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"abstract": "OBJECTIVE\nThis post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from Latin America.\n\n\nMETHODS\nAnalyses were performed in subgroups of patients from Latin America based on data from three individual, 26-week, placebo-controlled studies of canagliflozin (monotherapy [n = 116/584], add-on to metformin [n = 199/918], and add-on to metformin plus sulfonylurea [n = 76/469]) and three individual, 52-week, active-controlled studies of canagliflozin (add-on to metformin versus sitagliptin [n = 240/1101], add-on to metformin versus glimepiride [n = 155/1450], and add-on to metformin plus sulfonylurea versus sitagliptin [n = 156/755]).\n\n\nMETHODS\nChanges from baseline in HbA1c, body weight, and systolic blood pressure (BP) with canagliflozin 100 and 300 mg versus placebo or active comparator (i.e., sitagliptin or glimepiride) were evaluated in the overall study populations and Latin American subgroups. Safety was assessed based on adverse event (AE) reports.\n\n\nRESULTS\nCanagliflozin 100 and 300 mg provided reductions in HbA1c, body weight, and systolic BP across studies in patients from Latin America that were generally similar to those seen in the overall populations of patients with T2DM. The AE profile in patients from Latin America was equivalent to that in the overall populations; higher rates of genital mycotic infections and osmotic diuresis-related AEs were seen with canagliflozin versus comparators. Limitations of this study include the post hoc analysis of data and the small sample size of patients from Latin America.\n\n\nCONCLUSIONS\nCanagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America.\n\n\nBACKGROUND\nNCT01081834; NCT01106677; NCT01106625; NCT00968812; NCT01137812.",
"affiliations": "a a Universidad Autonoma de Nuevo Leon , Monterrey , Mexico.;b b Hospital Israelita Albert Einstein and CPClin Clinical Research Center , São Paulo , Brazil.;c c Hospital Cima, Centro de Investigacíon Clínica San Agustín , San José , Costa Rica.;d d Endocrinología, Medicina Interna , Bogota , Colombia.;e e Janssen Research & Development, LLC , Raritan, NJ , USA.;e e Janssen Research & Development, LLC , Raritan, NJ , USA.",
"authors": "Lavalle-González|Fernando J|FJ|;Eliaschewitz|Freddy G|FG|;Cerdas|Sonia|S|;Chacon|Maria Del Pilar|Mdel P|;Tong|Cindy|C|;Alba|Maria|M|",
"chemical_list": "D001786:Blood Glucose; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D000068896:Canagliflozin; C057619:glimepiride; D008687:Metformin; D000068900:Sitagliptin Phosphate",
"country": "England",
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"doi": "10.1185/03007995.2015.1121865",
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"issue": "32(3)",
"journal": "Current medical research and opinion",
"keywords": "Antihyperglycemic agent; Canagliflozin; Latin America; Phase 3 study; SGLT2 inhibitor; Type 2 diabetes",
"medline_ta": "Curr Med Res Opin",
"mesh_terms": "D000328:Adult; D000368:Aged; D001786:Blood Glucose; D001794:Blood Pressure; D001835:Body Weight; D000068896:Canagliflozin; D003924:Diabetes Mellitus, Type 2; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D007843:Latin America; D008297:Male; D008687:Metformin; D008875:Middle Aged; D000068900:Sitagliptin Phosphate; D013453:Sulfonylurea Compounds; D016896:Treatment Outcome",
"nlm_unique_id": "0351014",
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"pages": "427-39",
"pmc": null,
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"pubdate": "2016",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from Latin America.",
"title_normalized": "efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from latin america"
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"abstract": "BACKGROUND\nMacular edema and detachment at the first day after an uneventful cataract surgery is very rare, and has been reported previously with the use of high concentrations of intra-cameral cefuroxime. However, we hereby reported two cases of macular edema with extensive serous retinal detachment the first day after an uneventful phacoemulsification with intra-cameral injection of a standard dose of cefuroxime during the procedure.\n\n\nMETHODS\nA 68-year-old female and a 63-year-old male without any special history both underwent an uneventful phacoemulsification surgery and 1 mg/0.1 ml of cefuroxime solution was injected into the anterior chamber at the end of the procedure. Macular edema with extensive serous retinal detachment around macula and optic disc area were observed the first day after surgery. Without surgical intervention, a quick recovery of the macular edema and retinal detachment was observed by spectral domain optical coherence tomography 1 week later in both cases.\n\n\nCONCLUSIONS\nWe presume that the retina injury in the two cases may be attributed to cefuroxime toxicity even under a use of a standard dose. But the retinal damages are restorable and routine anti-inflammatory treatment is enough.",
"affiliations": "State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sun University, Xianlie South Road No 54, Guangzhou, 510060, China. drxh81@163.com.;State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sun University, Xianlie South Road No 54, Guangzhou, 510060, China. drliuxing@163.com.;State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sun University, Xianlie South Road No 54, Guangzhou, 510060, China. 582803057@qq.com.",
"authors": "Xiao|Hui|H|;Liu|Xing|X|;Guo|Xinxing|X|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002444:Cefuroxime",
"country": "England",
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"doi": "10.1186/s13104-015-1639-1",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central London 163910.1186/s13104-015-1639-1Case ReportMacular edema with serous retinal detachment post-phacoemulsification followed by spectral domain optical coherence tomography: a report of two cases Xiao Hui drxh81@163.com Liu Xing +86 20 87330434drliuxing@163.com Guo Xinxing 582803057@qq.com State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sun University, Xianlie South Road No 54, Guangzhou, 510060 China 4 11 2015 4 11 2015 2015 8 64710 12 2014 27 10 2015 © Xiao et al. 2015\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\nMacular edema and detachment at the first day after an uneventful cataract surgery is very rare, and has been reported previously with the use of high concentrations of intra-cameral cefuroxime. However, we hereby reported two cases of macular edema with extensive serous retinal detachment the first day after an uneventful phacoemulsification with intra-cameral injection of a standard dose of cefuroxime during the procedure.\n\nCase presentation\nA 68-year-old female and a 63-year-old male without any special history both underwent an uneventful phacoemulsification surgery and 1 mg/0.1 ml of cefuroxime solution was injected into the anterior chamber at the end of the procedure. Macular edema with extensive serous retinal detachment around macula and optic disc area were observed the first day after surgery. Without surgical intervention, a quick recovery of the macular edema and retinal detachment was observed by spectral domain optical coherence tomography 1 week later in both cases.\n\nConclusion\nWe presume that the retina injury in the two cases may be attributed to cefuroxime toxicity even under a use of a standard dose. But the retinal damages are restorable and routine anti-inflammatory treatment is enough.\n\nKeywords\nMacular edemaRetinal detachmentCefuroximePhacoemulsificationissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nMacular edema is one of the most common complications after cataract surgery that causes unfavorable visual outcomes and usually occurs in the surgical eye 4–16 weeks after the procedure [1, 2]. Acute macular edema with retinal detachment after cataract surgery is very rare, and has been reported previously with the use of high concentrations of intra-cameral cefuroxime [3, 4]. Cefuroxime is commonly used during phacoemulsification procedure [5] and has been proved to be safe with a standard dose previously [6–8]. However, we hereby report two cases of macular edema with extensive serous retinal detachment that was immediately detected by spectral domain optical coherence tomography (SD-OCT) the first day after an uneventful phacoemulsification with intra-cameral injection of standard doses of cefuroxime during the procedure. We presume that the retina injury in the two cases may be attributed to cefuroxime toxicity even under a use of a standard dose.\n\nCase presentation\nCase 1\nA 68-year-old female had an uncomplicated phacoemulsification surgery with folded in-the-bag intraocular lens (IOL) implantation in her left eye. Her systemic and ophthalmic histories were unremarkable. No diabetic, uveitis or any other remarkable retinal history was found prior to the surgery. Preoperatively, the refractive errors of her right and left eyes were −4.0 and −4.5 diopters (D), with axial lengths of 24.12 and 24.37 mm, respectively. The best-corrected visual acuity was 20/33 in the right and 20/40 in the left eye. The patient’s anterior segment and fundus were normal in both eyes, as revealed by regular examination. The surgery was performed using an Infiniti phacoemulsification unit (Alcon, Inc.). The nucleus chopping time was 5.8 s, and the average power was 6.8 %. A +18 D folded IOL (Acrysof SN60AT Alcon, Inc) was implanted in-the-bag. The surgery was completed without complications. At the end of the procedure, 1 mg/0.1 ml of cefuroxime solution was injected into the anterior chamber. We perform our dilution in the operating room: the nurse takes 750 mg of preservative-free vial cefuroxime and adds 7.5 ml of balanced salt solution (BSS), and then, the surgeon takes 0.1 ml of this first solution and adds another 0.9 ml of BSS to obtain the second solution. 0.1 ml of the second solution is finally injected in the anterior chamber of the patient. The patient is therefore supposed to receive 0.1 ml of 10 mg/ml solution of intra-cameral cefuroxime. The total length of the surgical time was approximately 10 min.\n\nThe first day after the operation, the visual acuity in her left eye was 20/200. There were no signs of remarkable inflammation or abnormality in the anterior segment, as well as in the vitreous. Fundus examination showed no foveal reflection in the macula. Diffuse retinal edema affected most of the posterior pole. Retinal wrinkles were found around the macula and disc area. No significant abnormality was found in the peripheral retina. SD-OCT (Carl Zeiss Meditec, Dublin, CA, USA) scanning was immediately performed and showed macular edema, especially at the outer nuclear layer, with extensive shallow serous retinal detachment around macula and optic disc area (Fig. 1). The retinal thickness of the fovea was 750 μm. No significant abnormality was found in the choroids and the subfoveal choroidal thickness was 350 μm. Vitreomacular traction was not found in the SD-OCT image. Topical dexamethasone 0.1 %/tobramycin 0.3 % (Tobradex®) eye drops and pranoprofen (Senju Pharmaceutical Co. Ltd) were prescribed four times a day. After 1 week of treatment, the patient’s vision in her left eye had improved to 20/20. The macular retina was scanned with the same area by SD-OCT and the image showed that the retinal thickness of the fovea returned within a normal range (194 μm), and the subfoveal choroidal thickness seemed not changed a lot (about 347 μm). The macular edema and subretinal fluid were absorbed completely. The integrated ellipsoid zone was preserved in the outer retina (Fig. 2). No recurrence of macular edema or retinal detachment was noted at the last follow-up (4 months post-operative).Fig. 1 Image of spectral domain optical coherence tomography (SD-OCT) on one day post-operation (case 1). The SD-OCT image demonstrated macular edema most manifested at the outer nuclear layer and shallow serous retinal detachment around the macula (a) and optic disc area (b)\n\nFig. 2 SD-OCT images of case 1 One week post-operation. Macular edema and subretinal fluid was absorbed and the central foveal thickness resumed to normal (a). The subretinal fluid was also absorbed around optic disc (b)\n\n\n\nCase 2\nA 63-year-old male underwent an uneventful phacoemulsification surgery with folded in-the-bag IOL implantation in the left eye. The systemic and ophthalmic histories were unremarkable. Preoperatively, the refractive error of his left eye was −2.75 D with an axial length of 23.93 mm. The best corrected visual acuity was 20/200. The right eye had IOL implanted 1 year ago with good visual acuity of 20/20. Findings of anterior segment and fundus examination were normal in both eyes. The phacoemulsification surgery was performed by the same doctor as in case 1. The nucleus chopping time was 32 s and the average power was 16.8 %. A +20.0 D folded IOL (Acrysof SN60AT Alcon, Inc) was implanted in-the-bag. The surgery was completed without complications. At the end of the procedure, 1 mg/0.1 ml of cefuroxime solution (diluted as case 1) was also injected into the anterior chamber. The total length of the surgical time was about 12 min.\n\nThe first day after the operation, the visual acuity in his left eye was finger count. No remarkable inflammations or abnormalities were found in the anterior segment and vitreous by slit-lamp examination. Fundus manifestation was similar to case 1. SD-OCT image also showed the same macular edema as case 1 (Fig. 3a). The retina thickness of the fovea was 794 μm. No significant abnormality was found in the choroids. The same drugs as in case 1 were adopted four times a day. After 1 week treatment, the patient’s visual acuity improved to 20/20. SD-OCT revealed macular edema and subretinal fluid were absorbed completely. The integrated ellipsoid zone was preserved in the outer retina (Fig. 3b). The retinal thickness of the fovea returned within a normal range (174 μm). No recurrence of macular edema or retinal detachment was noticed until the last follow-up (3 months after surgery).Fig. 3 SD-OCT images of case 2. The SD-OCT image demonstrated macular edema most manifested at the outer nuclear layer and extensive shallow serous retinal detachment around the macula (a) and optic disc area (c) the first day after surgery. Macular edema and subretinal fluid was absorbed and the central foveal thickness resumed to normal at 1 week post-operation (b). The subretinal fluid was also absorbed around optic nerve head at 1 week post-operation (d)\n\n\n\nConclusions\nWith modern cataract surgical techniques, the incidence of post-surgical cystoid macular edema (CME) has decreased to 0.1–2.35 % [9]. Several mechanisms may contribute to such macular edema, including the effects of vitreoretinal traction, light damage, production of prostaglandins and intraoperative complications [1, 10]. The rate of macular edema after cataract surgery is increased in the presence of diabetic retinopathy and uveitis [11, 12]. However, the two cases were notable for its unremarkable retinopathy and lack of history of diabetes or uveitis.\n\nJurecka et al. [13] found a positive statistical correlation between the real phacoemulsification time and the increase in macular retinal thickness after surgery. In the present cases, the real phacoemulsification time was not long, and the average power was low.\n\nCefuroxime toxicity may be one of the cause of macular edema and detachment. The recommended dose of intra-cameral cefuroxime injection is 0.1 ml of 10.0 mg/ml solution. The fact that excessive cefuroxime solution injections into the anterior chamber can cause early serous macular detachment and edema has been reported previously [3, 4]. The reported dose has been varied from 20 to 50 mg/ml. However, recently, Kontos et al. [14] reported a case with acute serous macular detachment and macular edema after a standard dose of subconjunctival cefuroxime injection in the phacoemulsification. Faure et al. [15] even reported a case occurred retinal toxicity the second day after surgery with a standard dose of intra-cameral cefuroxime injection in France. In the present two cases in China, early macular edema and extensive retinal detachment were found immediately the first day after surgery with a standard dose of intra-cameral cefuroxime injection at the end of the phacoemulsification. The visual loss was earlier in the present two cases than that of Faure et al. report. Though the visual loss time after surgery had little difference, the manifestations of these cases were similar. The interval time between the present two cases was about one month. No abnormality was found during the drug dilution process. Thus, we presume that the retina injury in the two cases may be also attributed to cefuroxime toxicity even under a use of a standard dose.\n\nIn these two cases, the location of the edema was unusual: Typically retinal edema was located in the outer plexiform layer. However, in these cases the outer plexiform layer appeared to be spared and the outer nuclear layer had large edema. There was extensive subretinal fluid without debris. These OCT characteristics were similar to the manifestation that has been identified in OCT of the retinal toxicity caused by excessive cefuroxime solution injections [3, 4], and might provide a marker for cefuroxime toxicity. The mechanism of this pattern of edema is unclear. The electroretinogram (ERG) results of animal experiments [16] and human clinical observation [15] prompted cefuroxime was toxic to retina, and may effect the Müller cell function. Previous study [3, 4] reported that fluorescein angiograms (FA) showed diffuse leakage without abnormal retinal perfusion in cefuroxime toxic eyes and indicated that the blood–retinal barrier at the retinal pigment epithelium (RPE) may be disrupted. It is a limitation that the FA was not obtained in the present two cases, but the SD-OCT images may suggest that the primary lesions were localized at the outer retinal and RPE.\n\nClear vitreous haze has been reported in ocular toxicity after intra-cameral injection of very high doses of cefuroxime during cataract surgery [4]. But, no sign of remarkable inflammation in the vitreous was found in the present cases. No abnormality in vitreous has also been reported by Buyukyildiz in two cases of retinal toxicity caused by 2 mg/0.1 ml cefuroxime intra-cameral injection [3]. The dose of cefuroxime injection was much higher in Delyfer et al. study [4] than the presented cases and Buyukyildiz et al. cases [3]. The different doses of cefuroxime injection during cataract surgery may lead to the different findings in vitreous.\n\nTopical nonsteroidal anti-inflammatory drugs and corticosteroids have been reported to be effective and safe therapy for preventing post-surgical ocular inflammatory and macular edema [17–20]. Thus combination of nonsteroidal anti-inflammatory drugs and corticosteroids was applied in the present cases topically as routine anti-inflammation treatment after phacoemulsification. The SD-OCT image revealed a quick recovery from the macular edema without any special surgical intervention 1 week later. Delyfer et al. [4] also reported that retinal injury and visual dysfunction induced by intra-cameral excessive cefuroxime injection were able to recover to normal without surgery intervention after 6 weeks. The recovery time was shorter in the present cases than previous report. That may be due to the much lower concentration of cefuroxime solution used in the two cases. These results suggest that early macular edema with extensive serous retinal detachment which may be attributed to cefuroxime toxicity are restorable. Routine anti-inflammatory treatment is sufficient and do not require excessive interventions.\n\nConsent\nWritten informed consent was obtained from the patients for publication of this case report and any accompanying images.\n\nAbbreviations\nSD-OCTspectral domain optical coherence tomography\n\nOCToptical coherence tomography\n\nIOLintraocular lens\n\nCMEcystoid macular edema\n\nFAfluorescein angiograms\n\nRPEretinal pigment epithelium\n\nAuthors’ contributions\nXH has made substantial contributions to analysis and interpretation of data; has been involved in drafting the manuscript or revising it critically for important intellectual content; and has given final approval of the version to be published. LX and GXX have been involved in revising it critically for important intellectual content; and have given final approval of the version to be published. All authors read and approved the final manuscript.\n\nAcknowledgements\nThis study was supported in part by grant 2012B050600032 from Science and Technology Planning Project of Guangdong Province and grant B2013139 from Medical Scientific Research Foundation of Guangdong Province, China.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Gulkilik G Kocabora S Taskapili M Engin G Cystoid macular edema after phacoemulsification: risk factors and effect on visual acuity Can J Ophthalmol. 2006 41 699 703 10.3129/i06-062 17224950 \n2. Rossetti L Autelitano A Cystoid macular edema following cataract surgery Curr Opin Ophthalmol. 2000 11 65 72 10.1097/00055735-200002000-00010 10724830 \n3. Buyukyildiz HZ Gulkilik G Kumcuoglu YZ Early serous macular detachment after phacoemulsification surgery J Cataract Refract Surg. 2010 36 1999 2002 10.1016/j.jcrs.2010.07.007 21029910 \n4. Delyfer MN Rougier MB Leoni S Zhang Q Dalbon F Colin J Korobelnik JF Ocular toxicity after intracameral injection of very high doses of cefuroxime during cataract surgery J Cataract Refract Surg. 2011 37 271 278 10.1016/j.jcrs.2010.08.047 21241909 \n5. Barry P Seal DV Gettinby G Lees F Peterson M Revie CW ESCRS Endophthalmitis Study Group ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery; preliminary results from a European multicenter study J Cataract Refract Surg. 2006 32 407 410 10.1016/j.jcrs.2006.02.021 16631047 \n6. Lam PT Young AL Cheng LL Tam PM Lee VY Randomized controlled trial on the safety of intracameral cephalosporins in cataract surgery Clin Ophthalmol. 2010 8 1499 1504 21191447 \n7. Gupta MS McKee HD Saldana M Stewart OG Macular thickness after cataract surgery with intracameral cefuroxime J Cataract Refract Surg. 2005 31 1163 1166 10.1016/j.jcrs.2004.10.074 16039491 \n8. Hann JV Lee LR Macular thickness after cataract surgery with intracameral cefuroxime J Cataract Refract Surg. 2006 32 545 10.1016/j.jcrs.2006.01.004 16698453 \n9. Loewenstein A Zur D Postsurgical cystoid macular edema Dev Ophthalmol. 2010 47 148 159 10.1159/000320078 20703048 \n10. Agange N Mosaed S Prostaglandin-induced cystoid macular edema following routine cataract extraction J Ophthalmol. 2010 21076526 \n11. Kim SJ Equi R Bressler NM Analysis of macular edema after cataract surgery in patients with diabetes using optical coherence tomography Ophthalmology. 2007 114 881 889 10.1016/j.ophtha.2006.08.053 17275910 \n12. Bélair ML Kim SJ Thorne JE Dunn JP Kedhar SR Brown DM Jabs DA Incidence of cystoid macular edema after cataract surgery in patients with and without uveitis using optical coherence tomography Am J Ophthalmol. 2009 148 128 135 10.1016/j.ajo.2009.02.029 19403110 \n13. Jurecka T Bátková Z Ventruba J Macular edema after an uncomplicated cataract surgery Cesk Slov Oftalmol. 2007 63 262 273 17682606 \n14. Kontos A Mitry D Althauser S Jain S Acute serous macular detachment and cystoid macular edema after uncomplicated phacoemulsification using standard dose subconjunctival cefuroxime Cutan Ocul Toxicol. 2013 24147948 \n15. Faure C Perreira D Audo I Retinal toxicity after intracameral use of a standard dose of cefuroxime during cataract surgery Doc Ophthalmol. 2014 \n16. Shahar J Zemel E Perlman I Physiological and toxicological effects of cefuroxime on the albino rabbit retina Invest Ophthalmol Vis Sci 2012 21 53 906 914 10.1167/iovs.11-8053 22159021 \n17. Asano S Miyake K Ota I Sugita G Kimura W Sakka Y Yabe N Reducing angiographic cystoid macular edema and blood-aqueous barrier disruption after small-incision phacoemulsification and foldable intraocular lens implantation: multicenter prospective randomized comparison of topical diclofenac 0.1% and betamethasone 0.1% J Cataract Refract Surg 2008 34 57 63 10.1016/j.jcrs.2007.08.030 18165082 \n18. Miyake K Ota I Miyake G Numaga J Nepafenac 0.1% versus fluorometholone 0.1% for preventing cystoid macular edema after cataract surgery J Cataract Refract Surg 2011 37 1581 1588 10.1016/j.jcrs.2011.03.052 21855758 \n19. Romac I Gabrić N Dekaris I Barisić A Resolution of pseudophakic cystoid macular edema with combination therapy of topical corticosteroids and nonsteroidal anti-inflammatory drugs Coll Antropol. 2011 35 281 284 22220453 \n20. Zur D Fischer N Tufail A Monés J Loewenstein A Postsurgical cystoid macular edema Eur J Ophthalmol. 2011 21 suppl S62 S68 10.5301/EJO.2010.6058 23264331\n\n",
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"mesh_terms": "D000368:Aged; D000867:Anterior Chamber; D000900:Anti-Bacterial Agents; D002444:Cefuroxime; D005260:Female; D006801:Humans; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D018918:Phacoemulsification; D012163:Retinal Detachment; D041623:Tomography, Optical Coherence",
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"title": "Macular edema with serous retinal detachment post-phacoemulsification followed by spectral domain optical coherence tomography: a report of two cases.",
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"abstract": "The local anesthetic systemic toxicity can be due to increased blood lignocaine levels or due to increased sensitivity to lignocaine. Several cases of lignocaine-induced central nervous system toxicity have been noted, but none have reported only loss of consciousness without any seizure-like activity. Intravenous lipid emulsion administration for the treatment of local anesthetic systemic toxicity is an emerging topic of discussion, and there are case reports where they had successfully been used. However, majority of them were used in the treatment of cardiovascular manifestations of local anesthetic toxicity. We report a case of a 19-year-old man who had unconsciousness on 2 separate occasions after local lignocaine infiltration to undergo surgery for dental malocclusion and the use of lipid emulsion in its management.",
"affiliations": "Department of Anaesthesiology, Lady Hardinge Medical College, New Delhi, India. Electronic address: nitin.hayaran@rediffmail.com.;Department of Anaesthesiology, Lady Hardinge Medical College, New Delhi, India. Electronic address: rashidoc.18@gmail.com.;Department of Anaesthesiology, Lady Hardinge Medical College, New Delhi, India.;Department of Anaesthesiology, Lady Hardinge Medical College, New Delhi, India.",
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"abstract": "Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) immune-mediated necrotizing myopathy is a subtype of idiopathic inflammatory myopathy which may be associated with statin exposure. It presents with severe proximal muscle weakness, high creatine kinase levels and muscle fiber necrosis. Treatment with intravenous immunoglobulins and immunosuppressants is often necessary. This entity is not commonly known among dermatologists as there are usually no extramuscular manifestations. We report a rare case of statin-associated anti-HMGCR immune-mediated necrotizing myopathy with dermatomyositis-like cutaneous features. The possibility of anti-HMGCR immune-mediated necrotizing myopathy should be considered in patients with cutaneous dermatomyositis-like features associated with severe proximal muscle weakness, highly elevated creatine kinase levels and possible statin exposure. This indicates the importance of muscle biopsy and specific autoantibody testing for accurate diagnosis, as well as significant therapeutic implications.",
"affiliations": "Division of Dermatology, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.;Division of Rheumatology, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.;Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada.;Department of Pathology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.;Division of Dermatology, Hôpital Pierre-Le Gardeur, Terrebonne, QC, Canada.;Department of Anatomopathology, Hôpital Pierre-Le Gardeur, Terrebonne, QC, Canada.;Division of Rheumatology, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.",
"authors": "Lim|Darosa|D|https://orcid.org/0000-0003-2707-8134;Landon-Cardinal|Océane|O|;Ellezam|Benjamin|B|;Belisle|Annie|A|;Genois|Annie|A|;Sirois|Jennifer|J|;Bourré-Tessier|Josiane|J|",
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"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X SAGE Publications Sage UK: London, England \n\n10.1177/2050313X20984120\n10.1177_2050313X20984120\nJCMS Case Report\nStatin-associated anti-HMGCR immune-mediated necrotizing myopathy with dermatomyositis-like features: A case report\nhttps://orcid.org/0000-0003-2707-8134Lim Darosa 1 Landon-Cardinal Océane 2 Ellezam Benjamin 3 Belisle Annie 4 Genois Annie 5 Sirois Jennifer 6 Bourré-Tessier Josiane 2 1 Division of Dermatology, Department of Medicine, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, QC, Canada\n2 Division of Rheumatology, Department of Medicine, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, QC, Canada\n3 Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada\n4 Department of Pathology, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, QC, Canada\n5 Division of Dermatology, Hôpital Pierre-Le Gardeur, Terrebonne, QC, Canada\n6 Department of Anatomopathology, Hôpital Pierre-Le Gardeur, Terrebonne, QC, Canada\nDarosa Lim, Division of Dermatology, Department of Medicine, Centre Hospitalier de l’Université de Montréal (CHUM), 1051 Sanguinet street, Montreal, QC H2X 3E4, Canada. Email: darosa.lim@umontreal.ca\n29 12 2020 \n2020 \n8 2050313X20984120© The Author(s) 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) immune-mediated necrotizing myopathy is a subtype of idiopathic inflammatory myopathy which may be associated with statin exposure. It presents with severe proximal muscle weakness, high creatine kinase levels and muscle fiber necrosis. Treatment with intravenous immunoglobulins and immunosuppressants is often necessary. This entity is not commonly known among dermatologists as there are usually no extramuscular manifestations. We report a rare case of statin-associated anti-HMGCR immune-mediated necrotizing myopathy with dermatomyositis-like cutaneous features. The possibility of anti-HMGCR immune-mediated necrotizing myopathy should be considered in patients with cutaneous dermatomyositis-like features associated with severe proximal muscle weakness, highly elevated creatine kinase levels and possible statin exposure. This indicates the importance of muscle biopsy and specific autoantibody testing for accurate diagnosis, as well as significant therapeutic implications.\n\nAnti-HMGCRdermatomyositisimmune-mediated necrotizing myopathystatinmyositiscover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nThe spectrum of idiopathic inflammatory myopathies (IIMs) includes dermatomyositis (DM), overlap myositis, inclusion body myositis (IBM) and immune-mediated necrotizing myopathy (IMNM).1 IMNMs are characterized by severe proximal muscle weakness, high creatine kinase (CK) levels, predominant muscle fiber necrosis and no extramuscular manifestations.2 Anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies (aAbs) are associated with IMNM, and statin exposure may trigger anti-HMGCR IMNM.\n\nWe report herein a rare case of statin-associated anti-HMGCR IMNM with DM-like cutaneous features. To our knowledge, this is only the fourth case documented with substantial serologic and histologic evidence.\n\nCase report\nA 54-year-old Caucasian woman presented to the Myositis Clinic in a tertiary medical center for a second medical opinion for an atypical clinical presentation of DM as requested by her internist who previously hospitalized her in a regional hospital center for an acute rash accompanied by muscle weakness. Her past medical history included dyslipidemia and pre-diabetes. Atorvastatin (40 mg/day) was introduced 11 months ago. There was no family history of muscle or autoimmune disorders. Two months ago, the patient developed a rash on photoexposed areas followed by a rapidly progressive and severe proximal muscle weakness and became bedridden. She also reported dysphagia, dyspnea and fatigue. Erythemato-violaceous plaques with poikiloderma (atrophy, telangiectasias and dyspigmentation) were noted on peri-orbital regions, anterior chest, upper back, extensor surfaces of arms, lateral thighs and dorsal finger’s joints (Figure 1). Slight periungual erythema was noted with normal cuticles. Muscle strength examination revealed severe weakness. Cardiopulmonary, abdominal and neurologic examinations were otherwise normal.\n\nFigure 1. DM rash presenting as erythemato-violaceous papules and plaques on (a) the anterior chest area (V sign) and (b) dorsal finger’s joints with periungual erythema.\n\nDM: dermatomyositis.\n\nCK levels were highly elevated at 20,305 IU/L. Complete blood count, creatinine and urinalysis were normal. Antinuclear antibody (ANA), extractable nuclear antigen (ENA), anti-double stranded DNA (anti-dsDNA) and the panel for myositis-specific and myositis-associated aAbs (Euroimmun, Luebeck, Germany) were negative. Anti-HMGCR aAbs (INOVA) were positive (24.56 absorbance units (AU), normal < 20). Magnetic resonance imaging showed T2 hypersignal in the obturator, quadriceps and semi-membranous muscles. The patient had a myopathic electromyogram (EMG). Pulmonary function tests showed a moderate restrictive ventilatory defect secondary to extrapulmonary involvement, suggestive of respiratory muscle weakness. Nailfold capillaroscopy was normal. Cancer screening including thoraco-abdominopelvic computerized tomography scan, mammography, positron emission tomography scan, pelvic ultrasound, esophagogastroduodenoscopy and colonoscopy was negative. Skin biopsy revealed rare necrotic keratinocytes with discrete vacuolization of the basal cell layer at the basement membrane zone, perivascular and periadnexial lymphocytic infiltrates and increased dermal interstitial mucin (Figure 2). Quadriceps muscle biopsy showed scattered necrotic and regenerative fibers without inflammatory infiltrates or perifascicular atrophy (Figure 3). There were no sarcolemmal overexpression of major histocompatibility complex (MHC)-1, capillary dropout or capillary C5b-9 deposition. Sarcolemmal C5b-9 deposition was noted sparsely on non-necrotic fibers. Sarcoplasmic expression of myxovirus resistance protein A (MxA) was negative. Electron microscopy did not reveal tubuloreticular inclusions.\n\nFigure 2. Skin histology. (a) A hematoxylin phloxine saffron–stained section at 20× magnification showing rare necrotic keratinocytes with discrete vacuolization of the basal cell layer at the basement membrane zone and perivascular lymphocytic infiltrates and (b) staining with blue Alcian (pH 2.5) at 10× magnification highlighting increased dermal mucin deposition.\n\nFigure 3. Muscle histology. (a) Hematoxylin and eosin section of semimembranosus muscle biopsy showing scattered purple staining necrotic and regenerative fibers without lymphocytic infiltration (200× magnification) and (b) immunohistochemical preparation for MHC-1 showing overexpression restricted to scattered necrotic fibers and lack of capillary dropout (100× magnification).\n\nMHC: major histocompatibility complex.\n\nA diagnosis of statin-associated anti-HMGCR IMNM with DM-like cutaneous features was made. Statin was discontinued early, and the patient was treated with high-dose corticosteroids including methylprednisolone (pulses of 500 mg, and 40 mg BID for 2 weeks) followed by prednisone 1 mg/kg/day that was then tapered. She also received intravenous immunoglobulins (IVIgs) (1 g/kg/2 weeks), subcutaneous methotrexate (25 mg/week), hydroxychloroquine (5 mg/kg/day) and betamethasone valerate 0.1% cream (twice a day on the body until resolution of rash). The patient initially necessitated parenteral nutrition for severe dysphagia. She fully recovered after 6 months of treatment with complete resolution of the DM rash, muscle strength (Medical Research Council Scale 5/5) and swallowing difficulties. At last follow-up after almost 2 years, there was no evidence of disease recurrence. A timeline of the history and treatments is presented in Figure 4.\n\nFigure 4. Timeline of medical history and treatments.\n\nIVIg: intravenous immunoglobulin; HCQ: hydroxychloroquine; MTX: methotrexate.\n\nDiscussion\nAnti-HMGCR aAb was discovered in 2010 among IMNM patients, where it recognized a 100-kDa protein corresponding to HMGCR antigen, a key enzyme in cholesterol biosynthesis targeted by statins.3,4 Anti-HMGCR aAbs may be pathogenic as their titers correlate with disease activity (muscle strength and CK levels),5 and in vitro aAbs induce muscle atrophy and impair muscle regeneration.2 These aAbs are highly specific for autoimmune myopathy as they were not found in most statin-exposed individuals, including those with self-limited statin-associated myopathy.6 The prevalence of anti-HMGCR was reported as highest in association with IMNM and only rarely in other IIM and connective tissue diseases (Figure 5).6–8 Pathophysiology of anti-HMGCR IMNM is not yet entirely understood, but genetic susceptibility has been described with HLA-DRB1*11:01.9 It is believed that this human leukocyte antigen (HLA) may present a strongly immunogenic HMGCR-derived peptide resulting from HMGCR overexpression with statin exposure.9\n\nFigure 5. Prevalence of anti-HMGCR aAbs among IIM, other connective tissue diseases, statin users and healthy controls according to Mammen et al.,6 Musset et al.7 and Hudson et al.8\n\nIMNM: immune-mediated necrotizing myopathy; DM: dermatomyositis; JDM: juvenile dermatomyositis; OM: overlap myositis; ASS: anti-synthetase syndrome; IBM: inclusion body myositis; pSS: primary Sjögren’s syndrome; SLE: systemic lupus erythematosus; SSc: systemic sclerosis; RA: rheumatoid arthritis; IIM: idiopathic inflammatory myopathy.\n\nAnti-HMGCR IMNM usually occurs between 40 and 60 years old, but pediatric cases were reported, and there is a female predominance.2,4,5 Association with statin exposure is noted in half to two-thirds of patients, and mean duration before CK elevation is 39 months (15–84 months).10 These patients present with a subacute onset of severe proximal muscle weakness, myalgias, highly elevated CK (mean around 8300 IU/L)4,5 and myopathic EMG findings. In a cohort of atorvastatin-associated anti-HMGCR IMNM, CK elevation could precede muscle weakness by months, or even years, suggesting that persistent CK elevation despite statin discontinuation and/or onset of muscle weakness should prompt for anti-HMGCR aAb testing.10 There is usually no significant extramuscular involvement.2,4,5 Muscle biopsy helps to differentiate from other myopathies and shows randomly distributed necrotic, regenerating and atrophic muscle fibers, and no or mild inflammatory infiltrates.2,5 C5b-9 deposits around fibers and/or capillaries are also observed, and MHC-I overexpression is usually negative, or slight and focal if present.11 Malignancy association with anti-HMGCR IMNM has been inconsistent.2,12\n\nTo our knowledge, our case is only the fourth reported case of statin-associated anti-HMGCR IMNM with typical cutaneous DM features with convincing serology and histology. This entity has rarely been described in few case reports and seldomly in some cohorts (including DM patients with anti-HMGCR aAbs in the latter).7,13–17 In case reports, patients were between 47 and 61 years old and were exposed to statins from 8 months to 10 years before seeking medical attention.13–15 They all presented characteristic DM rash and proximal muscle weakness for a period between 4 weeks and 4 years. CK levels were elevated (8674–37,527 IU/L) as well as anti-HMGCR aAbs. All muscle biopsies were compatible with IMNM without DM-specific findings. Skin biopsy was done in one patient and showed neutrophilic vacuolar interface dermatitis with lymphocytic and neutrophilic infiltrates in the dermis including perifollicular regions.14 Direct immunofluorescence revealed granular deposits of IgG, IgA and C3 along the dermoepidermal junction. Of note, in our patient, although the cutaneous biopsy showed periadnexial inflammatory infiltrates (more frequent in lupus erythematosus), this finding has been described in cutaneous DM18 and a diagnosis of DM-like features was retained to correlate with characteristic DM rash. All previously reported patients improved significantly within 2–12 months under high-dose corticosteroids, immunosuppressants (methotrexate or mycophenolate mofetil) and IVIgs. One patient required additional plasmapheresis to achieve near-complete remission.15\n\nIn statin-associated anti-HMGCR IMNM, statin withdrawal and corticosteroids alone are usually not sufficient.10 In a retrospective study of 55 patients, successful induction treatments were described with a combination of steroids, immunosuppressants and IVIgs in patients with muscle weakness.19 A shorter delay from presentation to treatment was significantly associated with an early remission and successful maintenance with immunosuppressant monotherapy, underlining the importance of early recognition and treatment of IMNM. The 2016 European Neuromuscular Center (ENMC) International Workshop has proposed similar treatment recommendations as the current standard of care for patients with anti-HMGCR IMNM.11 The treatments proposed in our patient are in agreement with those recommendations.\n\nIn the present case, a diagnosis of statin-associated anti-HMGCR IMNM was made instead of classic DM based on muscle biopsy consistent with IMNM, subacute and severe muscle weakness, high CK levels, statin exposure and anti-HMGCR aAb positivity.11 DM-specific myological features1 were not observed including sarcoplasmic MxA expression (77% sensitivity and 100% specificity for DM).20 This now more substantiated association has important implications on the diagnostic approach of patients who present with cutaneous features of DM since anti-HMGCR antibodies are not included in the myositis panel routinely used in most centers. In conclusion, the possibility of anti-HMGCR IMNM should be considered in patients with cutaneous DM-like features associated with severe proximal muscle weakness and highly elevated CK levels, particularly with a history of statin exposure. This indicates the importance of muscle biopsy and specific autoantibody testing for accurate diagnosis, as well as significant therapeutic implications.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship and/or publication of this article.\n\nInformed consent: The patient provided written consent for publication of the case report.\n\nORCID iD: Darosa Lim \nhttps://orcid.org/0000-0003-2707-8134\n==== Refs\nReferences\n1. \nBenveniste O Stenzel W Allenbach Y. \nAdvances in serological diagnostics of inflammatory myopathies\n. Curr Opin Neurol \n2016 ; 29 (5 ): 662 –673\n.27538058 \n2. \nAllenbach Y Benveniste O. \nPeculiar clinicopathological features of immune-mediated necrotizing myopathies\n. Curr Opin Rheumatol \n2018 ; 30 (6 ): 655 –663\n.30239349 \n3. \nChristopher-Stine L Casciola-Rosen LA Hong G , et al\nA novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy\n. Arthritis Rheum \n2010 ; 62 (9 ): 2757 –2766\n.20496415 \n4. \nMammen AL Chung T Christopher-Stine L , et al\nAutoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy\n. Arthritis Rheum \n2011 ; 63 (3 ): 713 –721\n.21360500 \n5. \nAllenbach Y Drouot L Rigolet A , et al\nAnti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin\n. Medicine (Baltimore) \n2014 ; 93 (3 ): 150 –157\n.24797170 \n6. \nMammen AL Pak K Williams EK , et al\nRarity of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in statin users, including those with self-limited musculoskeletal side effects\n. Arthritis Care Res (Hoboken) \n2012 ; 64 (2 ): 269 –272\n.21972203 \n7. \nMusset L Allenbach Y Benveniste O , et al\nAnti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: a history of statins and experience from a large international multi-center study\n. Autoimmun Rev \n2016 ; 15 (10 ): 983 –993\n.27491568 \n8. \nHudson M Luck Y Stephenson M , et al\nAnti-HMGCR antibodies in systemic sclerosis\n. Medicine (Baltimore) \n2016 ; 95 (44 ): e5280 .27858897 \n9. \nMammen AL Gaudet D Brisson D , et al\nIncreased frequency of DRB1*11:01 in anti-hydroxymethylglutaryl-coenzyme A reductase-associated autoimmune myopathy\n. Arthritis Care Res (Hoboken) \n2012 ; 64 (8 ): 1233 –1237\n.22422616 \n10. \nTroyanov Y Landon-Cardinal O Fritzler MJ , et al\nAtorvastatin-induced necrotizing autoimmune myositis: an emerging dominant entity in patients with autoimmune myositis presenting with a pure polymyositis phenotype\n. Medicine (Baltimore) \n2017 ; 96 (3 ): e5694 .28099331 \n11. \nAllenbach Y Mammen AL Benveniste O , et al\n224th ENMC international workshop: clinico-sero-pathological classification of immune-mediated necrotizing myopathies Zandvoort , The Netherlands , 14-16 October 2016 \nNeuromuscul Disord \n2018 ; 28 (1 ): 87 –99\n.29221629 \n12. \nAllenbach Y Keraen J Bouvier AM , et al\nHigh risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody\n. Brain \n2016 ; 139 (Pt8 ): 2131 –2135\n.27086869 \n13. \nLavian M Mozaffar T Goyal N. \nClinical dermatomyositis associated with anti-HMG-CoA reductase antibody positive immune mediated necrotizing myopathy: a case report (P2.125)\n. Neurology \n2017 ; 88 (16 Supplement ):P2125 .\n14. \nMerlant M Fite C Kottler D , et al\n[Dermatomyositis-like syndrome revealing statin-induced necrotizing autoimmune myopathy with anti-HMGCR antibodies]\n. Ann Dermatol Venereol \n2019 ; 146 (8-9 ): 550 –556\n.30929872 \n15. \nParikh P Tavee J Soltanzadeh P , et al\nAnti-3-hydroxy-3-methylglutaryl-coenzyme a reductase autoantibody-positive necrotizing autoimmune myopathy with dermatomyositis-like eruption\n. Muscle Nerve \n2018 ; 57 (6 ): E135 –E136\n.29346706 \n16. \nLimaye V Bundell C Hollingsworth P , et al\nClinical and genetic associations of autoantibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase in patients with immune-mediated myositis and necrotizing myopathy\n. Muscle Nerve \n2015 ; 52 (2 ): 196 –203\n.25521389 \n17. \nTiniakou E Pinal-Fernandez I Lloyd TE , et al\nMore severe disease and slower recovery in younger patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy\n. Rheumatology (Oxford) \n2017 ; 56 (5 ): 787 –794\n.28096458 \n18. \nWolstencroft PW Rieger KE Leatham HW , et al\nClinical factors associated with cutaneous histopathologic findings in dermatomyositis\n. J Cutan Pathol \n2019 ; 46 (6 ): 401 –410\n.30737826 \n19. \nMeyer A Troyanov Y Drouin J , et al\nStatin-induced anti-HMGCR myopathy: successful therapeutic strategies for corticosteroid-free remission in 55 patients\n. Arthritis Res Ther \n2020 ; 22 (1 ): 5 .31915059 \n20. \nUruha A Allenbach Y Charuel JL , et al\nDiagnostic potential of sarcoplasmic myxovirus resistance protein A expression in subsets of dermatomyositis\n. Neuropathol Appl Neurobiol \n2019 ; 45 (5 ): 513 –522\n.30267437\n\n",
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"keywords": "Anti-HMGCR; dermatomyositis; immune-mediated necrotizing myopathy; myositis; statin",
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"title": "Statin-associated anti-HMGCR immune-mediated necrotizing myopathy with dermatomyositis-like features: A case report.",
"title_normalized": "statin associated anti hmgcr immune mediated necrotizing myopathy with dermatomyositis like features a case report"
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"abstract": "Rare cases of Fournier gangrene (FG) possibly associated with sodium-glucose cotransporter 2 inhibitors have been reported. We present a case of a 66-year-old male patient with type 2 diabetes mellitus on oral metformin, glimepiride, and dapagliflozin therapy. He presented with pain in the perineum and scrotum for 5 days. The clinical finding, computed tomography finding, and laboratory data were matched with FG. Emergency surgical drainage, debridement of necrotic tissue, and diverting loop ileostomy formation were performed by a urologist and a surgeon. The patient had no complications from diabetes before the onset of FG, and serum glucose management was good at the onset of FG. This case shows an FG patient with good glucose management taking dapagliflozin and suggests a possible association between dapagliflozin and FG. Further evaluation and additional research on this relationship are needed.",
"affiliations": "Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea.;Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea.;Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea.;Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea.",
"authors": "Moon|Jae Young|JY|;Lee|Min Ro|MR|;Kim|Jong Hun|JH|;Ha|Gi Won|GW|",
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"fulltext": "\n==== Front\nAnn Coloproctol\nAnn Coloproctol\nAC\nAnnals of Coloproctology\n2287-9714\n2287-9722\nKorean Society of Coloproctology\n\n34044501\n10.3393/ac.2020.06.22\nac-2020-06-22\nCase Report\nFournier Gangrene in a Patient With Type 2 Diabetes Mellitus Treated With Dapagliflozin: A Case Report\nMoon Jae Young\nLee Min Ro\nKim Jong Hun\nhttp://orcid.org/0000-0001-9401-1760\nHa Gi Won\nResearch Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea\nCorrespondence to: Gi Won Ha, M.D. Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Korea Tel: +82-63-250-1570, Fax: +82-63-271-6197 E-mail: acts29@jbnu.ac.kr\n7 2021\n28 5 2021\n37 Suppl 1 S48S50\n12 2 2020\n11 6 2020\n22 6 2020\nCopyright © 2021 The Korean Society of Coloproctology\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nRare cases of Fournier gangrene (FG) possibly associated with sodium-glucose cotransporter 2 inhibitors have been reported. We present a case of a 66-year-old male patient with type 2 diabetes mellitus on oral metformin, glimepiride, and dapagliflozin therapy. He presented with pain in the perineum and scrotum for 5 days. The clinical finding, computed tomography finding, and laboratory data were matched with FG. Emergency surgical drainage, debridement of necrotic tissue, and diverting loop ileostomy formation were performed by a urologist and a surgeon. The patient had no complications from diabetes before the onset of FG, and serum glucose management was good at the onset of FG. This case shows an FG patient with good glucose management taking dapagliflozin and suggests a possible association between dapagliflozin and FG. Further evaluation and additional research on this relationship are needed.\n\nFournier gangrene\nDapagliflozin\nType 2 diabetes mellitus\n==== Body\nINTRODUCTION\n\nFournier gangrene (FG), first described by Jean Alfred Fournier in 1883 [1], is an adverse polymicrobial infection that typically results in cell death of the perineal and genital fasciae. Further, FG needs early recognition, aggressive debridement of devitalized tissue, antibiotics therapy, and a search for primary sources as the treatment of choice for FG [2]. As defined, FG is considered to be idiopathic. Various risk factors for FG have been reported, including diabetes mellitus (DM), alcohol abuse, poor hygiene, malignancies, and human immunodeficiency virus infections. Most of these risk factors have similar features, including impairment and immunosuppression in the microcirculation [3].\n\nGlycemic control is improved by sodium-glucose cotransporter 2 (SGLT2) inhibitors through inhibiting glucose reabsorption in kidney tubules, which thereby increases glucose excretion through urine [4]. To date, the U.S. Food and Drug Administration (FDA) has approved 4 SGLT2 inhibitors: dapagliflozin, empagliflozin, ertugliflozin, and canagliflozin [5]. SGLT2 inhibitors usage has been correlated with a higher risk of genital infection following increased glycosuria [6]. This has prompted the FDA to publish a warning about FG occurring in patients undergoing SGLT2 inhibitor therapy [7]. We describe the first patient who developed FG during dapagliflozin treatment at our institution.\n\nCASE REPORT\n\nThis study was approved by the Institutional Review Board of Jeonbuk National University Hospital (2020-06-012). The written informed consent and permission to use clinical images were received from the patient.\n\nA 66-year-old male patient came to our hospital with a 5-day history of pain in the scrotal and perianal area. The patient’s history revealed type 2 DM (T2DM), hypertension, acute myocardial infarction (percutaneous coronary intervention done 2 times in 2007 and 2014), smoking, and alcohol intake. He has been taking metformin 1,000 mg/day, glimepiride 4 mg/day, and dapagliflozin 10 mg/day as antidiabetic mediation. He started taking dapagliflozin in March 2017. He had no complications from DM and had well-controlled hygiene.\n\nVisiting our hospital, his body temperature was 36.3°C. He was not in a state of shock, and vital signs were stable: blood pressure, 99/60 mmHg; heart rate, 105 beats per minute; and respiratory rate, 20 breaths per minute. Skin redness, induration, swelling, and tenderness were observed in both the scrotum and perineum. Focal skin necrosis and a foul smell were observed, especially in the lower scrotal area. There was no trauma.\n\nRoutine laboratory data revealed a white blood cell (WBC) count of 15.03 × 103/μL, C-reactive protein at 211.46 mg/L, and hemoglobin A1c (HbA1c) at 6.7%. Urinary analysis showed no evidence of urinary infection (red blood cells, 0 to 2/high power field [HPF]; WBC, 3–5/HPF). A computed tomography (CT) scan of the lower abdomen and pelvis revealed findings consistent with FG (Fig. 1).\n\nAll antidiabetic drugs were stopped at admission. In the emergency room, a Foley catheter was inserted, and antibiotics (2 g of ceftriaxone and 500 mg of metronidazole) were given intravenously. The patient underwent emergency surgery under general anesthesia, and laparoscopy-assisted diverting loop ileostomy formation, surgical drainage, and debridement of the necrotic tissue on scrotum, groin, and perineum were performed. Due to the perioperative onset of shock with a need for catecholamine (0.05-μg/minute of norepinephrine) during the operation, the patient was admitted to the surgical intensive care unit (SICU). In the SICU, we changed antibiotics to more broad-spectrum antibiotics (4 g of piperacillin with 0.5 g of tazobactam). On postoperative day (POD) 1, the patient’s vital signs stabilized and he was transferred to a ward. On POD 2, a diet was started and antidiabetic drugs resumed without dapagliflozin. On POD 6, 100 mg of sitagliptin was added after an endocrinology consultation. On POD 7, wound debridement was performed under local anesthesia (Fig. 2). The patient was discharged on POD 15 and transferred to a local hospital for further dressing of the surgical wound with this antidiabetic medication.\n\nDISCUSSION\n\nDM usually presents with significant microvascular manifestations, as suggested by diabetic retinopathy, amputation, and nephropathy. FG may result from similar processes and may worsen as a result of relative immunosuppression. During the infection period, endogenous production of glucose increases due to an increased rate of catabolism. Adherence, chemotaxis, and bactericidal activities of phagocytes are affected by hyperglycemia; and reports show its detrimental effects on cellular immunity. Further, DM has been reported to be a predisposing factor in 32% to 66% of FG cases. Moreover, DM impacts the clinical course of the disease, associated with a longer hospital stay, younger age, and a different bacteriology spectrum [8].\n\nOne of the common causes of FG is anal fistula. According to the patient’s past history, physical exam, and CT review, we cannot determine suspicion for anal fistula. And in the operation field, we couldn’t find internal opening of anal fistula. So it’s hard to conclude that this case is related to anal fistula.\n\nAmong patients receiving SGLT2 inhibitors between March 2013 and January 2019, the FDA identified 55 cases of FG. Comparatively, only 19 FG cases were reported between 1984 and January 2019 among patients receiving different antidiabetic agents [7]. If FG were correlated with only DM and not SGLT2 inhibitors, significantly more cases should have been reported with different antidiabetic agents, especially in consideration of the larger 35-year timeframe and a greater number of agents. Nevertheless, there have been too few cases to have confidence that FG is related to SGLT2 inhibitor usage.\n\nThere are some case reports on FG in patients undergoing SGLT 2 therapy. Kumar et al. [9] reported a 41-year-old male patient with T2DM with an HbA1c of 11.2% using empagliflozin, and Onder et al. [10] reported a 64-year-old male patient with T2DM with an HbA1c of 7.4% using dapagliflozin. However, similar to our case, Nagano et al. [11] reported a 34-year-old male patient with T2DM with an HbA1c of 6.5% at the time of FG onset who was on sitagliptin, glibenclamide, and empagliflozin therapy. The patient had no additional complications from DM besides FG [11]. Thus, the risk for developing FG remains in spite of good glycemic management with SGLT2 inhibitors.\n\nGlycosuria can be anticipated with SGLT2 inhibitor treatment and is correlated with increased risk of urinary tract and urogenital infections [12, 13]. Additionally, the environment providing glycosuria-enhanced growth of urogenital flora also may provide an ideal environment for FG as the perineum is colonized already with organisms from the gastrointestinal tract [7].\n\nAdditional SGLT2 therapy and deranged glucose levels in the blood may lead potentially to extreme glucose levels in urine, which can provide a favorable environment for urinary infection. Coupled with local immunodeficiency (caused by DM and other comorbidities) and microvascular supply impairment, FG may result in some patients [14]. Nevertheless, the causal mechanism underlying the relationship between SGLT2 inhibitors and FG is still not understood. So FG among patients receiving SGLT 2 inhibitors is not always related to urinary tract infection.\n\nIn conclusion, FG only occurs in a minimum number of patients receiving SGLT 2 inhibitors. But a possible association between FG and SGLT2 inhibitors may exist, and patients treated with SGLT 2 inhibitors should be warned about the risk of FG, controlling hygiene, smoking, and quitting alcohol. Carefully monitored for its symptoms at follow up. And if FG occurs in those patients with SGLT 2 inhibitors, patients should visit the hospital immediately for proper management, and SGLT 2 inhibitors should be discontinued.\n\nFig. 1. Computed tomography scans of the lower abdomen (A, B) and pelvis (C, D) showing pathologic Fournier gangrene (arrows).\n\nFig. 2. An image of the groin and scrotum on postoperative day 8.\n\nNo potential conflict of interest relevant to this article was reported.\n==== Refs\nREFERENCES\n\n1 Fournier JA Jean-Alfred Fournier 1832-1914. Gangrène foudroyante de la verge (overwhelming gangrene). Sem Med 1883 Dis Colon Rectum 1988 31 984 8 3063473\n2 Park JH Park SC Jeon HM Jung JH Kim WW Oh ST Clinical analysis of Fournier‘s gangrene J Korean Soc Coloproctol 2000 16 309 15\n3 Chennamsetty A Khourdaji I Burks F Killinger KA Contemporary diagnosis and management of Fournier’s gangrene Ther Adv Urol 2015 7 203 15 26445600\n4 Riser Taylor S Harris KB The clinical efficacy and safety of sodium glucose cotransporter-2 inhibitors in adults with type 2 diabetes mellitus Pharmacotherapy 2013 33 984 99 23744749\n5 Powell J Garland SG Ertugliflozin: a new option in the SGLT-2 inhibitor market for the treatment of type 2 diabetes mellitus Ann Pharmacother 2019 53 478 85 30522346\n6 Cefalu WT Riddle MC SGLT2 inhibitors: the latest “new kids on the block”! Diabetes Care 2015 38 352 4 25715412\n7 Bersoff-Matcha SJ Chamberlain C Cao C Kortepeter C Chong WH Fournier gangrene associated with sodium-glucose cotransporter-2 inhibitors: a review of spontaneous postmarketing cases Ann Intern Med 2019 170 764 9 31060053\n8 Nisbet AA Thompson IM Impact of diabetes mellitus on the presentation and outcomes of Fournier’s gangrene Urology 2002 60 775 9 12429294\n9 Kumar S Costello AJ Colman PG Fournier’s gangrene in a man on empagliflozin for treatment of type 2 diabetes Diabet Med 2017 34 1646 8 28887847\n10 Onder CE Gursoy K Kuskonmaz SM Kocer U Culha C Fournier’s gangrene in a patient on dapagliflozin treatment for type 2 diabetes J Diabetes 2019 11 348 50 30604507\n11 Nagano Y Yakame NK Aoki H Yamakawa T Kondo NI Fournier’s gangrene in a patient with type 2 diabetes mellitus treated with empagliflozin: a case report Drug Saf Case Rep 2019 6 11 31628552\n12 Sarnoski-Brocavich S Hilas O Canagliflozin (invokana), a novel oral agent for type-2 diabetes P T 2013 38 656 66 24391386\n13 Johnsson KM Ptaszynska A Schmitz B Sugg J Parikh SJ List JF Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin J Diabetes Complications 2013 27 479 84 23806570\n14 Rodler S Weig T Finkenzeller C Stief C Staehler M Fournier’s gangrene under sodium-glucose cotransporter 2 inhibitor therapy as a life-threatening adverse event: a case report and review of the literature Cureus 2019 11 e5778 31723537\n\n",
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"issue": "37(Suppl 1)",
"journal": "Annals of coloproctology",
"keywords": "Dapagliflozin; Fournier gangrene; Type 2 diabetes mellitus",
"medline_ta": "Ann Coloproctol",
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"title": "Fournier Gangrene in a Patient With Type 2 Diabetes Mellitus Treated With Dapagliflozin: A Case Report.",
"title_normalized": "fournier gangrene in a patient with type 2 diabetes mellitus treated with dapagliflozin a case report"
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"abstract": "The immune checkpoint inhibitors (ICPIs) comprise a class of oncologic immunotherapies. The most recent US Food and Drug Administration-approved ICPI is cemiplimab (Libtayo®). Cemiplimab, like the other ICPIs, blocks checkpoint receptors in order to disinhibit T-cells so that they may detect and eliminate tumor cells. Consequently, treatment with ICPIs is associated with immune-related adverse events including uveitis.\nCase report.\nA 63-year-old man with a history of metastatic squamous cell carcinoma developed blurry vision 3 months after starting treatment with cemiplimab. The patient was found to have posterior uveitis with retinal vasculitis that was successfully controlled with discontinuation of the medication as well as treatment with local and systemic steroids.\nSimilar to other ICPIs, uveitis may be associated with cemiplimab. In the setting of posterior uveitis, treatment may require cessation of cemiplimab and intensive steroid treatment.",
"affiliations": "Stein Eye Institute, David Geffen of Medicine at UCLA, Los Angeles, California, USA.;Stein Eye Institute, David Geffen of Medicine at UCLA, Los Angeles, California, USA.;Stein Eye Institute, David Geffen of Medicine at UCLA, Los Angeles, California, USA.;Southern California Desert Retina Consultants, Palm Desert, California, USA.;Stein Eye Institute, David Geffen of Medicine at UCLA, Los Angeles, California, USA.",
"authors": "Dow|Eliot R|ER|;Hou|Kirk|K|;Ransome|Susan|S|;Abbassi|Sam|S|;Tsui|Edmund|E|https://orcid.org/0000-0001-7532-9191",
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"journal": "Ocular immunology and inflammation",
"keywords": "Immune checkpoint inhibitor; Libtayo; PD-1 inhibitor; cemiplimab; cemiplimab-rwlc; phlebitis; uveitis; vasculitis",
"medline_ta": "Ocul Immunol Inflamm",
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"publication_types": "D016428:Journal Article",
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"title": "Posterior Uveitis Associated with Cemiplimab.",
"title_normalized": "posterior uveitis associated with cemiplimab"
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"abstract": "Introduction - Valproic acid is an effective antiepileptic and mood stabilizer used in the treatment of many neurological and psychiatric disorders. Although there are frequently seen side effects, effusions between layers of pleural and pericardial membranes are rare to be seen. Case - Pleuropericardial effusion was detected in a 23 years old woman who was under valproic acid treatment because of epileptic seizure. After 1 year of valproic acid treatment, patient complained of dyspnea. As all the researches intended on etiology were usual, valproic acid has been thought to be responsible for the matter. Control examination after 1.5 months regarding the end of treatment revealed complete recovery of pleuropericardial effusion. Discussion - Pleural and pericardial effusions are rarely seen complications related to the use of valproic acid. It must also be kept in mind that valproic acid causes a potential for such side effects which can be blamed etiologically when the other possibilities for patients are excluded.",
"affiliations": "Neurology Department of Istanbul Yeni Yüzyıl University Medical School, Istanbul.",
"authors": "Demir|Ulku Figen|UF|0000-0002-2546-216X",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid",
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"doi": "10.18071/isz.73.0070",
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"issue": "73(1-2)",
"journal": "Ideggyogyaszati szemle",
"keywords": "pleuropericardial effusion; valproic acid",
"medline_ta": "Ideggyogy Sz",
"mesh_terms": "D000927:Anticonvulsants; D004827:Epilepsy; D005260:Female; D006801:Humans; D010490:Pericardial Effusion; D010996:Pleural Effusion; D014635:Valproic Acid; D055815:Young Adult",
"nlm_unique_id": "17510500R",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Valproic acid associated pleuropericardial effusion: case report.",
"title_normalized": "valproic acid associated pleuropericardial effusion case report"
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"abstract": "Our primary objective was to determine the adjusted quantitative associations of clinical predictors with QT prolongation, a defining cause of Torsades de Pointes (TdP).\n\n\n\nA retrospective cohort study was performed on consecutive emergency department patients identified by ECG acquisition date, and heart rate corrected QT (QTc) and QRS durations. QTc was modeled as a function of clinical predictors with multiple linear regression.\n\n\n\n1010 patients were included. The strongest predictors of QTc and their coefficients were: antidysrhythmic (26.1ms, 95% CI 15.6-36.6) and methadone (43.6ms, 95% CI 28.1-59.2) therapies, and genetic long QT syndrome diagnosis (32.6ms, 95% CI -4.7-70.0). The association of QTc with serum potassium was approximated by a two piecewise linear function that differed by sex. For potassium below 3.9mmol/L, QTc increased by 43.0ms (95% CI 26.2-59.7) and 29.5ms (95% CI 19.1-40.0) for every 1mmol/L decrease in potassium in women and men, respectively. TdP occurred in only 4/686 (0.6%) of patients with QTc≥500 and QRS<120, but mortality during the visit including hospitalization was 8.0%.\n\n\n\nQTc duration is highly sensitive to hypokalemia, particularly in women. Methadone prolongs QTc remarkably compared to other non-cardiologic medicines. QTc>500 with normal QRS often signifies profound illness and substantial mortality risk, though not necessarily imminent TdP.",
"affiliations": "Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: kmarill@partners.org.;Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.",
"authors": "Marill|Keith A|KA|;Miller|Emily S|ES|",
"chemical_list": "D009294:Narcotics; D008691:Methadone",
"country": "United States",
"delete": false,
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"issue": "50(4)",
"journal": "Journal of electrocardiology",
"keywords": "Cohort studies; Hypokalemia; Long QT syndrome; Methadone; Torsades de pointes",
"medline_ta": "J Electrocardiol",
"mesh_terms": "D000368:Aged; D004562:Electrocardiography; D004636:Emergency Service, Hospital; D005260:Female; D006760:Hospitalization; D006801:Humans; D007008:Hypokalemia; D008133:Long QT Syndrome; D008691:Methadone; D008875:Middle Aged; D009294:Narcotics; D012189:Retrospective Studies; D012307:Risk Factors; D016171:Torsades de Pointes",
"nlm_unique_id": "0153605",
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"references": "3338130;21355903;23860666;8196728;18440994;12388652;17239713;23355181;11551001;18184962;17344330;1519533;18929329;7083728;26964707;19419793;20921449;19813104;19747736;22001585;19142100;18187075;8903607;3370776;15132370;8522713;17394962;12793884;20868774;20185054;8565156;26802105;9337183;22474311;15781034;5639799;23819796;16643414;22561361;8230644;23100219;17329992",
"title": "Hypokalemia in women and methadone therapy are the strongest non-cardiologic factors associated with QT prolongation in an emergency department setting.",
"title_normalized": "hypokalemia in women and methadone therapy are the strongest non cardiologic factors associated with qt prolongation in an emergency department setting"
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"abstract": "We report a case of central serous chorioretinopathy (CSC) that developed 1 month after an intralesional injection of triamcinolone acetonide that was administered during removal of a chalazion. The subretinal fluid and ipsilateral visual acuity (VA) worsened with initial observation. The edema resolved with verteporfin photodynamic therapy (PDT) 1 month after diagnosis, but VA did not improve during short-term follow-up. We conclude that CSC can occur as a complication of low-dose intrapalpebral corticosteroid administration and provide another example of the therapeutic role of PDT in the management of this disease.",
"affiliations": "Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, USA.;Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, USA.;Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, USA.;Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, USA.;Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, USA.",
"authors": "Rosignoli|Luca|L|;Potter|Stephen Myles|SM|;Gonzalez|Andres|A|;Amin|Sarina|S|;Khurshid|Syed G|SG|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000492714",
"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000492714cop-0009-0416Case ReportDevelopment of Central Serous Chorioretinopathy following Chalazion Removal with Intralesional Triamcinolone Injection: A Case Report Rosignoli Luca *Potter Stephen Myles Gonzalez Andres Amin Sarina Khurshid Syed G. Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, USA*Luca Rosignoli, BS, University of Florida College of Medicine, Department of Ophthalmology, 1600 SW Archer Road, Gainesville, FL 32610 (USA), E-Mail lmrosignoli@gmail.comSep-Dec 2018 3 9 2018 3 9 2018 9 3 416 420 22 5 2018 6 8 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.We report a case of central serous chorioretinopathy (CSC) that developed 1 month after an intralesional injection of triamcinolone acetonide that was administered during removal of a chalazion. The subretinal fluid and ipsilateral visual acuity (VA) worsened with initial observation. The edema resolved with verteporfin photodynamic therapy (PDT) 1 month after diagnosis, but VA did not improve during short-term follow-up. We conclude that CSC can occur as a complication of low-dose intrapalpebral corticosteroid administration and provide another example of the therapeutic role of PDT in the management of this disease.\n\nKeywords\nChoroidEyelidPhotodynamic therapyRetinopathyRisk factors\n==== Body\nIntroduction\nCentral serous chorioretinopathy (CSC) is characterized by the subretinal accumulation of serous fluid leading to localized neurosensory retinal detachment. Although the pathophysiology of this disease is not entirely understood, two main hypotheses have been supported. The disease has been suggested to occur as a result of increased choroidal capillary permeability leading to damage of the retinal pigment epithelium (RPE), which in turn causes subretinal serous fluid accumulation [1]. An alternative theory suggests that RPE dysfunction is the primary etiology of the subretinal edema [2]. Multiple reports have identified corticosteroid use and hyperaldosteronism as a potential risk factor for the development of this disease [3]. Spontaneous resolution occurs in 60% of cases of CSC within 3 months [3]. Verteporfin photodynamic therapy (PDT), among others, has been reported as a valid therapeutic alternative in persistent cases [2, 4]. In this report, we describe a case of CSC following the intrapalpebral injection of triamcinolone acetonide within the excision margins from the removal of a chalazion.\n\nCase Report\nA 28-year-old male presented for evaluation of recurrent, central right-upper lid chalazion previously treated with incision and curettage (I&C). Conservative management with erythromycin ointment and warm compresses failed, prompting repeat I&C. Given the chronicity of chalazion, we also administered a 0.5-mL injection of triamcinolone acetonide (10 mg/mL) within the chalazion excision margins in an intrapalpebral fashion. One month following the procedure, the patient returned with concern of a “purple spot” in the central vision of his right eye (OD). OD examination showed unchanged visual acuity (VA) of 20/20, normal intraocular pressure, and intact visual fields. Fundus examination revealed subretinal fluid that was confirmed on optical coherence tomography (OCT) (Fig. 1a), which also revealed a small pigment epithelial detachment (PED) in OD (Fig. 1b); intravenous fluorescein angiography revealed pooling into the PED in the early phases along with an expansile dot pattern of leakage in later phases (Fig. 1c and d, respectively). The patient denied use of steroid-containing medications since presentation. At 1-month follow-up, VA OD had decreased to 20/50, and confrontational visual fields showed an ipsilateral central scotoma. OCT showed persistence of subretinal fluid with PED. He was treated with PDT with verteporfin 3 mg/m2 and 25 J/cm2 laser fluence. Twenty days following the procedure, VA OD was 20/100 with resolution of the central scotoma. OCT obtained at this time showed resolution of the subretinal fluid (Fig. 2). The patient was lost to follow-up after this visit, and his visual status is unknown.\n\nDiscussion\nPrevious reports have correlated the onset of CSC with various modes of steroid use, including both systemic and local applications [5]. This disease has also been reported as a complication of sub-Tenon's corticosteroid injection [6].\n\nCSC onset has been documented as early as 1 week following topical ocular and periorbital high-dose corticosteroid administration [6]. Our patient developed CSC within 1 month of the injection. We were unable to identify any literature clarifying the expected time frame between corticosteroid administration and CSC diagnosis. It is unlikely our patient developed CSC from another cause besides the intrapalpebral steroid injection, as there were no other established risk factors present for the condition.\n\nThe patient's subretinal edema and VA worsened with observation. Soon after treatment with PDT, the subretinal fluid and PED had resolved, although VA worsened. Subfoveal PEDs in CSC, as in our patient, have been found to have a poor visual prognosis with an average VA of 20/50 in one study [7]. We expected continued visual improvement over time after PDT; however, the patient was lost to follow-up. Regarding timeline to treatment, PDT and other therapeutic strategies are often initiated after 3 months for one isolated episode of CSC, due to the chance of spontaneous recovery during this period [2]. It is possible that our patient's CSC resolved on its own rather than as a result of the PDT given the natural time course of CSC, although the worsening VA and a new central scotoma were the reasons for initiating treatment with PDT.\n\nIn conclusion, our study identifies a new association between intrapalpebral low-dose corticosteroid administration and development of CSC and reports complete resolution of subretinal fluid with early phototherapy. To our knowledge, this is the first report of CSC secondary to injection of triamcinolone within the excision margins following chalazion excision.\n\nStatement of Ethics\nInformed consent for this case report was not obtained prior to our patient being lost to follow-up. However, no identifying information is included in this case report. The study was carried out without approval from our Institutional Review Board, as none is needed from our institution for case reports.\n\nDisclosure Statement\nOur institution receives an unrestricted grant from the Foundation of Research to Prevent Blindness (RPB) to support research and publications. RPB has no conflicts of interest with this work. This research did not receive any specific grant from funding agencies in the public, commercial, or nonprofit sectors. The following authors have no financial disclosures: L. Rosignoli, S. Potter, A. Gonzalez, S. Amin, S. Khurshid.\n\nAuthor Contributions\nLuca Rosignoli: Participated in drafting the manuscript, collection, analysis and interpretation of the data. Read and approved the final manuscript. Stephen Myles Potter: Participated in drafting the manuscript, collection, analysis and interpretation of the data. Read and approved the final manuscript. Andres Gonzalez: Participated in drafting the manuscript, collection, analysis, and interpretation of the data. Read and approved the final manuscript. Sarina Amin: Participated in drafting the manuscript, collection, analysis, and interpretation of the data. Read and approved the final manuscript. Syed G. Khurshid: concepted, analyzed, interpreted the data and revised it critically for intellectual content. Read the final manuscript and gave final approval of the version for submission.\n\nFig. 1. Spectral domain OCT showing preprocedure subretinal fluid (a) with PED (b). Standard intravenous fluorescein angiography in the early arteriovenous phase at 16 s (c) showing pooling into the PED (green arrow) and in the venous phase at 31 s (d) showing an expansile dot pattern (yellow arrow) with pooling into the PED (green arrow).\n\nFig. 2. Spectral domain OCT after PDT showing resolution of SRF.\n==== Refs\nReferences\n1 Ross A Ross AH Mohamed Q Review and update of central serous chorioretinopathy Curr Opin Ophthalmol 2011 5 22 (3) 166 73 21427570 \n2 Gemenetzi M De Salvo G Lotery AJ Central serous chorioretinopathy: an update on pathogenesis and treatment Eye (Lond) 2010 12 24 (12) 1743 56 20930852 \n3 Gong Q Sun XH Yuan ST Liu QH The relation of the serum aldosterone level and central serous chorioretinopathy - a pilot study Eur Rev Med Pharmacol Sci 2017 2 21 (3) 446 53 28239828 \n4 Wang M Munch IC Hasler PW Prünte C Larsen M Central serous chorioretinopathy Acta Ophthalmol 2008 3 86 (2) 126 45 17662099 \n5 Balakrishnan S Apsingi S Manjure SB Sudden loss of visual acuity following intra-articular steroid injection in to the knee joint: a case report Cases J 2008 12 1 (1) 428 19116023 \n6 Baumal CR Martidis A Truong SN Central serous chorioretinopathy associated with periocular corticosteroid injection treatment for HLA-B27-associated iritis Arch Ophthalmol 2004 6 122 (6) 926 8 15197074 \n7 Mudvari SS Goff MJ Fu AD McDonald HR Johnson RN Ai E The natural history of pigment epithelial detachment associated with central serous chorioretinopathy Retina 2007 Nov-Dec 27 (9) 1168 73 18046220\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1663-2699",
"issue": "9(3)",
"journal": "Case reports in ophthalmology",
"keywords": "Choroid; Eyelid; Photodynamic therapy; Retinopathy; Risk factors",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "416-420",
"pmc": null,
"pmid": "30323759",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "15197074;18046220;21427570;28239828;17662099;19116023;20930852",
"title": "Development of Central Serous Chorioretinopathy following Chalazion Removal with Intralesional Triamcinolone Injection: A Case Report.",
"title_normalized": "development of central serous chorioretinopathy following chalazion removal with intralesional triamcinolone injection a case report"
} | [
{
"companynumb": "US-CMP PHARMA-2019CMP00003",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
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"drugadditional": null,
... |
{
"abstract": "Serotonin syndrome (SS) is a potentially life-threatening adverse drug reaction that may occur in patients treated with serotonin agonist medications. Medications responsible for serotonin syndrome include commonly prescribed antidepressants, anxiolytics, analgesics, and antiemetics. Veterans with post-traumatic stress disorder (PTSD) are at risk for polypharmacy with serotoninergic medications, given their psychological comorbidities and service-related musculoskeletal injuries. The perioperative period is a particularly vulnerable time owing to the use of high-dose anxiolytics and antiemetics frequently administered in this period, and places PTSD patients at higher risk of SS. Herein, we present the first case of SS in a young veteran with combat-related PTSD following an uncomplicated L5-S1 revision discectomy that highlights the unique set of clinical challenges and dilemmas faced when treating SS in a patient with severe postsurgical pain. As we are likely to encounter increasing numbers of veterans treated for PTSD who require multiple surgical procedures to treat their service-related injuries, health care providers need to be familiar with prevention, recognition, and the clinical challenges in the management of SS in the postoperative period.",
"affiliations": "Anesthesia Services, VA Medical Center, 4150 Clement Street, San Francisco, CA 94121.;Anesthesia Services, VA Medical Center, 4150 Clement Street, San Francisco, CA 94121.;Anesthesia Services, VA Medical Center, 4150 Clement Street, San Francisco, CA 94121.;Anesthesia Services, VA Medical Center, 4150 Clement Street, San Francisco, CA 94121.;Anesthesia Services, VA Medical Center, 4150 Clement Street, San Francisco, CA 94121.;Surgery Services, VA Medical Center, 4150 Clement Street, San Francisco, CA 94121.;Surgery Services, VA Medical Center, 4150 Clement Street, San Francisco, CA 94121.;Anesthesia Services, VA Medical Center, 4150 Clement Street, San Francisco, CA 94121.",
"authors": "Schuch|Luiz Gustavo|LG|;Yip|Anita|A|;Nouri|Kiana Farah|KF|;Gregersen|Maren|M|;Cason|Brian|B|;Kukreja|Jasleen|J|;Wozniak|Curtis|C|;Brzezinski|Marek|M|",
"chemical_list": "D017366:Serotonin Receptor Agonists; D015283:Citalopram; D008803:Mianserin; D000078785:Mirtazapine",
"country": "England",
"delete": false,
"doi": "10.7205/MILMED-D-15-00461",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0026-4075",
"issue": "181(9)",
"journal": "Military medicine",
"keywords": null,
"medline_ta": "Mil Med",
"mesh_terms": "D000328:Adult; D015283:Citalopram; D017586:Diskectomy; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D017116:Low Back Pain; D008297:Male; D008803:Mianserin; D000078785:Mirtazapine; D019637:Orthopedic Procedures; D017366:Serotonin Receptor Agonists; D020230:Serotonin Syndrome; D013313:Stress Disorders, Post-Traumatic; D014728:Veterans",
"nlm_unique_id": "2984771R",
"other_id": null,
"pages": "e1185-8",
"pmc": null,
"pmid": "27612381",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serotonin Syndrome Following an Uncomplicated Orthopedic Surgery in a Patient With Post-Traumatic Stress Disorder.",
"title_normalized": "serotonin syndrome following an uncomplicated orthopedic surgery in a patient with post traumatic stress disorder"
} | [
{
"companynumb": "US-ALLERGAN-1805756US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nSuccessful use of acetylcysteine to control irritability and aggressive behaviors in a hospitalized adolescent patient with autism spectrum disorder (ASD) is described.\n\n\nCONCLUSIONS\nA 17-year-old Hispanic male with ASD and intellectual disability was hospitalized for inpatient psychiatric treatment due to impulsive and violent behavior. Despite receiving various medications in the initial weeks of hospitalization, including intramuscular lorazepam and diphenhydramine injections (four days a week on average), the patient continued to exhibit aggressive and unpredictable behaviors. Treatment with 20% acetylcysteine oral solution was initiated at a dosage of 600 mg twice daily as an adjunct to quetiapine therapy. Over the next six weeks, reductions in the patient's aggressive behavior, tantrums, and irritability were noted. The use of as-needed medications to control aggression was decreased, and the dosage of quetiapine was lowered from 700 to 400 mg daily over the course of the hospitalization. Acetylcysteine was well tolerated, with no observed or reported adverse effects. Unlike clonidine or guanfacine (other medications used for ASD-related behavioral symptoms), acetylcysteine is not sedating; moreover, it lacks the metabolic, extrapyramidal, and endocrine adverse effects of atypical antipsychotics. Published data from small controlled trials and case reports suggest that acetylcysteine use is associated with improvements in irritability and aggression in prepubertal children with ASD; these therapeutic benefits may be associated with acetylcysteine's glutamatergic, dopaminergic, antioxidant, and anti-inflammatory properties.\n\n\nCONCLUSIONS\nTreatment with acetylcysteine improved ASD symptoms, including irritability and aggression, in a teenage patient.",
"affiliations": "Danielle Stutzman, Pharm.D., is Postgraduate Year 2 Psychiatric Pharmacy Resident, University of Southern California (USC) School of Pharmacy, Los Angeles. Julie Dopheide, Pharm.D., BCPP, is Professor of Clinical Pharmacy, Psychiatry and the Behavioral Sciences, USC School of Pharmacy and Keck School of Medicine, Los Angeles.;Danielle Stutzman, Pharm.D., is Postgraduate Year 2 Psychiatric Pharmacy Resident, University of Southern California (USC) School of Pharmacy, Los Angeles. Julie Dopheide, Pharm.D., BCPP, is Professor of Clinical Pharmacy, Psychiatry and the Behavioral Sciences, USC School of Pharmacy and Keck School of Medicine, Los Angeles. dopheide@usc.edu.",
"authors": "Stutzman|Danielle|D|;Dopheide|Julie|J|",
"chemical_list": "D000975:Antioxidants; D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp150072",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "72(22)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000111:Acetylcysteine; D000293:Adolescent; D000374:Aggression; D000975:Antioxidants; D014150:Antipsychotic Agents; D000067877:Autism Spectrum Disorder; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D000069348:Quetiapine Fumarate; D016896:Treatment Outcome",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1956-9",
"pmc": null,
"pmid": "26541950",
"pubdate": "2015-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acetylcysteine for treatment of autism spectrum disorder symptoms.",
"title_normalized": "acetylcysteine for treatment of autism spectrum disorder symptoms"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0055291",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nEmpirical antifungal therapy prevents invasive fungal infections in patients with cancer. This study assessed the empirical efficacy of intravenous itraconazole in pediatric patients undergoing hematopoietic stem cell transplantation, and investigated the pharmacokinetics and clinical implications.\n\n\nMETHODS\nOral itraconazole syrup was started (2.5 mg/kg twice daily) for prophylaxis, and patients with persistent neutropenic fever for more than 2 days were switched to intravenous itraconazole (5 mg/kg twice daily for 2 days for induction and 5 mg/kg daily for maintenance) as empirical treatment. Empirical antifungal efficacy was assessed retrospectively in 159 transplantations, and a full pharmacokinetic study was prospectively conducted in six of these patients. Successful antifungal efficacy was defined as the fulfillment of all components of a five-part composite end point.\n\n\nRESULTS\nThe overall empirical antifungal success rate fulfilling all criteria was 42.1 %. No death or drug-related serious adverse events occurred during the study. Mean trough plasma concentration of itraconazole after oral prophylaxis and intravenous induction were 577.2 and 1659.7 μg/L, respectively. Mean area under the concentration-time curve of itraconazole and its metabolite at steady state were 42,837 ± 24,746 μg·h/L and 63,094 ± 19,255 μg·h/L.\n\n\nCONCLUSIONS\nIntravenous itraconazole was effective and safe as an empirical antifungal agent in pediatric patients; this was due to the fast and satisfactory increase in drug concentration by switching from oral to intravenous therapy.",
"affiliations": "Cancer Research Institute, Seoul National University College of Medicine, #28 Yongon-dong, Chongno-gu, Seoul, 110-744, Republic of Korea.",
"authors": "Kim|Hyery|H|;Shin|Donghoon|D|;Kang|Hyoung Jin|HJ|;Yu|Kyung-Sang|KS|;Lee|Ji Won|JW|;Kim|Sung Jin|SJ|;Kim|Min Sun|MS|;Song|Eun Sun|ES|;Jang|Mi Kyoung|MK|;Park|June Dong|JD|;Jang|In-Jin|IJ|;Park|Kyung Duk|KD|;Shin|Hee Young|HY|;Ahn|Hyo Seop|HS|",
"chemical_list": "D000935:Antifungal Agents; D017964:Itraconazole",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40261-015-0297-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1173-2563",
"issue": "35(7)",
"journal": "Clinical drug investigation",
"keywords": null,
"medline_ta": "Clin Drug Investig",
"mesh_terms": "D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D017964:Itraconazole; D008297:Male; D009369:Neoplasms; D012189:Retrospective Studies",
"nlm_unique_id": "9504817",
"other_id": null,
"pages": "437-46",
"pmc": null,
"pmid": "26022135",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "18359202;17430480;18462102;9154027;17517842;16398648;15459300;9884817;2561187;12690972;8591940;11807146;11560454;9950095;9674858;17048974;17530138;11550120;11422598;1326309;9527794;12714819;11219548;17999982;16944217;11302829;15905803;11181397;10546485;13680173;12121932;10680434;7814285;18367976",
"title": "Successful empirical antifungal therapy of intravenous itraconazole with pharmacokinetic evidence in pediatric cancer patients undergoing hematopoietic stem cell transplantation.",
"title_normalized": "successful empirical antifungal therapy of intravenous itraconazole with pharmacokinetic evidence in pediatric cancer patients undergoing hematopoietic stem cell transplantation"
} | [
{
