7/11 (64%) had daily seizures. At 1-year follow-up after vagus nerve stimulator, 7/11 (64%) reported improved seizure frequency and 6/11 (55%) reported fewer than 1 seizure per month. Three patients (27%) reported complications related to vagus nerve stimulator surgery, and no patients required device removal.\n\n\n\nIn children with medically intractable primary generalized epilepsy, vagus nerve stimulator is well tolerated and appears to lead to improvement in seizure frequency. Improvement was not attributable to epilepsy classification, age at vagus nerve stimulator implantation, output current, duty cycle, or follow-up duration.",
"affiliations": "1 Division of Pediatric Neurology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.;1 Division of Pediatric Neurology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.;1 Division of Pediatric Neurology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.",
"authors": "Welch|William P|WP|;Sitwat|Bilal|B|;Sogawa|Yoshimi|Y|",
"chemical_list": null,
"country": "United States",
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"issue": "33(7)",
"journal": "Journal of child neurology",
"keywords": "intractable epilepsy; pediatric epilepsy; primary generalized epilepsy; vagus nerve stimulator",
"medline_ta": "J Child Neurol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D000069279:Drug Resistant Epilepsy; D004829:Epilepsy, Generalized; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D011183:Postoperative Complications; D012189:Retrospective Studies; D012640:Seizures; D016896:Treatment Outcome; D055536:Vagus Nerve Stimulation",
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "449-452",
"pmc": null,
"pmid": "29651891",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Use of Vagus Nerve Stimulator on Children With Primary Generalized Epilepsy.",
"title_normalized": "use of vagus nerve stimulator on children with primary generalized epilepsy"
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"companynumb": "US-BAUSCH-BL-2018-022854",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LORAZEPAM"
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... |
{
"abstract": "OBJECTIVE\nTo present the interim findings of the Epilepsy Birth Control Registry (EBCR) regarding the impact of various contraceptive methods on seizures, stratified by antiepileptic drug (AED) type.\n\n\nMETHODS\nThis is an observational study that reports interim findings on the first 750 subjects.\n\n\nRESULTS\nThere are significantly greater relative risks (RR) for both seizure increase and decrease with hormonal contraception (HC) than with non-hormonal contraception (NHC). The rates of HC experiences associated with seizure increase (21.0%) are greater than with NHC (3.9%) (RR=5.39 [95% CI=3.77-7.73, p<0.0001]). The rates of HC experiences associated with seizure decrease (10.3%) are greater than with NHC (5.6%) (RR=1.85 [95% CI=1.30-2.62, p=0.0006]). While differences can reflect biological effects or reporting bias, the finding of a greater RR for seizure increase with hormonal patch than with combined oral contraceptive, perhaps related to the delivery of substantially higher concentrations of hormones, and a greater RR for seizure decrease with depomedroxyprogesterone, known to reduce seizure frequency when used in dosages which produce amenorrhea, support biological effects. All AED categories showed significantly higher frequencies of reports of seizure increase when combined with HC than with NHC. RR for seizure increase with HC was higher with valproate than with any other AED category. There were no significant differences among AEDs for seizure decrease with HC at this juncture of the study. Overall, NEIAEDs had the most favorable profile with regard to reports of seizure increase and decrease when used with HC.\n\n\nCONCLUSIONS\nInterim EBCR findings suggest that contraception category and interactions between contraception category and AED category are predictive factors for changes in seizure frequency in WWE.",
"affiliations": "Harvard Medical School, Harvard Neuroendocrine Unit, Beth Israel Deaconess Medical Center, Boston, MA 02481, USA. Electronic address: aherzog@bidmc.harvard.edu.",
"authors": "Herzog|Andrew G|AG|",
"chemical_list": "D000927:Anticonvulsants; D003270:Contraceptive Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-1311",
"issue": "28()",
"journal": "Seizure",
"keywords": "Antiepileptic drugs; Contraception; Epilepsy; Hormones; Seizures",
"medline_ta": "Seizure",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D003267:Contraception; D003270:Contraceptive Agents; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004827:Epilepsy; D005260:Female; D006801:Humans; D008875:Middle Aged; D012042:Registries; D012640:Seizures; D055815:Young Adult",
"nlm_unique_id": "9306979",
"other_id": null,
"pages": "71-5",
"pmc": null,
"pmid": "25770029",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Differential impact of antiepileptic drugs on the effects of contraceptive methods on seizures: Interim findings of the epilepsy birth control registry.",
"title_normalized": "differential impact of antiepileptic drugs on the effects of contraceptive methods on seizures interim findings of the epilepsy birth control registry"
} | [
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"companynumb": "AE-JNJFOC-20151201846",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"actiondrug": "5",
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"activesubstancename": "DROSPIRENONE"
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"abstract": "Novel therapies have potential to improve outcomes in patients with acute myeloid leukemia (AML) harboring FLT3-ITD mutations that have high risk of relapse and poor survival following standard of care (SOC) cytarabine/anthracycline-based induction/consolidation chemotherapy. Quizartinib is a selective and highly potent FLT3 inhibitor that has shown strong single-agent activity in relapsed or refractory (R/R) AML. This phase 1, open-label, sequential group dose-escalation trial (NCT 01390337) is the first evaluating safety and tolerability of quizartinib in combination with SOC chemotherapy in newly diagnosed AML (ndAML). Nineteen patients unselected for FLT3 mutational status received one of three quizartinib dihydrochloride dose levels (DL): 60 mg/d for 7 days (DL1; n = 6), 60 mg/d for 14 days (DL2; n = 7), and 40 mg/d for 14 days (DL-1; n = 6); administered orally starting on day 4 of chemotherapy. Median age was 43.8 years. Ten patients completed induction and consolidation. Three patients experienced dose-limiting toxicities (DLTs): 2 at DL2 (1 pericardial effusion; 1 febrile neutropenia, decreased platelet count, and QT prolongation); 1 at DL-1 (pericarditis). Maximum tolerated dose (MTD) was identified as DL-1. Most common grade 3/4 adverse events were febrile neutropenia (47%), neutropenia (42%), thrombocytopenia (32%), and anemia (26%). There were no apparent additional toxicities with addition of quizartinib to chemotherapy although grade ≤1 QT prolongation was observed at MTD. Sixteen patients (84%) achieved a response; 14 (74%) composite complete response; 2 (11%) morphologic leukemia-free state. The phase 3 QuANTUM-First trial (NCT02668653) is further evaluating the effect of quizartinib plus SOC chemotherapy in ndAML FLT3-ITD mutated patients.",
"affiliations": "Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.;Division of Hematology and Medical Oncology, Mayo Clinic Florida, Jacksonville, Florida.;Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Independent consultant, San Diego, California.;Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York.",
"authors": "Altman|Jessica K|JK|0000-0003-1987-1896;Foran|James M|JM|;Pratz|Keith W|KW|0000-0002-1284-8266;Trone|Denise|D|;Cortes|Jorge E|JE|;Tallman|Martin S|MS|",
"chemical_list": "D052160:Benzothiazoles; D010671:Phenylurea Compounds; C544967:quizartinib",
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.24974",
"fulltext": "\n==== Front\nAm J HematolAm. J. Hematol10.1002/(ISSN)1096-8652AJHAmerican Journal of Hematology0361-86091096-8652John Wiley and Sons Inc. Hoboken 10.1002/ajh.24974AJH24974Research ArticleResearch ArticlesPhase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia ALTMAN et al.Altman Jessica K. http://orcid.org/0000-0003-1987-1896j-altman@northwestern.edu \n1\nForan James M. \n2\nPratz Keith W. http://orcid.org/0000-0002-1284-8266\n3\nTrone Denise \n4\nCortes Jorge E. \n5\nTallman Martin S. \n6\n\n1 \nRobert H. Lurie Comprehensive Cancer Center, Northwestern University\nChicago\nIllinois\n\n2 \nDivision of Hematology and Medical Oncology\nMayo Clinic Florida\nJacksonville\nFlorida\n\n3 \nOncology, Johns Hopkins University School of Medicine\nBaltimore\nMaryland\n\n4 \nIndependent consultant\nSan Diego\nCalifornia\n\n5 \nDepartment of Leukemia, Division of Cancer Medicine\nThe University of Texas MD Anderson Cancer Center\nHouston\nTexas\n\n6 \nLeukemia Service, Department of Medicine\nMemorial Sloan‐Kettering Cancer Center and Weill Cornell Medical College\nNew York\nNew York\n* Correspondence Jessica K. Altman, Division of Hematology‐Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 E Superior, Chicago, IL 60611. Email: j-altman@northwestern.edu04 12 2017 2 2018 93 2 10.1002/ajh.v93.2213 221 11 10 2017 09 11 2017 12 11 2017 © 2017 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nNovel therapies have potential to improve outcomes in patients with acute myeloid leukemia (AML) harboring FLT3‐ITD mutations that have high risk of relapse and poor survival following standard of care (SOC) cytarabine/anthracycline‐based induction/consolidation chemotherapy. Quizartinib is a selective and highly potent FLT3 inhibitor that has shown strong single‐agent activity in relapsed or refractory (R/R) AML. This phase 1, open‐label, sequential group dose‐escalation trial (NCT 01390337) is the first evaluating safety and tolerability of quizartinib in combination with SOC chemotherapy in newly diagnosed AML (ndAML). Nineteen patients unselected for FLT3 mutational status received one of three quizartinib dihydrochloride dose levels (DL): 60 mg/d for 7 days (DL1; n = 6), 60 mg/d for 14 days (DL2; n = 7), and 40 mg/d for 14 days (DL‐1; n = 6); administered orally starting on day 4 of chemotherapy. Median age was 43.8 years. Ten patients completed induction and consolidation. Three patients experienced dose‐limiting toxicities (DLTs): 2 at DL2 (1 pericardial effusion; 1 febrile neutropenia, decreased platelet count, and QT prolongation); 1 at DL‐1 (pericarditis). Maximum tolerated dose (MTD) was identified as DL‐1. Most common grade 3/4 adverse events were febrile neutropenia (47%), neutropenia (42%), thrombocytopenia (32%), and anemia (26%). There were no apparent additional toxicities with addition of quizartinib to chemotherapy although grade ≤1 QT prolongation was observed at MTD. Sixteen patients (84%) achieved a response; 14 (74%) composite complete response; 2 (11%) morphologic leukemia‐free state. The phase 3 QuANTUM‐First trial (NCT02668653) is further evaluating the effect of quizartinib plus SOC chemotherapy in ndAML FLT3‐ITD mutated patients.\n\nDaiichi‐Sankyo\n source-schema-version-number2.0component-idajh24974cover-dateFebruary 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.4 mode:remove_FC converted:20.06.2019\n\n\nAltman \nJK \n, \n\nForan \nJM \n, \n\nPratz \nKW \n, \n\nTrone \nD \n, \n\nCortes \nJE \n, \n\nTallman \nMS \n. Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia . Am J Hematol . 2018 ;93 :213 –221 . 10.1002/ajh.24974 \n29139135\n==== Body\n1 INTRODUCTION\nOne of the most common molecular alterations observed in patients with ndAML is internal tandem duplication (ITD) mutation of the FLT3 receptor, a driver mutation for disease progression that occurs in approximately 25% of cases.1, 2, 3, 4, 5, 6 FLT3‐ITD mutation identifies a high‐risk population of AML patients with an increased risk of early relapse, increased mortality following SOC chemotherapy, and a high need for improved treatment options.2, 7, 8, 9 Point mutations within the tyrosine kinase domain of FLT3 have been reported in approximately 7% of patients with AML but they have not been definitively linked to patient prognosis.9, 10\n\n\nEarly clinical studies evaluating FLT3 inhibitors such as sunitinib and lestaurtinib in patients with AML demonstrated positive results.11, 12, 13, 14 However, these agents were limited by poor target selectivity, suboptimal pharmacokinetic (PK)/pharmacodynamic (PD) properties, and off‐target effects. In phase 2 trials, treatment with the multikinase inhibitor midostaurin demonstrated transient single‐agent antileukemic activity in patients with ndAML or R/R AML.15, 16 In more recent phase 1/2 studies, midostaurin in combination with chemotherapy induced hematologic responses in patients with ndAML or R/R AML, albeit with increased rates of hematologic and other toxicities.17, 18, 19, 20 The phase 3 RATIFY study (NCT00651261) demonstrated significant overall survival benefit for midostaurin in combination with standard induction and consolidation chemotherapy in patients with FLT3‐mutated ndAML.21 Based on results of RATIFY, midostaurin was approved in combination with chemotherapy for treatment of adult patients with ndAML characterized by a FLT3 mutation.\n\nAn important limitation of first generation, less potent, FLT3 inhibitors is that while they are able to clear blasts from peripheral blood when used at their MTD, they often have little effect on bone marrow blasts.22 Quizartinib is the first member of a next‐generation class of FLT3 inhibitors that demonstrates more potent binding to FLT3, more selective inhibition of FLT3 kinase activity, and more potent growth inhibitory activity in AML cells harboring FLT3‐ITD mutation vs multikinase inhibitors including midostaurin and lestaurtinib.23, 24, 25 Importantly, quizartinib has demonstrated very high single agent activity in patients with FLT3‐ITD mutated AML, with reported composite complete remission rates between 46% and 57%, overall response rates between 65% and 78%, and high rates (35%‐42%) of successful bridging to allogeneic hematopoietic stem cell transplantation (allo‐HSCT).26, 27, 28, 29, 30, 31 Here, we report results of the first phase 1 study to evaluate safety and tolerability of quizartinib in combination with standard cytarabine/daunorubicin induction and high‐dose cytarabine (HiDAC) consolidation chemotherapy in patients with ndAML. The study was focused on safety and tolerability of quizartinib in combination with chemotherapy, and patients enrolled in the study were unselected for FLT3 mutation status. However, baseline assessment of FLT3 permitted analysis of responses by mutational status.\n\n2 METHODS\n2.1 Study design\nStudy 2689‐CL‐0005 (NCT01390337) was a 2‐part, phase 1, multicenter, open‐label, sequential group dose‐escalation trial of quizartinib administered in combination with standard induction/consolidation chemotherapy in patients with ndAML. The study protocol was approved by Institutional Review Board (IRB)/Independent Ethics Committee (IEC) at participating centers. In accordance with applicable laws and regulations, all patients signed informed consent forms prior to screening.\n\nPrimary objectives of the study were determination of DLTs, definition of MTD, definition of recommended phase 2/3 dose, evaluation of safety and tolerability of quizartinib when combined with cytarabine/daunorubicin induction administered in a 7 + 3 schedule and HiDAC consolidation therapy, and definition of DLTs and MTD of quizartinib given as maintenance following induction/consolidation chemotherapy. Secondary objectives were characterization of the PK of quizartinib and AC886 (the pharmacologically active metabolite of quizartinib) when quizartinib is given in combination with induction/consolidation therapy, and as maintenance monotherapy post consolidation in ndAML. Efficacy of quizartinib in combination with cytarabine/daunorubicin induction administered in a 7 + 3 schedule was examined as an exploratory objective.\n\n2.2 Part 1: Quizartinib dose escalation\nQuizartinib dose escalation was planned in successive cohorts of 5 or 6 patients (with minimum of 3 females in each cohort) to determine MTD in combination with cytarabine/daunorubicin‐based chemotherapy. A modified 3 + 3 design was used, allowing for concurrent enrollment of 2 to 6 patients into a cohort based on number of evaluable patients enrolled, number experiencing DLTs, and number at risk for developing a DLT. Intrapatient dose escalations were not permitted.\n\nQuizartinib dihydrochloride (hereafter referred to as quizartinib) was administered as an oral solution at least 1 hour before or 2 hours after a meal. The first dose level tested (DL1) was quizartinib 60 mg/d (equivalent to 53 mg quizartinib free base) administered on days 4 through 10 of induction therapy. The next dose tested was DL2, 60 mg/d administered on days 4 through 17 of induction. The third dose level tested was DL‐1, quizartinib 40 mg/d (equivalent to 35.4 mg quizartinib free base) administered on days 4 through 17 of induction. Dose‐escalation decisions were made by a dose‐escalation committee consisting of sponsor's medical monitor and the principal investigator at each institution, based on DLTs that occurred during remission induction. If ≤1 of 6, or 0 of 5 patients experienced a DLT on DL1, dose was escalated to DL2. If DL2 was not tolerated (≥1 of 6 patients experienced a DLT), dose was reduced to DL‐1. For consolidation, patients received the same quizartinib dose and schedule in consolidation that they received during induction.\n\nDuring induction therapy cytarabine was administered as a continuous infusion at a dose of 200 mg/m2/d on days 1 through 7, and daunorubicin was administered at a dose of 60 mg/m2/d by intravenous (IV) infusion or IV push over approximately 15 minutes on days 1 through 3. Up to 2 cycles of induction therapy were allowed. For consolidation therapy administration of cytarabine was planned at a dose of 3 g/m2/d IV over 3 hours every 12 hours on days 1, 3, and 5, with initiation of next cycle after blood count recovery but no earlier than 22 days after first dose of prior cycle. Patients could proceed directly to HSCT after achieving a response or continue to receive quizartinib as maintenance therapy after consolidation. For maintenance, patients received the same daily dose of quizartinib that they received during induction, administered daily in 28 day cycles for up to 12 cycles.\n\nQuizartinib dosing was interrupted for patients experiencing asymptomatic grade 3 QT‐interval prolongation (corrected according to Friderica's formula; QTcF) until QTcF was ≤30 ms above baseline (day 4 pre‐quizartinib dose) with dose reduction during next induction/consolidation treatment cycle (reductions to <40 mg and re‐escalation were not permitted). Patients discontinued quizartinib treatment if QTcF did not return to ≤30 ms above baseline within 7 days.\n\nDLTs were defined as occurrence of any of the following events during the observation period and considered to be at least possibly related to study drug: a) any grade ≥3 nonhematologic toxicity occurring after first dose of quizartinib and by day 42 of last induction treatment cycle or before start of the first consolidation cycle, whichever was sooner, b) hematologic toxicities occurring after first dose of quizartinib that did not resolve by day 42 of last induction treatment cycle or before start of the first consolidation cycle, whichever was sooner, including peripheral absolute neutrophil count (ANC) <500/mm3 (grade 4), non–transfusion‐related platelet count <20,000/mm3 due to documented bone marrow aplasia/hypoplasia (overall marrow cellularity <20%), platelet count <50,000/mm3 (grade ≥3) associated with bleeding, or platelet count <25,000/mm3 (grade 4) requiring blood transfusion, or c) any other study drug–related toxicity that occurred after first dose of quizartinib and caused cessation of study drug during remission induction or during maintenance. MTD was defined as highest dose of quizartinib associated with occurrence of a DLT in <33% of patients in a cohort. MTD was estimated to be dose level at which ≤1 of 6 or 0 of 5 patients experienced a DLT and one dose level below lowest dose level at which ≥ 2 out of 2 to 6 patients experienced a DLT.\n\n2.3 Part 2: MTD evaluation\nThe planned second part of the study consisted of evaluation of safety, efficacy, and PK of quizartinib administered at MTD determined in part 1 of the study in combination with induction remission or consolidation chemotherapy in expanded cohort of patients. MTD was defined as highest dose associated with occurrence of DLTs at the rate at which lower bound of 95% CI was <25% using the adjusted Wald method. An additional part of the study designed to be conducted in parallel to parts 1 and 2 consisted of evaluation of MTD for quizartinib when administered continuously in 28‐day cycles for up to 12 cycles as maintenance therapy in patients who achieved composite complete remission (CRc) following induction or ≥1 cycle of consolidation chemotherapy. Quizartinib was to be dose‐escalated in successive cohorts of 5 or 6 patients to determine maintenance MTD. The first dose level planned was quizartinib 60 mg, administered daily, and dose‐escalation decisions were to be made based on DLTs that occurred during first 2 cycles (8 weeks) of maintenance therapy. Once maintenance MTD was determined, all remaining patients coming out of parts 1 and 2 of the study were to be treated at this dose. However, the study was terminated before the start of part 2 and prior to evaluation of maintenance MTD due to end of the collaboration agreement between the trial sponsors Ambit Biosciences and Astellas Pharma Inc., and total study enrollment consisted of 19 patients in part 1.\n\n2.4 Eligibility\nPatients aged between 18 and 60 years with previously untreated ndAML as defined by the World Health Organization (WHO) criteria,32 documented within 28 days prior to enrollment, and Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 and meeting the following criteria were enrolled: adequate renal, hepatic, and coagulation parameters (alkaline phosphatase, aspartate aminotransferase [AST], and alanine aminotransferase [ALT] ≤2.5 × institutional upper limit of normal [ULN]; total bilirubin ≤1.5 × institutional ULN; serum creatinine ≤1.5 × institutional ULN or an estimated glomerular filtration rate (eGFR) of >50 mL/min as calculated by Modification of Diet in Renal Disease equation); use of a medically approved method of contraception; negative serum or urine pregnancy test (sensitivity ≤25 IU human chorionic gonadotropin [hCG]/L) within 72 hours prior to start of study drug administration in women of childbearing potential, ability to comply with study procedures and follow‐up examinations.\n\nExclusion criteria included: diagnosis of acute promyelocytic leukemia (APL), French‐American‐British (FAB) classification M3 or WHO classification of APL with t(15;17)(q22;q12), BCR‐ABL–positive chronic myelogenous leukemia in blast crisis, AML following an antecedent hematologic disorder (myelodysplasia or myeloproliferative neoplasm), acute bilineal/biphenotypic leukemia, or therapy‐related AML; previous therapy for AML, with the exception of emergency leukapheresis, emergency treatment for hyperleukocytosis with hydroxyurea for ≤5 days, growth factor or cytokine support, or steroids for treatment of hypersensitivity or transfusion reactions; previous treatment with quizartinib; uncontrolled disseminated intravascular coagulation; central nervous system (CNS) leukemia; known positive test for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen; major surgery within 4 weeks prior to first dose of study drug; uncontrolled or significant cardiovascular disease; pre‐existing disorder predisposing patient to a serious or life‐threatening infection; active acute fungal, bacterial, viral, or other infection; concurrent disease that placed patient at undue risk to undergo induction therapy per protocol or that might obscure assessments of drug safety; requirement for treatment with concomitant drugs that prolong QT/QTc interval or strong CYP3A4 inhibitors or inducers, with the exception of antibiotics, antifungals, and antivirals that are used as SOC to prevent or treat infections and other such drugs that are considered absolutely essential for care of the patient; and requirement for treatment with anticoagulant therapy.\n\nStandard FLT3 testing was conducted locally by investigators. FLT3 mutational status was confirmed for 12 patients by Navigate BioPharma (Carlsbad, CA) using PCR analysis. Results were not collected centrally and enrolled patients were unselected for FLT3 mutation status.\n\n2.5 Tolerability and safety assessments\nSafety assessments were performed at baseline and throughout the study. Primary safety variables included adverse events (AEs), DLTs, physical examinations, vital signs, electrocardiograms (ECGs), complete blood counts (CBCs), chemistry evaluations, coagulation (PT, PTT, INR) evaluations, and urinalyses. All AEs were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0.33 Routine laboratory assessments were collected and analyzed at local accredited laboratories within participating centers.\n\n2.6 Exploratory efficacy assessments\nBone marrow aspirates and/or biopsies were required for determination of AML disease response at each scheduled assessment (days 15 and 29 of induction cycles; day 21 of consolidation cycles). Bone marrow biopsies could be omitted at discretion of the investigator if aspirate was considered adequate. Use of a bone marrow evaluation performed prior to informed consent for diagnosis as baseline evaluation was permitted. Response was determined with consideration of hematology labs, bone marrow evaluation, transfusion status, and cytogenetics if appropriate and was based on adaptation of published criteria.34, 35 CRc rate was the primary efficacy variable. Assessment of minimal residual disease was not required.\n\n2.7 PK assessments\nPK analyses were performed for patients with at least 1 measurable study drug concentration and exact date and time of blood sample collection and study drug dosing. PK parameters included area under the curve (AUC), maximum concentration (C\nmax), trough concentration (C\ntrough), and time to peak concentration (T\nmax).\n\n2.8 Statistical analyses\nPlanned study enrollment was up to 52 patients, with up to 18 patients in part 1 and up to 34 patients in part 2, allowing for treatment of minimum 20 patients at the MTD. Demographic information was summarized using descriptive statistics. All data processing, summarization, and analyses were performed using SAS® Version 9.2.\n\nSafety analyses consisted of data summaries for AEs, DLTs, physical examinations, vital signs, ECGs, complete blood counts, chemistry evaluations, coagulation evaluations, and urinalyses and were conducted on all patients receiving at least 1 dose of any study drug. Treatment‐emergent AEs were coded to system organ class and preferred term using MedDRA terminology. Number and percent of patients experiencing 1 or more AE(s), relationship to study drug and severity of AEs were summarized by cohort. AEs leading to permanent discontinuation of study drug, and SAEs were summarized by NCI‐CTCAE grade and relationship to study drug. Changes in laboratory values, including hematology, urinalysis, serum chemistry, and coagulation (PT, PTT, INR), vital signs, and ECG parameters were summarized by cohort using descriptive statistics.\n\nEfficacy data analyses were conducted on all patients who received at least 1 dose of any study drug and had at least 1 postbaseline efficacy measurement. Response was assessed at each visit, and best overall response was assigned at end of study by the investigator. Response rate was estimated as number of responders divided by number of patients in the analysis population. Patients with unknown, missing, or no information on response at end of study were treated as nonresponders. Number and percent of patients were summarized by category. 95% CIs were produced for best overall response rate based on Fisher's exact method.\n\nPlasma concentrations and PK parameters were summarized by cohort using descriptive statistics, including number of patients, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. PK data for quizartinib and AC886 were summarized for cohorts with sufficient data available on day 4 or 10.\n\n3 RESULTS\n3.1 Patient demographics\nA total of 19 patients were enrolled between November 2011 and July 2013. A CONSORT diagram is included as Supporting Information Figure S1. Six patients were treated with quizartinib DL1, 7 with DL2, and 6 with DL‐1. Eighteen patients received treatment with quizartinib. One patient assigned to DL2 had a serious AE (SAE; cerebrovascular accident) on day 1 and was discontinued from study on day 3 before receiving any quizartinib. Patient baseline characteristics were generally similar between the dose levels (Table 1). Median age was 43 years. Sixteen patients (84%) had ECOG performance status of 0 or 1. Nine patients (47%) were positive for FLT3‐ITD mutation, defined as FLT3‐ITD/WT FLT3 allelic ratio ≥10% (3 at DL1, 4 at DL2, and 2 at DL‐1).\n\nTable 1 Baseline patient characteristics\n\n\t\n60 mg/7‐day (DL1)\n\nN = 6\t\n60 mg/14‐day (DL2)\n\nN = 7a\n\t\n40 mg/14‐day (DL‐1)\n\nN = 6\t\nTOTAL N = 19 n (%)\t\nAge, median (min, max)\t48.5 (25, 59)\t43.0 (24, 59)\t36.0 (22, 60)\t43.0 (22, 60)\t\nSex\t\t\t\t\t\nMale\t3\t3\t2\t8 (42)\t\nFemale\t3\t4\t4\t11 (58)\t\nMedian time since diagnosis, days (min, max)\t6.5 (1, 19)\t4.0 (3, 7)\t5.0 (2, 11)\t5.0 (1, 19)\t\nECOG performance status\t\t\t\t\t\n0\t2\t1\t3\t6 (32)\t\n1\t3\t4\t3\t10 (53)\t\n2\t1\t2\t0\t3 (16)\t\nCytogenetic riskb\n\t\t\t\t\t\nFavorable\t0\t0\t1\t1 (5)\t\nIntermediate\t2\t3\t0\t5 (26)\t\nUnfavorable\t1\t0\t0\t1 (5)\t\nUnknown\t3\t3\t5\t11 (58)\t\nNPM1 mutation\t\t\t\t\t\nYes\t0\t1\t0\t1 (5)\t\nNo\t6\t6\t6\t18 (95)\t\nCEBPA mutation\t\t\t\t\t\nYes\t0\t0\t0\t0\t\nNo\t6\t7\t6\t19 (100)\t\nFLT3‐ITD mutation\t\t\t\t\t\nYes\t3\t4\t2\t9 (47)\t\nNo\t3\t3\t4\t10 (53)\t\nAML‐MRC\t\t\t\t\t\nYes\t0\t1\t1\t2 (11)\t\nNo\t6\t6\t5\t17 (89)\t\nAML, acute myeloid leukemia; CEBPA, CCAAT/enhancer binding protein alpha; DL, dose level; ECOG, Eastern Cooperative Oncology Group; FLT3, feline McDonough sarcoma (Fms)‐like tyrosine kinase 3; ITD, internal tandem duplication; max, maximum; min, minimum; MRC, myelodysplastic‐related changes; NPM1, nucleophosmin 1.\n\na One patient enrolled in the DL2 cohort discontinued on day 3 before receiving quizartinib.\n\nb Cytogenetic risk was only collected locally. One patient in the DL2 cohort is not included.\n\n3.2 Treatment exposure and patient disposition\nTen patients (53%) completed treatment, defined as having completed consolidation therapy, having responded to treatment and proceeded to HSCT, or having continued to maintenance therapy (Supporting Information Figure). Two patients treated at DL2 ended treatment due to study drug–related AEs: 1 patient had grade 3 palmar‐plantar erythrodysesthesia syndrome on day 23 and 1 patient had grade 3 nausea and grade 3 pericarditis, both classified as SAEs, starting on day 7. One patient ended treatment due to fatal cardiac arrest not considered to be related to study drug on day 53. No patients had dose reductions of quizartinib. Median duration of quizartinib induction therapy was 14.0 days (7.0 days for DL1, 16.5 days for DL2, and 14.0 days for DL‐1). Six patients had a second cycle of induction chemotherapy plus quizartinib (2 at DL1, 3 at DL2, and 1 at DL‐1). Nine patients (47%) received consolidation therapy (3 at DL1, 2 at DL2, and 4 at DL‐1). Median duration of quizartinib consolidation therapy was 14.0 days (7.0 days for DL1, 20.5 days for DL2, and 14.0 days for DL‐1). Nine patients (47%) proceeded to HSCT. One patient (5%) treated at DL1 completed 3 cycles of consolidation therapy on day 121 and continued to maintenance therapy with quizartinib through day 497.\n\nDuration of cytarabine was generally similar across cohorts during induction and consolidation therapy. Patients in the DL‐1 cohort received cytarabine for an average of 6 days vs 9 days for the DL1 cohort and 10 days for the DL2 cohort. Patients in the DL2 cohort received slightly higher doses of cytarabine than those in DL1 and DL‐1 cohorts only during cycle 1 of consolidation therapy. One patient treated at DL‐1 had cytarabine dose interrupted due to oropharyngeal pain. Duration and doses of daunorubicin during induction therapy were generally similar across cohorts. No patients had dose reductions of daunorubicin during the study. One patient treated at DL‐1 had had interruption of daunorubicin and cytarabine due to oropharyngeal pain.\n\n3.3 Safety\nA total of 3 patients had reports of DLTs. No DLTs were observed at DL1, which led to dose escalation to DL2 cohort where DLTs were observed in 2 of 6 patients (1 patient with grade 4 pericardial effusion [not study drug related]; 1 patient with febrile neutropenia [possibly study drug related], platelet count decreased, and grade 3 QT prolongation). Therefore, dose was reduced to DL‐1 where only 1 patient had a DLT (grade 3 pericarditis). DL‐1 was identified as the MTD. The most common treatment‐emergent AEs (all grades) reported included nausea (79%), diarrhea (63%), constipation (58%), hypokalemia (53%), hypomagnesemia (53%), neutropenia (53%), febrile neutropenia (47%), and vomiting (47%) (Table 2).\n\nTable 2 Most common (≥20%) treatment‐emergent adverse events by dose cohort\n\nPreferred Term\t\n60 mg/7‐day\n\n(DL1)\n\nN = 6\n\nn (%)\t\n60 mg/14‐day\n\n(DL2)\n\nN = 7a\n\n\nn (%)\t\n40 mg/14‐day\n\n(DL‐1)\n\nN = 6\n\nn (%)\t\nTOTAL\n\nN = 19\n\nn (%)\t\nNausea\t5 (83)\t6 (86)\t4 (67)\t15 (79)\t\nDiarrhea\t3 (50)\t4 (57)\t5 (83)\t12 (63)\t\nConstipation\t3 (50)\t5 (71)\t3 (50)\t11 (58)\t\nHypokalemia\t4 (67)\t4 (57)\t2 (33)\t10 (53)\t\nHypomagnesemia\t3 (50)\t5 (71)\t2 (33)\t10 (53)\t\nNeutropenia\t5 (83)\t3 (43)\t2 (33)\t10 (53)\t\nFebrile neutropenia\t3 (50)\t3 (43)\t3 (50)\t9 (47)\t\nVomiting\t4 (67)\t3 (43)\t2 (33)\t9 (47)\t\nFatigue\t2 (33)\t3 (43)\t2 (33)\t7 (37)\t\nHeadache\t2 (33)\t3 (43)\t2 (33)\t7 (37)\t\nHypophosphatemia\t4 (67)\t3 (43)\t0\t7 (37)\t\nHypotension\t2 (33)\t2 (29)\t3 (50)\t7 (37)\t\nPyrexia\t3 (50)\t2 (29)\t2 (33)\t7 (37)\t\nRash\t2 (33)\t2 (29)\t3 (50)\t7 (37)\t\nAnemia\t3 (50)\t2 (29)\t1 (17)\t6 (32)\t\nAnxiety\t2 (33)\t3 (43)\t1 (17)\t6 (32)\t\nHemorrhoids\t2 (33)\t1 (14)\t3 (50)\t6 (32)\t\nHypocalcemia\t3 (50)\t1 (14)\t2 (33)\t6 (32)\t\nThrombocytopenia\t4 (67)\t1 (14)\t1 (17)\t6 (32)\t\nAbdominal pain\t2 (33)\t1 (14)\t2 (33)\t5 (26)\t\nDrug eruption\t1 (17)\t4 (57)\t0\t5 (26)\t\nDyspepsia\t2 (33)\t2 (29)\t1 (17)\t5 (26)\t\nDyspnea\t2 (33)\t3 (43)\t0\t5 (26)\t\nHypertension\t4 (67)\t1 (14)\t0\t5 (26)\t\nHypoalbuminemia\t1 (17)\t2 (29)\t1 (17)\t4 (21)\t\nMucosal inflammation\t2 (33)\t2 (29)\t0\t4 (21)\t\nEdema, peripheral\t2 (33)\t0\t2 (33)\t4 (21)\t\nDL, dose level.\n\na One patient enrolled in the DL2 cohort discontinued on day 3 before receiving quizartinib.\n\nA total of 11 cardiac AEs were reported in a total of 5 patients. Five cardiac events (45%) were considered related to study drug. Of these 5 drug‐related cardiac events, grade ≥3 events were in 2 patients (DLT of grade 3 pericarditis and grade 4 cardiac tamponade). No cardiac AEs were reported in patients undergoing consolidation therapy but ECG QT prolongation was reported in 1 patient treated at MTD.\n\nSeventy‐nine percent of patients experienced grade ≥3 AEs. The most common grade 3/4 AEs were predominantly hematologic, and included febrile neutropenia (47%), neutropenia (42%), thrombocytopenia (32%), anemia (26%), and leukopenia (16%) (Table 3). Median time to neutrophil recovery for patients with serious neutropenia was 42.5 days for DL1, 52.0 days for DL2, and 50.0 days for DL‐1. Median time to platelet recovery for patients with serious thrombocytopenia was 24.5 days for DL1, 19.0 days for DL2, and 17.0 days for DL‐1. Nonhematologic grade 3/4 AEs reported in ≥10% of patients included hypophosphatemia, nausea, esophagitis, decreased appetite, drug eruption, and hypotension. Twelve patients (63%) experienced a maximum change in QTcF interval >30 ms and two patients (11%) had change >60 ms, both treated at DL2. Nine patients (47%) had QTcF interval >450 ms. Two patients (11%) experienced grade 3 QTcF prolongation; both were treated at DL2 and symptoms resolved with dose interruption. There were no cases of grade 2/3 QTcF prolongation in patients treated at DL1 and DL‐1, and no cases of grade 4 QTcF prolongation reported at any dose tested.\n\nTable 3 Treatment‐emergent grade ≥3 adverse events (≥10%)\n\nPreferred Termb\n\tMaximum CTCAE Gradea\n\t\nTOTAL\n\nN = 19\n\nn (%)\t\n\nGrade 3\n\nn (%)\t\nGrade 4\n\nn (%)\t\nGrade 5\n\nn (%)\t\nOverall\t5 (26)\t9 (47)\t1 (5)c\n\t15 (79)\t\nFebrile neutropenia\t9 (47)\t0\t0\t9 (47)\t\nNeutropenia\t0\t8 (42)\t0\t8 (42)\t\nThrombocytopenia\t0\t6 (32)\t0\t6 (32)\t\nAnemia\t5 (26)\t0\t0\t5 (26)\t\nHypophosphatemia\t4 (21)\t0\t0\t4 (21)\t\nLeukopenia\t0\t3 (16)\t0\t3 (16)\t\nNausea\t2 (11)\t0\t0\t2 (11)\t\nEsophagitis\t2 (11)\t0\t0\t2 (11)\t\nDrug eruption\t2 (11)\t0\t0\t2 (11)\t\nDecreased appetite\t2 (11)\t0\t0\t2 (11)\t\nHypotension\t2 (11)\t0\t0\t2 (11)\t\nAE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; DL, dose level.\n\na CTCAE grades: 3 = severe; 4 = life‐threatening; 5 = death.\n\nb At the preferred term level, patients reporting more than 1 AE were counted only once using the highest severity.\n\nc One grade 5 treatment‐emergent AE was reported at DL2 (cardiac arrest). The AE was not considered to be related to study drug.\n\n3.4 Exploratory efficacy\nOverall, 16 patients (84%) achieved a response to therapy (Table 4). Fourteen patients (74%) achieved CRc (9 CR, 2 CRp, 3 CRi) and 2 patients (11%) were leukemia‐free based on morphologic criteria. No recurrences or treatment failures were reported while on study. Four of 6 patients (67%) treated at the MTD of DL‐1 had complete remissions. Five patients (26%) required a second induction cycle to achieve a response. Six of 9 patients with FLT3‐ITD–mutations (67%) achieved CRc and 2 (22%) achieved MLFS. Eight of 10 patients (80%) with no FLT3‐ITD–mutation achieved CRc.\n\nTable 4 Best overall response (intent‐to‐treat analysis set)\n\n\t\n60 mg/7‐day\n\n(DL1)\n\nN = 6\n\nn (%)\t\n60 mg/14‐day\n\n(DL2)\n\nN = 7a\n\n\nn (%)\t\n40 mg/14‐day\n\n(DL‐1)\n\nN = 6\n\nn (%)\t\nTOTAL\n\nN = 19\n\nn (%)\t\nBest Overall Response\t\nMorphologic leukemia‐free stateb\n\t1 (17)\t1 (14)\t0\t2 (11)\t\nCRcc\n\t5 (83)\t5 (71)\t4 (67)\t14 (74)\t\nCRd\n\t4 (67)\t3 (43)\t2 (33)\t9 (47)\t\nCRpe\n\t1 (17)\t0\t1 (17)\t2 (11)\t\nCRif\n\t0\t2 (29)\t1 (17)\t3 (16)\t\nTreatment failureg\n\t0\t0\t0\t0\t\nNo response\t0\t0\t1 (17)\t1 (5)\t\nNot evaluable\t0\t1 (14)\t1 (17)\t2 (11)\t\nRecurrenceh\n\t0\t0\t0\t0\t\nCR, complete remission; CRc, composite complete remission; CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; DL, dose level.\n\na One patient enrolled in the DL2 cohort discontinued on day 3 before receiving quizartinib.\n\nb Defined as <5% bone marrow blasts in an aspirate sample with marrow spicules and with a count of ≥200 nucleated cells, no blasts with Auer rods, and no persistence of extramedullary disease.\n\nc Defined as rates of CR + CRp + CRi.\n\nd Defined as morphologic leukemia‐free state and absolute neutrophil count ≥1000/mm3, platelet count ≥100,000/mm3, patient independent of transfusions.\n\ne Defined as CR except for platelet count <100,000/mm3.\n\nf Defined as CR except for absolute neutrophil count <1000/mm3 with or without platelet count <100,000/mm3. Transfusion independence not required.\n\ng Defined as failure to achieve a CR, CRp, or CRi.\n\nh Defined as relapse after CR, new dysplastic changes, reappearance or development of cytologically proven extramedullary disease, or reappearance of cytogenetic or molecular abnormality.\n\n3.5 Pharmacokinetics\nThe analyses of PK was limited by the small number of patients enrolled and the limited availability of PK samples. Results of the PK analyses are presented in the Supporting Information content.\n\n4 DISCUSSION\nQuizartinib is a novel FLT3 inhibitor with greater selectivity and potency compared to other broad‐acting multikinase inhibitors,23, 24, 36, 37, 38 and has demonstrated robust single‐agent activity in clinical studies in heavily pretreated patients with R/R AML.26, 28, 39, 40, 41 The importance of FLT3‐ITD mutation as a negative prognostic factor in patients with AML has led to the hypothesis that targeted inhibition of this receptor may improve therapeutic outcomes in these patients. Key goals of this study were to examine safety and tolerability of quizartinib in combination with standard 7 + 3 cytarabine/daunorubicin‐based induction and HiDAC consolidation chemotherapy in patients with ndAML and identification of an MTD for future clinical studies.\n\nBased on our findings, the DL‐1 dose and schedule (40 mg/d of quizartinib for 14 days) was tolerated in combination with intensive induction chemotherapy. DL1 was also tolerated; however, DL‐1 was selected for future studies based on it being associated with DLTs in ≤1 out of 6 patients as well as leading to a higher median total dose of quizartinib administered versus DL1. The selection of the 40 mg dose is supported by prior monotherapy/combination studies showing complete inhibition of FLT3 in plasma inhibitory activity assay, in peripheral blood and bone marrow,40, 42 and by pharmacodynamic assays showing complete inhibition of FLT3‐ITD signaling with daily 30 mg dosing.29 Toxicities associated with quizartinib plus chemotherapy induction were manageable. DLTs were pericardial effusion (grade 4), febrile neutropenia, decreased platelet count, QT prolongation (grade 3), and pericarditis (grade 3). As anticipated, the majority of AEs reported were hematologic. Importantly, no significant additional or unexpected toxicities were observed with the combination regimen. Prolongation of QTcF following administration of quizartinib in combination with or just after standard cytotoxic chemotherapy did not result in serious clinical manifestations. No grade 4 QTcF prolongation was reported and no grade 3 QTcF prolongation was reported at the dose of 40 mg/d for 14 days. Notably, rates of grade ≥2 QTcF prolongation observed in this trial with the combination regimen were consistent with low rates of QTcF prolongation observed in a phase 2b trial in patients with R/R AML treated with quizartinib monotherapy at 30 or 60 mg/d.39\n\n\nA key finding of the study was early evidence of antileukemic activity of quizartinib in combination with standard chemotherapy. Responses were observed in 84% of patients, with a notable CRc rate of 74%, and full hematologic/platelet recovery in 75% of responders. Two‐thirds of patients treated at MTD had a CRc. Additionally, no relapses were observed over the course of the study. Forty‐seven percent of patients enrolled on trial underwent HSCT. One patient who completed induction and consolidation therapy with the combination regimen proceeded to receive maintenance therapy with single‐agent quizartinib at 60 mg/d through day 497 and was still in CR at completion of 12 cycles of therapy.\n\nAn important limitation of this study is the small size of the patient population. Total study enrollment was limited to 19 patients because of early study termination. This resulted in more limited readouts on safety, PK, and preliminary efficacy. However, the study provided strong evidence that quizartinib can be safely administered in combination with SOC induction/consolidation chemotherapy. Additionally, we observed early evidence of activity and potential to elicit strong responses with this combination regimen. This work supports further clinical evaluation of this regimen in patients with ndAML.\n\nThe phase 3 RATIFY study demonstrated significantly improved OS in FLT3 mutated ndAML with standard induction/consolidation chemotherapy plus midostaurin vs placebo.21 However, it is unclear if the benefit of midostaurin in these patients is related to inhibition of FLT3 activity or other actions of the drug. Given that FLT3‐ITD is a driver mutation in AML,4 it is possible that an agent such as quizartinib that has greater potency and selectivity toward FLT3‐ITD may have a more pronounced effect on the clinical course of disease. The phase 3 QuANTUM‐First trial (NCT02668653) is currently evaluating quizartinib 40 mg vs placebo in combination with SOC induction/consolidation chemotherapy and as maintenance therapy in patients with FLT3‐ITD mutated ndAML. Patients enrolled in QuANTUM‐First are undergoing cardiac monitoring to gain a better understanding of effects of quizartinib on risk of QTc prolongation as well as overall cardiac effects in a larger patient population. Additionally, the phase 3 QuANTUM‐R trial (NCT02039726) compares quizartinib vs salvage chemotherapy in patients with FLT3‐ITD–mutated R/R AML. These studies will provide important information regarding clinical benefit of sustained inhibition of ITD‐mutated FLT3 AML with a selective and highly potent inhibitor of FLT3.\n\nSupporting information\nAdditional Supporting Information may be found online in the supporting information tab for this article.\n\n Supporting Information\n\nClick here for additional data file.\n\n Supporting Information\n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nThis study was designed and funded by the sponsor. Data were collected by the investigators and analyzed by biostatisticians employed by the sponsor. All authors participated in study conduct, data interpretation, writing, reviewing, and/or amending the manuscript. All authors completed a disclosure declaration. The following authors have indicated a financial or other interest that is relevant to the subject matter covered in this article: DT is a former employee of the study sponsor. MST and JEC have served as consultants or in an advisory role for the study sponsor. JKA has served in an advisory role for Novartis Pharmaceuticals, Astellas Pharma, Celgene, Syros Pharmaceuticals, and Janssen Pharmaceuticals. JEC and JMF have received honoraria, research funding, or other remuneration from the study sponsor. KWP reports no conflicts of interest. Authors do not own Daiichi Sankyo stock. Preliminary results of this study were previously presented at the American Society of Hematology annual meeting in 2013. Editorial assistance was provided by Roy Garcia, PhD, ETHOS Health Communications, Yardley, Pennsylvania, with financial assistance from Daiichi‐Sankyo, Edison, New Jersey, in compliance with international guidelines on Good Publication Practice.\n==== Refs\nREFERENCES\n1 \n\nKiyoi \nH \n, \n\nNaoe \nT \n, \n\nNakano \nY \n, et al. Prognostic implication of FLT3 and N‐RAS gene mutations in acute myeloid leukemia . Blood. \n1999 ;93 (9 ):3074 –3080 .\n10216104 \n2 \n\nKottaridis \nPD \n, \n\nGale \nRE \n, \n\nFrew \nME \n, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials . Blood. \n2001 ;98 (6 ):1752 –1759 .\n11535508 \n3 \n\nSchnittger \nS \n, \n\nSchoch \nC \n, \n\nDugas \nM \n, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease . Blood. \n2002 ;100 (1 ):59 –66 .\n12070009 \n4 \n\nTesta \nU \n, \n\nPelosi \nE. \n\nThe impact of FLT3 mutations on the development of acute myeloid leukemias . Leuk Res Treatment. \n2013 ;2013 :275760 \n10.1155/2013/275760 .\n23936658 \n5 \n\nThiede \nC \n, \n\nSteudel \nC \n, \n\nMohr \nB \n, et al. Analysis of FLT3‐activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis . Blood. \n2002 ;99 (12 ):4326 –4335 .\n12036858 \n6 \n\nWhitman \nSP \n, \n\nArcher \nKJ \n, \n\nFeng \nL \n, et al. Absence of the wild‐type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study . Cancer Res. \n2001 ;61 (19 ):7233 –7239 .\n11585760 \n7 \n\nBoissel \nN \n, \n\nCayuela \nJM \n, \n\nPreudhomme \nC \n, et al. Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy . Leukemia. \n2002 ;16 (9 ):1699 –1704 .\n12200684 \n8 \n\nFey \nMF \n, \n\nBuske \nC. \n\non behalf of ESMO Guidelines Working Group. Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow‐up . Ann Oncol. \n2013 ;24 (suppl 6 ):vi138 –vi143 .\n23970018 \n9 \nNatonal Comprehensive Cancer Network \n. NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 3.2017. Available online at: https://www.nccn.org. Accessed November 7, 2017 .\n\n10 \n\nLevis \nM. \n\nFLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? . Hematol Am Soc Hematol Educ Progr. \n2013 ;2013 :220 –226 .\n\n11 \n\nFiedler \nW \n, \n\nServe \nH \n, \n\nDöhner \nH \n, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease . Blood. \n2005 ;105 (3 ):986 –993 .\n15459012 \n12 \n\nKnapper \nS \n, \n\nBurnett \nAK \n, \n\nLittlewood \nT \n, et al. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first‐line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy . Blood. \n2006 ;108 (10 ):3262 –3270 .\n16857985 \n13 \n\nO'Farrell \nAM \n, \n\nForan \nJM \n, \n\nFiedler \nW \n, et al. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients . Clin Cancer Res. \n2003 ;9 (15 ):5465 –5476 .\n14654525 \n14 \n\nSmith \nBD \n, \n\nLevis \nM \n, \n\nBeran \nM \n, et al. Single‐agent CEP‐701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia . Blood. \n2004 ;103 (10 ):3669 –3676 .\n14726387 \n15 \n\nFischer \nT \n, \n\nStone \nRM \n, \n\nDeAngelo \nDJ \n, et al. Phase IIB trial of oral midostaurin (PKC412), the FMS‐like tyrosine kinase 3 receptor (FLT3) and multi‐targeted kinase inhibitor, in patients with acute myeloid leukemia and high‐risk myelodysplastic syndrome with either wild‐type or mutated FLT3\n . J Clin Oncol. \n2010 ;28 (28 ):4339 –4345 .\n20733134 \n16 \n\nStone \nRM \n, \n\nDeAngelo \nDJ \n, \n\nKlimek \nV \n, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small‐molecule FLT3 tyrosine kinase inhibitor, PKC412 . Blood. \n2005 ;105 (1 ):54 –60 .\n15345597 \n17 \n\nCooper \nBW \n, \n\nKindwall‐Keller \nTL \n, \n\nCraig \nMD \n, et al. A phase I study of midostaurin and azacitidine in relapsed and elderly AML patients . Clin Lymphoma Myeloma Leuk. \n2015 ;15 (7 ):428 –432.e2 .\n25776192 \n18 \n\nStone \nRM \n, \n\nFischer \nT \n, \n\nPaquette \nR \n, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia . Leukemia. \n2012 ;26 (9 ):2061 –2068 .\n22627678 \n19 \n\nStrati \nP \n, \n\nKantarjian \nH \n, \n\nRavandi \nF \n, et al. Phase I/II trial of the combination of midostaurin (PKC412) and 5‐azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome . Am J Hematol. \n2015 ;90 (4 ):276 –281 .\n25530214 \n20 \n\nWilliams \nCB \n, \n\nKambhampati \nS \n, \n\nFiskus \nW \n, et al. Preclinical and phase I results of decitabine in combination with midostaurin (PKC412) for newly diagnosed elderly or relapsed/refractory adult patients with acute myeloid leukemia . Pharmacotherapy. \n2013 ;33 (12 ):1341 –1352 .\n23798029 \n21 \n\nStone \nRM \n, \n\nMandrekar \nSJ \n, \n\nSanford \nBL \n, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation . N Engl J Med. \n2017 ;377 (5 ):454 –464 .\n28644114 \n22 \n\nPratz \nKW \n, \n\nLevis \nMJ. \n\nBench to bedside targeting of FLT3 in acute leukemia . Curr Drug Targets. \n2010 ;11 (7 ):781 –789 .\n20370649 \n23 \n\nChao \nQ \n, \n\nSprankle \nKG \n, \n\nGrotzfeld \nRM \n, et al. Identification of N‐(5‐tert‐butyl‐isoxazol‐3‐yl)‐N′‐{4‐[7‐(2‐morpholin‐4‐yl‐ethoxy)imidazo[2,1‐b][1,3]benzothiazol‐2‐yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS‐like tyrosine kinase‐3 (FLT3) inhibitor . J Med Chem. \n2009 ;52 (23 ):7808 –7816 .\n19754199 \n24 \n\nZarrinkar \nPP \n, \n\nGunawardane \nRN \n, \n\nCramer \nMD \n, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML) . Blood. \n2009 ;114 (14 ):2984 –2992 .\n19654408 \n25 \n\nZorn \nJA \n, \n\nWang \nQ \n, \n\nFujimura \nE \n, \n\nBarros \nT \n, \n\nKuriyan \nJ. \n\nCrystal structure of the FLT3 kinase domain bound to the inhibitor quizartinib (AC220) . PLoS One. \n2015 ;10 (4 ):e0121177 . doi:10.1371/journal.pone.0121177.\n25837374 \n26 \n\nCortes \nJE \n, \n\nPerl \nAE \n, \n\nDombret \nH \n, et al. Response rate and bridging to hematopoietic stem cell transplantation (HSCT) with quizartinib (AC220) in patients with FLT3‐ITD positive or negative relapsed/refractory AML after second‐line chemotherapy or previous bone marrow transplant . J Clin Oncol. \n2013 ;31 (suppl ):7012 .\n\n27 \n\nDöhner \nH \n, \n\nPerl \nA \n, \n\nRousselot \nP \n, et al. Efficacy and safety of quizartinib (AC220) in patients age ≥60 years with FLT3‐ITD–positive relapsed/refractory acute myeloid leukemia (AML) . Haematologica. \n2013 ;98 (suppl 1 ):233 .\n\n28 \n\nLevis \nM \n, \n\nMartinelli \nG \n, \n\nPerl \nAE \n, et al. The benefit of treatment with quizartinib and subsequent bridging to HSCT for FLT3‐ITD(+) patients with AML . J Clin Oncol. \n2014 ;32(5)(suppl) :7093 .\n\n29 \n\nLevis \nMJ \n, \n\nCortes \nJE \n, \n\nGammon \nGM \n, et al. Laboratory and clinical investigations to identify the optimal dosing strategy for quizartinib (AC220) monotherapy in FLT3‐ITD‐positive (+) relapsed/refractory (R/R) acute myeloid leukemia (AML) . Blood. \n2016 ;128 (22 ):4042 .\n\n30 \n\nRussel \nN \n, \n\nTallman \nMS \n, \n\nGoldberg \nS \n, et al. Quizartinib (AC220) in patients with FLT3‐ITD(+) relapsed or refractory acute myeloid leukemia: final results of a randomized phase 2 study . Haematologica. \n2014 ;99 (suppl 1 ):36 .\n\n31 \n\nSchiller \nGJ \n, \n\nTallman \nMS \n, \n\nGoldberg \nSL \n, et al. Final results of a randomized phase 2 study showing the clinical benefit of quizartinib (AC220) in patients with FLT3‐ITD positive relapsed or refractory acute myeloid leukemia . J Clin Oncol. \n2014 ;32(5)(suppl) :7100 .\n\n32 \n\nSwerdlow \nSH \n, \n\nCampo \nE \n, \n\nHarris \nNL \n, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues . 4th ed. \nLyon, France : IARC/WHO Press ; 2008 .\n\n33 \nNational Institutes of Health \n. Cancer Therapy Evaluation Program (CTEP): Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Available online at: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed November 7, 2017 .\n\n34 \n\nCheson \nBD \n, \n\nBennett \nJM \n, \n\nKopecky \nKJ \n, et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia . J Clin Oncol. \n2003 ;21 (24 ):4642 –4649 .\n14673054 \n35 \n\nSievers \nEL \n, \n\nLarson \nRA \n, \n\nStadtmauer \nEA \n, for Mylotarg Study Group \n, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33‐positive acute myeloid leukemia in first relapse . J Clin Oncol. \n2001 ;19 (13 ):3244 –3254 .\n11432892 \n36 \n\nGunawardane \nRN \n, \n\nNepomuceno \nRR \n, \n\nRooks \nAM \n, et al. Transient exposure to quizartinib mediates sustained inhibition of FLT3 signaling while specifically inducing apoptosis in FLT3‐activated leukemia cells . Mol Cancer Ther. \n2013 ;12 (4 ):438 –447 .\n23412931 \n37 \n\nLevis \nM. \n\nQuizartinib in acute myeloid leukemia . Clin Adv Hematol Oncol. \n2013 ;11 (9 ):586 –588 .\n24518522 \n38 \n\nWander \nSA \n, \n\nLevis \nMJ \n, \n\nFathi \nAT. \n\nThe evolving role of FLT3 inhibitors in acute myeloid leukemia: quizartinib and beyond . Ther Adv Hematol. \n2014 ;5 (3 ):65 –77 .\n24883179 \n39 \n\nCortes \nJ \n, \n\nTallman \nMS \n, \n\nSchiller \nG \n, et al. Results of a phase 2 randomized, open‐label, study of lower doses of quizartinib (AC220; ASP2689) in subjects with FLT3‐ITD positive relapsed or refractory acute myeloid leukemia (AML) . Blood. \n2013 ;122 (21 ):494 .\n\n40 \n\nCortes \nJE \n, \n\nKantarjian \nH \n, \n\nForan \nJM \n, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS‐like tyrosine kinase 3–internal tandem duplication status . J Clin Oncol. \n2013 ;31 (29 ):3681 –3687 .\n24002496 \n41 \n\nCortes \nJE \n, \n\nPerl \nAE \n, \n\nDombret \nH \n, et al. Final results of a phase 2 open‐label, monotherapy efficacy and safety study of quizartinib (AC220) in patients ≥ 60 years of age with FLT3 ITD positive or negative relapsed/refractory acute myeloid leukemia . Blood. \n2012 ;120 (21 ):48 .\n\n42 \n\nBurnett \nAK \n, \n\nBowen \nD \n, \n\nRussell \nN \n, et al. AC220 (quizartinib) can be safely combined with conventional chemotherapy in older patients with newly diagnosed acute myeloid leukaemia: experience from the AML18 pilot trial . Blood. \n2013 ;122 (21 ):622 .\n\n",
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"title": "Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia.",
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"abstract": "Nowadays mesalamine is a common treatment for Crohn's disease and hypersensitive reactions to this product have been reported. Yet there is limited information concerning mesalamine-induced myocarditis and its mechanism is not known. We described a case of mesalamine-induced myocarditis in Crohn's disease of the colon.",
"affiliations": "Cardiology Department, Tenon University and Medical School, Assistance Publique-Hôpitaux de Paris, 4, rue de la Chine, 75020 Paris, France.",
"authors": "Merceron|Olivier|O|;Bailly|Clement|C|;Khalil|Antoine|A|;Pontnau|Florence|F|;Hammoudi|Nadjib|N|;Dorent|Richard|R|;Michel|Pierre-Louis|PL|",
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"fulltext": "\n==== Front\nCardiol Res PractCardiol Res PractCRPCardiology Research and Practice2090-80162090-0597SAGE-Hindawi Access to Research 2087183010.4061/2010/930190Case ReportMesalamine-Induced Myocarditis Merceron Olivier \n1, 2\n\n*Bailly Clement \n1, 2\n\nKhalil Antoine \n2, 3\n\nPontnau Florence \n1, 2\n\nHammoudi Nadjib \n1, 2\n\nDorent Richard \n1, 2\n\nMichel Pierre-Louis \n1, 2\n\n1Cardiology Department, Tenon University and Medical School, Assistance Publique-Hôpitaux de Paris, 4, rue de la Chine, 75020 Paris, France2Pierre et Marie Curie University, Paris, France3Radiology Department, Tenon University and Medical School, Assistance Publique-Hôpitaux de Paris, 4, rue de la Chine, 75020 Paris, France*Olivier Merceron: olivier.merceron@tnn.aphp.frAcademic Editor: Hugo Katus\n\n2010 13 9 2010 2010 9301906 4 2010 15 8 2010 24 8 2010 Copyright © 2010 Olivier Merceron et al.2010This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Nowadays mesalamine is a common treatment for Crohn's disease and hypersensitive reactions to this product have been reported. Yet there is limited information concerning mesalamine-induced myocarditis and its mechanism is not known. We described a case of mesalamine-induced myocarditis in Crohn's disease of the colon.\n==== Body\n1. Introduction\nMesalamine is a well-known treatment for inflammatory bowel disease and drug reactions to this product are uncommon. Although rare, myocarditis attributed to mesalamine has been reported but the mechanism by which mesalamine might prompt myocardial inflammation is not clearly identify. We report a case of mesalamine-induced myocarditis in Crohn's disease of the colon.\n\n2. Case Report\nA 41-year-old female with Crohn's disease on chronic treatment with mesalamine for several years was admitted to our hospital with severe “anginal” chest pain. The Crohn's disease course was well controlled with no exacerbation for the past two years. The patient had no personal and familial history of cardiac abnormality or dysfunction, no hypertension or diabetes, no known allergies, and no other home medication. There was no reported infection in the last 6 months. Physical examination was normal and there was no sign of cardiac failure. The chest radiograph on admission was normal. Initial electrocardiogram showed sinus rhythm, a first-degree AV block, and flattened T-waves associated with increased Q-waves in the D3 lead. Laboratory tests revealed an elevated cardiac troponin I of 6,2 μg/L (peak concentration of cardiac troponin I of 8,35 μg/L), a Creatin kinase (CK) concentration of 258 U/L, a C-reactive protein (CRP) concentration of 8 mg/dL, and others blood tests within normal parameters (including leucocytes and eosinophils concentrations). An echocardiogram showed a mildly dilated left atrium and limited hypokinesis of the apical half of the left ventricle's inferior wall. The estimated ejection fraction was normal at 65%. Coronary angiography was performed demonstrating normal epicardial vessels. Cardiac magnetic resonance imaging (MRI) with delayed enhancement showed epicardial enhancement in the apical inferior wall and transmural enhancement in the interventricular septum (Figures 1(a) and 1(b)). There was no sign of myocardial infarction and thus, the patient was diagnosed with acute myocarditis.\n\nOn the patient's admission, mesalamine was discontinued and two days after this withdrawal, the chest pain was gone and cardiac troponin I (7,73 μg/L) and CK decreased to normal levels. As mesalamine has not first been considered as a potential agent, it was administered once more. The reintroduction of mesalamine induced a reapparition of the symptoms with an increased cardiac troponin I concentration (15,44 μg/L) (Figure 2). The symptoms resolved without any treatment following a final withdrawal of mesalamine. The patient has done well since discharge. No other cardiac MRI was performed.\n\n3. Discussion\nCardiac diseases can be associated with Crohn's disease as extraintestinal manifestation of the Inflammatory Bowel Disease or as a consequence of drug-induced side effects. Mesalamine-induced myocarditis is a rare but potentially serious occurrence and several cases were described in the literature [1–4], generally during the first weeks of treatment but on occasion, following treatment extending over years [5]. Yet, the exact mechanism by which mesalamine might prompt myocardial inflammation is not clearly identified. Rarely, mesalamine can induce hypersensitive reactions such as, hypersensitivity pneumonitis, angioedema, skin rashes, hypereosinophilia and thus, a mechanism of hypersensitivity to the drug rather than a direct cytotoxic effect is suspected [1–6]. The diagnosis of hypersensitivity myocarditis (HSM) is also suggested by the fact that, in all of the cases identified as being the result of mesalamine toxicity [1–3], there had been a clear improvement following the discontinuation of the drug. An eosinophilic infiltration of the myocardium on endomyocardial biopsy has been described by Stelts et al. [3] which seems to confirm the link between mesalamine and HSM. \n\nIn our case, the clinical and biological evolution was considered as atypical for a viral myocarditis and the diagnosis of HSM was first evoked on the late gadolinium enhancement in the interventricular septum. This MRI feature has previously been described in multisystem disorders with hypersensitivity reaction such as, sarcoidosis. Moreover, this is the first time in the literature that a case has been described with a provocation test, carried out by administering the potential etiologic agent once more; as in the reports reviewed [2, 5], the severe clinical status of the patients made this study hazardous. In our case, this test was carried out unintentionally but it makes the hypersensitive reaction responsible of mesalamine-induced myocarditis indisputable. For this reason, no myocardial biopsy has been taken and no viral serum antibody titers were made but also due to the lack of official recommendation and the difficulty of viral isolation. Different mechanisms could explain HSM but the exact one has not yet been identified. The most probable hypothesis seems to be an inhibition of cyclooxygenase-1 (COX1) by the drug, which may accelerate the metabolism of arachidonic acid toward lipoxygenase products such as, leukotrienes [6]. This overproduction of leukotriene metabolites may induce proinflammatory signaling, initiating the hypersensitive reaction by liberating eosinophil-stimulating cytokines, and will lead to the myocarditis. Further examination methods such as, immunohistochemical or molecular biological techniques have not been established so far. \n\nHowever, this report shows that the risk of mesalamine-induced myocarditis may be underestimated and that the possibility of cardiac involvement needs to be considered in patients with Inflammatory Bowel Disease on chronic treatment with mesalamine and chest pain. In those cases, the majority of patients recover in a few days after withdrawal of the causative agent.\n\nFigure 1 Cardiac MR shows on the late enhancement sequence, transmural enhancement of the basal interventricular septum ((a) short axis, (b) long axis).\n\nFigure 2 Course of systemic inflammation and troponin after mesalamine re-introduction in a patient with mesalamine induced myocarditis in Crohn's disease of the colon.\n==== Refs\n1 García-Ferrer L Estornell J Palanca V Myocarditis by mesalazine with cardiac magnetic resonance imaging European Heart Journal 2009 30 8 p. 1015 \n2 Doganay L Akinci B Pekel N Simsek I Akpinar H Mesalazine-induced myopericarditis in a patient with ulcerative colitis International Journal of Colorectal Disease 2006 21 2 199 200 15726390 \n3 Stelts S Taylor MH Nappi J Van Bakel AB Mesalamine-associated hypersensitivity myocarditis in ulcerative colitis Annals of Pharmacotherapy 2008 42 6 904 905 18430794 \n4 Kirstensen KS Høegholm A Bohr L Friis S Fatal myocarditis associated with mesalazine Lancet 1990 335 8689 p. 605 \n5 García-Morán S Sáez-Royuela F Pérez-Alvarez J-C Gento E Téllez J Myopericarditis and mitral insufficiency associated with ulcerative colitis treated with mesalazine Inflammatory Bowel Diseases 2006 12 4 334 335 16633055 \n6 Kounis GN Kouni SA Chiladakis JA Kounis NG Comment: mesalamine-associated hypersensitivity myocarditis in ulcerative colitis and the Kounis syndrome Annals of Pharmacotherapy 2009 43 2 393 394 19141654\n\n",
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"title": "Mesalamine-induced myocarditis.",
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"abstract": "The case of a 56-year-old man with a history of type 2 diabetes mellitus who presented to the emergency department in diabetic ketoacidosis (DKA) with only mild hyperglycemia is presented. The patient was taking empagliflozin (Jardiance®), a sodium-glucose cotransporter -2 inhibitor, which has now been recognized as causing this unusual presentation of DKA. Emergency physicians need to be aware of this complication, as the euglycemia/mild hyperglycemia and a history of type 2 diabetes mellitus can make the correct diagnosis of DKA a challenge.",
"affiliations": "Eastern Virginia Medical School, Department of Emergency Medicine, Norfolk, Virginia.;Eastern Virginia Medical School, Department of Emergency Medicine, Norfolk, Virginia.",
"authors": "Gammons|D Taylor|DT|;Counselman|Francis L|FL|",
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"doi": "10.5811/cpcem.2017.12.36213",
"fulltext": "\n==== Front\nClin Pract Cases Emerg MedClin Pract Cases Emerg MedClinical Practice and Cases in Emergency Medicine2474-252XUniversity of California Irvine, Department of Emergency Medicine publishing Western Journal of Emergency Medicine 10.5811/cpcem.2017.12.36213cpcem-02-47Case ReportSodium-glucose Cotransporter-2 Induced Diabetic Ketoacidosis with Minimal Hyperglycemia Gammons D. Taylor MD*Counselman Francis L. MD*†\n* Eastern Virginia Medical School, Department of Emergency Medicine, Norfolk, Virginia\n† Emergency Physicians of Tidewater, Norfolk, VirginiaAddress for Correspondence: Francis L. Counselman, MD, Eastern Virginia Medical School, Department of Emergency Medicine, 600 Gresham Drive, Room 304, Raleigh Building, Norfolk, VA 23507. Email: counsefl@evms.edu.2 2018 11 1 2018 2 1 47 50 25 8 2017 04 12 2017 04 12 2017 © 2018 Gammons et al2018This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/The case of a 56-year-old man with a history of type 2 diabetes mellitus who presented to the emergency department in diabetic ketoacidosis (DKA) with only mild hyperglycemia is presented. The patient was taking empagliflozin (Jardiance®), a sodium-glucose cotransporter -2 inhibitor, which has now been recognized as causing this unusual presentation of DKA. Emergency physicians need to be aware of this complication, as the euglycemia/mild hyperglycemia and a history of type 2 diabetes mellitus can make the correct diagnosis of DKA a challenge.\n==== Body\nINTRODUCTION\nWe present the case of a 56-year-old man with a history of type 2 diabetes mellitus who presented to the emergency department in diabetic ketoacidosis (DKA) with only a slightly elevated serum glucose. The patient was taking empagliflozin (Jardiance®), a sodium-glucose cotransporter-2 inhibitor. There are increasing reports of this unusual complication in patients taking this class of medication. Emergency physicians need to be aware of this complication, as the euglycemia and history of type 2 diabetes mellitus can make the correct diagnosis of DKA challenging.\n\nCASE PRESENTATION\nA 56-year-old man presented to the emergency department (ED) with a five-day history of left upper quadrant abdominal pain and low-grade fever. The patient described the pain as achy, constant and worse with eating. The patient denied nausea, vomiting or diarrhea. There was no history of trauma or similar symptoms in the past. The past medical history was significant for coronary artery disease (requiring two stents), type 2 diabetes mellitus, hypertension and hypertriglyceridemia. The patient stated he was compliant with his medications, including losartan-hydrochlorothiazide 100/12.5 mg, metoprolol 50 mg, glipizide XL 10 mg, empagliflozin (Jardiance®) 25 mg, sitagliptin-metformin 500/1000 mg, prasugrel 10 mg, rosuvastatin 10 mg, and aspirin 81mg. He denied smoking cigarettes, but admitted to several drinks at “happy hour.” He denied any alcohol use in the previous five days.\n\nThe vital signs were heart rate 97 beats per minute; respiratory rate 18 breaths per minute; blood pressure 196/96 mm Hg; temperature of 99.2 °F (37.3 °C); and 94% oxygen saturation on room air. The patient appeared in no distress. The head, eyes, ears, nose and throat exam was normal, as were the heart and lung exams. The abdomen was soft, with mild tenderness in the epigastrum and left upper quadrant, without guarding or rebound. The remainder of the physical exam, including the extremities and neurologic, were normal.\n\nThe emergency physician (EP) ordered an electrocardiogram (ECG), complete blood count (CBC), basic metabolic profile (BMP), lipase, urinalysis and troponin T. The CBC was normal, as was the lipase. The BMP was remarkable for a glucose of 142 mg/dL, sodium of 128 mmol/L, chloride of 87 mmol and a bicarbonate of 19 mmol/L. The blood urea nitrogen, creatinine and potassium were normal. The urinalysis was remarkable for 80 mg/dL of ketones and greater than 500 mg/dL of glucose. The ECG revealed only non-specific ST and T-wave changes in the lateral leads. The patient’s anion gap was markedly elevated at 21.7. After reviewing the laboratory results, the EP was concerned about the large anion gap metabolic acidosis. Additional studies ordered included a serum acetone, beta-hydroxybutyrate and a lactic acid.\n\nThe EP ordered one liter of normal saline intravenous (IV) bolus and morphine 4 mg and ondensetron 4 mg IV for the abdominal pain. The EP went back and specifically asked the patient about possible causes of the anion gap metabolic acidosis, including ethylene glycol, propylene glycol or methanol ingestion, alcohol abuse, iron or isoniazid use, excessive salicylate use, and dieting (starvation). The patient denied all of these. The serum acetone was reported as “moderate,” the beta-hydroxybutyrate was elevated at 47.6 mg/dL (normal range 0.2 – 2.8 mg/dL) and a serum lactate of 1 mmol/L (normal range 0.5 – 2.2 mmol/L). A repeat BMP revealed the bicarbonate had decreased to 17 mmol/L.\n\nThe EP thought the patient was in diabetic ketoacidosis (DKA), but was confused by the only slightly elevated blood glucose and the fact that the patient was a type 2 diabetic. The EP performed a quick literature search and found that diabetic patients on sodium-glucose cotransporter-2 (SGLT2) inhibitors were at risk for DKA with euglycemia. This patient was on just such a medication (empagliflozin) and had been so for the preceding three years. The patient was admitted to the medicine service and started on an IV insulin drip with concomitant IV dextrose 5% in normal saline drip at 125 cc/hr.\n\nA computed tomography (CT) scan of the abdomen/pelvis with IV contrast was ordered to further evaluate the cause of the left upper quadrant abdominal pain. The CT demonstrated “findings of acute pancreatitis with confluent infiltrative phlegmon around the tail and left side of the pancreatic body, extending to lower portion of the spleen and to left anterior and lateral pararenal space. There was no definable pancreatic mass.” Gastroenterology (GI) was consulted and thought the patient had acute chemical pancreatitis secondary to the DKA and his underlying hypertriglyceridemia. Endocrinology was consulted; they felt the DKA was most likely due to the empagliflozin and that the patient needed to avoid this medication in the future. After four days on an insulin drip, the anion gap decreased to 14, there was no definable serum acetone, and the beta-hydroxybutyrate level returned to normal. The patient could then be weaned off the insulin drip and started on medications by mouth. The patient was discharged home on day five. The patient was instructed to stop taking the empagliflozin and to avoid all such similar medications in the future. His abdominal pain was much improved and he was eating a full diet. The patient was scheduled to follow up with GI and endocrinology in one week.\n\nDISCUSSION\nDiabetic ketoacidosis is a life-threatening complication of diabetes mellitus. It usually occurs in type 1 diabetics, but may occur in type 2 patients under moderate to severe physiologic stress. According to the American Diabetes Association, the diagnostic criteria for DKA includes a plasma glucose greater than 250 mg/dL, positive serum or urinary ketones, an arterial pH of less than 7.3, serum bicarbonate less than 18 mEq/L and a high anion gap. The key diagnostic feature is the elevated circulating total blood ketone concentration.1\n\nEuglycemic diabetic ketoacidosis is now defined as diabetic ketoacidosis with a blood glucose concentration of less than 200 mg/dL, and occurring primarily in patients with type 1 diabetes.2 Euglycemic DKA has been described in the past but is considered rare.3,4 Munro et al. described the first case series of euglycemic DKA in 1973, consisting of 37 episodes in 17 patients.5 They suggested that in type 1 diabetics who were unable to maintain sufficient carbohydrate intake, but maintained hydration status and continued their normal insulin intake, could develop severe ketoacidosis without pronounced hyperglycemia.5 Thawabi et al. presented two cases of euglycemic DKA in type 1 diabetic patients that were consistent with Munro’s physiologic explanation.1 One case was precipitated by an underlying infection; the other by acute pancreatitis.1\n\nCPC-EM Capsule\n\nWhat do we already know about this clinical entity?\n\nDiabetic ketoacidosis (DKA) is a life-threatening complication of diabetes mellitus. It usually occurs in patients with type 1 diabetes, and is associated with a blood glucose level of greater than 250mg/dL, a serum bicarbonate level less than 15 mEQ/dL, and a pH less than 7.3.\n\nWhat makes this presentation of disease reportable?\n\nWith the introduction of sodium-glucose co-transporter-2 inhibitor medications for the treatment of type 2 diabetes mellitus, this classic presentation of DKA no longer holds true.\n\nWhat is the major learning point?\n\nThese medications can cause DKA in a type 2 diabetic patient with euglycemia or only mild hyperglycemia.\n\nHow might this improve emergency medicine practice?\n\nEmergency physicians must be aware of this atypical presentation of DKA to ensure making the correct diagnosis.\n\nMore recently, there have been several reports of euglycemic DKA attributed to the use of SGLT2 inhibitors.6,7 Roach et al. described the first case of euglycemic DKA associated with the use of empagliflozin, the same medication as in our patient.6 The case involved a 64-year-old woman with type 2 diabetes who developed DKA following five days of empagliflozin use.6 The other SGLT2 inhibitors – canagliflozin and dapagliflozin -- have all been associated with euglycemic DKA.3,7,8 In fact, in May 2015 the U.S. Food and Drug Administration (FDA) issued a warning that the “SGLT2 inhibitors can cause too much acid in the blood,” and that patients should stop taking their SGLT2 inhibitor and seek medical attention immediately if they develop symptoms of ketoacidosis.9 This warning was based in part because of the FDA identifying 73 cases of ketoacidosis requiring hospitalization in patients on SGLT2 inhibitors between March 2013 and June 2015.3,9 The median time to onset of symptoms was 43 days, with a range of 1 to 365 days.3,9\n\nThe SGLT2 inhibitors are one of the newest class of oral hypoglycemic medications used to treat diabetes mellitus. These drugs are FDA approved for use in adults with type 2 diabetes. Canagliflozin was the first to be introduced, followed by dapagliflozin and empagliflozin.3 These medications are available as single-ingredient products, or in combination, usually with metformin. These drugs have a novel mechanism of action by inhibiting the enzyme SGLT located in the proximal renal tubules. This enzyme is responsible for reabsorbing approximately 90% of glucose found in the filtrate within the kidney.10 By blocking this enzyme, the blood glucose is decreased because of an increase in renal glucose excretion. These drugs have a relatively pronounced blood glucose lowering effect, with a low risk for hypoglycemia when administered as monotherapy.2 Given that these drugs promote excretion of glucose (an energy source) into the urine, treatment with these drugs also reduces body weight and have pleiotropic effects attributable to weight loss, including amelioration of insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease.2 In addition, empagliflozin was shown to reduce cardiovascular and all-cause mortality, and reduce hospitalization for heart failure, compared to placebo in over 7,000 adult patients with type 2 diabetes mellitus.11\n\nThese drugs, however, are not without adverse effects. In addition to ketoacidosis, they are associated with urinary tract infections (in some cases, leading to urosepsis) and vaginal candidiasis. However, it is the ketoacidosis, and specifically the euglycemic ketoacidosis, that is the most concerning. There are several proposed theories to explain the link between SGLT2 inhibitors and ketoacidosis. One possible mechanism involves a decreased secretion of insulin from pancreatic cells in response to the lowering of blood glucose via urinary excretion.4 This results in decreased circulating insulin and its antilipolytic activity, leading to increased free fatty acid production.4 One animal study suggests that SGLT2 inhibitors stimulate the secretion of the counterregulating hormone glucagon, which in turn contributes to the overproduction of ketone bodies.3,8,12 Finally, another animal study suggests that SGLT inhibitors might decrease the renal clearance of ketone bodies.3,4 The net result is a stimulation of the ketogenesis pathway and an increase in serum ketones, which predispose the body to ketoacidosis. This effect is compounded in the presence of physiologic stressors, such as starvation or dehydration.3\n\nCONCLUSION\nAlthough the reason behind SGLT2 inhibitors causing ketoacidosis, often euglycemic ketoacidosis, might not be fully understood, the association definitely exists. Emergency physicians must recognize that diabetic ketoacidosis can develop in type 2 diabetic patients with normal or only slightly elevated blood glucose levels in patients taking SGLT2 inhibitors.\n\nSection Editor: Rick A. McPheeters, DO\n\nFull text available through open access at http://escholarship.org/uc/uciem_cpcem\n\nConflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n==== Refs\nREFERENCES\n1 Thawabi M Studyvin S Euglycemic diabetic ketoacidosis, a misleading presentation of diabetic ketoacidosis N Am J Med Sci 2015 7 6 291 4 26199928 \n2 Ogawa W Sakaguci K Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors J Diabetes Invest 2016 7 2 135 8 \n3 Jazi M Porfiris G Euglycemic diabetic ketoacidosis in type 2 diabetes treated with a sodium-glucose cotransporter-2 inhibitor Can Fam Physician 2016 62 9 722 4 27629667 \n4 Simeon IT Blau JE Kristina IR SGLT2 inhibitors may predispose to ketoacidosis J Clin Endocrinol Metab 2015 100 8 2849 52 26086329 \n5 Munro JF Campbell IW McCuish AC Euglycaemic diabetic ketoacidosis Br Med J 1973 2 578 80 4197425 \n6 Roach P Skiercynski P Euglycemic diabetic ketoacidosis in a patient with type 2 diabetes after treatment with empagliflozin Diabetes Care 2016 39 1 e3 e3 26519331 \n7 Fralick M Schneeweiss S Paterno E Risk of diabetic ketoacidosis after initiation of an SGLT2 inhibitor N Engl J Med 2017 376 23 2300 2 28591538 \n8 Hayami T Kato Y Kamiya H Case of ketoacidosis by a sodium-glucose cotransporter 2 inhibitor in a diabetic patient with a low-carbohydrate diet J Diabetes Invest 2015 6 5 587 90 \n9 US Food and Drug Administration (website) FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warning about too much acid in the blood and serious urinary tract infections Silver Spring, MD US Food and Drug Administration 5 2015 Available at: www.fda.gov/Drugs/DrugSafety/ucm475487.htm Accessed 2017 Aug 23 \n10 Kim GW Chung SH Clinical implication of SGLT2 inhibitors in type 2 diabetes Arch Pharm Res 2014 37 8 957 66 24950857 \n11 Zinman B Wanner C Lachin JM Empagliflozin, cardiovascular outcomes, and morbidity in type 2 diabetes mellitus N Engl J Med 2015 373 22 2117 28 26378978 \n12 Kibbey RG SGLT-2 inhibition and glucagon: cause for alarm? Trends Endocrinol Metab 2015 26 7 337 8 26059706\n\n",
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"title": "Sodium-glucose Cotransporter-2 Induced Diabetic Ketoacidosis with Minimal Hyperglycemia.",
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"abstract": "Herein we report two cases of advanced and/or metastatic salivary duct carcinoma that relapsed after standard first-line chemotherapy. As overexpression of human epidermal growth factor receptor 2 (HER2) (3+) was observed by immunohistochemistry, the patients were treated with trastuzumab plus paclitaxel. One patient showed a complete response lasting over 2.5 years after the commencement of therapy; however, the other patient had no response to trastuzumab combined therapy. Dual fluorescence in situ hybridization was performed after the initiation of chemotherapy; the first case was positive for HER2 gene amplification, while the second case was negative. Our experiences suggest that therapy with HER2 blockers should be considered as options for treatment of HER2-positive salivary duct carcinoma. However, HER2 protein overexpression and gene amplification should be investigated further as therapeutic biomarkers.",
"affiliations": "Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.;Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.",
"authors": "Gibo|Takahiko|T|;Sekiguchi|Nodoka|N|;Gomi|Daisuke|D|;Noguchi|Takuro|T|;Fukushima|Toshirou|T|;Kobayashi|Takashi|T|;Ozawa|Takesumi|T|;Yamada|Shin-Ichi|SI|;Koizumi|Tomonobu|T|",
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"fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2019.1875MCO-0-0-1875ArticlesTargeted therapy with trastuzumab for epidermal growth factor receptor 2 (HER2)-positive advanced salivary duct carcinoma: A case report Gibo Takahiko 12Sekiguchi Nodoka 2Gomi Daisuke 2Noguchi Takuro 2Fukushima Toshirou 2Kobayashi Takashi 2Ozawa Takesumi 2Yamada Shin-Ichi 1Koizumi Tomonobu 21 Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan2 Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, JapanCorrespondence to: Professor Tomonobu Koizumi, Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan, E-mail: tomonobu@shinshu-u.ac.jp8 2019 10 6 2019 10 6 2019 11 2 111 115 16 7 2018 22 4 2019 Copyright: © Gibo et al.2019This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Herein we report two cases of advanced and/or metastatic salivary duct carcinoma that relapsed after standard first-line chemotherapy. As overexpression of human epidermal growth factor receptor 2 (HER2) (3+) was observed by immunohistochemistry, the patients were treated with trastuzumab plus paclitaxel. One patient showed a complete response lasting over 2.5 years after the commencement of therapy; however, the other patient had no response to trastuzumab combined therapy. Dual fluorescence in situ hybridization was performed after the initiation of chemotherapy; the first case was positive for HER2 gene amplification, while the second case was negative. Our experiences suggest that therapy with HER2 blockers should be considered as options for treatment of HER2-positive salivary duct carcinoma. However, HER2 protein overexpression and gene amplification should be investigated further as therapeutic biomarkers.\n\ndual fluorescence in situ hybridizationgene amplificationparotid gland tumorpaclitaxel\n==== Body\nIntroduction\nSalivary duct carcinoma (SDC), an aggressive and relatively rare tumor arising from the ductal epithelium of the salivary gland, accounts for approximately 10% of all salivary gland malignancies (1,2). Nearly 100 cases of SDC are diagnosed each year in the world, and it arises almost exclusively in the major salivary glands. SDC is three times more common in men, and usually occurs in patients over 50 years of age (1–3). Generally, its prognosis is favorable if the primary lesion is completely resected and no metastases are present (2–5). However, local recurrence and distant metastasis represent the most common forms of treatment failure (2–5). In a review of 104 cases of SDC, Barnes et al (3) reported that one third of patients experience local recurrence after curative treatment, with 59% developing positive regional lymph nodes and 46% showing systemic metastases (lungs and bones). In addition, 65% of patients die of their disease usually within 4 years of initial diagnosis. In 141 cases of SDC in Japan, the 3-year overall survival and disease-free survival rates were 70.5 and 38.2%, respectively (2). Treatment failure after initial surgery occurred in 78 patients, and 70% of these patients had distant metastases (2). Thus, the prognosis of progressive and metastatic diseases is poor, and effective systemic therapy is therefore important (2–5). Data regarding the efficacy of cytotoxic chemotherapeutic agents in cases of advanced and/or metastatic SDC are limited (2–5).\n\nThe histological findings of SDC are similar to those of ductal carcinoma of the breast (2,3,6–8). Several studies indicated that the tumor cells sometimes overexpress human epidermal growth factor receptor 2 (HER2) in patients with SDC, at rates ranging from 20 to 77% (6–9). The humanized monoclonal antibody against HER2, trastuzumab, is expected to be effective in such cases. Indeed, several cases of advanced and/or metastatic SDC showed good responses to treatment with trastuzumab alone or along with chemotherapy (10–21). Therefore, trastuzumab is increasingly being used in the management of HER2/erB2-positive SDC. However, there remains insufficient evidence regarding the efficacy of treatment because of the rarity of the disease itself, particularly in Japanese patients.\n\nHere, we describe two cases of HER2-overexpressing and advanced SDC treated with trastuzumab plus paclitaxel. A good response was obtained in one case, and the primary tumor mass and lymph node metastasis regressed with combined trastuzumab and paclitaxel therapy for over 2 years after initiation of treatment. Here, we report the clinical course of this case along with a review of the relevant literature focusing on HER-2 gene amplification.\n\nCase report\n\nCase 1\nA 59-year-old man was referred to our hospital for further examination of a right cervical swelling and pain. Head and neck computed tomography (CT) (Fig. 1A) and magnetic resonance imaging (MRI) showed a soft tissue mass shadow in the right cervical region. The soft tissue shadow spread into the trapezius muscle and broad neck muscles, masseter muscle, trapezius muscle, shoulder cap muscle, sternocleidomastoid muscle, carotid gap, pharyngopharyngeal space, and the subcutaneous soft tissue. Laboratory findings indicated increased carcinoembryonic antigen level (59.6 mg/ml). As percutaneous needle aspiration cytology revealed adenocarcinoma, open biopsy was performed and the histological diagnosis of SDC was confirmed (Fig. 2A). Chemotherapy with docetaxel (60 mg/m2, day 1), cisplatin (60 mg/m2, day 1), and 5-fluorouracil (700 mg/m2, days 2–5) was performed with a 28-day cycle. However, four cycles of chemotherapy failed to reduce the soft tissue mass and symptoms. During chemotherapy, immunohistochemistry (IHC) of the biopsy specimen was performed and revealed that tumor cells were positive for HER2 (Fig. 3A) and negative for estrogen and progesterone receptors. The patient was then treated with trastuzumab plus paclitaxel. Trastuzumab was administered at a loading dose of 4 mg/kg followed by 2 mg/kg weekly in combination with weekly paclitaxel at 80 mg/m2. There were no adverse effects, including cardiotoxicity, neurotoxicity, and hematotoxicity. The right cervical soft tissue mass decreased in size and disappeared 10 months after initiation of chemotherapy (Fig. 1B). Although the therapy was discontinued due to paclitaxel-induced neurotoxicity, we used trastuzumab for over 2 years after complete response due to concerns regarding early relapse. This patient remained well over 2 years after cessation of trastuzumab.\n\nCase 2\nA 68-year-old man was referred to our hospital for further chemotherapy as treatment for relapsed SDC. He underwent total right parotidectomy with cervical lymphadenectomy and facial nerve reconstruction using the femoral nerve. The pathological diagnosis was SDC. However, he developed pulmonary metastasis 6 months after the operation and received several chemotherapeutic regimens, including platinum compounds plus docetaxel or 5-fluorouracil, and cetuximab plus paclitaxel. However, the disease was progressive and chest CT showed multiple metastatic nodules in both lungs (Fig. 4A). IHC analysis of the resected primary tumor indicated that the tumor cells were positive for HER2 (Fig. 3B). Therefore, the patient was treated with trastuzumab plus paclitaxel at the same dose and according to the same schedule as in case 1. However, the therapy (six cycles of trastuzumab plus paclitaxel) failed to improve radiographic findings in the lungs (Fig. 4B), and the patient was followed up by best supportive care. The patient died due to respiratory failure 6 months later.\n\nThe treatment in both cases was approved by the institutional review board of Shinshu University Hospital (approval number: B0290) and was conducted in accordance with the principles of the Declaration of Helsinki. Dual fluorescence in situ hybridization was performed after initiation of trastuzumab combined with chemotherapy in both cases. Case 1 was positive for HER2 gene amplification (Fig. 3C), while the findings were negative in case 2 (Fig. 3D).\n\nDiscussion\nWe reported two cases of advanced and metastatic HER2-overexpressing SDC (3+) treated with trastuzumab and paclitaxel chemotherapy. One patient, who was positive for HER2 gene amplification, showed a complete response lasting for over 2.5 years after commencement of therapy. However, the other patient, who was negative for HER2 gene amplification, showed no response to trastuzumab combined therapy.\n\nRecently, Ghazali et al (13) reported a patient with HER2-positive metastatic salivary adenocarcinoma who showed complete response to trastuzumab, and summarized 15 published papers, including a prospective study and a case report, presenting details of 56 cases treated with trastuzumab monotherapy or combined chemotherapy. Although the dose and schedule of trastuzumab and combined chemotherapy agents were different between the reports, 22 patients achieved good response. In addition, there were disparities regarding the criteria for HER2 overexpression in these reports. A phase II trial of trastuzumab enrolled 14 patients with salivary grand carcinoma overexpressing HER2 over 2+ as determined by IHC, and showed only one case of partial response lasting longer than 2 years (16). HER2 was a potential therapeutic target in salivary grand carcinoma. However, HER2 overexpression evaluated by IHC was not always associated with significant efficacy of tumor response to trastuzumab.\n\nIn recent case reports showing the usefulness of trastuzumab in SDC, overexpression of HER2 was evaluated by both IHC and gene amplification (9–11,14–22). Limaye et al (17) reported five cases of SDC positive for both HER2 on IHC and for HER2 gene amplification, treated with trastuzumab combined with chemotherapy. All patients showed good response and the median duration of response was 18 months (range, 8–52 months). Thus, the response to trastuzumab chemotherapy in patients may be dependent on HER2 overexpression and gene amplification. Our case 1 showed good response, and was also positive for both HER2 overexpression and gene amplification. Based on these findings and our experience, we emphasize that both HER2 protein overexpression and gene amplification should be examined as therapeutic biomarkers in SDC.\n\nThere have been several studies regarding the coexistence of HER2 IHC and gene amplification in SDC. Thirteen of 14 Japanese cases of HER2 IHC (3+) were positive on FISH (6). Cornolti et al (7) reported eight cases of FISH positivity among 10 with grade 3+ IHC. Dagrada et al (8) reported a coexistence rate of 73% (8/11 cases) on IHC and FISH assessment. In addition, Skalova et al (11) reported three cases of FISH positivity among seven with IHC positivity over grade 3 (3+) in salivary gland carcinoma. These concordance rates were lower than that in breast adenocarcinomas (>90%) with high (3+) HER2 expression (22). Further case studies presenting details of HER2 examination and treatment for advanced salivary malignancies are warranted.\n\nIn addition, the therapeutic effects of trastuzumab are related to the immunological backgrounds (23). White blood cell and lymphocyte counts were 7,660 and 1,800 in case 1 and 6,140 and 1,600 in case 2 before trastuzumab therapy, respectively. Although we did not examine the specific immunological parameters in both cases, we should pay attention to the immunological examination in patients with HER-2 positive SDC.\n\nIn summary, our experiences indicated that HER2 should be examined in patients with advanced and/or metastatic SDC, and that findings of both HER2 overexpression and gene amplification define a group of patients with SDC who would benefit from targeted therapy with trastuzumab.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.\n\nAuthors' contributions\nTG, NS and TKoi wrote the manuscript and all authors TG, NS, DG, TN, TF, TKob, TO, SY and TKoi treated the patients. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe Ethics Committees of Shinshu University Hospital approved the treatment of two cases (approval number: B0290).\n\nPatient consent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1. Computed tomography (CT) findings in case 1 before and after treatment with trastuzumab plus paclitaxel. (A) The tumor extended along the right cervical space and had metastasized into the left cervical lymph node before therapy (arrow). (B) The both metastatic tumors were reduced after 10 months of treatment with trastuzumab plus paclitaxel.\n\nFigure 2. Pathological findings on hematoxylin and eosin (H&E) staining in both cases. (A) Case 1: Within the salivary gland tissue, heterozygous cells with eosinophilic cytoplasm and prominent nucleoli proliferated with comedo-like central necrosis. (B) Case 2: Heterotypic cells with nuclear enlargement invasively proliferated with atypical ductal epithelial cells in a cribriform growth pattern. H&E, ×40 magnification.\n\nFigure 3. Immunohistochemical (IHC) analysis and determination of HER2 gene amplification by dual-color in situ hybridization (DISH). HER2 overexpression was positive in tumor cells from both cases (A, case 1; B, case 2), but only case 1 was positive for HER2 gene amplification (C) while case 2 was negative (D) HER2 IHC ×40 magnification; HER2 DISH, ×100 magnification.\n\nFigure 4. Chest computed tomography findings before (A) and after (B) treatment with trastuzumab plus paclitaxel in case 2.\n==== Refs\nReferences\n1 McHugh JB Visscher DW Barnes EL Update on selected salivary gland neoplasms Arch Pathol Lab Med 133 1763 1774 2009 19886710 \n2 Otsuka K Imanishi Y Tada Y Kawakita D Kano S Tsukahara K Shimizu A Ozawa H Okami K Sakai A Clinical outcomes and prognostic factors for salivary duct carcinoma: A multi-institutional analysis of 141 patients Ann Surg Oncol 23 2038 2045 2016 10.1245/s10434-015-5082-2 26790669 \n3 Barnes L Rao U Krause J Contis L Schwartz A Scalamogna P Salivary duct carcinoma. Part I. A clinicopathologic evaluation and DNA image analysis of 13 cases with review of the literature Oral Surg Oral Med Oral Pathol 78 64 73 1994 10.1016/0030-4220(94)90119-8 8078666 \n4 Johnston ML Huang SH Waldron JN Atenafu EG Chan K Cummings BJ Gilbert RW Goldstein D Gullane PJ Irish JC Salivary duct carcinoma: Treatment, outcomes, and patterns of failure Head Neck 38 E820 E826 2016 10.1002/hed.24107 25916947 \n5 Lagha A Chraiet N Ayadi M Krimi S Allani B Rifi H Raies H Mezlini A Systemic therapy in the management of metastatic or advanced salivary gland cancers Oral Oncol 48 948 957 2012 10.1016/j.oraloncology.2012.05.004 22698431 \n6 Masubuchi T Tada Y Maruya S Osamura Y Kamata SE Miura K Fushimi C Takahashi H Kawakita D Kishimoto S Nagao T Clinicopathological significance of androgen receptor, HER2, Ki-67 and EGFR expressions in salivary duct carcinoma Int J Clin Oncol 20 35 44 2015 10.1007/s10147-014-0674-6 24553861 \n7 Cornolti G Ungari M Morassi ML Facchetti F Rossi E Lombardi D Nicolai P Amplification and overexpression of HER2/neu gene and HER2/neu protein in salivary duct carcinoma of the parotid gland Arch Otolaryngol Head Neck Surg 133 1031 1036 2007 10.1001/archotol.133.10.1031 17938328 \n8 Dagrada GP Negri T Tamborini E Pierotti MA Pilotti S Expression of HER-2/neu gene and protein in salivary duct carcinomas of parotid gland as revealed by fluorescence in-situ hybridization and immunohistochemistry Histopathology 44 301 302 2004 10.1111/j.1365-2559.2004.01781.x 14987238 \n9 Alotaibi AM Alqarni MA Alnobi A Tarakji B Human epidermal growth factor receptor 2 (HER2/neu) in salivary gland carcinomas: A review of literature J Clin Diagn Res 9 ZE04 ZE08 2015 25859537 \n10 Nabili V Tan JW Bhuta S Sercarz JA Head CS Salivary duct carcinoma: A clinical and histologic review with implications for trastuzumab therapy Head Neck 29 907 912 2007 10.1002/hed.20614 17563907 \n11 Skálová A Stárek Kucerová V Szépe P Plank L Salivary duct carcinoma-A highly aggressive salivary gland tumor with HER-2/neu oncoprotein overexpression Pathol Res Pract 197 621 626 2001 10.1078/0344-0338-00136 11569926 \n12 De Block K Vander Poorten V Dormaar T Nuyts S Hauben E Floris G Deroose CM Schöffski P Clement PM Metastatic HER-2-positive salivary gland carcinoma treated with trastuzumab and a taxane: A series of six patients Acta Clin Belg 71 383 388 2016 10.1080/17843286.2016.1173940 27285571 \n13 Ghazali N Parker L Settle K Lubek JE Sustained response of HER2-positive metastatic salivary adenocarcinoma, not otherwise specified, treated with trastuzumab Oral Surg Oral Med Oral Pathol Oral Radiol 122 292 299 2016 10.1016/j.oooo.2016.03.020 27289263 \n14 Kadowaki S Yatabe Y Hirakawa H Komori A Kondoh C Hasegawa Y Muro K Complete response to trastuzumab-based chemotherapy in a patient with human epidermal growth factor receptor-2-positive metastatic salivary duct carcinoma ex pleomorphic adenoma Case Rep Oncol 6 450 455 2013 10.1159/000355219 24163659 \n15 Iqbal MS Shaikh G Chatterjee S Cocks H Kovarik J Maintenance therapy with trastuzumab in her2 positive metastatic parotid ductal adenocarcinoma Case Rep Oncol Med 2014 16251634 2014 \n16 Haddad R Colevas AD Krane JF Cooper D Glisson B Amrein PC Weeks L Costello R Posner M Herceptin in patients with advanced or metastatic salivary gland carcinomas. A phase II study Oral Oncol 39 724 727 2003 10.1016/S1368-8375(03)00097-6 12907212 \n17 Limaye SA Posner MR Krane JF Fonfria M Lorch JH Dillon DA Shreenivas AV Tishler RB Haddad RI Trastuzumab for the treatment of salivary duct carcinoma Oncol 18 294 300 2013 \n18 Thorpe LM Schrock AB Erlich RL Miller VA Knost J Le-Lindqwister N Jujjavarapu S Ali SM Liu JJ Significant and durable clinical benefit from trastuzumab in 2 patients with HER2-amplified salivary gland cancer and a review of the literature Head Neck 39 E40 E44 2017 10.1002/hed.24634 28006087 \n19 Corrêa TS Matos GDR Segura M Dos Anjos CH Second-line treatment of HER2-positive salivary gland tumor: Ado-Trastuzumab emtansine (T-DM1) after progression on trastuzumab Case Rep Oncol 11 252 257 2018 10.1159/000488669 29867432 \n20 van Boxtel W Boon E Weijs WLJ van den Hoogen FJA Flucke UE van Herpen CML Combination of docetaxel, trastuzumab and pertuzumab or treatment with trastuzumab-emtansine for metastatic salivary duct carcinoma Oral Oncol 72 198 200 2017 10.1016/j.oraloncology.2017.06.023 28673692 \n21 Iguchi F Taniguchi Z Kusano J Takahashi Y Murai N A case of metastatic salivary duct carcinoma successfully treated with trastuzumab-based targeted therapy Nihon Jibiinkoka Gakkai Kaiho 117 1108 1114 2014 (Japanese) 10.3950/jibiinkoka.117.1108 25255650 \n22 Giltnane JM Molinaro A Cheng H Robinson A Turbin D Gelmon K Huntsman D Rimm DL Comparison of quantitative immunofluorescence with conventional methods for HER2/neu testing with respect to response to trastuzumab therapy in metastatic breast cancer Arch Pathol Lab Med 132 1635 1647 2008 18834223 \n23 Ethier JL Desautels D Templeton A Shah PS Amir E Prognostic role of neutrophil-to-lymphocyte ratio in breast cancer: A systematic review and meta-analysis Breast Cancer Res 19 2 2017 10.1186/s13058-016-0794-1 28057046\n\n",