"companynumb": "KR-JNJFOC-20150711437",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE\\SODIUM CHLORIDE"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nLarge wide-necked arterial bifurcation aneurysms present a unique challenge for endovascular coil embolization treatment. One technique described in the literature deploys a Neuroform stent into the neck of the aneurysm in the shape of a waffle-cone, thereby acting as a scaffold for the coil mass. This case series presents four patients with large wide-necked bifurcation aneurysms treated with the closed-cell Enterprise stent using the waffle-cone technique.\n\n\nMETHODS\nFour patients (59 ± 18 years of age) with large wide-necked arterial bifurcation aneurysms (three basilar apex and one MCA bifurcation) were treated with the waffle-cone technique using the Enterprise stent as a supporting device for stent-assisted coil embolization. Three of the patients presented with aneurysmal subarachnoid hemorrhage (Hunt-Hess 2-3; Fisher Grade 3-4). There was no procedural morbidity or mortality associated with treatment itself. One aneurysm was completely obliterated, and three had small residual necks. One patient developed an area of PCA infarct and visual field cut one month after the procedure and required recoiling of the residual neck. The flared ends of the Enterprise stent remodeled the aneurysm neck by conforming to the shape of the neck without any technical difficulty, resulting in a stable scaffold holding the coils into the aneurysm.\n\n\nCONCLUSIONS\nThe closed cell construction, flexibility, and flared ends of the Enterprise stent allow it to conform to the waffle-cone configuration and provide a stable scaffold for coil embolization of large wide-necked arterial bifurcation aneurysms. We have had excellent initial results using the Enterprise stent with the waffle-cone technique. However, this technique is higher risk than standard treatment methods and therefore should be reserved for large wide-necked bifurcation aneurysms where Y stenting is needed, but not possible, and surgical clip ligation is not an option.",
"affiliations": "Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, USA.",
"authors": "Padalino|David J|DJ|;Singla|Amit|A|;Jacobsen|Walter|W|;Deshaies|Eric M|EM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4103/2152-7806.106268",
"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSNISurgical Neurology International2229-50972152-7806Medknow Publications & Media Pvt Ltd India SNI-4-910.4103/2152-7806.106268Case ReportEnterprise stent for waffle-cone stent-assisted coil embolization of large wide-necked arterial bifurcation aneurysms Padalino David J. padalind@upstate.eduSingla Amit singlaa@upstate.eduJacobsen Walter jacobsw@mail.amc.edu1Deshaies Eric M. deshaiee@upstate.edu*Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, USA1 Department of Neurosurgery, Albany Medical Center, Albany, NY, USA* Corresponding author\n2013 28 1 2013 4 921 8 2012 18 12 2012 Copyright: © 2013 Padalino DJ2013This 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.Background:\nLarge wide-necked arterial bifurcation aneurysms present a unique challenge for endovascular coil embolization treatment. One technique described in the literature deploys a Neuroform stent into the neck of the aneurysm in the shape of a waffle-cone, thereby acting as a scaffold for the coil mass. This case series presents four patients with large wide-necked bifurcation aneurysms treated with the closed-cell Enterprise stent using the waffle-cone technique.\n\nCase Description:\nFour patients (59 ± 18 years of age) with large wide-necked arterial bifurcation aneurysms (three basilar apex and one MCA bifurcation) were treated with the waffle-cone technique using the Enterprise stent as a supporting device for stent-assisted coil embolization. Three of the patients presented with aneurysmal subarachnoid hemorrhage (Hunt-Hess 2-3; Fisher Grade 3-4). There was no procedural morbidity or mortality associated with treatment itself. One aneurysm was completely obliterated, and three had small residual necks. One patient developed an area of PCA infarct and visual field cut one month after the procedure and required recoiling of the residual neck. The flared ends of the Enterprise stent remodeled the aneurysm neck by conforming to the shape of the neck without any technical difficulty, resulting in a stable scaffold holding the coils into the aneurysm.\n\nConclusion:\nThe closed cell construction, flexibility, and flared ends of the Enterprise stent allow it to conform to the waffle-cone configuration and provide a stable scaffold for coil embolization of large wide-necked arterial bifurcation aneurysms. We have had excellent initial results using the Enterprise stent with the waffle-cone technique. However, this technique is higher risk than standard treatment methods and therefore should be reserved for large wide-necked bifurcation aneurysms where Y stenting is needed, but not possible, and surgical clip ligation is not an option.\n\nAneurysmcoilembolizationenterprisestentwaffle-conewide-necked\n==== Body\nINTRODUCTION\nCoil loop extrusion from the neck of large, wide-necked arterial bifurcation aneurysms poses a challenge for endovascular treatment in part because they can occlude the parent vessel or its branches.[6] Several techniques have been developed to overcome this problem, one of which is waffle-coning, initially described using the open-celled Neuroform stent and named for the appearance of the flared distal end within the aneurysm fundus.[4] The procedure deploys a stent within the confines of the aneurysm neck, thus acting as a scaffold to support the coil mass and protect parent branches from occlusion.\n\nThe Enterprise, a flexible closed-cell stent, was designed to bridge the opening of wide-necked aneurysms during stent-assisted coiling. Additionally, the closed-cell design allows for retrieval of partially deployed stents, thereby improving precise positioning.[37] Recently, there was a single case report describing the successful deployment of the Enterprise stent in the waffle-cone configuration of a large basilar trunk aneurysm.[2] This stenting technique can be potentially used in any large wide-necked arterial bifurcation aneurysm in which multiple branches originate from the aneurysm neck, making it difficult to protect against coil extrusion and distal arterial occlusion. We describe our initial experience using the Enterprise for stent-assisted waffle-cone coil embolization of wide-necked aneurysms in a series of four patients, three with basilar apex aneurysms (two ruptured, one unruptured) and the fourth being an MCA bifurcation aneurysm.\n\nCASE REPORTS\nApproval from SUNY Upstate Institutional Review Board was obtained to review these cases. All patients [Table 1] signed informed consent for the specific use of the Enterprise stent and another for stent-assisted coil embolization of the intracranial aneurysm.\n\nTable 1 Aneurysm characteristics of all patients treated with stent-assisted coil embolization using the enterprise stent in the waffle-cone configuration\n\nWaffle-cone technique\nThe waffle-cone technique, as described previously for the Neuroform stent,[4] was used with the Enterprise stent in all cases for these four large wide-necked bifurcation aneurysms [Figure 1]. Selective catheterization of the aneurysm and deployment of the Enterprise stent with the distal stent tines being deployed into the proximal neck of the aneurysm were carried out through a Prowler Select Plus microcatheter (Cordis Neurovascular, Miami, FL) in the waffle-cone conformation [Figure 2]. A point within the aneurysm neck measuring greater than the flared ends of the Enterprise stent (>4.5 mm) was identified for deployment of the distal tines to prevent injury and rupture of the aneurysm. This was then followed by packing the aneurysm with a series of appropriately sized coils for the individual aneurysm.\n\nFigure 1 (a) Enterprise stent with flared tines when deployed and closed-cell design are depicted. (b) Neuroform stent with parallel stent wall and tines when deployed and open-cell designs are depicted. Figure modified and reprinted from Wakhloo,[et al.[12]\n\nFigure 2 (a) Microcatheter and microwire in the aneurysm neck. (b) Enterprise stent being deployed into aneurysm. (c) Enterprise stent deployed with microwire in aneurysm. (d) Coils deployed through microcatheter in aneurysm. (e) Coiled aneurysm in waffle-cone configuration. Figure and legend modified and reprinted from Horowitz, et al.[4]\n\nAll ruptured aneurysm patients were placed on abciximab intravenous drip after coil embolization until external ventricular drainage was not needed, after which they were placed on aspirin 325 mg and clopidogrel 75 mg orally daily for three months, and then aspirin 81 mg daily. The unruptured aneurysm patient was premedicated for one week prior to the intervention with aspirin 325 mg and clopidogrel 75 mg orally daily, followed by the same postprocedure antiplatelet oral regimen described above for the ruptured aneurysms.\n\nPatient cases\nOne basilar apex aneurysm [Figure 3] had a small residual (2.5 × 3.0 mm) outside of the stent tines with an Aneurysm Embolization Grade (AEG)[111] of “C” [Table 2], where the P1 origin was incorporated into the aneurysm neck. This patient also had a delayed onset of a small posterior cerebral artery stroke with a visual field cut one month after the initial intervention and required the recoiling of the residual neck, which reduced the AEG to “B.” Two year follow-up imaging demonstrated a patent Enterprise stent with no significant in-stent stenosis and no recurrence of the aneurysm nor progression of PCA infarct.\n\nFigure 3 Patient 1 cerebral angiogram (left vertebral injection). (a) AP view showing a basilar apex aneurysm pretreatment. (b) Lateral view of the Enterprise stent deployed in the aneurysm dome. (c) Follow-up AP view showing small basilar apex aneurysm recurrence before redo treatment. (d) Follow-up AP view after redo coil embolization of recurrent aneurysm. (e) 27-month follow-up AP view after redo coil embolization showing no further recurrence\n\nTable 2 Aneurysm embolization grading scale for predicting likelihood of aneurysm recurrence based on angiographic flow characteristics through the aneurysm neck and dome after embolization. Table modified and reprinted from Deshaies, et al.[111]\n\nTwo other basilar apex aneurysms (one ruptured, one elective) had small residuals with delayed filling at the neck (AEG-“B”), again where the P1 origin was incorporated into the aneurysm neck [Figures 4 and 5]. These small residuals spontaneously thrombosed and the AEG improved from “B” to “A” on follow-up cerebral angiography performed during 1-3 month follow-up.\n\nFigure 4 Patient 2 cerebral angiogram (right vertebral injection). (a) AP view showing a basilar apex aneurysm pretreatment. (b) AP native view showing placement of the Enterprise stent deployed in the aneurysm dome. (c) AP subtracted view showing the basilar apex aneurysm postembolization\n\nFigure 5 Patient 3 cerebral angiogram (right vertebral injection). (a) AP subtracted view showing a basilar apex aneurysm pretreatment. (b) Lateral native view showing the Enterprise stent deployed in the aneurysm dome. (c) AP subtracted view showing the basilar apex aneurysm postembolization\n\nThe ruptured MCA bifurcation aneurysm was completely obliterated (AEG-“A”) during initial treatment with this technique, without occlusion or compromise of the branching arteries at the bifurcation [Figure 6]. All parent vessels and their respective branches remained patent after all procedures. Abciximab intravenous drip resulted in thrombocytopenia and had to be stopped prior to the intended date and the patient started on aspirin 325 mg orally until the ventriculostomy could be removed, after which time clopidogrel 75 mg daily was added to the regimen for three months.\n\nFigure 6 Patient 4 cerebral angiogram (left ICA injection). (a) AP subtracted view showing a left MCA bifurcation aneurysm pretreatment. (b) Lateral native view showing the Enterprise stent deployed in the aneurysm dome. (c) AP subtracted view showing the basilar apex aneurysm postembolization\n\nPeriprocedural complications\nThere were no intraprocedural or immediate postprocedure complications related to technique in any of these cases. None of these patients presented with any symptoms of mass effect or cranial neuropathy from the aneurysm and stent-coil embolization of these vascular lesions did not result in de novo neurological deficits. The electively stent-coiled aneurysm patient was discharged home the next day and the subarachnoid hemorrhage patients had uneventful courses within the neurocritical care unit.\n\nDISCUSSION\nLarge complex wide-necked intracranial aneurysms, such as those described here, present technical challenges that mandate thinking differently about treatment endeavors. The waffle-cone technique is one such technique that addresses the endovascular challenge of coiling these types of complex bifurcation aneurysms. An advantage of the Enterprise over the Neuroform stent is its flexible closed-cell design which allows it to be retrieved and repositioned when up to 70% is deployed.[3] The Neuroform stent cannot be retrieved once the first set of open cells are deployed, preventing stent repositioning. An additional edge provided by Enterprise is its flared ends that allow it to naturally conform to the waffle-cone shape in the aneurysm neck, unlike the parallel tubular shape of the Neuroform stent. Other closed-cell stents have been designed, such as the Solitaire-AB retrievable stent (eV3/Covidien, Irvine CA, USA),[5] but is currently not FDA approved for use in the United States and therefore not available to us.\n\nThe largest of the three basilar tip aneurysms was left with a residual neck at the junction of the P1 origin after initial treatment to avoid PCA occlusion and later required retreatment. This recurrence is consistent with reports in the literature of aneurysm, size greater than 10 mm is an independent predictor of recurrence, and also the fact that residual aneurysm neck was left intentionally to preserve the patency of the P1 origin in this case.[9] A potential downside to using a closed-cell stent is that it can limit access to the distal vascular tree, even though the cell size is 1.3 Fr and should allow passage of most endovascular microcatheters. An additional downside of the Enterprise stent is that the closed-cell design may limit blood flow from the parent artery through the stent tube into the branching arteries where it covers them at their origins. Although we did not encounter this problem in any of our patients and there were not any hemodynamic alterations noted on angiography, the open cell-design of the Neuroform stent would theoretically minimize these potential complications.\n\nAs with any stent-assisted coiling in the setting of subarachnoid hemorrhage, antiplatelet therapy is needed to reduce the risk of thromboembolic events from the stent, which increases the risk of hemorrhagic complications from the aneurysm itself or invasive procedures needed for hydrocephalus. Many of these patients will require external ventricular drains, ventriculperitoneal shunts, or other procedures and operations that are higher risk with antiplatelet usage. However, the risk from stent-assisted coiling must be weighed against that of surgical clip ligation of these complex aneurysms.\n\nWhen compared with the “Y”- stent technique, this approach uses a single stent helping to reduce cost and more importantly, reduce the surface area of exposed metal to the vessel lumen. Reduced exposure of blood to a metal surface should reduce the risk of thromboembolic events and the probability of in-stent stenosis; although some would argue that jailing of the branching artery origins by a closed-cell stent could actually increase the risk of immediate hemodynamic compromise, thromboembolic complications, and delayed in-stent stenosis. Currently, there are no studies that address any actual thromboembolic complication rates of these two stents with this technique. Other techniques of stent placement across the base of a wide-necked basilar apex aneurysm include placement via p-com across the basilar aneurysm neck by deploying into bilateral P1 segments. This technique requires a large p-com with favorable anatomy and also can jail out the P1 origins from the blood flow directed through the basilar artery.[810] The waffle-cone technique avoids the need for large communicating vessels with favorable anatomy and the placement of multiple stents needed for the “Y”-stent technique.\n\nHowever, caution with the waffle-cone technique is warranted, independent of the type of stent used to assist with coil embolization. Treatment of aneurysms with a relatively short dome height could be dangerous with the waffle-cone technique in the event that forward tension on the microcatheter results in forward migration of the stent during deployment. In this situation, aneurysm perforation could occur with disastrous results as it could with any procedure involving the treatment of aneurysms with short domes. Therefore, we believe that the waffle-cone technique is useful only for carefully selected aneurysm morphologies consistent with long dome heights and wide-necks that incorporate the bifurcating vessels, unable to be “Y” stented or surgically clipped. This technique is not recommended for aneurysms with narrow necks or short dome heights where deployment error could result in rupture, or aneurysms with necks less than 4.5 mm (size of the distal stent flare) where the opening distal end of the stent could perforate the aneursym.\n\nCONCLUSIONS\nCoil embolization of large wide-necked arterial bifurcation aneurysms has been described here using the waffle-cone technique with the Enterprise stent. The closed-cell design, flexibility, and flared ends of the Enterprise stent allow it to conform to the natural morphology of the aneurysm neck into the waffle-cone configuration providing a stable scaffold for coil embolization. We have had excellent initial results with this technique, but the interventionalist must keep in mind that the technical risk is higher than the traditional stent-assisted and balloon-assisted coiling procedures. Therefore, the waffle-cone technique should be reserved for those bifurcation aneurysms with wide necks incorporating the branching vessel origins, where “Y” stenting is needed but not possible due to the aneurysm neck morphology, and surgical clip ligation is not an option.[12]\n\nAvailable FREE in open access from: http://www.surgicalneurologyint.com/text.asp?2013/4/1/9/106268\n==== Refs\nREFERENCES\n1 Deshaies EM Adamo MA Boulos AS A prospective single-center analysis of the safety and efficacy of the hydrocoil embolization system for the treatment of intracranial aneurysms J Neurosurg 2007 106 226 33 17410704 \n2 Gruber TJ Ogilvy CS Hauck EF Levy EI Hopkins LN Siddiqui AH Endovascular treatment of a large aneurysm arising from a basilar trunk fenestration using the waffle-cone technique Neurosurgery 2010 67 3 Suppl Operative ons140 4 discussion ons144 20679936 \n3 Higashida RT Halbach VV Dowd CF Juravsky L Meagher S Initial clinical experience with a new self-expanding nitinol stent for the treatment of intracranial cerebral aneurysms: The Cordis Enterprise stent AJNR Am J Neuroradiol 2005 26 1751 6 16091525 \n4 Horowitz M Levy E Sauvageau E Genevro J Guterman LR Hanel R Intra/extra-aneurysmal stent placement for management of complex and wide-necked-bifurcation aneurysms: Eight cases using the waffle cone technique ;58:ONS-258-62 Neurosurgery 2006 58 ONS-258 62 discussion ONS-262 \n5 Klisch J Eger C Sychra V Strasilla C Basche S Weber J Stent-assisted coil embolization of posterior circulation aneurysms using solitaire ab: Preliminary experience Neurosurgery 2009 65 258 66 discussion 266 19625903 \n6 Lavine SD Meyers PM Application of new techniques and technologies: Stenting for cerebral aneurysm Clin Neurosurg 2007 54 64 9 18504898 \n7 Mocco J Snyder KV Albuquerque FC Bendok BR Alan SB Carpenter JS Treatment of intracranial aneurysms with the Enterprise stent: A multicenter registry J Neurosurg 2009 110 35 9 18976057 \n8 Moret J Ross IB Weill A Piotin M The retrograde approach: A consideration for the endovascular treatment of aneurysms AJNR Am J Neuroradiol 2000 21 262 8 10696006 \n9 Peluso JP van Rooij WJ Sluzewski M Beute GN Coiling of basilar tip aneurysms: Results in 154 consecutive patients with emphasis on recurrent haemorrhage and re-treatment during mid- and long-term follow-up J Neurol Neurosurg Psychiatry 2008 79 706 11 17846108 \n10 Pride GL Jr Welch B Novakovic R Rickert K White J Dutton-Johnson K Retrograde crossing stent placement strategies at the basilar apex for the treatment of wide necked aneurysms: Reconstructive and deconstructive opportunities J Neurointerv Surg 2009 1 132 5 21994282 \n11 Singla A Villwock MR Jacobsen W Deshaies EM Aneurysm embolization grade: A predictive tool for aneurysm recurrence after coil embolization Acta Neurochir (Wien) 2012 [In Press] \n12 Wakhloo AK Deleo MJ 3rd Brown MM Advances in interventional neuroradiology Stroke 2009 40 e305 12 19398765\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2152-7806",
"issue": "4()",
"journal": "Surgical neurology international",
"keywords": "Aneurysm; coil; embolization; enterprise; stent; waffle-cone; wide-necked",
"medline_ta": "Surg Neurol Int",
"mesh_terms": null,
"nlm_unique_id": "101535836",
"other_id": null,
"pages": "9",
"pmc": null,
"pmid": "23493649",
"pubdate": "2013",
"publication_types": "D002363:Case Reports",
"references": "18504898;17846108;17410704;21994282;20679936;19625903;16091525;16582648;23151771;19398765;10696006;18976057",
"title": "Enterprise stent for waffle-cone stent-assisted coil embolization of large wide-necked arterial bifurcation aneurysms.",
"title_normalized": "enterprise stent for waffle cone stent assisted coil embolization of large wide necked arterial bifurcation aneurysms"
} | [
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"activesubstancename": "ABCIXIMAB"
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{
"abstract": "Rituximab appears to be effective for treating pemphigus, although there are limited long-term data.\nThis retrospective single-center study evaluated patients with conventional treatment-resistant pemphigus who received rituximab during September 2010-December 2019. The first rituximab cycle was based on the rheumatoid arthritis protocol in all patients except one patient, and additional single doses (500 mg or 1000 mg) were administered after clinical and/or serological relapse. The consensus definitions were used for complete remission off therapy, complete remission on minimal therapy, and clinical relapse. Serological relapse was defined as a progressive ≥2-fold increase in anti-desmoglein titers (vs. previous the measurement).\nThe study included 52 patients with pemphigus vulgaris and 1 patient with pemphigus foliaceus. The mean number of infusions was 5 and the average follow-up after the first infusion was 56 months. The average time to clinical and/or serological relapse was 12 months. Complete remission was achieved in 84.9% of patients, including after the first rituximab cycle in 25 patients (47.1%). Two patients died during the follow-up period.\nAdditional rituximab cycles may help achieve and prolong remission in patients with moderate-to-severe pemphigus resistant to conventional therapies. However, prospective trials are needed to identify the optimal dosing protocol.",
"affiliations": "Dermatology and Venereology, Akdeniz University School of Medicine, Antalya, Turkey.;Dermatology and Venereology, Akdeniz University School of Medicine, Antalya, Turkey.;Dermatology and Venereology, Akdeniz University School of Medicine, Antalya, Turkey.",
"authors": "Bozca|Burçin Cansu|BC|https://orcid.org/0000-0001-7907-5037;Bilgiç|Aslı|A|https://orcid.org/0000-0001-7910-7908;Uzun|Soner|S|https://orcid.org/0000-0001-7059-5474",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09546634.2021.1919288",
"fulltext": null,
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"issn_linking": "0954-6634",
"issue": null,
"journal": "The Journal of dermatological treatment",
"keywords": "Rituximab; long-term efficacy; long-term safety; pemphigus",
"medline_ta": "J Dermatolog Treat",
"mesh_terms": null,
"nlm_unique_id": "8918133",
"other_id": null,
"pages": "1-8",
"pmc": null,
"pmid": "34027788",
"pubdate": "2021-06-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term experience with rituximab therapy for treatment-resistant moderate-to-severe pemphigus.",
"title_normalized": "long term experience with rituximab therapy for treatment resistant moderate to severe pemphigus"
} | [
{
"companynumb": "TR-ROCHE-2843966",
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{
"abstract": "Renal medullary carcinoma (RMC) is a highly aggressive and rare malignancy found almost exclusively in young patients with sickle cell trait (SCT). Metastatic disease is commonly present at diagnosis. There is very limited experience treating disseminated disease and the prognosis is dismal. We report the case of a young 9-year-old boy with SCT, who presented with 4 months' progression of abdominal pain, nausea and vomiting associated with cough spells, dysphagia, and weight loss. Upon evaluation, he was underweight, pale, and in mild respiratory distress. Cervical lymphadenopathy was evident and abdomen was diffusely tender. A whole-body CT scan showed a left kidney lesion with associated cervical, mediastinal, and retroperitoneal lymphadenopathy. Biopsy of a cervical lymph node revealed metastatic RMC. Patient was started on combination chemotherapy with paclitaxel, carboplatin, and gemcitabine followed by left adrenalectomy. In spite of having advanced disease, our patient achieved an excellent response with a progression-free survival of 17 months. Although SCT is thought to be a \"benign\" condition, RMC is one devastating complication associated with it. Considering its rarity, the near uniform associated fatality should prompt the question of whether clinical practice should change regarding proper counseling of these patients and raise awareness in the medical community.",
"affiliations": "Department of Pediatrics, Medicine-Pediatrics Residency Program, University of Puerto Rico Medical Sciences Campus, PO Box 365067, San Juan, PR, 00926-5067, USA. yamgova@gmail.com.;Division of Pediatric Hematology Oncology, Department of Pediatrics, University Pediatric Hospital, University of Puerto Rico, Medical Sciences Campus, San Juan, USA.;Division of Pediatric Hematology Oncology, Department of Pediatrics, University Pediatric Hospital, University of Puerto Rico, Medical Sciences Campus, San Juan, USA.;Department of Pathology, School of Medicine, University of Puerto Rico, Medical Sciences Campus, PO Box 365067, San Juan, PR, 00936-5067, USA.",
"authors": "Goenaga-Vázquez|Yamila|Y|;Colón|Gloria|G|;Barrios|Nilka|N|;Correa|María|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-018-0308-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "7(1)",
"journal": "CEN case reports",
"keywords": "Hematuria; Hemoglobinopathies; Kidney medulla; Renal medullary carcinoma; Sickle cell disease; Sickle cell trait; Sickling",
"medline_ta": "CEN Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "121-126",
"pmc": null,
"pmid": "29396817",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": "23348212;7528470;20002663;26053587;18068443;18649931;15602719;22686875;1607913;16549825;24099594;12475675;20979179;20656278",
"title": "Renal medullary carcinoma: a nearly fatal malignancy specifically affecting patients with a so-called benign condition.",
"title_normalized": "renal medullary carcinoma a nearly fatal malignancy specifically affecting patients with a so called benign condition"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/18/0098503",
"fulfillexpeditecriteria": "2",
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"activesubstancename": "GEMCITABINE"
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{
"abstract": "BACKGROUND\nIncreasing numbers of older people are receiving support with medicines management from community nursing services (CNSs) to enable them to live in their own homes. Little is known about these people and the support they receive.\n\n\nOBJECTIVE\nTo explore the characteristics of older people referred for medicines management support, type of support provided, medication errors and adverse medication events (AMEs).\n\n\nMETHODS\nA retrospective observational study of a random sample of 100 older people referred to a large non-profit CNS for medicines management support over a 3-month period was conducted. Measures were: demographics, referral source, current medical problems, medicines, medication aids, types of medication authorisations used by nurses, frequency of nurse visits and type of support provided, medication errors, AMEs and interdisciplinary teamwork among community nurses, general practitioners and pharmacists.\n\n\nRESULTS\nOlder people (median 80 years) were referred for medicines support most often by hospitals (39 %). Other referrals were from families/carers, case-managers, palliative care services and general practitioners. Multiple health conditions (median 5) and medicines (median 10) were common; 66 % used ≥5 medicines; 48 % used ≥1 high-risk medicines-most commonly opiates, anticoagulants and insulin. Medication aids were frequently used, mostly multi-compartment dose administration aids (47 %). Most people received regular community nurse visits (≥4 per week) to administer medicines or monitor medicine-taking. Only 16 % had a medication administration chart; for other clients nurses used medicine lists or letters from doctors for medication authorisation. Medication errors occurred in 41 % of people and 13 % had ≥1 AME requiring medical consultation or hospitalisation; 9/13 (64 %) AMEs were potentially preventable. There was little evidence of interdisciplinary teamwork or medication review.\n\n\nCONCLUSIONS\nCNS clients had multiple risk-factors for medication misadventure. Deficiencies in medicines management were identified, including low use of medication charts and interdisciplinary medication review. Strategies are needed to improve medicines management in the home-care setting.",
"affiliations": "Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia. rohan.elliott@austin.org.au.;Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.;RDNS Institute, Royal District Nursing Service, 31 Alma Road, St Kilda, VIC, 3182, Australia.;Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.;RDNS Institute, Royal District Nursing Service, 31 Alma Road, St Kilda, VIC, 3182, Australia.",
"authors": "Elliott|Rohan A|RA|;Lee|Cik Yin|CY|;Beanland|Christine|C|;Vakil|Krishna|K|;Goeman|Dianne|D|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40801-016-0065-6",
"fulltext": "\n==== Front\nDrugs Real World OutcomesDrugs Real World OutcomesDrugs - Real World Outcomes2199-11542198-9788Springer International Publishing Cham 270737536510.1007/s40801-016-0065-6Short CommunicationMedicines Management, Medication Errors and Adverse Medication Events in Older People Referred to a Community Nursing Service: A Retrospective Observational Study Elliott Rohan A. +61 3 9496 2334rohan.elliott@austin.org.au 12Lee Cik Yin 13Beanland Christine 3Vakil Krishna 1Goeman Dianne 341 Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052 Australia 2 Pharmacy Department, Austin Health, P.O. Box 5444, Heidelberg West, VIC 3081 Australia 3 RDNS Institute, Royal District Nursing Service, 31 Alma Road, St Kilda, VIC 3182 Australia 4 Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Commercial Rd, Prahran, VIC 3004 Australia 15 3 2016 15 3 2016 3 2016 3 1 13 24 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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.Background\nIncreasing numbers of older people are receiving support with medicines management from community nursing services (CNSs) to enable them to live in their own homes. Little is known about these people and the support they receive.\n\nObjectives\nTo explore the characteristics of older people referred for medicines management support, type of support provided, medication errors and adverse medication events (AMEs).\n\nMethods\nA retrospective observational study of a random sample of 100 older people referred to a large non-profit CNS for medicines management support over a 3-month period was conducted. Measures were: demographics, referral source, current medical problems, medicines, medication aids, types of medication authorisations used by nurses, frequency of nurse visits and type of support provided, medication errors, AMEs and interdisciplinary teamwork among community nurses, general practitioners and pharmacists.\n\nResults\nOlder people (median 80 years) were referred for medicines support most often by hospitals (39 %). Other referrals were from families/carers, case-managers, palliative care services and general practitioners. Multiple health conditions (median 5) and medicines (median 10) were common; 66 % used ≥5 medicines; 48 % used ≥1 high-risk medicines—most commonly opiates, anticoagulants and insulin. Medication aids were frequently used, mostly multi-compartment dose administration aids (47 %). Most people received regular community nurse visits (≥4 per week) to administer medicines or monitor medicine-taking. Only 16 % had a medication administration chart; for other clients nurses used medicine lists or letters from doctors for medication authorisation. Medication errors occurred in 41 % of people and 13 % had ≥1 AME requiring medical consultation or hospitalisation; 9/13 (64 %) AMEs were potentially preventable. There was little evidence of interdisciplinary teamwork or medication review.\n\nConclusion\nCNS clients had multiple risk-factors for medication misadventure. Deficiencies in medicines management were identified, including low use of medication charts and interdisciplinary medication review. Strategies are needed to improve medicines management in the home-care setting.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1007/s40801-016-0065-6) contains supplementary material, which is available to authorized users.\n\nissue-copyright-statement© The Author(s) 2016\n==== Body\nKey Points\nOlder people referred to a community nursing service (CNS) for support with medicines management received intensive assistance, often over a prolonged period; they had multiple risk-factors for adverse medication events but interdisciplinary collaboration and medication review was uncommon.\t\nMedication errors and adverse medication events requiring medical consultation occurred in 41 and 13 % of CNS clients respectively; a majority of adverse medication events were preventable.\t\nThere is a need to develop and test strategies to improve medication safety for CNS clients.\t\n\n\nIntroduction\nThe number of older Australians has increased by 65 % over the last 20 years [1]. Over the same period there has been a growing focus on supporting older people to remain living in their own homes for as long as possible [2], and an increase in the intensity of treatment for medical conditions that commonly affect older people (such as cardiovascular disease, diabetes, osteoporosis), leading to increased polypharmacy and medication regimen complexity [3]. Together these factors have led to increased demand for community nursing services (CNSs) to support older people with managing medicines at home [4]. A large Australian CNS recently reported that 56 % of its home nursing visits were primarily for the purpose of supporting medicines management [5]. Similar trends have been reported internationally [6].\n\nThere is evidence that older people receiving home nursing care are a group at high risk of medication-related problems and adverse medication events (AMEs) [7–10]. It has been suggested that the risk of medication-related problems among CNS clients may be greater than in other healthcare settings such as hospitals and residential aged-care facilities because of the unstructured environment and communication challenges in the home care setting [11]. For example, home care nurses have a less direct relationship and less contact with clients’ medical practitioners and pharmacies. There may be multiple prescribers and multiple pharmacies involved in the client’s care. Prescribers and pharmacists may not see the client regularly and may rely on the nurse to report medication-related problems. Home-care clients and their informal carers often participate in their own medicines management (by self-administering some medicines, attending medical appointments, purchasing over-the-counter medicines, etc.) which means there is potential for non-adherence and medication self-administration errors [11, 12].\n\nDespite large numbers of people receiving CNS support, there has been little research focusing on this group [12, 13]. In Australia, Johnson et al. used a convenience sample of 111 CNS clients to develop medication risk assessment criteria and test a nurse-led intervention to improve medicine use [7, 14], and While et al. [15–17] conducted a series of qualitative studies exploring issues related to medicines management in CNS clients and their carers. Whilst these studies, and similar studies from other countries [9, 10, 12], highlighted complexities and problems related to medicines management, they did not recruit representative samples of CNS clients or report the frequency or type of medicines management support provided or the prevalence of medication errors and AMEs. Knowing more about people who receive medicines management support from CNSs, the types of support they receive and medication-related problems and AMEs encountered, may help with identifying areas for improvement and planning future care needs for home-care clients.\n\nThe aim of this study was to describe the characteristics of community-dwelling older people referred to an Australian CNS for support with medicines management, their medicines management and medication errors and adverse medication events.\n\nMethods\nSetting\nThe study was conducted at two metropolitan sites of a large, not-for profit CNS in Melbourne, Australia. The sites employed 120 registered nurses (degree-qualified nurses), nine enrolled nurses (diploma- or certificate-qualified nurses) and eight community care aides (non-nurse professional care workers).\n\nSubjects\nOne hundred CNS clients were randomly selected (using a random number generator) from all people aged 50 years and over who were referred for medicines support between 16 July and 12 October 2012.\n\nData Collection\nData were collected (May–December 2013) by retrospective review of clients’ CNS records and telephone contact with clients’ general practitioners (GPs) and pharmacies, using a pre-piloted data collection form. Data collected, and definitions, are provided in Table 1.Table 1 Data collected and definitions\n\nData (definition)\t\n Source of referral to the CNS\t\n Reason for referral to the CNS\t\n Current medical problems (active medical problems at the time of admission to the CNS)\t\n Presence of cognitive impairment (documented dementia or mild cognitive impairment, Mini-Mental State Examination score <24 or Rowland Universal Dementia Assessment Scale score <23)\t\n Medicines used at the time of CNS admission (medicines listed on the clients’ first ‘medication authorisation’)\t\n Use of medicines associated with heightened risk of an adverse medication event if taken or administered incorrectly (high risk: anticoagulants, chemotherapeutic agents excluding hormonal agents, immunosuppressant agents, insulins, lithium, opioids; moderate risk: antibiotics, anticonvulsants, antipsychotics, benzodiazepines, loop diuretics, oral corticosteroids, oral hypogylcaemics) [42]\t\n Medication management aids used (e.g. dose administration/adherence aids)\t\n CNS visits in the first and last weeks of the CNS admissiona\n\t\n Types of medication authorisations (medication administration charts or other medicine lists or instructions signed by a medical practitioner authorising the CNS to administer medicines or support clients’ medicine self-administration) used during first and last weeks of admissiona\n\t\n Medication errors (deviations from the prescriber’s instructions, whether or not they led to harm)\t\n Adverse medication events (adverse drug reactions [ADRs] requiring medical consultation and unplanned medication-related hospital admissions)\t\n Evidence of interdisciplinary teamwork (documented communication between CNS staff and prescribers or pharmacists, Home Medicines Reviews,b Team Care Arrangements,c Case Conferencesd)\t\n Duration of CNS care (number of days from CNS admission to CNS discharge)e\n\t\n Discharge location\t\n\nCNS community nursing service\n\n\naFor clients who had not been discharged from the CNS at the time of the audit, the last week of admission for the purpose of data collection was taken to be the last week of available data (at least six months after admission to the CNS)\n\n\nbHome Medicines Review (HMR) is an Australian Government funded program that is available to patients in the community setting who are at risk of adverse medication events. A general practitioner can initiate an HMR by making a referral to an accredited consultant pharmacist\n\n\ncTeam Care Arrangement is an Australian Government funded (Medicare) service in which a general practitioner works with other health professionals involved in a patient’s management to prepare and implement a multidisciplinary care plan\n\n\ndCase conference is an Australian Government funded (Medicare) service in which a general practitioner organises, coordinates or participates in a meeting or discussion held to ensure that their patient’s multidisciplinary care needs are met through a planned and coordinated approach\n\n\neCNS episodes of care that were temporarily interrupted by a period of residential respite or an acute hospitalisation were counted as one episode of care\n\n\n\nReferral details, medical problems, cognitive function and use of medication aids were obtained from referral documents, CNS admission notes and care plans. Medicines used by clients were obtained from medication authorisations.\n\nCNS home visits, medication errors, AMEs and discharge location were identified by reviewing CNS progress notes and discharge records. Evidence of interdisciplinary teamwork was identified from CNS records and telephone calls to clients’ GPs and/or community pharmacies.\n\nData Analysis\nAge-adjusted Charlson Co-morbidity Index scores were calculated (a score of ≥ 5 indicates at high risk of mortality) [18]. The use of medicines associated with heightened risk of adverse events was determined by a pharmacist researcher, who compared clients’ medicine lists against a pre-defined list of ‘risk’ medicines (Table 1).\n\nPotential AMEs were reviewed by an expert panel to determine causality, preventability and contribution to hospital admission, using modified Hallas criteria [19, 20]. The panel comprised three clinical pharmacists and two registered nurses, each with over 15 years of experience encompassing hospital and community aged care. Panel members assessed each case independently. When there was disagreement, the case was discussed until consensus was reached. Severity was assessed using Pearson criteria [21], and the primary underlying cause of the AME was classified using Hepler and Strand’s classification [22]. The AME assessment criteria are provided in Supplementary File 1.\n\nData were analysed using SPSS (version 21, IBM Corporation, USA). Analyses were carried out using descriptive tests, with results reported as frequency and proportion for categorical variables and median and interquartile range (IQR) for discrete and non-normally distributed continuous variables.\n\nResults\nOne hundred and ninety-seven people aged 50 years or over were referred for medicines support. The characteristics of the 100 clients selected for the study, and their reasons for referral, are summarised in Table 2. CNS clients were visited a median of four to five days a week. In the first week of care the most common reason for medicines support visits was to administer medicines; in the last week it was to monitor medicine-taking (Table 3).Table 2 Client characteristics and medicines management (n = 100 clients)\n\nVariable\tData\n\nn (%) or median (IQR); range\t\nAge, years\t80 (73–87); 55–97\t\nGender female, n (%)\t60 (60 %)\t\nNo. of current medical conditions\t5 (3–7); 1–22\t\nType of medical conditionsa\n\t\n Cancer, leukemia, lymphoma (excluding skin cancer)\t32 (32 %)\t\n Diabetes\t32 (32 %)\t\n Respiratory disease\t17 (17 %)\t\n Dementia or Alzheimer’s disease\t16 (16 %)\t\n Myocardial infarction\t15 (15 %)\t\n Cerebrovascular accident\t14 (14 %)\t\n Renal disease\t11 (11 %)\t\n Congestive heart failure\t8 (8 %)\t\n Others\t8 (8 %)\t\nAge-adjusted Charlson Comorbidity Index score\t6 (5–8); 1–13\t\n Charlson score ≥5 (higher risk of mortality)\t77 (77 %)\t\nCognitive impairmentb\n\t30 (30 %)\t\nNumber of medicinesc\n\t10 (6–13); 2–26\t\nReason for referral to CNS\t\t\n Medicines management ONLYd\n\t81 (81 %)\t\n Medicines management plus OTHER caree\n\t19 (19 %)\t\nSource of referral to CNS\t\n Hospital\t39 (39 %)\t\n Family or informal carer\t12 (12 %)\t\n Palliative care service\t12 (12 %)\t\n Case manager\t11 (11 %)\t\n General practitioner\t10 (10 %)\t\n Aged Care Assessment Team\t6 (6 %)\t\n Medical specialist\t3 (3 %)\t\n Community health service\t2 (2 %)\t\n Self\t1 (1 %)\t\n Unknown\t4\t\nDuration of care (length of stay) with CNS\t\n 1–7 days\t25 (25 %)\t\n 8–30 days\t29 (29 %)\t\n 31–60 days\t21 (21 %)\t\n >60 days\t25 (25 %)\t\nDischarge location\t\n Home\t56 (56 %)\t\n With self-care or informal care\t41\t\n Client terminated care\t4\t\n With other formal care\t2\t\n Ongoing care not documented\t9\t\n Acute hospital\t20 (20 %)\t\n Subacute or palliative care hospital\t5 (5 %)\t\n Residential care\t9 (9 %)\t\n Died at home\t8 (8 %)\t\n Unknown\t2 (2 %)\t\nMulti-compartment dose administration aid (DAA)\t47 (47 %)f\n\t\n DAA packed by\t\t\n Community pharmacy\t42\t\n Client/carer/family member\t2\t\n Not documented\t3\t\nSingle-compartment DAA used by CNS for setting out evening doses when nurse visited in the morning\t12 (12 %)\t\nLocked box used by CNS to store medicines\t17 (17 %)g\n\t\n\nCNS community nursing service, DAA Dose Administration Aid\n\n\naConditions included in the Charlson Comorbidity Index\n\n\nbLikely to be an underestimate, because only 36 % clients had a MMSE or RUDAS score documented\n\n\ncNumber of medicines at the time of admission to RDNS (includes regular and when required medicines; when combination products were used the individual active ingredients were counted as separate medicines). Data not available for 15 clients\n\n\ndMonitoring medicine-taking, administering medicines, medicines prompting and assisting with self-administration\n\n\neWound care (n = 14), personal care such as hygiene or mobility assistance (n = 7), clinical monitoring such as blood pressure, weight, bowel function, pain, fluids (n = 7)\n\n\nf20/47 (42.6 %) clients using a multi-compartment DAA received CNS visits 7 days a week\n\n\ng11/47 (23.4 %) clients using a multi-compartment DAA had a locked box used to store the medicines\n\nTable 3 Community nursing service (CNS) visits\n\n\tFirst week of care (100 clients)\n\nn (%) clients\tLast week of care (71 clients)a\n\n\nn (%) clients\t\nNo. of days per week that CNS visited clients\t\n 1 to 2\t19 (19.0 %)\t28 (39.4 %)\t\n 3 to 4\t23 (23.0 %)\t8 (11.2 %)\t\n 5 to 6\t19 (19.0 %)\t14 (19.8 %)\t\n 7\t39 (39.0 %)\t21 (29.6 %)\t\n Median\t5 (IQR 3–7, range 1–7)\t4 (IQR 2–7, range 1–7)\t\nNo. of times CNS visited per day\t\n 1\t87 (87.0 %)\t64 (90.1 %)\t\n 2\t9 (9.0 %)\t5 (7.0 %)\t\n 3\t4 (4.0 %)\t2 (2.8 %)\t\nPrimary reason for CNS medicines support visits (as per care plan)\t\t\t\n Administering medicines\t44 (44 %)\t27 (38.0 %)\t\n Monitoring medicine-taking\t32 (32 %)b\n\t28 (39.4 %)\t\n Assisting with medicine-taking\t16 (16 %)\t7 (9.9 %)\t\n Prompting medicine-taking\t8 (8.0 %)\t6 (8.5 %)\t\n Other\t–\t3 (4.2 %)c\n\t\nType of medicine support provided by CNS (as per progress notes)d\n\t\n Assessment of medicines management\t14 (14 %)\t1 (1.4 %)\t\n Administering medicines\t52 (52 %)\t32 (45.1 %)\t\n Monitoring medicine-taking\t55 (55 %)\t39 (54.9 %)\t\n Assisting with medicine-taking\t32 (32 %)\t19 (26.8 %)\t\n Prompting medicine-taking\t16 (16 %)\t12 (16.9 %)\t\n Education about medicines management\t20 (20 %)\t3 (4.2 %)\t\n Liaising with community pharmacy or doctors about clients’ medicines\t8 (8 %)\t1 (1.4 %)\t\nMedicines support provided for\t\n All prescribed medicines\t50 (50 %)\t40 (56.3 %)\t\n Selected medicinese\n\t48 (48 %)\t26 (36.6 %)\t\n Not documented\t2 (2.0 %)\t5 (5.0 %)\t\n\naLast week data only includes clients whose length of stay with CNS was ≥14 days\n\n\nbSometimes combined with education (e.g. education and monitoring for clients newly commenced on insulin)\n\n\ncNo longer needing medicines management support in final week of care, but still receiving other care (monitoring blood sugar level n = 1; wound care n = 2)\n\n\ndMost clients had more than one type of medicines support documented\n\n\neSome clients self-administered most of their medicines but required support with particular medicines such as injectable medicines, warfarin, eye drops\n\n\n\nA minority of clients (n = 16) had a medication \nadministration chart during the first week of their CNS admission; 14 of these were handwritten by a hospital doctor and two were printed or handwritten by a GP. The remaining 84 clients’ treatment authorisations were printed or handwritten medicine lists provided by the client’s GP (n = 48), hospital doctor (n = 27), specialist (n = 1) or unknown source (n = 8). Use of medication administration charts remained low, with only 15 clients having one at the time of discharge. Twenty-two clients had more than one medication authorisation used concurrently (e.g. a GP medicine list plus a letter from a GP or specialist indicating a medicine change) during either the first or last week of their CNS admission.\n\nMedication authorisations for 85 clients included all of their medicines. The other 15 clients’ authorisations included a partial list only (usually parenteral medicines, because the CNS was involved in administering those medicines only). The 85 clients with a complete medicine list used a median of ten medicines (IQR 6–13, range 2–26), and 66 % used five or more. The median number of regular, long-term medicines (excluding ‘when required’ and short-term medicines) was eight (IQR 4–11, range 1–21). Forty-eight clients used one or more high risk medicines, most commonly opiates (28 % clients), anticoagulants (17 % clients) and insulins (14 % clients).\n\nOne hundred and thirty-seven medication errors were identified, affecting 41 (41 %) clients (Table 4). Twenty-three (23 %) clients had an unplanned hospital admission—after expert panel review 9/23 (39.1 %) of these were deemed to have been possibly medication-related (Table 5). Five clients had an ADR that required medical consultation without hospital admission. One client had both a medication-related hospital admission and an ADR without admission, so overall there were 13 (13 %) clients with one or more AME requiring medical consultation or hospitalisation (Table 5). Nine (64 %) AMEs were considered to have been potentially preventable. Eight clients died at home; all were receiving end-of-life care for a terminal illness prior to their death.Table 4 Medication errors (n = 100 clients)\n\nVariable\tData\n\nn (%) or median (IQR); range\t\nClients with one or more medication error\t41 (41 %)\t\nNumber of errors identified\t137\t\nNo. of medication errors per client\t\n 1\t14\t\n 2\t10\t\n 3 or more\t17\t\nType of medication errors\t\n Missed dose\t67 (48.9 %)\t\n Discrepancy between medication authorisation and client’s medicines\t26 (19.0 %)a\n\t\n Wrong dose taken/given\t13 (9.5 %)\t\n Medicine taken from wrong compartment of DAA\t12 (8.8 %)\t\n Extra dose taken/given\t15 (10.9 %)\t\n Wrong administration method\t2 (1.5 %)\t\n Wrong route of administration\t1 (0.7 %)\t\n Wrong dose time\t1 (0.7 %)\t\nErrors involving high-risk medicines\t\n Opiates\t10\t\n Insulins\t5\t\n Anticoagulants\t3\t\n Immunosuppressants\t3\t\n Lithium\t1\t\n Total\t22/137 (16.1 %)\t\nErrors involving moderate-risk medicines\t\n Oral hypogylcaemics\t6\t\n Benzodiazepines\t6\t\n Loop diuretics\t4\t\n Anticonvulsants\t4\t\n Antipsychotics\t3\t\n Oral corticosteroids\t2\t\n Antibiotics\t1\t\n Total\t23 (16.8 %)\t\nCauses of error(s)\t\n Client/carerb\n\t101 (73.7 %)\t\n Healthcare provider/systemc\n\t36 (26.3 %)\t\n\nDAA dose administration aid\n\n\naIn 22 cases the discrepancy involved a pharmacy-packed DAA\n\n\nbClient/carer errors (e.g. forgot to take medicine, accidentally took wrong dose, dropped tablet on the floor) or deliberate non-adherence (e.g. chose not to take a medicine or varied the dose). It was not possible to accurately quantify what proportion were unintended errors versus deliberate non-adherence using retrospective methodology; however, a large majority appeared to be errors\n\n\ncErrors caused by general practitioners and other prescribers, pharmacists and nurses. This includes prescribing errors, dispensing errors, administration errors and communication failures. The number of errors attributed to each of these categories could not be accurately quantified retrospectively, because often the specific cause could not be determined. For example, when there was a discrepancy between the medication authorisation and the client’s medicines (n = 26), it was not possible to determine whether this was due to an error on the authorisation, a dispensing/DAA packing error, or lack of communication between members of the healthcare team following a medicine change. Other provider/system errors were: medicines not available (not re-ordered or not delivered by pharmacy) (n = 3), multiple DAAs delivered resulting in client confusion and error (n = 3), patch not removed when new one applied (n = 1), problem with syringe driver (n = 1), delayed nurse visit (n = 1)\n\nTable 5 Adverse medication events (AMEs)\n\nPatient\tAME\tMedicine(s)\tUnderlying cause of AME\tCausality\tPreventability\tSeverity\tContribution to hospital admission\t\nEvents requiring medical consultation but no hospital admission\t\n 72 years female with dementia\tNausea and vomiting\tDonpezil 5 mg daily (recently commenced)\tIdiosyncratic response\tProbable\tNot preventable\tMild\t–\t\n 88 years male with dementia\tFatigue\tRivastigmine 9 mg patch daily (recently commenced)\tIdiosyncratic response\tPossible\tNot preventable\tMild\t–\t\n 86 years female with deep vein thrombosis\tBruising\tWarfarin 3 mg daily (recently commenced; 5 mg taken by client inadvertently on one occasion). Also on aspirin 100 mg daily\tPatient-related/Prescribing issue\tProbable\tPossibly preventable\tMild\t–\t\n 92 years female with atrial fibrillation, congestive cardiac failure and renal impairment\tBradycardia\tDigoxin 187.5 µg daily\tPrescribing issue\tProbable\tDefinitely preventable\tModerate\t–\t\n 80 years male with type 2 diabetes, discharged from hospital on a short course of prednisolone\tHypoglycaemia\tLantus (insulin) 22 units daily (recently commenced in hospital), gliclazide MR 120 mg daily, weaning prednisolone dose\tPrescribing issue\tDefinite\tDefinitely preventable\tModerate\t–\t\nEvents that contributed to an unplanned hospital admission\t\n 68 years female with breast cancer\tErythema multiforme\tDocetaxel (administered in hospital, but reaction occurred at home)\tIdiosyncratic response\tDefinite\tNot preventable\tModerate\tDominant\t\n 77 years female with recent major abdominal surgery\tUrethral bleed\tEnoxaparin 40 mg subcut daily\tIdiosyncratic response\tProbable\tNot preventable\tModerate\tPartly contributing\t\n 89 years female with multiple co-morbidities\tFall, fractured neck of femur\tPolypharmacy (15 regular medicines), including fall-risk increasing medicines (diazepam 5 mg at night, cyproheptadine 4 mg daily, amlodipine 10 mg daily, irbesartan 300 mg/hydrochlorothiazide 12.5 mg daily, atenolol 50 mg daily, carbamazepine 200 mg at night)\tPrescribing issue\tPossible\tPossibly preventable\tSevere\tDominant\t\n 74 years female with anxiety disorder discharged from hospital psychiatric unit\tExacerbation of anxiety disorder\tAbrupt cessation of quetiapine 75 mg/day (ceased by general practitioner).\tPrescribing issue\tProbable\tPossibly preventable\tModerate\tDominant\t\n 89 years female with multiple co-morbidities\tFall, fractured neck of femur\tPolypharmacy (5 regular medicines), including fall-risk increasing medicines (citalopram 20 mg daily, dipyridamole SR 200 mg daily, amlodipine 5 mg daily, trandolapril 1 mg daily)\tPrescribing issue\tPossible\tPossibly preventable\tSevere\tDominant\t\n 92 years female with atrial fibrillation and congestive cardiac failure\tSevere peripheral oedema and skin tear\tFrusemide 20 mg/day (no dose increase despite increasing oedema). Digoxin recently ceased. Also on bisoprolol 2.5 mg daily, telmisartan 80 mg daily\tPrescribing issue\tPossible\tPossibly preventable\tModerate\tPartly contributing\t\n 68 years female with metastatic breast cancer\tPain crisis\tSuspected non-adherence to oral analgesia\tPatient-related issue\tProbable\tDefinitely preventable\tModerate\tDominant\t\n 87 years female with metastatic adenocarcinoma\tPain/end of life care\tMorphine 5–10 mg, midazolam 0.5–2.0 mg and metoclopramide 10–40 mg subcut infusion (faulty syringe driver resulting in inadequate therapy)\tDelivery issue\tProbable\tPossibly preventable\tModerate\tDominant\t\n 91 years female with hypertension\tDehydration and hyponatraemia\tIrbesartan with hydrochlorothiazide 300 mg/12.5 mg daily\tIdiosyncratic response\tPossible\tNot preventable\tModerate\tDominant\t\nThe criteria used to determine adverse medication event causality, preventability, severity and contribution to hospital admission are provided in Supplementary File 1\n\n\n\nThere was little evidence of interdisciplinary teamwork. CNS nurses recorded contact with the clients’ GP or pharmacy for only eight clients in the first week of care and one in the final week. No client had a multidisciplinary case conference documented at any time during their CNS admission, and only one client had a Team Care Arrangement. One client had a Home Medicines Review (HMR) recorded in their CNS record; a further four had received an HMR according to their GP or community pharmacist.\n\nDiscussion\nCommunity nursing services play a vital role in helping frail older people to remain living in their own homes. This is the first study to quantify and describe medicines management support and medication-related problems in a representative sample of older people referred to a CNS. It found that CNS clients had a very high prevalence of risk-factors for medication-related problems, including multiple co-morbidities, cognitive impairment, polypharmacy and use of medicines associated with heightened risk. CNS clients used a median of ten medicines, which is higher than the average for community-dwelling older people [23].\n\nIn the first week of care most clients were visited on at least 5 days, mainly to administer medicines. In the last week of care, the number of visits was slightly lower and the most common form of support was monitoring medicine-taking. This may reflect the fact that some clients regained independence or semi-independence, or that some of the sickest and frailest individuals, with intensive care needs, were discharged to residential care or died.\n\nThe most common form of medication authorisation used by the CNS was medicine lists provided by GPs (usually summaries printed from GPs’ electronic patient records). Medication administration charts were infrequently used, and in some cases multiple medication authorisations were used concurrently. Reliance on GP medicine lists, letters from GPs and specialists and multiple medication authorisations stems from difficulty accessing GPs to obtain and maintain medication charts in the community setting. However, use of these types of authorisation and multiple authorisations is associated with risk of medication errors. It has been reported in several studies that GP medicine lists have a high rate of errors and discrepancies, for a variety of reasons including that the GP is often not the only prescriber and because patient records are not always updated when there are dose-changes and medicines ceased [9, 24, 25]. There were 26 medication errors related to discrepancies between medication authorisations and clients’ medicines (usually pharmacy-packed dose administration aids [DAAs]), which may reflect inaccurate medication authorisations and/or deficiencies in interdisciplinary communication (e.g. GP or other prescriber failing to notify the pharmacy of a medicine change for a DAA client, or GP being unaware of a medicine change initiated by another prescriber).\n\nMulti-compartment DAAs were used by nearly 50 % of CNS clients. Whilst these may simplify medicines management for some older people, they can also increase the cost and complexity of medicines management and there is evidence that they are sometimes used unnecessarily [12, 26]. In this study almost half of the clients who used a DAA were receiving CNS visits 7 days a week, and almost one quarter had their DAA stored in a locked box. It is likely that some of these clients could have been managed without a DAA since they were not self-administering their medicines.\n\nMedication errors were prevalent, with 41 % clients having one or more error identified. Almost three quarters resulted from clients (or carers) missing doses or taking medicines incorrectly. It is not surprising that client/carer errors were common given that CNS clients were older people with functional and/or cognitive decline who were referred for medicines management support, and many continued to have some involvement in taking their medicines (since the CNS could usually visit only once a day and medicines often needed to be taken at other times). However, it is also possible that healthcare providers and their systems contributed to some of the errors attributed to clients. For example, failure to simplify unnecessarily complex medication regimens or to choose the simplest dose-forms sometimes contributed to client errors. It is common practice for CNS nurses to set out the evening doses for clients when they visit in the morning, in order to avoid multiple daily visits, and this practice was sometimes associated with missed doses when the client forgot to take those medicines.\n\nMedication errors caused by CNS staff were uncommon, however this is likely to be an underestimate because these were difficult to detect using retrospective methodology (which was largely reliant on CNS staff identifying and documenting such errors) and with low usage of medication administration charts. In hospitals and residential care settings, using medication chart audits and direct observation of staff administering medicines, much higher error rates have been reported [27, 28].\n\nMissing the occasional dose of a medicine is unlikely to be clinically significant for most medicines, so whilst missed doses were the most common error, many were of minimal clinical importance. However, some errors had potential to cause harm, such as clients double-dosing, often due to confusion associated with the use of DAAs, clients taking an incorrect dose (including cases involving insulin, warfarin and prednisolone), clients potentially receiving incorrect medicines or doses as a result of inaccurate medicine lists, inter-professional communication failures, prescribing errors or dispensing errors and running out of medicines. One-third of errors involved medicines associated with moderate or high risk of AMEs if administered incorrectly.\n\nAMEs requiring medical attention were identified in 13 % of CNS clients, including medication-related hospital admissions in 9 % of clients. This may be an underestimate, as identification of AMEs relied on CNS documentation. It is possible that some AMEs were not recognised or documented by CNS nurses. A majority of AMEs were considered to be potentially preventable, which is consistent with studies in other populations [29, 30].\n\nThe most common cause of AMEs was prescribing problems (Table 5). This, plus the high number of medication errors, and in particular errors related to discrepancies between medication authorisations and pharmacy-packed DAAs, suggests that CNS clients could benefit from better interdisciplinary collaboration. Interdisciplinary collaboration is needed to enable a ‘best possible medication history’ and medication reconciliation [31] to occur on admission to the CNS (in order to ensure that the correct medicine regimen is implemented and all members of the healthcare team have access to the same medicine list) [6, 12], to increase the use of medication administration charts (which enable clear documentation of medication administration and improve medication safety), and to facilitate interdisciplinary medication reviews. Despite CNS clients’ high risk of AMEs, and eligibility for government-funded interdisciplinary care services, there was little evidence of formal interdisciplinary collaboration in relation to medicines management.\n\nInterdisciplinary medication reviews such as HMR have been shown to identify and address medicine discrepancies, medication-related problems and inappropriate prescribing, simplify medication regimens and reduce the risk of AMEs [6, 11, 32–35]. The CNS involved in this study, like most CNSs, does not employ its own pharmacists or medical practitioners, so the only way for an interdisciplinary medication review to occur is if the clients’ GP initiates an HMR (nurses are not able to initiate government-funded HMRs). The low use of HMR in this cohort is consistent with previous Australian studies in high-risk groups such as people referred to Aged Care Assessment Teams or residing in supported accommodation [34, 36]. Efforts to increase the uptake of HMRs, even in high-risk groups such as CNS clients, have had limited success [34, 37], suggesting that alternative methods to facilitate interdisciplinary medicines management are needed. One option is for the CNS to employ clinical pharmacists to work with its nurses to undertake medication reconciliation and medicines reviews, and liaise with clients’ GPs and community pharmacists. A pilot study exploring the role of clinical pharmacists in a CNS is currently underway [38].\n\nA limitation of our study was that it included only one metropolitan CNS. Further studies are warranted to determine the extent to which these findings are generalisable to other CNSs, in particular in rural and regional areas. Retrospective methodology may have led to underestimation of medicine use, medication errors, AMEs and interdisciplinary teamwork. A strength of the study was random selection of subjects to obtain a sample representative of the older people referred for medicines support. Another strength was review of clients’ complete CNS records, including nursing progress notes, to extract data, which is likely to have improved detection of errors and ADRs compared with reliance on spontaneous voluntary reporting by nurses.\n\nAlthough there has been little previous Australian research in the home nursing setting, research conducted internationally suggests that many of these issues are not unique to Australia. Studies from other countries (mainly the USA) have reported that home nursing clients often have multiple medicines-related risk factors (including polypharmacy, multiple healthcare providers, poor communication between providers and outdated medicine lists) leading to medication errors and AMEs [8–10, 39–41]. No Australian or international study has previously recruited a similar random sample and reported the type of medicines management support provided, so it is not possible to compare this data with other studies.\n\nConclusion\nOlder people referred to a CNS for medicines management support were a frail group of people with multiple risk-factors for AMEs. They received intensive medicines management support, often over a prolonged period. There was minimal formal interdisciplinary collaboration and infrequent medication review. Medication errors and AMEs were common. There is a need to develop and test strategies to improve medication safety for CNS clients.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary material 1 (DOC 56 kb)\n\n \n\nThe authors thank Ms Kira Harvey, Ms Ann Johnson, A/Prof Susan Koch, Ms Denise van den Bosch, Ms Barbara Petrie and Mr Neil Petrie for their assistance with this study.\n\nAuthor contributions\nRAE, CB and CYL conceived and designed the study. All authors contributed to data collection. CYL and RAE performed the data analyses, with input from all authors. RAE and CYL prepared the manuscript. All authors reviewed drafts and approved the final manuscript.\n\nCompliance with Ethical Standards\nEthical approval\nThe study was approved by the Royal District Nursing Service and Monash University Human Research Ethics Committees.\n\nConflict of interest\nRohan Elliott, Cik Yin Lee, Christine Beanland, Krishna Vakil and Dianne Goeman declare that they have no conflicts of interest.\n\nFunding\nNo financial assistance was received for the conduct of the study or preparation of the manuscript.\n==== Refs\nReferences\n1. Australian Bureau of Statistics. 3101.0—Australian Demographic Statistics, Jun 2013.\n2. Australian Institute of Health and Welfare. Residential aged care in Australia 2010–11: a statistical overview. Aged care statistics series no. 36. Cat. no. AGE 68. Canberra: AIHW; 2012.\n3. Wise J Polypharmacy: a necessary evil BMJ 2013 347 f7033 10.1136/bmj.f7033 24286985 \n4. 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Charlson M Szatrowski TP Peterson J Gold J Validation of a combined comorbidity index J Clin Epidemiol 1994 47 11 1245 1251 10.1016/0895-4356(94)90129-5 7722560 \n19. Hallas J Harvald B Gram LF Drug related hospital admissions: the role of definitions and intensity of data collection, and the possibility of prevention J Intern Med 1990 228 2 83 90 10.1111/j.1365-2796.1990.tb00199.x 2394974 \n20. Howard RL Avery AJ Howard PD Partridge M Investigation into the reasons for preventable drug related admissions to a medical admissions unit: observational study Qual Saf Health Care 2003 12 4 280 285 10.1136/qhc.12.4.280 12897361 \n21. Pearson TF Pittman DG Longley JM Grapes ZT Vigliotti DJ Mullis SR Factors associated with preventable adverse drug reactions Am J Hosp Pharm 1994 51 18 2268 2272 7801987 \n22. Hepler CD Strand LM Opportunities and responsibilities in pharmaceutical care Am J Hosp Pharm 1990 47 3 533 543 2316538 \n23. Morgan TK Williamson M Pirotta M Stewart K Myers SP Barnes J A national census of medicines use: a 24-hour snapshot of Australians aged 50 years and older Med J Aust 2012 196 1 50 53 10.5694/mja11.10698 22256935 \n24. Tse J You W How accurate is the electronic health record? A pilot study evaluating information accuracy in a primary care setting Stud Health Technol Inform 2011 168 158 164 21893924 \n25. Taylor S Welch S Harding A Accuracy of general practitioner medication histories for patients presenting to the emergency department Aust Fam Physician 2014 43 10 728 25286433 \n26. Elliott RA Appropriate use of dose administration aids Aust Prescriber. 2014 37 46 50 10.18773/austprescr.2014.020 \n27. Barber ND Alldred DP Raynor DK Care homes’ use of medicines study: prevalence, causes and potential harm of medication errors in care homes for older people Qual Saf Health Care 2009 18 5 341 346 10.1136/qshc.2009.034231 19812095 \n28. Keers RN Williams SD Cooke J Ashcroft DM Causes of medication administration errors in hospitals: a systematic review of quantitative and qualitative evidence Drug Saf 2013 36 11 1045 1067 10.1007/s40264-013-0090-2 23975331 \n29. Chan M Nicklason F Vial JH Adverse drug events as a cause of hospital admission in the elderly Intern Med J 2001 31 4 199 205 10.1046/j.1445-5994.2001.00044.x 11456032 \n30. Phillips AL Nigro O Macolino KA Hospital admissions caused by adverse drug events: an Australian prospective study Aust Health Rev 2014 38 1 51 57 10.1071/AH12027 24351707 \n31. Duguid M The importance of medication reconciliation for patients and practitioners Aust Prescriber. 2012 35 515 519 10.18773/austprescr.2012.007 \n32. Hatah E Braund R Tordoff J Duffull SB A systematic review and meta-analysis of pharmacist-led fee-for-services medication review Br J Clin Pharmacol 2014 77 1 102 115 10.1111/bcp.12140 23594037 \n33. Jokanovic N, Tan ECK, van den Bosch D, Kirkpatrick CM, Dooley MJ, Bell JS. Clinical medication review in Australia: a systematic review. Res Soc Adm Pharm. doi:10.1016/j.sapharm.2015.06.007\n34. Elliott RA Martinac G Campbell S Thorn J Woodward MC Pharmacist-led medication review to identify medication-related problems in older people referred to an Aged Care Assessment Team: a randomized comparative study Drugs Aging 2012 29 7 593 605 10.1007/BF03262276 22715865 \n35. Morrison C MacRae Y Promoting safer use of high-risk pharmacotherapy: impact of pharmacist-led targeted medication reviews Drugs-Real World Outcomes 2015 2 261 271 10.1007/s40801-015-0031-8 \n36. Lee CY George J Elliott RA Chapman C Stewart K Exploring medication risk among older residents in supported residential services: a cross-sectional study J Pharm Pract Res. 2011 41 98 101 10.1002/j.2055-2335.2011.tb00673.x \n37. Kyle G Nissen LM A community nurse referral system for HMRs: can it work? Aust Pharm 2006 25 326 331 \n38. Lee CY, Beanland C, Goeman D, Koch S, Elliott RA. Enhancing medication safety for older people receiving medication support from a community nursing service [abstract]. Paper presented at: Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists-British Pharmacological Society Joint Scientific Meeting 2015, Hong Kong.\n39. Meredith S Feldman PH Frey D Possible medication errors in home healthcare patients J Am Geriatr Soc 2001 49 6 719 724 10.1046/j.1532-5415.2001.49147.x 11454109 \n40. Gray SL Mahoney JE Blough DK Adverse drug events in elderly patients receiving home health services following hospital discharge Ann Pharmacother 1999 33 11 1147 1153 10.1345/aph.19036 10573310 \n41. Gray SL Mahoney JE Blough DK Medication adherence in elderly patients receiving home health services following hospital discharge Ann Pharmacother 2001 35 5 539 545 10.1345/aph.10295 11346058 \n42. Institute for Safe Medication Practices ISMP list of high-alert medications in Community/Ambulatory Healthcare 2011 Philadelphia Institute for Safe Medication Practices\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2198-9788",
"issue": "3(1)",
"journal": "Drugs - real world outcomes",
"keywords": null,
"medline_ta": "Drugs Real World Outcomes",
"mesh_terms": null,
"nlm_unique_id": "101658456",
"other_id": null,
"pages": "13-24",
"pmc": null,
"pmid": "27747809",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article",
"references": "10573310;11034227;11346058;11454109;11456032;12897361;15197376;15265227;15660555;15670323;17353705;19509525;19812095;21273229;21893924;22256935;22715865;2316538;23594037;2394974;23975331;24286985;24337637;24351707;25286433;27747572;7722560;7801987",
"title": "Medicines Management, Medication Errors and Adverse Medication Events in Older People Referred to a Community Nursing Service: A Retrospective Observational Study.",
"title_normalized": "medicines management medication errors and adverse medication events in older people referred to a community nursing service a retrospective observational study"
} | [
{
"companynumb": "AU-PFIZER INC-2017093259",
"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "METOCLOPRAMIDE HYDROCHLORIDE"
},
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{
"abstract": "Reversible cerebral vasoconstriction syndrome is a rare clinical syndrome characterized by sudden thunderclap headache often an under diagnosed neurological emergency. It is often provoked by postpartum state or exposure to provocative drugs. We report a rare case of Rizatriptan-induced reversible cerebral vasoconstriction syndrome presenting with thunderclap headache and paraparesis with complete recovery of neurological and imaging findings.",
"affiliations": "Yashoda Hospital, Malakpet, Hyderabad, Telangana, India.",
"authors": "Ramineni|Kiran K|KK|;Jakkani|Ravi K|RK|;Girgani|Suresh|S|;Balani|Ankit|A|;Satyanarayan|Sandeep|S|",
"chemical_list": "D014363:Tryptamines",
"country": "United States",
"delete": false,
"doi": "10.1097/NRL.0000000000000193",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1074-7931",
"issue": "23(5)",
"journal": "The neurologist",
"keywords": null,
"medline_ta": "Neurologist",
"mesh_terms": "D000328:Adult; D000072226:Computed Tomography Angiography; D005260:Female; D051270:Headache Disorders, Primary; D006801:Humans; D020335:Paraparesis; D014363:Tryptamines; D020301:Vasospasm, Intracranial",
"nlm_unique_id": "9503763",
"other_id": null,
"pages": "160-162",
"pmc": null,
"pmid": "30169369",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Triptan-induced Reversible Cerebral Vasoconstriction Syndrome Presenting With Thunderclap Headache and Paraparesis.",
"title_normalized": "triptan induced reversible cerebral vasoconstriction syndrome presenting with thunderclap headache and paraparesis"
} | [
{
"companynumb": "IN-MYLANLABS-2018M1079440",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIZATRIPTAN"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nLevetiracetam is a broad-spectrum antiepileptic drug (AED) which is currently licensed in the United States and the United Kingdom and Ireland for use as adjunctive treatment of focal-onset seizures and myoclonic seizures or generalized tonic-clonic seizures, occurring as part of generalized epilepsy syndromes. In the United Kingdom and Ireland, it is also licensed as monotherapy treatment for focal-onset seizures. Previous small studies have suggested a low risk for major congenital malformations (MCM) with levetiracetam use in pregnancy.\n\n\nMETHODS\nThe UK and Ireland Epilepsy and Pregnancy Registers are prospective, observational registration and follow-up studies that were set up to determine the relative safety of all AEDs taken in pregnancy. Here we report our combined results for first-trimester exposures to levetiracetam from October 2000 to August 2011.\n\n\nRESULTS\nOutcome data were available for 671 pregnancies. Of these, 304 had been exposed to levetiracetam in monotherapy, and 367 had been exposed to levetiracetam in combination with at least one other AED. There were 2 MCM in the monotherapy group (0.70%; 95% confidence interval [CI] 0.19%-2.51%) and 19 in the polytherapy group 5.56% (3.54%–8.56%) [corrected]. The MCM rate in the polytherapy group varied by AED regimen, with lower rates when levetiracetam was given with lamotrigine (1.77%; 95% CI 0.49%-6.22%) than when given with valproate (6.90%; 95% CI 1.91%-21.96%) or carbamazepine (9.38%; 95% CI 4.37%-18.98%).\n\n\nCONCLUSIONS\nThis study, in a meaningful number of exposed pregnancies, confirms a low risk for MCM with levetiracetam monotherapy use in pregnancy. MCM risk is higher when levetiracetam is taken as part of a polytherapy regimen, although further work is required to determine the risks of particular combinations. With respect to MCM, levetiracetam taken in monotherapy can be considered a safer alternative to valproate for women with epilepsy of childbearing age.",
"affiliations": "Neurology Department, Belfast Health and Social Care Trust, Royal Victoria Hospital, Belfast, Ireland.",
"authors": "Mawhinney|Ellen|E|;Craig|John|J|;Morrow|Jim|J|;Russell|Aline|A|;Smithson|W Henry|WH|;Parsons|Linda|L|;Morrison|Patrick J|PJ|;Liggan|Brenda|B|;Irwin|Beth|B|;Delanty|Norman|N|;Hunt|Stephen J|SJ|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D014635:Valproic Acid; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0b013e31827f0874",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "80(4)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000927:Anticonvulsants; D004359:Drug Therapy, Combination; D004829:Epilepsy, Generalized; D004830:Epilepsy, Tonic-Clonic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007231:Infant, Newborn; D007494:Ireland; D000077287:Levetiracetam; D008297:Male; D010889:Piracetam; D011247:Pregnancy; D011248:Pregnancy Complications; D011261:Pregnancy Trimester, First; D012042:Registries; D012307:Risk Factors; D006113:United Kingdom; D014635:Valproic Acid",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "400-5",
"pmc": null,
"pmid": "23303847",
"pubdate": "2013-01-22",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Levetiracetam in pregnancy: results from the UK and Ireland epilepsy and pregnancy registers.",
"title_normalized": "levetiracetam in pregnancy results from the uk and ireland epilepsy and pregnancy registers"
} | [
{
"companynumb": "IE-UNICHEM LABORATORIES LIMITED-UCM201509-000811",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"druga... |
{
"abstract": "OBJECTIVE\nTo determine the efficacy and feasibility of induction chemotherapy (ICT) with docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy and cetuximab (C) in patients with locally advanced head and neck cancer.\n\n\nMETHODS\nForty-nine previously untreated patients with local advanced stage III and IV squamous cell carcinoma of the head and neck (SCCHN) received three courses of ICT consisting of docetaxel 75mg/m(2) day 1, cisplatin 75mg/m(2) day 1 and infusional 5-fluorouracil 750mg/m(2)/day on days 1-5 followed by radiotherapy plus C at 250mg/m(2)/week (after an initial loading dose of 400mg/m(2)).\n\n\nRESULTS\nAfter completion of ICT 44 of 49 patients received radiotherapy plus C. Three months after therapy completion tumour response was observed in 33 patients and after two years, 25 patients were in complete remission (CR). The most common grade 4 toxicity during the whole treatment period was dermatitis (30%), followed by mucositis (27%) and neutropenia (17%) without fever. One toxic related death was observed during ICT. Two-year progression-free survival (PFS) rate was 59% and two-year overall survival (OS) rate was 63%, respectively.\n\n\nCONCLUSIONS\nConcurrent radiotherapy plus C after three courses of ICT was feasible and was associated with promising CR, PFS and OS rates. Further optimisation of dose and sequence is warranted.",
"affiliations": "Medical Dept. Int. Med. 3, Hematology and Oncology, Hanusch-Krankenhaus, Vienna, Austria. felix.keil@wgkk.at",
"authors": "Keil|Felix|F|;Selzer|Edgar|E|;Berghold|Andrea|A|;Reinisch|Sabine|S|;Kapp|Karin S|KS|;De Vries|Alexander|A|;Greil|Richard|R|;Bachtiary|Barbara|B|;Tinchon|Christoph|C|;Anderhuber|Wolfgang|W|;Burian|Martin|M|;Kasparek|Anne-Katrin|AK|;Elsäßer|Wolfgang|W|;Kainz|Herbert|H|;Riedl|Regina|R|;Kopp|Michael|M|;Kornek|Gabriela|G|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D043823:Taxoids; D000077143:Docetaxel; D000068818:Cetuximab; D002945:Cisplatin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "49(2)",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": null,
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D000068818:Cetuximab; D002945:Cisplatin; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D005472:Fluorouracil; D006258:Head and Neck Neoplasms; D006801:Humans; D060828:Induction Chemotherapy; D008297:Male; D008875:Middle Aged; D000077195:Squamous Cell Carcinoma of Head and Neck; D043823:Taxoids",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "352-9",
"pmc": null,
"pmid": "22981499",
"pubdate": "2013-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy with cetuximab for locally advanced squamous cell carcinoma of the head and neck.",
"title_normalized": "induction chemotherapy with docetaxel cisplatin and 5 fluorouracil followed by radiotherapy with cetuximab for locally advanced squamous cell carcinoma of the head and neck"
} | [
{
"companynumb": "AT-SANOFI-AVENTIS-2013SA043781",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": nul... |
{
"abstract": "Introduction: Osteoporosis is a devastating problem leading to significant morbidity and mortality. Patients with osteoporosis usually present with fractures from low-energy trauma and falls, commonly of the distal radius, which may precede more severe fractures like fracture of the neck of femur, but data from Thailand are limited. The objective of our study was to determine the prevalence of osteoporosis in patients with distal radius fracture from low-energy trauma. Materials and Methods: This was a descriptive retrospective study, performed at Thammasat University Hospital in Thailand, from January 2011 to June 2017. Patients aged more than 50 years with distal radial fractures from low-energy trauma with available bone mineral density (BMD) result were included. Patients with known secondary causes of osteoporosis were excluded. Patients were grouped by age, sex, and BMD status (normal, osteopenic and osteoporotic). Results: One hundred out of 351 patients with distal radial fractures had bone mineral density data but only 79 (73 females) met the inclusion criteria. Most patients were aged 60-69 years old (n=31, 42.5%). 47 (59.5%) patients were osteoporotic, 23 (29.1%) osteopenic, and 9 (11.4%) were normal. Seven (6 osteoporotic) patients suffered a more severe fracture subsequently. No deaths were recorded. Conclusion: Our study found a high rate of osteoporosis mostly in females, consistent with published literature. Assessing BMD is crucial in middle age and elderly patients with fractures to better manage osteoporosis and prevent more severe fractures in the future.",
"affiliations": "Department of Orthopaedics, Thammasat University, Pathum Thani, Thailand.;Department of Orthopaedics, Thammasat University, Pathum Thani, Thailand.;Department of Orthopedics, Chulabhorn International College of Medicine, Pathum Thani, Thailand.",
"authors": "Niempoog|S|S|;Sukkarnkosol|S|S|;Boontanapibul|K|K|",
"chemical_list": null,
"country": "Malaysia",
"delete": false,
"doi": "10.5704/MOJ.1911.003",
"fulltext": "\n==== Front\nMalays Orthop JMalays Orthop JmojMalaysian Orthopaedic Journal1985-25332232-111XMalaysian Orthopaedic Association Kuala Lumpur 3146764610.5704/MOJ.1911.003Original ArticlePrevalence of Osteoporosis in Patients with Distal Radius Fracture from Low-Energy Trauma Niempoog S MDSukkarnkosol S MDBoontanapibul K MD*Department of Orthopaedics, Thammasat University, Pathum Thani, Thailand* Department of Orthopedics, Chulabhorn International College of Medicine, Pathum Thani, ThailandDepartment of Orthopaedics, Faculty of Medicine, Thammasat University Hospital, 95 Moo 8, Phahon Yothin Road, Khlong Nueng Subdistrict, Khlong Luang District, Pathum Thani 12120, Thailand Email: sunyarn@hotmail.com11 2019 13 3 15 20 20 1 2019 17 7 2019 © 2019 Malaysian Orthopaedic Association (MOA). All Rights Reserved2019This 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 work is properly citedIntroduction: Osteoporosis is a devastating problem leading to significant morbidity and mortality. Patients with osteoporosis usually present with fractures from low-energy trauma and falls, commonly of the distal radius, which may precede more severe fractures like fracture of the neck of femur, but data from Thailand are limited. The objective of our study was to determine the prevalence of osteoporosis in patients with distal radius fracture from low-energy trauma. Materials and Methods: This was a descriptive retrospective study, performed at Thammasat University Hospital in Thailand, from January 2011 to June 2017. Patients aged more than 50 years with distal radial fractures from low-energy trauma with available bone mineral density (BMD) result were included. Patients with known secondary causes of osteoporosis were excluded. Patients were grouped by age, sex, and BMD status (normal, osteopenic and osteoporotic).\n\nResults: One hundred out of 351 patients with distal radial fractures had bone mineral density data but only 79 (73 females) met the inclusion criteria. Most patients were aged 60-69 years old (n=31, 42.5%). 47 (59.5%) patients were osteoporotic, 23 (29.1%) osteopenic, and 9 (11.4%) were normal. Seven (6 osteoporotic) patients suffered a more severe fracture subsequently. No deaths were recorded.\n\nConclusion: Our study found a high rate of osteoporosis mostly in females, consistent with published literature. Assessing BMD is crucial in middle age and elderly patients with fractures to better manage osteoporosis and prevent more severe fractures in the future.\n\nradiusradius fracturesosteoporosisprevalenceaccidental fall\n==== Body\nIntroduction\nOsteoporosis is a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk1. Osteoporosis is common and estimated to be 20% in Thailand2 and rates increase with increasing age. Rates of up to 50% have been recorded in individuals aged above 70 years2. The female to male ratio in individuals aged above 50 years reported by large series is 4:13. The prevalence of osteoporosis is increasing year on year parallel with the rise in the ageing population, especially in Asia. Osteoporosis is still under-diagnosed and under-treated in Asia4, 5.\n\nThe hall-mark clinical manifestation of osteoporosis is a fracture from low-energy trauma. The known common sites of fractures are the spine, hip and distal radius6. Several studies have shown that fractures of the distal radius from low-energy trauma are related to osteoporosis though not as strongly as hip or vertebral fractures. However, the fracture itself increases the risk for a subsequent hip fracture, which can have devastating consequences for activities of daily living and may lead to mortality7-12. Therefore, a distal radius fracture from low-energy trauma should be a reminder to practitioners to be aware of the possibility of underlying osteoporosis and to investigate accordingly.\n\nThe importance of distal radius fracture from low-energy trauma as a predictor of osteoporosis is well established but the prevalence of osteoporosis in patients with distal radius fracture from low-energy trauma in Thailand has not been determined and data from other countries are limited.\n\nØyen et al conducted a case-control study in Norway in 2003-2007 with 664 female and 85 male patients who had distal radius fractures and 554 female and 54 male controls.\n\nThe patients were in the age range of 50-99 years. The results showed that the prevalence of osteoporosis was 34% in female patients and 10% in female controls. The corresponding values were 17% in male patients and 13% in male controls7. Another case-control study also in Norway in 1998-2000, demonstrated that 64 out of 171 (37%) patients with forearm fractures had osteoporosis8. Another large research in Germany conducted between January 2002 to September 2003 found that 217 of 652 got BMD investigated after having distal radius fracture. Osteopenia was diagnosed in 25 (11.5%) and osteoporosis in 94 (43.3%)13.\n\nThere is also one study in Asia, conducted in Korea by Jung et al in 2006-2010 in which 206 patients older than 50 years with low-energy distal radius fracture had BMD investigation. One hundred and six (51.5%) were diagnosed with osteoporosis14.\n\nGiven the lack of data in Thailand, our study aimed to shed light on how common osteoporosis was in patients with distal radial fractures and to compare our findings with other countries. The primary objective was to determine the prevalence of osteoporosis in patients who sustained distal radius fracture from low-energy trauma seen at a referral hospital and the secondary objective was to evaluate prevalence of subsequent fracture in our patients and evaluate physicians’ awareness of osteoporosis by evaluating the time interval between fracture and the BMD obtained, percentage of patients who received anti-osteoporotic drugs with or without vitamin D and calcium supplement.\n\nMaterials and Methods\nThis study was a descriptive retrospective case note study. All the clinical notes of patients with a diagnosis of distal radius fracture, recorded by ICD-10 classification (10th revision of the International Statistical Classification of Diseases and Related Health Problems) (S52.5), who were above 50 years of age at the time of injury were reviewed by the authors. This included all patients who had attended our clinics or had been admitted to our hospital, from January 2011 to June 2017. Ethical approval of the Human Research Ethics Committee of our institution was obtained prior to commencing the study.\n\nAfter review, only patients who had bone mass density (BMD) data were included in the study. BMD values were obtained by dual energy radiograph absorptiometry (DEXA) scan (Hologic, software version 12.6, Model Discovery W, S/N 81495) at L1-L4 level and neck of femur of a non-dominant leg in our hospital using a native Japanese reference database. The data were recorded using the T-scores and the interpretation was done by radiologists using WHO criteria. These criteria defined osteoporosis as any T-score less than 2.5, osteopenia as any T-score between -2.5 and -1.0, and normal as any T-score above -1.015. The BMD taken into consideration for each patient in this study was the one closest to the time of injury and it could have been either pre-injury BMD or post-injury data.\n\nAll wrist radiographs were reviewed to confirm the diagnosis of distal radius fracture and the history was reviewed to confirm whether the mechanism of injury was a low-energy event. We defined a low-energy mechanism as falling from standing height or below. Excluded from this study were patients with a high energy fracture and those with known secondary osteoporosis, as associated with chronic steroid use, rheumatoid arthritis, hyperthyroidism and hyperparathyroidism.\n\nThe following data were recorded on standard case report forms: demographic data, underlying comorbidities, known underlying osteoporosis, drug treatment at the time of fracture, previous fractures, BMD values and BMD diagnoses (normal bone, osteopenia, osteoporosis), according to WHO criteria, date of fracture, date of BMD investigation, number of patients who sustained subsequent fracture and number of patients who had received post-fracture anti-osteoporotic drug with or without vitamin D and calcium supplement.\n\nDescriptive statistics were used: mean and standard deviation for continuous data, and percentages and 95% confidence interval for categorical data. Comparison between BMD in patients who had subsequent fracture and those who had not was performed using independent simple t-test.\n\nResults\nThere was a total of 723 cases of distal radius fracture (ICD-10: S52.5) in the hospital records during the period from January 2011 to June 2017. Of these, 351 (48.5%) patients were more than 50 years old. One hundred of the 351 patients (28.5%) had BMD results available in their hospital records. Eighty-three of these 100 patients with available BMD results had a low-energy fracture, 12 had a high-energy fracture, while in five patients, the mechanism of injury could not be determined as their medical records were missing. However, of these 83 patients, four had secondary osteoporosis, one each due to rheumatoid arthritis and prednisolone treatment for chronic lymphocytic leukaemia and two with hyperparathyroidism, and were excluded. Finally, 79 cases which satisfied all the inclusion criteria were studied. The STROBE flow diagram is shown (Fig. 1).\n\nFig. 1: STROBE flow diagram of the study.\n\nThe mean age of the 79 patients was 64 (range: 50-85) years old. The majority of the patients were female (92.4%), 0.84 – 0.96) and 31 of them were in the 60-69 years age group. The three most common co-morbidities were dyslipidaemia (n=40), hypertension (n=32), and diabetes mellitus (n=14). The mean BMD was -2.53 ± 1.15 (within the osteoporotic range). In total, 59.5% (0.48 – 0.70) of patients were osteoporotic, 29.1% (0.20 – 0.40) osteopenic and 11.4% (0.06 – 0.20) had normal BMDs. No patient above the age of 70 had a normal BMD. The overall detailed data is shown in Table I and data for specific age group in Table II and in Figure 2.\n\nTable I Bone status shown by Sex\n\nSample\tTotal\tNormal\t95% CI\tOsteopenia\t95% CI\tOsteoporosis\t95% CI\t\nMale\t6\t2 (33.3%)\t0.10 – 0.70\t3 (50%)\t0.19 – 0.81\t1 (16.7%)\t0.03 – 0.56\t\nFemale\t73\t7 (9.6%)\t0.05 – 0.19\t20 (27.4%)\t0.18 – 0.39\t46 (63.0%)\t0.52 – 0.73\t\nTotal\t79\t9 (11.4%)\t0.06 – 0.20\t23 (29.1%)\t0.20 – 0.40\t47 (59.5%)\t0.48 – 0.70\t\nTable 2 Bone Mineral Density Data Presented as T-scores by Age Category and Sex\n\nAge group\tSex\tAverage age\tNormal\tAverage BMD\t\tOsteopenia\tAverage BMD\tOsteoporosis\tAverage BMD\t\n50-59\tMale\t55\t1\t-0.8\t\t0\t\t0\t\t\n(n=19)\tFemale\t56 ± 3\t2\t-0.80 ± 0.28\t\t7\t-1.97 ± 0.42\t9\t-3.37 ± 0.77\t\n\tTotal\t56 ± 3\t3 (15.8%)\t-0.80 ± 0.20\t\t7 (36.8%)\t-1.97 ± 0.42\t9 (47.3%)\t-3.37 ± 0.77\t\n60-69\tMale\t62\t1\t-0.2\t\t0\t\t0\t\t\n(n=31)\tFemale\t64 ± 3\t5\t-0.28 ± 0.51\t\t9\t-1.86 ± 0.38\t16\t-2.98 ± 0.56\t\n\tTotal\t64 ± 6\t6 (19.5%)\t-0.27 ± 0.46\t\t9 (29.0%)\t-1.86 ± 0.39\t16 (51.6%)\t-2.98 ± 0.57\t\n70-79\tMale\t74 ± 1\t0\t\t\t2\t-1.50 ± 0.42\t1\t-3.7\t\n(n=20)\tFemale\t75 ± 3\t0\t\t\t2\t-2.10 ± 0.28\t15\t-3.03 ± 0.36\t\n\tTotal\t75 ± 3\t0\t\t\t4 (20.0%)\t-1.80 ± 0.45\t16 (80.0%)\t-3.08 ± 0.38\t\n≥80\tMale\t80\t0\t\t\t1\t-1.6\t0\t\t\n(n=9)\tFemale\t82 ± 2\t0\t\t\t2\t-2.10 ± 0.14\t6\t-4.15 ± 1.25\t\n\tTotal\t82 ± 2\t0\t\t\t3 (33.3%)\t-1.93 ± 0.31\t6 (66.7%)\t-4.15 ± 1.25\t\nFig. 2: Bone calcification based on bone mineral density as categorised by of age and sex.\n\nOf the 79 patients, 17 patients (21.5%, 0.14 – 0.32) had previous BMD studies before their fracture, ranging from one to 52 months, for a mean of 14 months. The BMD showed osteoporosis (n=10) and osteopenia (n=7) in the pre-fracture BMD patients. Ten patients (58.8%, 0.36 – 0.78) were on vitamin D with or without calcium supplement, six in the osteoporotic and four in the osteopenic groups. Five patients were already on anti-osteoporotic treatment, three in osteoporosis group and two in osteopenic group) with Alendronate (n=1), Zoledronic acid (n=1), or Denosumab (n=3). Sixty-two had their BMD investigations, mean 4 months (range 1-51) post-fracture. Following their fractures, a total of 37 patients, 31 for osteoporosis and six for osteopenia, had been treated with anti-osteoporotic drugs.\n\nAfter their distal radial fractures, six (12.8%), of 47 osteoporotic and one (4.3%), of 23 osteopenic patients had additional fractures. In osteoporosis group two patients sustained spinal fracture, one patient hip fracture, one proximal humerus fracture, one patient another opposite side distal radius fracture and one both hip and spinal fractures. In osteopenic group, the patients sustained spinal fracture. Patients with subsequent fracture had an average BMD of - 3.67±1.23 while patients without subsequent fracture had an average BMD of -2.41±1.09. Patients who had sustained subsequent fractures had significant lower BMD (p=0.035). Of the seven patients, four were on anti-osteoporotic treatment.\n\nDiscussion\nA distal radius fracture from low-energy trauma, such as falling from standing height, is a common presentation of osteoporosis. In our study of these fractures, about 60% and 30% of patients were osteoporotic and osteopenic, respectively.\n\nIn patients diagnosed with osteopenia or osteoporosis based on BMD, only 58% were receiving vitamins D with or without calcium supplements before they had their fractures and even fewer, 29.4%, were on anti-osteoporotic drugs. Post-fracture, just under two thirds of the osteoporotic patients had been prescribed anti-osteoporotic drug treatment.\n\nThe prevalence rate of osteoporosis in our sample of middle aged or geriatric Thai patients with radial fractures was around 60%, which is higher than the rates in other countries. In the Korean population prevalence rates of 52% of osteoporosis in females with distal radial fractures had been reported, while in Germany, Norway and Sweden the prevalence rates were 43, 34 and 37%, respectively7, 8, 13, 14. This disparity may be related to under diagnosis of osteoporosis in Asian countries than in USA and European countries, leading to lower numbers of patients treated which would result in a higher percentage of all osteoporotic fractures, including distal end radius fractures5, 16.\n\nAlthough the prevalence of osteoporosis in our group of hospitalised patients was high, little attention was given to investigate all patients for osteoporosis. Indeed, of the 351 cases of distal radius fracture in our middle aged and elderly patients, only 100 cases, less than one third, had undergone a BMD study. This missed opportunity to detect osteoporosis was unfortunate but nothing new. In Korea only 8.7% of women with wrist fractures had a BMD study17. In UK, patients with wrist fracture preceded more serious femoral neck fracture in the time frame of 1995 to 2000 were investigated. Only 8% of 74 patients were undergoing treatment for osteoporosis at the time of their wrist fracture and only 8% got osteoporosis investigated or treated between their wrist and femoral neck fracture18.\n\nThe results from our study and those from other countries emphasise the need to investigate fracture patients for osteoporosis even if the fractures are considered minor. Although it appears that many young physicians tend to recognise the need for investigating osteoporosis in more severe fractures like vertebral and hip fractures19, increased awareness is needed to investigate fractures resulting from low-energy trauma such as distal radius fracture since osteoporosis rates are high in this group as is the risk of a subsequent more severe fracture which in our study was approximately 13% in osteoporotic patients and approximately 4% in osteopenic patients.\n\nRoutine inclusion of BMD studies in patients with distal radius fractures seen in the emergency room or in the orthopaedic clinic could help to identify the patient at risk.\n\nHowever, DEXA scan, a gold standard for diagnosing osteoporosis, is not widely available in most of Asian countries including Thailand which had only 50 DEXA machines in 2009 (0.008 machines per 10000 population)5. Osteoporosis Self-Assessment Tool for Asians (OSTA) and the Khon Kaen Osteoporosis Study Score (KKOS) could be effective tools in selecting the most patient in need for DEXA scan.\n\nAlthough our overall rate of ordering a BMD was higher than other series17, 18, the proportion of patients with a prior BMD was low, approximately 13%. The time interval prior to the fracture varied widely from one month to more than four years, with a mean of four months. Ideally, the earlier osteoporosis or osteopenia is detected, the sooner can management be started, like general advice on maintaining active life, a healthy diet with sufficient calcium, investigation for secondary causes of osteoporosis, and specific treatment. The time to order a post-fracture BMD was also varied widely – an average of four months but up to more than four years.\n\nOur study was limited by its small size and being retrospective. This limited the amount of data that could be collected from patient records and the exclusion of 70% of patients because of the lack of a BMD. With our sample size of 79, the 60% prevalence of osteoporosis in this patient group had an error of 10%. Furthermore, the small sample size could be the cause of uncorrelated relationship between BMD and prevalence of osteoporosis in different age groups as shown in those above 80 years group which had lower BMD than 70-79 years group but had lower prevalence of osteoporosis and the same reason goes for the result that 50-59 years group had lower BMD than that of 60-69 years group. Nevertheless, our study has shed light on osteoporosis and fractures in an at-risk Thai population. Further studies are warranted to more accurately define the prevalence of osteoporosis in patients with distal radial fractures and to examine additional risk factors like comorbidities.\n\nConclusion\nOur study has identified a high rate of osteoporosis and osteopenia in middle aged and elderly patients with distal radius fractures from low-energy trauma. The need to increase awareness of problems arising from under-investigation of osteoporosis and missed opportunity for prompt treatment and prevention of subsequent more serious fractures is emphasised.\n\nAcknowledgement\nThe authors record their gratitude to Dr Walter Robert John Taylor for reviewing the manuscript.\n\nConflict of Interest\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n1 Consensus Development Conference: Diagnosis, Prophylaxis, and Treatment of Osteoporosis Am J Med. 1993 94 646 50 10.1016/0002-9343(93)90218-E 8506892 \n2 Limpaphayom KK Taechakraichana N Jaisamrarn U Bunyavejchevin S Chaikittisilpa S Poshyachinda M Prevalence of osteopenia and osteoporosis in Thai women Menopause. 2001 8 1 65 9 11201518 \n3 Alswat KA Gender Disparities in Osteoporosis J Clin Med Res. 2017 9 5 382 7 28392857 \n4 Mithal A Kaur P Osteoporosis in Asia: A Call to Action Curr Osteoporosis Rep. 2012 10 4 245 7 \n5 Mithal A Dhingra V Lau E. The Asian Audit: Epidemiology, costs and burden of osteoporosis in Asia 2009. International Osteoporosis Foundation 2009 \n6 Riggs BL Melton LJ 3rd The worldwide problem of osteoporosis: insights afforded by epidemiology Bone. 1995 17 5Suppl 505S 11S 8573428 \n7 Øyen J Brudvik C Gjesdal CG Tell GS Lie SA Hove LM Osteoporosis as a risk factor for distal radial fractures: a case-control study J Bone Joint Surg Am. 2011 93 4 348 56 21325586 \n8 Lofman O Hallberg I Berglund K Wahlstrom O Kartous L Rosenqvist AM Women with low-energy fracture should be investigated for osteoporosis Acta Orthop. 2007 78 6 813 21 18236189 \n9 Pongchaiyakul C Songpattanasilp T Taechakraichana N Burden of osteoporosis in Thailand J Med Assoc Thai. 2008 91 2 261 7 18389994 \n10 Cuddihy MT Gabriel SE Crowson CS O'Fallon WM Melton LJ 3rd Forearm fractures as predictors of subsequent osteoporotic fractures Osteoporosis Int. 1999 9 6 469 75 \n11 Haentjens P Autier P Collins J Velkeniers B Vanderschueren D Boonen S Colles fracture, spine fracture, and subsequent risk of hip fracture in men and women. A meta-analysis J Bone Joint Surg Am. 2003 85 10 1936 43 14563801 \n12 Papadimitriou N Tsilidis KK Orfanos P Benetou V Ntzani EE Soerjomataram I Burden of hip fracture using disability-adjusted life-years: a pooled analysis of prospective cohorts in the CHANCES consortium Lancet Public Health. 2017 2 5 e239 e46 29253489 \n13 Endres HG Dasch B Maier C Lungenhausen M Smektala R Trampisch HJ Diagnosis and treatment of osteoporosis in postmenopausal women with distal radius fracture in Germany Curr Med Res Opin. 2007 23 9 2171 81 17681113 \n14 Jung HJ Park HY Kim JS Yoon JO Jeon IH Bone Mineral Density and Prevalence of Osteoporosis in Postmenopausal Korean Women with Low-Energy Distal Radius Fractures J Korean Med Sci. 2016 31 6 972 5 27247508 \n15 Kanis JA Melton LJ 3rd Christiansen C Johnston CC Khaltaev N The diagnosis of osteoporosis J Bone Miner Res. 1994 9 8 1137 41 7976495 \n16 Cheung EYN Tan KCB Cheung CL Kung AWC Osteoporosis in East Asia: Current issues in assessment and management Osteoporos Sarcopenia. 2016 2 3 118 33 30775478 \n17 Gong HS Oh WS Chung MS Oh JH Lee YH Baek GH Patients with wrist fractures are less likely to be evaluated and managed for osteoporosis J Bone Joint Surg Am. 2009 91 10 2376 80 19797572 \n18 Smith MG Dunkow P Lang DM Treatment of osteoporosis: missed opportunities in the hospital fracture clinic Ann R Coll Surg Engl. 2004 86 5 344 6 15333170 \n19 Angthong C Rodjanawijitkul S Samart S Angthong W Prevalence of bone mineral density testing and osteoporosis management following low- and high-energy fractures Acta Orthop Traumatol Turc. 2013 47 5 318 22 24164940\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1985-2533",
"issue": "13(3)",
"journal": "Malaysian orthopaedic journal",
"keywords": "accidental fall; osteoporosis; prevalence; radius; radius fractures",
"medline_ta": "Malays Orthop J",
"mesh_terms": null,
"nlm_unique_id": "101564672",
"other_id": null,
"pages": "15-20",
"pmc": null,
"pmid": "31890105",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article",
"references": "28392857;14563801;11201518;10624452;15333170;29253489;21325586;24164940;8573428;7976495;30775478;27247508;17681113;18236189;19797572;22898971;8506892;18389994",
"title": "Prevalence of Osteoporosis in Patients with Distal Radius Fracture from Low-Energy Trauma.",
"title_normalized": "prevalence of osteoporosis in patients with distal radius fracture from low energy trauma"
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"companynumb": "TH-AMGEN-THASP2020006722",
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"activesubstancename": "DENOSUMAB"
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"abstract": "Secukinumab is administered at the labelled dose of 300 mg at weeks 0, 1, 2, 3, 4 (loading dose) and every 4 weeks thereafter.\n\n\n\nTo investigate the efficacy of secukinumab administered without the initial loading dose in patients with psoriasis.\n\n\n\nThis was a retrospective observational study including adult patients with psoriasis (n = 156) treated with secukinumab 300 mg administered either according to the labelled dose (n = 75) or without the initial loading dose (n = 81). Efficacy was evaluated by comparing the Psoriasis Area and Severity Index (PASI) 75 and PASI 90 response rates at week 8, 12, 16, 32 and 48.\n\n\n\nFor patients who received the labelled dose vs. those who did not, PASI 75 response rates were achieved at week 8, 12, 16, 32 and 48 by 60% vs. 40% (P < 0·01), 72% vs. 61% (P < 0·01), 77% vs. 75%, 85% vs. 77% and 79% vs. 78%, respectively. PASI 90 responses were achieved at the same time points by 45% vs. 31% (P < 0·01), 49% vs. 40% (P < 0·01), 54% vs. 47%, 55% vs. 47% and 57% vs. 54% for those who received the labelled dose vs. those who did not, respectively. A greater proportion of patients receiving secukinumab without the loading dose discontinued treatment because of inefficacy (25% vs. 13%, P < 0·05), particularly those with body weight greater than 80 kg.\n\n\n\nSecukinumab administered without the loading dose is associated with a higher proportion of primary inefficacy, and achieved inferior results compared with the labelled dose at week 8 and week 12, but showed similar efficacy thereafter. What's already known about this topic? Secukinumab is an interleukin (IL)-17A inhibitor for chronic plaque psoriasis administered by subcutaneous injections at the labelled dose of 300 mg at weeks 0, 1, 2, 3, 4 (loading dose) and every 4 weeks thereafter (maintenance dose). Dose adjustment is common in clinical practice, and can consist of dose reduction when a prolonged remission is obtained or a dose increase in order to improve efficacy. What does this study add? The efficacy of secukinumab administered without the initial weekly loading dose was significantly inferior compared with the labelled dose in the short term, but was similar after week 16 and up to week 48. A greater proportion of patients receiving secukinumab without the loading dose showed primary inefficacy, particularly those with body weight greater than 80 kg.",
"affiliations": "Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy.;Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy.;Dermatology Unit, Department of Medicine, University of Padua, Padua, Italy.;Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy.",
"authors": "Gisondi|P|P|0000-0002-1777-9001;Rovaris|M|M|0000-0003-3968-2136;Piaserico|S|S|;Girolomoni|G|G|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C555450:secukinumab",
"country": "England",
"delete": false,
"doi": "10.1111/bjd.18015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0963",
"issue": "182(1)",
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004311:Double-Blind Method; D006801:Humans; D011565:Psoriasis; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "0004041",
"other_id": null,
"pages": "175-179",
"pmc": null,
"pmid": "31004509",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Efficacy of secukinumab without the initial weekly loading dose in patients with chronic plaque psoriasis.",
"title_normalized": "efficacy of secukinumab without the initial weekly loading dose in patients with chronic plaque psoriasis"
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{
"companynumb": "PHHY2019IT131952",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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"activesubstancename": "SECUKINUMAB"
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"abstract": "To evaluate the intermediate-term efficacy and tolerance of statins in children and adolescents with familial hypercholesterolemia.\n\n\n\nA total of 131 children or adolescents treated with statins for familial hypercholesterolemia were prospectively included. The efficacy of treatment was established by the percentage of children who achieved low density lipoprotein-cholesterol (LDL-C) levels <160 mg/dL during treatment. Treatment tolerance was evaluated by the occurrence of clinical or laboratory side effects, regularity of increases in height and weight, and pubertal development.\n\n\n\nThe median duration of treatment with statins was 4 years. A median decrease of 32% in LDL-C levels was observed (P < .0001). The therapeutic target (LDL-C <160 mg/dL) was achieved in 67% of cases. Increases in height and weight and sexual maturation were not affected by the treatment. Minor side effects were reported for 24 (18.4%) patients including 3 cases of a clinically asymptomatic increase in creatine phosphokinase (CPK) levels, 2 cases of an increase in CPK levels with muscular symptoms, 14 cases of myalgia without an increase in CPK levels, 3 cases of abdominal pain, 1 case of dysuria, and 1 case of diffuse pain. None of these side effects led to the discontinuation of statin therapy, although a change of statin was required in 7 cases. This new statin was tolerated in all cases. No patients had abnormal liver function during treatment.\n\n\n\nThe results of this large cohort confirm the intermediate-term safety and efficacy of statin therapy in children with familial hypercholesterolemia.",
"affiliations": "Pediatric Nutrition and Gastroenterology Department, Trousseau Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France. Electronic address: nathalie.mamann@aphp.fr.;Pediatric Nutrition and Gastroenterology Department, Trousseau Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France.;Pediatric Nutrition and Gastroenterology Department, Trousseau Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France.;Pediatric Nutrition and Gastroenterology Department, Trousseau Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France.;Pediatric Nutrition and Gastroenterology Department, Trousseau Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France.;Pediatric Nutrition and Gastroenterology Department, Trousseau Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France.",
"authors": "Mamann|Nathalie|N|;Lemale|Julie|J|;Karsenty|Alexandra|A|;Dubern|Béatrice|B|;Girardet|Jean-Philippe|JP|;Tounian|Patrick|P|",
"chemical_list": "D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003402:Creatine Kinase",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpeds.2019.03.032",
"fulltext": null,
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"issn_linking": "0022-3476",
"issue": "210()",
"journal": "The Journal of pediatrics",
"keywords": "cardiovascular risk; familial hypercholesterolemia; lipid-lowering therapy; tolerability",
"medline_ta": "J Pediatr",
"mesh_terms": "D015746:Abdominal Pain; D000293:Adolescent; D002648:Child; D008078:Cholesterol, LDL; D003402:Creatine Kinase; D053159:Dysuria; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006938:Hyperlipoproteinemia Type II; D008297:Male; D063806:Myalgia; D010146:Pain; D011446:Prospective Studies",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "161-165",
"pmc": null,
"pmid": "31053349",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intermediate-Term Efficacy and Tolerance of Statins in Children.",
"title_normalized": "intermediate term efficacy and tolerance of statins in children"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1065255",
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"activesubstancename": "ROSUVASTATIN"
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"abstract": "BACKGROUND\nHigh-dose (HD) chemotherapy followed by autologous blood stem-cell transplantation (ASCT) is the standard treatment for multiple myeloma (MM) patients. However, the collection of sufficient peripheral blood stem cell (PBSC) grafts can be challenging, and the question arises whether reinfusion of low-dose grafts will lead to a hematopoietic recovery.\n\n\nMETHODS\nThe hematopoietic recovery of 148 MM patients who underwent HD melphalan chemotherapy and received PBSC transplants with varying CD34+ cells doses (3-4 × 106 [n = 86], 2-2.5 × 106 [n = 53], < 2 × 106 [n = 9] per kg body weight [bw]) was analyzed in this retrospective single-center study.\n\n\nRESULTS\nAll patients reached hematopoietic reconstitution, even those who received < 2 × 106 CD34+ cells/kg bw. 62 (42%) patients received granulocyte-colony-stimulating factor (G-CSF). The median duration to leukocyte recovery ≥1.0 × 109/L was 12 days in every group. The median duration to platelet recovery ≥20 × 109/L was 11, 13 and 13 days, respectively. In the multivariate analysis, a low number of reinfused CD34+ cells was associated with prolonged time until leukocyte reconstitution (p = 0.010, HR 0.607) and platelet recovery (p < 0.001, HR 0.438). G-CSF support significantly accelerated leukocyte (p < 0.001, HR 16.742) but not platelet reconstitution.\n\n\nCONCLUSIONS\nIn conclusion, reinfusion of low- and even very-low-dose PBSC grafts leads to sufficient hematopoietic reconstitution. No severe adverse events were observed during or after HD chemotherapy and ASCT in the analyzed cohort. While the impact of CD34+ cell dose is marginal, G-CSF significantly accelerates the leukocyte recovery.",
"affiliations": "Department of Hematology, Oncology and Rheumatology, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. sandra.sauer@med.uni-heidelberg.de.;Stem Cell Laboratory, IKTZ Heidelberg GmbH, Heidelberg, Germany.;Department of Hematology, Oncology and Rheumatology, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.;Department of Hematology, Oncology and Rheumatology, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.;Institute of Pathology, Heidelberg University, Heidelberg, Germany.;Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany.;Department of Hematology, Oncology and Rheumatology, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.;Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Württemberg - Hessen, Mannheim, Germany.;Department of Hematology, Oncology and Rheumatology, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.;Department of Hematology, Oncology and Rheumatology, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.",
"authors": "Sauer|Sandra|S|;Pavel|Petra|P|;Schmitt|Anita|A|;Cremer|Martin|M|;Kriegsmann|Mark|M|;Bruckner|Thomas|T|;Jordan|Karin|K|;Wuchter|Patrick|P|;Müller-Tidow|Carsten|C|;Kriegsmann|Katharina|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12885-020-06873-7",
"fulltext": "\n==== Front\nBMC Cancer\nBMC Cancer\nBMC Cancer\n1471-2407 BioMed Central London \n\n6873\n10.1186/s12885-020-06873-7\nResearch Article\nLow-dose peripheral blood stem cell graft after high-dose chemotherapy - an evaluation of hematopoietic reconstitution\nSauer Sandra sandra.sauer@med.uni-heidelberg.de 1 Pavel Petra 2 Schmitt Anita 1 Cremer Martin 1 Kriegsmann Mark 3 Bruckner Thomas 4 Jordan Karin 1 Wuchter Patrick 5 Müller-Tidow Carsten 1 Kriegsmann Katharina 1 1 grid.7700.00000 0001 2190 4373Department of Hematology, Oncology and Rheumatology, Heidelberg University, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany \n2 Stem Cell Laboratory, IKTZ Heidelberg GmbH, Heidelberg, Germany \n3 grid.7700.00000 0001 2190 4373Institute of Pathology, Heidelberg University, Heidelberg, Germany \n4 grid.7700.00000 0001 2190 4373Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany \n5 grid.7700.00000 0001 2190 4373Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Württemberg – Hessen, Mannheim, Germany \n25 4 2020 \n25 4 2020 \n2020 \n20 3538 8 2019 15 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\nHigh-dose (HD) chemotherapy followed by autologous blood stem-cell transplantation (ASCT) is the standard treatment for multiple myeloma (MM) patients. However, the collection of sufficient peripheral blood stem cell (PBSC) grafts can be challenging, and the question arises whether reinfusion of low-dose grafts will lead to a hematopoietic recovery.\n\nMethods\nThe hematopoietic recovery of 148 MM patients who underwent HD melphalan chemotherapy and received PBSC transplants with varying CD34+ cells doses (3–4 × 106 [n = 86], 2–2.5 × 106 [n = 53], < 2 × 106 [n = 9] per kg body weight [bw]) was analyzed in this retrospective single-center study.\n\nResults\nAll patients reached hematopoietic reconstitution, even those who received < 2 × 106 CD34+ cells/kg bw. 62 (42%) patients received granulocyte-colony-stimulating factor (G-CSF). The median duration to leukocyte recovery ≥1.0 × 109/L was 12 days in every group. The median duration to platelet recovery ≥20 × 109/L was 11, 13 and 13 days, respectively. In the multivariate analysis, a low number of reinfused CD34+ cells was associated with prolonged time until leukocyte reconstitution (p = 0.010, HR 0.607) and platelet recovery (p < 0.001, HR 0.438). G-CSF support significantly accelerated leukocyte (p < 0.001, HR 16.742) but not platelet reconstitution.\n\nConclusion\nIn conclusion, reinfusion of low- and even very-low-dose PBSC grafts leads to sufficient hematopoietic reconstitution. No severe adverse events were observed during or after HD chemotherapy and ASCT in the analyzed cohort. While the impact of CD34+ cell dose is marginal, G-CSF significantly accelerates the leukocyte recovery.\n\nKeywords\nPeripheral blood stem cellsInsufficient graftAutologous stem-cell transplantationMultiple myelomaissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nHigh-dose (HD) chemotherapy followed by autologous blood stem-cell transplantation (ASCT) is the standard of care and a highly effective therapy for multiple myeloma (MM) [1, 2]. Although HD/ASCT was initially established as a single therapy for first-line treatment of MM [3, 4], subsequent randomized trials demonstrated an overall survival benefit with tandem ASCT, particularly in patients who did not achieve at least partial remission (PR) [5, 6]. Later studies showed that salvage HD/ASCT may represent an effective treatment option for MM patients who relapse after a sustained remission that lasted longer than 1 year after a prior ASCT [7–9]. The indication for up to three HD/ASCTs might occur over the course of MM treatment.\n\nAs a prerequisite for ASCT, hematopoietic stem cells must be available. Peripheral blood stem cells (PBSCs) have become the most widely used source for hematopoietic stem cells in the setting of HD/ASCT treatment for MM [10, 11]. PBSCs (i.e., CD34+ cells) must be mobilized either with mobilization chemotherapy and granulocyte-colony-stimulating factor (G-CSF) or with G-CSF alone and subsequently collected by leukapheresis [12]. Usually, a successful collection of up to three sufficient PBSC grafts (> 2.0–2.5 × 106 CD34+ cells/kg body weight [bw] per graft) from MM patients can be achieved when the PBSC collection is performed after induction treatment i.e., prior to the first HD/ASCT [13, 14]. However, many factors, such as higher age, previous extensive chemotherapy, and treatment with melphalan or radiation therapy, might be associated with poor PBSC mobilization, despite the use of plerixafor, which results in borderline sufficient (< 2.0–2.5 × 106 CD34+ cells/kg bw) grafts [15–19]. In this case, transplant centers frequently face the question of whether reinfusion of grafts with marginal PBSC numbers will lead to a delay in hematopoietic recovery after HD chemotherapy and subsequently cause any complications or even severe adverse events due to prolonged neutropenia. This issue is of great relevance, particularly to MM patients who might significantly benefit from HD/ASCT treatment in terms of MM disease control.\n\nThe aim of this study was to demonstrate that hematopoietic reconstitution is not significantly delayed, even if a low (2.0–2.5 × 106/kg bw) or a very low (< 2.0 × 106/kg bw) number of PBSCs is reinfused during ASCT. Moreover, the question of whether the number of reinfused PBSCs affects the duration until achieving hematopoietic recovery will be answered.\n\nMethods\nPatient selection and data matching\nA retrospective single-center analysis of MM patients who underwent HD melphalan chemotherapy and ASCT between January 2016 and August 2018 at our university hospital was performed. The patients were grouped according to the number of reinfused CD34+ cells at ASCT, as follows: 3–4 × 106 CD34+ cells/kg bw (group 1), 2–2.5 × 106 CD34+ cells/kg bw (group 2), < 2 × 106 CD34+ cells/kg bw (group 3). Group 1 reflects the median reference value of reinfused CD34+ cells at our institution, as previously reported [20, 21]. To achieve homogenization between groups 1 and 2, only patients who received one round of HD/ASCT therapy in their course of treatment were included. As there were only few patients in group 3, the second or third HD/ASCT was also considered in this group. Patients in group 3 received in median 1,89 × 106 (range 1,74 to 1,99 × 106) CD34+ cells/kg bw. The clinical parameters (sex and age), ISS stage and Salmon and Durie stage at first diagnosis, type of monoclonal protein, modality of induction and mobilization therapy, remission status before and after each ASCT, number of transplanted CD34+ cells and hematological reconstitution data were collected retrospectively. The retrospective data analysis was approved by the Ethics Committee of the Medical Faculty, Heidelberg University.\n\nMultiple myeloma induction therapy\nMM treatment was initiated according to the SLiM-CRAB criteria [22]. The standard induction treatment was 4 cycles of VCD (bortezomib 1.3 mg/m2, s.c., days 1, 4, 8, 11; cyclophosphamide 1000 mg/m2, i.v., day 1; dexamethasone 40 mg, p.o., days 1, 2, 4, 5, 8, 9, 11, 12). Sixty-three patients received either 4 cycles of VRD (bortezomib 1.3 mg/m2, s.c., days 1, 4, 8, 11; lenalidomide 25 mg, p.o., days 1–14; dexamethasone 20 mg, p.o., days 1, 2, 4, 5, 8, 9, 11, 12, 15 optional) or elotuzumab (10 mg/kg, i.v., days 1, 8, 15 in cycle 1 and 2; days 1, 11 in cycles 3 and 4) in combination with VRD as induction therapy. The remission status was assessed according to international myeloma working group response criteria [23].\n\nPBSC mobilization, collection and quality assessment\nPBSC mobilization was performed as previously described [20]. In summary, CAD (cyclophosphamide 1000 mg/m2, i.v., day 1; doxorubicin 15 mg/m2, i.v., days 1–4; dexamethasone 40 mg, p.o., days 1–4) was administered as a standard chemomobilization regimen. Three patients received cyclophosphamide (1000 mg/m2/day, i.v., days 1–2) only. G-CSF (5–10 μg/kg per day) was injected subcutaneously starting 5 days after mobilization chemotherapy and was administered until the end of PBSC collection. The number of CD34+ cells was determined by flow cytometry as described previously when peripheral blood leukocytes reached ≥5.0 × 103/μl [24]. When the peripheral blood CD34+ cell count reached ≥20/μl, leukapheresis (LP) was initiated. Stem cell collection was performed at the Spectra Optia apheresis machine (MNC program, software version 7.2 and 11.2). In the case of poor mobilization (i.e. < 20 CD34+ cells/μL under G-CSF stimulation or less than one third of the individual collection goal reached with the first leukapheresis session), pre-emptive or rescue plerixafor (240 μg/kg) was administered subcutaneously 9 to 12 h before the LP session. The minimum number of CD34+ cells for one transplant was defined as ≥2.0 × 106/kg bw at our institution, with the goal of collecting sufficient CD34+ cells for three transplants to ensure the option for a tandem transplantation or anHD melphalan and ASCT in case of relapse.\n\nPBSCs processing and storage was in accordance with the German Medical Council and further scientific society’s guidelines [25–27]. The PBSCs were stored for 24–48 h at 2 to 6 °C until cryopreservation. The maximum nucleated cell (NC) concentration was 2 × 108/mL. After storage, the PBSC products were centrifuged and diluted with autologous plasma or resuspension medium (Plasmalyte A, Baxter, Unterschleissheim, Germany or Composol PS, Fresenius Kabi, Bad Homburg, Germany) and CryoSure-D dimethyl sulfoxide (DMSO, WAK-Chemie Medical, Steinbach, Germany). The target NC concentration was ≤5 × 108/mL and the total volume was 100 mL per bag. The final product included 10% DMSO and was stored in Cryocyte bags (Baxter, Unterschleissheim, Germany or CryoMACS Freezing bags (Miltenyi, Idarobrstein, Germany). The PBSCs controlled-rate freezed (Biofreeze BV50, Consarctic, Schoellkrippen, Germany). The storage conditions were vapor-phase nitrogen and a temperature of <− 140 °C. Upon transplantation, the cryopreserved bags were thawed at the bedside (Plasmatherm device, Barkey GmbH & Co. KG, Leopoldshoehe, Germany) at 37 °C. PBSCs were reinfused without previous washing within a maximum of 10 min of thawing using standard transfusion filters.\n\nFor quality assessment in accordance with the Stem Cell Enumeration Committee Guidelines of the International Society for Cell Transplantation, a an enumeration of NC and red blood cells, flow cytometry-based CD34+ cell quantification and volume determination were performed directly after PBSC collection [28]. A microbiological culture sample was obtained shortly before freezing. NC enumeration and NC viability measurements were performed in the PBSC aliquots 48 h after freezing and in samples that were stored for a duration > 36 months. Overall, the following target values were defined for the end product (one PBSC transplant): NC concentration ≤ 5 × 108/mL, CD34+ cell number ≥ 2 × 106/kg bw, a total volume of 100 mL per portion (up to 3 portions possible), no microbial growth, and a minimum NC viability of 50%. Viability testing was valid for a maximum duration of 3 years.\n\nHD chemotherapy and ASCT\nAll patients received melphalan (100 mg/m2, day − 3 and day − 2, one-hour infusion) as high dose chemotherapy conditioningregimen. When creatinine clearance was ≤40 mL/min, the melphalan dosage was reduced by 50%.. An supportive medication regimen (dexamethasone 4 mg p.o., day − 3; dexamethasone 2 mg p.o., day − 2 to day − 1, granisetron hydrochloride 2 mg p.o., days − 3 to day 0, aprepitant 125 mg p.o., day − 3, aprepitant 80 mg p.o., day − 2 to day 0) was used for prevention of chemotherapy-induced nausea and vomiting [29]. A minimum of 2.0 × 106 C34+ cells/kg bw was reinfused using supportive therapy (500 mg acetaminophen p.o., 2 mg clemastine i.v., 10 mg dihydrocodeine p.o.) on day 0. As antiviral and antibiotic prophylaxis, patients received daily acyclovir 2 × 400 mg p.o. for 6 months, dayli ciprofloxacin 2 × 500 mg p.o. until hematological reconstitution, and cotrimoxazole 960 mg p.o. three times a week for 3 months.\n\nOur analysis comprises MM patients who underwent HD melphalan chemotherapy and ASCT between January 2016 and August 2018 at our university hospital. At our institution antibiotic prophylaxis with ciprofloxacin or cotrimoxazole twice a day was stopped in January 2017 due to increasing prevalence of multidrug resistant bacteria and replaced by G-CSF support after ASCT and Pneumocystis jirovecii pneumonia prophylaxis with cotrimoxazole thrice a week in March 2017. Therefore, in a subset of patients, G-CSF (10 μg/kg bw per day) was administered starting from day 1 after ASCT until leukocyte recovery ≥1.0 × 109/L.\n\nAssessment of hematological reconstitution\nAfter HD melphalan and ASCT, blood counts were performed dayli until leukocyte and platelet engraftment. Leukocyte engraftment was defined by a leukocyte count of ≥1.0 × 109/L. Days in aplasia were defined as number of days with leukocytes < 1.0 × 109/L. Neutrophil recovery was defined as the first of three consecutive days with neutrophils ≥0.5 × 109/L. Platelet engraftment was defined as the first day of three consecutive values with platelet count ≥20 × 109/L without previous platelet transfusion for 7 days. We also calculated days until the platelet count ≥50 × 109/L as a variable for platelet engraftment, as the platelet count in some patients did not drop below 20 × 109/L or was not assessable due to platelet transfusion.\n\nStatistical analysis\nStatistical analysis was performed for the overall cohort and with regard to the number of reinfused CD34+ cells at ASCT. Due to the low number of patients in group 3, comparative statistics were performed between groups 1 and 2.\n\nDescriptive statistics and comparisons between groups were performed by R studio (Version 1.1.383, RStudio, Inc.). Data are presented as absolute numbers and percentages and as medians and ranges. To compare categorical variables, the chi-square test was used. To identify differences between group means, comparisons between the two groups were performed with unpaired two-tailed Student’s t-tests. The leukocyte, neutrophil and platelet recovery over time was calculated and plotted using Kaplan-Meier survival analysis. To calculate differences between the engraftment curves, a log-rank test was applied. The Cox proportional hazard model and the Breslow method were used for multivariate analysis. A p < 0.05 was considered statistically significant.\n\nResults\nPatient characteristics\nData from 148 MM patients (87 male and 61 female) were analyzed. The median age at first diagnosis was 60 (41–72) years. International Staging System (ISS) stage I was found in 85 (57%), ISS II in 25 (17%), and ISS III in 31 (21%) patients, in 7 patients ISS stage was not available. In patients with stage I and II disease (n = 11) according to the Salmon-Durie classification at first diagnosis, the indications for treatment initiation were based on the SLiM CRAB criteria and were abnormal kappa/lambda ratio/involved free light-chain level 100 mg/L or higher (n = 8), bone marrow infiltration by plasma cells above 60% (n = 1) and more than one focal lesion on magnetic resonance imaging (n = 2). The majority of patients (n = 70, 47%) received VCD for induction treatment. Patients who were treated within the GMMG HD6 trial received either VRD (n = 30, 20%) or elotuzumab-VRD (n = 33, 22%). The median number of induction treatment cycles was 4 (range 2–8). Nearly all patients (n = 143, 97%) received CAD/G-CSF for PBSC mobilization. To achieve the PBSC collection goal, plerixafor administration was necessary in 2 (1%) patients.\n\nTable 1 presents patient characteristics at first diagnosis and induction and mobilization therapy with regard to the overall cohort and subgroups defined by the number of transplanted CD34+ cells.\nTable 1 Patient characteristics and previous therapy regimens\n\nParameter\tOverall cohort\tGroup1 (3–4 × 106 CD34+ cells/kg bw)\tGroup 2 (2–2.5 × 106 CD34+ cells /kg bw)\tP value Group 1 vs. 2\tGroup 3 (< 2 × 106 CD34+ cells /kg bw)\t\nPatient number, n\t148\t86\t53\t/\t9\t\nSex, n (%)\t\t\t\t0.030\t\t\n Male\t87 (59)\t44 (51)\t37 (70)\t6 (67)\t\n Female\t61 (41)\t42 (49)\t16 (30)\t3 (33)\t\nDiagnosis of MM, n (%)\t\n Median age at first diagnosis, years (range)\t60 (41–72)\t60 (44–72)\t61 (41–71)\t0.854\t60 (46–72)\t\n Stage at first diagnosis\t\t\t\t/\t\t\n I\t7 (5)\t4 (5)\t3 (6)\t9 (100)\t\n II\t4 (3)\t3 (3)\t1 (2)\t0 (0)\t\n III\t136 (92)\t79 (92)\t48 (91)\t0 (0)\t\n NA\t1 (1)\t0 (0)\t1 (2)\t0 (0)\t\n A\t129 (87)\t78 (91)\t44 (83)\t/\t7 (78)\t\n B\t18 (12)\t8 (9)\t8 (15)\t2 (22)\t\n NA\t1 (1)\t0 (0)\t1 (2)\t0 (0)\t\n Heavy chain type\t\t\t\t0.767a\t\t\n IgG\t95 (64)\t56 (65)\t37 (70)\t2 (22)\t\n IgA\t29 (20)\t17 (20)\t8 (15)\t4 (44)\t\n IgD\t1 (1)\t1 (1)\t0 (0)\t0 (0)\t\n Light chain only\t23 (16)\t12 (14)\t8 (15)\t3 (33)\t\n Light chain type\t\t\t\t0.452\t\t\n kappa\t96 (65)\t53 (62)\t36 (68)\t7 (78)\t\n lambda\t52 (35)\t33 (38)\t17 (32)\t2 (22)\t\nInduction therapy, n (%)\t\n Median number of cycles (range)\t4 (2–8)\t4 (2–6)\t4 (3–8)\t\t4 (3–5)\t\n VCD\t70 (47)\t39 (45)\t28 (53)\t0.297b\t3 (33)\t\n VRD\t30 (20)\t22 (26)\t8 (15)\t0 (0)\t\n Elotuzumab-VRd\t33 (22)\t22 (26)\t10 (19)\t1 (11)\t\n Other/modifications\t15 (10)\t3 (3)\t7 (13)\t5 (56)\t\nMobilization therapy, n (%)\t\t\t\t/\t\t\n 1xCAD\t143 (97)\t85 (99)\t50 (94)\t8 (89)\t\n Other\t5 (3)\t1 (1)\t3 (6)\t1 (11)\t\nRemission prior PBSC collection, n (%)\t\n nCR\t25 (17)\t19 (22)\t5 (9)\t0.041c\t1 (11)\t\n VGPR\t52 (35)\t34 (40)\t17 (32)\t1 (11)\t\n PR\t54 (36)\t25 (29)\t25 (47)\t4 (44)\t\n MR\t8 (5)\t5 (6)\t2 (4)\t1 (11)\t\n SD\t1 (1)\t1 (1)\t0 (0)\t0 (0)\t\n NA\t8 (5)\t2 (2)\t4 (8)\t\t2 (22)\t\naIgD not included\n\nbOther/modifications not included\n\ncnCR/VGPR versus PR/MR/SD\n\nCAD cyclophosphamide, doxorubicin, dexamethasone; MM multiple myeloma; MR minimal response; NA not available; nCR near complete remission; PBSC peripheral blood stem cells; PR partial remission; SD stable disease; VCD bortezomib, VGPR very good partial remission; VRD(d) vincristine, lenalidomide (revlimid), dexamethasone; cyclophosphamide, dexamethasone; vs., versus\n\n\n\nCharacterization of HD/ASCT treatment according to the number of transplanted CD34+ cells\nTo answer the clinically important question whether the number of transplanted CD34+ cells impacts hematopoietic reconstitution after HD/ASCT therapy and achieving homogenization, we focused on the first HD/ASCT therapy in the patient’s course of treatment (groups 1 and 2). Fifty-three of the patients had a low dose graft (2–2.5 × 106 CD34+ cells/kg) and three of the patients had a very low dose graft (< 2 × 106 CD34+ cells/kg) for their first autologous transplant. However, reinfusion of < 2 × 106 CD34+ cells/kg at ASCT was a rare event. Therefore, patients undergoing second or third HD/ASCT treatment were included in group 3.\n\nIn the overall cohort, 88 (59%) patients had complete remission (CR), near complete remission (nCR) or very good partial remission (VGPR) prior to HD/ASCT treatment. The median age at HD/ASCT therapy was 61 (range 41–75) years. Melphalan dose modifications were performed for 2 (1%) patients. After HD/ASCT therapy, the number of patients who achieved CR, nCR or VGPR increased to 111 (74%).\n\nOther than the number of reinfused CD34+ cells (given by the definition of the groups), no statistically significant differences were found between groups 1 (3–4 × 106 CD34+ cells/kg bw) and 2 (2–2.5 × 106 CD34+ cells/kg bw) with regard to HD/ASCT treatment. Details of the HD/ASCT therapy for the overall cohort and the subgroups are summarized in Table 2.\nTable 2 High-dose chemotherapy/ASCT\n\nParameter\tOverall cohort\tGroup 1 (3–4 × 106 CD34+ cells /kg bw)\tGroup 2 (2–2.5 × 106 CD34+ cells /kg bw)\tP value Group 1 vs. 2\tGroup 3 (< 2 × 106 CD34+ cells /kg bw)\t\nASCTs analyzed, n\t148\t86\t53\t/\t9\t\nSequential ABSCTs, n (%)\t\t\t\t/\t\t\n First\t142 (96)\t86 (100)\t53 (100)\t3 (33)\t\n Second\t5 (3)\t0 (0)\t0 (0)\t5 (56)\t\n Third\t1 (1)\t0 (0)\t0 (0)\t1 (11)\t\nRemission pre ABSCT, n (%)\t\t\t\t0.168a\t\t\n CR\t2 (1)\t2 (2)\t0 (0)\t0 (0)\t\n nCR\t38 (26)\t28 (33)\t9 (17)\t1 (11)\t\n VGPR\t48 (32)\t26 (30)\t21 (40)\t1 (11)\t\n PR\t45 (30)\t21 (24)\t18 (34)\t6 (67)\t\n MR\t4 (3)\t3 (3)\t1 (2)\t0 (0)\t\n SD\t1 (1)\t0 (0)\t1 (2)\t0 (0)\t\n PD\t6 (4)\t2 (2)\t3 (6)\t1 (11)\t\n NA\t4 (3)\t4 (5)\t0 (0)\t0 (0)\t\nMedian age at ASCT, years (range)\t61 (41–75)\t61 (44–73)\t62 (41–72)\t0.886\t60 (50–75)\t\nTransplanted PBSCs\t\n Median transplanted CD34+ cells ×106/kg (range)\t3.2 (1.7–4.0)\t3.6 (3.0–4.0)\t2.3 (2.0–2.5)\t< 0.001\t1.9 (1.7–1.99)\t\n Median vitality, % (range)\t79 (53–93)\t76 (53–93)\t81 (58–93)\t0.012\t80 (66–93)\t\nHD chemotherapy, n (%)\t\t\t\t/\t\t\n Melphalan 2 × 100 mg/m2\t146 (99)\t85 (99)\t53 (100)\t8 (89)\t\n Dose reduction\t2 (1)\t1 (1)\t0 (0)\t1 (11)\t\nRemission post ASCT, n (%)\t\t\t\t0.316b\t\t\n CR\t15 (10)\t11 (13)\t4 (8)\t0 (0)\t\n nCR\t42 (28)\t30 (35)\t11 (21)\t1 (11)\t\n VGPR\t54 (36)\t27 (31)\t22 (42)\t5 (56)\t\n PR\t25 (17)\t11 (13)\t12 (23)\t2 (22)\t\n MR\t5 (3)\t3 (3)\t2 (4)\t0 (0)\t\n SD\t1 (1)\t1 (1)\t0 (0)\t0 (0)\t\n PD\t2 (1)\t2 (2)\t0 (0)\t0 (0)\t\n NA\t4 (3)\t1 (1)\t2 (4)\t1 (11)\t\na/bCR/nCR/VGPR versus PR/MR/SD/PD.\n\nASCT autologous blood stem cell transplantation; CR complete remission; HD high-dose; MR minimal response; NA not available; nCR near complete remission; PD progressive disease; PR partial remission; SD stable disease; VGPR very good partial remission; vs., versus\n\n\n\nHematopoietic reconstitution according to the number of transplanted CD34+ cells\nAll patients reached hematopoietic reconstitution after HD/ASCT treatment, even those who received < 2 × 106 CD34+ cells/kg bw (group 3). Since the number of patients in group 3 (< 2 × 106 CD34+ cells/kg bw) was very low (n = 9), statistical comparisons were performed between groups 1 (3–4 × 106 CD34+ cells/kg bw) and 2 (2–2.5 × 106 CD34+ cells/kg bw) only (Table 3).\nTable 3 Hematopoietic reconstitution after high-dose chemotherapy/ASCT by number of transplanted CD34+ cells\n\nParameter\tOverall cohort\tGroup 1 (3–4 × 106 CD34+ cells /kg bw)\tGroup 2 (2–2.5 × 106 CD34+ cells /kg bw)\tP value Group 1 vs. 2\tGroup 3 (< 2 × 106 CD34+ cells /kg bw)\t\nASCTs analyzed, n\t148\t86\t53\t\t9\t\nG-CSF support, n (%)\t\t\t\t0.271\t\t\n Yes\t62 (42)\t34 (40)\t26 (49)\t2 (22)\t\n No\t86 (58)\t52 (60)\t27 (51)\t7 (78)\t\nLeukocyte reconstitution\t\t\t\t0.393\t\t\n n available\t144\t82\t53\t9\t\n Days to L ≥ 1.0 × 109/L\t12 (9–24)\t12 (9–23)\t12 (10–24)\t12 (9–16)\t\nNeutrophil reconstitution\t\t\t\t/\t\t\n n available\t42\t17\t23\t2\t\n Days to N ≥ 0.5 × 109/L\t14 (9–19)\t14 (9–19)\t13 (10–18)\t13 (11–14)\t\nAplasia\t\t\t\t0.513\t\t\n n available\t116\t62\t46\t8\t\n Days in aplasia\t9 (4–20)\t9 (4–19)\t8 (5–20)\t9 (5–13)\t\nPlatelet reconstitution\t\t\t\t< 0.001\t\t\n n available\t144\t85\t51\t8\t\n Days to platelets ≥20 × 109/L\t12 (9–21)\t11 (9–16)\t13 (10–21)\t13 (9–19)\t\n n available\t81\t55\t23\t0.001\t3\t\n Days to platelets ≥50 × 109/L\t14 (10–22)\t14 (10–18)\t14 (13–22)\t15 (13–18)\t\nIf not otherwise indicated, the data are presented as the median (range)\n\nASCT autologous blood stem cell transplantation; G-CSF granulocyte-colony stimulating factor; L leukocytes, NA not available; N neutrophils; vs., versus\n\n\n\nThe median time to achieve leukocytes ≥1.0 × 109/L after PBSC reinfusion was 12 days in all groups and ranged between 9 and 23 days, 10–24 days and 9–16 days in groups 1, 2 and 3, respectively. No statistically significant difference in time to leukocyte engraftment was observed between groups 1 and 2 (Fig. 1A, p = 0.393). The median duration of aplasia was 9 (range 4–19), 8 (range 5–20) and 9 (5–13) days for groups 1, 2 and 3, respectively, and no statistically significant differences were found between groups 1 and 2.\nFig. 1 Hematopoietic reconstitution after HD/ASCT by the number of reinfused CD34+ cells. The relative number of patients with leukocyte recovery ≥1.0 × 109/L (a) and platelet recovery ≥20 × 109/L (b) is shown. The results are grouped according to the number of reinfused CD34+ cells (3–4 versus 2–2.5 × 106 CD34+ cells/kg bw)\n\n\n\nNeutrophil reconstitution was evaluated in a small proportion of patients (ngroup1 = 17, ngroup2 = 23, ngroup3 = 2) only. The median time from ASCT to neutrophil recovery was 14 (range 9–19), 13 (range 10–18) and 13 (11–14) days for groups 1, 2 and 3, respectively.\n\nThe median duration to platelet recovery ≥20 × 109/L was 11 (range 9–16), 13 (range 10–21) and 13 (9–19) days for groups 1, 2 and 3, respectively. Patients who received a high number of CD34+ cells (3–4 × 106 CD34+ cells/kg bw, group 1) showed a faster platelet ≥20 × 109/L recovery than patients who received a low number of reinfused CD34+ cells (2–2.5 × 106 CD34+ cells/kg bw, group 2) (Fig. 1B, p < 0.001).\n\nData on platelet recovery ≥50 × 109/L were available in a smaller proportion of patients (ngroup1 = 55, ngroup2 = 23, ngroup3 = 3) only. The median duration to platelet recovery ≥50 × 109/L was 14 (range 10–18), 14 (range 13–22) and 15 (13–18) days for groups 1, 2 and 3, respectively. Similar to platelet reconstitution ≥20 × 109/L, the log-rank comparison revealed a significantly faster platelet recovery ≥50 × 109/L in patients who received a high number of CD34+ cells than patients who received a low number of CD34+ cells (p = 0.001).\n\nOverall, the univariate analysis revealed an association between a higher number of reinfused CD34+ cells and fast platelet recovery after ASCT. But, this effect was not evident for leukocyte reconstitution. As a proportion of the analyzed patients (n = 62, 42%) received G-CSF support after ASCT, we hypothesized that G-CSF administration might significantly accelerate leukocyte reconstitution and mask the influence of the number of reinfused CD34+ cells. A subgroup analysis based on the number of reinfused CD34+ cells and G-CSF support status showed that the median time to leukocyte reconstitution was significantly shortened by G-CSF support from 14 to 10 days in the 3–4 × 106 CD34+ cells/kg bw group and from 14 to 11 days in the 2–2.5 × 106 CD34+ cells/kg bw group (p < 0.001, respectively; Fig. 2A). G-CSF administration significantly shortened the time to platelet recovery ≥20 × 109/L in the 2–2.5 × 106 CD34+ cells/kg bw group (p = 0.020) but not in the 3–4 × 106 CD34+ cells/kg bw group (p = 0.200, Fig. 2B). No statistically significant differences in time to platelet recovery ≥50 × 109/L were observed with regard to G-CSF administration either in the 3–4 × 106 CD34+ cells/kg bw group (p = 0.800) or in the 2–2.5 × 106 CD34+ cells/kg bw group (p = 0.200).\nFig. 2 Hematopoietic reconstitution after HD/ASCT by the number of reinfused CD34+ cells and by G-CSF support status. The relative number of patients with leukocyte recovery ≥1.0 × 109/L (a) and platelet recovery ≥20 × 109/L (b) is shown. The results are grouped according to the number of reinfused CD34+ cells (3–4 versus 2–2.5 × 106 CD34+ cells/kg bw) and G-CSF support status\n\n\n\nIn the multivariate analysis, neither age at ASCT nor remission status pre-ASCT affected the duration of hematopoietic reconstitution. However, the number of reinfused CD34+ cells significantly influenced the duration until hematopoietic recovery. A low number of reinfused CD34+ cells at ASCT was associated with significantly prolonged time until leukocyte reconstitution ≥1.0 × 109/L (p = 0.010) and platelet recovery ≥20 × 109/L (< 0.001) and ≥ 50 × 109/L (p = 0.003). As indicated by the univariate analysis, G-CSF support after ASCT significantly accelerated leukocyte reconstitution (p < 0.001) but not platelet reconstitution. The results of the multivariate analysis including the hazard ratio (HR) and 95% confidence interval (CI95%) are given in Table 4.\nTable 4 Hematopoietic reconstitution - multivariate analysis\n\nParameter\tLeukocyte reconstitution (≥1.0 × 109/L)\tAplasia\tPlatelet reconstitution (≥20 × 109/L)\tPlatelet reconstitution (≥50 × 109/L)\t\nn analyzed\t130\t103\t131\t76\t\n\tHR (CI95)\tP value\tHR (CI95)\tP value\tHR (CI95)\tP value\tHR (CI95)\tP value\t\nAge at ABSCT (≤60 vs. > 60 years)\t1.038 (0.730–1.476)\t0.837\t1.101 (0.725–1.669)\t0.652\t1.086 (0.762–1.547)\t0.649\t0.841 (0.529–1.336)\t0.463\t\nRemission pre ABSCT (CR/nCR/VGPR vs. PR/MR/SD/PD)\t0.989 (0.681–1.436)\t0.952\t1.129 (0.735–1.734)\t0.581\t1.098 (0.755–1.598)\t0.625\t1.060 (0.650–1.729)\t0.815\t\nG-CSF support (no vs. yes)\t16.742 (8.514–32.923)\t< 0.001\t9.634 (5.425–17.107)\t< 0.001\t1.365 (0.951–1.958)\t0.091\t1.084 (0.655–1.794)\t0.753\t\nCD34+ cells/kg bw transplanted (3–4 vs. 2–2.5 × 106)\t0.607 (0.416–0.885)\t0.010\t0.573 (0.375–0.875)\t0.010\t0.438 (0.299–0.642)\t< 0.001\t0.442 (0.258–0.755)\t0.003\t\nASCT autologous blood stem cell transplantation; CI confidence interval; CR complete remission; HR hazard ratio; G-CSF granulocyte-colony stimulating factor; MR minimal response; nCR near complete remission; PD progressive disease; PR partial remission; SD stable disease; VGPR very good partial remission; vs., versus\n\n\n\nNo severe adverse events were observed during or after the considered HD/ASCT in the analyzed cohort.\n\nDiscussion\nWe retrospectively analyzed the short-term hematopoietic reconstitution in MM patients who received a low-dose PBSC graft after HD chemotherapy with melphalan.\n\nA small cohort of MM patients (n = 9) received a very low (< 2.0 × 106/kg bw) number of CD34+ cells after HD chemotherapy. These numbers might be an insufficient PBSC graft, as defined by the current national guidelines and international agreements [14, 30]. However, despite the low CD34+ cell count of the transplant all of the patients in group 3 reached hematopoietic reconstitution. Although not assessable by comparative statistics due to low patient numbers, the median time until leukocyte recovery ≥1.0 × 109/L (12 days) and platelet recovery ≥20 × 109/L (13 days) in patients who received low numbers of CD34+ cells was similar or even identical to that of patients who received PBSC grafts with high numbers of CD34+ cells. This is in line with the results of earlier studies that demonstrated successful hematopoietic reconstitution in MM patients who received 1.0–2.0 × 106 CD34+ cells/kg as autologous grafts after HD therapy [31, 32]. Nevertheless these and further studies also demonstrated that the use of high CD34+ cell doses reduces the time until hematopoietic recovery and lowers the risk of graft failure [33]. An analysis of engraftment kinetics after myeloablative chemotherapy additionally showed a clear dose-response relationship between the number of CD34+ cells infused and neutrophil and platelet engraftment. Although a minimal threshold CD34+ cell dose could not be defined, ≥5.0 × 106 CD34+ cells/kg appeared to be optimal [34]. Furthermore in allogeneic T cell-depleted bone marrow transplants it has been reported that CD34+ cell dose was the only variable significantly associated with treatment-related mortality, primarily due to infections and cytopenia and therefore higher CD34+ cell doses may improve outcome in engrafting [35].\n\nAll MM patients who received low-dose (2–2.5 × 106 CD34+ cells/kg bw) PBSC grafts in this analysis also showed successful hematopoietic recovery after HD melphalan treatment. Due to the large number of evaluated patients, the cohort was accessible to comparative statistics. Therefore, MM patients who received 3–4 × 106 CD34+ cells/kg bw at ASCT were chosen as the comparator group. As previously reported, this number represents the median reference value of reinfused CD34+ cells at our institution [20, 21]. Both cohorts had similar age but not sex distributions. Importantly, the type of induction treatment and mobilization therapy was similar in both groups, and no statistically significant differences were identified with regard to remission status prior to ASCT. Therefore, the comparison between groups is based on highly homogeneous cohorts, which, in addition to relatively high case numbers, represents a major strength of the current analysis.\n\nThe time to leukocyte, neutrophil and platelet recovery after HD/ASCT treatment observed in patients who received 3–4 × 106 CD34+ cells/kg bw at ASCT was similar to that previously described in MM patients. In particular, Gerzt et al. reported a median 15 days until neutrophil and platelet recovery ≥50 × 109/L, which is in line with our findings [36].\n\nAs revealed by multivariate analysis, reinfusion of lower numbers of CD34+ cells (2–2.5 compared to 3–4 × 106 CD34+ cells/kg bw) was associated with significantly prolonged time to leukocyte recovery ≥1.0 × 109/L and platelet recovery ≥20 × 109/L and ≥ 50 × 109/L. This is in line with the findings of previous reports that emphasized the positive correlation between the CD34+ cell dose and time to hematopoietic reconstitution [30, 37, 38]. Remarkably a further study showed that patients who received lower stem cell doses had an increased risk of > 3 days of absolute neutropenia, compared to patients who received higher stem cell infusions, while at a median follow-up of 51 months, there was no difference in survival between patients with absolute neutropenia > 3 days versus patients with absolute neutropenia for ≤3 days [39]. On the other hand, it was reported that for older MM patients undergoing HD chemotherapy and ASCT infusion of higher stem cell doses did not yield a reduction in symptom burden or engraftment time in the first weeks after ASCT [40]. Also in accordance to this study multiple, fractionated stem cell infusions (days 0, + 2, + 4, + 6) following HD melphalan did not enhance engraftment kinetics or significantly alter MM patients’ clinical course following ASCT [41].\n\nG-CSF support after HD/ASCT treatment significantly shortened the time until leukocyte recovery ≥1.0 × 109/L but not until platelet recovery. These findings are consistent with previous studies, demonstrating that leukocyte and neutrophil engraftment after autologous progenitor cell transplantation can be accelerated by G-CSF support [42–44]. As reported by several studies a single dose of pegfilgrastim is a safe and efficacious alternative to daily injections of filgrastim while patients who received pegfilgrastim showed faster engraftment, lower incidence of febrile neutropenia and a shorter hospitalization [42, 45].\n\nAs demonstrated by multivariate analysis, G-CSF support accelerates leukocyte engraftment to a much higher extent than a large reinfusion dose of CD34+ cells (HR 16.742 versus 0.607). To the best of our knowledge, this is the first analysis to evaluate the mutual effect of G-CSF administration and CD34+ cell dose on hematopoietic recovery after ASCT.\n\nNo severe adverse events were observed during or after the considered HD/ASCT in the analyzed cohort of all 148 MM patients. Of note, during the analysis period we recorded one heavily pretreated 60-year-old female patient who presented with a severe adverse event (Pneumocystis jiroveci pneumonia) after a second HD/ASCT receiving a low-dose PBSC graft (2.15 × 106 CD34+ cells/kg bw). However, this patient did not meet the inclusion criteria of the current analysis (not first HD/ASCT) and was therefore not evaluated in the study cohort. Remarkably in contrast to that finding, none of the intensely pretreated patients in group 3 presented with a severe adverse event (no severe infections or transfer to intensive care unit was reported) after autologous transplant of a very low PBSC graft.\n\nSo far there is no reported clinical experience in the reinfusion of PBSC grafts below the minimum of 2.0 × 106 CD34+ cells/kg bw defined by international guidelines. Yet there are many factors, such as higher age of MM patients, prior extensive chemotherapy or radiation therapy, which are associated with poor PBSC mobilization. Triplet regimens that include the immunomodulatory agent lenalidomide have emerged as standard-of-care induction therapy in transplant-eligible patients with MM. However, lenalidomide has been reported to have an adverse effect on PBSC collection [46–48]. A correlation between the length of lenalidomide therapy and decrease in PBSC yield has been reported by different groups. Up to four cycles of lenalidomide exposure may have minimal negative impact on PBSC collection and Plerixafor may overcome these negative effects [49, 50]. Nevertheless, it may be challenging to achieve the target PBSC yield after lenalidomide-containing regimens and it may result in low-dose grafts with CD34+ cell doses < 2.0 × 106/kg bw. Reporting the few available patients, we aimed to exemplarily demonstrate an adequate engraftment of PBSC grafts with CD34+ cell count below the internationally accepted threshold of 2.0 × 106/kg bw and therefore to encourage other centers to perform ASCTs with very low dose PBSC grafts. This is particularly of outstanding importance in a clinical setting when a HD chemotherapy and ASCT represent a therapeutic option but an additional PBSC collection is not feasible.\n\nConclusion\nIn conclusion, our study demonstrates that quantitative and timely sufficient hematopoietic reconstitution is achievable upon reinfusion of low-dose PBSC grafts after HD therapy in MM patients. Further evaluation is required to confirm adequate hematopoietic engraftment in more MM patients who receive very low dose PBSC grafts with < 2.0 × 106 CD34+ cells/kg bw after HD chemotherapy. While the impact of the CD34+ cell dose is significant but clinically marginal, G-CSF support substantially accelerates the time until leukocyte recovery.\n\nAbbreviations\nASCTAutologous blood stem cell transplantation\n\nbwBody weight\n\nCADCyclophosphamide, doxorubicin, dexamethasone\n\nCIConfidence interval\n\nCRcomplete remission\n\nDMSOCryosure-D dimethyl sulfoxide\n\nG-CSFGranulocyte-colony-stimulating factor\n\nHDHigh-dose\n\nHRHazard ratio\n\nISSInternational Staging System\n\nLLiter\n\nLPLeukapheresis\n\nMMMultiple myeloma\n\nNCNucleated cell\n\nnCRNear complete remission\n\nPBSCPeripheral blood stem cell\n\np.o.Per os\n\nPRPartial remission\n\nVCDBortezomib, cyclophosphamide, dexamethasone\n\nVGPRVery good partial remission\n\nVRDBortezomib, lenalidomide, dexamethasone\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nNone.\n\nConsent for publcation\nNot applicable.\n\nAuthors’ contributions\nSSa and KK designed the study, acquired, analysed and interpreted the data and drafted the manuscript. TB, KK and MK performed biostatistics. SSa, PP, AS, MC, KJ, PW, CMT and KK were involved in patient selection as well as clinical decision making and contributed data for patient characteristics and/or transplantation parameters. All authors revised and approved the submitted manuscript.\n\nFunding\nnone.\n\nAvailability of data and materials\nThe datasets generated and/or analyzed during the current study are not publicly available due to current data protection directive but are available from the corresponding author on reasonable request within 6 months after publication of the manuscript.\n\nEthics approval and consent to participate\nThe study was performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (Ethic’s committee of the University of Heidelberg, S337/2009, S096/2017). Written informed consent for study participation was obtained from all patients.\n\nCompeting interests\nThe first author and all coauthors confirm that there are no potential conflicts of interest to disclose, except the following: Sandra Sauer: travel grants or honoraria for presentations for Celgene, BMS, Janssen, Takeda and Amgen. Patrick Wuchter: served on advisory boards for Sanofi. Carsten Müller-Tidow: research support and support for clinical trials from multiple pharmaceutical companies. Katharina Kriegsmann: research support from BMS, Celgene, Sanofi, Morphosys.\n==== Refs\nReferences\n1. Hubel K de la Rubia J Azar N Corradini P Current status of haematopoietic autologous stem cell transplantation in lymphoid malignancies: a European perspective Eur J Haematol 2015 94 12 22 10.1111/ejh.12362 24797118 \n2. Chute JP. Autologous stem cell transplantation for multiple myeloma: underutilized but highly effective. J Natl Cancer Inst. 2019;111(1):7–8.\n3. 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"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "20(1)",
"journal": "BMC cancer",
"keywords": "Autologous stem-cell transplantation; Insufficient graft; Multiple myeloma; Peripheral blood stem cells",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D036102:Peripheral Blood Stem Cell Transplantation; D000072916:Peripheral Blood Stem Cells; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D014182:Transplantation, Autologous",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "353",
"pmc": null,
"pmid": "32334570",
"pubdate": "2020-04-25",
"publication_types": "D016428:Journal Article",
"references": "24973360;23591714;23298856;29933906;11436102;15684827;24797118;8874224;23420184;29897483;27249749;9763111;19450756;14695409;18033320;19925876;25225424;8649495;8817388;30845862;7540888;29061534;28228122;19540167;22298390;7579367;7529066;17581613;24686988;24637898;27511158;21572461;26758672;21060027;24771277;23387937;26253006;20062102;24104408;23186983;28013016;12736280",
"title": "Low-dose peripheral blood stem cell graft after high-dose chemotherapy - an evaluation of hematopoietic reconstitution.",
"title_normalized": "low dose peripheral blood stem cell graft after high dose chemotherapy an evaluation of hematopoietic reconstitution"
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"companynumb": "DE-ALVOGEN-2020-ALVOGEN-108390",
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"actiondrug": "5",
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"activesubstancename": "MELPHALAN"
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... |
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"abstract": "Although intravascular thrombi and infarct-type necrosis have been reported in leiomyomas following tranexamic acid therapy, intratumoral vasculopathy resembling acute atherosis has not been reported to date in patients without exposure to gonadotropin receptor agonist. We describe a case of intratumoral vasculopathy resembling acute atherosis in a leiomyoma in a 49-year-old woman, with hereditary hemorrhagic telangiectasia and menorrhagia, treated with tranexamic acid. The patient had no exposure to gonadotropin receptor agonists. Pathologic examination of the hysterectomy specimen showed a 5.7-cm submucosal leiomyoma containing multiple arteries with fibrinoid change accompanied with abundant subintimal foamy macrophages and occasional luminal thrombi. The vascular media showed scant lymphocytic inflammation without necrosis. The leiomyoma contained numerous mast cells and edematous areas. Vessels outside of the leiomyoma showed neither fibrinoid changes nor inflammation. The patient is alive and well with no signs of systemic vasculitis. We demonstrate that intratumoral vasculopathy resembling acute atherosis may be seen in leiomyomas from patients taking tranexamic acid and postulate that this change results in vascular thrombosis, tumoral edema, and infarct-type necrosis.",
"affiliations": "Department of Pathology and Immunology (S.K., H.R.K.), Washington University School of Medicine, St Louis, Missouri.",
"authors": "Kudose|Satoru|S|;Krigman|Hannah R|HR|",
"chemical_list": "D014148:Tranexamic Acid",
"country": "United States",
"delete": false,
"doi": "10.1097/PGP.0000000000000337",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-1691",
"issue": "36(4)",
"journal": "International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists",
"keywords": null,
"medline_ta": "Int J Gynecol Pathol",
"mesh_terms": "D005260:Female; D006801:Humans; D007044:Hysterectomy; D007889:Leiomyoma; D008595:Menorrhagia; D008875:Middle Aged; D009336:Necrosis; D013683:Telangiectasia, Hereditary Hemorrhagic; D014148:Tranexamic Acid; D014592:Uterine Hemorrhage; D014594:Uterine Neoplasms; D014599:Uterus; D014657:Vasculitis",
"nlm_unique_id": "8214845",
"other_id": null,
"pages": "364-368",
"pmc": null,
"pmid": "27801754",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intratumoral Vasculopathy in Leiomyoma Treated With Tranexamic Acid.",
"title_normalized": "intratumoral vasculopathy in leiomyoma treated with tranexamic acid"
} | [
{
"companynumb": "US-MYLANLABS-2017M1049616",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "VITAMINS"
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"abstract": "The issue of antipsychotic treatment during pregnancy is subject to substantial uncertainty and some controversy among healthcare providers, specifically pertaining to second-generation antipsychotics (SGAs) that are subject to a large gap in safety data during pregnancy compared with antidepressants. The amount of safety data for the use of SGAs during pregnancy is rapidly increasing, thus constantly changing the level of evidence. We performed a clinically focused review on the safety of SGA during pregnancy. Twenty-three studies provided various pregnancy outcomes for 14,382 pregnant women exposed to an SGA during pregnancy. In utero exposure to aripiprazole, olanzapine, and quetiapine is not associated with increased risks of major congenital malformations, whereas risperidone and paliperidone may be associated with a very minor increased risk of congenital malformations. Safety data on ziprasidone and clozapine remain scarce and insufficient for a quantitative safety evaluation. No or minimal safety data are available for amisulpride, asenapine, lurasidone, and sertindole. For other pregnancy outcomes of interest, e.g. miscarriage, stillbirth, and small for gestational age, the available data overall do not suggest a clinically important increased risk, and do not allow for a meaningful stratification on individual drug level. Furthermore, for neonatal adaption and childhood neurodevelopment, the data do not allow for a meaningful risk assessment. It is imperative that factors in addition to safety data, e.g. individual disease history, characteristics and treatment response, adverse reaction profile, and patient preferences, be considered for the individual patient when choosing specific SGA treatment during pregnancy.",
"affiliations": "Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. pdamkier@health.sdu.dk.;Center for Neuropsychiatric Depression Research, Mental Health Center Glostrup, Glostrup, Denmark.",
"authors": "Damkier|Per|P|http://orcid.org/0000-0003-0591-7187;Videbech|Poul|P|http://orcid.org/0000-0003-0127-4348",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40263-018-0517-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1172-7047",
"issue": "32(4)",
"journal": "CNS drugs",
"keywords": null,
"medline_ta": "CNS Drugs",
"mesh_terms": "D014150:Antipsychotic Agents; D005260:Female; D006801:Humans; D001523:Mental Disorders; D011247:Pregnancy; D011248:Pregnancy Complications",
"nlm_unique_id": "9431220",
"other_id": null,
"pages": "351-366",
"pmc": null,
"pmid": "29637530",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "20473073;22474072;26688372;18480684;21471609;10917399;27852343;23764684;23559219;15883651;28768628;21208779;21381186;24011886;22752236;28440103;18450655;27029490;25224918;15904431;19572407;20824455;25683615;25171856;15978773;17343431;18378767;26791406;25536446;25909513;23902726;25972273;23218063;25822804;25932852;19137446;24163279;28495514;24275849;28585153;26344706;24787688;27540849;15816786;27866497;18185492;18056236;26274044;25844580;22926593;24566677;26162087;23852139;26236577;1615423;25509060;26441156;26930528",
"title": "The Safety of Second-Generation Antipsychotics During Pregnancy: A Clinically Focused Review.",
"title_normalized": "the safety of second generation antipsychotics during pregnancy a clinically focused review"
} | [
{
"companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2019-04693",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
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"abstract": "Catatonia is a symptom seen in a variety of neuropsychiatric conditions, including anti-N-Methyl D-aspartate receptor (NMDAR) encephalitis. When associated with anti-NMDAR encephalitis, catatonia is resistant to standard therapy. However, electroconvulsive therapy (ECT) has shown promising success in management. This case report presents a 25-year-old African American female who presented to the emergency room with nervousness, sweating, insomnia, and visual and auditory hallucinations. She was treated symptomatically for anxiety but returned to the hospital after she continued to experience worsening symptoms. Her anxiety worsened, and she became more agitated, warranting an extensive workup, including magnetic resonance imaging (MRI) and electroencephalogram (EEG), which showed normal findings. She also had an anti-NMDA receptor antibodies titer done, which showed a positive titer result. She was treated with intravenous steroids, intravenous immunoglobulin G (IgG), plasma exchange, and rituximab, which did not improve her symptoms, and she was discharged home after a prolonged hospital stay. On follow-up visits, she reported worsening confusion, aggression, and suicidal behaviors. The patient was readmitted, during which she experienced catatonia and psychiatric symptoms, and her anti-NMDAR titer had increased to 1:1280. Further treatments with intravenous steroids, intravenous IgG, plasma exchange, and rituximab, including haloperidol and clonazepam, failed to improve her condition. However, her condition improved remarkably following treatment with 12 rounds of ECT. No randomized control trial has been done to demonstrate the effectiveness of ECT in the treatment of anti-NMDAR encephalitis despite various reports of the effectiveness of this treatment modality. This case report adds to the growing clinical evidence in support of the use of ECT in anti-NMDAR encephalitis patients with catatonia. ECT can be incorporated as standard protocol in the treatment of catatonia and associated psychiatric symptoms when managing a patient with anti-NMDAR encephalitis associated with catatonic features.",
"affiliations": "Neurology, Tampa General Hospital, Tampa, USA.;Psychiatry, Reading Hospital Tower Health, West Reading, USA.;Psychiatry, Reading Hospital Tower Health, West Reading, USA.;Psychiatry and Behavioral Sciences, West Oaks Behavioral Hospital, Houston, USA.;Developmental Behavioral Pediatrics, Dell Children's Medical Center, Austin, USA.;Public Health, Georgia Department of Public Health, Savannah, USA.;Public Health, Greater Philadelphia Health Action, Philadelphia, USA.;Psychiatry, Drexel University College of Medicine, Philadelphia, USA.",