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"issue": "11(2)",
"journal": "Molecular and clinical oncology",
"keywords": "dual fluorescence in situ hybridization; gene amplification; paclitaxel; parotid gland tumor",
"medline_ta": "Mol Clin Oncol",
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"title": "Targeted therapy with trastuzumab for epidermal growth factor receptor 2 (HER2)-positive advanced salivary duct carcinoma: A case report.",
"title_normalized": "targeted therapy with trastuzumab for epidermal growth factor receptor 2 her2 positive advanced salivary duct carcinoma a case report"
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"abstract": "OBJECTIVE\nTo report the case of a clinically significant drug interaction between intravenous busulfan and oral metronidazole observed through busulfan therapeutic drug monitoring (TDM).\n\n\nMETHODS\nA 7-year-old boy with a history of myelodysplasia that progressed to acute myeloid leukemia received busulfan with therapeutic drug monitoring (TDM), clofarabine, and thiotepa as a pretransplant conditioning regimen for a cord blood transplant. The patient received metronidazole the day after a busulfan test dose of 0.5 mg/kg was administered. On the day of the first busulfan therapeutic dose, TDM was performed and the clearance of busulfan was significantly decreased by 46%. After 2 doses of busulfan therapy, the course area under the curve was exceeded, requiring discontinuation of busulfan. Metronidazole is not known to affect glutathione or the glutathione S-transferase A1 (GSTA1) enzyme system or cytochrome P450 (CYP) 3A4.\n\n\nCONCLUSIONS\nBusulfan is a bifunctional alkylating agent widely used in pretransplant conditioning regimens in patients undergoing stem cell transplantation for hematologic malignancies. Busulfan metabolism is best described by hepatic conjugation to glutathione by GSTA1, although some CYP-dependent pathways have been described. Currently there is 1 publication describing the drug interaction between oral busulfan and oral metronidazole, in which concomitant use of metronidazole resulted in higher busulfan trough concentrations and higher risk of veno-occlusive disease. Our case represents a possible drug interaction based on the Horn Drug Interaction Probability Scale.\n\n\nCONCLUSIONS\nThough the mechanistic basis for this interaction is unknown, the risks and benefits of using metronidazole during and in close proximity to busulfan should be carefully considered and therapeutic alternatives to metronidazole should be used when appropriate.",
"affiliations": "Division of Pharmacy, MD Anderson Cancer Center, Houston, TX, USA. amassaro@mdanderson.org",
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"mesh_terms": "D000900:Anti-Bacterial Agents; D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan; D002648:Child; D016360:Clostridioides difficile; D004347:Drug Interactions; D016903:Drug Monitoring; D004761:Enterocolitis, Pseudomembranous; D006207:Half-Life; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008657:Metabolic Clearance Rate; D008795:Metronidazole; D019653:Myeloablative Agonists; D019172:Transplantation Conditioning",
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"title": "Busulfan and metronidazole: an often forgotten but significant drug interaction.",
"title_normalized": "busulfan and metronidazole an often forgotten but significant drug interaction"
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{
"companynumb": "US-CLARIS PHARMASERVICES-1065642",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nIn our country, the national program for hepatitis C virus treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir was approved for patients with stage four of liver fibrosis and stage three associated with specific comorbidities. Our aim was to analyze the characteristics associated with the presence of adverse events in patients receiving this antiviral regimen, with ribavirin in cirrhotic patients.\n\n\nMETHODS\nWe prospectively studied a cohort of adults with hepatitis C virus infection with Child A cirrhosis, treated for 12 weeks with ombitasvir/paritaprevir/ritonavir/dasabuvir and ribavirin, which have been followed in an infectious diseases tertiary-care hospital.\n\n\nRESULTS\nWe included 137 adult patients diagnosed with compensated cirrhosis, hepatitis C virus genotype 1b infected, 82 (60%) previously treated. We recorded 201 adverse events in 98 (71.5%) patients, with a median number of events per patient of one. The intensity of adverse events was classified as mild, moderate and severe in 50%, 36% and 14% of cases, respectively. Forty-five (22%) episodes required medical intervention. The most frequently reported adverse events were pruritus 34(35%), asthenia 22(22%) and insomnia 15(15%). The presence of severe adverse events was associated with the presence of comorbidities (p = 0.01, OR : 9.5, 95% CI : 1.2-74.3) and with the presence of associated medication (p = 0.02, OR : 3.9, 95% CI : 1.08-14.2). At the end of current treatment, 136 (99.2%) patients had undetectable viral load.\n\n\nCONCLUSIONS\nWe found a high number of adverse events, but most of them were mild or moderate and only one quarter of them required medical intervention. Only severe adverse events were associated with comorbidities and associated medication.",
"affiliations": "\"Prof. Dr. Matei Bals\" National Institute for Infectious Diseases, Bucharest, Romania.;\"Dr. Carol Davila\" Central Military Emergency University Hospital, Bucharest, Romania.;\"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.;\"Prof. Dr. Matei Bals\" National Institute for Infectious Diseases, Bucharest, Romania.;\"Prof. Dr. Matei Bals\" National Institute for Infectious Diseases, Bucharest, Romania.;\"Prof. Dr. Matei Bals\" National Institute for Infectious Diseases, Bucharest, Romania.",
"authors": "Manea|E D|ED|;Stefan|I|I|;Olariu|C|C|;Calina|O C|OC|;Jipa|R E|RE|;Hristea|A|A|",
"chemical_list": "D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D012254:Ribavirin; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir",
"country": "Belgium",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3227",
"issue": "81(1)",
"journal": "Acta gastro-enterologica Belgica",
"keywords": "adverse events; cirrhosis; dasabuvir; hepatitis C virus; ombitasvir/paritaprevir/ritonavir",
"medline_ta": "Acta Gastroenterol Belg",
"mesh_terms": "D015081:2-Naphthylamine; D000368:Aged; D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D015897:Comorbidity; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic; D006801:Humans; D047029:Lactams, Macrocyclic; D008103:Liver Cirrhosis; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D011392:Proline; D011446:Prospective Studies; D012254:Ribavirin; D019438:Ritonavir; D012383:Romania; D013449:Sulfonamides; D016896:Treatment Outcome; D014498:Uracil; D014633:Valine",
"nlm_unique_id": "0414075",
"other_id": null,
"pages": "9-13",
"pmc": null,
"pmid": "29562372",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Safety assessment in Child A cirrhotic patients treated with Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir with Ribavirin.",
"title_normalized": "safety assessment in child a cirrhotic patients treated with ombitasvir paritaprevir ritonavir and dasabuvir with ribavirin"
} | [
{
"companynumb": "RO-ABBVIE-18P-135-2362784-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DASABUVIR"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nA long-acting somatostatin analogue (lanreotide) is used in the management of a diazoxide-unresponsive diffuse form of congenital hyperinsulinism (CHI). However, no reports of its use in patients with the focal form of CHI exist. Case 1: A 1-month-old boy diagnosed with diazoxide-unresponsive CHI due to a paternal heterozygous ABCC8 gene mutation showed partial response to octreotide. 18F-DOPA-PET/CT scan revealed a focal lesion in the pancreatic head. Surgical removal of the lesion was unsuccessful. He was switched to monthly lanreotide treatment at the age of 11 months, which stabilised his blood glucose over a 12-month period. Case 2: A 1-month-old boy with diazoxide-unresponsive CHI due to a paternal heterozygous KCNJ11 gene mutation was partially responsive to octreotide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. Over 6 months, he underwent 3 lesionectomies and afterwards responded to octreotide. At the age of 9 months, treatment was switched to monthly lanreotide. Currently, he is aged 3, with stable glycaemia, and improved fasting tolerance. Case 3: A 3-week-old girl with a paternal heterozygous ABCC8 gene mutation was unresponsive to diazoxide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. She responded to octreotide, and her parents preferred to avoid pancreatic surgery. At the age of 20 months, treatment was switched to monthly lanreotide, resulting in euglycaemia over the last 7 months.\n\n\nCONCLUSIONS\nCHI patients with focal pancreatic head lesions are challenging, especially if not surgically amenable. Conservative treatment is preferable, and lanreotide might be an option. The therapeutic impact of lanreotide treatment in patients with the focal forms of CHI should be confirmed in prospective studies with close monitoring of the side effects.",
"affiliations": "Endocrinology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.;Endocrinology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.;Endocrinology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.;Endocrinology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.;Salmaniya Medical Complex, Arabian Gulf University, Manama, Bahrain.;Department of Nuclear Medicine, University College London Hospitals NHS Foundation Trust, London, United Kingdom.;Department of Nuclear Medicine, University College London Hospitals NHS Foundation Trust, London, United Kingdom.;Department of Surgery, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.;Endocrinology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.;Endocrinology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom, pratik.shah@gosh.nhs.uk.",
"authors": "Dastamani|Antonia|A|;Güemes|Maria|M|;Pitfield|Catherine|C|;Morgan|Kate|K|;Rajab|Mansoor|M|;Rottenburger|Christof|C|;Bomanji|Jamshed|J|;De Coppi|Paolo|P|;Dattani|Mehul|M|;Shah|Pratik|P|",
"chemical_list": "C577507:ABCC8 protein, human; C489474:Kir6.2 channel; D010456:Peptides, Cyclic; D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; C060347:lanreotide; D013004:Somatostatin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000491101",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1663-2818",
"issue": "91(1)",
"journal": "Hormone research in paediatrics",
"keywords": "ABCC8 gene; Focal form; Hyperinsulinaemic hypoglycaemia; Lanreotide; Somatostatin analogue",
"medline_ta": "Horm Res Paediatr",
"mesh_terms": "D044903:Congenital Hyperinsulinism; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010182:Pancreatic Diseases; D010456:Peptides, Cyclic; D049268:Positron-Emission Tomography; D024661:Potassium Channels, Inwardly Rectifying; D013004:Somatostatin; D064233:Sulfonylurea Receptors; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101525157",
"other_id": null,
"pages": "56-61",
"pmc": null,
"pmid": "30114684",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "The Use of a Long-Acting Somatostatin Analogue (Lanreotide) in Three Children with Focal Forms of Congenital Hyperinsulinaemic Hypoglycaemia.",
"title_normalized": "the use of a long acting somatostatin analogue lanreotide in three children with focal forms of congenital hyperinsulinaemic hypoglycaemia"
} | [
{
"companynumb": "GB-IPSEN BIOPHARMACEUTICALS, INC.-2018-12508",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OCTREOTIDE"
},
"drugaddit... |
{
"abstract": "In renal allograft recipients, cytomegalovirus (CMV) typically causes tubulointerstitial nephritis. Only rarely glomeruli are involved. We present a rare case of CMV with collapsing glomerulopathy, necrotizing glomerulonephritis, and crescent formation in a renal allograft recipient. Immunohistochemistry confirmed CMV infection. The patient was started on valganciclovir and his renal function remained stable. A repeat renal biopsy performed three months later showed morphologically normal glomeruli and CMV immunostaining was also negative. Nephropathologists have to carefully screen for CMV in cases with crescentic or collapsing glomerulopathy as the later lesions resolve after treating the underlying viral infection. This study will add on to the various glomerular changes associated with CMV infection.",
"affiliations": "Department of Pathology, Center for Renal and Urological Pathology, Chennai, Tamil Nadu, India.;Department of Nephrology, Stanley Medical College, Royapuram, Chennai, Tamil Nadu, India.;Department of Pathology, Center for Renal and Urological Pathology, Chennai, Tamil Nadu, India.",
"authors": "Prema|K S J|KSJ|;Prasad|N D S|NDS|;Kurien|A A|AA|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijn.IJN_375_17",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India 30983753IJN-29-12210.4103/ijn.IJN_375_17Case ReportCytomegalovirus Induced Collapsing Glomerulopathy and Necrotizing Glomerulonephritis in a Renal Allograft Recipient Prema K. S. J. Prasad N. D. S. 1Kurien A. A. Department of Pathology, Center for Renal and Urological Pathology, Chennai, Tamil Nadu, India1 Department of Nephrology, Stanley Medical College, Royapuram, Chennai, Tamil Nadu, IndiaAddress for correspondence: Dr. A. A. Kurien, Renopath, Center for Renal and Urological Pathology, No. 27 and 28, VMT Nagar, Kolathur, Chennai - 600 099, Tamil Nadu, India. E-mail: anila_abraham08@yahoo.comMar-Apr 2019 29 2 122 124 Copyright: © 2019 Indian Journal of Nephrology2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.In renal allograft recipients, cytomegalovirus (CMV) typically causes tubulointerstitial nephritis. Only rarely glomeruli are involved. We present a rare case of CMV with collapsing glomerulopathy, necrotizing glomerulonephritis, and crescent formation in a renal allograft recipient. Immunohistochemistry confirmed CMV infection. The patient was started on valganciclovir and his renal function remained stable. A repeat renal biopsy performed three months later showed morphologically normal glomeruli and CMV immunostaining was also negative. Nephropathologists have to carefully screen for CMV in cases with crescentic or collapsing glomerulopathy as the later lesions resolve after treating the underlying viral infection. This study will add on to the various glomerular changes associated with CMV infection.\n\nKeywords:\nCellular crescentcollapsecytomegalovirus\n==== Body\nIntroduction\nCytomegalovirus (CMV) is a well-recognized cause of tubulointerstitial nephritis in renal allograft recipients. Only rarely is it associated with collapsing glomerulopathy or with necrotizing and crescentic glomerulonephritis. We present this case for the rare association of CMV-induced tubulointerstitial nephritis, collapsing glomerulopathy, and necrotizing glomerulonephritis with cellular crescent formation.\n\nCase Report\nA 58-year-old male patient with end-stage renal disease on hemodialysis underwent live donor renal transplantation on October 13, 2016. Triple regimen immunosuppression was given. Both the donor and recipient were CMV immunoglobulin G (IgG) antibody positive and IgM negative. He was discharged on October 22, 2016 under stable conditions. His serum creatinine was 1.1 mg/dl, blood urea nitrogen 17 mg/dl and potassium was 3.7 mEq/L at the time of discharge. Serum creatinine was maintained between 1.3 and 1.4 mg/dl.\n\nHe had graft dysfunction from December 28, 2016, with serum creatinine of 2.6 mg/dl. Urine routine examination showed 2+ proteinuria with bland urinary sediments. Urine protein creatinine ratio was 2. His hemoglobin was 11.5 mg/dl, total leukocyte count was 4100 cells/cumm and platelet count was 1,70,000/cumm. Liver function test was normal, total protein was 7.0 gm/dl and serum albumin 3.6 gm/dl. Serology for anti-neutrophil cytoplasmic auto-antibodies was negative. Renal biopsy was performed to identify the cause of graft dysfunction. Renal biopsy showed cellular crescent [Figure 1] along with segmental fibrinoid necrosis in one out of the 16 glomeruli. The segmental collapse of the capillary tuft was seen in another glomerulus [Figure 2]. The remaining glomeruli were normocellular with patent capillary loops.\n\nFigure 1 Cellular crescent encircles and compresses the glomerular capillary tuft (H and E, ×200)\n\nFigure 2 There is collapse of the glomerular capillary tuft with hyperplasia of the podocytes (PASM, ×200)\n\nIn two tubules, markedly enlarged 2–3 epithelial cells were seen with intranuclear and cytoplasmic viral inclusions. Immunohistochemistry (IHC) for CMV (Cell Marque, DDG9/CCH2) was positive over these cells, confirming the diagnosis of CMVnephritis [Figure 3]. C4d, IgG, IgM and IgA and complements C3 and C1q were negative. The diagnosis of CMV with necrotizing glomerulonephritis and cellular crescent was made based on the typical light microscopic and IHC findings.\n\nFigure 3 Intranuclear and cytoplasmic viral inclusion bodies are seen in markedly enlarged tubular epithelial cells. Immunohistochemical stain for cytomegalovirus was positive over these cells, confirming cytomegalovirus disease in this patient\n\nHe was treated with valganciclovir (450 mg), cyclosporine, mycophenolate mofetil, and everolimus. The initial CMV polymerase chain reaction (PCR) quantitative assay was 900 copies/ml of blood and after 3 weeks of treatment, it became negative. A repeat biopsy done on July 21, 2017 showed glomeruli which appeared morphologically normal. No viral inclusion bodies were identified. CMV IHC stain was negative on the renal tissue. Three months later, total leukocyte count was 9600 cells/cumm, protein creatinine ratio was 0.8, and the serum creatinine was 1.5 mg/dl.\n\nDiscussion\nCMV is one of the major viral pathogens complicating renal transplantation. It is a double-stranded DNA virus and belongs to the herpes viridae family. The human herpes virus family is composed of three subfamilies: alpha, beta, and gamma herpes virus. CMV belongs to the beta subfamily.[1] The transmission of CMV occurs through saliva, body fluids, or through tissue. Seroprevalence of CMV in India among voluntary blood donors was 95%.[2] In seronegative individuals, after primary infection, it establishes latency in CD34+ myeloid progenitor cells, CD14+ monocytes, megakaryocytes, and also in dendritic cells.[3] Active viral replication does not occur during latency. When the person becomes immunosuppressed, reactivation of CMV occurs. The characteristic features of herpes viruses are latency and reactivation. Once CMV activation occurs, according to the clinical presentation, it can be CMV infection or CMV disease.[4] CMV nephritis requires the detection of CMV along with histological features of CMV in a patient who has renal dysfunction.\n\nBefore transplantation anti-CMV IgG is used as it is more specific than IgM or combined IgG and IgM serologic tests. After transplantation, serology is not used to diagnose active CMV infection. The sensitivity of blood culture to diagnose CMV infection is poor. Viral load testing remains the cornerstone to diagnose and monitor CMV infection and disease. It can be done by pp65 antigenemia or by quantitative nucleic acid testing (QNAT).[5]\n\npp65 antigenemia assays are rapid, but leukocytes from fresh blood are essential as the sensitivity decreases when the blood is processed after six hours.[6] Its performance also decreases when the absolute neutrophil count is lower than 1000/mm3. QNAT is now the method of choice for diagnosis, preemptive treatment, and also for monitoring response to treatment. It uses DNA and its sensitivity does not decrease with blood storage. PCR-based methods can recognize CMV infection at least a week earlier than pp65 antigen assays. This helps in starting preemptive antiviral therapy.[7] CMV detection in the tissue specimen is the definitive method to diagnose tissue invasive infection, and it should be confirmed by immunostaining or in situ DNA hybridization.[7]\n\nThe risk of viral infection in transplant recipients is highest in the first few months following transplantation, when the patient is treated with high level of immunosuppressive drugs. CMV disease most often occurs in the first six months post transplantation.[8] Cytopathic changes caused by CMV in the kidney are very focal and are seen in tubular epithelial cell cytoplasm and nucleus. The cells infected by CMV are enlarged, nucleus contains a central inclusion which is surrounded by a halo giving the owl's eye appearance. Occasionally, intranuclear homogeneous, smudgy inclusions are observed. Basophilic, small, lumpy viral inclusions are seen frequently in the cytoplasm of the cells harboring these intranuclear inclusion bodies.[9]\n\nGlomerular involvement occurs only rarely. Macaulay Onuigbo et al. in 2002 described a case of CMV glomerulopathy in which there was focal necrosis of the glomerular tuft without any crescent formation.[10] Detwiler et al. in 1998 have published a case report of necrotizing and crescentic glomerulonephritis associated with CMV infection.[11] There are case reports of collapsing glomerulopathy associated with CMV infection. Grover et al.[12] reported a case of collapsing glomerulopathy associated with acute CMV infection in an immunocompetent host. Acute CMV infection was diagnosed based on the elevation of serum CMV DNA antibodies of both IgG and IgM and a high viral load. Although there were no CMV inclusions identified in the kidney biopsy by light microscopy and IHC stain, they attributed the etiology of the collapsing glomerulopathy to CMV infection as the patient's renal function improved with antiviral therapy for CMV. In our patient, we were able to demonstrate CMV infecting the kidney on light microscopy and it was confirmed by IHC. There was partial remission of proteinuria and creatinine decreased to 1.5 mg/dl with treatment. Furthermore, a repeat biopsy done after treatment showed no glomerular pathology. CMV IHC staining was negative on the biopsy post treatment. This is also the first case report having both necrotizing glomerulonephritis with cellular crescent and collapsing glomerulopathy associated with CMV infection.\n\nT-cell directed adaptive immunity is thought to play a major role in the development of crescentic glomerulonephritis.[13] It has been proposed that viral infections lead to collapsing glomerulopathy due to direct cytopathic effects or by activating immune system.[14] In our case, viral activation of the immune system is speculated to cause both collapsing glomerulopathy and cellular crescent with glomerular tuft necrosis.\n\nGanciclovir, foscarnet, and cidofovir are currently available for treating CMV infection. There are multiple studies showing the efficacy of ganciclovir in prophylaxis and treatment. Foscarnet is nephrotoxic. Experience with cidofovir is limited. Maribavir is also used.[15] Our patient responded well to valganciclovir.\n\nConclusion\nThis case highlights the importance of identifying CMV-induced necrotizing and collapsing glomerulonephritis, thereby enabling the appropriate management that would prevent allograft loss.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Naraqi S Belshe RB Cytomegaloviruses Textbook of Human Virology 1991 2nd ed St. Louis Mosby-Year Book 889 924 \n2 Kothari A Ramachandran VG Gupta P Singh B Talwar V Seroprevalence of cytomegalovirus among voluntary blood donors in Delhi, India J Health PopulNutr 2002 20 348 51 \n3 Sinclair J Sissons P Latency and reactivation of human cytomegalovirus J Gen Virol 2006 87 1763 79 16760381 \n4 Requião-Moura LR deMatos AC Pacheco-Silva A Cytomegalovirus infection in renal transplantation: Clinical aspects, management and the perspectives Einstein (Sao Paulo) 2015 13 142 8 25993081 \n5 Farrugia E Schwab TR Management and prevention of cytomegalovirus infection after renal transplantation Mayo ClinProc 1992 67 879 90 \n6 Baldanti F Lilleri D Gerna G Monitoring human cytomegalovirus infection in transplant recipients J ClinVirol 2008 41 237 41 \n7 Kotton CN Kumar D Caliendo AM Asberg A Chou S Danziger-Isakov L Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation Transplantation 2013 96 333 60 23896556 \n8 Ersan S Yorukoglu K Sert M Atila K Celik A Gulcu A Unusual case of severe late-onset cytomegalovirus-induced hemorrhagic cystitis and ureteritis in a renal transplant patient Ren Fail 2012 34 247 50 22251223 \n9 Ulrich W Schlederer MP Buxbaum P Stummvoll H Rockenschaub S Kovarik J The histopathologic identification of CMV infected cells in biopsies of human renal allografts. An evaluation of 100 transplant biopsies by in situ hybridization Pathol Res Pract 1986 181 739 45 3031636 \n10 Onuigbo M Haririan A Ramos E Klassen D Wali R Drachenberg C Cytomegalovirus-induced glomerular vasculopathy in renal allografts: A report of two cases Am J Transplant 2002 2 684 8 12201373 \n11 Detwiler RK Singh HK Bolin P Jr Jennette JC Cytomegalovirus-induced necrotizing and crescentic glomerulonephritis in a renal transplant patient Am J Kidney Dis 1998 32 820 4 9820453 \n12 Grover V Gaiki MR DeVita MV Schwimmer JA Cytomegalovirus-induced collapsing focal segmental glomerulosclerosis Clin Kidney J 2013 6 71 3 27818753 \n13 Tipping PG Holdsworth SR T cells in crescentic glomerulonephritis J Am SocNephrol 2006 17 1253 63 \n14 Albaqumi M Barisoni L Current views on collapsing glomerulopathy J Am SocNephrol 2008 19 1276 81 \n15 Chakravarti A Kashyap B Matlani M Cytomegalovirus infection: An Indian perspective Indian J Med Microbiol 2009 27 3 11 19172051\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "29(2)",
"journal": "Indian journal of nephrology",
"keywords": "Cellular crescent; collapse; cytomegalovirus",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "122-124",
"pmc": null,
"pmid": "30983753",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "12201373;12659416;1331630;16624930;16760381;18203657;18287560;19172051;22251223;23896556;25993081;27818753;3031636;9820453",
"title": "Cytomegalovirus Induced Collapsing Glomerulopathy and Necrotizing Glomerulonephritis in a Renal Allograft Recipient.",
"title_normalized": "cytomegalovirus induced collapsing glomerulopathy and necrotizing glomerulonephritis in a renal allograft recipient"
} | [
{
"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-207488",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"dr... |
{
"abstract": "An adolescent female patient presenting with subacute onset of dysphagia and hoarseness underwent a direct laryngoscopy, which revealed epiglottitis. After 2 hospitalizations and multiple consultations and biopsies, all infectious testing results for viral, bacterial, fungal, and acid-fast bacilli etiologies were negative. The patient's use of electronic cigarettes was the only exposure elicited with a likely role in her presentation. This case, combined with the growing body of evidence revealing the toxic effects of vaping and the increasing use of electronic cigarettes among adolescent patients, highlights the many unknowns and risks regarding the biological effects of this practice.",
"affiliations": "Divisions of Pediatric Infectious Diseases and mbozzella@childrensnational.org.;Hospitalist Medicine, Children's National Health System, Washington, District of Columbia; and.;Divisions of Pediatric Infectious Diseases and.;Divisions of Pediatric Infectious Diseases and.",
"authors": "Bozzella|Michael J|MJ|;Magyar|Matthew|M|;DeBiasi|Roberta L|RL|;Ferrer|Kathleen|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2019-2399",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "145(3)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000293:Adolescent; D003680:Deglutition Disorders; D066300:Electronic Nicotine Delivery Systems; D004826:Epiglottitis; D005260:Female; D006685:Hoarseness; D006801:Humans; D007828:Laryngoscopy; D000072137:Vaping",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32024750",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Epiglottitis Associated With Intermittent E-cigarette Use: The Vagaries of Vaping Toxicity.",
"title_normalized": "epiglottitis associated with intermittent e cigarette use the vagaries of vaping toxicity"
} | [
{
"companynumb": "US-TEVA-2020-US-1227992",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nBiologic therapy such as Etanercept, which is a tumor necrosis factor alpha (TNF-α) inhibitor, has been extensively used as election therapy in rheumatoid arthritis. The purpose of this case presentation was to inform about the possibility that lichen planus lesions could potentially become complicated by secondary infections in patients treated with Etanercept. Furthermore, we aimed at analyzing if the complication of the cutaneous lesion was coincidental or it was due to the immunosuppressive systemic therapy, and whether the infected lesion would respond to antibiotic therapy.\n\n\nMETHODS\nThe patient was a 59-year-old woman with rheumatoid arthritis and that have had lichen planus lesions for approximately 25 years. Only recently, she had been received immunosuppressive therapy (Etanercept and Methotrexate). Further on, the lichen planus flared up with a secondary infection determined by a Methicillin-sensitive Staphylococcus aureus. Uncommon myocardial complications were also characteristic of this case.\n\n\nRESULTS\nWhile a case report described already the appearance of lichen planus following Etanercept therapy (Battistella M et al., 2008), the possibility that the lesion could become secondary complicated following this therapy was never reported before, according to our knowledge. Additionally, we describe in this case the interplay between Etanercept therapy and hypertrophic cardiomyopathy.\n\n\nCONCLUSIONS\nOur case is not a lichen planus induced by Etanercept, but it is aggravated and secondary infected with Methicillin-sensitive Staphylococcus during the therapy. The additional cardiac complication (hypertrophic cardiomyopathy) may represent solely an evolutive sign of rheumatoid arthritis and therefore not influenced by Etanercept.",
"affiliations": "Department of Surgery, \"Grigore T. Popa\" University of Medicine and Pharmacy, Iassy, Romania; lilifoia@yahoo.co.uk.",
"authors": "Chiriac|Anca|A|;Foia|Liliana|L|;Chiriac|Anca E|AE|;Ancuţa|Codrina|C|;Manea|Paloma|P|;Profire|Lenuţa|L|;Filip|Florina|F|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1220-0522",
"issue": "54(3 Suppl)",
"journal": "Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie",
"keywords": null,
"medline_ta": "Rom J Morphol Embryol",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D001691:Biological Therapy; D004452:Echocardiography; D005260:Female; D006801:Humans; D008010:Lichen Planus; D008875:Middle Aged",
"nlm_unique_id": "9112454",
"other_id": null,
"pages": "829-31",
"pmc": null,
"pmid": "24322035",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lichen planus secondary complications associated with the use of biologic therapy for rheumatoid arthritis.",
"title_normalized": "lichen planus secondary complications associated with the use of biologic therapy for rheumatoid arthritis"
} | [
{
"companynumb": "PHHY2014RO090094",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": null,
"drug... |
{
"abstract": "A 66-year-old man with hypertension presented with complaints of excessive daytime sleepiness (Epworth Sleepiness Score 14/24), dyspnea upon exertion, and episodes of noninjurious dream-enacting behavior. He reported tongue biting when sleeping in the right lateral decubitus position. Medications included atenolol 12.5 mg, lovastatin 20 mg, doxazosin 2 mg, amlodipine 5 mg, isosorbide mononitrate 60 mg, and aspirin 81 mg. He denied headaches, visual changes, dysarthria, dysphagia, or localized weakness. He denied use of alcohol, tobacco, or drugs.",
"affiliations": "Department of Neurology, Division of Sleep Medicine, Louisiana State University School of Medicine, Shreveport, LA, USA.",
"authors": "DelRosso|Lourdes|L|;Gonzalez-Toledo|Eduardo|E|;Chesson|Andrew L|AL|;Hoque|Romy|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0b013e3182752cc9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "79(21)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000368:Aged; D006801:Humans; D008297:Male; D008526:Medulla Oblongata; D011187:Posture; D020182:Sleep Apnea, Central; D061205:Vascular Calcification; D014711:Vertebral Artery",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "2156-7",
"pmc": null,
"pmid": "23136263",
"pubdate": "2012-11-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Positional central apnea and vascular medullary compression.",
"title_normalized": "positional central apnea and vascular medullary compression"
} | [
{
"companynumb": "US-RANBAXY-2013US-65378",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXAZOSIN\\DOXAZOSIN MESYLATE"
},
"drugaddition... |
{
"abstract": "Strongyloides stercoralis (SS) can cause hyperinfection and disseminated infection in immunosuppressed individuals, with risk of mortality. We report the case of a cadaveric kidney transplant recipient who developed gastrointestinal symptoms and eosinophilia, approximately 3 months after transplantation. Stool examination and esophagogastroduodenoscopy with biopsies were positive for SS larvae. The patient was started on oral ivermectin and immunosuppression was reduced, but still the clinical picture got worse with metabolic ileus and respiratory symptoms, with the need for administration of subcutaneous ivermectin and combined therapy with albendazol. The patient survived and graft function was preserved. The patient was unlikely to be the source of infection. We also present a review of cases of SS infection in kidney transplant recipients.",
"affiliations": "Nephrology Department, Hospital Garcia de Orta, Almada, Portugal. Electronic address: joanaregosilva@gmail.com.;Nephrology Department, Hospital Garcia de Orta, Almada, Portugal.;Nephrology Department, Hospital Garcia de Orta, Almada, Portugal.;Nephrology Department, Hospital Garcia de Orta, Almada, Portugal.;Infectious Diseases Department, Hospital Garcia de Orta, Almada, Portugal.;Pharmacy, Hospital Garcia de Orta, Almada, Portugal.;Pharmacy, Hospital Garcia de Orta, Almada, Portugal.;Nephrology Department, Hospital Garcia de Orta, Almada, Portugal.;Nephrology Department, Hospital Garcia de Orta, Almada, Portugal.",
"authors": "Rego Silva|J|J|;Macau|R A|RA|;Mateus|A|A|;Cruz|P|P|;Aleixo|M J|MJ|;Brito|M|M|;Alcobia|A|A|;Oliveira|C|C|;Ramos|A|A|",
"chemical_list": "D000977:Antiparasitic Agents; D007559:Ivermectin; D015766:Albendazole",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.02.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "50(3)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D015766:Albendazole; D000818:Animals; D000977:Antiparasitic Agents; D001706:Biopsy; D004359:Drug Therapy, Combination; D004802:Eosinophilia; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D007559:Ivermectin; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis; D015163:Superinfection",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "861-866",
"pmc": null,
"pmid": "29661454",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Strongyloides stercoralis Hyperinfection in a Kidney Transplant Recipient: Case Report.",
"title_normalized": "successful treatment of strongyloides stercoralis hyperinfection in a kidney transplant recipient case report"
} | [
{
"companynumb": "PT-ACCORD-067447",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "OBJECTIVE\nPalliative Potts shunt has been proposed in children with suprasystemic pulmonary arterial hypertension (PAH).\n\n\nMETHODS\nA retrospective multicentre study was performed to assess short- and long-term outcomes after Potts shunt.\n\n\nRESULTS\nFrom 2003 to 2014, 24 children underwent a Potts shunt [19 surgical, median age: 7.7 years (1.5-17 years), median weight: 19.5 kg (10.2-47 kg) and 5 transcatheter, median age: 8.1 years (2.3-9.7 years), median weight: 22 kg (12.5-31 kg)] for drug-refractory PAH. For the first time in humans, we performed an unidirectional valved Potts anastomosis in a child with infrasystemic PAH on intravenous epoprostenol who experienced repeated central line infections. Severe postoperative complications occurred in 6 patients (25.0%, all from the surgical group) including 3 early deaths (12.5%) related to low cardiac output. After a median follow-up (FU) of 2.1 years (range, 3 months to 14.3 years, ≥8 years in 7 patients), World Health Organization (WHO) functional class was dramatically improved in the 21 survivors, all being in WHO-functional class 1 or 2 (P < 0.05); none experienced syncope during the FU; none had overt right ventricular failure; mean 6-min walk distance improved from 42.3 ± 10.0% to 81.2 ± 9.7% of adjusted values for age and sex (P < 0.001), BNP/NT-proBNP levels normalized in all; and weaning of intravenous epoprostenol was obtained in all patients who received triple combination as pre-Potts anastomosis therapy. Finally, all survivors caught up to normal growth curves. Arterial oxygen saturation gradient between upper and lower limbs persisted at the last FU (94.7 ± 3.6% vs 81.6 ± 5.1%, P < 0.001). One patient required double lung transplantation 6 years after a surgical Potts shunt.\n\n\nCONCLUSIONS\nPalliative Potts shunt allows prolonged survival and dramatic, long-lasting improvement in functional capacities in children with severe, drug-refractory PAH. The Potts shunt might be considered as a first surgical or interventional step in the management of children with severe, drug-refractory PAH, leaving the door open for further lung transplantation, if needed.",
"affiliations": "Marie Lannelongue Hospital, Pediatric and Congenital Cardiac Surgery, M3C, Reference Center for Complex Congenital Heart Diseases, Le Plessis Robinson, France Paris Sud University, Le Kremlin Bicêtre, France a.baruteau@gmail.com.;Marie Lannelongue Hospital, Pediatric and Congenital Cardiac Surgery, M3C, Reference Center for Complex Congenital Heart Diseases, Le Plessis Robinson, France.;AP-HP, Necker Hospital for Sick Children, Pediatric Cardiology, M3C, Reference Center for Complex Congenital Heart Diseases, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.;Marie Lannelongue Hospital, Pediatric and Congenital Cardiac Surgery, M3C, Reference Center for Complex Congenital Heart Diseases, Le Plessis Robinson, France.;AP-HP, Necker Hospital for Sick Children, Pediatric Cardiology, M3C, Reference Center for Complex Congenital Heart Diseases, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.;Paris Sud University, Le Kremlin Bicêtre, France AP-HP, Bicêtre Hospital, Pneumology, Reference Center for Severe Pulmonary Hypertension, TORINO, Le Kremlin-Bicêtre, France INSERM UMR 999, LabEx-LERMIT, Marie Lannelongue Hospital, Le Plessis Robinson, France.;Pediatric Cardiac Surgery, Bambino Gesu Children's Hospital, IRCCS, Rome, Italy.;Paris Sud University, Le Kremlin Bicêtre, France AP-HP, Bicêtre Hospital, Pneumology, Reference Center for Severe Pulmonary Hypertension, TORINO, Le Kremlin-Bicêtre, France INSERM UMR 999, LabEx-LERMIT, Marie Lannelongue Hospital, Le Plessis Robinson, France.;AP-HP, Necker Hospital for Sick Children, Pediatric Cardiology, M3C, Reference Center for Complex Congenital Heart Diseases, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.",
"authors": "Baruteau|Alban-Elouen|AE|;Belli|Emre|E|;Boudjemline|Younes|Y|;Laux|Daniela|D|;Lévy|Marilyne|M|;Simonneau|Gérald|G|;Carotti|Adriano|A|;Humbert|Marc|M|;Bonnet|Damien|D|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1093/ejcts/ezu445",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1010-7940",
"issue": "47(3)",
"journal": "European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery",
"keywords": "Paediatric; Potts shunt; Pulmonary arterial hypertension",
"medline_ta": "Eur J Cardiothorac Surg",
"mesh_terms": "D000293:Adolescent; D000714:Anastomosis, Surgical; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D007223:Infant; D008297:Male; D010166:Palliative Care; D012189:Retrospective Studies",
"nlm_unique_id": "8804069",
"other_id": null,
"pages": "e105-10",
"pmc": null,
"pmid": "25475943",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Palliative Potts shunt for the treatment of children with drug-refractory pulmonary arterial hypertension: updated data from the first 24 patients.",
"title_normalized": "palliative potts shunt for the treatment of children with drug refractory pulmonary arterial hypertension updated data from the first 24 patients"
} | [
{
"companynumb": "FR-ACTELION-A-CH2015-113271",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SILDENAFIL"
},
"drugadditional": null,
... |
{
"abstract": "Secondary neoplasias are well known consequences of radiotherapy or chemotherapy for a primary cancer. In this report, we describe two rare secondary neoplasias occurring in the same patient: a meningioma-like intracranial tumor and high-risk myelodysplastic syndrome (MDS) of donor-cells origin, both diagnosed simultaneously, 8 years after an allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic lymphocytic leukemia (CLL). Due to an engraftment failure during the first allo-HSCT of a matched related donor for CLL treatment, the salvage treatment was a second allo-HSCT. At the moment of meningioma-like tumor diagnosis, the patient was pancytopenic due to high-risk MDS, so it was decided to postpone a surgical intervention until hematological improvement. For the high-risk MDS of donor-cells origin the chosen treatment was induction with intensive chemotherapy. Due to refractory disease, the patient was treated with 5-azacitidine and donor-lymphocytes infusion with no response and, finally, a third allo-HSCT of a matched unrelated donor was performed. The patient died 6 months after the third allo-HSCT, in cytogenetic remission but without hematological recovery, due to an intracranial hemorrhage with origin in the meningioma-like tumor.",
"affiliations": "Serviço de Transplante de Medula Óssea, Instituto Português de Oncologia do Porto, Porto, Portugal.;Serviço de Transplante de Medula Óssea, Instituto Português de Oncologia do Porto, Porto, Portugal.;Serviço de Transplante de Medula Óssea, Instituto Português de Oncologia do Porto, Porto, Portugal.",
"authors": "Brás|G|G|0000-0001-7654-1151;Pinho-Vaz|C|C|;Campos|A|A|0000-0002-7110-0792",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2017/9674385",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2017/9674385Case ReportDonor-Cell Origin High-Risk Myelodysplastic Syndrome Synchronous with an Intracranial Meningioma-Like Tumor, 8 Years after Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia http://orcid.org/0000-0001-7654-1151Brás G. \n*\nPinho-Vaz C. http://orcid.org/0000-0002-7110-0792Campos A. Serviço de Transplante de Medula Óssea, Instituto Português de Oncologia do Porto, Porto, Portugal*G. Brás: gpaivabras@gmail.comAcademic Editor: Thomas R. Chauncey\n\n2017 3 8 2017 2017 967438526 3 2017 5 7 2017 Copyright © 2017 G. Brás et al.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Secondary neoplasias are well known consequences of radiotherapy or chemotherapy for a primary cancer. In this report, we describe two rare secondary neoplasias occurring in the same patient: a meningioma-like intracranial tumor and high-risk myelodysplastic syndrome (MDS) of donor-cells origin, both diagnosed simultaneously, 8 years after an allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic lymphocytic leukemia (CLL). Due to an engraftment failure during the first allo-HSCT of a matched related donor for CLL treatment, the salvage treatment was a second allo-HSCT. At the moment of meningioma-like tumor diagnosis, the patient was pancytopenic due to high-risk MDS, so it was decided to postpone a surgical intervention until hematological improvement. For the high-risk MDS of donor-cells origin the chosen treatment was induction with intensive chemotherapy. Due to refractory disease, the patient was treated with 5-azacitidine and donor-lymphocytes infusion with no response and, finally, a third allo-HSCT of a matched unrelated donor was performed. The patient died 6 months after the third allo-HSCT, in cytogenetic remission but without hematological recovery, due to an intracranial hemorrhage with origin in the meningioma-like tumor.\n==== Body\n1. Introduction\nAllogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT) is the only curative approach for the majority of hematooncological diseases. The major limitations of the Allo-HSCT are the short and long-term toxicities related to the procedure. The recent advances in transplantation techniques and supportive care were responsible for a decrease in therapy-related mortality and improvement of overall survival (OS). Increasing the OS leads us to the problematic secondary neoplasias. During the first year after HSCT, apart from relapse, posttransplant lymphoproliferative disorder is the most frequent secondary malignancy with a cumulative incidence between 0,6 and 1,4% in allo-HSCT and extremely rare in autologous HSCT (auto-HSCT). In terms of secondary solid cancers, the cumulative incidence increases over time: 1-2% at 5 years; 2–6% at 10 years, and 3–15% at 15 years. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have an incidence of 5–15% at 5 years after auto-HSCT, but extremely rare after allo-HSCT [1]. The main risk factors for MDS/AML in patients previously treated for hematological diseases are older age prior to HSCT, the type and intensity of pre-HSCT chemotherapy, and total-body irradiation (TBI) in allo-HSCT conditioning [2]. This report describes two rare events in the same patient: donor-cell origin MDS/leukemia and a meningioma-like intracranial tumor, both diagnosed simultaneously, 8 years after allo-HSCT. In a large retrospective survey of the European Group for Blood and Marrow Transplantation (EBMT), the estimated incidence of donor-cell origin MDS/leukemia after allo-HSCT was less than 1% [3]. The true incidence of meningioma after allo-HSCT is unknown. It has been more frequently described in children cancer survivors exposed to cranial radiotherapy [4]. In a retrospective cohort of acute lymphoblastic leukemia (ALL) childhood survivors, brain tumors were the most prevalent secondary solid cancer and 89% of those patients were exposed to cranial irradiation. In this cohort, the prevalence of meningiomas was 3,4% with a median time for presentation, since ALL diagnosis, of 16 (12–18) years [5]. Intracranial granulocytic sarcomas are an important differential diagnosis with meningiomas, in patients with concurrent acute myeloid leukemia. In a retrospective study of 21 reported cases of intracranial myeloid sarcoma, 11 (52,4%) presented with meningioma-like lesions [6].\n\n2. Case Report\nA 57-year-old Caucasian male was diagnosed with chronic lymphocytic leukemia (CLL), stage II-B in Rai-Binet System, and unknown cytogenetic risk, in 1998. The CLL was refractory to fludarabine and cyclophosphamide (FC). In September of 2001, an allo-HSCT of a matched related donor (brother) was performed with reduced-intensity conditioning (RIC) of fludarabine and busulfan (FluBu). The acute graft-versus-host disease (aGVHD) prophylaxis was cyclosporine (Csp) and mycophenolate mofetil (MMF). Engraftment failure occurred and a second allo-HSCT of the same donor after RIC with fludarabine and cyclophosphamide plus in vivo lymphodepletion with alemtuzumab was performed. The aGVHD prophylaxis was Csp and MMF again. After successful engraftment and hematological recovery, bone marrow evaluation confirmed complete remission (CR). During the posttransplant follow-up period, neither aGVHD nor chronic GHVD (cGVHD) was observed.\n\nIn March of 2009, due to headache and behavioural alterations, a cerebral magnetic resonance imaging (MRI) was performed and showed an intracranial extra-axial expansive lesion in the anterior cranial fossa measuring 2,7 × 2,7 × 3,3 cm of transversal, cranial-caudal, and anterior-posterior diameters, respectively, suggestive of olfactory groove meningioma (Figure 1). No cerebrospinal fluid evaluation (cytological or immunophenotypical) was made.\n\nDuring evaluation for neurosurgery, in May of 2009, after almost 8 years in CR for CLL, the patient presented with pancytopenia. A diagnosis of myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) was made based on a bone marrow smear with dysplastic features, blast count of 11%, and karyotype with monosomy 7 in 14 of 20 metaphases. Chimerism analysis by polymerase chain reaction of short tandem repeats (STR-PCR) showed full-donor chimerism in all lineages, which confirmed the donor-cell origin for the MDS. To investigate occult MDS, the donor bone marrow was evaluated and showed no dysplastic features or cytogenetic abnormalities. The donor is currently free of any hematological disease.\n\nNeurosurgical intervention was postponed until resolution of the hematological disease. The MDS-EB-2 was resistant to intensive chemotherapy (cytarabine, daunorubicin, and Csp). Between October of 2009 and February of 2010, the patient went on second-line treatment with 5-azacitidine, abandoned at the end of 4 cycles due to absence of hematological and cytogenetical response. Between May and August of 2010, donor lymphocyte infusions (DLI) were performed twice, with CD3 cells doses of 1 × 107/kg and 1 × 108/kg, respectively, with no response. In January of 2011, a matched unrelated donor (MUD) was identified, which allowed a third allo-HSCT in February of 2011. Prior to the HSCT, the patient was pancytopenic with a bone marrow blast count of 5,5% and a karyotype with monosomy 7. The chosen conditioning regimen was fludarabine and melphalan plus in vivo lymphodepletion with alemtuzumab. The aGVHD prophylaxis was tacrolimus and MMF. In March of 2011, within 1 month of allo-HSCT, the meningioma-like lesion was revaluated by MRI and there was a significant increase in its dimensions (5,5 cm × 3,8 cm cranial-caudal and transversal diameters), associated with oedema and mass effect (Figure 1). In May of 2011, 3 months after allo-HSCT, the patient was in cytogenetic remission, with full-donor chimerism of all lineages in peripheral blood and bone marrow, but with no hematological recovery (hemoglobin 86 g/L, leucocytes 2,7 × 109/L, neutrophils 2,2 × 109/L, and platelets 22 × 109/L). Cytomegalovirus (CMV) reactivation was also diagnosed and daily ganciclovir was started.\n\nIn June of 2011, the patient complained of headaches again. The meningioma-like lesion was reassessed by MRI, which showed an increase in size (4,5 × 4,8 × 5,9 cm of major diameters), in relation to intratumor hemorrhage, worsening of oedema, and mass effect (Figure 1). The neurosurgery group decision was conservative management until hematological recovery, given the risk of carrying out surgery with low platelets number. In July of 2011, the patient was hospitalized due to altered mental status and died of intracranial hemorrhage in the meningioma-like tumor.\n\n3. Discussion\nIn terms of etiology for donor-cell MDS/leukemia, the possible explanations are divided into two groups: donor-cell factors and host factors [7]. For donor-cell factors, the high proliferative demands after HSCT might increase the likelihood of replication errors, mutations, and telomeres shortening, ensuing clonal evolution of engrafted donor cells [7, 8]. The escape to immunosurveillance in posttransplant period, due to immunosupression, might be an explanation for the advantage and persistence of the abnormal clone. The exposure to chemotherapy prior to HSCT, namely, in conditioning, has been considered a possible risk factor to induce clonal changes in donor cells [8]. Another hypothesis is the transfer of occult leukemic cells or cells with mutations (clonal hematopoiesis) from the donor, with potential to evolve to MDS/leukemia [9, 10]. In terms of host factors, the bone marrow microenvironment suffers important changes after conditioning, favouring growth, and survival of abnormal clones: (a) chromosomal abnormalities were described in nonhematopoietic cells from the bone marrow of MDS and AML patients; (b) stromal cells of patients with MDS and AML can be permanently activated, with a pattern of cytokine and growth-factors expression that promotes proliferative advantage of abnormal clones [9]. The majority of donor-cell origin leukemias are acute myeloid leukemia, even when the previous disease is of lymphoid origin and this fact raises the hypothesis of an imbalance favouring the myeloid abnormal clonal differentiation, after HSCT [8]. The donor was evaluated to exclude occult hematological disease. He was evaluated by morphology and karyotype. Mutational studies were not performed, so we are unable to exclude a case of occult donor clonal hematopoiesis.\n\nThe first in vivo reports of donor-cell MDS/leukemia were made by cytogenetic evaluation of sex-mismatched allo-HSCT, showing abnormalities in a karyotype of different sex [11]. A few years later, the development of restriction fragment length polymorphisms (RFLP) techniques was the major contributor to diagnose donor-cell MDS/leukemia of donor/recipient sex matched allo-HSCT [12]. Nowadays, the STR genotyping has been the most widely used technique to determine the postengraftment chimerism status and the origin of relapsing MDS/leukemia in this type of allo-HSCT [3, 13]. In allo-HSCT with donor/recipient sex match, as this particular report, our centre uses STR-PCR because it is highly sensitive and fast and detects polymorphic regions distinctive of each individual, independent of sex-mismatching.\n\nThe treatment of donor-cell MDS/leukemia is also subject of debate. In a multicentre retrospective study, from 14 patients with donor-cell leukemia, 9 were treated with intensive chemotherapy, and CR was achieved in 6 (66,7%) patients [3]. Only one patient had monosomy 7 at the moment of donor-cell leukemia diagnosis and was in progression after rescue intensive chemotherapy, like our patient. Hypomethylating agents (HMA) have been used in MDS/AML relapsing after allo-HSCT. Two possible approaches have been proposed: HMA alone or followed by DLI [14, 15]. In our report, we decided to use 5-azacitidine alone. No response was achieved after 4 cycles. DLI was performed, not in a sequential strategy after HMA, but in context of refractory disease after HMA. There are no prospective and randomized trials comparing intensive chemotherapy versus HMA in relapse after allo-HSCT. In a retrospective cohort, the use of conventional salvage intensive chemotherapy, preferentially followed by DLI, was associated with better outcomes in terms of response and survival than HMA [16]. There is scarce data about the efficacy of DLI in donor-cell MDS/leukemia. In a single report, DLI was successfully used in donor-cell MDS and the rationale was the graft-versus-leukemia (GVL) effect of DLI, even against cells of the same donor [17]. The malignant cells probably acquire neoantigens during the transformation process that enables an immunological response. Additionally, lymphocytes produce IL-6, a cytokine that plays an important role in hematopoiesis stimulation to promote hematological recovery [17]. This report differs from ours in terms of disease characteristics: the blast count was 1% and the karyotype was normal. The only approach that led to a response, in our report, was a new allo-HSCT from a different donor. The rationale to choose a different donor was to potentiate the GVL effect against an aggressive disease that was resistant to conventional chemotherapy, HMA, and DLI. Although the patient did not achieve hematological recovery he was in complete cytogenetic remission with full-donor chimerism of all lineages in bone marrow and peripheral blood. The lack of hematological recovery might be explained by CMV reactivation or by an adverse microenvironment for a full engraftment, due to previous chemotherapy exposure or MDS itself.\n\nSecondary brain tumors are rare events after bone marrow transplantation [2]. Meningiomas are tumors of the meninges that occur sporadically with not known aetiology. The radiation exposure during cancer treatment (cranial radiotherapy or TBI in conditioning for allo-HSTC) has been recognized as the main risk factor for meningioma in cancer survivors [4]. Intrathecal methotrexate has also been implicated as risk factor [18]. In our report, there is no exposure to high doses of radiation or intrathecal methotrexate. There is no published data showing a relation between systemic chemotherapy and meningioma risk. Another hypothesis to be considered is the possibility that the meningioma-like lesion was actually a granulocytic sarcoma, due to a synchronous diagnosis with the MDS-EB-2. In a retrospective study, of 21 reported cases of intracranial myeloid sarcoma, 11 (52,4%) presented with meningioma-like lesions, and from those, 7 presented in association with vasogenic oedema [6]. There is a report of a granulocytic sarcoma mimicking a falx meningioma [19]. In that particular case, the diagnosis was confirmed after surgery and the cerebrospinal liquid analysis was negative for leukemic cells. In our report we were unable to perform histological diagnosis of the meningioma-like lesion. The lesion, apparently, remained stable between 2009 and 2011, period of the rescue intensive chemotherapy, 5-azacitidine, and DLI. The increase in tumor mass one month after allo-HSCT was due to intratumor hemorrhage, probably in relation to thrombocytopenia. Considering that central nervous system myeloid sarcomas may mimic meningioma lesions, efforts should be made to biopsy meningioma-like lesions in patients with myeloid malignancies. In a prospective study of postmortem evaluation of neuropathological complications after bone marrow transplantation, of 371 deaths in a cohort of 845 transplants, 180 autopsies with brain evaluation were performed. Central nervous system abnormalities were found in about one of every 2.3 deaths but brain tumors were not found, even in patients exposed to TBI [20]. In a retrospective cohort of 111 patients who underwent autopsy after HSCT, there were no cases of brain tumor reported. The premortem and postmortem diagnosis differed in 26% of cases, and the autopsy provided important clues to change the therapeutic approach in 4% [21]. Considering these data, the role of autopsy after HSCT might be controversial in cases of clinical obvious cause of death; nevertheless, postmortem diagnosis can be important in cases of unknown cause of death and cases with atypical and rare clinical presentation, like this report. The correlation between image and histology, even in postmortem evaluation, might be important to improve our knowledge about the radiologic patterns that different types of secondary brain tumors might present.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nFigure 1 Meningioma-like tumor evolution since diagnosis until patient death.\n==== Refs\n1 Majhail N. S. Secondary cancers following allogeneic haematopoietic cell transplantation in adults British Journal of Haematology 2011 154 3 301 310 2-s2.0-79960215975 10.1111/j.1365-2141.2011.08756.x 21615719 \n2 Majhail N. S. Old and new cancers after hematopoietic-cell transplantation Hematology 2008 2008 1 142 149 10.1182/asheducation-2008.1.142 \n3 Hertenstein B. Hambach L. Bacigalupo A. Development of leukemia in donor cells after allogeneic stem cell transplantation—a survey of the European Group for Blood and Marrow Transplantation (EBMT) Haematologica 2005 90 7 969 975 2-s2.0-22544456008 15996934 \n4 Sugden E. Taylor A. Pretorius P. Kennedy C. Bhangoo R. Meningiomas occurring during long-term survival after treatment for childhood cancer JRSM Open 2014 5 4, article 205427041452456 10.1177/2054270414524567 \n5 Schmiegelow K. Levinsen M. F. Attarbaschi A. Second malignant neoplasms after treatment of childhood acute lymphoblastic leukemia Journal of Clinical Oncology 2013 31 19 2469 2476 10.1200/JCO.2012.47.0500 2-s2.0-84883119415 23690411 \n6 Cervantes G. Cayci Z. Intracranial CNS manifestations of myeloid sarcoma in patients with acute myeloid leukemia: review of the literature and three case reports from the author’s institution Journal of Clinical Medicine 2015 4 5 1102 1112 10.3390/jcm4051102 26239467 \n7 Torra O. S. Loeb K. R. Donor cell-derived leukemia and myelodysplastic neoplasm: unique forms of leukemia American Journal of Clinical Pathology 2011 135 4 501 504 10.1309/AJCPXW8DKEG5QMTB 2-s2.0-79954618965 21411772 \n8 Flynn C. M. Kaufman D. S. Donor cell leukemia: insight into cancer stem cells and the stem cell niche Blood 2007 109 7 2688 2692 10.1182/blood-2006-07-021980 2-s2.0-33947574961 17132724 \n9 Wiseman D. H. Donor cell leukemia: a review Biology of Blood and Marrow Transplantation 2011 17 6 771 789 10.1016/j.bbmt.2010.10.010 2-s2.0-79956018813 20951819 \n10 Gondek L. P. Zheng G. Ghiaur G. Donor cell leukemia arising from clonal hematopoiesis after bone marrow transplantation Leukemia 2016 30 9 1916 1920 2-s2.0-84964048177 10.1038/leu.2016.63 26975880 \n11 Fialkow P. J. Bryant J. I. Thomas E. D. Neiman P. E. Leukaemic transformation of engrafted human marrow cells in vivo The Lancet 1971 297 7693 251 255 10.1016/s0140-6736(71)90998-6 2-s2.0-0015212414 \n12 Witherspoon R. P. Schubach W. Neiman P. Martin P. Thomas E. D. Donor cell leukemia developing six years after marrow grafting for acute leukemia Blood 1985 65 5 1172 1174 2-s2.0-0021928346 2986742 \n13 Khan F. Agarwal A. Agrawal S. Significance of chimerism in hematopoietic stem cell transplantation: new variations on an old theme Bone Marrow Transplantation 2004 34 1 1 12 10.1038/sj.bmt.1704525 2-s2.0-3543143611 15156163 \n14 Tessoulin B. Delaunay J. Chevallier P. Azacitidine salvage therapy for relapse of myeloid malignancies following allogeneic hematopoietic SCT Bone Marrow Transplantation 2014 49 4 567 571 2-s2.0-84897560646 10.1038/bmt.2013.233 24488048 \n15 Schroeder T. Rachlis E. Bug G. Treatment of Acute Myeloid Leukemia or Myelodysplastic Syndrome Relapse after Allogeneic Stem Cell Transplantation with Azacitidine and Donor Lymphocyte Infusions-A Retrospective Multicenter Analysis from the German Cooperative Transplant Study Group Biology of Blood and Marrow Transplantation 2015 21 4 653 660 2-s2.0-84924243091 10.1016/j.bbmt.2014.12.016 25540937 \n16 Motabi I. H. Ghobadi A. Liu J. Chemotherapy versus Hypomethylating Agents for the Treatment of Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndrome after Allogeneic Stem Cell Transplant Biology of Blood and Marrow Transplantation 2016 22 7 1324 1329 2-s2.0-84969228273 10.1016/j.bbmt.2016.03.023 27026249 \n17 Komrokji R. Ifthikharuddin J. J. Felgar R. E. Donor cell myelodysplastic syndrome after allogeneic stem cell transplantation responding to donor lymphocyte infusion: case report and literature review American Journal of Hematology 2004 76 4 389 394 10.1002/ajh.20111 2-s2.0-3342965841 15282676 \n18 Taylor A. Little M. P. Winter D. L. Population-based risks of central nervous system tumours in childhood cancer survivors: the British Childhood Cancer Survivor Study Journal of Clinical Oncology 2010 28 36 5287 5293 21079138 \n19 Ahn J. Y. Choi E. W. Kang S. H. Kim Y. R. Isolated meningeal chloroma (granulocytic sarcoma) in a child with acute lymphoblastic leukemia mimicking a falx meningioma Child's Nervous System 2002 18 3-4 153 156 2-s2.0-0036555988 10.1007/s00381-002-0553-8 \n20 Bleggi-Torres L. F. De Medeiros B. C. Werner B. Neuropathological findings after bone marrow transplantation: An autopsy study of 180 cases Bone Marrow Transplantation 2000 25 3 301 307 2-s2.0-0033970410 10.1038/sj.bmt.1702140 10673702 \n21 Hofmeister C. C. Marinier D. E. Czerlanis C. Stiff P. J. Clinical Utility of Autopsy after Hematopoietic Stem Cell Transplantation Biology of Blood and Marrow Transplantation 2007 13 1 26 30 2-s2.0-33845995825 10.1016/j.bbmt.2006.09.006 17222749\n\n",
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"title": "Donor-Cell Origin High-Risk Myelodysplastic Syndrome Synchronous with an Intracranial Meningioma-Like Tumor, 8 Years after Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia.",
"title_normalized": "donor cell origin high risk myelodysplastic syndrome synchronous with an intracranial meningioma like tumor 8 years after allogeneic hematopoietic stem cell transplantation for chronic lymphocytic leukemia"
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"abstract": "Severe prolonged hypotension developed in a hypertensive patient several hours after the initial doses of minoxidil therapy. Hemodynamic measurements revealed a markedly low systemic vascular resistance and a markedly high cardiac output. Other causes of hypotension were ruled out. The patient's hemodynamic abnormalities lasted three days after minoxidil therapy was discontinued, and she then reverted to hypertension. Thus, a 10-mg starting dose of minoxidil may produce profound life-threatening hypotension, which can last up to 72 hours.",
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"title": "Prolonged hypotension after initial minoxidil dose.",
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"abstract": "A 66-year-old woman with a history of diabetes presented with an intermittent low-grade fever, cough, shortness of breath, and decreased activity tolerance over a 3-month period. She is a farmer, and denied a history of chronic pulmonary disease. Her only medical history was type 2 diabetes managed without medication. She denied smoking or tobacco use. She did not report any recent travel and denied having birds at home. Imaging at a local hospital showed left lower lobe atelectasis with a small pleural effusion. An infection with mucormycosis was diagnosed through transbronchial biopsy. The patient was given nebulized amphotericin B along with concurrent IV liposomal amphotericin B for a total of 15 days. She experienced no significant improvement in symptoms during therapy and, in fact, developed worsening, progressive dyspnea.",
"affiliations": "Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, China.;Department of Pediatrics, Peking University First Hospital, Beijing, China.;Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China.;Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China.;Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, China.;Respiratory and Critical Care Medicine, Peking University First Hospital, Beijing, China. Electronic address: quechengli@bjmu.edu.cn.",
"authors": "Yu|Qing|Q|;Zhang|Qingping|Q|;Yu|Jin|J|;Song|Yinggai|Y|;Zhang|Wei|W|;Que|Chengli|C|",
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"title": "A 66-Year-Old Woman With Progressive Dyspnea and Obstructive Pneumonia.",
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"abstract": "Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder, and only a few cases have been reported to be complicated with autoimmune hemolytic anemia (AIHA). A 43-year-old man who presented with multiple swollen lymph nodes was diagnosed with iMCD. He was also diagnosed with AIHA based on laboratory findings, including the results of a bone marrow aspiration study. The patient was treated with tocilizumab; however, the effect was limited, probably due to anti-drug antibodies. Tocilizumab was therefore switched to rituximab, and his anemia was improved. Complication with AIHA should be carefully considered when iMCD patients present with severe anemia.",
"affiliations": "Department of Internal Medicine, Japan Self Defense Forces Central Hospital, Japan.;Department of Internal Medicine, Japan Self Defense Forces Central Hospital, Japan.;Department of Internal Medicine, Japan Self Defense Forces Central Hospital, Japan.;Department of Internal Medicine, Japan Self Defense Forces Central Hospital, Japan.;Department of Pathology, Japan Self Defense Forces Central Hospital, Japan.;Department of Pathology, Japan Self Defense Forces Central Hospital, Japan.;Department of Internal Medicine, Japan Self Defense Forces Central Hospital, Japan.",
"authors": "Tabata|Sakiko|S|;Higuchi|Tomoaki|T|;Tatsukawa|Seishiro|S|;Narimatsu|Kazuyuki|K|;Takeo|Hiroaki|H|;Matsukuma|Susumu|S|;Ito|Toshimitsu|T|",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3129238910.2169/internalmedicine.2989-19Case ReportIdiopathic Multicentric Castleman Disease with Autoimmune Hemolytic Anemia and Production of Anti-drug Antibody against Tocilizumab Tabata Sakiko 1Higuchi Tomoaki 1Tatsukawa Seishiro 1Narimatsu Kazuyuki 1Takeo Hiroaki 2Matsukuma Susumu 2Ito Toshimitsu 1\n1 Department of Internal Medicine, Japan Self Defense Forces Central Hospital, Japan\n2 Department of Pathology, Japan Self Defense Forces Central Hospital, JapanCorrespondence to Dr. Toshimitsu Ito, itohtm38@yahoo.co.jp\n\n10 7 2019 15 11 2019 58 22 3313 3318 7 3 2019 14 5 2019 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder, and only a few cases have been reported to be complicated with autoimmune hemolytic anemia (AIHA). A 43-year-old man who presented with multiple swollen lymph nodes was diagnosed with iMCD. He was also diagnosed with AIHA based on laboratory findings, including the results of a bone marrow aspiration study. The patient was treated with tocilizumab; however, the effect was limited, probably due to anti-drug antibodies. Tocilizumab was therefore switched to rituximab, and his anemia was improved. Complication with AIHA should be carefully considered when iMCD patients present with severe anemia. \n\nmulticentric Castleman diseaseautoimmune hemolytic anemiatocilizumabanti-drug antibody\n==== Body\nIntroduction\nCastleman disease (CD) is a rare lymphoproliferative disorder that is classified into two types: unicentric CD (UCD) and multicentric CD (MCD) (1). Approximately 50% of MCD cases are associated with human herpesvirus-8 (HHV-8) infection (1). Uncontrolled infection causes hypercytokinemia and polyclonal lymphoproliferation. The other half of MCD cases are HHV-8-negative and are called idiopathic MCD (iMCD). The etiology of iMCD is still unknown; however, excessive production of cytokines, including interleukin-6 (IL-6), is thought to enlarge the lymph nodes and give rise to other symptoms (2,3).\n\nAt present, four hypotheses propose that this so-called cytokine storm may be the consequence of uncontrolled infection with some pathogen other than HHV-8 (pathogen hypothesis), autoantibodies or auto-reactive T cells that activate immune reactions (autoimmune hypothesis), germline mutations regulating inflammation (autoinflammatory hypothesis), and somatic mutations in monoclonal lymph node cells that lead to ectopic cytokine secretion (paraneoplastic mechanisms) (3).\n\nThe diagnostic criteria of iMCD established by the international working group include the pathologic review of enlarged lymph nodes, typical clinical/laboratory findings, and the exclusion of other diseases that have MCD-like features (4). Common symptoms in patients with iMCD are a fever, night sweats, weight loss, an enlarged liver or spleen, edema, and ascites. Laboratory findings frequently show elevated levels of soluble interleukin 2 receptor (sIL-2R), IL-6, and C-reactive protein (CRP); an elevated erythrocyte sedimentation rate (ESR); hypoalbuminemia; and anemia (3). Patients with iMCD sometimes have, concomitantly, other autoimmune diseases, such as systemic lupus erythematosus and hemophagocytic lymphohistiocytosis (3). Although cases of iMCD accompanied by autoimmune hemolytic anemia (AIHA) have been reported, it remains a very rare complication (5-9).\n\nWe herein report a rare case of iMCD complicated with severe AIHA.\n\nCase Report\nA 43-year-old man was admitted to our hospital complaining of shortness of breath and general fatigue. He had noticed these symptoms 2 months before admission and had lost 8 kg of body weight in that same period. Starting from the day before he came to our hospital, he had developed a fever of 37°C, and the symptoms had substantially worsened.\n\nOn admission, his body temperature was 39°C, his blood pressure 100/52 mmHg, and his heart rate 100 bpm. A physical examination revealed jaundice; anemic conjunctiva; hepatosplenomegaly; systolic murmur; and swollen lymph nodes in the bilateral cervix, axilla, and inguen. Laboratory findings were as shown in Table 1. Serum protein immunoelectrophoresis showed polyclonal hypergammaglobulinemia with a free light chain κ/λ ratio of 1.57. Bence Jones protein was not detected in the urine analysis. Computed tomography (CT) showed the enlargement of the lymph nodes at multiple sites (bilateral cervix, axilla, inguen, mediastinum, and abdominal and retroperitoneal cavities) and splenomegaly. Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) revealed an abnormal uptake in the lymph nodes in the cervix [maximum standardized uptake value (SUVmax): right 4.65, left 3.80], axilla (SUVmax: right 4.51, left 4.51), inguen (SUVmax: right 4.50, left 4.30), mediastinum (SUVmax: right 3.96, left 4.06), and external iliac (SUVmax: right 4.94, left 5.03) (Fig. 1). A biopsy of a right posterior cervical lymph node revealed hyperplastic lymphoid follicles and plasma cell infiltration in the interfollicular areas, which was consistent with the plasma cell type of CD (Fig. 2).\n\nTable 1. Laboratory Data of the Present Case.\n\nHematology\tImmunology\t\nWBC\t7,484\t/µL\tCRP\t9.04\tmg/dL\t\nNeutro\t57.8\t%\tIL-6\t67.5\tpg/mL\t\nLymph\t31.5\t%\tIgG\t8,338\tmg/dL\t\nEosino\t1.4\t%\tIgA\t649\tmg/dL\t\nBaso\t0.9\t%\tIgM\t121\tmg/dL\t\nRBC\t220×104\t/µL\tsIL-2R\t2,134\tU/mL\t\nMCV\t90.2\tfL\tAntineuclear antibody\t(-)\t\t\nMCHC\t31.3\t%\tRherumatoid factor\t(-)\t\t\nHb\t2.2\tg/mL\tCold agglutinin\t(-)\t\t\nRet\t88.1\t‰\tDirect Coombs’ test\t(+)\t\t\nPlt\t32.5×104\t/µL\tIndirect Coombs’ test\t(+)\t\t\nBiochemistry\tInfection\t\nTotal bilirubin\t2.25\tmg/dL\tEBV-IgM\t(-)\t\t\nDirect bilirubin\t1.16\tmg/dL\tCMV-IgM\t(+)\t\t\nAST\t12\tU/L\tHHV-8 DNA PCR\t(-)\t\t\nALT\t6\tU/L\tHIV Ab\t(-)\t\t\nNa\t132\tmEq/L\tT-SPOT\t(-)\t\t\nK\t3.3\tmEq/L\t1,3-β-D-glucan\t12\tpg/mL\t\nCl\t103\tmEq/L\tUrine\t\nCa\t7\tmg/dL\tpH\t7.5\t\t\nFe\t34\tµg/L\tGravity\t1.022\t\t\nTIBC\t132\tµg/L\tUrobilinogen\t>8.0\tmg/dL\t\nFerritin\t263.9\tng/mL\tBilirubin\t(-)\t\t\nHaptoglobin\t166\tmg/dL\tProtein\t(+)\t\t\nLDH\t138\tU/L\tBlood\t(±)\t\t\nBUN\t15\tmg/dL\t\t\t\t\nCre\t0.89\tmg/dL\t\t\t\t\t\nTotal protein\t12.4\tg/dL\t\t\t\t\nAlbumin\t2.1\tg/dL\t\t\t\t\nFolic acid\t1.8\tng/mL\t\t\t\t\t\nVit. B12\t310\tpg/mL\t\t\t\t\nWBC: white blood cell, Neutro: neutrocyte, Lymph: lymphocyte, Eosino: eosinocyte, Baso: basocyte, RBC: red blood cell, MCV: mean corpuscular volume, MCHC: mean corpuscular hemoglobin concentration, Hb: hemoglobin, Ret: reticulocyte, Plt: platelet, AST: aspartate aminotransferase, ALT: alanine aminotransferase, TIBC: total iron-binding capacity, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, Cre: creatinine, CRP: C-reactive protein, EBV: Epstein Barr virus, CMV: cytomegalo virus, HHV-8 DNA PCR: human herpes virus-8, DNA polymerase chain reaction\n\nFigure 1. Contrast-enhanced computed tomography (CT) showing the enlargement of the lymph nodes at multiple sites, including the bilateral cervix, axilla, inguen, mediastinum, abdominal cavity, and retroperitoneal cavity (upper panel). Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET) findings revealed that FDG had accumulated at these sites as well (lower panel).\n\nFigure 2. The histopathological findings of a right posterior cervical lymph node revealed the parafollicular plasma cell proliferation that was consistent with plasma cell-type Castleman disease. Right panel: original magnification ×100. Left panel: original magnification ×400.\n\nLaboratory findings included severe normocytic anemia, spherocytosis, increased reticulocyte count, positive direct and indirect Coombs test results, total/indirect hyperbilirubinemia, and increased urine urobilinogen. In addition, the results of bone marrow aspiration indicated increased erythropoiesis. Based on the above findings, a diagnosis of iMCD and AIHA was made.\n\nInitially, the patient was treated with tocilizumab at a dose of 8 mg/kg biweekly. A few days after the first tocilizumab administration, the serum CRP levels and pyrexia improved, but the anemia showed no improvement. Six days after the first tocilizumab administration, oral prednisolone (60 mg/day) was added to the treatment. However, after the second administration of tocilizumab (30 days after his admission), the patient's laboratory results worsened: the CRP levels increased and Hb levels decreased. We shortened the interval of tocilizumab to 8 mg/kg weekly, but the patient responded poorly. A blood test revealed that anti-drug antibody (ADA) against tocilizumab had been produced (7.60 ng/mL; reference value upper limit was 3.91 ng/mL), and the serum tocilizumab levels were low (11.3 μg/mL) considering the drug dose (serum levels of tocilizumab, IL-6 and ADA against tocilizumab were measured via an enzyme-linked immunosorbent assay with the cooperation of Chugai Pharmaceutical). The serum IL-6 level was 47.7 pg/mL, which should have been much higher if tocilizumab had blocked the IL-6 receptors sufficiently and worked effectively. The relatively low serum IL-6 levels, low serum tocilizumab levels, and detected ADA suggested a neutralizing effect of ADA on tocilizumab (10).\n\nAfter 6 doses of tocilizumab, we switched the therapy to rituximab (10 mg/kg biweekly). The patient's CRP levels and anemia subsequently improved (Fig. 3). He was discharged from our hospital on the 99th day and continued rituximab until the 8th dose on an outpatient basis. After the 8th dose of rituximab, his anemia, swelling of lymph nodes, and general fatigue had improved, although mild fever was still shown, and the CRP level was high.\n\nFigure 3. The clinical course of our patient with AIHA associated with MCD. Day 0 is the day when the patient was admitted to our hospital. AIHA: autoimmune hemolytic anemia, MCD: multicentric castleman disease, RBC: Red blood cells, CRP: C-reactive protein, Hb: hemoglobin, ADA: anti-drug antibody, Ret: reticulocytes\n\nDiscussion\nThe treatment guideline established by the international working group and published in 2018 present treatment options for iMCD patients classified as severe or nonsevere based on their performance status and the presence of organ failure (11). Our case was categorized as nonsevere, as although our patient's Hb was 2.2 g/dL, which is lower than 8 g/dL, a diagnostic criterion of severe organ failure, his performance status was not poor, and renal or pulmonary failure and anasarca/ascites were not detected. First-line therapy for nonsevere patients is siltuximab or tocilizumab with or without corticosteroids. Roughly 50% of patients with iMCD will not respond to IL-6 therapy, and second-line therapy for inadequate responders is rituximab and steroids with or without immunomodulatory agents (11). In our case, we administered tocilizumab biweekly plus prednisolone 60 mg/day (1 mg/kg/day) as first-line therapy, which is consistent with the treatment guideline.\n\nAnemia is a common symptom of iMCD, and iMCD is occasionally accompanied by autoimmune diseases (3). In most cases, however, anemia is due to chronic inflammation, and complication with AIHA is quite rare. To our knowledge, only five cases of MCD accompanied by AIHA have been reported to date (5-9) (Table 2). In all of those cases, the patients were successfully treated with prednisolone plus an immunosuppressive agent (i.e., rituximab, chemotherapy, or tocilizumab). All but one case showed a substantial time difference between the occurrence of MCD and hemolytic anemia (5). The patients were in remission for years, and none of the symptoms of iMCD other than AIHA were identified. This suggests that AIHA can occur irrespective of the activity of MCD itself. In our patient, anemia was normocytic with increased reticulocytes and bilirubin levels. In contrast, LDH and haptoglobin levels were within the normal range, which is inconsistent with hemolytic anemia. Although detailed mechanisms have not been revealed, LDH is often decreased in iMCD patients (12).\n\nTable 2. Reports Describing Cases of AIHA Accompanied by IMCD.\n\nNo.\tReference\tAge & Sex\tDuration between diagnosis of MCD and AIHA\tTreatment\tHb at worst \n(g/dL)\tWBC \n(/μL)\tCRP \n(mg/dL)\tHb after treatment \n(g/dL)\tDirect Coomb’s test\tLDH \n(IU/L)\tHaptoglobin \n(mg/dL)\tRet \n(‰)\t\n1\t9\t49F\t9 years later\tpredonisolone, azathioprine, cyclophosphamid, vincristine, danazol, plasmapheresis\t4.7\t6,300\t12.4\t11.2\tpositive\t606\t9.6\t118\t\n2\t5\t72M\tat the same time\tCHOP\t5\t4,900\tnot mentioned\t9\tpositive\t312\tnot mentioned\tnot mentioned\t\n3\t7\t53M\t3 years later\tR-CHOP\t2.2\t9,420\t0.95\t9.9\tpositive\tnot mentioned\tnot mentioned\t113\t\n4\t6\t23M\tseveral times since the age of 7 until 2 years before the diagnosis of MCD\trituximab\tnormal\tnot mentioned\tnot mentioned\tnot mentioned\tnot mentioned\tnot mentioned\tnot mentioned\tnot mentioned\t\n5\t8\t58F\t13 years later\tpredonisolone, tocilizmab\t4.7\t8,300\t10.1\t10.5\tpositive\tnot mentioned\tnot mentioned\t188\t\nCHOP: cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone, R-CHOP: rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone\n\nThe pathogenesis of AIHA has not been fully elucidated. However, IL-6 may have an important role (13). AIHA patients reportedly have increased serum levels of IL-6 as well as IL-4, IL-10, IL-13, IL-17, and IL-21, whereas IFN-γ levels are reduced (11). Furthermore, the presence of T helper 2 (Th2) cells, regulatory T cells, and T helper 17 (Th17) cells, which can react with the Rh peptide fraction, has been reported, suggesting that these cytokine/cells are closely associated with the activity of the disease (14). Th2 cells secrete cytokines, including IL-6, as well as IL-4, IL-10, IL-13, and TGF-β, thus stimulating B-cells to produce antibodies. In addition, IL-6 induces Th17 differentiation, amplifying the proinflammatory and autoimmune responses (15,16). Taken together, the reported evidence indicates that increased IL-6 levels in iMCD can lead to autoimmunity, which is consistent with our case, where the patient showed elevated IL-6 levels.\n\nThe previous findings also suggest that monoclonal antibodies targeting IL-6 (IL-6 mAbs) are effective for the treatment of AIHA. Kunitomi et al. described a patient with AIHA that was successfully treated with tocilizumab (17). Yuzuriha et al. successfully treated AIHA accompanied by MCD with tocilizumab (8). These reports show that Il-6 mAbs are an attractive therapeutic option for iMCD, AIHA, and overlap cases.\n\nADA production might be the reason why tocilizumab was not sufficiently effective in our case. When the efficacy of tocilizumab was diminished, we detected the presence of ADA in the patient's serum, along with serum tocilizumab levels that were lower than the effective blood concentration. In addition, the fact that IL-6 levels did not rise as much as they should have if tocilizumab had properly inhibited the IL-6 receptors suggests that tocilizumab's effect was not at its maximum.\n\nTocilizumab's immunogenicity and its impact on drug effectiveness have been evaluated in several studies. Burmester et al. assessed the data of 8,974 rheumatoid arthritis patients from previous clinical trials who were treated with intravenous or subcutaneous tocilizumab for up to five years (18). ADA production was found in only 1.2-1.5% of all patients. This study showed that ADA does not affect tocilizumab's pharmacokinetics nor the emergence of adverse effects; in fact, none of the patients who developed ADA experienced a loss of efficacy. However, another study has shown statistically significant correlations between serum tocilizumab levels higher than 10 μg/ml and ESR, CRP, and the 28-joint disease activity score in 126 rheumatoid arthritis patients after 6 months of treatment (19). These findings strongly suggest that further research is needed to clarify the relationship between ADA and tocilizumab therapy.\n\nIn our case, anemia was improved (hemoglobin: 6.6 g/dL at the 126th hospital day), but the disease activity was not completely controlled, as the CRP levels remained high and a mild fever persisted. According to the guideline, switching the therapeutic regimen to chemotherapy or immunosuppressive agents should be considered when the symptoms are not fully ameliorated. However, tocilizumab remains a viable option to consider, as there are some reports that the production of ADA is not persistent (20).\n\nIn conclusion, we encountered a rare case of iMCD accompanied by AIHA in which the effect of tocilizumab might have been reduced, at least in part, because of ADA production. In addition, we want to highlight that measuring the serum levels of IL-6, tocilizumab, and ADA may be useful for evaluating the ADA production in iMCD patients and that the possibility of AIHA complications should be carefully considered in cases of iMCD presenting with severe anemia.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nFinalcial Support\nWe would like to thank Chugai Pharmaceutical for the measurement and interpretation of the serum levels of tocilizumab, IL-6, and ADA against tocilizumab.\n==== Refs\n1. \nFajgenbaum DC \nNovel insights and therapeutic approaches in idiopathic multicentric Castleman disease . Blood \n132 : 2323 -2330 , 2018 .30487129 \n2. \nKoga T , Sumiyoshi R , Kawakami A , Yoshizaki K \nA benefit and the prospects of IL-6 inhibitors in idiopathic multicentric Castleman's disease . Mod Rheumatol \n29 : 302 -305 , 2019 .30285516 \n3. \nLiu AY , Nabel CS , Finkelman BS , et al \nIdiopathic multicentric Castleman's disease: a systematic literature review . Lancet Haematol \n3 : E163 -E175 , 2016 .27063975 \n4. \nFajgenbaum DC , Uldrick TS , Bagg A , et al \nInternational, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease . Blood \n129 : 1646 -1657 , 2017 .28087540 \n5. \nLiberato NL , Bollati P , Chiofalo F , Filipponi M , Poli M \nAutoimmune hemolytic anemia in multicentric Castleman's disease . Haematologica \n81 : 40 -43 , 1996 .8900850 \n6. \nOcio EM , Sanchez-Guijo FM , Diez-Campelo M , et al \nEfficacy of rituximab in an aggressive form of multicentric Castleman disease associated with immune phenomena . Am J Hematol \n78 : 302 -305 , 2005 .15795923 \n7. \nTajima K , Yamamoto H , Suzuki I , et al \nAutoimmune hemolytic anemia with warm-reactive immunoglobulin M antibody in multicentric Castleman disease . Ann Hematol \n92 : 849 -851 , 2013 .23180435 \n8. \nYuzuriha A , Saitoh T , Koiso H , et al \nSuccessful treatment of autoimmune hemolytic anemia associated with multicentric Castleman disease by anti-interleukin-6 receptor antibody (tocilizumab) therapy . Acta Haematol \n126 : 147 -150 , 2011 .21757886 \n9. \nHisatake J , Ishiyama T , Akimoto Y , et al \nAutoimmune hemolytic anemia associated with multicentric Castleman's disease with a 28-year history . Rinsho Ketsueki (Jpn J Clin Hematol) \n35 : 768 -773 , 1994 .\n10. \nNishimoto N , Terao K , Mima T , Nakahara H , Takagi N , Kakehi T \nMechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease . Blood \n112 : 3959 -3964 , 2008 .18784373 \n11. \nvan Rhee F , Voorhees P , Dispenzieri A , et al \nInternational, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease . Blood \n132 : 2115 -2124 , 2018 .30181172 \n12. \nYoshizaki K \nA reference guide for management of Castleman disease . Rinsho Ketsueki (Jpn J Clin Hematol) \n58 : 97 -107 , 2017 .\n13. \nBarcellini W \nNew insights in the pathogenesis of autoimmune hemolytic anemia . Transfus Med Hemother \n42 : 287 -293 , 2015 .26696796 \n14. \nKamesaki T \nRecent progress of diagnosis and treatment for immune-mediated hematological diseases. Topics: III. Diagnosis and treatment; 2. Autoimmune hemolytic anemia . Nihon Naika Gakkai Zasshi (J Jpn Soc Intern Med) \n103 : 1599 -1608 , 2014 .\n15. \nXu L , Zhang T , Liu Z , Li Q , Xu Z , Ren T \nCritical role of Th17 cells in development of autoimmune hemolytic anemia . Exp Hematol \n40 : 994 -1004 , 2012 .22960264 \n16. \nKimura A , Kishimoto T \nIL-6: Regulator of Treg/Th17 balance . Eur J Immunol \n40 : 1830 -1835 , 2010 .20583029 \n17. \nKunitomi A , Konaka Y , Yagita M , Nishimoto N , Kishimoto T , Takatsuki K \nHumanized anti-interleukin 6 receptor antibody induced long-term remission in a patient with life-threatening refractory autoimmune hemolytic anemia . Int J Hematol \n80 : 246 -249 , 2004 .15540899 \n18. \nBurmester GR , Choy E , Kivitz A , et al \nLow immunogenicity of tocilizumab in patients with rheumatoid arthritis . Ann Rheum Dis \n76 : 1078 -1085 , 2017 .28007755 \n19. \nBenucci M , Meacci F , Grossi V , et al \nCorrelations between immunogenicity, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab . Biologics \n10 : 53 -58 , 2016 .27041992 \n20. \nSigaux J , Hamze M , Daien C , et al \nImmunogenicity of tocilizumab in patients with rheumatoid arthritis . Joint Bone Spine \n84 : 39 -45 , 2017 .27369643\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(22)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "anti-drug antibody; autoimmune hemolytic anemia; multicentric Castleman disease; tocilizumab",
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D000744:Anemia, Hemolytic, Autoimmune; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D005871:Castleman Disease; D006801:Humans; D008297:Male; D000069283:Rituximab",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3313-3318",
"pmc": null,
"pmid": "31292389",
"pubdate": "2019-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21757886;22960264;28087540;7933564;26696796;15540899;8900850;27041992;30487129;28321096;15795923;18784373;25154254;27063975;20583029;30181172;27369643;23180435;30285516;28007755",
"title": "Idiopathic Multicentric Castleman Disease with Autoimmune Hemolytic Anemia and Production of Anti-drug Antibody against Tocilizumab.",
"title_normalized": "idiopathic multicentric castleman disease with autoimmune hemolytic anemia and production of anti drug antibody against tocilizumab"
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"abstract": "Patients with cryoglobulinemic vasculitis (CV) can develop disease flare after rituximab administration. The objective of our study was to describe the prevalence, clinical characteristics, predisposing factors, and outcomes of patients with rituximab-associated flare of CV.\nWe conducted a retrospective study in a tertiary referral center until March 25, 2020.\nAmong 64 patients with CV who received rituximab therapy in our center, 14 (22%) developed disease flare. Median age was 67.5 years. Seven patients (50%) had type II CV and the other half had either type I (n = 6) or type III (n = 1). Twelve patients (86%) had an underlying B-cell lymphoproliferative disorder as the cause of their CV. CV flare occurred after a median time of 5.5 days (range: 2-8 days). The organ systems most involved were the skin (n = 10), kidneys (n = 5), and peripheral nerves (n = 3). Five patients (36%) developed acute kidney injury (AKI), 3 of whom presented with nephritic syndrome secondary to biopsy-proven membranoproliferative glomerulonephritis. Treatment was directed against the underlying disease in addition to supportive care. Patients who developed flare were more likely to have B-cell lymphoproliferative disorder as the underlying etiology of their CV (P = 0.03). Eight patients (57%) died after a median time of 27 months.\nRituximab-associated flare can occur in all types of CV, tends to arise approximately 2 days and less than 1 week after rituximab administration, and is more likely to happen in patients with an underlying B-cell lymphoproliferative disorder. It does not indicate treatment failure, and rituximab should not be abandoned altogether. AKI is a common manifestation, and mortality rate at 2 years is high.",
"affiliations": "Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.;Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.;Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.;Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.;Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Sy-Go|Janina Paula T|JPT|;Thongprayoon|Charat|C|;Herrera Hernandez|Loren P|LP|;Zoghby|Ziad|Z|;Leung|Nelson|N|;Manohar|Sandhya|S|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.ekir.2021.08.024",
"fulltext": "\n==== Front\nKidney Int Rep\nKidney Int Rep\nKidney International Reports\n2468-0249\nElsevier\n\nS2468-0249(21)01409-1\n10.1016/j.ekir.2021.08.024\nClinical Research\nRituximab-Associated Flare of Cryoglobulinemic Vasculitis\nSy-Go Janina Paula T. sy-go.janina@mayo.edu\n1∗\nThongprayoon Charat 1\nHerrera Hernandez Loren P. 2\nZoghby Ziad 1\nLeung Nelson 13\nManohar Sandhya 1\n1 Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA\n2 Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA\n3 Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA\n∗ Correspondence: Janina Paula T. Sy-Go, Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905, USA. sy-go.janina@mayo.edu\n04 9 2021\n11 2021\n04 9 2021\n6 11 28402849\n21 6 2021\n20 8 2021\n23 8 2021\n© 2021 International Society of Nephrology. Published by Elsevier Inc.\n2021\nInternational Society of Nephrology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nBackground\n\nPatients with cryoglobulinemic vasculitis (CV) can develop disease flare after rituximab administration. The objective of our study was to describe the prevalence, clinical characteristics, predisposing factors, and outcomes of patients with rituximab-associated flare of CV.\n\nMethods\n\nWe conducted a retrospective study in a tertiary referral center until March 25, 2020.\n\nResults\n\nAmong 64 patients with CV who received rituximab therapy in our center, 14 (22%) developed disease flare. Median age was 67.5 years. Seven patients (50%) had type II CV and the other half had either type I (n = 6) or type III (n = 1). Twelve patients (86%) had an underlying B-cell lymphoproliferative disorder as the cause of their CV. CV flare occurred after a median time of 5.5 days (range: 2–8 days). The organ systems most involved were the skin (n = 10), kidneys (n = 5), and peripheral nerves (n = 3). Five patients (36%) developed acute kidney injury (AKI), 3 of whom presented with nephritic syndrome secondary to biopsy-proven membranoproliferative glomerulonephritis. Treatment was directed against the underlying disease in addition to supportive care. Patients who developed flare were more likely to have B-cell lymphoproliferative disorder as the underlying etiology of their CV (P = 0.03). Eight patients (57%) died after a median time of 27 months.\n\nConclusions\n\nRituximab-associated flare can occur in all types of CV, tends to arise approximately 2 days and less than 1 week after rituximab administration, and is more likely to happen in patients with an underlying B-cell lymphoproliferative disorder. It does not indicate treatment failure, and rituximab should not be abandoned altogether. AKI is a common manifestation, and mortality rate at 2 years is high.\n\nGraphical abstract\n\nKeywords\n\ncryoglobulinemia\ncryoglobulinemic vasculitis\ndisease flare\nrituximab\n==== Body\npmcCryoglobulinemia is a rare clinical entity characterized by the presence of circulating cryoglobulins. Cryoglobulins are serum Igs that self-aggregate and precipitate at low temperatures (below 37°C) and dissolve on rewarming.1, 2, 3, 4, 5 Although many patients with cryoglobulinemia may be asymptomatic, many develop symptoms of multiorgan vasculitis, which is referred to as cryoglobulinemic syndrome or cryoglobulinemic vasculitis (CV).1,2 CV can be diagnosed clinically, serologically, and/or pathologically.1 CV tends to typically involve the small vessels, resulting in heterogeneous clinical features like purpura, necrotic ulcers, arthralgia, peripheral neuropathy, and kidney disease. Serologic features can include detectable cryoglobulin (CG) levels and evidence of complement activation like low serum complement 4 (C4). Histologically, leukocytoclastic vasculitis has been described in these patients.2\n\nRituximab is a humanized mouse chimeric anti-CD20 monoclonal antibody linked to human IgG1 and kappa constant regions.6 It is an important therapeutic option in the management of a variety of both hematologic and autoimmune disorders, including CV, and targets B cells. Case reports of a CV flare phenomenon with a rise in serum CG level (i.e., IgM) following rituximab administration have been described in patients with Waldenstrom macroglobulinemia (WM).6, 7, 8, 9 Desbois et al.10 described rituximab-associated autoimmune disease flare in 7 of 185 patients diagnosed with an autoimmune disease (3.8%), all of whom also had type II CV. The pathogenesis is not well understood, but hypotheses include rituximab-associated immune complex formation and deposition in multiple body sites, including skin and kidneys, and rapid Ig production because of increased interleukin 6 production.11, 12, 13, 14 This flare phenomenon can be a diagnostic challenge for many clinicians and could possibly be misinterpreted as a failure of response to treatment.6,7,9 Although rituximab is the most widely used anti-CD20 monoclonal antibody, new-generation anti-CD20 monoclonal antibodies, such as obinutuzumab, have been developed to try to overcome mechanisms of resistance to rituximab and to enhance therapeutic response.15,16 One such mechanism of resistance is the development of anti-rituximab antibodies.16 De Fremont et al.17 recently described a patient with Sjogren’s syndrome–associated refractory CV who was found to have anti-rituximab antibodies and developed disease flare after treatment with obinutuzumab.\n\nThe objective of our study was to assess and evaluate the cohort of patients with CV treated with rituximab in our center and describe the prevalence, clinical characteristics, predisposing factors, and outcomes of rituximab-associated flare of CV.\n\nMaterials and Methods\n\nAfter approval of the protocol and waiver of informed consent by the Mayo Clinic Institutional Review Board (ID: 20–003504), we used the Advanced Cohort Explorer database available at Mayo Clinic and obtained a list of all patients who had a positive result on CG testing until March 25, 2020. We cross-referenced this list with patients who had received rituximab therapy and had 70 unique patients, excluding those without research authorization. Six patients were further excluded because they had remotely received rituximab therapy before developing CV, had insufficient information, and had no follow-up. In total, we identified 64 patients with known CV who received rituximab therapy.\n\nWe defined disease flare as any clinical deterioration within 2 weeks following rituximab administration, including onset of a new organ involvement or worsening of the underlying autoimmune disease not clearly explained by disease progression alone, with or without laboratory evidence. A total of 14 patients fulfilled the criteria of disease flare. We also defined AKI as >1.5 times increase from the baseline creatinine.\n\nTo identify potential predisposing factors associated with the occurrence of disease flare following rituximab administration, we compared the clinical features of the 14 patients who had a disease flare (case) with those of the remaining 50 patients who did not have a disease flare (control). The following data were collected: demographic characteristics (age, sex, and race), comorbidities, type of CV, etiology of CV, symptoms of CV, laboratory findings before rituximab treatment (creatinine, CG, and C4), and other treatment modalities used before and together with current rituximab treatment (chemotherapy, corticosteroids, and plasmapheresis).\n\nStatistical Analyses\n\nContinuous variables were summarized as median (range) and were compared between patients with and without disease flare using Wilcoxon’s rank sum test. Categorical variables were summarized as frequency (percentages) and were compared between patients with and without disease flare using χ2 test. Two-sided P value of <0.05 was considered statistically significant. Statistical analyses were performed using JMP statistical software (version 14; SAS Institute, Cary, NC).\n\nResults\n\nBaseline Characteristics, Clinical Features, Laboratory Findings, and Treatments of All Patients With CV\n\nData are summarized in Table 1. We have a total of 64 patients with known CV who received rituximab therapy. The median age was 63 years (range: 24–91 years); 45% were men and 95% were Caucasians. The most common comorbidities were malignancy (75%), hypertension (53%), and chronic kidney disease (41%). Twenty-four patients (37.5%) had biopsy-proven membranoproliferative glomerulonephritis as the etiology of their chronic kidney disease. Most of the patients (69%) had type II CV followed by type I (27%) and type III (5%). In 50% of patients, their CV was ascribed to an underlying B-cell lymphoproliferative disorder. The most common organ systems involved were the skin (69%), kidneys (42%), and peripheral nerves (19%). Before rituximab treatment, the median creatinine was 1.0 mg/dl (interquartile range: 0.8–1.4 mg/dl), the median CG level was 7%, and the median C4 level was 6.5 mg/dl (reference range: 14–40 mg/dl). Together with rituximab, 55%, 45%, and 6% of patients also received corticosteroids, chemotherapy, and plasmapheresis, respectively.Table 1 Comparison of patients with cryoglobulinemic vasculitis according to the presence of a disease flare following rituximab\n\nVariables\tAll patients with vasculitis, n = 64\tPatients with vasculitis flare, n = 14\tPatients without vasculitis flare, n = 50\tP value\t\nDemographic characteristics\t\t\t\t\t\n • Age, median (range)\n\n\t63 (24–91)\t67.5 (38–91)\t63 (24–83)\t0.9\t\n • Sex, male\n\n\t29 (45)\t7 (50)\t22 (44)\t0.5\t\n • Race, white\n\n\t61 (95)\t14 (100)\t47 (94)\t0.4\t\nComorbidities\t\t\t\t\t\n • Hypertension\n\n\t34 (53)\t8 (57)\t26 (52)\t0.9\t\n • Diabetes\n\n\t5 (8)\t1 (7)\t4 (8)\t0.9\t\n • CKD or ESKD\n\n\t26 (41)\t4 (29)\t22 (44)\t0.3\t\n • Autoimmune disease\n\n\t24 (38)\t5 (36)\t19 (38)\t0.7\t\n • Malignancy\n\n\t48 (75)\t12 (86)\t36 (72)\t0.1\t\n • HCV infection\n\n\t14 (22)\t1 (7)\t13 (26)\t0.1\t\nType of cryoglobulinemic vasculitis\t\t\t\t0.2\t\n • I\n\n\t17 (27)\t6 (43)\t11 (22)\t\n • II\n\n\t44 (69)\t7 (50)\t37 (74)\t\n • III\n\n\t3 (5)\t1 (7)\t2 (4)\t\nEtiology of cryoglobulinemic vasculitis\t\t\t\t0.03\t\n • HCV infection\n\n\t12 (19)\t1 (7)\t11 (22)\t\n • B-cell lymphoproliferative disorder\n\n\t32 (50)\t12 (86)\t20 (40)\t\n • Autoimmune disease\n\n\t14 (22)\t1 (7)\t13 (26)\t\n • Unclear\n\n\t6 (9)\t0\t6 (12)\t\nOrgan involvement\t\t\t\t\t\n • Kidneys\n\n\t27 (42)\t6 (43)\t22 (44)\t0.7\t\n • Skin\n\n\t44 (69)\t10 (71)\t34 (68)\t0.7\t\n • Joints\n\n\t3 (5)\t1 (7)\t2 (4)\t0.6\t\n • Nerves\n\n\t12 (19)\t3 (21)\t9 (18)\t0.8\t\n • GI\n\n\t6 (9)\t1 (7)\t5 (10)\t0.7\t\n • CNS\n\n\t1 (2)\t1 (7)\t0\t0.06\t\n • Lungs\n\n\t2 (4)\t0\t2 (4)\t0.4\t\n • Heart\n\n\t1 (2)\t0\t1 (2)\t0.6\t\nLaboratory findings before RTX treatment\t\t\t\t\t\n • Cr (mg/dl), median (IQR)\n\n\t(0.8–1.4)\t0.8 (0.7–1.25)\t1.05 (0.8–1.625)\t0.01\t\n • Cryo (%), median (IQR)\n\n\t7 (4–16)\t12 (4–67)\t8 (4–13.75)\t0.7\t\n • C4 (mg/dl), median (IQR)\n\n\t5 (3–7)\t6.5 (3–7.5)\t5 (3–7)\t0.6\t\nTreatments prior to current RTX\t\t\t\t\t\n • Chemotherapy\n\n\t23 (36)\t8 (57)\t15 (30)\t0.06\t\n • Corticosteroids\n\n\t26 (41)\t5 (36)\t21 (42)\t0.7\t\n • Plasmapheresis\n\n\t11 (17)\t2 (14)\t9 (18)\t0.7\t\nConcurrent treatments with RTX\t\t\t\t\t\n • Chemotherapy\n\n\t29 (45)\t9 (64)\t20 (40)\t0.4\t\n • Corticosteroids\n\n\t35 (55)\t9 (64)\t26 (52)\t0.4\t\n • Plasmapheresis\n\n\t4 (6)\t3 (21)\t1 (2)\t0.03\t\nC4, complement C4; CKD, chronic kidney disease; CNS, central nervous system; Cr, creatinine; cryo, cryoglobulin; ESKD, end-stage kidney disease; GI, gastrointestinal; HCV, hepatitis C virus; IQR, interquartile range; RTX, rituximab.\n\nValues are n (%) unless otherwise indicated.\n\nItalic indicates P values that are <0.05 are considered statistically significant.\n\nPrevalence and Baseline Characteristics of Patients With Rituximab-Associated Flare of CV\n\nAmong 64 patients who were diagnosed with CV and were treated with rituximab, 14 of them (22%) developed a disease flare, including one who had 2 disease flares. Data are summarized in Tables 1 and 2. The median age was 67.5 years (range: 38–91 years); 50% were men and all were Caucasians. Twelve patients (86%) had an underlying malignancy as the cause of their CV, all of which were a B-cell lymphoproliferative disorder, with 4 of them having either concomitant skin cancer or sarcoma. Six had WM, 3 had non-Hodgkin’s lymphoma, 2 had chronic lymphocytic leukemia, and 1 had a nonspecific low-grade B-cell lymphoproliferative disorder. Hypertension (n = 8), autoimmune disease (n = 5), and chronic kidney disease (n = 4) were the other comorbidities present in our cohort, with the etiology of chronic kidney disease being membranoproliferative glomerulonephritis secondary to CV in all patients. One patient had chronic hepatitis C virus (HCV) infection, and another had Sjogren’s syndrome causing the CV.Table 2 Baseline demographic and clinical characteristics of patients with rituximab-associated flare of cryoglobulinemic vasculitis\n\nPatient\tAge\tSex\tRace\tHTN\tDM\tCKD\tCause of CKD\tAD\tMalignancy\tHepatitis\tType of hepatitis\tType of Ig\tType of cryo\tCause of cryo\t\n1\t58\tM\tW\tY\tN\tY\tMPGN secondary to cryoglobulinemic vasculitis\tN\tY\tN\t\tIgM kappa\tII\tWaldenstrom macroglobulinemia\t\n2\t80\tF\tW\tN\tN\tN\t\tN\tY\tN\t\tIgM kappa\tI\tB-cell non-Hodgkin’s lymphoma\t\n3\t38\tM\tW\tN\tN\tN\t\tY\tN\tY\tC\tIgM kappa\tII\tHepatitis C\t\n4\t62\tM\tW\tN\tY\tN\t\tN\tY\tN\t\tIgM kappa\tI\tLow-grade B-cell lymphoproliferative disorder\t\n5\t62\tF\tW\tN\tN\tN\t\tN\tY\tN\t\tIgM lambda\tI\tWaldenstrom macroglobulinemia\t\n6\t57\tF\tW\tY\tN\tY\tMPGN secondary to cryoglobulinemic vasculitis\tY\tY\tN\t\tIgM kappa\tI\tWaldenstrom macroglobulinemia\t\n7\t73\tF\tW\tN\tN\tN\t\tY\tY\tN\t\tIgG lambda\tI\tCLL\t\n8\t88\tF\tW\tN\tN\tN\t\tN\tY\tN\t\tIgM kappa\tIII\tSplenic marginal zone lymphoma\t\n9\t56\tM\tW\tY\tN\tY\tMPGN secondary to cryoglobulinemic vasculitis\tN\tY\tN\t\tIgM kappa\tII\tIgM monoclonal gammopathy suspicious for Waldenstrom macroglobulinemia\t\n10\t74\tF\tM\tN\tN\tN\t\tY\tY\tN\t\tIgA kappa\tII\tB-cell non-Hodgkin’s lymphoma\t\n11\t91\tF\tW\tY\tN\tN\t\tY\tY\tN\t\tIgM kappa\tII\tSjogren’s syndrome\t\n12\t73\tM\tW\tY\tN\tN\t\tY\tY\tN\t\tIgM kappa\tII\tWaldenstrom macroglobulinemia\t\n13\t80\tM\tW\tY\tN\tN\t\tN\tY\tN\t\tIgM kappa\tI\tWaldenstrom macroglobulinemia\t\n14\t57\tM\tW\tY\tN\tY\tMPGN secondary to cryoglobulinemic vasculitis\tN\tY\tY\tB\tIgM kappa\tII\tCLL\t\nAD, autoimmune disease; CKD, chronic kidney disease; CLL, chronic lymphocytic leukemia; cryo, cryoglobulinemia; DM, type 2 diabetes mellitus; F, female; HTN, hypertension; Ig, immunoglobulin; M, male; MPGN, membranoproliferative glomerulonephritis; N, no; W, white; Y, yes.\n\nHalf of the patients (n = 7) had type II CV, and the other half had either type I (n = 6) or type III (n = 1). The Ig involved in most of the patients was IgM kappa (n = 11), and the rest were IgG lambda (n = 1), IgM lambda (n = 1), and IgA kappa (n = 1). The median follow-up duration (defined as the time between the date of disease flare and either the date of last follow-up or the date of death) after disease flare was 32 months (range: 6–137 months).\n\nClinical Features and Treatments of Patients With Rituximab-Associated Flare of CV\n\nEleven of the 14 patients developed a disease flare during their first cycle of rituximab treatment, and 6 patients had the flare after the first dose. One patient had a flare after both his first and second doses. Most of them received weekly rituximab dosed at 375 mg/m2 and 1 patient received a dose of 1 g. Data are summarized in Table 3.Table 3 Clinical features and treatments of patients with rituximab-associated flare of cryoglobulinemic vasculitis\n\nPatient\tRTX cycle and dose\tTime to disease flare (d)\tOrgan involvement\tInfusion reaction\tRTX dose (mg)\tOther treatments received\t\nPrior to current RTX\tConcurrently with RTX\t\n1\t1st, 4th\t4\tSkin, GI, and kidneys\tN\t375 mg/m2\tNone\tCYC, vincristine, and CS\t\n2\t1st, 1st\t5\tCNS, nerves, and kidneys\tN\tNA\tFludarabine\tCYC, cladribine, and intrathecal methotrexate and CS\t\n3\t1st, 1st\t7\tSkin\tN\t375 mg/m2\tCS\tCS\t\n4\t3rd, 2nd\t2\tSkin and joints\tY\t375 mg/m2\tNone\tNone\t\n5\t1st, 3rd\t3\tNerves\tN\t375 mg/m2\tNone\tNone\t\n6\t2nd, 2nd\t5\tKidneys\tN\t375 mg/m2\tCYC, MM, CS, and RTX\tCYC and PLEX\t\n7\t1st, 1st\t7\tSkin\tN\tNA\tObinutuzumab\tCYC and CS\t\n8\t1st, 3rd\t7\tSkin\tY\t375 mg/m2\tChlorambucil\tChlorambucil\t\n9\t2nd, 1st\tUnclear\tSkin and kidneys\tN\tNA\tMethotrexate, CS, RTX, and PLEX\tCS\t\n10\t1st, 2nd\tUnclear\tSkin\tN\tNA\tRTX\tCYC and CS\t\n11\t1st, 1st\t2\tSkin and nerves\tN\t1000\tCS\tCS\t\n12\t1st, 3rd\t6\tSkin\tN\t375 mg/m2\tBortezomib, CS, and PLEX\tBendamustine\t\n13\t1st, 3rd\t8\tKidneys\tN\tNA\tNone\tChlorambucil, CS, and PLEX\t\n14\t1st, 1st and 2nd\tFew\tSkin and kidneys\tN\t375 mg/m2\tCYC\tCYC, CS, and PLEX\t\n\t2nd, 3rd\t7\tSkin and kidneys\tN\t375 mg/m2\tNone\tCS\t\nCNS, central nervous system; CS, corticosteroid; CYC, cyclophosphamide; GI, gastrointestinal; MM, mycophenolate mofetil; N, no; NA, not available; PLEX, plasma exchange; RTX, rituximab; Y, yes.\n\nNote: Patient 14 had 2 disease flares.\n\nThe median time to disease flare (defined as the time between the date of first rituximab infusion and the date of first symptom manifestation) was 5.5 days (range: 2–8 days). The following organ systems were involved: skin (n = 10), kidneys (n = 6), peripheral nerves (n = 3), joints (n = 1), gastrointestinal tract (n = 1), and central nervous system (n = 1). Symptoms were heterogeneous and included petechial and purpuric skin rash, leg ulcers, symptoms of volume overload resulting from AKI, peripheral neuropathy, arthralgia, weight loss, dysphagia, abdominal pain, headache, and confusion. Two patients had a minor infusion reaction.\n\nOther treatments administered concurrently with rituximab were chemotherapy (n = 9), corticosteroids (n = 9), and plasmapheresis (n = 3). The most used chemotherapeutic agent was cyclophosphamide (n = 6), and the rest included vincristine, cladribine, methotrexate, chlorambucil, and bendamustine.\n\nKidney Manifestations of Patients With Rituximab-Associated Flare of CV\n\nBefore rituximab treatment, the median creatinine was 0.8 mg/dl (interquartile range: 0.7–1.25 mg/dl). During disease flare, 5 patients (patients #2, #6, #9, #13, and #14) developed AKI with subsequent improvement in their kidney function after the episode (Figure 1). One patient (patient #14) had 2 disease flares and had AKI in both instances. Three of them (patients #6, #13, and #14) presented with hematuria and proteinuria of more than 1 g, and 1 patient (patient #2) had only proteinuria as his presenting feature. The median predicted 24-hour urine total protein was 5.9 g (range: 1.9–9.6 g).Figure 1 Serum creatinine trend of patients who developed AKI during disease flare.\n\nThe 3 patients who had both hematuria and proteinuria during disease flare underwent kidney biopsy, and the results were consistent with cryoglobulinemic glomerulonephritis with a membranoproliferative pattern of injury with IgM kappa deposits (Figure 2a–d).Figure 2 (a) Light microscopy, periodic acid-Schiff stain: glomerulus with moderate mesangial hypercellularity and segmental endocapillary proliferative changes with marginating mononuclear cells (black arrows). Magnification is 60×. (b–d) Immunofluorescence studies: granular mesangial and capillary loop staining with 2+ IgM (b), 2+ kappa light chain (c), and negative lambda light chain (d).\n\nLaboratory Findings of Patients With Rituximab-Associated Flare of CV\n\nBefore rituximab treatment, the median CG level was 12% and the median C4 level was 6.5 mg/dl (reference range: 14–40 mg/dl). Almost half of the patients had missing data for either parameter. Three patients also had elevated rheumatoid factor (RF) (range: 99–1430 IU/ml; reference range: <15 IU/ml), all of whom had either type II or type III CV. Most of the patients did not have their CG, C4, and RF checked during disease flare. There were a few exceptions: 1 patient (patient #13) did have a CG detected at a level of 63% and an elevated RF at 92 in his serum during disease flare, and 2 patients (patients #6 and #14) had low C4 levels at <3 mg/dl.\n\nInterventions During and Outcomes of Patients With Rituximab-Associated Flare of CV\n\nIn addition to initiation of chemotherapy, corticosteroids, and/or plasmapheresis, some patients were either switched from oral to i.v. corticosteroids (n = 1; 7%) or had the doses of their oral corticosteroids increased (n = 2; 14%) to better control the disease flare. Some patients (n = 3; 21%) were also managed symptomatically with diuretics for edema and gabapentin for peripheral neuropathy. All 6 patients recovered from their disease flare uneventfully. One patient (patient #14) developed complications of AKI, including recurrent hyperkalemia and volume overload, and required kidney replacement therapy in the form of intermittent hemodialysis, as well as admission to the intensive care unit. None of the patients required mechanical ventilation. Data are summarized in Table 4.Table 4 Interventions during and outcomes of patients with rituximab-associated flare of cryoglobulinemic vasculitis\n\nPatient\tIntervention (in addition to concurrent treatment)\tKRT\tType of KRT\tICU stay\tFollow-up duration after flare (mo)\tSubsequent treatments after flare\tDeath\tCause of death\t\n1\tIncreased dose of oral CS\tN\t\tN\t108\tRTX and CS\tN\t\t\n2\tSxT\tN\t\tN\t36\tRTX and bendamustine\tN\t\t\n3\tNone\tN\t\tN\t6\tCS\tY\tUnclear\t\n4\tSxT\tN\t\tN\t26\tRTX, CS, and PLEX\tY\tCryoglobulinemic crisis\t\n5\tNone\tN\t\tN\t28\tRTX, fludarabine, and CS\tY\tSeptic shock, acute MI, and acute intracranial hemorrhage\t\n6\tNone\tN\t\tN\t91\tRTX, CYC, and CS\tN\t\t\n7\tNone\tN\t\tN\t56\tNone\tN\t\t\n8\tNone\tN\t\tN\t18\tNone\tY\tMetastatic colorectal cancer progression\t\n9\tSxT\tN\t\tN\t6\tRTX, CYC, and CS\tN\t\t\n10\tNone\tN\t\tN\t74\tRTX, bendamustine, lenalidomide, and PLEX\tY\tUnclear\t\n11\tSwitched to i.v. CS\tN\t\tN\t23\tRTX and CS\tY\tUnclear\t\n12\tIncreased dose of oral CS\tN\t\tN\t26\tNone\tN\t\t\n13\tNone\tN\t\tN\t133\tRTX, CYC, CS, chlorambucil, and bortezomib\tY\tUnclear\t\n14\tNone\tY\tiHD\tY\t\t\tN\t\t\n\tNone\tN\t\tN\t137\tCS, PLEX, and ibrutinib\tY\tAcute cholecystitis complications\t\nCS, corticosteroid; ICU, intensive care unit; iHD, intermittent hemodialysis; KRT, kidney replacement therapy; MI, myocardial infarction; N, no; PLEX, plasma exchange; RTX, rituximab; SxT, symptomatic treatment; Y, yes.\n\nNote: Patient 14 had 2 disease flares.\n\nEleven of the 14 patients continued treatment after the flare with chemotherapy, corticosteroids, and/or plasmapheresis. Rituximab was continued in 10 of these patients with the addition of cyclophosphamide, bortezomib, chlorambucil, or fludarabine for those with WM and bendamustine and/or lenalidomide for those with non-Hodgkin’s lymphoma. On the other hand, it was discontinued in 1 patient in the setting of a very minimal B-cell clonal population on repeat bone marrow aspirate and biopsy, and he was started on ibrutinib instead.\n\nOverall, 8 patients died, with 1 patient’s cause of death being cryoglobulinemic crisis. Three patients died from non–CV-related problems, and 4 patients died from unclear causes.\n\nPredisposing Factors Related to Rituximab-Associated Flare of CV\n\nPatients who developed disease flare were more likely to have B-cell lymphoproliferative disorder as the underlying etiology of their CV (P = 0.03), had lower creatinine levels before rituximab treatment (0.8 vs. 1.05 mg/dl, P = 0.01), and received more treatments with plasmapheresis together with rituximab (P = 0.03) compared with those who did not develop disease flare (Table 1). Other variables, including demographic characteristics, comorbidities, type of CV, symptoms of CV, CG level, C4 level, and treatments received in the past, did not influence the occurrence of rituximab-associated flare of CV.\n\nSubgroup Analysis of Patients With CV Secondary to a B-Cell Lymphoproliferative Disorder Based on IgM Level and Serum Viscosity\n\nFifty percent of the patients had CV secondary to a B-cell lymphoproliferative disorder, 12 of whom had a disease flare, whereas 20 of whom did not. Among these 12 patients, however, only 10 of them had an IgM protein (71%), and 2 of them had IgG and IgA proteins respectively. As shown in Table 5, compared with those who did not develop disease flare but also had CV secondary to a B-cell lymphoproliferative disorder, their median IgM level was 129 mg/dl (vs. 1570 mg/dl, P = 0.1), and their median serum viscosity was 1.6 centipoises (vs. 1.7 centipoises, P = 0.8) before rituximab treatment.Table 5 Subgroup analysis of patients with cryoglobulinemic vasculitis secondary to a B-cell lymphoproliferative disorder according to the presence of a disease flare following rituximab based on IgM level and serum viscosity\n\nVariables\tPatients with BCLPD with vasculitis flare, n = 10a\tPatients with BCLPD without vasculitis flare, n = 20\tP value\t\nIgM (mg/dl), median (IQR)\nRange: 37–286 mg/dl\t129 (80–1690)\t1570 (261–3603)\t0.1\t\nSerum viscosity (centipoise), median (IQR)\nRange: 0–1.5 centipoise/s\t1.6 (1.35–1.68)\t1.7 (1.6–2.1)\t0.8\t\nBCLPD, B-cell lymphoproliferative disorder; IQR, interquartile range.\n\na Although there were 12 patients who had cryoglobulinemic vasculitis secondary to a B-cell lymphoproliferative disorder and developed a disease flare, only 10 of them had IgM protein and 2 of them had IgG and IgA proteins respectively.\n\nDiscussion\n\nIn our retrospective study, we found that 14 of the 64 patients (22%) who received rituximab developed a CV flare. In comparison with other reported studies, our patient cohort had varying types of underlying cryoglobulinemia with type I, type II, and type III in 6 (42%), 7 (50%), and 1 (7.1%) patient(s), respectively. Five of these 14 patients (36%) had AKI during flare, 3 of whom presented with nephritic syndrome, with kidney biopsy showing cryoglobulinemic glomerulonephritis.\n\nCGs are classified according to Brouet’s classification into 3 subtypes based on the clonality of the Ig, as outlined in Table 6. Many hypotheses have been proposed to explain their formation, including genetic susceptibility, sustained antigenic stimulation, monoclonal or polyclonal activation of B-lymphocytes, aberrant autoantibody production, reduced clearance of immune complexes by the liver, and possible cross-reactivity with other antigens.1, 2, 3, 4, 5 The reversible cryoprecipitability of CGs is influenced by several environmental factors like temperature, pH, structure, salt and protein concentrations, and amino acid composition.18 That is why not all Igs are cryoprecipitable. Type I CGs typically tend to self-associate, resulting in aggregates and do not form immune complexes, so clinically, these patients manifest more commonly with signs of vascular obstruction rather than of vasculitis.19 These aggregates are frequently amorphous material but can present as crystals, which can cause more severe manifestations of vessel occlusion and necrosis like in cryoglobulinemic glomerulonephritis.18,20 In these patients, highly concentrated type I CG precipitates in the relatively “warmer” glomeruli as a result of the high protein content. Type II and III CGs typically form immune complexes and form a precipitate in the vasculature resulting in an inflammatory response. The cryoprecipitation of type II and III CGs are likely in part related to the Fc-Fc interaction. In patients with HCV infection, the immune complexes are formed by IgM with RF activity that are linked to IgG with anti-HCV reactivity.19Table 6 Brouet’s classification of cryoglobulins with relative incident frequency among patients with cryoglobulinemia and commonly associated diseases\n\nType of cryoglobulin\tIg\tIncidence, %\tCommonly associated diseases\t\nType I (1)\tIsolated monoclonal Ig (most commonly IgM, can be IgG but very rarely IgA)\t10–15\tHematologic disorders like Waldenstrom macroglobulinemia, multiple myeloma, and chronic lymphocytic leukemia\t\nType II (2)\tMonoclonal Igs (typically IgM but rarely can be IgG or IgA) with rheumatoid factor activity (against a polyclonal IgG)\nAND polyclonal IgG\t50–60\tInfections like chronic hepatitis C virus, hematologic disorders, and autoimmune diseases like Sjogren’s syndrome and systemic lupus erythematosus\t\nType III (3)\tPolyclonal Igs of various types (like IgM and IgG)\t20–30\tInfections like chronic hepatitis C virus, hematologic disorders, and autoimmune diseases like Sjogren’s syndrome and systemic lupus erythematosus\t\n\nAs a B-cell depleting agent, rituximab has been at the forefront of immunosuppressive management in both HCV and non–HCV-associated CV. A clinical flare phenomenon following rituximab administration has been described since the early 2000s, and all cases involved WM leading to either type I or type II CV.6, 7, 8, 9 Ghobrial et al.7 described a patient with WM resulting in type II CV with predominant skin manifestations and a CG level of 3%, which, after receiving weekly 375 mg/m2 rituximab therapy, increased to 9.7% during the first week without any clinical changes before showing improvement. The same authors did a follow-up study looking at their cohort of patients with WM and showed that there was a rise in IgM levels in 54% of their patients after rituximab therapy, most of whom eventually had a decrease in their IgM levels within 4 months after administration of medication.9 In addition, Treon et al.,8 in their series of 11 patients with WM, showed that the IgM levels increased by more than 25% in most of their patients after rituximab therapy, with one of them developing a subdural hemorrhage before showing improvement. This phenomenon is also referred to as IgM flare, which is characterized by a transient increase in IgM level and can occur within hours to days following initiation of rituximab therapy.6, 7, 8, 9 When the IgM level exceeds 5000 mg/dl or when serum viscosity exceeds 4.0 centipoises, signs and symptoms of hyperviscosity, such as headache, dizziness, visual impairment, coma, and seizures, may occur.21,22\n\nIn our study, we included patients with both clinical and laboratory evidence of a disease flare. The prevalence of such a flare was relatively high at 22% (14 of 64 patients) with AKI in 5 patients. The incidence of AKI in cryoglobulinemia is reported to be approximately 10% to 17%, with 20% to 50% of patients presenting with nephrotic syndrome and 20% to 30% of patients with nephritic syndrome.23 Histologically, membranoproliferative glomerulonephritis is the most described pattern of injury.23 Without a kidney biopsy, this diagnosis is very difficult to make considering that these patients likely have hemodynamic insults and/or concurrent use of nephrotoxic agents that may also explain their AKI. Our patients developed AKI after they had started treatment for their underlying disease, making the diagnosis and management challenging. We speculated if the overall Ig burden before rituximab therapy could be a contributing factor to a flare; however, many of our patients had received cytoreductive measures like cyclophosphamide either before or concurrently with rituximab.\n\nThe mechanism of rituximab-associated CV flare remains poorly understood. Because type II CGs consist of a combination of monoclonal IgM with RF activity and polyclonal IgG, rituximab-associated CV flares have typically been seen in type II CV because of the hypothesized immune-mediated reaction between an antigenic portion of rituximab and complement-fixing IgM and IgG antibodies.10,11 Potential pathogenic complexes consisting of IgM with RF activity and rituximab have previously been postulated, wherein these Igs were said to have the ability to recognize and bind the IgG1 portion of rituximab.10,11,24,25 This theory was further supported by the histological presence of IgM-, IgG1-, and rituximab-positive staining of endomembranous deposits and thrombi within kidney lesions on immunofluorescence analysis performed in one study.10 The kidney lesions could ultimately be the result of endocapillary proliferation secondary to immune complex deposition and glomerular obstruction by cryoglobulinemia and rituximab. Another hypothesis is that rituximab stimulates interleukin-6 production by bystander immune cells, including monocytes and B cells, resulting in the rapid production of Igs.13,14\n\nSeveral important conclusions can be drawn from our study. Not all cases of rituximab-associated CV flare occur after the first dose of the medication. In our experience, most of the patients had the flare after their second or subsequent dose. The flare also occurred more than once in a treatment cycle. Clinicians therefore need to be aware of this possibility. Furthermore, disease flare occurred after a median time of 5.5 days following rituximab administration. In addition, compared with patients who did not have a CV flare after being treated with rituximab, those who had a flare were more likely to have a B-cell lymphoproliferative disorder as the underlying etiology of their CV. It is important to note that most of these patients had IgM protein, rendering them susceptible to IgM flare. Based on our study, however, it appears that the presence of CGs is independent of IgM level and serum viscosity in determining IgM flare. They received more treatments with plasmapheresis because of the flare, all of whom had kidney involvement. They were also incidentally found to have a lower creatinine level before rituximab treatment. We do not have a clear explanation for this finding, which, in a larger study, possibly may not be statistically significant. In the study by Debois et al.,10 exacerbations were noted to occur more likely in patients with kidney involvement, a higher CG level, and a lower C4 level, which were not present in our study.\n\nIn terms of management, almost all our patients received chemotherapy, corticosteroids, and/or plasmapheresis during their disease flare and continued to require these treatments, which were directed against their underlying diseases, even after it resolved. Although 3 of the 14 patients had their corticosteroid regimen intensified during disease flare, it is difficult to interpret if this change in therapy resulted in any impact to the patients’ overall clinical trajectory. It is important to note that this flare phenomenon does not indicate failure of response to treatment, and rituximab should not be abandoned altogether. In addition, approximately 60% of our patients who experienced rituximab-associated flare of their underlying CV died within a median period of 27 months after exacerbation but with only 1 confirmed case of cryoglobulinemic crisis being the cause of death.\n\nOur study has several limitations. In our initial search strategy, we may have missed patients with CV who did not undergo CG testing. Most of the patients who had a disease flare did not have pertinent laboratory parameters trended, including CG, C4, and RF, either immediately before, during, or subsequent to resolution of the flare, so these missing data were not included in the statistical analyses. In some of the patients who had their CG checked, the results were read as “trace,” and these results were also not included. The disease flares were at times documented by the treating clinician, but in many instances, these flares had to be interpreted in retrospect based on the consensus of the authors, hence possibly leading to bias.\n\nConclusion\n\nRituximab-associated flare of CV is not uncommon (22%) and can occur in any type of CV. Disease flares tend to arise after 2 days and less than 1 week after rituximab administration and are more likely to occur in patients with a B-cell lymphoproliferative disorder as the underlying etiology of their CV. Five (36%) patients developed AKI during disease flare, with kidney biopsy showing cryoglobulinemic glomerulonephritis. Management involves continuing treatment of the underlying disease while providing supportive care during disease flare with possibly intensified corticosteroid regimen and/or plasmapheresis. Mortality rate at 2 years is high at 60% in these patients. Because it is an underrecognized clinical entity with potentially dire consequences, clinicians should be cognizant of its existence and have a high index of suspicion, particularly in patients who are at high risk of developing disease flare. It is not indicative of treatment failure, so rituximab should be resumed or continued appropriately and as necessary.\n\nDisclosure\n\nNL reports grants from AbbVie, grants from Omeros, other from Takeda, and grants from Alnylam, all of which are outside the submitted work. All the other authors declared no competing interests\n\nPatient Consent\n\nThe authors declare that waiver of informed consent was approved by the Mayo Clinic Institutional Review Board.\n==== Refs\nReferences\n\n1 Roccatello D. Saadoun D. Ramos-Casals M. Cryoglobulinaemia Nat Rev Dis Primers 4 2018 11 30072738\n2 Desbois A.C. Cacoub P. Saadoun D. Cryoglobulinemia: An update in 2019 Joint Bone Spine 86 2019 707 713 30731128\n3 Silva F. Pinto C. Barbosa A. New insights in cryoglobulinemic vasculitis J Autoimmun 105 2019 102313 31383568\n4 Takada S. Shimizu T. Hadano Y. Cryoglobulinemia (review) Mol Med Rep 6 2012 3 8 22484457\n5 Muchtar E. Magen H. Gertz M.A. How I treat cryoglobulinemia Blood 129 2017 289 298 27799164\n6 Shaikh A. Habermann T.M. Fidler M.E. Acute renal failure secondary to severe type 1 cryoglobulinemia following rituximab therapy for Waldenstrom’s macroglobulinemia Clin Exp Nephrol 12 2008 292 295 18288560\n7 Ghobrial I.M. Uslan D.Z. Call T.G. Initial increase in the cryoglobulin level after rituximab therapy for type II cryoglobulinemia secondary to Waldenström macroglobulinemia does not indicate failure of response Am J Hematol 77 2004 329 330 15551276\n8 Treon S.P. Branagan A.R. Hunter Z. Paradoxical increases in serum IgM and viscosity levels following rituximab in Waldenstrom’s macroglobulinemia Ann Oncol 15 2004 1481 1483 15367407\n9 Ghobrial I.M. Fonseca R. Greipp P.R. Initial immunoglobulin M ‘flare’ after rituximab therapy in patients diagnosed with Waldenstrom macroglobulinemia Cancer 101 2004 2593 2598 15493038\n10 Desbois AC, Biard L, Sène D, et al. Rituximab-associated vasculitis flare: incidence, predictors, and outcome. J Rheumatol. 2020;47:896–902.\n11 Sène D. Ghillani-Dalbin P. Amoura Z. Rituximab may form a complex with iGmκ mixed cryoglobulin and induce severe systemic reactions in patients with hepatitis C virus–induced vasculitis Arthritis Rheum 60 2009 3848 3855 19950292\n12 Misbah S.A. Rituximab-induced accelerated cryoprecipitation in hepatitis C virus–associated mixed cryoglobulinemia has parallels with intravenous immunoglobulin–induced immune complex deposition in mixed cryoglobulinemia: Comment on the article by Sène et al Arthritis Rheum 62 2010 3122 3123 20662059\n13 Jones J.D. Hamilton B.J. Skopelja S. Rigby W.F. Induction of interleukin-6 production by rituximab in human B cells Arthritis Rheum 66 2014 2938 2946\n14 Yang G. Gong P. Ioakimidis T. The IgM flare following rituximab and IVIG administration in Waldenstrom's macroglobulinemia is related to IL-6 production by bystander immune cells, possibly through stimulation of the Fcgriia receptor Blood 114 2009 761\n15 Freeman C.L. Sehn L.H. A tale of two antibodies: obinutuzumab versus rituximab Br J Haematol 182 2018 29 45 10.1111/bjh.15232 29741753\n16 Boyer-Suavet S. Andreani M. Lateb M. Neutralizing anti-rituximab antibodies and relapse in membranous nephropathy treated with rituximab Front Immunol 10 2020 3069 10.3389/fimmu.2019.03069 31998325\n17 Martin de Fremont G. Chiron A. Krzysiek R. Flare of a mixed cryoglobulinaemic vasculitis after obinutuzumab infusion Clin Exp Rheumatol 39 Suppl 129 2021 52 55\n18 Kolopp-Sarda M.N. Cryoglobulins Miossec P. an update on detection, mechanisms and clinical contribution Autoimmun Rev 17 2018 457 464 29526627\n19 Tedeschi A. Baratè C. Minola E. Morra E. Cryoglobulinemia Blood Rev 21 2007 183 200 17289231\n20 Podell D.N. Packman C.H. Maniloff J. Abraham G.N. Characterization of monoclonal IgG cryoglobulins: fine-structural and morphological analysis Blood 69 1987 677 681 3801676\n21 Chen Y.P. Cheng H. Rui H.L. Dong H.R. Cryoglobulinemic vasculitis and glomerulonephritis: concerns in clinical practice Chin Med J (Engl) 132 2019 1723 1732 31283654\n22 Kumar A. Khamkar K. Gopal H. Serum sickness and severe angioedema following rituximab therapy in RA Int J Rheum Dis 15 2012 e6 e7 22324965\n23 Hellerstedt B. Ahmed A. Delayed-type hypersensitivity reaction or serum sickness after rituximab treatment Ann Oncol 14 2003 1792\n24 Stone M.J. Waldenström's macroglobulinemia: hyperviscosity syndrome and cryoglobulinemia Clin Lymphoma Myeloma 9 2009 97 99 19362986\n25 MacKenzie M.R. Babcock J. Studies of the hyperviscosity syndrome. II. Macroglobulinemia J Lab Clin Med 85 1975 227 234 803540\n\n",
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"journal": "Kidney international reports",
"keywords": "cryoglobulinemia; cryoglobulinemic vasculitis; disease flare; rituximab",
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"title": "Rituximab-Associated Flare of Cryoglobulinemic Vasculitis.",
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"abstract": "Differential diagnosis of post-transplant infections should include rare/uncommon foci and pathogens. We present a rare case of life-threatening infection, a splenic abscess in a 53-year-old woman who was transplanted with a cadaveric kidney 5 months previously. The patient was admitted to our clinic with chills, shivering, and fever. She required a kidney transplant because of end-stage renal disease secondary to systemic lupus erythematosus, which had previously been treated by means of peritoneal dialysis for 7 years, until encapsulated sclerosing peritonitis developed, at which time therapy was changed to hemodialysis for 1 year. On physical examination, the patient was slightly lethargic and had tenderness in the left upper quadrant of the abdomen. Laboratory evaluation revealed leukocytosis and high acute phase reactant. Abdominal ultrasonography (US) revealed multiple abscesses in the spleen, but splenectomy was not recommended because of her history of sclerosing peritonitis. Percutaneous drainage catheters were placed under US guidance. Culture of blood and fluid drained from the abscess revealed imipenem-sensitive Escherichia coli and Klebsiella spp. Imipenem (500 mg IV q6hr) was initiated, and the drainage volume was 40 to 50 mL/day in the first week and gradually decreased through the third week. The abscess was completely drained over a period of 6 weeks, as confirmed by computed tomography; percutaneous catheters were then removed. Although splenic abscesses are life-threatening, especially for immunocompromised patients, this case suggests that percutaneous drainage guided by US or computed tomography is an efficient treatment alternative to splenectomy.",
"affiliations": "Nephrology Department, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey. Electronic address: drmrtgc@hotmail.com.;Nephrology Department, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey.;Nephrology Department, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey.;Nephrology Department, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey.;Nephrology Department, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey.;Radiology Department, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey.;Nephrology Department, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey.;General Surgery and Transplantation Department, Haydarpasa Numune Research and Training Hospital, Istanbul, Turkey.",
"authors": "Tuğcu|M|M|;Ruhi|Ç|Ç|;Boynueğri|B|B|;Kasapoğlu|U|U|;Can|Ö|Ö|;Kiliçoğlu|G|G|;Şahin|G|G|;Titiz|M|M|",
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"issue": "47(5)",
"journal": "Transplantation proceedings",
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"medline_ta": "Transplant Proc",
"mesh_terms": "D000038:Abscess; D004322:Drainage; D004926:Escherichia coli; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D007709:Klebsiella; D008875:Middle Aged; D010538:Peritonitis; D013158:Splenic Diseases; D018084:Ultrasonography, Interventional",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Successful Ultrasound-Guided Percutaneous Drainage of Multiple Splenic Abscesses in a Kidney Transplant Patient With Encapsulated Sclerosing Peritonitis: A Case Report.",
"title_normalized": "successful ultrasound guided percutaneous drainage of multiple splenic abscesses in a kidney transplant patient with encapsulated sclerosing peritonitis a case report"
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"abstract": "Myocardial injury is associated with excess mortality in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, and the mechanisms of injury are diverse. Coagulopathy associated with this infection may have unique cardiovascular implications.\nWe present a case of 62-year-old male who presented after experiencing syncope and cardiac arrest. Given the clinical presentation and electrocardiographic findings, there was concern for acute coronary syndrome. However, coronary angiogram did not reveal significant coronary obstruction. Due to the unclear nature of his presentation, a bedside echocardiogram was rapidly performed and was indicative of right ventricular strain. Due to these findings, a pulmonary angiogram was performed that revealed massive pulmonary embolism. He successfully underwent catheter-directed thrombolysis and, after a prolonged hospital stay, was discharged home on lifelong anticoagulation.\nThe impact of coronavirus disease-2019 (COVID-19) on the cardiovascular system has been prominent and multifaceted. COVID-19 can have wide-ranging effects on the cardiovascular system due to coagulopathy with resultant venous and arterial thrombo-embolism. Due to the critical condition of many patients affected by COVID-19, imaging for thrombo-embolic events is often delayed. With the use of bedside echocardiogram, observation of right ventricular strain may be critical in raising suspicion for pulmonary embolism, especially when atypical features are noted on electrocardiogram.",
"affiliations": "Internal Medicine-Pediatrics Residency Program, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.;Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.;Section of Interventional Cardiology, Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.;Section of Heart Failure and Transplantation Cardiology, Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.",
"authors": "Sang|Charlie J|CJ|0000-0003-1716-1524;Heindl|Brittain|B|0000-0002-0961-3562;Von Mering|Gregory|G|;Rajapreyar|Indranee|I|0000-0003-2043-3789",
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"doi": "10.1093/ehjcr/ytaa223",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n33089057\n10.1093/ehjcr/ytaa223\nytaa223\nCase Reports\nOther\nAcademicSubjects/MED00200\nMassive pulmonary embolism in a COVID-19 patient: a case report\nhttp://orcid.org/0000-0003-1716-1524\nSang Charlie J III 1\nhttp://orcid.org/0000-0002-0961-3562\nHeindl Brittain 2\nVon Mering Gregory 3\nhttp://orcid.org/0000-0003-2043-3789\nRajapreyar Indranee 4\nDeharo Pierre Handling Editor\nKanakakis John Editor\nRampat Rajiv Editor\nCamm Christian Fielder Editor\nThomson Ross Editor\n1 Internal Medicine—Pediatrics Residency Program, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA\n2 Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA\n3 Section of Interventional Cardiology, Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA\n4 Section of Heart Failure and Transplantation Cardiology, Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA\nCorresponding author. Internal Medicine—Pediatrics Residency Program, University of Alabama at Birmingham, 1600 7th Avenue, 3rd Floor W, McWane Bld, Birmingham, AL 35233, USA. Tel: +1 252 367 0742, Fax: +1 205 638 9977, Email: csang@uabmc.edu\n10 2020\n21 7 2020\n21 7 2020\n4 FI1 Focus Issue on COVID-19 15\n1 5 2020\n15 5 2020\n23 6 2020\n© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2020\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground\n\nMyocardial injury is associated with excess mortality in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, and the mechanisms of injury are diverse. Coagulopathy associated with this infection may have unique cardiovascular implications.\n\nCase summary\n\nWe present a case of 62-year-old male who presented after experiencing syncope and cardiac arrest. Given the clinical presentation and electrocardiographic findings, there was concern for acute coronary syndrome. However, coronary angiogram did not reveal significant coronary obstruction. Due to the unclear nature of his presentation, a bedside echocardiogram was rapidly performed and was indicative of right ventricular strain. Due to these findings, a pulmonary angiogram was performed that revealed massive pulmonary embolism. He successfully underwent catheter-directed thrombolysis and, after a prolonged hospital stay, was discharged home on lifelong anticoagulation.\n\nDiscussion\n\nThe impact of coronavirus disease-2019 (COVID-19) on the cardiovascular system has been prominent and multifaceted. COVID-19 can have wide-ranging effects on the cardiovascular system due to coagulopathy with resultant venous and arterial thrombo-embolism. Due to the critical condition of many patients affected by COVID-19, imaging for thrombo-embolic events is often delayed. With the use of bedside echocardiogram, observation of right ventricular strain may be critical in raising suspicion for pulmonary embolism, especially when atypical features are noted on electrocardiogram.\n\nCoronavirus disease 2019\nSevere acute respiratory syndrome coronavirus 2\nST-segment elevation myocardial infarction\nPulmonary embolism\nCoagulopathy\nCase report\n==== Body\nLearning points\n\nCOVID-19 is associated with a coagulopathy leading to increased rates of thrombo-embolic events.\n\nEarly recognition of right ventricular strain with the use of bedside echocardiogram can be critical in raising suspicion for diagnosis.\n\nEarly prophylactic anticoagulation should be considered in those with COVID-19 due to higher risk of thrombotic complications.\n\nIntroduction\n\nIn December 2019, mysterious cases of pneumonia emerged in Wuhan, China. Since this time, the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread to 185 countries infecting >2 500 000 people and causing over 180 000 deaths.1 The impact of coronavirus disease 2019 (COVID-19) on the cardiovascular system has been prominent and multifaceted.2 Interestingly, COVID-19 may have wide-ranging effects on coagulation and contribute to venous and arterial thrombo-embolism.3 In an effort to aid clinicians caring for these patients, we describe a case of massive pulmonary embolism presenting as an out-of-hospital cardiac arrest in a patient with COVID-19.\n\nTimeline\n\nDay 0\tExperiences syncope and out-of-hospital cardiac arrest.\n\nECG en rute to hospital concerning for ST-elevations in anterior leads\n\n\t\nDay 0: 1 h\tECG on arrival with slow, wide complex tachycardia. Due to concern for acute coronary syndrome, coronary angiogram performed but did not reveal coronary stenosis.\t\nDay 0: 6 h\tBedside echocardiogram with depressed right ventricular function. Pulmonary angiogram with bilateral pulmonary emboli. Catheter-directed thrombolysis administered\t\nDay 4\tComputed tomography of chest obtained with persistent ground-glass opacities. COVID-19 testing performed and positive\t\nDay 8\tExtubated\t\nDay 28\tDischarged home on lifelong anticoagulation\t\n\nTable 1 Lab results on admission\n\nLab\tValue\tReference range\t\nLactic acid\t19 (mmol/L)\t0.5–2.2 (mmol/L)\t\nTroponin I initial\t77 (ng/L)\t3–20 (ng/L)\t\nTroponin I peak\t6424 (ng/L)\t3–20 (ng/L)\t\nBrain natriuretic peptide\t127 (pg/mL)\t0–100 (pg/mL)\t\nProthrombin time\t18.2 (s)\t12–14.5 (s)\t\nInternational normalized ratio\t1.51\t(NA)\t\nPartial thromboplastin time\t28 (s)\t25–35 (s)\t\nFibrinogen\t193 (mg/dL)\t220–498 (mg/dL)\t\nD-dimer\t>20 000 (ng/mL)\t0–240 (ng/mL)\t\n\nCase presentation\n\nA 62-year-old male with hypertension and hyperlipidaemia presented to an urgent care clinic with 7 days of dizziness, fatigue, nausea, and vomiting. He was transported to the emergency department, evaluated, and discharged home. Approximately 4 days later, emergency medical services were called after the patient experienced syncope. Electrocardiogram (ECG) obtained en route reported anterior ST-segment elevations. Before arrival at the hospital he developed ventricular fibrillation. Cardiac defibrillation was successful and endotracheal intubation was performed. Upon arrival at the emergency department, ventricular fibrillation recurred, and resuscitative efforts restored sinus rhythm and spontaneous circulation. Following return of spontaneous circulation, exam was notable for heart rate of 77 b.p.m., a regular rhythm, and hypotension (86 mmHg/48 mmHg). There were no appreciable murmurs. There was no lower extremity oedema. The extremities were cool to touch. On pulmonary exam, he required mechanical ventilation with a rate of 28, tidal volume 500 mL, FiO2 100%, and positive end-expiratory pressure of 8 cmH2O. Breath sounds were present bilaterally. The subsequent ECG showed wide complex rhythm consistent with slow ventricular tachycardia with right bundle branch block morphology and left axis deviation. (Figure 1).\n\nFigure 1 ECG showing wide complex rhythm consistent with slow ventricular tachycardia with right bundle branch block morphology and left axis deviation.\n\nGiven the report of ST elevations prior to ventricular fibrillation, along with the ECG at presentation, there was high suspicion for acute coronary syndrome. He received aspirin, ticagrelor, and heparin for a presumed ST-segment elevation myocardial infarction. Epinephrine infusion was started due to bradycardia with hypotension. He was emergently taken to the catheterization lab, but coronary angiography did not reveal coronary stenosis. Right heart catheterization revealed elevated right-sided filling pressures with a right atrial pressure of 22 mmHg, pulmonary artery pressure 61/28 (39) mmHg, pulmonary capillary wedge pressure 15 mmHg, and Fick cardiac index 2.6 L/min/m2. Due to the unclear nature of his presentation, point-of-care echocardiogram was performed, and demonstrated a dilated right ventricle with severely reduced function. Based on point-of-care echocardiogram findings, there was concern for pulmonary embolism. Immediate pulmonary angiography was performed and revealed large, bilateral pulmonary emboli (Supplementary material online, Video 1). EkoSonic™ endovascular thrombolysis catheters were advanced into both main pulmonary arteries and 5 mg of tissue plasminogen activator was delivered through each catheter, followed by 2 mg/catheter/h for 2 h, then 1 mg/catheter/h for 16 h. Infusion was guided by fibrinogen monitoring as per institutional protocol.\n\nUpper and lower extremity Doppler ultrasounds were obtained but showed no evidence of venous thrombosis. Formal transthoracic echocardiogram confirmed depressed right ventricular function (Supplementary material online, Video 2). Computed tomography (CT) of the chest showed bilateral peripheral ground-glass opacities with wedge-shaped opacities in the right lung (Figure 2). These were thought to represent pulmonary infarctions, but, given refractory hypotension requiring vasopressors, he was started on broad-spectrum antibiotics for pneumonia. A viral respiratory panel was negative, but tracheal aspirate culture was positive for methicillin-resistant Staphylococcus aureus. Following completion of catheter-directed thrombolysis, repeat ECG showed sinus rhythm with first-degree atrioventricular (AV) block, left axis deviation, incomplete right bundle branch block, and prolonged QTc interval (498 ms) (Figure 3). Over the following 4 days, he developed anaemia, and CT of the chest, abdomen, and pelvis showed a mediastinal haematoma and persistent ground-glass opacities (Figure 4). Given his radiographic findings, and growing prevalence of COVID-19, he was tested for SARS-CoV-2 and found to be positive. He was transferred to a COVID-19-dedicated intensive care unit where he was placed under enhanced contact precautions and received supportive care. He was extubated 4 days later. Following extubation, he did well. He was admitted to an inpatient rehabilitation facility and discharged home on lifelong apixaban 5 mg twice daily. At 1 month follow-up, he described mild exertional dyspnoea that was improving. Transthoracic echocardiogram at that visit noted improvement of right ventricular dilation and systolic function (Supplementary material online, Video 3).\n\nFigure 2 CT chest revealing bilateral peripheral ground-glass opacities with peripheral wedge-shaped opacities in the right lung.\n\nFigure 3 ECG showing sinus rhythm with first-degree AV block, left axis deviation, incomplete right bundle branch block, and prolonged QTc interval (498 ms)\n\nFigure 4 CT chest revealing mediastinal haematoma and persistent ground-glass opacities.\n\nDiscussion\n\nThis patient presented with syncope, ventricular fibrillation, and shock secondary to a massive pulmonary embolism in the setting of SARS-CoV-2 infection. The overall prevalence of venous thrombo-embolism in the setting of COVID-19 is poorly defined, with current case series suggesting as many as 20.6–25% of patients admitted may have concurrent thrombo-embolic phenomena.4,5\n\nIt is recognized that COVID-19 causes a coagulopathy associated with elevated D-dimer, prolonged prothrombin time, and reduced fibrinogen. The mechanisms behind the coagulopathy are unclear, and some theories postulate the up-regulation of cytokines as possible contributors, while others believe hepatic dysfunction with resultant coagulopathy may play a role.3 Regardless of the mechanism, it is apparent that there is increased prevalence of thrombotic events in patients with COVID-19.\n\nThis coagulopathy often progresses to disseminated intravascular coagulation,6 causing both venous and arterial thrombosis, and portends a poor prognosis. One report found that 71.4% of patients who died from COVID-19 met criteria for disseminated intravascular coagulation.6 In COVID-19, many patients meet the Third International Consensus Definitions for Sepsis and Septic Shock.7 Disseminated intravascular coagulation represents a major cause of organ dysfunction in sepsis, and the use of anticoagulant therapy in this setting is controversial.8 The term sepsis-induced coagulopathy (SIC) was coined by the International Society of Thrombosis and Hemostasis, and represents an earlier phase in the progression of disseminated intravascular coagulation. Using a SIC score, administration of systemic anticoagulation may be helpful in improving the hypercoagulable state, organ dysfunction, and hospitalizations associated with sepsis.8 In a retrospective, single-centre study, administration of prophylactic low molecular weight heparin was associated with reduced 28-day mortality in severe COVID-19 patients with concurrent coagulopathy, defined as a SIC score >4 (40% vs. 64.2%, P = 0.029) or D-dimer >3 μg/mL (32.8% vs. 52.4%, P = 0.017).9\n\nGiven the prevalence of the disease and associated coagulopathy, patients with unexplained deep venous thrombosis or pulmonary embolism should raise concern for COVID-19. However, the diagnosis of venous thrombo-embolism remains challenging in this setting. Many barriers to routine imaging for these conditions include patient instability, poor image quality due to patient management parameters (i.e. proning), and increased exposure risk to healthcare workers.3 Our case highlights the importance of echocardiography, particularly at the bedside. Evaluation of decreased right ventricular function was critical in raising suspicion for, and ultimately diagnosing, his pulmonary embolism. As such, it is reasonable to consider echocardiography to assess for right ventricular dysfunction as a clue to diagnosis in this setting.3\n\nIn our patient, his rapid recovery, despite the acuity of his illness, was surprising. Catheter-directed thrombolysis contributed to his recovery, but his course would probably have benefited from anticoagulation, independent of its effects on the pulmonary embolism. To our knowledge, this is the first case of COVID-19-associated pulmonary embolism successfully treated with catheter-directed thrombolysis.\n\nWith these limitations, empiric thromboprophylaxis with low molecular weight heparin may provide benefit in this population. As such, expert opinion recommends prophylactic low molecular weight heparin be administered to all COVID-19 patients requiring hospitalization unless thrombocytopenia is present (defined as platelet count <25 × 109/L) or fibrinogen levels are <0.5 g/L.10\n\nConclusions\n\nCOVID-19-associated coagulopathy may present with incidental thrombo-embolic phenomena. It is imperative to maintain a high index of suspicion for these complications when caring for patients with COVID-19. Empiric thromboprophylaxis may have clinical benefit in reducing these complications. Furthermore, as standard imaging may not be feasible, echocardiogram may offer further evidence to raise suspicion of pulmonary embolism.\n\nLead author biography\n\nCharlie Sang III was born in Greenville, NC, USA in September 1991. He received his undergraduate degree in Exercise and Sport Science at the University of North Carolina at Chapel Hill and studied medicine at the Brody School of Medicine at East Carolina University. He is currently training in a combined residency in Internal Medicine–Paediatrics at the University of Alabama at Birmingham. He has a broad interest in cardiovascular disease in both the paediatric and adult populations.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal – Case Reports online.\n\nSupplementary Material\n\nytaa223_Supplementary_Data Click here for additional data file.\n\nAcknowledgements\n\nThe authors would like to acknowledge Brigitta Brott, MD and Robert Kopf, DNP for their contributions to this case.\n\n \n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: Despite repeated attempts by the authors, they were unable to contact the patient to obtain informed consent. The authors confirm they have obtained approval from the University of Alabama at Birmingham, Birmingham, AL, USA Institutional Review Board for the creation and publication of this manuscript and are in compliance with national and institutional ethical standards. The case has been fully anonymised. This has been discussed and agreed with the editors.\n\nConflict of interest: none declared.\n==== Refs\nReferences\n\n1 Dong E , Du H , Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis 2020;20 :533–534.32087114\n2 Bonow RO , Fonarow GC , O’Gara PT , CW Yancy Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality. JAMA Cardiol 2020;doi: 10.1001/jamacardio.2020.1105.\n3 Bikdeli B , Madhavan MV , Jimenez D , Chuich T , Dreyfus I , Driggin E , Nigoghossian C , Ageno W , Madjid M , Guo Y , Tang LV , Hu Y , Giri J , Cushman M , Quéré I , Dimakakos EP, , Gibson CM , Lippi G , Favaloro EJ , Fareed J , Caprini JA , Tafur AJ , Burton JR , Francese DP , Wang EY , Falanga A , McLintock C , Hunt BJ , Spyropoulos AC , Barnes GD , Eikelboom JW , Weinberg I , Schulman S , Carrier M , Piazza G , Beckman JA , Steg PG , Stone GW , Rosenkranz S , Goldhaber SZ , Parikh SA , Monreal M , Krumholz HM , Konstantinides SV , Weitz JI , Lip GYH; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. JACC State-of-the-Art Review. J Am Coll Cardiol 2020;75 :2950–2973.32311448\n4 Poissy J , Goutay J , Caplan M , Parmentier E , Duburcq T , Lassalle F , Jeanpierre E , Rauch A , Labreuche J , Susen S ; Lille ICU Haemostasis COVID-19 group. Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence. Circulation 2020;doi: 10.1161/CIRCULATIONAHA.120.047430.\n5 Cui S , Chen S , Li X , Liu S , Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost 2020;18 :1421–1424.32271988\n6 Tang N , Li D , Wang X , Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18 :844–847.32073213\n7 Singer M , Deutschman CS , Seymour CW , Shankar-Hari M , Annane D , Bauer M , Bellomo R , Bernard GR , Chiche JD, , Coopersmith CM , Hotchkiss RS , Levy MM, , Marshall JC, , Martin GS , Opal SM , Rubenfeld GD , van der Poll T , Vincent JL , Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315 :801–810.26903338\n8 Iba T , Levy JH , Warkentin TE , Thachil J , van der Poll T , Levi M ; Scientific and Standardization Committee on DIC, and the Scientific and Standardization Committee on Perioperative and Critical Care of the International Society on Thrombosis and Haemostasis. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost 2019;17 :1989–1994.31410983\n9 Tang N , Bai H , Chen X , Gong J , Li D , Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020;18 :1094–1099.32220112\n10 Lee AY , Connors JM , Kreuziger LB , Murphy M , Gernsheimer T , Lin Y. COVID-19 and coagulopathy: frequently asked questions. American Society of Hematology. https://www.linksmedicus.com/news/covid-19-coagulopathy-frequently-asked-questions/\n\n",
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"keywords": "Case report; Coagulopathy; Coronavirus disease 2019; Pulmonary embolism; ST-segment elevation myocardial infarction; Severe acute respiratory syndrome coronavirus 2",
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"abstract": "Patients with refractory or relapsed lymphoma diagnosed with bulky disease at relapse or with residual disease after salvage treatment are considered to have a dismal outcome, even after autologous hematopoietic stem-cell transplantation, as a result of disease recurrence. To minimize the risk of relapse after receipt of a transplant, involved-field radiotherapy (IFRT) to sites of either bulky or localized residual disease has been utilized; however, the ideal timing for irradiation remains controversial. The aim of this study was to assess the safety and efficacy of IFRT in the early period after transplantation.\n\n\n\nWe retrospectively evaluated the outcome of 24 autografted patients with relapsed/refractory lymphoma who presented with bulky disease at relapse or who had a persistent localized residual mass after salvage treatment and consolidated with IFRT within 4 months after autografting.\n\n\n\nNo significant toxicity was noticed during the early postradiotherapy period, while graft function was not impaired. After a median follow-up of 3 years for survivors, 21 patients were alive, 19 of whom were event free, while 2 patients died of disease recurrence and 1 died of treatment-related myelodysplastic syndrome. The 3-year overall, lymphoma relapse-free, and event-free survival rates were 86%, 86%, and 82%, respectively.\n\n\n\nTaking into consideration the poor-risk features of the study cohort, IFRT provided early after autologous hematopoietic stem-cell transplantation showed a safe and well-tolerated toxicity profile and demonstrated long-term effective tumor control, as reflected in the promising survival rates.",
"affiliations": "Adult Hematology and Stem Cell Transplantation Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia. Electronic address: pkaloyannidis@yahoo.gr.;Adult Hematology and Stem Cell Transplantation Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia.;Radiation Oncology Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia.;Adult Hematology and Stem Cell Transplantation Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia.;Adult Hematology and Stem Cell Transplantation Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia.;Radiation Oncology Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia.;Department of Pathology and Laboratory Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia.;Department of Pathology and Laboratory Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia.;Department of Medical Imaging, King Fahad Specialist Hospital, Dammam, Saudi Arabia.;Adult Hematology and Stem Cell Transplantation Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia.;Adult Hematology and Stem Cell Transplantation Department, King Fahad Specialist Hospital, Dammam, Saudi Arabia.",
"authors": "Kaloyannidis|Panayotis|P|;Omari|Rawan|R|;Eldebawy|Eman|E|;Al Shaibani|Eshrak|E|;Apostolidis|John|J|;Hindi|Taghreed|T|;Raslan|Heba|H|;Al Garni|Ayed|A|;Al Buali|Ahmed|A|;Al Anezi|Khalid|K|;Al Hashmi|Hani|H|",
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"keywords": "Autologous hematopoietic stem-cell transplantation; Hodgkin Lymphoma; Non Hodgkin Lymphoma; Radiotherapy; Refractory lymphoma",
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"title": "Favorable Outcome After Adjuvant Involved-Field Radiotherapy After Autologous Hematopoietic Stem-Cell Transplantation in Patients With High-Risk Relapsed/Refractory Lymphoma: A Single-Center Experience.",
"title_normalized": "favorable outcome after adjuvant involved field radiotherapy after autologous hematopoietic stem cell transplantation in patients with high risk relapsed refractory lymphoma a single center experience"
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"abstract": "Angiosarcomas are vascular malignancies with a tendency to spread extensively both locally and systemically. We report a case of cutaneous angiosarcoma of the face in a 53-year-old man that was originally misdiagnosed as an abscess. Initially small, the lesion enlarged over a four-to-six-month period and began to bleed. Two shave biopsies were performed that returned a diagnosis of angiosarcoma. The patient underwent radical resection and lymph node dissection, which revealed positive margins and ten of forty-six positive lymph nodes. The patient was treated with paclitaxel and concurrent radiation therapy (RT). Restaging scans showed a new sclerotic lesion of the T10 vertebra, three hepatic lesions, and an adrenal lesion, all concerning for metastasis. Biopsy of one of the hepatic lesions was consistent with metastatic angiosarcoma. In this review, we discuss the presentation of cutaneous angiosarcoma, the importance of early diagnosis, and the treatment options available for metastatic disease that has failed first-line chemotherapy.",
"affiliations": "Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, Lebanon NH, USA.;Drexel Hematology/Oncology, 230 N Broad St, Philadelphia PA, USA.;Drexel Hematology/Oncology, 230 N Broad St, Philadelphia PA, USA.;Drexel Hematology/Oncology, 230 N Broad St, Philadelphia PA, USA.;Drexel Hematology/Oncology, 230 N Broad St, Philadelphia PA, USA.;Drexel Hematology/Oncology, 230 N Broad St, Philadelphia PA, USA.",
"authors": "Lara-Martinez|Hugo|H|https://orcid.org/0000-0003-1087-6324;Weinberg|Molly|M|;Baratam|Praneeth|P|;Horn|Jeffrey|J|;Ward|Kristine|K|;Styler|Michael|M|",
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"doi": "10.1155/2021/8823585",
"fulltext": "\n==== Front\nCase Rep Oncol Med\nCase Rep Oncol Med\nCRIONM\nCase Reports in Oncological Medicine\n2090-6706\n2090-6714\nHindawi\n\n10.1155/2021/8823585\nCase Report\nAngiosarcoma of the Face: A Case Study and Literature Review of Local and Metastatic Angiosarcoma\nhttps://orcid.org/0000-0003-1087-6324\nLara-Martinez Hugo hugo.r.lara-martinez@hitchcock.org\n1\nWeinberg Molly 2\nBaratam Praneeth 2\nHorn Jeffrey 2\nWard Kristine 2\nStyler Michael 2\n1Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, Lebanon NH, USA\n2Drexel Hematology/Oncology, 230 N Broad St, Philadelphia PA, USA\nAcademic Editor: Raffaele Palmirotta\n\n2021\n1 7 2021\n2021 882358515 7 2020\n28 5 2021\nCopyright © 2021 Hugo Lara-Martinez et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nAngiosarcomas are vascular malignancies with a tendency to spread extensively both locally and systemically. We report a case of cutaneous angiosarcoma of the face in a 53-year-old man that was originally misdiagnosed as an abscess. Initially small, the lesion enlarged over a four-to-six-month period and began to bleed. Two shave biopsies were performed that returned a diagnosis of angiosarcoma. The patient underwent radical resection and lymph node dissection, which revealed positive margins and ten of forty-six positive lymph nodes. The patient was treated with paclitaxel and concurrent radiation therapy (RT). Restaging scans showed a new sclerotic lesion of the T10 vertebra, three hepatic lesions, and an adrenal lesion, all concerning for metastasis. Biopsy of one of the hepatic lesions was consistent with metastatic angiosarcoma. In this review, we discuss the presentation of cutaneous angiosarcoma, the importance of early diagnosis, and the treatment options available for metastatic disease that has failed first-line chemotherapy.\n==== Body\n1. Introduction\n\nAngiosarcomas are rare vascular malignancies that present with metastases in approximately 20% of patients more often than with other types of soft tissue sarcoma [1]. Spread to local lymph nodes occurs more often with angiosarcoma than with other types of soft tissue sarcomas. Resection is the initial therapy for local disease, and chemotherapy such as paclitaxel and doxorubicin is commonly used for recurrent or metastatic disease. Tyrosine kinase inhibitors, angiogenesis inhibitors, and combinations of the aforementioned with cytotoxic agents are currently being used in clinical trials [2]. The case presented here demonstrates the importance of early, accurate diagnosis of angiosarcomas due to their tendency to metastasize widely. Following treatment failure, determination of second-line therapy in the recurrent or metastatic setting is difficult at present due to the lack of prospective studies.\n\n2. Case Presentation\n\nA 53-year-old African American male with a past medical history of chronic obstructive pulmonary disease (COPD), current smoker (20 pack-years), was initially presented in July 2016 to the dermatology department with a fungating mass on the left nasal sidewall. The mass appeared four to six months prior to presentation as a small lesion. At that time, multiple physicians told him that it was an abscess; however, it was never drained. The lesion then continued to enlarge and started bleeding significantly. The bleeding became so severe that he began having symptoms of shortness of breath with exertion, fatigue, and weakness that required an intensive care unit (ICU) stay for symptomatic anemia.\n\nOn exam, there were several hyperpigmented patches with papules extending to the right nasal sidewall and a 4 mm flesh-colored papule on the right cheek (Figure 1(a)). There is a 10 cm fungating verrucous plaque with central ulceration and friable areas on the left nasal sidewall extending to the left cheek (Figure 1(b)).\n\nThe patient had significant left submental and postauricular lymphadenopathy. Dermatology performed two shave biopsies of the mass (left nasal sidewall and left nasal bridge) and cauterized the bleeding areas. Results returned as angiosarcoma as seen in (Figure 2). Punch biopsies were then performed by dermatology to evaluate for multifocality, and the patient was referred to oncology for further management. He was staged with a CT maxillofacial, CT neck, CT chest, CT abdomen and pelvis, and MRI brain (Figure 3). Radiation oncology and surgery teams evaluated the patient. Staging workup was completed, and tumor was staged at III (T1b, N1M0). Incidentally, a right hilar lung mass and node were found (Figure 4). A core biopsy of this lesion showed lung adenocarcinoma, staged at Ia (T1b, N0, M0); no additional mutation studies were ordered at that time.\n\nIn September 2016, the patient underwent a left radical maxillectomy, left excision of facial tumor, left orbital exploration with medial canthotomy and medial canthus repair, resection of left lacrimal apparatus, endoscopic left anterior and posterior ethmoidectomy, and left modified neck dissection. He subsequently underwent skin grafting to the left face from an anterolateral thigh flap graft. Management of the lung adenocarcinoma was deferred until recovery from facial surgery. Pathology results from the resection showed positive margins and gross residual tumor. Ten of the 46 lymph nodes dissected were positive.\n\nFollowing the surgery, hematology and oncology along with radiation oncology planned for chemoradiation with paclitaxel. There was, however, a gap in care for a few months due to social issues with the patient. He also required dental extractions prior to starting radiation. In February 2017, the patient was able to have two dental extractions and was cleared to start radiation treatment. He began treatment with CT simulation in March 2017 and completed 8 cycles of paclitaxel 50 mg/m2 and 66.6 Gy of RT in two phases over 37 fractions in May 2017. He experienced mucosal toxicity and skin desquamation from the radiation treatment, but this completely recovered over three months. Definitive management of the lung adenocarcinoma was deferred due to not being able to tolerate both treatments simultaneously.\n\nFollowing completion of chemoradiation, restaging PET CT in September 2017 showed small residual FDG activity with a SUV of 5.6 in the left maxilla and avid known RUL mass abutting the medial pleura now larger in size. His lung adenocarcinoma was upstaged to IIIA (T2, N2, M0). He received CT simulation of the lung lesion in October 2017 followed by 9 cycles of carboplatin/paclitaxel with RT and two additional doses of carboplatin/paclitaxel consolidation.\n\nIn April 2018, restaging scans showed an interval decrease of the right hilar mass but a new nonspecific T10 sclerotic lesion, three new hepatic lesions, and a new left adrenal gland lesion, all concerning for metastasis (Figure 5). CT of the maxillofacial region also showed progression of soft tissue in the right maxillary sinus with slightly increased overlying infiltration of the right premalar and right paranasal soft tissues concerning for malignancy and effacement of the left piriform sinus which is new.\n\nA hepatic lesion was biopsied in June 2018 that was consistent with metastatic angiosarcoma. The patient was then lost to follow-up.\n\n3. Discussion\n\nAngiosarcomas are a very aggressive and rare type of soft tissue sarcoma accounting for 1.6% of soft tissue sarcomas [3]. Location of the primary tumor can vary; however, they most commonly occur in the head and neck, followed by the breasts and extremities [4]. They appear to have a male predilection with most studies demonstrating a 2 : 1 distribution [5]. They can appear at any age, but the cutaneous form seems to be more common in older white males [4]. The exact aetiology is unknown, and most arise spontaneously.\n\nThere are some risk factors associated with developing angiosarcomas which include chronic lymphedema, radiation, exogenous toxins such as vinyl chloride, arsenic, and thorium, neurofibromatosis type 1, Maffucci syndrome, and mutations on BRCA 1 or BRCA 2 [6].\n\nThe diagnosis of angiosarcomas can often be delayed due to misdiagnosis as a fungal infection, bacterial infection, Kaposi's sarcoma, melanoma, or ulcers since they have a wide range of appearance [4]. Clinical presentation can vary depending on time of presentation.\n\nAngiosarcomas can initially appear as bruises or raised purplish papules but can further grow and look like ulcerated, fungating masses [7]. They often haemorrhage as with our patient.\n\nThe pathology of angiosarcomas can differ but often is characterized by irregular, anastomosing, and dilated vasculature similar to that in benign lymphangioendothelioma [8]. They can express the endothelial markers CD31, CD34, vWF, vascular endothelial growth factor (VEGF), and U europaeus agglutinin 1 [9]. These can aid in the diagnosis.\n\nAngiosarcomas have a poor prognosis compared to other soft tissue sarcomas, with a five-year survival of 35% [10]. Survival is higher in those with localized disease. Some factors associated with a worse prognosis include old age, high tumor grade, large tumors greater than five centimeters, metastatic disease, and poor performance status [6, 11, 12].\n\nInterestingly, it should be noted that ever-smoking is a poor prognosis and associated with a decrease in disease-specific survival in patients with angiosarcomas compared to nonsmokers [13]. This could be related to the fact that smoking has been linked to progression and metastasis likely due to its effect in the cell cycle and apoptosis [14]. It is unclear if smoking cessation can improve outcomes, but it has been shown that smoking cessation for 3 months can improve pulmonary function capacity [15].\n\nTreatment varies depending if disease is localized or metastatic. The treatment of choice in patients with localized disease is radical surgery with complete resection [16]. It is recommended to resect with wide margins due to the aggressiveness of the disease. Patients with limited disease should receive adjuvant radiation therapy at 50 Gy with wide treatment fields due to the high likelihood of local recurrence [16]. A retrospective analysis of treatment of angiosarcoma of the scalp and face showed that combination of surgery and radiation offered the best survival at 45.8% at 2 years, whereas either treatment alone only afforded 11.1% survival at 2 years [17]. In patients with later stage or advanced disease, the use of chemotherapy using cytotoxic agents is appropriate [4].\n\nIn patients with metastatic disease, cytotoxic chemotherapy is the primary treatment option. First-line treatment is a single-agent regimen with paclitaxel, doxorubicin, bevacizumab, sunitinib, or sorafenib [16].\n\nA retrospective study of the EORTC soft tissue and bone sarcoma group found paclitaxel to be an active agent in angiosarcomas particularly in those of the face and scalp with a response rate of 75% and time to progression of 9.5 months [18]. However, Italiano et al. [19] have shown that using single-agent doxorubicin or weekly paclitaxel appears to have similar efficacy in metastatic angiosarcomas, but cutaneous angiosarcomas respond more favorably to weekly paclitaxel. Many patients, however, have treatment failure or recurrent disease. One medication that has shown to be promising is pazopanib, a multiple target tyrosine kinase inhibitor that has received approval to treat certain soft tissue sarcoma. In a phase III randomized trial comparing pazopanib vs. placebo in patients with metastatic angiosarcoma, it was shown a progression-free survival of 4.6 months in the pazopanib group compared to the placebo 1.6 months [20]. Another small trial that was conducted by Pasquier et al. demonstrated a strong synergism between propranolol and vincristine in an in vitro model and interestingly lead to 100% response in patients with inoperable angiosarcoma [21].\n\nOur patient has unfortunately failed therapy with paclitaxel-based regimens used as an adjunct to radiation or along with carboplatin as part of his lung cancer treatment, although the metastatic recurrence happened after a 3-month long hiatus with no therapy due to patient compliance issues. He now has distant metastasis to multiple sites. We are considering the use of pazopanib or restarting weekly paclitaxel therapy if he can tolerate another course of treatment. We are also considering radiation therapy if he chooses a palliative option. Due to the lack of prospective studies and the limited number of cases, it can be difficult to determine the standard of care for treatment of angiosarcomas.\n\nTargeted therapies have shown promising results, such as the use of VEGF inhibitors such as bevacizumab, PDGF inhibitors such as olaratumab, and tyrosine kinase inhibitors such as pazopanib [20].\n\n4. Conclusion\n\nA case of angiosarcoma of the face has been presented in this report. This case helps us understand the clinical presentation of angiosarcomas and the importance of arriving at the correct diagnosis initially. It is also important to be diligent with nonhealing ulcers or wounds. In early stages, localized radical resection and radiation therapy may be a sufficient form of treatment. In metastatic disease, however, doxorubicin or paclitaxel are suitable as first-line agents. One should note that paclitaxel has a better response in the cutaneous form of angiosarcomas, especially of the scalp and face. Novel targeted therapy looks promising for the future of treatment.\n\nSince our patient has failed first-line paclitaxel-based therapy and is now presenting with diffuse metastatic disease, a trial of pazopanib appears to be the appropriate next action.\n\nData Availability\n\nThe data used to support the findings of this study have not been made available because of hospital closure.\n\nConsent\n\nPatients provided consent for photos and publication as guided per institution.\n\nConflicts of Interest\n\nThe authors declare that there is no conflict of interest regarding the publication of this paper.\n\nFigure 1 (a) Right nasal sidewall of patient's angiosarcoma. (b) Left nasal sidewall of patient's angiosarcoma.\n\nFigure 2 H&E staining of patient's left facial angiosarcoma.\n\nFigure 3 CT neck with contrast imaging of left nasal mass.\n\nFigure 4 CT chest with contrast imaging of right hilar mass.\n\nFigure 5 CT with contrast imaging of liver metastasis (arrow).\n==== Refs\n1 Morrison W. H. Byers R. M. Garden A. S. Evans H. L. Ang K. K. Peters L. J. Cutaneous angiosarcoma of the head and neck. A therapeutic dilemma 1995 76 2 Cancer 10.1002/1097-0142(19950715)76:2<319::AID-CNCR2820760224>3.0.CO;2-8 8625109\n2 Malangani M. A. Rosen M. J. Sabiston textbook of surgery.The biological basis of modern surgical practice Sabiston Textbook of Surgery.The Biological Basis of Modern Surgical Practice 2012\n3 Rouhani P. Fletcher C. D. M. Devesa S. S. Toro J. R. Cutaneous soft tissue sarcoma incidence patterns in the U.S.: an analysis of 12,114 cases 2008 113 3 Cancer 10.1002/cncr.23571 2-s2.0-49049096901\n4 Young R. J. Brown N. J. Reed M. W. Hughes D. Woll P. J. Angiosarcoma The Lancet Oncology 2010 11 10 983 991 10.1016/S1470-2045(10)70023-1 2-s2.0-77957331576 20537949\n5 Wang L. Lao I. W. Yu L. Wang J. Clinicopathological features and prognostic factors in angiosarcoma: a retrospective analysis of 200 patients from a single Chinese medical institute 2017 Oncol. Lett 10.3892/ol.2017.6892 2-s2.0-85030175819\n6 Fayette J. Martin E. Piperno-Neumann S. Angiosarcomas, a heterogeneous group of sarcomas with specific behavior depending on primary site: a retrospective study of 161 cases 2007 18 12 Ann. Oncol 10.1093/annonc/mdm381 2-s2.0-37349120536 17974557\n7 Dossett L. Harrington M. Cruse C. Gonzalez R. Cutaneous angiosarcoma Current Problems in Cancer 2015 4 39 258 263\n8 Shustef E. Kazlouskaya V. Prieto V. G. Ivan D. Aung P. P. Cutaneous angiosarcoma: a current update Journal of Clinical Pathology 2017 70 11 917 925 10.1136/jclinpath-2017-204601 2-s2.0-85032581451 28916596\n9 Ohsawa M. Naka N. Tomita Y. Kawamori D. Kanno H. Aozasa K. Use of immunohistochemical procedures in diagnosing angiosarcoma. Evaluation of 98 cases 1995 75 12 Cancer 10.1002/1097-0142(19950615)75:12<2867::AID-CNCR2820751212>3.0.CO;2-8 7773935\n10 Fury M. G. Antonescu C. R. Van Zee K. Brennan M. E. Maki R. G. A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy 2005 11 3 Cancer J 10.1097/00130404-200505000-00011 2-s2.0-33749545556 16053668\n11 Park J. T. Roh J. L. Kim S. O. Prognostic factors and oncological outcomes of 122 head and neck soft tissue sarcoma patients treated at a single institution Annals of Surgical Oncology 2015 22 1 248 255 10.1245/s10434-014-3870-8 2-s2.0-84939890358 25001093\n12 Lee B. L. Chen C. F. Chen P. C. H. Investigation of prognostic features in primary cutaneous and soft tissue angiosarcoma after surgical resection Annals of Plastic Surgery 2017 78 3 S41 S46 10.1097/SAP.0000000000001004 2-s2.0-85010867716 28118230\n13 Yeang M. S. Tay K. Ong W. S. Outcomes and prognostic factors of post-irradiation and de novo sarcomas of the head and neck: a histologically matched case-control study Annals of Surgical Oncology 2013 20 9 3066 3075 10.1245/s10434-013-2979-5 2-s2.0-84881479242 23604715\n14 Pezzuto A. Citarella F. Croghan I. Tonini G. The effects of cigarette smoking extracts on cell cycle and tumor spread: novel evidence Futur. Sci. OA 2019 5 5 p. FSO394 10.2144/fsoa-2019-0017 2-s2.0-85066847437 31205749\n15 Pezzuto A. Carico E. Effectiveness of smoking cessation in smokers with COPD and nocturnal oxygen desaturation: functional analysis The Clinical Respiratory Journal 2020 14 1 29 34 10.1111/crj.13096 31613417\n16 National Comprehensive Cancer Network (NCCN) NCCN Clinical Practice Guidelines in Oncology Soft tissue sarcoma (Version2.2018) 2018\n17 Ogawa K. Takahashi K. Asato Y. Treatment and prognosis of angiosarcoma of the scalp and face: a retrospective analysis of 48 patients British Journal of Radiology 2012 85 1019 e1127 e1133 10.1259/bjr/31655219 2-s2.0-84868024238 22806620\n18 Schlemmer M. Reichardt P. Verweij J. Paclitaxel in patients with advanced angiosarcomas of soft tissue: a retrospective study of the EORTC soft tissue and bone sarcoma group European Journal of Cancer 2008 44 16 2433 2436 10.1016/j.ejca.2008.07.037 2-s2.0-54449099288 18771914\n19 Italiano A. Cioffi A. Penel N. Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas Cancer 2012 118 13 3330 3336 10.1002/cncr.26599 2-s2.0-84862509604 22045619\n20 van der Graaf W. T. A. Blay J. Y. Chawla S. P. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double- blind, placebo-controlled phase 3 trial 2012 379 9829 Lancet 10.1016/S0140-6736(12)60651-5 2-s2.0-84861098484\n21 Pasquier E. André N. Street J. Effective management of advanced angiosarcoma by the synergistic combination of propranolol and vinblastine-based metronomic chemotherapy: a bench to bedside study 2016 6 EBioMedicine 10.1016/j.ebiom.2016.02.026 2-s2.0-84959060674 27211551\n\n",
"fulltext_license": "CC BY",
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"issue": "2021()",
"journal": "Case reports in oncological medicine",
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"pages": "8823585",
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"pmid": "34306782",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
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"title": "Angiosarcoma of the Face: A Case Study and Literature Review of Local and Metastatic Angiosarcoma.",
"title_normalized": "angiosarcoma of the face a case study and literature review of local and metastatic angiosarcoma"
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"abstract": "OBJECTIVE\nTo review intestinal complications associated with ibuprofen treatment of patent ductus arteriosus (PDA).\n\n\nMETHODS\nData from preterm infants treated with ibuprofen were retrospectively reviewed. χ(2) test and Fischer's exact test were used for univariate analyses. Multivariate analyses with logistic regression modeling were used to identify risk factors.\n\n\nRESULTS\nOne hundred and two infants were treated with ibuprofen for PDA. Nine (9/102, 8.8%) infants developed spontaneous intestinal perforation (SIP), whereas 93/102 (91.2%) did not. The mean (± s.d.) gestational age (GA) at birth in infants with and without SIP was 25.2 (± 1.3) vs 27.6 (± 2.4) weeks (P=0.02) and the median (interquartile) length of stay (LOS) was 109.5 (91.0 to 116.5) vs 75.0 (53.0 to 94.5) days (P=0.002), respectively. The mean (± s.d.) age at starting ibuprofen was 3.3 (± 1.3) vs 5.8 (± 3.5) days in infants with and without SIP, respectively (P=0.03). In logistic regression analyses, increasing GA and later initiation of ibuprofen treatment were protective against risk of SIP; odds ratio, 95% confidence interval (OR, 95% CI)=0.26 (0.09 to 0.75), P=0.01 and 0.63 (0.41 to 0.95), P=0.03, respectively.\n\n\nCONCLUSIONS\nInfants at lower GA are at risk of SIP when treated early with ibuprofen for symptomatic PDA.",
"affiliations": "Division of Newborn Medicine, Washington University in St Louis, St Louis, MO 63110, USA. rao_r@kids.wustl.edu",
"authors": "Rao|R|R|;Bryowsky|K|K|;Mao|J|J|;Bunton|D|D|;McPherson|C|C|;Mathur|A|A|",
"chemical_list": "D016861:Cyclooxygenase Inhibitors; D007052:Ibuprofen",
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"doi": "10.1038/jp.2010.199",
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"issue": "31(7)",
"journal": "Journal of perinatology : official journal of the California Perinatal Association",
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"medline_ta": "J Perinatol",
"mesh_terms": "D015331:Cohort Studies; D016001:Confidence Intervals; D016861:Cyclooxygenase Inhibitors; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004374:Ductus Arteriosus, Patent; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007052:Ibuprofen; D015994:Incidence; D007231:Infant, Newborn; D007234:Infant, Premature; D007416:Intestinal Perforation; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D016017:Odds Ratio; D012189:Retrospective Studies; D018570:Risk Assessment; D015996:Survival Rate; D014463:Ultrasonography",
"nlm_unique_id": "8501884",
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"pages": "465-70",
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"pmid": "21252965",
"pubdate": "2011-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Gastrointestinal complications associated with ibuprofen therapy for patent ductus arteriosus.",
"title_normalized": "gastrointestinal complications associated with ibuprofen therapy for patent ductus arteriosus"
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"abstract": "Primary pituitary lymphoma (PPL) is an extremely rare disease with poor prognosis. Although PPL has been shown to be different from classical primary central nervous system lymphoma because of the embryological origin of structures, individual and precise treatment of PPL remains unknown.\n\n\n\nA 61-year-old man and a 65-year-old woman both diagnosed with primary pituitary diffuse large B cell lymphoma underwent genetic analysis of cerebrospinal fluid and tumor tissue by next generation sequencing.\n\n\n\nIn the first case, partial remission was achieved following R²-MTX chemotherapy. In the other case with TP53 mutation and BCL6-LPP fusion, disease progressed although different chemotherapy regimens were given.\n\n\n\nThe gene mutation of TP53 and BCL6 may be identified as a marker responsible for prognostic difference in patients with PPL. Genetic analysis may provide a novel approach for precise management and prognosis prediction.",
"affiliations": "Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China.;Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China.;Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China.;Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China.;Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China.;Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China.;Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China.;Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China.;Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China.;Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China.",