"authors": "Olaleye|Kehinde T|KT|;Oladunjoye|Adeolu O|AO|;Otuada|David|D|;Anugwom|Gibson O|GO|;Basiru|Tajudeen O|TO|;Udeogu|Jennifer E|JE|;Opaleye-Enakhimion|Taiwo|T|;Espiridion|Eduardo D|ED|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.15706",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.15706\nNeurology\nPsychiatry\nThe Effectiveness of Electroconvulsive Therapy on Catatonia in a Case of Anti-N-Methyl-D-Aspartate (Anti-NMDA) Receptor Encephalitis\nMuacevic Alexander\nAdler John R\nOlaleye Kehinde T 1\nOladunjoye Adeolu O 23\nOtuada David 2\nAnugwom Gibson O 45\nBasiru Tajudeen O 6\nUdeogu Jennifer E 7\nOpaleye-Enakhimion Taiwo 8\nEspiridion Eduardo D 91011122\n1 Neurology, Tampa General Hospital, Tampa, USA\n2 Psychiatry, Reading Hospital Tower Health, West Reading, USA\n3 Medical Critical Care, Boston Children's Hospital, Boston, USA\n4 Psychiatry and Behavioral Sciences, West Oaks Behavioral Hospital, Houston, USA\n5 Psychiatry and Behavioral Sciences, Houston Behavioral Healthcare Hospital, Houston, USA\n6 Developmental Behavioral Pediatrics, Dell Children's Medical Center, Austin, USA\n7 Public Health, Georgia Department of Public Health, Savannah, USA\n8 Public Health, Greater Philadelphia Health Action, Philadelphia, USA\n9 Psychiatry, Drexel University College of Medicine, Philadelphia, USA\n10 Psychiatry, West Virginia School of Osteopathic Medicine, Lewisburg, USA\n11 Psychiatry, West Virginia University School of Medicine, Martinsburg, USA\n12 Psychiatry, Philadelphia College of Osteopathic Medicine, Philadelphia, USA\nEduardo D. Espiridion edjen19meg@gmail.com\n17 6 2021\n6 2021\n13 6 e1570617 6 2021\nCopyright © 2021, Olaleye et al.\n2021\nOlaleye et al.\nhttps://creativecommons.org/licenses/by/3.0/ 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.\nThis article is available from https://www.cureus.com/articles/61968-the-effectiveness-of-electroconvulsive-therapy-on-catatonia-in-a-case-of-anti-n-methyl-d-aspartate-anti-nmda-receptor-encephalitis\nCatatonia is a symptom seen in a variety of neuropsychiatric conditions, including anti-N-Methyl D-aspartate receptor (NMDAR) encephalitis. When associated with anti-NMDAR encephalitis, catatonia is resistant to standard therapy. However, electroconvulsive therapy (ECT) has shown promising success in management. This case report presents a 25-year-old African American female who presented to the emergency room with nervousness, sweating, insomnia, and visual and auditory hallucinations. She was treated symptomatically for anxiety but returned to the hospital after she continued to experience worsening symptoms. Her anxiety worsened, and she became more agitated, warranting an extensive workup, including magnetic resonance imaging (MRI) and electroencephalogram (EEG), which showed normal findings. She also had an anti-NMDA receptor antibodies titer done, which showed a positive titer result. She was treated with intravenous steroids, intravenous immunoglobulin G (IgG), plasma exchange, and rituximab, which did not improve her symptoms, and she was discharged home after a prolonged hospital stay. On follow-up visits, she reported worsening confusion, aggression, and suicidal behaviors. The patient was readmitted, during which she experienced catatonia and psychiatric symptoms, and her anti-NMDAR titer had increased to 1:1280. Further treatments with intravenous steroids, intravenous IgG, plasma exchange, and rituximab, including haloperidol and clonazepam, failed to improve her condition. However, her condition improved remarkably following treatment with 12 rounds of ECT. No randomized control trial has been done to demonstrate the effectiveness of ECT in the treatment of anti-NMDAR encephalitis despite various reports of the effectiveness of this treatment modality. This case report adds to the growing clinical evidence in support of the use of ECT in anti-NMDAR encephalitis patients with catatonia. ECT can be incorporated as standard protocol in the treatment of catatonia and associated psychiatric symptoms when managing a patient with anti-NMDAR encephalitis associated with catatonic features.\n\nelectro-convulsive therapy\nbush francis catatonia scale\ncatatonia\nanti nmda receptor encephalitis\nencephalitis\nThe 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\n\nAnti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare autoimmune encephalitis that was first described by Josep Dalmau and his colleague in 2007 [1]. It is suggested to be the most common autoimmune cause of encephalitis after demyelinating encephalitis [2]. Although anti-NMDAR encephalitis can occur at any age and in both sexes, about 80% of cases are females, mostly 18 years and younger [3]. In many published cases, patients have underlying tumors, with ovarian teratomas being the most implicated [3-4]. Frequently, symptoms of anti-NMDAR encephalitis manifest with acute neuropsychiatric presentations such as mania, visual and auditory hallucinations, personality change, cognitive decline, catatonia, and new-onset behavioral problems [3,5-6]. \n\nThe management of anti-NMDAR encephalitis is challenging, as its neuropsychiatric manifestations often mask the underlying etiology. This is especially challenging for psychiatrists who are usually the first to assess approximately 77% of these patients [3,7] and can be treated as a case of schizophrenia because of the similar presentation of psychotic symptoms in NMDAR encephalitis [4,8]. The diagnosis is confirmed by identifying anti-NMDAR antibodies in cerebrospinal fluid (CSF) [1,5]. It has been suggested that early treatment is essential, especially in children [9-10], which is why prompt diagnosis is paramount. Presently, the mortality rate is as high as 7%, and the chances of complete recovery decrease with disease progression [3]; therefore, it is important that the treatment options for NMDAR encephalitis are effective [5]. The current treatment options available for the underlying etiology include plasmapheresis and immunomodulatory agents. Based on current evidence, immunotherapy alone does not adequately treat this condition. Available literature suggests that electroconvulsive therapy (ECT) improves the associated symptoms of stupor, catatonia, mutism, delusions, and psychosis [4,8,11]. Very few studies describe the consistent use of ECT for anti-NMDA encephalitis with catatonia and its associated psychiatric symptoms.\n\nIn this report, we present a case of a 25-year-old female with severe psychiatric symptoms, including psychotic symptoms, aggressive symptoms, and catatonia, despite treatment with immunotherapy, plasma exchange, rituximab, and intravenous (IV) steroids. Currently, there is limited information in the literature regarding the consistent use of ECT in the management of the acute, debilitating neuropsychiatric symptoms of anti-NMDAR encephalitis with catatonia.\n\nCase presentation\n\nHistory of present illness\n\nA 25-year-old African American female with no known past medical history or psychiatric history was brought to the hospital by her mother due to changes in her behavior (nervousness, sweating, lack of sleep) and palpitation. The patient experienced auditory and visual hallucinations (yelled at people she alone could see to keep them away from her). The patient's mother stated that she thought the patient was suicidal when she heard her saying, \"I am going to die,\" prompting her to call 911. However, there was no evidence of suicidality at this time. The patient's mother reported the patient's occasional use of cannabis and alcohol. At the emergency room (ER), a diagnosis of anxiety was made, and she was treated and discharged home on hydroxyzine 25 mg every six hours. However, her symptoms persisted and even worsened despite compliance with medications. She spent the next two days in her room, unable to sleep, anxious, and repeating the exact words, \"you are going to be okay.\" Her anxiety worsened and became more agitated warranting readmission and an extensive workup that included anti-NMDA receptor antibodies showing an NMDA titer of 1:320 in her CSF and confirming anti-NMDA receptor encephalitis. IV steroids, plasma exchange, and rituximab were then administered during this patient's long hospital stay. She completed numerous lab tests, including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG), which were negative. She was then discharged home for later follow-up visits.\n\nAfter two days, she returned to the hospital with a report of worsening combativeness, confusion, and aggression at home. She exhibited suicidal behaviors, including possessing a razor blade to hurt herself and overdosing on a handful of unspecified medications. NMDA titers were repeated and showed increased levels of 1:1280. IV immunoglobulins (IVIG) and intravenous methylprednisolone and rituximab were repeated. She was later transferred to a higher level care center due to the concern of no improvement in her aggression and combativeness with new features of catatonia, including mutism, sitting abnormally still, staring, catalepsy, waxy flexibility, occasional impulsivity, and occasional aggression. At this center, she received lorazepam for 10 days with no significant improvement in her symptoms and was then commenced on emergency ECT treatment. Catatonia due to another medical condition was considered during the patient's treatment course. The differential diagnoses considered during her treatment were hepatitis B virus, primary central nervous system vasculitis, neuroleptic malignant syndrome, and hypersensitivity to first-generation antipsychotics such as haloperidol. The possibility of neuropsychiatric systemic lupus erythematosus (SLE) was considered in this patient given the sociodemographic and symptomatic profile but the physicians who managed this patient did not consider her as having SLE.\n\nExamination\n\nDuring the assessment, the patient was alert and mute but followed simple commands and nodded yes/no in response to questions. Pupils were equal and reactive to light; she blinked to threat in all visual fields. Intact extraocular movements without nystagmus or ptosis were observed. Her facial sensations were intact and symmetric to light touch on the V1-V3 distribution. Her face was symmetric with a smile and tight eye closure. Uvula and palate rose midline. Shoulder shrug/head turns were symmetric with 5/5 strength. The tongue was midline with no protrusion. There was an increased tone in all her four extremities but no abnormal movements. Strength in all extremities was ⅗, and reflexes of 2+ were present symmetrically in her biceps, brachioradialis, patellar, and Achilles. However, she exhibited catatonic features, which lasted from minutes to hours. Her Bush-Francis Catatonia Rating Scale (BFCRS) was 13 (1 for mobility, 3 for mutism, 2 for staring, 1 for posturing, 3 for waxy flexibility, 1 for impulsivity, 1 for combativeness).\n\nMental status examination revealed a young lady, well-groomed, with casual wear. She was cooperative and calm. She exhibited minimal psychomotor retardation with a lack of movement. Her speech was slow, with a latency of about 5 seconds. Her affect was flat and mood dysphoric. She was awake, alert, and oriented to time, place, person, and event. Her thought process was linear and concrete. Her judgment and insight were fair.\n\nInvestigation\n\nThe following investigations were completed during her latest hospital stay. Complete metabolic panel showed; sodium 137 meq/l (normal range: 135 - 148 meq/l), potassium 4.4 meq/l (normal range: 3.5 - 5.3 meq/l), chloride 102 meq/l (normal range: 98 - 107 meq/l), Co2 28 meq/l (normal range: 22 - 29 meq/l), blood urea nitrogen (BUN) 16 mg/dl (normal range: 6 - 20 mg/dl), serum glucose 100 mg/dl (normal range: 70 - 110 mg/dl), blood creatinine 0.9 mg/dl (normal range: 0.57 - 1.11 mg/dl), calcium 9.1 mg/dl (normal range: 8.5 - 10.5 mg/dl), anion gap 7 meq/l (normal range: 5 - 13 meq/l), BUN/creatinine ratio 18 (normal range: 10 - 20). Complete blood count (CBC) showed white blood cell (WBC) 17.55 103/ul (normal range: 4.6 - 10.2 103/ul), RBC 4.77 106/ul (normal range: 4.04 - 5.48 106/ul), hemoglobin 11.9 g/dl (normal range: 12.2 - 16.2 g/dl), hematocrit 37.6% (normal range: 37.7 - 47.9%), mean corpuscular volume (MCV) 78.8 fl (normal range: 80 - 97 fl), mean corpuscular hemoglobin (MCH) 24.9 pg (normal range: 27.0 - 31.2 pg), mean corpuscular hemoglobin concentration (MCHC) 31.6 g/dl (normal range: 31.8 - 35.4 g/dl), platelet count 508 X 103/ul (normal range: 142.0 - 424.0 X 103/ul), mean platelet volume (MPV) 10.2 fl (normal range: 9.4 - 12.4 fl), red cell distribution width (RDW) 17.3% (normal range: 11.6 - 14.6%). Thyriod stimulating hormone (TSH) was 1.03 mIU/L (0.5 to 5.0 mIU/L). The hepatitis B viral panel showed a negative hepatitis B surface antigen and positive hepatitis B core antibody. Malignancy work-up, including transvarginal ultrasound and pelvic MRI, was negative for any malignancy ruling out ovarian teratoma. There were no suspicious adnexal masses.\n\nAnti-NMDAR antibodies were positive at the most recent visit with a serum NMDA titer increase to 1:1280 from the previous 1:320 at the initial diagnosis of NMDAR encephalitis. A brain MRI showed no mass lesion, hemorrhage, or acute infarct. There was no leptomeningeal or intraparenchymal enhancement (Figure 1). The ventricular system, cisterns, and sulci were of normal size, shape, and contour. EEG showed normal findings. Other imaging investigations done were CT chest, abdomen, and pelvis, all of which showed no primary malignancy or metastatic lesion.\n\nFigure 1 Magnetic resonance imaging (MRI) of the brain\n\nNormal brain MRI with no abnormal leptomeningeal or intraparenchymal enhancement (red arrows). No hemorrhage, mass, or acute infarct seen.\n\nTreatment \n\nAt her initial visit, after the diagnosis of anti-NMDAR encephalitis, she received intravenous immunoglobulins (IVIG) and intravenous methylprednisolone. However, when the NMDA titer was found to be elevated, the decision was made to repeat IVIG, intravenous methylprednisolone, and add rituximab. She received IVIG 2 g/kg over five days, was continued on rituximab and IVIG 1 g. Haloperidol 5 mg three times daily, memantine 5 mg daily, clonazepam 1 mg three times daily, and gabapentin. During her hospitalization, she had extensive long-term electroencephalographic monitoring that did not disclose any seizure activity.\n\nFurther immunotherapies were considered. The patient received a third dose of rituximab and was started on prednisone 60 mg daily. Due to concerns for catatonia, lorazepam 2 mg every six hours was commenced and titrated to a high dose. Because she had only a minimal response, amantadine 100 mg twice a day was added. Nonetheless, these treatments proved to be of limited benefit, as the patient remained symptomatic while on admission for about 10 days. An emergent ECT was performed, and she subsequently had 12 ECT sessions, after which her BFCRS score decreased to 0 with significant improvement in her catatonia, cognitive function, and overall mental status. The patient was started on a prolonged prednisone taper and was later discharged on 40 mg four times daily, with instructions on tapering it down. She was recommended for follow-up with psychiatry and neurology.\n\nDiscussion\n\nPsychiatric symptoms are the most common presentation in patients with anti-NMDAR encephalitis, with an incidence of about 65%-80% [1,12]. Most patients with anti-NMDAR encephalitis, as seen in this patient, will present with catatonia during their illness [1]. Benzodiazepine has been identified as a safe and effective treatment for catatonia, and a study by Petrides et al. proposed that once benzodiazepine is ineffective for catatonia, ECT should be commenced immediately in these patients to improve clinical outcomes [13]. They propose that the treatment algorithm should use benzodiazepine and/or ECT in addition to immunotherapy to target antibody development [13].\n\nThis case adds to available literature in which ECT was found to be very effective in the treatment of catatonia in patients with anti-NMDAR encephalitis [13-14]. A recent systematic review in which young adult patients with anti-NMDAR encephalitis complicated by severe psychiatric symptoms (primarily catatonia) significantly improved with ECT, with complete (60%) or partial (30%) recovery of the illness [14]. These cases, including ours, represent a breakthrough in treating a newly described autoimmune encephalitis diagnosis that has been challenging to manage for years. Some studies propose that benzodiazepine or ECT should be used to augment first-line treatment like immunotherapy when treating catatonia, a severe psychiatric feature of anti-NMDAR encephalitis [4,6]. Unlike our patient, who received several rounds of first-line therapy, immunotherapy, and plasmapheresis, and then second-line therapy, rituximab, with no significant improvement, some studies have found ECT treatment complementing treatment with plasmapheresis and/or immunotherapy to be beneficial. Our patient's catatonic symptoms only resolved after ECT was commenced, leading to the complete resolution of symptoms. \n\nNevertheless, ECT is still essential to prevent worsening clinical conditions such as catatonia, dysautonomia, and psychotic features in anti-NMDAR encephalitis patients. Catatonia is a severe and life-threatening neuropsychiatric syndrome associated with multiple medical disorders, including anti-NMDAR encephalitis. ECT is thought to help GABAergic enhancement in the CNS, leading to anti-catatonic action [15]. A study proposed that ECT may be responsible for the regeneration of autoantibody-damaged NMDAR in the hippocampus by improving its glutamate subunit binding [16]. It is reported that ECT improves patients' recovery and leads to shorter hospital lengths of stay [4]. Our patient improved after 12 rounds of ECT treatment, with full recovery of her catatonic symptoms.\n\nOne of the challenges in managing anti-NMDAR encephalitis is the lack of well-established diagnostic criteria and the long duration, which may take weeks to months before identifying NMDAR antibodies in CSF and blood [17]. When the antibodies are identified, the severity of anti-NMDAR encephalitis is closely associated with titer levels. It has been reported that patients who improve clinically have a concomitant decrease in titer levels and vice versa [1]. This finding is consistent with what was found in our patient whose clinical condition increased in severity as her anti-NMDAR antibody titer increased from 1:320 at initial diagnosis of anti-NMDAR encephalitis to 1:1280 before the commencement of ECT. Further research needs to be done to assess how best to monitor patients' improvement even though titers seem to correlate with the clinical progression of the illness [18]. Hence, a high index of suspicion and prompt treatment are needed to avoid misdiagnoses or delays in treatment, which may further worsen the clinical condition.\n\nDue to the rarity of the disease, there are no clear-cut outlines of treatments, but as seen in our patient and other reported cases of anti- NMDAR encephalitis, ECT is very effective. A study reported that 26 of 30 cases of NMDAR encephalitis managed with ECT showed no safety concerns [14]. The four cases that had their ECT prematurely stopped made full recovery with immunotherapy. A transient cognitive side effect is the most concerning risk [19]. However, severe catatonia treated with ECT shows improvement in cognition as their catatonia decreases in response to ECT treatment [17,20].\n\nIn our case, there was no observed improvement in the patient's catatonia and other psychiatric symptoms with the initial administration of benzodiazepines, immunotherapies, and antipsychotic therapy. However, remarkable improvement in the catatonia and other psychiatric symptoms was seen after initiating ECT. Studies have also shown that incorporating ECT in the management of catatonia associated with anti-NMDAR encephalitis improves patient recovery, shortening recovery time, reducing patients' cost, and shortening hospital stay. As seen in our case report, ECT therapy represents a way to help patients return to normalcy. ECT is the most effective treatment for catatonia regardless of the etiology and, in particular, due to medical illness as is in this case.\n\nConclusions\n\nThe successful remission of catatonia associated with anti-NMDAR encephalitis using ECT treatment in our patient adds to the growing list of successful treatments reported in previous studies. ECT should be incorporated as standard protocol in the management of catatonia associated with anti-NMDAR encephalitis used in treating catatonia and associated psychiatric symptoms seen in these patients. Early treatment can be associated with better clinical outcomes.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies Lancet Neurol Dalmau J Gleichman AJ Hughes EG 1091 1098 7 2008 18851928\n2 Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study Lancet Infect Dis Granerod J Ambrose HE Davies NW 835 844 10 2010 20952256\n3 Anti-NMDA receptor encephalitis: an emerging differential diagnosis in the psychiatric community Ment Health Clin Nichols TA 297 303 6 2016 29955485\n4 Anti-N-methyl d-aspartate receptor encephalitis and electroconvulsive therapy: literature review and future directions Child Adolesc Psychiatr Clin N Am Tanguturi YC Cundiff AW Fuchs C 79 89 28 2019 30389078\n5 Anti-N-methyl-d-aspartate receptor encephalitis: review of clinical presentation, diagnosis and treatment BJPsych Bull Barry H Byrne S Barrett E Murphy KC Cotter DR 19 23 39 2015 26191419\n6 Developing consensus in the assessment and treatment pathways for autoimmune encephalitis in child and adolescent psychiatry Front Psychiatry Mooneyham GC Ferrafiat V Stolte E Fuchs DC Cohen D 638901 12 2021 33854451\n7 Management of psychiatric symptoms in anti-NMDAR encephalitis: a case series, literature review and future directions Gen Hosp Psychiatry Kuppuswamy PS Takala CR Sola CL 388 391 36 2014 24731834\n8 Electroconvulsive therapy and/or plasmapheresis in autoimmune encephalitis? World J Clin Cases Gough JL Coebergh J Chandra B Nilforooshan R 223 228 4 2016 27574610\n9 Earlier treatment of NMDAR antibody encephalitis in children results in a better outcome Neurol Neuroimmunol Neuroinflamm Byrne S Walsh C Hacohen Y 0 2 2015\n10 Does early treatment improve outcomes in N-methyl-D-aspartate receptor encephalitis? Dev Med Child Neurol Byrne S McCoy B Lynch B Webb D King MD 794 796 56 2014 24641688\n11 Electroconvulsive therapy can improve psychotic symptoms in anti-NMDA-receptor encephalitis Psychiatry Clin Neurosci Matsumoto T Matsumoto K Kobayashi T Kato S 242 243 66 2012\n12 Anti-N-methyl-d-aspartate receptor encephalitis in Korea: clinical features, treatment, and outcome J Clin Neurol Lim JA Lee ST Jung KH 157 161 10 2014 24829602\n13 Synergism of lorazepam and electroconvulsive therapy in the treatment of catatonia Biol Psychiatry Petrides G Divadeenam KM Bush G Francis A 375 381 42 1997 9276078\n14 Electroconvulsive therapy for anti-N-methyl-d-aspartate (NMDA) receptor encephalitis: a systematic review of cases Brain Stimul Warren N Grote V O'Gorman C Siskind D 329 334 12 2019 30528383\n15 Increased cortical GABA concentrations in depressed patients receiving ECT Am J Psychiatry Sanacora G Mason GF Rothman DL 577 579 160 2003 12611844\n16 Differential effects of electroconvulsive shock on the glutamate receptor mRNAs for NR2A, NR2B and mGluR5b Mol Brain Res Watkins CJ Pei Q Newberry NR 108 113 61 1998 9795172\n17 Pediatric anti-NMDA receptor encephalitis with catatonia: treatment with electroconvulsive therapy Pediatr Rheumatol Online J Moussa T Afzal K Cooper J Rosenberger R Gerstle K Wagner-Weiner L 8 17 2019 30777097\n18 Autoimmune encephalitis update Neuro Oncol Dalmau J Rosenfeld MR 771 778 16 2014 24637228\n19 Adverse effects of electroconvulsive therapy Psychiatr Clin North Am Andrade C Arumugham SS Thirthalli J 513 530 39 2016 27514303\n20 Refractory catatonia due to N-methyl-D-aspartate receptor encephalitis responsive to electroconvulsive therapy: the clinical use of the clock drawing test J ECT Medina M Cooper JJ 223 224 33 2017 28658010\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(6)",
"journal": "Cureus",
"keywords": "anti nmda receptor encephalitis; bush francis catatonia scale; catatonia; electro-convulsive therapy; encephalitis",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e15706",
"pmc": null,
"pmid": "34277291",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": "30528383;24641688;9795172;12611844;29955485;18851928;27574610;20952256;30389078;30777097;33854451;26191419;24731834;9276078;27514303;28658010;24829602;26236759;24637228;22443247",
"title": "The Effectiveness of Electroconvulsive Therapy on Catatonia in a Case of Anti-N-Methyl-D-Aspartate (Anti-NMDA) Receptor Encephalitis.",
"title_normalized": "the effectiveness of electroconvulsive therapy on catatonia in a case of anti n methyl d aspartate anti nmda receptor encephalitis"
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"abstract": "Mycobacterium wolinskyi belongs to the Mycobacterium smegmatis group, which comprises rapidly growing non-tuberculous mycobacteria. The number of case reports on M. wolinskyi infections associated with postoperative wounds has increased in recent years. We herein report a case of peritonitis due to M. wolinskyi after peritoneal catheter embedment surgery. Identification was achieved based on 16S ribosomal RNA and rpoB gene sequencing of the isolate. The patient recovered following catheter removal and treatment with levofloxacin and minocycline for one month.",
"affiliations": "Center for Infectious Diseases, Nara Medical University, Japan.;Center for Infectious Diseases, Nara Medical University, Japan.;Center for Infectious Diseases, Nara Medical University, Japan.;Center for Infectious Diseases, Nara Medical University, Japan.;Center for Infectious Diseases, Nara Medical University, Japan.;Center for Infectious Diseases, Nara Medical University, Japan.;Center for Infectious Diseases, Nara Medical University, Japan.;Center for Infectious Diseases, Nara Medical University, Japan.;Center for Infectious Diseases, Nara Medical University, Japan.;Center for Infectious Diseases, Nara Medical University, Japan.;Department of Urology, Nara Medical University, Japan.;Department of Urology, Nara Medical University, Japan.;First Department of Internal Medicine, Nara Medical University, Japan.;First Department of Internal Medicine, Nara Medical University, Japan.;First Department of Internal Medicine, Nara Medical University, Japan.;Department of Microbiology and Infectious Diseases, Nara Medical University, Japan.;Center for Infectious Diseases, Nara Medical University, Japan.",
"authors": "Fujikura|Hiroyuki|H|;Kasahara|Kei|K|;Ogawa|Yoshihiko|Y|;Hirai|Nobuyasu|N|;Yoshii|Seiya|S|;Yoshihara|Shingo|S|;Ogawa|Taku|T|;Yonekawa|Shinsuke|S|;Imakita|Natsuko|N|;Nishioka|Yuichi|Y|;Yoneda|Tatsuo|T|;Yoshida|Katsunori|K|;Samejima|Ken-Ichi|KI|;Tanabe|Kaori|K|;Saito|Yoshihiko|Y|;Yano|Hisakazu|H|;Mikasa|Keiichi|K|",
"chemical_list": "D012336:RNA, Ribosomal, 16S",
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"doi": "10.2169/internalmedicine.8871-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2894357110.2169/internalmedicine.8871-17Case Report\nMycobacterium wolinskyi Peritonitis after Peritoneal Catheter Embedment Surgery Fujikura Hiroyuki 1Kasahara Kei 1Ogawa Yoshihiko 1Hirai Nobuyasu 1Yoshii Seiya 1Yoshihara Shingo 1Ogawa Taku 1Yonekawa Shinsuke 1Imakita Natsuko 1Nishioka Yuichi 1Yoneda Tatsuo 2Yoshida Katsunori 2Samejima Ken-ichi 3Tanabe Kaori 3Saito Yoshihiko 3Yano Hisakazu 4Mikasa Keiichi 1\n1 Center for Infectious Diseases, Nara Medical University, Japan\n2 Department of Urology, Nara Medical University, Japan\n3 First Department of Internal Medicine, Nara Medical University, Japan\n4 Department of Microbiology and Infectious Diseases, Nara Medical University, JapanCorrespondence to Dr. Kei Kasahara, kassan@naramed-u.ac.jp\n\n25 9 2017 15 11 2017 56 22 3097 3101 15 1 2017 15 3 2017 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article 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/).Mycobacterium wolinskyi belongs to the Mycobacterium smegmatis group, which comprises rapidly growing non-tuberculous mycobacteria. The number of case reports on M. wolinskyi infections associated with postoperative wounds has increased in recent years. We herein report a case of peritonitis due to M. wolinskyi after peritoneal catheter embedment surgery. Identification was achieved based on 16S ribosomal RNA and rpoB gene sequencing of the isolate. The patient recovered following catheter removal and treatment with levofloxacin and minocycline for one month. \n\n16S rRNA sequenceMycobacterium wolinskyinon-tuberculous mycobacteriaperitoneal dialysisrapidly growing mycobacteriarpoB sequence\n==== Body\nIntroduction\nPeritoneal dialysis (PD) is an important modality for the management of end-stage renal disease (ESRD). Infection is a serious complication that may result in cessation of PD and catheter loss (1-3). Various efforts have been undertaken to decrease the incidence of infectious complications of PD and peritoneal catheter embedment; the Moncrief and Popovich technique represents one successful procedure (4).\n\nThe most common PD-related infectious complication is catheter-associated peritonitis, of which the causative organisms are usually aerobic skin inhabitants such as Staphylococcus species (5). Recently, reports of PD-related peritonitis caused by non-tuberculous mycobacteria (NTM) have increased (6-9). We herein report a case of peritonitis due to Mycobacterium wolinskyi, a rare, rapidly growing NTM, after peritoneal catheter embedment surgery via the Moncrief and Popovich technique.\n\nCase Report\nA 66-year-old Japanese man with ESRD secondary to diabetic nephropathy was admitted to our hospital with a fever, generalized fatigue, and weight loss of 6 kg over 2 months. Two months prior to admission, he underwent PD catheter insertion by stepwise initiation using the Moncrief and Popovich technique (4). One month prior to admission, he noticed discharge from the surgical site and visited a nearby clinic, where he received wound care with gentamicin ointment. No microbiological evaluation was performed during the visit, and the discharge persisted. Upon admission to our hospital, he complained of tingling pain around the abdominal surgical site with a small amount of discharge. His vital signs were as follows: blood pressure, 136/80 mmHg; pulse, 84 beats per minute; temperature, 36.8℃; and respiratory rate, 12 breaths per minute. On a physical examination, a small amount of serous discharge was noted at the surgical site. His abdomen was not distended. No rebound tenderness or muscle guarding was observed.\n\nLaboratory findings on admission were as follows: total white blood cell (WBC) count of 12,000 cells/mm3 with 85% neutrophils, 6% lymphocytes, 1% basophils, and 8% monocytes; serum potassium, 6.6 mEq/L; blood urea nitrogen, 167 mg/dL; creatinine, 12.54 mg/dL; C-reactive protein, 17.8 mg/dL; and procalcitonin, 3.29 ng/mL. Both abdominal computed tomography and abdominal echography demonstrated a small amount of ascites without other notable abnormal findings. An intravascular catheter was inserted via the right femoral vein, and emergency hemodialysis was performed. The PD catheter was exteriorized, and cloudy ascites obtained through the catheter showed a WBC count of 2,000 per mm3 nucleated cells (37% neutrophils, 48% lymphocytes, and 14% monocytes).\n\nThe discharge and two paired blood cultures were obtained for a microbiological evaluation on admission. Ascitic fluid was inoculated into blood culture bottles (BacT/Alert SA and SN bottles; Sysmex bioMérieux, Tokyo, Japan). No bacteria were observed on the Gram stain of the discharge. Treatment with intravenous ceftriaxone (2 g/day) was commenced and later switched to cefazolin (1 g/day) and ceftazidime (1 g/day), owing to a persistent fever. On the fifth day of hospitalization, small white colonies grew on a sheep blood agar plate (Kyokuto, Tokyo, Japan) from the culture of the discharge; Gram staining demonstrated Gram-positive bacilli of moderate length (Figure A) that were also positive for Ziehl-Neelsen staining (Figure B). The blood cultures were negative. The ascitic fluid in an aerobic blood culture bottle also became positive and grew similar colonies on a sheep blood agar plate. Initially, these organisms were determined as “unidentified Gram-positive rods.” Thirteen days after admission, the PD catheter was removed, and the pus obtained this time grew similar colonies to the ascitic fluid. It was only at 21 days following admission that the laboratory identified these organisms as rapidly growing mycobacteria, at which time the patient's general condition had improved.\n\nFigure. A: Gram staining of colonies revealing Gram-positive bacilli of moderate length (×1,000). B: Ziehl-Neelsen staining of colonies revealing red bacilli (×1,000).\n\nOn the 27th day of hospitalization, the susceptibility of the organism, performed via the microdilution method and interpreted based on Clinical and Laboratory Standards Institute M24 A-2, revealed unexpectedly high minimum inhibitory concentrations toward clarithromycin, imipenem, and tobramycin (Table 1) (10). Identification of the organism by DNA-DNA hybridization (DDH mycobacterium “Kyokuto”; Kyokuto Pharmaceutical Industrial, Tokyo, Japan) indicated the isolation of either Mycobacterium fortuitum or Mycobacterium peregrinum. As the patient's condition at that time was favorable, we withheld the commencement of antibiotics until the results of the 16S ribosomal RNA (rRNA) and rpoB gene analyses were obtained. We used the EzTaxon-e Database (http://www.ezbiocloud.net) and BLAST database (http://blast.ddbj.nig.ac.jp/blastn) for the 16S rRNA and rpoB gene sequences, respectively. The bacterial 16S rRNA gene sequence detected in the ascitic fluid was 100% (996 bp) identical to M. wolinskyi ATCC 700010T. M. peregrinum was the most closely-related species in the 16S rRNA gene sequence (99.6%). The result of the amplified rpoB gene sequences (650 bp) showed high similarity (99%) with M. wolinskyi ATCC 700010T, Mycobacterium jacuzzi, and M. wolinskyi CRM-0267. Thus, the isolate was ultimately identified as M. wolinskyi. No other microorganisms grew in the blood cultures or ascites cultures.\n\nTable 1. Antimicrobial Susceptibility Testing for the Isolated Mycobacterium wolinskyi.\n\nAntibiotics\tMIC (µg/mL)\tMIC (µg/mL) for category\t\nSusceptible\tIntermediate\tResistant\t\nAmikacin\t4\t≤16\t32\t≥64\t\nTobramycin\t≥16\t≤2\t4\t≥8\t\nCefmetazolea\t8\t≤16\t32-64\t≥128\t\nImipenem\t8\t≤4\t8-16\t≥32\t\nClarithromycin\t≥32\t≤2\t4\t≥8\t\nMinocyclineb\t≤0.25\t≤1\t2-4\t≥8\t\nCiprofloxacin\t0.5\t≤1\t2\t≥4\t\nMoxifloxacin\t≤0.5\t≤1\t2\t≥4\t\nTrimethoprim-sulfamethoxazole\t≤2/38\t≤2/38\t\t≥4/76\t\nLinezolid\t3\t≤8\t16\t≥32\t\nThe data of breakpoints are derived from ref (10).\n\na. The breakpoints are derived from those for cefoxitin.\n\nb. The breakpoints are derived from those for doxycycline.\n\nMIC: minimum inhibitory concentration\n\nBased on the identification and susceptibility results, oral levofloxacin (750 mg, then 500 mg every other day) and minocycline (100 mg twice daily) were administered. Amikacin was not initiated, as the patient's condition was stable and the surgical site had improved upon removal of the PD catheter. Thirty-nine days later, antibiotics were discontinued due to development of thrombocytopenia. Thereafter, the platelet counts improved. There was no recurrence of a fever or abdominal symptoms at the six-month follow-up.\n\nDiscussion\nPeritonitis is a major cause of morbidity and mortality in patients receiving PD that may lead to cessation of PD (1-3). The usual causative pathogens of PD-related peritonitis are aerobic bacteria such as coagulase negative staphylococci, Staphylococcus aureus, and Pseudomonas aeruginosa; however, up to 30% of cases are so-called “culture-negative” (2,5,6,11). It is speculated that most culture-negative cases are a result of empirical antibiotic administration prior to the procurement of microbiological specimens; however, pathogens that are difficult to identify, such as fungi and mycobacteria, also cause PD-related peritonitis.\n\nM. wolinskyi belongs to the Runyon classification type IV NTM, also known as rapidly growing mycobacteria (RGM); this means that it has the ability to grow within seven days on artificial media (12). NTM, including RGM, are important emerging pathogens in PD-associated peritonitis. In 2012, Song et al. performed a literature review of 41 articles on PD-associated NTM peritonitis; more than half of the reported cases were due to RGM (M. fortuitum: 38.6%; M. chelonae: 14%) (7).\n\nRGM are ubiquitous in soil, dust, and water, as well as much of the natural environment. Most reported cases of PD-associated RGM peritonitis developed while patients were on PD, suggesting that the patients may have acquired RGM during PD manipulation. Our patient developed infection soon after catheter embedment surgery via the Moncrief and Popovich technique, and the catheter was not used for dialysis; therefore, our case may well be a surgical site infection. Recently, outbreaks of RGM infection after cardiac surgery have been reported, and the contamination of the water in the heater-cooler unit has been reported (13). Such units are not usually used in urological surgery, and the exact route of infection in our case remains unclear. To date, we have detected only one case of M. wolinskyi infection in our hospital.\n\nDue to its rarity and variability in antimicrobial susceptibility, recommendations for specific antibiotic treatment or duration of therapy are lacking. The combination of at least two antibiotics guided by susceptibility testing is generally recommended (14). The typical M. wolinskyi susceptibility profile has been reported as follows: susceptibility towards amikacin, cefoxitin, imipenem, doxycycline, and ciprofloxacin, with resistance towards sulfamethoxazole, clarithromycin, and tobramycin (8,15). Gentamicin ointment is reportedly effective in the prophylaxis of catheter exit site infections (16). However, cross resistance to gentamicin in tobramycin-resistant organisms is common, and the gentamicin ointment/cream used in our case may have selected M. wolinskyi (17). Although a macrolide is often described as a key treatment component for NTM infection, M. wolinskyi possesses the erm gene, inducing inherent macrolide resistance (18). The length of treatment is determined mainly by the clinical response (3). In a review of NTM peritonitis, the treatment duration ranged between 2 days and 24 months and lasted >1 month in 93.3% of cases (7). We performed a literature review of case reports of M. wolinskyi infection (Table 2); however, the study by Brown et al. was excluded because their data for susceptibility testing and treatment were lacking (8,12,15,19-26). Most cases are uniformly resistant towards clarithromycin and tobramycin, and a combination of amikacin, minocycline, doxycycline, ciprofloxacin, levofloxacin, moxifloxacin, and linezolid was used. The total treatment duration was typically 6 months.\n\nTable 2. Literature Review of Infection Type, Susceptibility, and Treatment of Mycobacterium wolinskyi infection.\n\nReference\tInfection type\tSusceptibility of \nM. wolinskyi\tAntibiotics and treatment duration\tSurgical procedure\t\n(19)\tHip prosthetic infection\tS: AMK, CPFX, IPM, LZD, MFLX, MINO, OFLX \nI: CXT \nR: CAM, TOB\tAMK+MFLX+MINO for 1 month, then MFLX+MINO for 5 months\tDebridement\t\n(20)\tBacteremia in a patient with chronic myelogenous leukemia\tS: AMK, CPFX, CXT, DOXY, IPM, LVFX, MINO, ST \nR: CAM, TOB\tAMK+MINO+LVFX for 1 month, then MINO+LVFX for 5 months\tNone\t\n(15)\tBacteremia and multiple joint infection in a patient with non-Hodgkin lymphoma\tS: AMK, CPFX, CXT, DOXY, IPM \nR: CAM, ST, TOB\tAMK+MFLX+MINO for 1 month, then MFLX+MINO for 6 months \tDebridement\t\n(21)\tSurgical site infection after knee replacement arthroplasty for primary osteoarthritis\tR: CAM, CXT, IPM, RFP, ST, TOB\tAMK+CPFX+DOXY, duration N/A \tDebridement\t\n(23)\tFacial skin abscess after cosmetic procedures\tS: AMK, CPFX, MFLX \nI: CXT, IPM \nI or R: CAM \nR: ST\tDOXY+CPFX for 5 months\tDrainage and debridement\t\n(22)\tMultiple breast abscesses after mammoplasty\tS: AMK, CPFX \nS or I: MFLX (≤2) \nI: CXT, DOXY \nR: CAM, ST, TOB\tAMK+CPFX+DOXY for 10 weeks, then CPFX+DOXY 14 weeks\tDrainage and debridement\t\n(8)\tPeritonitis in a chronic peritoneal dialysis patient\tS: AMK, CPFX, DOXY, LZD, ST\tDOXY+LZD+MFLX for 4 weeks\tPeritoneal dialysis catheter removal\t\n(24)\tCase 1: Sternal wound infection after aortic valve replacement \nCase 2: Incisional infection after bilateral lung transplant \nCase 3: Prosthetic graft infection after aortic root replacement \nCase 4: Pacemaker pocket infection after CABG, aortic valve replacement, and pacemaker placement \nCase 5: Sternal osteomyelitis after CABG \nCase 6: Sternal wound infection after aortic valve replacement\tNA\tCase 1: IPM+MFLX+ST for 1 month, then MFLX+ST for 5 months \nCase 2: DOXY+MFLX for 3 months \nCase 3: AMK+DOXY+MFLX for 1 month, then DOXY+MFLX+ST for 6 months, then ST lifelong \nCase 4: CPFX+MINO for 6 months \nCase 5: DOXY+MINO for 6 months \nCase 6: NA, debridement\tCase 1: debridement \nCase 2: debridement \nCase 3: graft replacement \nCase 4: pacemaker removal \nCase 5: debridement with sternectomy \nCase 6: debridement\t\n(26)\tProsthetic infection after aortic valve replacement for aneurysm of the ascending aorta\tNA\tAMK+DOXY+LZD+MFLX for 6 months\tReplacement of a bioprosthetic aortic valve and an aortic prosthesis with a vascular homograft. \t\n(25)\tRecurrent subcutaneous abdominal wall abscesses and ulcer after insulin injection\tS: CPFX, LVFX, LZD, MINO, FLX \nI: IPM \nR: CAM, DOXY, TOB\tAMK+MFLX+MINO for 1 month, then MFLX+MINO for 5 months\tDebridement\t\nAMK: amikacin, CABG: coronary artery bypass grafting, CAM: clarithromycin, CPFX: ciprofloxacin, CXT: cefoxitin, I: intermediate, IPM: imipenem/cilastatin, LVFX: levofloxacin, LZD: linezolid, MFLX: moxifloxacin: MINO: minocycline, NA: not available, OFLX: ofloxacin, R: resistant, S: susceptible, ST: sulfamethoxazole, TOB: tobramycin\n\nWe used a combination of levofloxacin and minocycline in this patient, guided by antibiotic susceptibility testing. When we initiated the therapy, the patient was in a stable condition; therefore, amikacin was not included in the regime. Although we planned to continue the antibiotics for six months, the patient only managed to receive treatment for one month due to the development of thrombocytopenia. Fortunately, the patient exhibited no signs of relapse at the six-month follow up. Surgical debridement or removal of foreign material is often necessary in cases of PD-associated peritonitis. Catheter removal was performed in the majority of reported cases of NTM peritonitis, as in our case (7).\n\nConventional identification methods such as DDH may not identify rare Mycobacterium species. Therefore, stepwise identification using 16S rRNA sequence and rpoB gene analyses is recommended (27). Our patient is the second reported case of PD-related peritonitis due to M. wolinskyi; however, there may have been other potential cases in previous reports of M. fortuitum or other rare Mycobacterial species that were identified by conventional methods (8,9). As mentioned, M. wolinskyi is typically resistant to clarithromycin and tobramycin, both of which can be used for the treatment of RGM infections. Furthermore, as RGMs can grow in usual blood culture plates and are stained by Gram staining, clinical microbiology laboratories sometimes confuse RGMs for unidentified Gram-positive rods, as in our case. It is therefore crucial to communicate with doctors and clinical microbiologists to facilitate the precise and timely identification with susceptibility testing. The correct identification of microorganisms is critical, since various NTM species display different antibiotic susceptibility patterns; M. wolinskyi is one example that exhibits resistance towards clarithromycin, an antibiotic generally used for the treatment of NTM infections.\n\nIn conclusion, we herein reported a case of M. wolinskyi-induced peritonitis after peritoneal catheter embedment surgery. Correct identification and appropriate antibiotic susceptibility testing are critical in patient management. Given the increasing trend in numbers of RGM infections, the elucidation of risk factors and preventive measures is warranted.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nAkoh JA \nPeritoneal dialysis associated infections: an update on diagnosis and management . World J Nephrol \n1 : 106 -122 , 2012 .24175248 \n2. \nDavenport A \nPeritonitis remains the major clinical complication of peritoneal dialysis: the London, UK, peritonitis audit 2002-2003 . Perit Dial Int \n29 : 297 -302 , 2009 .19458302 \n3. \nWilkie M \nThe 2016 ISPD update on prevention and treatment of peritonitis-grading the evidence . Perit Dial Int \n36 : 469 -470 , 2016 .27659924 \n4. \nMoncrief JW , Popovich RP , Broadrick LJ , He ZZ , Simmons EE , Tate RA \nThe Moncrief-Popovich catheter. A new peritoneal access technique for patients on peritoneal dialysis . ASAIO J \n39 : 62 -65 , 1993 .8439683 \n5. \nPort FK , Held PJ , Nolph KD , Turenne MN , Wolfe RA \nRisk of peritonitis and technique failure by CAPD connection technique: a national study . Kidney Int \n42 : 967 -974 , 1992 .1453589 \n6. \nSzeto CC , Leung CB , Chow KM , et al \nChange in bacterial aetiology of peritoneal dialysis-related peritonitis over 10 years: experience from a centre in south-east Asia . Clin Microbiol Infect \n11 : 837 -839 , 2005 .16153259 \n7. \nSong Y , Wu J , Yan H , Chen J \nPeritoneal dialysis-associated nontuberculous mycobacterium peritonitis: a systematic review of reported cases . Nephrol Dial Transplant \n27 : 1639 -1644 , 2012 .21891775 \n8. \nKarakala N , Steed LL , Ullian ME \nPeritonitis from Mycobacterium wolinskyi in a chronic peritoneal dialysis patient . Int Urol Nephrol \n45 : 289 -291 , 2013 .22127408 \n9. \nHamade A , Pozdzik A , Denis O , et al \nMycobacterium fortuitum and polymicrobial peritoneal dialysis-related peritonitis: a case report and review of the literature . Case Rep Nephrol \n2014 : 323757 , 2014 .25028616 \n10. \nWoods GL ; Clinical and Laboratory Standards Institute . \nSusceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard . 2nd ed. \nClinical and Laboratory Standards Institute , Wayne, PA , 2011 .\n11. \nKavanagh D , Prescott GJ , Mactier RA \nPeritoneal dialysis-associated peritonitis in Scotland (1999-2002) . Nephrol Dial Transplant \n19 : 2584 -2591 , 2004 .15304559 \n12. \nBrown BA , Springer B , Steingrube VA , et al \nMycobacterium wolinskyi sp. Nov. and Mycobacterium goodii sp. Nov., two new rapidly growing species related to Mycobacterium smegmatis and associated with human wound infections: a cooperative study from the International Working Group on Mycobacterial Taxonomy . Int J Syst Bacteriol 49 Pt \n4 : 1493 -1511 , 1999 .\n13. \nSax H , Bloemberg G , Hasse B , et al \nProlonged outbreak of Mycobacterium chimaera infection after open-chest heart surgery . Clin Infect Dis \n61 : 67 -75 , 2015 .25761866 \n14. \nGriffith DE , Aksamit T , Brown-Elliott BA , et al \nAn official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases . Am J Respir Crit Care Med \n175 : 367 -416 , 2007 .17277290 \n15. \nChen YC , Jou R , Huang WL , et al \nBacteremia caused by Mycobacterium wolinskyi . Emerg Infect Dis \n14 : 1818 -1819 , 2008 .18976585 \n16. \nChu KH , Choy WY , Cheung CC , et al \nA prospective study of the efficacy of local application of gentamicin versus mupirocin in the prevention of peritoneal dialysis catheter-related infections . Perit Dial Int \n28 : 505 -508 , 2008 .18708544 \n17. \nGrayson ML , Kucers A \nKucers' The Use of Antibiotics: A Clinical Review of Antibacterial, Antifungal, Antiparasitic, and Antiviral Drugs . 6th ed. \nHodder Arnold , London , 2010 .\n18. \nNash KA , Andini N , Zhang Y , Brown-Elliott BA , Wallace RJ Jr \nIntrinsic macrolide resistance in rapidly growing mycobacteria . Antimicrob Agents Chemother \n50 : 3476 -3478 , 2006 .17005837 \n19. \nPulcini C , Vandenbussche E , Podglajen I , et al \nHip prosthesis infection due to Mycobacterium wolinskyi . J Clin Microbiol \n44 : 3463 -3464 , 2006 .16954303 \n20. \nOhno T , Kishimoto W , Chihara D , et al \nFirst case report of sepsis caused by Mycobacterium wolinskyi in chronic myelogenous leukemia . Diagn Microbiol Infect Dis \n62 : 433 -436 , 2008 .18929459 \n21. \nJeong JH , Seo YH , Kim KH , Ahn JY , Park PH , Park YK \nMycobacterium wolinskyi infection confirmed by rpoB gene sequencing . J Clin Lab Anal \n26 : 325 -327 , 2012 .23001976 \n22. \nSantos Lima A , Carneiro Neves MM , Machado Gomes K , et al \nFirst case report of infection by Mycobacterium wolinskyi after mammoplasty in Brazil . Infect Dis Rep \n5 : e12 , 2013 .24470962 \n23. \nYoo SJ , Lee KH , Jung SN , Heo ST \nFacial skin and soft tissue infection caused by Mycobacterium wolinskyi associated with cosmetic procedures . BMC Infect Dis \n13 : 479 , 2013 .24131522 \n24. \nNagpal A , Wentink JE , Berbari EF , et al \nA cluster of Mycobacterium wolinskyi surgical site infections at an academic medical center . Infect Control Hosp Epidemiol \n35 : 1169 -1175 , 2014 .25111926 \n25. \nBossart S , Schnell B , Kerl K , Urosevic-Maiwald M \nUlcers as a sign of skin infection with Mycobacterium wolinskyi: report of a case and review of the literature . Case Rep Dermatol \n8 : 151 -155 , 2016 .27462223 \n26. \nDupont C , Terru D , Aguilhon S , et al \nSource-case investigation of Mycobacterium wolinskyi cardiac surgical site infection . J Hosp Infect \n93 : 235 -239 , 2016 .27210271 \n27. \nKazumi Y , Mitarai S \nThe evaluation of an identification algorithm for Mycobacterium species using the 16s rRNA coding gene and rpoB . Int J Mycobacteriol \n1 : 21 -28 , 2012 .26786945\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "56(22)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "16S rRNA sequence; Mycobacterium wolinskyi; non-tuberculous mycobacteria; peritoneal dialysis; rapidly growing mycobacteria; rpoB sequence",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D002404:Catheterization; D006801:Humans; D008297:Male; D009165:Mycobacterium Infections, Nontuberculous; D010530:Peritoneal Dialysis; D010538:Peritonitis; D011183:Postoperative Complications; D012336:RNA, Ribosomal, 16S",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3097-3101",
"pmc": null,
"pmid": "28943571",
"pubdate": "2017-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27462223;24131522;17005837;26786945;16153259;27659924;25111926;24175248;23001976;15304559;1453589;17277290;18976585;24470962;19458302;27210271;18708544;25761866;22127408;21891775;10555330;25028616;16954303;8439683;18929459",
"title": "Mycobacterium wolinskyi Peritonitis after Peritoneal Catheter Embedment Surgery.",
"title_normalized": "mycobacterium wolinskyi peritonitis after peritoneal catheter embedment surgery"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R3-157144",
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"activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE"
... |
{
"abstract": "BACKGROUND\nTemozolomide (TMZ) is an oral alkylating agent that has been used over the past 8 years to treat aggressive pituitary tumors resistant to conventional therapy. To date, only 25 patients treated with TMZ for ACTH producing pituitary tumors (14 adenomas and 11 carcinomas) have been reported.\n\n\nMETHODS\nWe present a retrospective review of the medical records of three patients with aggressive ACTH producing adenomas treated with TMZ. In the three cases there was evidence of progression to conventional therapy before starting TMZ. We used the conventional scheme for the treatment of gliomas until completing 7, 12 and 6 cycles respectively. Reduction in tumor size was evident after the 3rd, 5th and 4th cycle of TMZ and progression free survival was 25, 19 and more than 12 months in the three patients respectively. Improvement of the ocular and visual symptoms was evident after the 4th cycle of treatment in all cases. Normalization of urinary free cortisol levels was achieved after the 3rd and 9th cycle in the two cases with hypercortisolism. Two of the three patients received a second course of treatment when the disease progressed but it did not stop tumor progression. The principal side effects were G3 neutropenia, G1 and G2 thrombocytopenia, G1 lymphopenia, asthenia and nausea.\n\n\nCONCLUSIONS\nThe treatment with TMZ is effective and safe in patients with aggressive corticotrophin tumors resistant to conventional therapy. Nevertheless once the disease progresses, a second course of treatment does not seem to be effective.",
"affiliations": "Department of Endocrinology, Hospital Universitario Puerta de Hierro Majadahonda, Calle Manuel de Falla 1 Majadahonda, 28222, Madrid, Spain. mcampdera@gmail.com.;Department of Endocrinology, Hospital Universitario Puerta de Hierro Majadahonda, Calle Manuel de Falla 1 Majadahonda, 28222, Madrid, Spain.;Department of Endocrinology, Hospital Universitario Puerta de Hierro Majadahonda, Calle Manuel de Falla 1 Majadahonda, 28222, Madrid, Spain.;Department of Radiation Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Calle Manuel de Falla 1 Majadahonda, 28222, Madrid, Spain.;Laboratory of Molecular Pathology, Department of Pathology, Hospital Universitario Puerta de Hierro Majadahonda, Calle Manuel de Falla 1 Majadahonda, 28222, Madrid, Spain.;Department of Neuroradiology, Hospital Universitario Puerta de Hierro Majadahonda, Calle Manuel de Falla 1 Majadahonda, 28222, Madrid, Spain.;Department of Endocrinology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.;Department of Endocrinology, Hospital Universitario Puerta de Hierro Majadahonda, Calle Manuel de Falla 1 Majadahonda, 28222, Madrid, Spain.",
"authors": "Campderá|Mariana|M|;Palacios|Nuria|N|;Aller|Javier|J|;Magallón|Rosa|R|;Martín|Paloma|P|;Saucedo|Gertrudis|G|;Lilienfeld|Howard|H|;Estrada|Javier|J|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D006854:Hydrocortisone; D000077204:Temozolomide",
"country": "United States",
"delete": false,
"doi": "10.1007/s11102-015-0694-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-341X",
"issue": "19(2)",
"journal": "Pituitary",
"keywords": "ACTH; Molecular markers; Pituitary tumor; Temozolomide",
"medline_ta": "Pituitary",
"mesh_terms": "D049913:ACTH-Secreting Pituitary Adenoma; D000236:Adenoma; D000328:Adult; D018906:Antineoplastic Agents, Alkylating; D017024:Chemotherapy, Adjuvant; D003606:Dacarbazine; D018450:Disease Progression; D006801:Humans; D006854:Hydrocortisone; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D012189:Retrospective Studies; D000077204:Temozolomide; D017211:Treatment Failure",
"nlm_unique_id": "9814578",
"other_id": null,
"pages": "158-66",
"pmc": null,
"pmid": "26586560",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8988897;23955641;18757334;22419713;8692397;20870708;20668043;22105169;20496311;21496012;16984254;19589911;16328527;14762579;9332462;23400299;23365123;21918831;19960369;17926052;16698415;20972839;12945944;24226425;18437578;21917845;25485838;17897837;22822048",
"title": "Temozolomide for aggressive ACTH pituitary tumors: failure of a second course of treatment.",
"title_normalized": "temozolomide for aggressive acth pituitary tumors failure of a second course of treatment"
} | [
{
"companynumb": "ES-TEVA-657189ISR",
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"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
"d... |
{
"abstract": "A 64-year-old-female presented with progressive left foot weakness, low back and radicular pain after a left sided S1 transforaminal epidural steroid injection (ESI). Magnetic resonance imaging revealed left side L5-S1 large extradural heterogeneous mass with layering areas suggesting different stages of hematoma formation. Past medical history was significant for peripheral vascular disease and transient ischemic attacks, for which she took aspirin and clopidogrel (antiplatelet agent). These medications were discontinued one week prior to ESI. Although synovial cysts associated with facet arthropathy are common, hemorrhagic cyst is not. To the best of the authors' knowledge, this is the first reported case of symptomatic hemorrhagic lumbar facet synovial cyst following ESI on a patient taking anti-platelet medications.",
"affiliations": "Hossein Elgafy, Nicholas Peters, Justin E Lea, Robert M Wetzel, Department of Orthopedic Surgery, University of Toledo Medical Center, Toledo, OH 43614, United States.;Hossein Elgafy, Nicholas Peters, Justin E Lea, Robert M Wetzel, Department of Orthopedic Surgery, University of Toledo Medical Center, Toledo, OH 43614, United States.;Hossein Elgafy, Nicholas Peters, Justin E Lea, Robert M Wetzel, Department of Orthopedic Surgery, University of Toledo Medical Center, Toledo, OH 43614, United States.;Hossein Elgafy, Nicholas Peters, Justin E Lea, Robert M Wetzel, Department of Orthopedic Surgery, University of Toledo Medical Center, Toledo, OH 43614, United States.",
"authors": "Elgafy|Hossein|H|;Peters|Nicholas|N|;Lea|Justin E|JE|;Wetzel|Robert M|RM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5312/wjo.v7.i7.452",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2218-5836",
"issue": "7(7)",
"journal": "World journal of orthopedics",
"keywords": "Anti-platelet therapy; Epidural injection; Hemorrhage; Lumbar synovial cyst",
"medline_ta": "World J Orthop",
"mesh_terms": null,
"nlm_unique_id": "101576349",
"other_id": null,
"pages": "452-7",
"pmc": null,
"pmid": "27458557",
"pubdate": "2016-07-18",
"publication_types": "D002363:Case Reports",
"references": "20052816;17596676;21384274;21790519;15996615;20402175;19927101;16531204;12173390;15105680;8814156;14609693;17450063;20488765;11317123;10879758;23255653;19769520",
"title": "Hemorrhagic lumbar synovial facet cyst secondary to transforaminal epidural injection: A case report and review of the literature.",
"title_normalized": "hemorrhagic lumbar synovial facet cyst secondary to transforaminal epidural injection a case report and review of the literature"
} | [
{
"companynumb": "US-BAYER-2016-153080",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Neurosarcoidosis occurs in about 5-15% of patients with sarcoidosis. Therapy with corticosteroids is generally accepted as the first-line medication, followed by various immunomodulating and cytotoxic agents or combined therapy. However, some patients show an unsatisfactory outcome or have adverse events and require novel treatment strategies.\nWe describe three patients with systemic sarcoidosis and central nervous system involvement who received CD20-targeted B-cell depletion with rituximab.\nTreatment with rituximab was well tolerated and followed by marked remission in patients nonresponsive to other immunosuppressive agents.\nRituximab may be used for patients with neurosarcoidosis who are nonresponsive to established treatment regimes.",
"affiliations": "Department of Neurology at St. Josef Hospital, Medical Faculty of the Ruhr-University Bochum, Gudrunstr. 56, D-44791 Bochum, Germany Department of Neurology at Katholische Kliniken Ruhrhalbinsel Essen, Heidbergweg 22-24, D-45257 Essen, Germany.;Department of Neurology at St. Josef Hospital, Medical Faculty of the Ruhr-University Bochum, Bochum, Germany.;Department of Neurology at St. Josef Hospital, Medical Faculty of the Ruhr-University Bochum, Bochum, Germany.;Department of Neurology at St. Josef Hospital, Medical Faculty of the Ruhr-University Bochum, Bochum, Germany.;Department of Neurology at St. Josef Hospital, Medical Faculty of the Ruhr-University Bochum, Bochum, Germany Department of Neurology at Katholische Kliniken Ruhrhalbinsel Essen, Essen, Germany.;Department of Neurology at Katholische Kliniken Ruhrhalbinsel Essen, Essen, Germany.",
"authors": "Zella|Samis|S|https://orcid.org/0000-0002-0815-9820;Kneiphof|Janina|J|;Haghikia|Aiden|A|;Gold|Ralf|R|;Woitalla|Dirk|D|;Thöne|Jan|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1756286418805732",
"fulltext": "\n==== Front\nTher Adv Neurol DisordTher Adv Neurol DisordTANsptanTherapeutic Advances in Neurological Disorders1756-28561756-2864SAGE Publications Sage UK: London, England 10.1177/175628641880573210.1177_1756286418805732Case SeriesSuccessful therapy with rituximab in three patients with probable neurosarcoidosis https://orcid.org/0000-0002-0815-9820Zella Samis Department of Neurology at St. Josef Hospital, Medical Faculty of the Ruhr-University Bochum, Gudrunstr. 56, D-44791 Bochum, Germany Department of Neurology at Katholische Kliniken Ruhrhalbinsel Essen, Heidbergweg 22-24, D-45257 Essen, GermanyKneiphof Janina Department of Neurology at St. Josef Hospital, Medical Faculty of the Ruhr-University Bochum, Bochum, GermanyHaghikia Aiden Department of Neurology at St. Josef Hospital, Medical Faculty of the Ruhr-University Bochum, Bochum, GermanyGold Ralf Department of Neurology at St. Josef Hospital, Medical Faculty of the Ruhr-University Bochum, Bochum, GermanyWoitalla Dirk Department of Neurology at St. Josef Hospital, Medical Faculty of the Ruhr-University Bochum, Bochum, Germany Department of Neurology at Katholische Kliniken Ruhrhalbinsel Essen, Essen, GermanyThöne Jan Department of Neurology at Katholische Kliniken Ruhrhalbinsel Essen, Essen, Germanymaria.zella@ruhr-uni-bochum.de26 10 2018 2018 11 175628641880573212 2 2018 7 9 2018 © The Author(s), 20182018SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Background:\nNeurosarcoidosis occurs in about 5–15% of patients with sarcoidosis. Therapy with corticosteroids is generally accepted as the first-line medication, followed by various immunomodulating and cytotoxic agents or combined therapy. However, some patients show an unsatisfactory outcome or have adverse events and require novel treatment strategies.\n\nMethods:\nWe describe three patients with systemic sarcoidosis and central nervous system involvement who received CD20-targeted B-cell depletion with rituximab.\n\nResults:\nTreatment with rituximab was well tolerated and followed by marked remission in patients nonresponsive to other immunosuppressive agents.\n\nConclusion:\nRituximab may be used for patients with neurosarcoidosis who are nonresponsive to established treatment regimes.\n\nB-cell depletionCD-20infliximabneurosarcoidosissIL-2Rcover-dateJanuary-December 2018\n==== Body\nIntroduction\nSarcoidosis is a clinicopathological syndrome of unknown etiology characterized by noncaseous epithelioid granulomas which show a predilection for the lungs, skin and lymph nodes, but may affect any other organ.1 Usually the disease starts between the ages of 20–40 years. The prevalence of central nervous system (CNS) involvement (neurosarcoidosis; NS) is about 5–15%.2,3 Clinical features of NS include, among other things, cranial neuropathy, seizure, aseptic meningitis, hydrocephalus and myelitis.2–4\n\nThe most commonly used diagnostic criteria for NS were proposed by Zajicek and colleagues.5 The gold standard is histopathological confirmation from biopsy tissue; however, CNS tissue is rarely biopsied due to the risk of bleeding and subsequent neurological deterioration. Thus, diagnosis of NS may be challenging and is often made by exclusion of other entities using a combination of clinical presentation, imaging and laboratory work-up. Magnetic resonance imaging (MRI) often shows leptomeningeal involvement of the basilar meninges but virtually any portion of the CNS may be affected.2,4 Currently, no reliable serologic marker exists. Laboratory testing includes serum angiotensin converting enzyme and soluble interleukin-2 receptor (sIL-2R) but both may also be negative in patients with biopsy proof of NS.2 In contrast, cerebrospinal fluid (CSF) sIL-2R value was found to have a high sensitivity in NS.6\n\nCorticosteroids are generally accepted as the first-line therapy. In severe and recurrent cases or in cases of steroid resistance immunomodulating or cytotoxic agents such as azathioprine (AZA), methotrexate (MTX), mycophenolate mofetil, chloroquine, and cyclophosphamide (CYP) can be considered as monotherapy or in combination with corticosteroids. Furthermore, the monoclonal immunoglobulin (Ig)G1 antibody, infliximab, has been employed in patients not responsive to other treatment strategies.\n\nHere we report on three patients with progressive CNS sarcoidosis consecutively and successfully treated with rituximab. So far, only isolated case reports have described beneficial effects in patients who are refractory to first-line therapy.7,8\n\nPatients and methods\nBetween 2013 and 2017 three patients diagnosed with definitive systemic sarcoidosis and consistent neurological involvement underwent B-cell targeted therapy with the anti-CD20 antibody, rituximab. Routine laboratory testing, including serological markers of other immune disease, were without pathological findings. Other viral or bacterial infections were excluded in the CSF and serum.\n\nCD20 is a transmembrane protein present on the surface of most B-cell lymphocytes.9 Patients were treated and followed at the Department of Neurology at St. Josef Hospital Bochum, Germany and at the Department of Neurology at Katholische Kliniken Ruhrhalbinsel, Essen Germany. Inclusion criteria were clinical and histological proof of sarcoidosis and a probable diagnosis of NS based on the diagnostic criteria proposed by Zajicek and colleagues.5 All patients did not respond to first-line therapy with corticosteroids nor to alternative treatment regimes, nor showed adverse events. In one case treatment was changed because of the detection of anti-infliximab antibodies accompanied by a low serum drug concentration. There is no consensus about the optimum rituximab administration scheme and especially in patients who previously received other immunosuppressive agents, there is a potential risk of severe infections with the use of rituximab. After microbial screening and urine analysis, all patients received one 500 mg rituximab infusion systematically together with methylprednisolone 100 mg, paracetamol and antihistamine single-shot premedication. In all patients, rituximab led to a complete B-cell depletion, defined as CD19 count <1%, and was followed by maintenance rituximab infusions (250–500 mg) every 6–9 months before CD19 repopulation occurred, because B-cell repopulation increases the risk of relapse.\n\nThe present case series was discussed with the responsible ethics committee of the Ruhr-University in Bochum, Germany. The ethics committee did not consider an ethical application necessary owing to the small number of patients included and the retrospective nature of the analysis. All participants provided written informed consent before undergoing any procedures and provided written informed consent for publication of the data in an international medical journal. The data concerning this study were stored separately from the hospital charts of the patients.\n\nCase reports\nCase 1\nA 51-year-old woman with a history of pulmonary sarcoidosis and a syringomyelia (initial diagnose in 2002) between Th4 and Th5 presented in 2012 with dizziness, headache, left thigh hypoesthesia and progressive fatigue. Her treatment regime included AZA (100 mg/day) and MTX (5 mg/week). Neurological examination on admission confirmed a mild left thigh hypoesthesia without dermatome reference. A cerebral MRI demonstrated numerous T2-hyperintense lesion in proximity of the frontal horn of the left and right ventricle. Thoracic MRI was unchanged to previous MRI examinations. Syringomyelia was unrelated to NS.\n\nUnder the suspect of CNS involvement her treatment regime was changed to AZA (100 mg/day) and infliximab (5 mg/kg body weight) which led to a clinical and radiological stability over 24 months.\n\nIn 2014 a severe increase of serum transaminases forced treatment discontinuation. Following normalization of serum transaminases treatment was changed to infliximab (5 mg/kg body weight every 4 weeks) and dimethyl fumarate (DMF; 5 mg/kg body weight). However, recurrent infections like a sacroiliac joint infection and a plantar fasciitis again necessitated treatment interruption.\n\nThe authors decided to finish treatment with infliximab and to initialize treatment with rituximab. Subsequent to rituximab, the patient was progression-free and reported on a significant amelioration of fatigue. So far, she received 500 mg rituximab three times. At the last visit (September 2017) clinical stability was constantly demonstrated and neuroradiological screening also did not reveal disease progression. Additionally, the patient was free of recurrent infections.\n\nCase 2\nA 50-year-old woman with a known sarcoidosis mimicking a vasculitis presented in 2011 with sensory disturbances of both legs described as a feeling of heaviness and clumsiness. Neurological examination on admission revealed a mild gait disturbance. At that time, an immunosuppressive therapy with corticosteroids (60 mg/day) was already ongoing. MRI showed an intramedullary lesion in the cervical and thoracic cord between C2 and Th3 vertebras. The lesion was mostly isointense on T2-weighted sequences and showed contrast enhancement (Figure 1). The diagnosis of NS was considered and treatment with infliximab (5 mg/kg body weight, every 4 weeks) started. Follow-up examinations every 4–6 weeks after the beginning of infliximab showed a progressive clinical improvement until an almost complete remission after eight treatment cycles. For some reason, treatment with infliximab was not continued in the course and apart from corticosteroids (60 mg/day) no other immunosuppressive medication was started. A few weeks after the suspension of infliximab, the patient developed the same gait disturbances as at the first presentation. An externally induced immunosuppression with AZA (200 mg/day) was without any beneficial effect and the patient reported progressive sensory disturbances in both legs. Neurological examination revealed an ascending hypoesthesia of both legs and gait ataxia. The patient was unable to walk >500 m without rest. The authors decided to interrupt AZA and to reuptake therapy with infliximab (5 mg/kg body weight). Again, infliximab led to a significant neurological improvement.\n\nFigure 1. MRI of patient 2: Sagittal T1- (a) and T2-weighted (b) MRI depicts a new lesion in the thoracic cord (arrow) with contrast enhancement on the corresponding T1-weighted images (c).\n\nMRI, magnetic resonance imaging.\n\nAt the 13th infusion after the restarting of infliximab, anti-infliximab antibodies were detected in the serum. In parallel, the infliximab serum concentration was low (⩽0.1 µg/ml). At that point in time, the patient showed neither clinical nor neuroradiological signs of disease progression. Nevertheless, infliximab therapy was switched to rituximab followed by maintenance rituximab infusions (500 mg) every 6–9 months. Following rituximab, there was continuous neurological stability. To date, the patient has received rituximab 500 mg three times. At the last follow up (October 2017) the patient demonstrated no neurological deficits and reported being well. The neuroradiological screening was also inconspicuous and no adverse events occurred.\n\nCase 3\nA 57-year-old man with an history of pulmonary sarcoidosis presented in March 2012 with a residual left facial paralysis and a right hemiparesis after left middle cerebral artery stroke in January 2012.\n\nAt hospitalization, his medication included AZA (100 mg/day). A cerebral T2-weighted MRI revealed a left parietal high-intensity lesion, unchanged to previous examination. A subsequent catheter angiography showed a segmental multiple narrowing in the distal part of the middle cerebral artery and multiple venous occlusions in the affected parietal area, high consistent with the hypothesis of a vasculitis associated with NS. In addition to AZA, infliximab (5 mg/kg body weight every 4 weeks) was started. Apart from that, the patient received aspirin 100 mg/day and underwent cardiologic work-up, including transesophageal echocardiography and continuous halter electrocardiograph monitoring.\n\nUnder combined therapy, the patient developed several adverse events like fever, fatigue, hip bone pain and ischemic strokes in September 2012, with the involvement of cranial nerves. Therefore, treatment with CYP (cumulative dose 670 mg/m2) was initiated instead of AZA with neurological and neuroradiological stability over a year.\n\nIn November 2013, a progressive third nerve palsy was reported. Due to disease progression and after microbial screening, we initiated treatment with rituximab. A decent clinical improvement was demonstrated. Currently, the patient receives rituximab (250–500 mg) every 6 months depending on his B-cell count, aiming to remain 0–5 cells/µl. No further ischemic strokes occurred and at the last visit the patient was still neurologically and neuroradiologically progression-free.\n\nDiscussion\nDespite great efforts, sarcoidosis is still a disease of unknown etiology. Current pathogenetic concepts assume an exaggerated immune response which occurs in genetically susceptible individuals following exposure to a yet unidentified pathogenic antigen. While formation of noncaseating granulomas at sites of ongoing inflammation was basically considered as an antigen-mediated Th1 response, the involvement of Th17 inflammatory cascades, B cells and different cytokines is now obvious.12 A Th1 response, promoting by cytokines like interferon gamma, is basically based on a proinflammatory cascade aimed to kill intracellular parasites.13 This process is able to start an autoimmune response and to keep it going. In order to avoid uncontrolled tissue damage, Th2 cytokines yield an anti-inflammatory response.13 Interleukin-17 and its cascade also play a strong role in the inflammatory process, producing CD4+ T cells and differentiating from classic Th1 and Th2 responses.14 B cells play a role in the humoral immunity by secreting antibodies, presenting antigens and secreting cytokines.15\n\nIn NS, noncaseating granulomas mostly affect the CNS even if there are few cases of a primary involvement of the peripheral nervous system (PNS).2,3 In CNS, granulomas have tropism for meninges, more rarely for pure cerebral tissue, in PNS for spinal root sheaths, which are an extension of pachymeninges.\n\nIn contrast with other organs, NS is less likely to spontaneously remit. Usually patients are treated with second- and third-line agents, including infliximab, early during disease.2 Although blockage of tumor necrosis factor (TNF)-α with infliximab is effective in many patients, ongoing disease progression, development of anti-infliximab antibodies and adverse reactions may warrant treatment modification. In our case reports, infliximab was discontinued because of (a) recurrent infections, (b) disease progression and (c) detection of anti-infliximab antibodies. Anti-infliximab antibodies are thought to be the result of an immunological process, whereby, in the course of therapy, the patient mounts an immune response to infliximab. However, detection of anti-infliximab antibodies does not necessarily have to be followed by treatment failure and treatment discontinuation, because patients with high infliximab and low anti-infliximab antibody trough levels often maintain a clinical benefit. However, in the contrary case (high anti-infliximab antibody and low infliximab trough level) the predisposition for therapeutic failure grows.16,17\n\nAll patients were switched to rituximab. Treatment with rituximab led to neurological improvement in two cases and to disease stabilization in one case and was generally well tolerated. No severe infections or malignancies were recorded during the whole follow up.\n\nIn literature, there are solely two case reports of refractory NS successfully treated with rituximab with variable dosing regimens.7,8 Rituximab is a monoclonal IgG1 chimeric antibody that selectively targets the protein CD20 expressed on the surface of B-cell lymphocytes. Treatment with rituximab induces depletion of circulating CD20+ B cells.10,11 The US Food and Drug Association and European Medicines Agency approved rituximab for the treatment of non- Hodgkin’s lymphoma and rheumatoid arthritis but given the probably autoimmune-inflammatory etiology and limited therapies available, especially in aggressive forms of NS, rituximab might be an interesting alternative. In line, rituximab is used off-label in various inflammatory-autoimmune disorders of the CNS such as multiple sclerosis and neuromyelitis optica.18,19 The mechanisms of action by which rituximab exerts its effects in immunological disease and sarcoidosis are manifold. B cells produce autoreactive antibodies, act as antigen-specific antigen-presenting cells for T cells and secrete cytokines and costimulatory molecules that activate macrophages, induces Th1 and Th2 differentiation and stimulate further B-cell proliferation.18,19 Moreover, B-cell depletion with rituximab reduces the local Th17 response, which in turn reduces inflammation.\n\nOur results support the hypothesis that rituximab is beneficial and well tolerated in managing refractory NS. We propose that B-cell-directed therapies may become an attractive option. Further controlled studies are needed to confirm the efficacy and safety of rituximab in NS patients.\n\nDirk Woitalla and Jan Thöne are co-senior authors for this work.\n\nFunding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nConflict of interest statement: The authors declare that there is no conflict of interest.\n\nORCID iD: Samis Zella \nhttps://orcid.org/0000-0002-0815-9820\n==== Refs\nReferences\n1. \nValeyre D Prasse A Nunes H et al \nSarcoidosis . Lancet \n2014 ; 383 : 1155 –1167 .24090799 \n2. \nCulver D Ribeiro Neto M Moss B et al \nNeurosarcoidosis . Semin Respir Crit Care Med \n2017 ; 38 : 499 –513 .28750463 \n3. \nFritz D van de Beek D Brouwer M. \nClinical features, treatment and outcome in neurosarcoidosis: systematic review and metaanalysis . BMC Neurol \n2016 ; 16 : 220 27846819 \n4. \nCação G Branco A Meireles M et al \nNeurosarcoidosis according to Zajicek and Scolding criteria: 15 probable and definite cases, their treatment and outcomes . J Neurol Sci \n2017 ; 379 : 84 –88 .28716286 \n5. \nZajicek J Scolding N Foster O et al \nCentral nervous system sarcoidosis–diagnosis and management . QJM \n1999 ; 92 : 103 –117 .10209662 \n6. \nPetereit H Reske D Tumani H et al \nSoluble CSF interleukin 2 receptor as indicator of neurosarcoidosis . J Neurol \n2010 ; 257 : 1855 –1863 .20556411 \n7. \nBomprezzi R Pati S Chansakul C et al \nA case of neurosarcoidosis successfully treated with rituximab . Neurology \n2010 ; 75 : 568 –570 .20697110 \n8. \nSawaya R Radwan W. \nSarcoidosis associated with neuromyelitis optica . J Clin Neurosci \n2013 ; 20 : 1156 –1158 .23683743 \n9. \nNagashima M Osaka H Ikeda T et al \nRituximab was effective for acute disseminated encephalomyelitis followed by recurrent optic neuritis with anti-myelin oligodendrocyte glycoprotein antibodies . Brain Dev \n2018 ; 40 : 607 –611 .29661590 \n10. \nSellier-Leclerc AL Baudouin V Kwon T et al \nRituximab in steroid-dependent idiopathic nephrotic syndrome in childhood–follow-up after CD19 recovery . Nephrol Dial Transplant \n2012 ; 27 : 1083 –1089 .21810762 \n11. \nSmith MR. \nRituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance . Oncogene \n2003 ; 22 : 7359 –7368 .14576843 \n12. \nSakthivel P Bruder D. \nMechanism of granuloma formation in sarcoidosis . Curr Opin Hematol \n2017 ; 24 : 59 –65 .27755127 \n13. \nGereda JE Leung DYM Thatayatikom A et al \nRelationship between house dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma . Lancet \n2000 ; 355 : 1680 –1683 .10905243 \n14. \nOuyang W Kolls JK Zheng Y. \nThe biological functions of T helper 17 cell effector cytokines in inflammation . Immunity \n2008 ; 28 : 454 –467 .18400188 \n15. \nCooper MD. \nThe early history of B cells . Nat Rev Immunol \n2015 ; 15 : 191 –197 .25656707 \n16. \nSvenson M Geborek P Saxne T et al \nMonitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies . Rheumatology (Oxford) . 2007 ; 46 : 1828 –1834 .18032541 \n17. \nChaparro M Guerra I Muñoz-Linares P et al \nSystematic review: antibodies and anti-TNF-α levels in inflammatory bowel disease . Aliment Pharmacol Ther . 2012 ; 35 :971 –986 .22443153 \n18. \nAbulayha A Bredan A El Enshasy H et al \nRituximab: modes of action, remaining dispute and future perspective . Future Oncol \n2014 ; 10 : 2481 –2492 .25525856 \n19. \nBittner S Ruck T Wiendl H et al \nTargeting B cells in relapsing- remitting multiple sclerosis: from pathophysiology to optimal clinical management . Ther Adv Neurol Disord \n2017 ; 10 : 51 –66 .28450895\n\n",
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"keywords": "B-cell depletion; CD-20; infliximab; neurosarcoidosis; sIL-2R",
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"title": "Successful therapy with rituximab in three patients with probable neurosarcoidosis.",
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"abstract": "Acute kidney injury with severe loin pain and patchy renal ischaemia after anaerobic exercise (ALPE) is a rare clinical syndrome. ALPE has predominantly been described in Japanese and Korean populations to date. Many cases and most recurrent examples are associated with renal hypouricaemia. We describe a 28-year-old New Zealand European male without renal hypouricaemia who developed recurrent ALPE whilst performing elite-level sport. Avoiding elite-level anaerobic exercise was successful at preventing further episodes. This report confirms the first known case of ALPE in a New Zealand European male and raises the possibility that ALPE is an under-recognized condition. Long-term outcomes of recurrent ALPE remain unclear, and preventative strategies should be implemented to preserve renal function. Avoiding intense anaerobic exercise is an effective preventative strategy.",
"affiliations": "Auckland District Health Board, Auckland, New Zealand.;Department of Renal Medicine, Auckland District Health Board, Auckland, New Zealand.;Adult Emergency Department, Auckland District Health Board, Auckland, New Zealand.",
"authors": "Kelly|Richard|R|;Semple|David|D|;Harper|Alana|A|",
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"fulltext": "\n==== Front\nCase Rep Nephrol Dial\nCase Rep Nephrol Dial\nCND\nCase Reports in Nephrology and Dialysis\n2296-9705\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000517114\ncnd-0011-0176\nSingle Case\nRecurrent Acute Kidney Injury with Severe Loin Pain and Patchy Renal Ischaemia after Anaerobic Exercise without Renal Hypouricaemia in a New Zealand European Male\nKelly Richard a*\nSemple David bc\nHarper Alana de\naAuckland District Health Board, Auckland, New Zealand\nbDepartment of Renal Medicine, Auckland District Health Board, Auckland, New Zealand\ncSchool of Medicine, University of Auckland, Auckland, New Zealand\ndAdult Emergency Department, Auckland District Health Board, Auckland, New Zealand\neAuckland Rescue Helicopter Trust, Auckland, New Zealand\n*Richard Kelly, richkelly@adhb.govt.nz\nMay-Aug 2021\n5 7 2021\n5 7 2021\n11 2 176182\n24 10 2020\n7 5 2021\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nAcute kidney injury with severe loin pain and patchy renal ischaemia after anaerobic exercise (ALPE) is a rare clinical syndrome. ALPE has predominantly been described in Japanese and Korean populations to date. Many cases and most recurrent examples are associated with renal hypouricaemia. We describe a 28-year-old New Zealand European male without renal hypouricaemia who developed recurrent ALPE whilst performing elite-level sport. Avoiding elite-level anaerobic exercise was successful at preventing further episodes. This report confirms the first known case of ALPE in a New Zealand European male and raises the possibility that ALPE is an under-recognized condition. Long-term outcomes of recurrent ALPE remain unclear, and preventative strategies should be implemented to preserve renal function. Avoiding intense anaerobic exercise is an effective preventative strategy.\n\nKeywords\n\nAcute kidney injury\nLoin pain\nPatchy renal ischaemia\nAnaerobic exercise\nWithout renal hypouricaemia\n==== Body\nIntroduction\n\nThe first case of acute kidney injury (AKI) with loin pain after anaerobic exercise was described in 1981 [1]. After that, reports of similar cases began to accumulate. In the most extensive review to date, Ishikawa reviewed 118 cases and described the following features of ALPE [1]: (1) the patients are mostly young males; (2) renal hypouricaemia is a predisposing factor; (3) severe loin or abdominal pain develops several hours after intense anaerobic exercise; (4) laboratory tests show AKI without significant rhabdomyolysis; (5) delayed computed tomography (CT) after administration of contrast medium shows patchy wedge-shaped enhancements; and (6) the short-term prognosis is good.\n\nThis report describes recurrent ALPE without renal hypouricaemia in a New Zealand European male. The diagnosis was difficult to make because of the lack of knowledge of ALPE in New Zealand and would have been missed had the patient not presented for a second time.\n\nCase Report\n\nA 28-year-old New Zealand European male was admitted to our hospital with two episodes of AKI whilst participating in selection testing for an elite-level sporting team. He was normally fit and well with no family history of renal disease. His premorbid renal function was normal, with a serum creatinine of 87 μmol/L and an estimated glomerular filtration rate >90 mL/min/1.73 m2. His premorbid serum uric acid was 0.38 mmol/L. He had not previously engaged in elite-level training or competition.\n\nAfter performing an intense anaerobic upper body exercise, the patient developed bilateral loin pain, nausea, and vomiting. He ingested 400 mg of ibuprofen. The symptoms persisted beyond 24 hours, at which point he presented to the emergency department. There was no history of preceding flu-like symptoms. He had no myalgia, and his urine was of normal colour and volume. Physical examination was unremarkable; he was normotensive, and no costovertebral tenderness was appreciated. Laboratory tests revealed an AKI with an elevated serum creatinine level of 509 μmol/L. Creatine kinase and uric acid were mildly elevated at 369 IU/L and 0.49 mmol/L, respectively. Complete blood count was normal. Urinalysis was positive for microscopic haematuria and negative for myoglobinuria and proteinuria. Ultrasound of the renal tract was unremarkable except for mild renal echogenicity. The diagnosis was thought to be a multifactorial AKI due to dehydration, non-steroidal anti-inflammatory drugs (NSAIDs), and a mild degree of rhabdomyolysis. The patient's symptoms and renal function improved with intravenous fluids, paracetamol, and anti-emetics. He was discharged after 48 hours and advised to keep well hydrated, avoid NSAIDs, and avoid strenuous exercise until his renal function normalized. The creatinine level returned to normal limits, defined as <110 μmol/L, after three weeks. However, it fluctuated between 100 and 130 μmol/L when he recommenced his training without any symptoms (Fig. 1).\n\nThree months later, the patient suffered from a second episode of bilateral loin pain, nausea, and vomiting after the same intense anaerobic exercise. He did not ingest any NSAIDs this time and presented to the hospital within a couple of hours of symptom onset. He was mildly hypovolaemic on examination with a blood pressure of 91/56 mm Hg and a heart rate of 110 beats per minute. The laboratory findings on admission are shown in Table 1. An AKI was evident with a serum creatinine of 182 μmol/L. Creatine kinase and uric acid were mildly elevated at 250 IU/L and 1.32 mmol/L, respectively. There was a reactive leucocytosis. Inflammatory markers were normal. Streptococcal serology was negative. Urinalysis was positive for microscopic haematuria and proteinuria with a protein/creatinine ratio of 110 mg/μmol and negative for myoglobinuria. A dual-phase contrast-enhanced CT scan of the kidneys was performed, revealing patchy areas of hypoperfusion (Fig. 2).\n\nAfter reviewing the medical literature, ALPE was diagnosed based on the characteristic history, laboratory findings, and CT findings. Both AKI episodes were due to this condition with variable levels of concomitant dehydration. The patient was discharged after his renal function improved with intravenous fluids. The creatinine level returned to normal limits after two weeks. Ongoing management and care included input from both renal and sports medicine specialists. In order to prevent ALPE recurrence, the patient was advised to avoid elite-level anaerobic exercise. He subsequently ended his elite-level sports career, which was very disappointing. However, he was able to undertake normal and even relatively high-level exercise without symptoms or alteration in his renal function when followed up at one month, six months, and one year post-discharge (Fig. 1). The serum uric acid level was 0.25 mmol/L at the one-year follow-up with a corresponding serum creatinine of 85 μmol/L, again confirming that he did not have renal hypouricaemia.\n\nDiscussion\n\nALPE has predominantly been described in Japanese and Korean populations to date. It has been suggested that this trend is due to a higher prevalence of renal hypouricaemia in Japan and Korea [1, 2, 3]. However, international data on the prevalence of renal hypouricaemia is lacking, and half of ALPE cases do not have renal hypouricaemia [1]. Alternatively, this trend may reflect an increased awareness and recognition of ALPE in these countries. A few isolated cases of ALPE have been described in European [4, 5, 6] and Middle Eastern populations [7, 8]. This report confirms the first known case of ALPE in a New Zealand European male. We suspect that ALPE is possibly under-recognized in populations around the world and may not be ascribable to specific population genotypes.\n\nPatients with ALPE present with severe loin or abdominal pain that develops several hours after anaerobic exercise, typically track sprinting [1, 2, 3]. The pain is sharp and stabbing in nature and lasts one to five days [1]. Associated symptoms can include nausea and vomiting, a low-grade fever, fatigue, and prodromal flu-like symptoms [1, 2, 3]. Urine volume and colour are normal or in keeping with mild dehydration [1]. Myoglobin-induced AKI due to exertional rhabdomyolysis is an important differential diagnosis. In comparison, this condition occurs after intense aerobic exercise, typically marathon running, and patients present with myalgia, low urine output, and reddish-brown urine [9].\n\nLaboratory tests in ALPE show AKI without significant rhabdomyolysis. Creatinine levels are elevated, whilst creatine kinase and myoglobin levels are normal or only slightly elevated (no greater than nine and seven times the upper limit of normal, respectively) [1]. Approximately half of ALPE cases are associated with renal hypouricaemia [1]. The present case did not have renal hypouricaemia, with a normal serum uric acid level measured premorbid and after the creatinine level returned to normal. Approximately one quarter of cases have abnormal urinalysis results consistent with acute tubular necrosis [1], and most renal biopsy samples also show acute tubular necrosis [1, 3].\n\nA delayed renal CT scan taken 24–72 hours after contrast administration is recommended to confirm patchy wedge-shaped enhancements in the kidneys [1, 2, 3]. This finding is relatively specific for ALPE, reflecting patchy renal ischaemia [1, 2, 3]. Contrast does not initially enter the ischaemic areas because of hypoperfusion. Following reperfusion, contrast can enter the ischaemic areas, but then excretion is delayed due to renal function impairment. A CT scan taken immediately after contrast administration may capture the initial hypoperfusion phase, as in the present case, but this is variable [2]. Alternative imaging methods should be considered in patients with severe renal dysfunction to avoid contrast use. Colour Doppler ultrasound [10], bone scintigraphy with 99mTc-methylene disphosphonate [11], and diffusion-weighted magnetic resonance imaging [12] all perform well at detecting patchy renal ischaemia.\n\nThe pathogenesis of ALPE is not entirely understood. Anaerobic exercise appears to induce vasoconstriction of intra-renal arteries, leading to patchy renal ischaemia, acute tubular necrosis, and loin pain [1, 2, 3]. Although the mechanism of vasoconstriction is unclear, two hypotheses have been proposed. The first hypothesis is that type two muscle fibres are damaged by anaerobic exercise and release non-myoglobin vasoactive mediators [1]. The second hypothesis is that oxygen free radicals, which have a vasoactive function, accumulate with anaerobic exercise [1, 2, 3]. Plasma uric acid is a powerful antioxidant [13], and therefore, renal hypouricaemia may enhance the latter mechanism by reducing oxygen free radical elimination. Concurrent NSAID use and hypovolaemia may worsen the ischaemic injury by decreasing renal perfusion [1]. Uric acid nephropathy due to exertional changes in uric acid excretion was previously considered to have a pathogenic role [1, 2, 3]. However, no patients demonstrated uric acid crystallisation on renal biopsy in the reviews by Ishikawa and Ohta et al. [1, 3].\n\nALPE has a good short-term prognosis. Renal function generally recovers within three days to several weeks [1]. Early correction of hypovolaemia with intravenous fluids accelerates recovery [3]. Haemodialysis may be required in patients with severe renal failure, but they likewise make a good recovery [1, 2, 3]. In the present case, the maximum serum creatinine level was higher in the first ALPE episode, possibly due to a delayed presentation and commencement of intravenous fluids. The renal function trended abnormally after this episode, indicating that recurrence without any symptoms might have occurred.\n\nThe long-term prognosis of ALPE remains unclear due to a lack of long-term data. Kikuchi et al. [14] demonstrated chronic renal lesions in a 38-year-old male who experienced at least four ALPE episodes [14]. ALPE recurrence occurs in up to a quarter of patients, with most cases in patients with renal hypouricaemia [1, 3]. The present case had ALPE recurrence without hypouricaemia. He will likely continue to suffer from recurrent episodes with ongoing intense anaerobic exercise, and we predict that this will eventually cause a permanent renal deficit and result in a negative outcome. Therefore, we advised the patient to avoid intense elite-level anaerobic exercise.\n\nFurther reasoning for the patient having to discontinue elite-level sport was that the professional sports team's management could not continue his employment after considering their health and safety responsibilities. Recurrent episodes of renal injury caused by elite-level sport could effectively be construed as a workplace injury in New Zealand. Similar employment challenges may present for other professional athletes and occupations that require intense exercise. There have been cases in Japan of work-related ALPE in a police officer and a professional cyclist, although they continued their careers despite the ongoing risk of recurrence [15]. Whilst prohibiting intense anaerobic exercise is an effective strategy to prevent ALPE recurrence, this can have significant social, economic, and psychological implications for patients.\n\nIn summary, ALPE is possibly an under-recognized condition worldwide and may not be ascribable to specific population genotypes. The diagnosis of ALPE should be considered in all patients who present with loin or abdominal pain accompanied by AKI. Long-term outcomes of recurrent ALPE remain unclear and preventative strategies should be implemented to preserve renal function. The present case highlights that patients with or without renal hypouricaemia can develop recurrent ALPE, that recurrent ALPE might occur without symptoms, and that successful prevention can be achieved by avoiding intense anaerobic exercise.\n\nStatement of Ethics\n\nThis study was approved by the Auckland Health Research Ethics Committee. Written informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\n\nNo funding was required for this study.\n\nAuthor Contributions\n\nRichard Kelly, Alana Harper, and David Semple were responsible for the clinical assessment and management of the patient. Richard Kelly prepared the draft manuscript. All the authors participated in editing the final manuscript.\n\nFig. 1 Trend in serum creatinine (μmol/L) over time.\n\nFig. 2 CT performed immediately after contrast administration revealing patchy renal hypoperfusion (red arrows). CT, computed tomography.\n\nTable 1 Laboratory data on the second admission\n\nUrinalysis\t\tBiochemistry\t\tComplete blood count\t\t\nWhite cells (<10 E + 6/L)\t<10 E + 6/L\tSodium (135–145 mmol/L)\t140 mmol/L\tHaemoglobin (130–175 g/L)\t172 g/L\t\nRed cells (<1 E + 6/L)\t<1 E + 6/L\tPotassium (3.5–5.2 mmol/L)\t4.0 mmol/L\tRBC (4.3–6 E + 12/L)\t5.77 E + 12/L\t\nEpithelial cells (<1 E + 6/L)\t<1 E + 6/L\tChloride (95–110 mmol/L)\t100 mmol/L\tWBC (4–11 E + 9/L)\t17.76 E + 9/L\t\nBacteria (−)\tNone detected\tUrea (3.2–7.7 mmol/L)\t10.8 mmol/L\tNeutrophils (1.9–7.5 E + 9/L)\t11.19 E + 9/L\t\nHyaline casts (non-specified)\t6E + 6/L\tCreatinine (60–105 µmol/L)\t173 µmol/L\tPlatelet count (150–400 E + 9/L)\t279 E + 9/L\t\nPCR (0–23 mg/mmol)\t110 mg/mmol\tUrate (0.23–0.42 mmol/L)\t1.32 mmol/L\t\t\t\nHaemoglobin pigments (−)\t+\tCK (60–220 U/L)\t250 U/L\t\t\t\nMyoglobin (−)\t−\tBilirubin (0–24 µmol/L)\t5 µmol/L\t\t\t\nSerology\t\tGGT (0–60 U/L)\t18 U/L\tVenous blood gas\t\t\nCRP (0–5 mg/L)\nESR (1–10 mm in 1 h)\nASOT (<240 IU/mL)\nAnti DNAse-B (<680 U/mL)\t<0.6 mg/L\n1 mm in 1 h\n38 IU/mL\n<100 U/mL\tALP (40–110 U/L)\nALT (0–45 U/L)\nAST (0–45 U/L)\nGlucose (3.5–5.4 mmol/L)\nPhosphate (0.7–1.5 mmol/L)\t64 U/L\n30 U/L\n26 U/L\n4.5 mmol/L\n1.12 mmol/L\tpH (7.35–7.45)\nPCO2(5.3–6.7 kPa)\nHCO3− (22–32 mmol/L)\nLactate (<2 mmol/L)\t7.36\n6.0 kPa\n23 mmol/L\n1.6 mmol/L\t\n\t\tCalcium (2.1–2.55 mmol/L)\t2.78 mmol/L\t\t\t\n\t\tMagnesium (0.7–1 mmol/L)\t2.32 mmol/L\t\t\t\n\t\tLDH (120–150 U/L)\t212 U/L\t\t\t\nThe reference values for each variable are presented in parenthesis to the right.\n==== Refs\nReferences\n\n1 Ishikawa I Acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise in patients with or without renal hypouricemia Nephron 2002 91 (4) 559 70 12138255\n2 Lee J Lee SW Lee JW Chin HJ Joo KW Kim YS Clinical characteristics of acute renal failure with severe loin pain and patchy renal vasoconstriction Kidney Res Clin Pract 2012 31 (3) 170 6 26894023\n3 Ohta T Sakano T Igarashi T Itami N Ogawa T Exercise-induced acute renal failure associated with renal hypouricaemia: results of a questionnaire-based survey in Japan Nephrol Dial Transplant 2004 19 (6) 1447 53 15150354\n4 Stiburkova B Taylor J Marinaki AM Sebesta I Acute kidney injury in two children caused by renal hypouricaemia type 2 Pediatr Nephrol 2012 27 (8) 1411 5 22527535\n5 Simpson A Dornan R Turner A Recurrent AKI with loin pain in a Caucasian competitive cyclist. Urate is part of the story UK Kidney Week 2019 Brighton June 3-June 5. Abstract 428\n6 Ouellet G Lin S Nolin L Bonnardeaux A Hereditary renal hypouricemia in a Caucasian patient: a case report and review of the literature Nephrol Ther 2009 5 (6) 568 71 19464979\n7 Bahat H Dinour D Ganon L Feldman L Holtzman EJ Goldman M Non-urate transporter 1-related renal hypouricemia and acute renal failure in an Israeli-Arab family Pediatr Nephrol 2009 24 (5) 999 1003 19189137\n8 Bardak S Turgutalp K Kiykim A Exercise-induced acute kidney injury: a case of renal hypouricemia Turk Neph Dial Transpl 2015 24 (2) 217 9\n9 Bagley WH Yang H Shah KH Rhabdomyolysis Intern Emerg Med 2007 2 (3) 210 8 17909702\n10 Furumatsu Y Nagasawa Y Hamano T Iwatani H Imai E Acute renal failure with severe loin pain after anaerobic exercise (ALPE): detection of patchy renal ischaemia by contrast-enhanced colour Doppler NDT Plus 2007 1 (2) 120 1 30792797\n11 Ishikawa I Ishii H Saito T Yuri T Shinoda A Urashima S Increased patchy renal accumulation of 99mTc-methylene diphosphonate in a patient with severe loin pain after exercise Nephron 1987 47 (1) 29 31 3627334\n12 Ohta K Yokoyama T Shimizu M Mizuno K Sakazume S Fujiki T Diffusion-weighted MRI of exercise-induced acute renal failure (ALPE) Pediatr Nephrol 2011 26 (8) 1321 4 21594743\n13 Ames BN Cathcart R Schwiers E Hochstein P Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis Proc Natl Acad Sci U S A 1981 78 (11) 6858 62 6947260\n14 Kikuchi Y Koga H Yasutomo Y Kawabata Y Shimizu E Naruse M Patients with renal hypouricemia with exercise-induced acute renal failure and chronic renal dysfunction Clin Nephrol 2000 53 (6) 467 72 10879667\n15 Shimizu Y Wakabayashi K Totsuka A Hayashi Y Nitta S Hara K Exercise-induced acute kidney injury in a police officer with hereditary renal hypouricemia Case Rep Nephrol Dial 2019 9 (2) 92 101 31602378\n\n",
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"title": "Recurrent Acute Kidney Injury with Severe Loin Pain and Patchy Renal Ischaemia after Anaerobic Exercise without Renal Hypouricaemia in a New Zealand European Male.",
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"abstract": "Outbreak of the new type coronavirus infection, known as coronavirus infection 2019 (COVID-19), has begun in December 2019, in Wuhan, China. As of today, 3 April 2020, 972,640 people affected and 50,325 people died from Severe Acute Respiratory Syndrome-Coronavirus 2. There is not any standard treatment for coronavirus infection 2019; however, there are promising data for hydroxychloroquine and some anti-retroviral drugs. Programmed death-1 (PD-1)/programmed death ligand-1 (PDL-1) pathway is an important target for the cancer immunotherapy. However, there is a robust pre-clinical and clinical data regarding inhibitor effect of this pathway on the acute or chronic viral infections. Thus, blockade of this pathway may lead to an anti-viral effect and decrease viral load. Here, we report the clinical course of coronavirus infection 2019 infection of a patient in whom older aged, having multiple co-morbidities, and taking nivolumab for metastatic malignant melanoma. In contrast to her older age, comorbidities, and cancer diagnosis, she was in a good condition, and there was also no pneumonia finding. We think that this good clinical course of coronavirus infection 2019 infection may be related to blockade of PD-1/PDL-1 pathway with nivolumab. It is impossible to say that blockade of PD-1/PDL-1pathway is a treatment option for COVID-19; however, we want to share our experience.",
"affiliations": "Department of Medical Oncology, Ankara University, Ankara, Turkey.;Department of Medical Oncology, Ankara University, Ankara, Turkey.;Department of Infectious Disease and Clinical Microbiology, Ankara University, Ankara, Turkey.;Department of Internal Medicine, Ankara University, Ankara, Turkey.;Department of Radiology, Ankara University, Ankara, Turkey.;Department of Infectious Disease and Clinical Microbiology, Ankara University, Ankara, Turkey.;Department of Medical Oncology, Ankara University, Ankara, Turkey.;Department of Medical Oncology, Ankara University, Ankara, Turkey.",
"authors": "Yekedüz|Emre|E|https://orcid.org/0000-0001-6819-5930;Dursun|Bengü|B|;Aydın|Güle Ç|GÇ|;Yazgan|Satı C|SC|;Öztürk|Halis H|HH|;Azap|Alpay|A|;Utkan|Güngör|G|;Ürün|Yüksel|Y|https://orcid.org/0000-0002-9152-9887",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000998:Antiviral Agents; D061026:Programmed Cell Death 1 Receptor; D053139:Oseltamivir; D000077594:Nivolumab; D006886:Hydroxychloroquine; D017963:Azithromycin",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220924084",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "COVID-19; SARS-CoV2; immunotherapy",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D000998:Antiviral Agents; D017963:Azithromycin; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008175:Lung Neoplasms; D008545:Melanoma; D000071069:Multiple Chronic Conditions; D000077594:Nivolumab; D053139:Oseltamivir; D058873:Pandemics; D011024:Pneumonia, Viral; D061026:Programmed Cell Death 1 Receptor; D000086402:SARS-CoV-2; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1289-1294",
"pmc": null,
"pmid": "32423324",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinical course of COVID-19 infection in elderly patient with melanoma on nivolumab.",
"title_normalized": "clinical course of covid 19 infection in elderly patient with melanoma on nivolumab"
} | [
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"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-256388",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
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"activesubstancename": "HYDROXYCHLOROQUINE"
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"abstract": "Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) sometimes occur following Anti-thymocyte globulin (ATG) administration for allogenic stem cell transplantation but are rare in aplastic anemia (AA) patients. A 55-year-old woman with AA following ATG developed refractory fever and was diagnosed with EBV-LPD. She was successfully treated with weekly rituximab monotherapy; however, she developed EBV encephalitis. She was admitted to the intensive care unit and finally recovered from unconsciousness. EBV-LPD should be considered after ATG for AA when symptoms appear. Because EBV-LPD following ATG for AA can rapidly progress, weekly monitoring of EBV-DNA and early intervention may be necessary.",
"affiliations": "Department of Oncology and Hematology, The Jikei University School of Medicine, Japan.",
"authors": "Mashima|Kiyomi|K|;Yano|Shingo|S|;Yokoyama|Hiroki|H|;Saito|Takeshi|T|;Machishima|Tomohito|T|;Shimada|Takaki|T|;Yahagi|Yuichi|Y|;Takahara|Shinobu|S|;Sugiyama|Katsuki|K|;Ogasawara|Yoji|Y|;Minami|Jiro|J|;Kamiyama|Yutaro|Y|;Katsube|Atsushi|A|;Suzuki|Kazuhito|K|;Ohshima|Sayaka|S|;Yamada|Hisashi|H|;Usui|Noriko|N|;Aiba|Keisuke|K|",
"chemical_list": "D000961:Antilymphocyte Serum",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.56.7722",
"fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.56.7722Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 28321074Case ReportEpstein-Barr Virus-associated Lymphoproliferative Disorder with Encephalitis Following Anti-thymocyte Globulin for Aplastic Anemia Resolved with Rituximab Therapy: A Case Report and Literature Review Mashima Kiyomi 1Yano Shingo 1Yokoyama Hiroki 1Saito Takeshi 1Machishima Tomohito 1Shimada Takaki 1Yahagi Yuichi 1Takahara Shinobu 1Sugiyama Katsuki 1Ogasawara Yoji 1Minami Jiro 1Kamiyama Yutaro 1Katsube Atsushi 1Suzuki Kazuhito 1Ohshima Sayaka 1Yamada Hisashi 2Usui Noriko 3Aiba Keisuke 11 Department of Oncology and Hematology, The Jikei University School of Medicine, Japan2 Research Center for Medical Science, Core Research Facilities for Basic Science (Molecular Genetics), The Jikei University School of Medicine, Japan3 Department of Oncology and Hematology, The Jikei University School of Medicine, Daisan Hospital, JapanCorrespondence to Dr. Keisuke Aiba, aiba@jikei.ac.jp\n\n15 3 2017 56 6 701 706 18 5 2016 3 7 2016 The Internal Medicine is an Open Access article 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/).Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) sometimes occur following Anti-thymocyte globulin (ATG) administration for allogenic stem cell transplantation but are rare in aplastic anemia (AA) patients. A 55-year-old woman with AA following ATG developed refractory fever and was diagnosed with EBV-LPD. She was successfully treated with weekly rituximab monotherapy; however, she developed EBV encephalitis. She was admitted to the intensive care unit and finally recovered from unconsciousness. EBV-LPD should be considered after ATG for AA when symptoms appear. Because EBV-LPD following ATG for AA can rapidly progress, weekly monitoring of EBV-DNA and early intervention may be necessary. \n\nAnti-thymocyte globulinEpstein-Barr virusaplastic anemiaencephalitisrituximablymphoproliferative disorder\n==== Body\nIntroduction\nEpstein-Barr virus (EBV) is a gammaherpesvirus that latently infects approximately 90% of human adults. The main targets of EBV infection are naïve B-cells, which are activated to proliferating blasts. Infection by EBV and the spread of EBV are controlled by host antibodies and cytotoxic T lymphocytes (CTLs). However, the host immune system cannot completely eliminate EBV; therefore, infected B cells can persist at low levels (1).\n\nAnti-thymocyte globulin (ATG) is a rabbit-derived polyclonal antibody with a high affinity for T cells and leukocyte surface antigens. ATG reduces the levels of antigen-reactive T cells in the peripheral blood. Impairment of the CTL response is associated with abnormal proliferation of B cells. Post-transplant lymphoproliferative disorders (PTLDs) are lymphoid or plasmatic proliferation disorders that develop after solid organ transplantation or allogeneic hematopoietic stem cell transplantation (allo-HSCT) because of immunosuppression (2). ATG-containing conditioning regimens have been reported to increase the risk of PTLDs (3-5). The recommended strategy for the prevention of PTLDs is the reduction of immunosuppression with or without preemptive rituximab therapy, based on regular monitoring of EBV deoxyribonucleic acid (EBV-DNA) loads in peripheral blood. Preemptive rituximab therapy has been reported to prevent the development of PTLDs in approximately 90% of cases (6).\n\nThe initial treatment of newly diagnosed acquired severe aplastic anemia is allogeneic bone marrow transplantation (BMT) from a human leucocyte antigen (HLA)-identical sibling donor, if available, for patients <40 year of age (7,8). Immunosuppressive therapy is recommended for patients ≥40 years of age or with no HLA-identical sibling donor (9). In the setting of allo-HSCT, ATG is associated with an increased risk of EBV reactivation and PTLD (10). Scheinberg et al. reported that EBV reactivation occurred in 100% of EBV-seropositive patients after receiving rabbit ATG at a dose of 3.5 mg/kg with cyclosporin A (CsA) therapy for severe aplastic anemia (11).\n\nThe risk factors for EBV-LPD following treatment for aplastic anemia have not yet been determined. With regard to PTLD following allo-SCT, the risk factors include a T cell depletion treatment regimen, patient age >50 years, second allo-HCT, the presence of graft-versus-host disease, the use of cord blood, and haploidentical transplant (6). In patients with aplastic anemia, the reactivation of EBV following treatment using rabbit ATG was reportedly more severe than that following treatment using horse ATG or alemtuzumab (11,12).\n\nTen cases of EBV reactivation and/or LPDs following immunosuppressive therapy for aplastic anemia have been reported in the literature. However, to our knowledge, the outcome of EBV encephalitis following ATG therapy has not been reported (13-22). EBV-associated lymphoproliferative disorders (EBV-LPDs) following ATG therapy for aplastic anemia are rapidly progressive and often fatal. Reduction of immunosuppression and rituximab monotherapy with or without combination chemotherapy have been reported as treatment options for EBV-LPDs and PTLDs. We herein report a case of a patient with aplastic anemia who developed EBV-LPD and EBV encephalitis following ATG therapy who was successfully treated using rituximab monotherapy.\n\nCase Report\nA 55-year-old woman was referred to our hospital because of pancytopenia. Her medical history included lumpectomy and adjuvant radiochemotherapy for breast cancer at 49 years of age. Because her peripheral blood count had gradually decreased, she was admitted to our department in May 2012. On a physical examination, the patient had conjunctival pallor and local purpura of her lower legs. Laboratory studies revealed pancytopenia with an absolute neutrophil count of 0.4×109/L, reticulocyte count of 47.8×109/L, and platelet count of 17×109/L. Bone marrow aspiration and biopsy showed severely hypoplastic marrow with 90% of the normal tissue replaced by adipose tissue and no evidence of increased blast cells, dysplasia, or atypical cells (Fig. 1). A chromosome analysis showed no abnormalities in 20 metaphases. Magnetic resonance imaging (MRI) of the spine revealed severely fatty marrow. Indium chloride bone marrow scintigraphy showed decreased uptake of indium chloride by the bone marrow, which was consistent with aplastic anemia. The patient was diagnosed with severe aplastic anemia. The proportion of paroxysmal nocturnal hemoglobinuria (PNH)-type granulocytes was 0.0387% (>0.003%) and PNH-type red blood cells was 0.067% (>0.005%), which is considered to be a predictor of response to ATG and CsA therapy (7). A serological analysis showed that she was seropositive for antibodies to cytomegalovirus and EBV; therefore, we initiated treatment using rabbit ATG and CsA.\n\nFigure 1. Photomicrograph of the patient’s bone marrow smear at the time of diagnosis of aplastic anemia. Ninety percent of the normal bone marrow tissue was replaced by adipose tissue with no blasts or mature cells. There were no atypical or malignant cells present. Magnification×100. Hematoxylin and Eosin staining.\n\nHer clinical course is shown in Fig. 2. ATG (3.75 mg/kg) was administered from Days 1 to 5, methylprednisolone (2 mg/kg) was administered, and CsA (6 mg/kg) on Day 6. On Day 28, she developed a high fever, which was unresponsive to antibiotics. CsA administration was discontinued on Day 39 because of liver injury and renal failure, indicated by elevated levels of total bilirubin (8.9 mg/dL), aspartate aminotransferase (147 U/L), alanine aminotransferase (35 U/L), lactate dehydrogenase (LDH) (795 U/L), serum creatinine (2.58 mg/dL), and C-reactive protein (42.9 mg/dL). Ferritin had increased sharply to 66,320 ng/mL. Atypical lymphocytes were detected in her peripheral blood. On Day 41, a computed tomography (CT) scan (Fig. 3) revealed hepatosplenomegaly, thickening of the gallbladder wall because of acute hepatitis, and enlargement of multiple abdominal lymph nodes. Lymph node biopsy could not be performed because there were no superficial lymphadenopathies. In addition, the patient developed respiratory failure and was transferred to the intensive care unit and immediately intubated. The serum LDH level increased to >3,000 U/L, and the serum EBV-DNA level increased to 1.1×106 copies/106 cells. These clinical signs and laboratory data strongly suggested the development of EBV-LPD; therefore, we administered rituximab at 375 mg/m2 once per week. She was afebrile a few days after the first administration of rituximab. EBV-LPD was confirmed because of the monoclonality of EBV-DNA in her peripheral blood by Southern blotting hybridization (Fig. 4). Following a second cycle of rituximab, she recovered from respiratory failure and was extubated.\n\nFigure 2. Clinical course of the patient. Forty-five days after ATG initiation, the serum LDH level was elevated to more than 3,000 U/L, and the serum EBV-DNA level increased to 1.1×106 copies/106 cells. Following rituximab therapy, these levels rapidly decreased. Rituximab was administered once a week for 8 weeks.\n\nFigure 3. Abdominal computed tomography before the initiation of rituximab. Abdominal computed tomography demonstrated hepatosplenomegaly, increased thickness of the gallbladder wall, and multiple enlarged abdominal lymph nodes.\n\nFigure 4. Southern blot analysis demonstrated monoclonality of the EBV-infected cells. M’ represents the size marker of the DNA; No. 1 is the positive control, No. 2 is the negative control, and No. 3 is the patient’s peripheral blood sample.\n\nAlthough her general status and laboratory data had improved, she suddenly fell unconscious three days after the second cycle of rituximab. Cranial T2-weighted MRI and fluid-attenuated inversion recovery (Fig. 5) showed high-intensity lesions in her cerebral cortex. A polymerase chain reaction (PCR) analysis for herpes simplex virus 1, 2 (HSV-1, 2), EBV, human herpes virus 6 (HHV-6), varicella zoster virus (VZV), and cytomegalovirus (CMV) was performed using the cerebrospinal fluid (CSF), and EBV-DNA was detected in the CSF sample. After EBV encephalitis with LPD was diagnosed, we administered ganciclovir and intravenous immunoglobulin (IVIG). As shown in Fig. 2, a real-time PCR analysis showed that the serum EBV-DNA level had rapidly decreased, and she regained consciousness. After eight subsequent courses of rituximab treatment, the EBV-DNA loads decreased below the detection limit, and the symptoms of EBV-LPDs and EBV encephalitis disappeared. A CT scan also revealed that there was no evidence of hepatosplenomegaly, enlarged gallbladder, or abdominal lymphoadenopathy (Fig. 6). Twenty-two months following ATG initiation, she achieved a partial response for aplastic anemia according to the response criteria previously described by Camitta (8). To date, EBV-LPD recurrence has not been observed.\n\nFigure 5. Cranial magnetic resonance imaging (MRI) fluid attenuation inversion recovery imaging. Cranial MRI fluid attenuation inversion recovery imaging revealed high-intensity lesions in the cerebral cortex, in keeping with a diagnosis of viral (EBV) encephalitis.\n\nFigure 6. Abdominal computed tomography after the eight cycles of rituximab. A CT scan revealed that there was no evidence of hepatosplenomegaly, enlarged gallbladder, or abdominal lymphoadenopathy after treatment with rituximab.\n\nDiscussion\nThis case report demonstrated that EBV-associated LPD with EBV encephalitis following ATG therapy for aplastic anemia can be successfully treated with rituximab. This finding may have implications for future patient treatment because it suggests that early detection of EBV-DNA and EBV reactivation may be beneficial for patients receiving ATG treatment for aplastic anemia.\n\nTen previously reported cases of EBV reactivation and/or LPD following immunosuppressive therapy for aplastic anemia from the literature can be compared with this case, although no case included EBV encephalitis (13-22). As shown in Table, six previously reported patients with LPD achieved a complete response (CR) with reduction of immunosuppression and/or combination chemotherapy (14,16-19,22). The initial signs of EBV-LPDs are a fever, general fatigue, loss of appetite, lymphadenopathy, hepatosplenomegaly, appearance of atypical lymphocytes in peripheral blood, and/or elevation of serum LDH (13-22). In our case, the cessation of immunosuppressive agents did not improve the symptoms of EBV-LPD; however, rituximab monotherapy resulted in a CR.\n\nTable. Previous Case Reports of Lymphoproliferative Disorders Following Immunosuppressive Treatment for Aplastic Anemia.\n\nAge/sex\tDose and a type of ATG treatment\tTime to appearance of initial symptoms of EBV-LPD following ATG\tTime to diagnosis\tDiagnosis\tPeak EBV-viral loads\tTreatment for LPD\tOutcome\tReferences\t\n36/M\t0.75 mg/kg/d 9 days\t\t9 days\tEBV-LPDs\t\t\tDied\t[13]\t\n42/F\tRabbit, 12.5 mg/kg/d\t2 weeks\t2 weeks\tDLBCL\t4 × 106 copies/mL\tRituximab, CPM\tCR\t[14]\t\n54/M\tRabbit, 3.75 mg/kg/d 5 days\t26 days\t26 days\tEBV-LPDs\t3.3 × 106 copies/106 WBC\t\tDied\t[15]\t\n38/M\t1st: Rabbit, 3.5 mg/kg/d for 5 days 2nd: Horse 3.5 mg/kg/d for 1 day\t19 days\t24 days\tInfectious mononucleosis\t30,000/150,000 cells\tCessation of CsA, Rituximab\tCR\t[16]\t\n55/M\tHorse\tLess than a month\t7 days after the appearance of initial symptoms\tDiffuse atypical/clonal plasma cell hyperplasia\t60,060 copies/mL\tRituximab\tCR\t[17]\t\n55/M\tRabbit, 3.75 mg/kg/d for 5 days\tAbout 3 months\t84 days\tAtypical lymphocytes proliferation\t140 copies/106 WBC\tCessation of CsA\tCR\t[18]\t\n46/F\tRabbit, 3.75 mg/kg/d for 5 days\t26 days\t33 days\tEBV-LPDs\t7.9 × 106 copies/mL\tCessation of CsA\tCR\t[19]\t\n81/M\tRabbit, 3.3 mg/kg/d for 5 days\t31 days\t34 days\tEBV-LPDs\t4 × 106 copies/mL\tCessation of CsA, rituximab\tDied\t[20]\t\n69/W\tRabbit\tAbout 30 days\t54 days\tEBV-LPDs\t3 × 105 copies/mL\t\tDied\t[21]\t\n26/M\tRabbit, 3.75 mg/kg/d for 5 days\t2 months\t\tEBV-LPDs\t120 copies/mL\tReduction of CsA, rituximab\tCR\t[22]\t\n55/F\tRabbit, 3.75 mg/kg/d 5 days\t28 days\t36 days\tEBV-LPDs\t1.1 × 106 copies/106 cells\tCessation of CsA, rituximab\tCR\tOur case\t\nF: female, M: male, mg/kg/d: mg/kg/day, ATG: antithymocyte globulin, EBV: Epstein - Barr virus, EBV-LPD: EBV-associated lymphoproliferative disorder, IM: infectious mononucleosis, DLBCL: diffuse large B cell lymphoma, CsA: cyclosporin A, CPM: cyclophosphamide, CR: complete response \n\nTime to diagnosis indicates the duration from Day 1 on recent immunosuppression therapy to the appearance of the first symptom of LPD.\n\nWeekly monitoring of the peripheral EBV-DNA load is recommended for high-risk patients following allo-HSCT (23). The peak incidence of early PTLDs occurs 6-12 months following allo-HSCT (24). EBV-LPDs in patients with aplastic anemia may occur earlier than in patients with PTLDs. Therefore, it may be reasonable to begin monitoring within a week after ATG initiation.\n\nWith regard to allo-HSCT, patients with EBV reactivation and sufficient T cells improved only by reduction of immunosuppression (25). Among patients who developed PTLDs following allo-HSCT, the response rate for rituximab with the reduction of immunosuppression was 84%, whereas the rate was only 61% without a reduction of immunosuppression (26). Our patient did not improve following reduction of immunosuppression; therefore, an anticancer agent was administered. This indicates that the reduction of immunosuppression following the development of LPDs may be less effective for EBV-LPDs after ATG than for PTLDs, which may be partly because EBV-LPDs following ATG for aplastic anemia generally develop before T cell reconstitution.\n\nOther EBV-associated diseases sometimes concurrently develop with PTLDs. Three major EBV end-organ diseases in recipients of allo-HSCT are pneumonitis, encephalitis/myelitis, and hepatitis (27). Reportedly, EBV-associated diseases are more refractory to rituximab than other agents (27). The MRI features of central nervous system (CNS)-involved PTLD that develop after solid-organ transplantation are multiple contrast-enhancing, intra-axial lesions associated with extensive peritumoral edema (28). CNS-involved PTLD masses are generally hypercellular, appearing hypo- to isointense on both plain T1- and T2-weighted MRI (29). Unlike CNS-involved PTLD, EBV encephalitis is reported to appear hyperintense on plain T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI (30). Because EBV-DNA was detected in the CSF and cranial MRI T2-weighted and FLAIR revealed a high-intensity cerebral cortex without masses or peritumoral edema, we suspected our patient of having EBV encephalitis and not EBV-LPD with CNS involvement.\n\nIn conclusion, we reported a case of EBV-LPD with EBV encephalitis following ATG therapy in a patient with aplastic anemia who was successfully treated using rituximab. This case demonstrates that, in patients with aplastic anemia who are treated using ATG therapy, the initial symptoms of EBV-LPD should be considered. Because EBV-LPD following treatment for aplastic anemia progresses more rapidly than PTLD, weekly monitoring of EBV-DNA may be necessary. If EBV-LPD develops during treatment for aplastic anemia, a reduction in immunosuppressive treatment may be insufficient; therefore, preemptive treatment using rituximab should be considered.\n\nThe authors state that they have no Conflict of Interest (COI).\nConsent for publication\nInformed consent was obtained form the patient for publication.\n\nAuthor contributions\nKM, SY, and HY were the physicians in charge of the case. All of the authors contributed to the composition of this article and have read and approved the final manuscript.\n\nAcknowledgement\nWe thank Ms. Yumiko Inui (Kobe University) for the useful advice regarding our medical practice.\n==== Refs\n1. \nThorley-Lawson DA , Gross A \nPersistence of the Epstein-Barr virus and the origins of associated lymphomas . N Engl J Med \n350 : 1328 -1337 , 2004 .15044644 \n2. \nSwerdlow SH , Campo E , Harris NL , et al \nWHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed . Volume 2. \n2008 .\n3. \nLandgren O , Gilbert ES , Rizzo JD , et al \nRisk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation . Blood \n13 : 4992 -5001 , 2009 .\n4. \nMeijer E , Slaper-Cortenbach IC , Thijsen SF , Dekker AW , Verdonck LF \nIncreased incidence of EBV-associated lymphoproliferative disorders after allogeneic stem cell transplantation from matched unrelated donors due to a change of T cell depletion technique . Bone Marrow Transplant \n29 : 335 -339 , 2002 .11896431 \n5. \nvan der Velden WJ , Mori T , Stevens WB , et al \nReduced PTLD-related mortality in patients experiencing EBV infection following allo-SCT after the introduction of a protocol incorporating pre-emptive rituximab . Bone Marrow Transplant \n48 : 1465 -1471 , 2013 .23749107 \n6. \nRasche L , Kapp M , Einsele H , Mielke S \nEBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT . 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Blood \n98 : 972 -978 , 2001 .11493441 \n11. \nScheinberg P , Fischer SH , Li L , et al \nDistinct EBV and CMV reactivation patterns following antibody-based immunosuppressive regimens in patients with severe aplastic anemia . Blood \n109 : 3219 -3224 , 2007 .17148582 \n12. \nViola GM , Zu Y , Baker KR , Aslam S \nEpstein-Barr virus-related lymphoproliferative disorder induced by equine anti-thymocyte globulin therapy . Med Oncol \n28 : 1604 -1608 , 2011 .20680523 \n13. \nRaghavachar A , Ganser A , Freund M , Heimpel H , Herrmann F , Schrezenmeier H \nLong-term interleukin-3 and intensive immunosuppression in the treatment of aplastic anemia . Cytokines Mol Ther \n2 : 215 -223 , 1996 .9384707 \n14. \nWondergem MJ , Stevens SJ , Janssen JJ , et al \nMonitoring of EBV reactivation is justified in patients with aplastic anemia treated with rabbit ATG as a second course of immunosuppression . Blood \n111 : 1739 , author reply; 1739 -1740 , 2008 .18223173 \n15. \nOhata K , Iwaki N , Kotani T , Kondo Y , Yamazaki H , Nakao S \nAn Epstein-Barr virus-associated leukemic lymphoma in a patient treated with rabbit antithymocyte globulin and cyclosporine for hepatitis-associated aplastic anemia . Acta Haematol \n127 : 96 -99 , 2012 .22178718 \n16. \nCalistri E , Tiribelli M , Battista M , et al \nEpstein-Barr virus reactivation in a patient treated with anti-thymocyte globulin for severe aplastic anemia . Am J Hematol \n81 : 355 -357 , 2006 .16628717 \n17. \nViola GM , Zu Y , Baker KR , Aslam S \nEpstein-Barr virus-related lymphoproliferative disorder induced by equine anti-thymocyte globulin therapy . Med Oncol \n28 : 1604 -1608 , 2011 .20680523 \n18. \nSugimoto-Sekiguchi H , Tashiro H , Shirasaki R , et al \nColonic EBV-associated lymphoproliferative disorder in a patient treated with rabbit antithymocyte globulin for aplastic anemia . Case Rep Gastrointestl Med \n2012 : 395801 , 2012 .\n19. \nNakanishi R , Ishida M , Hodohara K , et al \nOccurrence of Epstein-Barr virus-associated plasmacytic lymphoproliferative disorder after antithymocyte globulin therapy for aplastic anemia: a case report with review of the literature . International Journal of Clinical and Experimental Pathology \n7 : 1748 -1756 , 2014 .24817974 \n20. \nTakahashi Tohru , Maruyama Yumiko , Saitoh Mayuko , Itoh Hideto , Yoshimoto Mitsuru , Tsujisaki Masayuki \nFatal Epstein-Barr virus reactivation in an acquired aplastic anemia patient treated with rabbit antithymocyte globulin and cyclosporine . A Case Reports in Hematology Volume , in press.\n21. \nHanaoka N , Murata S , Hosoi H , et al \nB-cell-rich T-cell lymphoma associated with Epstein-Barr virus-reactivation and T-cell suppression following antithymocyte globulin therapy in a patient with severe aplastic anemia . Hematol Rep \n7 : 5906 , 2015 .26487932 \n22. \nTsukamoto S , Nagao Y , Yamazaki A , et al \nSuccessful allogeneic stem cell transplantation for severe aplastic anemia after treatment of lymphoproliferative disorder caused by rabbit antithymocyte globulin . Intern Med \n54 : 3197 -3200 , 2015 .26666612 \n23. \nStyczynski J , Reusser P , Einsele H , et al \nManagement of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia . Bone Marrow Transplant \n43 : 757 -770 , 2009 .19043458 \n24. \nBollard CM , Rooney CM , Heslop HE \nT-cell therapy in the treatment of post-transplant lymphoproliferative disease . Nat Rev Clin Oncol \n9 : 510 -519 , 2012 .22801669 \n25. \nWorth A , Conyers R , Cohen J , et al \nPre-emptive rituximab based on viraemia and T cell reconstitution: a highly effective strategy for the prevention of Epstein-Barr virus-associated lymphoproliferative disease following stem cell transplantation . Br J Haematology \n155 : 377 -385 , 2011 .\n26. \nStyczynski J , Gil L , Tridello G , et al \nResponse to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation . Clin Infect Dis \n57 : 794 -802 , 2013 .23771985 \n27. \nXuan L , Jiang X , Sun J , et al \nSpectrum of Epstein-Barr virus-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation . Transplantation \n96 : 560 -566 , 2013 .23842192 \n28. \nCastellano-Sanchez AA , Li S , Qian J , Lagoo A , Weir E , Brat DJ \nPrimary central nervous system posttransplant lymphoproliferative disorders . Am J Clin Pathol \n121 : 246 -253 , 2004 .14983939 \n29. \nKempf C , Tinguely M , Rushing EJ \nPosttransplant lymphoproliferative disorder of the central nervous system . Pathobiology \n80 : 310 -318 , 2013 .24013167 \n30. \nKalita J , Maurya PK , Kumar B , Misra UK \nEpstein Barr virus encephalitis: clinical diversity and radiological similarity . Neurology India \n59 : 605 -607 , 2011 .21891943\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "56(6)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000741:Anemia, Aplastic; D000961:Antilymphocyte Serum; D004660:Encephalitis; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D008232:Lymphoproliferative Disorders; D008875:Middle Aged",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "701-706",
"pmc": null,
"pmid": "28321074",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15044644;23842192;23832092;11493441;19264919;10705154;16179371;14983939;23050175;24013167;16628717;21891943;23749107;11896431;22178718;9384707;23771985;21910716;19673883;24817974;19043458;17148582;26425376;20680523;18223173;26487932;26666612;22801669",
"title": "Epstein-Barr Virus-associated Lymphoproliferative Disorder with Encephalitis Following Anti-thymocyte Globulin for Aplastic Anemia Resolved with Rituximab Therapy: A Case Report and Literature Review.",
"title_normalized": "epstein barr virus associated lymphoproliferative disorder with encephalitis following anti thymocyte globulin for aplastic anemia resolved with rituximab therapy a case report and literature review"
} | [
{
"companynumb": "PHJP2017JP014671",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "A 79-year-old female diagnosed with T cell/histiocyte-rich large B cell lymphoma in complete remission after six cycles of rituximab-combined chemotherapy developed severe anemia, reticulocytopenia, and bone marrow erythroid hypoplasia. She was diagnosed with pure red cell aplasia (PRCA) accompanied by Coombs-negative autoimmune hemolytic anemia evidenced by a lack of glycophorin-A-positive cells in the bone marrow, haptoglobin under the detection level, and a high titer of RBC-bound IgG. Anti-erythropoietin receptor (EPOR) antibody was detected in the serum, and oligoclonal α/β and γ/δ T cells were also detected in her peripheral blood by Southern blotting analysis. Parvovirus B19 DNA was not detected by PCR. Although the treatment with rituximab had limited efficacy (specifically, only for hemolysis), subsequent cyclosporine therapy led to prompt recovery of erythropoiesis with the disappearance of anti-EPOR antibody and oligoclonal T cells. This is the first case report of anti-EPOR antibody-associated PRCA in a patient with malignant lymphoma treated successfully with cyclosporine.",
"affiliations": "Department of Hematology and Oncology, Oji General Hospital, 3-4-8 Wakakusa-Cho, Tomakomai, 053-8506, Japan, akihito.fujimi@ojihosp.or.jp.",
"authors": "Fujimi|Akihito|A|;Kamihara|Yusuke|Y|;Kanisawa|Yuji|Y|;Hashimoto|Akari|A|;Nakajima|Chisa|C|;Hayasaka|Naotaka|N|;Uemura|Naoki|N|;Okuda|Toshinori|T|;Minami|Shinya|S|;Iyama|Satoshi|S|;Takada|Koichi|K|;Sato|Tsutomu|T|;Hara|Akinori|A|;Iwata|Yasunori|Y|;Furuichi|Kengo|K|;Wada|Takashi|T|;Kato|Junji|J|",
"chemical_list": "D000911:Antibodies, Monoclonal; D017467:Receptors, Erythropoietin; D019788:Fluorodeoxyglucose F18",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-014-1652-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "100(5)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000368:Aged; D000744:Anemia, Hemolytic, Autoimmune; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D019788:Fluorodeoxyglucose F18; D006644:Histiocytes; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D017467:Receptors, Erythropoietin; D012010:Red-Cell Aplasia, Pure; D013601:T-Lymphocytes; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "490-3",
"pmc": null,
"pmid": "25096221",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23099924;17577777;15870490;19105232;12802933;17640861;19195037;8535198;3499930;20350659;11167735;1690829;18055869;16933263;9920952;23151030",
"title": "Anti-erythropoietin receptor antibody-associated pure red cell aplasia accompanied by Coombs-negative autoimmune hemolytic anemia in a patient with T cell/histiocyte-rich large B cell lymphoma.",
"title_normalized": "anti erythropoietin receptor antibody associated pure red cell aplasia accompanied by coombs negative autoimmune hemolytic anemia in a patient with t cell histiocyte rich large b cell lymphoma"
} | [
{
"companynumb": "PHHY2015JP090347",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
"dru... |
{
"abstract": "OBJECTIVE\nTo assess the dynamics of parameters of myocardial electrical instability in patients with ST-elevation (STE) myocardial infarction (MI) treated with various doses of atorvastatin.\n\n\nMETHODS\nPatients with STEMI (n=70), who received atorvastatin 20 or 80 mg/day for 48 weeks, were divided into two groups: group \"Е\" - 38 patients (54.3 %) in whom by 48‑th week target values of low density lipoprotein cholesterol (LDLC) were achieved, and group \"NE\" - 32 patients (45.7 %) in whom these levels were not achieved. On days 7-9, at 24th and 48th weeks after onset of MI the patients underwent 24‑hour 12‑leads ECG monitoring with subsequent analysis of parameters of myocardial electrical inhomogeneity: late ventricular potentials (LVP), dispersion of QT-interval duration, heart rate variability (HRV) and turbulence.\n\n\nRESULTS\nAfter of treatment with atorvastatin target value of LDLC was achieved in 73.5 and 36.1 % of patients receiving 80 and 20 mg/day, respectively. In the group \"E\" we observed positive dynamics of LVP parameters (QRSf - p.",
"affiliations": "Federal State Budgetary Educational Institution of Higher Education, \"Penza State University\".;Federal State Budgetary Educational Institution of Higher Education, \"Penza State University\".;Federal State Budgetary Educational Institution of Higher Education, \"Penza State University\".;Federal State Budgetary Educational Institution of Higher Education, \"Penza State University\".;Federal State Budgetary Educational Institution of Higher Education, \"Penza State University\".",
"authors": "Oleynikov|V E|VE|;Dushina|E V|EV|;Barmenkova|Y A|YA|;Lukyanova|M V|MV|;Salyamova|L I|LI|",
"chemical_list": "D008078:Cholesterol, LDL; D000069059:Atorvastatin",
"country": "Russia (Federation)",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-9040",
"issue": null,
"journal": "Kardiologiia",
"keywords": "QT; atorvastatin; heart rate variability; late potentials; myocardial infarction; turbulence",
"medline_ta": "Kardiologiia",
"mesh_terms": "D000069059:Atorvastatin; D008078:Cholesterol, LDL; D004562:Electrocardiography; D006801:Humans; D000072657:ST Elevation Myocardial Infarction",
"nlm_unique_id": "0376351",
"other_id": null,
"pages": "18-24",
"pmc": null,
"pmid": "30131038",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Impact of Effective Therapy With Atorvastatin on the Dynamics of Parameters of Electrical Instability in Patients with ST-Elevation Myocardial Infarction.",
"title_normalized": "the impact of effective therapy with atorvastatin on the dynamics of parameters of electrical instability in patients with st elevation myocardial infarction"
} | [
{
"companynumb": "PHHY2019RU043304",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nCandida peritonitis accounts for the majority of fungal peritonitis in continuous ambulatory peritoneal dialysis (CAPD), but the Candida species were not routinely subtyped in previous studies. The clinical course and the outcome of Candida parapsilosis peritonitis remain unclear.\n\n\nOBJECTIVE\nTo study the clinical course and outcome of C. parapsilosis peritonitis in CAPD patients.\n\n\nMETHODS\nPeritoneal dialysis unit in a regional hospital.\n\n\nMETHODS\nA retrospective study on seven cases of C. parapsilosis peritonitis occurring in a single center over 3 years.\n\n\nRESULTS\nThe 7 patients included 4 males and 3 females. Their mean age was 62 +/- 11.5 years. Two (29%) were diabetic. Three (43%) had a history of preceding peritonitis and 5 (71 %) had received broad spectrum antibiotic within the previous 1 month. All presented with cloudy dialysate, abdominal pain, and fever. The mean dialysate white cell count was 300 +/- 168/mm3 with a predominance of neutrophils (81.4% +/- 13.1%). The mean time from onset of symptoms to diagnosis was 5.7 +/- 3.1 days. All had been treated with immediate catheter removal within 24 hours of diagnosis and antifungal therapy, including oral fluconazole, intravenous (IV) amphotericin, or their sequential combination. Environmental samplings were negative for C. parapsilosis. The overall complication rate was exceptionally high (71%), with three (43%) complicated by abscess formation requiring surgical drainage, one peritoneal adhesion (14%), and one mortality (14%). In the end, only two (29%) could resume CAPD.\n\n\nCONCLUSIONS\nThe outcome of this study group appeared worse than those previously described in the literature, and the optimal treatment for this group of patients remains unclear.",
"affiliations": "Department of Medicine, Kwong Wah Hospital, Hong Kong, China. apnwong@medi.net.hk",
"authors": "Wong|P N|PN|;Mak|S K|SK|;Lo|K Y|KY|;Tong|G M|GM|;Wong|A K|AK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0896-8608",
"issue": "20(1)",
"journal": "Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis",
"keywords": null,
"medline_ta": "Perit Dial Int",
"mesh_terms": "D002177:Candidiasis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010531:Peritoneal Dialysis, Continuous Ambulatory; D010538:Peritonitis; D012189:Retrospective Studies",
"nlm_unique_id": "8904033",
"other_id": null,
"pages": "76-9",
"pmc": null,
"pmid": "10716588",
"pubdate": "2000",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A retrospective study of seven cases of Candida parapsilosis peritonitis in CAPD patients: the therapeutic implications.",
"title_normalized": "a retrospective study of seven cases of candida parapsilosis peritonitis in capd patients the therapeutic implications"
} | [
{
"companynumb": "HK-PFIZER INC-2020480538",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Dropped head (DH) syndrome is a phenomenon of disproportionate neck anteflexion that has been reported in patients with Parkinson disease (PD). Antiparkinsonian medications such as dopaminergic agonists (DAs) have been implicated in the onset of DH episodes. Deep brain stimulation (DBS) is an important therapeutic option after the failure of conventional treatments such as DA therapy in patients with PD. Here, we report the case of a patient with rigid-akinetic parkinsonism who developed DH syndrome after the initiation of DA treatment. Dopaminergic agonist treatment was required to stabilize motor dysfunction during a period of 5 years; yet, the patient experienced no improvements in DH during this time. Thus, we initiated DBS as an alternative therapy and gradually withdrew DA therapy. The patient recovered from long-term DH after the discontinuation of rotigotine treatment. Accordingly, this case highlights DA treatment as a possible cause of DH and the use of DBS to allow the discontinuation of DA treatment while preserving motor function in patients with PD.",
"affiliations": "Departments of Neuromodulation and Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan.",
"authors": "Mano|Tomoo|T|",
"chemical_list": "D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000243",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "40(5)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000978:Antiparkinson Agents; D046690:Deep Brain Stimulation; D018491:Dopamine Agonists; D005260:Female; D006801:Humans; D008875:Middle Aged; D018908:Muscle Weakness; D010300:Parkinson Disease; D013577:Syndrome; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D028761:Withholding Treatment",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "219-220",
"pmc": null,
"pmid": "28816836",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reversal of Dropped Head Syndrome After the Cessation of Dopaminergic Agonist Treatment in Parkinson Disease.",
"title_normalized": "reversal of dropped head syndrome after the cessation of dopaminergic agonist treatment in parkinson disease"
} | [
{
"companynumb": "JP-GLENMARK PHARMACEUTICALS-2018GMK032279",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBIDOPA\\LEVODOPA"
},
"dru... |
{
"abstract": "Histoplasmosis is the most common endemic mycoses among HIV-infected people. Patients with suppressed cell immunity mainly due to HIV are at increased risk of disseminated disease. Dermatological manifestations of immune reconstitution inflammatory syndrome (IRIS) and cutaneous manifestations of histoplasmosis similar to an IRIS event have been previously described. We report the case of a 43-year-old male who presented with cutaneous disseminated histoplasmosis due to Histoplasma capsulatum var. capsulatum 4 months after the onset of the antiretroviral therapy and some improvement in the immune reconstitution. After 2 weeks of amphotericin B and itraconazole therapy, the scheduled treatment involved fluconazole maintenance therapy, which resulted in an improvement of his skin lesions.",
"affiliations": "College of Health Sciences - Infectious Disease Institute - Makerere University, Kampala - Uganda .;College of Health Sciences - School of Medicine - Makerere University, Kampala - Uganda .;College of Health Sciences - School of Medicine - Makerere University, Kampala - Uganda .;College of Health Sciences - Infectious Disease Institute - Makerere University, Kampala - Uganda.; Department of Medicine - University of Minnesota, Minneapolis/MN - USA.;College of Health Sciences - School of Biomedical Sciences - Makerere University, Kampala - Uganda .",
"authors": "Kiggundu|Reuben|R|;Nabeta|Henry W|HW|;Okia|Richard|R|;Rhein|Joshua|J|;Lukande|Robert|R|",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": "10.4322/acr.2016.048",
"fulltext": "\n==== Front\nAutops Case RepAutops Case RepAutopsy & Case Reports2236-1960São Paulo, SP: Universidade de São Paulo, Hospital Universitário autopsy-06-0402710.4322/acr.2016.048Article / Clinical Case ReportUnmasking histoplasmosis immune reconstitution inflammatory syndrome in a patient recently started on antiretroviral therapy Unmasking histoplasmosis immune reconstitution inflammatory syndrome in a patient recently started on antiretroviral therapyKiggundu R, Nabeta HW, Okia R, Rhein J, Lukande RKiggundu Reuben aNabeta Henry W bOkia Richard bRhein Joshua acLukande Robert da College of Health Sciences - Infectious Disease Institute - Makerere University, Kampala – Uganda.b College of Health Sciences - School of Medicine - Makerere University, Kampala – Uganda.c Department of Medicine - University of Minnesota, Minneapolis/MN – USA.d College of Health Sciences - School of Biomedical Sciences - Makerere University, Kampala – Uganda.Conflict of interest: None\n\nCorrespondence\nReuben Kiggundu \nCollege of Health Sciences - Infectious Disease Institute - Mulago Hospital Complex - Makerere University\nP.O. Box 22418 – Kampala – Uganda\nreubenkaaja@yahoo.com30 12 2016 Oct-Dec 2016 6 4 27 33 07 7 2016 09 9 2016 Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2016.2016Autopsy and Case ReportsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided the article is properly cited.Histoplasmosis is the most common endemic mycoses among HIV-infected people. Patients with suppressed cell immunity mainly due to HIV are at increased risk of disseminated disease. Dermatological manifestations of immune reconstitution inflammatory syndrome (IRIS) and cutaneous manifestations of histoplasmosis similar to an IRIS event have been previously described. We report the case of a 43-year-old male who presented with cutaneous disseminated histoplasmosis due to Histoplasma capsulatum var. capsulatum 4 months after the onset of the antiretroviral therapy and some improvement in the immune reconstitution. After 2 weeks of amphotericin B and itraconazole therapy, the scheduled treatment involved fluconazole maintenance therapy, which resulted in an improvement of his skin lesions.\n\nKeywords: \nHistoplasmosisImmune Reconstitution Inflammatory SyndromeAntiretroviral Therapy, Highly Active, Fluconazole\n==== Body\nINTRODUCTION\nHistoplasmosis is a systemic fungal infection caused by the intracellular dimorphic fungus Histoplasma capsulatum. It is endemic in the USA, but has been reported in South America and Africa.1,2 Clinical presentation of histoplasmosis is nonspecific, and 95% of the patients with H. capsulatum infections are asymptomatic. Therefore, the clinical presentation of histoplasmosis may vary from asymptomatic to disseminated disease depending on the patient’s immunological status.3-5 Histoplasmosis is an AIDS-defining opportunistic infection presenting as an invasive form.6-8\n\nImmune reconstitution inflammatory syndrome (IRIS)-related dermatological manifestations of HIV are common, and cutaneous histoplasmosis following antiretroviral therapy (ART) was previously described.9,10 We report the case of an HIV-infected patient who presented with cutaneous histoplasmosis 4 months after the onset of ART, with viral suppression and immunological recovery, which were consistent with an IRIS event. The clinical manifestations, diagnosis, and management of histoplasmosis IRIS are reviewed.\n\nCASE REPORT\nA 43-year-old male, known to be HIV infected for 6 months, was referred by his primary HIV clinic to the Mulago National Referral Hospital in Uganda with a 2-month history of nodular lesions in the face. Skin findings were also associated with a nonproductive cough, dyspnea, and fever over the past month. The skin nodules started to appear 2 months after ART was initiated, and began as small lesions on the nose that progressed in size and number throughout the face. The patient was initially and empirically treated with azithromycin with the hypothesis of atypical Mycobacterium cuneiform infection, with mild clinical improvement. The patient was started on ART (tenofovir 300 mg/day, lamivudine 300 mg/day, and efavirenz 600 mg/day) and trimethoprim/sulfamethoxazole for prophylaxis at the time of HIV infection diagnosis.\n\nHis past medical history included the diagnosis of HIV infection 6 months earlier, with a nadir CD4 determination of 42 cells/mm3.\n\nOn examination, his general condition was fair, with no lymphadenopathy, normal vital signs, and a clear chest exam. Skin examination showed hyper-pigmented nodular lesions on his face with varying diameters. The larger lesions (approximately 2 cm × 3.5 cm) were on the nose (Figure 1). The abdominal examination did not reveal hepatosplenomegaly.\n\nFigure 1 Cutaneous lesions throughout on the face before the antifungal treatment.\nThe patient’s chest x-ray was normal; thoracic computed tomography was not performed. Laboratory investigations revealed normal hematological indices and serum electrolytes.\n\nThe serological test for HIV was positive. The viral load for HIV was undetectable, and CD4 was 108 cells/mm3. Diagnoses of Kaposi sarcoma, bacillary angiomatosis, squamous cell carcinoma, and invasive mycosis were considered. A punch biopsy was obtained from two lesions of the face. Histological examination showed granulomatous dermatitis with round cytoplasmic organelles within the macrophages consistent with H. capsulatum var. capsulatum (Figure 2 and Figure 3).\n\nFigure 2 Photomicrography of the skin biopsy. A - Normal epidermis and infiltrated dermis (H&E, 100X); B, C, and D - Small, oval, narrow based yeasts consistent with Histopolasma capsulatum (H&E, 400X).\nFigure 3 Photomicrography of the skin biopsy showing in A - multiple oval-shaped structures consistent with Histoplasma sp (Grocott, 1000X); in B - PAS staining spores appearing as round or oval structures within the cytoplasm of the macrophages (PAS, 1000X).\nA diagnosis of unmasking mucocutaneous histoplasmosis IRIS was made. The patient was started on intravenous amphotericin B (1 mg/kg) daily and oral itraconazole (400 mg daily) for 2 weeks, besides potassium and magnesium supplementation, paracetamol, and 3 L of intravenous saline daily during hospitalization. Antiretroviral therapy was continued. The patient’s renal function and complete blood count remained within normal ranges during the course of amphotericin.\n\nOn completion of the amphotericin treatment, the patient’s symptoms regressed and he was discharged after 14 days on oral fluconazole 400 mg daily, as he could not afford the high cost of itraconazole. The patient has been monitored monthly since hospital discharge and continues to improve on fluconazole therapy and ART. His clinical status is favorable; the skin lesions are healing but leaving enduring scarring and partial destruction of the nasal cartilage (Figure 4).\n\nFigure 4 Skin examination after 6 months of treatment.\nDISCUSSION\nHistoplasmosis is a common AIDS-defining illness11 caused by H. capsulatum, a dimorphic fungus, which is distributed worldwide and is endemic in both South and North America, particularly in the Ohio and Mississippi river valleys in the latter. H. capsulatum var. capsulatum and H. capsulatum var. duboisii are the variants that cause human disease.12,13\nH. capsulatum var. duboisii is described only in Africa; however, both variants are endemic in Uganda. Spores of H. capsulatum are found in the soil and caves inhabited by birds and bats.4\n\nPrimary lung infection results from the inhalation of microconidia, which turn into yeast in the lungs. The yeast is then spread to the reticuloendothelial system within 2-3 weeks by tissue macrophages.5,14\n\nThe clinical presentation of histoplasmosis depends on the integrity of the immune system. Nearly 95% of the infected people with normal immune systems will remain asymptomatic,1,15 and the remaining will present acute or chronic pulmonary histoplasmosis.15\n\nHowever, individuals with immunosuppressive disorders affecting cell-mediated immunity may present with disseminated histoplasmosis. HIV-infected people with a CD4 cell count below 100 cells/mm3 are at increased risk for the development of disseminated histoplasmosis,14,15 which was the case with our patient, who had a CD4 cell count of 42 cells/mm3.\n\nCough, fever, malaise, weight loss, and hepatosplenomegaly represent the most common clinical features of disseminated histoplasmosis. Although gastrointestinal symptoms are rare, 70% of patients with this disease present gastrointestinal involvement on autopsy.1,16,17 Disseminated histoplasmosis may be misdiagnosed as tuberculosis or malaria due to the nonspecificity of the symptoms in many health facilities, especially when the laboratory work-up is limited.\n\nCutaneous presentation is found in 6% of patients with disseminated histoplasmosis.5,16,18 However, mucocutaneous involvement varies by geographic location and occurs more commonly in AIDS patients, particularly in those with suspected IRIS.9,19 A review of the clinical manifestations of disseminated histoplasmosis showed that the dermatological manifestation was more common and more extensive in Brazilian HIV-infected people when compared with North American counterparts.9 A similar tropism for skin and lymph nodes involvement has been observed in African histoplasmosis. Nacher et al.20 described a higher incidence of disseminated histoplasmosis among patients that recently started on antiretroviral therapy, suggesting that this treatment can lead to unmasking IRIS. Passos et al.21 reported the case of paradoxical histoplasmosis IRIS following re-introduction of HAART in a Brazilian patient that voluntarily stopped his HAART and itraconazole prophylaxis. Breton et al.22 presented four patients with HIV-associated with unmasking and paradoxical disseminated histoplasmosis IRIS. At the time of presentation, our patient was on ART for 4 months, with immunological response and viral suppression, which are features consistent with unmasking IRIS.23,24\n\nDiverse diagnostic modalities with varying sensitivity and specificity are available for the diagnosis of histoplasmosis, including tissue cultures, fungal stains, and serologic tests for detecting antibodies or antigens.5 Isolation of the pathogen in culture media (BACTEC™, Becton Dickinson, Sabouraud’s agar) is the gold standard for the diagnosis; however, the isolation takes more than 4 weeks, which limits its clinical applicability.25,26 Culture specimens can be obtained from urine, blood, sputum, lymph nodes, bronchoalveolar lavage, or bone marrow aspirate. Serology, although rapid and sensitive, is limited by low specificity because of the cross-reactivity with other fungi. Moreover, serology shows reduced sensitivity in disseminated histoplasmosis and immune suppressed patients, and the antibodies remain elevated for an extended time, limiting its use for differentiating relapse from an earlier infection.25-27 Urinary antigen testing offers rapid diagnosis with the sensitivity of 90% for patients with disseminated histoplasmosis and can be used for monitoring the response to therapy.2,25 Assays of histoplasma antigen in our patient’s body fluids were not performed as they are not readily available in Uganda.\n\nHistological examination with the aid of Giemsa, Wright, the periodic acid of Schiff (PAS), or methenamine silver stainings provides a less expensive and rapid diagnosis, but has loose sensitivity for the antigenic tests. H. capsulatum appears in macrophages as ovoid or spherical uninucleate yeasts of 2–4 micrometers with narrow base buds.5\nPneumocystis jiroveci, Toxoplasma gondii, Penicillium marneffei, Candida glabrata, Leishmania donovani, and Cryptococcus neoformans may appear similar to H. capsulatum on direct microscopy. However, most of the serologic tests are expensive and barely available in Uganda. In our case, the diagnosis was based on the histologic examination of the skin biopsy.\n\nOur patient received amphotericin B and itraconazole for 2 weeks, which is the regimen of choice for the management of disseminated histoplasmosis where liposomal or lipid formulations of amphotericin are not available.5,15 The Infectious Diseases Society of America guidelines recommend that patients with disseminated histoplasmosis and HIV should be treated with amphotericin B (0.7-1 mg/kg per day) for 2 weeks followed by itraconazole for at least 12 months.15 Secondary prophylaxis with itraconazole maintenance therapy (200 mg/day) should be considered for extended periods of immunosuppression. Some literature data suggest withdrawing prophylaxis at CD4 > 150 cells/mm3.12,28 Upon discharge, this patient was started on fluconazole instead of itraconazole because of the cost of the treatment and the unavailability of free dispensing of itraconazole in Uganda. Although fluconazole has some activity against histoplasmosis, it is less efficacious than itraconazole, and has been associated with higher resistance rates.29-31\n\nAntiretroviral therapy substantially improves the outcomes of HIV-infected people with disseminated histoplasmosis. Additionally, there is evidence suggesting that patients on ART who develop disseminated histoplasmosis IRIS should continue on the ART.32-34\n\nLiterature data recommend continuing prophylaxis until the clinical and the laboratory results normalize.29 Our patient received fluconazole 400 mg daily and was monitored monthly in the outpatient clinic. We intend to taper the dose of fluconazole to 200 mg at the twelfth week and withdraw it when the CD4 count exceeds 150 cells/mm3 and, if available, a normal laboratory antigen assay is achieved. Although our patient is showing immunological improvement, there is a risk of relapse since he is receiving a less suitable drug. Additional studies are needed concerning the management and length of treatment of histoplasmosis with fluconazole to provide a second choice where itraconazole remains prohibitively expensive. We also recommend that clinicians should consider a diagnosis of cutaneous histoplasmosis in HIV-infected persons that present with Kaposi sarcoma-like lesions.\n\nNote: The patient signed an informed consent authorizing the publication the pictures of his face.\n\nACKNOWLEDGEMENTS\nThe authors wish to thank Dr. Tugume Lillian and Dr. Odong Daniel for participating in patient care.\n\nKiggundu R, Nabeta HW, Okia R, Rhein J, Lukande R. Unmasking histoplasmosis immune reconstitution inflammatory syndrome in a patient recently started on antiretroviral therapy. Autopsy Case Rep [Internet]. 2016;6(4):27-33. http://dx.doi.org/10.4322/acr.2016.048.\n==== Refs\nREFERENCES\n1 Wheat LJ . Histoplasmosis: a review for clinicians from non-endemic areas . Mycoses . 2006 ;49 (4 ):274 -82 . http://dx.doi.org/10.1111/j.1439-0507.2006.01253.x. PMid:.16784440 \n2 Cottle LE , Gkrania-Klotsas E , Williams HJ , et al . A multinational outbreak of histoplasmosis following a biology field trip in the Ugandan rainforest . J Travel Med . 2013 ;20 (2 ):83 -7 . http://dx.doi.org/10.1111/jtm.12012. PMid:.23464714 \n3 Regional T , Unit R , Helier S . Caecal perforation in a renal transplant patient with disseminated histoplasmosis . 1988 ;41 (9 ):992 -5 . PMid:.3056989 \n4 Kurowski R , Ostapchuk M . Overview of histoplasmosis . Am Fam Physician . 2002 ;66 (12 ):2247 -52 . PMid:.12507161 \n5 Kauffman CA . Histoplasmosis: a clinical and laboratory update . Clin Microbiol Rev . 2007 ;20 (1 ):115 -32 . http://dx.doi.org/10.1128/CMR.00027-06. PMid:.17223625 \n6 Pervez MM , Cobb B , Matin N , Shahrin L , Ford ER , Pietroni M . Disseminated histoplasmosis in a patient with advanced HIV disease-lessons learnt from Bangladesh . J Health Popul Nutr . 2010 ;28 (3 ):305 -7 . http://dx.doi.org/10.3329/jhpn.v28i3.5561. PMid:.20635643 \n7 Gutierrez ME , Canton A , Sosa N , Puga E , Talavera L . Disseminated histoplasmosis in patients with AIDS in Panama: a review of 104 cases . Clin Infect Dis . 2005 ;40 (8 ):1199 -202 . http://dx.doi.org/10.1086/428842. PMid:.15791523 \n8 Wheat LJ , Chetchotisakd P , Williams B , Connolly P , Shutt K , Hajjeh R . Factors associated with severe manifestations of histoplasmosis in AIDS . Clin Infect Dis . 2000 ;30 (6 ):877 -81 . http://dx.doi.org/10.1086/313824. PMid:.10854363 \n9 Lehloenya R , Meintjes G . Dermatologic manifestations of the immune reconstitution inflammatory syndrome . Dermatol Clin . 2006 ;24 (4 ):549 -70 . http://dx.doi.org/10.1016/j.det.2006.06.007. PMid:.17010783 \n10 Amerson EH , Maurer TA . Immune reconstitution inflammatory syndrome and tropical dermatoses . Dermatol Clin . 2011 ;29 (1 ):39 -43 . http://dx.doi.org/10.1016/j.det.2010.09.007. PMid:.21095526 \n11 Centers for Disease Control – CDC . Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Council of State and Territorial Epidemiologists; AIDS Program, Center for Infectious Diseases . MMWR Suppl . 1987 ;36 (1 ):1S -15S . PMid:.3039334 \n12 Loulergue P , Bastides F , Baudouin V , et al . Literature review and case histories of Histoplasma capsulatum var. dubloisii infections in HIV-infected patients . Emerg Infect Dis . 2007 ;13 (11 ):1647 -52 . PMid:.18217546 \n13 Gugnani HC . Histoplasmosis in Africa: a review . Indian J Chest Dis Allied Sci . 2000 ;42 (4 ):271 -7 . PMid:.15597674 \n14 Chaturvedi S , Frame P , Newman SL . Macrophages from human immunodeficiency virus-positive persons are defective in host defense against Histoplasma capsulatum . J Infect Dis . 1995 ;171 (2 ):320 -7 . PMid:.7844367 \n15 Wheat LJ , Freifeld AG , Kleiman MB , et al . Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America . Clin Infect Dis . 2007 ;45 (7 ):807 -25 . http://dx.doi.org/10.1086/521259. PMid:.17806045 \n16 Bradsher RW . Histoplasmosis and blastomycosis . Clin Infect Dis . 1996 ;22 (Suppl 2 ):S102 -11 . PMid:.8722836 \n17 Kahi CJ , Wheat LJ , Allen SD , Sarosi GA . Gastrointestinal histoplasmosis . Am J Gastroenterol . 2005 ;100 (1 ):220 -31 . http://dx.doi.org/10.1111/j.1572-0241.2005.40823.x. PMid:15654803 \n18 Verma SB . Chronic disseminated cutaneous histoplasmosis in an immunocompetent individual - a case report . Int J Dermatol . 2006 ;45 (5 ):573 -6 . http://dx.doi.org/10.1111/j.1365-4632.2006.02762.x. PMid:16700795 \n19 Delfino E , di Biagio A , Chandrapatham K , Viscoli C , Prinapori R . Disseminated histoplasmosis with mucocutaneous immune reconstitution inflammatory syndrome in an HIV-infected patient . AIDS Res Hum Retroviruses . 2015 ;31 (3 ):274 -5 . http://dx.doi.org/10.1089/aid.2014.0329. PMid:25723353 \n20 Nacher M , Sarazin F , El Guedj M , et al . Increased incidence of disseminated histoplasmosis following highly active antiretroviral therapy initiation . J Acquir Immune Defic Syndr . 2006 ;41 (4 ):468 -70 . http://dx.doi.org/10.1097/01.qai.0000209927.49656.8d. PMid:.16652055 \n21 Passos L , Talhari C , Santos M , Ribeiro-Rodrigues R , Ferreira LC , Talnari S . Histoplasmosis-associated immune reconstitution inflammatory syndrome . An Bras Dermatol . 2011 ;86 (4 \nSuppl 1):S168 -72 . http://dx.doi.org/10.1590/S0365-05962011000700044. PMid:.22068802 \n22 Breton G , Adle-Biassette H , Therby A , et al . Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis . AIDS . 2006 ;20 (1 ):119 -21 . http://dx.doi.org/10.1097/01.aids.0000199014.66139.39. PMid:.16327328 \n23 Haddow LJ , Easterbrook PJ , Mosam A , et al . Defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus 2 case definitions in a South African cohort . Clin Infect Dis . 2009 ;49 (9 ):1424 -32 . http://dx.doi.org/10.1086/630208. PMid:.19788360 \n24 Robertson J , Meier M , Wall J , Ying J , Fichtenbaum CJ . Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy . Clin Infect Dis . 2006 ;42 (11 ):1639 -46 . http://dx.doi.org/10.1086/503903. PMid:.16652323 \n25 Gómez BL , Figueroa JI , Hamilton AJ , et al . Detection of the 70-kilodalton Histoplasma capsulatum antigen in serum of histoplasmosis patients: correlation between antigenemia and therapy during follow-up . J Clin Microbiol . 1999 ;37 (3 ):675 -80 . PMid:.9986830 \n26 Durkin MM , Connolly PA , Wheat LJ . Comparison of radioimmunoassay and enzyme-linked immunoassay methods for detection of Histoplasma capsulatum var. capsulatum Antigen . J Clin Microbiol . 1997 ;35 (9 ):2252 -5 . PMid:.9276396 \n27 Gomez BL , Figueroa JI , Hamilton AJ , et al . Development of a novel antigen detection test for histoplasmosis . J Clin Microbiol . 1997 ;35 (10 ):2618 -22 . PMid:.9316918 \n28 Murata M , Furusyo N , Otaguro S , Nabeshima S , Ariyama I , Hayashi J . HIV infection with concomitant cerebral toxoplasmosis and disseminated histoplasmosis in a 45-year-old man . J Infect Chemother . 2007 ;13 (1 ):51 -5 . http://dx.doi.org/10.1007/s10156-006-0486-3. PMid:.17334730 \n29 Wheat J , Hafner R , Korzun AH , et al . Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome . Am J Med . 1995 ;98 (4 ):336 -42 . http://dx.doi.org/10.1016/S0002-9343(99)80311-8. PMid:.7709945 \n30 Wheat LJ , Connolly P , Smedema M , Brizendine E , Hafner R . Emergence of resistance to fluconazole as a cause of failure during treatment of histoplasmosis in patients with acquired immunodeficiency disease syndrome . Clin Infect Dis . 2001 ;33 (11 ):1910 -3 . http://dx.doi.org/10.1086/323781. PMid:.11692303 \n31 Wheat J , Marichal P , Vanden Bossche H , Le Monte A , Connolly P . Hypothesis on the mechanism of resistance to fluconazole in Histoplasma capsulatum . Antimicrob Agents Chemother . 1997 ;41 (2 ):410 -4 . PMid:.9021199 \n32 Goldman M , Zackin R , Fichtenbaum CJ , et al . Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy . Clin Infect Dis . 2004 ;38 (10 ):1485 -9 . http://dx.doi.org/10.1086/420749. PMid:.15156489 \n33 Agudelo CA , Rosero DS , Ochoa JE , et al . Disseminated Histoplasmosis: a comparative study between patients with acquired immunodeficiency syndrome and non-human immunodeficiency virus – infected individuals . Am Soc Trop Med Hyg. \n2005 ;73 (3 ):576 -82 . PMid:.16172484 \n34 Jenny-Avital E . Successful discontinuation of high-dose fluconazole for Histoplasma capsulatum meningitis in an AIDS Patient after sustained immune reconstitution . J Chem Inf Model . 2004 ;39 (8 ):1261 -2 . http://dx.doi.org/10.1086/424753. PMid:.15486865\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2236-1960",
"issue": "6(4)",
"journal": "Autopsy & case reports",
"keywords": "Antiretroviral Therapy, Highly Active, Fluconazole; Histoplasmosis; Immune Reconstitution Inflammatory Syndrome",
"medline_ta": "Autops Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101640070",
"other_id": null,
"pages": "27-33",
"pmc": null,
"pmid": "28210571",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "9986830;23464714;15654803;8722836;9316918;15156489;10854363;16172484;16652323;7709945;3039334;3056989;7844367;17334730;21095526;9276396;11692303;15791523;18217546;15597674;17223625;17806045;9021199;16652055;20635643;25723353;16700795;19788360;16784440;17010783;22068802;12507161;16327328;15486865",
"title": "Unmasking histoplasmosis immune reconstitution inflammatory syndrome in a patient recently started on antiretroviral therapy.",
"title_normalized": "unmasking histoplasmosis immune reconstitution inflammatory syndrome in a patient recently started on antiretroviral therapy"
} | [
{
"companynumb": "UG-VIIV HEALTHCARE LIMITED-UG2017029870",
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{
"abstract": "OBJECTIVE\nIntrathecal drug delivery systems (intrathecal pumps) are used to treat patients with chronic refractory pain syndromes and spasticity. The objective of our case report was to demonstrate that intrathecal pump malfunction can lead to intrathecal overdosing of drugs.\n\n\nMETHODS\nWe present 2 cases of intrathecal pump malfunction leading to overinfusion. The first case concerns a patient with an intrathecal pump that was implanted almost 5 years before the reported incident. During a refill procedure, 12.5 mL was aspirated instead of the expected 21.8 mL. Analysis of the pump revealed that the pump was overinfusing. The second case concerns a patient with an intrathecal pump that was implanted more than 5 years before the reported incident. Ten hours after a regular refill of the pump, she was found in a comatose state, and when the intrathecal pump was emptied, only 16 mL was aspirated instead of the 19.6 mL expected. Analysis of the pump revealed that the inner tubing was not running smoothly over the roller arms, possibly causing spurts, which could have caused an overinfusion.\n\n\nCONCLUSIONS\nWe present 2 cases of intrathecal pump malfunction, which most likely led to overinfusion of fentanyl intrathecally. To reduce the risk of this complication, particular attention should be paid to drug reservoir volume discrepancies and overdose symptoms reported by patients.",
"affiliations": "From the *Centro per la Terapia del Dolore EOC, Neurocentro della Svizzera Italiana, Lugano, Switzerland; and †Department of Anesthesiology, VU University Medical Center, Amsterdam, the Netherlands.",
"authors": "Maino|Paolo|P|;Koetsier|Eva|E|;Perez|Roberto S G M|RS|",
"chemical_list": "D000701:Analgesics, Opioid; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1097/AAP.0000000000000132",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-7339",
"issue": "39(5)",
"journal": "Regional anesthesia and pain medicine",
"keywords": null,
"medline_ta": "Reg Anesth Pain Med",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D062787:Drug Overdose; D004868:Equipment Failure; D005260:Female; D005283:Fentanyl; D006801:Humans; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D017116:Low Back Pain; D008875:Middle Aged; D010148:Pain, Intractable",
"nlm_unique_id": "9804508",
"other_id": null,
"pages": "434-7",
"pmc": null,
"pmid": "25075457",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fentanyl overdose caused by malfunction of SynchroMed II intrathecal pump: two case reports.",
"title_normalized": "fentanyl overdose caused by malfunction of synchromed ii intrathecal pump two case reports"
} | [
{
"companynumb": "CH-MYLANLABS-2014M1005290",
"fulfillexpeditecriteria": "1",
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"patient": {
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"actiondrug": "1",
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"activesubstancename": "FENTANYL"
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... |
{
"abstract": "A 21-year-old first trimester primagravida woman with hyperemesis gravidarum was noted to have incidental subcutaneous emphysema during thyroid ultrasound. Follow-up radiograph demonstrated supraclavicular subcutaneous emphysema, left apical pneumothorax and pneumomediastinum. The patient was transferred to the intensive care unit and evaluated for esophageal rupture. Because no defects were seen on swallow studies/endoscopy and the patient was stable, she was treated conservatively with antibiotics and monitored. The patient's condition improved, and she was discharged on hospital day 6. Subcutaneous emphysema secondary to hyperemesis gravidarum is a rare but potentially life-threatening condition in which the source of the mediastinal leak needs to be immediately determined. After the more serious sources of mediastinal air have been excluded, conservative management is suitable.",
"affiliations": "Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center School of Medicine, Amarillo, Texas, USA.;Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center School of Medicine, Amarillo, Texas, USA.;Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center School of Medicine, Amarillo, Texas, USA robert.kauffman@ttuhsc.edu.",
"authors": "Foley|David|D|;Holmes|Heather J|HJ|;Kauffman|Robert P|RP|http://orcid.org/0000-0003-3589-9979",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-234001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(2)",
"journal": "BMJ case reports",
"keywords": "materno-fetal medicine; pregnancy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D004939:Esophageal Perforation; D005260:Female; D006801:Humans; D006939:Hyperemesis Gravidarum; D008478:Mediastinal Emphysema; D011030:Pneumothorax; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011859:Radiography; D013352:Subcutaneous Emphysema",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32041752",
"pubdate": "2020-02-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous pneumomediastinum: an unusual complication of hyperemesis gravidarum.",
"title_normalized": "spontaneous pneumomediastinum an unusual complication of hyperemesis gravidarum"
} | [
{
"companynumb": "NVSC2020US067626",
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"occurcountry": "US",
"patient": {
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"activesubstancename": "ONDANSETRON"
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{
"abstract": "Amid the coronavirus disease 2019 pandemic, uncertainty exists about the potential for vertical transmission from mothers infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the fetus in utero. In this case report, we aim to demonstrate the occurrence of a fetal inflammatory response syndrome associated with maternal SARS-CoV-2 infection resulting in neonatal morbidity. In this report we describe an infant of a SARS-CoV-2-positive mother born prematurely with late-onset fever, thrombocytopenia, and elevated levels of inflammatory markers, all of which are consistent with a systemic inflammatory response. The neonate was tested for SARS-CoV-2 by using 2 nasopharyngeal swabs 24 hours apart, and results of both were negative. The result of a full workup for additional infectious pathogens was also negative. Although initially in critical condition in the perinatal period, the infant recovered completely before discharge. We hypothesize that this systemic inflammation occurred in response to maternal viral infection in the absence of vertical transmission of the virus. During the coronavirus disease 2019 pandemic, it will be important to consider the virus as a nidus for a fetal inflammatory response syndrome and resulting morbidity, even in the setting of a negative SARS-CoV-2 testing result in the infant.",
"affiliations": "Children's Mercy Hospital, Kansas City, Missouri; and kmccarty@cmh.edu.;Children's Mercy Hospital, Kansas City, Missouri; and.;The University of Kansas Hospital, Kansas City, Kansas.;The University of Kansas Hospital, Kansas City, Kansas.",
"authors": "McCarty|Kyra L|KL|;Tucker|Megan|M|;Lee|Gene|G|;Pandey|Vishal|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2020-010132",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "147(4)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D005260:Female; D005315:Fetal Diseases; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D018746:Systemic Inflammatory Response Syndrome",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33122348",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Fetal Inflammatory Response Syndrome Associated With Maternal SARS-CoV-2 Infection.",
"title_normalized": "fetal inflammatory response syndrome associated with maternal sars cov 2 infection"
} | [
{
"companynumb": "US-SYNEX-T202102427",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFEPIME HYDROCHLORIDE"
},
"drugadditional": null,... |
{
"abstract": "A 61-year-old man with a 30-year history of uncontrolled hypertension was unable to tolerate conventional antihypertensive medications from all classes. At the time of referral to our centre he had discontinued all antihypertensive drugs and felt well. However, his average home blood pressure (HBP) reading was 179/125 mm Hg and echocardiography demonstrated moderate concentric left ventricular hypertrophy. A novel stratified medicines algorithm was used to guide treatment entailing transdermal clonidine patch therapy instead of tablet formulations. Sixteen months later, his average HBP was 147/106 mm Hg with no side effects and the left ventricular hypertrophy had completely regressed. Our experience has taught us that multiple drug intolerance is a common, often overlooked, cause of non-adherence to antihypertensive medication. This case demonstrates the benefit of a novel approach to optimise blood pressure control and emphasises the important role of hypertension specialists in managing complex, high-risk patients unable to tolerate guideline-based therapy.",
"affiliations": "Barts BP Centre of Excellence, William Harvey Research Institute, London, UK.;Barts BP Centre of Excellence, William Harvey Research Institute, London, UK.;Barts BP Centre of Excellence, William Harvey Research Institute, London, UK.;Barts BP Centre of Excellence, William Harvey Research Institute, London, UK.",
"authors": "Schuster Bruce|Catherine|C|;Rull|Gurvinder|G|;Sotiris|Antoniou|A|;Lobo|Melvin D|MD|",
"chemical_list": "D000959:Antihypertensive Agents; D003000:Clonidine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-226045",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "11(1)",
"journal": "BMJ case reports",
"keywords": "cardiovascular medicine; cardiovascular system; drug interactions; hypertension",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000279:Administration, Cutaneous; D000959:Antihypertensive Agents; D001794:Blood Pressure; D003000:Clonidine; D019468:Disease Management; D004359:Drug Therapy, Combination; D006801:Humans; D006973:Hypertension; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30567232",
"pubdate": "2018-12-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12829555;24881995;28461599;26306794;23245609;12493255;27033502;2044252",
"title": "Novel stratified medicines approach to manage uncontrolled hypertension due to multiple drug intolerances.",
"title_normalized": "novel stratified medicines approach to manage uncontrolled hypertension due to multiple drug intolerances"
} | [
{
"companynumb": "GB-PFIZER INC-2019019224",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SPIRONOLACTONE"
},
"drugadditional": null,
... |
{
"abstract": "A 77-year-old man with chronic hepatitis C underwent transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) for early-stage hepatocellular carcinoma (HCC) in segment 8 of the liver. Necrosis was confirmed radiologically. After 19 months, recurrent HCC in segment 6 was treated with TACE and RFA. There was no recurrence. Direct-acting antiviral (DAA) therapy 24 months after the initial procedure led to a sustained virologic response. AFP-L3 markedly increased 11 months after DAA therapy, and MRI 6 months after that showed a solitary lymph node near the common bile duct. Because no intrahepatic recurrence or other lymph nodes were seen, the solitary node was excised. Histopathology showed metastatic HCC. There has been no subsequent recurrence over 13 months of follow-up.",
"affiliations": "Department of Gastroenterology, Osaka City Juso Hospital.;Department of Surgery, Osaka City Juso Hospital.;Department of Gastroenterology, Osaka City Juso Hospital.;Department of Gastroenterology, Osaka City Juso Hospital.;Department of Gastroenterology, Osaka City Juso Hospital.;Department of Gastroenterology, Osaka City Juso Hospital.;Department of Gastroenterology, Osaka City Juso Hospital.;Department of Gastroenterology, Osaka City Juso Hospital.;Department of Gastroenterology, Osaka City Juso Hospital.;Department of Gastroenterology, Osaka City Juso Hospital.",
"authors": "Yamaguchi|Seiko|S|;Tsukamoto|Tadashi|T|;Kawamura|Etsushi|E|;Nakauchi|Shusuke|S|;Ono|Hiroshi|H|;Miyano|Masato|M|;Ueda|Wataru|W|;Aoki|Tetsuya|T|;Kurai|Osamu|O|;Okawa|Kiyotaka|K|",
"chemical_list": "D000998:Antiviral Agents",
"country": "Japan",
"delete": false,
"doi": "10.11405/nisshoshi.116.764",
"fulltext": null,
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"issn_linking": "0446-6586",
"issue": "116(9)",
"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
"keywords": null,
"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D017115:Catheter Ablation; D016461:Chemoembolization, Therapeutic; D003131:Combined Modality Therapy; D019698:Hepatitis C, Chronic; D006801:Humans; D007564:Japan; D008113:Liver Neoplasms; D008198:Lymph Nodes; D008297:Male; D009364:Neoplasm Recurrence, Local; D000078703:Radiofrequency Ablation; D016896:Treatment Outcome",
"nlm_unique_id": "2984683R",
"other_id": null,
"pages": "764-772",
"pmc": null,
"pmid": "31511463",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Solitary lymph node metastasis from early-stage hepatocellular carcinoma after transcatheter arterial chemoembolization and radiofrequency ablation: a case report and review of the Japanese literature.",
"title_normalized": "solitary lymph node metastasis from early stage hepatocellular carcinoma after transcatheter arterial chemoembolization and radiofrequency ablation a case report and review of the japanese literature"
} | [
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"companynumb": "JP-GUERBET-JP-20190222",
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"abstract": "Immune checkpoint inhibitors, the new standard in cancer therapy, present durable responses in numerous solid tumors and hematologic malignancies, as well as resulting in an increased incidence of immune-related adverse events (irAEs). Diarrhea is a common irAE, with an incidence rate of approximately 10% to 13%. It is important to distinguish between diarrhea symptomatic of an infection, which is the main differential diagnosis, and immune-related diarrhea. Here, we report a case of an advanced lung cancer patient who presented with diarrhea as a result of treatment with tislelizumab, a novel PD-1 inhibitor. Although the patient initially responded to corticosteroid treatment, diarrhea recurred upon dosage tapering, and eventually improved on treatment with ganciclovir and vancomycin. Therefore, clinicians must remain highly vigilant against infection and carefully distinguish symptoms of infection from irAEs by performing repeated blood or fecal examinations for pathogens, colonoscopy, and biopsy.",
"affiliations": "Department of Pulmonary and Critical Care Medicine, Peking Union Medical Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.;Department of Pulmonary and Critical Care Medicine, Peking Union Medical Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.;Department of Pulmonary and Critical Care Medicine, Peking Union Medical Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.",
"authors": "Ni|Jun|J|0000-0002-5939-8856;Zhang|Xiaotong|X|;Zhang|Li|L|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C000707970:tislelizumab",
"country": "Singapore",
"delete": false,
"doi": "10.1111/1759-7714.13401",
"fulltext": "\n==== Front\nThorac Cancer\nThorac Cancer\n10.1111/(ISSN)1759-7714\nTCA\nThoracic Cancer\n1759-7706 1759-7714 John Wiley & Sons Australia, Ltd Melbourne \n\n10.1111/1759-7714.13401\nTCA13401\nCase Report\nCase Reports\nOpportunistic bowel infection after corticosteroid dosage tapering in a stage IV lung cancer patient with tislelizumab‐related colitis\nBowel infection post immunotherapyJ. Ni et al.Ni Jun https://orcid.org/0000-0002-5939-8856nijun666525@126.com \n1\n\n†\n Zhang Xiaotong \n1\n\n†\nzhanglipumch@aliyun.com Zhang Li \n1\n \n1 \nDepartment of Pulmonary and Critical Care Medicine, Peking Union Medical Hospital\nChinese Academy of Medical Science & Peking Union Medical College\nBeijing\nChina\n\n* Correspondence\n\nLi Zhang, Department of Pulmonary and Critical Care Medicine, Peking Union Medical Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China.\n\nTel: +86 13911339836\n\nFax: (010) 86‐10‐69155039\n\nEmail: zhanglipumch@aliyun.com\n† Jun NI and Xiaotong Zhang contributed equally.\n\n\n02 4 2020 \n6 2020 \n11 6 10.1111/tca.v11.61699 1702\n23 12 2019 03 3 2020 03 3 2020 © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Immune checkpoint inhibitors, the new standard in cancer therapy, present durable responses in numerous solid tumors and hematologic malignancies, as well as resulting in an increased incidence of immune‐related adverse events (irAEs). Diarrhea is a common irAE, with an incidence rate of approximately 10% to 13%. It is important to distinguish between diarrhea symptomatic of an infection, which is the main differential diagnosis, and immune‐related diarrhea. Here, we report a case of an advanced lung cancer patient who presented with diarrhea as a result of treatment with tislelizumab, a novel PD‐1 inhibitor. Although the patient initially responded to corticosteroid treatment, diarrhea recurred upon dosage tapering, and eventually improved on treatment with ganciclovir and vancomycin. Therefore, clinicians must remain highly vigilant against infection and carefully distinguish symptoms of infection from irAEs by performing repeated blood or fecal examinations for pathogens, colonoscopy, and biopsy.\n\nClostridium difficilecolitiscytomegalovirusdiarrheaimmunotherapy source-schema-version-number2.0cover-dateJune, 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.3 mode:remove_FC converted:01.06.2020\n==== Body\nIntroduction\nMonoclonal antibodies targeting immune checkpoint proteins or immune checkpoint inhibitors (ICIs) have become a new standard of care for diverse cancers.1 Although immune‐related adverse events (irAEs) are mostly well tolerated, in some cases, they may be severe and even life‐threatening. A retrospective review2 reported that diarrhea, the most common irAE, occurred in 10% to 13% of patients, of whom 1%–2% discontinued immunotherapy due to intolerable diarrhea. In this report, we describe an interesting case of severe diarrhea of different etiology that occurred during immunotherapy.\n\nCase report\nA 73‐year‐old man with an irritating dry cough was diagnosed with cT3N3M1c, stage IVB lung adenocarcinoma, with metastases in the right supraclavicular lymph node, left scapula, and right pubic bone. Mutational analyses of ALK, EGFR, ROS1, cMET, and BRAF (V600E) were negative. The patient was recruited to the BGB‐A317 clinical trial and started on a first‐line treatment with pemetrexed (500 mg/m2, 1025 mg, per 21 days), carboplatin (AUC = 5, 600 mg, per 21 days), and a novel PD‐1 inhibitor “tislelizumab” made by a Chinese company (200 mg, per 21 days), from 28 November 2018 to 12 February 2019. The best objective response noted was stable disease. This was followed with pemetrexed and tislelizumab as maintenance therapy from 5 March 2019 to 29 May 2019. Two weeks after the last dose (mid‐June, 2019), the patient was admitted to our unit reporting watery diarrhea (8 to 10 times a day) without fever, asthenia, nausea, or vomiting. The stool assay results were negative. The abdominal computed tomography (CT) scan showed thickening of the pan‐colon wall and marked thickening of the ascending colon. Colonoscopy showed erythematous mucosa in the colon (29 June 2019; Fig 1a), and immune‐related colitis up to grade three was subsequently diagnosed. Tislelizumab treatment was stopped and supportive symptomatic treatments were prescribed. Diarrhea was alleviated by methylprednisolone administration (2 mg/kg/day; 160 mg/day) for three days without antibiotics. During the tapering of methylprednisolone dosage to 60 mg/day, the patient complained of recurrent diarrhea (4 to 5 times a day) with fever and weakness. On this occasion, cytomegalovirus (CMV) DNA polymerase chain reaction (PCR) test and the Clostridium difficile detection assay results were positive. The abdominal CT results were similar to the first scan results. The second colonoscopy showed nonulcerative inflammation in the entire colon mucosa (Fig 1b). Biopsy showed acute and chronic inflammation with cryptitis and crypt abscess, with occasional CMV inclusion bodies (Fig 2). Recurrent diarrhea rapidly resolved after two weeks of treatment with the antiviral drug, ganciclovir (375 mg intravenously, q.12 hours; and 500 mg capsules, t.i.d.), and the antibiotic, vancomycin (125 mg orally, q.i.d.). Meanwhile, corticosteroid dosage was rapidly decreased (by 25 mg per week), and its administration was stopped on 22 August 2019. Subsequent colonoscopy showed only scattered congestion in small portions of the mucous membrane (27 August 2019; Fig 1c). Histological examination revealed that the texture of the rectal blood vessels was blurred without CMV inclusions (Fig 3). Clostridium difficile assay and CMV PCR test results were negative. At the last follow‐up (25 November 2019), the patient had no diarrhea and had recovered his energy and strength. However, due to a new hepatic metastasis, the patient subsequently dropped out of the trial.\n\nFigure 1 (a) Colonoscopy of the ascending colon, transverse colon, descending colon, and sigmoid colon showed rectal mucosal erosion, most consistent with PD‐1 related colitis. (b) All colorectal mucosa showed loss of normal vascular pattern, erythematous mucosa and edema, shallow erosion, mucosal crispness, and bleeding tendency. (c) Colorectal mucosa manifested state, with only scattered congestion in small portions of erythematous mucosa and edema.\n\nFigure 2 Colon biopsy following colonoscopy on 1 August 2019 showed colonic mucosa with abundant inflammatory cells and crypt abscesses (arrow in a) and CMV inclusion bodies (arrow in b). Hematoxylin and eosin stain (a) x40 and (b) x100.\n\nFigure 3 Colon biopsy following colonoscopy on 27 August 2019 showed colonic mucosa with acute and chronic inflammation. Hematoxylin and eosin stain x100.\n\nDiscussion\nImmune‐related colitis is being recognized as one of the most common adverse events,1 with severity ranging from mild to life‐threatening. The main clinical abnormalities observed are nonspecific, including anemia, increased serum C‐reactive protein, and low serum albumin levels. While immune‐related gastrointestinal adverse events seem to arise due to severe disruption of the immune homeostasis,3, 4 their pathogenesis is not fully clear,5 and a predictive biomarker for routine clinical use is yet to be determined. Several biomarkers (inflammation‐induced proteins lipocalin 2, calprotectin, intestinal fatty acid binding‐proteins and tight junction proteins) present in blood, feces, or urine have been used to measure gut immune homeostasis and gut epithelial integrity.6 However, these biomarkers and assay are likely to be of limited clinical use.\n\nColonoscopy is an essential examination used to identify the cause of diarrhea. Previous retrospective studies7, 8 have reported that characteristic endoscopic findings are associated with disease outcomes in ICI‐related colitis and can thus inform treatment. These findings include exudates, granularity, loss of vascular pattern, and pancolonic ulcerations. Due to the large overlap of gross description and colitis distribution between immune‐related colitis and bowel infection, endoscopy may be unsuitable to distinguish between these conditions. Biopsy is the gold standard for diagnosis and can be used to identify the less common causes of diarrhea, such as the CMV infection in the patient reported here.\n\nDuring immunotherapy, the cellular components of intestinal bacteria interact with pattern recognition receptors to promote intestinal dendritic cell activation, boost differentiation and activation of Th17 cells9; this is a high‐risk factor for severe gastrointestinal infections, such as Clostridium difficile infection (CDI).10 Additionally, long‐term systematic corticosteroid treatment (>30 days)2 and immunosuppression may be associated with an increased risk of gut infection, or virus reactivation.11 Corticosteroids have an immunosuppressive effect mainly by disrupting T lymphocyte and monocyte functions and blocking the production of inflammatory cytokines; thus, there is a major risk of CDI with long‐term corticosteroid administration.12, 13 Considering those factors, patients with immune‐related colitis possibly have a high risk of bowel infection.\n\nThe secondary infection was treated with ganciclovir and vancomycin. Retrospective studies14 have shown that the effective median course of treatment with ganciclovir is 14 days. For patients with immunodeficiency combined with CMV enteritis, the course of treatment is for 3–6 weeks, or until symptoms disappear.\n\nAs ICI‐related diarrhea can mimic the clinical manifestations of infectious diarrhea, and its treatment can itself trigger infection, the differential diagnosis of diarrhea in the context of immunotherapy needs to be done carefully. It is imperative to detect pathogens early for effective diagnosis and treatment; thus, we highly recommend that clinicians should rule out infectious colitis when diagnosing patients with immune‐related diarrhea.\n\nDisclosure\nThe authors have no potential conflict of interest to disclose.\n\nAcknowledgments\nThe authors would like to thank the patient and his family for providing information on this case.\n==== Refs\nReferences\n1 \n\nKennedy \nLB \n, \nSalama \nAKS \n. A review of cancer immunotherapy toxicity\n. CA Cancer J Clin \n2020 \n10.3322/caac.21596 .\n2 \n\nWang \nY \n, \nAbu‐Sbeih \nH \n, \nMao \nE \n\net al\nImmune‐checkpoint inhibitor‐induced diarrhea and colitis in patients with advanced malignancies: Retrospective review at MD Anderson\n. J Immunother Cancer \n2018 ; 6 : 37 .29747688 \n3 \n\nGopalakrishnan \nV \n, \nSpencer \nCN \n, \nNezi \nL \n\net al\nGut microbiome modulates response to anti‐PD‐1 immunotherapy in melanoma patients\n. Science \n2018 ; 359 : 97 –103\n.29097493 \n4 \n\nMatson \nV \n, \nFessler \nJ \n, \nBao \nR \n\net al\nThe commensal microbiome is associated with anti‐PD‐1 efficacy in metastatic melanoma patients\n. Science \n2018 ; 359 : 104 –8\n.29302014 \n5 \n\nBerner \nF \n, \nBomze \nD \n, \nDiem \nS \n\net al\nAssociation of checkpoint inhibitor‐induced toxic effects with shared cancer and tissue antigens in non‐small cell lung cancer\n. JAMA Oncol \n2019 ; 5 : 1043 –7\n.31021392 \n6 \n\nWells \nJM \n, \nBrummer \nRJ \n, \nDerrien \nM \n\net al\nHomeostasis of the gut barrier and potential biomarkers\n. Am J Physiol Gastrointest Liver Physiol \n2017 ; 312 : G171 –G93\n.27908847 \n7 \n\nAbu‐Sbeih \nH \n, \nAli \nFS \n, \nLuo \nW \n, \nQiao \nW \n, \nRaju \nGS \n, \nWang \nY \n. Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor‐induced colitis\n. J Immunother Cancer \n2018 ; 6 : 95 .30253811 \n8 \n\nWright \nAP \n, \nPiper \nMS \n, \nBishu \nS \n, \nStidham \nRW \n. Systematic review and case series: Flexible sigmoidoscopy identifies most cases of checkpoint inhibitor‐induced colitis\n. Aliment Pharmacol Ther \n2019 ; 49 : 1474 –83\n.31035308 \n9 \n\nAnderson \nR \n, \nTheron \nAJ \n, \nRapoport \nBL \n. Immunopathogenesis of immune checkpoint inhibitor‐related adverse events: Roles of the intestinal microbiome and Th17 cells\n. Front Immunol \n2019 ; 10 : 2254 .31616428 \n10 \n\nSaleh \nMM \n, \nFrisbee \nAL \n, \nLeslie \nJL \n\net al\nColitis‐induced Th17 cells increase the risk for severe subsequent Clostridium difficile infection\n. Cell Host Microbe \n2019 ; 25 : 756 –65\n e5.31003940 \n11 \n\nLankes \nK \n, \nHundorfean \nG \n, \nHarrer \nT \n\net al\nAnti‐TNF‐refractory colitis after checkpoint inhibitor therapy: Possible role of CMV‐mediated immunopathogenesis\n. Onco Targets Ther \n2016 ; 5 : e1128611.\n12 \n\nFuruya‐Kanamori \nL \n, \nStone \nJC \n, \nClark \nJ \n\net al\nComorbidities, exposure to medications, and the risk of community‐acquired Clostridium difficile infection: A systematic review and meta‐analysis\n. Infect Control Hosp Epidemiol \n2015 ; 36 : 132 –41\n.25632995 \n13 \n\nKo \nJH \n, \nPeck \nKR \n, \nLee \nWJ \n\net al\nClinical presentation and risk factors for cytomegalovirus colitis in immunocompetent adult patients\n. Clin Infect Dis \n2015 ; 60 : e20 –6\n.25452594 \n14 \n\nGoodman \nAL \n, \nMurray \nCD \n, \nWatkins \nJ \n, \nGriffiths \nPD \n, \nWebster \nDP \n. CMV in the gut: A critical review of CMV detection in the immunocompetent host with colitis\n. Eur J Clin Microbiol Infect Dis \n2015 ; 34 : 13 –8\n.25097085\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1759-7706",