"authors": "Zhang|Yi|Y|;Ma|Liyuan|L|;Liu|Jie|J|;Zhu|Huijuan|H|;Lu|Lin|L|;Deng|Kan|K|;Ma|Wenbin|W|;Pan|Hui|H|;Wang|Renzhi|R|;Yao|Yong|Y|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fendo.2021.673908",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)\nFront Endocrinol (Lausanne)\nFront. Endocrinol.\nFrontiers in Endocrinology\n1664-2392\nFrontiers Media S.A.\n\n10.3389/fendo.2021.673908\nEndocrinology\nCase Report\nCase Report: Identification of Potential Prognosis-Related TP53 Mutation and BCL6-LPP Fusion in Primary Pituitary Lymphoma by Next Generation Sequencing: Two Cases\nZhang Yi 1 †\n\nMa Liyuan 2 †\nLiu Jie 1 †\nZhu Huijuan 2\nLu Lin 2\nDeng Kan 1\nMa Wenbin 1\nPan Hui 2\nWang Renzhi 1\nYao Yong 1 *\n\n1 Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China\n2 Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China\nEdited by: Congxin Dai, Capital Medical University, China\n\nReviewed by: Sergei I. Bannykh, Cedars Sinai Medical Center, United States; Murat Aydin Sav, Yeditepe University, Turkey\n\n*Correspondence: Yong Yao, tigerfreeyy@126.com\n†These authors have contributed equally to this work\n\nThis article was submitted to Pituitary Endocrinology, a section of the journal Frontiers in Endocrinology\n\n26 7 2021\n2021\n12 67390828 2 2021\n20 5 2021\nCopyright © 2021 Zhang, Ma, Liu, Zhu, Lu, Deng, Ma, Pan, Wang and Yao\n2021\nZhang, Ma, Liu, Zhu, Lu, Deng, Ma, Pan, Wang and Yao\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground\n\nPrimary pituitary lymphoma (PPL) is an extremely rare disease with poor prognosis. Although PPL has been shown to be different from classical primary central nervous system lymphoma because of the embryological origin of structures, individual and precise treatment of PPL remains unknown.\n\nMethods\n\nA 61-year-old man and a 65-year-old woman both diagnosed with primary pituitary diffuse large B cell lymphoma underwent genetic analysis of cerebrospinal fluid and tumor tissue by next generation sequencing.\n\nResults\n\nIn the first case, partial remission was achieved following R²-MTX chemotherapy. In the other case with TP53 mutation and BCL6-LPP fusion, disease progressed although different chemotherapy regimens were given.\n\nConclusion\n\nThe gene mutation of TP53 and BCL6 may be identified as a marker responsible for prognostic difference in patients with PPL. Genetic analysis may provide a novel approach for precise management and prognosis prediction.\n\nprimary pituitary lymphoma\nTP53\nBCL6\nhigh-dose methotrexate\ndiffuse large B cell lymphoma\nnext generating sequencing\nChinese Academy of Medical Sciences Initiative for Innovative Medicine10.13039/501100019018Peking Union Medical College Hospital10.13039/501100008235\n==== Body\nIntroduction\n\nPrimary pituitary lymphoma (PPL) is an extremely rare clinical entity with much poorer prognosis, while it has an emerging trend these years (1, 2). It is commonly limited in the sellar and parasellar areas without systematic involvement. Histologically, B-cell lymphoma is the most common cell type, followed by T cell type and NK/T cell type (1). The diagnosis of PPL usually can only be determined by pathological analysis since the clinical history, radiological findings and physical examinations do not show significant distinctions with other intracranial neoplasms (1). Although previous studies tend to consider PPL as different primary central nervous system lymphoma (PCNSL) because of embryological origin, the treatment of PPL often follows the management protocol of PCNSL. However, we noticed that the sensitivity and effectiveness of treatment varied in the patients of PPL (3–5). Genetic analysis might provide a novel approach to selecting the most appropriate regimen and predicting the prognosis of PPL patients. Here we reported two cases of PPL undergoing genetic analysis of cerebrospinal fluid (CSF) and tumor tissue by next generation sequencing (NGS). We firstly found that the gene mutation of TP53 and BCL6 might be responsible for prognostic difference in patients with PPL.\n\nMaterial and Methods\n\nCSF was collected in Streck tubes (Streck, Omaha, NE, USA) from each patient for lymphoma gene detection. Tumor tissue samples and peripheral blood as controls were collected for Whole Exome Sequencing (WES). Library construction was performed using protocols of the Illumina TruSeq DNA library preparation kit (Illumina, San Diego, CA), and then hybridized to custom-designed biotinylated oligonucleotide probes (Roche NimbleGen, Madison, WI, USA). Targeted sequencing was carried out using Illumina HiSeq 3000 platform (Geneplus, Beijing, China). Reads were further aligned to human genome (hg19) using Burrows–Wheeler Aligner (BWA, version 0.7.12-r1039). Somatic single nucleotide variants (SNVs), small insertions and deletions (InDels) and fussion were detected using GATK toolkit (version 3.4). CNV(copy number variation) were identified by CNVKit (version: 0.9.2.dev0).\n\nCase Presentation\n\nCase 1\n\nA 61-year-old man suffered from increasing right-side headache and blurred vision for 10 months and right eye lid ptosis for 4 months. Laboratory tests, including blood routine and biochemistry, immunological indices, thorax, abdominal and pelvis CT and lumbar puncture were normal. Endocrine investigation disclosed multiple anterior pituitary hypofunction: adrenocorticotrophic hormone of 21.34 pg/ml, morning cortisol of 40.6 nmol/L (NR: 166–507 nmol/L); Thyroid function: FT3 3.09 ng/L, FT4 0.31 ng/dL, TSH 0.11 μIU/ml; Gonadal hormone: LH 1.0 mIU/ml, FSH 2.5 IU/ml, E <18 pmol/L, P <0.159 nmol/L, testosterone <0.087 nmol/L, DHEA 0.1 μmol/L, prolactin of 792 mIU/L (NR: 166–507 nmol/L); GH 1.2 ng/ml. Pituitary magnetic resonance imaging (MRI) 10 and 5 months ago both demonstrated suspected “pituitary microadenoma” on the right side ( Figures 1A, B ). The patient was twice diagnosed with “autoimmune hypophysitis” and treated with hydrocortisone or prednisone together with azathioprine, and twice diagnosed with “viral encephalitis” and received pulsed methylprednisolone in different local hospitals in these 10 months. However, his symptoms didn’t improve but worsened. The MRI three months ago showed the mass in sella turcica enlarged to 1.3 × 0.9 cm, involving the right cavernous sinus and internal carotid artery ( Figure 1C ). The remaining past medical, personal and family history was unremarkable.\n\nFigure 1 The pituitary images in different period of Case 1. (A, B) Pituitary magnetic resonance imaging (MRI) 10 and 5 months ago both demonstrated suspected “pituitary microadenoma” on the right side. (C) Three months ago, enhanced MRI showed the mass in sella turcica enlarged to 1.3 × 0.9 cm, involving the right cavernous sinus and internal carotid artery. (D) One months ago, the pituitary MRI showed the mass might be “pituitary macroadenoma” (12.7 × 6.7 × 11.1 mm, demonstrating equal T1 and equal T2 signal with slightly homogeneous enhancement) in the sellar region with the right cavernous sinus invasion (Knosp IV). (E) Pituitary MRI reexamination half months after biopsy surgery showed the mass enlarged compared with before, involving bilateral cavernous sinus. (F, G) Enhanced head MRI + DWI and Pituitary gland plain scan + enhanced MRI showed the mass was significantly smaller than before after three months’ chemotherapy.\n\nLast month, the patient visited our hospital. Blood test work up showed hypothalamus–pituitary dysfunction similar with before. The pituitary MRI showed the mass might be “pituitary macroadenoma” (12.7 × 6.7 × 11.1 mm, demonstrating equal T1 and equal T2 signal with slightly homogeneous enhancement) in the sellar region with the right cavernous sinus invasion (Knosp IV) ( Figure 1D ). Physical examination after admission revealed right third cranial nerve palsy and classic signs of Cushing’s syndrome resulting from glucocorticoids treatment.\n\nA presumptive diagnosis of nonsecretory pituitary macroadenoma was made, and the mass caused anterior pituitary hypofunction. Endoscopic endonasal transsphenoidal surgery was performed for biopsy in our hospital. Pathological examination confirmed diffuse large B cell lymphoma (DLBCL) (germinal center-like). Immunohistochemical staining showed the tumor cells to be immunoreactive for B-cell marker CD20 and negative for the T-cell marker CD3. Further marker studies showed the tumor cells to be positive for Bcl-2, Bcl-6, CD5, CD20, C-MYC (index 60%) and P53. Markers Mum-1, CD10, CD23, CD3, Cyclin D1, CD30 (Ki-1), AE1/AE3, CAM5.2, ER, PIT-1, T-PIT were negative. Cell proliferation index Ki-67 was 70%. In situ hybridization showed EBER ISH (−).\n\nA total body PET/CT, bone marrow biopsy and CSF analysis confirmed the absence of systemic involvement. Testing for the HIV were negative.\n\nThus, the diagnose of primary central nervous system lymphoma (DLBCL, GCB type, double positive expression, Ann Arbor stage IE A) was made. Further genetic testing for lymphoma by NGS of CSF sample showed the patient contained MYD88 (c.794T>C), TNFRSF14 (c.95C>T), ETV6 (c.26G>A) and ETV6 (c.33+1G>A) mutations ( Table 1 ). NGS result of tumor tissue was similar to it.\n\nTable 1 Gene mutations of cerebrospinal fluid sample in two patients.\n\nGene\tTranscript\tMutation\tAmino acid\tFunction Zones\tVariation frequency\t\nCase 1\t\n MYD88\tNM_002468.4\tc.794T>C\tp.L265P\tEX5\t5.0%\t\n TNFRSF14\tNM_003820.2\tc.95C>T\tp.A32V\tEX2\t4.7%\t\n ETV6\tNM_001987.4\tc.26G>A\tp.S9N\tEX1\t1.6%\t\n ETV6\tNM_001987.4\tc.33+1G>A\t–\tIVS1\t1.6%\t\nCase 2\t\n MYD88\tNM_002468.4\tc.794T>C\tp.L265P\tEX5\t55.8%\t\n TP53\tNM_000546.5\tc.401T>G\tp.F134C\tEX5\t39.0%\t\n CD79B\tNM_000626.2\tc.68-1G>C\t–\tIVS1\t23.7%\t\n PCLO\tNM_033026.5\tc.6632C>T\tp.T2211I\tEX5\t11.7%\t\n JAK2\tNM_004972.3\tc.678G>T\tp.R226S\tEX7\t3.6%\t\n JAK2\tNM_004972.3\tAmplification\t–\t9p24.1\t14.2\t\n CD274\tNM_014143.3\tAmplification\t–\t9p24.1\t13.6\t\n PDCD1LG2\tNM_025239.3\tAmplification\t–\t9p24.1\t7.1\t\n BCL6-LPP\tNM_001706.4 /NM_001167672.1\tFusion\t–\t3q27.3/3q28\t38.4%\t\n\nPituitary MRI reexamination half months after biopsy surgery showed the mass enlarged compared with before, involving bilateral cavernous sinus ( Figure 1E ). Three courses of R²-MTX chemotherapy (800 mg iv d1 of Rituximab, 7 g iv d2 of methotrexate, and 25 mg d1–14 of lenalidomide) were administrated in the next three months. MRI scan showed marked reduction of the tumor size ( Figures 1F, G ). The symptom of eyelids ptosis, blurred vision and headache gradually improved. He is considered to be in partial remission.\n\nCase 2\n\nA 65-year-old woman had paroxysmal headache with no obvious inducement from 2 months ago, accompanied with nausea, denying vomiting, blurred vision or slurred speech. The patient also had dry mouth, polydipsia and polyuria with loss of appetite and fatigue. For past medical history, she received an operation of right adnexectomy and total hysterectomy because of mucinous cystadenoma of right ovary 10 years ago.\n\nLast month in local hospital, endocrines test showed hypopituitarism: FT4 8 pmol/L, TSH 0.11 mIU/ml; LH <0.01 mIU/ml, FSH 1.16 mIU/ml; 0 ACTH 1.88 pmol/L, serum cortisol 0.506, 8 ACTH 1.91 pmol/L, serum cortisol 0.536; GH 0.803 ng/ml, IGF-1 150 ng/ml. The tumor marker NSE was of 21.77 ng/ml (0–16.3), while AFP and CEA were normal. IgG4 was of 0.47 g/L. Pituitary MRI showed a mass appeared as soft tissue density in sellar area with a size of about 1.5 × 1.3 × 2.2 cm, and partial of it had no clear boundary between optic chiasma. PET-CT showed the mass (2.3 × 2.0 cm) in pituitary gland with increased FDG uptake and SUVmax of 75.7 ( Figure 2 ). The patient was treated orally with desmopressin 0.05 mg bid, prednisone acetate 5 mg qd, and euthyrox 25 μg qd. The symptoms of thirst and polyuria were obviously relieved, but headache and nausea were not relieved.\n\nFigure 2 PET-CT one month ago showed the mass (2.3 × 2.0 cm) in pituitary gland with increased FDG uptake and SUVmax of 75.7 in Case 2.\n\nTwo weeks ago, the headache worsened with persistent pain, accompanied by nausea and vomiting. She went to the department of emergency in our hospital with a blood pressure of 85/66 mmHg. After symptomatic treatment, the patient was admitted to the department of neurosurgery. Physical examination revealed normal vision and visual field. Further examination was finished, which showed: TSH 30.014 μIU/ml, FT3 1.55 pg/ml; Tumor markers: CEA 2.3 ng/ml, CA 125 10.9 μ/ml; IgG4 506 mg/L, ESR 44 mm/h.\n\nMass in sellar area which might be metastatic pituitary cancer was considered and endoscopic endonasal transsphenoidal surgery was performed for biopsy. Pathological examination showed the tumor was consistent with DLBCL (B cell derived from germinal center). The immunohistochemical staining showed: CD20(++), Bcl-2(+), Mum-1(10%+), Bcl-6(95%+), C-MYC(80%+), P53(+), CD3(scattered+), CD5(scattered+), CD15(−), CD10(−), CD30(Ki-1)(−), PAX-5(+), AE1/AE3(−), CgA(−), NUT(−), HMB45(−), Syn(−), S-100(−), Ki-67(index 90%). In situ hybridization showed EBER ISH (−).\n\nNGS testing for lymphoma-related genes of CSF sample showed the patient contained point mutations of MYD88 (c.794T>C), TP53 (c.401T>G), CD79B (c.68-1G>C), PCLO (c.6632C>T) and JAK2 (c.678G>T), amplification of gene JAK2, CD274, PDCD1LG2 and fusion of gene BCL6-LPP ( Table 1 ). Figures 3 and 4 schematically display two mutations closely related to poor prognosis of lymphoma, TP53 (c.401T>G) mutation and BCL6-LPP fusion, which existed in patient 2 but not in patient 1. Result of WES of tumor tissue was consistent with CSF.\n\nFigure 3 Diagram of TP53 c.401T>G (p.F134C) alteration in Case 2. (A) The base of c.401 mutated from T to G and amino acid changed from phenylalanine to cysteine. (B) The 3-dimentional model structure of TP53 wild-type analyzed by SWISSMODEL. (C) The Phe134 of TP53. (D) The Cys134 of mutated TP53.\n\nFigure 4 Schematic representation of the BCL6-LPP fusion in Case 2. An 838 kb-sized deletion of chromosome 3q27.3–3q28 (base 187461439 on chromosome 3q27 to base 188299507 on chromosome 3q28), resulting in a fusion of the BCL6 with the LPP gene.\n\nCT of the chest, abdomen, and pelvis as well as bone marrow biopsy were negative for dissemination. Then the patient received chemotherapy in local hospital, including one course of R-HDMTX (rituximab and high-dose methotrexate) chemotherapy regimen, one course of rituximab associated to temozolomide and one course of R-MT protocol (580 mg d0 of rituximab, 2.0 g d1 of methotrexate, and 200 mg d2-5 of temozolomide). A pituitary MRI at two months from the beginning of chemotherapy demonstrated the tumor (size of about 2 × 1.5 × 3.2 cm) was larger than before without cavernous sinus involving ( Figure 5 ). Thus, the treatment of chemotherapy continued.\n\nFigure 5 Pituitary MRI at two months from the beginning of chemotherapy demonstrated the tumor (size of about 2 × 1.5 × 3.2 cm) was larger than before without cavernous sinus involving in Case 2.\n\nDiscussion\n\nWe present two cases of PPL using genetic analysis to guide treatment and predict prognosis. To the best of our knowledge, this is the first attempt to distinguish PPL from PCNSL genetically and manage PPL based on gene sequencing and we administered different treatment modality of chemotherapy and targeted therapy accordingly. We also identified that gene mutation of TP53 and BCL6 was responsible for prognostic difference. Normally, the treatment of PPL often follows the management protocol of PCNSL consisting of surgery, chemotherapy and/or radiotherapy (6). However, it is said that surgical intervention suggests no obvious benefits in the outcome of PCNSL and the neurotoxic effects of radiotherapy should be noted (3, 5). Therefore, the therapeutic regimen consisting of HD-MTX combined with rituximab and other cytostatic drugs that penetrate the blood–brain barrier is highly recommended (3, 4). Both of our patients initiated chemotherapy immediately after the diagnosis of PPL was confirmed pathologically, but one patient seemed not to be sensitive to such regimen. Genetic analysis was thus performed to predict prognosis and adjust treatment modality. Since the two patients showed different prognosis, we identified gene mutation of TP53 and BCL6 as a distinct characteristic after genetic comparison was made. Some other typical gene mutations of PPL are also investigated here which we believe are highly likely to make a difference.\n\nTP53 is mutated in 20–25% of aggressive B-cell lymphoma. The negative prognostic impact of TP53 mutations in DLBCL has been reported in a number of studies (7). Mutation and copy loss of TP53 are independent negative prognostic factors in DLBCL (8), while recent studies indicated that the prognostic role should be validated when combined with other indexes (9). For instance, Dobashi et al. found that TP53 mutations and TP53 deletions were confirmed to be poor prognostic factors for overall survival (OS) and progression-free survival (PFS) only when both aberrations co-existed (10). In the patients of DLBCL treated with R-CHOP, TP53 mutation significantly correlate with worse survival in either ABC- or GCB-DLBCL (11). Such a negative correlation could also be seen in chemotherapy ± rituximab (CCT-treated) PCNSL patients, with hotspot/direct DNA contact MUT-TP53 being predictive of poor outcome (12). Todorovic et al. investigated that TP53 was the only gene harboring mutations in all surveyed PCNSL patients, which showed a more frequent mutation incidence than DLBCL (13). Therefore, we believe the unfavorable prognostic effect of TP53 mutation is more likely to be employed in PCNSL and PPL patients. TP53 alterations can either give rise to a loss-of-function or a gain-of-function phenotype (14). In the cases of TP53 loss-of-function, they might undergo two sequential events. The first event is mutation or methylation of the TP53 promoter, leading to appearance of a cell with increased risk of malignant transformation. The second event is the loss of an intact allele of the gene; this change is necessary for tumorigenesis (15). The gain-of-function mutations could partly account for the observation of TP53 overexpression in haematological malignancies and resistance to conventional chemotherapeutic agents, leading to poor survival (14). The drug resistance could be seen in studies pointing out that response to both CHOP and R-CHOP treatments was significantly inferior in patients with TP53 mutation and that the Hodgkin Reed-Sternberg cell lines with drug resistance all contained TP53 defects (7, 14). One of our patients showed TP53 mutation without sufficient drug effect and prognosis was not well, which might indicate a potentially predictive role of TP53 in the prognosis of PPL.\n\nIn DLBCL, The BCL6 locus can fuse with different partner genes. Ueda et al. found that non-immunoglobulin/BCL6 gene fusion in DLBCL is a poor prognostic indicator and plays a pathogenetic role in a proportion of DLBCL (16). In PCNSLs, the BCL6 gene fusion with its partner genes such as lipoma-preferred partner (LPP) in band 3q27, may contribute to aberrant expression of BCL6 protein (17). A deletion in 3q leads to loss of an 837-kb fragment extending from the first intron of BCL6 to the third intron of the LPP gene, which may bring the BCL6 gene under the control of regulatory elements of the LPP gene or the miRNA-28 gene located in intron 4 of LPP (17). One of our patients showed BCL6-LPP gene fusion and the prognosis was not good. Whether BCL6 can be considered as a prognostic factor of PCNSL is still controversial. Cady et al. investigated that BCL6 was associated with inferior OS alone or concomitant with del (6) (q22) (18). However, the expression of BCL6 was paradoxically correlated with the prognosis of PCNSL. Kreher et al. found that BCL6 expression was associated with shorter Progression-free survival (PFS) (19), while Lossos et al. found BCL6 expression had improved survival (20) and Niparuck et al. found that BCL6 expression showed no significant predictive effect in PFS and OS (21). Considering the high relative expression of BCL6 can be detected in the majority of PCNSL cases, a potential role for BCL6 antagonists in the next generation of therapies for PCNSL could be explored (22).\n\nConclusion\n\nGenerally, we presented two extremely rare cases of PPL and developed genetic analysis as a novel approach for prognosis prediction and treatment adaption where gene mutation of TP53 and BCL6 were identified as a marker for prognostic difference of PPL. We believe such an attempt will inspire clinicians to yield more precise and effective management approaches of PPL and more details about genetic analysis in PPL should be validated in larger prospective studies.\n\nData Availability Statement\n\nThe data presented in the study are deposited in the NCBI Sequence Read Archive (SRA) repository, accession numbers (SRR14774001, SRR14774002, SRR14783994, SRR14783995, SRR14783996).\n\nEthics Statement\n\nThe ethical approvals for this study were granted by the PUMCH Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nConception and design: YY, RW, and YZ. Development of methodology: HP, WM, and YZ. Acquisition and analysis of data: YZ, LM, JL, and KD. Writing, review and revision of manuscript: YZ, LM, and JL. Technical and material support: HJZ and LL. Study supervision: YY, RW, and HJZ. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis study was supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2016-I2M-1-002) from YY: providing conception and design and supervision. Youth Science Foundation of Peking Union Medical College Hospital (No. pumch201911867) from YZ: analysis of data and writing manuscript.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nGlossary\n\nABC-DLBCL\tactivated B-cell-like lymphoma-DLBCL\t\nACTH\tadrenocorticotropic hormone\t\nAFP\talpha-fetoprotein\t\nBcl-2\tB-cell lymphoma 2 protein\t\nBCL6\tB-cell lymphoma 6 gene\t\nCA125\tcarbohydrate antigen 125\t\nCD79B\tCluster of Differentiation 79B gene\t\nCEA\tcarcinoembryonic antigen\t\nCgA\tchromogranin-A\t\nCNV\tcopy number variation\t\nCSF\tcerebrospinal fluid\t\nDHEA\tDehydroepiandrosterone\t\nDLBCL\tdiffuse large B cell lymphoma\t\nE\testrogen\t\nEBER ISH\tin situ hybridization of EBV-encoded RNA\t\nER\tEstrogen receptor\t\nESR\terythrocyte sedimentation rate\t\nETV6\ttranslocation-Ets-leukemia virus 6 gene\t\nFDG\tfluorodeoxyglucose\t\nFSH\tfollicle-stimulating hormone\t\nFT3\tfree triiodothyronine\t\nFT4\tfree thyroxine\t\nGCB\tgerminal center B-cell-like lymphoma\t\nGH\tgrowth hormone\t\nHIV\tHuman Immunodeficiency Virus\t\nHMB45\tHuman Melanoma Black 45\t\nIGF-1\tinsulin-like growth factor 1\t\nIgG4\timmunoglobin G4\t\nInDel\tInsertion and Deletion\t\nJAK2\tJanus kinase 2 gene\t\nLH\tluteinizing hormone\t\nLPP\tlipoma-preferred partner gene\t\nMRI\tmagnetic resonance imaging\t\nMum-1\tMultiple myeloma antigen 1\t\nMYD88\tMyeloid differentiation primary response 88 gene\t\nNGS\tnext generation sequencing\t\nNR\tnormal range\t\nNSE\tneuron-specific enolase\t\nNUT\tnuclear protein in testis\t\nOS\toverall survival\t\nP\tprogesterone\t\nPAX-5\tpaired-box domain 5\t\nPCLO\tPiccolo gene\t\nPCNSL\tprimary central nervous system lymphoma\t\nPDCD1LG2\tProgrammed cell death 1 ligand 2 gene\t\nPET-CT\tpositron emission tomography-computed tomography\t\nPFS\tprogression-free survival\t\nPPL\tprimary pituitary lymphoma\t\nR²-MTX\tRituximab and methotrexate\t\nR-CHOP\tRituximab-Cyclophosphamide\t\nHydroxyldaunorubicin\tOncovin and Prednisone\t\nS-100\tS-100 protein\t\nSNV\tsingle nucleotide variant\t\nSUV\tstandard uptake value\t\nSyn\tsynaptophysin\t\nTNFRSF14\ttumor necrosis factor receptor superfamily member 14 gene\t\nTP53\ttumor protein p53 gene\t\nTSH\tthyroid stimulating hormone\t\nWES\tWhole Exome Sequencing\n==== Refs\nReferences\n\n1 Tarabay A Cossu G Berhouma M Levivier M Daniel RT Messerer M . Primary Pituitary Lymphoma: An Update of the Literature. J Neurooncol (2016) 130 :383–95. 10.1007/s11060-016-2249-z\n2 Giustina A Gola M Doga M Rosei EA . Clinical Review 136: Primary Lymphoma of the Pituitary: An Emerging Clinical Entity. J Clin Endocrinol Metab (2001) 86 :4567–75. 10.1210/jcem.86.10.7909\n3 Batchelor TT . Primary Central Nervous System Lymphoma: A Curable Disease. Hematol Oncol (2019) 37 Suppl 1 :15–8. 10.1002/hon.2598\n4 von Baumgarten L Illerhaus G Korfel A Schlegel U Deckert M Dreyling M . The Diagnosis and Treatment of Primary Cns Lymphoma. Dtsch Arztebl Int (2018) 115 :419–26. 10.3238/arztebl.2018.0419\n5 Hoang-Xuan K Bessell E Bromberg J Hottinger AF Preusser M Rudà R . Diagnosis and Treatment of Primary CNS Lymphoma in Immunocompetent Patients: Guidelines From the European Association for Neuro-Oncology. Lancet Oncol (2015) 16 :e322–32. 10.1016/S1470-2045(15)00076-5\n6 Li Y Zhang Y Xu J Chen N . Primary Pituitary Lymphoma in an Immunocompetent Patient: A Rare Clinical Entity. J Neurol (2012) 259 :297–305. 10.1007/s00415-011-6179-6 21932128\n7 Zenz T Kreuz M Fuge M Klapper W Horn H Staiger AM . TP53 Mutation and Survival in Aggressive B Cell Lymphoma. Int J Cancer (2017) 141 :1381–8. 10.1002/ijc.30838\n8 Cao Y Zhu T Zhang P Xiao M Yi S Yang Y . Mutations or Copy Number Losses of CD58 and TP53 Genes in Diffuse Large B Cell Lymphoma Are Independent Unfavorable Prognostic Factors. Oncotarget (2016) 7 :83294–307. 10.18632/oncotarget.13065\n9 Chan A Dogan A . Prognostic and Predictive Biomarkers in Diffuse Large B-Cell Lymphoma. Surg Pathol Clin (2019) 12 :699–707. 10.1016/j.path.2019.03.012 31352982\n10 Dobashi A Togashi Y Tanaka N Yokoyama M Tsuyama N Baba S . TP53 and OSBPL10 Alterations in Diffuse Large B-Cell Lymphoma: Prognostic Markers Identified Via Exome Analysis of Cases With Extreme Prognosis. Oncotarget (2018) 9 :19555–68. 10.18632/oncotarget.24656\n11 Xu-Monette ZY Wu L Visco C Tai YC Tzankov A Liu WM . Mutational Profile and Prognostic Significance of TP53 in Diffuse Large B-Cell Lymphoma Patients Treated With R-CHOP: Report From an International Dlbcl Rituximab-CHOP Consortium Program Study. Blood (2012) 120 :3986–96. 10.1182/blood-2012-05-433334\n12 Munch-Petersen HD Asmar F Dimopoulos K Areškevičiūtė A Brown P Girkov MS . TP53 Hotspot Mutations Are Predictive of Survival in Primary Central Nervous System Lymphoma Patients Treated With Combination Chemotherapy. Acta Neuropathol Commun (2016) 4 :40. 10.1186/s40478-016-0307-6 27101868\n13 Todorovic Balint M Jelicic J Mihaljevic B Kostic J Stanic B Balint B . Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses. Int J Mol Sci (2016) 17 (5 ). 10.3390/ijms17050683\n14 Cheung KJ Horsman DE Gascoyne RD . The Significance of TP53 in Lymphoid Malignancies: Mutation Prevalence, Regulation, Prognostic Impact and Potential as a Therapeutic Target. Br J Haematol (2009) 146 :257–69. 10.1111/j.1365-2141.2009.07739.x\n15 Voropaeva EN Pospelova TI Voevoda MI Maksimov VN Orlov YL Seregina OB . Clinical Aspects of TP53 Gene Inactivation in Diffuse Large B-Cell Lymphoma. BMC Med Genomics (2019) 12 :35. 10.1186/s12920-019-0484-9 30871527\n16 Ueda C Akasaka T Ohno H . Non-Immunoglobulin/BCL6 Gene Fusion in Diffuse Large B-Cell Lymphoma: Prognostic Implications. Leuk Lymphoma (2002) 43 :1375–81. 10.1080/10428190290033305\n17 Schwindt H Akasaka T Zühlke-Jenisch R Hans V Schaller C Klapper W . Chromosomal Translocations Fusing the BCL6 Gene to Different Partner Loci Are Recurrent in Primary Central Nervous System Lymphoma and May Be Associated With Aberrant Somatic Hypermutation or Defective Class Switch Recombination. J Neuropathol Exp Neurol (2006) 65 :776–82. 10.1097/01.jnen.0000229988.48042.ae\n18 Cady FM O'Neill BP Law ME Decker PA Kurtz DM Giannini C . Del(6)(q22) and BCL6 Rearrangements in Primary CNS Lymphoma Are Indicators of an Aggressive Clinical Course. J Clin Oncol (2008) 26 :4814–9. 10.1200/jco.2008.16.1455\n19 Kreher S Jöhrens K Strehlow F Martus P Borowiec K Radke J . Prognostic Impact of B-Cell Lymphoma 6 in Primary CNS Lymphoma. Neuro Oncol (2015) 17 :1016–21. 10.1093/neuonc/nov046\n20 Lossos C Bayraktar S Weinzierl E Younes SF Hosein PJ Tibshirani RJ . LMO2 and BCL6 Are Associated With Improved Survival in Primary Central Nervous System Lymphoma. Br J Haematol (2014) 165 :640–8. 10.1111/bjh.12801\n21 Niparuck P Boonsakan P Sutthippingkiat T Pukiat S Chantrathammachart P Phusanti S . Treatment Outcome and Prognostic Factors in PCNSL. Diagn Pathol (2019) 14 :56. 10.1186/s13000-019-0833-1 31189479\n22 Ponzoni M Issa S Batchelor TT Rubenstein JL . Beyond High-Dose Methotrexate and Brain Radiotherapy: Novel Targets and Agents for Primary CNS Lymphoma. Ann Oncol (2014) 25 :316–22. 10.1093/annonc/mdt385\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2392",
"issue": "12()",
"journal": "Frontiers in endocrinology",
"keywords": "BCL6; TP53; diffuse large B cell lymphoma; high-dose methotrexate; next generating sequencing; primary pituitary lymphoma",
"medline_ta": "Front Endocrinol (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101555782",
"other_id": null,
"pages": "673908",
"pmc": null,
"pmid": "34381423",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "27825110;24571259;30871527;29999484;31189479;16896311;29731965;12389616;18645192;31352982;31187523;19500100;27164089;21932128;22955915;27101868;25817328;24265352;27581598;26149884;11600505;28614910",
"title": "Case Report: Identification of Potential Prognosis-Related TP53 Mutation and BCL6-LPP Fusion in Primary Pituitary Lymphoma by Next Generation Sequencing: Two Cases.",
"title_normalized": "case report identification of potential prognosis related tp53 mutation and bcl6 lpp fusion in primary pituitary lymphoma by next generation sequencing two cases"
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"abstract": "Nitrous oxide is a recreational drug gaining in popularity for its deemed innocence. However, side effects have recently been reported. In this case, a patient suffered major aortic arch thrombus resulting in arterial occlusion of his arm and temporary cerebral infarction and later deep venous thrombosis and pulmonary embolism. No common causes for thrombus in this high-flow vessel were identified. The authors state that the patient's chronic nitrous oxide abuse might have led to this thrombus, although it has never been described previously. This hypothesis is supported with laboratory tests at several presentations.",
"affiliations": "Department of Vascular Surgery, Spaarne Gasthuis, Haarlem, The Netherlands.;Department of Vascular Surgery, Spaarne Gasthuis, Haarlem, The Netherlands.;Department of Vascular Surgery, Spaarne Gasthuis, Haarlem, The Netherlands.;Department of Vascular Surgery, Spaarne Gasthuis, Haarlem, The Netherlands.;Department of Vascular Surgery, Diakonessenhuis, Utrecht, The Netherlands.",
"authors": "den Uil|Sjoerd H|SH|;Vermeulen|Erik G J|EGJ|;Metz|Roderik|R|;Rijbroek|Abraham|A|;de Vries|Mattijs|M|",
"chemical_list": null,
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"doi": "10.1016/j.jvscit.2018.01.001",
"fulltext": "\n==== Front\nJ Vasc Surg Cases Innov TechJ Vasc Surg Cases Innov TechJournal of Vascular Surgery Cases and Innovative Techniques2468-4287Elsevier S2468-4287(18)30018-210.1016/j.jvscit.2018.01.001Case reportAortic arch thrombus caused by nitrous oxide abuse den Uil Sjoerd H. MD, MScsdenuil@spaarnegasthuis.nla∗Vermeulen Erik G.J. MD, PhD, MScaMetz Roderik MD, PhDaRijbroek Abraham MD, PhDade Vries Mattijs MD, PhDba Department of Vascular Surgery, Spaarne Gasthuis, Haarlem, The Netherlandsb Department of Vascular Surgery, Diakonessenhuis, Utrecht, The Netherlands∗ Correspondence: Sjoerd H. den Uil, MD, MSc, Department of Surgery, Spaarne Gasthuis, Boerhaavelaan 22, 2035 RC Haarlem, The Netherlands sdenuil@spaarnegasthuis.nl12 4 2018 6 2018 12 4 2018 4 2 80 82 22 10 2017 4 1 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Nitrous oxide is a recreational drug gaining in popularity for its deemed innocence. However, side effects have recently been reported. In this case, a patient suffered major aortic arch thrombus resulting in arterial occlusion of his arm and temporary cerebral infarction and later deep venous thrombosis and pulmonary embolism. No common causes for thrombus in this high-flow vessel were identified. The authors state that the patient's chronic nitrous oxide abuse might have led to this thrombus, although it has never been described previously. This hypothesis is supported with laboratory tests at several presentations.\n==== Body\nCase report\nA 32-year-old man with no medical history presented to the emergency department with severe pain and numbness in his right arm. A pale limb without arterial pulses was seen, and emergency computed tomography (CT) angiography revealed an occlusion of the axillary artery, derived from two large free-floating mural thrombi in the ascending aorta (Figs 1 and 2). Embolectomy of the right brachial artery was performed successfully, and pathologic and microbiologic analysis of the blood clots revealed no abnormalities. Continuous heparin perfusion was started, to which we pragmatically added clopidogrel (Plavix). One day after surgery, he suffered an infarction in his right hemisphere, with paralysis of the facial nerve and left arm and leg, inadequate eye tracking movements, and dysarthria. On cerebral CT scan, we identified an infarction of the territory of the right medial cerebral artery. Because of clinical recovery within hours, lack of clarity with respect to the exact duration of this infarction, and adequate activated partial thromboplastin time because of heparin treatment, it was decided not to administer additional thrombolytic therapy. Finally, heparin was replaced by warfarin treatment and later rivaroxaban.Fig 1 Large free-floating thrombus in the aortic arch on computed tomography (CT) scan, transverse view.\n\nFig 2 Large free-floating thrombus in the aortic arch on computed tomography (CT) scan, coronal view.\n\n\n\nThe patient finally recovered from both events without any residual symptoms. In follow-up, CT and magnetic resonance angiography studies revealed complete resolution of the floating thrombus in the aortic arch in approximately 2 weeks, without signs of aortic wall irregularities, dissection, intimal flaps, or new occlusions. Transthoracic ultrasound examination of the heart also showed these thrombi initially without other structural abnormalities, such as a patent foramen ovale or valvulopathy. The analysis of potential risk factors revealed severe abuse of nitrous oxide, which he used for a more intense perception of sound while building speakers. Furthermore, a heterozygous factor II mutation was found. Consultation with a vascular medicine expert revealed no other signs of common hypercoagulable defects, such as factor V Leiden and antiphospholipid syndrome. Protein C and protein S were not analyzed because the patient had already started warfarin treatment. However, after the patient stopped using warfarin, he had normal activated partial thromboplastin time and partial thromboplastin time. Furthermore, there was no prolonged immobility and no family history of hypercoagulability, and there were no relatives with vascular events.\n\nIn this report, we discuss our hypothesis about the effect of chronic nitrous oxide abuse on blood coagulation. The patient's consent was obtained for publication of his data.\n\nDiscussion\nThe incidence of acute peripheral arterial occlusion is around 1.5 cases per 10,000 persons a year,1 but thrombus formation in high-flow vascular regions like the aortic arch are rare.2 Some cases of spontaneous aortic thrombus have been described previously, and those cases are characterized by a prolonged quest for a single identifiable cause.3, 4 As in those cases, we were not able to identify a single well-known cause for arterial thrombus. The heterozygous factor II mutation is related to increased risk for venous blood clot formation but has not been linked to thrombus formation in arterial high-flow regions. This leaves only the patient's chronic nitrous oxide abuse, with recurrent laboratory abnormalities concurring with nitrous oxide abuse and vascular events. Although this has never been linked to human vascular events before, this led to our hypothesis, with a plausible biologic background.\n\nNitrous oxide, known since the 19th century for its role in anesthetics,5 was already used centuries ago in “laughing gas parties” and is currently regaining popularity in the recreational scene because of its availability, presumed innocence, rapid action, and short duration. Furthermore, it can be simply obtained, for instance, from nitrous oxide whippets for whipped cream.\n\nThe relation between nitrous oxide abuse and thrombus formation might be explained by a combined two-step pathway, of which both steps are well known individually. First, nitrous oxide is known to decrease levels of active vitamin B12 when it is used chronically.6 This phenomenon is widely used to create animal models with vitamin B12 deficiency. Second, this inactivation of vitamin B12 is known to inhibit methionine synthase, which plays a key role in the metabolism of methionine and folate. This inhibited process results in hyperhomocysteinemia. This hyperhomocysteinemia might be the missing link to arterial thrombus formation in this case because it is a known long-term cardiovascular risk factor. It is related to venous thromboembolism and peripheral arterial disease by degradation of collagen, elastin, and proteoglycans.7\n\nTo test our hypothesis, we performed blood tests within 1 week after the patient's event, which indeed showed homocysteine levels to be above detection levels of our laboratory (>55 μmol/L) and an extremely low level of vitamin B12 (116 nmol/L) for a young and otherwise healthy man. During the first 6 months of follow-up, while the patient abandoned his nitrous oxide abuse completely, the homocysteine level dropped (19 μmol/L) and the vitamin B12 level increased (276 nmol/L) without any vitamin supplementation. MTHFR gene mutation was not assessed but seems unlikely because our patient had normal homocysteine levels between two periods of severe abuse. Other chronic vitamin B12 deficiency is unlikely because he had normal levels at some point too.\n\nUnfortunately, our patient relapsed into his nitrous oxide abuse. He visited our emergency department several times with deep venous thrombosis, pulmonary embolism, and post-stroke epilepsy. At diagnosis of the deep venous thrombosis, vitamin B12 level had dropped again to 204 nmol/L, with a homocysteine level of >50 μmol/L. At diagnosis of pulmonary embolism, vitamin B12 levels were even lower, 162 nmol/L. Both times, there were no other laboratory abnormalities.\n\nConclusions\nThis report seems to indicate that chronic nitrous oxide use could be related to vitamin B12 deficiency in humans too. In addition to myelopathy described recently,8 this may lead to hyperhomocysteinemia, increasing the risk for cardiovascular events. This indicates a new potential risk of this popular and previously assumed innocent drug.\n\nOur hypothesis is supported by combining two independent but well-known biologic mechanisms—nitrous oxide and vitamin B12 deficiency, and vitamin B12 deficiency and hyperhomocysteinemia. Laboratory tests support this hypothesis, with improving results in a period without abuse and worsening results in a renewed period with severe abuse. There might be new or other unrecognized factors that contributed to his hypercoagulable state. All common causes were excluded, however, except for a heterozygous factor II mutation. Because our patient suffered thrombi in a high-flow arterial region, there must be a strong additional factor, which we believe could be nitrous oxide in this case.\n\nIn this case, conservative treatment with regard to the aortic thrombi was successful. Only surgery for his ischemic arm was performed; the thrombi resolved with anticoagulants alone.\n\nAlthough it is reasonably supported by the results in this case, appropriately designed future studies are needed to confirm the relation of chronic nitrous oxide use with thrombus formation. The abuse of nitrous oxide is gaining in popularity, and both national and international media repeatedly report about this phenomenon. This should result in the attention of health care professionals as well. Therefore, this report contributes to the awareness of the risks of this upcoming and until recently deemed innocent party drug.\n\nAuthor conflict of interest: none.\n\nThe editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.\n==== Refs\nReferences\n1 Creager M.A. Kaufman J.A. Conte M.S. Clinical practice. Acute limb ischemia N Engl J Med 366 2012 2198 2206 22670905 \n2 Jaworski L. Fijalkowski M. Rogowski J. Giant thrombus in ascending aorta and aortic arch J Thorac Cardiovasc Surg 145 2013 1668 1669 23414627 \n3 Rossi P.J. Desai T.R. Skelly C.L. Curi M.A. Glagov S. Schwartz L.B. Paravisceral aortic thrombus as a source of peripheral embolization—report of three cases and review of the literature J Vasc Surg 36 2002 839 843 12368747 \n4 Sawada T. Shimokawa T. Giant thrombus in the ascending aorta that caused systemic embolism Interact Cardiovasc Thorac Surg 12 2011 1048 1050 21422157 \n5 Emmanouil D.E. Quock R.M. Advances in understanding the actions of nitrous oxide Anesth Prog 54 2007 9 18 17352529 \n6 Chanarin I. The effects of nitrous-oxide on cobalamins, folates, and on related events Crit Rev Toxicol 10 1982 179 213 6127188 \n7 Selhub J. Jacques P.F. Bostom A.G. DAgostino R.B. Wilson P.W. Belanger A.J. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis N Engl J Med 332 1995 286 291 7816063 \n8 Shoults K. Case report: neurological complications of nitrous oxide abuse BCMJ 58 2016 192 194\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2468-4287",
"issue": "4(2)",
"journal": "Journal of vascular surgery cases and innovative techniques",
"keywords": null,
"medline_ta": "J Vasc Surg Cases Innov Tech",
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"other_id": null,
"pages": "80-82",
"pmc": null,
"pmid": "29942888",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports",
"references": "6127188;12368747;21422157;7816063;23414627;22670905;17352529",
"title": "Aortic arch thrombus caused by nitrous oxide abuse.",
"title_normalized": "aortic arch thrombus caused by nitrous oxide abuse"
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"companynumb": "NL-ALSI-201800309",
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"activesubstancename": "NITROUS OXIDE"
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{
"abstract": "Fixed drug eruption (FDE) consists of recurrent dusky-red to brownish macules or patches at the same sites after the readministration of the causative drug. It usually presents as a solitary lesion, but generalized eruptions have been described. The most frequently implied drugs are antibiotics, anticonvulsants, and analgesics. Only 2 cases due to metformin have been reported. Histopathologic features of FDE include vacuolar degeneration of the basal layer, necrotic keratinocytes, and superficial and deep perivascular lymphocytic infiltrate. Cutaneous hemophagocytosis in the context of a FDE has not been previously reported. We describe the case of an 86-year-old man who developed a pruritic generalized macular eruption of reddish to violaceous patches. Skin biopsy was performed and the dermal infiltrate was immunohistochemically studied. Histopathology showed interface dermatitis with vacuolar degeneration of the basal layer, necrotic keratinocytes, and superficial and deep perivascular lymphohistiocytic infiltrate. In deep dermis, histiocytes with engulfed cells inside their cytoplasm were seen. Lymphoid enhancer binding factor 1 immunostain demonstrated that most of these cells were lymphocytes. We present the first case with cutaneous hemophagocytosis in the context of a metformin-induced generalized FDE. In this particular case, hemophagocytosis was just a histopathologic finding with no systemic consequences for the patient.",
"affiliations": "Departments of *Dermatology, and †Pathology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.",
"authors": "Ramírez-Bellver|Jose Luis|JL|;Lopez|Joaquin|J|;Macias|Elena|E|;Fuertes|Laura|L|;Andres|Irene|I|;Alegria|Victoria|V|;Gimeno|Ignacio|I|;Perez|Alejandra|A|;Perez|Yosmar|Y|;Requena|Luis|L|",
"chemical_list": "D007004:Hypoglycemic Agents; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D008687:Metformin; D000068900:Sitagliptin Phosphate",
"country": "United States",
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"doi": "10.1097/DAD.0000000000000800",
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"issn_linking": "0193-1091",
"issue": "39(6)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000369:Aged, 80 and over; D001706:Biopsy; D003924:Diabetes Mellitus, Type 2; D003875:Drug Eruptions; D057915:Drug Substitution; D006644:Histiocytes; D006801:Humans; D007004:Hypoglycemic Agents; D007150:Immunohistochemistry; D008214:Lymphocytes; D051359:Lymphohistiocytosis, Hemophagocytic; D051821:Lymphoid Enhancer-Binding Factor 1; D008297:Male; D008687:Metformin; D000068900:Sitagliptin Phosphate; D012867:Skin; D016896:Treatment Outcome",
"nlm_unique_id": "7911005",
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"pages": "471-475",
"pmc": null,
"pmid": "27906695",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metformin-Induced Generalized Fixed Drug Eruption With Cutaneous Hemophagocytosis.",
"title_normalized": "metformin induced generalized fixed drug eruption with cutaneous hemophagocytosis"
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"abstract": "We aimed to characterize the safety profile of pembrolizumab in advanced melanoma patients at our center to better reflect 'real-world' data on anti-PD-1 inhibitors.\nAt our institution, 58 ipilimumab-naive and 30 ipilimumab-treated patients with advanced melanoma who have received pembrolizumab between June 2014 and June 2017 were included for analysis.\nIncidence of any-grade and grade 3/4 toxicities were 81.8% (n = 72) and 12.5% (n = 11), respectively. The most common side effects were skin-related (61.4%, n = 54) and gastrointestinal-related (51.1%, n = 45) events. In total, 25% of patients required oral steroids to manage immune-related adverse events with a median cumulative prednisolone dose of 683 mg (range: 40-3745 mg).\nPembrolizumab is well tolerated in 'real-world' patients and severe toxicities can be effectively managed with systemic steroids.",
"affiliations": "Faculty of Biology, Medicine, & Health, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK.;Faculty of Biology, Medicine, & Health, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK.",
"authors": "So|Alfred Cp|AC|;Board|Ruth E|RE|",
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"country": "England",
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"doi": "10.2217/mmt-2017-0028",
"fulltext": "\n==== Front\nMelanoma ManagMelanoma ManagMMTMelanoma Management2045-08852045-0893Future Medicine Ltd London, UK 10.2217/mmt-2017-0028Research ArticleReal-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK So & BoardReal-world experience with pembrolizumab toxicities in advanced melanoma patientsSo Alfred CP \n1\n\n2\nBoard Ruth E *\n1\n\n2\n\n1 Faculty of Biology, Medicine, & Health, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK\n2 Oncology Department, Lancashire Teaching Hospitals NHS Trust, Sharoe Green Lane, Fulwood, Preston, PR2 9HT, UK*Author for correspondence: Tel.: +44 1772 522916; @ruth.board@lthtr.nhs.uk6 2018 24 4 2018 5 1 MMT0509 11 2017 08 3 2018 24 4 2018 © 2018 Ruth Board & Alfred So2018This work is licensed under a Creative Commons Attribution 4.0 License\nAim:\nWe aimed to characterize the safety profile of pembrolizumab in advanced melanoma patients at our center to better reflect ‘real-world’ data on anti-PD-1 inhibitors.\n\nMaterials & methods:\nAt our institution, 58 ipilimumab-naive and 30 ipilimumab-treated patients with advanced melanoma who have received pembrolizumab between June 2014 and June 2017 were included for analysis.\n\nResults:\nIncidence of any-grade and grade 3/4 toxicities were 81.8% (n = 72) and 12.5% (n = 11), respectively. The most common side effects were skin-related (61.4%, n = 54) and gastrointestinal-related (51.1%, n = 45) events. In total, 25% of patients required oral steroids to manage immune-related adverse events with a median cumulative prednisolone dose of 683 mg (range: 40–3745 mg).\n\nConclusion:\nPembrolizumab is well tolerated in ‘real-world’ patients and severe toxicities can be effectively managed with systemic steroids.\n\nKeywords: \nanti-PD-1 therapyimmune-related adverse eventsmelanomapembrolizumabreal-world experienceretrospective study\n==== Body\nPractice points\nPembrolizumab is generally well tolerated by advanced melanoma patients.\n\nSkin-related and gastrointestinal-related events are the most common immune-related adverse events (irAEs) experienced with pembrolizumab.\n\nEndocrine toxicities, such as hypothyroidism, are a permanent side effect of pembrolizumab, and patients will require lifelong replacement with thyroxine.\n\nMany patients will require systemic steroids at some point during their treatment to manage immune-irAEs, the long-term implications of which are still uncertain.\n\nWe observed higher incidences of irAEs in our patients compared with pivotal trials, reflecting the underrepresentation of patients in clinical studies.\n\nMore ‘real-world’ data from observational studies is required to guide clinical decision-making and information provision to patients.\n\nFurther work is needed to clarify the long-term effects of anti-PD-1 therapy.\n\nMelanoma is the fifth most common cancer and the 18th most common cause of cancer death in the UK [1]. Before the advent of checkpoint inhibitors, treatment options for metastatic melanoma were limited and patients had poor survival rates with median overall survival (OS) of ≤1 year [2]. The use of checkpoint inhibitors has extended both progression-free survival and OS in advanced melanoma patients (stage III/IV) [3,4]. Furthermore, the approvals of anti-PD-1 antibodies such as pembrolizumab and nivolumab have since superseded ipilimumab (an anti-CTLA-4 antibody) as the current standard first-line treatment in the UK for many patients with metastatic melanoma due to their superior efficacies and favorable toxicity profiles.\n\nThe regulation of T-cell activation through checkpoint pathways is an important part of self-tolerance. This discrimination between self and nonself is essential to prevent immune-mediated tissue damage. However, as checkpoint inhibitors block these pathways, overstimulation of the immune system can overcome self-tolerance resulting in inflammatory responses termed immune-related adverse events (irAEs). The most common nonimmune adverse events (AEs) of checkpoint inhibitors are fatigue, diarrhea, pruritus, and nausea [3–7]. However, irAEs can occur in any tissues most commonly the skin, GI tract, thyroid gland, pituitary gland, lungs and liver [8].\n\nAlthough the range of irAEs is quite similar across checkpoint inhibitors, there are differences in frequency of toxicities. Grade 3/4 toxicities are less commonly observed with PD-1 inhibitors compared with CTLA-4 inhibitors [8]. Furthermore, PD-1 inhibitors have higher rates of thyroiditis and pneumonitis compared with CTLA-4 inhibitors [8]. Other factors that may influence toxicity profiles include combination therapies, treatment sequencing, tumor type and preexisting autoimmune conditions such as rheumatoid arthritis and inflammatory bowel disease [9,10].\n\nPembrolizumab is generally well tolerated but severe irAEs can lead to significant patient morbidity. Majority of grade 3/4 irAEs can be managed with oral (and intravenous) steroids. In steroid-refractory cases, other immunomodulatory drugs may be used including infliximab, mycophenolate mofetil and calcineurin inhibitors [11].\n\nIt is a common concern among clinicians that the incidence of AEs in clinical trials do not necessarily reflect ‘real-world’ experiences due to underrepresentation of the patient population [12]. While early identification of AEs is dependent on both the clinician and self-reporting by patients, underrepresented data can hinder effective clinical practice. Moreover, published real-life data on irAEs with pembrolizumab are limited. In the UK, the PD-1 inhibitors, pembrolizumab and nivolumab, are funded by the NHS for use in melanoma. The majority of patients in our institution receive pembrolizumab rather than nivolumab due to its less intense 3-weekly schedule (2-weekly for nivolumab). In this study, we analyzed the incidence and management of pembrolizumab-associated irAEs in our hospital to guide medical decision-making and health information provision for patients.\n\nMaterials & methods\nPatient sample\nWe retrospectively analyzed the data on all patients with advanced melanoma who received pembrolizumab (2 mg/kg every 3 weeks) at a single UK center between 15th June 2014 and 15th June 2017. Inclusion criteria included adequate documentation of the treatment course and histologically confirmed advanced cutaneous melanoma. Patients who received treatment as part of an expanded patient access program were also included (n = 5). Patient-specific information was collected using our hospital's electronic databases. Data collected included patient demographics, tumor characteristics (Tumor, Node, Metastasis (TNM) staging, brain metastasis, baseline LDH, BRAF\nV600 status), previous systemic therapies, date of first immunotherapy dose, date of death (or the last follow-up), baseline WHO performance status (PS), number of treatment doses and deferrals, best overall response and AEs. Data were also collected on the management of irAEs including cumulative steroid dose.\n\nData analysis\nAEs were graded using the Common Terminology Criteria for Adverse Events v4.0. Select AEs of interest were categorized into organ-specific groups for analysis. Of note, ‘general’ AEs encompass nonspecific symptoms including fatigue/lethargy, asthenia, pyrexia, and decreased appetite. Due to the limitations of retrospective grading of toxicities, diarrhea and colitis were grouped together. AEs were grouped into grades 1/2 and 3/4 due to inherent difficulties in retrospective grading from some clinical notes.\n\nEstimated total steroid dose per patient was calculated based on documented prescriptions and steroid-tapering guidelines. All steroids were converted to the equivalent prednisolone dose for ease of comparison. Any steroids prescribed for hormone-replacement therapy in adrenal insufficiency and for non-irAEs, such as brain metastasis and radiation-induced pneumonitis, were excluded from analysis. Time to first grade 3/4 AE was defined as time from first treatment dose to time of first reported AE. Patients who did not experience grade 3/4 AEs were censored at time of last follow-up. OS was defined as time from first dose of pembrolizumab to death of any cause. Patients who were still alive at data cutoff were censored at time of the last follow-up. Median follow-up time was defined as time from first treatment dose to time of the last follow-up. Patients who have died prior to data cutoff were censored at their date of death. Best overall response was identified based on documented responses, and was not formally assessed retrospectively using the immune-related Response Evaluation Criteria In Solid Tumors (ir-RECIST). The TNM staging system used was version 7 of the American Joint Committee on Cancer staging (AJCC). Kaplan–Meier survival curves were produced using GraphPad Prism 7. 95% CI were calculated using the Anderson's method (1993). We compared the incidence of AEs in the study groups using the Chi-square test, where p = 0.05 was considered statistically significant.\n\nResults\nPatient demographics\nA total of 88 patients with melanoma were identified as suitable for inclusion and analysis. In total, 58 patients received pembrolizumab as first-line immunotherapy (ipilimumab-naive group) and 30 patients received pembrolizumab following ipilimumab therapy (ipilimumab-treated group). Demographics are shown in Table 1. The median age was 69 years (range: 21–91) and 61.5 years (range: 31–86) old in ipilimumab-naive and ipilimumab-treated patients, respectively. Of the total 88 patients, 62.5% were male, 92.0% had a PS of 0–1, 61.4% had stage M1c disease and 12.5% had brain metastases. 40.9% of the patients were positive for BRAF\nV600 mutation, of which 36.1% had received prior BRAF ± MEK inhibitor therapy. 89.7% of ipilimumab-naive patients have not received prior systemic treatments for their melanoma. Baseline LDH levels were unknown in 46 patients, the majority due to hemolysed blood samples. We recognize that this can affect staging, however, 18 out of 46 patients’ staging would not have been affected by LDH levels as they were already staged M1c disease. At data cutoff, the median duration of follow-up in the ipilimumab-naive and ipilimumab-treated cohorts were 12 months (range: 0.8–18.3) and 23 months (range: 4.5–31.3), respectively.\n\nTable 1. \nPatient demographics.\n\nCharacteristics\tSubcategory\tIpilimumab-naive (n = 58), No. (%)\tIpilimumab-treated (n = 30), No. (%)\t\nAge (years)\tMedian\t69\t61.5\t\n\t\n \tRange\t21–91\t31–86\t\n\t\nSex\tMale\t38 (65.5)\t17 (56.7)\t\n\t\n \tFemale\t20 (34.5)\t13 (43.3)\t\n\t\nECOG PS\t0\t39 (67.2)\t17 (56.7)\t\n\t\n \t1\t14 (24.1)\t11 (36.7)\t\n\t\n \t≥2\t5 (8.6)\t1 (3.3)\t\n\t\n \tNot reported\t0\t1 (3.3)\t\n\t\nMetastasis\tM0, M1a, M1b\t25 (43.1)\t9 (30.0)\t\n\t\n \tM1c\t33 (56.9)\t21 (70.0)\t\n\t\nBrain metastases\tYes\t5 (8.6)\t6 (20.0)\t\n\t\n \tNo\t53 (91.4)\t23 (80.0)\t\n\t\nLDH\tNormal\t8 (13.8)\t7 (23.3)\t\n\t\n \tRaised\t15 (25.9)\t12 (40.0)\t\n\t\n \tUnknown\t35 (60.3)\t11 (36.7)\t\n\t\nBRAFV600\tMutation\t25 (43.1)\t11 (36.7)\t\n\t\n \tWild-type\t33 (56.9)\t19 (63.3)\t\n\t\nNumber of previous systemic treatment(s)\t0\t52 (89.7)\t0\t\n\t\n \t1\t6 (10.3)\t20 (66.7)\t\n\t\n \t≥2\t0\t10 (33.3)\t\n\t\nPrevious treatment\tIpilimumab\t0\t30 (100.0)\t\n\t\n \tChemotherapy\t0\t3 (10.0)\t\n\t\n \tBRAF ± MEK\t6 (10.3)\t7 (23.3)\t\nECOG PS: Eastern cooperative oncology group performance status.\n\nAdverse events\nThe incidence of any-grade and grade 3/4 AEs were 77.6 and 10.3% in ipilimumab-naive patients, and 90.0 and 16.7% in ipilimumab-treated patients (Table 2). No treatment-related deaths were observed. The most common any-grade AEs in ipilimumab-naive and ipilimumab-treated patients were fatigue/lethargy (34.5 and 26.7%), pruritus (20.7 and 36.4%), rash (22.4 and 40.0%), diarrhea/colitis (26.8 and 46.7%), endocrine-related toxicities (29.3 and 26.7%) and musculoskeletal-related toxicities (19.0 and 20.0%). Compared with ipilimumab-naive patients, ipilimumab-treated patients experienced significantly higher incidences of any-grade skin toxicities (90.0 vs 46.6%; p < 0.01) and diarrhea/colitis (46.7 vs 26.8%; p = 0.028). Grade 3/4 diarrhea/colitis was observed in 3.4 and 13.3% of ipilimumab-naive and ipilimumab-treated patients, respectively. Of interest, three patients were diagnosed with biopsy proven immunotherapy-related sarcoidosis, of which one patient was symptomatic from a skin lesion and required oral steroids. All three patients were incidentally diagnosed on follow-up CT to assess for treatment response and were shown to have new bilateral hilar lymphadenopathy and mediastinal lymphadenopathy. All patients had raised ACE levels and endobronchial ultrasound-guided biopsy was performed on all patients to rule out new metastatic lesions and confirmed the histological diagnosis of sarcoidosis.\n\nTable 2. \nSelect adverse events of interest.\n\nAEs\tIpilimumab-naive (n = 58), No. (%)\tIpilimumab-treated (n = 30), No. (%)\tp-value\t \t \t\n\t\n \tAny grade\tGrade 3/4\tAny grade\tGrade 3/4\tAny grade\tGrade 3/4\t \t \t\nAny AEs\t45 (77.6)\t6 (10.3)\t27 (90.0)\t5 (16.7)\t0.071\t0.150\t\n\t\nGeneral\t25 (43.1)\t1 (1.7)\t11 (36.7)\t0\t0.187\t0.168\t\n\t\nSkin\t27 (46.6)\t1 (1.7)\t27 (90.0)\t0\t<0.001\t0.168\t\n\t\n– Pruritus\t12 (20.7)\t0\t11 (36.7)\t0\t0.053\t–\t\n\t\n– Rash\t13 (22.4)\t1 (1.7)\t12 (40.0)\t0\t0.045\t0.168\t\n\t\nGastrointestinal\t28 (48.3)\t2 (3.4)\t17 (56.7)\t4 (13.3)\t0.165\t0.042\t\n\t\n– Diarrhea/colitis\t15 (26.8)\t2 (3.4)\t14 (46.7)\t4 (13.3)\t0.028\t0.042\t\n\t\nHPB\t6 (10.3)\t0\t4 (13.3)\t1 (3.3)\t0.206\t0.075\t\n\t\n– Hepatitis\t5 (8.6)\t0\t4 (13.3)\t1 (3.3)\t0.173\t0.075\t\n\t\n– Pancreatitis\t1 (1.7)\t0\t0\t0\t0.168\t–\t\n\t\nEndocrine\t17 (29.3)\t0\t8 (26.7)\t0\t0.221\t–\t\n\t\n– Hypothyroidism\t11 (19.0)\t0\t4 (13.3)\t0\t0.176\t–\t\n\t\n– Hyperthyroidism\t6 (10.3)\t0\t2 (6.7)\t0\t0.189\t–\t\n\t\n– Hypoadrenalism\t0\t0\t2 (6.7)\t0\t0.027\t–\t\n\t\nPulmonary\t4 (6.9)\t0\t1 (3.3)\t0\t0.174\t–\t\n\t\n– Pneumonitis\t4 (6.9)\t0\t1 (3.3)\t0\t0.174\t–\t\n\t\nRenal\t1 (1.7)\t0\t2 (6.7)\t0\t0.098\t–\t\n\t\nNeurological\t2 (3.4)\t0\t1 (3.3)\t0\t0.230\t–\t\n\t\nMusculoskeletal\t11 (19.0)\t2 (3.4)\t6 (20.0)\t0\t0.149\t0.124\t\n\t\n– Arthritis\t3 (5.2)\t1 (1.7)\t3 (10.0)\t0\t0.149\t0.168\t\n\t\n– Myositis\t1 (1.7)\t1 (1.7)\t0\t0\t0.168\t0.168\t\n\t\nEye\t0\t0\t2 (6.7)\t0\t0.027\t–\t\n\t\nHematological\t5 (8.6)\t0\t4 (13.3)\t0\t0.173\t–\t\n\t\nOthers\t1 (1.7)\t0\t2 (6.7)\t0\t0.098\t–\t\n\t\n – Sarcoidosis\t1 (1.7)\t0\t2 (6.7)\t0\t0.098\t–\t\np-values were calculated using Chi-square test.\n\nAE: Adverse event; HPB: Hepatopancreato-biliary.\n\nOf the total 88 patients, 15 patients (17.0%) were diagnosed with hypothyroidism during treatment, of which, eight patients (53.3%) were preceded with biochemical hyperthyroidism. Only one of these eight patients was symptomatic, requiring treatment with β-blockers. Furthermore, two ipilimumab-treated patients required long-term steroid replacement due to primary and secondary adrenal insufficiency.\n\nTime to adverse event\nMedian times to any grade AE were 1.5 months (95% CI: 0.7–2.3) and 2.0 months (95% CI: 1.5–2.5) in ipilimumab-naive and ipilimumab-treated patients, respectively (Figure 1A & C). The majority of grade 3/4 AEs occurred within 4 months of starting pembrolizumab. 43.1 and 36.7% of ipilimumab-naive and ipilimumab-treated patients, respectively, experienced their first any-grade AE after one cycle of treatment. Gastrointestinal-related toxicities were the most common AE postcycle 1 in ipilimumab-naive (28.9%) and ipilimumab-treated (42.9%) patients. The majority of new AEs occurred between cycles 1 and 4 in all cohorts with the frequency of new events gradually decreasing as treatment time progressed. In the ipilimumab-treated group, there was a rise in the number of new skin-related toxicities from cycle 2 onward. It should be noted that a number of side effects did not occur until after ten cycles of treatment.\n\nFigure 1. \nAny-grade adverse events.\n\nTime to first any-grade immune-related adverse event (irAE) in (A) ipilimumab-naive and (C) ipilimumab-treated patients. New any-grade irAE in relation to treatment cycle number in (B) ipilimumab-naive and (D) ipilimumab-treated patients. The median durations to any-grade adverse event were 1.5 and 2.0 months in ipilimumab-naive (A) and ipilimumab-treated patients (C), respectively.\n\nGI: Gastrointestinal; HPB: Hepatopancreato-biliary; MSK: Musculoskeletal.\n\nManagement of irAEs\nOf the 88 patients, 22 patients required oral steroids to manage side effects of pembrolizumab (ipilimumab-naive, n = 12 [20.7%] and ipilimumab-treated, n = 10 [33.3%]). Although systemic steroids are primarily used in the management of grade 3/4 irAEs, we observed a number of patients with grade 1/2 irAEs requiring systemic steroids for persistent symptoms. In our series, no patients required further management with infliximab or other immunosuppressive agents. However, one patient required admission for intravenous steroids to treat grade 3/4 colitis.\n\nAll patients on systemic treatment for irAEs experienced symptomatic relief. The median total duration and cumulative dose of systemic steroids used to manage irAEs were 31.5 days (range: 1–259 days) and 683 mg (range: 40–3745 mg), respectively. One patient developed diabetes due to prolonged exposure to high-dose steroids (estimated cumulative dose of prednisolone = 630 mg; Table 3). There were two patients who were unable to wean off steroids at data cutoff due to ongoing symptoms from immune-related arthritis.\n\nTable 3. \nManagement of immune-related adverse events.\n\nVariable\tIpilimumab-naive (n = 58), No. (%)\tIpilimumab-treated (n = 30), No. (%)\t\nPatients requiring immunosuppresion\t12 (20.7)\t10 (33.3)\t\n\t\nType of immunosuppression\t\n\t\n– Steroid (oral)\t12 (20.7)\t10 (33.3)\t\n\t\n – Steroid (IV)\t1 (1.7)\t0\t\n\t\nEstimated total duration of steroid treatment\t\n\t\n– Mean (SD)\t49.2 (40.3)\t60.3 (73.5)\t\n\t\nMedian (range)\t40 (1–122)\t29.5 (3–259)\t\n\t\nEstimated cumulative prednisolone dose\t\n\t\n– Mean (SD)\t1057.7 (1074.6)\t1206 (1202.8)\t\n\t\n – Median (range)\t587.5 (120–2257.5)\t965 (40–3745)\t\nIV: Intravenous; SD: Standard deviation.\n\nPatients with autoimmune conditions\nFourteen patients had autoimmune conditions prior to the start of their treatment, which included polymyalgia (n = 1), rheumatoid arthritis (n = 2), seronegative-inflammatory arthritis (n = 1), psoriasis (n = 1), Crohn's disease (n = 1), ulcerative colitis (n = 1), thyroid peroxidase antibody (TPO)-positive thyroiditis (n = 1), lichen sclerosus (n = 1) and sarcoidosis (n = 1). 11 of the 14 (78.6%) patients had flare-ups of their underlying conditions on pembrolizumab. These were: polymyalgia, rheumatoid arthritis, seronegative-inflammatory arthritis, Crohn's disease, ulcerative colitis, and TPO-positive thyroiditis. Oral steroids were used to manage these ‘flare-ups’ of autoimmune disease with good effect, particularly with respect to arthritis. The patient with preexisting ulcerative colitis required intravenous steroids to treat grade 3/4 colitis unresponsive to oral steroids.\n\nTreatment response\nThe median numbers of treatment cycles administered to ipilimumab-naive and ipilimumab-treated patients were six (range: 2–26) and 10 (range: 2–38), respectively; the proportions of patients continuing treatment at the time of data cutoff were 58.6 and 20.0%, respectively. Three patients permanently discontinued their treatment due to immune-related skin rash (n = 1), pneumonitis (n = 1) and sarcoidosis (n = 1). The proportions of ipilimumab-naive and ipilimumab-treated patients requiring treatment deferral were 29.3 and 43.3%, respectively, of which 36.4 and 35.0% were related to treatment toxicity, respectively. Patient choice, such as vacation plans, was also a major contributing factor to treatment deferral.\n\nA total of 30 deaths occurred at the time of data cutoff. Overall response rates (ORRs) in ipilimumab-naive and ipilimumab-treated patients were 48.3% (95% CI: 40.1–56.5) and 50.0% (95% CI: 37.3–62.7), respectively. Median OS was 23.5 months (95% CI: 13.9–33.1) in the ipilimumab-treated cohort, and was not reached in the ipilimumab-naive cohort. One-year estimates of survival were 64.9% (95% CI: 47.1–78.1) and 69.4% (95% CI: 49.3–82.8) in ipilimumab-naive and ipilimumab-treated patients, respectively. The median OS and 1-year survival rate in all patients were 23.5 months (95% CI: 22.0–25.0) and 67.5% (95% CI: 54.9–77.3), respectively (Figure 2 and Table 4). Further statistical analyses were not performed on the survival data as the differences in ORR is minimal and unlikely to be of clinical significance.\n\nTable 4. \nTreatment response.\n\nVariable\tSubcategory\tIpilimumab-naive (n = 58), No. (%)\tIpilimumab-treated (n = 30), No. (%)\t\nBOR – number (%)\tComplete response\t1 (1.7)\t0\t\n\t\n \tPartial response\t27 (46.6)\t15 (50.0)\t\n\t\n \tStable disease\t7 (12.1)\t5 (16.7)\t\n\t\n \tProgressive disease\t20 (34.5)\t9 (30.0)\t\n\t\n \tNot determined\t3 (5.2)\t1 (3.3)\t\n\t\nORR (complete + partial response)\tNumber\t28\t15\t\n\t\n \t% (95% CI)\t48.3 (40.1–56.5)\t50.0 (37.3–62.7)\t\n\t\n \tMedian OS in months (95% CI)\tNot reached\t23.5 (13.9–33.1)\t\n\t\n \t1-year estimates of survival % (95% CI)\t64.9 (47.1–78.1)\t69.4 (49.3–82.8)\t\nBOR: Best overall response; ORR: Overall response rate; OS: Overall survival.\n\nFigure 2. \nOverall survival rates.\n\nKaplam–Meier estimates of (A) ipilimumab-naive patients and (B) ipilimumab-treated patients, and (C) all patients. The median overall survival was 23.5 months in the ipilimumab-treated patients (B) and not reached in the ipilimumab-naive (A) patients. Dashed lines represent 95% CI.\n\nHaving a preexisting autoimmune condition, receiving systemic steroids for irAEs, or having a BRAF-mutant positive status, did not appear to significantly affect response to pembrolizumab. A comparison of median OS in patients who had one of these factors to patients who did not was not possible, as the median OS was not reached in the majority of the subpopulations. Median OS of ipilimumab-treated patients who received systemic steroids for irAEs was lower compared with those who did not receive steroids (5.75 vs 24.0 months, respectively). However, we recommend that these comparisons should be interpreted with caution due to our small sample size.\n\nDiscussion\nThe success of immunotherapies has led to pembrolizumab being established as a successful treatment option for advanced melanoma. However, there are currently limited published data on ‘real-world’ experiences with pembrolizumab in melanoma patients, particularly the incidence and management of irAEs. The primary objective of this study was to characterize our center's experience of pembrolizumab use. The KEYNOTE-002 and KEYNOTE-006 clinical trials were used as comparators as they demonstrated superiority of pembrolizumab against the previous standard of care in ipilimumab-treated and ipilimumab-naive patients, respectively [3,4].\n\nPatient baseline characteristics in both cohorts were comparable to pivotal studies with regard to age, gender, and PS. There was a higher incidence of brain metastases in our series than the clinical trials, which is to be expected in a real-world population. Interestingly, our cohorts had less M1c disease at baseline and were less heavily pretreated compared with trial participants. ORRs in ipilimumab-naive and ipilimumab-treated patients were 48.3% (95% CI: 40.1–56.5) and 50.0% (95% CI: 37.3–62.7) compared with 32.9% (95% CI: 27.4–38.7) and 21.1% (95% CI: 15–28) in KEYNOTE-006 and KEYNOTE-002, respectively [3,4]. Although ORRs were more favorable in our cohort, this could be a result of not formally assessing treatment response using the (ir)RECIST criteria in clinical practice, thus reflecting one of the limitations with retrospective studies. One-year estimates of survival were similar between our ipilimumab-naive cohort (64.9%; 95% CI: 47–1–78.1) and KEYNOTE-006 (68.4%; 95% CI: 62.5–73.6) [4]. However, median OS was superior in our ipilimumab-treated cohort (23.5 months; 95% CI: 13.9–33.1) compared with KEYNOTE-002 (13.4 months; 95% CI: 11.0–16.4), which could reflect the better prognostic features of the patients in our series [3].\n\nIn ipilimumab-naive patients, overall incidence of total any-grade and grade 3/4 AEs was similar between our cohort (77.6 and 10.3%) and KEYNOTE-006 (72.9 and 10.1%) [5]. However, we observed higher rates of diarrhea/colitis (26.8 vs 18.1%), rash (20.7 vs 14.1%), pruritus (22.4 vs 13.4%), constipation (10.3 vs 1.8%), hypothyroidism (19.0 vs 8.7%), and hyperthyroidism (10.3 vs 3.2%) [4].\n\nIn ipilimumab-treated patients, incidence of total any-grade and grade 3/4 irAEs was higher in our cohort (90.0 and 16.7%) compared with KEYNOTE-002 (67.4 and 10.7%) [3]. Specific irAEs that were more prevalent in our cohort included diarrhea/colitis (46.7 vs 9.6%), pruritus (36.7 vs 20.8%), rash (40.0 vs 14.6%), hypothyroidism (13.3 vs 5.1%), and dry skin (10.0 vs 5.1%) [3].\n\nIn the Phase II randomized CheckMate-064 trial comparing the safety of sequential administration of nivolumab and ipilimumab, higher incidences of grade 3/4 irAEs were observed in the second induction period compared with the first induction period in either sequences [13]. This suggests that patients who were previously primed to a class of checkpoint inhibitor (e.g., anti-CTLA-4) are at an increased risk of more toxicities with a different class (e.g., anti-PD-1). This may explain the higher incidence of toxicities in our ipilimumab-treated patients compared with ipilimumab-naive patients.\n\nThe frequency of oral steroids administered for any-grade irAEs were 12 (20.7%) and 10 (33.3%) in ipilimumab-naive and ipilimumab-treated patients. This is a significant proportion of our cohort requiring steroids for irAEs and one patient developed steroid-related diabetes. The cumulative dose of steroids received was significant and the long-term outcomes and implications of long-term steroid use in this group of patients have been poorly studied. In the retrospective setting, it was difficult to measure other steroid-related AEs such as proximal weakness and weight gain. The short-term and long-term implications of steroid use in cancer patients have already been extensively reviewed in other papers [14,15]. Some of the severe sequelae of chronic steroid use include an increase in the risk of opportunistic infections, metabolic syndrome, adrenal suppression, osteoporosis and neuropsychiatric disorders. Moreover, prolonged steroid use could theoretically reduce the efficacy of checkpoint inhibitors, although this is still an area of uncertainty [16]. We recommend that there should be more research in this area as patients survive for longer after immunotherapy treatment.\n\nThere is little published literature documenting real life experiences with pembrolizumab. There are some small retrospective series that also highlight the increased incidence of irAEs in clinical practice in comparison to clinical trials [17–19]. A single-center observational study of 39 ipilimumab-treated patients receiving anti-PD-1 therapy reported any-grade and grade 3/4 irAEs of 48.7 and 15.4%, respectively [20]. Although the incidence of severe irAEs was similar to our results, there was a large difference in any-grade irAEs. One important difference between our results and those in clinical studies is the incidence of thyroid disorders, in particular hypothyroidism. Incidence of hypothyroidism reported in the KEYNOTE-002 and KEYNOTE-006 studies was 5.1 and 8.7%, respectively. In comparison, the incidence of hypothyroidism in our ipilimumab-treated and ipilimumab-naive patients was 13.3 and 19.0%, respectively. This has been similarly reported in a small observational study of ipilimumab-treated patients with a reported incidence of approximately 15% [20]. It is important that thyroid function tests are monitored regularly on pembrolizumab treatment and is important to recognize that this is a permanent side effect.\n\nEarly recognition of irAEs is key to management and can potentially reverse it, thus avoiding long-term sequelae [21]. Early identification of irAEs (and non-irAEs) is often dependent on self-reporting by patients. Patient self-reporting of systemic anticancer treatment (SACT) toxicities can occur either in clinician/nurse-led consultations or through a nurse-led 24 h helpline. The UK National Chemotherapy Board has proposed two approaches to promote early identification of SACT toxicities: Empowerment and Proactive monitoring [22]. It is recommended that patients starting on SACT receive information about the treatment and provide appropriate consent. Studies such as ours highlight the need for specific preimmunotherapy information to be given to patients, carers and health professionals involved in the patient's care.\n\nThere are inherent limitations in a retrospective study that have to be acknowledged. In particular, accuracy of grading and reporting of irAEs in clinical records and documentation of cumulative steroid exposure. Although these limitations can impact the reliability of the data, our series reflects a more realistic ‘real-world’ experience with pembrolizumab treatment. We were also able to confirm that patients with preexisting autoimmune conditions can be safely treated with PD-1 inhibitors but need to be counseled about the significant risk of exacerbating their underlying autoimmune condition [10]. We recognize that our median follow-up time of 12 months is relatively short. However, the majority of the irAEs appear early on in the treatment course, from within a few weeks to up to 3 months, and therefore a 12-month follow-up is sufficient.\n\nConclusion\nWe observed a higher incidence of irAEs with ‘real-world’ patients with metastatic melanoma. The need for more ‘real-world’ data from observational studies is required to guide clinical decision-making and information provision to patients. Furthermore, with the recent positive results for checkpoint inhibitors in the adjuvant setting and the approval for combination ipilimumab/nivolumab in advanced melanoma patients in the UK, there will an increasing number of patients with melanoma-receiving immunotherapy. Immunotherapy treatments are increasingly licensed in other tumor types, such as lung and renal cancer, and vigilance is needed in identifying and treating these side effects. Further work to clarify the long-term effects of immunotherapy toxicity and treatment is required.\n\n\nAcknowledgements\n\nThe authors thank all the patients and family members who have been involved in the development and making of the preimmunotherapy video. The authors would also like to acknowledge all of the staff members of Rosemere Cancer Foundation and Royal Preston Hospital Cancer Centre, our patient information advisor group, and our medical illustration and Blended eLearning teams for their support and role to this project.\n\n\nFinancial & competing interests disclosure\n\n\nThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.\n\nNo writing assistance was utilized in the production of this manuscript.\n\n\nOpen access\n\n\n This work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/\n\n\n\nEthical conduct of research\n\n\nThe authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.\n==== Refs\nReferences\n1 Cancer Research UK Skin cancer statistics 2016 www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/skin-cancer#heading-Zero \n2 Garbe C Eigentler TK Keilholz U Hauschild A Kirkwood JM Systematic review of medical treatment in melanoma: current status and future prospects Oncologist 16 1 5 24 2011 21212434 \n3 Ribas A Puzanov I Dummer R Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, Phase 2 trial Lancet Oncol. 16 8 908 918 2015 26115796 \n4 Robert C Schachter J Long GV Pembrolizumab versus ipilimumab in advanced melanoma N. Engl. J. Med. 372 26 2521 2532 2015 25891173 \n5 Robert C Long GV Brady B Nivolumab in previously untreated melanoma without BRAF mutation N. Engl. J. Med. 372 4 320 330 2015 25399552 \n6 Larkin J Chiarion-Sileni V Gonzalez R Combined nivolumab and ipilimumab or monotherapy in untreated melanoma N. Engl. J. Med. 373 1 23 34 2015 26027431 \n7 Bellmunt J De Wit R Vaughn DJ Pembrolizumab as second-line therapy for advanced urothelial carcinoma N. Engl. J. Med. 376 11 1015 1026 2017 28212060 \n8 Weber JS Yang JC Atkins MB Disis ML Toxicities of immunotherapy for the practitioner J. Clin. Oncol. 33 18 2092 2099 2015 25918278 \n9 Johnson DB Sullivan RJ Ott PA Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders JAMA Oncol. 2 2 234 240 2016 26633184 \n10 Menzies AM Johnson DB Ramanujam S Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab Ann. Oncol. 28 2 368 376 2017 27687304 \n11 Spain L Diem S Larkin J Management of toxicities of immune checkpoint inhibitors Cancer Treat. Rev. 44 51 60 2016 26874776 \n12 Booth CM Tannock IF Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence Br. J. Cancer 110 3 551 555 2014 24495873 \n13 Weber JS Gibney G Sullivan RJ Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, Phase 2 trial Lancet Oncol. 17 7 943 955 2016 27269740 \n14 Twycross R The risks and benefits of corticosteroids in advanced cancer Drug Saf. 11 3 163 178 1994 7811399 \n15 Wooldridge JE Anderson CM Perry MC Corticosteroids in advanced cancer Oncology (Williston Park). 15 2 225 234 2001 11252935 \n16 Horvat TZ Adel NG Dang TO Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center J. Clin. Oncol. 33 28 3193 3198 2015 26282644 \n17 Cimminiello C Guardo L Vecchio M Tolla G De Braud F Cavalieri S Single center institution experience of pembrolizumab for unresectable or metastatic melanoma Presented at XXII IMI (Intergruppo Melanoma Italiano) Congress Ragusa, Sicily, Italy 13–15 November 2016 \n18 Jansen Y Schreuer M Neyns B Single-center ‘real life experience’ with pembrolizumab (PEMBRO) in pretreated advanced melanoma patients J. Clin. Oncol. 34 e21049 2016 \n19 Lomax A Lim J Cheng R Metastatic melanoma and pembrolizumab toxicity in a real-world setting: practical management of common toxicities Asia-Pac. J. Clin. Oncol. 12 60 2016 \n20 Amode R Baroudjian B Kowal A Anti-programmed cell death protein 1 tolerance and efficacy after ipilimumab immunotherapy: observational study of 39 patients Melanoma Res. 27 2 110 115 2017 27926587 \n21 Haanen J Carbonnel F Robert C Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann. Oncol. 28 Suppl. 4 iv119 iv142 2017 28881921 \n22 Oakley C Chambers P Board R National Chemotherapy Board good practice guideline: promoting early identification of systemic anti-cancer therapies side effects: two approaches Cancer Nurs. Pract. 15 9 19 22 2016\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-0885",
"issue": "5(1)",
"journal": "Melanoma management",
"keywords": "anti-PD-1 therapy; immune-related adverse events; melanoma; pembrolizumab; real-world experience; retrospective study",
"medline_ta": "Melanoma Manag",
"mesh_terms": null,
"nlm_unique_id": "101649842",
"other_id": null,
"pages": "MMT05",
"pmc": null,
"pmid": "30190931",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": "26633184;21212434;24495873;27926587;11252935;26282644;7811399;25399552;27269740;25891173;28881921;26115796;26874776;28212060;27687304;25918278;26027431",
"title": "Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK.",
"title_normalized": "real world experience with pembrolizumab toxicities in advanced melanoma patients a single center experience in the uk"
} | [
{
"companynumb": "GB-EDENBRIDGE PHARMACEUTICALS, LLC-GB-2018EDE000288",
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"occurcountry": "GB",
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"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
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"... |
{
"abstract": "BACKGROUND\nAggrenox is used in the secondary prevention of stroke. Acute renal failure, potentially associated with Aggrenox, has been observed in several patients.\n\n\nOBJECTIVE\nThe objective of this study was to determine if Aggrenox was associated with acute renal failure and to determine whether it was acetylsalicylic acid, dipyridamole or the combination that led to decline in renal function.\n\n\nMETHODS\nA case series of three patients suffering severe nausea, vomiting, diarrhea, renal dysfunction and clinical decline during Aggrenox therapy was examined. Serum creatinine and Blood Urea Nitrogen (BUN) were measured to evaluate renal function.\n\n\nRESULTS\nAnalysis of this patient group revealed that Patient 1 experienced nausea, emesis, anorexia, diarrhea and significant clinical decline during treatment with Aggrenox. Patients 2 and 3 also presented with complaints of nausea and emesis. Lab measurements along with clinical symptoms indicated that all three patients experienced acute renal failure, having increases in serum creatinine of 186%, 144% and 249%, respectively. Symptoms and lab work returned to baseline following discontinuation of Aggrenox.\n\n\nCONCLUSIONS\nIt is biologically plausible that Aggrenox may contribute to renal dysfunction in patients under certain pathophysiological circumstances.",
"affiliations": "St. Joseph's Care Group, Thunder Bay, Ontario, Canada. joyk@tbh.net",
"authors": "Joy|Kerry|K|;Dubois|Sacha|S|;Gibbons|Carrie|C|;Hargadon|John|J|;Bédard|Michel|M|",
"chemical_list": "D000068342:Aspirin, Dipyridamole Drug Combination; D004338:Drug Combinations; D004176:Dipyridamole; D003404:Creatinine; D001241:Aspirin",
"country": "Australia",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "2561-8741",
"issue": "17(2)",
"journal": "Journal of population therapeutics and clinical pharmacology = Journal de la therapeutique des populations et de la pharmacologie clinique",
"keywords": null,
"medline_ta": "J Popul Ther Clin Pharmacol",
"mesh_terms": "D058186:Acute Kidney Injury; D001241:Aspirin; D000068342:Aspirin, Dipyridamole Drug Combination; D003404:Creatinine; D004176:Dipyridamole; D004338:Drug Combinations; D006801:Humans",
"nlm_unique_id": "101530023",
"other_id": null,
"pages": "e262-8",
"pmc": null,
"pmid": "20664119",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A multi-case report of acute renal failure in patients treated with Aggrenox.",
"title_normalized": "a multi case report of acute renal failure in patients treated with aggrenox"
} | [
{
"companynumb": "CA-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2008-CN-00245CN",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "FLUTICASONE PROPIONATE"
... |
{
"abstract": "BACKGROUND\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening spectra of mucocutaneous delayed hypersensitivity reactions. Prodromal viral-like symptoms are followed by a characteristic diffuse rash caused by keratinocyte apoptosis and epidermal detachment.\n\n\nMETHODS\nThree adolescents were admitted with SJS/TEN and vulvovaginal involvement following initiation of lamictal, bactrim, and phenobarbital. The patients received intravenous immunoglobulin and intravenous steroids. One patient received etanercept. Topical emollients and strict perineal hygiene were initiated. No permanent sequelae were noted following vaginoscopy.\n\n\nCONCLUSIONS\nVulvovaginal involvement in SJS/TEN can occur and may result in permanent architectural changes. Basic management includes withdrawal of causative medication, intravenous steroids, intravenous immunoglobulin (IVIG), and supportive care. Early initiation of perineal hygiene, vaginal barrier creams, and menstrual suppression should be employed. Vaginoscopy may be used to document full recovery.",
"affiliations": "Childrens' Mercy Hospital and University of Missouri Kansas City, Kansas City, Missouri, and Department of Obstetrics and Gynecology, University of Missouri Kansas City, Kansas City, Missouri; Department of Women's Health, Dell Medical School, The University of Texas, Austin, Texas. Electronic address: max.holtz@austin.utexas.edu.;Division of Gynecology, Division of Surgery, Boston Children's Hospital, Boston, Massachusetts; Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, Massachusetts.;Childrens' Mercy Hospital and University of Missouri Kansas City, Kansas City, Missouri, and Department of Obstetrics and Gynecology, University of Missouri Kansas City, Kansas City, Missouri.;Department of Dermatology, Johns Hopkins Hospital, Baltimore, Maryland.;Childrens' Mercy Hospital and University of Missouri Kansas City, Kansas City, Missouri, and Department of Obstetrics and Gynecology, University of Missouri Kansas City, Kansas City, Missouri.;Eunice Kennedy Shriver National Institute of Health and Human Development, National Institutes of Health, Bethesda, Maryland.",
"authors": "Holtz|Max|M|;Grimstad|Frances|F|;Higgins|Jeannette|J|;Denny|George|G|;Strickland|Julie|J|;Dowlut-McElroy|Tazim|T|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpag.2021.03.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-3188",
"issue": "34(5)",
"journal": "Journal of pediatric and adolescent gynecology",
"keywords": "Pediatric Adolescent Gynecology; Pediatric Dermatology; Stevens-Johnson syndrome; Toxic epidermal necrolysis; Vaginoscopy",
"medline_ta": "J Pediatr Adolesc Gynecol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D012189:Retrospective Studies; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9610774",
"other_id": null,
"pages": "745-748",
"pmc": null,
"pmid": "33915265",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": "10951229;30702955;23947089;23389396;9469290;29188475;22921694;11882797;22014021;16374461;21126137;12106751;9109082;28329382;3347438;29026478;28144971",
"title": "Vulvovaginal Involvement in Pediatric Stevens-Johnson Syndrome: A Case Series.",
"title_normalized": "vulvovaginal involvement in pediatric stevens johnson syndrome a case series"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2019-01764",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditio... |
{
"abstract": "Trifluridine/tipiracil is currently approved for metastatic colorectal cancer (mCRC) refractory to available therapies. However, there is no consensus on factors that predict treatment outcomes in daily practice. We assessed the early clinical experience with trifluridine/tipiracil in Spain and potential survival markers. This was a retrospective cohort study of mCRC patients who participated in the trifluridine/tipiracil early clinical experience programme in Spain. The primary outcome was overall survival (OS). Associations between OS and patient characteristics were assessed using multivariate Cox regression analyses. A total of 379 patients were included in the study. Trifluridine/tipiracil was administered for a median of 3.0 cycles and discontinued mainly due to disease progression (79.2%). The median OS was 7.9 months, with a 12-month OS rate of 30.5%. Cox analyses revealed that the following variables independently enhanced OS: ≤2 metastatic sites, no liver metastasis, alkaline phosphatase < 300 IU, trifluridine/tipiracil dose reductions, and neutrophil/lymphocyte ratio < 5. Grade ≥ 3 toxicities were reported in 141 (37.2%) patients, including mainly afebrile neutropaenia (23.2%), anaemia (12.1%), and thrombocytopaenia (5.3%). This study supports the real-life efficacy and safety of trifluridine/tipiracil for refractory mCRC and identifies tumour burden, liver metastasis, alkaline phosphatase, dose reductions, and neutrophil/lymphocyte ratio as survival markers.",
"affiliations": "Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain.;Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain.;Department of Medical Oncology, Hospital Universitario Virgen del Rocío, 41013 Seville, Spain.;Department of Medical Oncology, Hospital Universitario Central de Asturias, ISPA, 33011 Oviedo, Spain.;Department of Medical Oncology, Hospital Universitari Parc Taulí, 08208 Sabadell, Spain.;Department of Medical Oncology, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.;Department of Medical Oncology, UGC Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, IBIMA, 29010 Málaga, Spain.;Department of Medical Oncology, Hospital Universitari Vall d'Hebrón, 08035 Barcelona, Spain.;Department of Medical Oncology, Hospital Universitario Clínico San Cecilio, 18016 Granada, Spain.;Department of Medical Oncology, Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain.;Department of Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Majadahonda, Spain.;Department of Medical Oncology, Hospital Universitario La Paz, CIBERONC, 28046 Madrid, Spain.;Translational Medical Oncology Group, Department of Medical Oncology, Hospital Clínico Universitario e Instituto de Investigación Sanitaria (IDIS), CIBERONC, Facultad de Medicina de la Universidad de Santiago de Compostela, 15706 Santiago de Compostela, Spain.;Department of Medical Oncology, Hospital General Universitario Morales Meseguer, 30008 Murcia, Spain.;Department of Medical Oncology, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain.;Department of Medical Oncology, Hospital Universitario Reina Sofía, IMIBIC, Universidad de Córdoba, CIBERONC, Instituto de Salud Carlos III, 14004 Córdoba, Spain.",
"authors": "García-Alfonso|Pilar|P|0000-0002-4373-9978;Muñoz|Andrés|A|0000-0001-6977-8249;Jiménez-Castro|Jerónimo|J|;Jiménez-Fonseca|Paula|P|0000-0003-4592-3813;Pericay|Carles|C|;Longo-Muñoz|Federico|F|;Reyna-Fortes|Carmen|C|;Argilés-Martínez|Guillem|G|;González-Astorga|Beatriz|B|0000-0002-9160-4680;Gómez-Reina|María José|MJ|;Ruiz-Casado|Ana|A|0000-0002-7672-2638;Rodríguez-Salas|Nuria|N|;López-López|Rafael|R|;Carmona-Bayonas|Alberto|A|;Conde-Herrero|Verónica|V|;Aranda|Enrique|E|;On Behalf Of The Ros Study Group|||",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/cancers13184514",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694\nMDPI\n\n10.3390/cancers13184514\ncancers-13-04514\nArticle\nEarly Clinical Experience with Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: The ROS Study\nhttps://orcid.org/0000-0002-4373-9978\nGarcía-Alfonso Pilar 1*†\nhttps://orcid.org/0000-0001-6977-8249\nMuñoz Andrés 1\nJiménez-Castro Jerónimo 2\nhttps://orcid.org/0000-0003-4592-3813\nJiménez-Fonseca Paula 3\nPericay Carles 4\nLongo-Muñoz Federico 5\nReyna-Fortes Carmen 6\nArgilés-Martínez Guillem 7\nhttps://orcid.org/0000-0002-9160-4680\nGonzález-Astorga Beatriz 8\nGómez-Reina María José 9\nhttps://orcid.org/0000-0002-7672-2638\nRuiz-Casado Ana 10\nRodríguez-Salas Nuria 11\nLópez-López Rafael 12\nCarmona-Bayonas Alberto 13\nConde-Herrero Verónica 14\nAranda Enrique 15†\non behalf of the ROS Study Group‡\nRoncucci Luca Academic Editor\nPapavassiliou Athanasios G. Academic Editor\n1 Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain; andresmunmar@hotmail.com\n2 Department of Medical Oncology, Hospital Universitario Virgen del Rocío, 41013 Seville, Spain; jerojc@gmail.com\n3 Department of Medical Oncology, Hospital Universitario Central de Asturias, ISPA, 33011 Oviedo, Spain; palucaji@hotmail.com\n4 Department of Medical Oncology, Hospital Universitari Parc Taulí, 08208 Sabadell, Spain; cpericay@gmail.com\n5 Department of Medical Oncology, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; fedelongomunoz@hotmail.com\n6 Department of Medical Oncology, UGC Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, IBIMA, 29010 Málaga, Spain; c.reyna.fortes@gmail.com\n7 Department of Medical Oncology, Hospital Universitari Vall d’Hebrón, 08035 Barcelona, Spain; gargiles@vhio.net\n8 Department of Medical Oncology, Hospital Universitario Clínico San Cecilio, 18016 Granada, Spain; bea_astorga@hotmail.com\n9 Department of Medical Oncology, Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain; mariajose.gomezreina@gmail.com\n10 Department of Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Majadahonda, Spain; arcasado@salud.madrid.org\n11 Department of Medical Oncology, Hospital Universitario La Paz, CIBERONC, 28046 Madrid, Spain; nuria.rodriguez@salud.madrid.org\n12 Translational Medical Oncology Group, Department of Medical Oncology, Hospital Clínico Universitario e Instituto de Investigación Sanitaria (IDIS), CIBERONC, Facultad de Medicina de la Universidad de Santiago de Compostela, 15706 Santiago de Compostela, Spain; rafael.lopez.lopez@sergas.es\n13 Department of Medical Oncology, Hospital General Universitario Morales Meseguer, 30008 Murcia, Spain; alberto.carmonabayonas@gmail.com\n14 Department of Medical Oncology, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain; berenice2es@yahoo.es\n15 Department of Medical Oncology, Hospital Universitario Reina Sofía, IMIBIC, Universidad de Córdoba, CIBERONC, Instituto de Salud Carlos III, 14004 Córdoba, Spain; earandaa@seom.org\n* Correspondence: pgarcaalfonso@gmail.com; Tel.: +34-915868000\n† These authors contributed equally to this work.\n\n‡ ROS Study Group are listed in acknowledgments.\n\n08 9 2021\n9 2021\n13 18 451402 8 2021\n20 8 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSimple Summary\n\nTrifluridine/tipiracil is an oral combination therapy currently approved as a salvage-line treatment in patients with metastatic colorectal cancer refractory to, or not, candidates for available therapies. However, there is no consensus on the specific factors that should be considered to select patients who benefit the most from trifluridine/tipiracil in clinical practice. The aim of our retrospective cohort study was to assess the early clinical experience with trifluridine/tipiracil in Spain and identify potential survival markers. Our findings endorse the real-life efficacy and safety of trifluridine/tipiracil for refractory metastatic colorectal cancer, as well as revealing the presence of ≤2 metastatic sites, absence of liver metastasis, alkaline phosphatase levels < 300 IU, trifluridine/tipiracil dose reductions, and neutrophil/lymphocyte ratio < 5 as survival markers. Combinations of these markers may help physicians to identify subsets of patients with refractory metastatic colorectal cancer that may benefit the most from trifluridine/tipiracil in their daily practice.\n\nAbstract\n\nTrifluridine/tipiracil is currently approved for metastatic colorectal cancer (mCRC) refractory to available therapies. However, there is no consensus on factors that predict treatment outcomes in daily practice. We assessed the early clinical experience with trifluridine/tipiracil in Spain and potential survival markers. This was a retrospective cohort study of mCRC patients who participated in the trifluridine/tipiracil early clinical experience programme in Spain. The primary outcome was overall survival (OS). Associations between OS and patient characteristics were assessed using multivariate Cox regression analyses. A total of 379 patients were included in the study. Trifluridine/tipiracil was administered for a median of 3.0 cycles and discontinued mainly due to disease progression (79.2%). The median OS was 7.9 months, with a 12-month OS rate of 30.5%. Cox analyses revealed that the following variables independently enhanced OS: ≤2 metastatic sites, no liver metastasis, alkaline phosphatase < 300 IU, trifluridine/tipiracil dose reductions, and neutrophil/lymphocyte ratio < 5. Grade ≥ 3 toxicities were reported in 141 (37.2%) patients, including mainly afebrile neutropaenia (23.2%), anaemia (12.1%), and thrombocytopaenia (5.3%). This study supports the real-life efficacy and safety of trifluridine/tipiracil for refractory mCRC and identifies tumour burden, liver metastasis, alkaline phosphatase, dose reductions, and neutrophil/lymphocyte ratio as survival markers.\n\nbiomarkers\nchemotherapy\ncolorectal cancer\ncombination therapy\nreal-life\ntrifluridine/tipiracil\n==== Body\npmc1. Introduction\n\nColorectal cancer is one of the three most commonly diagnosed cancers and the second leading cause of cancer death worldwide [1]. Only 39% of colorectal cancer patients are diagnosed with localised disease, and despite the improvements achieved in its management, the 5-year survival of patients with distant metastases drops to 14% [2]. Current therapies for metastatic colorectal cancer (mCRC) involve several active drugs administered either as monotherapy or in combination, including cytotoxic agents such as fluoropyrimidines, irinotecan or oxaliplatin, and targeted therapies against epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) [3,4]. However, the therapeutic management of mCRC refractory to these therapies remains challenging.\n\nTrifluridine/tipiracil is an oral combination therapy consisting of an antineoplastic thymidine-based nucleoside analogue (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride). Trifluridine is the active cytotoxic component, responsible for preventing tumour cell proliferation by interfering with DNA function [5,6], while tipiracil improves trifluridine bioavailability by inhibiting its catabolism [7,8]. Trifluridine/tipiracil administration is currently approved as a salvage-line treatment in patients with mCRC refractory to, or not candidates for, available therapies based on the pivotal phase III RECOURSE trial. Its findings revealed a median overall survival (OS) of 7.1 months with trifluridine/tipiracil versus 5.3 months with placebo [9]. Trifluridine/tipiracil improved OS irrespective of age, KRAS status, time from first metastasis or geographic region, and also enhanced progression-free survival (PFS), disease control, and performance status [9,10,11]. Subsequent post hoc analyses also pointed to neutropaenia as a surrogate marker of trifluridine/tipiracil efficacy [12], and supported low tumour burden, indolent disease, and absence of liver metastasis as prognostic factors [13].\n\nCompassionate use programmes and cohort studies endorsed the use of trifluridine/tipiracil in non-trial conditions [14,15,16,17,18,19]. Many of them also addressed the unmet need of identifying prognostic or predictive factors, which included pre-treatment performance status [15,16,18,19,20], KRAS status [18], time to metastasis [19], number of metastases [15], time from metastasis diagnosis [19] or first-line therapy [17], alkaline phosphatase levels [15,18], platelet and leucocyte counts [15,18], and neutrophil/leucocyte ratio [15,20], as well as on-treatment neutropaenia [15,17,19,21], and dose reductions [15,16]. However, there is no consensus on the specific factors that should be considered to select patients who benefit the most from trifluridine/tipiracil.\n\nIn light of the above, this study aimed to provide further insights into the efficacy and safety of trifluridine/tipiracil for refractory mCRC in the early clinical experience in Spain, and to identify factors that may help physicians to predict better outcomes in daily practice.\n\n2. Materials and Methods\n\nROS was a retrospective cohort study conducted in the Departments of Medical Oncology at 35 Spanish hospitals according to Good Pharmacoepidemiology Practices, the Declaration of Helsinki, and national regulations. The study was approved by the ethics committee of Hospital General Universitario Gregorio Marañón (Madrid, Spain) and alive patients gave their written informed consent; informed consent was waived in deceased and lost-to-follow-up patients.\n\n2.1. Patient Population\n\nThe study included patients aged over 18 years, with histologically or cytologically confirmed colorectal adenocarcinoma, and who had participated in the early clinical experience programme for trifluridine/tipiracil. To participate in this program, patients had to be previously treated with, or not considered candidates for, available therapies (fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapies, anti-VEGF or anti-EGFR agents). Eligible patients must have completed the early clinical treatment with trifluridine/tipiracil at study enrolment. Patients who had received other investigational drugs or anticancer therapies (chemotherapy, immunotherapy, biological response modifiers, or endocrine therapy) while receiving trifluridine/tipiracil were excluded.\n\n2.2. Study Treatment\n\nTrifluridine/tipiracil (Lonsurf®, Laboratoires Servier, Suresnes, France) was taken orally at a starting dose decided at the discretion of the treating oncologist and administered twice daily, after breakfast and dinner, on days 1 to 5 and 8 to 12 of each 28-day cycle. Patients were treated by the supervising physicians according to the recommendations included in the product information. Dose adjustments, delays, and discontinuations were performed according to clinical criteria.\n\n2.3. Assessments\n\nAll study data were retrospectively collected from patient medical charts, progress reports submitted to the health authorities, and a data log owned by Laboratorios Servier S.L. containing previously collected information on compassionate use of trifluridine/tipiracil.\n\nThese data included demographics and baseline clinical characteristics, including the Eastern Cooperative Oncology Group (ECOG) performance status, medical history of colorectal cancer, and antitumour therapies prior to trifluridine/tipiracil. Dates and doses of trifluridine/tipiracil were collected at the first treatment cycle, along with subsequent treatment modifications and the total number of administered cycles. Data available on follow-up ECOG performance status, radiologic progression and best response to trifluridine/tipiracil according to Response Evaluation Criteria in Solid Tumours (version 1.1) were also retrieved [22], as well as grade ≥ 3 adverse events attributed to trifluridine/tipiracil. These events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) and their severity graded by National Cancer Institute Common Toxicity Criteria (version 4.03) [23]. Other therapies received after ending trifluridine/tipiracil and the survival status (alive, dead, or lost to follow-up) at data collection were also retrieved.\n\n2.4. Outcomes\n\nThe primary study outcome was OS, which was defined as the time from trifluridine/tipiracil start to patient death from any cause. Secondary efficacy outcomes included PFS measured as the time from trifluridine/tipiracil start to radiologic disease progression or death from any cause, and PFS measured as the time from trifluridine/tipiracil start to clinical disease progression or death from any cause. Other secondary efficacy outcomes were OS and PFS rates at 2, 4, 6, 8, 10, and 12 months, overall response rate (percentage of patients with a complete or partial response), disease control rate (percentage of patients with complete or partial response or stable disease, with stable disease assessed at least 6 weeks after starting trifluridine/tipiracil), changes in ECOG performance status (improved, maintained, or worsened), and associations between OS and patient characteristics. Trifluridine/tipiracil exposure/management and grade ≥ 3 treatment-related adverse events were additional secondary outcomes.\n\n2.5. Statistical Considerations\n\nSample size calculation was based on the median OS reported in the RECOURSE trial [9], a two-sided test, power of 99%, type I error of 0.01, loss rate ≤ 10%, and maximum follow-up of 12 months. The estimated sample size was 467 patients, for which the lower and higher critical values were 6.1 and 8.4 months, respectively.\n\nKaplan–Meier analyses were performed to assess OS and PFS, including survival curves, median estimates, and 95% confidence intervals (CIs). Descriptive statistics were used to determine survival rates, overall response rate, disease control rate, changes in ECOG performance status, trifluridine/tipiracil exposure/management, and treatment-related adverse events. Bivariate Cox regression analyses assessed associations between OS and the following characteristics: age ≥ 65 or <65 years, sex, ECOG performance status 0–1 or ≥2, time from metastasis diagnosis < 18 or ≥18 months, number of metastatic sites ≤2 or ≥3, presence or absence of liver metastatic lesions, synchronous or metachronous metastases, right or left colon primary tumour location, primary tumour molecular status (KRAS, RAS [KRAS + NRAS], BRAF, PI3K, HER2, and microsatellite instability), primary tumour surgery, previous antitumour lines < 3 or ≥3, and laboratory data prior to the first trifluridine/tipiracil cycle (platelet count ≥ 400 × 109/L or <400 × 109/L, leukocyte count ≥ 10 × 109/L or <10 × 109/L, alkaline phosphatase level ≥ 300 or <300 IU, and haemoglobin level ≥ 11 or <11 g/dL). A multivariate Cox regression model was built using characteristics with p < 0.20 in bivariate analyses, including the calculation of hazard ratios (HRs) and 95% CIs. Another multivariate Cox regression model was built adding neutropaenia, neutrophil/lymphocyte ratio, and dose reduction to the previously mentioned characteristics. OS in the prognostic subsets of patients with low tumour burden (≤2 metastatic sites), indolent disease (≥18 months from metastasis diagnosis), and absence of liver metastases [13] was also explored using log-rank tests and Cox regressions.\n\nMissing data were not considered in the analyses, and a significance level of 0.05 was used for statistical testing. The statistical analyses were performed with IBM SPSS Statistics version 22.0 (IBM Corp., Armonk, NY, USA).\n\n3. Results\n\n3.1. Patient Characteristics\n\nA total of 402 patients were screened between June and November 2019, 23 of whom were not eligible (Supplementary Figure S1). Thus, 379 patients were finally included in this study, whose baseline characteristics and tumour molecular status are described in Table 1 and Table 2, respectively.\n\n3.2. Study Treatment\n\nThe planned dose of trifluridine/tipiracil at the first cycle ranged from 25.0 to 35.0 mg/m2 twice daily, with a median (interquartile range, IQR) of 35.0 (35.0–35.0) mg/m2 (Supplementary Table S1). A total of 116 patients needed at least one of the 145 dose reductions and 191 patients needed at least one of the 294 dose delays reported during the trifluridine/tipiracil treatment. The median (IQR) number of administered cycles was 3.0 (2.0–4.0), and end of treatment was due mainly to disease progression (79.2%), followed by general state impairment (12.7%), toxicity (4.5%), patient decision (1.8%), and other reasons (1.8%).\n\nOne hundred and fifty-five (40.9%) patients received other anticancer therapies after trifluridine/tipiracil, including: chemotherapy n = 78 (20.6%; capecitabine n = 24, 5-fluorouracil n = 46, oxaliplatin n = 33, and irinotecan n = 23), anti-EGFR therapies n = 15 (4.0%; cetuximab n = 7, and panitumumab n = 8), anti-VEGF therapies n = 32 (8.4%; bevacizumab n = 30, and aflibercept n = 2), regorafenib n = 51 (13.5%), and other therapies n = 39 (10.3%).\n\n3.3. Efficacy\n\nAfter a median (IQR) follow-up of 7.6 (3.7–12.9) months from the start of trifluridine/tipiracil, the median OS was 7.9 months (95% CI 7.1–8.7; Figure 1). The OS rates at 2, 4, 6, 8, 10, and 12 months were 92.6% (95% CI 90.0–95.2%), 74.5% (95% CI 70.1–78.9%), 61.5% (95% CI 56.5–66.4%), 49.1% (95% CI 44.0–54.2%), 37.7% (95% CI 32.8–42.7%), and 30.5% (95% CI 25.7–35.2%), respectively. The multivariate Cox regression analysis revealed longer OS in patients with ≤2 metastatic sites (HR = 0.6, 95% CI 0.5–0.8, p < 0.001), absence of liver metastasis (HR = 0.7, 95% CI 0.5–0.9, p = 0.004), and alkaline phosphatase levels < 300 IU (HR = 0.6, 95% CI 0.4–0.8, p < 0.001) (Table 3). When neutropaenia, neutrophil/lymphocyte ratio, and dose reduction were included in the multivariate Cox regression analysis, longer OS was associated with ≤2 metastatic sites (HR = 0.6, 95% CI 0.5–0.8, p < 0.001), alkaline phosphatase levels <300 IU (HR = 0.5, 95% CI 0.4–0.7, p < 0.001), dose reductions (HR = 0.6, 95% CI 0.4–0.8, p < 0.001), and neutrophil/lymphocyte ratio < 5 (HR = 0.5, 95% CI 0.4–0.7, p < 0.001) (Table 3). Furthermore, the exploratory analysis of prognostic subsets with low tumour burden and indolent disease revealed longer OS in patients with ≤2 metastatic sites and ≥18 months from metastasis diagnosis than those with ≥3 metastatic sites and/or <18 months (HR = 0.6, 95% CI 0.5–0.8, p < 0.001; Figure 2a). The OS was even longer when liver metastases were absent versus present in both subsets of patients: ≤2 metastatic sites and ≥18 months (HR = 0.6, 95% CI 0.4–0.8, p < 0.001; Figure 2b) and ≥3 metastatic sites and/or <18 months (HR = 0.6, 95% CI 0.4–1.0, p = 0.029; Figure 2c).\n\nThe median PFS measured until radiologic disease progression or death was 3.2 months (95% CI 3.0–3.4; Figure 3a), with PFS rates at 2, 4, 6, 8, 10, and 12 months of 82.9% (95% CI 79.0–86.8%), 34.1% (95% CI 29.1–39.2%), 21.3% (95% CI 16.9–25.6%), 14.5% (95% CI 10.7–18.3%), 9.8% (95% CI 6.6–13.1%), and 6.4% (95% CI 3.7–9.0%), respectively. When its definition included clinical disease progression, the median PFS was 3.0 months (95% CI 2.8–3.2; Figure 3b) and PFS rates at 2, 4, 6, 8, 10, and 12 months were 77.2% (95% CI 72.9–81.4%), 30.7% (95% CI 26.1–35.4%), 18.4% (95% CI 14.5–22.4%), 12.6% (95% CI 9.2–15.9%), 8.3% (95% CI 5.5–11.1%), and 5.3% (95% CI 3.1–7.6%), respectively.\n\nECOG performance status was assessed in 375 patients during trifluridine/tipiracil treatment, which was maintained in 176 (46.9%) patients and improved in 31 (8.3%). Worsening of ECOG performance status was observed in 168 (44.8%) patients.