"issue": "11(6)",
"journal": "Thoracic cancer",
"keywords": "\nClostridium difficile; colitis; cytomegalovirus; diarrhea; immunotherapy",
"medline_ta": "Thorac Cancer",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000305:Adrenal Cortex Hormones; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D003092:Colitis; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009367:Neoplasm Staging; D009894:Opportunistic Infections",
"nlm_unique_id": "101531441",
"other_id": null,
"pages": "1699-1702",
"pmc": null,
"pmid": "32239681",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": "29747688;31616428;31021392;25097085;29302014;31003940;27471608;27908847;31944278;30253811;25632995;29097493;31035308;25452594",
"title": "Opportunistic bowel infection after corticosteroid dosage tapering in a stage IV lung cancer patient with tislelizumab-related colitis.",
"title_normalized": "opportunistic bowel infection after corticosteroid dosage tapering in a stage iv lung cancer patient with tislelizumab related colitis"
} | [
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"companynumb": "CN-PFIZER INC-2020162693",
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"activesubstancename": "METHYLPREDNISOLONE"
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{
"abstract": "BACKGROUND Amiodarone, an anti-arrhythmic medication, has been associated with the development of multiple organ toxicities. Most of these toxicities develop insidiously. However, in rare cases, these toxicities manifest with more acute symptoms. We present an unusual case of amiodarone toxicity which manifested with multiorgan failure and systemic inflammatory response syndrome that mimicked sepsis. CASE REPORT A 73-year-old man who was being treated with chronic oral amiodarone for atrial fibrillation presented with flu-like symptoms and fever, pulmonary infiltrate, acute kidney injury, and thrombocytopenia. The patient did not improve with antibiotics and fluid resuscitation. The results of an extensive infectious and non-infectious workup were negative. His symptoms worsened during hospitalization, which correlated with the loading of intravenous amiodarone given for his acute worsening of atrial fibrillation. Amiodarone-induced drug toxicity was contemplated by the treating medical team. Amiodarone was stopped, and the patient was treated with steroids, which improved his symptoms and organ dysfunctions. Subsequent bronchoscopy with lung biopsy showed foamy macrophages with organizing pneumonia and fibrinoid changes. CONCLUSIONS This case highlights an atypical and rare presentation of a complication of chronic amiodarone use that presented with acute onset of fever, systemic inflammatory response syndrome, and multiorgan failure masquerading as sepsis. The patient's symptoms and organ dysfunctions improved with the discontinuation of amiodarone and institution of steroids.",
"affiliations": "Department of Pulmonary and Critical Care Medicine, Baylor Scott and White Medical Center, Waxahachie, TX, USA.;Department of Pulmonary and Critical Care Medicine, Baylor Scott and White Medical Center, Waxahachie, TX, USA.;Department of Pulmonary and Critical Care Medicine, Baylor Scott and White Medical Center, Waxahachie, TX, USA.;Department of Infectious Disease, Baylor Scott and White Medical Center, Waxahachie, TX, USA.",
"authors": "Kugasia|Irfanali R|IR|;Ijaz|Mohsin|M|;Khan|Ahsan|A|;Jasti|Yashwanth|Y|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000638:Amiodarone",
"country": "United States",
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"doi": "10.12659/AJCR.926929",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n33095757\n10.12659/AJCR.926929\n926929\nArticles\nAmiodarone Toxicity Presenting with Acute Onset of Systemic Inflammatory Response Syndrome and Multiorgan Failure Mimicking Sepsis\nKugasia Irfanali R. ABCDEF1 Ijaz Mohsin CDE1 Khan Ahsan BC1 Jasti Yashwanth FG2 \n1 Department of Pulmonary and Critical Care Medicine, Baylor Scott and White Medical Center, Waxahachie, TX, U.S.A.\n\n2 Department of Infectious Disease, Baylor Scott and White Medical Center, Waxahachie, TX, U.S.A.\nCorresponding Author: Irfanali R. Kugasia, e-mail: irfanali102@gmail.comAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n23 10 2020 \n21 e926929-1 e926929-7\n19 6 2020 31 8 2020 16 9 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 73-year-old\n\nFinal Diagnosis: Amiodarone induced SIRS response and organizing pneumonia\n\nSymptoms: Abdominal pain • fever • nausea • vomiting\n\nMedication: —\n\nClinical Procedure: Bronchoalveolar lavage • bronchoscopy • trans-bronchial biopsy\n\nSpecialty: Critical Care Medicine\n\nObjective:\nUnusual clinical course\n\nBackground:\nAmiodarone, an anti-arrhythmic medication, has been associated with the development of multiple organ toxicities. Most of these toxicities develop insidiously. However, in rare cases, these toxicities manifest with more acute symptoms. We present an unusual case of amiodarone toxicity which manifested with multiorgan failure and systemic inflammatory response syndrome that mimicked sepsis.\n\nCase Report:\nA 73-year-old man who was being treated with chronic oral amiodarone for atrial fibrillation presented with flu-like symptoms and fever, pulmonary infiltrate, acute kidney injury, and thrombocytopenia. The patient did not improve with antibiotics and fluid resuscitation. The results of an extensive infectious and non-infectious workup were negative. His symptoms worsened during hospitalization, which correlated with the loading of intravenous amiodarone given for his acute worsening of atrial fibrillation. Amiodarone-induced drug toxicity was contemplated by the treating medical team. Amiodarone was stopped, and the patient was treated with steroids, which improved his symptoms and organ dysfunctions. Subsequent bronchoscopy with lung biopsy showed foamy macrophages with organizing pneumonia and fibrinoid changes.\n\nConclusions:\nThis case highlights an atypical and rare presentation of a complication of chronic amiodarone use that presented with acute onset of fever, systemic inflammatory response syndrome, and multiorgan failure masquerading as sepsis. The patient’s symptoms and organ dysfunctions improved with the discontinuation of amiodarone and institution of steroids.\n\nMeSH Keywords:\nAmiodaroneFeverMultiple Organ Failure\n==== Body\nBackground\nAmiodarone is one of the most effective anti-arrhythmic medications used to treat a wide range of arrhythmias. It was introduced in the 1960s and is now the most popular anti-ar-rhythmic drug in use [1]. Amiodarone has been commonly associated with the development of various organ toxicities. Onset of these toxicities is typically insidious and correlates with the cumulative dose of amiodarone [2]. Although rare, the acute onset of toxicities has been described with either the chronic use or initiation of amiodarone [3–7]. Herein, we describe an unusual case of amiodarone toxicity that presented with acute onset of fever, multiorgan failure, and systemic inflammatory response syndrome that masqueraded as sepsis from a low cumulative dose of approximately 75 g.\n\nCase Report\nA 73-year-old man presented to our hospital in February 2020 with fever and flu-like symptoms of body aches, fatigue, and malaise for 10 days. This was associated with diffuse non-localized abdominal pain with nausea and vomiting for 3 days prior to hospitalization. The patient denied dyspnea or cough. He also denied any recent travel, family gatherings, or sick contacts. He endorsed an active lifestyle and attended the gym daily prior to getting sick.\n\nThe patient’s past medical history was significant for a difficult-to-control atrial flutter/fibrillation, which had been treated with dronedarone since 2016. The dronedarone was switched to amiodarone in March 2019 after the recurrence of atrial fibrillation with a rapid ventricular rhythm. The patient was started on a loading dose of oral amiodarone of 400 mg daily for 1 month, and after undergoing direct current cardioversion, he was switched to oral amiodarone 200 mg daily; he had a cumulative dose of approximately 75 g at the time of hospitalization. The patient denied smoking or any history of lung disease. His other oral medications included apixaban 5 mg orally twice daily, tamsulosin 0.4 mg once daily, and finasteride 5 mg once daily. The patient denied any recent change in his amiodarone dose. He also denied taking any over-the-counter medications or herbal supplements.\n\nOn initial presentation, the patient was noted to have fever, atrial fibrillation with rapid ventricular rate, warm extremities, and low systolic blood pressure, but with a mean arterial pressure consistently greater than 65 mmHg. He was mildly tachypneic, with stable oxygen saturation at more than 95% on room air. The patient’s significant laboratory findings on presentation are summarized in Table 1. In brief, laboratory evaluation showed a negative rapid influenza antigen test, normal absolute white blood cell count with significant bandemia of 35%, severe lymphopenia with an absolute lymphocyte count 50/uL, and thrombocytopenia of 50 000/uL. Urinalysis results showed moderate bacteriuria without leukocyte esterase or nitrites. Blood chemistry results showed elevated BUN/creatinine levels of 13.5/0.16 mmol/L, elevated AST and ALT levels of 193 U/L and 186 U/L, respectively, and total bilirubin of 27.4 µmol/L. The procalcitonin level was 3.65 ng/ml, and TSH was 2.27 uIU/ml. The other laboratory values were non-contributory. The chest X-ray showed a new consolidation of the left upper lung (Figure 1A, 1B).\n\nThe patient was started on intravenous ceftriaxone 2 g daily for presumed sepsis of pulmonary origin and fluid resuscitation with a total of 3 L of crystalloids. His oral amiodarone was continued to help control his atrial fibrillation and apixaban was discontinued because of his thrombocytopenia.\n\nOver the next 48 h, the patient continued to have high-grade fever without much improvement in clinical status (Figure 2, Table 2). Repeated laboratory test results showed increasing BUN and creatinine levels, increasing leukocytosis, persistent bandemia ranging from 38% to 58%, and persistent thrombocytopenia (Figure 2, Table 1). The patient’s 2 sets of peripheral blood cultures, respiratory multiplex real-time polymerase chain reaction (RT-PCR, Table 3), urine culture, and HIV test were negative. A chest computed tomography (CT) scan without contrast showed dense consolidation with surrounding ground-glass opacification in the left upper lobe of the lung with small bilateral pleural effusions and mediastinal lymphadenopathy, favoring reactive enlargement. Radiographic findings favored pneumonia (Figure 1C). A CT scan of the abdomen and pelvis without contrast showed mild nonspecific splenomegaly, minimal sludge in the gallbladder without evidence of acute cholecystitis, colonic diverticulosis without evidence of acute diverticulitis, and no other acute abnormalities. No hyperdensity or increased attenuation of the liver or spleen was reported.\n\nDue to the patient’s persistent fevers and nonresolving symptoms after 48 h of presentation, the antibiotic regimen was escalated to intravenous piperacillin/tazobactam 4.5 g every 6 h and a nasal swab for a SARS-CoV-2 was sent for PCR testing. At 72 h after admission, the patient was given a loading dose of amiodarone with a 150-mg intravenous push followed by an intravenous infusion of 1 mg/h for 6 h and 0.5 mg/h for 18 h, to control his worsening tachycardia with atrial fibrillation. Beta blockers and calcium channel blockers were avoided owing to his hypotension. Subsequently, his fevers, leukocytosis, and creatinine levels worsened exponentially (Figure 2A, 2B), with a Tmax of 39.9°C. This was associated with worsening nausea and vomiting, along with an increasingly toxic appearance and delirium.\n\nAfter consultation with an infectious disease specialist and ruling out of other differential diagnoses as mentioned in Table 4, drug-induced fever and pulmonary toxicity from amiodarone was considered as the potential cause of the patient’s symptoms. Amiodarone and piperacillin/tazobactam infusions were discontinued. Bronchoscopy was planned but delayed because the patient’s SARS-CoV-2 PCR test results were pending. In the interim, the patient was started on 1 mg/kg of intravenous methylprednisolone empirically because of his severe symptoms.\n\nWithin 12 h of starting systemic steroids, the patient’s fever, tachypnea, delirium, platelet count, and creatinine level started improving, and normalized in the next 48 h (Figure 2). The SARS-CoV-2 PCR test result was negative. Because of the improving blood pressure, metoprolol was started orally at 25 mg twice daily to control the ventricular rate from atrial fibrillation. On day 6 of hospitalization, the patient underwent bronchoscopy with bronchoalveolar lavage from the left upper lobe with transbronchial lung biopsies to obtain a definitive diagnosis and rule out malignancy and atypical fungal, mycobacterial, and viral infection. The cell count on bronchoalveolar lavage showed 26% lymphocytes and 13% neutrophils, with the rest being monocyte-histiocytes. Lung biopsies revealed focal organizing fibrin in air spaces, consistent with organizing pneumonia and foamy macrophages (Figure 3). All cultures from the bronchoscopy and biopsies were negative for bacteria, fungus, and acid-fast bacilli. Biopsies from the consolidation were negative for any malignant cells. The bronchoalveolar lavage specimen was also negative for respiratory multiplex RT-PCR.\n\nThe patient was discharged home on oral prednisone 40 mg once daily, metoprolol 100 mg twice daily, and apixaban 5 mg twice daily. Amiodarone was discontinued. Over the next 6 weeks, prednisone was slowly tapered off without any recurrence of symptoms, and a follow-up chest CT scan at week 6 showed complete resolution of the consolidation. The patient’s atrial fibrillation remained well controlled with oral metoprolol.\n\nDiscussion\nThe adverse effects of amiodarone include corneal microdeposits (seen in >90% of patients), optic neuritis (1%), photosensitivity (25–75%), skin discoloration (<10%), hypothyroidism (4– 22%), hyperthyroidism (2–12%), pulmonary toxicity(2%), and hepatotoxicity ranging from elevated transaminase levels in 15–30% of patients to the development of hepatitis and cirrhosis in <3% of patients [1]. Most of these complications develop insidiously. The primary determinants for the development of severe toxicities to amiodarone are the daily dose, duration of treatment, and cumulative dose of the drug [2]. For example, clinically significant amiodarone-induced pulmonary toxicity is commonly seen in patients who are on 400 mg of amiodarone daily for more than 2 months, 200 mg daily for more than 2 years [2,8], or have a cumulative dose of approximately 140–230 g [9]. Due to its high lipid solubility, amiodarone has a large volume of distribution and tends to accumulate in tissues with high lipid content and high blood flow such as the lungs, liver, spleen, skin, and adipose tissue [8]. This gives amiodarone a prolonged half-life that can range from 15 to 142 days and depends on factors including the age of the patient, total cumulative dose, and fat content of the body. As a result, amiodarone’s toxicities can persist long after the discontinuation of exogenous intake [2,10,11]. There is also a poor correlation between blood amiodarone levels and development of toxicities due to its tendency to accumulate in certain tissues and subsequent slow continuous release from those tissues [1,2]. The development of amiodarone toxicity is thought to be through direct toxicity from the accumulation of phospholipids due to its inhibition of lysosomal phospholipase A. It can also directly increase oxidative free radical production in the organs in which it accumulates. Amiodarone is also proposed to cause systemic toxicity indirectly through the activation of an inflammatory response, but the mechanism of activation of the inflammatory response is not known [12,13].\n\nAmiodarone-induced toxicities are primarily identified by diagnosis of exclusion. In the presented case, a multitude of other etiologies for the patient’s symptoms and organ dysfunctions were considered and ruled out by extensive, systematic evaluation before amiodarone drug toxicity was presumed. These are summarized in Table 4. Although the patient clinically improved with the discontinuation of amiodarone and administration of empiric systemic steroids, there was a lack of a definitive diagnosis of amiodarone toxicity. As a result, the decision was made to perform bronchoscopy since there remained a remote possibility of atypical infections and non-infectious etiologies, such as lymphoma and lung malignancy, which could potentially have a similar presentation. Additionally, a presumptive diagnosis of amiodarone-induced drug toxicity would have long-term implications on the choice of future anti-arrhythmic medications for the patient. The patient underwent bronchoscopy with bronchoalveolar lavage and biopsies which were all negative for any alternate diagnosis.\n\nOrganizing pneumonia diagnosed on transbronchial lung biopsies is a rare manifestation of amiodarone-induced pulmonary toxicity, which can be associated with fevers and malaise [14]. However, the patient’s fever curve acutely worsened with intravenous amiodarone, which should not have occurred if the fevers were only secondary to the organizing pneumonia (Figure 1). Also, the other organ dysfunctions seen in this case have not been previously reported with organizing pneumonia [14,15]. This portends a systemic inflammatory response in which organizing pneumonia was one of its manifestations rather than its cause.\n\nAcute toxicities from amiodarone are rare, but have been documented [3–7,9–11]. In the case of our patient, acute toxicity from amiodarone was the most likely explanation for the constellation of fever, organizing pneumonia, acute kidney injury, thrombocytopenia, and the other clinical symptoms seen. Systemic steroids, although nonspecific, have been described in the literature for treating severe amiodarone-induced pulmonary toxicities, with a good response in most cases [2,10,11]. The conventional wisdom is to taper the systemic steroids over weeks to months to avoid recurrence of toxicity symptoms due to amiodarone’s extended half-life [2,10,11].\n\nFrom a review of the English-language literature in PubMed from 1980 to 2020, we believe the presented case report is the first amiodarone toxicity presenting with acute onset of systemic inflammatory response syndrome with constellations of fever and multiple organ dysfunctions.\n\nConclusions\nThis case highlights a novel presentation of acute toxicity from long-term amiodarone therapy. Through this case, we would like to inform other clinicians that chronic low-dose amiodarone can cause toxicities that present acutely with multiple organ dysfunctions, which could masquerade as sepsis. And if these toxicities are severe, we recommend clinicians consider using systemic steroids to help reverse such toxicities.\n\nThe authors would like to thank Dr. Douglas Toler of the Department of Pathology at Baylor Scott and White Medical Center, Waxahachie, for providing us with pathology images from transbronchial lung biopsies.\n\nConflict of interest\n\nNone.\n\nFigure 1. (A) Posteroanterior view of chest X-ray showing left upper-lobe consolidation obscuring the left mediastinal border. (B) Lateral view of chest X-ray showing left upper-lobe consolidation. (C) CT scan of chest showing left upper-lung consolidation with surrounding ground-glass and air bronchogram.\n\nFigure 2. (A) Trend of temperature and heart rate during patient’s hospitalization correlated with amiodarone dose oral, intravenous, and systemic steroids. (B) Trend of creatinine levels and platelets counts during patient’s hospitalization correlated with amiodarone dose oral, intravenous and systemic steroids.\n\nFigure 3. (A) Transbronchial lung biopsies from left upper lung showing pulmonary foamy macrophages and desquamated pneumocytes. (B) Thin prep from bronchoalveolar lavage with foamy macrophage. (C) Transbronchial lung biopsies from left upper lung showing organizing pneumonia. (D) Transbronchial biopsies from left upper lung show0ing acute fibrinous change.\n\nTable 1. Pertinent laboratory values with reference ranges.\n\nLaboratory test\tDay 0\tDay 3\tDay 6\tReference range\t\nBUN\t13.5\t61\t56\t2.5–6.42 mmol/L\t\nCreatinine\t0.16\t2.4\t1\t0.06–0.12 mmol/L\t\nAST\t193\t94\t61\t15–37 U/L\t\nALT\t186\t111\t76\t16–61 U/L\t\nBilirubin\t27.4\t22.2\t17\t3.42–17 µmol/L\t\nLDH\t373\t280\t\t85–227 U/L\t\nProcalcitonin\t3.65\t\t\t<0.25 µg/L\t\nTSH\t\t2.27\t\t0.36–3.74 uIU/mL\t\nHaptoglobin\t16.8\t\t\t4–24 µmol/L\t\nWBC\t5.3\t11.3\t12.7\t4.5–11.0 K/uL\t\nHgb\t12.8\t11\t10.8\t13.5–18.0 g/dL\t\nPlatelets\t50\t58\t153\t140–440 K/uL\t\nBands\t35\t38\t1\t%\t\nReticulocyte count\t0.48\t\t\t0.50–2.00%\t\npH\t7.4\t\t\t7.35–7.45\t\npCO2\t31\t\t\t35–46 mmHg\t\npO2\t68\t\t\t60–80 mmHg\t\nTCO2\t20\t\t\t21–32 mmol/L\t\nHCO3\t19.1\t\t\t21.0–26.0 mmol/L\t\nBase excess\t−6\t\t\t−2.0–3.0 mmol/L\t\nBUN – blood urea nitrogen; AST – aspartate transaminase; ALT – alanine transaminase; LDH – lactate dehydrogenase; TSH – thyroid stimulating hormone; WBC – white blood cell; Hgb – hemoglobin; PCO2 – partial pressure of CO2; PO2 – partial pressure of oxygen; TCO2 – total CO2 content of the serum; HCO3 – calculated serum bicarbonate ion; O2 – oxygen.\n\nTable 2. Vital signs during the first 5 days.\n\nVitals\tDay 0\tDay 1\tDay 2\tDay 3\tDay 4\tDay 5\t\nTemperature (°C)\t39\t37\t39.1\t39.9\t37.2\t37\t\nHeart rate (beats/min)\t129\t114\t131\t136\t84\t77\t\nBlood pressure (mmHg)\t100/64\t93/62\t121/81\t87/46\t132/79\t109/67\t\nO2 saturation (%)\t94\t92\t97\t91\t97\t98\t\nRespiratory (breaths/min)\t21\t25\t30\t28\t18\t26\t\nTable 3. Respiratory infective organism ruled out with the respiratory multiplex real-time polymerase chain reaction.\n\n1\tAdenovirus\t\n2\tCoronavirus 229E\t\n3\tCoronavirus HKU1\t\n4\tCoronavirus NL63\t\n5\tCoronavirus OC43\t\n6\tHuman Metapneumovirus\t\n7\tRhinovirus/Enterovirus\t\n8\tInfluenza A\t\n9\tInfluenza A/H1(2009)\t\n10\tInfluenza A/H1\t\n11\tInfluenza A/H3\t\n12\tInfluenza B\t\n13\tParainfluenza Virus 1\t\n14\tParainfluenza Virus 2\t\n15\tParainfluenza Virus 3\t\n16\tParainfluenza Virus 4\t\n17\tRespiratory Syncytial Virus\t\n18\tBordetella pertussis\t\n19\tChlamydophila pneumoniae\t\n20\tMycoplasma pneumonia\t\nTable 4. Differential diagnoses considered as the possible cause of patient’s clinical symptoms and tests done to rule them out.\n\nSr. No.\tDifferential diagnoses\tTests done to rule it out\t\n1.\tInfectious etiology\tNegative results from: Multiple blood cultures Sputum cultures Respiratory multiplex RT-PCR from nasal swab. Broncho-alveolar lavage tested for: bacterial culture and sensitivity, fungal smear and culture, AFB smear and culture, legionella culture, Nocardia cultures, respiratory multiplex RT-PCR. SARS CoV2 PCR nasal swab CT chest, abdomen and pelvis negative for any infectious etiology\t\n2.\tHyperthyroidism\tNormal TSH, T3, T4, no exogenous ingestion of thyroid hormone\t\n3.\tTTP/HUS\tNormal peripheral smear, haptoglobin level and LDH level\t\n4.\tLymphoma\tFlow cytometry from needle aspiration of mediastinal lymph node\t\n5.\tPiperacillin/Tazobactam Drug fever\tDiscordant timeframe of symptom onset. Symptoms present prior to starting of the medications, persistent even after its discontinuation\t\n6.\tOTC Drug interaction\tNone per history\t\n7.\tMalignancy\tNegative on lung biopsy\n==== Refs\nReferences:\n1. Epstein AE Olshansky B Naccarelli GV Practical management guide for clinicians who treat patients with amiodarone Am J Med 2016 129 5 468 75 26497904 \n2. Colunga Biancatelli RM Congedo V Calvosa L Adverse reactions of Amiodarone J Geriatr Cardiol 2019 16 7 552 66 31447894 \n3. Ott MC Khoor A Leventhal JP Pulmonary toxicity in patients receiving low-dose amiodarone Chest 2003 123 2 646 51 12576397 \n4. Lardinois D Handschin A Weder W Acute amiodarone-induced pulmonary toxicity after lung operation Ann Thorac Surg 2002 73 6 2033 34 \n5. Kaushik S Hussain A Clarke P Lazar HL Acute pulmonary toxicity after low-dose amiodarone therapy Ann Thorac Surg 2001 72 5 1760 61 11722091 \n6. Abuzaid A Saad M Ayan M Acute amiodarone pulmonary toxicity after drug holiday: A case report and review of the literature Case Rep Cardiol 2015 2015 927438 26075108 \n7. Paudel R Dogra P Suman S Acute liver and renal failure: A rare adverse effect exclusive to intravenous amiodarone Case Rep Crit Care 2016 2016 5232804 27672457 \n8. Wolkove N Baltzan M Amiodarone pulmonary toxicity Can Respir J 2009 16 2 43 48 19399307 \n9. Cheng HC Wang JH Wang ML Adverse effect of low-dose amiodarone mimicking pulmonary malignancy Int J Angiol 2010 19 1 e51 53 22477578 \n10. Nacca N Bhamidipati CM Yuhico LS Severe amiodarone induced pulmonary toxicity J Thorac Dis 2012 4 6 667 70 23205299 \n11. Ashrafian H Davey P Is amiodarone an underrecognized cause of acute respiratory failure in the ICU? Chest 2001 120 1 275 82 11451849 \n12. Martin WJ 2nd Rosenow EC 3rd Amiodarone pulmonary toxicity. Recognition and pathogenesis (Part I) Chest 1988 93 5 1067 75 3282816 \n13. Martin WJ 2nd Rosenow EC 3rd Amiodarone pulmonary toxicity. Recognition and pathogenesis (Part 2) Chest 1988 93 6 1242 48 3286141 \n14. Cordier JF Cryptogenic organising pneumonia Eur Respir J 2006 28 2 422 46 16880372 \n15. Epler GR Drug-induced bronchiolitis obliterans organizing pneumonia Clin Chest Med 2004 25 1 89 94 15062600\n\n",
"fulltext_license": "CC BY-NC-ND",
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"journal": "The American journal of case reports",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D000368:Aged; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D006801:Humans; D008297:Male; D009102:Multiple Organ Failure; D018805:Sepsis; D018746:Systemic Inflammatory Response Syndrome",
"nlm_unique_id": "101489566",
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"pages": "e926929",
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"pmid": "33095757",
"pubdate": "2020-10-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26075108;12078825;19399307;22477578;11722091;11451849;3286141;15062600;27672457;26497904;12576397;16880372;23205299;3282816;31447894",
"title": "Amiodarone Toxicity Presenting with Acute Onset of Systemic Inflammatory Response Syndrome and Multiorgan Failure Mimicking Sepsis.",
"title_normalized": "amiodarone toxicity presenting with acute onset of systemic inflammatory response syndrome and multiorgan failure mimicking sepsis"
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"abstract": "Under the hypothesis that early natural killer cell infusion (NKI) following haploidentical stem cell transplantation (haplo-SCT) will reduce relapse in the early post-transplant period, we conducted a pilot study to evaluate the safety and feasibility of NKI following haplo-SCT in children with recurrent neuroblastoma who failed previous tandem high-dose chemotherapy and autologous SCT.\n\n\n\nWe used the high-dose 131I-metaiodobenzylguanidine and cyclophosphamide/fludarabine/anti-thymocyte globulin regimen for conditioning and infused 3 × 107/kg of ex-vivo expanded NK cells derived from a haploidentical parent donor on days 2, 9, and 16 post-transplant. Interleukin-2 was administered (1 × 106 IU/m2/day) subcutaneously to activate infused donor NK cells on days 2, 4, 6, 9, 11, 13, 16, 18, and 20 post-transplant.\n\n\n\nSeven children received a total of 19 NKIs, and NKI-related acute toxicities were fever (n = 4) followed by chills (n = 3) and hypertension (n = 3); all toxicities were tolerable. Grade ≥II acute GVHD and chronic GVHD developed in two and five patients, respectively. Higher amount of NK cell population was detected in peripheral blood until 60 days post-transplant than that in the reference cohort. Cytomegalovirus and BK virus reactivation occurred in all patients and Epstein-Barr virus in six patients. Six patients died of relapse/progression (n = 5) or treatment-related mortality (n = 1), and one patient remained alive.\n\n\n\nNKI following haplo-SCT was relatively safe and feasible in patients with recurrent neuroblastoma. Further studies to enhance the graft-versus-tumor effect without increasing GVHD are needed.",
"affiliations": "Department of Pediatrics, Chungbuk National University Hospital, Cheongju, Republic of Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University Bundang Hospital, Sungnam, Republic of Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Cell Therapy Research Center, GC LabCell, Yongin, Republic of Korea.;MOGAM Institute for Biomedical Research, Yongin, Republic of Korea.;Cell Therapy Research Center, GC LabCell, Yongin, Republic of Korea.;Cell Therapy Research Center, GC LabCell, Yongin, Republic of Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.",
"authors": "Choi|Young Bae|YB|0000-0001-7016-8827;Son|Meong Hi|MH|;Cho|Hee Won|HW|;Ma|Youngeun|Y|;Lee|Ji Won|JW|;Kang|Eun-Suk|ES|;Yoo|Keon Hee|KH|;Her|Jung Hyun|JH|;Lim|Okjae|O|;Jung|Miyoung|M|;Hwang|Yu Kyeong|YK|;Sung|Ki Woong|KW|;Koo|Hong Hoe|HH|",
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"doi": "10.1371/journal.pone.0225998",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0225998PONE-D-19-00423Research ArticleBiology and life sciencesCell biologyCellular typesAnimal cellsBlood cellsWhite blood cellsNK cellsBiology and life sciencesCell biologyCellular typesAnimal cellsImmune cellsWhite blood cellsNK cellsBiology and life sciencesImmunologyImmune cellsWhite blood cellsNK cellsMedicine and health sciencesImmunologyImmune cellsWhite blood cellsNK cellsMedicine and Health SciencesOncologyCancers and NeoplasmsBlastomasNeuroblastomaBiology and Life SciencesToxicologyToxicityMedicine and Health SciencesPathology and Laboratory MedicineToxicologyToxicityMedicine and Health SciencesOncologyCancer TreatmentMedicine and Health SciencesSurgical and Invasive Medical ProceduresBlood and Lymphatic System ProceduresStem Cell TransplantationMedicine and Health SciencesSurgical and Invasive Medical ProceduresTransplantationCell TransplantationStem Cell TransplantationBiology and Life SciencesGeneticsHeredityGenetic MappingHaplotypesMedicine and Health SciencesPharmacologyAdverse ReactionsMedicine and Health SciencesDiagnostic MedicineSigns and SymptomsFeversMedicine and Health SciencesPathology and Laboratory MedicineSigns and SymptomsFeversSafety and immune cell kinetics after donor natural killer cell infusion following haploidentical stem cell transplantation in children with recurrent neuroblastoma NK cell infusion after haplo-SCT for recurrent neuroblastomahttp://orcid.org/0000-0001-7016-8827Choi Young Bae Data curationFormal analysisWriting – original draftWriting – review & editing1Son Meong Hi Data curationWriting – review & editing2Cho Hee Won Data curationWriting – review & editing2Ma Youngeun Data curationWriting – review & editing3Lee Ji Won Data curationWriting – review & editing2Kang Eun-Suk Formal analysisWriting – review & editing4Yoo Keon Hee Writing – review & editing2Her Jung Hyun Formal analysisMethodologyWriting – review & editing5Lim Okjae Formal analysisMethodologyWriting – review & editing6Jung Miyoung Formal analysisMethodologyWriting – review & editing5Hwang Yu Kyeong Formal analysisMethodologyWriting – review & editing5Sung Ki Woong ConceptualizationFormal analysisWriting – original draftWriting – review & editing2*Koo Hong Hoe Writing – review & editing21 \nDepartment of Pediatrics, Chungbuk National University Hospital, Cheongju, Republic of Korea2 \nDepartment of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea3 \nDepartment of Pediatrics, Seoul National University Bundang Hospital, Sungnam, Republic of Korea4 \nDepartment of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea5 \nCell Therapy Research Center, GC LabCell, Yongin, Republic of Korea6 \nMOGAM Institute for Biomedical Research, Yongin, Republic of KoreaBertolini Francesco EditorEuropean Institute of Oncology, ITALYCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: kwsped@skku.edu13 12 2019 2019 14 12 e02259986 1 2019 19 11 2019 © 2019 Choi et al2019Choi et alThis 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.Introduction\nUnder the hypothesis that early natural killer cell infusion (NKI) following haploidentical stem cell transplantation (haplo-SCT) will reduce relapse in the early post-transplant period, we conducted a pilot study to evaluate the safety and feasibility of NKI following haplo-SCT in children with recurrent neuroblastoma who failed previous tandem high-dose chemotherapy and autologous SCT.\n\nMethods\nWe used the high-dose 131I-metaiodobenzylguanidine and cyclophosphamide/fludarabine/anti-thymocyte globulin regimen for conditioning and infused 3 × 107/kg of ex-vivo expanded NK cells derived from a haploidentical parent donor on days 2, 9, and 16 post-transplant. Interleukin-2 was administered (1 × 106 IU/m2/day) subcutaneously to activate infused donor NK cells on days 2, 4, 6, 9, 11, 13, 16, 18, and 20 post-transplant.\n\nResults\nSeven children received a total of 19 NKIs, and NKI-related acute toxicities were fever (n = 4) followed by chills (n = 3) and hypertension (n = 3); all toxicities were tolerable. Grade ≥II acute GVHD and chronic GVHD developed in two and five patients, respectively. Higher amount of NK cell population was detected in peripheral blood until 60 days post-transplant than that in the reference cohort. Cytomegalovirus and BK virus reactivation occurred in all patients and Epstein-Barr virus in six patients. Six patients died of relapse/progression (n = 5) or treatment-related mortality (n = 1), and one patient remained alive.\n\nConclusion\nNKI following haplo-SCT was relatively safe and feasible in patients with recurrent neuroblastoma. Further studies to enhance the graft-versus-tumor effect without increasing GVHD are needed.\n\nSMC Research and Development Grant[#CRO1130611Sung Ki Woong This study was supported by SMC Research and Development Grant [#CRO1130611] (Ki Woong Sung received the fund). No additional external funding was received for this study. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityWe are unable to share our data set according to the restriction imposed by the Institutional Review Board of Samsung Medical Center because it contains sensitive information about patients. The data underlying the results presented in the study are available from Samsung Medical Center (Tel. +82-2-3410-2980, Email: dm.cha@samsung.com, Fax: +82-2-3410-3617).Data Availability\nWe are unable to share our data set according to the restriction imposed by the Institutional Review Board of Samsung Medical Center because it contains sensitive information about patients. The data underlying the results presented in the study are available from Samsung Medical Center (Tel. +82-2-3410-2980, Email: dm.cha@samsung.com, Fax: +82-2-3410-3617).\n==== Body\nIntroduction\nThe development of high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) has improved treatment outcomes of patients with high-risk neuroblastoma in recent decades [1–4]. However, many patients with high-risk neuroblastoma experience relapse after HDCT/auto-SCT, and in these patients, allogeneic SCT (allo-SCT) with graft-versus-tumor (GVT) effects might be a treatment option [4]. Recently, haploidentical SCT (haplo-SCT) with or without high-dose 131I-metaiodobenzylguanidine (HD-MIBG) treatment has been performed as an attempt to increase the anti-tumor effect for patients with recurrent neuroblastoma and showed tolerable toxicity and potential anti-tumor effects [5,6].\n\nIn haplo-SCT in which T cells are usually depleted to prevent unacceptable graft-versus-host disease (GVHD), donor natural killer (NK) cells may play an important role in eliminating residual tumor cells until T cell recovery [7]. NK cells are innate effector lymphocytes and have cytotoxicity against tumor cells with decreased expression of major histocompatibility class I antigen [8,9]. The activity of NK cells is controlled by networking of activating and inhibitory receptors [10]. Previous studies have shown that selection of donors with killer cell immunoglobulin-like receptors (KIR) mismatched with recipient HLA or group B KIR haplotype improved transplant outcomes in several malignancies [11–15]. Neuroblastoma cells have been reported to have decreased class I HLA expression, which suggests that NK cell therapy may be effective in killing neuroblastoma cells [16]. Our previous study showed that KIR/HLA-ligand mismatched haplo-SCT might improve outcomes in children with recurrent neuroblastoma; however, most relapse/progression occurred in the early post-transplant period, suggesting the need for further effective treatment to prevent early relapse after haplo-SCT [17].\n\nClinical trials exploring the feasibility of donor-derived NK cell infusion (NKI) after haplo-SCT have been performed in patients with several malignancies [18–21]. Although clinical trials using NKI for recurrent neuroblastoma have been reported recently [22,23], studies on NKI after haplo-SCT in children with neuroblastoma are limited [24]. Thus, under the hypothesis that donor NKI after haplo-SCT may be helpful in preventing early relapse and improving survival, we performed a pilot study to explore the safety and feasibility of NKI following haplo-SCT in children with recurrent neuroblastoma who failed tandem HDCT/auto-SCT.\n\nMaterials and methods\nEthics statement\nThis study was approved by the Institutional Review Board of Samsung Medical Center and The Korean Food and Drug Administration and is registered at ClinicalTrials.gov with the registration number #NCT01807468. All parents gave written informed consent before enrollment. Patient records/information were anonymized and de-identified prior to analysis.\n\nPatients\nPatients with neuroblastoma who experienced relapse/progression after tandem HDCT/auto-SCT from January 2012 to December 2014 without major organ dysfunction were eligible for this study.\n\nTreatment prior to haplo-SCT\nSalvage chemotherapy was administered in order to reduce the tumor burden as much as possible prior to haplo-SCT. An ICE (ifosfamide + carboplatin + etoposide) regimen was used for first-line salvage treatment, and a TC (topotecan + cyclophosphamide) regimen was used for second-line salvage chemotherapy in patients with severe bone marrow suppression or refractory response with the first-line regimen. The duration of salvage chemotherapy prior to haplo-SCT depended on tumor response and patient tolerance. Tumors were surgically resected whenever possible. Local radiotherapy was also delivered to recurrent or metastatic sites whenever possible.\n\nDonor selection\nTyping of HLA A, B, C, DRB1, and DQB1 was performed using high-resolution PCR sequence-based typing, and KIR genotyping was performed from donor DNA samples using a PCR-based sequence-specific oligonucleotide technique. A KIR/HLA-ligand mismatch was defined by incompatibility between the inhibitory donor KIR and recipient HLA class I alleles, as previously described [25]. Donor KIR haplotypes were categorized as AA (homozygous for group A KIR haplotypes) or BX [either one (A/B heterozygotes) or two (B/B homozygotes) group B haplotypes]. The KIR B haplotype-defining loci were KIR2DL5, 2DS1, 2DS2, 2DS3, 2DS5, or 3DS1 [11]. Genotypes were also assigned for the centromeric and telomeric regions of the KIR locus. A haploidentical parent donor with KIR/HLA-ligand mismatch and/or KIR BX haplotype was preferred.\n\nNK cell generation and stem cell collection\nFor NK cell production, haploidentical parent donors underwent lymphapheresis on day -28, and CD3+ cell–depleted peripheral blood mononuclear cells (PBMCs) were frozen at -196°C. Peripheral blood mononuclear cells were thawed (days -12, -5, and 2) 14 days before each of the three planned infusions (days 2, 9, and 16) to allow each preparation and infusion of fresh cells. The thawed PBMCs expanded as described previously under good manufacturing practice conditions [26]. Briefly, CD3+ cell–depleted PBMCs were expanded at a seeding concentration of 2 × 105 cells/mL in CellGro SCGM serum-free medium (CellGenix, Germany) with 1% autologous plasma, 1 × 106 cells/mL irradiated (2,000 rad) autologous PBMCs, 10 ng/mL anti-CD3 monoclonal antibody (Orthoclon, Switzerland), and 500 IU/mL of interleukin-2 (IL-2; Proleukin, Switzerland) in an A-350N culture bag (NIPRO, Japan). NK cells were fed fresh medium with 500 IU/mL of IL-2 every 2 days until they were harvested after 14 days. The cytotoxicity of ex-vivo expanded donor NK cells was measured using K562, SK-N-SH, and NB-1691 cells by calcein releasing assay. For peripheral blood stem cell (PBSC) collection, haploidentical parent donors received 5–10 μg/kg of G-CSF subcutaneously once daily for four days; PBSCs were collected and transplanted without manipulation on day 0.\n\nConditioning\nAt 21 days prior to transplant, all children received a single 1-hour intravenous infusion of 131I-MIBG (18 mCi/kg) with potassium iodide for thyroid protection and intravenous hydration. A cyclophosphamide (cyclophosphamide 60 mg/kg on days -7 and -6) + fludarabine (30 mg/m2 on days -5 to -1) + rabbit anti-thymocyte globulin (Thymoglobulin, Genzyme; 2.5 mg/kg on days -4 to -1) regimen was used for conditioning.\n\nNKI\nPatients received 3 × 107/kg of ex-vivo expanded donor NK cells on days 2, 9, and 16 post-transplant. Donor NK cells were infused over 1 hour through a central venous catheter after pheniramine pre-treatment. Patients received IL-2 (1 × 106 IU/m2/day) subcutaneously to activate infused donor NK cells on days 2, 4, 6, 9, 11, 13, 16, 18, and 20. On the day of NKI, IL-2 was administered after a 4-hour observation period post-NKI.\n\nGVHD prophylaxis and treatment\nCyclosporine (CSA) and short-course methotrexate were used to prevent GVHD. CSA was administered from day -1 at a dose adjusted to maintain blood concentration in the range of 150–300 ng/mL. Methotrexate was administered at a dose of 15 mg/m2 on day 1 and at 10 mg/m2 on days 3 and 6, followed by folic acid rescue. The timing and speed of CSA tapering were determined by GVHD and tumor status of each patient. If the patient did not achieve complete response (CR), early tapering of CSA was considered to enhance GVT. If acute GVHD developed during CSA prophylaxis or tapering, the CSA dose was increased. If ≥ grade II acute GVHD continued despite an increase in CSA dose, methylprednisolone (1–2 mg/kg/day) was added with subsequent tapering in responsive cases. In refractory GVHD, mycophenolate mofetil was added to reduce use of steroid. Acute and chronic GVHD were assigned grades and stages based on previously described standard clinical criteria [27].\n\nInfection surveillance and prophylaxis\nAntifungal prophylaxis was administered until hospital discharge or during steroid treatment. Acyclovir was used to prevent viral reactivation by day 30, and trimethoprim-sulfamethoxazole was used from engraftment to day 180 or until immunosuppressant discontinuation. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and BK virus (BKV) surveillance were performed weekly during the first three months post-transplant and then monthly thereafter if no viral reactivation occurred. If CMV or EBV load was increasing, ganciclovir or rituximab was started as preemptive therapy, respectively.\n\nChimerism study and immune monitoring\nDonor/recipient chimerism was evaluated at 30, 60, 90, and 180 days post-transplant in peripheral blood. Immunologic recovery was assessed by immunophenotyping of PBMCs (CD3+, CD19+, and CD16+CD56+CD3– cells) from recipients at 16, 30, 60, 90, 180, and 270 days post-transplant. In three patients (patient #4, #5, and #7), granulocyte-derived myeloid-derived suppressor cells (MDSCs) by lymphogating of Lin–CD14–HLA-DR–CD11b+CD33+CD15+ cells were analyzed to identify the association between the levels of these immune cells and relapse/progression [28].\n\nToxicity and response assessment\nNKI-related immediate adverse reactions were defined as adverse reactions that developed from initiation of NKI to 4 hours after completion of NKI. Toxicity was recorded according to the common toxicity criteria (version 4.0) outlined by the US National Cancer Institute. Tumor response evaluation was performed prior to HD-MIBG treatment and every three months for the first year post-transplant. International response criteria for neuroblastoma were used to evaluate treatment response [29].\n\nStatistical analysis\nTo serve as a reference cohort, we identified seven patients who experienced recurrent/progressive neuroblastoma between March 2012 and October 2014 from our previously reported cohort who underwent HD-MIBG treatment and haplo-SCT without NKI in our hospital [17]. Briefly, the reference cohort received ICE or TC regimens (± local radiotherapy) to reduce the tumor burden prior to haplo-SCT. Further 131I-MIBG (18 mCi/kg) was administered prior to reduced-intensity conditioning (cyclophosphamide + fludarabine + rabbit anti-thymocyte globulin) without NKI. Six of the 7 patients in the reference cohort experienced acute GVHD (grade I in five and grade III in one), and four patients experienced chronic GVHD (two mild and two severe). The differences in immune reconstitution after haplo-SCT were analyzed between the cohort in this study and the reference cohort using repeated measures ANOVA and Mann–Whitney test. Relapse/progression-free survival was calculated using Kaplan–Meier method and comparisons between survival curves were performed using the log-rank test. The results with a P value of < 0.05 were considered significant.\n\nResults\nPatients\nSeven patients with recurrent neuroblastoma underwent a total of 19 NKIs after haplo-SCT; six patients completed 3 scheduled NKIs, and one patient (patient #6) received only the first NKI on day 2 due to failure of NK cell production thereafter. Patient characteristics prior to haplo-SCT are listed in Table 1. Patients received 4–7 cycles of salvage chemotherapy prior to haplo-SCT. Two patients underwent surgery, and four patients received local radiotherapy. Tumor status at haplo-SCT was CR in one patient, very good partial response in two, and partial response in four.\n\n10.1371/journal.pone.0225998.t001Table 1 Patient characteristics.\nPatient #\tAge (y) at Dx.\tStage at Dx\tMYCN status\tHDCT1 regimen\tHDCT2 regimen\tInterval (m) to relapsea\tAge (y) at relapse\tRelapsed sites\tTreatment prior to haplo-SCT\tTumor status at haplo-SCT\t\n1\t3.3\t4\tNA\tCEC\tMIBG-TM\t16\t5.6\tLNs\tCT×4, L-RT\tPR\t\n2\t3.5\t4\tA\tCEC\tMIBG-TM\t32\t7.2\tBone, BM\tCT×6\tVGPR\t\n3\t1.5\t4\tA\tTTC\tMEC\t75\t8.6\tBone, BM, brain\tCT×5\tPR\t\n4\t2.4\t4\tNA\tCEC\tMIBG-TM\t12\t4.4\tPrimary, LNs\tSurgery, CT×6, L-RT\tCR\t\n5\t3.1\t4\tNA\tCEC\tMIBG-TM\t12\t5.2\tBrain, bone\tSurgery, CT×7, L-RT\tVGPR\t\n6\t3.3\t4\tA\tCEC\tMIBG-TM\t45\t5.9\tBone, BM, brain\tCT×6\tPR\t\n7\t1.5\t4\tNA\tCEC\tMIBG-TM\t19\t4.1\tLNs\tCT×5, L-RT\tPR\t\nDx, diagnosis; NA, not amplified; A, amplified; HDCT1, first high-dose chemotherapy; HDCT2, second HDCT; RIST, reduced intensity stem cell transplantation; CEC, carboplatin + etoposide + cyclophosphamide; MIBG-TM, high-dose 131I-metaiodobenzylguanidine treatment + thiotepa + melphalan; MEC, melphalan + carboplatin + etoposide; LN, lymph node; BM, bone marrow; LMS, leptomeningeal seeding; CT, chemotherapy; L-RT, local radiotherapy; PR, partial response; MR, mixed response; VGPR, very good PR.\n\naInterval between HDCT2 and relapse/progression.\n\nGraft composition\nGraft information is shown in Table 2. Six haploidentical donors had at least one KIR/HLA-ligand mismatch, and five donors had BX haplotype. A median of 22.7 × 108 (range, 16.8–35.3) total nucleated cells/kg including medians of 13.1 (range, 6.5–30.1) × 106 CD34+ cells/kg and 5.6 (range, 2.1–6.5) × 108 CD3+ cells/kg were transplanted.\n\n10.1371/journal.pone.0225998.t002Table 2 Graft information, engraftment, and chimerism.\nPatient #\tDonor relation\tHLA match\tKIR/HLA-ligand mismatch\tDonor KIR haplotype (Cen/Tel)\tNo. of cells transplanted\tEngraftment (day)\tDonor chimerism (%)\t\nTNC (108/kg)\tCD34+ (106/kg)\tCD3+ (108/kg)\tANC 500/μL\tPLT 20,000/μL\tDay 30\tDay 60\tDay 90\t\n1\tMother\t9/10\tNone\tA/A, A/A\t35.3\t11.0\t5.6\t12\t18\t100\t100\t100\t\n2\tMother\t5/10\t2DL1a, 3DL2a\tA/A, A/B\t17.1\t9.2\t4.8\t13\t27\t100\t100\t100\t\n3\tFather\t5/10\t2DL1\tA/A, A/A\t16.8\t13.1\t2.6\t11\t16\t99.8\t99.8\t99.2\t\n4\tFather\t6/10\t2DL1, 3DL2\tA/A, A/B\t32.3\t30.1\t5.8\t11\t19\t100\t100\t100\t\n5\tFather\t5/10\t2DL1a, 3DL1, 3DL2\tA/A, A/B\t16.8\t13.6\t2.1\t12\t20\t100\t100\t100\t\n6\tMother\t6/10\t2DL1, 3DL2a\tA/B, A/A\t28.0\t6.5\t6.5\t13\t14\t100\t100\t100\t\n7\tMother\t5/10\t2DL1a, 3DL2a\tA/B, A/A\t22.7\t15.7\t6.5\t12\t17\t100\t99.1\t100\t\nHLA, human leukocyte antigen; KIR, killer cell immunoglobulin-like receptor; Cen, centromere; Tel, telomere; TNC, total nucleated cells; ANC, absolute neutrophil count; PLT, platelet count.\n\naUnlicensed KIR/HLA-ligand mismatch between donor and recipient.\n\nCharacterization of ex vivo-expanded NK cells\nNK cells were composed of enriched CD16+CD56+ cells (97.18 ± 1.33%) with minimal contamination of CD3+ cells (0.35 ± 0.25%), CD14+ cells (0.45 ± 0.49%), and CD19+ cells (0.10 ± 0.40%; Fig 1A). In a cytotoxicity assay, NK cells showed potent cytolytic activity against K562 cells, SK-N-SH cells, and NB-1691 cells (Fig 1B).\n\n10.1371/journal.pone.0225998.g001Fig 1 Characterization of ex vivo-expanded NK cells.\n(A) The percentages of CD16+CD56+, CD3+, CD14+, and CD19+ cells were analyzed by flow cytometric analyses. (B) Cytotoxicity of expanded NK cells against the K562, SK-N-SH, and NB-1691 cell line was analyzed by calcein releasing assay with the indicated E:T ratio. Each point represents mean ± SD.\n\nNKI-related immediate adverse reactions\nNKI-related immediate adverse reactions observed during or after NKI are summarized in Table 3. Out of 19 NKIs in seven patients, fever (n = 4) was most the common adverse reaction, followed by chills (n = 3) and hypertension (n = 3); however, these adverse reactions were manageable and transient. One patient (patient #3) experienced grade 3 hypertension after NKI, which disappeared after anti-hypertensive treatment. The only adverse reaction related to IL-2 treatment was fever, which occurred in all patients.\n\n10.1371/journal.pone.0225998.t003Table 3 NKI-related immediate toxicity profiles in 19 NKIs.\nToxicities\tGrade 1–2\tGrade 3–4\tTotal\t\nFever\t4 (21.1%)\t0\t4 (21.1%)\t\nChills\t3 (15.8%)\t0\t3 (15.8%)\t\nHypertension\t2 (10.5%)\t1 (5.3%)\t3 (15.8%)\t\nNKI, natural killer cell infusion.\n\nRegimen-related short-term toxicities\nThere were no short-term toxicities related to HD-MIBG treatment. After reduced-intensity conditioning, neutropenic fever (n = 7), hypokalemia (n = 6), elevated liver enzymes without veno-occlusive disease (n = 3), and diarrhea (n = 1) were common conditioning regimen-related grade ≥ 3 toxicities. However, these toxicities were manageable, and there was no regimen-related death.\n\nHematologic recovery and chimerism\nThe median times required to reach an absolute neutrophil count of 500/μL and a platelet count of 20,000/μL without transfusion for 7 days were 12 (range, 11–13) days and 18 (range, 14–27) days, respectively (Table 2). Complete donor chimerism (> 99%) was achieved at day 30 in all patients and was maintained thereafter.\n\nGVHD\nAcute GVHD developed in all patients (grade I in five and grade II in two), and chronic GVHD developed in five patients (mild in two, moderate in two, and severe in one; Table 4). CSA was tapered before 2 months post-transplant in four patients who showed PR or VGPR to enhance GVT effects, of which two patients (patients #3 and #5) showed no chronic GVHD and the remaining two patients (patients #6 and #7) showed mild and moderate chronic GVHD, respectively.\n\n10.1371/journal.pone.0225998.t004Table 4 GVHD and final outcome.\nPatient #\tAcute GVHD\tOnset of acute GVHD (d)\tOnset of CSA tapering (d)\tChronic GVHDa\tOnset of chronic GVHD (d)\tFirst time of discontinuation of CSA (m)\tTumor status at haplo-SCT\tTumor status at day 90\tFinal outcome (Follow-up from transplant)\t\nSkin\tGut\tLiver\tOverall\t\n1\t1\t0\t0\tI\t22\t194\tSevere\t56\t–\tPR\tPR\tDOD at 16 m, PD at 9 m\t\n2\t2\t0\t0\tI\t13\t100\tMild\t138\t–\tVGPR\tCR\tDOD at 23 m, relapse at 9 m\t\n3\t2\t0\t0\tI\t6\t51\tNone\t–\t22\tPR\tCR\tDOD at 29 m, relapse at 9 m\t\n4\t3\t1\t0\tII\t11\t131\tModerate\t103\t15\tCR\tCR\tDOD at 16 m, relapse at 6 m\t\n5\t2\t0\t0\tI\t5\t47\tNone\t–\t15\tVGPR\tVGPR\tAlive at 45 m in CR, PD at 6 m\t\n6\t2\t0\t0\tI\t1\t54\tMild\t42\t7\tPR\tPD\tDOD at 8 m in PD, PD at 2 m\t\n7\t3\t0\t0\tII\t3\t33\tModerate\t180\t4\tPR\tPR\tTRM in PR at 10 m\t\nGVHD, graft-versus-host disease; CSA, cyclosporine; haplo-SCT, haploidentical stem cell transplantation; PR, partial response; DOD, died of disease; VGPR, very good PR; CR, complete response; PD, progressive disease; TRM, treatment-related mortality.\n\naChronic GVHD was graded according to the National Institutes of Health consensus criteria.\n\nInfectious complications\nBloodstream bacterial infection developed in two patients. No patient developed invasive fungal infection. All seven patients experienced CMV reactivation and received preemptive ganciclovir treatment, and no patient experienced CMV disease. EBV reactivation was observed in six patients, four of whom received preemptive treatment with rituximab. One patient (patient #5) developed post-transplant lymphoproliferative disease, which improved after rituximab treatment. BKV reactivation was observed in all seven patients, and two patients (patient #2 and #6) experienced BKV-associated hemorrhagic cystitis. A patient (patient #7) with moderate chronic GVHD died from Pneumocystis jirovecii pneumonia at 10 months post-transplant without tumor progression.\n\nImmune monitoring\nImmune reconstitution was evaluated in six patients who completed three scheduled NKIs. CD16+CD56+CD3– cells were the predominant lymphocyte population until day 30, CD3+ cells were predominant at day 60, and CD19+ cells began to increase after day 180 (Fig 2A). When this study’s cohort was compared with the reference cohort, the reconstitution of CD3+ cells and CD19+ cells was found to be similar (not shown). However, the number of CD16+CD56+CD3– cells was higher until day 60 in the study cohort (Fig 2B). The number of granulocyte-derived MDSCs decreased after NKI (Fig 3). In two patients (patient #4 and #5), the number of granulocyte-derived MDSCs increased from day 90, and tumor relapse/progression had occurred at the six-month tumor evaluation. On the other hand, the number of granulocyte-derived MDSCs did not increase in patient #7, who remained progression-free.\n\n10.1371/journal.pone.0225998.g002Fig 2 Immune reconstitution after NKI following haplo-SCT.\n(A) Immune reconstitution after NKI following haplo-SCT in six patients who completed three scheduled NKIs. Median values for cell numbers are presented. (B) The number of NK cells was higher until day 60 in the study cohort compared to the reference cohort, who underwent haplo-SCT without NKI.\n\n10.1371/journal.pone.0225998.g003Fig 3 Changes in granulocyte-derived MDSCs after NKI following haplo-SCT.\nThe number of granulocyte-derived MDSCs decreased after NKI. In two patients (patient #3 and #4), the number of granulocyte-derived MDSCs increased from day 90 and tumor relapse/progression had occurred at the six-month tumor evaluation. On the other hand, the number of granulocyte-derived MDSCs did not increase in patient #7, who remained progression-free.\n\nResponse and survival\nAt the three-month tumor evaluation, two patients achieved CR, four patients maintained the same status as at haplo-SCT, and one patient experienced progression (Table 4). During follow-up after NKI following haplo-SCT, a total of six patients experienced relapse/progression at a median of 7.5 (range, 2–9) months post-transplant. Five of them died at a median of 16 (range, 8–29) months post-transplant, and the remaining one remained alive in CR at 45 months post-transplant after salvage treatment including surgery, radiotherapy, and TC chemotherapy. Treatment-related mortality occurred in one patient (patient 7) without tumor progression, as mentioned above. The median time to relapse/progression in the current cohort was 7.5 months post-transplant, which was relatively longer than that in the reference cohort; however there was no statistical difference between the cohorts (P = 0.323; Fig 4).\n\n10.1371/journal.pone.0225998.g004Fig 4 Kaplan-Meier curves in the patients with relapse/progression.\nThe median time to relapse/progression in the current cohort was 7.5 months post-transplant, and that in the reference cohort who underwent haplo-SCT without NKI was 2.5 months post-transplant.\n\nDiscussion\nOur previous study suggested that incorporation of HD-MIBG treatment into KIR/HLA-ligand mismatched haplo-SCT might improve outcomes in children with recurrent neuroblastoma [17]. However, in that study, tumor relapse/progression occurred in the early post-transplant period at a median of 2.5 (range, 2–9) months post-transplant. In the current study, under the hypothesis that NKI during the early post-transplant period might prevent early relapse in patients with recurrent neuroblastoma, we evaluated the safety and feasibility of early NKI after haplo-SCT. Our results showed that NKI-related immediate adverse reactions were tolerable, and the incidence of GVHD and infectious complications was similar to those in our previous study [17].\n\nAcute toxicities during NKI were uncommon in previous studies [30–33]. Lee et al. reported that most NKI-related acute toxicities were mild except one patient who experienced a grade 2 allergic reaction [34]. Another study reported transient neurologic toxicities such as headache, confusion, delirium, and generalized seizure after NKI; however, those authors reported that these neurologic complications might be related to haplo-SCT toxicity [19]. In the current study, NKI-related acute toxicities were manageable and included fever, chills, and hypertension, and there were no allergic reactions or neurologic complications.\n\nThe role of NK cells in the development of GVHD is controversial. Previous studies reported that NK cells had GVT effects without aggravating or inducing GVHD [7,35]. To the contrary, Shah et al. reported that ex vivo-expanded NK cells may aggravate acute GVHD in T cell-depleted allo-SCT [36]. In the current study, acute GVHD occurred in all patients; however, it was mild to moderate and tolerable. In terms of chronic GVHD, we tapered immune suppression relatively early to enhance GVT if patients could not achieve CR, which may have resulted in the higher incidence of chronic GVHD in our cohort. It is therefore unclear whether NKI increases the incidence of chronic GVHD after haplo-SCT. Further studies are needed to evaluate the association between NKI and development of GVHD.\n\nThe number of infused NK cells is an important factor in their persistence after infusion [37]. The optimal doses or times of NKI have not yet been determined. We administered three weekly NKIs with a dose of 3 × 107/kg cells and found that the number of NK cells was higher until day 60 in the study cohort compared to the reference cohort, who underwent haplo-SCT without NKI. Also, it should be noted that the persistence of NK cells was far enhanced as compared with other clinical trials with NKI, in which allogeneic NK cells persisted for 1 to 2 weeks when administered along with immunosuppressive regimens in order to dampen the host T-cell response [33,38,39]. Thus, we suggest that our NKI protocol could maintain a high level of NK cells during the early post-transplant period.\n\nMDSCs can inhibit innate and adaptive immune responses, which may promote tumor angiogenesis, invasion, and metastasis [40]. We found that the number of MDSCs decreased after NKI, like in a previous study in which ex vivo-expanded NKI reduced MDSC number [37]. Our data showed that the number of granulocyte-derived MDSCs increased prior to definite tumor progression, consistent with previous studies in which an increased number of MDSCs was associated with tumor progression [41,42]. Overall, our observations that NKI reduced MDSC populations, and enhanced persistency of NK cells suggest that NKI following haplo-SCT could be an effective therapy against cancer.\n\nThere are several limitations in this study. First, the number of patients was small. Second, the timing and speed in the tapering of immune suppression were different among patients according to GVHD and tumor status, making the association between NKI and GVHD unclear. Third, although the time to relapse/progression was relatively longer in the study cohort compared to the reference cohort, there was no difference in long-term outcomes between the two cohorts. Therefore, further efforts will be needed to improve long-term outcomes without increasing GVHD, such as the use of anti-GD2 antibody with NKI [43], TCRα/β-depleted [44], CD45RA-depleted grafts [45], or chimeric antigen receptor-modified NK cells [46]. Fourth, failure of stable NK cell production remains a problem. NK cells from universal healthy donors, particularly those who have the KIR BX haplotype or mismatched KIR/HLA-ligand, might be an option in improving transplant outcomes [37].\n\nIn summary, our data are supportive of the safety of NKI following haplo-SCT for treating patients with recurrent neuroblastoma. However, the number of patients in our study was too small to draw any definitive conclusions. Therefore, further studies are needed with a larger cohort and new treatment modalities that can improve GVT effects without increasing GVHD to improve outcomes.\n\nSupporting information\nS1 File Clinical trial protocol is available as supporting file.\n(DOCX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 George RE , Li S , Medeiros-Nancarrow C , Neuberg D , Marcus K , Shamberger RC , et al\nHigh-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update . 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Bone Marrow Transplant . 2007 ; 39 :809 –10 . 10.1038/sj.bmt.1705681 \n17450181 \n5 Sung KW , Park JE , Chueh HW , Lee SH , Yoo KH , Koo HH , et al\nReduced-intensity allogeneic stem cell transplantation for children with neuroblastoma who failed tandem autologous stem cell transplantation . Pediatr Blood Cancer . 2011 ; 57 :660 –5 . 10.1002/pbc.23035 \n21681924 \n6 Toporski J , Garkavij M , Tennvall J , Ora I , Gleisner KS , Dykes JH , et al\nHigh-dose iodine-131-metaiodobenzylguanidine with haploidentical stem cell transplantation and posttransplant immunotherapy in children with relapsed/refractory neuroblastoma . Biol Blood Marrow Transplant . 2009 ; 15 :1077 –85 . 10.1016/j.bbmt.2009.05.007 \n19660720 \n7 Ruggeri L , Capanni M , Urbani E , Perruccio K , Shlomchik WD , Tosti A , et al\nEffectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants . Science . 2002 ; 295 :2097 –100 . 10.1126/science.1068440 \n11896281 \n8 Kiessling R , Klein E , Pross H , Wigzell H . \"Natural\" killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell . Eur J Immunol . 1975 ; 5 :117 –21 . 10.1002/eji.1830050209 \n1086218 \n9 Miller JS . The biology of natural killer cells in cancer, infection, and pregnancy . Exp Hematol . 2001 ; 29 :1157 –68 . 10.1016/s0301-472x(01)00696-8 \n11602317 \n10 Caligiuri MA . Human natural killer cells . Blood . 2008 ; 112 :461 –9 . 10.1182/blood-2007-09-077438 \n18650461 \n11 Cooley S , Trachtenberg E , Bergemann TL , Saeteurn K , Klein J , Le CT , et al\nDonors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia . Blood . 2009 ; 113 :726 –32 . 10.1182/blood-2008-07-171926 \n18945962 \n12 Symons HJ , Leffell MS , Rossiter ND , Zahurak M , Jones RJ , Fuchs EJ . Improved survival with inhibitory killer immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative, HLA-haploidentical bone marrow transplantation . Biol Blood Marrow Transplant . 2010 ; 16 :533 –42 . 10.1016/j.bbmt.2009.11.022 \n19961944 \n13 Leung W , Iyengar R , Turner V , Lang P , Bader P , Conn P , et al\nDeterminants of antileukemia effects of allogeneic NK cells . J Immunol . 2004 ; 172 :644 –50 . 10.4049/jimmunol.172.1.644 \n14688377 \n14 Perez-Martinez A , Leung W , Munoz E , Iyengar R , Ramirez M , Vicario JL , et al\nKIR-HLA receptor-ligand mismatch associated with a graft-versus-tumor effect in haploidentical stem cell transplantation for pediatric metastatic solid tumors . Pediatr Blood Cancer . 2009 ; 53 :120 –4 . 10.1002/pbc.21955 \n19215002 \n15 Park S , Kim K , Jang JH , Kim SJ , Kim WS , Kang ES , et al\nKIR alloreactivity based on the receptor-ligand model is associated with improved clinical outcomes of allogeneic hematopoietic stem cell transplantation: Result of single center prospective study . Hum Immunol . 2015 ; 76 :636 –43 . 10.1016/j.humimm.2015.09.009 \n26407827 \n16 Wolfl M , Jungbluth AA , Garrido F , Cabrera T , Meyen-Southard S , Spitz R , et al\nExpression of MHC class I, MHC class II, and cancer germline antigens in neuroblastoma . Cancer Immunol Immunother . 2005 ; 54 :400 –6 . 10.1007/s00262-004-0603-z \n15449039 \n17 Lee JW , Kang ES , Sung KW , Yi E , Lee SH , Yoo KH , et al\nIncorporation of high-dose (131) I-metaiodobenzylguanidine treatment into killer immunoglobulin-like receptor/HLA-ligand mismatched haploidentical stem cell transplantation for children with neuroblastoma who failed tandem autologous stem cell transplantation . Pediatr Blood Cancer . 2017 ; 64 10.1002/pbc.26399 \n28012219 \n18 Choi I , Yoon SR , Park SY , Kim H , Jung SJ , Jang YJ , et al\nDonor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study . Biol Blood Marrow Transplant . 2014 ; 20 :696 –704 . 10.1016/j.bbmt.2014.01.031 \n24525278 \n19 Choi I , Yoon SR , Park SY , Kim H , Jung SJ , Kang YL , et al\nDonor-Derived Natural Killer Cell Infusion after Human Leukocyte Antigen-Haploidentical Hematopoietic Cell Transplantation in Patients with Refractory Acute Leukemia . Biol Blood Marrow Transplant . 2016 ; 22 :2065 –76 . 10.1016/j.bbmt.2016.08.008 \n27530969 \n20 Shaffer BC , Le Luduec JB , Forlenza C , Jakubowski AA , Perales MA , Young JW , et al\nPhase II Study of Haploidentical Natural Killer Cell Infusion for Treatment of Relapsed or Persistent Myeloid Malignancies Following Allogeneic Hematopoietic Cell Transplantation . Biol Blood Marrow Transplant . 2016 ; 22 :705 –9 . 10.1016/j.bbmt.2015.12.028 \n26772158 \n21 Perez-Martinez A , Fernandez L , Valentin J , Martinez-Romera I , Corral MD , Ramirez M , et al\nA phase I/II trial of interleukin-15—stimulated natural killer cell infusion after haplo-identical stem cell transplantation for pediatric refractory solid tumors . Cytotherapy . 2015 ; 17 :1594 –603 . 10.1016/j.jcyt.2015.07.011 \n26341478 \n22 Federico SM , McCarville MB , Shulkin BL , Sondel PM , Hank JA , Hutson P , et al\nA Pilot Trial of Humanized Anti-GD2 Monoclonal Antibody (hu14.18K322A) with Chemotherapy and Natural Killer Cells in Children with Recurrent/Refractory Neuroblastoma . Clin Cancer Res . 2017 ; 23 :6441 –9 . 10.1158/1078-0432.CCR-17-0379 \n28939747 \n23 Modak S , Le Luduec JB , Cheung IY . Adoptive immunotherapy with haploidentical natural killer cells and Anti-GD2 monoclonal antibody m3F8 for resistant neuroblastoma: Results of a phase I study . 2018 ; 7 :e1461305 \n10.1080/2162402X.2018.1461305 \n30221057 \n24 Kanold J , Paillard C , Tchirkov A , Lang P , Kelly A , Halle P , et al\nNK cell immunotherapy for high-risk neuroblastoma relapse after haploidentical HSCT . Pediatr Blood Cancer . 2012 ; 59 :739 –42 . 10.1002/pbc.24030 \n22180305 \n25 Ruggeri L , Capanni M , Casucci M , Volpi I , Tosti A , Perruccio K , et al\nRole of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation . Blood . 1999 ; 94 :333 –9 . 10381530 \n26 Lim O , Lee Y , Chung H , Her JH , Kang SM , Jung MY , et al\nGMP-compliant, large-scale expanded allogeneic natural killer cells have potent cytolytic activity against cancer cells in vitro and in vivo . PLoS One . 2013 ; 8 :e53611 \n10.1371/journal.pone.0053611 \n23326467 \n27 Filipovich AH , Weisdorf D , Pavletic S , Socie G , Wingard JR , Lee SJ , et al\nNational 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 . 2005 ; 11 :945 –56 . 10.1016/j.bbmt.2005.09.004 \n16338616 \n28 Zea AH , Rodriguez PC , Atkins MB , Hernandez C , Signoretti S , Zabaleta J , et al\nArginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion . Cancer Res . 2005 ; 65 :3044 –8 . 10.1158/0008-5472.CAN-04-4505 \n15833831 \n29 Matthay KK , Tan JC , Villablanca JG , Yanik GA , Veatch J , Franc B , et al\nPhase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to Neuroblastoma Therapy Consortium Study . J Clin Oncol . 2006 ; 24 :500 –6 . 10.1200/JCO.2005.03.6400 \n16421427 \n30 Passweg JR , Tichelli A , Meyer-Monard S , Heim D , Stern M , Kuhne T , et al\nPurified donor NK-lymphocyte infusion to consolidate engraftment after haploidentical stem cell transplantation . Leukemia . 2004 ; 18 :1835 –8 . 10.1038/sj.leu.2403524 \n15457184 \n31 Rizzieri DA , Storms R , Chen DF , Long G , Yang Y , Nikcevich DA , et al\nNatural killer cell-enriched donor lymphocyte infusions from A 3-6/6 HLA matched family member following nonmyeloablative allogeneic stem cell transplantation . Biol Blood Marrow Transplant . 2010 ; 16 :1107 –14 . 10.1016/j.bbmt.2010.02.018 \n20188202 \n32 Yoon SR , Lee YS , Yang SH , Ahn KH , Lee JH , Lee JH , et al\nGeneration of donor natural killer cells from CD34(+) progenitor cells and subsequent infusion after HLA-mismatched allogeneic hematopoietic cell transplantation: a feasibility study . Bone Marrow Transplant . 2010 ; 45 :1038 –46 . 10.1038/bmt.2009.304 \n19881555 \n33 Iliopoulou EG , Kountourakis P , Karamouzis MV , Doufexis D , Ardavanis A , Baxevanis CN , et al\nA phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer . Cancer Immunol Immunother . 2010 ; 59 :1781 –9 . 10.1007/s00262-010-0904-3 \n20703455 \n34 Lee DA , Denman CJ , Rondon G , Woodworth G , Chen J , Fisher T , et al\nHaploidentical Natural Killer Cells Infused before Allogeneic Stem Cell Transplantation for Myeloid Malignancies: A Phase I Trial . Biol Blood Marrow Transplant . 2016 ; 22 :1290 –8 . 10.1016/j.bbmt.2016.04.009 \n27090958 \n35 Locatelli F , Pende D , Mingari MC , Bertaina A , Falco M , Moretta A , et al\nCellular and molecular basis of haploidentical hematopoietic stem cell transplantation in the successful treatment of high-risk leukemias: role of alloreactive NK cells . Front Immunol . 2013 ; 4 :15 \n10.3389/fimmu.2013.00015 \n23378843 \n36 Shah NN , Baird K , Delbrook CP , Fleisher TA , Kohler ME , Rampertaap S , et al\nAcute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation . Blood . 2015 ; 125 :784 –92 . 10.1182/blood-2014-07-592881 \n25452614 \n37 Gabrilovich DI , Nagaraj S . Myeloid-derived suppressor cells as regulators of the immune system . Nat Rev Immunol . 2009 ; 9 :162 –74 . 10.1038/nri2506 \n19197294 \n38 Yang Y , Lim O , Kim TM , Ahn YO , Choi H , Chung H , et al\nPhase I Study of Random Healthy Donor-Derived Allogeneic Natural Killer Cell Therapy in Patients with Malignant Lymphoma or Advanced Solid Tumors . Cancer Immunol Res . 2016 ; 4 :215 –24 . 10.1158/2326-6066.CIR-15-0118 \n26787822 \n39 Zhang B , Wang Z , Wu L , Zhang M , Li W , Ding J , et al\nCirculating and tumor-infiltrating myeloid-derived suppressor cells in patients with colorectal carcinoma . PLoS One . 2013 ; 8 :e57114 \n10.1371/journal.pone.0057114 \n23437326 \n40 Diaz-Montero CM , Salem ML , Nishimura MI , Garrett-Mayer E , Cole DJ , Montero AJ . Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy . Cancer Immunol Immunother . 2009 ; 58 :49 –59 . 10.1007/s00262-008-0523-4 \n18446337 \n41 Curti A , Ruggeri L , D'Addio A , Bontadini A , Dan E , Motta MR , et al\nSuccessful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients . Blood . 2011 ; 118 :3273 –9 . 10.1182/blood-2011-01-329508 \n21791425 \n42 Ruggeri L , Mancusi A , Capanni M , Urbani E , Carotti A , Aloisi T , et al\nDonor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value . Blood . 2007 ; 110 :433 –40 . 10.1182/blood-2006-07-038687 \n17371948 \n43 Yu AL , Gilman AL , Ozkaynak MF , London WB , Kreissman SG , Chen HX , et al\nAnti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma . N Engl J Med . 2010 ; 363 :1324 –34 . 10.1056/NEJMoa0911123 \n20879881 \n44 Lang P , Feuchtinger T , Teltschik HM , Schwinger W , Schlegel P , Pfeiffer M , et al\nImproved immune recovery after transplantation of TCRalphabeta/CD19-depleted allografts from haploidentical donors in pediatric patients . Bone Marrow Transplant . 2015 ; 50 Suppl 2 :S6 –10 . 10.1038/bmt.2015.87 \n26039210 \n45 Triplett BM , Shook DR , Eldridge P . Rapid memory T-cell reconstitution recapitulating CD45RA-depleted haploidentical transplant graft content in patients with hematologic malignancies . 2015 ; 50 :968 –77 . 10.1038/bmt.2014.324 \n25665048 \n46 Liu D , Tian S , Zhang K , Xiong W , Lubaki NM , Chen Z , et al\nChimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV . Protein Cell . 2017 ; 8 :861 –77 . 10.1007/s13238-017-0415-5 \n28488245\n\n",
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"mesh_terms": "D015415:Biomarkers; D002452:Cell Count; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000074243:Immune Reconstitution; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D007223:Infant; D007694:Killer Cells, Natural; D008297:Male; D009367:Neoplasm Staging; D009447:Neuroblastoma; D018183:Transplantation Chimera; D000075442:Transplantation, Haploidentical; D016896:Treatment Outcome",
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"title": "Safety and immune cell kinetics after donor natural killer cell infusion following haploidentical stem cell transplantation in children with recurrent neuroblastoma.",
"title_normalized": "safety and immune cell kinetics after donor natural killer cell infusion following haploidentical stem cell transplantation in children with recurrent neuroblastoma"
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"abstract": "The purpose of this study was to determinate disease-free interval (DFI) and overall survival (OS) in HER2-positive breast cancer patients who received adjuvant trastuzumab at the University Clinic of Nis, Serbia, and to investigate the influence of clinicopathological and biological characteristics of the tumor on prognosis. The second aim was to determinate the most frequent cause for the treatment discontinuation, recurrence rate, as well as the site of most common localization of the first recurrence of disease.\n\n\n\nThis research was conducted as a retrospective study at the University Oncology Clinic, Clinical Centre in Nis. The study included 238 patients who were operated and treated for HER2-positive breast cancer between January 1st, 2007 to September 30th, 2012 and followed up until December 31st, 2016. Trastuzumab was administered concurrently with taxanes, if administered, or after the completed anthracycline-based chemotherapy.\n\n\n\nAfter a median follow up of 69 months the 5-year DFI was 65.9% and 5-year OS was 81.8% and, as expected, significantly longer in the group of patients with smaller tumors, a smaller number of positive axillary lymph nodes, as well as a lower stage of disease (p<0.0001). Patients older than 65 years had a longer DFI compared to the 45-65 and under 45 age groups of patients (p=0.01). No statistical significance was found in the length of DFI in relation to the histological tumor subtype, tumor grade, or the status of hormone receptors. Unlike DFI, a longer OS was recorded in the group of patients with lower tumor grade (p=0.03) and there was no statistically significant difference in survival regarding the age of patients (p=0.07). Recurrence occurred in approximately one third of the patients (38.23%), mostly in the form of local recurrence. Adjuvant therapy with trastuzumab was not completely carried out in 18.49% of the patients, the most common reason being the progression of disease.\n\n\n\nA long median follow up period of 69 months indicated that anti-HER2 monoclonal antibody trastuzumab, after anthracycline-based chemotherapy or concurrently with taxanes, is efficient and safe in treating early breast cancer.",
"affiliations": "Medical Faculty, University of Nis, Nis, Serbia.",
"authors": "Cvetanovic|Ana|A|;Filipovic|Sladjana|S|;Zivkovic|Nikola|N|;Popovic|Lazar|L|;Kostic|Milos|M|;Djordjevic|Miodrag|M|;Karanikolic|Aleksandar|A|;Krtinic|Dane|D|",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D018719:Receptor, ErbB-2; D012189:Retrospective Studies; D055771:Serbia; D043823:Taxoids; D000068878:Trastuzumab",
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"title": "Ten years of using adjuvant trastuzumab in breast cancer in Serbia - Single institution experience.",
"title_normalized": "ten years of using adjuvant trastuzumab in breast cancer in serbia single institution experience"
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"abstract": "Gingival enlargement sometimes has an adverse effect of certain systemic drugs such as the use of anticonvulsants, phenytoin, antihypertensive, calcium channel blockers and immunosuppressant, cyclosporine. Amlodipine, a relatively newer calcium channel blocker drugs, exhibit adverse effect of gingival enlargement in middle to older aged adults. There are very few reports of amlodipine-induced gingival enlargement at a lower dose (5 mg). In this article, three cases of amlodipine-induced gingival enlargement in the age range of 50-65 years old hypertensive patient with a lower dose of amlodipine (5 mg).",
"affiliations": "Department of Periodontology, Career Postgraduate Institute of Dental Sciences and Hospital, Lucknow, Uttar Pradesh, India.;Department of Periodontology, Dr. R. Ahmed Dental College, Kolkata, West Bengal, India.;Department of Periodontology, Career Postgraduate Institute of Dental Sciences and Hospital, Lucknow, Uttar Pradesh, India.;Department of Periodontology, Career Postgraduate Institute of Dental Sciences and Hospital, Lucknow, Uttar Pradesh, India.",
"authors": "Tripathi|Amitandra Kumar|AK|;Mukherjee|Sudarshana|S|;Saimbi|Charanjit Singh|CS|;Kumar|Vivek|V|",
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"fulltext": "\n==== Front\nContemp Clin DentContemp Clin DentCCDContemporary Clinical Dentistry0976-237X0976-2361Medknow Publications & Media Pvt Ltd India CCD-6-10710.4103/0976-237X.149303Case ReportLow dose amlodipine-induced gingival enlargement: A clinical case series Tripathi Amitandra Kumar Mukherjee Sudarshana 1Saimbi Charanjit Singh Kumar Vivek Department of Periodontology, Career Postgraduate Institute of Dental Sciences and Hospital, Lucknow, Uttar Pradesh, India1 Department of Periodontology, Dr. R. Ahmed Dental College, Kolkata, West Bengal, IndiaCorrespondence: Dr. Amitandra Kumar Tripathi, Departments of Periodontology, 16/29, New Sohbatia Bagh, Allahabad - 661 003, Uttar Pradesh, India. E-mail: amitandrakgmu@gmail.comJan-Mar 2015 6 1 107 109 Copyright: © Contemporary Clinical Dentistry2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Gingival enlargement sometimes has an adverse effect of certain systemic drugs such as the use of anticonvulsants, phenytoin, antihypertensive, calcium channel blockers and immunosuppressant, cyclosporine. Amlodipine, a relatively newer calcium channel blocker drugs, exhibit adverse effect of gingival enlargement in middle to older aged adults. There are very few reports of amlodipine-induced gingival enlargement at a lower dose (5 mg). In this article, three cases of amlodipine-induced gingival enlargement in the age range of 50-65 years old hypertensive patient with a lower dose of amlodipine (5 mg).\n\nCalcium channel blockergingival enlargementhypertension\n==== Body\nIntroduction\nGingival enlargement first reported in 1939 by Kimball due to use of antiepileptic drugs phenytoin.[1] Currently, more than 20 drugs are associated with gingival enlargement and according to their therapeutic actions these drugs are classified into three major groups namely, anticonvulsants, immunosuppressant, and calcium channel blockers.[2]\n\nAmlodipine is the derivatives of dihydropyridine and used in the management of both hypertension and angina. In comparison to other calcium channel blocker amlodipine-induced gingival enlargement is less prevalent. Jorgensen, 1997 had reported the prevalence of amlodipine-induced gingival enlargement as 3.3%.\n\nThere are very few reports of gingival enlargement with amlodipine at dose of 5 mg, even after taking it for more than 6 months.[34]\n\nPresenting here with three cases of gingival hyperplasia at a lower dose (5 mg) with long duration of time.\n\nCase Report\nAll the three case has a similar complaint of generalized swelling in the gums with bleeding. The medical histories of three cases were suffering of hypertension and on amlodipine therapy.\n\nIn first case, 50-year-old patient has a positive history of hypertension and taken antihypertensive drugs amlodipine 5 mg since last 2 years. Intra-oral examination revealed generalized enlargement of attached gingiva extending up to marginal and interdental gingiva with surface lobulations and loss of scalloping [Figures 1-3].\n\nFigure 1 Preoperative photograph of case 1\n\nFigure 2 Preoperative photograph of case 2\n\nFigure 3 Preoperative photograph of case 3\n\nThe remaining two cases also hypertensive and taken antihypertensive drugs amlodipine 5 mg since last 2-3 years. Clinical examination revealed generalized diffuse gingival overgrowth in both the arches and bleeding on probing with plaque and calculus deposits.\n\nBased on drug history and clinical evaluation, a provisional diagnosis of amlodipine-induced gingival enlargement superimposed with inflammation was established.\n\nThe treatment of three cases was performed as follows phase-I therapy was done and patients were advised to consult with a physician for the drug substitution.\n\nFollowed by oral prophylaxis and substitution of amlodipine, significant improvements in the gingival tissue were observed [Figure 4]. Gingival contours were un-esthetic, difficult to maintain and favored plaque accumulation, hence in phase-II an internal bevel gingivectomy and flap operation were performed. Excised tissues were sent for histopathological examination, which revealed the presence of parakeratinized epithelium with elongated rete pegs, connective tissue fibrosis with inflammatory cells [Figure 5]. On the basis of above findings a diagnosis of drug-associated gingival enlargement was confirmed.\n\nFigure 4 Six months follow-up after phase-I therapy and drug substitution of case 1\n\nFigure 5 Histopathological photographs showed the presence of parakeratinized epithelium with elongated rete pegs, connective tissue fibrosis with inflammatory cells\n\nPostoperative healing was satisfactory and desired crown lengthening was achieved. Esthetics was significantly improved in terms of gingival appearance after surgical excision of enlarged gingival tissue. Patient was put in the follow-up program at 1, 3, 6 months interval, followed by after 1 and 2 years. There was no recurrence of the disease even after 2 years follow-up [Figures 6-8].\n\nFigure 6 Two years postoperative photograph of case 1\n\nFigure 7 Two years postoperative photograph of case 2\n\nFigure 8 Two years postoperative photograph of case 3\n\nDiscussion\nAmlodipine-induced gingival enlargement usually begins at the interdental papilla, which occurs within 6 months of starting drug therapy at a dose of 10 mg/day. In few cases of amlodipine-induced gingival enlargement were reported at a dose of 5 mg amlodipine when used more than 6 months.\n\nMany studies showed that when amlodipine given 5 mg once daily dose more than 6 months could not induce gingival enlargement and gingival enlargement only occurred when 10 mg/day dose of amlodipine given.[5]\n\nThe present cases are unique because 5 mg/day dose of amlodipine caused gingival hyperplasia after 6 months of used.\n\nSeymour et al.[5] given the multifactorial model on the pathogenesis of drug-induced gingival overgrowth, which are involving an interaction of several factors, which expands on the interaction between drug and metabolite with the gingival fibroblasts. Predisposing factors for these changes are age, genetic predisposition, pharmacokinetic variables, drug-induced alterations in gingival connective tissue homeostasis, histopathology, ultrastructural factors and inflammatory changes, and drug-induced action on growth factors.\n\nTreatment consists of substitution of drugs if possible with patient's physician consent, in substitution of amlodipine with isradipine, lercanidipine and lacidipine, which are the newer fourth-generation dihydropyridines or other classes of antihypertensives such as beta blockers, angiotensin converting enzyme inhibitors or thiazide derivatives may be given.\n\nDiscontinuing the causative drug reduction in the size of the gingival overgrowth has been reported,[6] but to maintain the plaque control and esthetic point of view surgical correction may be deemed necessary. In cases where no underlying bone loss, external bevel gingivectomy and gingivoplasty are done and cases where presence of attachment loss and underlying osseous defects, internal bevel gingivectomy with flap operation is performed.[78] In present, all the three cases that are presented had some degree of moderate to severe alveolar bone loss and hence internal bevel gingivectomy with flap operation surgery was the treatment of choice. Postoperative after 2 years follow-up in these cases no recurrences were seen.\n\nSource of Support: Nil.\n\nConflict of Interest: None declared.\n==== Refs\n1 Kimball OP The treatment of epilepsy with sodium diphenyl hydantoinate J Am Med Assoc 1939 112 1244 5 \n2 Rees TD Levine RA Systemic drugs as a risk factor periodontal disease initiation and progression Compend Contin Educ Dent 1995 16 20 42 \n3 Jorgensen MG Prevalence of amlodipine-related gingival hyperplasia J Periodontol 1997 68 676 8 9249639 \n4 Triveni MG Rudrakshi C Mehta DS Amlodipine-induced gingival overgrowth J Indian Soc Periodontol 2009 13 160 3 20379416 \n5 Seymour RA Thomason JM Ellis JS The pathogenesis of drug-induced gingival overgrowth J Clin Periodontol 1996 23 165 75 8707974 \n6 Westbrook P Bednarczyk EM Carlson M Sheehan H Bissada NF Regression of nifedipine-induced gingival hyperplasia following switch to a same class calcium channel blocker, isradipine J Periodontol 1997 68 645 50 9249636 \n7 Seymour RA Effects of medications on the periodontal tissues in health and disease Periodontol 2000 2006 40 120 9 16398689 \n8 Camargo PM Melnick PR Pirih FQ Lagos R Takei HH Treatment of drug-induced gingival enlargement: Aesthetic and functional considerations Periodontol 2000 2001 27 131 8 11551304\n\n",
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"issn_linking": "0976-2361",
"issue": "6(1)",
"journal": "Contemporary clinical dentistry",
"keywords": "Calcium channel blocker; gingival enlargement; hypertension",
"medline_ta": "Contemp Clin Dent",
"mesh_terms": null,
"nlm_unique_id": "101552967",
"other_id": null,
"pages": "107-9",
"pmc": null,
"pmid": "25684923",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "9249636;8707974;11551304;9249639;7758039;16398689;20379416",