\n\n3.4. Safety\n\nA total of 141 (37.2%) patients reported having experienced at least one grade ≥3 treatment-related adverse event, which mainly included (frequency ≥ 1%): afebrile neutropaenia (23.2%), anaemia (12.1%), thrombocytopaenia (5.3%), diarrhoea (4.0%), asthenia (3.4%), febrile neutropaenia (2.9%), nausea (2.1%), and vomiting (1.3%) (Supplementary Table S2).\n\n4. Discussion\n\nThe results from the ROS cohort study support the efficacy and safety of trifluridine/tipiracil for refractory mCRC in the early clinical experience in Spain. More than half of patients maintained or even improved their performance status, nearly one-third achieved disease control, and median PFS and OS reached 3 months and almost 8 months, respectively. These results are in line with the benefits observed with trifluridine/tipiracil in the RECOURSE trial [9,10,11], along with other compassionate use programmes and observational studies that confirm the use of trifluridine/tipiracil as a feasible treatment alternative for refractory mCRC in a real-life setting [14,15,18,19,20].\n\nPFS is a commonly used outcome for refractory mCRC that is usually reported until radiologic disease progression or death. However, the real disease progression usually occurs between two radiologic assessments [14,24], and the data available on PFS measured until clinical progression or death is still limited. This study shed some light on this issue, supporting the achievement of similar findings when considering clinical progression. Nonetheless, it is noteworthy that PFS seems to be poorly correlated with OS after second-line treatment and OS remains the most robust outcome estimate when assessing treatment efficacy for mCRC [25]. In this regard, our findings also revealed that the median OS might even reach 12.4 months in the subset of patients with ≤2 metastatic sites, ≥18 months from metastasis diagnosis, and absence of liver metastasis. These data support the exploratory analysis of Tabernero et al. [13], who defined a subgroup of patients with good prognostic characteristics including low tumour burden (<3 metastatic sites) and indolent disease (≥18 months from metastasis) and another with poor prognostic characteristics that included high tumour burden and/or aggressive disease. The reported median OS in these subgroups were 9.3 and 5.3 months, respectively. Our findings are in line with these data, showing that the 231 patients with ≤2 metastatic sites and ≥18 months from metastasis showed a median OS of 9.1 months versus 6.0 months in the 148 patients with ≥3 metastatic sites and/or <18 months. However, as in our study, the best prognosis could be identified within the subset of patients with good prognostic factors and absence of liver metastasis, with a median OS that reached 16.4 months [13].\n\nIn addition to the tumour burden and liver metastasis, our study supports the role of alkaline phosphatase levels, dose reductions, and neutrophil/lymphocyte ratios as survival markers. These findings agree with recently published observational studies that also revealed longer OS in patients with a single metastatic site [15], liver metastases [26], alkaline phosphatase levels < 200 or ≤500 IU/L [15,18], trifluridine/tipiracil dose reductions [15,16], and neutrophil/lymphocyte ratios < 5 [15,20]. However, they also found the potential influence of other factors such as ECOG performance status [15,16,18,19,20,26], platelet count ≤ 350 × 109/L [15], KRAS status [18], time to synchronous or metachronous metastasis [19], leukocyte count < 8 × 109/L [18], or neutropaenia as an adverse event [15,17,19,21], which did not independently affect survival in our study. Based on these findings, some attempts have been made to achieve nomograms to screen for the patients who can benefit the most from trifluridine/tipiracil. These include the nomogram reported by Fernández-Montes et al. (2020) in mCRC patients treated with trifluridine/tipiracil, which considered the ECOG performance status, presence of multiple metastatic sites, carcinoembryonic antigen > 10 ng/mL, platelet counts > 350 × 109/L, and phosphatase > 500 IU/L [15]. Another was the Colon Life nomogram, based on refractory mCRC patients treated with trifluridine/tipiracil, regorafenib, or other treatments, that included the ECOG performance status, primary tumour resection, lactate dehydrogenase, and peritoneal involvement [27]. Likewise, the REGOTAS study developed a scoring system to predict OS after trifluridine/tipiracil, including the ECOG performance status, aspartate transaminase > 40 IU/L, C-reactive protein ≥ 1.0 mg/dL, and cancer antigen 19–9 > 37.0 U/mL, as well as another for regorafenib including aspartate transaminase > 40 IU/L, C-reactive protein ≥ 1.0 mg/dL, number of metastatic sites ≥ 3, and <18 months from first-line chemotherapy [26]. A common scoring model for trifluridine/tipiracil and regorafenib was also reported based on the ECOG performance status, ≤18 months form metastasis diagnosis, and prior chemotherapy for ≥2 months beyond the progressive disease [28]. Furthermore, the REBECCA study proposed another score for regorafenib based on the ECOG performance status, time from metastasis diagnosis, initial regorafenib dose, number of metastatic sites, liver metastases, and KRAS mutations [29]. However, no specific nomogram or scoring system has been validated for refractory mCRC, and further assessments of prognostic/predictive factors are still needed to make the best therapeutic decisions.\n\nThe safety profile of trifluridine/tipiracil was consistent with that previously reported in clinical trials [30], compassionate use programmes [17,18,19], and other observational studies [15,16,20,21]. No new safety concern arose and the main ≥3 grade treatment-related adverse events included afebrile neutropaenia, anaemia, and thrombocytopaenia. In addition, most of these adverse events could be managed with dose reductions or delays, and only led to treatment discontinuation in 4.5% of patients.\n\nAlthough the prescribing conditions of compassionate use programmes are less strict than clinical trials and more clearly reflect routine clinical practice, the retrospective data extraction from medical charts entailed limitations due to data availability. We cannot therefore exclude the potential underestimation of treatment-related adverse events, or the influence of missing data in the lack of association observed between tumour molecular markers and OS. Likewise, we cannot discern how the low prevalence of variables such as the mutated KRAS might have affected the study findings, and the absence of association between ECOG performance status and OS is likely derived from the limited number of patients with ECOG 2. Another limitation is the absence of a central review of scans performed at each participating site. Furthermore, the study design included no comparator group, which would have enabled the magnitude of improvement derived from trifluridine/tipiracil to be quantified. Likewise, a comparator group would have been needed to assess whether the identified survival markers might also affect patients not receiving trifluridine/tipiracil and further clarify their role in colorectal cancer. However, it is noteworthy that this study assessed a wide range of patient characteristics as potential markers of survival and provides additional insight into real-life use of trifluridine/tipiracil in 35 Spanish hospitals, enhancing the generalisability of its findings and expanding the information to consider when treating mCRC in daily practice.\n\n5. Conclusions\n\nThis study endorses the real-life efficacy and safety of trifluridine/tipiracil for refractory mCRC, as well as supporting the role of specific survival markers such as tumour burden, liver metastasis, alkaline phosphatase, dose reductions, and neutrophil/lymphocyte ratio. Combinations of these markers may help physicians to identify subsets of patients that may benefit the most from trifluridine/tipiracil. Further studies are still needed to confirm our findings, support the most appropriate combination of prognostic/predictive factors to optimise trifluridine/tipiracil treatment, and clarify the role of the best supportive care in patients supposed to have poor response to chemotherapy and worse survival.\n\nAcknowledgments\n\nThe authors would like to thank participating patients and both medical and nursing staff involved in the conduct of the study. The authors would also like to acknowledge the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD) for sponsoring the study (funded by Laboratorios Servier S.L.), and the following specific people for their cooperation and support: the study chairs Pilar García-Alfonso (Hospital General Universitario Gregorio Marañón, Madrid, Spain) and Enrique Aranda (Hospital Universitario Reina Sofía, Córdoba, Spain), and the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD) staff I. Ruiz de Mena and S. Rodríguez. Medical writing support was provided by Esther Álvarez-García at Dynamic Science S.L. during the preparation of this paper, funded by the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD). The ROS Study Group included the following investigators: Alberto Carmona-Bayonas (Hospital General Universitario Morales Meseguer, Murcia, Spain), Ana María López-Muñoz (Hospital Universitario de Burgos, Burgos, Spain), Ana Ruiz-Casado (Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Spain), Andrea Illán-Varela (Hospital Virgen del Puerto, Plasencia, Spain), Andrés Muñoz (Hospital General Universitario Gregorio Marañón, Madrid, Spain), Beatriz González-Astorga (Hospital Universitario Clínico San Cecilio, Granada, Spain), Carles Pericay (Hospital Universitari Parc Taulí, Sabadell, Spain), Carmen Castañón-López (Hospital Universitario de León, León, Spain), Carmen Reyna-Fortes (Hospital Universitario Regional y Virgen de la Victoria, Málaga, Spain), Cristina Grávalos-Castro (Hospital Universitario 12 de Octubre, Madrid, Spain), Elena Mata-Velasco (Complejo Hospitalario de Navarra, Pamplona, Spain), Enrique Aranda (Hospital Universitario Reina Sofía, Córdoba, Spain), Federico Longo-Muñoz (Hospital Universitario Ramón y Cajal, Madrid, Spain), Fernando Rivera-Herrero (Hospital Universitario Marqués de Valdecilla, Santander, Spain), Guillem Argilés-Martínez (Hospital Universitari Vall d’Hebrón, Barcelona, Spain), Isabel Fernández-Rañada (Hospital Universitario Guadalajara, Guadalajara, Spain), Isabel Siso-García (Hospital Universitario Severo Ochoa, Leganés, Spain), Javier Sastre (Hospital Universitario Clínico San Carlos, Madrid, Spain), Jerónimo Jiménez-Castro (Hospital Universitario Virgen del Rocío, Sevilla, Spain), Jesús Rodríguez-Pascual (Centro Integral Oncológico Clara Campal, Madrid, Spain), José Carlos Méndez-Méndez (Centro Oncológico de Galicia, A Coruña, Spain), Juan Carlos Quero-Guillén (Hospital Quirónsalud Sagrado Corazón, Sevilla, Spain), Juan José Reina-Zoilo (Hospital Universitario Virgen Macarena, Sevilla, Spain), Manuel Benavides-Orgaz (Hospital Universitario Regional y Virgen de la Victoria, Málaga, Spain), María Ángeles Moreno-Santos (Hospital Universitario Puerto Real, Cádiz, Spain), María José Gómez-Reina (Hospital Universitario Puerta del Mar, Cádiz, Spain), María José Safont (Hospital General Universitari de València, Valencia, Spain), María Teresa Delgado-Ureña (Hospital Comarcal Santa Ana, Motril, Spain), María Ruth Afonso-Gómez (Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain), Marta Llanos (Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain), Nuria Rodríguez-Salas (Hospital Universitario La Paz, Madrid, Spain), Paola Patricia Pimentel-Cáceres (Hospital General Universitario Santa Lucía, Cartagena, Spain), Paula Jiménez-Fonseca (Hospital Universitario Central de Asturias, Oviedo, Spain), Pilar García-Alfonso (Hospital General Universitario Gregorio Marañón, Madrid, Spain), Rafael López-López (Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain), Rosana Grández-Ladrón-de-Guevara (Hospital Reina Sofía, Tudela, Spain), Verónica Conde-Herrero (Hospital Universitario Virgen de las Nieves, Granada, Spain), and Vicente Alonso-Orduña (Hospital Universitario Miguel Servet, Zaragoza, Spain).\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/cancers13184514/s1, Supplementary Figure S1: Summary of patient disposition, Supplementary Table S1: Trifluridine/tipiracil exposure and management (n = 379), Supplementary Table S2: Grade ≥ 3 treatment-related adverse events (n = 379).\n\nClick here for additional data file.\n\nAuthor Contributions\n\nConceptualization, P.G.-A. and E.A.; formal analysis, P.G.-A. and E.A.; resources, P.G.-A., A.M., J.J.-C., P.J.-F., C.P., F.L.-M., C.R.-F., G.A.-M., B.G.-A., M.J.G.-R., A.R.-C., N.R.-S., R.L.-L., A.C.-B. and V.C.-H.; writing—original draft preparation, P.G.-A. and E.A.; writing—review and editing, P.G.-A., E.A., A.M., J.J.-C., P.J.-F., C.P., F.L.-M., C.R.-F., G.A.-M., B.G.-A., M.J.G.-R., A.R.-C., N.R.-S., R.L.-L., A.C.-B. and V.C.-H. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis work was supported by the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD) through a grant provided by Laboratorios Servier S.L. (grant reference number: not applicable).\n\nInstitutional Review Board Statement\n\nThe study was conducted according to Good Pharmacoepidemiology Practices, the Declaration of Helsinki, and national regulations. It was approved by the Ethics Committee of Hospital General Universitario Gregorio Marañón (Madrid, Spain) (protocol code: TTD-TRI-2018-01; approval: date 17 December 2018, reference number 23/2018).\n\nInformed Consent Statement\n\nAlive patients gave their written informed consent; informed consent was waived in deceased and lost-to-follow-up patients.\n\nData Availability Statement\n\nAll data relevant to the study are included in the article or uploaded as supplementary information. Further data are available from the authors upon reasonable request and with permission of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD).\n\nConflicts of Interest\n\nThis work received funding from Laboratorios Servier S.L. J.J.C. acted as a consultant for Sanofi-Aventis outside the submitted work. C.R.F. received personal fees from Sanofi and grants from Servier, Roche, Merck, Lilly Oncology, and Bristol-Myers Squibb outside the submitted work; her husband has been working for Baush and Lomb. A.R.C. received personal fees from Sanofi, Amgen, and Servier outside the submitted work. E.A. has received honoraria for advisory role from Amgen, Bayer, Celgene, Merck, Roche, and Sanofi. The remaining authors declared no conflict of interest to disclose.\n\nFigure 1 Kaplan–Meier plot for overall survival. CI: confidence interval, OS: overall survival.\n\nFigure 2 Kaplan–Meier plots for overall survival in the exploratory analysis of prognostic subsets. They included the comparison of patients with ≤2 metastatic sites and ≥18 months from metastasis diagnosis versus those with ≥3 metastatic sites and/or <18 months (a), patients with ≤2 metastatic sites, ≥18 months from metastasis diagnosis and absence of liver metastasis versus those with ≤2 metastatic sites, ≥18 months from metastasis diagnosis and liver metastasis (b), and patients with ≥3 metastatic sites and/or <18 months from metastasis diagnosis and absence of liver metastasis versus those with ≥3 metastatic sites and/or <18 months from metastasis diagnosis and liver metastasis (c). CI: confidence interval, HR: hazard ratio, OS: overall survival.\n\nFigure 3 Kaplan–Meier plots for progression-free survival considering radiologic disease progression (a) and clinical disease progression (b). CI: confidence interval, PFS: progression-free survival.\n\ncancers-13-04514-t001_Table 1 Table 1 Baseline patient characteristics (n = 379).\n\nCharacteristics\tValue\t\nAge (years)\t\t\n Median (IQR)\t65 (58–71)\t\n ≥65 years, n (%)\t189 (49.9)\t\n ≥70 years, n (%)\t108 (28.5)\t\nMale, n (%)\t226 (59.6)\t\nCaucasian, n (%)\t355 (93.7)\t\nECOG performance status, n (%)\t\t\n 0\t117 (30.9)\t\n 1\t255 (67.3)\t\n 2\t7 (1.8)\t\nSite of primary tumour, n (%)\t\t\n Colon\t222 (58.6)\t\n Rectum\t129 (34.0)\t\n Colon and rectum\t27 (7.1)\t\n Unknown\t1 (0.3)\t\nPrimary tumour surgery, n (%)\t316 (83.4)\t\nTiming of metastases from initial diagnosis, n (%)\t\t\n Synchronous (≤6 months)\t231 (60.9)\t\n Metachronous (>6 months)\t148 (39.1)\t\nSite of metastasis (frequency ≥10%), n (%) a\t\t\n Liver\t262 (69.1)\t\n Lung\t256 (67.5)\t\n Peritoneum\t93 (24.5)\t\n Distant node\t70 (18.5)\t\n Bone\t29 (7.7)\t\nNumber of metastatic sites, n (%)\t\t\n ≤2\t279 (73.6)\t\n ≥3\t100 (26.4)\t\nLines of treatment, n (%)\t\t\n <3\t126 (33.2)\t\n ≥3\t253 (66.8)\t\nPrevious therapies in ≥1 line, n (%) a\t\t\n Fluoropyrimidines\t379 (100)\t\n Oxaliplatin\t333 (87.9)\t\n Irinotecan\t378 (99.7)\t\n Anti-VEGF\t339 (89.4)\t\n Anti-EGFR\t117 (46.7)\t\n Regorafenib\t60 (15.8)\t\n Other\t83 (21.9)\t\nTime from the initial diagnosis to start trifluridine/tipiracil (years), median (IQR)\t3.3 (2.2–5.3)\t\nTime from metastasis diagnosis to start trifluridine/tipiracil (years)\t\t\n Median (IQR)\t2.5 (1.7–4.2)\t\n ≥18 months, n (%)\t320 (84.4)\t\nECOG: Eastern Cooperative Oncology Group, EGFR: epidermal growth factor receptor, IQR: interquartile range, VEGF: vascular endothelial growth factor. a Multi-response variable.\n\ncancers-13-04514-t002_Table 2 Table 2 Primary tumour molecular status (n = 379).\n\nMolecular Status\tValue\t\nMicrosatellite instability, n (%)\t\t\n No\t128 (33.8)\t\n Yes\t50 (13.2)\t\n Unknown\t201 (53.0)\t\nKRAS status, n (%)\t\t\n Wild type\t179 (47.2)\t\n Mutated\t175 (46.2)\t\n Unknown\t25 (6.6)\t\nRAS (KRAS + NRAS) status, n (%)\t\t\n Wild type\t88 (23.2)\t\n Mutated\t190 (50.1)\t\n Unknown\t101 (26.6)\t\nBRAF status, n (%)\t\t\n Wild type\t71 (18.7)\t\n Mutated\t7 (1.8)\t\n Unknown\t301 (79.4)\t\nPI3K status, n (%)\t\t\n Wild type\t24 (6.3)\t\n Mutated\t6 (1.6)\t\n Unknown\t349 (92.1)\t\nHER2 status, n (%)\t\t\n Positive\t2 (0.5)\t\n Negative\t22 (5.8)\t\n Unknown\t355 (93.7)\t\n\ncancers-13-04514-t003_Table 3 Table 3 Patient characteristics associated with overall survival in multivariate Cox analyses.\n\nCharacteristics\tOS (Months)\tCox 1\tCox 2\t\nMedian (95% CI)\tHR (95% CI)\tp\tHR (95% CI)\tp\t\nNumber of metastatic sites\t\t\t\t\t\t\n ≤2\t8.6 (7.5–9.7)\t0.6 (0.5–0.8)\t<0.001\t0.6 (0.5–0.8)\t<0.001\t\n ≥3 a\t5.6 (4.7–6.6)\t\nLiver metastasis\t\t\t\t\t\t\n No\t10.7 (8.8–12.7)\t0.7 (0.5–0.9)\t0.004\t-\t-\t\n Yes a\t6.6 (5.6–7.5)\t\nAlkaline phosphatase level\t\t\t\t\t\t\n <300 IU\t9.8 (8.5–11.0)\t0.6 (0.4–0.8)\t<0.001\t0.5 (0.4–0.7)\t<0.001\t\n ≥300 IU a\t4.1 (2.5–5.7)\t\nDose reductions\t\t\t\t\t\t\n Without dose reductions a\t6.4 (5.1–7.6)\t-\t-\t0.6 (0.4–0.8)\t<0.001\t\n With dose reductions\t10.7 (8.8–12.7)\t\nNeutrophil/lymphocyte ratio\t\t\t\t\t\t\n <5\t9.0 (8.0–10.0)\t-\t-\t0.5 (0.4–0.7)\t<0.001\t\n ≥5 a\t4.1 (3.0–5.1)\t\nCI: confidence interval, HR: hazard ratio, OS: overall survival. a Reference category.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Bray F. Ferlay J. Soerjomataram I. Siegel R.L. Torre L.A. Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J. Clin. 2018 68 394 424 10.3322/caac.21492 30207593\n2. American Cancer Society Colorectal Cancer Facts & Figures 2017–2019 American Cancer Society Atlanta, GA, USA 2017\n3. National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Colon Cancer. Version 4.2020 Available online: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf (accessed on 15 July 2020)\n4. Van Cutsem E. Cervantes A. Adam R. Sobrero A. van Krieken J.H. Aderka D. Aranda Aguilar E. Bardelli A. Benson A. Bodoky G. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer Ann. Oncol. 2016 27 1386 1422 10.1093/annonc/mdw235 27380959\n5. Emura T. Suzuki N. Yamaguchi M. Ohshimo H. Fukushima M. A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA Int. J. Oncol. 2004 25 571 578 10.3892/ijo.25.3.571 15289858\n6. Tanaka N. Sakamoto K. Okabe H. Fujioka A. Yamamura K. Nakagawa F. Nagase H. Yokogawa T. Oguchi K. Ishida K. Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models Oncol. Rep. 2014 32 2319 2326 10.3892/or.2014.3487 25230742\n7. Fukushima M. Suzuki N. Emura T. Yano S. Kazuno H. Tada Y. Yamada Y. Asao T. Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2′-deoxyribonucleosides Biochem. Pharmacol. 2000 59 1227 1236 10.1016/S0006-2952(00)00253-7 10736423\n8. Emura T. Suzuki N. Fujioka A. Ohshimo H. Fukushima M. Potentiation of the antitumor activity of α, α, α-trifluorothymidine by the co-administration of an inhibitor of thymidine phosphorylase at a suitable molar ratio in vivo Int. J. Oncol. 2005 27 449 455 10.3892/ijo.27.2.449 16010427\n9. Mayer R.J. Van Cutsem E. Falcone A. Yoshino T. Garcia-Carbonero R. Mizunuma N. Yamazaki K. Shimada Y. Tabernero J. Komatsu Y. Randomized trial of TAS-102 for refractory metastatic colorectal cancer N. Engl. J. Med. 2015 372 1909 1919 10.1056/NEJMoa1414325 25970050\n10. Longo-Muñoz F. Argiles G. Tabernero J. Cervantes A. Gravalos C. Pericay C. Gil-Calle S. Mizuguchi H. Carrato-Mena A. Limón M.L. Efficacy of trifluridine and tipiracil (TAS-102) versus placebo, with supportive care, in a randomized, controlled trial of patients with metastatic colorectal cancer from Spain: Results of a subgroup analysis of the phase 3 RECOURSE trial Clin. Transl. Oncol. 2017 19 227 235 10.1007/s12094-016-1528-7 27443414\n11. Van Cutsem E. Mayer R.J. Laurent S. Winkler R. Grávalos C. Benavides M. Longo-Munoz F. Portales F. Ciardiello F. Siena S. The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer Eur. J. Cancer 2018 90 63 72 10.1016/j.ejca.2017.10.009 29274618\n12. Yoshino T. Cleary J. Van Cutsem E. Mayer R. Ohtsu A. Shinozaki E. Falcone A. Yamazaki K. Nishina T. Garcia-Carbonero R. Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials Ann. Oncol. 2020 31 88 95 10.1016/j.annonc.2019.10.005 31912801\n13. Tabernero J. Argiles G. Sobrero A.F. Borg C. Ohtsu A. Mayer R.J. Vidot L. Moreno Vera S.R. Van Cutsem E. Effect of trifluridine/tipiracil in patients treated in RECOURSE by prognostic factors at baseline: An exploratory analysis ESMO Open 2020 5 e000752 10.1136/esmoopen-2020-000752 32817131\n14. Andersen S.E. Andersen I.B. Jensen B.V. Pfeiffer P. Ota T. Larsen J.S. A systematic review of observational studies of trifluridine/tipiracil (TAS-102) for metastatic colorectal cancer Acta Oncol. 2019 58 1149 1157 10.1080/0284186X.2019.1605192 31002008\n15. Fernandez Montes A. Vazquez Rivera F. Martinez Lago N. Covela Rua M. Cousillas Castineiras A. Gonzalez Villarroel P. de la Camara Gomez J. Mendez Mendez J.C. Salgado Fernandez M. Candamio Folgar S. Efficacy and safety of trifluridine/tipiracil in third-line and beyond for the treatment of patients with metastatic colorectal cancer in routine clinical practice: Patterns of use and prognostic nomogram Clin. Transl. Oncol. 2020 22 351 359 10.1007/s12094-019-02130-x 31073972\n16. Carriles C. Jimenez-Fonseca P. Sánchez-Cánovas M. Pimentel P. Carmona-Bayonas A. García T. Carbajales-Álvarez M. Lozano-Blázquez A. Trifluridine/tipiracil (TAS-102) for refractory metastatic colorectal cancer in clinical practice: A feasible alternative for patients with good performance status Clin. Transl. Oncol. 2019 21 1781 1785 10.1007/s12094-019-02154-3 31209792\n17. Skuja E. Gerina-Berzina A. Hegmane A. Zvirbule Z. Vecvagare E. Purkalne G. Duration of previous treatment as a prognostic factor in metastatic colorectal cancer treated with trifluridine/tipiracil Mol. Clin. Oncol. 2018 8 699 702 10.3892/mco.2018.1600 29725539\n18. Kwakman J.J.M. Vink G. Vestjens J.H. Beerepoot L.V. De Groot J.W. Jansen R.L. Opdam F.L. Boot H. Creemers G.J. Van Rooijen J.M. Feasibility and effectiveness of trifluridine/tipiracil in metastatic colorectal cancer: Real-life data from The Netherlands Int. J. Clin. Oncol. 2018 23 482 489 10.1007/s10147-017-1220-0 29204933\n19. Cremolini C. Rossini D. Martinelli E. Pietrantonio F. Lonardi S. Noventa S. Tamburini E. Frassineti G.L. Mosconi S. Nichetti F. Trifluridine/tipiracil (TAS-102) in refractory metastatic colorectal cancer: A multicenter register in the frame of the Italian compassionate use program Oncologist 2018 23 1178 1187 10.1634/theoncologist.2017-0573 29739893\n20. Matsuda A. Yamada T. Matsumoto S. Sakurazawa N. Kawano Y. Shinozuka E. Sekiguchi K. Suzuki H. Yoshida H. Pretreatment neutrophil–to–lymphocyte ratio predicts survival after TAS-102 treatment of patients with metastatic colorectal cancer Anticancer Res. 2019 39 4343 4350 10.21873/anticanres.13602 31366528\n21. Giuliani J. Bonetti A. The onset of grade ≥3 neutropenia is associated with longer overall survival in metastatic colorectal cancer patients treated with trifluridine/tipiracil Anticancer Res. 2019 39 3967 3969 10.21873/anticanres.13551 31262929\n22. Eisenhauer E.A. Therasse P. Bogaerts J. Schwartz L. Sargent D. Ford R. Dancey J. Arbuck S. Gwyther S. Mooney M. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) Eur. J. Cancer 2009 45 228 247 10.1016/j.ejca.2008.10.026 19097774\n23. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Available online: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf (accessed on 26 May 2020)\n24. Panageas K.S. Ben-Porat L. Dickler M.N. Chapman P.B. Schrag D. When you look matters: The effect of assessment schedule on progression-free survival J. Natl. Cancer Inst. 2007 99 428 432 10.1093/jnci/djk091 17374832\n25. Cicero G. De Luca R. Dieli F. Progression-free survival as a surrogate endpoint of overall survival in patients with metastatic colorectal cancer OncoTargets Ther. 2018 11 3059 3063 10.2147/OTT.S151276\n26. Moriwaki T. Fukuoka S. Masuishi T. Takashima A. Kumekawa Y. Kajiwara T. Yamazaki K. Esaki T. Makiyama A. Denda T. Prognostic scores for evaluating the survival benefit of regorafenib or trifluridine/tipiracil in patients with metastatic colorectal cancer: An exploratory analysis of the REGOTAS study Int. J. Clin. Oncol. 2020 25 614 621 10.1007/s10147-019-01600-0 31838590\n27. Pietrantonio F. Miceli R. Rimassa L. Lonardi S. Aprile G. Mennitto A. Marmorino F. Bozzarelli S. Antonuzzo L. Tamburini E. Estimating 12-week death probability in patients with refractory metastatic colorectal cancer: The Colon Life nomogram Ann. Oncol. 2017 28 555 561 10.1093/annonc/mdw627 27864220\n28. Tanaka A. Sadahiro S. Suzuki T. Okada K. Saito G. Miyakita H. Retrospective study of regorafenib and trifluridine/tipiracil efficacy as a third-line or later chemotherapy regimen for refractory metastatic colorectal cancer Oncol. Lett. 2018 16 6589 6597 10.3892/ol.2018.9421 30344762\n29. Adenis A. De La Fouchardiere C. Paule B. Burtin P. Tougeron D. Wallet J. Dourthe L.-M. Etienne P.-L. Mineur L. Clisant S. Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: Results from a multicenter study (REBECCA) nested within a compassionate use program BMC Cancer 2016 16 412 10.1186/s12885-016-2440-9 27389564\n30. Chen D. Wu Y.-S. Lin H. Wang Y. Li L. Zhang T. Efficacy and safety of TAS-102 in refractory metastatic colorectal cancer: A meta-analysis Cancer Manag. Res. 2018 10 2915 2924 10.2147/CMAR.S174584 30214286\n\n",
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"title": "Early Clinical Experience with Trifluridine/Tipiracil for Refractory Metastatic Colorectal Cancer: The ROS Study.",
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"title": "Exacerbation of Graves ophthalmopathy with interferon-alpha therapy.",
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"abstract": "BACKGROUND\nCatecholamine agents are commonly used to support circulation; however, they may cause unexpected hypotension in a special situation. Here we describe the first unexpected case of hypotension in response to catecholamine agents.\n\n\nMETHODS\nA 29-year-old Japanese man with schizophrenia was transferred to our emergency department. He was in shock and in coma. After fluid resuscitation, we induced catecholamine agents; however, his blood pressure decreased to 59/40 mmHg in response to catecholamine infusion. On the other hand, after we started vasopressin, his blood pressure markedly improved, and he finally became stable. On day 2, he admitted to ingesting a large amount of risperidone, and we diagnosed risperidone overdose. We believe that this unexpected hypotension in response to catecholamine infusion was caused by an α-adrenergic blockade effect of risperidone. Animal experiments proved that the simultaneous administration of adrenaline with an α-adrenergic blockade provoked a fall in blood pressure; this phenomenon is called \"adrenaline reversal.\" In our case, catecholamine infusion under the α-adrenergic blockade effect of risperidone might have caused a fall in blood pressure in the same mechanism; we call this phenomenon \"catecholamine reversal.\" In such a situation, because the mechanism of vasopressin is different from that of catecholamine, we recommend vasopressin for maintaining the blood pressure.\n\n\nCONCLUSIONS\nWe described the first clinical case of \"catecholamine reversal\" and highlighted that if unexpected hypotension occurs in response to catecholamine infusion, we should suspect the use of α-adrenergic antagonists. In such situations, we should consider the administration of vasopressin instead.",
"affiliations": "Department of Emergency and Critical Care Medicine, Japanese Red Cross Society Kyoto Daini Red Cross Hospital, 355-5 Haruobicho Kamigyoku, Kyoto, 602-8026, Japan. okadayohei1127@yahoo.co.jp.;Department of Emergency and Critical Care Medicine, Japanese Red Cross Society Kyoto Daini Red Cross Hospital, 355-5 Haruobicho Kamigyoku, Kyoto, 602-8026, Japan.;Department of Emergency and Critical Care Medicine, Japanese Red Cross Society Kyoto Daini Red Cross Hospital, 355-5 Haruobicho Kamigyoku, Kyoto, 602-8026, Japan.;Department of Emergency and Critical Care Medicine, Japanese Red Cross Society Kyoto Daini Red Cross Hospital, 355-5 Haruobicho Kamigyoku, Kyoto, 602-8026, Japan.",
"authors": "Okada|Yohei|Y|http://orcid.org/0000-0002-2266-476X;Ishi|Wataru|W|;Narumiya|Hiromichi|H|;Liduka|Ryoji|R|",
"chemical_list": "D014150:Antipsychotic Agents; D002395:Catecholamines; D018967:Risperidone",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-017-1442-9",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 144210.1186/s13256-017-1442-9Case ReportUnexpected hypotension in catecholamine reversal: a case report http://orcid.org/0000-0002-2266-476XOkada Yohei +81(75)2315171okadayohei1127@yahoo.co.jp Ishi Wataru wataruaug0804@lily.ocn.ne.jp Narumiya Hiromichi pyroli1117@gmail.com Liduka Ryoji iizukar@kyoto2.jrc.or.jp Department of Emergency and Critical Care Medicine, Japanese Red Cross Society Kyoto Daini Red Cross Hospital, 355-5 Haruobicho Kamigyoku, Kyoto, 602-8026 Japan 6 10 2017 6 10 2017 2017 11 2852 12 2016 28 8 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nCatecholamine agents are commonly used to support circulation; however, they may cause unexpected hypotension in a special situation. Here we describe the first unexpected case of hypotension in response to catecholamine agents.\n\nCase presentation\nA 29-year-old Japanese man with schizophrenia was transferred to our emergency department. He was in shock and in coma. After fluid resuscitation, we induced catecholamine agents; however, his blood pressure decreased to 59/40 mmHg in response to catecholamine infusion. On the other hand, after we started vasopressin, his blood pressure markedly improved, and he finally became stable. On day 2, he admitted to ingesting a large amount of risperidone, and we diagnosed risperidone overdose. We believe that this unexpected hypotension in response to catecholamine infusion was caused by an α-adrenergic blockade effect of risperidone. Animal experiments proved that the simultaneous administration of adrenaline with an α-adrenergic blockade provoked a fall in blood pressure; this phenomenon is called “adrenaline reversal.” In our case, catecholamine infusion under the α-adrenergic blockade effect of risperidone might have caused a fall in blood pressure in the same mechanism; we call this phenomenon “catecholamine reversal.” In such a situation, because the mechanism of vasopressin is different from that of catecholamine, we recommend vasopressin for maintaining the blood pressure.\n\nConclusions\nWe described the first clinical case of “catecholamine reversal” and highlighted that if unexpected hypotension occurs in response to catecholamine infusion, we should suspect the use of α-adrenergic antagonists. In such situations, we should consider the administration of vasopressin instead.\n\nKeywords\nAdrenaline reversalAlpha-adrenergic blockadeVasopressinNoradrenalineSide effectRisperidoneCase reportissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nCatecholamine is commonly used to support circulation, and each catecholamine agent has different effects on different receptors. Catecholamine action on α-adrenergic receptors promotes peripheral vasoconstriction, on β1-adrenergic receptors it increases chronotropic and inotropic effects, and on β2-adrenergic receptors it increases vasodilation (Fig. 1) [1]. In distributive shocks such as septic shock, we generally use catecholamine agents, including noradrenaline and dopamine, to promote vasoconstriction because they mainly affect the α-adrenergic receptor [1]. However, in a special situation, these catecholamine agents may cause unexpected hypotension. Here we describe a case of unexpected hypotension in response to the use of catecholamine agents.Fig. 1 Alpha-adrenergic and β-adrenergic effects of vasoactive catecholamines. Alpha-adrenergic receptors promote peripheral vasoconstriction, β1-adrenergic receptors increase chronotropic and inotropic effects, and β2-adrenergic receptors increase vasodilation. If α-adrenergic receptor antagonists are simultaneously administered with catecholamine agents, α-adrenergic effects are masked, and β-adrenergic effects are predominantly enhanced. Consequently, vasodilation occurs and blood pressure decreases. HR heart rate\n\n\n\n\nCase presentation\nA 29-year-old Japanese man with schizophrenia was transferred to our emergency department. On arrival, he presented with shock and coma. His blood pressure (BP) was 57/29 mmHg, heart rate (HR) was 135 beats per minute (bpm), respiratory rate was 40/minute, and his body temperature was 35.6 °C. His Glasgow Coma Scale score was (E1V1M1) 3. We immediately performed intubation because of his shock and coma. Fluid resuscitation of 3000 ml crystalloid temporarily increased his BP to 73/28 mmHg, but his shock still persisted. Before a central venous line was inserted, we tentatively initiated dopamine infusion at 5 μg/kg per minute, which was increased to 10 μg/kg per minute; however, his hypotension gradually worsened to 66/37 mmHg (Fig. 2). Sixty minutes after arrival, we inserted the central venous line and initiated noradrenaline infusion at 0.1 μg/kg per minute, which was subsequently increased to 0.3 μg/kg per minute. Moreover, 90 minutes after arrival, we initiated dobutamine at 5 μg/kg per minute. However, his BP unexpectedly decreased to 59/40 mmHg. Head computed tomography, enhanced chest-abdominal computed tomography, point of care sonography, and laboratory data (Table 1) did not reveal the cause of coma and hypotension. His systemic vascular resistance index (SVRI) was very low (432 dynes/second/cm/m2; normal range, 1970 to 2400 dynes/second/cm/m2; Vigileo FloTrac™, Edwards, USA). Thus, we suspected unknown distributive shock refractory to a large amount of catecholamine infusion. Therefore, in addition to catecholamine infusion, we initiated vasopressin at 3 U/hour 150 minutes after arrival. Subsequently, his BP markedly improved to 135/45 mmHg. Three hours after arrival, we transferred him to our intensive care unit. We performed continuous hemodiafiltration because of the presence of metabolic acidosis (Table 2). We gradually decreased the amount of catecholamine infused. Approximately 12 hours after arrival, his SVRI improved to 2271 dynes/second/cm/m2 and his hemodynamic state became stable: BP, 140/80 mmHg; HR, 95 bpm. Subsequently, we completely terminated catecholamine infusion. Moreover, we terminated continuous hemodiafiltration because his metabolic acidosis was improved: pH, 7.386; partial pressure of oxygen in arterial blood (PaO2), 73.8 mmHg; partial pressure of carbon dioxide in arterial blood (PaCO2), 39.3 mmHg; bicarbonate (HCO3\n-), − 1.2 mmol/l; lactate (Lac), 1.5 mmol/l; and fraction of inspired oxygen (FiO2), 0.3. On day 2, we terminated vasopressin infusion. After extubation, his condition was stable: BP, 123/75 mmHg; HR, 100 bpm; and Glasgow Coma Scale score (E4V5M6), 15. He was transferred to our general ward. He admitted to ingesting approximately 150 mg risperidone to attempt suicide. The risperidone concentration in his blood sample on admission was very high (398 ng/ml at admission, recommended therapeutic range, 20 to 60 ng/ml [2]), which decreased to 3.60 ng/ml on day 2. Consequently, we diagnosed risperidone overdose. Subsequently, his condition was stable without any event, and he was transferred to a psychiatric ward for psychiatric care on day 5.Fig. 2 Clinical course after admission. Blood pressure gradually decreased in response to an increase in catecholamine administration. After initiating vasopressin, hypotension markedly improved. BP blood pressure, CHDF continuous hemodiafiltration, DBP diastolic blood pressure, DOA dopamine, DOB dobutamine, HR heart rate, NAD noradrenaline, SBP systemic blood pressure, VAS vasopressin\n\n\nTable 1 Laboratory data on admission\n\nComplete blood count\tCoagulation\t\nWBC\t5600/μl\tPT-INR\t1.09\t\nRBC\t458 × 104/μl\tAPTT\t23.9\t\nHb\t13.1 g/dl\tFib\t218 mg/d\t\nHt\t40.3%\t\t\t\nPlt\t17.9 × 104/μl\tArterial blood gas\t\nChemistry\tpH\t7.364\t\nAST\t21 U/L\tpCO2\n\t36.8 mmHg\t\nALT\t16 U/L\tpO2\n\t483 mmHg\t\nCPK\t136 U/L\tHCO3\n-\n\t20.4 mmol/l\t\nCr\t1.21 mg/d\tBase excess\t−3.9 mmol/l\t\nBUN\t15.2 mg/d\tLac\t4.9 mmol/l\t\nNa\t141 meq/l\t\t(FiO2 1.0)\t\nK\t2.7 meq/l\t\t\t\nCl\t103 meq/l\t\t\t\nCRP\t0.08 mg/d\t\t\t\nPCT\t0.03 ng/d\t\t\t\n\nALT alanine aminotransferase, APTT activated partial thromboplastin time, AST aspartate aminotransferase, BUN blood urea nitrogen, Cl chlorine, CPK creatine phosphokinase, Cr creatinine, CRP C-reactive protein, Fib fibrinogen, FiO\n2 fraction of inspired oxygen, Hb hemoglobin, HCO\n3\n- bicarbonate, Ht hematocrit, K potassium, Lac lactate, Na sodium, pCO\n2 partial pressure of carbon dioxide, PCT procalcitonin, pH potential of hydrogen, Plt platelets, pO\n2 partial pressure of oxygen, PT-INR prothrombin time-international normalized ratio, RBC red blood cells, WBC white blood cells\n\n\nTable 2 Arterial blood gas analysis in intensive care unit\n\nPaCO2\n\t34.8 mmHg\t\nPaO2\n\t214 mmHg\t\nHCO3\n-\n\t14.6 mmol/l\t\nBase excess\t−11.4 mmol/l\t\nNa+\n\t141 mmol/l\t\nK+\n\t2.8 mmol/l\t\nCl-\n\t107 mmol/l\t\nLac\npH\t12.6 mmol/l\n7.246\t\n(FiO2 0.6)\t\n\nCl\n- chloride ion, FiO\n2 fraction of inspired oxygen, HCO\n3\n- bicarbonate, K\n+ potassium ion, Lac lactate, Na\n+ sodium ion, PaCO\n2 partial pressure of carbon dioxide in arterial blood, PaO\n2 partial pressure of oxygen in arterial blood, pH potential of hydrogen\n\n\n\n\nDiscussion\nWe experienced unexpected hypotension in response to catecholamine infusion, and we believe that this unexpected hypotension was caused by a pharmacological phenomenon: the catecholamine effect under the α-adrenergic blockade effect of risperidone. In animal experiments, if adrenaline is simultaneously administered with α-adrenergic receptor blockers such as phentolamine, the α-adrenergic effects are masked and the β2-adrenergic effects are predominantly enhanced (Fig. 1) [3]. Consequently, vasodilation occurs and the BP decreases. This unique phenomenon is called “adrenaline reversal” [3]. Adrenaline reversal has also been reported in clinical situations; paradoxical hypotension due to adrenaline infusion has been reported in a case of massive quetiapine overdose because quetiapine has an α-adrenergic blockade effect [4]. This report suggested that adrenaline reversal occurs even in cases of massive antipsychotic overdose. This report recommended selecting noradrenaline for hypotension under an α-adrenergic blockade effect, such as an overdose of quetiapine; however, we disagree with this. This is because other animal experiments proved that noradrenaline could also cause the same phenomenon as “noradrenaline reversal” [5], although noradrenaline has stronger α-adrenergic effects than β-adrenergic effects. Therefore, we suggest that we should avoid noradrenaline in such a situation.\n\nDopamine and dobutamine also have both α-adrenergic and β-adrenergic effects [6]; we think that there is a possibility that dopamine and dobutamine also may cause catecholamine reversal. Thus, catecholamine agents other than adrenaline can potentially provoke “catecholamine reversal” in patients who have used α-adrenergic antagonists. In our case, because risperidone has an α-adrenergic blockade effect, a large amount of catecholamine infused under the effect of an α-adrenergic blockade might have caused hypotension in the same mechanism.\n\nOn the other hand, vasopressin is a type of vasoactive agent that increases peripheral vasoconstriction via V1 receptors [3] and is commonly used to maintain vasoconstriction, particularly in distributive shock [1]. In our patient, severe hypotension immediately improved after administering vasopressin. This could be attributed to the fact that the mechanism action of vasopressin is different from that of catecholamines. Thus, vasopressin may be useful to support circulation in patients who have used α-adrenergic antagonists.\n\nThis is the first clinical case to describe unexpected hypotension as “catecholamine reversal.” Most antipsychotic agents have α-adrenergic blockade; thus, this educational case highlights that we should determine which vasoactive agent should be selected for the patient who uses these medicines.\n\nConclusions\nWe described the first clinical case of “catecholamine reversal” and highlighted that if unexpected hypotension occurs in response to catecholamine infusion, we should suspect that the patient has used α-adrenergic antagonists. In such a situation, we should consider administration of vasopressin instead.\n\nAcknowledgements\nWe thank Dr Hatsuko Yano for providing clinical support.\n\nFunding\nNo funding was received for this study.\n\nAvailability of data and materials\nThe authors agree to make the raw data and materials described in our manuscript freely available.\n\nAuthors’ contributions\nYO was the major contributor in writing the manuscript. RL, WI, and HN supervised the whole work. All authors have read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Hollenberg SM Vasoactive drugs in circulatory shock Am J Respir Crit Care Med 2011 183 847 55 10.1164/rccm.201006-0972CI 21097695 \n2. Baumann P Hiemke C Ulrich S Eckermann G Gaertner I Gerlach M The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry Pharmacopsychiatry 2004 37 243 65 10.1055/s-2004-832687 15551191 \n3. Grundy HC Grundy HF Proceedings: The mechanism of “adrenaline reversal” in the anesthetized cat and rabbit Br J Pharmacol 1975 55 282 3 \n4. Grace RF Newell SD Paradoxical and severe hypotension in response to adrenaline infusions in massive quetiapine overdose: the case for lipid rescue Crit Care Resusc 2009 11 162 19485883 \n5. Karim SM The mechanism of the depressor action of noradrenaline in the cat Br J Pharmacol Chemother 1964 23 592 9 10.1111/j.1476-5381.1964.tb01612.x 14256816 \n6. Overgaard CB Dzavik V Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease Circulation 2008 118 1047 56 10.1161/CIRCULATIONAHA.107.728840 18765387\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "11(1)",
"journal": "Journal of medical case reports",
"keywords": "Adrenaline reversal; Alpha-adrenergic blockade; Case report; Noradrenaline; Risperidone; Side effect; Vasopressin",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D002395:Catecholamines; D062787:Drug Overdose; D006801:Humans; D007022:Hypotension; D008297:Male; D018967:Risperidone",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "285",
"pmc": null,
"pmid": "28982383",
"pubdate": "2017-10-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21097695;14256816;19485883;15551191;116;18765387",
"title": "Unexpected hypotension in catecholamine reversal: a case report.",
"title_normalized": "unexpected hypotension in catecholamine reversal a case report"
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"companynumb": "JP-CIPLA LTD.-2017JP18572",
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"activesubstance": {
"activesubstancename": "DOPAMINE\\DOPAMINE HYDROCHLORIDE"
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{
"abstract": "BACKGROUND\nComplications arising from use of the levonorgestrel-releasing intrauterine system (LNG-IUS) are uncommon. Perforation of the uterus by an LNG-IUS leading to small bowel obstruction (SBO) has not been reported in the literature.\n\n\nMETHODS\nA 29-year-old woman presented to the emergency department with abdominal pain, constipation, nausea, and vomiting. CT scan revealed dilated loops of small bowel suggestive of SBO and an IUD that did not appear within the uterine cavity. Laparoscopy revealed a dense adhesive band of tissue extending from 2 cm caudad to the umbilical port site to 1 arm of the perforated LNG-IUS at the posterior uterine wall. Two bowel loops were twisted around the adhesive band multiple times. The band was taken down at the IUD and the bowel loops were spontaneously freed. The LNG-IUS was removed.\n\n\nCONCLUSIONS\nUse of the LNG-IUS is on the rise in the United States and is a recommended first-line contraceptive agent in the obese patient. Management of perforated IUD in an obese patient should take into account individual patient characteristics. Laparoscopic management of a SBO due to a perforated IUD in an obese patient is possible.",
"affiliations": "Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.",
"authors": "Loveless|Alita|A|;Dhari|Ammar|A|;Kilpatrick|Charlie C|CC|",
"chemical_list": "D016912:Levonorgestrel",
"country": "United States",
"delete": false,
"doi": null,
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"issn_linking": "0024-7758",
"issue": "59(11-12)",
"journal": "The Journal of reproductive medicine",
"keywords": null,
"medline_ta": "J Reprod Med",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007415:Intestinal Obstruction; D007436:Intrauterine Devices, Medicated; D016912:Levonorgestrel; D009765:Obesity; D014595:Uterine Perforation",
"nlm_unique_id": "0173343",
"other_id": null,
"pages": "611-3",
"pmc": null,
"pmid": "25552138",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Perforated levonorgestrel-releasing intrauterine system resulting in small bowel obstruction: a case report.",
"title_normalized": "perforated levonorgestrel releasing intrauterine system resulting in small bowel obstruction a case report"
} | [
{
"companynumb": "US-BAYER-2015-001756",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe outpatient management of stroke prevention for patients with atrial fibrillation has recently been published and provides insight into the benefits and risks of the new direct-acting oral anti-coagulants. However, real-world use of these agents for hospital inpatients requires additional study.\n\n\nOBJECTIVE\nTo determine prescribing patterns for dabigatran at 3 Canadian hospitals, specifically adherence with the hospitals' prescribing restriction limiting dabigatran to patients with nonvalvular atrial fibrillation and creatinine clearance above 30 mL/min (primary outcome) and assessment of age-related prescribing, prescribing of medications with defined contraindications or potential for interaction when given concurrently with dabigatran, and use of risk stratification tools (secondary outcomes).\n\n\nMETHODS\nA retrospective chart review of patients for whom dabigatran was prescribed from August to October 2011 was performed at 3 hospitals in Toronto, Ontario. Descriptive statistics were used for all outcomes assessed.\n\n\nRESULTS\nOverall, dabigatran was prescribed for 69 inpatients, of whom 16 (23%) were new users (dabigatran initiated during hospital admission) and 53 (77%) were prior users (dabigatran prescribed before admission to hospital). Fifty-eight patients (84%; 14 new users and 44 prior users) received dabigatran according to the hospitals' prescribing restriction. For the remaining 11 patients, dabigatran therapy did not meet prescribing restrictions for use because of valvular disease or presence of prosthetic valve (10 patients [14% of the total sample]) and impaired renal function (1 patient [1%]). Among those whose dabigatran therapy met the prescribing restrictions for use, amiodarone and acetylsalicylic acid were the most common concurrently prescribed medications (17 patients [29%] and 14 patients [24%], respectively). Stroke and bleeding risk were documented for only 27 patients (47%) and 10 patients (17%), respectively.\n\n\nCONCLUSIONS\nAt the study hospitals, dabigatran was appropriately prescribed for the indication of nonvalvular atrial fibrillation in patients without renal impairment in most cases. However, greater consideration of cardiac history (including valvular disease and presence of prosthetic valves), drug interactions, and documentation of risks and benefits is warranted. These research findings highlight the importance of and opportunity for pharmacist review and involvement in assessment and selection of patients with indications for anticoagulant therapy, particularly when agents are new to the market.",
"affiliations": "PharmD, is a Critical Care Pharmacist with the Department of Pharmacy Services, Toronto Western Hospital, University Health Network, and an Adjunct Lecturer, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario.;PharmD, is the Research Coordinator and a Pharmacotherapy Specialist with the Department of Pharmacy Services and OpenLab, University Health Network, and an Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario.;PharmD, is a Clinical Site Leader with the Department of Pharmacy Services and the Peter Munk Cardiac Centre and Family Health Team, University Health Network, and an Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario.;PharmD, was, at the time of the study, a Drug Utilization Coordinator with the University Health Network, Toronto, Ontario. She is now a Pharmacy Quality Coordinator with the Department of Pharmacy Services, Toronto General Hospital, University Health Network.",
"authors": "Carter|Aleesa A|AA|;Leblanc|Kori|K|;Woods|Amita|A|;Lowe|Donna|D|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.4212/cjhp.v68i5.1483",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-4123",
"issue": "68(5)",
"journal": "The Canadian journal of hospital pharmacy",
"keywords": "arrhythmia; drug use evaluation; hospital prescribing; novel oral anticoagulants",
"medline_ta": "Can J Hosp Pharm",
"mesh_terms": null,
"nlm_unique_id": "0215645",
"other_id": null,
"pages": "369-77",
"pmc": null,
"pmid": "26478582",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "24275632;23271794;18283199;21111555;10075613;21047252;15477396;25359164;20299623;21309657;19717844;23484796;12941677;23991661;21830957;25077110;25056265;16908915",
"title": "Utilization of Dabigatran for Atrial Fibrillation at 3 Tertiary Care Centres.",
"title_normalized": "utilization of dabigatran for atrial fibrillation at 3 tertiary care centres"
} | [
{
"companynumb": "CA-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-59916BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "A 31-year-old woman with systemic lupus erythematosus and lupus nephritis was treated with prednisone and immunosuppressants. After her lupus nephritis symptoms worsened, both high-dose steroid and cyclophosphamide pulse therapy were administered. The patient developed an intestinal perforation, and laparoscopic Hartmann's surgery was performed on the sigmoid colon. Serum Cytomegalovirus (CMV) antigen C7HRP was detected, and the patient was diagnosed with CMV colitis and underwent a colon resection. Severe hematochezia continued despite ganciclovir administration, and the patient underwent laparoscopic total colectomy and partial ileostomy. CMV enteritis should be considered in patients treated with prednisone and immunosuppressants and those who have abdominal pain and hematochezia. Immunocompromised patients with intestinal perforation due to CMV enteritis have a poor prognosis. We report a case with along with the results of a literature review.",
"affiliations": "Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan. keigo@juntendo.ac.jp.;Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.;Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.;Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan.;Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.;Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan.;Department of Pathology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan.;Department of Surgery, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan.;Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.;Department of Internal Medicine and Rheumatology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka Urayasu-shi, Chiba, 279-0021, Japan.",
"authors": "Ikeda|Keigo|K|;Nakajima|Shihoko|S|;Tanji|Kana|K|;Hirai|Takuya|T|;Uomori|Kaori|K|;Morimoto|Shinji|S|;Tomita|Shigeki|S|;Fukunaga|Masaki|M|;Tamura|Naoto|N|;Sekigawa|Iwao|I|",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D001623:Betamethasone; D011239:Prednisolone; D015774:Ganciclovir; D016559:Tacrolimus",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-017-3693-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "37(8)",
"journal": "Rheumatology international",
"keywords": "Colitis; Cytomegalovirus; Intestinal perforation; Systemic lupus erythematosus",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D001623:Betamethasone; D003092:Colitis; D012809:Colon, Sigmoid; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004751:Enteritis; D005260:Female; D015774:Ganciclovir; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007416:Intestinal Perforation; D008181:Lupus Nephritis; D011239:Prednisolone; D016559:Tacrolimus",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "1395-1399",
"pmc": null,
"pmid": "28283734",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "3005424;26927444;11868605;19750578;9863901;9665982;25553288;1847039;9806049;12175116;25109743;22020267;12729328;19688181;19011502;1313313;2983175;15229955;14747370;14749990;24405983;18087722;16014060",
"title": "Intestinal perforation due to hemorrhagic Cytomegalovirus enteritis in a patient with severe uncontrolled lupus nephritis: a case and review of the literature.",
"title_normalized": "intestinal perforation due to hemorrhagic cytomegalovirus enteritis in a patient with severe uncontrolled lupus nephritis a case and review of the literature"
} | [
{
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"abstract": "Facial nerve paralysis (FNP) after super-selective intra-arterial chemotherapy (SSIAC) is a relatively rare local side effect of SSIAC to the maxillary artery (MA) or the middle meningeal artery (MMA). The incidence and prognosis of FNP after SSIAC in 381 patients with oral cancer (133 with catheterization of the MA, 248 without) was investigated retrospectively. Only three patients (two male and one female) had FNP, for an incidence of 0.8%. All patients with FNP had undergone catheterization of the MA, and the incidence of FNP in this group was 2.3% (3/133). One of the three patients with FNP had paralysis of the third branch of the trigeminal nerve. FNP occurred a mean of 8.7 days (range 5-11 days) after initial SSIAC, and the mean total dose of cisplatin was 55.8mg (range 42.5-67.2mg) and of docetaxel was 25.4mg (range 17.0-33.6mg). FNP resolved completely a mean of 12.7 months (range 6-19 months) after onset. Because the administration of anticancer agents via the MA or MMA carries a risk of FNP, this information will be useful when obtaining informed consent from patients before treatment.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.;Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan. Electronic address: iwai104oams@yahoo.co.jp.;Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.;Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.;Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.;Department of Oral and Maxillofacial Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.",
"authors": "Sugiyama|S|S|;Iwai|T|T|;Oguri|S|S|;Koizumi|T|T|;Mitsudo|K|K|;Tohnai|I|I|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1016/j.ijom.2017.01.011",
"fulltext": null,
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"issn_linking": "0901-5027",
"issue": "46(6)",
"journal": "International journal of oral and maxillofacial surgery",
"keywords": "complication; facial nerve paralysis; intra-arterial chemotherapy; oral cancer; super-selective intra-arterial chemotherapy",
"medline_ta": "Int J Oral Maxillofac Surg",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D002404:Catheterization; D005158:Facial Paralysis; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008438:Maxillary Artery; D008576:Meningeal Arteries; D008875:Middle Aged; D009062:Mouth Neoplasms; D011379:Prognosis; D012189:Retrospective Studies",
"nlm_unique_id": "8605826",
"other_id": null,
"pages": "682-686",
"pmc": null,
"pmid": "28209378",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Facial nerve paralysis after super-selective intra-arterial chemotherapy for oral cancer.",
"title_normalized": "facial nerve paralysis after super selective intra arterial chemotherapy for oral cancer"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1036694",
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"occurcountry": "JP",
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"activesubstance": {
"activesubstancename": "CISPLATIN"
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{
"abstract": "We report a 17-yr-old boy who developed a microangiopathic hemolytic anemia presumed secondary to tacrolimus shortly following a living-related donor renal transplant. This was initially managed by plasmapheresis. Reinstitution of calcineurin inhibition using cyclosporine led to recurrence of hemolysis, so an alternative agent was needed. He was commenced on monthly intravenous belatacept, with no further recurrence of the hemolysis, and subsequent stable graft function. Modulation via CTLA-4 offers an alternative immunosuppressive tactic if current regimens produce graft threatening adverse effects. The method of administration and frequency of dosage of belatacept also lends itself well to the high-risk period of adolescence and transition. We propose that belatacept may therefore also have utility in difficult cases complicated by poor concordance, common in the adolescent age group.",
"affiliations": "Department of Paediatric Nephrology, Great North Children's Hospital, Newcastle upon Tyne, UK.",
"authors": "Reynolds|B C|BC|;Talbot|D|D|;Baines|L|L|;Brown|A|A|",
"chemical_list": "D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D019703:Calcineurin; D016559:Tacrolimus",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12278",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "18(5)",
"journal": "Pediatric transplantation",
"keywords": "calcineurin inhibitors; maintenance immunosuppression; patient non-adherence; pediatric kidney transplant; tacrolimus toxicity",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000069594:Abatacept; D000293:Adolescent; D000743:Anemia, Hemolytic; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D019703:Calcineurin; D006084:Graft Rejection; D006461:Hemolysis; D006801:Humans; D018796:Immunoconjugates; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D010956:Plasmapheresis; D011183:Postoperative Complications; D012008:Recurrence; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "E140-5",
"pmc": null,
"pmid": "24815506",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of belatacept to maintain adequate early immunosuppression in calcineurin-mediated microangiopathic hemolysis post-renal transplant.",
"title_normalized": "use of belatacept to maintain adequate early immunosuppression in calcineurin mediated microangiopathic hemolysis post renal transplant"
} | [
{
"companynumb": "GB-WATSON-2015-09267",
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"activesubstancename": "CYCLOSPORINE"
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... |
{
"abstract": "We report four cases of acute pulmonary edema that occurred during treatment by intravenous tocolysis using nicardipine in pregnancy patients with no previous heart problems. Clinical severity justified hospitalization in intensive care unit (ICU) each time. Acute dyspnea has begun at an average of 63 hours after initiation of treatment. For all patients, the first diagnosis suspected was pulmonary embolism. The patients' condition improved rapidly with appropriate diuretic treatment and by modifying the tocolysis. The use of intravenous nicardipine is widely used for tocolysis in France even if its prescription does not have a marketing authorization. The pathophysiological mechanisms of this complication remain unclear. The main reported risk factors are spontaneous preterm labor, multiple pregnancy, concomitant obstetrical disease, association with beta-agonists, and fetal lung maturation corticotherapy. A better knowledge of this rare but serious adverse event should improve the management of patients. Nifedipine or atosiban, the efficiency of which tocolysis was also studied, could be an alternative.",
"affiliations": "Service d'Anesthésie-Réanimation, Hôpital Mère Enfant, 08 avenue Dominique Larrey, 87000 Limoges, France ; Service de Réanimation Polyvalente, CIC 0801, CHU Dupuytren, 02 avenue Martin Luther King, 87000 Limoges, France.;Service de Réanimation Polyvalente, CIC 0801, CHU Dupuytren, 02 avenue Martin Luther King, 87000 Limoges, France.;Service d'Anesthésie-Réanimation, Hôpital Mère Enfant, 08 avenue Dominique Larrey, 87000 Limoges, France.;Service d'Anesthésie-Réanimation, Hôpital Mère Enfant, 08 avenue Dominique Larrey, 87000 Limoges, France ; Service de Réanimation Polyvalente, CIC 0801, CHU Dupuytren, 02 avenue Martin Luther King, 87000 Limoges, France.;Service de Réanimation Polyvalente, CIC 0801, CHU Dupuytren, 02 avenue Martin Luther King, 87000 Limoges, France.;Service d'Anesthésie-Réanimation, Hôpital Mère Enfant, 08 avenue Dominique Larrey, 87000 Limoges, France.;Service de Réanimation Polyvalente, CIC 0801, CHU Dupuytren, 02 avenue Martin Luther King, 87000 Limoges, France.",
"authors": "Serena|Claire|C|;Begot|Emmanuelle|E|;Cros|Jérôme|J|;Hodler|Charles|C|;Fedou|Anne Laure|AL|;Nathan-Denizot|Nathalie|N|;Clavel|Marc|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2014/242703",
"fulltext": "\n==== Front\nCase Rep Crit CareCase Rep Crit CareCRICCCase Reports in Critical Care2090-64202090-6439Hindawi Publishing Corporation 10.1155/2014/242703Case ReportNicardipine-Induced Acute Pulmonary Edema: A Rare but Severe Complication of Tocolysis Serena Claire \n1\n\n2\nBegot Emmanuelle \n2\nCros Jérôme \n1\nHodler Charles \n1\n\n2\nFedou Anne Laure \n2\nNathan-Denizot Nathalie \n1\nClavel Marc \n2\n*1Service d'Anesthésie-Réanimation, Hôpital Mère Enfant, 08 avenue Dominique Larrey, 87000 Limoges, France2Service de Réanimation Polyvalente, CIC 0801, CHU Dupuytren, 02 avenue Martin Luther King, 87000 Limoges, France*Marc Clavel: marc.clavel@chu-limoges.frAcademic Editor: Chiara Lazzeri\n\n2014 19 8 2014 2014 24270326 6 2014 4 8 2014 5 8 2014 Copyright © 2014 Claire Serena et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We report four cases of acute pulmonary edema that occurred during treatment by intravenous tocolysis using nicardipine in pregnancy patients with no previous heart problems. Clinical severity justified hospitalization in intensive care unit (ICU) each time. Acute dyspnea has begun at an average of 63 hours after initiation of treatment. For all patients, the first diagnosis suspected was pulmonary embolism. The patients' condition improved rapidly with appropriate diuretic treatment and by modifying the tocolysis. The use of intravenous nicardipine is widely used for tocolysis in France even if its prescription does not have a marketing authorization. The pathophysiological mechanisms of this complication remain unclear. The main reported risk factors are spontaneous preterm labor, multiple pregnancy, concomitant obstetrical disease, association with beta-agonists, and fetal lung maturation corticotherapy. A better knowledge of this rare but serious adverse event should improve the management of patients. Nifedipine or atosiban, the efficiency of which tocolysis was also studied, could be an alternative.\n==== Body\n1. Introduction\nIn industrialized countries, prematurity is the main cause of perinatal morbidity and mortality and is a major public health issue in obstetrics. Its incidence varies across the country from 5 to 11% [1]. About 75% of premature births are due to spontaneous premature labor [2] which is also the most frequent cause of hospitalization [3]. Tocolytics are used to inhibit uterine contractions so that a fetal lung maturation corticotherapy can be administrated. Whether to prescribe a tocolysis as well as the choice of the molecule to use is still discussed. Massive use of β\n2-adrenergic agonists in premature labor treatments induced adverse effects and sometimes severe complications especially acute pulmonary edemas (APE) [4, 5]. Other therapeutic classes are thus more and more preferred. Even if they are prescribed without marketing authorization, calcium channel blockers from the dihydropyridine group, that is, nicardipine (Loxen) and nifedipine (Adalat), have become the first line tocolytic treatments in many French centers [6–9]. After several years of use, rare observations of APE induced by nicardipine are described.\n\nWe are reporting four additional observations of APE (from January 2009 to December 2013) occurring in patients hospitalized for premature labor after nicardipine administration. Clinical severity justified hospitalization in intensive care unit (ICU) each time. The objective of this work is to better explain to the physician this rare but classic complication and so to improve its management by preventing inappropriate treatments and especially useless further investigation.\n\n2. Case Reports\n2.1. Case 1\nA 31 year-old patient, nullipara, without relevant history and with a single pregnancy, was hospitalized for premature labor at 33 weeks of amenorrhea + 1 day associated with preeclampsia. Her blood pressure had been checked twice a week by a nurse since the 22nd week of amenorrhea as she presented with pregnancy-induced hypertension (PIH). At admission she also presented with a proteinuria higher than 0.3 g/24 h. First she was treated with nicardipine (Loxen) 20 mg × 3/days per os (PO), and 48 hours later as contractions persisted, calcium channel blockers dosage was increased (intravenous (IV) nicardipine, 3.5 mg/h injected with an automatic syringe). Fetal lung maturation corticotherapy was started (two intramuscular (IM) injections of betamethasone 12 mg (Celestene) performed 24 h apart). About 12 hours after tocolytics increase, the patient exhibited a sudden dyspnea with oxygen desaturation at 86% associated with dry cough but without clear signs of acute respiratory distress. She was transferred to ICU for clinical suspicion of pulmonary embolism. Hypoxemia improved under 3 L/min nasal oxygen therapy (SaO2 = 96%). Lung examination disclosed crepitant rales at both bases. Arterial blood gas disclosed an uncompensated respiratory alkalosis (pH = 7.50, arterial carbon dioxide tension [PaCO2] = 28.2 mmHg, bicarbonates = 21.7 mmol/L, base excess = −1.1 mmol/L, and arterial oxygen tension [PaO2] = 107 mmHg) and an increased BNP at 2,474 ng/L. Electrocardiogram (ECG) was normal. A bilateral alveolar-interstitial syndrome was revealed by the chest X-ray. Transthoracic echocardiography (TTE) evidenced a nondilated left ventricle (LV) with a usual systolic function (LV ejection fraction (LVEG) = 70–75%), increased left filling pressures (E/E′ = 13), and moderately dilated right cavities with pulmonary hypertension (systolic pulmonary artery pressure (SPAP) estimated at 48 mmHg) without paradoxical septum and a noncompliant superior vena cava (SVC) of limited size. Pleural ultrasound showed bilateral pleural effusions measuring around 2 cm. Acute pulmonary edema was diagnosed in light of the X-ray and ultrasound data. Nicardipine was stopped and replaced by atosiban (Tractocile) at a dosage of 8 mL/h IV with an automatic syringe (dilution = 1 ampule, i.e., 37.5 mg in 48 mL).\n\nFollowing a symptomatic treatment, the disease improved quickly; the 24 h diuresis was equal to 3,050 mL after an IV injection of 80 mg furosemide (Lasilix). Pulmonary disorders disclosed at examination disappeared after 24 h and the chest X-ray was normal again. However the patient still needed oxygen therapy for 36 hours. She was discharged from the ICU at D2 still under furosemide 20 mg/day. At 34 weeks of amenorrhea, that is, D6, emergency cesarean section was decided because of an acute fetal distress with heart rhythm disorders. The newborn was a boy weighing 1,890 grams with an Apgar score of 10/10/10 at 1, 5, and 10 minutes, respectively. No incident occurred after the delivery and the control cardiac and nephrologic assessment performed at 4 months did not disclose any disorder.\n\n2.2. Case 2\nA 28-year-old patient, G3P1, with a spontaneous monochorionic diamniotic twin pregnancy was hospitalized for premature labor at 26 weeks of amenorrhea + 1 day. She successively received a tocolytic treatment with nicardipine (Loxen) IV with an automatic syringe, then atosiban (Tractocile) IV with an automatic syringe, and finally nifedipine (Adalat) PO and salbutamol PO. She also received a fetal lung maturation corticotherapy with betamethasone (Celstene; two IM injections of 12 mg 24 h apart). At D4, because of uterine contraction recurrence, a treatment with nicardipine IV with an automatic syringe at 3 and then 4 mg/h was initiated again. The patient suffered from severe back pain radiating toward the nape, associated with polypnea and desaturation (94% under 15 L/min oxygen in a nonrebreather (NRB) mask). She also presented with photophobia, headaches, and visual disorders induced by nicardipine. Clinical observation revealed no sensory motor deficiency and quick tendon reflexes. Nicardipine therapy was stopped and replaced by atosiban (Tractocile) IV with an automatic syringe. A first TTE disclosed a 70% LVEF, a grade 2 mitral insufficiency, and an aspect similar to an acute cor pulmonale especially a paradoxical septum. In light of the acute respiratory distress with suspected pulmonary embolism, the patient was transferred to ICU. Hemodynamics parameters was stable and there was a jugular turgidity without lower limb edema. The patient still suffered from hypoxia with 90% saturation under 15 L/min oxygen in a NRB mask. A polypnea with supraclavicular indrawing was noted. Examination showed hypoventilation of both bases. Arterial blood gas disclosed an uncompensated respiratory alkalosis (pH = 7.47, PaCO2 = 31.2 mmHg, bicarbonates = 22.3 mmol/L, and base excess = −0.9 mmol/L) with hypoxia (PaO2 = 59 mmHg under 15 L/min oxygen in a NRB mask) and an increased BNP at 3,686 ng/L. The ECG presented a regular sinus rhythm without conduction or repolarization disorders. Chest X-ray evidenced an alveolar-interstitial infiltrate of both bases (Figure 1). A new TTE confirmed that there was no LV systolic dysfunction but a moderate mitral insufficiency (grade 2); it also revealed increased LV filling pressures (E/E′ = 15) and pulmonary hypertension (SPAP estimated at 55 mmHg). The aspect of the acute cor pulmonale was not confirmed. Pleural ultrasound revealed two pleural effusions.\n\nWe thus assumed that it was an APE induced by the high doses of nicardipine. The patient was treated with diuretics (furosemide Lasilix, 80 mg as bolus then 250 mg/24 h) to which she responded (diuresis of 3,520 mL in 20 h) and with noninvasive ventilation sessions which were not very efficient. As the uterine contractions persisted under atosiban and as a chorioamnionitis was suspected, the patient was intubated and mechanically ventilated to perform an emergency delivery by C-section at 26 weeks of amenorrhea + 5 days. The newborns were two girls weighing 933 and 763 grams hospitalized in neonatal ICU. The patient was extubated 24 hours later as she exhibited respiratory improvement thanks to the diuretics. The patient was discharged at D3 from the ICU still under diuretic treatment. Control echocardiography performed 2 months later was normal.\n\n2.3. Case 3\nA 28-year-old patient, G2P0, with history of spontaneous miscarriage one year ago (without curettage) was followed in a level 1 maternity for a single pregnancy complicated with an incompetent cervix due to recurrent uterine contractions. She was hospitalized at 29 weeks of amenorrhea + 5 days as uterine contractions were frequent and efficient resulting in cervix dilatation. Premature labor was thus suspected. A tocolytic treatment was started with nicardipine (Loxen) IV with an automatic syringe at doses which rapidly increased up to 4 mg/h. Dyspnea progressively appeared with sensation of thoracic oppression and palpitations. The sensation became more intense during the night of the 5th hospitalization day. The patient presented with febricula at 38.5° and a desaturation at 89% so that nasal oxygen therapy was initiated. At the same time, uterine contractions became more and more intense and fetal lung maturation corticotherapy with betamethasone (Celestene, two IM injections of 12 mg 24 h apart) was started. Laboratory tests revealed an inflammatory syndrome (hyperleukocytosis = 19,000 white blood cells/mm3, CRP at 70 mg/L). BNP equaled 660 ng/L with normal troponin. The ECG presented a regular sinus rhythm without any relevant disorder. The TTE disclosed a maintained LVEF with no dilatation of the right cavities. LV filling pressures were normal. SPAP was estimated at 35 + 10 mmHg. As a new desaturation episode occurred, the patient was transferred in ICU. She was still dyspneic with saturation at 89% under oxygen therapy at 6 L/min in a face mask and tended to have high blood pressure. Lung examination disclosed crepitant rales on both lungs especially on the bases. There was no cyanosis or sign of acute respiratory distress. Arterial blood gas revealed an uncompensated respiratory alkalosis (pH = 7.48, PaCO2 = 26.7 mmHg, bicarbonates = 19.9 mmol/L, and base excess = −3 mmol/L) associated with hypoxemia (PaO2 = 73 mmHg under 6 L/min oxygen). The remaining laboratory tests were normal. Chest X-ray showed bilateral alveolar-interstitial infiltrate in a butterfly distribution without noticeable pneumonia focus (Figure 2). APE induced by tocolysis with nicardipine was diagnosed. The patient was treated with diuretics (furosemide Lasilix, 40 mg PO) and oxygen therapy. Tocolytic treatment was replaced by suppository salbutamol associated with phloroglucinol (Spasfon). The diuretic-induced water and sodium depletion (diuresis of 1,460 mL within 12 h) allowed for a clear improvement of ventilation: polypnea and crepitant rales in the lung disappeared. Under nasal oxygen therapy at 3 L/min, the patient was eupneic with an improved hematosis (PaO2 = 187 mmHg). She was discharged from the ICU at D2 still under furosemide 20 mg/day. She gave birth at 35 weeks of amenorrhea + 7 days by vaginal delivery and underwent at 4 months a control TTE that was normal.\n\n2.4. Case 4\nA 35-year-old patient, primipara, presented with a single pregnancy after in vitro fertilization due to altered tubes. She had a history of smoking, which was weaned, substituted hypothyroidism, and a previous in vitro fertilization which resulted in an ectopic pregnancy. She was hospitalized in a level 1 maternity for premature labor occurring at 34 weeks of amenorrhea. She received nicardipine (Loxen) which she tolerated well (IV with an automatic syringe at 4 mg/h), associated with suppository salbutamol. Betamethasone was administered (Celestene, two IM injections of 12 mg 24 h apart) for fetal lung maturation. Forty-eight hours after nicardipine administration, the patient suddenly exhibited dyspnea associated with a sensation of thoracic oppression and dry cough with apyrexia. Arterial blood gas disclosed a “shunt” effect (PaO2 = 69 mmHg and PaCO2 = 27 mmHg). As pulmonary embolism was suspected, a treatment with heparin IV with an automatic syringe, preceded by a bolus, was initiated. The patient was then transferred to the emergency department without relevant complication. Under nicardipine, patient hemodynamics was stable so the treatment was stopped. The patient was apyretic. Regarding ventilation, the patient was eupneic under high flow oxygen therapy (saturation at 100% under 15 L/min in a NRB mask). Arterial blood gas disclosed a compensated metabolic acidosis (pH = 7.42, PaCO2 = 29.7 mmHg, bicarbonates = 19.3 mmol/L, and base excess = −4.3 mmol/L) with an impaired hematosis (PaO2 at 107 mmHg under 15 L/min oxygen). Anemia at 10.3 g/dL and hyperlactatemia at 3.16 mmol/L were also noticed. The ECG presented a regular sinus rhythm without any relevant disorder. Chest X-ray evidenced bilateral diffuse infiltrative lesions. TTE showed normal size of the LV with a LVEF estimated at 70%. The presence of a minimal mitral insufficiency was noticed and LV filling pressures were normal. SPAP was estimated at 19 + 10 mmHg. Pulmonary embolism diagnosis was ruled out thanks to a thoracic angioscan. It however disclosed a slight bilateral pleural effusion associated with large nonsystematized bilateral alveolar opacities (Figure 3). In light of the tests, APE induced by nicardipine was diagnosed and the patient was transferred to the ICU. Thanks to a symptomatic treatment (oxygen therapy at 6 L/min in face mask) and diuretics (iterative bolus of furosemide for a total dose of 180 mg), the health of the patient rapidly improved. The 24 h diuresis equaled 4,210 mL which allowed for the water and sodium balance to become negative again (−2,928 mL). At discharge, patient was eupneic in ambient air but discrete crepitant rales persisted at both lung bases. She was discharged from the ICU at D2 still under furosemide 40 mg/day. After her delivery, the cardiologic assessment was strictly normal.\n\nPatients' characteristics are reported in Table 1.\n\n3. Discussion\nPremature labour diagnosis was defined in association with uterine contractions (regular and effective) and cervix changes occurring at 22 weeks of amenorrhea and 36 weeks of amenorrhea + 6 D. Without any medical intervention, they lead to premature delivery. All patients had undergone a vaginal palpation and a systematic cervical ultrasound. A 30-minute fetal monitoring was performed on admission and then once a day. Obstetric ultrasound was also performed. The occurrence of uterine contractions which are essential for the labor to begin is regulated by the increase of intracellular calcium concentration in myometrial cells. Calcium channel blockers (CCBs) from dihydropyridine family, that is, nicardipine (Loxen) and nifedipine (Adalat), fix themselves on α\n1c subunit of the L-type voltage-gated calcium channels. This way, they block the opening of the channel and prevent the calcium to enter into the cell which explains their tocolytic mechanism [1] (Figure 4). CCBs also inhibit the activating effect of some substances such as α\n1-adrenergic receptors, angiotensin II, and endothelin-1 that usually lead to the contraction of smooth muscle fibers [6]. These molecules are arterial vasodilators that decrease the afterload and lead to an increased cardiac flow [2, 10].\n\nAdverse effects linked to β\n2-adrenergic agonists, especially APE during pregnancy, resulted in the use of CCBs as tocolytic treatment [11, 12]. In obstetrics, the most studied molecule is nifedipine. Its tocolytic efficacy has been widely evidenced by several randomized trials [13–20]. Several meta-analyses confirm that it is equally efficient as β\n2-adrenergic agonists and better tolerated with a decrease in neonatal morbidity [10, 21–24]. These results have led to recommend the use of CCBs as tocolytics in the CNGOF (Collège National des Gynécologues et Obstétriciens Français) Clinical Practice Guidelines in 2002 [25]. Clinical studies on nicardipine are rare in the literature. But paradoxically, even if there is no scientific proof of its superiority, nicardipine is more used than nifedipine in French centers because of its IV administration [8]. A first open randomized prospective study by Jannet et al., conducted on 90 patients, compared nicardipine with IV salbutamol; it did not find any difference of tocolytic efficacy but it did find less adverse effects in nicardipine group [26]. Recently, a prospective randomized study conducted on 48 patients with the same molecules confirmed the equal efficacy with a statistically significant difference regarding the adverse effects in favor of nicardipine (8% for nicardipine versus 47% for salbutamol, P = 0.02) [27].\n\nCCBs thus appear as preferred tocolytics with a better tolerance than the β\n2-adrenergic agonists even if they do not have a marketing authorization [28]. Since they have been used for this indication, minor adverse effects have progressively been described: tachycardia, low blood pressure, palpitations, flushes, headaches, constipation, nausea, and dizziness linked with the vasodilator effect [2].\n\nAPE during pregnancy occurs in 0.08–0.5% of the cases regardless of the etiology [29]. Out of 900 patients with a tocolytic indication, nicardipine was used in 742 patients between January 2009 and December 2013 in our hospital (55 births a week). We report here 4 cases of APE in patients who needed to be transferred in ICU regarding the severity of their condition. The incidence of this complication remains low which confirms already published data [30]. In our series, only one patient gave birth to twins whereas most cases in the literature report twin pregnancies [30–33]. No patient had cardiovascular history. The mean time of APE occurrence is 63 hours after nicardipine therapy initiation (Table 1). This mean time is comparable with the published case reports [30–34]. The initial symptoms are not very specific, dyspnea and oxygen desaturation for all cases. Dry cough, signs of acute respiratory distress, thoracic oppression, and palpitations are also found. 50% of our patients had tachycardia. Pulmonary examination disclosed crepitant rales in 50% of cases (Cases 1 and 3). Characteristic crepitant rales can be absent at the beginning but the diagnostic must not be ruled out as they can appear later.\n\nFor all 4 patients, the first diagnosis mentioned was pulmonary embolism. One patient even received a heparin bolus with a prescription of heparin at efficient continuous IV doses before she underwent a thoracic angioscan. The normal ECG and troponin rate, when it is performed (50% of cases), rapidly rule out an ischemic origin (Table 1). To our knowledge, only one case of myocardial infarction during tocolytic treatment with nifedipine has been reported in the literature [35]. Laboratory tests revealed an increased BNP each time it was measured (3/4) but a normal result should not rule out the diagnosis as a false negative is possible in case of “flash” APE [36]. Despite the guidelines for pregnant women of the European Society of Cardiology, D-dimer assay which is usually very frequent was not performed in our patients [37]. If a negative result had been obtained, it could have prevented a useless thoracic angioscan. Chest X-ray contributed to APE diagnosis in each case. Regarding echocardiography data, all patients have a maintained LV systolic function. 50% of cases have increased LV filling pressures, and pulmonary hypertension is noted in 75% of cases (Table 1). Tocolytic treatment modalities are reported in Table 2.\n\nThe patients receive high doses of nicardipine. However, water and sodium intake linked to nicardipine remains low: a 0.5 mg/mL dilution is used. The maximal volume received equals 1,150 mL over 4 days for the patient who received the highest cumulative dose of nicardipine. In Vaast and Janower series, physiologic saline solution intake due to nicardipine administration reached 1500 mL per day during 4 days [31, 34]. It is always difficult to calculate a precise water balance outside the ICU so we cannot confirm that none of our patients presented blood volume overload out of the nicardipine intake. Our patients presented associated risk factors; a half received tocolytics associated with salbutamol and had a concomitant obstetrical disease; all received a fetal lung maturation corticotherapy which favors sodium and water retention (Table 2). Other published case reports on nicardipine-induced APE are reported in Table 3. APE occurring during a tocolytic treatment with nifedipine or atosiban seem rather rare [38–40].\n\nThe pathophysiology of APE during tocolytic treatment with nicardipine is still unclear. The mechanism of action of CCBs does not interact with the determining factors usually at the origin of APE. Maternal physiological adaptation during pregnancy makes the women prone to sodium and water retention. Pregnancy also induces an increase of cardiac flow due to heart rate and systolic ejection volume increase [41]. CCBs from the dihydropyridine family have cardiovascular effects that maximize these physiological adaptations. Their antihypertension action induces a reflex sympathetic stimulation which causes an increase of tachycardia in pregnant women [42, 43]. Nicardipine-induced APE could be an APE due to altered diastolic compliance [44, 45]. Moreover, the sympathetic stimulation activates the renin-angiotensin-aldosterone system which increases sodium and water retention. Finally, in obstetrics, other risk factors are clearly identified: multiple pregnancy, spontaneous premature labor, tocolytic association, fetal lung maturation corticotherapy, preeclampsia or HELLP syndrome, overhydration with physiologic saline solution, valvular heart diseases, and finally infectious environment especially chorioamnionitis [2, 30].\n\nTreatment of nicardipine-induced APE includes discontinuation of the involved medication and a symptomatic treatment associating oxygen therapy with diuretics. With an adapted treatment, the condition improved quickly in our 4 cases; this is comparable to the other cases described in the literature. Some authors suggested using noninvasive ventilation in case of severe hypoxemia in order to postpone orotracheal intubation [46, 47].\n\n4. Conclusion\nNicardipine used as tocolytic is more and more frequent in France even if its prescription does not have a marketing authorization. Our series agrees with the 17 cases that have been published since 2004. However pathophysiological mechanisms causing nicardipine-induced APE are still unclear. In the literature, the main reported risk factors for nicardipine-induced APE are spontaneous premature labor, multiple pregnancy, cardiovascular history, concomitant obstetrical disease, in association with other tocolytics, and fetal lung maturation corticotherapy. This complication remains rare but it is advised to use with caution IV nicardipine as a tocolytic in patients with APE risk factors and to avoid association with β\n2-adrenergic agonists. A better knowledge of this serious adverse event should allow for an improvement of the diagnostic and therapeutic management in order to avoid useless or even dangerous examination or treatments. Other tocolytics can be used instead such as nifedipine or oxytocin antagonists [48].\n\nAcknowledgment\nThe authors thank Sarah Demai (CIC 1435) for her help in the preparation of the paper.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Chest X-ray face-on in prone position (Case 2).\n\nFigure 2 Chest X-ray face-on in prone position (Case 3).\n\nFigure 3 Thoracic angioscan (Case 4).\n\nFigure 4 Mode of action of calcium channel blockers.\n\nTable 1 Clinical and paraclinical characteristics in our series.\n\n \tAge\tTerm\tPregnancy\tECG\tBNP\n(ng/L)\tTroponin\tTTE\nLVEG\tTTE\nLVFP\tTTE\nPH\tN-APE\ntime\t\nCase 1\t31\t33 WA + 1 d\tG1P0\tN\t2474\tND\t70%\t↑\tYes\t60 h\t\nCase 2\t28\t26 WA + 1 d\tG3P1, TwP\tN\t3686\tND\t>60%\t↑\tYes\t24 h\t\nCase 3\t28\t29 WA + 5 d\tG2P0\tN\t660\tN\tN\tN\tYes\t≈96 h\t\nCase 4\t35\t34 WA\tG2P0, IVF\tN\tND\tN\t70%\tN\tNo\t≈72 h\t\nWA: weeks of amenorrhea; ECG: electrocardiography; TTE: thoracic echocardiography; LVEG: LV ejection fraction; LVFP: LV filling pressures; PH: pulmonary hypertension; N-APE time: time between treatment initiation and acute pulmonary edema occurrence; TwP: twin pregnancy; IVF: in vitro fertilization; N: normal; ND: not done.\n\nTable 2 Tocolytic treatment modalities and APE risk factors.\n\n \tMax flow N (mg/h)\tTotal dose (mg)\tSalbutamol associated\tCorticoT\tTachycardia\tOther RFs associated\t\nCase 1 \t3.5\t162\tNo\tYes\tNo\tPreeclampsia\t\nCase 2\t4\t96\tYes \tYes\tYes\tChorioamnionitis, TwP\t\nCase 3\t6\t576\tNo\tYes\tYes\tNo\t\nCase 4\t4\t288\tYes \tYes\tNo\tSmoking\t\nN: nicardipine; CorticoT: corticotherapy; RF: risk factors; TwP: twin pregnancy.\n\nTable 3 Published case reports on APE occurring during a tocolytic treatment with nicardipine. \n\nAuthors\t\nN\n\tPremature labor term\tNicardipine maximal flow rate\tAssociated treatments\tPatients characteristics\t\n\nVaast et al. [31]\t5 cases\t29.2 WA (mean)\t6 mg/h\tIM corticosteroids\t2 TwP, 1 TrP, GDM, and cardiovascular history\t\n\nBal et al. [49]\t1 case\t27 WA\t2 mg/h\tIM corticosteroids\tNo history\t\n\nChapuis et al. [32]\t1 case\t30 WA + 2 days\t2.2 mg/h\tIM corticosteroids and IV salbutamol\tTwP and 2 abortions\t\n\nJanower et al. [34]\t3 cases\t29 WA (mean)\t4 mg/h\tIM corticosteroids and IV salbutamol\tGDM\t\n\nPhilippe et al. [33]\t3 cases\t31 WA (mean)\tMD\tIM corticosteroids and IV atosiban\tSmoking and 1 TwP\t\n\nAkerman et al. [30]\t4 cases\t29 WA (mean)\tMD\tIM corticosteroids, sup. salbutamol, and IV atosiban\t3 TwP and IDD\t\n\nN: number of cases; WA: weeks of amenorrhea; IM: intramuscular; IV: intravenous; TwP: twin pregnancy; TrP: triplet pregnancy; MD: missing data; GDM: gestational diabetes mellitus; sup.: suppository; IDD: insulin dependent diabetes.\n==== Refs\n1 Gáspár R Hajagos-Tóth J Calcium channel blockers as tocolytics: principles of their actions, adverse effects and therapeutic combinations Pharmaceuticals 2013 6 6 689 699 24276256 \n2 Oei SG Calcium channel blockers for tocolysis: a review of their role and safety following reports of serious adverse events European Journal of Obstetrics Gynecology and Reproductive Biology 2006 126 2 137 145 2-s2.0-33646814762 \n3 Savitz DA Blackmore CA Thorp JM Epidemiologic characteristics of preterm delivery: etiologic heterogeneity American Journal of Obstetrics and Gynecology 1991 164 2 467 471 2-s2.0-0026011964 1992685 \n4 Clesham GJ Scott J Oakley CM \nβ Adrenergic agonists and pulmonary oedema in preterm labour British Medical Journal 1994 308 6923 260 262 2-s2.0-0028217265 8111264 \n5 Samet A Bayoumeu F Longrois D Laxenaire MC Acute pulmonary edema associated with the use of beta2-mimetic tocolytic agents Annales Françaises d'Anesthésie et de Réanimation 2000 19 35 38 \n6 Tsatsaris V Carbonne B Tocolysis with calcium-channel-blockers Journal de Gynécologie Obstétrique et Biologie de la Reproduction 2001 30 246 251 \n7 Vayssière C Special management for threatened preterm delivery in multiple pregnancies Journal de Gynécologie Obstétrique et Biologie de la Reproduction 2002 31 5 S114 S123 \n8 Tsatsaris V Goffinet F Carbonne B Abitayeh G Cabrol D Tocolysis by first intention with nifedipine Gynecologie Obstetrique Fertilite 2005 33 4 263 265 2-s2.0-19344365970 \n9 Bekkari Y Lucas J Beillat T Chéret A Dreyfus M Tocolysis with nifedipine: its use in current practice Gynécologie Obstétrique & Fertilité 2005 33 7-8 483 487 2-s2.0-22844443131 \n10 Tsatsaris V Papatsonis D Goffinet F Dekker G Carbonne B Tocolysis with nifedipine or beta-adrenergic agonists: a meta-analysis Obstetrics and Gynecology 2001 97 5 840 847 2-s2.0-0035047436 11336775 \n11 de La Chapelle A Benoit S Bouregba M Durand-Reville M Raucoules-Aimé M The treatment of severe pulmonary edema induced by beta adrenergic agonist tocolytic therapy with continuous positive airway pressure delivered by face mask Anesthesia & Analgesia 2002 94 6 1593 1594 2-s2.0-0036264842 12032034 \n12 Pisani RJ Rosenow EC III Pulmonary edema associated with tocolytic therapy Annals of Internal Medicine 1989 110 9 714 718 2-s2.0-0024519859 2648928 \n13 Ferguson JE II Dyson DC Schutz T Stevenson DK A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome American Journal of Obstetrics and Gynecology 1990 163 1 105 111 2-s2.0-0025079381 2197860 \n14 Meyer WR Randall HW Graves WL Nifedipine versus ritodrine for suppressing preterm labor Journal of Reproductive Medicine for the Obstetrician and Gynecologist 1990 35 6 649 653 2-s2.0-0025323064 2359062 \n15 Bracero LA Leikin E Kirshenbaum N Tejani N Comparison of nifedipine and ritodrine for the treatment of preterm labor The American Journal of Perinatology 1991 8 6 365 369 2-s2.0-0026040798 1814297 \n16 Kupferminc M Lessing JB Yaron Y Peyser MR Nifedipine versus ritodrine for suppression of preterm labour British Journal of Obstetrics and Gynaecology 1993 100 12 1090 1094 2-s2.0-0027138152 8297841 \n17 Smith CS Woodland MB Clinical comparison of oral nifedipine and subcutaneous terbutaline for initial tocolysis The American Journal of Perinatology 1993 10 4 280 284 2-s2.0-0027218801 8397562 \n18 Papatsonis DNM van Geijn HP Adèr HJ Lange FM Bleker OP Dekker GA Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial Obstetrics and Gynecology 1997 90 2 230 234 2-s2.0-0030857517 9241299 \n19 García-Velasco JA González González A A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor Journal of the International Federation of Gynaecology and Obstetrics International Federation of Gynaecology and Obstetrics 1998 61 239 244 \n20 Koks CA Brölmann HA de Kleine MJ Manger PA A randomized comparison of nifedipine and ritodrine for suppression of preterm labor European Journal of Obstetrics & Gynecology and Reproductive Biology 1998 77 171 176 9578274 \n21 Oei SG Mol BWJ De Kleine MJK Brölmann HAM Nifedipine versus ritodrine for suppression of preterm labor: a meta-analysis Acta Obstetricia et Gynecologica Scandinavica 1999 78 9 783 788 2-s2.0-0032863020 10535341 \n22 King JF Flenady VJ Papatsonis DN Dekker GA Carbonne B Calcium channel blockers for inhibiting preterm labour Cochrane Database of Systematic Reviews 2003 1 CD002255 2-s2.0-18344399202 \n23 Conde-Agudelo A Romero R Kusanovic JP Nifedipine in the management of preterm labor: a systematic review and metaanalysis American Journal of Obstetrics and Gynecology 2011 204 2 134.e1 134.e20 2-s2.0-79551490993 21284967 \n24 Haas DM Caldwell DM Kirkpatrick P McIntosh JJ Welton NJ Tocolytic therapy for preterm delivery: systematic review and network meta-analysis The British Medical Journal 2012 345 7879 e6226 2-s2.0-84867774233 \n25 Carbonne B Tsatsaris V Which tocolytic drugs in case of preterm labor? Journal de Gynécologie Obstétrique et Biologie de la Reproduction 2002 31 5S96 5S104 \n26 Jannet D Abankwa A Guyard B Carbonne B Marpeau L Milliez J Nicardipine versus salbutamol in the treatment of premature labor. A prospective randomized study European Journal of Obstetrics Gynecology and Reproductive Biology 1997 73 1 11 16 2-s2.0-0030945667 \n27 Trabelsi K Taib HH Amouri H Nicardipine versus salbutamol in the treatment of premature labor: comparison of their efficacy and side effects Tunisie Medicale 2008 86 1 43 48 2-s2.0-67649216400 19472699 \n28 Rozenberg P Licensed or non-licensed tocolysis? Gynécologie, Obstétrique & Fertilité 2005 33 4 p. 259 \n29 Sciscione AC Ivester T Largoza M Manley J Shlossman P Colmorgen GHC Acute pulmonary edema in pregnancy Obstetrics and Gynecology 2003 101 3 511 515 2-s2.0-0037335410 12636955 \n30 Akerman G Mignon A Tsatsaris V Jacqmin S Cabrol D Goffinet F Pulmonary edema during calcium-channel blockers therapy: Role of predisposing or pharmacologic factors? Journal de Gynecologie Obstetrique et Biologie de la Reproduction 2007 36 4 389 392 2-s2.0-34249328106 \n31 Vaast P Dubreucq-Fossaert S Houfflin-Debarge V Acute pulmonary oedema during nicardipine therapy for premature labour; report of five cases European Journal of Obstetrics & Gynecology and Reproductive Biology 2004 113 1 98 99 15036720 \n32 Chapuis C Menthonnex E Debaty G Acute pulmonary edema during nicardipine and salbutamol therapy for preterm labor in twin pregnancy Journal de Gynecologie Obstetrique et Biologie de la Reproduction 2005 34 5 493 496 2-s2.0-24144439825 \n33 Philippe H-J Le Trong A Pigeau H Acute pulmonary edema occurred during tocolytic treatment using nicardipine in a twin pregnancy. Report of three cases Journal de Gynécologie Obstétrique et Biologie de la Reproduction 2009 38 1 89 93 2-s2.0-58349089150 \n34 Janower S Carbonne B Lejeune V Apfelbaum D Boccara F Cohen A Acute pulmonary edema during preterm labor: Role of nicardipine tocolysis (three cases) Journal de Gynecologie Obstetrique et Biologie de la Reproduction 2005 34 8 807 812 2-s2.0-29444457703 \n35 Oei SG Oei SK Brölmann HA Myocardial infarction during nifedipine therapy for preterm labor The New England Journal of Medicine 1999 340 2 p. 154 2-s2.0-0033552875 \n36 Mueller C Scholer A Laule-Kilian K Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea The New England Journal of Medicine 2004 350 7 647 654 2-s2.0-1442265589 14960741 \n37 Torbicki A Perrier A Konstantinides S Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC) European Heart Journal 2008 29 18 2276 2315 18757870 \n38 Abbas OM Nassar AH Kanj NA Usta IM Acute pulmonary edema during tocolytic therapy with nifedipine The American Journal of Obstetrics and Gynecology 2006 195 4 e3 e4 2-s2.0-33748792050 \n39 Kutuk MS Ozgun MT Uludag S Dolanbay M Yildirim A Acute pulmonary failure due to pulmonary edema during tocolytic therapy with nifedipine Archives of Gynecology and Obstetrics 2013 288 4 953 954 2-s2.0-84875186965 23525630 \n40 Seinen LHM Simons SO van der Drift MA van Dillen J Vandenbussche FPHA Lotgering FK Maternal pulmonary oedema due to the use of atosiban in cases of multiple gestation Nederlands Tijdschrift voor Geneeskunde 2013 157 1 A5316 2-s2.0-84874419978 \n41 Hunter S Robson SC Adaptation of the maternal heart in pregnancy British Heart Journal 1992 68 6 540 543 2-s2.0-0026719380 1467047 \n42 Abernethy DR Schwartz JB Calcium-antagonist drugs The New England Journal of Medicine 1999 341 19 1447 1457 2-s2.0-0033523858 10547409 \n43 Triggle DJ Calcium, calcium channels, and calcium channel antagonists Canadian Journal of Physiology and Pharmacology 1990 68 11 1474 1481 2-s2.0-0025651088 1962736 \n44 Ware LB Matthay MA Acute pulmonary edema The New England Journal of Medicine 2005 353 26 2788 2796 2-s2.0-29544447206 16382065 \n45 Jessup M Brozena S Medical progress: heart failure The New England Journal of Medicine 2003 348 20 2007 2018 2-s2.0-0037883399 12748317 \n46 Perbet S Constantin J Bolandard F Non-invasive ventilation for pulmonary edema associated with tocolytic agents during labour for a twin pregnancy Canadian Journal of Anesthesia 2008 55 11 769 773 2-s2.0-56049108401 19138917 \n47 Fujita N Tachibana K Takeuchi M Kinouchi K Successful perioperative use of noninvasive positive pressure ventilation in a pregnant woman with acute pulmonary edema Masui 2014 63 557 560 24864580 \n48 Royal College of Obstetricians and Gynaecologists Tocolytic Drugs for the Women in Preterm Labour. Clinical Guideline No. 1(B) 2002 \n49 Bal L Thierry S Brocas E Adam M van de Louw A Tenaillon A Pulmonary edema induced by calcium-channel blockade for tocolysis Anesthesia and Analgesia 2004 99 3 910 911 2-s2.0-4143054898 15333430\n\n",
"fulltext_license": "CC BY",
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"issue": "2014()",
"journal": "Case reports in critical care",