"title": "Low dose amlodipine-induced gingival enlargement: A clinical case series.",
"title_normalized": "low dose amlodipine induced gingival enlargement a clinical case series"
} | [
{
"companynumb": "IN-DRREDDYS-USA/IND/15/0046548",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nSerotonin syndrome (SS) is a common disease entity and could result in death if missed. The incidence of SS is underestimated due to misdiagnosis of many cases, especially the ones with less severe presentation. Many medications have been depicted as the source of SS. We present a case of SS in a patient who received intravenous tramadol and oral gabapentin as pain management after spine surgery.\n\n\nMETHODS\nA 66-year-old man was admitted to our outpatient clinic with walking difficulties for 2 months. He was neurologically intact. However, he had neurologic claudication. He was on insulin, telmisartan-hydrochlorothiazide, amlodipine, and albuterol before the surgery, and these drugs were continued after the surgery. After he was diagnosed with lumbar spinal stenosis, he underwent total laminectomies of L3 and L4 and bilateral transpedicular screw placement from L1 to L5. He received tramadol 100 mg once daily intravenously and gabapentin 300 mg thrice daily orally after the spine surgery. He became confused, aggressive, and agitated during his stay in the hospital postoperatively. He became frustrated with even his children and wife. He started receiving haloperidol and quetiapine after psychiatry consultation. Because he worsened immediately after quetiapine and haloperidol, his medications were ceased in a step-by-step manner (first, tramadol and second, gabapentin). He became stable in a few hours, and his symptoms have improved since then.\n\n\nCONCLUSIONS\nPhysicians treating spine patients should be alert about SS in patients using both tramadol and gabapentin.",
"affiliations": "Department of Neurosurgery, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, Turkey. Electronic address: muratsakireksi@gmail.com.;Department of Neurosurgery, Antalya Atatürk State Hospital, Antalya, Turkey.;Department of Physical Medicine and Rehabilitation, Bahçeşehir University School of Medicine, İstanbul, Turkey.;Department of Neurosurgery, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, Turkey.;Department of Internal Medicine, Antalya Research and Education Hospital, Antalya, Turkey.;Department of Neurosurgery, Acıbadem Mehmet Ali Aydınlar University School of Medicine, İstanbul, Turkey.",
"authors": "Ekşi|Murat Şakir|MŞ|;Turgut|Veli Umut|VU|;Özcan-Ekşi|Emel Ece|EE|;Güngör|Abuzer|A|;Tükel Turgut|Fahriye Nur|FN|;Pamir|M Necmettin|MN|",
"chemical_list": "D000700:Analgesics; D014147:Tramadol; D000077206:Gabapentin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2019.03.092",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "126()",
"journal": "World neurosurgery",
"keywords": "Delirium; Gabapentin; Serotonin syndrome; Tramadol",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000368:Aged; D000700:Analgesics; D000077206:Gabapentin; D006801:Humans; D007796:Laminectomy; D008297:Male; D010149:Pain, Postoperative; D020230:Serotonin Syndrome; D013123:Spinal Fusion; D013130:Spinal Stenosis; D014147:Tramadol",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "261-263",
"pmc": null,
"pmid": "30898741",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serotonin Syndrome Following Tramadol and Gabapentin Use After Spine Surgery.",
"title_normalized": "serotonin syndrome following tramadol and gabapentin use after spine surgery"
} | [
{
"companynumb": "TR-ARBOR PHARMACEUTICALS, LLC-TR-2019ARB000760",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditi... |
{
"abstract": "Background: Atypical antipsychotics (AAPs) with mood stabilizers are recommended as a first-line treatment for patients with bipolar disorder. No studies have compared the inpatient health care resource utilization for patients with bipolar disorder treated with lurasidone as adjunctive therapy with mood stabilizers compared with other oral AAPs. Objective: To compare the risk of hospitalization for adult Medicaid beneficiaries with bipolar I disorder when treated with lurasidone compared with other oral AAPs as adjunctive therapy with mood stabilizers. Methods: This retrospective cohort study used the MarketScan Research Databases Multi-State Medicaid Database (IBM, Armonk, NY) claims data to assess patients with bipolar I disorder between January 1, 2014, and June 30, 2019. Adult patients who initiated oral AAP treatment with mood stabilizers (index date) and who were continuously enrolled 12 months before (pre-index) and 24 months after (post-index) the index date were included. Treatment categories assigned by patient-month included lurasidone, aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone with mood stabilizers; no/minimal treatment; AAP monotherapy; and other. Marginal structural models were performed to estimate the all-cause and psychiatric hospitalization rates and hospital length of stay associated with each adjunctive AAP therapy by controlling for both time-invariant and time-varying confounders. Results: Adults with bipolar I disorder (N = 11,426; mean age = 39.4 years; female=73%) treated with an adjunctive oral AAP with mood stabilizers during the index month were categorized into lurasidone (12%), aripiprazole (17%), olanzapine (7%), quetiapine (32%), risperidone (11%), ziprasidone (7%), or other (15%) treatment groups. The adjusted odds of all-cause and psychiatric hospitalization were significantly higher for olanzapine (all causes: adjusted odds ratio [aOR] = 1.59; 95% CI, 1.13-2.25; psychiatric: aOR = 1.61, 95% CI, 1.12-2.32), quetiapine (all-causes: aOR = 1.27, 95% CI, 1.01-1.58; psychiatric: aOR = 1.28, 95% CI, 1.02-1.59), and ziprasidone (all-causes: aOR = 1.68, 95% CI, 1.05-2.66; psychiatric: aOR = 1.55, 95% CI, 1.02-2.35) compared with lurasidone with mood stabilizers. The adjusted odds of all-cause and psychiatric hospitalizations were numerically lower for lurasidone compared with aripiprazole. The all-cause hospital length of stay per 100 patient-months was significantly higher for olanzapine (20.3 days) and quetiapine (16.0 days) compared with lurasidone (12.2 days, both P values < 0.05). Conclusions: In a Medicaid population, adults with bipolar I disorder treated with lurasidone as adjunctive therapy with mood stabilizers had significantly lower all-cause and psychiatric hospitalization rates compared with olanzapine, quetiapine, and ziprasidone. Fewer hospitalizations may reduce the economic burden associated with bipolar disorder. (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX).",
"affiliations": "Sunovion Pharmaceuticals Inc, Marlborough, Massachusetts.;PRECISIONheor, Los Angeles, California.;Sunovion Pharmaceuticals Inc, Marlborough, Massachusetts.;Sunovion Pharmaceuticals Inc, Marlborough, Massachusetts.;PRECISIONheor, Los Angeles, California.;PRECISIONheor, Los Angeles, California.;Sunovion Pharmaceuticals Inc, Marlborough, Massachusetts.;Sunovion Pharmaceuticals Inc, Marlborough, Massachusetts.",
"authors": "Niu|Xiaoli|X|;Dennen|Syvart|S|;Dembek|Carole|C|;Laubmeier|Kimberly|K|;Liu|Yanmei|Y|;Veeranki|Phani|P|;Tocco|Michael|M|;Williams|G Rhys|GR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.curtheres.2021.100629",
"fulltext": "\n==== Front\nCurr Ther Res Clin Exp\nCurr Ther Res Clin Exp\nCurrent Therapeutic Research, Clinical and Experimental\n0011-393X\n1879-0313\nElsevier\n\nS0011-393X(21)00007-2\n10.1016/j.curtheres.2021.100629\n100629\nOriginal Research\nHospitalization Risk for Adults with Bipolar I Disorder Treated with Oral Atypical Antipsychotics as Adjunctive Therapy with Mood Stabilizers: A Retrospective Analysis of Medicaid Claims Data\nNiu Xiaoli PhD xiaoli.niu@sunovion.com\na⁎\nDennen Syvart MPhil b\nDembek Carole MS a\nLaubmeier Kimberly PhD a\nLiu Yanmei MS b\nVeeranki Phani MD, DrPH b\nTocco Michael PhD a\nWilliams G. Rhys ScD a\na Sunovion Pharmaceuticals Inc, Marlborough, Massachusetts\nb PRECISIONheor, Los Angeles, California\n⁎ Address correspondence to: Xiaoli Niu, Sunovion Pharmaceuticals Inc, 84 Waterford Dr, Marlborough, MA 01752 xiaoli.niu@sunovion.com\n27 3 2021\n2021\n27 3 2021\n94 1006291 2 2021\n18 3 2021\n© 2021 Sunovion Pharmaceuticals Inc.\n2021\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/).\nHighlights\n\n• Adult Medicaid patients with bipolar I disorder treated with adjunctive oral AAPs.\n\n• Lurasidone had lower hospitalizations vs. olanzapine, quetiapine, and ziprasidone.\n\n• Lurasidone had fewer all-cause hospital days vs. olanzapine and quetiapine.\n\n• Fewer hospitalizations, fewer hospital days could indicate reduced disease burden.\n\nBackground: Atypical antipsychotics (AAPs) with mood stabilizers are recommended as a first-line treatment for patients with bipolar disorder. No studies have compared the inpatient health care resource utilization for patients with bipolar disorder treated with lurasidone as adjunctive therapy with mood stabilizers compared with other oral AAPs.\n\nObjective: To compare the risk of hospitalization for adult Medicaid beneficiaries with bipolar I disorder when treated with lurasidone compared with other oral AAPs as adjunctive therapy with mood stabilizers.\n\nMethods: This retrospective cohort study used the MarketScan Research Databases Multi-State Medicaid Database (IBM, Armonk, NY) claims data to assess patients with bipolar I disorder between January 1, 2014, and June 30, 2019. Adult patients who initiated oral AAP treatment with mood stabilizers (index date) and who were continuously enrolled 12 months before (pre-index) and 24 months after (post-index) the index date were included. Treatment categories assigned by patient-month included lurasidone, aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone with mood stabilizers; no/minimal treatment; AAP monotherapy; and other. Marginal structural models were performed to estimate the all-cause and psychiatric hospitalization rates and hospital length of stay associated with each adjunctive AAP therapy by controlling for both time-invariant and time-varying confounders.\n\nResults: Adults with bipolar I disorder (N = 11,426; mean age = 39.4 years; female=73%) treated with an adjunctive oral AAP with mood stabilizers during the index month were categorized into lurasidone (12%), aripiprazole (17%), olanzapine (7%), quetiapine (32%), risperidone (11%), ziprasidone (7%), or other (15%) treatment groups. The adjusted odds of all-cause and psychiatric hospitalization were significantly higher for olanzapine (all causes: adjusted odds ratio [aOR] = 1.59; 95% CI, 1.13–2.25; psychiatric: aOR = 1.61, 95% CI, 1.12–2.32), quetiapine (all-causes: aOR = 1.27, 95% CI, 1.01–1.58; psychiatric: aOR = 1.28, 95% CI, 1.02–1.59), and ziprasidone (all-causes: aOR = 1.68, 95% CI, 1.05–2.66; psychiatric: aOR = 1.55, 95% CI, 1.02–2.35) compared with lurasidone with mood stabilizers. The adjusted odds of all-cause and psychiatric hospitalizations were numerically lower for lurasidone compared with aripiprazole. The all-cause hospital length of stay per 100 patient-months was significantly higher for olanzapine (20.3 days) and quetiapine (16.0 days) compared with lurasidone (12.2 days, both P values < 0.05).\n\nConclusions: In a Medicaid population, adults with bipolar I disorder treated with lurasidone as adjunctive therapy with mood stabilizers had significantly lower all-cause and psychiatric hospitalization rates compared with olanzapine, quetiapine, and ziprasidone. Fewer hospitalizations may reduce the economic burden associated with bipolar disorder. (Curr Ther Res Clin Exp. 2021; 82:XXX–XXX)\n\nKey words\n\nAtypical antipsychotics\nBipolar I disorder\nHospitalization\nlurasidone\nMedicaid\n==== Body\nIntroduction\n\nBipolar disorder is a chronic psychiatric mood disorder with an annual US prevalence of 2.8% among adults.1 Patients with bipolar disorder experience periods without symptoms (euthymia) interspersed with mania (bipolar I disorder) or hypomania (bipolar II disorder) and depression.2 Symptomatic time is more often spent in depressive episodes, which on average last 50% longer than manic or mixed episodes.3,4 Patients with bipolar disorder in depressive episodes (bipolar depression) have an increased risk of attempting suicide,3 treatment noncompliance,5 and hospitalization.6,7\n\nAnnual direct health care costs for bipolar disorder are estimated to be $40 to $50 billion in the United States.8 A large proportion (almost 30%) of direct health care costs for patients with bipolar disorder are attributed to inpatient hospitalizations.9,10 High rates of cardiometabolic comorbidities (eg, metabolic disorders, obesity, and diabetes) and psychiatric comorbidities (eg, anxiety and substance abuse) among patients with bipolar disorder contribute to increased all-cause and psychiatric hospitalizations and longer hospital length of stay.11, 12, 13\n\nAtypical antipsychotics (AAPs) and mood stabilizers are first-line treatments for patients with bipolar disorder. Although patients with bipolar disorder often initiate treatment with monotherapy (eg, single AAP or mood stabilizer), up to 70% of patients with bipolar disorder receive adjunctive therapy such as an AAP and a mood stabilizer after 1 year.14 International bipolar disorder treatment guidelines recommend AAPs (eg, quetiapine, aripiprazole, risperidone, and asenapine) with mood stabilizers (eg, lithium and divalproex) for first-line combination treatment of bipolar mania.15 For bipolar depression, lurasidone with mood stabilizers (lithium or divalproex) is the only AAP that is recommended as a first-line adjunctive treatment.15 AAPs may also be prescribed with other mood stabilizers such as lamotrigine and carbamazepine, which are also approved by the Food and Drug Administration for the treatment of bipolar disorder.11,16,17\n\nState Medicaid programs cover a disproportionate share of the adult population with mental illness (21% vs 14% of general population), including bipolar disorder.18 Among adult Medicaid patients with bipolar disorder, approximately 35% of average annual costs (average annual costs = $16,038 [2015 dollars]) are due to inpatient care.19,20 Adult Medicaid patients with bipolar disorder have a similar rate of treatment with adjunctive AAPs as the overall population.14 The 2019-2020 Florida Best Practice Psychotherapeutic Medication Guidelines for Adults recommend lurasidone with lithium or divalproex as a first-line combination treatment for bipolar depression in patients previously prescribed and optimized on mood stabilizers.21\n\nPrevious studies have compared the inpatient health care resource utilization for patients with bipolar disorder treated with lurasidone monotherapy compared with other oral AAPs.22,23 However, no studies have compared the inpatient health care resource utilization for patients with bipolar disorder treated with lurasidone as adjunctive therapy with mood stabilizers compared with other oral AAPs. This retrospective cohort study compared the inpatient health care resource utilization for adult Medicaid patients diagnosed with bipolar I disorder treated with lurasidone compared with other oral AAPs as adjunctive therapy.\n\nMethods\n\nData source\n\nThis retrospective analysis used US Medicaid claims data from the MarketScan Research Databases Multi-State Medicaid Database (IBM, Armonk, NY) from January 1, 2014, to June 30, 2019. The MarketScan data include medical claims, outpatient pharmacy claims, and enrollment data for more than 44 million Medicaid enrollees from geographically dispersed states. The data were de-identified and extracted in compliance with the Health Insurance Portability and Accountability Act of 1996.24 Therefore, institutional review board approval was not required for this study.\n\nPatient selection\n\nPatients were eligible for inclusion in the analysis if they initiated an oral AAP (ie, asenapine, aripiprazole, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, quetiapine, olanzapine, paliperidone, risperidone, or ziprasidone) with ≥24 days of overlap with a mood stabilizer (ie, carbamazepine, lamotrigine, lithium, oxcabazepine, or valproate) during the study period. Adjunctive treatment was defined as having at least 24 days (ie, 80% of days during a 30-day month) of overlap between the oral AAP and a mood stabilizer. No limits on dose ranges for oral AAPs or mood stabilizers were required. The date of the first evidence of an adjunctive oral AAP and mood stabilizer was defined as the index date. Patients were followed for 12 months before the index date (pre-index period) to 24 months after the index date (post-index period).\n\nPatients were included in the analysis in the case that they had a diagnosis of bipolar I disorder (International Classification of Diseases, Ninth Revision, Clinical Modifications [ICD-9-CM] codes: 296.0X, 296.1X, 296.4X, 296.5X, 296.6X, 296.7X, 296.80, and 296.81; 10th revision [ICD-10-CM] codes: F30.XX, F31.0, F31.1X, F31.2, F31.3X, F31.4, F31.5, F31.6X, F31.7X, F31.89, and F31.9) during the pre-index period or on the index date; were adults (age at index date ≥18 years); and were continuously enrolled during the pre-index and post-index periods. Patients were excluded from the analysis in the case that they had a diagnosis of schizophrenia (ICD-9-CM code: 295.X; ICD-10-CM code: F20.X) during the study period; used long-acting injectable AAPs such as the long-acting injectable formulations of aripiprazole Healthcare Common Procedure Coding System (HCPCS: J1942, C9470, J0400, J0401), olanzapine (HCPCS: J2358), paliperidone (HCPCS: J2426), risperidone (HCPCS: J2794, S0163, C9125, C9037), or ziprasidone (HCPCS: J3486, C9204) during the study period; or were pregnant (ICD-9-CM code: 630.xx-679.xx; ICD-10-CM code: O00.xx-O9x.xx) during the study period. The patient inclusion/exclusion criteria are similar to a previous retrospective comparison of oral AAPs and inpatient health care resource utilization.23\n\nAdjunctive oral AAP treatment categories\n\nThe primary treatments of interest were oral AAPs with mood stabilizers. Treatment was assigned in 30-day intervals (ie, months) during the post-index period, and the patient treatment-month was the primary unit of analysis. Individual categories of adjunctive therapy were defined as months in which patients received oral lurasidone, aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone with mood stabilizers (≥24 days’ supply and overlap between oral AAP and mood stabilizer). In addition, an other treatment category included oral AAPs with ≥24 days of mood stabilizers with a small sample size (ie, asenapine, brexpiprazole, cariprazine, iloperidone, paliperidone, clozapine); treatment with multiple oral AAPs; 8 to 23 days’ supply of 1 or more oral AAPs; any oral AAP with 8 to 23 days’ supply of mood stabilizers; or monotherapy with mood stabilizers. Additional classifications after the index month included oral AAP monotherapy and no/minimal AAP treatment. AAP monotherapy was defined as ≥24 days of oral AAP treatment during the month without concurrent treatment (≤7 days’ supply) with other oral AAPs or mood stabilizers. The oral AAP monotherapy group was a combination of all oral AAPs in this study (ie, asenapine, aripiprazole, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, quetiapine, olanzapine, paliperidone, risperidone, and ziprasidone). No or minimal AAP treatment was defined as no treatment with oral AAPs or ≤7 days of any oral AAP therapy.\n\nInpatient health care resource utilization\n\nThe primary outcomes of interest were all-cause and psychiatric hospitalization rates per 100 patient months and days hospitalized (hospital length of stay [LOS]) per 100 patient-months. Psychiatric hospitalizations were identified by a mental health disorder diagnosis (see Supplemental Table 1 in the online version at doi.10.1016/j.curtheres.2021.100629) in any diagnosis code field. Hospital LOS included the emergency department visit for patients directly admitted to an inpatient facility.\n\nDemographic characteristics, comorbidities, and other variables\n\nDemographic variables, including age, sex, race/ethnicity (White, Black, Hispanic, other, or missing), and plan type were recorded at the index date. Clinical variables were calculated using claims from the pre-index period. These included the Charlson comorbidity index25; diagnoses of diabetes (ICD-9-CM code: 250.0–250.7; ICD-10-CM code: E10-E14), hyperlipidemia (ICD-9-CM code: 272.0x-272.4x; ICD-10-CM codes: E78.0x - E78.4x, E78.5), hypertension (ICD-9-CM codes: 401.xx - 405.xx, 437.2, 362.11; ICD-10-CM codes: H35.03x, I10.xx -I15.xx, I67.4, N26.2), and obesity (ICD-9-CM codes: 278.0x, V85.3x, V85.4x; ICD-10-CM codes: E66.xx, Z68.3x, Z68.4x); diagnoses of bipolar II disorder, anxiety, major depressive disorder (MDD), and substance abuse (alcohol, opioids, cannabis, cocaine, and other stimulants) (see Supplemental Table 1 in the online version at doi.10.1016/j.curtheres.2021.100629); the pre-index hospitalization rate; the pre-index hospital LOS; and pre-index psychotropic medication use including antidepressants, mood stabilizers, oral AAPs, and anxiolytics. Additional clinical variables were calculated monthly for the post-index period, including the substance abuse indicators and office visits.\n\nStatistical analysis\n\nDescriptive statistics were reported for categorical variables (frequency and percent) and continuous variables (mean and standard deviation) during the pre-index period by the index month treatment category. Statistical significance was tested with t tests for continuous variables and pairwise tests of proportions for categorical variables using lurasidone with mood stabilizers as the reference category.\n\nMarginal structural models (MSMs) were used to estimate the association of each treatment category with the hospitalization rate and hospital LOS. MSMs account for time-varying confounding such as treatment switching by weighting the data by the probability of receiving each treatment in each time period.26 For each month in the post-index period, stabilized inverse probability of treatment weights were calculated to predict assignment to each of the 9 treatment categories using multinomial logistic regressions. Time-invariant covariates included age (restricted cubic spline), sex, race/ethnicity, plan type, pre-index period Charlson comorbidity index indicators, pre-index period comorbidities (diabetes, hypertension, obesity, bipolar II disorder, and substance abuse indictors), the pre-index period dependent variable, pre-index period office visits, index month number of psychiatric ED visits, and index year. Time-varying covariates included the prior-month dependent variable, the prior-month alcohol abuse indicator, the prior-month substance abuse indicator, an indicator for a new diagnosis of anxiety or MDD during either the pre-index period or the prior month that was permanently set to 1 in the following months, the prior-month treatment history indicators (no or minimal treatment, other treatment, or AAP monotherapy), and a restricted cubic spline for time. Separate generalized linear models with logit link and clustering by patient were used to model all-cause and psychiatric hospitalization rates. Zero-inflated Poisson regression models were used to model all-cause and psychiatric hospital LOS. All models were weighted using the inverse probability of treatment weights. Covariates included the treatment category for the current month and all the previously mentioned time-invariant variables.\n\nThe statistical analysis was conducted using SAS version 9.4 (SAS Institute Inc, Cary, North Carolina) and Stata version 16 (StataCorp, College Station, Texas). Statistical significance was indicated for P < 0.01 and P < 0.05.\n\nResults\n\nPatient characteristics\n\nThe analysis included 11,426 adult patients with bipolar I disorder at the index month. Figure 1 shows details of the patient selection process.Figure 1 Patient inclusion flow chart. AAP = atypical antipsychotic; LAI = long-acting injectable.\n\nFigure 1\n\nPatient characteristics during the pre-index period and at the index month are reported in Table 1. Patients were assigned to lurasidone (11.6%), aripiprazole (17.0%), olanzapine (6.9%), quetiapine (32.0%), risperidone (10.9%), ziprasidone (6.5%), or other treatment (15.0%) during the index month. The most common mood stabilizer used with the AAPs at the index month was lamotrigine (47.8%) followed by lithium (22.3%), oxcarbazepine (14.5%), carbamazepine (8.8%), multiple mood stabilizers (6.1%), and valproate (0.4%) (see Supplemental Table 2 in the online version at doi.10.1016/j.curtheres.2021.100629).Table 1 Pre-index patient demographic characteristics, comorbidities, and health care utilization by treatment group at index.*\n\nTable 1\tLurasidone†\tAripiprazole\tOlanzapine\tQuetiapine\tRisperidone\tZiprasidone\tOther treatment\t\nSample size at index‡\t1330 (11.6)\t1947 (17.0)\t792 (6.9)\t3652 (32.0)\t1248 (10.9)\t746 (6.5)\t1711 (15.0)\t\nAge (y)§\t39.0 (10.5)\t38.8 (12.0)\t39.1 (12.4)\t40.7 (11.8)||\t38.7 (12.5)\t39.2 (12.1)\t38.3 (11.8)\t\nFemale‡\t1110 (83.5)\t1450 (74.5)||\t484 (61.1)||\t2710 (74.2)||\t837 (67.1)||\t597 (80.0)\t1163 (68.0)||\t\nRace‡\t\n White\t1084 (81.5)\t1572 (80.7)\t591 (74.6)||\t2722 (74.5)||\t874 (70.0)||\t577 (77.3)¶\t1337 (78.1)¶\t\n Black\t127 (9.5)\t172 (8.8)\t105 (13.3)¶\t472 (12.9)||\t193 (15.5)||\t53 (7.1)¶\t179 (10.5)\t\n Hispanic\tnr\t16 (0.8)\tnr\t59 (1.6)||\t15 (1.2)¶\tnr\t14 (0.8)\t\n Other\tnr\t45 (2.3)\tnr\t39 (1.1)\t19 (1.5)\tnr\t29 (1.7)\t\n Missing\t91 (6.8)\t142 (7.3)\t72 (9.1)\t360 (9.9)||\t147 (11.8)||\t94 (12.6)||\t152 (8.9)¶\t\nIndex year‡\t\n 2015\t815 (61.3)\t1344 (69.0)||\t484 (61.1)\t2497 (68.4)||\t908 (72.8)||\t542 (72.7)||\t1098 (64.2)\t\n 2016\t419 (31.5)\t491 (25.2)||\t240 (30.3)\t955 (26.2)||\t278 (22.3)||\t165 (22.1)||\t496 (29.0)\t\n 2017\t96 (7.2)\t112 (5.8)\t68 (8.6)\t200 (5.5)¶\t62 (5.0)¶\t39 (5.2)\t117 (6.8)\t\nPlan type‡\t\n HMO\t825 (62.0)\t1262 (64.8)\t440 (55.6)||\t2301 (63.0)\t722 (57.9)¶\t445 (59.7)\t984 (57.5)¶\t\n Comprehensive\t505 (38.0)\t685 (35.2)\t352 (44.4)||\t1351 (37.0)\t526 (42.1)¶\t301 (40.3)\t727 (42.5)¶\t\nCCI§\t0.8 (1.2)\t0.8 (1.3)\t0.8 (1.4)\t0.9 (1.3)\t0.8 (1.2)\t0.8 (1.2)\t0.9 (1.4)\t\nPsychiatric comorbidities‡\t\n Anxiety\t807 (60.7)\t1077 (55.3)||\t405 (51.1)||\t2077 (56.9)¶\t602 (48.2)||\t391 (52.4)||\t910 (53.2)||\t\n Major depressive disorder\t744 (55.9)\t1032 (53.0)\t397 (50.1)||\t1961 (53.7)\t580 (46.5)||\t350 (46.9)||\t844 (49.3)||\t\n Substance abuse#\t368 (27.7)\t471 (24.2)¶\t253 (31.9)¶\t1121 (30.7)¶\t294 (23.6)¶\t173 (23.2)¶\t476 (27.8)\t\nPhysical comorbidities‡\t\n Hypertension\t499 (37.5)\t699 (35.9)\t303 (38.3)\t1477 (40.4)\t448 (35.9)\t283 (37.9)\t645 (37.7)\t\n Hyperlipidemia\t393 (29.5)\t567 (29.1)\t217 (27.4)\t1127 (30.9)\t377 (30.2)\t242 (32.4)\t546 (31.9)\t\n Obesity\t446 (33.5)\t607 (31.2)\t150 (18.9)||\t930 (25.5)||\t315 (25.2)||\t264 (35.4)\t506 (29.6)¶\t\n Diabetes\t289 (21.7)\t367 (18.8)¶\t121 (15.3)||\t638 (17.5)||\t226 (18.1)¶\t157 (21.0)\t307 (17.9)||\t\nPsychotropic medication use‡\t\n Antidepressants\t1047 (78.7)\t1583 (81.3)\t568 (71.7)||\t2816 (77.1)\t921 (73.8)||\t581 (77.9)\t1309 (76.5)\t\n Mood stabilizers\t1057 (79.5)\t1571 (80.7)\t590 (74.5)||\t2637 (72.2)||\t982 (78.7)\t597 (80.0)\t1239 (72.4)||\t\n Oral AAPs\t1001 (75.3)\t1571 (80.7)||\t583 (73.6)\t2907 (79.6)||\t978 (78.4)\t618 (82.8)||\t1470 (85.9)||\t\n Anxiolytics\t646 (48.6)\t851 (43.7)||\t323 (40.8)||\t1578 (43.2)||\t453 (36.3)||\t349 (46.8)\t767 (44.8)¶\t\nHospitalization rate per 100 patient-months\t\n All causes\t2.54\t2.52\t3.20||\t2.69\t2.34\t2.40\t2.78\t\n Psychiatric\t2.35\t2.34\t2.99||\t2.52\t2.14\t2.25\t2.55\t\nHospital LOS days per 100 patient-months\t\n All causes\t20.76\t20.54\t35.51||\t24.86\t23.45\t19.48\t29.00||\t\n Psychiatric\t17.64\t18.57\t32.22||\t22.43||\t18.97\t16.89\t26.36||\t\nAAP = atypical antipsychotics; CCI = Charlson comorbidity index; HMO = health maintenance organization; nr = not reported.\n\n⁎ Boldface type indicates significant differences between lurasidone and other oral atypical antipsychotics or other treatment at P < 0.05. Cells with <11 patients are not reported in accordance with Centers for Medicare and Medicaid Services cell size suppression policy.\n\n† Reference category.\n\n‡ Values are presented as n (%).\n\n§ Values are presented as mean (standard deviation).\n\n|| Indicates significance versus lurasidone at P < 0.01.\n\n¶ Indicates significance versus lurasidone at P < 0.05.\n\n# Substance abuse includes alcohol, opioids, cannabis, cocaine, hallucinogens, sedatives, inhalants, and other stimulants (eg, amphetamine and psychostimulant) abuse.\n\nThe average age for patients initiating an adjunctive oral AAP with mood stabilizers was 39.4 years (lurasidone mean age = 39.0 years vs aripiprazole = 38.8 years [P ≥ 0.05] vs olanzapine = 39.1 years [P ≥ 0.05] vs quetiapine = 40.7 years [P < 0.01] vs risperidone = 38.7 years [P ≥ 0.05] vs ziprasidone = 39.2 years [P ≥ 0.05]). Compared with patients who were treated with other oral AAPs, a significantly higher proportion of patients who were treated with lurasidone were female (lurasidone = 83.5% vs aripiprazole = 74.5% [P < 0.01] vs olanzapine = 61.1% [P < 0.01] vs quetiapine = 74.2% [P < 0.01] vs risperidone = 67.1% [P < 0.01]) and White (lurasidone = 81.5% vs olanzapine = 74.6% [P < 0.01] vs quetiapine = 74.5% [P < 0.01] vs risperidone = 70.0% [P < 0.01] vs ziprasidone = 77.3% [P < 0.05]).\n\nDuring the pre-index period, patients who were treated with lurasidone compared with other AAPs were significantly more likely to have a history of anxiety diagnoses (lurasidone = 60.7% vs aripiprazole = 55.3% [P < 0.01] vs olanzapine = 51.1% [P < 0.01] vs quetiapine = 56.9% [P < 0.05] vs risperidone = 48.2% [P < 0.01] vs ziprasidone = 52.4% [P < 0.01]). The proportion of patients with substance abuse was significantly higher for patients treated with lurasidone (27.7%) compared with aripiprazole (24.2% [P < 0.05]), risperidone (23.6% [P < 0.05]), and ziprasidone (23.2% [P < 0.05]) but lower compared with olanzapine (31.9% [P < 0.05]) and quetiapine (30.7% [P < 0.05]). A significantly higher percentage of patients treated with lurasidone had been diagnosed with obesity (lurasidone = 33.5% vs olanzapine = 18.9% [P < 0.01] vs quetiapine = 25.5% [P < 0.01] vs risperidone = 25.2% [P < 0.01]) and diabetes (lurasidone = 21.7% vs aripiprazole = 18.8% [P < 0.05] vs olanzapine = 15.3% [P < 0.01] vs quetiapine = 17.5% [P <0.01] vs risperidone = 18.1% [P < 0.05]).\n\nA significantly higher proportion of patients treated with lurasidone had at least 1 prescription for anxiolytics (lurasidone = 48.6% vs aripiprazole = 43.7% [P < 0.01] vs olanzapine = 40.8% [P < 0.01] vs quetiapine = 43.2% [P < 0.01] vs risperidone = 36.3% [P < 0.01]) during the pre-index period. The proportion of patients with at least 1 prescription for antidepressant agents during the pre-index period was significantly higher for patients treated with lurasidone (78.7%) compared with olanzapine (71.7% [P < 0.01]) and risperidone (73.8% [P < 0.01]).\n\nUnadjusted hospitalization rate and hospital LOS during the 24-month post-index period\n\nThe unadjusted hospitalization rate and hospital LOS by treatment group during the post-index period are reported in Table 2.Table 2 Unadjusted all-cause and psychiatric hospitalizations and hospital length of stay (LOS) during the 24-month follow-up period.*\n\nTable 2\tLurasidone†\tAripiprazole\tOlanzapine\tQuetiapine\tRisperidone\tZiprasidone\tNo/Minimal treatment\tOther Treatment\tAAP Monotherapy\t\nTreatment months\t10,863\t17,554\t7028\t32,813\t11,355\t7600\t59,370\t87,402\t28,813\t\nHospitalizations rate, per 100 patient months\t\n All-cause\t2.12\t2.21\t2.96‡\t2.66‡\t1.60‡\t2.21\t2.35\t3.29§\t3.26§\t\n Psychiatric\t1.78\t1.85\t2.40‡\t2.24‡\t1.30‡\t1.91\t2.08\t2.91§\t2.77§\t\nHospital LOS, per 100 patient months\t\n All-cause\t10.15\t11.50\t16.70§\t13.64‡\t8.80\t10.88\t15.18§\t18.62§\t18.54§\t\n Psychiatric\t8.75\t8.73\t12.66‡\t10.93\t6.75\t9.03\t12.78§\t16.09§\t14.93§\t\nAAP = atypical antipsychotics.\n\n⁎ Boldface type indicates significance of outcomes in comparison to lurasidone at P < 0.05.\n\n† Reference category.\n\n‡ Indicates significance versus lurasidone at P < 0.05.\n\n§ Indicates significance versus lurasidone at P < 0.01.\n\nDuring the 24-month post-index period, the unadjusted all-cause and psychiatric hospitalization rates per 100 patient-months were significantly lower for lurasidone (all-cause hospitalization rate = 2.12 and psychiatric hospitalization rate = 1.78) compared with olanzapine (all-cause hospitalization rate = 2.96 [P < 0.05] and psychiatric hospitalization rate = 2.40 [P < 0.05]), quetiapine (all-cause hospitalization rate = 2.66 [P <0.05] and psychiatric hospitalization rate = 2.24 [P < 0.05]), and AAP monotherapy (all cause hospitalization rate = 3.26 [P < 0.01] and psychiatric hospitalization rate = 2.77 [P < 0.01]). The hospitalization rates were significantly higher for lurasidone compared with risperidone (all-cause hospitalization rate = 1.60 [P < 0.05] and psychiatric hospitalization rate = 1.30 [P < 0.05]).\n\nThe unadjusted all-cause hospital LOS per 100 patient-months was significantly shorter for lurasidone (10.2 days) compared with olanzapine (16.7 days [P < 0.01]), quetiapine (13.6 days [P < 0.05]), and AAP monotherapy (18.6 days [P < 0.01]). Similarly, the unadjusted psychiatric hospital LOS was significantly shorter for lurasidone (8.8 days) compared with olanzapine (12.7 days [P < 0.05]) and AAP monotherapy (14.9 days [P < 0.01]).\n\nMSMs\n\nThe MSM adjusted odds of hospitalization and risk of hospital LOS are presented in Figure 2 and Figure 3, respectively. Table 3 shows the adjusted hospitalization rate and hospital LOS controlling for time-invariant and time-varying covariates during the 24-month post-index period.Figure 2 Marginal structural model-adjusted risk of all-cause and psychiatric hospitalizations during 24-month follow-up period. Adjusted rates control for patient demographic characteristics, clinical characteristics, and health care utilization as well as time-varying indicators of key clinical characteristics, health care utilization, and time trends. Bold text indicates statistical significance based on 95% CI. OR = odds ratio.\n\nFigure 2\n\nFigure 3 Marginal structural model-adjusted risk of all-cause and psychiatric hospital length of stay during 24-month follow-up period. Adjusted rates control for patient demographic characteristics, clinical characteristics, and health care utilization as well as time-varying indicators of key clinical characteristics, health care utilization, and time trends. Bold text indicates statistical significance based on 95% CI. IRR = incidence rate ratio.\n\nFigure 3\n\nTable 3 Adjusted risk of all-cause and psychiatric hospitalizations and hospital length of stay (LOS) during the 24-month follow-up period.*\n\nTable 3\tLurasidone†\tAripiprazole\tOlanzapine\tQuetiapine\tRisperidone\tZiprasidone\tNo/minimal treatment\tOther treatment\tAAP monotherapy\t\nTreatment months\t10,863\t17,554\t7028\t32,813\t11,355\t7600\t59,370\t87,402\t28,813\t\nHospitalizations rate, per 100-patient mo\t\n All causes\t2.36\t2.70\t3.67‡\t2.96§\t2.30\t3.85§\t2.19\t3.52‡\t3.03§\t\n Psychiatric\t1.97\t2.24\t3.11§\t2.49§\t1.96\t2.99§\t1.84\t3.13‡\t2.55§\t\nHospital LOS, per 100-patient mo\t\n All causes\t12.21\t15.14\t20.29§\t16.02§\t13.86\t18.70\t14.19\t20.25‡\t17.72‡\t\n Psychiatric\t10.51\t11.32\t16.35\t12.48\t10.86\t14.11\t11.48\t17.54‡\t13.96§\t\nAAP = atypical antipsychotics.\n\n⁎ Boldface type indicates significance of outcomes in comparison to lurasidone at P < 0.05. Adjusted rates control for patient demographic characteristics, clinical characteristics, and health care utilization as well as time-varying indicators of key clinical characteristics, health care utilization, and time trends. Adjusted hospitalization rates will not precisely match adjusted odds ratios. Adjusted rates are calculated at the patient-level from each patient's predicted log odds, then averaged across the sample. The nonlinear conversion from log odds to predicted rates leads to minor differences if adjusted odds ratios are then back-calculated from the predicted rates.\n\n† Reference category.\n\n‡ Indicates significance versus lurasidone at P < 0.01.\n\n§ Indicates significance versus lurasidone at P < 0.05.\n\nAfter adjusting for time-invariant and time-varying covariates, the all-cause hospitalization rates per 100 patient-months remained significantly lower for lurasidone (2.36) compared with olanzapine (3.67) (adjusted odds ratio [aOR] = 1.59; 95% CI, 1.13–2.25; P < 0.01), quetiapine (2.96) (aOR = 1.27; 95% CI, 1.01–1.58; P < 0.05), and AAP monotherapy (3.03) (aOR = 1.30; 95% CI, 1.02–1.65; P < 0.05). The all-cause hospitalization rate for lurasidone (2.36) became statistically significantly lower compared with ziprasidone (3.85) (aOR = 1.68; 95% CI, 1.05–2.66; P < 0.05).\n\nThe psychiatric hospitalization rate remained significantly lower for lurasidone (1.97) compared with olanzapine (3.11) (aOR = 1.61; 95% CI, 1.12–2.32; P < 0.05), quetiapine (2.49) (aOR = 1.28; 95% CI, 1.02–1.59; P < 0.05), and AAP monotherapy (2.55) (aOR = 1.31; 95% CI, 1.03–1.66; P < 0.05) after controlling for time-invariant and time varying covariates. The psychiatric hospitalization rate for lurasidone (1.97) became statistically significantly lower compared with ziprasidone (2.99) (aOR = 1.55; 95% CI, 1.02–2.35; P < 0.05). The results for lurasidone compared with risperidone were no longer significantly different after controlling for time-invariant and time-varying covariates.\n\nThe all-cause hospital LOS remained significantly shorter for lurasidone (12.2 days) compared with olanzapine (20.3 days) (adjusted incidence rate ratio [aIRR] = 1.66; 95% CI, 1.10–2.23; P < 0.05), quetiapine (16.0 days) (aIRR = 1.31, 95% CI, 1.01–1.61; P < 0.05), and AAP monotherapy (17.7 days) (aIRR = 1.45, 95% CI, 1.13–1.77; P < 0.01). The psychiatric hospital LOS remained significantly shorter for lurasidone (10.5 days) compared with AAP monotherapy (14.0 days) (aIRR = 1.33; 95% CI, 1.01–1.65; P < 0.05).\n\nDiscussion\n\nThis retrospective claims database analysis is the first study to compare hospitalization risk among adult Medicaid patients with bipolar I disorder treated with lurasidone as adjunctive therapy with mood stabilizers versus other adjunctive oral AAPs. During 24-months of follow-up, adult Medicaid patients with bipolar I disorder treated with lurasidone had statistically significantly lower all-cause and psychiatric hospitalization rates compared with those who were treated with olanzapine, quetiapine, or ziprasidone. In addition, treatment with lurasidone was also associated with significantly shorter all-cause hospital LOS compared with olanzapine or quetiapine.\n\nThe results from this study are consistent with 2 earlier studies of patients with bipolar I disorder treated with lurasidone monotherapy compared with other oral AAPs.22,23 In a Medicaid population, the odds of all-cause hospitalizations per 100 patient-months were significantly higher for olanzapine and quetiapine compared with lurasidone monotherapy.23 In a commercially insured population, the odds of psychiatric hospitalizations per 100 patient-months were significantly higher for olanzapine, quetiapine, risperidone, and ziprasidone compared with lurasidone monotherapy.22 The odds of hospitalization for aripiprazole, olanzapine, quetiapine, and ziprasidone with mood stabilizers compared with lurasidone were directionally the same (favoring lurasidone) in this study.\n\nTreatment switching is frequent in patients receiving antipsychotic agents and complicates the estimation of the association of treatments with outcomes when using an intent-to-treat approach. The MSM methods used in this study reduced potential confounding from treatment switching by not only adjusting for the time-invariant variables, including patient demographic characteristics, clinical characteristics, and health care resource utilization before treatment initiation, but also accounting for time-varying variables, including clinical characteristics and health care utilization that may have an influence on treatment selection over time.26 In addition, by requiring a medication possession ratio ≥80% (ie, 24 days out of 30 days in the patient treatment-month), the potential confounding from treatment noncompliance, which has been associated with increased hospitalizations,27,28 was also reduced.\n\nThe safety and efficacy of lurasidone with lithium or divalproex for the treatment of bipolar depression has been established in short- and long-term trials.29, 30, 31 However, the comparative efficacy of lurasidone with mood stabilizers compared with other AAPs with mood stabilizers has not been directly studied in patients with bipolar disorder. Indirect comparisons, such as network meta-analyses, have focused on monotherapy treatment and found that patients treated with lurasidone monotherapy (without mood stabilizers) have greater odds of response and remission compared with aripiprazole, olanzapine, and quetiapine monotherapy32,33 and significantly less weight gain compared with olanzapine and quetiapine,32 which may help explain the lower hospitalization rates for patients treated with lurasidone compared with aripiprazole, olanzapine, and quetiapine. Lurasidone has also been found to be associated with a relatively low risk for developing metabolic syndrome,34 which may help explain the shorter hospital LOS for patients treated with lurasidone compared with olanzapine or quetiapine.12\n\nIn this study, the adjusted psychiatric hospitalization rate accounted for approximately 80% of the all-cause hospitalization rate across treatment cohorts. Inpatient hospitalizations are a high-cost component of bipolar disorder care.35 In addition to cost, greater recurrence of mood episodes has been associated with higher odds of psychiatric hospitalizations for patients with bipolar I disorder in a community sample and prospectively associated with greater risk of disability, unemployment, and poor functioning in the same sample.7 Reductions in psychiatric hospitalizations among patients with bipolar disorder could reduce health care resource utilization and costs and be associated with improvements in health outcomes for patients with bipolar disorder.\n\nThere are several limitations to this study. First, this study used administrative health care claims data. The primary purpose of claims data is for billing, and it does not capture information about symptoms, severity of illness, chronicity, and functional status and may include coding errors and misclassifications. Second, the study results may not be generalizable to populations other than adult US Medicaid beneficiaries with bipolar I disorder such as patients outside the United States, with commercial insurance, with Medicare coverage, or without health insurance. Third, unobserved confounders such as socioeconomic status and severity of disease could still be different between the treatment cohorts and have an influence on the outcomes. To minimize this possibility, a large number of observable time-invariant and time-varying variables known to be associated with inpatient health care resource utilization and severity of disease, including psychiatric-related emergency department use, pre-index office visits, and the prior month-dependent variable among patients with bipolar disorder were controlled for using marginal structural models. Fourth, although a new diagnosis of anxiety or MDD during each month was used as a proxy for other medication use and was controlled for in the outcome models, concomitant anxiolytic or antidepressant use may confound the association of oral AAPs with hospitalizations in the study population. Fifth, the focus of this study was on all-cause and psychiatric hospitalizations. Further studies could look at phase-specific hospitalizations for bipolar disorder. Finally, all pharmacotherapy combinations used by patients with bipolar I disorder could not be analyzed in this study due to sample size considerations. However, the use of AAPs with mood stabilizers is a large proportion of bipolar I disorder treatment strategies.\n\nConclusions\n\nIn a Medicaid population, adults with bipolar I disorder treated with lurasidone with mood stabilizers had significantly lower all-cause and psychiatric hospitalization rates compared with those treated with olanzapine, quetiapine, and ziprasidone with mood stabilizers. Reducing the hospitalization rates could help reduce economic burden for payers and patients with bipolar disorder.\n\nConflicts of Interest\n\nThis study was funded by Sunovion Pharmaceuticals Inc. X. Niu, C. Dembek, K. Laubmeier, G. R. Williams, and M. Tocco are employees of Sunovion Pharmaceuticals Inc. S. Dennen, Y. Liu, and P. Veeranki are employees of PRECISIONheor, which received funding from Sunovion Pharmaceuticals Inc to conduct this study. The authors have indicated that they have no other conflicts of interest regarding the content of this article.\n\nAppendix Supplementary materials\n\nImage, application 1\n\nAcknowledgments\n\nThe authors thank Barbara Blaylock, PhD, from Blaylock Health Economics LLC for providing medical writing support.\n\nAll authors approved the final manuscript. X. Niu, C. Dembek, K. Laubmeier, G. R. Williams, and M. Tocco were involved in the study conception and design, interpretation of study findings, drafting/editing the manuscript, and providing final approval. S. Dennen and Y. Liu were involved in the study conception and design, conducting the analyses, interpretation of study findings, drafting/editing the manuscript, and providing final approval. P. Veeranki oversaw the data analysis.\n\nSupplementary material associated with this article can be found, in the online version, at doi:10.1016/j.curtheres.2021.100629.\n==== Refs\nReferences\n\n1 Merikangas KR Jin R He JP Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative Arch Gen Psychiatry 68 3 Mar 2011 241 251 21383262\n2 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 5th ed. 2013 Arlington, VA\n3 McIntyre RS Calabrese JR. Bipolar depression: the clinical characteristics and unmet needs of a complex disorder Curr Med Res Opin 35 11 Nov 2019 1993 2005 31311335\n4 Miller S Dell'Osso B Ketter TA. The prevalence and burden of bipolar depression J Affect Disord 169 Suppl 1 Dec 2014 S3 S11 25533912\n5 García S Martínez-Cengotitabengoa M López-Zurbano S Adherence to antipsychotic medication in bipolar disorder and schizophrenic patients: a systematic review J Clin Psychopharmacol 36 4 Aug 2016 355 371 27307187\n6 Perlick DA Rosenheck RA Clarkin JF Symptoms predicting inpatient service use among patients with bipolar affective disorder Psychiatr Serv 50 6 Jun 1999 806 812 10375151\n7 Peters AT West AE Eisner L The burden of repeated mood episodes in bipolar I disorder: results from the National Epidemiological Survey on Alcohol and Related Conditions J Nerv Ment Dis 204 2 Feb 2016 87 94 26588078\n8 Bessonova L Ogden K Doane MJ The economic burden of bipolar disorder in the United States: a systematic literature review ClinicoEconomics and Outcomes Research 12 2020 481 497 32982338\n9 Kleine-Budde K Touil E Moock J Cost of illness for bipolar disorder: a systematic review of the economic burden Bipolar Disord 16 4 Jun 2014 337 353 24372893\n10 Cloutier M Greene M Guerin A The economic burden of bipolar I disorder in the United States in 2015 J Affect Disord 226 Jan 15 2018 45 51 28961441\n11 Carvalho AF Firth J Vieta E. 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Data from the European drug surveillance program AMSP BMC Psychiatry 12 Sep 21 2012 153 22998655\n17 Fornaro M De Berardis D Koshy AS Prevalence and clinical features associated with bipolar disorder polypharmacy: a systematic review Neuropsychiatr Dis Treat 12 2016 719 735 27099503\n18 Kaiser Family Foundation Medicaid's role in financing behavioral health services for low-income individuals 2017 Available from: https://www.kff.org/medicaid/issue-brief/medicaids-role-in-financing-behavioral-health-services-for-low-income-individuals/\n19 Guo JJ Keck PE Li H Treatment costs related to bipolar disorder and comorbid conditions among Medicaid patients with bipolar disorder Psychiatr Serv 58 8 Aug 2007 1073 1078 17664518\n20 Chapel JM Ritchey MD Zhang D Prevalence and medical costs of chronic diseases among adult Medicaid beneficiaries Am J Prev Med 53 6s2 Dec 2017 S143-S154\n21 Florida Medicaid Drug Therapy Management Program for Behavioral Health. 2019–2020 Florida Best Practice Psychotherapeutic Medication Guidelines for Adults 2020 University of South Florida\n22 Ng-Mak D Halpern R Rajagopalan K Hospitalization risk in bipolar disorder patients treated with lurasidone versus other atypical antipsychotics Curr Med Res Opin 35 2 Feb 2019 211 219 29625538\n23 Niu X Veeranki P Dennen S Hospitalization risk among adults with bipolar I disorder treated with oral atypical antipsychotics: a long-term retrospective analysis of Medicaid claims data Psych Congress 2020 September 10-13, Virtual Conference, USA 2020\n24 United States Congress. Health Insurance Portability and Accountability Act of 1996. 104-191 Aug 21, 1996. Available from: https://www.gpo.gov/fdsys/pkg/PLAW-104publ191/html/PLAW-104publ191.htm\n25 Quan H Sundararajan V Halfon P Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data Med Care 43 11 Nov 2005 1130 1139 16224307\n26 Faries DE Kadziola ZA. Analysis of longitudinal observational data using marginal structural models. Analysis of observational health care data using SAS 2010 SAS Institute. Cary, NC 211 219\n27 Lage MJ Hassan MK. The relationship between antipsychotic medication adherence and patient outcomes among individuals diagnosed with bipolar disorder: a retrospective study Ann Gen Psychiatry 8 Feb 18 2009 7 19226463\n28 Broder MS Greene M Chang E Atypical antipsychotic adherence is associated with lower inpatient utilization and cost in bipolar I disorder J Med Econ 22 1 Jan 2019 63 70 30376745\n29 Loebel A Cucchiaro J Silva R Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study Am J Psychiatry 171 2 Feb 2014 169 177 24170221\n30 Calabrese JR Pikalov A Streicher C Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder Eur Neuropsychopharmacol 27 9 Sep 2017 865 876 28689688\n31 Pikalov A Tsai J Mao Y Long-term use of lurasidone in patients with bipolar disorder: safety and effectiveness over 2 years of treatment Int J Bipolar Disord 5 1 Dec 2017 9 28168632\n32 Ostacher M Ng-Mak D Patel P Lurasidone compared to other atypical antipsychotic monotherapies for bipolar depression: A systematic review and network meta-analysis World J Biol Psychiatry 19 8 Dec 2018 586 601 28264635\n33 Bahji A Ermacora D Stephenson C Comparative efficacy and tolerability of pharmacological treatments for the treatment of acute bipolar depression: A systematic review and network meta-analysis J Affect Disord 269 May 15 2020 154 184 32339131\n34 Tocco M Newcomer JW Mao Y 160 Lurasidone and metabolic syndrome: results from short- and long-term clinical studies in patients with bipolar depression CNS Spectrums 25 2 2020 302 303\n35 Stensland M Watson PR Grazier KL. An examination of costs, charges, and payments for inpatient psychiatric treatment in community hospitals Psychiatr Serv 63 7 Jul 2012 666 671 22588167\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0011-393X",
"issue": "94()",
"journal": "Current therapeutic research, clinical and experimental",
"keywords": "Atypical antipsychotics; Bipolar I disorder; Hospitalization; Medicaid; lurasidone",
"medline_ta": "Curr Ther Res Clin Exp",
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"pages": "100629",
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"pmid": "34306269",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "24170221;28168632;32921337;28203265;28961441;22588167;22998655;16224307;34127103;21383262;27099503;27307187;17664518;32339131;19226463;29153115;29536616;32609982;29950839;30376745;26588078;25533912;31311335;32982338;30556736;10375151;28689688;29625538;24372893;28264635",
"title": "Hospitalization Risk for Adults with Bipolar I Disorder Treated with Oral Atypical Antipsychotics as Adjunctive Therapy with Mood Stabilizers: A Retrospective Analysis of Medicaid Claims Data.",
"title_normalized": "hospitalization risk for adults with bipolar i disorder treated with oral atypical antipsychotics as adjunctive therapy with mood stabilizers a retrospective analysis of medicaid claims data"
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"abstract": "Apremilast is an oral selective phosphodiesterase-4 inhibitor developed recently for psoriasis treatment. The aim of this study is to assess the real-life outcomes of use of apremilast in patients with psoriasis in everyday clinical practice. A total of 159 adult patients (90 males) with plaque psoriasis were included in the study. Fifty of the patients (31%) had psoriatic arthritis. All patients started apremilast at the time of enrolment. There was a marked improvement in Psoriasis Area and Severity Index, body surface area and Dermatology Life Quality Index scores across the follow-up period (12 months). The improvements in these scores were also consistent when the patients were stratified according to increasing body mass index. Only 10.6% of the patients discontinued apremilast, because of no response. In conclusion, apremilast is an effective and safe treatment in patients with psoriasis, and its effect is not influenced by body mass index.",
"affiliations": "Dermatology Unit, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Va Vallone Petrara snc, Reggio Calabria, Italy. E-mail: Giovannamalara1@gmail.com.",
"authors": "Malara|Giovanna|G|;Politi|Cristina|C|;Trifirò|Caterina|C|;Verduci|Chiara|C|;D'Arrigo|Graziella|G|;Testa|Alessandra|A|;Tripepi|Giovanni|G|",
"chemical_list": "D013792:Thalidomide; C505730:apremilast",
"country": "Sweden",
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"doi": "10.2340/00015555-3846",
"fulltext": "\n==== Front\nActa Derm Venereol\nActa Derm Venereol\nActaDV\nActa Dermato-Venereologica\n0001-5555\n1651-2057\nSociety for Publication of Acta Dermato-Venereologica\n\n34043021\nActaDV-101-9-220\n10.2340/00015555-3846\nClinical Report\nEffectiveness of Apremilast in Real Life in Patients with Psoriasis: A Longitudinal Study\nMALARA Giovanna 1\nPOLITI Cristina 2\nTRIFIRÒ Caterina 1\nVERDUCI Chiara 3\nD’ARRIGO Graziella 2\nTESTA Alessandra 2\nTRIPEPI Giovanni 2\n1 Dermatology Unit, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”\n2 Consiglio Nazionale delle Ricerche-Istituto di Fisiologia Clinica, Section of Clinical Epidemiology and Biostatistics, Reggio Calabria\n3 Department, Magna Grecia University, Catanzaro, Italy\nCorr: Giovanna Malara, Dermatology Unit, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, Va Vallone Petrara snc, Reggio Calabria, Italy. E-mail: giovannamalara1@gmail.com\n15 9 2021\n2021\n101 9 22026 5 2021\n© 2021 Acta Dermato-Venereologica\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license\nApremilast is an oral selective phosphodiesterase-4 inhibitor developed recently for psoriasis treatment. The aim of this study is to assess the real-life outcomes of use of apremilast in patients with psoriasis in everyday clinical practice. A total of 159 adult patients (90 males) with plaque psoriasis were included in the study. Fifty of the patients (31%) had psoriatic arthritis. All patients started apremilast at the time of enrolment. There was a marked improvement in Psoriasis Area and Severity Index, body surface area and Dermatology Life Quality Index scores across the follow-up period (12 months). The improvements in these scores were also consistent when the patients were stratified according to increasing body mass index. Only 10.6% of the patients discontinued apremilast, because of no response. In conclusion, apremilast is an effective and safe treatment in patients with psoriasis, and its effect is not influenced by body mass index.\n\nKey words\n\npsoriasis\npsoriatic arthritis\napremilast\nobesity\nretention rate\n==== Body\npmcPsoriasis is a common chronic systemic inflammatory skin disease that affects people of all ages worldwide (1). The prevalence rate of psoriasis is highly variable, depending on the geographical area (ranging from 0.09% to 11.4%) (2), and, in the Western population, is estimated as 2–4% (1). Although the aetiology of the disease is unclear, psoriasis is widely regarded as a complex disorder caused by the interaction between inherited susceptibility alleles and environmental risk factors denominated triggers (e.g. trauma, bacterial and virus infectious diseases, smoking, stress, obesity, and alcohol consumption) (3–5). The common type is plaque psoriasis, which is characterized by inflammatory plaques on the skin. These papulo-squamous lesions, often pruritic and/or painful, can arise in a classic skin sites, such as knees, elbows, scalp, and lumbar area, but also in difficult areas of the skin (nails, scalp, palms of the hands and soles of the feet) (6). The main molecular signatures of the disease are the over-production of inflammatory cytokines that lead an alteration of the immune response. In particular, myeloid dendritic cells play a key role, secreting interleukin (IL)-12 and IL-23 that activate T-helper-cells, which produce IL-17, tumour necrosis factor (TNF), interferon (IFN)γ and IL-22. This mechanism causes premature maturation of keratinocytes, infiltration of the dermis by leukocytes, and dilatation of blood vessels, leading to hyperproliferation of the epidermal layer with consequent plaque formation (7, 8). Given its multifactorial nature, the disease may present heterogeneous manifestations; several studies have reported that one-third of patients present concomitant psoriatic arthritis (PsA), an inflammatory spondyloarthropathy, and others several metabolic diseases, such as obesity, diabetes, fatty liver disease, metabolic syndrome, and cardiovascular diseases (9–12). The complexity of the possible manifestations lead the patients to experience reduced health-related quality of life (QoL), resulting in physical and mental disability (13, 14). Treatments for psoriatic disease are numerous, they can be topical and/or photo-therapies for the patients with mild disease, whereas those with moderate-to-severe disease require traditional systemic therapies (disease-modifying anti-rheumatic drugs; DMARD), such as fumaric acid esters, retinoids, methotrexate, cyclosporine, or newer biologic systemic therapies (e.g. infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab) (15, 16). Because of the chronic nature of psoriatic disease, long-term treatment is often required (17). Patients’ dissatisfaction with the current treatments often lead to reduced compliance with therapy and, consequently, worsening of the disease (18). This may be due to a deterioration in health status due to tolerability issues, safety concerns (e.g. concerns over infection or malignancy with biological agents) and lack or loss of effectiveness, but also for psychological reasons, such as the administration modality (e.g. the burden imposed by subcutaneous or intravenous routes of administration) (19,20). A therapeutic alternative for patients with psoriasis and/or PsA who fail to respond to, or have contraindications to, other systemic therapies is apremilast, an oral selective phosphodiesterase-4 (PDE4) inhibitor approved by the US Food and Drug Administration (FDA) in 2014 and by the European Medicines Agency (EMA) in 2015 (21, 22). PDE4 regulates the inflammatory response by degrading cyclic adenosine 3,5-monophosphate (cAMP), an intracellular second messenger. Inhibition of PDE4 increases the level of cAMP, which results in decreased production of pro-inflammatory cytokine (IFN-γ,TNF-α, IL-12, IL-17, and IL-23) and an increase in anti-inflammatory mediator (IL-10) (23). The efficacy and good safety profiles of apremilast have been documented by different randomized trials (24–29), whereas data on real-life prospective studies in patients with psoriasis and or PsA in treatment with apremilast are scarce (8, 30–32).\n\nSIGNIFICANCE\n\nApremilast is an oral selective phosphodiesterase-4 inhibitor developed recently for psoriasis treatment. In 159 adult patients with psoriasis (90 males; 50 patients had psoriatic arthritis), the real-life outcomes of apremilast use were assessed in everyday clinical practice. All patients started apremilast treatment at the time of enrolment and were followed up for 12 months. There was a marked improvement in the clinical index related to disease severity and psychological distress. The effectiveness of apremilast was not influenced by body mass index. Only 10.6% of the patients discontinued apremilast, indicating that it is a safe treatment.\n\nTherefore, the aim of this observational, prospective, longitudinal, real-world study is to assess the long-term real-life effectiveness, safety and tolerability of apremilast among patients with psoriasis and/or PsA, paying particular attention at drug survival (time until drug discontinuation), because this is an important factor reflecting a drug’s long-term effectiveness in real life.\n\nMETHODS\n\nThe protocol was approved by the ethics committee of Unit of Dermatology, Grande Ospedale Metropolitano BMM di Reggio Calabria, Italy and all participants provided written informed consent.\n\nPatients\n\nThis real-life prospective, observational study included a total of 159 patients with a diagnosis of plaque psoriatic (90 males; 50 patients had PsA). Adult patients (> 18 years of age) were recruited from the Unit of Dermatology of Reggio Calabria Hospital, Italy. All patients with a diagnosis of psoriasis and/or PsA were included and, at the time of enrolment, they started treatment with apremilast (incident users or new users). The drug was used according to the labelled indications and posology. At the baseline visit demographic and clinical-anamnestic data of the patients were collected, such as sex, age, height, weight, body mass index (BMI), smoking status, family history of psoriasis and/or PsA, joint involvement, age of onset of the disease, previous conventional anti-psoriatic therapies (topical, systemic and/or biologic), the presence of other comorbidities and related therapies. As for effectiveness endpoints (Psoriasis Area and Severity Index (PASI), body surface area (BSA) and Dermatology Life Quality Index (DLQI)), the patients were followed up for 1 year. Information on drug discontinuation was collected over a period of 38 months. All participants were in stable clinical condition, none were pregnant or affected by cancer or diseases in the terminal phase. Data collection was performed between 16 May 2016 and 2 February 2020.\n\nDrug administration/dose\n\nAccording to the FDA and EMA indications, all enrolled patients received apremilast according to the labelled indications and posology (10 mg per os (PO)), which was titrated up to the maintenance dose of 30 mg PO twice daily.\n\nInclusion/exclusion criteria\n\nData from both male and female consecutive patients who started treatment with apremilast, aged ≥18 years and who accepted to take part into the study, with moderate-to-severe plaque psoriasis who had failed at least one systemic therapy or relapsed immediately after achieving significant improvement or had contraindications for standard systemic therapies, were considered for inclusion in this study. According to the national prescription rules established by AIFA (Italian Medicines Agency), the PASI has to be either >10 or < 10 if special if specific areas of the body are affected (face, palm-plantar, nails, genitals). Topical anti-psoriatic treatment, but not concomitant systemic therapy for PsA and/or psoriasis, was allowed.\n\nOutcome assessment\n\nThe severity of psoriasis was assessed with the PASI, which is a measure of the average redness, thickness, and scaling of the lesions (each graded on a 0–4 scale), weighted by the area of involvement. The percentage of BSA involved was also measured in categories of 0%, 1–3%, 4–9%, 10–20%, 21– 29%, 30–50% and 51–100%. Quality of life was assessed with the DLQI. These outcomes were collected in all patients, at baseline, 3, 6 and 12 months. Outcome variables PASI 50, PASI 75, PASI 90 and PASI 100 were also considered. Relapse was defined as loss of 50% of PASI improvement from baseline in patients who achieve a clinically meaningful response.\n\nSafety assessment\n\nSafety assessment was performed by analysing the adverse events (AEs) reported by the patients during treatment. The primary safety endpoint was the percentage of patients experiencing grade 3–4 AEs during 24 weeks of treatment.\n\nStatistical analysis\n\nDescriptive statistics were calculated for each variable, using frequencies and percentage for categorical variables, mean ± standard deviation (SD) for normally distributed data or median and interquartile range (IQR) for non-normally distributed data. As a measure of uncertainty around an estimate (see Table SI1) the 95% confidence interval (95% CI) was adopted. Comparisons between 2 groups were made with Student’s t-test, Mann–Whitney test or χ2 test, while comparisons among more than 2 groups were performed by analysis of variance (ANOVA) and Kruskal–Wallis test, as appropriate. To evaluate the treatment effectiveness the following outcome variables were considered: PASI, BSA, and DLQI. The values of these measures were considered as absolute score and as median and IQR value at each patient’s visit (3, 6, and 12 months). Psoriasis severity was classified based on PASI/BSA/DLQI scores as mild when all 3 scores were < 10 and as moderate–severe when at least 1 of these parameters was ≥ 10. Safety and tolerability outcomes were evaluated by collecting the adverse events (AEs) in the course of apremilast treatment. Reasons for treatment withdrawal were also recorded as primary inefficacy, secondary failure and AEs. Kaplan–Meier statistical analysis was used to estimate the free “drug discontinuation” cumulative survival; censored patients were those who were still on treatment on May 2020 (the lock date), or patients who were lost to follow-up. The statistical significance of the PASI, BSA and DLQI changes over time was investigated by linear mixed models, a method that specifically allows missing values to be taken into account, as well as by linear regression analyses weighted by patient’s identifier. The effect of BMI on the time to drug discontinuation was investigated by Cox regression analysis. In this analysis, data were expressed as hazard ratio, 95% CI and p-value. Data analysis was performed with a standard statistical package (SPSS for Windows, Version 19, Chicago, IL, USA).\n\nRESULTS\n\nThe main demographic and clinical characteristics of patients enrolled in the study are shown in Table I. Their mean age was 53 years, 57% were males and 17.6 were habitual smokers. Forty-seven patients had hypertension, 36 dyslipidaemia, and 28 were diabetic. At baseline, the median values of PASI, BSA and DLQI were 7.0, 8.0, and 14, respectively. The remaining clinical characteristics of patients are shown in Table I.\n\nTable I Demographic and clinical characteristics at baseline of treatment with Apremilast in a population of 159 patients with psoriasis and/or psoriatic arthritis\n\nCharacteristics\t\t\nDemographic and clinical characteristics\t\nAge, years, mean ± SD\t53 ± 15\t\nMale sex, n (%)\t90 (56.6)\t\nSmoker, n (%)\t28 (17.6)\t\nBody mass index, kg/m2, mean ± SD\t27.9 ± 5.1\t\nBody mass index>25 kg/m2, n (%)\t111 (69.8)\t\nComorbidities, n (%)\t\nHypertension\t47 (29.6)\t\nDyslipidaemia\t36 (22.6)\t\nDiabetes mellitus\t28 (17.6)\t\nPsoriatic disease\t\nPsoriatic disease familiar history, n (%)\t47 (29.6)\t\nAge at onset, years, mean ± SD\t39 ± 16\t\nPlaque psoriatic, n (%)\t109 (68.6)\t\nPsoriatic arthritis, n (%)\t50 (31.4)\t\nBaseline Psoriasis Area and Severity Index, median (IQR)\t7.0 (5.3–10.9)\t\nBaseline Body surface area, median (IQR)\t8.0 (6.0–13.2)\t\nBaseline Dermatology Life Quality Index, median (IQR)\t14 (10–18)\t\nPsoriatic lesions distribution, n (%)\t\nPalmoplantar areas\t38 (23.9)\t\nScalp\t27 (17.0)\t\nGenital areas\t24 (15.1)\t\nFace\t17 (10.7)\t\nNails\t16 (10.1)\t\nLower limbs\t7 (4.4)\t\nSubmammary area\t3 (1.9)\t\nUpper limbs\t2 (1.3)\t\nPrior anti-psoriatic treatment, n (%)\t\nTopic\t158 (99.4)\t\nSystemic\t95 (59.7)\t\nBiologic\t32 (20.1)\t\nSD: standard deviation; IQR: interquartile range.\n\nLongitudinal analysis of response to apremilast in the whole study sample\n\nThe evolution over time of PASI, BSA and DLQI as continuous variables as shown in Fig. 1. As plotted in the figure, both the indicators of disease severity (PASI and BSA, Fig. 1a, b) and of quality of life (DLQI, Fig. 1c) improved significantly over time. Of note, linear mixed model analysis, which accounts for missing values over time, showed that PASI, BSA and DLQI reduced by 0.58, 0.65 and 0.75 per month, and such improvements were highly significant (Fig. 1). The analysis of PASI≥50, PASI≥75, PASI≥90, and PASI 100 (Table SI1) confirmed a gradual and sustained improvement in the disease across visits.\n\nFig. 1 Median (interquartile range) of (a) Psoriasis Area and Severity Index (PASI), (b) body surface area (BSA) and (c) Dermatology Life Quality Index (DLQI) in patients treated with apremilast at the scheduled follow-up visits (TO, T3, T6, T12).\n\nLongitudinal analysis of response to apremilast by body mass index categories\n\nPatients were stratified according to BMI tertiles (<25.3, 25.3–29.4 and >29.4 kg/m2). The effect of BMI on the response to apremilast in terms of PASI, BSA and DLQI was investigated by considering these outcomes as continuous variables (Fig. 2). This analysis showed a sustained improvement across visits for the disease and quality of life, which was of a similar degree across BMI categories. The same analysis by BMI strata carried out according to PASI≥50, PASI≥75, PASI≥90 and PASI 100 provided similar results (Fig. S11).\n\nFig. 2 Median (interquartile range) of (a) Psoriasis Area and Severity Index (PASI), (b) body surface area (BSA) and (c) Dermatology Life Quality Index (DLQI) in patients treated with apremilast at the scheduled follow-up visits (TO: white bar, T3: light-grey bar, T6: grey bar, T12: dark-grey bar) stratified according to body mass index (BMI) tertiles.\n\nSafety and drug discontinuation\n\nAt the end of the follow-up, the majority of patients were still on treatment with apremilast (Fig. 3a), whereas 2 patients interrupted the study because of disease resolution. A total of 28 patients were lost to follow-up, 1 patient died and 17 patients discontinued the study because of no response (Fig. 3a). The Kaplan–Meier analysis of time to drug discontinuation in 17 patients who discontinued apremilast is shown in Fig. 3b. The median time to drug discontinuation was 6.3 months (95% CI 5.7–7.0 months). Of note, BMI was largely unrelated to the time to the drug discontinuation (hazard ratio 1.03, 95% CI 0.93–1.14, p = 0.56). No major adverse events were observed across the follow-up period.\n\nFig. 3 (a) Events during follow-up. Only 17 patients were nonresponders to the apremilast treatment (10.6%); (b) Kaplan– Meier survival curve showing the time to “drug discontinuation” in 17 patients who were non-responders to apremilast. The follow-up time corresponding to the condition of 111 patients still on treatment (mean ± standard error) 11.9 ± 0.9 months. Patients “lost to follow-up” included those who changed residence and/or were unwilling to participate in the scheduled follow-up visits.\n\nDISCUSSION\n\nThis real-life study confirms the effectiveness and safety of treatment with apremilast in patients with psoriasis, and documented that such protective effect is consistent across BMI categories.\n\nInflammation is an evolutionary conservative process that protects the host from bacteria, viruses, toxins and infections through the activation of immune and non-immune cells by eliminating pathogens and promoting tissue recovery and repair (33, 34). It is also the driving factor in many diseases, including infections, cancer, immune-mediated, metabolic and neurodegenerative disorders (35). For many years, non-steroidal anti-inflammatory drugs (NSAIDs) (36) and corticosteroids have made a major contribution to treating inflammatory diseases; nevertheless, their long term use can cause severe organ toxicity and several other side-effects. To date, numerous new therapeutic options, particularly designed for long-term use, have emerged for better controlling the inflammatory processes, underling the above-mentioned diseases (37–40). Beyond biologicals, which control immunological dysregulation by inhibiting extracellular inflammatory molecules (extracellular pathways), other molecules, such as apremilast, a phosphodiesterase-4 inhibitor (PDE-4), act in an intracellular manner (41). PDE4 inhibition results in the accumulation of the intracellular second messenger cAMP, downstream activation of protein kinase A (PKA), and subsequent phosphorylation of the transcription factor cAMP-response element binding protein (CREB). Activation of this pathway modulates gene transcription of numerous cytokines, and results in the suppression of TNFα production and other pro-inflammatory cytokines. PDE4 inhibition can also increase the production of anti-inflammatory cytokines from macrophages, and interfere with the phenotype and function of B cells. In addition, it can promote the barrier function of keratinocytes and epithelial cells via suppression of the inflammatory mediator production (41, 42). As a consequence of its wide anti-inflammatory activities, apremilast, a PDE4 inhibitor, has been evaluated for the treatment of several skin disorders or rheumatic diseases, such as psoriasis and PsA (41). Much of the data supporting the efficacy and safety of apremilast in the treatment of psoriasis and PsA come from clinical trials (24–29). Real-life treatment outcomes may differ from clinical trial results, due to preselected patient cohorts in clinical trials. This study documented a marked improvement in PASI, BSA and DLQI across an extended follow-up period (12 months). Indeed, PASI 75 increased from 17.7% (T0) to 69.1% (T12) and PASI 90 and PASI 100 increased from 4.2% and 2.1% (T0) to 41.2% and 20.6%, respectively, at T12. Of note, these results were confirmed by an additional analysis by linear mixed models, an analytical approach, which specifically takes into account the presence of missing values over time. The proportion of patients who achieved PASI 75 after approximately 16 weeks of treatment with apremilast was higher in a study by Papp (25) than was found in the current study (33.1% vs 17.7%). This difference probably depends on differences in baseline characteristics of patients between the 2 studies. Compared with those enrolled in the current study, patients enrolled in Papp’s study (25) were younger (46 vs 53 years) and displayed more severe disease (PASI score, 19 vs 9; BSA score, 25 vs 10). It is a consolidated notion that the higher the severity of the disease, the higher the margin of improvement. Thus, the difference in PASI 75 response rate at 3 months between the current study and Papp’s study probably depends on the higher severity of the disease in patients in Papp’s study (25). In Papp’s study, no obese patient achieved PASI 50, which may depend on the fact that only 6 patients in their study were obese. In the current study 47 patients had a BMI >30 kg/m2. The higher the number of obese patients, the greater the possibility of observing any disease improvement occurring in this patient category.\n\nAs mentioned above, psoriasis is a chronic skin inflammatory disease, with an estimated prevalence of approximately 2–3% among the Caucasian population (43), of whom 2–3% develop PsA (44). Psoriasis has also been identified as a multisystem chronic inflammatory disorder associated with multiple comorbidities, including cardio-metabolic disorders (type 2 diabetes, dyslipidaemia, metabolic syndrome, obesity, hypertension, non alcoholic liver fatty disease) and chronic kidney disease (45, 46). Patients with psoriasis are more frequently overweight or obese than the general population, and the severity of psoriasis correlates with BMI (47).\n\nThe current study found that the improvements in PASI (either as continuous (Fig. 2) or categorical (Fig. S11) variables), BSA and DLQI were consistent across BMI categories indicating that overweight/obesity does not affect the real-life effectiveness of apremilast in patients with psoriasis. The pathophysiological mechanisms connecting psoriasis and obesity lie in the increased systemic inflammation induced by adipose tissue, particularly by visceral adipose tissue, which acts as an endocrine organ releasing adipokines. The between pro- and anti-inflammatory adipokines imbalance in obsesity provides the development of a chronic low-grade inflammatory state, which could trigger or worsen psoriasis (48). In psoriatic patients, obesity may predict lower efficacy for systemic conventional and biologic drugs, especially for those with fixed-dose (49, 50). However, no meaningful effect of BMI on the effectiveness of apremilast was found in the current study.\n\nIn the study population, only 17 patients out of 159 (i.e. 10.6%) discontinued apremilast because of no response, and the Kaplan–Meier analysis in these patients showed that the median time to drug discontinuation was 7 months. No grade 3/4 AEs were observed across the follow-up period. The difference in the number of AEs between the current study and that of Vujic et al. (8) can be explained by the fact that the current study protocol involved collection only of grades 3–4 AEs.\n\nIn conclusion, apremilast is an effective and safe treatment in patients with psoriasis, and this effect is not influenced by BMI.\n\nThe authors have no conflicts of interest to declare.\n\n1 https://doi.org/10.2340/00015555-3846\n==== Refs\nREFERENCES\n\n1 Michalek IM, Loring B, John SM. A systematic review of worldwide epidemiology of psoriasis. J Eur Acad Dermatol Venereol 2017; 31 : 205–212.27573025\n2 Parisi R, Symmons DP, Griffiths CE, Ashcroft DM; Identification and Management of Psoriasis and Associated ComorbidiTy (IMPACT) project team. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol 2013; 133 : 377–385.23014338\n3 Caputo V, Strafella C, Termine A, Dattola A, Mazzilli S, Lanna C, et al . Overview of the molecular determinants contributing to the expression of psoriasis and psoriatic arthritis phenotypes. J Cell Mol Med 2020; 24 : 13554–13563.33128843\n4 Capon F. The genetic basis of psoriasis. Int J Mol Sci 2017; 18 : 2526.\n5 Chandra A, Ray A, Senapati S, Chatterjee R. Genetic and epigenetic basis of psoriasis pathogenesis. Mol Immunol 2015; 64 : 313–323.25594889\n6 Vangipuram R, Alikhan A. Apremilast for the management of moderate to severe plaque psoriasis. Expert Rev Clin Pharmacol 2017; 10 : 349–360.28276777\n7 Zerilli T, Ocheretyaner E. Apremilast (Otezla): a new oral treatment for adults with psoriasis and psoriatic arthritis. P T 2015; 40 : 495–500.26236137\n8 Vujic I, Herman R, Sanlorenzo M, Posch C, Monshi B, Rappersberger K, et al . Apremilast in psoriasis – a prospective real-world study. J Eur Acad Dermatol Venereol 2018; 32 : 254–259.28925560\n9 Gisondi P, Galvan A, Idolazzi L, Girolomoni G. Management of moderate to severe psoriasis in patients with metabolic comorbidities. Front Med (Lausanne) 2015; 2 : 1.25654080\n10 Carrascosa JM, Bonanad C, Dauden E, Botella R, Olveira-Martín A; en nombre del Grupo de Trabajo en Inflamación Sistémica en Psoriasis. psoriasis and nonalcoholic fatty liver disease. Actas Dermosifiliogr 2017; 108 : 506–514.28318525\n11 Takeshita J, Grewal S, Langan SM, Mehta NN, Ogdie A, Van Voorhees AS, et al . Psoriasis and comorbid diseases: epidemiology. J Am Acad Dermatol 2017; 76 : 377–390.28212759\n12 Masson W, Lobo M, Molinero G. Psoriasis and cardiovascular risk: a comprehensive review. Adv Ther 2020; 37 : 2017–2033.32314303\n13 Nicholas MN, Gooderham M. Psoriasis, depression, and suicidality. Skin Therapy Lett 2017; 22 : 1–4.\n14 Sendrasoa FA, Razanakoto NH, Ratovonjanahary V, Raharolahy O, Ranaivo IM, Andrianarison M, et al . Quality of life in patients with psoriasis seen in the Department of Dermatology, Antananarivo, Madagascar. Biomed Res Int 2020; 2020 : 9292163.33015185\n15 Gisondi P, Girolomoni G. Apremilast in the therapy of moderate-to-severe chronic plaque psoriasis. Drug Des Devel Ther 2016; 10 : 1763–1770.\n16 Keating GM. Apremilast: A review in psoriasis and psoriatic arthritis. Drugs 2017; 77 : 459–472.28213862\n17 Kim WB, Jerome D, Yeung J. Diagnosis and management of psoriasis. Can Fam Physician 2017; 63 : 278–285.28404701\n18 Belinchón I, Rivera R, Blanch C, Comellas M, Lizán L. Adherence, satisfaction and preferences for treatment in patients with psoriasis in the European Union: a systematic review of the literature. Patient Prefer Adherence 2016; 10 : 2357–2367.27895471\n19 Seale L, Cardwell LA, Feldman SR. Adherence to biologics in patients with psoriasis. Expert Rev Clin Immunol 2018; 14 : 155–161.29327643\n20 Augustin M, Holland B, Dartsch D, Langenbruch A, Radtke MA. Adherence in the treatment of psoriasis: a systematic review. Dermatology 2011; 222 : 363–374.21757881\n21 Fala L. Otezla (apremilast), an oral PDE-4 inhibitor, receives FDA approval for the treatment of patients with active psoriatic arthritis and plaque psoriasis. Am Health Drug Benefits 2015; 8 : 105–110.26629274\n22 European Medicines Agency. (2015). Otezla summary of product characteristics. Available from https://www.ema.europa.eu/en/documents/product-information/otezlaeparproductinformationen.pdf.\n23 Schafer PH, Parton A, Capone L, Cedzik D, Brady H, Evans JF, et al . Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal 2014; 26 : 2016–2029.24882690\n24 Mease PJ. Apremilast: a phosphodiesterase 4 inhibitor for the treatment of psoriatic arthritis. Rheumatol Ther 2014; 1 : 1–20.27747762\n25 Papp K, Reich K, Leonardi CL, Kircik L, Chimenti S, Langley RG, et al . Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol 2015; 73 : 37–49.26089047\n26 Paul C, Cather J, Gooderham M, Poulin Y, Mrowietz U, Ferrandiz C, et al . Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol 2015; 173 : 1387–1399.26357944\n27 Cutolo M, Myerson GE, Fleischmann RM, Lioté F, Díaz-González F, Van den Bosch F, et al . A Phase III, Randomized, controlled trial of apremilast in patients with psoriatic arthritis: results of the PALACE 2 trial. J Rheumatol 2016; 43 : 1724–1734.27422893\n28 Edwards CJ, Blanco FJ, Crowley J, Birbara CA, Jaworski J, Aelion J, et al . Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3). Ann Rheum Dis 2016; 75 : 1065–1073.26792812\n29 Reich K, Gooderham M, Green L, Bewley A, Zhang Z, Khanskaya I, et al . The efficacy and safety of apremilast, etanercept, and placebo, in patients with moderate to severe plaque psoriasis: 52-week results from a phase 3b, randomized, placebo controlled trial (LIBERATE) J Eur Acad Dermatol Venereol 2016; 31 : 507–517.27768242\n30 Fink C, Schank TE, Trenkler N, Uhlmann L, Schäkel K. Quality of life, treatment satisfaction and efficacy of non-biological systemic therapies in patients with plaque psoriasis: study protocol for a prospective observational study. BMJ Open 2017; 7 : e014279.\n31 Knuckles MLF, Levi E, Soung J. Treating moderate plaque psoriasis: prospective 6-month chart review of patients treated with apremilast. J Dermatolog Treat 2019; 30 : 430–434.30339049\n32 Balato A, Campione E, Cirillo T, Malara G, Trifirò C, Bianchi L, et al . Long-term efficacy and safety of apremilast in psoriatic arthritis: focus on skin manifestations and special populations. Dermatol Ther 2020; 33 : e13440.32306448\n33 Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, et al . Chronic inflammation in the etiology of disease across the life span. Nat Med 2019; 25 : 1822–1832.31806905\n34 Uguccioni M, Teixeira MM, Locati M, Mantovani A. Editorial: regulation of inflammation, its resolution and therapeutic targeting. Front Immunol 2017; 8 : 415.28458666\n35 Netea MG, Balkwill F, Chonchol M, Cominelli F, Donath MY, Giamarellos-Bourboulis EJ, et al . A guiding map for inflammation. Nat Immunol 2017; 18 : 826–831.28722720\n36 Hart FD, Huskisson EC. Non-steroidal anti-inflammatory drugs. Current status and rational therapeutic use. Drugs 1984; 27 : 232–255.6368185\n37 Baumgart DC, Misery L, Naeyaert S, Taylor PC. Biological therapies in immune-mediated inflammatory diseases: can biosimilars reduce access inequities? Front Pharmacol 2019; 10 : 279.30983996\n38 Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Ann Rheum Dis 2018; 77 : 175–187.28765121\n39 Malara G, Trifirò C, Bartolotta A, Giofré C, D’Arrigo G, Testa A, et al . Real-world effectiveness and safety of Guselkumab for the treatment of psoriasis: a 6-month prospective study in a series of psoriatic patients. Eur Rev Med Pharmacol Sci 2021; 25 : 406–412.33506930\n40 Gisondi P, Talamonti M, Chiricozzi A, Piaserico S, Amerio P, Balato A, et al . Treat-to-target approach for the management of patients with moderate-to-severe plaque psoriasis: Consensus Recommendations. Dermatol Ther (Heidelb) 2021; 11 : 235–252.33426634\n41 Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 2014; 13 : 290–314.24687066\n42 Kumar N, Goldminz AM, Kim N, Gottlieb AB. Phosphodiesterase 4-targeted treatments for autoimmune diseases. BMC Med 2013; 11 : 96.23557064\n43 Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, et al . Identification of 15 new psoriasis susceptibility loci high lights the role of innate immunity. Nat Genet 2012; 44 : 1341–1348.23143594\n44 Palfreeman AC, McNamee KE, McCann FE. New developments in the management of psoriasis and psoriatic arthritis: a focus on apremilast. Drug Des Devel Ther 2013; 7 : 201–210.\n45 Gisondi P, Farina S, Giordano M V, Girolomoni G. Usefulness of the Framingham risk score in patients with chronic psoriasis. Am J Cardiol 2010; 106 : 1754–1757.21055711\n46 Gisondi P, Girolomoni G. Cardio-metabolic comorbidities and the approach to patients with psoriasis. Actas Dermosifiliogr 2009; 100 : 14–21.20096157\n47 Kumar S, Han J, Li T, Qureshi A. Obesity, waist circumference, weight change and the risk of psoriasis in US women. J Eur Acad Dermatol Venereol 2013; 27 : 1293–1298.23057623\n48 Davidovici BB, Sattar N, PrinzJ C, Jörg PC, Puig L, Emery P, et al . Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and comorbid conditions. J Invest Dermatol 2010; 130 : 1785–1796.20445552\n49 Zweegers J, van den Reek JM, van de Kerkhof PC, Otero ME, Kuijpers AL, Koetsier MI, et al . Body mass index predicts discontinuation due to ineffectiveness and female sex predicts discontinuation due to side-effects in patients with psoriasis treated with adalimumab, etanercept or ustekinumab in daily practice: a prospective, comparative, long-term drug-survival study from the BioCAPTURE registry. Br J Dermatol 2016; 175 : 340–347.26989852\n50 Paroutoglou K, Papadavid A, Christodoulatos GS, Dalamaga M. Deciphering the association between psoriasis and obesity: current evidence and treatment considerations. Curr Obes Rep 2020; 9 : 165–178.32418186\n\n",
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"keywords": " apremilast; obesity; psoriatic arthritis; retention rate; psoriasis",
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"mesh_terms": "D000328:Adult; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D011565:Psoriasis; D012720:Severity of Illness Index; D013792:Thalidomide",
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"title": "Effectiveness of Apremilast in Real Life in Patients with Psoriasis: A Longitudinal Study.",
"title_normalized": "effectiveness of apremilast in real life in patients with psoriasis a longitudinal study"
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"abstract": "Severe, life-threatening adverse reactions to capecitabine sometimes occur in the treatment of solid tumors. Screening for dihydropyrimidine dehydrogenase (DPYD) deficiency is encouraged before start of treatment, but the genetic variants that are commonly analyzed often fail to explain toxicities seen in clinical practice. Here we describe the case of a 79-year-old Caucasian female with breast cancer who presented with life-threatening, rapidly increasing toxicity after 1 week of treatment with capecitabine and for whom routine genetic DPYD test resulted negative. DPYD exon sequencing found variant c.2242+1G>T at the donor splicing site of exon 19. This variant is responsible for skipping of exon 19 and subsequent generation of a non-functional DPYD enzyme. This variant has not been described previously but was found in three other members of the patient's family. With this case, we show that exon sequencing of DPYD in patients who experience marked toxicity to fluoropyrimidines and test negative for commonly evaluated variants can prove extremely useful for identifying new genetic variants and better explain adverse reactions causality.",
"affiliations": "Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, luis.lopez@iisgm.com.;Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.;Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, luis.lopez@iisgm.com.;Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, luis.lopez@iisgm.com.;Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, luis.lopez@iisgm.com.;Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, luis.lopez@iisgm.com.;Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.;Department of Pharmacology, Institut Claudius-Regaud, CRCT, Université de Toulouse, Inserm, UPS, Toulouse, France.;Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, luis.lopez@iisgm.com.;Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, luis.lopez@iisgm.com.;Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.;Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, luis.lopez@iisgm.com.",
"authors": "García-González|Xandra|X|;López-Tarruella|Sara|S|;García|María Isabel|MI|;González-Haba|Eva|E|;Blanco|Carolina|C|;Salvador-Martin|Sara|S|;Jerez|Yolanda|Y|;Thomas|Fabienne|F|;Jarama|María|M|;Sáez|María Sanjurjo|MS|;Martín|Miguel|M|;López-Fernández|Luis Andrés|LA|",
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"doi": "10.2147/CMAR.S174470",