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"pages": "242703",
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"pmid": "25215245",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "2648928;16319773;15894213;15333430;18757870;11398000;24276256;12535434;16567033;2197860;18954944;16382065;12454631;23298725;10751953;19472699;1992685;1962736;12454633;10535341;17446008;23048010;9241299;2359062;8297841;19138917;15894215;9688484;12032034;9917222;15036720;16846586;10547409;16005668;9175683;16142141;12748317;14960741;1467047;9578274;11336775;8111264;1814297;12636955;24864580;21284967;8397562;23525630",
"title": "Nicardipine-induced acute pulmonary edema: a rare but severe complication of tocolysis.",
"title_normalized": "nicardipine induced acute pulmonary edema a rare but severe complication of tocolysis"
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"abstract": "BACKGROUND\nPancreatic ductal adenocarcinoma (PDA) has a very poor prognosis. Treatment with FOLFIRINOX has been shown to improve outcomes, but can be associated with significant toxicity.\n\n\nMETHODS\nA retrospective review was performed of all patients with locally advanced or metastatic PDA treated with FOLFIRINOX at the Royal Marsden between November 2010 and November 2013. Efficacy, tolerability, and potential prognostic factors were evaluated.\n\n\nRESULTS\nTwenty-seven patients with metastatic PDA and 22 patients with locally advanced PDA were treated with FOLFIRINOX. Patients received a median of 9 cycles (range, 1-26) of FOLFIRINOX. The overall response rate was 41% (20 patients), and a further 17 patients (35%) had stable disease. Thirty-five patients (71%) received FOLFIRINOX in the first-line setting, with a median progression-free survival and overall survival, respectively, of 12.9 months and 18.4 months for patients with locally advanced disease; and 8.4 months and 12.2 months for patients with metastatic disease. The most frequently occurring Grade 3/4 toxicities were neutropenia (29%), fatigue (18%), febrile neutropenia (14%), thromboembolism (12%), and thrombocytopenia (10%). In a univariate analysis, reduction in CA 19-9 of >50% (P < .001), normalization of CA19-9 (P < .001), surgery after FOLFIRINOX (P = .004), and use of prophylactic pegfilgrastim (P = .005) were prognostic for overall survival.\n\n\nCONCLUSIONS\nThe efficacy and tolerability of FOLFIRINOX for PDA at our institution is similar to that reported in clinical trials. Careful selection of patients and monitoring of response (according to CA19-9) and toxicities can help maximize advantage in this patient population.",
"affiliations": "Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Surrey, United Kingdom.;Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Surrey, United Kingdom.;Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Surrey, United Kingdom.;Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Surrey, United Kingdom.;Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Surrey, United Kingdom.;Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Surrey, United Kingdom.;Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Surrey, United Kingdom. Electronic address: ian.chau@rmh.nhs.uk.",
"authors": "Moorcraft|Sing Yu|SY|;Khan|Khurum|K|;Peckitt|Clare|C|;Watkins|David|D|;Rao|Sheela|S|;Cunningham|David|D|;Chau|Ian|I|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "United States",
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"issn_linking": "1533-0028",
"issue": "13(4)",
"journal": "Clinical colorectal cancer",
"keywords": "CA 19-9; Granulocyte-colony stimulating factor; Nab-paclitaxel; Response; Toxicity",
"medline_ta": "Clin Colorectal Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D021441:Carcinoma, Pancreatic Ductal; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "101120693",
"other_id": null,
"pages": "232-8",
"pmc": null,
"pmid": "25442814",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "FOLFIRINOX for locally advanced or metastatic pancreatic ductal adenocarcinoma: the Royal Marsden experience.",
"title_normalized": "folfirinox for locally advanced or metastatic pancreatic ductal adenocarcinoma the royal marsden experience"
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"companynumb": "GB-TEVA-547848ISR",
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"abstract": "A 60-year-old atopic female was admitted for investigation of progressive neurological deficits involving her left hand, arm, and shoulder. A computed tomography scan demonstrated a right parietal lesion of her brain, which was removed. Increasing intracranial pressure necessitated the administration of mannitol 20% 250 ml. The patient stated she had a \"tightness\" in her chest during the mannitol administration. Five days later, rises in intracranial pressure again necessitated the infusion of mannitol 20% 150 ml. After 100 ml of the solution had been infused, the patient experienced mild respiratory distress, cyanosed lips, and hives of her abdomen. Supportive therapy, including aminophylline and diphenhydramine administration, abated her distress. Anaphylaxis to mannitol administration has only been reported twice previously, despite mannitol's widespread use. Physicians and pharmacists should be aware that severe hypersensitivity reactions may occur, especially in patients with a history of atopy.",
"affiliations": null,
"authors": "McNeill|I Y|IY|",
"chemical_list": "D008353:Mannitol",
"country": "United States",
"delete": false,
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"issue": "19(7-8)",
"journal": "Drug intelligence & clinical pharmacy",
"keywords": null,
"medline_ta": "Drug Intell Clin Pharm",
"mesh_terms": "D004342:Drug Hypersensitivity; D005260:Female; D005909:Glioblastoma; D006801:Humans; D007427:Intracranial Pressure; D008353:Mannitol; D008875:Middle Aged",
"nlm_unique_id": "0212457",
"other_id": null,
"pages": "552-3",
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"pubdate": "1985",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypersensitivity reaction to mannitol.",
"title_normalized": "hypersensitivity reaction to mannitol"
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"activesubstancename": "MANNITOL"
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... |
{
"abstract": "While neuroleptic malignant syndrome (NMS) is typically characterised by delirium, motor rigidity, fever and dysautonomia, the syndrome is not pathognomonic, and NMS remains a diagnosis of exclusion. Here, we describe the case of a 44-year-old woman, with no relevant psychiatric history, admitted to a nephrology unit due to acute renal failure. After administration of antipsychotics, she presented with mental status alteration, generalised tremor, rigidity and autonomic nervous system dysfunction. Fever and rhabdomyolysis, however, were not prominent, and NMS was not considered initially in the differential diagnosis. The resulting delay in diagnosis, with continued administration of antipsychotics, led to progressive clinical deterioration. Once NMS was considered, however, antipsychotics were withdrawn and the patient was treated with electroconvulsive therapy (ECT), followed by administration of a dopamine receptor agonist, with close to full remission of all symptoms. Importantly, during outpatient follow-up, sustained mild and asymmetric tremor and rigidity was noted, leading to a diagnosis of Parkinson's disease. While this raises questions regarding differential diagnosis between NMS in Parkinson's disease, versus worsening of Parkinson's disease due to antipsychotic treatment, the former is supported by the acute and rapidly progressive onset of exuberant autonomic dysfunction and clouded conscience, after administration of a neuroleptic. Ultimately, a definitive distinction between these two alternatives for diagnosis of the inaugural neurological presentation in this patient is not possible. Nevertheless, we believe this case illustrates that NMS can be easily missed, particularly in atypical cases, delaying appropriate treatment, and that a flexible multimodal treatment approach, involving ECT, should be considered for complex clinical cases. Furthermore, it also underlines the importance of post-NMS follow-up, to investigate underlying neurological or medical disorders, particularly in those patients who do not have a full recovery.",
"affiliations": "Department of Psychiatry and Mental Health, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.;Department of Psychiatry and Mental Health, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.;Department of Psychiatry and Mental Health, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.;Department of Psychiatry and Mental Health, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.",
"authors": "Velosa|Ana|A|;Neves|António|A|;Barahona-Corrêa|J Bernardo|JB|;Oliveira-Maia|Albino J|AJ|",
"chemical_list": "D000927:Anticonvulsants; D014150:Antipsychotic Agents; D001971:Bromocriptine; D008140:Lorazepam",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225840",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(6)",
"journal": "BMJ case reports",
"keywords": "drugs: psychiatry; psychiatry (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000927:Anticonvulsants; D014150:Antipsychotic Agents; D001971:Bromocriptine; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008140:Lorazepam; D008297:Male; D009459:Neuroleptic Malignant Syndrome; D006435:Renal Dialysis; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31213433",
"pubdate": "2019-06-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10078727;16199797;8093494;15817019;18472502;2673115;28027111;22193353;3605730;8686483;28144147;27504054;23983836;26512569;24778709;10928001;24864649;10544988;28811916;7334388;25438028",
"title": "Neuroleptic malignant syndrome: a concealed diagnosis with multitreatment approach.",
"title_normalized": "neuroleptic malignant syndrome a concealed diagnosis with multitreatment approach"
} | [
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"companynumb": "PT-JNJFOC-20190720803",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
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"actiondrug": "1",
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"activesubstancename": "HALOPERIDOL"
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"drugadditional": "1",
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{
"abstract": "BACKGROUND\nPatients with solid cancers and hematopoietic malignancy can experience systemic symptoms compatible with adult-onset Still's disease (AOSD). The newly described VEXAS, associated with somatic UBA1 mutations, exhibits an overlap of clinical and/or biological pictures with auto inflammatory signs and myelodysplastic syndrome (MDS).\n\n\nOBJECTIVE\nTo describe a cohort of patients with signs of undifferentiated systemic autoinflammatory disorder (USAID) concordant with AOSD and MDS/chronic myelomonocytic leukemia (CMML) and the prevalence of VEXAS proposed management and outcome.\n\n\nMETHODS\nA French multicenter retrospective study from the MINHEMON study group also used for other published works with the support of multidisciplinary and complementary networks of physicians and a control group of 104 MDS/CMML.\n\n\nRESULTS\nTwenty-six patients were included with a median age at first signs of USAID of 70.5 years with male predominance (4:1). Five patients met the criteria for confirmed AOSD. The most frequent subtypes were MDS with a blast excess (31%) and MDS with multilineage dysplasia (18%). Seven patients presented with acute myeloid leukemia and twelve died during a median follow-up of 2.5 years. Six out of 18 tested patients displayed a somatic UBA1 mutation concordant with VEXAS, including one woman. High-dose corticosteroids led to a response in 13/16 cases and targeted biological therapy alone or in association in 10/12 patients (anakinra, tocilizumab, and infliximab). Azacytidine resulted in complete or partial response in systemic symptoms for 10/12 (83%) patients including 3 VEXAS.\n\n\nCONCLUSIONS\nSystemic form of VEXAS syndrome can mimic AOSD. The suspicion of USAID or AOSD in older males with atypia should prompt an evaluation of underlying MDS and assessment of somatic UBA1 mutation.",
"affiliations": "Service de Médecine Interne, Centre de Référence des Maladies Autoinflammatoires et des Amyloses (CEREMAIA), AP-HP, Hôpital Tenon, Sorbonne Université, 75020 Paris, France.;Service de Médecine Interne, CHU de Caen, Hôpital de la Côte de Nacre, 14033 Caen, France.;Service d'Hématologie Biologique, INSERM, Centre de Recherche Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Sorbonne Université, 75012 Paris, France.;Service d'Hématologie Seniors, AP-HP, Hôpital Saint-Louis, 75010 Paris, France.;Service de Médecine Interne, Centre Hospitalier Georges Charpak, 44600 Saint Nazaire, France.;Service d'Hématologie Biologique, INSERM, Centre de Recherche Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Sorbonne Université, 75012 Paris, France.;Service d'Hématologie, AP-HP, Hôpital Pitié Salpêtrière, 75013 Paris, France.;Service de Médecine Interne, Centre Hospitalier Marc Jacquet, 77000 Melun, France.;Service d'Hématologie Biologique, INSERM, Centre de Recherche Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Sorbonne Université, 75012 Paris, France.;Department of Hematology and Transfusion Medicine, National Institute of Health, Yerevan 0051, Armenia.;Service de Médecine Interne, Hôpital Foch, 92150 Suresnes, France.;Service de Médecine Interne, CHU Hôpital Henri Mondor, 94000 Créteil, France.;Service de Médecine Interne, CHRU Jean Minjoz, 25000 Besançon, France.;Service de Médecine Interne, CHU de Caen, Hôpital de la Côte de Nacre, 14033 Caen, France.;Laboratoire de Génétique CHU de Caen, Hôpital de la Côte de Nacre, 14000 Care, France.;Service de Médecine Interne, CHU Hôpital Charles Nicolle, 76000 Rouen, France.;Service de Médecine Interne, CH de Valenciennes, 59300 Valenciennes, France.;Service d'Hématologie Adultes, AP-HP, Hôpital Necker-Enfants Malades, 75015 Paris, France.;Service de Médecine Interne, CHU Hôpital Purpan, 31059 Toulouse, France.;Service d'Hématologie Seniors, AP-HP, Hôpital Saint-Louis, 75010 Paris, France.;Service de Médecine Interne, CHR Lille, Sorbonne Université, 75005 Paris, France.;Department of Hematology and Transfusion Medicine, National Institute of Health, Yerevan 0051, Armenia.;Department of Hematology and Transfusion Medicine, National Institute of Health, Yerevan 0051, Armenia.;Service de Médecine Interne, Centre de Référence des Maladies Autoinflammatoires et des Amyloses (CEREMAIA), AP-HP, Hôpital Tenon, Sorbonne Université, 75020 Paris, France.;Service de Médecine Interne, AP-HP, Hôpital Saint Antoine, Sorbonne Université, 75012 Paris, France.",
"authors": "Delplanque|Marion|M|;Aouba|Achille|A|;Hirsch|Pierre|P|;Fenaux|Pierre|P|;Graveleau|Julie|J|;Malard|Florent|F|;Roos-Weil|Damien|D|;Belfeki|Nabil|N|;Drevon|Louis|L|;Oganesyan|Artem|A|0000-0003-1039-4835;Groh|Matthieu|M|;Mahévas|Matthieu|M|;Razanamahery|Jerome|J|;Maigne|Gwenola|G|;Décamp|Matthieu|M|;Miranda|Sébastien|S|;Quemeneur|Thomas|T|;Rossignol|Julien|J|;Sailler|Laurent|L|;Sébert|Marie|M|;Terriou|Louis|L|;Sevoyan|Anna|A|;Hakobyan|Yervand|Y|;Georgin-Lavialle|Sophie|S|;Mekinian|Arsène|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm10235586",
"fulltext": "\n==== Front\nJ Clin Med\nJ Clin Med\njcm\nJournal of Clinical Medicine\n2077-0383\nMDPI\n\n10.3390/jcm10235586\njcm-10-05586\nArticle\nUSAID Associated with Myeloid Neoplasm and VEXAS Syndrome: Two Differential Diagnoses of Suspected Adult Onset Still’s Disease in Elderly Patients\nDelplanque Marion 1\nAouba Achille 2\nHirsch Pierre 3\nFenaux Pierre 4\nGraveleau Julie 5\nMalard Florent 3\nRoos-Weil Damien 6\nBelfeki Nabil 7\nDrevon Louis 3\nhttps://orcid.org/0000-0003-1039-4835\nOganesyan Artem 8\nGroh Matthieu 9\nMahévas Matthieu 10\nRazanamahery Jerome 11\nMaigne Gwenola 2\nDécamp Matthieu 12\nMiranda Sébastien 13\nQuemeneur Thomas 14\nRossignol Julien 15\nSailler Laurent 16\nSébert Marie 4\nTerriou Louis 17\nSevoyan Anna 8\nHakobyan Yervand 8\nGeorgin-Lavialle Sophie 1†\nMekinian Arsène 18*†‡on behalf of MINHEMON and CEREMAIA\n\nYvan Jamilloux Academic Editor\nGerfaud-Valentin Mathieu Academic Editor\n1 Service de Médecine Interne, Centre de Référence des Maladies Autoinflammatoires et des Amyloses (CEREMAIA), AP-HP, Hôpital Tenon, Sorbonne Université, 75020 Paris, France; marion.delplanque@outlook.com (M.D.); sophie.georgin-lavialle@aphp.fr (S.G.-L.)\n2 Service de Médecine Interne, CHU de Caen, Hôpital de la Côte de Nacre, 14033 Caen, France; aouba-a@chu-caen.fr (A.A.); maigne-g@chu-caen.fr (G.M.)\n3 Service d’Hématologie Biologique, INSERM, Centre de Recherche Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Sorbonne Université, 75012 Paris, France; pierre.hirsch@aphp.fr (P.H.); florent.malard@aphp.fr (F.M.); louis.drevon@aphp.fr (L.D.)\n4 Service d’Hématologie Seniors, AP-HP, Hôpital Saint-Louis, 75010 Paris, France; pierre.fenaux@aphp.fr (P.F.); marie.sebert@aphp.fr (M.S.)\n5 Service de Médecine Interne, Centre Hospitalier Georges Charpak, 44600 Saint Nazaire, France; julie.graveleau@chu-nantes.fr\n6 Service d’Hématologie, AP-HP, Hôpital Pitié Salpêtrière, 75013 Paris, France; damien.roos-weil@aphp.fr\n7 Service de Médecine Interne, Centre Hospitalier Marc Jacquet, 77000 Melun, France; nabil.belfeki@ghsif.fr\n8 Department of Hematology and Transfusion Medicine, National Institute of Health, Yerevan 0051, Armenia; a.t.oganesyan@gmail.com (A.O.); sevoyananna6@gmail.com (A.S.); yero75@yahoo.com (Y.H.)\n9 Service de Médecine Interne, Hôpital Foch, 92150 Suresnes, France; m.groh@hopital-foch.com\n10 Service de Médecine Interne, CHU Hôpital Henri Mondor, 94000 Créteil, France; matthieu.mahevas@aphp.fr\n11 Service de Médecine Interne, CHRU Jean Minjoz, 25000 Besançon, France; jerome.razanamahery@hotmail.fr\n12 Laboratoire de Génétique CHU de Caen, Hôpital de la Côte de Nacre, 14000 Care, France; decamp-m@chu-caen.fr\n13 Service de Médecine Interne, CHU Hôpital Charles Nicolle, 76000 Rouen, France; sebastien.miranda@chu-rouen.fr\n14 Service de Médecine Interne, CH de Valenciennes, 59300 Valenciennes, France; quemeneur-t@ch-valenciennes.fr\n15 Service d’Hématologie Adultes, AP-HP, Hôpital Necker-Enfants Malades, 75015 Paris, France; julien.rossignol@aphp.fr\n16 Service de Médecine Interne, CHU Hôpital Purpan, 31059 Toulouse, France; sailler.l@chu-toulouse.fr\n17 Service de Médecine Interne, CHR Lille, Sorbonne Université, 75005 Paris, France; louis.terriou@chru-lille.fr\n18 Service de Médecine Interne, AP-HP, Hôpital Saint Antoine, Sorbonne Université, 75012 Paris, France\n* Correspondence: arsene.mekinian@aphp.fr; Tel.: +33-1-49-28-23-92; Fax: +33-1-49-28-28-85\n† Both authors contributed equally (codirected the work).\n\n‡ Collaborators of CEREMAIA and MINHEMON who participate in this study are cited in the authors list.\n\n27 11 2021\n12 2021\n10 23 558630 9 2021\n23 11 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nBackground: Patients with solid cancers and hematopoietic malignancy can experience systemic symptoms compatible with adult-onset Still’s disease (AOSD). The newly described VEXAS, associated with somatic UBA1 mutations, exhibits an overlap of clinical and/or biological pictures with auto inflammatory signs and myelodysplastic syndrome (MDS). Objectives: To describe a cohort of patients with signs of undifferentiated systemic autoinflammatory disorder (USAID) concordant with AOSD and MDS/chronic myelomonocytic leukemia (CMML) and the prevalence of VEXAS proposed management and outcome. Methods: A French multicenter retrospective study from the MINHEMON study group also used for other published works with the support of multidisciplinary and complementary networks of physicians and a control group of 104 MDS/CMML. Results: Twenty-six patients were included with a median age at first signs of USAID of 70.5 years with male predominance (4:1). Five patients met the criteria for confirmed AOSD. The most frequent subtypes were MDS with a blast excess (31%) and MDS with multilineage dysplasia (18%). Seven patients presented with acute myeloid leukemia and twelve died during a median follow-up of 2.5 years. Six out of 18 tested patients displayed a somatic UBA1 mutation concordant with VEXAS, including one woman. High-dose corticosteroids led to a response in 13/16 cases and targeted biological therapy alone or in association in 10/12 patients (anakinra, tocilizumab, and infliximab). Azacytidine resulted in complete or partial response in systemic symptoms for 10/12 (83%) patients including 3 VEXAS. Conclusions: Systemic form of VEXAS syndrome can mimic AOSD. The suspicion of USAID or AOSD in older males with atypia should prompt an evaluation of underlying MDS and assessment of somatic UBA1 mutation.\n\nadult-onset Still’s disease\nmyelodysplastic syndrome\nSAID\nUSAID\nVEXAS\nazacytidine\n==== Body\npmc1. Introduction\n\nRecently, the concept of autoinflammatory disorders keep evolving and an increasing number of new monogenic diseases are identified but numerous autoinflammatory diseases are still to be characterized. Systemic autoinflammatory disorders (SAID) are unprovoked episodic or chronic sterile inflammation which are secondary to innate immune system dysregulation [1]. If well-characterized monogenic diseases such as familial Mediterranean fever are part of it, more than 50% patients presenting with clinical features resembling SAIDs still do not carry any of the know pathogenic mutations in autoinflammatory disease genes [2]. Some patients with SAID fit the criteria for polygenic forms of autoinflammatory diseases, such as adult-onset Still’s disease (AOSD); however, some of them do not. They are defined as undifferentiated systemic autoinflammatory disorders (USAID) [1,3].\n\nMyelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are part of a heterogeneous group of clonal hematopoietic stem cell diseases characterized by ineffective hematopoiesis, peripheral cytopenia with an increased risk of progression, to acute myeloid leukemia (AML) [4]. About 10 to 20% of MDS/CMML could be associated with various extra hematological features, e.g., neutrophilic dermatoses, systemic vasculitis, inflammatory arthritis, pseudo-Behçet’s disease, and relapsing polychondritis [5,6,7,8]. For years now, the state of autoinflammatory disorders associated with neoplasia reported in the literature were mainly associated with solid cancer but also MDS/CMML, myeloproliferative disorders, and lymphoma, and identified in the literature as “paraneoplastic AOSD” or “malignant associated AOSD” [8,9,10,11,12,13,14,15,16,17].\n\nRecently, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), a newly established X-linked disease associated with a somatic mutation in a gene encoding ubiquitin-like modifier activating enzyme 1 (UBA1) characterized by lipid vacuole inclusions in myeloid precursors of bone marrow examination, has been described [18]. These patients often develop hematologic malignancies, and especially MDS.\n\nIn this French nationwide study, our objective was to describe patients with MDS/CMML with unexplained recurrent fever and extra hematological signs, concordant or close to AOSD, and fulfilling the definition of USAID, their management, outcomes, overall survival, and the specific risk of progression to AML. We evaluated the prevalence of the newly described VEXAS syndrome in this group of patients and specifically reported their features.\n\n2. Materials and Methods\n\n2.1. Study Design\n\nData for patients with MDS or CMML and unexplained recurrent fever associated or not to extra hematological signs, concordant with USAID diagnosed between 2010 and June 2020 were retrospectively collected. All patients provided informed consent, and the study followed the Helsinki declaration and received the approval from the Institutional Review Board of Cochin Hospital (CLEP Decision N°: AAA-2021-08040). In agreement with the Committee for the Protection of Individuals—Regional Health Agency of Ile-de-France, given the retrospective nature of this French study, written informed consent from the patients was not required but the non-opposition of patients was necessary for inclusion. Three hundred and ninety patients were included in the MINHEMON registry across France for extra-hematological features associated to MDS/CMML. From this cohort, we selected patients which presented at least fever of unknown origin and elevated phase reactant. Physicians were also asked by Société Nationale Française de Médecine Interne” (SNFMI), “Club Rhumatisme et Inflammation” group (CRI), “Club Médecine INterne, HEMatologie et ONcologie” (MINHEMON) and the “Centre de référence des maladies auto-inflammatoires et des amyloses d’origine inflammatoire” CEREMAIA to report cases of patients with these features associated with MDS or CMML. Inclusion criteria were as follows: (1) MDS or CMML (WHO criteria); (2) AOSD with complete criteria (Yamaguchi and/or Fautrel criteria), or suspicion of AOSD (at least 3 from 5 criteria including fever) consistent with USAID; and (3) an established diagnosis of AOSD and MDS/CMML within the period of 5 years to avoid any fortuitous association. Exclusion criteria was defined as a diagnosis compatible with another autoimmune, infectious, drug-induced or systemic disease at the time of the inclusion. The diagnosis of suspected AOSD or USAID was made based on a consensus by two specialists (MD, AM) and a senior physician from the reference center of autoinflammatory diseases (SG). We compared our patients with a control group of MDS without extra hematological symptoms. Finally, we decided to screen the included patients for the newly described VEXAS to identify if it could be a new phenotype of this disease.\n\n2.2. MDS, CMML\n\nMDS and CMML were diagnosed based on peripheral blood and bone marrow examinations and classified according to the WHO 2016 criteria [19]. Patients were graded using the Revised International Prognostic Scoring System (IPSS-R) [20] for MDS: very low, low, intermediate, high, and very high risk groups; and the new CMML-specific Prognostic Scoring System (CPSS) for CMML: low, intermediate, and high. Karyotypes, the percentage of medullar blasts, and somatic mutations were assessed at the time of MDS diagnosis.\n\n2.3. Genetic Analysis for VEXAS\n\nSomatic UBA1 mutation was explored by incorporating the targeted gene in a homemade 75-gene panel for the next generation sequencing (NGS) of circulating mononucleated cells with a 2% threshold of detection already used in previous work [21]. Only patients alive or dead with available DNA were tested for UBA1. Tested samples were collected in a single center except for one tested in his reference center. UBA1 exon 3 sequences were determined by specific PCR followed by Sanger sequencing reaction using BigDye ™ Terminator (Applied Biosystems, Waltham, MA, USA) according to the manufacturer’s instructions and using the following primers: (forward) 5′-GTGGGTGGGAAAGTCTTTTGT-3′ and (reverse) 5′-TTACAGCTGCCGGGAGTAAAG-3′. A 3500xL-Dx Genetic Analyzer sequencing system was used, and sequences were analyzed with SeqScape software (Applied Biosystems). As MDS patients from the control group did not show any extra hematological features, they were not screened for UBA1 mutation. UBA1 mutated patients were identified and included in French VEXAS group cohort whom data could be used for other studies. The patients used in different studies are represented with an asterisk* in corresponding table.\n\n2.4. USAID\n\nPatient’s clinical files were screened for other autoinflammatory diagnostics. Symptoms of AOSD were specifically recorded and highlighted: fever, skin rash, arthritis or arthralgia, myalgia, pharyngitis or sore throat, nodes, or splenomegaly as well as these severe complications pericarditis, pleuritis, myocarditis, reactive hemophagocytic syndrome (RHS), disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), and interstitial lung disease (ILD).\n\nData from the laboratory test included complete blood count, liver enzymes, C-reactive protein (CRP), ferritin, and glycosylated ferritin levels.\n\nUSAID complete clinical and biological response was defined as a total disappearance of all clinical features present at baseline in exclusion of those possible reliable to MDS and/or CMML and a complete normalization of acute-phase reactants. Partial response was defined as an improvement of at least one the clinical sign without an increase of any other features and at least 50% improvement of acute-phase reactants. Patients treated with corticosteroids as first line were differentiated into two groups: high dosage (0.8 to 1 mg/kg/day of prednisone-equivalent) and low dosage. USAID diagnosis was considered concomitant with MDS/CMML or AML when the diagnosis of both diseases was made within ±3 months before or after MDS/CMML were diagnosed. The overall survival, the cause of death and the progression toward AML, were recorded, as well as the date of the last visit.\n\n2.5. Control Group\n\nThe control group consisted of 104 patients from the “Groupe Francophone des Myelodysplasies” registry of MDS/CMML which were seen at least once by the internal medicine specialists (AM, OF). These patients did not exhibit any systemic inflammatory or autoimmune features and were selected without matching.\n\n2.6. Ethics\n\nAll patients provided informed consent, and the study followed the Helsinki declaration.\n\n2.7. Statistical Analysis\n\nDescriptive data included medians and interquartile ranges (IQR) for continuous variables and frequencies (expressed in percentages) for categorical variables. To account for missing data, results were expressed as observed data (missing data were not replaced). The Chi-square or Fischer’s exact tests were used to compare categorical variables, and the Student’s t-test or Mann–Whitney U test were applied for the comparison of continuous variables. The significance of findings was determined by a p-value of 0.05 or less. Statistical analyses were performed using 2009 GraphPad software, San Diego, CA, USA v6.1.\n\n3. Results\n\n3.1. Characteristics of Patients\n\nAll 26 patients with USAID presented with recurrent unexplained fever and elevated acute phase reactants (Figure 1). The median age of appearance of USAID’s symptoms was 70.5 years (IQR: 64.3–78.9) with 76% being male (Table 1). Besides unexplained recurrent fever, clinical features of USAID included arthritis (n = 16, 62%) and skin rash (n = 11, 42%). Severe complications were noted at the time of diagnosis or during the follow-up period in nine patients (35%). These included RHS (n = 5), myopericarditis (n = 3), interstitial lung disease (n = 3), and ARDS (n = 1) (Table 1). Five patients among the initially identified USAID, presented symptoms concordant with a diagnosis of AOSD according to Yamaguchi (n = 5) and Fautrel (n = 4) criteria [22,23]. Nine patients with USAID, reported atypical signs for AOSD including other skin lesions (n = 7, 78%) such as ulcers, nodules, angioedema, erythema nodosum, urticaria, eczematous lesions; non-infectious ileitis (n = 2, 25%), recurrent superficial venous thrombosis (n = 1, 11%), and periorbital headache (n = 1, 11%).\n\nMDS/CMML characteristics (WHO classification, cytogenetics, and prognostic scores) are shown in Table 2. The most frequent subtype was MDS with excess blasts (30.8% of the patients) (MDS EB-1: 11.5%, MDS EB-2: 19.2%), with a median R-IPSS of 3.7 (IQR: 2–5). NGS somatic mutations screening was available for 17 patients and showed TET2 (n = 5), ASXL1 (n = 4), IDH1 (n = 3), and KRAS (n = 3) mutations (Supplementary Table S1). The diagnosis of USAID co-occurred with preceded and appeared after respectively the diagnosis of MDS/CMML in eight (32%), twelve patients (48%), and five patients (24%). The median time between USAID and MDS/CMML diagnosis was one year (IQR: 0.2–2). Specific hematological treatments were initiated in seventeen cases (65%) within half a year (IQR: 0.2–1.2) after the diagnosis of MDS. First-line treatment mostly consisted of azacytidine (Supplementary Table S2).\n\nAmong the 26 patients included, 18 had samples available to be tested for UBA1 mutation was tested in 18 patients and revealed six 33% positive cases, five out six were males (Figure 1 and Table 3). None of these patients progressed to AML during the 2.2 median years of follow up (ranges 1.2 to 5.6 years). Among these six individuals with VEXAS syndrome, none had a confirmed AOSD, including one with incomplete AOSD criteria sets and five remainders presenting additional unusual clinical features for AOSD. None had polychondritis, one patient hand interstitial pneumonia, one alveolitis, and five had cutaneous features distinct from a rash.\n\nCompared to MDS/CMML controls without any inflammatory features (n = 104), USAID-associated MDS/CMML patients were younger (71.4 (IQR: 36–85) vs. 78 years (IQR: 42–92); p = 0.0005), without any other statistically significant differences for demography, MDS/CMML subtype, survival. Even if the rates of deaths were higher in the study group (46% vs. 25%; p = 0.02), the overall survival and the time to progression to AML were not significantly different between the groups (Figure 2).\n\n3.2. Treatment and Outcomes\n\nTwenty-two patients (85%) received specific treatment for USAID. Corticosteroids were used as a first-line treatment in 19 cases (86%) alone (n = 17) or combined with anakinra or infliximab in the other 2 cases. A complete clinical and biological response to first-line treatment was observed in 14 cases (64%) but 5 cases of secondary steroid dependency were described. Thirteen patients (59%) required a second-line treatment because of a resistance to steroids, primary inefficiency, or relapse, with a response in eight (73%) patients. Targeted biological therapy alone or in association with corticosteroids enabled either a partial or complete response in 9 out of 11 patients (anakinra n = 8/9, tocilizumab n = 0/1, and infliximab n = 1/1). Azacytidine used for MDS or steroid dependent autoinflammatory disease (n = 12) resulted in a complete or partial response of systemic features in 10 (83%) cases. Seven patients (26%) progressed to AML and 12 died (46%), all except one in the VEXAS negative group during the follow-up (Supplementary Table S2 and Figure S1).\n\nAmong the six patients with VEXAS, four responded temporarily and/or partially to corticosteroids: relapses and steroid dependency were observed in all cases. Anakinra was used in five cases with a complete or partial response in four cases. Tocilizumab was ineffective in one remaining case. When available, azacytidine led to a response on systemic features in all 3 cases.\n\n4. Discussion\n\nPatients with MDS/CMML can develop USAID with various extra hematological features including pattern suggestive of AOSD. This is the first multidisciplinary series (involving both rheumatologists, hematologists, and clinical immunologists) reporting on USAID associated with MDS/CMML features and the prevalence of VEXAS in such cohort(s). The results of the present study have several important implications. In the case of MDS/CMML with recurrent and unexplained fever, our cohort, although limited, shows that VEXAS syndrome represents 33% (6/18) of cases, these inflammatory situations remaining rare. Moreover, over a median follow-up of 26 month, none of the 6 cases of MDS/CMML VEXAS + progressed to AML, versus 23% of MDS/CMML with USAID and 40% of classic MDS/CMML without inflammatory manifestations. At last, although the numbers are small therefore caution must remain prevalent, there could be a potential interest of biological therapies or even azacytidine when UBA1 is mutated.\n\nPatients with MDS and unexplained recurrent fever should be first tested for the UBA1 mutation. The recent work by Beck et al. which identified VEXAS, implying that somatic mutations may be a more frequent cause of human disease than previously recognized [18,24]. A third of our patients screened for UBA1 were positive for this mutation (including one woman). As a cohort of comparison, in relapsing chondritis, a frequently associated clinical picture usually described with VEXAS, only 7.6% had UBA1 mutations [25]. USAID appeared as a new pattern of VEXAS. Interestingly, 50% of our VEXAS patients experienced RHS. In the future, the order of UBA1 screening could be debated: integrated into the first-line genetic exploration of MDS as well as the MDS/SMP NGS panel or rather screened in the case of MDS/CMML with systemic features in particular USAID.\n\nIn contrast to other dysimmune manifestations with a near equal frequency distribution before, simultaneously, and after the diagnosis of MDS/CMML (USAID and systemic features of VEXAS tend to precede the diagnosis of hematological diseases) [9]; hence, the importance of an early identification of warning signs to carefully consider an underlying neoplasia, in particular hematological malignancy. Nearly 20% of the patients matched with the criteria concordant with AOSD, but some atypia should raise the physicians’ attention in patients with newly-diagnosed AOSD, with some features such as late-onset disease [26], male sex [27] as well as cytopenia in particular the absence of leukocytosis (a hallmark feature of AOSD), and macrocytosis and monocytosis [9,11]. In a recent Dutch case series of VEXAS, among patients with unclassified autoinflammation, two among the twelve retrospectively identified were initially suspected with AOSD [28]. Thus, elderly patients with late AOSD diagnosis or suspicion as described in some series [29,30] could also benefit from UBA1 mutation screening.\n\nAs described previously for systemic inflammatory and autoimmune disorders associated with MDS/CMML, MDS EB, and MDS MLD were the most frequently associated subtypes in USAID patients not UBA1 mutated [6,31]. No association with a specific karyotype was identified but interestingly TET2 and IDH mutation already associated with systemic inflammatory and auto immune disease and T cell dysregulation in a recent work [32] were also frequently found in our cohort. Two out of the six VEXAS patients presented DNMT3A also described in other VEXAS patients [18,28,33,34], but significance is yet unclear. None of the patients with VEXAS had CMML, which is consistent with the recent report published by Zhao et al. [35]. The prognosis of MDS-associated autoimmune disorders remains unclear, as depending on the types of autoimmune disease in each cohort, the impact on survival could be different [7] but we must notice that in our group, despite a high rate of transformation (more than 25%), the twelve death: only one was UBA1 mutated and none of the VEXAS patients transformed into AML.\n\nThe treatment of symptoms of patients with malignant associated features concordant or close to AOSD is challenging. Corticosteroids response was similar to AOSD’s but with a high percentage of steroid dependency or secondary failure [27]. Methotrexate, usually used for its steroid-sparing effect, was rarely applied, presumably due to the risk of cytopenia, explaining the frequent use of biologic agents. The preferential utilization of interleukin-1R antagonists rather than TNF-a antagonists usually used in articular rheumatism is justified by the dominance of the systemic character of the disease with frequent spikes in fever and seemed efficient. Most treatments were only transiently effective, but hematological treatment allowed control of the USAID symptoms for 11 patients in our cohort. As in autoimmune and inflammatory disorders, azacytidine, appears to have a beneficial effect on these systemic manifestations [36,37]. Similarly, in a recent retrospective, Bourbon et al.’s study of the hypomethylating agent and signaling inhibitors seemed to achieve interesting results in VEXAS syndrome patients [38]. The occurrence of USAID or AOSD compatible features over the course of myelodysplastic diseases may prompt a hematological treatment, especially in its refractory form, despite the absence of a direct hematological indication. Thus, azacytidine could be a therapeutical hypothesis for USAID associated with MDS as well as it could be for UBA1 mutated patients.\n\nOur study has several important limitations. First, the retrospective design used here carries an inherited risk of bias and missing data. Second, despite the scarcity of the described clinical syndrome, a small sample size limits the generalizability of the findings reported. Herein we chose to select only patient with occurrence of USAID/AOSD suspicion and MDS/CMML within the period of 5 years to avoid any fortuitous association. Further studies should aim at improving study designs with a prospective nature, larger sample size, and detailed comprehensive information collection.\n\n5. Conclusions\n\nSystemic form of VEXAS syndrome can mimic AOSD, especially in the elderly. USAID symptoms including a pattern suggestive of AOSD associated with MDS/CMML was identified in 33% cases with VEXAS syndrome, thereby further expanding the spectrum of this new syndrome. UBA1 should be sequenced in this population, especially in case of macrocytic associated anemia and chronically elevated CRP among old males, but not exclusively. Although the optimal management of UBA1/MDS overlap patients remains to be determined in larger scale cohorts, biological therapies and/or hypomethylating agents seem promising in this situation.\n\nKey messages:\n\nPatients with MDS/CMML can develop a recurrent fever with various extra hematological features suggestive of USAID;\n\nPseudo-Still disease or USAID associated with a myelodysplastic syndrome are a new phenotype of VEXAS syndrome;\n\nUBA1 mutation should be screened in case of such association.\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/jcm10235586/s1, Figure S1: Different lines of USAID treatments and treatment responses. Twenty-two patient (85%) received specific treatment for USAID and 14 (64%) experienced complete response. Fifty-nine percent of the patient needed a second line treatment and 54% a third line, Table S1: Main features of MDS/CMML patients with USAID, Table S2: USAID including pattern suggestive of AOSD natural history and therapeutical management.\n\nClick here for additional data file.\n\nAuthor Contributions\n\nConceptualization, M.D. (Marion Delplanque), S.G.-L. and A.M.; Supervision, S.G.-L. and A.M.; Writing—original draft, M.D. (Marion Delplanque); Writing—review & editing, M.D. (Marion Delplanque), A.A., P.H., P.F., J.G., F.M., D.R.-W., N.B., L.D., A.O., M.G., M.M., J.R. (Jerome Razanamahery), G.M., M.D. (Matthieu Décamp), S.M., T.Q., J.R. (Julien Rossignol), L.S., M.S., L.T., A.S., Y.H., S.G.-L. and A.M. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Cochin Hospital Institutional Review Board (CLEP Decision N°: AAA-2021-08040).\n\nInformed Consent Statement\n\nIn agreement with the Committee for the Protection of Individuals—Regional Health Agency of Ile-de-France, given the retrospective nature of this French study, written informed consent from the patients was not required but the non-opposition of patients was necessary for inclusion.\n\nData Availability Statement\n\nData are available on request from the corresponding author.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nAbbreviations\n\nA\tArthritis/arthralgia\t\nAML\tAcute myeloid leukemia\t\nANA\tAntinuclear antibody\t\nAOSD\tAdult-onset Still’s disease\t\nARDS\tAcute respiratory distress syndrome\t\nC\tCytolysis\t\nCBC\tComplete blood count\t\nCC\tCorticosteroids\t\nCMML\tChronic myelomonocytic leukemia\t\nCPSS\tCMML-specific prognostic scoring system\t\nCR\tComplete remission\t\nCRP\tC-reactive protein\t\nDIC\tDisseminated intravascular coagulation\t\nF\tFemale\t\nF\tFever\t\nFr\tHigh ferritin\t\nG\tLow glycosylated ferritin\t\nIL\tInterleukin\t\nILD\tinterstitial lung disease\t\nL\tLymph nodes and splenomegaly\t\nM\tMale\t\nM/F\tMale-to-female ratio\t\nMAS\tMacrophage activation syndrome\t\nMDS\tMyelodysplastic syndrome\t\nMDS MLD\tMDS with multilineage dysplasia\t\nMDS SLD\tMDS with single lineage dysplasia\t\nMDS-EB1\tMDS with excess of blasts <5%\t\nMDS-EB2\tMDS with excess of blasts >5%\t\nMDS-RS\tMDS with ring sideroblasts\t\nMM\tMyelodysplastic malignancy\t\nMTX\tMethotrexate\t\nPNN\tPolymorphonuclear neutrophils >80%\t\nPET scan\tPositron emission tomography scan\t\nPR\tPartial remission\t\nRF\tRheumatoid factor\t\nRHS\tReactive hemophagocytic syndrome\t\nR-IPPS\tRevised International Prognostic Scoring System\t\nSAID\tSystemic autoinflammatory disorder\t\nS\tSkin rash\t\nT\tSore throat\t\nTNF\tTumor necrosis factor\t\nUBA1\tUbiquitin-like modifier activating enzyme 1\t\nUSAID\tUndifferentiated systemic autoinflammatory disorder\t\nVEXAS\tVacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome\t\nW\tLeukocytosis\t\nYrs\tYears\t\n\nFigure 1 Flow-chart depicting patient selection. From the 46 patients screened, 26 were included. Six UBA1 mutated patients identified from the included patients.\n\nFigure 2 Kaplan–Meier curves of overall survival (a), progression to AML (b) in MDS patients with and without USAID. Data were censored at time of last visit or death. The response MDS control group is in blue and the one with autoinflammatory features is in red.\n\njcm-10-05586-t001_Table 1 Table 1 Baseline characteristics of USAID including pattern suggestive of AOSD.\n\n\tPatients (n = 26)\tNo VEXAS (n = 18)\tVEXAS (n = 6)\t\nEpidemiology\t\t\t\t\nMale-to-female ratio\t3.16\t2.8\t4\t\nAge at 1st signs (years) (range)\t70.5 (64.3–78.9)\t71 (65.5–79.3)\t64.3 (63.6–68.2)\t\nTime between USAID and MDS (years) (range)\t1.0 (0.2–2)\t0.9 (1.8–0.2)\t1.2 (1.1–3)\t\nMedical history (%)\t\t\t\t\nPersonal or familial history of autoimmunity\t2 (9)\t1 (6)\t1 (25)\t\nSymptoms (%)\t\t\t\t\nFever\t26 (100)\t18(100)\t6 (100)\t\nSkin rash\t11 (42)\t6 (33)\t5 (83)\t\nArthritis/arthralgia\t16 (62)\t14 (78)\t2 (33)\t\nPharyngitis/sore throat\t5 (19)\t1 (22)\t1 (17)\t\nMyalgia\t5 (19)\t3 (17)\t2 (33)\t\nLymph nodes or splenomegaly\t12 (46)\t8 (44)\t4 (67)\t\nBlood test results (%)\t\t\t\t\nLeukocytosis > 10,000/mm3\t10 (38)\t9 (50)\t1 (17)\t\nGranulocytes ≥ 80%\t7 (26)\t6 (67)\t1 (17)\t\nCRP >30 mg/L\t26 (100)\t18 (100)\t6 (100)\t\nElevated liver enzymes\t9 (35)\t7 (39)\t2 (67)\t\nHigh ferritin\t19/20 (95)\t15 (94)\t4 (100)\t\n>2000 µg/L\t14/20 (70)\t13 (81)\t1 (25)\t\nGlycosylated ferritin < 20%\t4/11 (36)\t3 (30)\t1 (50)\t\nSevere complications\t\t\t\t\nPericarditis\t3 (12)\t3 (18)\t0 (0)\t\nMyocarditis\t0 (0)\t0 (0)\t0 (0)\t\nDIC\t0 (0)\t0 (0)\t0 (0)\t\nRHS\t5 (19)\t2 (11)\t3 (50)\t\nARDS\t1 (4)\t1 (4)\t0 (0)\t\nILD, alveolitis\t3 (12)\t1 (4)\t2 (67)\t\nPleurisy\t6 (23)\t6 (33)\t0 (0)\t\nAOSD, adult-onset Still’s disease; ARDS, acute respiratory distress syndrome; CRP, C-reactive protein; DIC, disseminated intravascular syndrome; ILD, interstitial lung disease; MDS, myelodysplastic syndrome; RHS, reactive hemophagocytic syndrome.\n\njcm-10-05586-t002_Table 2 Table 2 Main features of MDS/CMML patients with USAID.\n\n\tMDS-Related USAID\nn = 26 (%)\tMDS/CMML Controls\nn = 104 (%)\t\nMean age at diagnosis (range)\t71.4 (36–85)\t78 (42–92) *\t\nMale\t19 (76)\t79 (76)\t\nMyelodysplastic syndrome (MDS)\t23 (89)\t83 (80)\t\nMDS with single lineage dysplasia\t3 (12)\t14 (13)\t\nMDS with ring sideroblasts (MDS-RS)\t2 (8)\t6 (6)\t\nMDS with multilineage dysplasia\t5 (19)\t33 (32)\t\nMDS with excess blasts (EB)\t8 (31)\t14 (13)\t\nMDS with isolated del(5q)\t0\t4 (4)\t\nMDS, unclassifiable/missing data\t5 (19)\t7 (7)\t\nChronic myelomonocytic leukemia (CMML)\t3 (12)\t21 (20)\t\nAcute myeloid leukemia (AML) (progressed to)\t7 (27)\t11 (10)\t\nIPPS-R (IQR)\t3.7 (2–5)\t2.5 (0–8)\t\nDeaths\t12 (46)\t26 (25) *\t\nFollow-up (range)\t16.8 (0–104)\t21.5 (0–86)\t\n* p value < 0.05.\n\njcm-10-05586-t003_Table 3 Table 3 Main features of the patients with UBA1 mutations (VEXAS syndrome).\n\nPatient\tSex\tType MDS\tAge at Diagnosis of MDS\tCharacteristics of MDS\tAge at USAID Onset\tSigns of USAID\tOther Symptoms\tEvolution\t\nPatient #1 *\tM\tMDS UL\t59.8\tIPPS = NS\t58.8\tFever, rash, cytolysis, high ferritin, RHS\tRecurrent superficial veinous thrombosis, cutaneous atypia\tAzacytidine for MDS just begun\t\nNGS: DNMT3A, BRCA2, and ZRSR2 mutated\nBone marrow: vacuoles in myeloid precursor cells\tNo response to CTC high dose rapidly completed with cyclosporine permitting, PR\t\nDel 6q Blasts: NS\tAlive under azacytidine, CTC 20 mg and cyclosporine\t\nPatient #2 *\tM\tMDS EB1\t64.5\tIPPS = 4\t63.3\tFever, arthralgia, leukocytosis, lymphadenopathy, splenomegaly, granulocytes, cytolysis\t\tCR under azacytidine for MDS\t\nNGS: Normal\tPeriorbital headache, skin nodules, edema, diarrhea, abdominal pain\tMultiple lines of treatments: response and relapses to high-dose CTC and anakinra; no response to infliximab, tocilizumab, IV Ig, cyclosporine\t\nBlasts: 7%\t\tAlive and disappearance of systemic features under azacytidine and CTC 20 mg/day\t\nPatient #3 *\tM\tUnclassifiable MDS\t73.5\tIPPS-R: 2\t73.5\tFever, rash, lymphadenopathy, splenomegaly, high ferritin, RHS\tRecurrent face edema, urticaria, skin nodules and eczematous skin lesions\tPR with azacytidine for MDS\t\nNGS: DNMT3A mutated 31.7%\tNo response to high-dose CTC and anakinra\t\nBlasts: 0%\tAlive, PR and systemic symptoms with azacytidine\t\nPatient #4\tF\tUnclassifiable MDS\t64.3\tIPPS-R: NS\tNS\tFever, rash, RHS\t\tUnknown response with hydroxyurea\t\nDel X Blasts: NS\tInterstitial pneumonia, diarrhea\tCR with high-dose CTC, steroid dependence; CR with anakinra and CTC\t\n\t\tAlive at last visit\t\nPatient #5 *\tM\tMDS MLD\t69.4\tIPPS-R: 2\nNGS: TET2 mutated 3%\t65.8\tFever, rash, arthritis, sore throat, lymphadenopathy, splenomegaly, high ferritin, myalgia\tPustular eruption and other cutaneous atypia\tCR with azacytidine; failure with methotrexate; leflunomide stopped early due to cytopenia; CR (with few relapses) with CTC and anakinra\t\nPatient #6\tM\tUnclassifiable MDS\tNS\tIPPS-R: NS\nNGS: normal\t69\tFever, rash, high ferritin, myalgia\tOedema, angioedema chronic urticaria, alveolitis\tNo hematological treatment CR under high dose CTC but CTC dependency, CR under anakinra and CTC stopped for neutropenia\nDeath at 73 years from sepsis and cardiac failure and anakinra\t\nMedian (yrs) (IQ 25;75) n = (%)\tM/F = 5:1\tFollow up 2.2 (1.5; 3.3)\t64.5 (64.3; 69.4)\t\t\tFever (n = 6, 100%), skin rash (n = 5, 83%), arthralgia arthritis (n = 2, 33%), lymph nodes/splenomegaly n = 3 (50), sore throat (n = 1, 17%), RHS n = 3 (50), leukocytosis (n = 1, 17%), granulocytosis (n = 1, 17%), cytolysis (n = 2, 33%), high ferritin (n = 4, 67%)\t\nCR, complete remission; CTC, corticosteroids; Ig, immunoglobulin; IPPS-R, Revised International Prognostic Scoring System; IV, intravenous; MDS, myelodysplastic syndrome; MDS EB1, MDS with excess of blasts < 5%; MDS: myelodysplastic syndrome; NGS, next-generation sequencing; NS, not significant; PR, partial response; RHS, reactive hemophagocytic syndrome; MDS SLD, MDS with single lineage dysplasia; MDS UL. Patients marked with an * were identified and included in French VEXAS group cohort and could have been used in other published studies.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Papa R. Rusmini M. Volpi S. Caorsi R. Picco P. Grossi A. Caroli F. Bovis F. Musso V. Obici L. Next generation sequencing panel in undifferentiated autoinflammatory diseases identifies patients with colchicine-responder recurrent fevers Rheumatology 2020 59 344 360 10.1093/rheumatology/kez270 31325311\n2. Rusmini M. Federici S. Caroli F. Grossi A. Baldi M. Obici L. Insalaco A. Tommasini A. Caorsi R. Gallo E. Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases Ann. Rheum. Dis. 2016 75 1550 1557 10.1136/annrheumdis-2015-207701 26386126\n3. Harrison S.R. McGonagle D. Nizam S. Jarrett S. van der Hilst J. McDermott M.F. Savic S. Anakinra as a diagnostic challenge and treatment option for systemic autoinflammatory disorders of undefined etiology JCI Insight 2016 1 e86336 10.1172/jci.insight.86336 27699261\n4. Adès L. Itzykson R. Fenaux P. Myelodysplastic syndromes Lancet 2014 383 2239 2252 10.1016/S0140-6736(13)61901-7 24656536\n5. Fain O. Braun T. Stirnemann J. Fenaux P. Systemic and autoimmune manifestations in myelodysplastic syndromes Rev. Med. Interne 2011 32 552 559 10.1016/j.revmed.2010.08.005 20850913\n6. Mekinian A. Grignano E. Braun T. Decaux O. Liozon E. Costedoat-Chalumeau N. Kahn J.-E. Hamidou M. Park S. Puéchal X. Systemic inflammatory and autoimmune manifestations associated with myelodysplastic syndromes and chronic myelomonocytic leukaemia: A French multicentre retrospective study Rheumatology 2016 55 291 300 10.1093/rheumatology/kev294 26350487\n7. Grignano E. Jachiet V. Fenaux P. Ades L. Fain O. Mekinian A. Autoimmune manifestations associated with myelodysplastic syndromes Ann. Hematol. 2018 97 2015 2023 10.1007/s00277-018-3472-9 30091023\n8. Lee S.J. Park J.K. Lee E.Y. Joo S.H. Jung K.C. Lee E.B. Song Y.W. Yoon S.-S. Certain Autoimmune Manifestations Are Associated with Distinctive Karyotypes and Outcomes in Patients with Myelodysplastic Syndrome: A Retrospective Cohort Study Medicine 2016 95 e3091 10.1097/MD.0000000000003091 27043672\n9. Hofheinz K. Schett G. Manger B. Adult onset Still’s disease associated with malignancy-Cause or coincidence? Semin. Arthritis Rheum. 2016 45 621 626 10.1016/j.semarthrit.2015.10.003 26581485\n10. Liozon E. Ly K.H. Vidal-Cathala E. Fauchais A.-L. Adult-onset Still’s disease as a manifestation of malignancy: Report of a patient with melanoma and literature review Rev. Med. Interne 2014 35 60 64 10.1016/j.revmed.2013.02.014 24094701\n11. Sun N.Z. Brezinski E.A. Berliner J. Haemel A. Connolly M.K. Gensler L. McCalmont T.H. Shinkai K. Updates in adult-onset Still disease: Atypical cutaneous manifestations and associations with delayed malignancy J. Am. Acad. Dermatol. 2015 73 294 303 10.1016/j.jaad.2015.04.063 26054431\n12. Sugawara T. Tsukada T. Wakita Y. Wake Y. Kouyama K. Tamaki S. Tanigawa M. Iwasaki E. Ohta C. Kageyama S. A case of myelodysplastic syndrome progressing to acute myelocytic leukemia in which adult-onset Still’s disease had occurred 6 years before Int. J. Hematol. 1993 59 53 57 8161735\n13. Kacar M. Fitton J. Gough A.K. Buch M.H. McGonagle D.G. Savic S. Mixed results with baricitinib in biological-resistant adult-onset Still’s disease and undifferentiated systemic autoinflammatory disease RMD Open 2020 6 e001246 10.1136/rmdopen-2020-001246 32669454\n14. Nagasaki Y. Miyamoto T. Henzan H. Nagafuji K. Harada M. Akashi K. Longstanding remission of adult onset Still’s disease under imatinib therapy in a patient with chronic myelogenous leukemia J. Rheumatol. 2009 36 1349 1351 10.3899/jrheum.081159 19509096\n15. Nakagawa Y. Furusyo N. Taniai H. Henzan H. Tsuchihashi T. Hayashi J. Chronic myelogenous leukemia that occurred two years after the diagnosis of adult Still’s disease Intern. Med. 2005 44 994 997 10.2169/internalmedicine.44.994 16258220\n16. Sono H. Matsuo K. Miyazato H. Sakaguchi M. Matsuda M. Hamada K. Tatsumi Y. Maeda Y. Funauchi M. Kanamaru A. A case of adult-onset Still’s disease complicated by non-Hodgkin’s lymphoma Lupus 2000 9 468 470 10.1191/096120300678828514 10981654\n17. Trotta F. Dovigo L. Scapoli G. Cavazzini L. Castoldi G. Immunoblastic malignant lymphoma in adult onset Still’s disease J. Rheumatol. 1993 20 1788 1792 8295197\n18. Beck D.B. Ferrada M.A. Sikora K.A. Ombrello A.K. Collins J.C. Pei W. Balanda N. Ross D.L. Ospina Cardona D. Wu Z. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease N. Engl. J. Med. 2020 383 2628 2638 10.1056/NEJMoa2026834 33108101\n19. Arber D.A. Orazi A. Hasserjian R. Thiele J. Borowitz M.J. Le Beau M.M. Bloomfield C.D. Cazzola M. Vardiman J.W. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia Blood 2016 127 2391 2405 10.1182/blood-2016-03-643544 27069254\n20. Greenberg P.L. Tuechler H. Schanz J. Sanz G. Garcia-Manero G. Solé F. Bennett J.M. Bowen D. Fenaux P. Dreyfus F. Revised international prognostic scoring system for myelodysplastic syndromes Blood 2012 120 2454 2465 10.1182/blood-2012-03-420489 22740453\n21. Oganesyan A. Jachiet V. Chasset F. Hirsch P. Hage-Sleiman M. Fabiani B. Duriez P. Georgin-Lavialle S. Delhommeau F. Hakobyan Y. VEXAS syndrome: Still expanding the clinical phenotype Rheumatology 2021 60 e321 e323 10.1093/rheumatology/keab225 33693570\n22. Lebrun D. Mestrallet S. Dehoux M. Golmard J.L. Granger B. Georgin-Lavialle S. Arnaud L. Grateau G. Pouchot J. Fautrel B. Validation of the Fautrel classification criteria for adult-onset Still’s disease Semin. Arthritis Rheum. 2018 47 578 585 10.1016/j.semarthrit.2017.07.005 28760536\n23. Yamaguchi M. Ohta A. Tsunematsu T. Kasukawa R. Mizushima Y. Kashiwagi H. Kashiwazaki S. Tanimoto K. Matsumoto Y. Ota T. Preliminary criteria for classification of adult Still’s disease J. Rheumatol. 1992 19 424 430 1578458\n24. Levy-Lahad E. King M.-C. Hiding in Plain Sight–Somatic Mutation in Human Disease N. Engl. J. Med. 2020 383 2680 2682 10.1056/NEJMe2030754 33108100\n25. Ferrada M.A. Sikora K.A. Luo Y. Wells K.V. Patel B. Groarke E.M. Ospina Cardona D. Rominger E. Hoffmann P. Le M.T. Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients with VEXAS Syndrome Arthritis Rheumatol. 2021 73 1886 1895 10.1002/art.41743 33779074\n26. Kalyoncu U. Solmaz D. Emmungil H. Yazici A. Kasifoglu T. Kimyon G. Balkarli A. Bes C. Ozmen M. Alibaz-Oner F. Response rate of initial conventional treatments, disease course, and related factors of patients with adult-onset Still’s disease: Data from a large multicenter cohort J. Autoimmun. 2016 69 59 63 10.1016/j.jaut.2016.02.010 26970681\n27. Giacomelli R. Ruscitti P. Shoenfeld Y. A comprehensive review on adult onset Still’s disease J. Autoimmun. 2018 93 24 36 10.1016/j.jaut.2018.07.018 30077425\n28. van der Made C.I. Potjewijd J. Hoogstins A. Willems H.P.J. Kwakernaak A.J. de Sevaux R.G.L. van Daele P.L.A. Simons A. Heijstek M. Beck D.B. Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS J. Allergy Clin. Immunol. 2021 10.1016/j.jaci.2021.05.014 34048852\n29. Suda T. Zoshima T. Takeji A. Suzuki Y. Mizushima I. Yamada K. Nakashima A. Yachie A. Kawano M. Elderly-onset Still’s Disease Complicated by Macrophage Activation Syndrome: A Case Report and Review of the Literature Intern. Med. 2020 59 721 728 10.2169/internalmedicine.3727-19 31708548\n30. Mollaeian A. Chen J. Chan N.N. Nizialek G.A. Haas C.J. Adult onset Still’s disease in the elderly: A case-based literature review BMC Rheumatol. 2021 5 12 33875007\n31. de Hollanda A. Beucher A. Henrion D. Ghali A. Lavigne C. Lévesque H. Hamidou M. Subra J.F. Ifrah N. Belizna C. Systemic and immune manifestations in myelodysplasia: A multicenter retrospective study Arthritis Care Res. 2011 63 1188 1194 10.1002/acr.20504 21584947\n32. Zhao L.-P. Boy M. Azoulay C. Clappier E. Sébert M. Amable L. Klibi J. Benlagha K. Espeli M. Balabanian K. MDS/CMML with TET2 or IDH mutation Are Associated with Systemic Inflammatory and Autoimmune Diseases (SIAD) and T Cell Dysregulation Blood 2020 136 31 32 10.1182/blood-2020-141228\n33. Gurnari C. Pagliuca S. Durkin L. Terkawi L. Awada H. Kongkiatkamon S. Zawit M. Hsi E.D. Carraway H.E. Rogers H.J. Vacuolization of hematopoietic precursors: An enigma with multiple etiologies Blood 2021 137 3685 3689 10.1182/blood.2021010811 33690844\n34. Obiorah I.E. Patel B.A. Groarke E.M. Wang W. Trick M. Ombrello A.K. Ferrada M.A. Wu Z. Gutierrez-Rodrigues F. Lotter J. Benign and malignant hematologic manifestations in patients with VEXAS syndrome due to somatic mutations in UBA1 Blood Adv. 2021 5 3203 3215 10.1182/bloodadvances.2021004976 34427584\n35. Zhao L.-P. Schell B. Sébert M. Kim R. Lemaire P. Boy M. Mathis S. Larcher L. Chauvel C. Dhouaieb M.B. Prevalence of UBA1 mutations in MDS/CMML patients with systemic inflammatory and auto-immune disease Leukemia 2021 35 2731 2733 10.1038/s41375-021-01353-8 34344988\n36. Fraison J.-B. Mekinian A. Grignano E. Kahn J.-E. Arlet J.-B. Decaux O. Denis G. Buchdahl A.-L. Omouri M. Maigne G. Efficacy of Azacitidine in autoimmune and inflammatory disorders associated with myelodysplastic syndromes and chronic myelomonocytic leukemia Leuk. Res. 2016 43 13 17 10.1016/j.leukres.2016.02.005 26922775\n37. Frietsch J.J. Dornaus S. Neumann T. Scholl S. Schmidt V. Kunert C. Sayer H.G. Hochhaus A. La Rosée P. Paraneoplastic inflammation in myelodysplastic syndrome or bone marrow failure: Case series with focus on 5-azacytidine and literature review Eur. J. Haematol. 2014 93 247 259 10.1111/ejh.12311 24635656\n38. Bourbon E. Heiblig M. Gerfaud Valentin M. Barba T. Durel C.-A. Lega J.C. Barraco F. Sève P. Jamilloux Y. Sujobert P. Therapeutic options in VEXAS syndrome: Insights from a retrospective series Blood 2021 137 3682 3684 10.1182/blood.2020010177 33619558\n\n",
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"title": "USAID Associated with Myeloid Neoplasm and VEXAS Syndrome: Two Differential Diagnoses of Suspected Adult Onset Still's Disease in Elderly Patients.",
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"abstract": "Lymphoproliferative disorders (LPDs) occur more frequently in rheumatoid arthritis (RA) patients treated with immunosuppressive agents than in the non-RA population. However, the various forms of disease progression have not yet been elucidated in detail. We encountered a case of Epstein-Barr virus (EBV)-positive atypical polymorphous LPD in the cervical and intraabdominal lymph nodes with hepatosplenomegaly in an 88-year-old female with RA who had taken infliximab and methotrexate (MTX) for six years. Although spontaneous remission occurred following the withdrawal of infliximab and MTX, reversible LPD evolved into hepatosplenic Hodgkin lymphoma without lymphadenopathy presenting as a cholestatic febrile illness. Our findings suggest that the recurrent lesions of MTX-associated LPDs may not always coincide with the primary lesion and may present unexplained findings based on various extranodal diseases.",
"affiliations": "a Division of Gastroenterology, National Hospital Organization National Kochi Hospital , Kochi , Japan.;b Department of Clinical Investigation , National Hospital Organization National Kochi Hospital , Kochi , Japan.;a Division of Gastroenterology, National Hospital Organization National Kochi Hospital , Kochi , Japan.;c Division of Pathology, National Hospital Organization National Kochi Hospital , Kochi , Japan.;d Division of Hematology, National Hospital Organization National Kochi Hospital , Kochi , Japan.;a Division of Gastroenterology, National Hospital Organization National Kochi Hospital , Kochi , Japan.",
"authors": "Tsukazaki|Yuki|Y|;Shinohara|Tsutomu|T|;Tanaka|Kumiko|K|;Naruse|Keishi|K|;Iwahara|Yoshihito|Y|;Inoue|Shuji|S|",
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"abstract": "We present the case of a 55-year-old Caucasian male with a history of schizophrenia presenting with severe hyponatremia attributed to long-acting injectable risperidone treatment. Antipsychotic-induced hyponatremia is an uncommon but serious side effect that should be considered when assessing individuals on chronic psychiatric regimens. In this report, we will discuss our treatment plan for the patient when water deprivation and hypertonic saline failed to correct his serum sodium levels. The goal of this case report is to raise awareness of severe hyponatremia as a side effect of long-acting risperidone, and to encourage further studies to create guidelines for its management when current protocols fail to correct sodium levels.",
"affiliations": "Medical Student, Department of Medicine, Raleigh General Hospital, Beckley, Wv.;Medical Student, Department of Medicine, Raleigh General Hospital, Beckley, Wv.;Department of Emergency Medicine, Lincoln Memorial University-Debusk College of Osteopathic Medicine.;Lincoln Memorial University, Raleigh General Hospital, Beckley, Wv.;Pre-Medical Student, Department of Sciences, Queens University of Charlotte, Nc.;Assistant Clinical Professor of Internal Medicine, West Virginia University School of Medicine.",
"authors": "Chowdhury|Waliul|W|;Lodhi|Muhammad Uzair|MU|;Kuzel|Aaron R|AR|;Johnson|Peter|P|;Rahim|Umar|U|;Rahim|Mustafa|M|",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.2657Family/General PracticeInternal MedicinePsychiatryManagement of Persistent Hyponatremia Induced by Long-acting Injectable Risperidone Therapy Muacevic Alexander Adler John R Chowdhury Waliul 1Lodhi Muhammad Uzair 1Kuzel Aaron R 2Johnson Peter 3Rahim Umar 4Rahim Mustafa 5\n1 \nMedical Student, Department of Medicine, Raleigh General Hospital, Beckley, Wv \n2 \nDepartment of Emergency Medicine, Lincoln Memorial University-Debusk College of Osteopathic Medicine \n3 \nLincoln Memorial University, Raleigh General Hospital, Beckley, Wv \n4 \nPre-Medical Student, Department of Sciences, Queens University of Charlotte, Nc \n5 \nAssistant Clinical Professor of Internal Medicine, West Virginia University School of Medicine \nWaliul Chowdhury walichowdhury48@gmail.com20 5 2018 5 2018 10 5 e26577 5 2018 20 5 2018 Copyright © 2018, Chowdhury et al.2018Chowdhury et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/12407-management-of-persistent-hyponatremia-induced-by-long-acting-injectable-risperidone-therapyWe present the case of a 55-year-old Caucasian male with a history of schizophrenia presenting with severe hyponatremia attributed to long-acting injectable risperidone treatment. Antipsychotic-induced hyponatremia is an uncommon but serious side effect that should be considered when assessing individuals on chronic psychiatric regimens. In this report, we will discuss our treatment plan for the patient when water deprivation and hypertonic saline failed to correct his serum sodium levels. The goal of this case report is to raise awareness of severe hyponatremia as a side effect of long-acting risperidone, and to encourage further studies to create guidelines for its management when current protocols fail to correct sodium levels.\n\nfamily medicinepsychiatrysiadhhyponatremiatolvaptandemeclocyclinemanagement of persistent hyponatremiapreventive medicineThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nRisperidone is a long-acting second-generation antipsychotic drug which is generally well tolerated with few side effects [1]. However, hyponatremia secondary to syndrome of inappropriate antidiuretic hormone (SIADH) is a well-known associated adverse effect of these medications [2]. If water deprivation and hypertonic saline fail to correct the patient’s hyponatremia, treating SIADH in-patients with tolvaptan compared to demeclocycline could be a more effective approach [3]. Cases of antipsychotic-induced hyponatremia have been reported in the literature. However, long-acting depot injections of risperidone causing hyponatremia have been seldom reported. Also, there are currently no clear guidelines as to how to manage patients with SIADH from long-acting risperidone treatment and who fail to recover with water deprivation and hypertonic saline. This was the reason for presenting this case report. The dilemma in our case was that we were not able to correct hyponatremia from long-acting risperidone therapy after the failure of water restriction and hypertonic saline. Discontinuing risperidone in this case also showed no acute benefit as its half-life is four to six days in the body [4]. We will also discuss the effectiveness of tolvaptan, as it was effective in our case when all other measures failed. \n\nCase presentation\nHistory and physical examination\n\nA 55-year-old Caucasian male presented to the emergency department with the complaint of fainting spells with associated dizziness that persisted for several days. The patient stated that he had no associated alleviating or aggravating factors and had a significant tobacco use history. The patient reported a significant medical history of chronic obstructive pulmonary disease (COPD), hyperlipidemia, congestive heart failure, and gastro-esophageal reflux disease (GERD). In addition, the patient reveals that he is receiving treatment for psychiatric disorders that include schizophrenia and anxiety disorder. His medications included pantoprazole 40 mg once daily, risperidone 50 mg of intramuscular injections every two weeks, atorvastatin 10 mg oral once daily, buspirone 10 mg oral twice daily, clopidogrel 75 mg oral once daily, metoprolol 25 mg oral once daily, and nifedipine 60 mg oral once daily. The patient denied any recent changes in medication or travel history. He denied any fever or chills, orthopnea, or paroxysmal nocturnal dyspnea (PND). In addition, he denied any recent weight changes, nausea, vomiting, diarrhea, melena, odynophagia or dysphagia, heartburn, or intravenous drug abuse. No other symptoms of arthritis, mouth sores or mouth ulcers, photosensitive rash, or redness or swellings in the small joints of the hands were reported.\n\nUpon physical examination, the patient seemed to be in no acute distress. He did appear slightly confused upon questioning, but was oriented in time, place, and person with no signs of focal neurological deficits. The functioning of all cranial nerves was intact. The patient appeared to be euvolemic at the time of examination and vital signs were within normal limits. Pulmonary examination revealed diffuse expiratory wheezes in both the anterior and posterior lung fields. The rest of the physical examination was unremarkable. \n\nHospital course\n\nLaboratory workup of the patient revealed a critically low serum sodium level of 114 mmol/L. His serum osmolarity was 212 mOsm/kg and urine osmolality was 320 mOsm/kg. His urine sodium level was 63 mmol/L and serum uric acid level was 2.3 mg/dL. Given the patient's low serum osmolarity, high urine osmolarity, and urine sodium level greater than 40 mmol/L, these findings directed the medical team towards the diagnosis of SIADH.\nA chest X-ray was taken to look for any abnormalities, given his bilateral wheezing on physical examination. The findings showed a right-sided lobar consolidation and a widened mediastinum, as shown in Figure 1. A noncontrast computed tomography (CT) scan of the chest was clear of any abnormal masses, as shown in Figure 2. He was treated with ceftriaxone and azithromycin for pneumonia and his breathing difficulty reduced, but his hyponatremia still persisted. There was a high suspicion that his long-acting risperidone had contributed to this hyponatremia as an adverse effect, as he had been on chronic injections of risperidone for years. The medical team decided to withdraw the patient’s risperidone. However, this did not change his serum sodium levels as it was still severely low. This was expected because long-acting risperidone has a half-life of about four to six days in the body [4]. Water withdrawal and hypertonic saline were also initiated, but his serum sodium levels persisted at levels less than 120 mmol/L. Some 30 mg of tolvaptan was then administrated. Following the administration of 30 mg of tolvaptan, the patient’s serum sodium levels improved over the course of two days and subsequently remained above 130 mmol/L. His serum sodium level was 133 mmol/L during his two-week and one-month outpatient follow-up. This is still below normal, but it is definitely an improvement compared to his initial sodium levels, and his signs of mental confusion were not present on follow-up. \n\nFigure 1 Chest X-ray, showing a right-sided lobar consolidation (red circle) and a widened mediastinum (yellow bar).\nFigure 2 Noncontrast chest computed tomography scan, showing no abnormalities in the chest.\nDiscussion\nTolvaptan has been shown to have dose-dependent effects on water excretion in healthy volunteers up to a dose of 60 mg, after which a plateau effect develops [5]. Kim et al. conducted single and multiple dose studies to evaluate the pharmacokinetics, pharmacodynamics, and safety of tolvaptan in healthy Japanese volunteers. These studies were all randomized, placebo-controlled, and single or double-blinded. In the single-dose study, volunteers were given a single oral dose of either tolvaptan or placebo at 15–120 mg. In the multiple dose studies, the volunteers were given tolvaptan or placebo at doses of 30, 60, 90, or 120 mg once daily for seven days. After a single administration of tolvaptan at a dose of 15–120 mg, the maximum concentration of plasma (Cmax) and area under the curve (AUC) for plasma concentration versus time increased proportionately with higher doses. The increase in 24-hour cumulative urine volume was also dose-dependent. The maximum urine excretion rate reached a plateau at doses above 60 mg, but increased dose-dependently when doses were below 60 mg. A decrease in urine osmolality and an increase in the clearance of free water were seen in the subjects who received tolvaptan. Serum sodium concentrations were higher in subjects receiving tolvaptan compared to placebo, even one day after administration of tolvaptan. The most common side effect associated with tolvaptan was mild thirst [5]. This indicated that in comparison to placebo, tolvaptan effectively induces urinary excretion of water and increases serum sodium levels dose-dependently, with the effect reaching a plateau at doses greater than 60 mg.\n\nDemeclocycline is of the tetracycline class of antibiotics and acts to block antidiuretic hormone (ADH) vasopressin-2 receptors in the distal collecting tubules of the kidney. In comparison, tolvaptan blocks ADH receptors in the renal tubules of the kidney [6]. The reason tolvaptan was selected in this case over demeclocycline was because tolvaptan has been shown to lower in-patient hospital costs and number of admissions compared to demeclocycline [2].\n\nA retrospective cohort study by Grant et al. examined 3,060 patients who were hospitalized for SIADH. Demeclocycline was given to 927 of these patients and 120 patients were treated with tolvaptan. The rest of the patients were managed with fluid restriction, hypertonic saline, or no treatment. Patients who were treated with tolvaptan had shorter hospital stays and lower in-patient care expenses compared to patients treated with demeclocycline. However, demeclocycline was associated with lower outpatient appointments compared to patients on tolvaptan. This shows that the more cost-effective treatment option for in-patients with SIADH is tolvaptan followed by switching to demeclocycline upon discharge [2].\n\nBefore considering tolvaptan for treatment, patients should be checked for underlying liver disease. Torres et al. conducted a three-year double-blinded placebo-controlled trial on tolvaptan therapy in 1,400 patients with autosomal dominant polycystic kidney disease. They noticed that three patients treated with tolvaptan developed significantly increased levels of alanine aminotransferase (ALT) and serum total bilirubin. All three patients’ abnormal liver enzymes improved when tolvaptan was discontinued [7]. Although only three out of 1,400 patients in this study developed liver complications, it remains an adverse effect that physicians should be aware of prior to administrating tolvaptan.\n\nThe underlying association between second-generation antipsychotics like risperidone and hyponatremia could be multifactorial. In addition to risperidone causing SIADH, some data also suggest that risperidone could increase dopamine levels and reset the osmo-receptors in the brain causing polydipsia and dilutional hyponatremia [8]. This could be the underlying pathophysiology behind antipsychotics like risperidone causing SIADH as a side effect. Further research to better understand the underlying pathophysiology behind antipsychotic-induced hyponatremia is needed, in order to develop more tailored antidotes in the future.\n\nConclusions\nLong-acting antipsychotics are commonly used as a first-line treatment for chronic schizophrenic patients. However, hyponatremia is a serious adverse effect that physicians should be prepared for. Our case was unique because the patient’s hyponatremia was persistent despite discontinuing the long-acting antipsychotic and restricting fluids. When all attempts failed to increase the patients’ serum sodium levels in this case, a one-time 30 mg oral dose of tolvaptan was shown to be effective. It must be noted that tolvaptan should be avoided in patients with a history of underlying liver disease. Further studies are needed to develop specific guidelines on how to manage severe long-acting antipsychotic-induced hyponatremia that fails to respond to current management protocols like water deprivation. \n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Long-acting risperidone: a review of its use in schizophrenia CNS Drugs Harrison TS Goa KL 113 132 18 2004 14728058 \n2 Antipsychotic-induced hyponatraemia: a systematic review of the published evidence Drug Saf Meulendijks D Mannesse CK Jansen PA van Marum RJ Egberts TC 101 114 33 2010 20082537 \n3 Use of ADH antagonists results in lower hospital resource usage: a retrospective cohort study Endocrine Abstracts Grant P Jamookeeah C Dhanjal P Griffith G 15 38 2015 \n4 Pharmacokinetics and D2 receptor occupancy of long-acting injectable risperidone (Risperdal Consta) in patients with schizophrenia Int J Neuropsychopharmacol Gefvert O Eriksson B Persson P 27 36 8 2005 15710053 \n5 Pharmacokinetics, pharmacodynamics and safety of tolvaptan, a novel, oral, selective nonpeptide AVP V 2-receptor antagonist: results of single-and multiple-dose studies in healthy Japanese male volunteers Cardiovasc Drugs Ther Kim SR Hasunuma T Sato O Okada T Kondo M Azuma J 5 17 25 2011 \n6 Hyponatremia treatment guidelines 2007: expert panel recommendations Am J Med Verbalis JG Goldsmith SR Greenberg A Schrier RW Sterns RH 1 21 120 2007 17208069 \n7 Tolvaptan in patients with autosomal dominant polycystic kidney disease New Engl J Med Torres VE Chapman AB Devuyst O 2407 2418 367 2012 23121377 \n8 Amphetamine reinstates polydipsia induced by chronic exposure to quinpirole, a dopaminergic D2 agonist, in rats Behav Brain Res Fraioli S Cioli I Nencini P 199 215 89 1997 9475627\n\n",
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{
"abstract": "The 2016 World Health Organization guidelines recommend all children <3 years start antiretroviral therapy (ART) on protease inhibitor-based regimens. But lopinavir/ritonavir (LPV/r) syrup has many challenges in low-income countries, including limited availability, requires refrigeration, interactions with anti-tuberculous drugs, twice-daily dosing, poor palatability in young children, and higher cost than non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. Successfully initiating LPV/r-based ART in HIV-infected children aged <2 years raises operational challenges that could be simplified by switching to a protease inhibitor-sparing therapy based on efavirenz (EFV), although, to date, EFV is not recommended in children <3 years.\n\n\n\nThe MONOD ANRS 12026 study is a phase 3 non-inferiority open-label randomised clinical trial conducted in Abidjan, Côte d'Ivoire, and Ouagadougou, Burkina Faso (ClinicalTrial.gov registry: NCT01127204). HIV-1-infected children who were tuberculosis-free and treated before the age of 2 years with 12-15 months of suppressive twice-daily LPV/r-based ART (HIV-1 RNA viral load (VL) <500 copies/mL, confirmed) were randomised to two arms: once-daily combination of abacavir (ABC) + lamivudine (3TC) + EFV (referred to as EFV) versus continuation of the twice-daily combination zidovudine (ZDV) or ABC + 3TC + LPV/r (referred to as LPV). The primary endpoint was the difference in the proportion of children with virological suppression by 12 months post-randomisation between arms (14% non-inferiority bound, Chi-squared test).\n\n\n\nBetween May 2011 and January 2013, 156 children (median age 13.7 months) were initiated on ART. After 12-15 months on ART, 106 (68%) were randomised to one of the two treatment arms (54 LPV, 52 EFV); 97 (91%) were aged <3 years. At 12 months post-randomisation, 46 children (85.2%) from LPV versus 43 (82.7%) from EFV showed virological suppression (defined as a VL <500 copies/mL; difference, 2.5%; 95% confidence interval (CI), -11.5 to 16.5), whereas seven (13%) in LPV and seven (13.5%) in EFV were classed as having virological failure (secondary outcome, defined as a VL ≥1000 copies/mL; difference, 0.5%; 95% CI, -13.4 to 12.4). No significant differences in adverse events were observed, with two adverse events in LPV (3.7%) versus four (7.7%) in EFV (p = 0.43). On genotyping, 13 out of 14 children with virological failure (six out of seven EFV, seven out of seven LPV) had a drug-resistance mutation: nine (five out of six EFV, four out of seven LPV) had one or more major NNRTI-resistance mutations whereas none had an LPV/r-resistance mutation.\n\n\n\nAt the VL threshold of 500 copies/mL, we could not conclusively demonstrate the non-inferiority of EFV on viral suppression compared to LPV because of low statistical power. However, non-inferiority was confirmed for a VL threshold of <1000 copies/mL. Resistance analyses highlighted a high frequency of NNRTI-resistance mutations. A switch to an EFV-based regimen as a simplification strategy around the age of 3 years needs to be closely monitored.\n\n\n\nClinicalTrial.gov registry n° NCT01127204 , 19 May 2010.",
"affiliations": "MONOD Project, ANRS 12206, Centre de Recherche Internationale pour la Santé, Ouagadougou, Burkina Faso.;Paediatric Department, Centre Hospitalier Universitaire of Cocody, Abidjan, Côte d'Ivoire.;Inserm, Unité U1219, Université de Bordeaux, Bordeaux, France.;PACCI Programme, Site ANRS, Projet MONOD, Abidjan, Côte d'Ivoire.;MONOD Project, ANRS 12206, Centre de Recherche Internationale pour la Santé, Ouagadougou, Burkina Faso.;Department of Infection and Immunity, Luxembourg Institute of Health, Luxembourg City, Luxembourg.;Laboratory CeDReS, Abidjan, Côte d'Ivoire.;Laboratory, Centre Hospitalier Universitaire de Ouagadougou, Ouagadougou, Burkina Faso.;EA 8, Université Paris Descartes, Paris, France.;Paediatric Department, Centre Hospitalier Universitaire Yalgado Ouédraogo, Ouagadougou, Burkina Faso.;Paediatric Department, Centre Hospitalier Universitaire de Yopougon, Abidjan, Côte d'Ivoire.;Paediatric Department, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium.;PACCI Programme, Site ANRS, Projet MONOD, Abidjan, Côte d'Ivoire.;Paediatric Department, Centre Hospitalier Universitaire Charles de Gaulle, Ouagadougou, Burkina Faso.;UMR 1058, Pathogenesis and control of chronic infections, Inserm/Université de Montpellier/EFS, Montpellier, France.;CePReF-enfants, Yopougon, Abidjan, Côte d'Ivoire.;Paediatric Department, Centre Hospitalier Universitaire Yalgado Ouédraogo, Ouagadougou, Burkina Faso.;Inserm, Unité U1219, Université de Bordeaux, Bordeaux, France.;Centre Muraz, Bobo-Dioulasso, Burkina Faso.;Paediatric Department, Centre Hospitalier Universitaire de Yopougon, Abidjan, Côte d'Ivoire.;Inserm, Unité U1027, Université Toulouse 3, Toulouse, France. valeriane.leroy@inserm.fr.",
"authors": "Dahourou|Désiré Lucien|DL|;Amorissani-Folquet|Madeleine|M|;Malateste|Karen|K|;Amani-Bosse|Clarisse|C|;Coulibaly|Malik|M|;Seguin-Devaux|Carole|C|;Toni|Thomas|T|;Ouédraogo|Rasmata|R|;Blanche|Stéphane|S|;Yonaba|Caroline|C|;Eboua|François|F|;Lepage|Philippe|P|;Avit|Divine|D|;Ouédraogo|Sylvie|S|;Van de Perre|Philippe|P|;N'Gbeche|Sylvie|S|;Kalmogho|Angèle|A|;Salamon|Roger|R|;Meda|Nicolas|N|;Timité-Konan|Marguerite|M|;Leroy|Valériane|V|;|||",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D004338:Drug Combinations; D018894:Reverse Transcriptase Inhibitors; C492871:abacavir, lamivudine drug combination; D061466:Lopinavir; D019259:Lamivudine; C098320:efavirenz; D019438:Ritonavir",
"country": "England",
"delete": false,
"doi": "10.1186/s12916-017-0842-4",
"fulltext": "\n==== Front\nBMC MedBMC MedBMC Medicine1741-7015BioMed Central London 84210.1186/s12916-017-0842-4Research ArticleEfavirenz-based simplification after successful early lopinavir-boosted-ritonavir-based therapy in HIV-infected children in Burkina Faso and Côte d’Ivoire: the MONOD ANRS 12206 non-inferiority randomised trial Dahourou Désiré Lucien ddahourou@gmail.com 123Amorissani-Folquet Madeleine amorissanifolquet@hotmail.fr 4Malateste Karen Karen.Malateste@isped.u-bordeaux2.fr 3Amani-Bosse Clarisse abclarisse@yahoo.fr 5Coulibaly Malik coulmalik@yahoo.fr 1Seguin-Devaux Carole Carole.Devaux@lih.lu 6Toni Thomas ta_toni@yahoo.com 7Ouédraogo Rasmata ramaouedtra@yahoo.fr 8Blanche Stéphane stephane.blanche@aphp.fr 910Yonaba Caroline caroyonaba@yahoo.fr 11Eboua François ebouatk@yahoo.fr 12Lepage Philippe Philippe.LEPAGE@huderf.be 13Avit Divine divineshine2005@yahoo.fr 5Ouédraogo Sylvie ouedraogo_sylvie@yahoo.fr 14Van de Perre Philippe p-van_de_perre@chu-montpellier.fr 1516N’Gbeche Sylvie ngmariesyl@yahoo.ca 17Kalmogho Angèle zangele2001@yahoo.fr 11Salamon Roger Roger.Salamon@isped.u-bordeaux2.fr 3Meda Nicolas 218Timité-Konan Marguerite timite_marguerite@yahoo.fr 12Leroy Valériane +33 5 61 14 59 57/+33 6 72 43 26 36valeriane.leroy@inserm.fr 19on behalf of the MONOD Study Group 1 0000 0000 8737 921Xgrid.218069.4MONOD Project, ANRS 12206, Centre de Recherche Internationale pour la Santé, Ouagadougou, Burkina Faso 2 0000 0004 0564 1122grid.418128.6Centre Muraz, Bobo-Dioulasso, Burkina Faso 3 0000 0001 2106 639Xgrid.412041.2Inserm, Unité U1219, Université de Bordeaux, Bordeaux, France 4 grid.414369.dPaediatric Department, Centre Hospitalier Universitaire of Cocody, Abidjan, Côte d’Ivoire 5 PACCI Programme, Site ANRS, Projet MONOD, Abidjan, Côte d’Ivoire 6 grid.451012.3Department of Infection and Immunity, Luxembourg Institute of Health, Luxembourg City, Luxembourg 7 Laboratory CeDReS, Abidjan, Côte d’Ivoire 8 0000 0000 8737 921Xgrid.218069.4Laboratory, Centre Hospitalier Universitaire de Ouagadougou, Ouagadougou, Burkina Faso 9 0000 0001 2188 0914grid.10992.33EA 8, Université Paris Descartes, Paris, France 10 0000 0004 0593 9113grid.412134.1Immunology, Hematology, Rhumatologie Unit, Hopital Necker-Enfants Malades–Assistance Publique–Hopitaux de Paris, Paris, France 11 0000 0004 0524 0740grid.461879.5Paediatric Department, Centre Hospitalier Universitaire Yalgado Ouédraogo, Ouagadougou, Burkina Faso 12 grid.414389.3Paediatric Department, Centre Hospitalier Universitaire de Yopougon, Abidjan, Côte d’Ivoire 13 0000 0001 2348 0746grid.4989.cPaediatric Department, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium 14 Paediatric Department, Centre Hospitalier Universitaire Charles de Gaulle, Ouagadougou, Burkina Faso 15 UMR 1058, Pathogenesis and control of chronic infections, Inserm/Université de Montpellier/EFS, Montpellier, France 16 0000 0000 9961 060Xgrid.157868.5Department of Bacteriology-Virology, CHU Montpellier, Montpellier, France 17 CePReF-enfants, Yopougon, Abidjan, Côte d’Ivoire 18 0000 0000 8737 921Xgrid.218069.4University of Ouagadougou, Ouagadougou, Burkina Faso 19 grid.457379.bInserm, Unité U1027, Université Toulouse 3, Toulouse, France 24 4 2017 24 4 2017 2017 15 8531 10 2016 22 3 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe 2016 World Health Organization guidelines recommend all children <3 years start antiretroviral therapy (ART) on protease inhibitor-based regimens. But lopinavir/ritonavir (LPV/r) syrup has many challenges in low-income countries, including limited availability, requires refrigeration, interactions with anti-tuberculous drugs, twice-daily dosing, poor palatability in young children, and higher cost than non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. Successfully initiating LPV/r-based ART in HIV-infected children aged <2 years raises operational challenges that could be simplified by switching to a protease inhibitor-sparing therapy based on efavirenz (EFV), although, to date, EFV is not recommended in children <3 years.\n\nMethods\nThe MONOD ANRS 12026 study is a phase 3 non-inferiority open-label randomised clinical trial conducted in Abidjan, Côte d’Ivoire, and Ouagadougou, Burkina Faso (ClinicalTrial.gov registry: NCT01127204). HIV-1-infected children who were tuberculosis-free and treated before the age of 2 years with 12–15 months of suppressive twice-daily LPV/r-based ART (HIV-1 RNA viral load (VL) <500 copies/mL, confirmed) were randomised to two arms: once-daily combination of abacavir (ABC) + lamivudine (3TC) + EFV (referred to as EFV) versus continuation of the twice-daily combination zidovudine (ZDV) or ABC + 3TC + LPV/r (referred to as LPV). The primary endpoint was the difference in the proportion of children with virological suppression by 12 months post-randomisation between arms (14% non-inferiority bound, Chi-squared test).\n\nResults\nBetween May 2011 and January 2013, 156 children (median age 13.7 months) were initiated on ART. After 12–15 months on ART, 106 (68%) were randomised to one of the two treatment arms (54 LPV, 52 EFV); 97 (91%) were aged <3 years. At 12 months post-randomisation, 46 children (85.2%) from LPV versus 43 (82.7%) from EFV showed virological suppression (defined as a VL <500 copies/mL; difference, 2.5%; 95% confidence interval (CI), −11.5 to 16.5), whereas seven (13%) in LPV and seven (13.5%) in EFV were classed as having virological failure (secondary outcome, defined as a VL ≥1000 copies/mL; difference, 0.5%; 95% CI, −13.4 to 12.4). No significant differences in adverse events were observed, with two adverse events in LPV (3.7%) versus four (7.7%) in EFV (p = 0.43). On genotyping, 13 out of 14 children with virological failure (six out of seven EFV, seven out of seven LPV) had a drug-resistance mutation: nine (five out of six EFV, four out of seven LPV) had one or more major NNRTI-resistance mutations whereas none had an LPV/r-resistance mutation.\n\nConclusions\nAt the VL threshold of 500 copies/mL, we could not conclusively demonstrate the non-inferiority of EFV on viral suppression compared to LPV because of low statistical power. However, non-inferiority was confirmed for a VL threshold of <1000 copies/mL. Resistance analyses highlighted a high frequency of NNRTI-resistance mutations. A switch to an EFV-based regimen as a simplification strategy around the age of 3 years needs to be closely monitored.\n\nTrial registration\nClinicalTrial.gov registry n°NCT01127204, 19 May 2010.\n\nKeywords\nAfricaHIVEarly antiretroviral treatmentInfantsProtease inhibitorsLopinavirEfavirenzRandomised clinical trialVirological outcomesTreatment simplificationANRS12206http://dx.doi.org/10.13039/501100001713European and Developing Countries Clinical Trials PartnershipIP.2007.33011.002FNR-LxembourgFrench ANRS12206-B89issue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nDespite effective interventions to prevent mother-to-child transmission (PMTCT) in sub-Saharan Africa [1], the seriousness of the paediatric epidemic remains real, mainly for operational reasons. According to UNAIDS, in 2013, 3.2 million children <15 years of age were living with HIV and 240,000 children were newly HIV-infected worldwide [2]. In the absence of antiretroviral therapy (ART), HIV-related infant mortality in Africa is dramatically high and occurs early, reaching 52% by the age of 2 years [3]. The 12-month efficacy of early ART initiated in all HIV-infected children reported in the CHER trial in South Africa showed a significant reduction of 76% in infant mortality among children treated immediately from 12 weeks of age, compared to those deferred according to the 2006 World Health Organization (WHO) recommendations [4]. Consequently, ART initiation was recommended for all HIV-infected children <12 months of age in 2008 [5], extended to all children <24 months in 2010 [6], and at the earliest convenience in all those <5 years in 2013 [7]. In 2015, WHO recommended that ART be initiated in everyone living with HIV at any CD4 cell count [8].\n\nIn low-income countries, the first-line therapy recommended for all children <36 months is based on a boosted protease inhibitor, lopinavir-boosted ritonavir (LPV/r), regardless of perinatal non-nucleoside reverse transcriptase inhibitor (NNRTI) exposure [7, 8]. Two trials have demonstrated the superiority of first-line LPV/r-based ART compared to first-line nevirapine (NVP) in populations of young children with or without pre-exposure to NVP for PMTCT [9, 10]. LPV/r is a potent drug, with a high genetic barrier against resistance, and is especially effective when combined with two nucleoside reverse transcriptase inhibitors (NRTIs) [11]. First-line LPV/r also leads to longer life expectancy and is cost saving compared to first-line NVP [12]. The backbone recommended is based on two NRTIs: abacavir (ABC), preferentially, or zidovudine (AZT), and lamivudine (3TC).\n\nThe choice of LPV/r-based therapy may nevertheless be operationally challenging, with many drawbacks restraining its use as a first-choice therapy in young children in Africa. The currently available oral syrup forms of LPV/r for infants have a thermostability issue that requires the use of refrigeration for storage and distribution [13], as well as having poor palatability. LPV/r is also used as a second-line drug owing to the current scarcity of antiretroviral drugs adapted to paediatric use. In addition, there are potential metabolic complications and interactions with anti-tuberculous drugs [14]. In May 2015, the United State Food and Drug Administration (FDA) approved the use of LPV/r oral pellets in children (http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/205425Orig1s000TAltr.pdf), which has overcome the challenges of the cold chain. However, these pellets still need to be assessed in Africa. Consequently, we explored whether it would be possible to substitute this initial LPV-based regimen in children with confirmed virological suppression with a once-daily ART that is easier to handle and more acceptable, while saving protease inhibitors for later use if virological failure occurs, in the context of poor access to second-line treatments. We selected efavirenz (EFV) dosed once daily with paediatric-friendly formulations, which is well tolerated and can be used in combination with anti-tuberculous drugs [15].\n\nWe hypothesised that, for children who were started on a twice-daily LPV-based ART and who were virologically suppressed after an initial 12–15-month period, ART could be simplified in the long term with a once-daily EFV-based therapy.\n\nMethods\nStudy design\nThe MONOD ANRS 12206 study is a non-inferiority, open-label phase 3 randomised clinical trial conducted in Ouagadougou, Burkina Faso, and Abidjan, Côte d’Ivoire (ClinicalTrial.gov registry number: NCT01127204, first registered on 19 May 2010). Study sites were the Abobo-Avocatier urban health clinic, the CePReF-enfant and the Yopougon and Cocody University Hospitals in Abidjan, and the Yalgado Ouédraogo and the Charles de Gaulle University Hospitals in Ouagadougou. The protocol was approved by the Comité d’Ethique pour la Recherche en Santé du Burkina Faso and the Comité National d’Ethique et de la Recherche en Côte d’Ivoire.\n\nParticipants\nAn initial therapeutic cohort included all children with an HIV-1 infection confirmed by HIV-1 DNA polymerase chain reaction (PCR) who were aged <24 months, free of tuberculosis, and antiretroviral-naïve except for exposure to PMTCT interventions. Both parents had to provide written consent. This initial cohort received 12–15 months of treatment with two NRTIs (ABC or AZT and 3TC) and LPV/r given twice daily, together with prophylaxis against opportunistic infections with cotrimoxazole and therapeutic education. Exclusion criteria were age ≥24 months; on current ART; a known intolerance to at least one of the drugs; HIV-2-infected or HIV-1 and -2 co-infected; tuberculosis; or a haemoglobin level <7 g/dL, neutrophils ≤750/mm3, creatinine ≥5× normal range, or aspartate transaminase (AST) or alanine transaminase (ALT) ≥5× normal range. After the initial cohort period, children with an undetectable HIV-1 RNA viral load (VL) <500 copies/mL at 12 months (confirmed at a 3-month interval) were randomised to either switch to once-daily ABC + 3TC + EFV (hereafter referred to as EFV) therapy or stay on the twice-daily LPV regimen (AZT + 3TC + LPV/r or ABC + 3TC + LPV/r). Children with a detectable VL were not randomised and were maintained on a LPV regimen with therapeutic education reinforcement.\n\nRandomisation\nA centralised computer-generated sequentially numbered block randomisation list, stratified according to country, was drawn up and included in an online software randomisation system to allocate the treatment arm through a secure website set up by the data management centre in Bordeaux, France. After the programme verified all pre-specified inclusion criteria, children were automatically randomly assigned to one arm (1:1), either the control strategy (LPV-based therapy) the simplified strategy (EFV-based therapy). After randomisation, an automatic printout showing the treatment decision and the ID number of the randomised arm was forwarded to the trial coordinator.\n\nTrial treatments\nIn the control strategy, children received twice-daily triple therapy: (ZDV) (syrup 10 mg/mL, 4 mg/kg every 12 hours) or ABC (syrup 20 mg/mL, 8 mg/kg every 12 hours) + 3TC (syrup 10 mg/mL, 4 mg/kg every 12 hours) + LPV/r (syrup 80/20 mg/mL, 12 mg/kg every 12 hours). In the simplified strategy, children received once-daily triple therapy: ABC (syrup 20 mg/mL, 16 mg/kg every morning) + 3TC (syrup 10 mg/mL, 8 mg/kg every morning) + EFV (syrup 30 mg/mL, 25 mg/kg every morning on an empty stomach). Although EFV is not recommended for children <3 years or <10 kg, according to the WHO guidelines [7], we used EFV in children younger than the recommended age and at a dosage of 25 mg/kg, according to a paediatric pharmacokinetic (PK) study conducted in Burkina Faso [16]. As recommended by the WHO, all children systematically received prophylaxis for opportunistic infections with cotrimoxazole syrup: sulfamethoxazole (20 mg/kg) + trimethoprim (4 mg/kg) once daily during the entire study. The assistant pharmacist and social worker systematically delivered therapeutic education when the drugs were given to families.\n\nThe drugs were provided by the national AIDS programmes under the responsibility of the country coordinating centres in charge of supplies and qualification of the batches. The inclusion process in the initial cohort started in May 2011. In 2012, in Abidjan, the national AIDS control programme introduced oro-dispersible fixed-dose formulation tablets for ABC and 3TC using WHO weight band dosing to substitute for the syrup formulations.\n\nProcedures\nA pre-inclusion visit, 4 weeks before ART initiation, included informed consent, an interview to assess medical history (perinatal or neonatal PMTCT exposure), a complete clinical examination (weight, height and WHO clinical staging), tuberculosis screening (chest X-ray), a standard blood test (haematology, creatinine, urea, AST, ALT, total bilirubin, glucose, alkaline phosphatases, amylase, lipase, lipid assessment [total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, very low-density lipoprotein], fasting blood glucose), a CD4 lymphocyte sub-population count (percentage and absolute count), and a confirmation of HIV status (quantitative HIV-1 RNA in plasma and quantitative proviral DNA). Where symptoms suggested tuberculosis (prolonged fever, chronic cough, recent malnutrition or failure of classic antibiotics for an infectious syndrome) the diagnosis was completed with a tuberculin skin test, gastric lavage on three consecutive days and stool examination for Mycobacterium tuberculosis.\n\nAll children were followed for 12–15 months after inclusion (defined as ART initiation), then for 12 months after randomisation. After inclusion, children had monthly clinical follow-up visits recording all clinical events, including adverse effects, weight- and height-for-age z-scores calculated using the WHO software, drug uptake, measurement of adherence (doses taken in the past 4 days), delivery of drugs and therapeutic education. Screening for clinical neurological/sleep adverse events was performed at each monthly visit by trained paediatricians who systematically looked for sleeping adverse events and performed a neurological examination.\n\nStandard blood tests were repeated every 6 months. CD4 cell counts and VL were measured quarterly at the Laboratoire du CeDreS in Abidjan and the Reference Laboratory of CHU Charles de Gaulle in Ouagadougou using a FACScan flow cytometer (Becton Dickinson, Mountain View, CA). VLs were measured with real-time PCR using a commercial assay (Generic HIV Charge Virale, Biocentric, Bandol, France) [17]. These methods were being used at that time according to the manufacturer’s protocol in both Abidjan and Ouagadougou, where this method was validated. At the time of study implementation, in 2011, the manufacturer’s threshold for VL was 400 copies/mL as written in the protocol, but the threshold validated at the country level differed: it was 400 copies/mL in the Abidjan laboratory and 500 copies/mL in the Ouagadougou laboratory. The laboratory in Ouagadougou was not able to guarantee results below 500 copies/mL. Therefore, we decided to homogenise the threshold to <500 copies/mL at both sites to define viral suppression. HIV-1 genotypic resistance testing was performed upon virological failure (HIV-1 RNA ≥1000 copies/mL, the commonly used threshold to guide treatment strategies [8]) and at enrolment before ART initiation in Abidjan for samples collected in Côte d’Ivoire and in Luxembourg for samples collected in Burkina Faso. The ANRS consensus technique (www.hivfrenchresistance.org) was used to genotype protease and reverse transcriptase genes. Sequences were edited with Bio-Edit sequence Alignment Editor (version 7.0) and trees constructed with Mega 4. Relevant drug-resistance mutations were interpreted according to the Stanford University HIV Drug Resistance Database (HIVdb Program, http://hivdb.stanford.edu) and the ANRS-v24 interpretation rule (http://www.hivfrenchresistance.org/2011/Algo-2011.pdf). HIV-1 subtypes were assigned using REGA (http://www.bioafrica.net/rega-genotype/html/index.html) and COMET (http://comet.retrovirology.lu) HIV-1 subtyping tools against reference HIV-1 group M sequences from GenBank (http://www.ncbi.nlm.nih.gov/Genbank/index.html). Blood samples were collected from children and transferred for processing within 4 hours. Two plasma samples were prepared and stored at −80 °C: one to perform VL measurement and one for resistance testing if the VL was >1000 copies/mL. Quality controls were performed for diagnostic PCR and VL (CDC, Atlanta, GA, USA) every 6 months and for genotyping (ANRS, Paris, France or Quality Controls in Molecular Diagnostics, Utrecht, the Netherlands) on a yearly basis.\n\nOutcomes\nThe primary outcome was the proportion of children alive and with virological suppression (defined as HIV-1 RNA <500 copies/mL) at 12 months post-randomisation; this specific time point was considered regardless of any detectable VL between randomisation and 12 months. Secondary outcomes were virological failure (defined as HIV-1 RNA ≥1000 copies/mL, the commonly used threshold to guide treatment strategies [8]) at 12 months post-randomisation, adverse events, resistance mutation profiles, the clinical-immunological response, the pharmacokinetic parameters, adherence, and cost.\n\nStatistical analysis\nFor a non-inferiority trial, the statistical parameter of interest is the difference in successful viral suppression rate 12 months after the switch, defined in this instance as the rate of viral suppression in the LPV arm (control) minus the rate in the EFV arm, using a Chi-squared test. If this difference is >0, outcomes favour the control group [18]. We aimed to obtain virological success of at least 76% at 12 months post-switch. We pre-specified that a margin of <14% for the 95% confidence interval (CI) of the difference in the primary outcome between the two arms would meet our criteria for non-inferiority. Both an intention-to-treat analysis conducted using all available data, and a per-protocol analysis were conducted as recommended for non-inferiority trials [19]. Based on our anticipated enrolment of 146 children with 73 children per arm, we expected an 80% power to detect this difference. In the CHER trial, the 12-month survival probability in infants on a LPV/r-based triple therapy was 96% [4]. Because virological data were not yet available at the time of our protocol, we expected a 95% response on LPV according to the Yeni 2008 report [11]. Thus, assuming a 12-month virological suppression among survivors on LPV of 90%, we anticipated recruited 162 children in the initial LPV-based cohort. To compare the characteristics of the study population, we used Chi-squared or Fisher’s exact tests for categorical variable and t tests or Mann–Whitney tests for continuous variables. We analysed the correlates of viral suppression at 12 months post-randomisation, using a multivariate logistic regression. All p values were two sided and p < 0.05 was considered statistically significant. Analyses were performed using SAS version 9.1.3.\n\nResults\nTrial profile and baseline characteristics\nBetween May 2011 and January 2013, 226 children were referred to the study clinics (Fig. 1). Of these, 65 children (28%) were not initiated on ART, mainly due to parent’s refusal (12%), early deaths (10%), a false-positive dried blood spot HIV DNA PCR result (4%) or other reasons (2%). That left 161 children (72%) who were initiated on ART before 24 months of age [20]. Among them, five were initiated on EFV-based ART because of tuberculosis co-infection at inclusion.Fig. 1 MONOD ANRS 12206 Trial profile in Abidjan, Côte d’Ivoire, and Ouagadougou, Burkina Faso, 2011–2015. ART antiretroviral therapy, EFV efavirenz-based ART, LPV lopinavir-boosted-based ART\n\n\n\n\nThe remaining 156 children were initiated on LPV-based ART (Fig. 1). Their median age at HIV-1 diagnosis was 8.5 months, and at ART initiation was 13.7 months. After 12–15 months on ART, only 68% were alive and showed virological suppression: 13 had died (8%), two were lost to follow-up (1%), three withdrew (2%) and 32 had virological failure (21%). Details on this cohort are presented elsewhere [21].\n\nOf the 106 children who were eligible for randomisation, that is, alive and showing virological suppression, 54 were randomised to maintain LPV therapy, and 52 to switch to EFV (Fig. 1); all were included in the intention-to-treat analysis. Among the children randomised, 91% (97 out of 106) were aged <3 years (49 in the LPV arm and 48 in the EFV arm).\n\nThere were no significant differences between the two groups’ baseline characteristics at the time of randomisation (Table 1). Overall, 67.0% lived in Abidjan, 55.7% were girls, the father was the main caregiver for 17.0%, 39.6% had not been exposed to any PMTCT intervention or maternal ART, 30.2% were exposed to perinatal PMTCT prophylaxis alone, 8.5% were born to mothers on ART, and 21.7% were exposed to postnatal maternal ART initiated during breastfeeding (Table 1). At the time of ART initiation, the children already had advanced HIV-disease progression: 54.7% were WHO stage 3 or 4 [6], the median CD4 percentage was 20.8% and their mean VL was 6.1 log10 copies/mL (SD: 1). After 12–15 months on ART, at the time of randomisation, the median age was 26.8 months and median CD4% had increased to 35.9%; the CD4% for both groups was within the normal range. Overall, children were virologically suppressed for a median of 6 months before randomisation.Table 1 Baseline characteristics according to randomisation arm of the 106 HIV-1-infected children randomised in the ANRS 12206 MONOD trial (Abidjan and Ouagadougou, May 2011–April 2014)\n\nCharacteristics\tTotal N = 106\tAZT or ABC + 3TC + LPV/r (twice daily) N = 54\tABC + 3TC + EFV (once daily) N = 52\t\np value\t\nPre-trial characteristics\t\n Abidjan site, n (%)\t71 (67.0)\t36 (66.7)\t35 (67.3)\t0.94\t\n Age (months) at HIV-1 diagnosis, median (IQR)\t8. 5 (3.3–15.6)\t8.4 (3.8–16.5)\t9.8 (2.8–15.4)\t0.84\t\n Age (months) at ART initiation, median (IQR)\t13.7 (7.9–18.4)\t12.8 (8.1–18.4)\t14.2 (7.6–18.4)\t0.96\t\n Female, n (%)\t59 (55.7)\t35 (64.8)\t24 (46.2)\t0.05\t\n Father or other as main caregiver, n (%)\t18 (17.0)\t10 (18.5)\t8 (15.4)\t0.67\t\n Tap water at home, n (%)\t78 (73.6)\t39 (72.2)\t39 (75.0)\t0.74\t\n Electricity at home, n (%)\t84 (79.2)\t43 (79.6)\t41 (78.9)\t0.92\t\n Ever breastfed from birth, n (%)\t92 (86.8)\t45 (83.3)\t47 (90.4)\t0.28\t\n Breastfeeding duration (months) for those breastfed, median (IQR)\t13.8 (7.6–21.4)\t16.0 (7.5–21.5)\t12.0 (7.7–19.6)\t0.49\t\nHistory of antiretroviral drug exposure\t\n Prenatal maternal ART, n (%)\t9 (8.5)\t5 (9.3)\t4 (7.7)\t1.00\t\n AZT/TDF + 3TC/FTC + NVP\t8 (88.9)\t4 (80.0)\t4 (100.0)\t\t\n AZT + 3TC + EFV\t1 (11.1)\t1 (20.0)\t0 (0.0)\t\t\n PMTCT and postnatal maternal ART\t10 (9.4)\t7 (13.0)\t3 (5.8)\t0.32\t\n PMTCT\t\t\t\t1.00\t\n sdNVP-based PMTCT\t2 (20.0)\t2 (28.6)\t0 (0.0)\t\t\n Other than sdNVP-based PMTCT\t8 (80.0)\t5 (71.4)\t3 (100.0)\t\t\n Postnatal maternal HAART\t\t\t\t1.00\t\n AZT/TDF + 3TC/FTC + NVP\t8 (80.0)\t5 (71.4)\t3 (100.0)\t\t\n AZT + 3TC + LPV/r\t2 (20.0)\t2 (28.6)\t0 (0.0)\t\t\n PMTCT only\t32 (30.2)\t15 (27.8)\t17 (32.7)\t0.58\t\n Only sdNVP-based PMTCT\t5 (15.6)\t3 (20.0)\t2 (11.8)\t\t\n Other than sdNVP-based PMTCT\t27 (84.4)\t12 (80.0)\t15 (88.2)\t\t\n Postnatal maternal ART only\t13 (12.3)\t7 (13.0)\t6 (11.5)\t0.82\t\n D4T/AZT + 3TC + NVP\t8 (61.5)\t4 (57.1)\t4 (66.7)\t\t\n AZT/D4T/TDF + 3TC/FTC + EFV\t3 (23.1)\t2 (28.6)\t1 (16.7)\t\t\n D4T + 3TC + LPV/r\t1 (7.7)\t0 (0.0)\t1 (16.7)\t\t\n Missing\t1 (7.7)\t1 (14.3)\t0 (0.0)\t\t\n No previous exposure to any PMTCT or maternal ART\t42 (39.6)\t20 (37.0)\t22 (42.3)\t0.58\t\nZ-scores at child’s ART initiation, mean (SD)\t\n Weight-for-age\t−2.3 (1.5)\t−2.3 (1.4)\t−2.3 (1.6)\t0.81\t\n Height-for-age\t−2.2 (1.7)\t−2.1 (1.7)\t−2.3 (1.7)\t0.53\t\n Weight-for-height\t−1.5 (1.4)\t−1.5 (1.3)\t−1.4 (1.5)\t0.84\t\n WHO stage\t\t\t\t0.86\t\n Stage 1 or 2, n (%)\t48 (45.3)\t24 (44.4)\t24 (46.2)\t\t\n Stage 3 or 4, n (%)\t58 (54.7)\t30 (55.6)\t28 (53.9)\t\t\n Haemoglobin (g/dL), median (IQR)\t9.2 (8.4–9.9)\t9.1 (8.5–10.0)\t9.4 (8.4–9.9)\t0.75\t\n CD4 %, median (IQR)\t20.8 (14.2–28.1)\t18.9 (13.9–27.4)\t21.2 (15.0–28.8)\t0.65\t\n Viral load (log10 copies/mL), median (SD)\t6.1 (1.0)\t6.2 (1.0)\t6.0 (1.0)\t0.51\t\n Viral load ≥6 log10 copies/mL, n (%)\t58 (54.7)\t30 (55.6)\t28 (53.8)\t0.86\t\n First-line NRTI backbone\t\t\t\t0.31\t\n ZDV-3TC, n (%)\t95 (89.6)\t50 (92.6)\t45 (86.5)\t\t\n ABC-3TC, n (%)\t11 (10.4)\t4 (7.4)\t7 (13.5)\t\t\n Ever start cotrimoxazole, n (%)\t104 (98.1)\t53 (98.1)\t51 (98.1)\t1.00\t\nAt randomisation\t\n Age (months), median (IQR)\t26.8 (21.5–31.5)\t26.0 (21.8–31.3)\t27.2 (20.8–31.5)\t0.84\t\n Duration on HAART (months), median (IQR)\t12.7 (12.1–13.0)\t12.7 (12.1–13.0)\t12.6 (12.1–13.0)\t0.86\t\n Weight (kg), median (IQR)\t10.2 (9.2–11.4)\t10.2 (9.3–11.2)\t10.2 (9.1–11.6)\t0.92\t\n WHO stage 3 or 4, n (%)\t49 (46.2)\t25 (46.3)\t24 (46.1)\t0.99\t\n CD4 %, median (IQR)\t35.9 (28.5–40.9)\t36.4 (28.5–40.7)\t34.9 (28.5–41.1)\t0.63\t\n On cotrimoxazole, n (%)\t106 (100.0)\t54 (100.0)\t52 (100.0)\t–\t\n\nAZT Zidovudine, ABC Abacavir, 3TC Lamivudine, LPV/r Lopinavir-boosted ritonavir, EFV Efavirenz, IQR Interquartile range, ART Antiretroviral therapy, TDF Tenofovir, FTC Emtricitabine, NVP Nevirapine, PMTCT Prevention of mother-to-child-transmission, sdNVP Single-dose nevirapine, HAART Highly active antiretroviral therapy, D4T Stavudine, SD Standard deviation, WHO World Health Organization, NRTI Nucleoside reverse transcriptase inhibitor\n\n\n\n\nVirological suppression\nAt 12 months post-randomisation, all children were alive and followed up, without any missing data on VL outcomes (Table 2). In an intention-to-treat analysis, 46 out of 54 children (85.2%) in the LPV arm vs. 43 out of 52 (82.7%) in the EFV arm had a VL <500 copies/mL (p = 0.72). The difference was 2.5% (95% CI, −11.5 to 16.5), tending to favour the LPV arm. The 95% CI included the pre-specified non-inferiority margin of 14%; therefore, this analysis was deemed inconclusive. The actual statistical power to detect a difference was 67%. Among the children aged <3 years, 42 out of 49 (85.7%) in the LPV arm vs. 39 out of 48 (81.3%) in the EFV arm had a VL <500 copies/mL (p = 0.55).Table 2 Twelve-month post-randomisation primary and secondary outcomes in the 106 HIV-1-infected children randomised in the ANRS 12206 MONOD study according to arm (Abidjan and Ouagadougou, February 2013–April 2015)\n\n12-month outcomes\tTotal N = 106\tArm 1: AZT + 3TC + LPV/r (twice daily) N = 54\tArm 2: ABC + 3TC + EFV (once daily) N = 52\t\np value\t\nFollow-up (months), median (IQR)\t12.7 (12.1–13.0)\t12.7 (12.1–13.0)\t12.6 (12.1–13.0)\t0.44\t\nDeath\t0 (0.0)\t0 (0.0)\t0 (0.0)\t-\t\nLoss to follow-up\t0 (0.0)\t0 (0.0)\t0 (0.0)\t-\t\nWithdrawal\t0 (0.0)\t0 (0.0)\t0 (0.0)\t-\t\nVirological success (VL < 500 copies/mL)\t89 (84.0)\t46 (85.2)\t43 (82.7)\t0.72\t\nVirological failure (500 ≥ VL < 1000 copies/mL)\t3 (2.8)\t1 (1.8)\t2 (3.8)\t-\t\nVirological failure (VL ≥ 1000 copies/mL)\t14 (13.2)\t7 (13.0)\t7 (13.5)\t0.59\t\nCD4 %, median (IQR)\t37.3 (31.6–41.9)\t37.3 (31.3–41.6)\t37.1 (31.6–42.0)\t0.85\t\nImmunodeficiency for agea\n\t\t\t\t0.59\t\n None\t57 (53.8)\t32 (59.3)\t25 (48.1)\t\t\n Mild\t38 (35.9)\t17 (31.5)\t21 (40.4)\t\t\n Severe\t3 (2.8)\t2 (3.7)\t1 (1.9)\t\t\n Missing\t8 (7.6)\t3 (5.6)\t5 (9.6)\t\t\nZ-score, mean (SD)\t\t\t\t\t\n Weight-for-age\t−1.2 (0.9)\t−1.3 (0.8)\t−1.2 (1.0)\t0.63\t\n Height-for-age\t−1.4 (1.1)\t−1.5 (1.1)\t−1.4 (1.2)\t0.84\t\n Weight-for-height\t−0.6 (0.8)\t−0.6 (0.9)\t−0.5 (0.8)\t0.62\t\n\nAZT Zidovudine, ABC Abacavir, 3TC Lamivudine, LPV/r Lopinavir-boosted ritonavir, EFV Efavirenz, IQR Interquartile range, VL Viral load, SD Standard deviation\n\n\naSevere immunodeficiency for age: CD4 < 25% if aged <2 years, CD4 < 20% if aged ≥2 years; mild immunodeficiency for age: CD4 between 25 and 35% if aged <2 years, CD4 between 20 and 35% if aged ≥2 years; No immunodeficiency for age if CD4 > 35%\n\n\n\n\nWith regards our secondary outcome of virological failure using the threshold of >1000 copies/mL, in the intention-to-treat analysis, 7 out of 54 children (13.0%) in the LPV arm failed vs. 7 out of 52 (13.5%) in the EFV arm (p = 0.59). The difference between these rates was −0.5% (95% CI, −13.4 to 12.4). The 95% CI does not include the pre-specified non-inferiority margin of 14%; therefore, at the 1000 copies/mL threshold, EFV was considered non-inferior to LPV in our trial.\n\nThere were no significant differences in children’s characteristics according to virological success (Tables 3 and 4). For the 17 children who failed to show virological suppression (≥500 copies/mL) at 12 months, 10 failures occurred within the first 6 months. Drug modifications occurred in two children, who were switched from EFV to LPV: one for sleeping disorders persisting 10 months after randomisation, and one for hyper-transaminasaemia due to a cytotoxic treatment administrated by a healer (Table 5). The sensitivity per-protocol analysis gave similar results compared to the intention-to-treat analysis: 46 children (85.2%) in the LPV arm vs. 42 (84.0%) in the EFV arm had a VL <500 copies/mL, a difference of 1.2% (95% CI, −12.7 to 15.1). Using the 1000 copies/mL threshold, seven children (13.0%) in the LPV arm showed virological suppression vs. six (12.0%) in the EFV arm, with a difference of one (95% CI, −11.7 to 13.7).Table 3 Factors associated with 12-month virological success (<500 copies/mL) in the 106 HIV-1-infected children randomised in the ANRS 12206 MONOD study (Abidjan and Ouagadougou, February 2013–February 2015)\n\n\tTotal N = 106\tVirological success (<500 copies/mL) N = 89\tVirological failure (≥500 copies/mL) N = 17\t\np value\t\nCountry\t\t\t\t0.83\t\n Abidjan\t71 (67.0)\t60 (67.4)\t11 (64.7)\t\t\n Ouagadougou\t35 (33.0)\t29 (32.6)\t6 (35.3)\t\t\nSex\t\t\t\t0.81\t\n Female\t59 (55.7)\t50 (56.2)\t9 (52.9)\t\t\n Male\t47 (44.3)\t39 (43.8)\t8 (47.1)\t\t\nTreatment arm\t\t\t\t0.73\t\n AZT/ABC + 3TC + LPV/r\t54 (50.9)\t46 (51.7)\t8 (47.1)\t\t\n ABC + 3TC + EFV\t52 (49.1)\t43 (48.3)\t9 (52.9)\t\t\nMain caregiver for children\t\t\t\t1.00\t\n Mother main caregiver\t88 (83.0)\t74 (83.2)\t14 (82.4)\t\t\n Father/other in charge of care\t18 (17.0)\t15 (16.8)\t3 (17.6)\t\t\nFather informed of the child’s HIV status\t\t\t\t0.30\t\n No\t44 (41.5)\t35 (39.3)\t9 (52.9)\t\t\n Yes\t62 (58.5)\t54 (60.7)\t8 (47.1)\t\t\nHistory of antiretroviral drug exposure\t\t\t\t0.63\t\n Prenatal maternal ART\t9 (8.5)\t7 (7.9)\t2 (11.8)\t\t\n PMTCT only\t32 (30.2)\t27 (30.3)\t5 (29.4)\t\t\n Postnatal maternal ART only\t13 (12.3)\t12 (13.5)\t1 (5.9)\t\t\n PMTCT and postnatal maternal ART\t10 (9.4)\t7 (7.9)\t3 (17.6)\t\t\n No previous exposure to any PMTCT or ART\t42 (39.6)\t36 (40.4)\t6 (35.3)\t\t\nAge at randomisation\t\t\t\t0.39\t\n <24 months\t41 (38.7)\t36 (40.4)\t5 (29.4)\t\t\n ≥24 months\t65 (61.3)\t53 (59.6)\t12 (70.6)\t\t\nWHO clinical stage at randomisation\t\t\t\t\t\n Stage 1, 2, 3\t83 (78.3)\t73 (82.0)\t10 (58.8)\t0.05\t\n Stage 4\t23 (21.7)\t16 (18.0)\t7 (41.2)\t\t\nZ-score Weight-for-age at ART initiation\t\t\t\t0.35\t\n Normal\t50 (47.2)\t44 (49.4)\t6 (35.3)\t\t\n Moderate\t22 (20.7)\t19 (21.4)\t3 (17.6)\t\t\n Severe\t34 (32.1)\t26 (29.2)\t8 (47.1)\t\t\nZ-score Height-for-age at ART initiation\t\t\t\t0.09\t\n Normal\t55 (51.9)\t50 (56.2)\t5 (29.4)\t\t\n Moderate\t21 (19.8)\t15 (16.8)\t6 (35.3)\t\t\n Severe\t30 (28.3)\t24 (27.0)\t6 (35.3)\t\t\nCD4 % at ART initiation\t\t\t\t0.60\t\n >35%\t13 (12.3)\t10 (11.2)\t3 (17.6)\t\t\n 25–35%\t19 (17.9)\t17 (19.1)\t2 (11.8)\t\t\n <25% or missing\t74 (69.8)\t62 (69.7)\t12 (70.6)\t\t\nData are presented as n (%)\n\n\nAZT Zidovudine, 3TC Lamivudine, ABC Abacavir, EFV Efavirenz, LPV/r Lopinavir-boosted ritonavir, ART Antiretroviral therapy, PMTCT Prevention of mother-to-child-transmission, WHO World Health Organization. Normal: Z-score ≥ 2 Standard Deviations (SD); Z-score <-2 SD corresponds to moderate malnutrition, being severe form at a Z-score<-3 SD\n\n\nTable 4 Factors associated with 12-month virological success (<500 copies/mL) in the 106 HIV-1-infected children randomised in the ANRS 12206 MONOD study (Abidjan and Ouagadougou, February 2013–February 2015): logistic regression\n\n\tUnivariate\tAdjusted modela\n\t\n\tOR\tCI (95%)\t\np value\taOR\tCI (95%)\t\np value\t\nAbidjan vs. Ouagadougou\t1.13\t(0.38–3.35)\t0.83\t0.64\t(0.17–2.41)\t0.51\t\nFemale vs. Male\t1.14\t(0.40–3.23)\t0.81\t1.26\t(0.41–3.93)\t0.68\t\nTreatment arm\t\t\t0.73\t\t\t0.66\t\n AZT/ABC + 3TC + LPV/r\tRef.\t–\t\tRef.\t–\t\t\n ABC + 3TC + EFV\t0.83\t(0.29–2.35)\t\t0.78\t(0.26–2.38)\t\t\nMother main caregiver vs. father or other\t1.06\t(0.27–4.14)\t0.94\t–\t–\t\t\nFather informed of HIV status of the child\t1.74\t(0.61–4.93)\t0.30\t–\t–\t\t\nHistory of antiretroviral drug exposure\t\t\t0.68\t\t\t0.34\t\n No previous exposure to any PMTCT or ART\tRef.\t–\t\tRef.\t–\t\t\n Prenatal maternal ART\t0.58\t(0.10–3.51)\t\t0.32\t(0.04–2.32)\t\t\n Exposure to PMTCT only\t0.90\t(0.25–3.26)\t\t0.64\t(0.15–2.68)\t\t\n Exposure to postnatal maternal ART only\t2.00\t(0.22–18.33)\t\t1.95\t(0.20–19.24)\t\t\n PMTCT and postnatal maternal ART\t0.39\t(0.08–1.94)\t\t0.19\t(0.03–1.21)\t\t\nAge at randomisation <24 months\t1.63\t(0.53–5.03)\t0.39\t–\t–\t\t\nWHO clinical stage at randomisation\t\t\t0.04\t\t\t0.01\t\n Stage 1, 2, 3\tRef.\t–\t\tRef.\t–\t\t\n Stage 4\t0.31\t(0.10–0.95)\t\t0.18\t(0.05–0.72)\t\t\n\nOR Odds ratio, CI Confidence interval, aOR Adjusted odds ratio, AZT Zidovudine, 3TC Lamivudine, LPV/r Lopinavir-boosted ritonavir, ABC Abacavir, EFV Efavirenz, PMTCT Prevention of mother-to-child-transmission, ART Antiretroviral therapy, WHO World Health Organization\n\n\naForced variables: country, sex, treatment arm and history of antiretroviral drug exposure\n\n\nTable 5 Incidence of post-randomisation grade 3 and 4 adverse events in the 106 HIV-1-infected children randomised in the ANRS 12206 MONOD study according to arm (Abidjan and Ouagadougou, February 2013–April 2015)\n\nOutcomes\tTotal N = 106\tArm 1: AZT/ABC + 3TC + LPV/r (twice daily) N = 54\tArm 2: ABC + 3TC + EFV (once daily) N = 52\t\np value\t\nSAE\t\n Hospitalisations and clinical SAE\t6 (5.7)\t2d (3.7)\t4e (7.7)\t0.43\t\n Grade 3 or 4 adverse eventsa\n\t1 (0.9)\t0 (0.0)\t1 (1.9)\t0.90\t\n Toxicity causing ART modificationb\n\t3 (2.8)\t1 (1.9)\t2 (3.8)\t0.61\t\n Sleeping disorders declared by caregivers\t9 (8.5)\t4 (7.4)\t5 (9.6)\t0.74\t\nSpecific biological adverse eventsc\n\t\n Anaemia, grade 3 and 4\t3 (2.8)\t1 (1.9)\t2 (3.8)\t0.61\t\n Neutropenia, grade 3 and 4\t10 (9.4)\t9 (16.7)\t1 (1.9)\t0.02\t\n Thrombopenia, grade 3 and 4\t1 (0.9)\t1 (1.9)\t0 (0.0)\t1.00\t\n Hyperglycaemia, grade 3 and 4\t0 (0.0)\t0 (0.0)\t0 (0.0)\t-\t\n Hypercholesterolemia, grade 3\t0 (0.0)\t0 (0.0)\t0 (0.0)\t-\t\n Hypertriglyceridemia, grade 3 and 4\t0 (0.0)\t0 (0.0)\t0 (0.0)\t-\t\n Hypercreatininaemia, grade 3 and 4\t0 (0.0)\t0 (0.0)\t0 (0.0)\t-\t\n Hypertransaminasaemia AST or ALT, grade 3 and 4\t2 (1.9)\t1 (1.9)\t1 (1.9)\t1.00\t\n Hyperbilirubinaemia, grade 3 and 4\t5 (4.7)\t3 (5.6)\t2 (3.9)\t1.00\t\n Hyperamylasaemia, grade 3 and 4\t2 (1.9)\t0 (0.0)\t2 (3.9)\t0.24\t\n Hyperlipasaemia, grade 3 and 4\t0 (0.0)\t0 (0.0)\t0 (0.0)\t-\t\nData are presented as n (%)\n\n\nAZT Zidovudine, 3TC Lamivudine, LPV/r Lopinavir-boosted ritonavir, ABC Abacavir, EFV Efavirenz, SAE Serious adverse events, ART Antiretroviral therapy, AST Aspartate transaminase, ALT Alanine transaminase\n\n\naHepatitis due to a cytotoxic treatment administrated by a healer\n\n\nbOne toxicity substitution in a child randomised to LPV/r was from AZT to ABC for neutropenia. Two toxicity substitutions in children randomised to EFV to LPV arm: one for sleeping disorders persisting 10 months after randomisation and one for hypertransaminasaemia due to a cytotoxic treatment administrated by a healer\n\n\ncNo other biological SAE including glycaemia, cholesterolaemia, triglyceridaemia, creatininaemia, lipaseamia\n\n\nd2 gastroenteritis\n\n\ne1 gastroenteritis, 1 pneumonia, 1 upper respiratory infection with malaria, 1 malaria\n\n\n\n\nOther secondary outcomes\nAfter 12 months, 53.8% of children overall were non-immunodeficient, and there were no significant differences in CD4% between arms: the median CD4% was 37.3% in the LPV arm vs. 37.1% in the EFV arm (p = 0.85; Table 2). Children in the LPV arm had a 0.1 lower mean z-score for weight-for-age, height-for-age and weight-for-height, although this difference was not significant between arms. There were no significant differences in the occurrence of severe adverse events after randomisation (Table 5): two hospitalisations occurred in the LPV arm vs. four in the EFV arm, all due to infectious diseases (p = 0.43). One grade 4 adverse event occurred in the EFV arm, with hepatitis due to cytotoxic treatment administered by a healer, but this was not judged as antiretroviral-related. There were no significant differences in day-time or night-time sleeping disorders declared by caregivers between the arms, with four in the LPV arm vs. five in the EFV arm, though one child in the EFV arm did have persistent day-time and night-time sleeping disorders leading to a treatment substitution to LPV after 10 months. No clinical seizures were reported. There was no difference in the number of higher grade (grade 3 or 4) biological adverse events between the EFV and LPV arms, although we noted a significantly higher rate of neutropenia in the LPV arm, often associated with ZDV (p = 0.02).\n\nDrug-resistance profiles\nAt 12 months post-randomisation, 13 out of 14 children with plasma HIV-1 RNA >1000 copies/ml underwent viral resistance genotyping (one viral sequence could not be amplified). Of these 13 children who showed virological failure, 10 (77%) showed at least one major drug-resistance mutation, mainly against NNRTIs (9 out of 13; 69%) or against NRTIs (6 out of 13; 46%) (Table 6). NNRTI-resistance mutations were mainly K103N and Y181C; NRTI-resistance mutations were primarily against 3TC (M184V). Four children with NNRTI-resistant viruses exhibited cross-resistance to second-generation NNRTI treatment with etravirine and rilpivirine. No protease inhibitor resistance was detected. In these 14 children with virological failure at 12 months post-switch, samples prior to ART initiation were analysed retrospectively: three out of seven (43%) from each arm had pre-ART NNRTI-resistance mutations. When comparing the resistance profile 12 months post-randomisation to that observed prior to ART initiation, a non-significant trend towards a higher rate of emerging NNRTI resistance mutations was observed in the EFV arm compared to the LPV arm: five out of six (83%) vs. two out of seven (29%), respectively (Fisher’s exact test, p = 0.10). We also noted a high NNRTI-resistance mutation rate prior to ART initiation in the LPV group, reaching 46% (6 out of 13) in children failing at 12 months, even if they were not exposed to PMTCT interventions, probably acquired postnatally via breastmilk from their mother who was initiated on ART before the child. In contrast, five out of six children (83%) in the EFV arm developed a new incident NNRTI-resistance mutation that emerged after the switch. Of note, one child in the EFV arm, prior to ART initiation, harboured a virus resistant to both NRTIs and NNRTIs (mutations M41L, L74I, V108I, M184V, L210W, T215Y, K101E, Y181C, P225H); he/she was born to a mother who had been on ART (AZT-3TC-NVP) for seven years. The four children (two in each arm) exposed to maternal ART through breast milk had new mutations to NNRTI at virological failure.Table 6 Description of the 14 children with virological failure (HIV RNA >1000 copies/mL) after the switch\n\nNumber\tCountry\tArm\tHIV-1 subtype\tExposure to prenatal ART, maternal or child PMTCT or postnatal ART via breast milk\tHIV RNA at ART initiation (copies/mL)\tMutations at ART initiation\t\tHIV RNA at 12- month post-randomisation (copies/mL)\tMutations at failure post-switch\t\n\t\t\t\t\t\tNRTI\tNNRTI\tPI\t\tNRTI\tNNRTI\tPI\t\n1\tBF\tEFV\tCRF02_AG\tNo exposure\t19,900,000\tNone\tNone\tNone\t6109\tNone\tK103N\tNone\t\n2\tCI\tEFV\tCRF02_AG\tExposure to child PMTCT (AZT + sdNVP) and postnatal maternal ART (AZT + 3TC + NVP)\t242,757\tM184V\tK103N\tNone\t2091\tM184V\tK103N, H221Y\tNone\t\n3\tCI\tEFV\tCRF02_AG\tExposure to maternal PMTCT (AZT) and to child PMTCT (AZT+ sdNVP)\t3,573,953\tNone\tNone\tNone\t62,866\tNone\tNone\tNone\t\n4\tCI\tEFV\tCRF02_AG\tNo exposure\t1,321,600\tNone\tNone\tNone\t102,417\tM184V\tK103N\tNone\t\n5\tCI\tEFV\tCRF02_AG\tExposure to maternal PMTCT (AZT + 3TC + NVP) and to child PMTCT (AZT + sdNVP)\t3,459,135\tNone\tNone\tNone\t1564\tNot amplified\tNot amplified\tNot amplified\t\n6\tCI\tEFV\tCRF02_AG\tExposure to postnatal maternal ART (AZT + 3TC + NVP)\t608,578\tNone\tV90I, V179I\tNone\t21,397\tM184V\tV90I, V179I, K103N\tNone\t\n7\tCI\tEFV\tCRF02_AG\tExposure to prenatal maternal ART (AZT + 3TC + NVP) initiated 7 years before delivery\t12,466,057\tM41L, V108I, M184V, L210W, T215Y\tY181C, P225H\tNone\t61,199\tM41L, V108I, M184V, L210W, T215Y, L74I\tK101E, Y181C, P225H\tNone\t\n8\tBF\tLPV/r\tCRF02_AG\tExposure to maternal PMTCT (AZT) \t7,780,000\tNone\tNone\tNone\t7,920,000\tNone\tNone\tNone\t\n9\tBF\tLPV/r\tURF-GK\tExposure to maternal PMTCT (AZT+3TC+NVP) and to child PMTCT (sdNVP) and to postnatal maternal ART (TDF + 3TC + NVP)\t4,720,000\tNone\tK103N\tNone\t261,914\tNone\tK103N, Y181C\tNone\t\n10\tBF\tLPV/r\tCRF02_AG\tExposure to maternal PMTCT (AZT + 3TC + NVP) and child PMTCT (sdNVP)\t56,600,000\tNone\tY181C\tNone\t25,054\tNone\tY181C\tNone\t\n11\tCI\tLPV/r\tCRF02_AG\tExposure to child PMTCT (AZT + sdNVP)\t254,456\tNone\tNone\tNone\t2603\tNone\tNone\tNone\t\n12\tCI\tLPV/r\tCRF02_AG\tNo exposure\t451,590\tNone\tNone\tNone\t67,342\tM184V\tNone\tNone\t\n13\tCI\tLPV/r\tCRF02_CPX\tNo exposure\t915,685\tNone\tK103N, V90I, K101EK\tNone\t3,879,063\tNone\tK103N, V90I, K101EK\tNone\t\n14\tCI\tLPV/r\tCRF02_AG\tExposure to maternal PMTCT (unknown) and to postnatal maternal ART (AZT + 3TC + LPV/r)\t2,710,000\tNone\tNone\tNone\t1848\tM184V\tK103N\tNone\t\n\nART, Antiretroviral therapy, PMTCT Prevention of mother-to-child-transmission, NRTI Nucleoside reverse transcriptase inhibitor, NNRTI Non-nucleoside reverse transcriptase inhibitor, PI Protease inhibitor, BF Burkina Faso, CI Cote d’Ivoire, EFV Efavirenz, LPV/r Lopinavir-boosted ritonavir, AZT Zidovudine, sdNVP single-dose nevirapine, 3TC Lamivudine, NVP Nevirapine, TDF\n\n\n\n\n\nDiscussion\nOur trial provides original findings in the West African context among young HIV-infected children both exposed and not exposed to PMTCT intervention, and virologically suppressed after 12–15 months of a LPV-based ART initiated before 2 years of age. Despite a high-quality follow-up, our randomised trial could not demonstrate non-inferiority for a switch to EFV from LPV/r with regard to the primary outcome (a VL <500 copies/mL) when using both intention-to-treat and per-protocol analyses. Based on completed trial data, the actual statistical power was 67% to detect the planned difference in this outcome. When considering the secondary outcome of HIV RNA <1000 copies/mL, which is commonly used to inform ART switching decisions worldwide, we did demonstrate the non-inferiority of EFV compared to LPV/r. We also showed that switching to a simplified EFV-based therapy in virologically suppressed children below 3 years of age is safe, with no deaths and very few severe adverse events, all of which were infectious in nature. However, the pre-switch resistance profiles observed among children with virological failure at 12 months post-switch revealed high rates of NNRTI resistance prior to ART initiation, even in those not exposed to single-dose NVP for PMTCT in both groups. We presume this is due to PMTCT exposure and to postnatal antiretroviral drug exposure through breast milk. New NNRTI mutations were also observed in the EFV arm in children for whom virological suppression failed. We therefore recommend that any simplification switch to EFV needs to be closely monitored.\n\nTo date, LPV-sparing strategies have been explored in two paediatric trials in South Africa. These results were firstly reported in the NEVEREST-2 trial, with a switch to a NVP-based ART after first-line ART based on LPV/r [22]. Results from NEVEREST-2 showed that virological suppression at <50 copies/mL at 52 weeks was significantly more common in the NVP “Switch” group (56%) compared to the LPV/r “Stay” group (42%), but remained low overall. However, when the outcome measure was a virological response at <1000 copies/mL, the LPV/r group did significantly better, with 98% suppression vs. 78% for the NVP group (p < 0.001). The second protease inhibitor-sparing trial was the NEVEREST-3 trial, published in November 2015, which evaluated a switch to EFV-based ART after LPV/r, similar to our trial [23]. At the time of randomisation, children were on average 4 years of age and had been on treatment for 3.5 years. NEVEREST-3 reported a significantly higher rate of viral rebound to >50 copies/mL in the LPV/r group (n = 148) than in the EFV group (n = 150), therefore in favour of EFV: 28% of children in the LPV/r experienced an episode of viral rebound vs. 18% in the EFV group. For the second primary endpoint, virological failure (≥1000 copies/mL), there was no significant difference between the groups: 2% of children in LPV/r experienced confirmed virological failure vs. 2.7% of children in the EFV group. The authors concluded that children previously exposed to NVP prophylaxis for PMTCT and initially suppressed on a LPV/r-based regimen did not experience higher rates of viral rebound or virological failure, and can safely switch to an EFV-based regimen [22]. Among the seven children with virological failure, genotyping revealed that three children (42%) had a NNRTI-resistance mutation (K103N) at failure. However, there are several differences between the NEVEREST-3 trial and our trial: all children from NEVEREST-3 were systematically exposed to single-dose NVP for PMTCT and mainly issued from a trial study design; rates of malnutrition (interacting with antiretroviral pharmacokinetics) are lower in South Africa, and viral subtypes differ. Children were younger at ART initiation (median of 9.3 months in NEVEREST-3 vs. 13.7 months in MONOD); at the time of switch, children were 2 years older in NEVEREST-3 compared to MONOD (median 4.3 years vs. 26.8 months, respectively), with, consequently, a 36-month longer duration of viral suppression before randomisation for the switch (3.5 years vs. 12 months); the EFV dosage was higher in the MONOD trial compared to the NEVEREST-3 trial (200 mg/day for a weight of 10–13.9 kg). Our eligibility criteria at randomisation considered children aged <3 years. Currently, EFV is not recommended in children <3 years due to dosing difficulties and the concern for neurological adverse events [24]. However, the FDA approved dosing for children aged 3 months to <3 years as follows: 3.5–5 kg, two 50 mg capsules; 5–7.5 kg, three 50 mg capsules; 7.5–15 kg, one 200 mg capsule (http://www.who.int/hiv/pub/guidelines/arv2013/download/en/index.html). The dosing of EFV in our trial was 25 mg/kg, higher than that recommended [7]. While the minimum age of children in the modelling study of EFV PKs was 2.7 years [16], PK studies are ongoing to identify the appropriate dosage in this population and to provide guidance. Importantly, we did not observe any severe neurological adverse events in our children. Although we were not able to provide data using the <50 copies/mL threshold given the available laboratory assays in our trial, we found similar outcomes to the NEVEREST-3 trial when considering the difference between arms outcome of ≥1000 copies/mL.\n\nWe observed high rates of NNRTI resistance in those children who failed to develop virological suppression both before and after failure in both arms. A high frequency of transmitted NNRTI-resistance mutations is expected after exposure to NNRTI-based ART for PMTCT [25]. In addition, we show here that children who have not been exposed to PMTCT are at a very high risk of developing a number of resistance mutations through their exposure to suboptimal doses of maternal antiretroviral drugs through maternal breast milk. Multiclass resistance arises frequently in HIV-infected breastfeeding infants whose mothers are initiated on ART postnatally [26, 27]. These emerging mutations are expected to increase in the context of a large scale-up in maternal ART coverage through the rollout of Option B+. These drug-resistance mutations might negatively impact on future antiretroviral strategies in children who become HIV-infected in a context of limited therapeutic options. However, we did not observe higher rates of failure in the EFV switch arm relative to the LPV/r arm, despite these high pre-ART rates. The accumulation of new NNRTI-resistance mutations was common in children switching to EFV. This suggests that more children who experience virological failure could be expected to accumulate NNRTI-resistance mutations [28]. No resistance mutations to protease inhibitors were detected in our study. Therefore, it is critical that the first-line ART for the growing number of HIV-infected children frequently exposed to suboptimal doses of antiretroviral drugs includes medications with high genetic barriers against resistance.\n\nFinally, it is noteworthy that the implementation of our trial project was operationally complex, resulting in delayed ART initiation at a median age of 14 months, and high mortality in HIV-infected children before ART. During the recruitment period, the national AIDS programmes in both study countries had very low early infant diagnosis (EID) coverage, estimated at 29% in Ouagadougou [29] and 16% in Abidjan [30], mainly due to the post-electoral crisis in 2011. Partially because of this late access to care for infants with HIV infection, the proportion of children alive, in care, and with virological suppression after 12–15 months of LPV was lower than expected: 68% overall, instead of the 90% expected. This led to fewer children with a confirmed undetectable VL at a 3-month interval being eligible for randomisation, affecting the actual statistical power of our trial. We extended the inclusion period to increase the number of children randomised, but for funding reasons, it was not possible to extend this recruitment period beyond February 2013. This highlights that access to EID and early ART before the age of 2 years still remains challenging in real life in 2015. The scale-up of recommended early ART (before 12 months of age) remains one of the major public health challenges in resource-limited settings [29, 31]. Indeed, access to ART in infants requires systematic EID by virological testing in the first weeks of life. EID is complex, expensive and poorly accessible in many African settings [31, 32]. Rollout of EID has been limited, particularly in West African settings where HIV prevalence is low [29, 30, 33]. While LPV-based first-line ART remains the most effective regimen for children aged <3 years, a place for NVP-based first-line ART might be also acknowledged when protease inhibitors are not accessible, even in children exposed to single-dose NVP. Indeed, the ARROW randomised trial recently showed no differences in virological suppression and in resistance to NRTIs or NNRTIs at week 144 between children exposed or unexposed to single-dose NVP prophylaxis receiving NNRTI-based ART and aged <3 years [34].\n\nSeveral pitfalls should be considered in our trial. The use of a high cut-off to define viral suppression could have led to the accumulation of antiretroviral drug-resistance mutations in the long term. However, this should not have affected the comparability between arms. Also, we were unable to explore the minimal duration of first-line therapy needed to allow a successful switch; our results suggest that it should be at least 12 months. In our trial, the switch to an EFV strategy was conducted only in children with documented virological suppression, leading to a limited generalisability of our approach in settings where HIV VL monitoring is less available, but this was considered to be more ethical to avoid a lack of equipoise in children failing the initial LPV-based therapy. Finally, we were not able to accurately assess adherence using caregiver questionnaires about missing doses during the last 4 days before each monthly visit, but we are currently investigating these data using PK measurements.\n\nConclusions\nBoth the NEVEREST-3 [22] and the MONOD trials provide guidance on the feasibility of switching a child initiated on LPV-based ART to EFV. In our trial, we were unable to conclude on the non-inferiority of EFV compared to LPV at the 500 copies/mL threshold, due to the large confidence interval of the difference, but it was conclusive beyond 1000 copies/mL, similar to the NEVEREST-3 trial. However, given the high rate of NNRTI-resistance mutations at ART initiation in children who failed to develop virological suppression, and the emergence of newly acquired mutations at 12-months post-randomisation (compared to those mutations present at ART initiation) in these children, we would like to be cautious in recommending this switching strategy as a routine public health strategy in low-income countries: this switch strategy needs to be considered only in children with good adherence profiles, and when VL monitoring is available to detect early virological failure after the switch. In settings where ART is delayed and treating young infants remains a significant challenge, with potential exposure to suboptimal doses of maternal antiretroviral drugs through maternal breast milk, it will be particularly crucial to preserve those on suppressive ART of any type, but ideally with a high genetic barrier. In situations where VL monitoring is available before and after the switch, a switch to an EFV-based regimen may be a valuable individualised option in virologically suppressed children with good clinical and adherence profiles. Finally, new formulations of LPV/r that are more palatable and less costly, as well as other future drug options, are still urgently needed to increase ART response in children. Minitab sprinkles formulations of LPV/r are now available but remain poorly palatable [35]. Because treating young children remains challenging in Africa, there is an urgent need to develop formulations appropriate for young children and to make protease inhibitors more widely available, in order to improve the initial response to ART in children. Futures studies are also needed to assess its field response in routine programmes. The potent integrase inhibitor dolutegravir, which has a very low risk for drug-resistance mutations and is currently being formulated for paediatric populations, may represent a valuable option as a first-line therapy or to replace EFV in a switch strategy and needs to be assessed in the future [36].\n\nAcknowledgements\nWe thank the children, their families and the staff from all participating centres for their dedication. We warmly thank Andrea Ciaranello for her helpful comments on an early draft, Valérie Journot for her helpful statistical advice, and Sophie Desmonde for editing. We thank the MONOD ANRS 12206 trial independent data monitoring committee meeting: Dominique Costagliola (Chair; Paris, France), Mark Cotton (Cape Town, South Africa), Carlo Giaquito (Bologna, Italie), Diana Gibb (London, UK) and Elisabeth Menu (Paris, France). Désiré Dahourou PhD was funded by the ANRS (ANRS12206-B89). Malik Coulibaly PhD was funded by EDCTP-ANRS-LIH.\n\nThe ANRS 12206 MONOD Collaboration Study Group (as of 7 July 2015):\n\nParticipating sites.\n\nBurkina Faso, Ouagadougou: Centre de Recherche International pour la Santé: Malik Coulibaly, Désiré Lucien Dahourou, Nicolas Meda (co-investigator), Colette Ouédraogo, Mamadou Sawadogo, Wilfried Somé, Désiré Sondo, Elisabeth Thio. CHU Charles De Gaulle: Mamadou Barry, William Hiembo, Fla Kouéta, Adama Ouattara, Moussa Ouédraogo, Rasmata Ouédraogo, Sylvie Ouédraogo, Bernadette Congo, Rose Barry, Diarra Yé. CHU Yalgado Ouédraogo: Malika Congo, Edouard Minéné, Marie Coulibaly, Pierre Innocent Guissou Angèle Kalmogho, Ludovic Kam, Emile Ouédraogo, Lassana Sangaré, Caroline Yonaba. Programme Sectoriel Santé de Lutte contre le SIDA et les IST: Sylvestre Tiendrebeogo. Programme d’Appui au Monde Associatif et Communautaire (PAMAC): Odette Ky-Zerbo.\n\nCôte d’Ivoire, Abidjan: Programme PACCI: Xavier Anglaret, Clarisse Amani-Bossé, Divine Avit, Christine Danel, Serge Eholié, Didier Ekouévi, Eulalie Kanga, Suzanne Kouadio, Séverin Lennaud, Maxime Aimé Oga, Thérèse N’Dri-Yoman. CHU Cocody: Madeleine Amorissani-Folquet, Evelyne Dainguy, Beugre Kouassi, Jean-Claude Kouassi, Gladys Oka. CHU Yopougon: Kader Keita, Jean Yves Lambin, François Eboua Tanoh, Marguerite Timité-Konan (co-investigator). Site Abobo-Avocatier: Véronique Mea-Assande. Site CePReF-enfants: Addi Edmond Aka, Hortense Aka-Dago, Sylvie N’Gbeche, Eugène Messou. Laboratory CeDReS: Arlette Emieme, Fatoumata Koné, Hervé Menan, Thomas Toni, Vincent Yapo. Programme National de Prise en Charge: Kouamé Abo, Irma Ahoba, David Aka. FSU Abobo-Avocatier: Gbaméné Kouassi. Pharmacie de la Santé Publique: Carine Kodo. Implementers: Touré Siaka, Pety Touré (ACONDA), Fassinou Ekouevi (EGPAF), Ida Viho (ICAP), Anthony Richard Tanoh, Olivier Blé (Fondation ARIEL GLASER). Community representatives: Yaya Coulibaly (RIP+), Philomène Takouo (ONG Bayema). Programme ESTHER: Jean Marie Massumbuko. CIRBA: Kouadio Kouakou. Programme National de Santé Infantile: Dorothée Koumi. Programme Elargi de Vaccination: Berté Koné.\n\nMethodology and Data Management Center: Inserm U897, Institut de Santé Publique, d’Épidémiologie et de Développement, University of Bordeaux, France: Sophie Dattez, Sophie Desmonde, Julie Jesson, Sophie Karcher, Jérôme Le Carrou, Valériane Leroy (coordinating investigator), Karen Malateste, Camille Ndondoki, Pierre Touret. Methodological support: Caroline Bouyssou, Geneviève Chêne, Valérie Conte, Delphine Gabillard, Valérie Journot, Roger Salamon.\n\nMEREVA, Bordeaux. Website: http://mereva.isped.u-bordeaux2.fr/monod/Accueil.aspx\n\n\nSupporting teams:\n\nLuxembourg Institute of Health, Luxemburg: Vic Arendt (co-investigator), Carole Devaux, Jean-Claude Schmit.\n\nHôpital Universitaire Des Enfants Reine Fabiola, Brussels, Belgium: Philippe Lepage (co-investigator)\n\nHôpital Necker-Enfants Malades–Assistance Publique–Hopitaux de Paris and EA8, Université Paris Descartes: Stéphane Blanche (co-investigator), Deborah Hirt, Christine Rouzioux, Claire Pressiat, Jean-Marc Treluyer, Saik Urien. Commissariat à l’Energie Atomique: Alain Pruvost (CEA), Laboratoire de Virologie, Hopital Saint-Louis: Marie-Laure Chaix-Baudier.\n\nUMR 1058 “Pathogenesis and Control of Chronic Infections” INSERM-Université Montpellier-EFS, Montpellier, France: Philippe Van de Perre (co-investigator).\n\nAdministrative team: Elodie Vernoux (Bordeaux, France), Aminata Paré-Karambiri (Ouagadougou, Burkina Faso), Zouma Tinto (Ouagadougou, Burkina Faso), Adoulaye Cisse (Abidjan, Côte d’Ivoire), Madikona Dosso (Abidjan, Côte d’Ivoire).\n\nMONOD ANRS 12206 Scientific Steering Committee: Roger Salamon (Chair; Bordeaux, France), Valériane Leroy (coordinating investigator; Bordeaux, France), Nicolas Meda (co-investigator; Ouagadougou, Burkina Faso), Marguerite Timite-Konan (co-investigator; Abidjan, Côte d’Ivoire), Vic Arendt (co-investigator; Luxembourg), Stéphane Blanche (co-investigator; Paris, France), Philippe Lepage (co-investigator; Brussels, Belgium), Philippe Van de Perre (co-investigator; Montpellier, France), François Dabis (Bordeaux, France), Jean-Claude Schmit (CRP-Santé, Luxembourg).\n\nPromoter: Inserm-ANRS, France: Jean-François Delfraissy (Director), Brigitte Bazin, Marie de Solère, Claire Rekacewicz.\n\nThe content is solely the responsibility of the authors and does not necessarily represent the official views of the French Inserm-ANRS, European Developing Countries Clinical Trials Partnership, or University of Bordeaux.\n\nFunding\nEuropean Developing Countries Clinical Trials Partnership (reference: IP.2007.33011.002), Inserm-ANRS, FNR-Luxembourg. DLD is a PhD student fellow funded by the ANRS (ANRS12206-B89).\n\nAuthors’ contributions\nVL, SB, PL, PVdP, RS, NM and MTK designed the trial. DD, MC, CY, SO, AK performed the trial in Ouagadougou. MAF, CAB, FE, DA, SN and MTK performed the trial in Abidjan. CSD, RO and TT were in charge of laboratory analysis. VL and KM wrote the analysis plan. KM did the analysis. VL wrote the first draft of the report. All authors critically revised the manuscript, and read and approved the final version.\n\nCompeting interests\nThe authors declare that they no competing interests.\n\nEthical approval and consent to participate\nThe protocol was approved by the Comité d’Ethique pour la Recherche en Santé du Burkina Faso, and the Comité National d’Ethique et de la Recherche en Côte d’Ivoire. Both parents, if alive, gave their written informed consent for their child to participate.\n\nThe sponsor, the French National Agency for Research on AIDS and Viral Hepatitis (ANRS), had no role in the conduct of the study or the interpretation of the data.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. UNAIDS Global report UNAIDS report on the global AIDS epidemic 2013 2013 Geneva UNAIDS 272 \n2. UNAIDS The Gap Report 2014. ISBN 978-92-9253-062-4. Updated September 2014 2014 Geneva UNAIDS 1 422 \n3. Newell M-L Coovadia H Cortina-Borja M Rollins N Gaillard P Dabis F Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis Lancet 2004 364 9441 1236 43 10.1016/S0140-6736(04)17140-7 15464184 \n4. Violari A Cotton MF Gibb DM Babiker AG Steyn J Madhi SA Jean-Philippe P McIntyre JA Early antiretroviral therapy and mortality among HIV-infected infants N Engl J Med 2008 359 21 2233 44 10.1056/NEJMoa0800971 19020325 \n5. Report of the WHO Technical Reference Group, Paediatric HIV/ART Care Guideline Group Meeting. Revised treatment recommendations for infants http://www.who.int/hiv/pub/paediatric/WHO_Paediatric_ART_guideline_rev_mreport_2008.pdf. Accessed 7 Apr 2017.\n6. Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach. Revision 2010. https://www.ncbi.nlm.nih.gov/pubmed/23741772. Accessed 7 Apr 2017.\n7. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach - second edition. http://www.who.int/hiv/pub/arv/arv-2016/en/.\n8. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf?ua=1.\n9. Palumbo P Lindsey JC Hughes MD Cotton MF Bobat R Meyers T Bwakura-Dangarembizi M Chi BH Musoke P Kamthunzi P Antiretroviral treatment for children with peripartum nevirapine exposure N Engl J Med 2010 363 16 1510 20 10.1056/NEJMoa1000931 20942667 \n10. Violari A Lindsey JC Hughes MD Mujuru HA Barlow-Mosha L Kamthunzi P Chi BH Cotton MF Moultrie H Khadse S Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children N Engl J Med 2012 366 25 2380 9 10.1056/NEJMoa1113249 22716976 \n11. Yeni P. Rapport du Groupe d’Experts 2008 sur la prise en charge médicale des patients infectées par le VIH, sous la direction du Pr Patrick Yeni. 2008. p. 409. http://social-sante.gouv.fr/IMG/pdf/Rapport_2010_sur_la_prise_en_charge_medicale_des_personnes_infectees_par_le_VIH_sous_la_direction_du_Pr-_Patrick_Yeni.pdf\n12. Ciaranello AL Doherty K Penazzato M Lindsey JC Harrison L Kelly K Walensky RP Essajee S Losina E Muhe L Cost-effectiveness of first-line antiretroviral therapy for HIV-infected African children less than 3 years of age AIDS 2015 29 10 1247 59 10.1097/QAD.0000000000000672 25870982 \n13. Pau AK Moodley NK Holland DT Fomundam H Matchaba GU Capparelli EV Instability of lopinavir/ritonavir capsules at ambient temperatures in sub-Saharan Africa: relevance to WHO antiretroviral guidelines AIDS 2005 19 11 1233 4 10.1097/01.aids.0000176227.01850.9e 15990580 \n14. Ren Y Nuttall JJ Egbers C Eley BS Meyers TM Smith PJ Maartens G McIlleron HM Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis J Acquir Immune Defic Syndr 2008 47 5 566 9 10.1097/QAI.0b013e3181642257 18197120 \n15. Larru B Eby J Lowenthal ED Antiretroviral treatment in HIV-1 infected pediatric patients: focus on efavirenz Pediatric Health Med Ther 2014 5 29 42 25937791 \n16. Hirt D Urien S Olivier M Peyriere H Nacro B Diagbouga S Zoure E Rouet F Hien H Msellati P Is the recommended dose of efavirenz optimal in young West African human immunodeficiency virus-infected children? Antimicrob Agents Chemother 2009 53 10 4407 13 10.1128/AAC.01594-08 19635964 \n17. Rouet F Ekouevi DK Chaix ML Burgard M Inwoley A Tony TD Danel C Anglaret X Leroy V Msellati P Transfer and evaluation of an automated, low-cost real-time reverse transcription-PCR test for diagnosis and monitoring of human immunodeficiency virus type 1 infection in a West African resource-limited setting J Clin Microbiol 2005 43 6 2709 17 10.1128/JCM.43.6.2709-2717.2005 15956387 \n18. Piaggio G Elbourne DR Pocock SJ Evans SJ Altman DG Group C Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement JAMA 2012 308 24 2594 604 10.1001/jama.2012.87802 23268518 \n19. Jones B Jarvis P Lewis JA Ebbutt AF Trials to assess equivalence: the importance of rigorous methods BMJ 1996 313 7048 36 9 10.1136/bmj.313.7048.36 8664772 \n20. Dahourou DL Amorissani-Folquet M Coulibaly M Avit-Edi D Meda N Timite-Konan M Arendt V Ye D Amani-Bosse C Salamon R Missed opportunities of inclusion in a cohort of HIV-infected children to initiate antiretroviral treatment before the age of two in West Africa, 2011 to 2013 J Int AIDS Soc 2016 19 1 20601 10.7448/IAS.19.1.20601 27015798 \n21. Amani Bosse C, Dahourou D, Malateste K, M A-F, Coulibaly M, Dattez S, Emieme A, Barry M, Rouzioux C, N'Gbeche M-S, et al. Virological response and resistances over 12 months among HIV–infected children less than 2 years receiving first-line lopinavir /ritonavir-based antiretroviral therapy in Cote d’Ivoire and Burkina Faso: the MONOD ANRS 12206 cohort. J Int AIDS Soc. 2017; in press. \n22. Coovadia A Abrams EJ Stehlau R Meyers T Martens L Sherman G Hunt G Hu CC Tsai WY Morris L Reuse of nevirapine in exposed HIV-infected children after protease inhibitor-based viral suppression: a randomized controlled trial JAMA 2010 304 10 1082 90 10.1001/jama.2010.1278 20823434 \n23. Coovadia A Abrams EJ Strehlau R Shiau S Pinillos F Martens L Patel F Hunt G Tsai WY Kuhn L Efavirenz-based antiretroviral therapy among nevirapine-exposed HIV-infected children in South Africa: a randomized clinical trial JAMA 2015 314 17 1808 17 10.1001/jama.2015.13631 26529159 \n24. Van de Wijer L Schellekens AF Burger DM Homberg JR de Mast Q van der Ven AJ Rethinking the risk-benefit ratio of efavirenz in HIV-infected children Lancet Infect Dis 2016 16 5 e76 81 10.1016/S1473-3099(16)00117-1 27599655 \n25. Arrive E Newell ML Ekouevi DK Chaix ML Thiebaut R Masquelier B Leroy V Perre PV Rouzioux C Dabis F Prevalence of resistance to nevirapine in mothers and children after single-dose exposure to prevent vertical transmission of HIV-1: a meta-analysis Int J Epidemiol 2007 36 5 1009 21 10.1093/ije/dym104 17533166 \n26. Fogel J Li Q Taha TE Hoover DR Kumwenda NI Mofenson LM Kumwenda JJ Fowler MG Thigpen MC Eshleman SH Initiation of antiretroviral treatment in women after delivery can induce multiclass drug resistance in breastfeeding HIV-infected infants Clin Infect Dis 2011 52 8 1069 76 10.1093/cid/cir008 21460326 \n27. Zeh C Weidle PJ Nafisa L Lwamba HM Okonji J Anyango E Bondo P Masaba R Fowler MG Nkengasong JN HIV-1 drug resistance emergence among breastfeeding infants born to HIV-infected mothers during a single-arm trial of triple-antiretroviral prophylaxis for prevention of mother-to-child transmission: a secondary analysis PLoS Med 2011 8 3 e1000430 10.1371/journal.pmed.1000430 21468304 \n28. Babiker A Castro nee Green H Compagnucci A Fiscus S Giaquinto C Gibb DM Harper L Harrison L Hughes M McKinney R First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial Lancet Infect Dis 2011 11 4 273 83 10.1016/S1473-3099(10)70313-3 21288774 \n29. Coulibaly M Meda N Yonaba C Ouedraogo S Congo M Barry M Thio E Siribie I Koueta F Ye D Missed opportunities for early access to care of HIV-infected infants in Burkina Faso PLoS One 2014 9 10 e111240 10.1371/journal.pone.0111240 25360551 \n30. Avit D Folquet-Amorissani M Amani-Bosse C Eliam-Kouakou J Mea-Assande VT Aka A Ahoba I Ekouévi D Timite Konan M Leroy V Access to early infant diagnosis and antiretroviral therapy in Abidjan, Côte d’Ivoire, 2011-2013 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014), 3–6 March 2014, Boston, MA 2014 San Francisco, CA CROI Foundation/IAS–USA \n31. Penazzato M Revill P Prendergast AJ Collins IJ Walker S Elyanu PJ Sculpher M Gibb DM Early infant diagnosis of HIV infection in low-income and middle-income countries: does one size fit all? Lancet Infect Dis 2014 14 7 650 5 10.1016/S1473-3099(13)70262-7 24456814 \n32. Ciaranello AL Park J Ramirez-Avila L Freedberg KA Walensky RP Leroy V Early infant HIV-1 diagnosis programs in resource-limited settings: opportunities for improved outcomes and more cost-effective interventions BMC Med 2011 9 59 10.1186/1741-7015-9-59 21599888 \n33. Ndondoki C Brou H Timite Konan M Oga M Amani Bosse C Menan H Ekouévi D Leroy V Universal HIV screening at postnatal points of care: which public health approach for early infant diagnosis in Africa? The Côte d’Ivoire study case PLoS One 2013 8 8 e67996 10.1371/journal.pone.0067996 23990870 \n34. Musoke P Szubert AJ Musiime V Nathoo K Nahirya-Ntege P Mutasa K Williams DE Prendergast AJ Spyer M Walker AS Single-dose nevirapine exposure does not affect response to antiretroviral therapy in HIV-infected African children aged below 3 years AIDS 2015 29 13 1623 32 10.1097/QAD.0000000000000749 26193705 \n35. Kekitiinwa A Musiime V Thomason MJ Mirembe G Lallemant M Nakalanzi S Baptiste D Walker AS Gibb DM Judd A Acceptability of lopinavir/r pellets (minitabs), tablets and syrups in HIV-infected children Antivir Ther 2016 21 7 579 85 10.3851/IMP3054 27128199 \n36. Dehority W Abadi J Wiznia A Viani RM Use of integrase inhibitors in HIV-infected children and adolescents Drugs 2015 75 13 1483 97 10.1007/s40265-015-0446-2 26242765\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1741-7015",
"issue": "15(1)",
"journal": "BMC medicine",
"keywords": "Africa; Early antiretroviral treatment; Efavirenz; HIV; Infants; Lopinavir; Protease inhibitors; Randomised clinical trial; Treatment simplification; Virological outcomes",
"medline_ta": "BMC Med",
"mesh_terms": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D002050:Burkina Faso; D002675:Child, Preschool; D007560:Cote d'Ivoire; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019259:Lamivudine; D061466:Lopinavir; D008297:Male; D018894:Reverse Transcriptase Inhibitors; D019438:Ritonavir; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "101190723",
"other_id": null,
"pages": "85",
"pmc": null,
"pmid": "28434406",
"pubdate": "2017-04-24",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "15464184;15956387;15990580;17533166;18197120;19020325;19635964;20823434;20942667;21288774;21460326;21468304;21599888;22716976;23268518;23990870;24456814;25360551;25870982;25937791;26193705;26242765;26529159;27015798;27128199;27599655;28453240;8664772",
"title": "Efavirenz-based simplification after successful early lopinavir-boosted-ritonavir-based therapy in HIV-infected children in Burkina Faso and Côte d'Ivoire: the MONOD ANRS 12206 non-inferiority randomised trial.",
"title_normalized": "efavirenz based simplification after successful early lopinavir boosted ritonavir based therapy in hiv infected children in burkina faso and c te d ivoire the monod anrs 12206 non inferiority randomised trial"
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"abstract": "Staphylococcus haemolyticus is a rare cause of bacterial meningitis and most commonly occurs as a nosocomial infection in patients' post-neurosurgery. We report a patient post-allogenic stem cell transplant, with no prior history of neurosurgical procedures, who developed S. haemolyticus meningitis and bacteremia following central catheter-related bloodstream infection. The patient failed therapy with vancomycin and daptomycin but was successfully treated with a prolonged course of linezolid. We review the pharmacological management of coagulase negative Staphylococcus (CoNS) meningitis, with a focus on the pharmacokinetic properties of vancomycin, daptomycin and linezolid within the cerebrospinal fluid (CSF).",
"affiliations": "Department of Infectious Diseases, Middlemore Hospital, 100 Hospital Road, Auckland 2025, New Zealand.;Department of Haematology, Auckland City Hospital, 2 Park Road, Grafton, Auckland 1023, New Zealand.;Department of Infectious Diseases, Auckland City Hospital, 2 Park Road, Grafton, Auckland 1023, New Zealand.",
"authors": "Bryce|Aliya N|AN|;Doocey|Richard|R|;Handy|Rupert|R|",
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"doi": "10.1016/j.idcr.2021.e01259",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00215-8\n10.1016/j.idcr.2021.e01259\ne01259\nCase Report\nStaphylococcus haemolyticus meningitis and bacteremia in an allogenic stem cell transplant patient\nBryce Aliya N. Aliya.bryce@doctors.org.uk\na⁎\nDoocey Richard b\nHandy Rupert c\na Department of Infectious Diseases, Middlemore Hospital, 100 Hospital Road, Auckland 2025, New Zealand\nb Department of Haematology, Auckland City Hospital, 2 Park Road, Grafton, Auckland 1023, New Zealand\nc Department of Infectious Diseases, Auckland City Hospital, 2 Park Road, Grafton, Auckland 1023, New Zealand\n⁎ Corresponding author. Aliya.bryce@doctors.org.uk\n24 8 2021\n2021\n24 8 2021\n26 e012591 8 2021\n15 8 2021\n21 8 2021\n© 2021 The Authors. Published by Elsevier Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nStaphylococcus haemolyticus is a rare cause of bacterial meningitis and most commonly occurs as a nosocomial infection in patients’ post-neurosurgery. We report a patient post-allogenic stem cell transplant, with no prior history of neurosurgical procedures, who developed S. haemolyticus meningitis and bacteremia following central catheter-related bloodstream infection. The patient failed therapy with vancomycin and daptomycin but was successfully treated with a prolonged course of linezolid. We review the pharmacological management of coagulase negative Staphylococcus (CoNS) meningitis, with a focus on the pharmacokinetic properties of vancomycin, daptomycin and linezolid within the cerebrospinal fluid (CSF).\n\nKeywords\n\nmeningitis\ncoagulase-negative Staphylococcus\ndaptomycin\nlinezolid\nimmunosuppression\n==== Body\npmcIntroduction\n\nStaphylococcus haemolyticus is a coagulase negative Staphylococcus (CoNS) and common skin colonizer. S. haemolyticus can cause nosocomial meningitis in association with neurosurgical device implantation or traumatic brain injury [1], [2], [3]; however, CoNS are an extremely rare cause of bacterial meningitis in adult patients without history of traumatic or iatrogenic disruption to the blood-brain barrier. Here, we present an immunosuppressed, post-allogenic stem cell transplant patient without significant neurosurgical history, who presented with S. haemolyticus meningitis and persistent bacteremia. We review the pharmacological management of S. haemolyticus and CoNS meningitis, with a focus on the pharmacokinetic properties of vancomycin, daptomycin and linezolid within the cerebrospinal fluid (CSF).\n\nCase presentation\n\nThe patient, a 42-year old woman, presented to the Emergency Department with a one-week history of increasing lethargy and musculoskeletal pains. Her medical history was significant for HLA (Human Leukocyte Antigen) identical sibling donor allogeneic stem cell transplant 98-days prior to presentation. The patient was febrile to 38 °C with neck stiffness, photophobia and sluggish pupils. She had no intravenous catheters or prosthetic devices and no other focus of infection was identified on clinical examination. Laboratory examination revealed a neutrophil count of 9.5 × 109/L and normal creatinine (48 μmol/L). A midstream urinalysis and culture did not identify evidence of urine infection. Her chest radiograph was unremarkable. Early hydrocephalus was present on brain computed tomogram (CT). Cerebrospinal fluid parameters were consistent with bacterial meningitis with 1370 × 106 nucleated cells and 94% polymorphs (Table 1). A Gram stain of CSF revealed gram positive cocci; cultures subsequently grew S. haemolyticus.Table 1 Collated cerebrospinal fluid (CSF) analysis. Day 0 represents the day of presentation. The patient started linezolid on Day 24 and completed 28 days of therapy on Day 52.\n\nTable 1Days post-admission\tDay 0\tDay 22\tDay 29\tDay 36\tDay 57\tDay 64\t\nNucleated Cells (×106)\t1370\t155\t12\t1\t7\t6\t\nRBC (×106)\t<1\t3\t7\t2\t<1\t<1\t\nPolymorphs\t94%\t95%\t75%\t13%\t34%\t3%\t\nProtein (g/L)\t2.16\t0.58\t0.78\t0.55\t0.42\t0.41\t\nGlucose (mmol/L)\t0.6\t<0.5\t1.6\t2.3\t2.4\t2.5\t\nCulture\tS.haemolyticus\tS.haemolyticus\tNo growth\tNo growth\tNo growth\tNo growth\t\n\nThe patient had been diagnosed with poor-risk acute myeloid leukemia (AML) six months previously and had achieved a complete remission following induction treatment with Fludarabine, Cytarabine (Ara-C), Granulocyte-Colony Stimulating Factor and Idarubicin (FLAG-IDA) chemotherapy. Her second cycle of FLAG-IDA was complicated by neutropenic fever with S. haemolyticus isolated from multiple peripheral and catheter blood cultures over a 72 h period. The isolate was reported susceptible to vancomycin (Mean Inhibitory Concentration (MIC) = 2 mg/L) and resistant to penicillin, erythromycin and flucloxacillin on disc testing (Table 2). Central venous catheter associated line infection was suspected as the source. The patient’s peripherally inserted central catheter (PICC) was removed and she received a 7-day course of intravenous vancomycin. Four days after completing therapy, neutropenic fever returned and blood cultures again repeatedly isolated S. haemolyticus. Investigations including transthoracic echocardiogram, whole-body Magnetic Resonance Imaging (MRI) and CT of the chest, abdomen and pelvis did not reveal a source for bacteremia. She remained bacteremic for 3 days with sterilization of blood cultures following line removal. Vancomycin was continued for 14 days with a good clinical response.Table 2 Susceptibility profiles of S. haemolyticus in CSF and blood cultures during recurrent episodes of bacteremia.\n\nTable 2\tPeripheral blood cultures\tCSF\t\n\t1st episode\t2nd episode\t3rd episode\t3rd episode\t\n\tDay 1\tDay 3\tDay 1\tDay 3\tDay 5\tDay 8\tDay 16\tDay 24\tDay 0\tDay 22\t\nPenicillin\tR\tR\tR\tR\tR\tR\tR\tR\tR\tR\t\nErythromycin\tR\tR\tR\tR\tR\tR\tR\tR\tR\tR\t\nDoxycycline\tS\tS\tS\tS\tS\tS\tS\tS\tS\tS\t\nVancomycin\tSa\tS\tSa\tS\tS\tSa\tS\tS\tS\tS\t\nDaptomycin\t\t\t\t\t\t\tSb\tR\t\t\t\nLinezolid\t\t\t\t\t\t\tS\t\t\tSc\t\nCiprofloxacin\t\t\t\t\t\t\tR\t\t\t\t\nCotrimoxazole\t\t\t\t\t\t\tR\t\t\t\t\nGentamicin\t\t\t\t\t\t\tR\t\t\t\t\nRifampicin\t\t\t\t\t\t\tS\t\t\t\t\nAbbreviations: R = resistant, S = susceptible. Sa = MIC performed = 2 mg/L (Susceptible), Sb = MIC performed = 0.06 mg/L (Susceptible), Sc = MIC performed = 1.0 mg/L (Susceptible).\n\nThree weeks later, the patient underwent myeloablative allogeneic peripheral blood stem cell transplant with cells donated from an HLA-identical sibling sister. Prophylactic therapy with valganciclovir, cotrimoxazole and fluconazole was commenced post-transplant in line with local protocols. Successful engraftment was achieved albeit with slow count recovery. The patient had been monitored closely for 2 months in the outpatient setting and appeared to be progressing well until her deterioration and admission with meningitis.\n\nFollowing the diagnosis of S. haemolyticus meningitis, treatment with vancomycin was resumed. Whilst her neurological status improved, symptomatic fevers continued. S. haemolyticus was isolated repeatedly from daily blood cultures. The isolate remained susceptible to vancomycin (MIC = 2 mg/L). After 6 days with minimal clinical response, vancomycin was discontinued and intravenous daptomycin 500 mg every 24 h (8 mg/kg) was initiated. The patient remained persistently bacteremic over a 19-day period despite treatment with daptomycin and multiple peripherally inserted central catheter changes. MRI of the brain and spine, CT pulmonary angiogram, CT abdomen and whole-body positron emission tomography showed no focus of infection. Transesophageal echocardiogram did not demonstrate vegetations.\n\nAfter 17 days of persistent bacteremia, lumbar puncture was repeated (Table 1) demonstrating 155 nucleated cells (95% polymorphs). CSF cultures again grew S. haemolyticus. At this point all intravenous catheters were removed. Daptomycin was discontinued and the patient was commenced on oral linezolid 500 mg every 12 h. The patient subjectively improved and fevers ceased after 48 h of linezolid therapy. Five days later, CSF demonstrated improving pleocytosis (Table 1) and was culture negative. The patient was discharged and completed a 28-day course of linezolid with weekly outpatient follow-up for symptomatic review, lumbar puncture and blood cultures. She tolerated the therapy well with no adverse effects reported. Repeat CSF sampling exhibited improving parameters and all subsequent blood cultures remained sterile. One year following discharge, the patient remains well and has returned to full time work.\n\nDiscussion\n\nS. haemolyticus is a coagulase negative Staphylococcus and predominately an innocuous skin colonizing organism. CoNS, such as S. haemolyticus, may be implicated as nosocomial pathogens in device-related infections and can cause bacteremia in patients with chemotherapy-induced neutropenia [1]. CoNS are an uncommon cause of bacterial meningitis, occurring predominately when there is disruption of protective central nervous system (CNS) structures such as in traumatic brain injury [3], [4] or craniotomy. CoNS form biofilms and are often implicated in neurosurgical device associated meningitis and ventriculitis [2]. S. haemolyticus has been described as a causative pathogen in both neonatal meningitis and device related meningitis [2] however, to our knowledge, this is the first reported case of S. haemolyticus meningitis in adult patient without history of neurosurgery. The patient’s initial bacteremia, prior to transplant, occurred in the context of central line infection and immunosuppression. The subsequent S. haemolyticus meningitis presumably occurred secondary to haematogenous spread. It is unusual the patient remained asymptomatic for almost 4 months, particularly whilst extensively immunosuppressed. It was strongly suspected that a persisting nadir of infection, such as an infected thrombus was present however this could not be identified on extensive investigations.\n\nDue to their rarity, the majority of literature pertaining to treatment of CoNS meningitis relates to nosocomial neurosurgical device infection and resultant meningitis or ventriculitis. In this setting, good treatment outcomes have been described with a combination of device removal and intravenous vancomycin (median 12.5 days duration post-device removal) [2]. In patients without a neurosurgical device, and therefore no option for source control, descriptions of treatment are limited to case reports [4]. Successful management of a patient with Staphylococcus epidermidis bacteremia and meningitis on a background of AML, and no history of neurosurgery, was achieved with a 39-day course of intravenous vancomycin and oral rifampin [5].\n\nAntimicrobial management of CoNS meningitis is further complicated by a propensity towards intrinsic or acquired beta-lactam resistance. Vancomycin, a glycopeptide antibiotic, is frequently used as a first-line agent in CoNS meningitis [2], [6] but was ultimately unsuccessful in curing our patient. The vancomycin MIC for the S. haemolyticus isolate was 2 μg/mL, suggestive of susceptibility as per European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria, although close to the 4 μg/mL breakpoint [7]. The MIC remained stable during subsequent bacteremia suggesting acquisition of drug resistance is unlikely (Table 2). While vancomycin was an appropriate antimicrobial during initial bacteremia, if occult seeding to the CNS had occurred, the target 24 h area under the concentration-time curve (AUC24) may not have been adequate for CSF sterilization. Indeed, IDSA guidelines for Healthcare-Associated Ventriculitis and Meningitis recommend considering an alternative antimicrobial if the vancomycin MIC is ≥1 μg/mL [6]. Vancomycin is thought to penetrate poorly across the blood brain barrier due to its large mass and hydrophilic properties. Inflammation of the meninges during acute meningitis may enhance penetration but this appears highly variable between patients with a recent systematic review reporting serum to CSF penetration ratios between 6% and 81% [8].\n\nWe utilized therapeutic drug monitoring (TDM) of vancomycin through each treatment course with a target trough level of 15–20 mg/L and intermittent bolus administration. Dosing was calculated using Nextdose software, a web-based Bayesian forecasting dose optimization tool with a target AUC of 400–600 µg/mL. During the second episode of bloodstream infection, a supratherapeutic trough level (27.5 mg/L) was recorded after 48 h of therapy resulting in dose reduction. Persistently subtherapeutic trough levels (4.3–8.7 mg/L) were then subsequently recorded through treatment despite dose modifications. This could have precipitated the development of an occult CNS nadir of infection potentiated by patient immunosuppression. During the 6 days of treatment for meningitis, trough levels ranged from 8.6 to 20.9 mg/L.\n\nDaptomycin, a lipopeptide antibiotic effective against a wide variety of gram-positive bacteria, also failed to achieve S. haemolyticus clearance despite a favorable MIC of 0.06 μg/mL. This agent is recommended as a potential second line agent for staphylococcus meningitis at a dose of 6–10 mg/kg when vancomycin cannot be used [6]. There is minimal literature on the effectiveness of daptomycin in meningitis however, it’s large molecular size and high protein-binding would indicate CSF penetration is likely limited [9]. This was supported in a clinical pharmacokinetic study by Piva et al. which estimated plasma daptomycin to CSF penetration of 0.45% in patients with ventriculostomy associated meningitis [10]. Daptomycin may act synergistically with rifampicin, this combination has been described in case reports of enterococcus and methicillin resistant Staphylococcus aureus (MRSA) device-associated meningitis [11]. However, there is minimal literature on the efficacy of this combination and no specific studies in CoNS meningitis [1] or in those without indwelling devices.\n\nLinezolid, a predominately bacteriostatic antimicrobial of the oxazolidinone class, achieves much higher levels of CSF penetration than daptomycin with a CSF to serum penetration of around 66% [12]. A retrospective case series by Sipahi et al. [13] regarding utilization of linezolid in multi-resistant staphylococcus post-neurosurgical meningitis reported microbiological clearance of 8 of 9 patients with multi-resistant CoNS meningitis treated with linezolid twice daily for 18–21 days. Of note, all patients achieving clearance had sterile CSF samples after 5 days of treatment. Linezolid has excellent oral bioavailability making it an attractive choice. Relative success of linezolid therapy has also been reported in a small retrospective analysis of S. aureus meningitis by Pintado et al. [14]. The authors conclude no significant difference in mortality from use of linezolid when compared to vancomycin (MRSA) or cloxacillin (methicillin susceptible S. aureus) as well as a favorable side effect profile. The duration of treatment for healthcare-associated meningitis as per IDSA is recommended as 10–14 days after the last positive culture [6]. We elected to extend to 28 days due to ongoing concern of an unidentified infected thrombus as a focus.\n\nConclusion\n\nIn conclusion, this is the first reported case of S. haemolyticus meningitis in an adult patient without history of neurosurgical device implantation. A number of factors may have resulted in a poor clinical response to vancomycin, the most commonly indicated antimicrobial for CoNS CNS infection. However, it is notable that an extended course of daptomycin also failed to eradicate bloodstream infection or meningitis despite microbiological evidence of susceptibility. A rapid and sustained bacterial clearance was achieved with 28-days of linezolid treatment which appears to be a promising candidate for the treatment of S. haemolyticus meningitis.\n\nAuthors statement\n\nAB wrote the initial draft of the case report and performed the literature search. Both RH and RD were involved in the patients care and reviewed and edited the final manuscript.\n\nDeclaration of Competing Interest\n\nThe authors declare that they have no competing interests. Verbal and written consent has been provided by the patient for publication of this case report.\n==== Refs\nReferences\n\n1 Becker K. Heilmann C. Peters G. Coagulase-negative Staphylococci Clin Microbiol Rev 27 4 2014 870 926 25278577\n2 Huang C.R. Lu C.H. Wu J.J. Chang H.W. Chien C.C. Lei C.B. Coagulase-negative Staphylococcal meningitis in adults: clinical characteristics and therapeutic outcomes Infection 33 2 2005 56 60 15827871\n3 Baltas I. Tsoulfa S. Sakellariou P. Vogas V. Fylaktakis M. Kondodimou A. Posttraumatic meningitis: bacteriology, hydrocephalus, and outcome Neurosurgery 35 3 1994 422 426 7800133\n4 Azimi T. Mirzadeh M. Sabour S. Nasser A. Fallah F. Pourmand M.R. Coagulase-negative Staphylococci (CoNS) meningitis: a narrative review of the literature from 2000 to 2020 N Microbes N Infect 37 2020 100755\n5 Noguchi T. Nagao M. Yamamoto M. Matsumura Y. Kitano T. Takaori-Kondo A. Staphylococcus epidermidis meningitis in the absence of a neurosurgical device secondary to catheter-related bloodstream infection: a case report and review of the literature J Med Case Rep 12 2018 106 29690925\n6 Tunkel A.R. Hasbun R. Bhimraj A. Byers K. Kaplan S.L. Scheld W.M. Infectious Diseases Society of America’s clinical practice guidelines for healthcare-associated ventriculitis and meningitis Clin Infect Dis 64 6 2017 34 65 2017 27678084\n7 The European Committee on Antimicrobial Susceptibility Testing. Breakpoint Tables for Interpretation of MICs and Zone Diameters. 2020. [Online]. Available: http://www.eucast.org. [Accessed October 2020].\n8 Beach J.E. Perrott J. Turgeon R.D. Ensom M. Penetration of vancomycin into the cerebrospinal fluid: a systematic review Clin Pharmacokinet 56 12 2017 1479 1490 28528396\n9 Kumta N. Roberts J.A. Lipman J. Cotta M.O. Antibiotic distribution into cerebrospinal fluid: can dosing safely account for drug and disease factors in the treatment of ventriculostomy-associated infections? Clin Pharmacokinet 57 4 2018 439 454 28905331\n10 Piva S. Di Paolo A. Galeotti L. Ceccherini F. Cordoni F. Signorini L. Daptomycin plasma and CSF levels in patients with healthcare-associated meningitis Neurocrit Care 31 1 2019 116 124 30607829\n11 Antony S.J. Hoffman-Roberts H.L. Foote B.S. Use of daptomycin as salvage therapy in the treatment of central nervous system infections including meningitis and shunt infections Infect Dis Clin Pract 20 2012 161 163\n12 Myrianthefs P. Markantonis S.L. Vlachos K. Anagnostaki M. Boutzouka E. Panidis D. Serum and cerebrospinal fluid concentrations of linezolid in neurosurgical patients Antimicrob Agents Chemother 50 12 2006 3971 3976 16982782\n13 Sipahi O.R. Bardak S. Turhan T. Arda B. Pullukcu H. Ruksen M. Linezolid in the treatment of methicillin-resistant Staphylococcal post-neurosurgical meningitis: a series of 17 cases Scand J Infect Dis 43 10 2011 757 764 21671825\n14 Pintado V. Pazos R. Jiménez-Mejías M.E. Rodríguez-Guardado A. Díaz-Pollán B. Cabellos C. Linezolid for therapy of Staphylococcus aureus meningitis: a cohort study of 26 patients Infect Dis 52 11 2020 808 815\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "26()",
"journal": "IDCases",
"keywords": "coagulase-negative Staphylococcus; daptomycin; immunosuppression; linezolid; meningitis",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e01259",
"pmc": null,
"pmid": "34485080",
"pubdate": "2021",
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"title": "Staphylococcus haemolyticus meningitis and bacteremia in an allogenic stem cell transplant patient.",
"title_normalized": "staphylococcus haemolyticus meningitis and bacteremia in an allogenic stem cell transplant patient"
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"abstract": "Hepatic Veno-Occlusive Disease (VOD) is a potentially severe complication of hematopoietic stem cell transplantation (HSCT). Here we report two patients receiving an allogeneic HSCT who developed late onset VOD with atypical clinical features. The two patients presented with only few risk factors, namely, advanced acute leukemia, a myeloablative busulphan-containing regimen and received grafts from an unrelated donor. The first patient did not experience painful hepatomegaly and weight gain and both patients showed only a mild elevation in total serum bilirubin level. Most importantly, the two patients developed clinical signs beyond day 21 post-HSCT. Hepatic transjugular biopsy confirmed the diagnosis of VOD. Intravenous defibrotide was promptly started leading to a marked clinical improvement. Based on our experience, liver biopsy may represent a useful diagnostic tool when the clinical features of VOD are ambiguous. Early therapeutic intervention with defibrotide represents a crucial issue for the successful outcome of patients with VOD.",
"affiliations": "A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, Ematologia, Torino, Italy.;SODc Terapie Cellulari e Medicina Trasfusionale, AOU Careggi, Firenze.;A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, SSD Trapianto allogenico di cellule staminali, Torino, Italy.;SODc Terapie Cellulari e Medicina Trasfusionale, AOU Careggi, Firenze.;SODc Terapie Cellulari e Medicina Trasfusionale, AOU Careggi, Firenze.;SODc Terapie Cellulari e Medicina Trasfusionale, AOU Careggi, Firenze.;A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, SSD Trapianto allogenico di cellule staminali, Torino, Italy.;A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, Ematologia, Torino, Italy.;A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, SSD Trapianto allogenico di cellule staminali, Torino, Italy.;A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, SSD Trapianto allogenico di cellule staminali, Torino, Italy.;A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, SSD Trapianto allogenico di cellule staminali, Torino, Italy.;A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, SSD Trapianto allogenico di cellule staminali, Torino, Italy.;A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, SSD Trapianto allogenico di cellule staminali, Torino, Italy.;S.C. Anatomia Patologica 1, A.O.U. Città della Salute e della Scienza di Torino.;A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, SSD Trapianto allogenico di cellule staminali, Torino, Italy.",
"authors": "Castellino|Alessia|A|;Guidi|Stefano|S|;Dellacasa|Chiara Maria|CM|;Gozzini|Antonella|A|;Donnini|Irene|I|;Nozzoli|Chiara|C|;Manetta|Sara|S|;Aydin|Semra|S|;Giaccone|Luisa|L|;Festuccia|Moreno|M|;Brunello|Lucia|L|;Maffini|Enrico|E|;Bruno|Benedetto|B|;David|Ezio|E|;Busca|Alessandro|A|",
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"fulltext": "\n==== Front\nMediterr J Hematol Infect DisMediterr J Hematol Infect DisMediterranean Journal of Hematology and Infectious DiseasesMediterranean Journal of Hematology and Infectious Diseases2035-3006Università Cattolica del Sacro Cuore 10.4084/MJHID.2018.001mjhid-10-1-e2018001Case ReportLate-Onset Hepatic Veno-Occlusive Disease after Allografting: Report of Two Cases with Atypical Clinical Features Successfully Treated with Defibrotide Castellino Alessia 1Guidi Stefano 2Dellacasa Chiara Maria 3Gozzini Antonella 2Donnini Irene 2Nozzoli Chiara 2Manetta Sara 3Aydin Semra 1Giaccone Luisa 3Festuccia Moreno 3Brunello Lucia 3Maffini Enrico 3Bruno Benedetto 3David Ezio 4Busca Alessandro 3\n1 A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, Ematologia, Torino, Italy\n2 SODc Terapie Cellulari e Medicina Trasfusionale, AOU Careggi, Firenze\n3 A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, SSD Trapianto allogenico di cellule staminali, Torino, Italy\n4 S.C. Anatomia Patologica 1, A.O.U. Città della Salute e della Scienza di TorinoCorrespondence to: Castellino Alessia MD, A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, Ematologia, Torino, Italy. Corso Bramante 88, 10126 Torino. Tel: +39 0116335359 FAX: +39 011 6335759. E-mail: acastellino@cittadellasalute.to.it2018 01 1 2018 10 1 e201800102 8 2017 05 11 2017 2018This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Hepatic Veno-Occlusive Disease (VOD) is a potentially severe complication of hematopoietic stem cell transplantation (HSCT). Here we report two patients receiving an allogeneic HSCT who developed late onset VOD with atypical clinical features. The two patients presented with only few risk factors, namely, advanced acute leukemia, a myeloablative busulphan-containing regimen and received grafts from an unrelated donor. The first patient did not experience painful hepatomegaly and weight gain and both patients showed only a mild elevation in total serum bilirubin level. Most importantly, the two patients developed clinical signs beyond day 21 post-HSCT. Hepatic transjugular biopsy confirmed the diagnosis of VOD. Intravenous defibrotide was promptly started leading to a marked clinical improvement. Based on our experience, liver biopsy may represent a useful diagnostic tool when the clinical features of VOD are ambiguous. Early therapeutic intervention with defibrotide represents a crucial issue for the successful outcome of patients with VOD.\n\nLeukemiaAllogeneic Hematopietic stem cell transplantationVeno-occlusive diseaseVOD\n==== Body\nIntroduction\nVeno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT).1 The diagnosis of VOD is primarily based on clinical criteria defined almost 20 years ago, including the triad of painful hepatomegaly, jaundice and fluid retention.2–4 This observation could at least partially explain the highly variable incidence of VOD reported in the literature, ranging from 8% to 14%. VOD usually develops within 20–30 days after HSCT. However, few cases of late-onset VOD have been reported.5 According to this observation, the European Group for Bone marrow Transplantation (EBMT) recently endorsed the revised diagnostic criteria for VOD/SOS, which now include either a classical form of VOD and a late-onset variant (Table 1).6\n\nHere we describe two HSCT recipients who developed late-onset VOD with atypical clinical features.\n\nCase 1\nA 55-year-old male was diagnosed with acute myeloid leukemia in May 2015. He failed to achieve the complete remission (CR) after two induction chemotherapy courses with high dose cytarabine, idarubicin and etoposide and salvage treatment with fludarabine and idarubicin. The presence of a matched unrelated donor in the International Marrow Donor Registries prompted us to proceed with an allogeneic HSCT following a “sequential” conditioning regimen. The patient was initially treated with mitoxantrone (6 mg/sqm/day), etoposide (80 mg/sqm/day) and cytarabine (1 g/sqm/day for four days), followed, 10 days later, by a conditioning which included i.v. Busulphan (3.2 mg/kg/day) and Fludarabine (50 mg/mq/day) for four days and the infusion of mobilized donor peripheral blood stem cells (PBSC). Graft-vs.-Host disease (GVHD) prophylaxis consisted of anti-thymocyte globulin, cyclosporine and a short course of methotrexate. An absolute neutrophil count higher than 0.5 × 109/L and a platelet count higher than 20.000/mcl were achieved on day + 13. On day + 33, the patient suddenly showed abdominal distension with ascites, increase in liver enzymes (AST 391 U/l, ALT 245 U/l) and in total bilirubin (1.2 mg/dL) and signs of liver and renal insufficiency (INR 1.43; aPTT 65.5″; serum creatinine value 3.04 mg/dL). The patient did not present either painful hepatomegaly or weight gain >2%, or signs of intestinal or cutaneous acute GVHD. Viral hepatitis was ruled out by microbiological testing. Ultrasonography showed normal liver parenchyma, regular biliary tract, moderate splenomegaly (15 cm) with ascites and right pleural effusion. Doppler exam ruled out portal vein thrombosis but showed increased portal vein diameter (10 mm) suggestive of portal hypertension. Paracentesis was performed and showed presence of transudate fluid (serum albumin = 3 mg/dL, ascites albumin 1.5 mg/dL, serum-ascites albumin ratio= 2).\n\nGiven that clinical symptoms and laboratory tests did not allow to discriminate between VOD, acute GVHD, toxicity or infective causes, a hepatic transjugular biopsy was performed. Histology studies showed the expansion of the hepatic sinusoid spaces, with gaps in the sinusoidal barrier which were highly suggestive of hepatic VOD in the light of the involvement of zone 3, zone 2 and partially zone 1 of the hepatic acinus (Figure 1).\n\nIntravenous defibrotide was started at the dose of 6.25 mg/kg QID on day + 37 for 21 days, along with ancillary therapy including albumin replacement and low dose diuretics; nonsteroids have been administered. Two-three days after the beginning of defibrotide, the patient showed a marked clinical improvement with gradual improvement and normalization of liver and renal function tests (Figure 2). One week after the beginning of defibrotide, the patient developed hemorrhagic cystitis, treated with 2 bladder instillations of hyaluronic acid which led to progressive improvement and complete resolution upon regular discontinuation of defibrotide after 21 days of treatment. Hemorrhagic cystitis did not require an earlier discontinuation of defibrotide. During the treatment course, platelet count remained low between 10.000 to 20.000/mmc even with transfusion support. The patient was discharged on day + 76 in complete remission of his underlying disease on low doses of cyclosporine.\n\nCase 2\nA 46-year old male was diagnosed with acute myeloid leukemia - normal karyotype, FLT3, and NPM1 wild-type - in May 2015. The patient was treated with idarubicin plus etoposide and cytarabine with no hematologic response. Complete remission was subsequently obtained with a course of high-dose cytarabine, followed consolidation with 2 additional courses of high-dose cytarabine. An unrelated marrow donor search was started and a partially (one-antigen mismatched) HLA-matched donor was identified. The patient received mobilized donor HSCT after a conditioning regimen with Thiotepa (5 mg/kg/day for 2 days), Busulphan (3,2 mg/kg/day for 3 days) and Fludarabine (50 mg/kg/day for 3 days). GvHD prophylaxis included cyclosporine, short course methotrexate, and anti-thymocyte globulin ATG (2,5 mg/kg/day for 3 days). Neutrophil and platelet engraftment occurred on day +14 and +12 respectively. The patient experienced a transient skin rash suggestive of grade I acute GVHD on day +19, and 3 episodes of CMV reactivation on days +27,+ 43 and + 82 successfully treated with preemptive valganciclovir and immunoglobulins.\n\nThe patient was readmitted because of severe anemia and thrombocytopenia (Hb 5,8 gr/dl; platelet 5000/ul) and complaints of right abdominal pain with melena on day +89. Significant weight gain (+7 kg) along with abdominal distension and anasarca were observed on day +91. Laboratory exams showed total bilirubin 3,30 mg/dl, AST/ALT 140/164 UI, GGT 725 Ul, INR 1,7; aPTT 41,3″, serum creatinine 2,0 mg/dl; platelet count was 20.000/mmc. An abdominal CT scan revealed ascites and hepatic veins compression. Transjugular measurement of the hepatic venous pressure gradient showed severe sinusoidal portal hypertension with a significant transhepatic/caval gradient diagnostic for severe VOD. Transjugular liver biopsy showed sinusoidal dilation and bleeding with erythrocytes in the Disse space, and significant iron overload. Histology studies were consistent with severe VOD.\n\nIntravenous defibrotide was promptly started at the dose of 6.25 mg/kg QID for 22 days. Ancillary therapy included plasma and red blood cells transfusions, no steroid have been administered. A complete and sustained response was achieved. The patient was discharged on day +121. The patient is currently alive, 188 days after transplant, with normal liver function, no evidence of GvHD, or any other relevant clinical complication. A bone marrow aspirate showed complete remission of his underlying disease.\n\nDiscussion\nRecognition of potential risk factors for VOD is a key point for early diagnosis and prompt therapeutic intervention. Recently, the EBMT group has categorized these risk factors as transplant-, hepatic-, patient- and disease-related.7–9 Interestingly, our patients presented with only a few risk factors, namely, advanced acute leukemia, a myeloablative busulphan-containing conditioning and an unrelated donor. Moreover, both patients did not show the typical clinical VOD features described by the Seattle2–3 and Baltimore4 criteria. In particular, the first patient did not experience either painful hepatomegaly or weight gain, and only a mild elevation in total serum bilirubin level was observed after the development of ascites, while the second patient showed only mild hyper-bilirubinemia concurrent with painful hepatomegaly and significant weight gain. Most importantly, both patients developed clinical signs beyond day 21 post-HSCT (on days + 33 and + 89 respectively). In this respect, it should be emphasized that the EBMT consensus6 has now recognized the existence of a “late onset” VOD, defined with less stringent diagnostic criteria and where hyper-bilirubinemia should no longer be mandatory for diagnosis. Overall, in these two patients, the short time between the onset of clinical symptoms and the final diagnosis, and the higher than 5 fold increase in transaminases combine to diagnose a severe form of VOD by the new EBMT criteria (Table 1)\n\nBoth the British guidelines10 and the EBMT recommendations indicate that liver biopsy should be reserved for those patients in whom the diagnosis of VOD is unclear, and there is an urgent need to rule out other possible causes of liver dysfunction. In our experience, a transjugular liver biopsy was safe despite severe thrombocytopenia and, most importantly, was conclusive for the diagnosis of VOD ruling out drug toxicities, viral infections, sepsis or GVHD.11–13 In keeping with our findings, Kis et al. reported only 1.8% of major complications during 166 transjugular liver biopsies.14\n\nDefibrotide is the only agent approved for the treatment of VOD in Europe. Defibrotide has been shown to have antithrombotic and anti-inflammatory properties and may promote revascularization inducing endothelial cell proliferation and angiogenesis.15 In our patients, the combination of clinical features and histology studies prompted us to start defibrotide only a few days after the onset of symptoms. Our experience strengthens the observation reported by Richardson et al.,16 that the timely administration of defibrotide may represent a crucial issue for the successful outcome of patients with VOD. Sixty % of patients were alive when defibrotide was started within 2 days from the onset of symptoms as compared with 14% when treatment was delayed and started after 7 days. Similar results were reported by Corbacioglu et al.17 Our patients began defibrotide treatment within 7 days from the onset of symptoms but within 1 day from the histological diagnosis. They did not fall exactly in the early treatment category. Nevertheless, defibrotide has been initiated within 7 days, representing the crucial threshold to achieve a good outcome. Phase 2 and 3 studies18–22 demonstrated that defibrotide was generally well tolerated with manageable toxicity. Hemorrhagic complications were reported as the most frequent adverse event. Hemorrhagic cystitis, which occurred in one of our patients, is a common complication in HSCT recipients. Though other causes may have been involved, we could not rule out that it may have been related to defibrotide treatment given its prompt resolution upon drug discontinuation.22\n\nConclusions\nVOD should be considered in the differential diagnosis of HSCT recipients who present with unexplained liver injuries, ascites and/or MOF. Liver biopsy may represent a useful diagnostic tool when the clinical criteria for VOD are not entirely fulfilled. Early therapeutic intervention with defibrotide may improve the clinical outcomes of these patients.\n\nCompeting interests: The authors have declared that no competing interests exist.\n\nFigure 1 Images of hepatic transjugular biopsy: in the middle, the red arrows showed the expansion of hepatic sinusoid spaces, on the right the figure showed a centrilobular vein.\n\nFigure 2 Diagnostic interventions with liver function profile from clinical onset of VOD until resolution, and treatment of VOD in case 1.\n\nFigure 3 Diagnostic interventions with liver function profile from clinical onset of VOD until resolution, and treatment of VOD in case 2.\n\nTable 1 Criteria for definition of Late-Onset VOD (according to “The new classification from the European Society for Blood and Marrow Transplantation”, BMT 2016).6\n\nLate Onset VOD (> 21 Days after HSCT)\t\nClassical VOD/SOS beyond day 21:\nBilirubin ≥ 2 mg/dL and two of the following criteria:\n\nPainful hepatomegaly OR weight gain > 5% OR ascites\n\n\t\nOR\n Histologically proven VOD/SOS\t\nOR\n Two or more of the following criteria:\nBilirubin ≥ 2 mg/dL (or 34 micromols/L) OR\n\nPainful hepatomegaly OR weight gain > 5% OR ascites\n\n moreover, hemodynamical or/and ultrasound evidence of VOD/SOS\t\nAbbreviations: EBMT =European Society for Blood and Marrow Transplantation; SOS =sinusoidal obstruction syndrome; VOD =veno-occlusive disease. These symptoms/signs should not be attributable to other causes.\n==== Refs\nReferences\n1 Carreras E Veno-occlusive disease of the liver after hemopoietic cell transplantation Eur J Haematol 2000 64 281 291 https://doi.org/10.1034/j.1600-0609.2000.9r200.x 10863974 \n2 McDonald GB Hinds MS Fisher LD Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients Annals of Internal Medicine 1993 118 255 267 https://doi.org/10.7326/0003-4819-118-4-199302150-00003 8420443 \n3 Jones RJ Lee KS Beschorner WE Venoocclusive disease of the liver following bone marrow transplantation Transplantation 1987 44 778 783 https://doi.org/10.1097/00007890-198712000-00011 3321587 \n4 Lee JL Gooley T Bensinger W Veno-occlusive disease of the liver after busulfan, melphalan, and thiotepa conditioning therapy: incidence, risk factors, and outcome Biology of Blood and Marrow Transplantation 1999 5 306 315 https://doi.org/10.1016/S1083-8791(99)70006-6 10534061 \n5 Coppell JA Richardson PG Soiffer R Martin PL Kernan NA Chen A Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome Biol Blood Marrow Transplant 2010 16 157 168 https://doi.org/10.1016/j.bbmt.2009.08.024 19766729 \n6 Mohty M Malard F Abecassis M Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation BMT 2016 1 7 \n7 Bearman SI The syndrome of hepatic veno-occlusive disease after marrow transplantation Blood 1995 85 3005 20 7756636 \n8 Carreras E Bertz H Arcese W Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: A prospective cohort study of the European Group for Blood and Marrow Transplantation: European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party Blood 1998 92 3599 604 9808553 \n9 Cesaro S Pillon M Talenti E A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation Haematologica 2005 90 1396 1404 16219577 \n10 Dignan FL Wynn RF Hadzic N BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation BJH 2013 163 444 457 https://doi.org/10.1111/bjh.12558 24102514 \n11 DeLeve LD Shulman HM McDonald GB 2002 Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease) Seminars in Liver Disease 22 27 https://doi.org/10.1055/s-2002-23204 11928077 \n12 Shulman HM Gown AM Nugent DJ 1987 Hepatic veno-occlusive disease after bone marrow transplantation. Immunohistochemical identification of the material within occluded central venules The American Journal of Pathology 127 549 558 2438942 \n13 Shulman HM Fisher LB Schoch HG Henne KW McDonald GB 1994 Veno-occlusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms Hepatology 19 1171 1181 https://doi.org/10.1002/hep.1840190515 8175139 \n14 Kis b Pamarthi V Fan C-M Safety and Utility of Transjugular Liver Biopsy in Hematopoietic Stem Cell Transplant Recipients J Vasc Interv Radiol 2013 24 85 89 https://doi.org/10.1016/j.jvir.2012.09.011 23200125 \n15 Richardson PG Elias AD Krishnan A Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population Blood 1998 92 737 744 9680339 \n16 Richardson PG Smith AR Triplett BM Early Initiation of Defibrotide in Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome Following Hematopoietic Stem Cell Transplantation Improves Day +100 Survival ASH 2015 Poster Abs \n17 Corbacioglu S Greil J Peters C Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention BMT 2004 1 33 2 189 95 https://doi.org/10.1038/sj.bmt.1704329 \n18 Bearman SI Anderson GL Mori M Hinds MS Shulman HM McDonald GB 1993 Venoocclusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation Journal of Clinical Oncology 11 1729 1736 https://doi.org/10.1200/JCO.1993.11.9.1729 8355040 \n19 Chopra R Eaton JD Grassi A Potter M Shaw B Salat C Defibrotide for the treatment of hepatic veno-occlusive disease: Results of the European compassionate-use study Br J Haematol 2000 111 1122 9 https://doi.org/10.1046/j.1365-2141.2000.02475.x 11167751 \n20 Richardson PG Murakami C Jin Z Warren D Momtaz P Hoppensteadt D Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome Blood 2002 100 4337 43 https://doi.org/10.1182/blood-2002-04-1216 12393437 \n21 Richardson PG Soiffer R Antin J Jin Z Kurtzberg J Martin P Defibrotide (DF) for the treatment of severe veno-occlusive disease (sVOD) and multi-organ failure (MOF) post SCT: Final results of a multi-center, randomized, dose-finding trial Blood 2006 108 178 \n22 Richardson PG Riches ML Kernan NA Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure Blood 2016 127 13 1656 65 https://doi.org/10.1182/blood-2015-10-676924 26825712\n\n",
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"issue": "10(1)",
"journal": "Mediterranean journal of hematology and infectious diseases",
"keywords": "Allogeneic Hematopietic stem cell transplantation; Leukemia; VOD; Veno-occlusive disease",
"medline_ta": "Mediterr J Hematol Infect Dis",
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"title": "Late-Onset Hepatic Veno-Occlusive Disease after Allografting: Report of Two Cases with Atypical Clinical Features Successfully Treated with Defibrotide.",
"title_normalized": "late onset hepatic veno occlusive disease after allografting report of two cases with atypical clinical features successfully treated with defibrotide"
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"abstract": "Rheumatoid arthritis (RA) is accompanied by a variety of nephropathies. It is often difficult to distinguish between disease-associated and drug-associated renal diseases. Three hundred and seventy-six RA patients with renal involvement were included in our study; they were subjected to full history and clinical examination, kidney function, 24-h urinary protein, and kidney biopsy. All our patients were on methotrexate, low dose steroids, and nonsteroidal anti-inflammatory drugs, in addition to the previous medications. About 79.3%, 20.7%, 6.9%, and 5.9% of our patients were on leflunomide, hydroxychloroquine, etanercept, and infliximab, respectively. Renal presentation was in the form of nephrotic syndrome (33.5%), persistent subnephrotic proteinuria (12.2%), persistent proteinuria and recurrent hematuria (13.3%), acute nephritis (23.9), recurrent hematuria (7.4%), and creatinine >1.5 mg/dL (10.6%). Renal biopsies were glomerular amyloidosis (28.1%), mesangioproliferative (19.1%), membranous (6.1%), crescent (16.8%), focal segmental glomerulosclerosis (18.6%), and minimal changes (11.7%). There was a statistically significant difference in the incidence of membranous nephritis between patients who took leflunomide, and hydroxychloroquine and those did not. Etanercept in our study seems not to be related to any form of renal involvement, while infliximab is related to focal segmental sclerosis and amyloidosis of tubulointerstitial type. Kidney involvement in RA is not a rare complication. Any type of histopathological changes can be present, with amyloidosis on top of the list. Hydroxychloroquine and leflunomide are accused in membranous nephropathy. Infliximab is associated with focal segmental sclerosis and amyloidosis of tubulointerstial type, and etanercept appear to be safe as regards kidney affection.",
"affiliations": "Department of Internal Medicine, Nephrology Unit, Cairo University, Cairo, Egypt.;Department of Internal Medicine, Nephrology Unit, Cairo University, Cairo, Egypt.;Department of Pathology, Cairo University, Cairo, Egypt.;Department of Internal Medicine, Rheumatology and Immunology Unit, School of Medicine, Cairo University, Cairo, Egypt.",
"authors": "Fayed|Ahmed|A|;Shaker|Amr|A|;Hamza|Wael M|WM|;Wadie|Mary|M|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D013256:Steroids; D008727:Methotrexate",
"country": "Saudi Arabia",
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"issue": "30(4)",
"journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia",
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"medline_ta": "Saudi J Kidney Dis Transpl",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001172:Arthritis, Rheumatoid; D004534:Egypt; D005260:Female; D005921:Glomerulonephritis; D006785:Hospitals, University; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D007668:Kidney; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D018570:Risk Assessment; D012307:Risk Factors; D013256:Steroids",
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"publication_types": "D016428:Journal Article",
"references": null,
"title": "Spectrum of glomerulonephritis in Egyptian patients with rheumatoid arthritis: A University Hospital experience.",
"title_normalized": "spectrum of glomerulonephritis in egyptian patients with rheumatoid arthritis a university hospital experience"
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{
"abstract": "A 63-year-old man was hospitalized with an increased serum prostate specific antigen (PSA) level (72 ng/ml). A prostate biopsy was performed, and histological examinations indicated moderately and poorly differentiated adenocarcinoma with positive staining for carcinoembryonic antigen (CEA). The patient was diagnosed as having prostate cancer (clinical stage : T3bN0M0) and received radiotherapy and hormonal therapy. Five years after the diagnosis, the serum CEA level increased to 153.8 ng/dl, and the patient complained of abdominal pain. His serum PSA level remained normal (<0.1 ng/dl). Computed topography indicated multiple bone metastasis and the involvement of multiple lymph glands. A biopsy of a cervical lymph gland revealed poorly differentiated adenocarcinoma with positive staining for CEA. Gastrointestinal examination showed no evidence of abnormality. The diagnosis of metastatic prostate cancer was made, and docetaxel (60-70 mg/m2) was administered. Eight courses of docetaxel therapy led to an approximately 20% reduction in lymph volume, and the serum CEA level decreased. However, liver metastases developed 12 months later, and the patient died at 18 months after the diagnosis of metastatic prostate cancer with a high serum CEA level. We encountered a case of recrudescence of prostate cancer positive for CEA with a low serum PSA level and report the effect of docetaxel therapy for atypical prostatic carcinoma.",
"affiliations": "The Department of Urology, Federation of National Public Service and Affiliated Personnel Mutual Aid Association Otemae Hospital.",
"authors": "Fujita|Masahiro|M|;Goto|Takayasu|T|;Uchida|Kinya|K|;Saiki|Shigeru|S|;Arima|Ryoichi|R|",
"chemical_list": "D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; D043823:Taxoids; D000077143:Docetaxel; D017430:Prostate-Specific Antigen",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-1994",
"issue": "59(3)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
"keywords": null,
"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000230:Adenocarcinoma; D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; D000077143:Docetaxel; D006801:Humans; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms; D012008:Recurrence; D043823:Taxoids",
"nlm_unique_id": "0421145",
"other_id": null,
"pages": "183-8",
"pmc": null,
"pmid": "23633635",
"pubdate": "2013-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recrudescent prostate cancer with a low serum PSA level and a high serum CEA level treated with docetaxel : a case report.",
"title_normalized": "recrudescent prostate cancer with a low serum psa level and a high serum cea level treated with docetaxel a case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-110206",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"druga... |
{
"abstract": "We describe the successful use of recombinant factor VIIa (rFVIIa) in the control of massive haemoptysis in a 17-year-old patient with a Fontan circulation. The patient was intubated and ventilated in the ICU with deteriorating gas exchange. Conventional methods to control the haemoptysis were ineffective, and rFVIIa was successfully administered as a rescue therapy. rFVIIa is a powerful pro-thrombotic agent, which is only licensed in haemophiliacs with acquired inhibitors to anticoagulation. It has been used off-license in the treatment of massive haemorrhage, although a Cochrane review did not show any significant benefit; however, it may have a role as a rescue therapy where alternatives options have been exhausted after careful risk-benefit analysis.",
"affiliations": "1Critical Care,St Thomas' Hospital, Guys and St Thomas' NHS foundation trust,London,United Kingdom.;1Critical Care,St Thomas' Hospital, Guys and St Thomas' NHS foundation trust,London,United Kingdom.;2Adult Congenital Cardiology,St Thomas' Hospital, Guys and St Thomas' NHS foundation trust,London,United Kingdom.",
"authors": "Mason|Thomas W|TW|;Retter|Andrew|A|;Morgan|Gareth J|GJ|",
"chemical_list": "D011994:Recombinant Proteins; C103587:recombinant FVIIa; D015942:Factor VIIa",
"country": "England",
"delete": false,
"doi": "10.1017/S1047951117001007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1047-9511",
"issue": "28(1)",
"journal": "Cardiology in the young",
"keywords": "Fontan; factor VIIa; haemoptysis; rFVIIa",
"medline_ta": "Cardiol Young",
"mesh_terms": "D000293:Adolescent; D015942:Factor VIIa; D018729:Fontan Procedure; D006330:Heart Defects, Congenital; D006469:Hemoptysis; D006801:Humans; D008297:Male; D056687:Off-Label Use; D013902:Radiography, Thoracic; D011994:Recombinant Proteins",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "144-146",
"pmc": null,
"pmid": "28889826",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recombinant factor VIIa as a rescue therapy in severe haemoptysis in a patient with a Fontan circulation.",
"title_normalized": "recombinant factor viia as a rescue therapy in severe haemoptysis in a patient with a fontan circulation"
} | [
{
"companynumb": "GB-MYLANLABS-2019M1015944",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRANEXAMIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "We present a 15 year male patient with more than 2 years of clinical symptoms. Patient has abdominal pain with episodes of partial intestinal occlusion, recurrent diarrhea, weight loss and fever. Lab findings were PCR: 92, 17: albumine: 3,2 gr/dl, microcitic hipocromic anemia (10 gr%). Hepatoesplenomegaly in the Echo in TAC there was a thickness of the distal ileum and right colon with free liquid in the abdominal cavity. Intestinal transit: Stenosis of the distal ileum. In a colonoscopy: ulcers in the right colon with biopsies that suggest Crohn disease. Endoscopic capsule: ulcerative ileitis. The patient was discharged with prednisone and azatioprine but because there were new episodes of intestinal occlusion surgery was decided. The outcome was good and in the post surgery treatment Infliximab was used. We discuss medical and surgical treatment options.",
"affiliations": "Servicio de Gastroenterología, Hospital Nacional Guillermo Almenara Irigoyen. Lima, Perú.;Servicio de Coloproctología, Hospital Nacional Guillermo Almenara Irigoyen. Lima, Perú.;Servicio de Coloproctología, Hospital Nacional Guillermo Almenara Irigoyen. Lima, Perú.;Servicio de Gastroenterología, Hospital Nacional Guillermo Almenara Irigoyen. Lima, Perú.",
"authors": "Otoya Moreno|Guillermo|G|;Borda|Luis|L|;Chiroque|Luis|L|;Grazia Venturelli|María|M|",
"chemical_list": null,
"country": "Peru",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-5129",
"issue": "34(4)",
"journal": "Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru",
"keywords": null,
"medline_ta": "Rev Gastroenterol Peru",
"mesh_terms": "D000293:Adolescent; D003424:Crohn Disease; D006801:Humans; D008297:Male",
"nlm_unique_id": "9108294",
"other_id": null,
"pages": "339-44",
"pmc": null,
"pmid": "25594759",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Crohn's disease: clinical case and review of the literature.",
"title_normalized": "crohn s disease clinical case and review of the literature"
} | [
{
"companynumb": "PE-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-98500",
"fulfillexpeditecriteria": "1",
"occurcountry": "PE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"dru... |
{
"abstract": "Certain aggressive non-Hodgkin lymphoma subtypes are increasingly being treated with infusional DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), which requires a central venous catheter. This study aims to identify the rates and predictors of line-associated complications (LACs) associated with DA-EPOCH-R therapy in NHL.\n\n\n\nWe retrospectively identified all patients treated with DA-EPOCH-R at our institution between March 2011 and July 2016. We also identified a concurrent cohort of patients with diffuse large B-cell lymphoma treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).\n\n\n\nForty-three patients received DA-EPOCH-R during the study period; 17 (39.5%; 95% confidence interval, 0.25-0.56) patients experienced at least 1 LAC (including venous thromboembolism, chemotherapy extravasation, and line-associated infection). Forty-four patients received R-CHOP during the study period; 8 (18.2%; 95% confidence interval, 0.08-0.32) patients experienced at least 1 complication. Compared with the R-CHOP cohort, patients treated with DA-EPOCH-R experienced a significantly higher rate of these complications (P = .03). In the DA-EPOCH-R cohort, grade 3 toxicity was seen in 41% (7/17). In univariate analysis, body mass index ≥ 35 kg/m2 and using a peripherally inserted central catheter line were significantly associated with an increased risk of venous thromboembolism (P = .04 and P = .02, respectively).\n\n\n\nForty percent of patients receiving DA-EPOCH-R therapy developed LACs, almost one-half of whom experienced grade 3 toxicities. The complication rate was significantly greater in patients undergoing therapy with DA-EPOCH-R compared with those undergoing R-CHOP therapy. Clinicians need to balance these risks when selecting therapy. Future studies are needed to evaluate prophylactic anticoagulation strategies in this population.",
"affiliations": "Wilmot Cancer Institute, Strong Memorial Hospital, Rochester, NY. Electronic address: racheljdavid84@gmail.com.;Wilmot Cancer Institute, Strong Memorial Hospital, Rochester, NY.;Wilmot Cancer Institute, Strong Memorial Hospital, Rochester, NY.;Wilmot Cancer Institute, Strong Memorial Hospital, Rochester, NY.;Wilmot Cancer Institute, Strong Memorial Hospital, Rochester, NY.;Wilmot Cancer Institute, Strong Memorial Hospital, Rochester, NY.;Wilmot Cancer Institute, Strong Memorial Hospital, Rochester, NY.",
"authors": "David|Rachel J|RJ|;Baran|Andrea|A|;Loh|Kah Poh|KP|;Casulo|Carla|C|;Barr|Paul M|PM|;Friedberg|Jonathan W|JW|;Reagan|Patrick M|PM|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2018.08.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "18(12)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Bacteremia; Central venous access device; Extravasation; Thrombosis",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D002986:Clinical Trials as Topic; D003520:Cyclophosphamide; D004317:Doxorubicin; D064420:Drug-Related Side Effects and Adverse Reactions; D005047:Etoposide; D005260:Female; D006801:Humans; D015994:Incidence; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011241:Prednisone; D012042:Registries; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "781-787",
"pmc": null,
"pmid": "30262330",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Complications Associated With Dose-adjusted EPOCH-rituximab Therapy for Non-Hodgkin Lymphoma.",
"title_normalized": "complications associated with dose adjusted epoch rituximab therapy for non hodgkin lymphoma"
} | [
{
"companynumb": "PHHY2018US192732",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Breast cancer is the most commonly diagnosed cancer in women, mainly at an early stage, allowing treatment with curative intent. Aromatase inhibitors are widely used in the adjuvant treatment of oestrogen receptor-positive breast cancer, mainly in postmenopausal women. The most frequent adverse events associated with these therapies are musculoskeletal symptoms and an increased risk of bone fractures. Cutaneous adverse events have been rarely described. Sweet's syndrome can present as an idiopathic disorder in addition to being malignancy-associated or drug-induced.\nWe report the case of a 69-year old woman, diagnosed with early stage breast cancer, who underwent breast-conserving surgery, followed by adjuvant radio and endocrine treatment with letrozole 2.5 mg daily, for a foreseeable duration of 5 years. Three months after starting letrozole, she presented with sudden fever and exuberant and painful erythematous skin papules and plaques on her upper body. After a full work-up and exclusion of other potential causes, a skin biopsy confirmed the presence of dermal oedema and a diffuse neutrophilic infiltrate, suggesting Sweet's syndrome. After discontinuation of letrozole and treatment with corticosteroids, the patient fully recovered. She resumed adjuvant treatment with tamoxifen, without symptom recurrence.\nSweet's syndrome is a rare condition and an association with aromatase inhibitors has not been previously reported. Although its occurrence has already been observed in the onset of malignancies such as breast cancer, aromatase inhibitors must be added to the list of potential causes of drug-induced Sweet's syndrome.\nAromatase inhibitors are widely used in the treatment of breast cancer and, though infrequent, it is important to recognize possible cutaneous adverse events.Sweet's syndrome is a rare but troublesome condition. Prompt recognition and management are crucial to alleviate symptoms.Drug-induced Sweet's syndrome associated with aromatase inhibitors has not been previously reported and should be considered when evaluating treatment toxicities.",
"affiliations": "Medical Oncology Department, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal.;Medical Oncology Department, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal.;Medical Oncology Department, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal.;Medical Oncology Department, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal.;Pathology Department, Hospital de Cascais Dr. José Almeida, Cascais, Portugal.;Medical Oncology Department, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal.;Medical Oncology Department, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal.",
"authors": "Cardoso|Debora|D|;Coelho|Andreia|A|;Fernandes|Leonor|L|;Matos|Leonor Vasconcelos|LV|;Serrano|Isabel|I|;Miranda|Helena|H|;Martins|Ana|A|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2020_001435",
"fulltext": "\n==== Front\nEur J Case Rep Intern Med\nEuropean Journal of Case Reports in Internal Medicine\n2284-2594 SMC Media Srl \n\n32206641\n10.12890/2020_001435\n1435-1-11606-1-10-20200203\nArticles\nSweet’s Syndrome Induced by Aromatase Inhibitor in the Treatment of Early Breast Cancer\nCardoso Debora 1 Coelho Andreia 1 Fernandes Leonor 1 Matos Leonor Vasconcelos 1 Serrano Isabel 2 Miranda Helena 1 Martins Ana 1 \n1 Medical Oncology Department, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal\n\n2 Pathology Department, Hospital de Cascais Dr. José Almeida, Cascais, Portugal\n2020 \n07 2 2020 \n7 3 00143518 12 2019 31 12 2019 © EFIM 20202020This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseBackground\nBreast cancer is the most commonly diagnosed cancer in women, mainly at an early stage, allowing treatment with curative intent. Aromatase inhibitors are widely used in the adjuvant treatment of oestrogen receptor-positive breast cancer, mainly in postmenopausal women. The most frequent adverse events associated with these therapies are musculoskeletal symptoms and an increased risk of bone fractures. Cutaneous adverse events have been rarely described. Sweet’s syndrome can present as an idiopathic disorder in addition to being malignancy-associated or drug-induced.\n\nCase presentation\nWe report the case of a 69-year old woman, diagnosed with early stage breast cancer, who underwent breast-conserving surgery, followed by adjuvant radio and endocrine treatment with letrozole 2.5 mg daily, for a foreseeable duration of 5 years. Three months after starting letrozole, she presented with sudden fever and exuberant and painful erythematous skin papules and plaques on her upper body. After a full work-up and exclusion of other potential causes, a skin biopsy confirmed the presence of dermal oedema and a diffuse neutrophilic infiltrate, suggesting Sweet’s syndrome. After discontinuation of letrozole and treatment with corticosteroids, the patient fully recovered. She resumed adjuvant treatment with tamoxifen, without symptom recurrence.\n\nConclusions\nSweet’s syndrome is a rare condition and an association with aromatase inhibitors has not been previously reported. Although its occurrence has already been observed in the onset of malignancies such as breast cancer, aromatase inhibitors must be added to the list of potential causes of drug-induced Sweet’s syndrome.\n\nLEARNING POINTS\nAromatase inhibitors are widely used in the treatment of breast cancer and, though infrequent, it is important to recognize possible cutaneous adverse events.\n\nSweet’s syndrome is a rare but troublesome condition. Prompt recognition and management are crucial to alleviate symptoms.\n\nDrug-induced Sweet’s syndrome associated with aromatase inhibitors has not been previously reported and should be considered when evaluating treatment toxicities.\n\nAromatase inhibitorsbreast cancercutaneous adverse eventsSweet’s syndrome\n==== Body\nBACKGROUND\nBreast cancer (BC) is the most commonly diagnosed malignancy and is the leading cause of cancer-related death in women[1]. Due to screening, a significant number of cases are diagnosed at an early stage, allowing treatment with curative intent. Adjuvant systemic treatment after surgery reduces the risk of recurrence and should be considered. The decision is based on individual risk of relapse and predicted sensitivity to a particular treatment modality by Ki-67, oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status[2, 3].\n\nAromatase inhibitors (AIs) are commonly part of adjuvant treatment in postmenopausal women with BC, showing a survival benefit in this population. Letrozole is a non-selective AI approved for adjuvant treatment in postmenopausal women with early stage, hormone receptor-positive BC. The most frequent adverse events associated with AIs are myalgia, arthralgia and an increased risk of bone fractures. More rarely, their use may be complicated with cutaneous events such as alopecia, dry skin, urticaria, pruritus and different skin rashes[4,5].\n\nSweet’s syndrome (SS), also referred to as acute febrile neutrophilic dermatosis, is an uncommon inflammatory disease, and can present as an idiopathic condition in addition to being malignancy-associated or drug-induced. A constellation of clinical and pathological findings characterizes SS, which includes: sudden onset of fever; an elevated neutrophil count; tender erythematous to violaceous skin lesions as papules, nodules and plaques; and a diffuse infiltrate of mature neutrophils located in the upper dermis. Corticosteroid therapy is the treatment of choice[6].\n\nCASE DESCRIPTION\nA 69-year old, postmenopausal woman was diagnosed with early BC in February 2015. After left breast-conservative surgery and sentinel lymph node biopsy, the pathology report showed an invasive lobular carcinoma, stage IA (pT1cN0) and immunohistochemistry assessment revealed ER 95%, PR negative, HER2 negative, Ki-67 15%.\n\nThe patient’s relevant personal history included: in 2009, diagnosis of early cervical cancer, treated with radiotherapy; in 2011, diagnosis of a colonic adenocarcinoma, managed with right hemicolectomy followed by adjuvant chemotherapy; type 2 diabetes mellitus; hypertension. She was medicated for several years with antihypertensive drugs and metformin.\n\nAfter case discussion within the cancer multidisciplinary team, the patient was proposed to begin adjuvant radio and endocrine therapy with an AI. She started 2.5 mg of letrozole daily in March 2015, with a foreseeable duration of therapy of 5 years.\n\nThree months after letrozole initiation, the patient presented with sudden onset of fever (39ºC, tympanic) and an exuberant, painful and expanding skin erythema, associated with a burning sensation, located on the left trunk. She denied other symptoms, such as arthralgia, myalgia, headache or general malaise. She also denied recent viral infection of the respiratory or gastrointestinal tracts.\n\nPhysical examination revealed painful, brightly erythematous papules, some coalesced, forming plaques, with asymmetrical distribution in the neck, left trunk, back and upper extremities.\n\nMethods and Procedures\nThe patient’s full medical history was reviewed. Laboratory work-up revealed no signs of inflammation, with a total leucocyte count of 4,800 cells/mm3 with 69% neutrophils. The haemoglobin level was 12.6 g/dl and the liver function test, kidney function test and C-reactive protein levels were within normal limits. Blood cultures were negative. There was also no evidence of malignant disease recurrence.\n\nSince no diagnosis could be made based on previous findings, the patient was referred to the dermatology clinics and skin biopsies were performed. Pathological examination revealed dermal oedema and a dense, diffuse neutrophilic infiltrate, compatible with SS (Figs. 1 and 2).\n\nOn the basis of these results, drug-induced SS was considered and letrozole was immediately discontinued. An oral course of systemic corticosteroids, with prednisolone, was started at a dose of 1 mg/kg per day for 1 week. Skin lesions improved within the first 24 hours. Prednisolone was tapered down for 7 weeks and then discontinued. Letrozole was not re-introduced and tamoxifen was started. After 4 years of follow-up, there is no evidence of SS or BC recurrence.\n\nDISCUSSION\nSS can present in different clinical settings. Although malignancy-associated SS has already been described in the onset of BC [7–11], it is more likely to occur in association with haematologic malignancies than with solid tumours, with acute myelogenous leukaemia being the most frequently associated malignancy[12]. SS could also be associated with cancer recurrence.\n\nDrug-induced SS accounts for up to 5% of cases, most commonly associated with granulocyte colony-stimulating factor. Diagnostic criteria for drug-induced SS were established by Walker and Cohen. All 5 criteria are required for the diagnosis: 1) abrupt onset of painful erythematous plaques or nodules; 2) histopathologic evidence of a dense neutrophilic infiltrate without evidence of leucocytoclastic vasculitis; 3) pyrexia >38ºC; 4) temporal relationship between drug ingestion and clinical presentation, or temporally related recurrence after oral challenge; 5) temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids [13].\n\nIn the presented case, as described, all 5 criteria for drug-induced SS were present. The quick resolution after AI discontinuation strongly suggests a cause–effect relationship, and no relapse was observed with suspension of corticosteroid therapy. Presentation with fever also favours a drug-induced aetiology. In addition, in malignancy-associated SS, the onset of dermatosis is temporally related with the diagnosis of a new cancer or with the recurrence of malignancy in a patient with a previously diagnosed cancer. Fortunately, this was not our patient’s case, who remains cancer-free.\n\nAcknowledgements\nWe acknowledge the important contribution of the patient, with her willingness to collaborate as this case was conducted. We also thank the Head of the Department of Dermatology, Dr Felicidade Trindade, MD, for her contribution, revision and comments and Dr Emanuel Gonçalves, MD, from the Department of Medical Oncology, for his insights.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 Haematoxylin and eosin staining with identification of oedema of the dermis and inflammatory infiltrate at 100×\n\nFigure 2 Haematoxylin and eosin staining for identification of inflammatory infiltrate of the dermis, rich in polymorphonuclear neutrophils, 400×\n==== Refs\nREFERENCES\n1 Forouzanfar MH Foreman KJ Delossantos AM Lozano R Lopez AD Murray CJL Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis Lancet 2011 378 1461 1484 21924486 \n2 Berry DA Cronin KA Plevritis SK Fryback DG Clarke L Zelen M Effect of screening and adjuvant therapy on mortality from breast cancer N Engl J Med 2005 353 1784 1792 16251534 \n3 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials Lancet 2005 365 1687 1717 15894097 \n4 BIG 1–98 Collaborative Group Mouridsen H Giobbie-Hurder A Goldhirsch A Thürlimann B Paridaens R Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer N Engl J Med 2009 361 766 776 19692688 \n5 Moscetti L Agnese Fabbri M Sperduti I Fabrizio N Frittelli P Massari A Adjuvant aromatase inhibitor therapy in early breast cancer: what factors lead patients to discontinue treatment? Tumori 2015 101 5 469 473 26108239 \n6 Cohen PR Sweet’s syndrome – a comprehensive review of an acute febrile neutrophilic dermatosis Orphanet J Rare Dis 2007 2 34 17655751 \n7 Cohen PR Holder WR Tucker SB Kono S Kurzrock R Sweet syndrome in patients with solid tumors Cancer 1993 72 2723 2731 8402496 \n8 Antony F Holdern CA Sweet’s syndrome in association with generalized granuloma annulare in a patient with previous breast carcinoma Clin Exp Dermatol 2001 26 668 670 11722452 \n9 Coskun U Gunel N Senol E Ilter N Dursun A Tuzun D A case of Sweet’s syndrome developed after the treatment of herpes simplex infection in a metastatic breast cancer patient J Cutan Pathol 2002 29 301 304 12100632 \n10 Jacobi D Vidal C Gironet N Machet MC Machet L Pancytopenia and macular rash in a woman with a history of breast cancer Rev Med Intern 2003 24 399 400 \n11 Teng JMC Draper BK Boyd AS Sweet’s panniculitis associated with metastatic breast cancer J Am Acad Dermatol 2007 56 S61 S62 17224394 \n12 Cohen PR Talpaz M Kurzrock R Malignancy-associated Sweet’s syndrome: review of the world literature J Clin Oncol 1988 6 1887 1897 3058878 \n13 Walker DC Cohen PR Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet’s syndrome J Am Acad Dermatol 1996 34 918 923 8621829\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2284-2594",
"issue": "7(3)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Aromatase inhibitors; Sweet’s syndrome; breast cancer; cutaneous adverse events",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001435",
"pmc": null,
"pmid": "32206641",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "17224394;11722452;15894097;8402496;3058878;26108239;16251534;8621829;19692688;21924486;17655751;12814830;12100632",
"title": "Sweet's Syndrome Induced by Aromatase Inhibitor in the Treatment of Early Breast Cancer.",
"title_normalized": "sweet s syndrome induced by aromatase inhibitor in the treatment of early breast cancer"
} | [
{
"companynumb": "PT-INDICUS PHARMA-000657",
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"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Intravenous drug abuse unfortunately remains an extremely common problem worldwide, accounting for innumerable medical issues ranging from the transmission of human immunodeficiency virus (HIV) and other blood-borne diseases to skin necrosis to vasculitis to death [1]. We present a case of intra-arterial injection of alprazolam into the right femoral artery resulting in microembolization, acute ischemia and rhabdomyolysis of the thigh, as documented by magnetic resonance (MR) and laboratory findings.",
"affiliations": null,
"authors": "Wang|Eric C|EC|;Chew|Felix S|FS|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.2484/rcr.v1i3.33",
"fulltext": "\n==== Front\nRadiol Case RepRadiol Case RepRadiology Case Reports1930-0433Elsevier S1930-0433(15)30335-610.2484/rcr.v1i3.33ArticleMR Findings of Alprazolam Injection into the Femoral Artery with Microembolization and Rhabdomyolysis Wang Eric C. ewangmd@gmail.com1Chew Felix S. 11 Eric C. Wang and Felix S. Chew are from the University of Washington, Department of Radiology, Seattle, WA, United States of America.\n\n06 11 2015 2006 06 11 2015 1 3 99 102 © 2006 The Authors.2006This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nIntravenous drug abuse unfortunately remains an extremely common problem worldwide, accounting for innumerable medical issues ranging from the transmission of human immunodeficiency virus (HIV) and other blood-borne diseases to skin necrosis to vasculitis to death [1]. We present a case of intra-arterial injection of alprazolam into the right femoral artery resulting in microembolization, acute ischemia and rhabdomyolysis of the thigh, as documented by magnetic resonance (MR) and laboratory findings.\n\nAbbreviations\nHIV, human immunodeficiency virusMR, magnetic resonanceIV, intravenousED, emergency departmentSTIR, short tau inversion recoveryFSE, fast spin echo\n==== Body\nCase Report\nA 29 year old intravenous (IV) drug user presented to the emergency department (ED) with complaints of acute excruciating right leg pain. On the morning of admission, the patient crushed three tablets of alprazolam 0.5 mg, filtered it through sterile water, and attempted to inject his right femoral vein but mistakenly injected the femoral artery, as evidenced by a reported large backflow of blood. The patient's right lower extremity then immediately turned cold and mottled, with what he described as 10/10 pain.\n\nThe patient's past medical history was remarkable for polysubstance abuse, abscess drainange one month prior, and methadone treatment. Current medications included methadone 49 mg once per day.\n\nOn physical exam, the patient refused to move the right lower extremity, which was mottled and blanched with palpation. Ankle-brachial indices were greater than 1.0, normal and symmetric bilaterally. Vascular ultrasound evaluation demonstrated normal arterial flow of the right distal external iliac, common femoral, proximal profunda and superficial femoral arteries with normal waveform contour and velocities. The right common femoral, profunda and femoral veins also demonstrated normal, spontaneous, phasic flow. However, the right greater saphenous vein was occluded, likely unrelated to this episode.\n\nUrinalysis was positive for opiates, benzodiazepines, and methamphetamines. At presentation leukocyte count was minimally elevated at 12,000 cells/µL (normal 4,300-10,000). Serum creatine kinase and myoglobin were extremely elevated at 16,060 U/L (normal 30-285) and 1,281 ng/mL (normal 18-124) respectively. Urine myoglobin was also extremely elevated at 50,300 µg/L (normal 0-52). Serum creatinine remained normal throughout the hospital stay.\n\nMagnetic resonance imaging of the right thigh demonstrated extensive high short tau inversion recovery (STIR) signal abnormality in the thigh musculature, involving portions of the anterior, adductor, and posterior compartments. In the anterior compartment, the greatest involvement was of the vastus lateralis and rectus femoris, with less involvement of the vastus medialis and vastus intermedius. The sartorius and gracilis were involved to a moderate extent. In the adductor compartment, the adductor magnus was most severely involved, with lesser involvement of the adductor longus and brevis. In the posterior compartment, the semimembranosus was most involved with minimal involvement of the biceps femoris and virtual sparing of the semitendinosus. Subfascial fluid collections were present surrounding all compartments, greatest along the lateral aspect of the anterior compartment (Figure 1, Figure 2a, Figures 2 b-c, Figure 2d). Vascular surgery was consulted and agreed with nonoperative treatment. Medical therapy consisting of low molecular weight heparin, aspirin, and amlodipine was initiated in order to prevent vessel spasm and thrombosis. Leukocytosis ensued on hospital day two with peak of 29,600 per microliter, at which point vancomycin was started empirically for presumed bacteremia secondary to intravenous drug use. However, it was eventually decided the leukocytosis was secondary to rhabdomyolysis, and the vancomycin was discontinued after two days. Pain in the right lower extremity decreased, and the patient was discharged home the following day and scheduled to follow-up in methadone clinic.\n\nDiscussion\nIntravenous drug users often develop bacteremia, endocarditis, cutaneous infections, ulcers, and abscesses from their activities [1, 2]. However, inadvertent or deliberate intra-arterial injection also occurs commonly, causing severe tissue ischemia and necrosis. Immediately after injection, the patient feels intense pain and burning, followed by edema and cyanosis of the arterial territory within hours [3, 4]. In the most severe of cases, necrosis may occur, leading to amputation. Several differing mechanisms have been suggested that might explain the cause of such vascular injury. The drug itself may cause direct vasoconstriction as in the case of cocaine or amphetamines, or the additives in the drugs may cause vasospasm or thrombosis [5]. Finally, the drug mixture microparticles may act as emboli, especially when oral drug formulations are injected [6, 7].\n\nIn this case, the intra-arterial injection of alprazolam caused microembolism resulting in right thigh muscle ischemia and rhabdomyolysis in the vascular distribution of the femoral artery. Fortunately, there was no compartment syndrome and the patient escaped without surgery.\n\nMR is a highly sensitive technique for the imaging of skeletal muscle. It is extremely sensitive for evaluating pathologic processes including inflammation, infection, autoimmune disease, neoplasm, and trauma, among others. However, while the signal changes in skeletal muscle on MR may be extremely sensitive, they may not always be specific, and oftentimes the interpretation is highly affected by clinical history, laboratory findings, and histologic findings. In this case the history of intra-arterial drug injection provides important relevant data to guide the MR interpretation of necrosis and rhabdomyolysis.\n\nSubfascial fluid collections were also present, and in the appropriate clinical setting necrotizing fasciitis should be considered. Gadolinium has a role in distinguishing between necrotizing and non-necrotizing fasciitis; necrotizing fasciitis will not demonstrate enhancement of the fascia [8]. However, gadolinium was not administered for this patient because of the credible history given by the patient and the low clinical suspicion for necrotizing fasciitis. Furthermore, it should be emphasized that although necrotizing fasciitis may be suggested by certain MR, computed tomography, and even ultrasound findings, the diagnosis of necrotizing fasciitis is not solely an imaging diagnosis and is highly reliant on clinical picture and laboratory findings [8].\n\nOur institution utilizes a protocol of T1 FSE, STIR, and T1 FSE with fat saturation on most non-neoplastic skeletal and soft tissue MR examinations. The T1 sequence is crucial to evaluate for mass lesions, fatty infiltration, blood products, or proteinaceous material. The STIR sequence is highly sensitive for free water and used primarily for evaluation of muscle edema.\n\nThe management of intra-arterial drug injection resulting in only mild to moderate limb ischemia has traditionally been nonsurgical, consisting of heparin as well as limb elevation and pain control [4]. Many other medical treatment regimens have been utilized, including vasodilators, anticoagulants, and corticosteroids [9, 10, 11], but clinical efficacy has yet to be rigorously established. If edema and ischemia are more severe and lead to compartment syndrome, emergent faciotomy is necessary to preserve the limb and to avoid possible amputation.\n\nIn summary, patients with a known history of intravenous drug use and reported sudden onset of extremity pain after injection should be under high suspicion for intra-arterial injection with microembolism. Such patients are best evaluated with MR utilizing a T1 and STIR and/or T2 fat saturation sequence. Given this history, the diagnosis of muscle ischemia or necrosis is a relatively straight forward one, and the MR findings are sensitive and specific for detecting muscle edema and ischemia.\n\nPublished: September 7, 2006\n\nFigure 1 Axial tau fast spin echo (FSE) of the right thigh demonstrating normal musculature with extensive subcutaneous and subfascial edema. [Powerpoint Slide]\n\nFigure 2a Axial STIR images of the right thigh in axial planes demonstrating extensive high signal abnormality in the adductor, anterior, and posterior compartments, representing edema and ischemia from alprazolam microembolism. [Powerpoint Slide]\n\nFigures 2 b-c STIR images of the right thigh in axial planes demonstrating extensive high signal abnormality in the adductor, anterior, and posterior compartments, representing edema and ischemia from alprazolam microembolism. [Powerpoint Slide]\n\nFigure 2d Coronal STIR image of the right thigh in coronal planes demonstrating extensive high signal abnormality in the adductor, anterior, and posterior compartments, representing edema and ischemia from alprazolam microembolism. [Powerpoint Slide]\n==== Refs\nReferences\n1 Cherubin CE Sapira JD The medical complications of drug addiction and the medical assessment of the intravenous drug user: 25 years later Ann Intern Med 119 10 1993 Nov 15 1017 1028 [PubMed] 8214979 \n2 Beaufoy A Infections in intravenous drug users: a two-year review Can J Infect Control 8 1 1993 Spring 7 9 [PubMed] 8324242 \n3 Woodburn KR Murie JA Vascular complications of injecting drug misuse Br J Surg 83 10 1996 Oct 1329 1334 [PubMed] 8944446 \n4 Treiman GS Yellin AE Weaver FA Barlow WE Treiman RL Gaspar MR An effective treatment protocol for intraarterial drug injection J Vasc Surg 12 4 1990 Oct 456 465 discussion 465-6 [PubMed] 1698998 \n5 Heng MC Feinberg M Haberfelde G Erythematous cutaneous nodules caused by adulterated cocaine J Am Acad Dermatol 21 1989 570 572 [PubMed] 2674218 \n6 Somers WJ Lowe FC Localized gangrene of the scrotum and penis: a complication of heroin injection into the femoral vessels J Urol 136 1986 111 113 [PubMed] 3712594 \n7 Bahia H Moazzam A Ramakrishnan A Penoscrotal necrosis complicating intravenous drug abuse Br J Plast Surg 52 1999 324 325 [PubMed] 10624310 \n8 Fugitt JB Puckett ML Quigley MM Kerr SM Necrotizing fasciitis Radiographics 24 5 2004 Sep-Oct 1472 1476 [PubMed] 15371620 \n9 Silverman SH Turner WW Jr Intraarterial drug abuse: new treatment options J Vasc Surg 14 1 1991 Jul 111 116 [PubMed] 2061951 \n10 Stueber K The treatment of intraarterial pentazocine injection injuries with intraarterial reserpine Ann Plast Surg 18 1 1987 Jan 41 46 [PubMed] 3827130 \n11 Andreev A Kavrakov T Petkov D Penkov P Severe acute hand ischemia following an accidental intraarterial drug injection, successfully treated with thrombolysis and intraarterial Iloprost infusion Angiology 46 10 1995 Oct 963 967 [PubMed] 7486219\n\n",
"fulltext_license": "CC BY-NC-ND",
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"keywords": "ED, emergency department; FSE, fast spin echo; HIV, human immunodeficiency virus; IV, intravenous; MR, magnetic resonance; STIR, short tau inversion recovery",
"medline_ta": "Radiol Case Rep",
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"pmc": null,
"pmid": "27298694",
"pubdate": "2006",
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"references": "2674218;8214979;1698998;8324242;8944446;3827130;7486219;2061951;15371620;10624310;3712594",
"title": "MR Findings of Alprazolam Injection into the Femoral Artery with Microembolization and Rhabdomyolysis.",
"title_normalized": "mr findings of alprazolam injection into the femoral artery with microembolization and rhabdomyolysis"
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"activesubstancename": "ALPRAZOLAM"
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"abstract": "Selective serotonin reuptake inhibitor (SSRI) exposure during pregnancy can result in symptoms of serotonin syndrome or serotonin withdrawal. In contrast to other SSRIs, reports of serotonin behavioral syndrome following in utero exposure to escitalopram and citalopram are limited. We describe a case of suspected toxicity following in utero exposure to 20 mg escitalopram throughout pregnancy. The infant was transferred to our neonatal intensive unit at 9 hours of life for further evaluation of lethargy, weak cry, bradycardia, and non-reactive pupils. Hypoxic ischemic encephalopathy was suspected upon presentation, despite APGAR scores of 8 and 9. Upon admission, symptoms progressed to signs of hypertonia, irritability, high-pitched cry, and posturing. The patient was loaded with phenobarbital for empiric management of suspected seizures versus drug withdrawal. Both electroencephalogram and computed tomography scan results were normal; however, an electrocardiogram revealed a prolonged QTc interval of 531 milliseconds. Signs of irritability and QTc prolongation continued through day of life (DOL) 5. The infant was discharged on DOL 10 with no further symptoms. We hypothesize that this represented a case of serotonin toxicity due to in utero exposure to escitalopram and recommend close monitoring for neonatal behavioral syndrome symptoms and QTc prolongation in infants exposed to escitalopram during pregnancy.",
"affiliations": "University of Virginia Health System Children's Hospital, Charlottesville, Virginia.;Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas.",
"authors": "Degiacomo|Jessica|J|;Luedtke|Sherry|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-21.6.522",
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"issue": "21(6)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "adverse drug effect; behavioral syndrome; citalopram; escitalopram; in utero; neonatal behavioral syndrome; pregnancy; selective serotonin reuptake inhibitor",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "522-526",
"pmc": null,
"pmid": "28018155",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "10941349;11391127;12269673;12860776;12902002;15900008;19032728;19081700;20707986;22506805;23438790;29955465",
"title": "Neonatal Toxicity From Escitalopram Use In Utero: A Case Report.",
"title_normalized": "neonatal toxicity from escitalopram use in utero a case report"
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"abstract": "OBJECTIVE\nThe hepatotoxic potential of statins is controversial. The objectives of this study were to describe the relative frequency of hepatotoxicity caused by statins and the phenotypes found in Spain.\n\n\nMETHODS\nThe incidence of hepatotoxicity attributed to statins in the Spanish Hepatotoxicity Registry (REH) were studied and compared with those attributed to other drugs.\n\n\nRESULTS\nBetween April 1994 and August 2012, the REH included a total of 858 cases of which 47 (5.5 %) were attributed to statins. Of these, 16 were due to atorvastatin (34 %); 13 to simvastatin (27.7 %); 12 to fluvastatin (25.5 %); 4 to lovastatin (8.5 %) and 2 to pravastatin (4.3 %). Statins represented approximately half of the cardiovascular group which occupied 3rd place (10 %), after anti-infectious agents (37 %) and central nervous system drugs (14 %). The hepatocellular pattern was predominant, especially in the simvastatin group (85%), the cholestatic/mixed pattern was more frequent with fluvastatin (66 %) and had a similar distribution to atorvastatin. Patients with statin-induced toxicity were older (62 years versus 53 years, p < 0.001) and more often demonstrated anautoimmune hepatitis phenotype (8.5 % versus 1.4 %, p < 0.003).\n\n\nCONCLUSIONS\nStatins are not a common cause of hepatotoxicity in Spain. Atorvastatin is the statin involved in the greatest number of incidents. The liver injury pattern varies among the different statins. The hepatitis phenotype with autoimmune features appears to be a characteristic signature of statin-induced hepatotoxicity.",
"affiliations": null,
"authors": "Perdices|E V|EV|;Medina-Cáliz|I|I|;Hernando|S|S|;Ortega|A|A|;Martín-Ocaña|F|F|;Navarro|J M|JM|;Peláez|G|G|;Castiella|A|A|;Hallal|H|H|;Romero-Gómez|M|M|;González-Jiménez|A|A|;Robles-Díaz|M|M|;Lucena|M I|MI|;Andrade|R J|RJ|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors",
"country": "Spain",
"delete": false,
"doi": null,
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"issn_linking": "1130-0108",
"issue": "106(4)",
"journal": "Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva",
"keywords": null,
"medline_ta": "Rev Esp Enferm Dig",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D013030:Spain; D055815:Young Adult",
"nlm_unique_id": "9007566",
"other_id": null,
"pages": "246-54",
"pmc": null,
"pmid": "25075655",
"pubdate": "2014-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hepatotoxicity associated with statin use: analysis of the cases included in the Spanish Hepatotoxicity Registry.",
"title_normalized": "hepatotoxicity associated with statin use analysis of the cases included in the spanish hepatotoxicity registry"
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"companynumb": "ES-BAMAGV-2022.00090",
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"activesubstancename": "LOVASTATIN"
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"abstract": "To analyze the effect of adjunctive brexpiprazole on metabolic parameters and body weight in adults with major depressive disorder (MDD) based on pooled data from 4 short-term studies and 1 long-term extension study.\n\n\n\nThe short-term studies (June 2011 to November 2016) were randomized, double-blind, placebo-controlled studies in outpatients with MDD (DSM-IV-TR criteria) and inadequate response to 1-3 prior antidepressant treatments (ADTs) plus 1 prospective ADT. Patients were randomized to adjunctive brexpiprazole (fixed or flexible doses in the range of 1-3 mg/d; n = 1,032) or placebo (n = 819) for 6 weeks. The long-term study (October 2011 to May 2017) was a 52-week (amended to 26 weeks), open-label, uncontrolled study of adjunctive brexpiprazole 0.5-3 mg/d (flexible dose; n = 2,938). Mean changes from baseline and categorical shifts in fasting metabolic parameters (cholesterol, triglycerides, and glucose) and body weight were analyzed.\n\n\n\nMean changes from baseline in metabolic parameters were small after 6 weeks (all < 2 mg/dL) and 52 weeks (all < 4 mg/dL, except triglycerides, 15.83 mg/dL) of treatment. In most cases, the incidence of unfavorable shifts in metabolic parameters was lower than the incidence of favorable shifts. Mean body weight increase at last visit in the short-term studies was 1.5 kg with ADT + brexpiprazole and 0.3 kg with ADT + placebo. During long-term treatment, mean body weight increased by 3.8 kg over 58 weeks.\n\n\n\nAdjunctive brexpiprazole was associated with small changes in metabolic parameters and moderate weight gain during short- and long-term treatment.\n\n\n\nClinicalTrials.gov identifiers: NCT01360645, NCT01360632, NCT02196506, NCT01727726, NCT01360866.",
"affiliations": "Thriving Mind South Florida, 7205 Corporate Center Dr, Ste 200, Miami, FL 33126. jnewcomer@thrivingmind.org.;H. Lundbeck A/S, Valby, Copenhagen, Denmark.;Otsuka Pharmaceutical Development & Commercialization Inc, Princeton, New Jersey, USA.;H. Lundbeck A/S, Valby, Copenhagen, Denmark.;Otsuka Pharmaceutical Development & Commercialization Inc, Princeton, New Jersey, USA.",
"authors": "Newcomer|John W|JW|;Eriksson|Hans|H|;Zhang|Peter|P|;Meehan|Stine R|SR|;Weiss|Catherine|C|",
"chemical_list": "D000928:Antidepressive Agents; D001786:Blood Glucose; D015363:Quinolones; D013876:Thiophenes; D014280:Triglycerides; C000591922:brexpiprazole; D002784:Cholesterol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-6689",
"issue": "80(6)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000328:Adult; D000928:Antidepressive Agents; D001786:Blood Glucose; D001835:Body Weight; D002784:Cholesterol; D003865:Depressive Disorder, Major; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008134:Long-Term Care; D008297:Male; D008875:Middle Aged; D015363:Quinolones; D013876:Thiophenes; D014280:Triglycerides",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31577867",
"pubdate": "2019-10-01",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Changes in Metabolic Parameters and Body Weight in Patients With Major Depressive Disorder Treated With Adjunctive Brexpiprazole: Pooled Analysis of Phase 3 Clinical Studies.",
"title_normalized": "changes in metabolic parameters and body weight in patients with major depressive disorder treated with adjunctive brexpiprazole pooled analysis of phase 3 clinical studies"
} | [
{
"companynumb": "US-OTSUKA-2019_035387",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BREXPIPRAZOLE"
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"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report a rare case of extreme leukocytosis and leukemoid reaction associated with lung sarcomatoid carcinoma (LSC) and increase people's awareness of the disease.\n\n\nMETHODS\nA 58-year-old male patient was diagnosed with LSC; however, after the end of the second course of chemotherapy, his white blood cells increased gradually without fever or use of medications such as granulocyte colony-stimulating factor and steroids. A bone marrow biopsy then confirmed it to be a leukemoid reaction.\n\n\nRESULTS\nThe patient died of multiple organ failure 2 months after being diagnosed with leukocytosis.\n\n\nCONCLUSIONS\nLSC associated with leukemoid reaction is very rare and the prognosis is poor. When a patient's white blood cells are extremely elevated, we should think of the possible causes of the tumor itself and identify it with other diseases. However, more data and evidence are still needed to find an effective adjuvant therapy for these patients.",
"affiliations": "Department of Hematopathy, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.;Department of Hematopathy, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.;Department of Hematopathy, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.;Department of Hematopathy, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.",
"authors": "Wang|Danyang|D|;Zhang|Haiyan|H|;Yu|Fengkuan|F|;Fang|Baijun|B|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IJGM.S102524",
"fulltext": "\n==== Front\nInt J Gen MedInt J Gen MedInternational Journal of General MedicineInternational Journal of General Medicine1178-7074Dove Medical Press 10.2147/IJGM.S102524ijgm-10-007Case ReportExtreme leukocytosis and leukemoid reaction associated with the lung sarcomatoid carcinoma: an unusual case report Wang Danyang Zhang Haiyan Yu Fengkuan Fang Baijun Department of Hematopathy, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaCorrespondence: Baijun Fang, Department of Hematopathy, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, People’s Republic of China, Email fdation@126.com.cn2017 23 12 2016 10 7 9 © 2017 Wang et al. This work is published and licensed by Dove Medical Press Limited2017The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Purpose\nTo report a rare case of extreme leukocytosis and leukemoid reaction associated with lung sarcomatoid carcinoma (LSC) and increase people’s awareness of the disease.\n\nPatients and methods\nA 58-year-old male patient was diagnosed with LSC; however, after the end of the second course of chemotherapy, his white blood cells increased gradually without fever or use of medications such as granulocyte colony-stimulating factor and steroids. A bone marrow biopsy then confirmed it to be a leukemoid reaction.\n\nResults\nThe patient died of multiple organ failure 2 months after being diagnosed with leukocytosis.\n\nConclusion\nLSC associated with leukemoid reaction is very rare and the prognosis is poor. When a patient’s white blood cells are extremely elevated, we should think of the possible causes of the tumor itself and identify it with other diseases. However, more data and evidence are still needed to find an effective adjuvant therapy for these patients.\n\nKeywords\nlung sarcomatoid carcinomaleukemoid reaction\n==== Body\nIntroduction\nLung sarcomatoid carcinomas (LSCs) are very rare, mostly reported in the form of case reports, and leukemoid reactions has rarely been described in patients with LSC, to the best of our knowledge. Meanwhile, the mechanism of leukocytosis is not very clear. Here, we discuss an unusual case of extreme leukocytosis and a leukemoid reaction associated with the LSC. We summarize the relevant reports, hoping to provide some help for other clinicians when they encounter similar disease or symptoms.\n\nCase presentation\nA 58-year-old male patient had symptoms of intermittent cough and hemoptysis with no incentives in June 2014, and accompanying chest tightness and shortness of breath. He was first admitted to a local hospital, where computed tomography of the chest showed a left lung mass, suggesting a probability of tuberculosis. Therefore, he was treated for tuberculosis, but had no significant relief of symptoms. He then visited our hospital, where he underwent computed tomography-guided biopsy; the pathology results showed poorly differentiated adenocarcinoma (left lung). He then underwent surgery for resection of the mass; pathological examination showed poorly differentiated peripheral pulmonary carcinoma with the tumor being composed of mononuclear and multinucleated tumor giant cells with significant atypia. Immunohistochemistry showed: creatine kinase (CK) (−), P63 (−), thyroid transcription factor (TTF)-1 (−), CK18 (+), Napsin A (−), CK (+), vimentin (+), smooth muscle actin (SMA) (−), desmin (−), epidermal growth factor receptor (EGFR) (++), Ki-67 (+60%), epithelial membrane antigen (EMA) (+); the consideration is sarcomatoid carcinoma (giant cell carcinoma). The patient received two courses of chemotherapy in our hospital after surgery, gemcitabine 1.4 D1and 8 + cisplatin 30 mg D1–4 and tolerated it well.\n\nHowever, the patient’s white blood cells (WBCs) increased gradually without fever or use of medications, such as granulocyte colony-stimulating factor (G-CSF) and steroids, after the end of the second course (Figure 1), and neutrophils accounted for ~93%. While his hemoglobin and platelets were within the normal range. We initially used antibiotics empirically, which was ineffective. Next, a bone marrow biopsy was performed; the results showed myeloid and erythroid focal hyperplasia and significant partial immature myeloid cell proliferation (Figure 2). Immunohistochemistry showed individual lymphocytes CD3 (+), individual lymphocytes CD20 (+), erythroid CD235a (+), megakaryocytes CD61 (+), CD34 (−), individual monocytes CD14 (+), individual plasma cells CD138 (+), a large number of myeloid myeloperoxidase (MPO) (+) (Figure 3). Finally, the patient was diagnosed with leukocytosis, then he and his family refused further chemotherapy, so we put the patient on “hydroxyurea” to control the leukocytosis. The patient died of multiple organ failure 2 months after being diagnosed with leukocytosis. This study was approved by the Ethics Committee of The Affiliated Cancer Hospital of Zhengzhou University.\n\nDiscussion\nSarcomatoid carcinoma is a poorly differentiated malignant cancer, which is composed of both carcinomatous and sarcomatous elements. It can occur in many parts of the body, but most commonly affects the respiratory tract, lungs, breasts, and kidneys. Clinically, sarcomatoid carcinoma originating in the lung (LSC) is very rare, accounting for 0.3%–4.7% of all lung malignancies.1 LSC is a non-small-cell lung carcinoma, which has a high degree of malignancy, and is more aggressive than the average lung cancers. The effects of radiotherapy and chemotherapy are not very good; therefore, the prognosis of LSC is poor.2–4\n\nLeukemoid reaction is defined as a WBC count >50×109/L without evidence of leukemia or infection.5 Leukemoid reaction is a potential cause for leukocytosis, especially in the presence of predominately mature granulocytic leukocytosis. A leukemoid reaction is caused by an exaggerated myeloid; it has been associated with infections, allergies, burns, intoxications, acute hemorrhage, malignant neoplasms, and several other stimuli.6–9\n\nLSC associated with leukemoid reaction is very rare. The mechanism of leukemoid reaction is not very clear. Cancer-related symptoms, may be caused by G-CSF secreted by the tumor cells.10–12 Chen et al13 indicated that, in cases of leukemoid reaction, leukocytosis is frequently mediated by tumor-related cytokines and CSF including G-CSF, granulocyte-macrophage CSF, interleukin 6 or 1α.\n\nJardin et al14 have reported a case with lung sarcoma and leukemoid reaction. The patient’s G-CSF concentration increase was observed after the first cycle of chemotherapy (>20,000 pg/mL). Dramatically, the highest G-CSF concentration level was observed when the WBC count was lowest, suggesting that a massive cytokine release appeared after tumor lysis related to chemotherapy.14 We also observed a similar phenomenon in our report; after chemotherapy, the patient’s WBC experienced dramatic increases. For various reasons, we have not measured G-CSF concentration level, but we can speculate that perhaps the reason was the same.\n\nLeukemoid reaction always indicates a high degree of malignancy, high probability of metastasis, and recurrence and wretched prognosis. In our report, the patient died of multiple organ failure 2 months after being diagnosed with leukocytosis. This is consistent with other reports correlating leukemoid reactions with advanced and aggressive tumor cell growth and poor outcome.6,15\n\nIn conclusion, LSC associated with leukemoid reaction is very rare and the prognosis is poor. When a patient’s WBC is extremely elevated, we should think of possible causes of the tumor itself and identify it with other diseases. However, more data and evidence are still needed to find an effective adjuvant therapy for these patients.\n\nAcknowledgments\nWritten informed consent was obtained from this patient for publication of this case report and any accompanying images.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 WBC gradually increased postoperatively.\n\nNotes: “A” represents the day the patient took hydroxyurea 0.5 g tid po; “B” represents the day the patient took hydroxyurea 1.0 g tid po; “C” represents the day the patient took hydroxyurea 2.0 g bid po; “D” represents the day the patient took hydroxyurea 1.0 g tid po; “E” represents the day the patient did not take the hydroxyurea; “F” represents the day the patient took hydroxyurea 1.0 g tid po. The patient was discharged on March 30, 2015.\n\nAbbreviations: bid, twice daily; po, per os; tid, three times a day; WBC, white blood cell.\n\nFigure 2 Bone marrow biopsy (hematoxylin and eosin 10×40).\n\nFigure 3 Immunohistochemistry (MPO 10×40).\n\nAbbreviation: MPO, myeloperoxidase.\n==== Refs\nReferences\n1 Pelosi G Sonzogni A De Pas T Pulmonary sarcomatoid carcinomas: a practical overview Int J Surg Patho1 2010 18 2 103 120 \n2 Martin LW Correa AM Ordonez NG Sarcomatoid carcinoma of the lung: a predictor of poor prognosis Ann Thorac Surg 2007 84 3 973 980 17720411 \n3 Venissac N Pop D Lassalle S Berthier F Hofman P Mouroux J Sarcomatoid lung cancel(spindle/giant cells): an aggressive disease? J Thorac Cardiovasc Surg 2007 134 3 619 623 17723808 \n4 Yuki T Sakuma T Ohbayashi C Pleomorphic carcinoma of the lung: a surgical outcome J Thorac Cardiovasc Surg 2007 134 2 399 404 17662779 \n5 McKee L Excess leukocytosis (leukemoid reactions) associated with malignant diseases South Med J 1985 78 12 1475 1482 3877987 \n6 Stav K Leibovici D Siegel YI Lindner A Leukemoid reaction associated with transitional cell carcinoma Isr Med Assoc J 2002 4 3 223 224 11908271 \n7 Marinella MA Extreme leukemoid reaction associated with retroperitoneal hemorrhage Arch Intern Med 1998 158 3 300 301 9472215 \n8 Pina-Ceballos VM Montemayor-Garza R Gonzalez-Oritz J Leukemoid reaction secondary to prenatal use of betamethasone in a premature neonate Rev Mex Pediatr 1997 64 197 200 \n9 Abramson N Melton B Leukocytosis: basics of clinical assessment Am Fam Physician 2000 62 9 2053 2060 11087187 \n10 Nimieri HS Makoni SN Madziwa FH Nemiary DS Leukemoid reaction response to chemotherapy and radiotherapy in a patient with cervical carcinoma Ann Hematol 2003 82 5 316 317 12739065 \n11 Turalic H Deamant FD Reese JH Paraneoplastic production of granulocyte colony-stimulating factor in a bladder carcinoma Scand J Urol Nephrol 2006 40 5 429 432 17060092 \n12 Lee MY Kaushansky K Judkins SA Lottsfeldt JL Waheed A Shad-duck RK Mechanism of tumor-induced neutroneutrophilia: constitutive production of colony-stimulating factors and their synergistic actions Blood 1989 74 115 122 2473793 \n13 Chen YM Whang-Peng J Liu JM Leukemoid reaction resulting from multiple cytokine production in metastatic mucoepidermoid carcinoma with central necrosis Jpn J Clin Oncol 1995 25 4 168 172 7545252 \n14 Jardin F Vasse M Debled M Paraneoplastic neutrophilic leukemoid reaction related to a G-CSF-secreting lung sarcoma Am J Hematol 2005 80 3 243 245 16247754 \n15 Kasuga I Makino S Kiyokawa H Katoh H Ebihara Y Ohyashiki K Tumor-related leukocytosis is linked with poor prognosis in patients with lung carcinoma Cancer 2001 92 9 2399 2405 11745296\n\n",
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"keywords": "leukemoid reaction; lung sarcomatoid carcinoma",
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"title": "Extreme leukocytosis and leukemoid reaction associated with the lung sarcomatoid carcinoma: an unusual case report.",
"title_normalized": "extreme leukocytosis and leukemoid reaction associated with the lung sarcomatoid carcinoma an unusual case report"
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"abstract": "Alveolar rhabdomyosarcoma (AR) in adult patients is an exceptional malignancy. Management of AR is based on (neo)adjuvant chemotherapy combining ifosfamide, vincristine, and actinomycin D and local curative-intent surgery/radiotherapy. In cases of relapsing AR, the combination of temozolomide/irinotecan is regarded as a possible option. Here we describe life-threatening long-lasting toxicity related to the 1st cycle of irinotecan-based chemotherapy in a 56-year-old woman suffering from locally advanced and metastatic head and neck AR. The patient experienced grade 4 vomiting and diarrheas resulting in acute functional renal failure, associated with grade 4 neutropenia complicated by severe septic shock. The hospital stay duration was 40 days. The analysis of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene revealed homozygous UGT1A1 ⁎28 polymorphism with an associated homozygous mutation c.-3275T>G; the latter is associated with a decrease of about 80% of UGT1A1 transcription explaining this irinotecan induced toxicity. Physician must be aware of the potential hematological (mainly neutropenia and infectious disease) and digestive (mainly diarrhea) toxicities caused by irinotecan and especially when the patient presents a UGT1A1 ⁎28 homozygous allele. UGT1A genotyping performed before initiating treatment is useful to anticipate severe toxic reaction to irinotecan and improve the benefit/risk ratio of its use.",
"affiliations": "Lille II University Medical School, Lille, France.;CHU Lille, Service de Toxicologie et Génopathies, Lille, France.;Medical Oncology Department, Oscar Lambret Cancer Centre, Lille, France.;Medical Oncology Department, Amiens University Hospital, Amiens, France.;Medical Oncology Department, Oscar Lambret Cancer Centre, Lille, France.",
"authors": "Jannin|Arnaud|A|;Hennart|Benjamin|B|;Adenis|Antoine|A|;Chauffert|Bruno|B|;Penel|Nicolas|N|0000-0001-5243-1548",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2017/2683478Case ReportLife-Threatening Irinotecan-Induced Toxicity in an Adult Patient with Alveolar Rhabdomyosarcoma: The Role of a UGT1A1 Polymorphism Jannin Arnaud \n1\nHennart Benjamin \n2\nAdenis Antoine \n3\nChauffert Bruno \n4\nhttp://orcid.org/0000-0001-5243-1548Penel Nicolas n-penel@o-lambret.fr\n3\n\n1Lille II University Medical School, Lille, France\n2CHU Lille, Service de Toxicologie et Génopathies, Lille, France\n3Medical Oncology Department, Oscar Lambret Cancer Centre, Lille, France\n4Medical Oncology Department, Amiens University Hospital, Amiens, FranceAcademic Editor: Jose I. Mayordomo\n\n2017 26 9 2017 2017 26834788 6 2017 17 8 2017 Copyright © 2017 Arnaud Jannin et al.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Alveolar rhabdomyosarcoma (AR) in adult patients is an exceptional malignancy. Management of AR is based on (neo)adjuvant chemotherapy combining ifosfamide, vincristine, and actinomycin D and local curative-intent surgery/radiotherapy. In cases of relapsing AR, the combination of temozolomide/irinotecan is regarded as a possible option. Here we describe life-threatening long-lasting toxicity related to the 1st cycle of irinotecan-based chemotherapy in a 56-year-old woman suffering from locally advanced and metastatic head and neck AR. The patient experienced grade 4 vomiting and diarrheas resulting in acute functional renal failure, associated with grade 4 neutropenia complicated by severe septic shock. The hospital stay duration was 40 days. The analysis of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene revealed homozygous UGT1A1 ⁎28 polymorphism with an associated homozygous mutation c.-3275T>G; the latter is associated with a decrease of about 80% of UGT1A1 transcription explaining this irinotecan induced toxicity. Physician must be aware of the potential hematological (mainly neutropenia and infectious disease) and digestive (mainly diarrhea) toxicities caused by irinotecan and especially when the patient presents a UGT1A1 ⁎28 homozygous allele. UGT1A genotyping performed before initiating treatment is useful to anticipate severe toxic reaction to irinotecan and improve the benefit/risk ratio of its use.\n==== Body\n1. Introduction\nAlveolar rhabdomyosarcoma (AR) is a very rare malignancy. Adult cases of AR are exceptional [1]. AR management includes treatment with (neo) adjuvant chemotherapy, combining ifosfamide, vincristine, actinomycin D, and local curative intent surgery/radiotherapy [2]. In cases of relapsing AR, there is no consensus on second-line treatment; however, the combination of temozolomide and irinotecan has been considered a possible option [3].\n\nIn this case report, we describe life-threatening, long-lasting toxicity occurring after the first cycle of irinotecan-based chemotherapy. This case stresses the role of a uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism in the magnitude of observed toxicity.\n\n2. Case Description\nA 56-year-old Caucasian woman presented with locally advanced (meningeal and bone skull extension) and metastatic (massive cervical lymph nodes and diffuse vertebral involvement) head and neck AR. The patient experienced a complete response after 5 cycles of ifosfamide/vincristine and actinomycin D combination and conformational radiotherapy on the primary site (50.4 Gray). The first-line chemotherapy was well tolerated without dose reduction or severe toxicity. Unfortunately, twelve months later, the patient presented with a metastatic relapse with retroperitoneal lymph node and pancreatic metastases. Before starting treatment, hematological and biological parameters (including liver parameters) were within normal ranges. Second-line chemotherapy was administered. The 5-day treatment regimen consisted of temozolomide (125 mg/m2) administered per os daily and irinotecan (50 mg/m2) administered by IV daily. However, on the 4th day of treatment, the patient experienced grade 4 vomiting and grade 4 diarrhea, requiring a hospital stay. The diarrhea and vomiting led to dehydration and acute functional renal failure. On day 4, biological analyses revealed grade 4 neutropenia (228 neutrophils/mm3), grade 3 anemia (hemoglobin 6.9 g/l), grade 4 thrombocytopenia (10 652 platelets/mm3), and hepatic cytolysis (transaminases were 3 times the upper limit of normal). Severe stomatitis precluded oral alimentation, requiring a hospital stay and enteral alimentation for 13 days. On day 9, the patient experienced septic shock related to severe diverticulitis and ileitis, which required management in an intensive care unit and treatment with large spectrum antibiotherapy (piperacillin-tazobactam and amikacin). The neutropenia lasted 14 days, and the diarrhea lasted 18 days. The total duration of the hospital stay was 40 days. During the stay, she received 3 units of red blood cells and 5 units of platelets. Because of progressive disease, a third-line treatment with gemcitabine/dacarbazine is in progress.\n\nIn parallel, we hypothesized the presence of a predisposing pharmacogenetics condition. Our analysis of the UGT1A1 gene revealed that the patient possessed a UGT1A1 ∗28 polymorphism. This polymorphism is frequently identified in the Caucasian population (0.387) [4]. Furthermore, genetic analysis revealed an associated homozygous mutation c.-3275T>G. The mutation associated with this polymorphism has been described to be responsible for a decrease in UGT1A1 transcription by approximately 80% [5].\n\n3. Discussion\nAR occurs rarely in adults and is associated with a poor prognosis [1]. There is no standardized treatment described for adults, and this is likely related to the limited number of studies in this group. The chemotherapy backbone for metastatic AR contains ifosfamide, vincristine, and actinomycin D (IVA protocol). After this first line of treatment and in the case of progression, temozolomide combined with irinotecan could be a therapeutic option [3].\n\nIrinotecan is an anticancer agent widely used for advanced stage colorectal cancer. The activation and metabolism of this drug involve the sequential activation of SN-38 (7-ethyl-10-hydroxycamptothecin), the potent topoisomerase inhibitor, and detoxification of SN-38 to the pharmacologically inactive SN-38 glucuronide (SN-38G) by UGT1A1 [6]. The UGT1A1 enzyme is responsible for hepatic bilirubin glucuronidation. Reduced UGT1A1 gene expression leads to Gilbert's syndrome, Crigler–Najjar syndrome [7], and irinotecan toxicity. More than 60 variants of UGT1A1 have been described. Expression of UGT1A1 is, in part, controlled by a polymorphic dinucleotide repeat sequence within the UGT1A1 promoter TATA box, consisting of between five and eight copies of a TA repeat ([TA]nTAA). The (TA)6TAA allele is the most common (considered wild-type), and (TA)7TAA is the most frequently recorded variant allele (usually denoted by UGT1A1 ∗28). The presence of seven or eight TA repeats in the UGT1A1 promoter region leads to reduced glucuronidation, reduced SN-38G formation, and increased irinotecan-induced toxicity.\n\nThe frequency of the UGT1A1 ∗28 allele has been assessed worldwide. The UGT1A1 ∗28 allele is present in approximately one-third of Caucasians. This variant is a major predictive pharmacogenetic marker of severe toxicity during irinotecan-based chemotherapy [8]. Indeed, the association between drug toxicity and UGT1A1 ∗28 was analyzed in the Phase III TRIBE trial, which investigated the combination of bevacizumab-FOLFOXIRI versus bevacizumab-FOLFIRI. Among 443 evaluable patients, those carrying the UGT1A1 ∗28/ ∗28 homozygous variant were at higher risk of developing grade 3/4 neutropenia compared with 1 ∗/28 and 1 ∗/1 carriers (59 versus 35% p = 0.003) irrespective of the treatment arm [9]. Several studies utilizing the FOLFIRI protocol have suggested that the highest tolerated dose of irinotecan in patients with the UGT1A1 ∗28 genotype was 130 mg/m2 [8, 10].\n\nIn the present case, the patient carries homozygous UGT1A1 ∗28 polymorphisms and NM_000463.2 (UGT1A1): c.-3275T>G mutations. The presence of both genotypes explains the long-lasting, severe hematological, and digestive toxicity. Our patient presented neither with jaundice nor isolated elevation of serum bilirubin levels, both of which might have suggested the presence of the UGT1A polymorphism. UGT1A1 genotyping performed prior to the initiation of irinotecan treatment could have allowed us to anticipate the development of this toxicity, but this genotyping is not a standard of care. However, the use of UGT1A1 genotyping in routine practice is debated, especially in the setting of colorectal cancer. The 2016 ESMO guidelines suggest UGT genotyping in the following situations [11]: patients with a suspicion of UGT1A1 deficiency and patients receiving a dose of irinotecan > 180 mg/m2. Similarly, the National Comprehensive Cancer Network guidelines version 2.2016 states that irinotecan should be used with caution and at a decreased dose in patients with Gilbert syndrome. Nevertheless, routine testing of UGT SNPs is not recommended, and dose modifications according to genotyping are not a standard practice [12]. Recently, a note was added to the irinotecan FDA label suggesting an initial dose reduction for patients carrying homozygous UGT1A1 ∗28 alleles [13]. The French National Network of Pharmacogenetics group has recently suggested that UGT1A1 genotyping is advisable for standard irinotecan doses and essential for intensified doses (>240 mg/m2) [14]. For doses between 180 and 230 mg/m2, this group recommends a 25% to 30% dose reduction in homozygous UGT1A1 ∗28 allele patients [14]. As recommended, our patient received a 50 mg/m2 dose of irinotecan per day from day 1 to day 5, so she received 250 mg/m2 in total [3]. According to the current recommendations of ESMO [11], all AR patients receiving the temozolomide/irinotecan in combination should receive UGT1A1 genotyping.\n\nOne reason for the nonimplementation of this genotyping test in clinical practice is its financial cost. An Italian study has precisely shown that the mean cost per patient was higher when genotyping was not implemented: ∗28/ ∗28 (€4.886) versus ∗1/ ∗1 (€812) (regression coefficient 1.79, 95% confident interval [1.31–2.28]; p < 0.001). This study also showed that, in Italy, the cost of toxicity management far exceeds the costs required to genotype all patients prior to initiating irinotecan treatment [15]. A prospective randomized European study is needed to determine if preemptive UGT1A1 genotyping could effectively reduce toxicity occurrence and related costs.\n\n4. Conclusion\nFollowing an IVA protocol in adults, refractory AR may require the use of irinotecan in combination with temozolomide. Clinicians must be extremely attentive to hematological (mainly neutropenia and infectious disease) and digestive (mainly diarrhea) toxicities when prescribing irinotecan, especially in patients with homozygous UGT1A1 ∗28 alleles. UGT1A1 genotyping performed before the initiation treatment could anticipate severe toxic reactions to irinotecan and improve the benefit/risk ratio of its use.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this article.\n==== Refs\n1 Ruiz-Mesa C. Goldberg J. M. Coronado Munoz A. J. Dumont S. N. Trent J. C. Rhabdomyosarcoma in Adults: New Perspectives on Therapy Current Treatment Options in Oncology 2015 16 6 2-s2.0-84929222695 10.1007/s11864-015-0342-8 \n2 Oberlin O. Rey A. Sanchez De Toledo J. Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study Journal of Clinical Oncology 2012 30 20 2457 2465 10.1200/JCO.2011.40.3287 2-s2.0-84864057707 22665534 \n3 Bagatell R. Norris R. Ingle A. M. Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: a children's oncology group study Pediatric Blood and Cancer 2014 61 5 833 839 10.1002/pbc.24874 2-s2.0-84895743330 24249672 \n4 Beutler E. Gelbart T. Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proceedings of the National Academy of Sciences of the United States of America 1998 95 14 8170 8174 10.1073/pnas.95.14.8170 2-s2.0-0032493441 9653159 \n5 Matsui K. Maruo Y. Sato H. Takeuchi Y. Combined effect of regulatory polymorphisms on transcription of UGT1A1 as a cause of Gilbert syndrome BMC Gastroenterology 2010 10, article no. 57 2-s2.0-77953126166 10.1186/1471-230X-10-57 \n6 Iyer L. King C. D. Whitington P. F. Genetic predisposition to the metabolism of irinotecan (CPT-11): role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes The Journal of Clinical Investigation 1998 101 4 847 854 10.1172/jci915 2-s2.0-0032519431 9466980 \n7 Kadakol A. Ghosh S. S. Sappal B. S. Sharma G. Chowdhury J. R. Chowdhury N. R. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: Correlation of genotype to phenotype Human Mutation 2000 16 4 297 306 2-s2.0-0033799997 10.1002/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z 10.1002/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z 11013440 \n8 Innocenti F. Kroetz D. L. Schuetz E. Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics Journal of Clinical Oncology 2009 27 16 2604 2614 2-s2.0-66849111193 10.1200/JCO.2008.20.6300 19349540 \n9 Del Re M. Cremolini C. Loupakis F. DPYD c.1905 + 1G > A and c.2846A > T and UGT1A1 * 28 allelic variants as predictors of toxicity: pharmacogenetic translational analysis from the Phase III TRIBE study in metastatic colorectal cancer Journal of Clinical Oncology 2015 33 3532 \n10 Marcuello E. Páez D. Paré L. A genotype-directed phase I-IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer British Journal of Cancer 2011 105 1 53 57 2-s2.0-79959763841 10.1038/bjc.2011.206 21654688 \n11 Cutsem E. V. Cervantes A. Adam R. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer Annals of Oncology 2016 27 1386 1422 27380959 \n12 NCCN Guidelines–Colon Cancer, 2017, http://www.jnccn.org/content/15/3/370.full.pdf+html \n13 Camptosar [prescribing information], 2017, http://labeling.pfizer.com/ShowLabeling.aspx?id=533 \n14 Quaranta S. Thomas F. Pharmacogenetics of anti-cancer drugs: state of the art and implementation—recommendations of the French National Network of Pharmacogenetics Therapie 2017 72 2 205 215 10.1016/j.therap.2017.01.005 2-s2.0-85014363423 28262261 \n15 Roncato R. Cecchin E. Montico M. Cost Evaluation of Irinotecan-Related Toxicities Associated With the UGT1A1 * 28 Patient Genotype Clinical Pharmacology and Therapeutics 2017 10.1002/cpt.615 2-s2.0-85016241783\n\n",
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"title": "Life-Threatening Irinotecan-Induced Toxicity in an Adult Patient with Alveolar Rhabdomyosarcoma: The Role of a UGT1A1 Polymorphism.",
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"abstract": "Entamoeba histolytica, a pathogenic protozoan that causes amoebiasis, remains the second leading cause of death from parasitic infections worldwide. We present a case series of patients presenting to metropolitan tertiary gastroenterology units in Melbourne, Australia, highlighting the complexities of diagnosing amoebic colitis and the potential for misdiagnosis. These cases illustrate four key lessons in the identification of amoebic colitis: (i) obtaining a thorough travel and exposure history, (ii) having a high index of suspicion, (iii) understanding the limitations of available investigations, and (iv) being aware that amoebic colitis may masquerade as other common conditions.",
"affiliations": "Department of Gastroenterology Monash Health Clayton Victoria Australia.;Department of Gastroenterology Alfred Health Melbourne Victoria Australia.;Department of Gastroenterology Monash Health Clayton Victoria Australia.;Department of Gastroenterology Monash Health Clayton Victoria Australia.;Department of Gastroenterology Monash Health Clayton Victoria Australia.",
"authors": "Abasszade|Joshua Haron|JH|https://orcid.org/0000-0001-5469-4317;Little|Robert|R|;Yeaman|Fiona|F|;Robertson|Marcus|M|;Bell|Sally|S|",
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"fulltext": "\n==== Front\nJGH Open\nJGH Open\n10.1002/(ISSN)2397-9070\nJGH3\nJGH Open: An Open Access Journal of Gastroenterology and Hepatology\n2397-9070\nWiley Publishing Asia Pty Ltd Melbourne\n\n10.1002/jgh3.12484\nJGH312484\nCase Report\nCase Reports\nAmoebic colitis: A case series of a recurring missed diagnosis\nAmoebic colitis\nJH Abasszade et al.\nAbasszade Joshua Haron https://orcid.org/0000-0001-5469-4317\n1 josh.abasszade@gmail.com\n\nLittle Robert 2\nYeaman Fiona 1\nRobertson Marcus 1 3\nBell Sally 1 3\n1 Department of Gastroenterology Monash Health Clayton Victoria Australia\n2 Department of Gastroenterology Alfred Health Melbourne Victoria Australia\n3 Department of Medicine Monash University Melbourne Victoria Australia\n* Correspondence\nJoshua Abasszade, Department of Gastroenterology, Monash Health, Clayton, Vic., 3168, Australia. Email: josh.abasszade@gmail.com\n\n22 12 2020\n3 2021\n5 3 10.1002/jgh3.v5.3 404407\n02 12 2020\n10 12 2020\n© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.\nThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nEntamoeba histolytica, a pathogenic protozoan that causes amoebiasis, remains the second leading cause of death from parasitic infections worldwide. We present a case series of patients presenting to metropolitan tertiary gastroenterology units in Melbourne, Australia, highlighting the complexities of diagnosing amoebic colitis and the potential for misdiagnosis. These cases illustrate four key lessons in the identification of amoebic colitis: (i) obtaining a thorough travel and exposure history, (ii) having a high index of suspicion, (iii) understanding the limitations of available investigations, and (iv) being aware that amoebic colitis may masquerade as other common conditions.\n\nEntamoeba histolytica is the pathogenic protozoan responsible for amoebic colitis, a common parasitic infection, and the second leading cause of death from parasitic infections worldwide. The clinical presentation of amoebic colitis is varied, and diagnosis remains challenging in many cases. We present a case series of four patients in whom diagnosis of Entamoeba histolytica highlight the challenges and pitfalls of diagnosing amoebic colitis in developed countries where the incidence is low.\n\namoebic colitis\nantibiotics\nEntamoeba histolytica\ntravel history\nsource-schema-version-number2.0\ncover-dateMarch 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.9 mode:remove_FC converted:06.03.2021\nDeclaration of conflict of interest: None.\n\nAuthor contribution: Joshua Haron Abasszade, Robert Little, Fiona Yeaman, Marcus Robertson, and Sally Bell conceived and designed the case study, were primarily responsible for the manuscript preparation, and were part of the treating team.\n==== Body\nIntroduction\n\nEntamoeba histolytica (E. histolytica) is the pathogenic protozoan responsible for amoebic colitis, a common parasitic infection, 1 and the second leading cause of death from parasitic infections worldwide. 2 The clinical presentation of amoebic colitis is varied and may include cramping abdominal pain, watery and/or bloody diarrhea, weight loss, fever, and anemia. Complications such as toxic megacolon, perianal ulceration, and colonic perforation are described, 3 and extraintestinal complications may arise secondary to hematogenous spread to sites such as the liver, brain, and lungs. 3\n\nWe present a case series of four patients diagnosed with amoebic colitis. These cases highlight the importance of obtaining a thorough travel and exposure history, maintaining a high index of suspicion, and understanding the limitations of available investigations in order to differentiate amoebiasis from common differential diagnoses such as inflammatory bowel disease (IBD), bacterial colitis, and colorectal cancer. 3\n\nCase series presentations\n\nCase 1\n\nA 36‐year‐old Indian woman with a medical history significant for thalassemia minor was diagnosed with ulcerative proctitis in India in May 2019. She was treated with sulfasalazine and corticosteroids. A flare of ulcerative colitis (UC) was documented following medication noncompliance, which settled with oral metronidazole prescribed by a local general practitioner. Following travel to Australia, her symptoms recurred and persisted for several months until she presented to hospital with bloody diarrhea, nausea, vomiting, and loss of weight; she was also noted to be 24 weeks' pregnant. Treatment with rectal and oral 5‐aminosalicylic acid and oral prednisolone was commenced with an initial improvement in symptoms. Given her pregnancy status and improvement with medical management, endoscopy was not performed. She subsequently re‐presented with severe bloody diarrhea associated with tachycardia, anemia (hemoglobin 76 g/L), and leukocytosis. Intravenous corticosteroids were commenced, and a sigmoidoscopy demonstrated Mayo 3 proctitis (Fig. 1a). Fecal microscopy and tissue histology both demonstrated E. histolytica organisms, consistent with amoebic colitis. Intravenous metronidazole (750 mg three times a day) and metronidazole suppositories were commenced with rapid resolution of rectal bleeding. She was discharged with a seven‐day course of oral metronidazole (400 mg three times a day) followed by paromomycin (500 mg three times a day). She remained well and delivered a healthy child at term.\n\nFigure 1 (a) Severe proctitis in the rectum. (b) CT angiography (portal‐venous phase) demonstrating hypodense lesions scattered throughout the liver. (c) Inflammation and ulceration of the colon. (d) Histology of the sigmoid colon demonstrating Entamoeba histolytica organisms with ingested red cells (arrows). Credit: David Hugo Romero.\n\nCase 2\n\nA 75‐year‐old previously well man, on holiday from India, presented to hospital with a two‐week history of abdominal pain, fever, watery, nonbloody diarrhea and anorexia. On examination, he was tachycardic (heart rate 115 beats per minute), tachypneic (respiratory rate 28 breaths/min), and febrile (38.1°C). Abdominal examination revealed a soft abdomen with right iliac fossa tenderness. Initial laboratory findings demonstrated an elevated white cell count (39.2 × 109/L) and C‐reactive protein (CRP) (379 mg/L). A CT abdomen revealed a phlegmonous mass adjacent to the caecum, raising the possibility of appendicitis along with multiple ill‐defined hepatic lesions.\n\nThe patient underwent a laparotomy where a perforated caecal mass with peritonitis was found. Intraoperative colonoscopy demonstrated ulceration of the rectum and transverse colon, and a subtotal‐colectomy with end‐ileostomy was performed. Postoperatively, worsening transaminitis was noted, and a CT liver demonstrated innumerable hypodense hepatic lesions consistent with liver abscesses (Fig. 1b), which were subsequently biopsied. Human immunodeficiency virus (HIV), amoebic, and Echinococcus serology and Mycobacterial microscopy and culture were all negative.\n\nHistology of the resected bowel demonstrated numerous E. histolytica organisms with ulceration and caecal perforation; cultures from other sites were negative for amoebiasis. The patient required serial drainage of hepatic abscesses and ultimately recovered following intravenous metronidazole and prolonged oral paromomycin.\n\nCase 3\n\nA 45‐year‐old healthy man presented with four weeks of worsening nonbloody diarrhea, 11 kg of weight loss, and a perianal abscess with a communicating anal fistula. Prior to admission, his general practitioner had treated him for suspected food poisoning and commenced oral metronidazole following a positive stool culture for Blastocystis hominis. The patient denied recent travel or receptive anal intercourse. In hospital, a fistulotomy was performed, and intravenous hydrocortisone and antibiotics were commenced for ongoing diarrhea. A sigmoidoscopy demonstrated an anal fistula and deep ulceration with rectal sparing. A presumptive diagnosis of Crohn's disease was made. Subsequent magnetic resonance enterography showed no small bowel involvement. The patient was transferred to a tertiary center following large‐volume rectal bleeding.\n\nOn arrival, the patient was anemic (hemoglobin 70 g/L) with an elevated CRP of 172 mg/L. Three fecal specimens were obtained and tested, and ova‐cyst‐parasite (OCP) analysis and amoebiasis, schistosomiasis, strongyloides, and syphilis serology were negative. A colonoscopy revealed moderate ileitis and multiple pancolonic serpiginous ulcers (Fig. 1c), further supporting a diagnosis of atypical ileocolonic and perianal Crohn's disease, and infliximab 10 mg/kg was commenced. Three days later, the patient deteriorated with fever and left iliac fossa pain. A CT abdomen demonstrated spontaneous sigmoid colon perforation with intraperitoneal free gas. He underwent an emergency laparotomy and Hartmann's procedure; histopathology demonstrated acute colitis and copious E. histolytica organisms (Fig. 1d). Intravenous metronidazole (750 mg tds) was commenced, and the patient made a full recovery.\n\nCase 4\n\nA 24‐year‐old Indian woman presented to hospital with a 10‐day history of abdominal pain, weight loss, and severe bloody diarrhea on a background of known UC. Her UC was diagnosed in India in 2018 and managed with mesalazine monotherapy.\n\nOn examination, vital signs were within normal limits, and abdominal examination revealed right‐sided involuntary guarding and tenderness. The patient was anemic (hemoglobin 93 g/L) with normal inflammatory markers. A CT abdomen showed rectal mucosal hyperenhancement. Intravenous hydrocortisone was commenced for a suspected UC flare, and a flexible sigmoidoscopy demonstrated Mayo 2 proctitis. HIV, hepatitis, and mycobacterium serology were negative. Stool microscopy was positive for E. histolytica organisms. Oral metronidazole followed by paromomycin were commenced, corticosteroids were weaned, and mesalazine was ceased. Bowel histology did not demonstrate amoebiasis.\n\nDiscussion\n\nThese cases highlight the challenges and pitfalls of diagnosing amoebic colitis in developed countries where the incidence is low. Significant variation in presenting symptoms, previous misdiagnosis, and amoebiasis masquerading as other common conditions all contribute to missed or late diagnoses, which can result in development of life‐threatening complications. In addition, these cases highlight the importance of a comprehensive travel history and maintaining an index of suspicion, even in patients with diagnosed IBD. We recommend that clinicians consider invasive amoebiasis in their list of differentials and be aware that it is both a local and imported disease. 1\n\nE. histolytica infection begins with ingestion of cysts, typically through fecally contaminated water or food. In the small bowel, excystation occurs with the formation of mobile and invasive trophozoites, which aggregate in the mucin layer of the intestines, forming cysts and destroying colonic epithelium. 3 Approximately 90% of cases are self‐limiting and asymptomatic, 4 with spontaneous clearance of infection. 1 Symptoms of abdominal pain, watery and/or bloody diarrhea, weight loss, and fevers occur in 10% cases, and extraintestinal spread is noted in <1%. 4\n\nE. histolytica is endemic to India, Southeast Asia, Egypt, and Mexico. 1 , 2 van Hal et al. reported that invasive amoebiasis has been prevalent in northern Australia, leading to locally acquired cases. 1 High‐risk populations in Australia include indigenous Australians, immigrants, residents returning from endemic countries, and men who have sex with men. 1 In this series, three of four patients had recently traveled to India; however, one case acquired E. histolytica despite no domestic or international travel. This has not previously been reported and illustrates the potential for local transmission.\n\nDiagnostic tools for intestinal amoebiasis include: fecal microscopy, fecal polymerase chain reaction (PCR), fecal and/or serum antigen detection, serology, and histologic examination of colonic biopsy specimens. 5 Fecal microscopy is the most common first‐line investigation, particularly in developing countries; however, the sensitivity to identify cysts and/or trophozoites is suboptimal at 25–60%. 4 Given that organism excretion can vary, three specimens taken on separate days are recommended to increase the diagnostic yield. 5 Fecal PCR has a sensitivity >70% and a specificity >90%. 6 The sensitivity of antigen detection in feces is 90%, and in serum is 65% in the acute setting. 3 , 4 Detection of Entamoeba antibodies in serum is possible in 70–90% of individuals within 5–7 days of acute infection; however, this is not helpful in differentiating acute from previous infections. 3 , 4 , 5 Finally, colonic biopsy specimens are not considered a routine diagnostic tool, and visualization of amoeba is rare. Nonspecific histopathological findings such as hemorrhagic regions of the colon, flask‐shaped ulcerations, necrosis of intestinal wall, and focal perforation may be associated with amoebic colitis, and the diagnostic yield may be increased with specialized stains such as the periodic acid‐Schiff stain. 4\n\nDespite these tools, diagnosis of amoebic colitis remains challenging. This is highlighted in Case 3, where serology and serial fecal cultures were negative, possibly as a result of a prior course of metronidazole. In two cases, diagnosis was made on bowel histology, which is not common, and only one case was diagnosed by noninvasive means. Other published series have documented the diagnostic challenges associated with amoebic colitis; however, the majority are from developing countries where the incidence is higher. Gupta et al. demonstrated a fatal case of amoebic colitis in India, in which a patient was misdiagnosed and treated for IBD before developing fulminant necrotizing amoebic colitis, leading to multiorgan failure and death. 7 Cases 2 and 3 in our cohort also demonstrate the dangers of delayed diagnosis as these patients required emergency laparotomy following colonic perforation. Den et al. also reported the difficulties of diagnosing amoebic colitis whereby repeated colonic biopsies and stool cultures were negative for E. histolytica; diagnosis was ultimately confirmed serologically with resolution of symptoms following appropriate antimicrobial therapy. 8 Finally, Tufail et al. described a case series of amoebic colitis in the United Kingdom masquerading as IBD. 9 Guidelines were suggested by the authors to screen for E. histolytica in all patients presenting with colitis, with amoebic antimicrobial cover to be empirically commenced in patients receiving immunosuppression until results are available. 9\n\nThe Australian Therapeutic Guidelines recommend treatment of acute amoebic colitis (dysentery) using metronidazole 600 mg orally every eight hours for seven days. 10 However, if severe (i.e. blood in the stools, perforation, peritonitis), then escalated doses of metronidazole of either 750 mg intravenously or 800 mg orally every eight hours for seven days are required. 10 Once treatment is completed, an intraluminal cyst eradication agent, paromomycin 500 mg orally, every eight hours for seven days, should be used. 10 Paromomycin prevents relapse given that treatment failure may occur in up to 40–60% of patients treated with metronidazole alone. 4\n\nIn conclusion, this case series highlights the challenges in diagnosing amoebic colitis and the potentially life‐threatening consequences of misdiagnosis, inappropriate immunosuppression, and delayed antimicrobial therapy.\n\nAcknowledgements\n\nWe acknowledge David Hugo Romero for his contributions to the graphic design.\n==== Refs\nReferences\n\n1 van Hal SJ , Stark DJ , Fotedar R , Marriott D , Ellis JT , Harkness J . Amoebiasis: current status in australia. Med. J. Aust. 2007; 186 : 412–6.17437396\n2 Stanley S Jr . Amoebiasis. Lancet. 2003; 361 : 1025–34.12660071\n3 Bercu TE , Petri WA , Behm JW . Amebic colitis: new insights into pathogenesis and treatment. Curr. Gastroenterol. Rep. 2007; 9 : 429–33.17991346\n4 Haque R , Huston CD , Hughes M , Houpt E , Petri WA Jr . Amebiasis. N. Engl. J. Med. 2003; 348 : 1565–73.12700377\n5 Leder K , Weller PF . Intestinal Entamoeba histolytica amebiasis. In: Post TW (ed.). UpToDate. Waltham, MA: UpToDate, 2020.\n6 Tanyuksel M , Petri WA Jr . Laboratory diagnosis of amebiasis. Clin. Microbiol. Rev. 2003; 16 : 713–29.14557296\n7 Gupta SS , Singh O , Shukla S , Raj MK . Acute fulminant necrotizing amoebic colitis: a rare and fatal complication of amoebiasis: a case report. Cases J. 2009; 2 : 6557.19918532\n8 Den Y , Kinoshita J , Deshpande GA , Hiraoka E . Amoebiasis masquerading as inflammatory bowel disease. BMJ Case Rep. 2015; 2015 : 1–2.\n9 Tufail Q , O'Meara D , Thi A , Lim F , Richards C . P853 Amoebic colitis mimicking inflammatory bowel disease: a report of four cases. J. Crohn's Colitis. 2020; 14 (Suppl. 1): S656–S7.\n10 Gastrointestinal Protozoa . eTG Complete [digital]. Melbourne: Therapeutic Guidlines Limited, 2019.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2397-9070",
"issue": "5(3)",
"journal": "JGH open : an open access journal of gastroenterology and hepatology",
"keywords": "Entamoeba histolytica; amoebic colitis; antibiotics; travel history",
"medline_ta": "JGH Open",
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"pages": "404-407",
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"pmid": "33732890",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": "14557296;12660071;17437396;17991346;19918532;12700377",
"title": "Amoebic colitis: A case series of a recurring missed diagnosis.",
"title_normalized": "amoebic colitis a case series of a recurring missed diagnosis"
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