"fulltext": "\n==== Front\nCancer Manag ResCancer Manag ResCancer Management and ResearchCancer Management and Research1179-1322Dove Medical Press 10.2147/CMAR.S174470cmar-10-4517Case ReportSevere toxicity to capecitabine due to a new variant at a donor splicing site in the dihydropyrimidine dehydrogenase (DPYD) gene García-González Xandra 1*López-Tarruella Sara 2*García María Isabel 1González-Haba Eva 1Blanco Carolina 1Salvador-Martin Sara 1Jerez Yolanda 2Thomas Fabienne 3Jarama María 1Sáez María Sanjurjo 1Martín Miguel 2López-Fernández Luis Andrés 1\n1 Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain, luis.lopez@iisgm.com\n2 Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain\n3 Department of Pharmacology, Institut Claudius-Regaud, CRCT, Université de Toulouse, Inserm, UPS, Toulouse, FranceCorrespondence: Luis Andrés López-Fernández, General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Servicio de Farmacia, Doctor Esquerdo 46, 28007, Madrid, Spain, Tel +34 91 426 5026, Email luis.lopez@iisgm.com* These authors contributed equally to this work\n\n2018 11 10 2018 10 4517 4522 © 2018 García-González et al. This work is published and licensed by Dove Medical Press Limited2018The 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.Severe, life-threatening adverse reactions to capecitabine sometimes occur in the treatment of solid tumors. Screening for dihydropyrimidine dehydrogenase (DPYD) deficiency is encouraged before start of treatment, but the genetic variants that are commonly analyzed often fail to explain toxicities seen in clinical practice. Here we describe the case of a 79-year-old Caucasian female with breast cancer who presented with life-threatening, rapidly increasing toxicity after 1 week of treatment with capecitabine and for whom routine genetic DPYD test resulted negative. DPYD exon sequencing found variant c.2242+1G>T at the donor splicing site of exon 19. This variant is responsible for skipping of exon 19 and subsequent generation of a non-functional DPYD enzyme. This variant has not been described previously but was found in three other members of the patient’s family. With this case, we show that exon sequencing of DPYD in patients who experience marked toxicity to fluoropyrimidines and test negative for commonly evaluated variants can prove extremely useful for identifying new genetic variants and better explain adverse reactions causality.\n\nKeywords\npharmacogeneticsadverse drug reactionfluoropyrimidinebreast cancer\n==== Body\nIntroduction\nCapecitabine is an oral prodrug of 5-fluorouracil (5-FU) that is rapidly and extensively absorbed in the intestine before conversion to 5-FU.1 Severe, life-threatening, and even fatal toxicity has been associated with deficient dihydropyrimidine dehydrogenase (DPYD) activity in patients receiving fluoropyrimidine-based chemotherapy at standard doses.2 Capecitabine-induced adverse reactions include severe hand-foot syndrome, gastrointestinal toxicity, hematological toxicity, and cardiotoxicity.3,4\n\nLow DPYD activity is partly explained by genetic variability in the DPYD gene, which is highly polymorphic.5,6 However, only a few variants (ie, rs3918290 [DPYD*2A], rs55886062 [DPYD*13], and rs67376798) have been clearly associated with severe toxicity to fluoropyrimidines. In our hospital, genotyping of these three variants is available on request for patients starting fluoropyrimidine therapy and has proved to be cost-effective.7 Nonetheless, this test enables us to avoid only 10%–15% of capecitabine-related severe adverse reactions, thus strongly suggesting that other genetic variants in DPYD or in other genes might also be implicated.8 DPYD phenotyping based on the measurement of the enzyme activity in peripheral blood mononuclear cells is another proposed approach to minimize life-threatening toxicity.9 It is yet to be discerned which of these approaches offers the better predictive value and is the most cost-effective to implement or whether a combination of both would be the preferred choice.\n\nCase report\nA 79-year-old Caucasian woman was diagnosed with poorly differentiated carcinoma that appeared to have originated in breast tissue. She underwent a second-line chemotherapy based on capecitabine (2 weeks on and 1 week off, total dose of 2,600 mg/day in days 1–14).\n\nAfter 8 days of treatment, she visited the emergency room with progressive asthenia, grade 1 diarrhea, and grade 1 mucositis and was discharged after parenteral fluid support and intensive treatment with loperamide. Capecitabine was discontinued after 48 hours (cumulative dose 26 g) owing to rapidly increasing toxicity despite oral rehydration and a standard dose of loperamide. The main symptoms were diarrhea (grade 2), nausea (grade 2), odynophagia (grade 2), severe solid dysphagia, painful mucositis (grade 3), and progressive asthenia (grade 2) associated with low-grade fever. She was admitted to hospital immediately for close monitoring with intensive fluid and nutritional support, broad-spectrum antibiotics (piperacillintazobactam, vancomycin, and fluconazole), and pain relievers.\n\nBoth hematological toxicity (grade 4 neutropenia and grade 2 thrombocytopenia) and non-hematological toxicity (grade 1 palmar-plantar erythrodysesthesia, grade 2 diarrhea, and grade 3 mucositis) worsened rapidly. Her white blood cell count dropped, reaching a zero nadir at day +16 and remaining unchanged for over 6 days despite treatment with granulocyte colony-stimulating factor. The patient also developed anemia requiring erythrocyte and platelet transfusions. Her platelet nadir started to recover slowly at day +17.\n\nBesides support with blood derivatives, she required third-step analgesia with strong opioids (morphine infusion pump) and intensive nutritional support with parenteral nutrition. The consequences of the severe mucositis and diarrhea resulted in low blood levels of potassium, calcium, phosphate, magnesium, and protein, with significant weight loss (up to 5 kg). In addition, the international normalized ratio was increased, with normal liver transaminases. Hand-foot syndrome progressed more slowly during hospitalization, with progressive, painful swelling and numbness on the palms and soles (up to grade 2), together with progressive alopecia that started 20 days after the withdrawal of capecitabine and lasted for more than 3 months. After 23 days in hospital, the patient was discharged with oral nutritional supplements that were necessary for over 2 months until she could tolerate a normal diet.\n\nDPYD deficiency was suspected as a potential explanation for the life-threatening toxicity that developed after such a short interval of exposure to fluoropyrimidine, in the absence of liver or renal dysfunction and other potential drug interactions. The patient did not receive treatment with fluoropyrimidines again. After two further chemotherapy lines, first cyclophosphamide+ zolendronic acid and later vinorrelbine, the patient died due to disease progression.\n\nA routine genetic DPYD test was carried out in our hospital because of the strong suspicion of DPYD deficiency. The three DPYD single-nucleotide polymorphisms (SNPs) were genotyped according to the recommendations of the Clinical Pharmacogenetics Implementation Consortium at the time.10 The SNPs were genotyped using real-time PCR and TaqMan probes. None of the three variants were detected. However, the presence of a DPYD deficit continued to be suspected. Therefore, after receiving written informed consent, we performed complete sequencing of the 23 DPYD exons. A total of 23 pairs of oligonucleotides (Table 1) were used to amplify and sequence DPYD exons. We identified two variants in DPYD exons, c.1601G>A (rs1801158, p.Ser534Asn, DPYD*4) and a previously unreported splice site mutation at position 2242+1G>T, after the end of exon 19 (Figure 1). This variant was most probably affecting splicing as confirmed using Human Splicing Finder v3.1.11\n\nThe effect of this second SNP on the donor splicing site was analyzed. RNA was isolated from peripheral blood mononuclear cells and processed to cDNA. A cDNA fragment from exon 18–20 was amplified using specific primers (forward [5′-TTAAAATCTGATGGCACACCTTG] and reverse [5′-TGCTTTTCAGATAAAGCAGGGCT]). PCR product sizes were estimated using electrophoresis. Sequencing of PCR products revealed skipping of exon 19 of DPYD in the patient’s mRNA (Figure 2). DPYD generated a truncated protein of 795 amino acids lacking the correct sequence from 767 to the end (1025) (Figure 3). This region is considered essential for the functionality of the protein because it is part of the pyrimidine-binding domain (from 525 to 847).12\n\nDue to the interest of this novel discovery and its potential clinical implications, genotyping of the mutation was later performed in the patient’s offspring: one son, one daughter, and one granddaughter (a daughter descendant). For this purpose, a TaqMan probe was synthesized for 2242+1G>T. All individuals carried the 2242+1G>T mutation in heterozygosis. None of them presented the DPYD* four allele.\n\nDPYD phenotype assessment was performed by pretreatment measurement of plasma uracil (U) and dihydrouracil (UH2) in the descendants.13 Unfortunately, we were not able to analyze a sample from the original patient because at the time this analysis was performed, she was already deceased.\n\nTwo samples showed DPYD deficiency according to established criteria (uracil concentration >16 ng/mL and/or UH2/U ratio <6). The other sample showed values that were close to the limit but within the normal activity range. Phenotyping results are shown in Table 2.\n\nA TaqMan probe was synthesized for genotyping of 2242+1G>T in a cohort of 487 anonymous DNA samples from colorectal cancer patients (mainly Caucasians from Iberian ancestry). None of the samples analyzed, except that of the present case, carried this mutation, indicating that it is a rare variant in our setting.\n\nDiscussion\nThe severe toxicity can be explained by the presence of the variant c.2242+1G>T, which generates shorter mRNA and protein, thus rendering a non-functional DPYD protein that lacks a sequence in the pyrimidine-binding domain (Figure 3). The SNP is just located in the first nucleotide after the end of exon 19. Other DPYD variants affecting donor splicing sites have also demonstrated skipping of the corresponding exon12,14 or generation of an in-frame insertion of small fragments causing severe and occasionally fatal adverse reactions to fluoropyrimidine.15\n\nIn this patient, a non-synonymous variant, c.1601G>A (rs1801158, p.Ser534Asn), was also observed. This variant defines the DPYD* four allele and decreases protein activity by 20%. However, although this allele has previously been related to the risk of fluoropyrimidine-induced toxicity,16,17 a recent meta-analysis did not find any significant association between c.1601G>A and severe fluoropyrimidine-induced toxicity.18 The DPYD deficiency observed in two out of three members of the family carrying the c.2242+1G>T mutation supports the effect of this variant on the fluoropyrimidine metabolism. The fact that none of them presented variant c.1601G>A further backs the theory that this new variant may be responsible for the descent in activity. As previously described, individuals carrying one functional and one nonfunctional allele of DPYD are likely to display a partial deficiency with 1.5<UH2/U<69. The third family member carrying this mutation showed a UH2/U ratio within the normal activity range, although close to the limit (6.6). This could be explained by factors not studied, such as copy number variants increasing the activity of the functional allele, or additional mutations in the other members.\n\nThe frequency of the DPYD variant c.2242+1G>T variant is lower than 0.002% in our setting, which suggests that it is a rare variant and its inclusion in our routine genotyping tests would not significantly increase their predictive value. Testing for this variant in other populations (since our sample is mainly integrated by Caucasian individuals of Iberian ancestry) would be very interesting as it could help to investigate its possible origins. This is definitely a line of investigation to be pursued in future works.\n\nConclusion\nWe consider the newly described variant 2242+1G>T in DPYD to be the most probable cause of very severe toxicity following the first cycle of treatment with capecitabine in a patient with breast cancer. DPYD phenotyping in patient’s offspring carrying the mutation showed decreased enzymatic activity, further supporting this conclusion. Whole DPYD sequencing is an interesting approach for the identification of causal variants in patients with suspected DPYD deficiency in whom routine DPYD tests yield negative results.\n\nEthics\nWritten informed consent was obtained from the three patient’s family members that were tested for DPYD defiency and from all patients in the colorectal cancer cohort that were tested for the presence of c.2242+1G>T. Written informed consent from the patient’s next of kin was provided to have this case published since the patient was deceased at that time.\n\nAcknowledgments\nWe would like to thank Luis Fernández Pacios at Universidad Politécnica de Madrid, for his support in modeling the DPYD 3D structure. The study was partially supported by the Ministry of Economy and Competitiveness grant PTA2013-8539-I (MIG), ISCIII-FIS grant PI12/00056, “Programa Miguel Servet II grant MSII13/00008” (LALF), and by “Consejería de Educación y Deporte de la Comunidad de Madrid” grant PEJ15/BIO/TL-0603 (CB) and PEJ16/MED/AI-1260 (LALF). All grants were cofunded by the European Regional Development Fund (ERDF [Fondo Europeo de Desarrollo Regional]) Funds from the European Commission “A way of making Europe.” XGG was supported by a grant from Gregorio Marañón Health Research Institute.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Sequence electropherogram of the 2242+1G>T variant. Blue, dCTP; green, dATP; black, dGTP; red, dTTP.\n\nAbbreviations: dATP, deoxyadenosine triphosphate; dCTP, deoxycytidine triphosphate; dGTP, deoxyguanosine triphosphate; DPYD, dihydropyrimidine dehydrogenase; dTTP, deoxythymidine triphosphate.\n\nFigure 2 Exon skipping sequence.\n\nNotes: Left: Electrophoresis of amplified cDNA from peripheral blood mononuclear cells of a patient carrying the 2242+1G>T variant. Right, upper: Graphic representation of skipping of exon 19. Right, lower: Sequence electropherogram using the primer Ex18F. A double sequence is observed for 85 nucleotides corresponding to overlapping of exons 19 and 20.\n\nFigure 3 Structures of wild-type DPYD and truncated DPYD.\n\nNotes: The interpretation of mutation effect and the molecular modeling were performed by using Deep View Swiss-PDB viewer and Tasser. (A) Modeling of wild-type DPYD; (B) modeling of truncated DPYD.\n\nTable 1 List of primers used for DPYD exon sequencing\n\nExon number\tForward\tReverse\tFragment size\t\nEXON 1\tACTTGGCTCTCTGGCTGGAGCTT\tAAACTTTCCCGCGTCTCTCACTC\t234\t\nEXON 2\tTTAGCCAGGTGTGGTAGCGTAC\tTGCCTTACAATGTGTGGAGTG\t410\t\nEXON 3\tTGAGACTTCTGTGACAGCTGTA\tCCTCAAGGGAAGTCTCTCCAC\t442\t\nEXON 4\tGGAGTGCCAAAGATGAAACACA\tTGGATTTGCTAAGACAAGCTG\t362\t\nEXON 5\tTCCTATGTGTCAAATACTCTGCT\tTGGGTATCAACAGAGCACCA\t444\t\nEXON 6\tAGGAGGCATGACTCTAGAAAGG\tCCATTAAAAGAAATATTCACAGGGCT\t719\t\nEXON 7\tAGAATGTAGATGTCCTCATGCA\tTGCATGACATTTGCTGTTAATC\t331\t\nEXON 8\tAGCCCTTAATAGAACATGTTCCT\tTGAAGGCAGTCATTCTTCTGG\t374\t\nEXON 9\tTGCTTACAGATGTTTTCCTCT\tACAATGTGCTGCTGAGCTTG\t324\t\nEXON 10\tTGGAAAACTGCAAGATGCAA\tAGCCCTTGAGTATTGACAAAG\t312\t\nEXON 11\tTGGTGAAAGAAAAAGCTGCAT\tGTTCTTTTCAATACTTGCCACT\t548\t\nEXON 12\tTGTGTTGTTAACTCCAATATTTCGT\tTCAAGCATCCTCCCGCTT\t621\t\nEXON 13\tTTCGGATGCTGTGTTGAAGT\tAATGTGTAATGATAGGTCTTGTCAAA\t443\t\nEXON 14\tGCTTTTCTTTGTCAAAAGGAGAC\tAGCTTCACATTGTGTGGGTT\t409\t\nEXON 15\tTAATTCCAAAGCCCCAAATG\tTTTCTCATGGCAGCTCTTTATTT\t346\t\nEXON 16\tTCAACGGTGAAAGCCTATTG\tAGCTTCCCTCATTTTCCACT\t318\t\nEXON 17\tTTTGTCTTGCACGTCTCCAG\tAGGATCTTGTGTTTCCAGATCA\t437\t\nEXON 18\tTGAGAAAGTAAAGTTGTGGTAATT\tGGGATCATAAAGGGCACAAA\t423\t\nEXON 19\tTCCAGTGACGCTGTCATCA\tACAGGACAGGAAATAAACCTCA\t434\t\nEXON 20\tAGACGGCTACTGATCCATCA\tTCTGAAATAGAAACCAAGGCTGA\t375\t\nEXON 21\tCCCATTTTTCTCTTCTCTGAGC\tATGCATGCTTGCCAGTGT\t423\t\nEXON 22\tTCTTTCAGAAGACAAACATCTAAGC\tCAGAAAATGCTTTCTGCCGTA\t402\t\nEXON 23\tACGCTAAAATGGGGACATTG\tACATAAGACAACTGGCAGTG\t517\t\nEXON SKIPPING\tTTAAAATCTGATGGCACACCTTG\tTGCTTTTCAGATAAAGCAGGGCT\t\t\nTable 2 DPYD phenotyping results\n\nUH2 concentration, ng/mL\tU concentration, ng/mL\tUH2/U concentration ratio\tActivitya\t\n89.32\t13.47\t6.6\tNormal\t\n85.16\t24.13\t3.5\tDeficient\t\n47.19\t18.45\t2.6\tDeficient\t\nNotes:\n\na Criteria for activity deficiency: uracil concentration >16 ng/mL and/or UH2/U ratio <6.\n\nAbbreviations: UH2, dihydrouracil; U, uracil.\n==== Refs\nReferences\n1 Mercier C Ciccolini J Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy Clin Colorectal Cancer 2006 6 4 288 296 17241513 \n2 Saif MW Syrigos K Mehra R Mattison LK Diasio RB Deficiency dehydrogenase (DPD) in GI malignancies: experience of 4-years Pakistan J Med Sci 2007 23 6 832 839 \n3 Leicher LW de Graaf JC Coers W Tascilar M de Groot JW Tolerability of capecitabine monotherapy in metastatic colorectal cancer: a real-world study Drugs R D 2017 17 1 117 124 27848234 \n4 Saif MW Katirtzoglou NA Syrigos KN Capecitabine: an overview of the side effects and their management Anticancer Drugs 2008 19 5 447 464 18418212 \n5 Rosmarin D Palles C Pagnamenta A A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS Gut 2015 64 1 111 120 24647007 \n6 Milano G Highlight on DPYD gene polymorphisms and treatment by capecitabine Scand J Clin Lab Invest Suppl 2016 245 S30 S33 27454530 \n7 Cortejoso L García-González X García MI García-Alfonso P Sanjurjo M López-Fernández LA Cost-effectiveness of screening for DPYD polymorphisms to prevent neutropenia in cancer patients treated with fluoropyrimidines Pharmacogenomics 2016 17 9 979 984 27248859 \n8 Terrazzino S Cargnin S Del Re M Danesi R Canonico PL Genazzani AA DPYD IVS14+1G>A and 2846A>T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis Pharmacogenomics 2013 14 11 1255 1272 23930673 \n9 Thomas F Hennebelle I Delmas C Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio Clin Pharmacol Ther 2016 99 2 235 242 26265035 \n10 Caudle KE Thorn CF Klein TE Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing Clin Pharmacol Ther 2013 94 6 640 645 23988873 \n11 Desmet FO Hamroun D Lalande M Collod-Béroud G Claustres M Béroud C Human Splicing Finder: an online bioinformatics tool to predict splicing signals Nucleic Acids Res 2009 37 9 e67 19339519 \n12 van Kuilenburg AB Meijer J Maurer D Severe fluoropyrimidine toxicity due to novel and rare DPYD missense mutations, deletion and genomic amplification affecting DPD activity and mRNA splicing Biochim Biophys Acta 2017 1863 3 721 730 \n13 Etienne-Grimaldi MC Boyer JC Beroud C New advances in DPYD genotype and risk of severe toxicity under capecitabine PLoS One 2017 12 5 e0175998 28481884 \n14 van Kuilenburg AB Haasjes J Richel DJ Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene Clin Cancer Res 2000 6 12 4705 4712 11156223 \n15 Fleger M Willomitzer J Meinsma R Dihydropyrimidine dehydrogenase deficiency: metabolic disease or biochemical phenotype? JIMD Rep 2017 37 49 54 28275972 \n16 Loganayagam A Arenas Hernandez M Corrigan A Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity Br J Cancer 2013 108 12 2505 2515 23736036 \n17 Kleibl Z Fidlerova J Kleiblova P Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy Neoplasma 2009 56 4 303 316 19473056 \n18 Meulendijks D Henricks LM Sonke GS Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data Lancet Oncol 2015 16 16 1639 1650 26603945\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-1322",
"issue": "10()",
"journal": "Cancer management and research",
"keywords": "adverse drug reaction; breast cancer; fluoropyrimidine; pharmacogenetics",
"medline_ta": "Cancer Manag Res",
"mesh_terms": null,
"nlm_unique_id": "101512700",
"other_id": null,
"pages": "4517-4522",
"pmc": null,
"pmid": "30349384",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "27848234;23736036;23930673;18418212;27454530;26603945;28275972;17241513;28024938;23988873;19473056;24647007;27248859;19339519;11156223;28481884;18846242;26265035",
"title": "Severe toxicity to capecitabine due to a new variant at a donor splicing site in the dihydropyrimidine dehydrogenase (DPYD) gene.",
"title_normalized": "severe toxicity to capecitabine due to a new variant at a donor splicing site in the dihydropyrimidine dehydrogenase dpyd gene"
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"companynumb": "ES-MYLANLABS-2018M1098175",
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"activesubstancename": "CAPECITABINE"
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"abstract": "BACKGROUND\nCytomegalovirus retinitis (CMVR) is one of the most common opportunistic infection in immunocompromised individuals. Intravitreal ganciclovir injection has been used successfully but no standard regimen was established. Risks of drug toxicity, endophthalmitis, and injection-related complications increased with number and frequency of injection. The aim of this study is to evaluate the outcomes of reduced-dose intravitreal ganciclovir (2 mg/0.04 mL) for the treatment of CMVR.\n\n\nMETHODS\nA prospective observational cohort study involving 67 eyes of 49 patients with CMVR was performed. Induction therapy involved intravenous ganciclovir (10 mg/kg/day) for 2 weeks unless contraindicated or patients refused. Patients were then treated with reduced-dose intravitreal ganciclovir every week for 4 weeks, and then every other week until the lesion healed. The patients' demographic data were recorded, and vision parameters were examined every visit.\n\n\nRESULTS\nTwenty eyes (29.9 %) presented with initial visual acuities less than 6/60. The majority of patients were diagnosed with CMVR in zones 1 or 2 (63 eyes, 94 %), and, at least, one quadrant of the retina was involved (56 eyes, 83.6 %). Forty-one eyes (61.2 %) completely resolved after treatment within the 6-month follow-up. There was no significant difference in healing time, whether or not patients received induction treatment with intravenous ganciclovir (111.00 ± 12.96 vs 105.00 ± 28.32 days, p = 0.8). Five eyes (12.2 %) of patients with healed CMVR had visual acuities less than 6/60.\n\n\nCONCLUSIONS\nReduced-dose intravitreal ganciclovir is a safe and effective treatment option. It provides comparable results to other weekly regimens. Induction with intravenous ganciclovir is not crucial in a resolution of retinitis, although it may be necessary to reduce systemic cytomegalovirus loads and mortality rates.\n\n\nBACKGROUND\nThe trial was registered with Thai Clinical Trials Registry (TCTR) on 16 March 2016 - TCTR20160316001 .",
"affiliations": "Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand. pitipol.cho@mahidol.edu.;Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.;Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.;Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.;Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.;Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.",
"authors": "Choopong|Pitipol|P|;Vivittaworn|Kamolporn|K|;Konlakij|Duanphen|D|;Thoongsuwan|Somanus|S|;Pituksung|Auengporn|A|;Tesavibul|Nattaporn|N|",
"chemical_list": "D000998:Antiviral Agents; D015774:Ganciclovir",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-016-1490-6",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 149010.1186/s12879-016-1490-6Research ArticleTreatment outcomes of reduced-dose intravitreal ganciclovir for cytomegalovirus retinitis Choopong Pitipol 662-4198037pitipol.cho@mahidol.edu Vivittaworn Kamolporn Konlakij Duanphen Thoongsuwan Somanus Pituksung Auengporn Tesavibul Nattaporn Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700 Thailand 18 4 2016 18 4 2016 2016 16 1646 10 2015 31 3 2016 © Choopong et al. 2016\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\nCytomegalovirus retinitis (CMVR) is one of the most common opportunistic infection in immunocompromised individuals. Intravitreal ganciclovir injection has been used successfully but no standard regimen was established. Risks of drug toxicity, endophthalmitis, and injection-related complications increased with number and frequency of injection. The aim of this study is to evaluate the outcomes of reduced-dose intravitreal ganciclovir (2 mg/0.04 mL) for the treatment of CMVR.\n\nMethods\nA prospective observational cohort study involving 67 eyes of 49 patients with CMVR was performed. Induction therapy involved intravenous ganciclovir (10 mg/kg/day) for 2 weeks unless contraindicated or patients refused. Patients were then treated with reduced-dose intravitreal ganciclovir every week for 4 weeks, and then every other week until the lesion healed. The patients’ demographic data were recorded, and vision parameters were examined every visit.\n\nResults\nTwenty eyes (29.9 %) presented with initial visual acuities less than 6/60. The majority of patients were diagnosed with CMVR in zones 1 or 2 (63 eyes, 94 %), and, at least, one quadrant of the retina was involved (56 eyes, 83.6 %). Forty-one eyes (61.2 %) completely resolved after treatment within the 6-month follow-up. There was no significant difference in healing time, whether or not patients received induction treatment with intravenous ganciclovir (111.00 ± 12.96 vs 105.00 ± 28.32 days, p = 0.8). Five eyes (12.2 %) of patients with healed CMVR had visual acuities less than 6/60.\n\nConclusions\nReduced-dose intravitreal ganciclovir is a safe and effective treatment option. It provides comparable results to other weekly regimens. Induction with intravenous ganciclovir is not crucial in a resolution of retinitis, although it may be necessary to reduce systemic cytomegalovirus loads and mortality rates.\n\nTrial registration\nThe trial was registered with Thai Clinical Trials Registry (TCTR) on 16 March 2016 – TCTR20160316001.\n\nKeywords\nCytomegalovirus retinitisGanciclovirIntravitreal injectionsTreatment outcomesSiriraj Development Research Fund (managed by Rountine to Research)R015335027Choopong Pitipol issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nCytomegalovirus (CMV) is a DNA virus of the Herpesviridae family. After primary infection, the virus becomes latent in monocytes and endothelial cells for the remaining lifetime of the patient. Reactivation of CMV infection may occur when the host immune system is compromised. The most common presentation is CMV retinitis (CMVR), especially in HIV/AIDS, lymphoma, and organ-transplanted patients, and primary immunodeficiency diseases. The most common manifestation of CMVR is the classic or fulminant form, described as segmental necrotic retinitis with intraretinal haemorrhage along the major vessels of the retina [1]. The two other manifestations, granular and perivascular forms, are less common. If left untreated, retinitis will progress, leading to blindness from the optic nerve or foveal involvement, and retinal detachment.\n\nGanciclovir is recommended for treatment of CMVR [2]. It interferes with DNA polymerase, resulting in inhibition of viral replication. The Food and Drug Administration of the US has approved two routes of administration of ganciclovir for treatment of CMVR, an intravenous route and an intraocular implant. The intravenous ganciclovir (IVG) showed a benefit of systemic CMV control and reduction of mortality rate but the major complication is agranulocytosis or pancytopenia. Intraocular implants demonstrated local control of CMVR in the affected eye for 6 months without systemic side effects [3, 4]. The need for retinal surgery and the high risk of retinal detachment make this method unfavourable. Both approved methods are expensive and may not be appropriate for low- or middle-income countries. Alternatively, intravitreal injection of ganciclovir (IVTG) has been introduced [5–7]. This method is easy and safe and provides fast and high intraocular drug concentrations. The reported dose varies from 0.2 to 5 mg of ganciclovir [5–11]. To date, there was no standard regimen in the treatment of CMVR with intravitreal ganciclovir injection. The recommended injection interval is twice weekly for 2 weeks, maintained with continuous weekly injections until the patient’s immune system reaches a reconstitution state and the lesion becomes a scar. The potential complications from intraocular injection include endophthalmitis, vitreous haemorrhage, and retinal vascular occlusion; additionally, retinal detachment increases with increased numbers and frequencies of injection [12].\n\nTherefore, a less frequent injection should decrease the risk of these complications and also lessened the burden on compliance of patients and workload of healthcare personals, especially in low socioeconomic settings. In 2005, Yutthitham and Ruamviboonsuk reported a successful result of high-dose (4 mg/0.1 ml), alternate-week intravitreal injection of ganciclovir [11]. However, high dose (4 mg) ganciclovir could result in toxicity, for example, we reported a case of crystallization of 4-mg intravitreal ganciclovir injection leading to retinal arterial occlusion and optic atrophy [13]. With a consideration of toxicity from high dose ganciclovir, we consequently reduced the regimen to 2-mg ganciclovir. From our observation, CMVR lesion stopped in 2-4 weeks after induction with systemic ganciclovir. Therefore, in our regimen, the standard induction with intravenous ganciclovir was introduced for 2 weeks if the patient agreed to stay at the hospital and there was no contraindication. After systemic induction, 4 weekly injections were given before reduction to alternated week injection. We considered this regimen to balance the efficacy, side effects, and burden to patients and health workers in low-middle income settings as our institute. We thus proposed a reduced dose of four weekly 2-mg ganciclovir intravitreal injections, followed by alternate week maintenance for the treatment of CMVR, to reduce the frequency and side effects of the intraocular injection.\n\nMethods\nThis prospective observational cohort study was conducted at the CMVR clinic of Siriraj Hospital, from November 2009 to September 2012. The study was approved by the institutional review board of Siriraj Hospital, and adhered to the tenets of the Declaration of Helsinki. Patients over 18 years of age with CMVR were recruited. Exclusion criteria included previously treated CMVR or other concurrent retinal diseases. The diagnosis of cytomegalovirus retinitis (CMVR) was made clinically by indirect ophthalmoscopic findings. The CMVR findings included areas of necrotic retinal infiltration with or without haemorrhage. In addition, aqueous polymerase chain reaction (PCR) for herpes CMV was performed to confirm the diagnosis in some cases with controversial findings. After informed consent was obtained, the patient was encouraged to receive induction treatment in the hospital with IVG at 5 mg/kg/dose every 12 h for 2 weeks, except for patients who were contraindicated or were unable to remain at the hospital. After the induction, patients were treated with reduced-dose IVTG as directed. The reduced-dose IVTG regimen included weekly injections of 2 mg/0.04 mL ganciclovir for 4 weeks, followed by the same dosage every other week until there was complete resolution of CMVR.\n\nThe IVTG was prepared at the date of injection using the following protocol under sterile conditions. Ganciclovir (Cymevene®; 500 mg; Roche, Basel, Switzerland) was diluted with 10 mL of distilled water to give a 50-mg/mL solution. Ganciclovir (2 mg/0.04 mL) was drawn and kept in a 1-mL syringe. The injection was performed in the treatment room. After being anaesthetized with topical 0.5 % tetracaine eye drops, the patient’s eye was cleaned with 10 % povidone-iodine and applied with 5 % povidone-iodine eye drops before the operation. The intravitreal injection was performed 4 mm from the limbus, using a 30-gauge needle under sterile conditions. Topical 0.3 % ofloxacin eye drops were given immediately after the injection, four times daily for 3 days.\n\nThe patients’ demographic data were recorded, including age, sex, laterality, underlying diseases, HIV infection, CD4 count, and antiretroviral treatment. Best corrected Snellen visual acuity (VA), intraocular pressure (IOP) measurement, and a full eye examination using a slit-lamp biomicroscope and indirect ophthalmoscope were performed initially and at every follow-up visit. Full fundus photography was done initially and at 4-week intervals.\n\nStatistical analysis was performed using descriptive statistics for the proportion of eyes with the resolution of CMVR within 6 months. A Kaplan–Meier graph and Cox regression analysis were used to evaluate median time-to-resolution and factors affecting healing times of CMVR. Subgroup analysis was compared between patients who received IVG with IVTG and with IVTG alone. Chi-squared and paired t-tests were used to compare the results between each group. All analyses were performed using SPSS software, version 18.0 (SPSS Inc., Chicago, IL, USA).\n\nResults\nSixty new CMVR cases were diagnosed from November 2009 to September 2012. Eleven patients were excluded because of concomitant retinal detachment, because they were already receiving standard IVG, or because of an inability to follow the proposed IVTG regimen. Sixty-seven eyes of 49 patients were analysed in the cohort. Twenty-six patients (53.1 %) received complete treatment with IVG followed by IVTG; the remaining patients received only IVTG. Twelve patients withdrew from the protocol (eight lost in follow-up, one because of low platelets, one with no light perception, and two died from sepsis). The patient demographic data are summarized in Table 1. The mean age was 39.5 ± 9.4 years, with a slight male preponderance (57.1 %). Thirty-one patients (63.3 %) presented with unilateral CMVR. Most of the unilateral cases (61.3 %) received IVTG without IVG. Forty-six patients (93.9 %) were HIV positive with median CD4 counts of 21 cells/mm3 (range, 1–482). Five HIV positive patients (10.9 %) had CD4 counts greater than 100 cells/mm3. Thirty-four patients (73.9 %) received antiretroviral treatment before the diagnosis of CMVR. Of 37 patients treated in Siriraj hospital, all patients received a fixed-dose combination of lamivudine (3TC) 150 mg, stavudine (d4T) 30 mg, and nevirapine (NVP) 200 mg before or concurrent with CMVR treatment. The three non-HIV cases included two patients with systemic lymphoma and one patient who had received a kidney transplant. Eight cases underwent aqueous aspiration for Herpes virus PCR. All of them were CMV positive. One patient had co-infection with VZV.Table 1 Baseline characteristics of patients with cytomegalovirus retinitis\n\n\tIVTG alone\tIVG + IVTG\tTotal\t\n\nPatient-specific characteristics\n\t\nN = 23\n\t\nN = 26\n\t\nN = 49\n\t\nAge in years (mean ± SD)\t40.52 ± 11.62\t38.62 ± 7.01\t39.51 ± 9.40\t\nMale (%)\t12 (52.17)\t16 (61.54)\t28 (57.14)\t\nBilateral involvement (%)\t4 (17.39)\t14 (53.85)\t18 (36.73)\t\nHIV infection (%)\t20 (86.96)\t26 (100)\t46 (93.88)\t\nConcurrent anti-retroviral therapy (%)\t13 (56.52)\t21 (80.77)\t34 (69.39)\t\nMean initial CD4 (cells/mm3)(range)\t49.50 (1–482)\t45.60 (2–200)\t47.23 (1–482)\t\n\nEye-specific characteristics\n\t\nN = 27\n\t\nN = 40\n\t\nN = 67\n\t\nInitial visual acuity (%)\t\n -6/60 or better\t19 (70.37)\t28 (70.00)\t47 (70.15)\t\n -worse than 6/60 to HM\t6 (22.22)\t10 (25.00)\t16 (23.88)\t\n -worse than HM\t2 (7.41)\t2 (5.00)\t4 (5.97)\t\nInitial IOP in mmHg (mean ± SD)\t12.00 ± 5.90\t10.58 ± 2.81\t11.15 ± 4.34\t\nInitial anterior chamber cella (%)\t\n -2+ or less\t23 (85.19)\t33 (82.50)\t56 (83.58)\t\n -more than 2+\t4 (14.81)\t7 (17.50)\t11 (16.42)\t\nInitial vitreous cella (%)\t\n -2+ or less\t25 (92.59)\t37 (92.50)\t62 (92.54)\t\n -more than 2+\t2 (7.41)\t3 (7.50)\t5 (7.46)\t\nWorst location involvedb (%)\t\n -Zone 1\t12 (44.45)\t21 (52.50)\t33 (49.25)\t\n -Zone 2\t14 (51.85)\t16 (40.00)\t30 (44.78)\t\n -Zone 3\t1 (3.70)\t3 (7.50)\t4 (5.97)\t\nLocation size (%)\t\n -less than 25 %\t6 (22.22)\t5 (12.50)\t11 (16.42)\t\n -25–49 %\t18 (66.67)\t31 (72.50)\t49 (73.13)\t\n -50 % and more\t3 (11.11)\t4 (10.00)\t7 (10.45)\t\nFrosted branch angiitis presented (%)\t17 (62.96)\t30 (75.00)\t47 (70.15)\t\nPapillitis presented (%)\t8 (29.63)\t6 (15.00)\t14 (20.89)\t\nFoveal involvement (%)\t9 (33.33)\t13 (32.50)\t22 (32.84)\t\n\nIVTG intravitreal ganciclovir, IVG intravenous ganciclovir, IOP intraocular pressure, HM hand motion, SD standard deviation\n\n\naAnterior and vitreous reaction according to the Standardization of Uveitis Nomenclature guideline\n\n\nbWorst zone of retina involved; Zone 1, lesions located in the area of the retina within 1500 microns from the edge of the optic nerve or within 3000 microns from the centre of the fovea. Zone 2, lesion located from the edge of zone 1 anteriorly to the circle of the vortex vein. Zone 3, lesion located anteriorly from zone 2 to the ora serrata\n\n\n\nForty-seven eyes (70.2 %) initially had a VA equal to or better than 6/60, while 20 eyes (29.9 %) presented with less than 6/60. The mean IOP before treatment was 11.15 ± 4.34 mmHg. Only one patient presented with IOP of more than 20 mmHg and was successfully treated with antiglaucoma eye drops. Most cases showed zero to moderate anterior and vitreous inflammation. There were 56 (83.58 %) and 62 (92.54 %) eyes with grade 2+ cells or less in the anterior and vitreous chambers, respectively.\n\nHalf of the patients were diagnosed with CMVR in zone 1 (33 eyes, 49.3 %). Forty-one eyes (61.2 %) had retinitis extending equally to or less than one quadrant. Forty-seven eyes (70.1 %) showed vasculitis before treatment in at least one of the four major vessels. Papillitis and foveal involvement were found in 14 eyes (20.9 %) and 22 eyes (32.8 %), respectively.\n\nComplete resolution of CMVR was observed in 41 eyes (61.2 %) within a 6-month follow-up (Table 2). Excluding patients lost to follow-up, the resolution percentage was 73.2 %. The mean number of injections was 8.5 ± 3.1 times. The average time-to-resolution of CMVR was 97.2 ± 42.5 days (range, 21–188 days). In subgroup analysis, IVG with IVTG required slightly longer time to resolve than IVTG alone, although there was no statistically significant difference in time-to-resolution between the two groups (mean ± SD; 99.5 ± 45.3 vs 93.1 ± 38.3 days, respectively, p = 0.65). No recurrence was seen during the follow-up period. In cases of unilateral CMVR, there were no patients with a second eye involvement during the follow-up period. Thirty-four eyes (82.9 %) involving successful resolution of CMVR had a VA that was stable or improved after treatment. Thirty-six eyes (87.8 %) had a VA equal to or better than 6/60. The mean IOP was 11.6 ± 2.5 mmHg in eyes with complete resolution. During treatment, there were no patients with IOPs that exceeded 20 mmHg. In subgroup analyses, there were no statistical differences between patients treated with or without IVG, including the healing percentage, final VA, and final IOP (Table 2). Thirteen of 67 eyes experienced complications during treatment. Patients with CMVR resolution had fewer side effects (5/41 eyes, 12.2 %; one patient with transient acute visual loss, two patients with subconjunctival haemorrhages, and two patients with retinal detachments) than patients who failed the regimen (8/26 eyes, 30.8 %; one patient with permanent visual loss, two patients with severe pain, two patients with subconjunctival haemorrhages, one patient with retinal detachment, and two patients with vitreous haemorrhages).Table 2 Results of reduced-dose intravitreal ganciclovir treatment for CMVR\n\n\tIVTG alone\tIVG + IVTG\tTotal\t\nHealed CMVR (%)\t15/27 (55.56)\t26/40 (65.00)\t41/67 (61.19)\t\nVisual acuity in healed CMVR (%)\t\n -6/60 or better\t14 (93.33)\t22 (84.62)\t36 (87.81)\t\n -worse than 6/60 to HM\t1 (6.67)\t3 (11.54)\t4 (9.75)\t\n -worse than HM\t0 (0.00)\t1 (3.84)\t1 (2.44)\t\nIOP in mmHg (mean ± SD)\t12.20 ± 1.69\t11.23 ± 2.86\t11.59 ± 2.52\t\nComplications (%)\t2 (13.3)\t3 (11.5)\t5 (12.2)\t\n\nIVTG intravitreal ganciclovir, IVG intravenous ganciclovir, CMVR cytomegalovirus retinitis, HM hand motion, IOP intraocular pressure, SD standard deviation\n\n\n\nKaplan–Meier survival analysis showed that the regimen reached a median resolution time at 111.00 ± 12.82 days (95 % CI; 85.88–136.12). There was no significant difference in resolution time whether or not the patient received IVG induction treatment (p = 0.8, log-rank test) (Fig. 1). Multivariate Cox regression analysis indicated a shorter resolution time in patients initially presenting with an age younger than 45 years (HR 0.40; 95 % CI 0.17–0.93, p = 0.03), with no vasculitis (HR 3.45; 95 % CI 1.52–7.83, p = 0.003), or with no foveal involvement (HR 2.65; 95 % CI 1.14–6.11, p = 0.023) (Table 3). The VA stabilization or improvement was affected by the absence of vasculitis (HR 2.55; 95%CI 1.30–5.00, p = 0.007) and by the absence of retinitis in zone 1 (HR 0.51; 95 % CI 0.28–0.94, p = 0.03) (Table 4).Fig. 1 Kaplan–Meier graph showing complete resolution of cytomegalovirus (CMVR) lesions in eyes that received reduced-dose intravitreal ganciclovir injection alone, compared with eyes that received reduced-dose intravitreal combined with intravenous ganciclovir injection\n\nTable 3 Univariate and multivariate Cox regression analyses of factors involving healing time\n\nFactors\tUnivariate\tMultivariate\t\n\t\np\n\t\nHR (95 % CI)\n\t\np\n\t\nHR (95 % CI)\n\t\nAge younger than 45 years old\t0.013\t2.86 (1.25–6.67)\t0.033\t2.5 (1.08–5.88)\t\nMale\t0.247\t1.46 (0.77–2.67)\t0.382\t1.51 (0.60–3.83)\t\nInduction with intravenous ganciclovir\t0.798\t1.09 (0.57–2.07)\t0.494\t1.26 (0.65–2.44)\t\nInitial CD4 > 100\t0.287\t1.58 (0.68–3.67)\t\t\t\nConcurrent anti-retroviral therapy\t0.324\t1.43 (0.70–2.92)\t\t\t\nInitial visual acuity of 6/60 or better\t0.335\t1.42 (0.69–2.92)\t\t\t\nNo zone 1 involvement\t0.717\t1.12 (0.60–2.08)\t0.091\t0.50 (0.23–1.12)\t\nArea of retinitis less than 25 %\t0.258\t1.45 (0.76–2.78)\t0.500\t1.41 (0.52–3.83)\t\nNo foveal involvement\t0.162\t1.64 (0.82–3.29)\t0.023\t2.65 (1.14–6.11)\t\nNo disc involvement\t0.345\t1.43 (0.68–3.01)\t\t\t\nFrosted branch angiitis not presented\t0.007\t2.58 (1.29–5.16)\t0.003\t3.45 (1.52–7.83)\t\n\nHR hazard ratio, CI confidence interval\n\n\naZone 1, lesions located in the area of the retina within 1500 microns from the edge of the optic nerve or within 3000 microns from the centre of the fovea\n\nTable 4 Univariate and multivariate Cox regression analyses of factors involving vision stabilization or improvement\n\nFactors\tUnivariate\tMultivariate\t\n\t\np\n\t\nHR (95 % CI)\n\t\np\n\t\nHR (95 % CI)\n\t\nAge younger than 45 years old\t0.054\t2.04 (0.99–4.17)\t0.062\t1.96 (0.96–4.00)\t\nMale\t0.044\t1.87 (1.02–3.42)\t0.197\t1.54 (0.80–2.95)\t\nInduction with intravenous ganciclovir\t0.372\t0.77 (0.44–1.36)\t0.533\t0.83 (0.46–1.49)\t\nInitial CD4 > 100\t0.467\t0.68 (0.24–1.92)\t\t\t\nConcurrent anti-retroviral therapy\t0.958\t1.02 (0.55–1.88)\t\t\t\nInitial visual acuity of 6/60 or better\t0.312\t0.74 (0.41–1.33)\t\t\t\nNo zone 1 involvementa\n\t0.122\t0.64 (0.36–1.13)\t0.030\t1.96 (1.07–3.58)\t\nArea of retinitis less than 25 %\t0.252\t0.71 (0.39–1.28)\t0.192\t0.59 (0.27–1.30)\t\nNo foveal involvement\t0.885\t0.96 (0.53–1.72)\t\t\t\nNo disc involvement\t0.670\t1.15 (0.60–2.22)\t\t\t\nFrosted branch angiitis not presented\t0.017\t2.18 (1.15–4.13)\t0.007\t2.55(1.30–5.00)\t\n\nHR hazard ratio, CI confidence interval\n\n\naZone 1, lesions located in the area of the retina within 1500 microns from the edge of the optic nerve or within 3000 microns from the centre of the fovea\n\n\n\nDiscussion\nBased on the present study, a reduced dose regimen for IVTG, with a low percentage of complications, was effective in controlling CMVR. Although systemic anti-CMV therapy is the major treatment for CMVR, it is not usually available in middle- and low-income countries such as Thailand. IVG and oral valganciclovir are very expensive for the general population, and these treatments have limited use because of systemic side effects. Alternative treatments with various doses of IVTG have been successful in many countries [5–11, 14–16], but the suggested protocols still need frequent follow-up visits. It is difficult for patients with low socioeconomic status to follow these protocols, because of other burdens, especially transportation costs.\n\nOur reduced-dose protocol attempted to decrease expenses, patient visits, and medical personnel workloads while producing reasonable results. It demonstrated 73.2 % complete resolution of CMVR, without recurrence, within 6 months of treatment. The average healing time was about 14 weeks (3–27 weeks) with an average of 8.3 injections. Resolution of the lesion needed longer times than weekly maintenance protocols. This agrees with other reports of alternate week regimens [11, 15]. This is probably due to insufficient drug concentration in the vitreous that is below the 50 % minimal inhibitory concentration (MIC50) during the second week, although other factors may help cessation of CMVR, such as antiretroviral treatment and improvement of the patient’s immune status. Increasing the dosage of ganciclovir may elevate the vitreous concentration and shorten the healing time, but may also result in optic nerve or macular toxicity [13, 17]. Using subgroup analyses, there was no statistical significance in healing times and healing percentages between eyes with or without IVG induction.\n\nAt the conclusion of treatment, VA was stable or improved in 73 % of all eyes. In patients with complete resolution, VA improved or stabilized in 83 % of eyes. Eyes treated with IVTG alone resulted in even better vision preservation than those with IVG induction. This is probably because of the smaller area of retinitis. Our protocol showed better results in preserving vision than previous reports of IVG treatment [11, 15, 16, 18]. A previous report, involving alternate week injections of 4 mg/0.1 mL, showed a better resolution percentage of 82.4 % within about 12 weeks (2–36 weeks) but only 51 % of patients had vision preserved [11]. It demonstrated that a higher dose of ganciclovir injection may increase the percentages of resolution, but also increases the risk of ganciclovir toxicity, with a decreased final vision.\n\nYoung et al. reported a 100 % success percentage with three biweekly 2 mg/0.1 mL of IVTG followed by weekly IVTG maintenance. However, it resulted in a 7 % relapse with median relapse time of 42 weeks [19]. In our cohort, there was no relapse after stopping the medication, but the follow-up time was limited to 24 weeks, which was probably insufficient to evaluate the actual relapse time of IVTG. Nonetheless, it was much longer than the 8-week relapsing period of the IVG. Owing to cost limitations, we did not evaluate the CD4 counts at the time of CMVR resolution, but a cessation of injections without recurrence or progression of lesions may signify the recovery of the patient’s immune system.\n\nThe complication percentage from our cohort was 16.4 % compared with 8.3 to 20.6 % using other IVTG regimens [11, 15, 16, 19]. Most complications were minor, including subconjunctival haemorrhage, pain, and transient visual loss, except for three eyes with rhegmatogenous retinal detachment and one eye with an acute permanent visual loss. There was no endophthalmitis in our study while it was reported in other IVTG studies with comparable patient numbers [11, 16]. The absence of endophthalmitis in our study may result from improvements in injection techniques and use of antibiotics.\n\nIn our study, the median time-to-resolution of CMVR was about 16 weeks. There was no significant difference whether or not patients received IVG prior to IVTG. Therefore, our findings indicated that IVG induction was not needed for the resolution of CMVR. However, because IVG helps in eradication of the systemic CMV viral load, prevents the risk of extraocular or second eye involvement, and reduces the mortality rate of patients, we still encourage induction with IVG if available or not contraindicated [20].\n\nBased upon regression analyses, patients younger than 45 years old, without vasculitis, and without foveal lesions were associated with shorter time-to-resolution of CMVR. Gender, VA, induction with IVG, CD4 counts, and extent or zone of retinitis at presentation showed no associations with healing times. Younger patients may possess a better immune function, despite their CD4 counts, and may, therefore, respond faster to treatment. Vascular and foveal involvement may indicate more complicated cases, requiring longer healing periods. Patients with retinitis not involving zone 1 and with an absence of vasculitis were associated with improvement or preservation of the final VA. These results indicate that the central retina and vascular structure play crucial roles in visual prognosis.\n\nThere were limitations in our study, including it being a nonrandomized trial with a small sample size. However, we selectively excluded CMVR patients with other retinal diseases to minimize the bias of the treatment results. Our study is the first prospective cohort study from Thailand; we thus believe our results could be relevant to real ophthalmic clinical settings specifically for low- to middle-income countries. A larger randomised control trial should be conducted in the future to provide a better understanding of the different regimens.\n\nConclusions\nIn conclusion, our reduced-dose regimen of IVTG for CMVR represents an efficacious and safe alternative therapy, especially for resource-scarce settings. The resolution of CMVR was achieved in favourable numbers of patients within 6 months, When compared with other regimens, the final visual outcome was better, while the complication rates were similar. IVG induction may be required to eradicate systemic CMV viral loads, but is not necessary for treatment of ocular CMVR. With an average of eight injections per person, both workloads and patient visits are reduced. We, therefore, recommend this reduced-dose regimen for treatment of CMVR, particularly in low- or middle-socioeconomic settings.\n\nAvailability of data and materials\nThe data analysed in this study can be accessed by sending a request to the corresponding author.\n\nEthics approval\nSiriraj Hospital Institutional Review Board, Siriraj hospital Mahidol University, Bangkok, Thailand #Si 158/2010. Consent form was obtained from each patient.\n\nAbbreviations\nCMVCytomagalovirus\n\nCMVRCytomegalovirus retinitis\n\nIOPIntraocular pressure\n\nIVGIntravenous ganciclovir\n\nIVTGIntravitreal ganciclovir\n\nVAVisual acuity\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nP Choopong: contribution to concept and design, analysis of the data, writing manuscript. K Vivittaworn, D Konlakit, A Pituksung: contribution to collection and analysis of data, S Thoongsuwan: reviewing of manuscript. N Tesavibul: concept and design, reviewing of manuscript. All authors give final approval of the version to be published.\n\nAcknowledgements\nThe authors wish to acknowledge the help of Miss Mathuwan Srikong, from the Medical Education Technology Center of the Faculty of Medicine, Mahidol University, for providing us the figure.\n\nFunding\nSiriraj Development Research Fund (managed by Routine to Research:R2R), Siriraj Hospital, Mahidol University #R015335027.\n==== Refs\nReferences\n1. Moorthy RS. 2011-2012 Basic and Clinical Science Course, Section 9: Intraocular Inflammation and Uveitis (Basic & Clinical Science Course). Revised edition. San Francisco, CA: American Academy of Ophthalmology; 2011. p.204\n2. Whitley RJ Jacobson MA Friedberg DN Holland GN Jabs DA Dieterich DT Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society-USA Arch Intern Med 1998 158 9 957 969 10.1001/archinte.158.9.957 9588429 \n3. Anand R Nightingale SD Fish RH Smith TJ Ashton P Control of cytomegalovirus retinitis using sustained release of intraocular ganciclovir Arch Ophthalmol 1993 111 2 223 227 10.1001/archopht.1993.01090020077027 8141855 \n4. Martin DF Parks DJ Mellow SD Ferris FL Walton RC Remaley NA Treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant. A randomized controlled clinical trial Arch Ophthalmol 1994 112 12 1531 1539 10.1001/archopht.1994.01090240037023 7993207 \n5. Henry K Cantrill H Fletcher C Chinnock BJ Balfour HH Use of intravitreal ganciclovir (dihydroxy propoxymethyl guanine) for cytomegalovirus retinitis in a patient with AIDS Am J Ophthalmol 1987 103 1 17 23 10.1016/S0002-9394(14)74163-7 3026186 \n6. Daikos GL Pulido J Kathpalia SB Jackson GG Intravenous and intraocular ganciclovir for CMV retinitis in patients with AIDS or chemotherapeutic immunosuppression Br J Ophthalmol 1988 72 7 521 524 10.1136/bjo.72.7.521 2843218 \n7. Cochereau-Massin I LeHoang P Lautier-Frau M Zazoun L Marcel P Robinet M Efficacy and tolerance of intravitreal ganciclovir in cytomegalovirus retinitis in acquired immune deficiency syndrome Ophthalmology 1991 98 9 1348 1353 10.1016/S0161-6420(91)32135-3 1658703 \n8. Young SH Morlet N Heery S Hollows FC Coroneo MT High dose intravitreal ganciclovir in the treatment of cytomegalovirus retinitis Med J Aust 1992 157 6 370 373 1333036 \n9. Hodge WG Lalonde RG Sampalis J Deschênes J Once-weekly intraocular injections of ganciclovir for maintenance therapy of cytomegalovirus retinitis: clinical and ocular outcome J Infect Dis 1996 174 2 393 396 10.1093/infdis/174.2.393 8699072 \n10. Arevalo JF Garcia RA Mendoza AJ High-dose (5000-microg) intravitreal ganciclovir combined with highly active antiretroviral therapy for cytomegalovirus retinitis in HIV-infected patients in Venezuela Eur J Ophthalmol 2005 15 5 610 618 16167292 \n11. Yutthitham K Ruamviboonsuk P The high-dose, alternate-week intravitreal ganciclovir injections for cytomegalovirus retinitis in acquired immune deficiency syndrome patients on highly active antiretroviral therapy J Med Assoc Thai 2005 88 Suppl 9 S63 S68 16681054 \n12. Sampat KM Garg SJ Complications of intravitreal injections Curr Opin Ophthalmol 2010 21 3 178 183 10.1097/ICU.0b013e328338679a 20375895 \n13. Choopong P Tesavibul N Rodanant N Crystallization after intravitreal ganciclovir injection Clin Ophthalmol 2010 4 709 711 10.2147/OPTH.S10949 20689786 \n14. Visser L Managing CMV, retinitis in the developing world Community Eye Health 2003 16 47 38 39 17491844 \n15. Teoh SC Ou X Lim TH Intravitreal Ganciclovir Maintenance Injection for Cytomegalovirus Retinitis: Efficacy of a Low-Volume, Intermediate-Dose Regimen Ophthalmology 2011 119 3 588 595 10.1016/j.ophtha.2011.09.004 22137552 \n16. Ausayakhun S Yuvaves P Ngamtiphakom S Prasitsilp J Treatment of cytomegalovirus retinitis in AIDS patients with intravitreal ganciclovir J Med Assoc Thai 2005 88 Suppl 9 S15 S20 16681046 \n17. Saran BR Maguire AM Retinal toxicity of high dose intravitreal ganciclovir Retina 1994 14 3 248 252 10.1097/00006982-199414030-00010 7973120 \n18. Montero MC Pastor M Buenestado C Lluch A Atienza M Intravitreal ganciclovir for cytomegalovirus retinitis in patients with AIDS Ann Pharmacother 1996 30 7-8 717 723 8826547 \n19. Young S Morlet N Besen G Wiley CA Jones P Gold J High-dose (2000-μg) intravitreous ganciclovir in the treatment of cytomegalovirus retinitis Ophthalmology 1998 105 8 1404 1410 10.1016/S0161-6420(98)98020-4 9709750 \n20. Kempen JH Jabs DA Wilson LA Dunn JP West SK Tonascia J Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome Clin Infect Dis 2003 37 10 1365 1373 10.1086/379077 14583871\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "16()",
"journal": "BMC infectious diseases",
"keywords": "Cytomegalovirus retinitis; Ganciclovir; Intravitreal injections; Treatment outcomes",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000998:Antiviral Agents; D015331:Cohort Studies; D003587:Cytomegalovirus; D017726:Cytomegalovirus Retinitis; D003710:Demography; D005260:Female; D015774:Ganciclovir; D006801:Humans; D016867:Immunocompromised Host; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016896:Treatment Outcome; D014792:Visual Acuity",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "164",
"pmc": null,
"pmid": "27090644",
"pubdate": "2016-04-18",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "16681046;7973120;7993207;8699072;16167292;9588429;2843218;20689786;22137552;20375895;14583871;8141855;17491844;1658703;16681054;1333036;9709750;8826547;3026186",
"title": "Treatment outcomes of reduced-dose intravitreal ganciclovir for cytomegalovirus retinitis.",
"title_normalized": "treatment outcomes of reduced dose intravitreal ganciclovir for cytomegalovirus retinitis"
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"abstract": "BACKGROUND\nSigmoid volvulus in pregnancy is a rare cause of intestinal obstruction with high maternal and fetal morbidity and mortality if not diagnosed and managed early.\n\n\nMETHODS\nA 29-year-old female (Chagga by tribe) presented with clinical features of intestinal obstruction 24 weeks into her second pregnancy. She had symptoms for one week. An emergency laparotomy was performed whereby gangrenous sigmoid volvulus was found; thus, it was resected and Hartmann's colostomy was raised. Unfortunately, she experienced intrauterine fetal death post-operatively. She was discharged clinically stable.\n\n\nCONCLUSIONS\nEarly diagnosis and management can prevent adverse effects such as bowel ischemia and preterm labor. Because classic clinical and radiological features may not be evident, high degree of suspicion is warranted.",
"affiliations": "Department of General Surgery, Kilimanjaro Christian Medical Centre, P O Box 3010, Moshi, Tanzania. jaylodhia06@gmail.com.;Department of General Surgery, Kilimanjaro Christian Medical Centre, P O Box 3010, Moshi, Tanzania.;Department of General Surgery, Kilimanjaro Christian Medical Centre, P O Box 3010, Moshi, Tanzania.;Department of General Surgery, Kilimanjaro Christian Medical Centre, P O Box 3010, Moshi, Tanzania.;Department of General Surgery, Kilimanjaro Christian Medical Centre, P O Box 3010, Moshi, Tanzania.;Department of General Surgery, Kilimanjaro Christian Medical Centre, P O Box 3010, Moshi, Tanzania.",
"authors": "Lodhia|Jay|J|;Magoma|Joachim|J|;Tendai|Joylene|J|;Msuya|David|D|;Suleiman|Jamil|J|;Chilonga|Kondo|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-03151-3",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n3151\n10.1186/s13256-021-03151-3\nCase Report\nSigmoid volvulus in pregnancy: a case report\nLodhia Jay jaylodhia06@gmail.com\n\n12\nMagoma Joachim 1\nTendai Joylene 1\nMsuya David 12\nSuleiman Jamil 1\nChilonga Kondo 12\n1 grid.415218.b 0000 0004 0648 072X Department of General Surgery, Kilimanjaro Christian Medical Centre, P O Box 3010, Moshi, Tanzania\n2 Kilimanja Christian Medical University College, P O Box 2240, Moshi, Tanzania\n10 11 2021\n10 11 2021\n2021\n15 55422 3 2021\n14 10 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open 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.\nIntroduction\n\nSigmoid volvulus in pregnancy is a rare cause of intestinal obstruction with high maternal and fetal morbidity and mortality if not diagnosed and managed early.\n\nCase presentation\n\nA 29-year-old female (Chagga by tribe) presented with clinical features of intestinal obstruction 24 weeks into her second pregnancy. She had symptoms for one week. An emergency laparotomy was performed whereby gangrenous sigmoid volvulus was found; thus, it was resected and Hartmann’s colostomy was raised. Unfortunately, she experienced intrauterine fetal death post-operatively. She was discharged clinically stable.\n\nConclusion\n\nEarly diagnosis and management can prevent adverse effects such as bowel ischemia and preterm labor. Because classic clinical and radiological features may not be evident, high degree of suspicion is warranted.\n\nKeywords\n\nIntestinal obstruction\nPregnancy\nSigmoid volvulus\nTanzania\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nSigmoid volvulus is a rare cause of intestinal obstruction in pregnancy, with incidence ranging from 1 in 1500 to 1 in 66,431 deliveries [1]. Other common causes include adhesions, hernia, malignancies, and intussusceptions [2]. This pathology is associated with high maternal and fetal complications due to the delayed presentations, and accurate diagnosis is difficult to make because of the normal anatomical and physiological changes during pregnancy [2]. Overall outcome depends on timely diagnosis and management. We present a young female who, in her second trimester, presented with intestinal obstruction (IO) that was found to be caused by sigmoid volvulus intraoperatively.\n\nCase presentation\n\nA 29-year-old female (Chagga by tribe) 24 weeks pregnant was referred from the regional hospital to our center (a referral hospital) with a 1-week history of abdominal pain and constipation. The pain started gradually and was generalized and cramping in nature. It was associated with vomiting containing food material. She denied history of fever. She reported a decrease in fetal movements and denied any history of abdominal trauma or vaginal discharge. Her past medical history was insignificant. This was her second pregnancy; the first was delivered by cesarean section because of preeclampsia, and the child is growing well. For her index pregnancy, she was on iron and folate supplements.\n\nUpon examination, she was ill looking, conscious, alert, mildly pale, and dehydrated, with a temperature of 38 ℃ and a nasogastric tube (NGT) in situ draining fecal content. Her blood pressure (BP) was 112/81 mmHg, pulse 136 beats per minute, and saturation 96% on room air. Her abdomen was symmetrically distended and moving with respiration, had a Pfannenstiel incision scar, and was tense and tender on palpation with a symphysiofundal height correlating to 23 weeks. Muscle guarding could not be elicited because of the tense abdomen, and hypertympanic note on percussion and no bowel sounds were heard on auscultation. There was nothing abnormal detected on rectal and vaginal examination. Other systems were unremarkable.\n\nHer complete blood count on admission showed a normal leukocyte count of 9.17 × 109/L, anemia of 9.4 g/dl, and platelet count of 441 × 109/L. She had mild hypokalemia of 2.52 mmol/L, which was corrected by intravenous potassium chloride. Initial abdominal ultrasonography revealed gaseous abdomen with a viable intrauterine pregnancy of 24 weeks. Abdominal X-ray was done that was suggestive of intestinal obstruction with a differential of perforated hollow viscus (Fig. 1). She was kept nil orally and on intravenous fluids for resuscitation.Fig. 1 Erect abdominal X-ray showing high air–fluid level and distended gastric bubble\n\nShe was consented for an emergency laparotomy whereby the abdomen was opened through a midline incision. A gravid uterus, approximately 500 ml of amber-colored ascites, and a 360° anticlockwise sigmoid volvulus around its mesentery, which was gangrenous and distended, were found (Fig. 2). The bowels proximal to the volvulus were distended. Thus, derotation of the volvulus and resection of sigmoid colon were done followed by a Hartman’s colostomy. Hemostasis was achieved, abdominal lavage was done, and the abdomen was closed in layers. She received 450 milliliters of whole blood intraoperatively. She was then nursed at the intensive care unit, where on day one she expelled a male fetus weighing 800 g with no signs of life.Fig. 2 A Gangrenous sigmoid volvulus and gravis uterus. B Grossly dilated sigmoid colon post resection\n\nDuring her stay in ICU, she was kept on intravenous antibiotics, and was transfused with one more unit of blood. Her control hemoglobin was 11.5 g/dl. On day 7 postoperatively, she continued to do well clinically with a functioning colostomy and was thus discharged home with instructions on colostomy care and to continue follow-up as an outpatient. Six weeks post discharge, she was reviewed at the outpatient clinic, where she was clinically stable with functioning colostomy and unremarkable histology for the sigmoid colon; she was scheduled for an elective colostomy closure after a normal distal loopogram (barium enema). She was also reviewed by the obstetrics and gynecology team and started her on oral combined contraceptive pills to regulate her menstrual cycle. Six weeks post-colostomy closure, she was clinically stable with no abdominal complaints and, hence, discharged.\n\nDiscussion\n\nSigmoid volvulus is a rare cause of intestinal obstruction in pregnancy with high maternal and fetal mortality [2]. It is said to be caused by a redundant sigmoid colon, high-fiber diet (attributed to African origin), chronic constipation, and pregnancy, especially in the third trimester, owing to the displacement and partial compression of the sigmoid colon by the gravid uterus [2, 3]. In our case, it appears that the sigmoid was displaced and compressed by the gravid uterus, causing sigmoid volvulus, though redundant sigmoid cannot be ruled out.\n\nClassic presentation of sigmoid volvulus is abdominal distension, constipation, and abdominal pain, which were present in the index case; however, obstructive symptoms can be unspecific in pregnancy as they can be related to the pregnancy. Nevertheless, common features of IO in pregnancy include abdominal pain (98%), vomiting (82%), and constipation (30%) [1, 2, 4]. Vomiting was a strong feature in our case as the NGT was draining fecal contents to support the diagnosis of IO. Generally, these women are 15–35 years of age and 75% are multiparous and 66% in their third trimester, all of which was true for our case [1]. Other causes of IO in pregnancy include appendicitis, intraabdominal neoplasms, adhesions from previous surgeries, intussusceptions, and hernias [3].\n\nDelay in the diagnosis hence leads to delay in the management, culminating in devastating outcomes; 5% maternal mortality has been reported if the bowels are viable and over 50% if perforation occurs. Fetal mortality is said to be 30% [2]. Other maternal complications include perforation, peritonitis, and sepsis, and fetal complications include preterm delivery, intrauterine fetal death, and neonatal sepsis [4].\n\nClinical examination is limited due to the gravid uterus, and radiological evaluation presents another challenge due to the risks of teratogenicity of the fetus. In our case, the age of pregnancy was 24 weeks, and thus reduced risk, whereas generally the health of the mother takes priority over the fetus [2]. Plain abdominal X-ray has a sensitivity of 90% in diagnosing IO, whereas ultrasound can show dilated bowels and maybe show a transition point [3]. “Coffee-bean” sign on plain X-ray is a feature of volvulus as seen in the case reported by Ghahremani et al. [5]. X-ray in our case was suggestive of IO, but the ultrasound was not informative as the colon was grossly distended.\n\nManagement of IO in pregnancy requires a multidisciplinary approach including obstetric and pediatric teams. Before laparotomy, resuscitation is vital with decompression, fluids, and correcting electrolytes [1]. Midline incision is ideal for best exposure, and a cesarean section can be done if the uterus is obstructing the operative field. Resection (sigmoidectomy) and colostomy are generally advised, but some surgeons perform primary anastomosis with or without colonic washout. However, this carries a risk of anastomotic leak due to the edematous and paretic bowel status posing future risks [2]. Hartmann’s colostomy was raised in our case because the colon was grossly distended and bowels were edematous due to the late presentation; on the contrary, Ghahremani et al. reported a sigmoidopexy because the bowel was not gangrenous and the pregnancy survived due to the early presentation [5].\n\nEndoscopy can be another diagnostic and therapeutic option, allowing for derotation and decompression of the volvulus with success rates between 50% and 80% in nonpregnancy states. However, controversies of recurrences and failures of endoscopic management especially in the third trimester are still debatable [4].\n\nConclusion\n\nSigmoid volvulus in pregnancy is a rare condition, and its early diagnosis is a challenge. A high index of suspicion and early surgical intervention are key for favorable maternal and fetal outcomes.\n\nAbbreviations\n\nNGT Nasogastric tube\n\nICU Intensive care unit\n\nIO Intestinal obstruction\n\nAcknowledgements\n\nThe authors would like to thank the patient for permission to share her medical history for educational purposes and publication.\n\nAuthors’ contributions\n\nJL and JM conceptualized the manuscript. JT, JS, DM, and KC collected and reviewed the medical records. JL, JT, and KC were the lead surgeons. All authors read and approved the final manuscript.\n\nFunding\n\nThere was no funding towards this research.\n\nAvailability of data and materials\n\nAll data used in this study are available from the corresponding author upon request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe hospital institutional review board has approved the publication of this case report. Facial images identifying the patients have not been used. The patient has provided written informed consent for the surgery and to participate in this study. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\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. Atamanalp SS Kisaoglu A Ozogul B Kantarci M Disci E Bulut OH Aksungur N Atamanalp RS Sigmoid volvulus complicating pregnancy: a case report Eurasian J Med 2015 47 1 75 10.5152/eajm.2014.0105 25745351\n2. Al Maksoud AM Barsoum AK Moneer MM Sigmoid volvulus during pregnancy: a rare non-obstetric complication. Report of a case and review of the literature Int J Surg Case Rep. 2015 17 61 64 10.1016/j.ijscr.2015.10.030 26551555\n3. Tesnière M Arnoult A Roger N Sigmoid volvulus in pregnancy J Emerg Med 2018 54 6 e129 e131 10.1016/j.jemermed.2018.02.038 29681418\n4. Serafeimidis C Waqainabete I Creaton A Vakamacawai E Kumar R Sigmoid volvulus in pregnancy: case report and review of literature Clin Case Rep 2016 4 8 759 10.1002/ccr3.617 27525078\n5. Ghahremani S Razmjouei P Layegh P Tavakolian A Ghazanfarpour M Shoaee F Moeindarbary S A case of sigmoid volvulus in pregnancy: a rare emergency in pregnancy Int J Pediatr 2020 8 1 10743 10747\n\n",
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"affiliations": "*The Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China †Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH ‡Center for Pediatric Liver Diseases, Children's Hospital of Fudan University §Department of Pediatrics, Shanghai Medical College of Fudan University, Shanghai, China ||Institut für Pathologie, Medizinische Universität Graz, Graz, Austria.",
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"abstract": "Cytomegalovirus (CMV) is a major cause of morbidity and mortality in cardiac transplant recipients. Use of induction immunosuppression in cardiac transplantation may have an impact on the incidence of CMV, but literature is limited.\n\n\n\nSingle-center, retrospective cohort study comparing the risk of CMV infection and disease in cardiac transplant patients receiving antithymocyte globulin (ATG) induction therapy to those receiving no antibody induction.\n\n\n\nA total of 75 patients were included in our analysis, 50 who received ATG induction and 25 who did not. CMV infection occurred in 10 (20%) and 5 (20%) patients in the ATG and No ATG groups, respectively (P > 0.99). CMV disease occurred in 10 (20%) and 4 (16%) patients in the ATG and No ATG groups, respectively (P = 0.763). The median time from transplant to CMV infection was 200.0 [142.5, 364.5] days in the ATG group vs 221.0 [192.0, 299.0] days in the No ATG group (P = 0.723). The median time from end of CMV prophylaxis to CMV infection was 94.5 [66.5, 151.0] days in the ATG group vs 53.0 [41.0,149.5] days in the No ATG group (P = 0.202). Freedom from CMV infection was highest in the D+/R+ group and lowest in the D+/R- group.\n\n\n\nIn cardiac transplant recipients, ATG induction was not associated with an increased incidence of CMV infection or disease in the setting of valganciclovir prophylaxis and an initial maintenance immunosuppression regimen of primarily steroids, mycophenolate mofetil, and tacrolimus.",
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"abstract": "Necrolytic migratory erythema is characterized by waves of irregular erythema in which a central bulla develops, and subsequently erodes and becomes crusted. It usually occurs in patients with an alpha-islet cell tumor of the pancreas. However, necrolytic migratory erythema has also been observed in patients without an associated glucagonoma. We describe a woman with iatrogenic necrolytic migratory erythema. She received intravenous glucagon for hypoglycemia associated with an insulin-like growth factor II-secreting hemangiopericytoma. After chemotherapy, she developed necrolytic migratory erythema. The characteristics of the previously reported patients with nonglucagonoma-associated necrolytic migratory erythema are reviewed. In patients with nonglucagonoma-associated necrolytic migratory erythema, the dermatosis-related conditions most commonly observed were celiac disease or malabsorption, cirrhosis, malignancy, and pancreatitis; less common conditions included hepatitis, inflammatory bowel disease, heroin abuse, and odontogenic abscess. Although the pathogenesis of necrolytic migratory erythema remains unknown, hyperglucagonemia appears to have had a causative role in the development of this dermatosis in our patient. Patients who develop necrolytic migratory erythema should be evaluated for the presence of a glucagonoma; if a glucagonoma is ruled out, evaluation for other conditions known to occur with necrolytic migratory erythema, such as liver disease, malabsorptive disorders, and nonislet-cell tumors is warranted.",
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"abstract": "Cutaneous metastasis (CM) from internal malignancies is commonly seen. Sometimes, skin metastases can be the first sign of advanced cancer or an indicator of cancer recurrence. Cases of breast cancer with cutaneous progression after or during trastuzumab therapy have been described in the past, frequently associated with systemic disease progression. However, CM during adjuvant trastuzumab therapy is very rare. It has been hypothesized that cancer cells located in the skin survive and take proliferative advantage by virtue of an immune-tolerance mechanism that hampers trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity. We describe a case of human epidermal growth factor receptor-2-overexpressing breast cancer presenting with diffuse CM during adjuvant trastuzumab therapy.",
"affiliations": "Department of Medical Oncology, Dharamshila Narayana Superspeciality Hospital, New Delhi, India.;Department of Pathology, Dharamshila Narayana Superspeciality Hospital, New Delhi, India.;Department of Medical Oncology, Dharamshila Narayana Superspeciality Hospital, New Delhi, India.",
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"fulltext": "\n==== Front\nIndian J DermatolIndian J DermatolIJDIndian Journal of Dermatology0019-51541998-3611Medknow Publications & Media Pvt Ltd India IJD-63-42410.4103/ijd.IJD_234_18Case ReportMetastatic Dermatosis in Breast Carcinoma on Adjuvant Trastuzumab: Is Skin a Sanctuary Site in Human Epidermal Growth Factor Receptor-2-Amplified Disease? Sehrawat Amit Kotwal Sumedha A. 1Parthasarathy K. M. From the Department of Medical Oncology, Dharamshila Narayana Superspeciality Hospital, New Delhi, India1 Department of Pathology, Dharamshila Narayana Superspeciality Hospital, New Delhi, IndiaAddress for correspondence: Dr. Amit Sehrawat, Department of Medical Oncology, Dharamshila Narayana Superspeciality Hospital, Vasundhara Enclave, New Delhi - 110 096, India. E-mail: dramitsehrawat@gmail.comSep-Oct 2018 63 5 424 426 5 2018 6 2018 Copyright: © 2018 Indian Journal of Dermatology2018This 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.Cutaneous metastasis (CM) from internal malignancies is commonly seen. Sometimes, skin metastases can be the first sign of advanced cancer or an indicator of cancer recurrence. Cases of breast cancer with cutaneous progression after or during trastuzumab therapy have been described in the past, frequently associated with systemic disease progression. However, CM during adjuvant trastuzumab therapy is very rare. It has been hypothesized that cancer cells located in the skin survive and take proliferative advantage by virtue of an immune-tolerance mechanism that hampers trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity. We describe a case of human epidermal growth factor receptor-2-overexpressing breast cancer presenting with diffuse CM during adjuvant trastuzumab therapy.\n\nBreast cancercutaneous metastasishuman epidermal growth factor receptor-2trastuzumab\n==== Body\nIntroduction\nCutaneous metastasis (CM) from internal malignancies is common. CM from solid cancers occurs in about 1% of cases.[1] This incidence is about 2.5% in carcinoma breast patients. However, because of the relatively high incidence of breast cancers, it accounts for almost 33% of CM.[2] Cases of cutaneous progression after or during trastuzumab therapy have been described in the past and are frequently associated with systemic disease progression.[34] This supports the hypothesis by Graziano et al.[5] that cancer cells located in the skin would survive and take proliferative advantage by virtue of an immune-tolerance mechanism that hampers trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we present one such case of human epidermal growth factor receptor-2 (HER2)-positive locally advanced breast cancer which progressed on adjuvant trastuzumab, first with CM and then systemic spread.\n\nCase Report\nA 60-year-old postmenopausal woman presented in December 2014 with a right breast lump. There were no other comorbidities. Core needle biopsy from the lump on histopathological examination (HPE) revealed invasive ductal carcinoma, no specific type, and Nottingham score 3. Immunohistochemistry for molecular biomarkers showed negative estrogen receptor and progesterone receptor with Allred score of 0/8 for each. HER2 was positive (3+) and Ki-67 index was 50%. Positron emission tomography–computed tomography (PET-CT) showed a fluorodeoxyglucose (FDG)-avid 3.6 cm × 3.5 cm × 2.5 cm (maximum standardized uptake value [SUVmax]: 10.8) right upper outer quadrant breast lesion with overlying skin thickening (SUVmax: 3.5) along with level one axillary lymph node 1.4 cm (SUVmax: 3.7) - clinically a cT4N1M0 disease. For this, she received four cycles of dose-dense anthracycline and cyclophosphamide followed by four cycles of 3 weekly taxane (docetaxel) with trastuzumab.\n\nOn completion of neoadjuvant chemotherapy, PET-CT showed a reduced size and avidity of the lesion (2.9 cm × 5.4 cm) with overlying skin infiltration. She then underwent right mastectomy and histopathological examination (HPE) showed residual microscopic foci of ductal carcinoma with lymphovascular invasion and uninvolved ipsilateral axillary lymph nodes (00/14). Postsurgery, the patient was given 50.4 Gy in 28 fractions’ radiotherapy (RT) to chest wall and nodal regions, followed by 5.4 Gy in 3 fractions’ local electron boost to by image-guided radiation therapy (IGRT). She tolerated RT well except Grade 2 skin reactions at the end of treatment. Adjuvant trastuzumab was continued every 3 weeks. In March 2016, post 15th dose of adjuvant trastuzumab, she started developing diffuse erythematous rash over the right chest wall, supraclavicular fossa, and right arm within and outside the radiation field. As she was suspected to have radiation recall, adjuvant treatment was put on hold. This was treated symptomatically after dermatologist review. Initially, lesions improved with local treatment, analgesics, and supportive care. Adjuvant treatment was resumed, and two more cycles were given. On follow-up, she was found to have persistent and progressive skin lesions [Figure 1] with a palpable right cervical, level 2 lymph node. There was no evidence of local lesion clinically or radiologically. Biopsy from anterior chest wall skin lesion showed metastatic carcinoma with molecular profile similar to primary breast tumor [Figure 2] and Ki-67 index of 65%. She defaulted on follow-up and took alternative ayurvedic medicines. Seven months later, she came back with extensive skin lesions over the ipsilateral arm and anterior chest wall and progressive dyspnea. Workup with PET-CT revealed disease progression in the form of FDG-avid metastatic skin lesions, cervical lymph nodes, and pleural effusion [Figure 3]. She was started on trastuzumab emtansine (Kadcyla) 3.6 mg/kg every 3 weeks, and since then, the disease was showing partial response to the therapy.\n\nFigure 1 Multiple erythematous papules and few hemorrhagic vesicles with excoriation over the right arm\n\nFigure 2 Skin metastasis, tumor emboli, and HER2 expression. (a) Metastatic deposits in superficial dermis (×100), (b) lymphovascular tumor embolus in deep dermis (×400), (c) positive HER2 (3+) in skin metastasis; strong complete membranous staining >10% tumor cells (×200)\n\nFigure 3 Positron emission tomography–computed tomography images showing fluorodeoxyglucose-avid cutaneous deposits, cervical lymph nodes, and right pleural effusion\n\nDiscussion\nSkin metastases though uncommon can be the first sign of advanced cancer or an indicator of cancer recurrence. Our case presented with diffuse CM from HER2-overexpressing breast cancer occurring during adjuvant trastuzumab therapy. Pathogenesis of skin metastasis is suggested to be through tumor cells reaching the dermis through several routes such as contiguous invasion or embolization through lymphatics and blood vessels as well as accidental implantation at the time of surgery. Clinically, various patterns of CM are seen like skin nodule which is the most common presentation and relatively less commonly ulcers. Rarely, erythematous patches or plaques can be seen. The CM may also mimic benign dermatologic lesions such as erythema annulare, contact dermatitis, tinea infections, erysipelas, cellulitis, or cutaneous mucinosis.[3] Most skin metastases from solid cancers are associated with advanced stage of cancer, whereas CM of carcinoma breast can arise in locally advanced disease or in early metastatic phase of the disease. CM patterns in breast cancer vary with the molecular subtypes, and diffuse cutaneous metastases without distant spread have been reported in HER2-amplified disease.[5]\n\nMost of the CMs appear as direct contiguous lesions in relation with the breast primary.[4] Noncontiguous diffuse CMs are almost always seen in advanced disease with systemic spread. Such a condition is very difficult to manage even with multimodality treatment in the form of surgery, RT, chemotherapy, and targeted treatment. Published data suggest that CM from HER-2-overexpressed breast cancer is seen in early stages of systemic spread, as was seen in our patient. Usual pattern identified in the HER2-positive CM is initial response to the targeted therapy which is followed by flare-up while on treatment.\n\nIn patients on HER2-targeted therapy, the concept of “immune privilege” in CM has been suggested, the exact mechanisms of which remain unclear, but it may be due to lack of major histocompatibility complex (MHC) Class II expression in antigen-presenting cells, resulting in impaired immune function in the inferior portions of hair follicles.[6] This can possibly result in immune-tolerance mechanism that hampers trastuzumab-mediated ADCC, as hypothesized by Graziano et al.[5] They suggested that a change occurred in the cutaneous microenvironment of cancer cells leading to the establishment of a “sanctuary-like site” where tumor cells could easily escape from anti-HER2-directed antibodies resulting in the development of CM. Eventually, other possible mechanisms[7] for trastuzumab resistance set in and systemic spread manifests. Further research in this direction can help in developing newer strategies to alter the disease course and reduce the incidence of CM in HER2-positive patients.\n\nConclusion\n\nCM in HER2-positive breast cancer can show initial response to therapy followed by progression on targeted therapy, due to resistance. This can be the early sign of systemic spread; therefore, physicians should perform a detailed physical examination including that of skin even during adjuvant trastuzumab therapy. This will help in identifying these patients for appropriate therapeutic intervention. Skin as a sanctuary site for metastatic tumor cells in HER2-amplified breast cancer appears to be a promising hypothesis and requires further research and validation.\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\n1 Hu SC Chen GS Wu CS Chai CY Chen WT Lan CC Rates of cutaneous metastases from different internal malignancies: Experience from a Taiwanese medical center J Am Acad Dermatol 2009 60 379 87 19056145 \n2 Wong CY Helm MA Helm TN Zeitouni N Patterns of skin metastases: A review of 25 years’ experience at a single cancer center Int J Dermatol 2014 53 56 60 23432658 \n3 Braverman IM Skin manifestations of internal malignancy Clin Geriatr Med 2002 18 1 19 v 11913734 \n4 Cho J Park Y Lee JC Jung WJ Lee S Case series of different onset of skin metastasis according to the breast cancer subtypes Cancer Res Treat 2014 46 194 9 24851112 \n5 Graziano V Scognamiglio MT Zilli M Giampietro J Vici P Natoli C Is the skin a sanctuary for breast cancer cells during treatment with anti-HER2 antibodies? Cancer Biol Ther 2015 16 1704 9 26552483 \n6 Gilhar A Paus R Kalish RS Lymphocytes, neuropeptides, and genes involved in alopecia areata J Clin Invest 2007 117 2019 27 17671634 \n7 Luque-Cabal M García-Teijido P Fernández-Pérez Y Sánchez-Lorenzo L Palacio-Vázquez I Mechanisms behind the resistance to trastuzumab in HER2-amplified breast cancer and strategies to overcome it Clin Med Insights Oncol 2016 10 21 30 27042153\n\n",
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"journal": "Indian journal of dermatology",
"keywords": "Breast cancer; cutaneous metastasis; human epidermal growth factor receptor-2; trastuzumab",
"medline_ta": "Indian J Dermatol",
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"title": "Metastatic Dermatosis in Breast Carcinoma on Adjuvant Trastuzumab: Is Skin a Sanctuary Site in Human Epidermal Growth Factor Receptor-2-Amplified Disease?",
"title_normalized": "metastatic dermatosis in breast carcinoma on adjuvant trastuzumab is skin a sanctuary site in human epidermal growth factor receptor 2 amplified disease"
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"abstract": "BACKGROUND\nIpilimumab (IPI), an anti-CTLA-4 antibody, and vemurafenib (VEM), a BRAF inhibitor, have distinct mechanisms of action and shared toxicities (e.g., skin, gastrointestinal [GI] and hepatobiliary disorders) that may preclude concomitant administration. Concurrent administration of IPI and VEM previously showed significant dose-limiting hepatotoxicity in advanced melanoma. This single-arm, open-label, phase II study evaluated a sequencing strategy with these two agents in previously untreated patients with BRAF-mutated advanced melanoma.\n\n\nMETHODS\nThis study was divided into two parts. During Part 1 (VEM1-IPI), patients received VEM 960 mg twice daily for 6 weeks followed by IPI 10 mg/kg every 3 weeks for 4 doses (induction), then every 12 weeks (maintenance) beginning at week 24 until disease progression or unacceptable toxicity. During Part 2 (VEM2), patients who progressed after IPI received VEM at their previously tolerated dose. The primary objective was to estimate the incidence of grade 3/4 drug-related skin adverse events (AEs) during VEM1-IPI.\n\n\nRESULTS\nAll patients who were initially treated with VEM (n = 46) received IPI induction therapy; 8 received IPI maintenance and 19 were treated during VEM2. During VEM1-IPI, the incidence of grade 3/4 drug-related AEs associated with the skin, GI tract, and hepatobiliary system was 32.6 %, 21.7 %, and 4.3 %, respectively. There were no drug-related deaths. At a median follow-up of 15.3 months, median overall survival was 18.5 months. Median progression-free survival was 4.5 months.\n\n\nCONCLUSIONS\nVEM (960 mg twice daily for 6 weeks) followed by IPI 10 mg/kg has a manageable safety profile. The benefits/risks of BRAF inhibitors followed by immunotherapy should be evaluated further in light of continuing developments in treatment options for metastatic melanoma.\n\n\nBACKGROUND\nClinicalTrials.gov identifier: NCT01673854 (CA184-240) Registered 24 August 2012.",
"affiliations": "Levine Cancer Institute, Carolinas Healthcare System, Medical Oncology, 1021 Morehead Medical Drive, Charlotte, NC 28204 USA.;Winship Cancer Institute of Emory University, Atlanta, GA USA.;Duke Cancer Institute, Durham, NC USA.;Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH USA.;Baptist Cancer Institute, Jacksonville, FL USA.;MD Anderson Cancer Center Orlando, Orlando, FL USA.;John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA USA.;University of New Mexico Cancer Center, Albuquerque, NM USA.;Bristol-Myers Squibb, Princeton, NJ USA ; Current Address: KBP BioSciences, Princeton, NJ USA.;Bristol-Myers Squibb, Princeton, NJ USA.;Dana-Farber Cancer Institute, Boston, MA USA.",
"authors": "Amin|Asim|A|;Lawson|David H|DH|;Salama|April K S|AK|;Koon|Henry B|HB|;Guthrie|Troy|T|;Thomas|Sajeve S|SS|;O'Day|Steven J|SJ|;Shaheen|Montaser F|MF|;Zhang|Bin|B|;Francis|Stephen|S|;Hodi|F Stephen|FS|",
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"doi": "10.1186/s40425-016-0148-7",
"fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central London 14810.1186/s40425-016-0148-7Research ArticlePhase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma Amin Asim Asim.Amin@carolinashealthcare.org 1Lawson David H. dlawson@emory.edu 2Salama April K.S. april.salama@duke.edu 3Koon Henry B. henry.koon@case.edu 4Guthrie Troy Jrguthriepmc@aol.com 5Thomas Sajeve S. Sajeve.Thomas@orlandohealth.com 6O’Day Steven J. stevenjoday@gmail.com 7Shaheen Montaser F. moshaheen@salud.unm.edu 8Zhang Bin binzhang28@gmail.com 911Francis Stephen stephen.francis@bms.com 9Hodi F. Stephen Stephen_Hodi@dfci.harvard.edu 101 Levine Cancer Institute, Carolinas Healthcare System, Medical Oncology, 1021 Morehead Medical Drive, Charlotte, NC 28204 USA 2 Winship Cancer Institute of Emory University, Atlanta, GA USA 3 Duke Cancer Institute, Durham, NC USA 4 Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH USA 5 Baptist Cancer Institute, Jacksonville, FL USA 6 MD Anderson Cancer Center Orlando, Orlando, FL USA 7 John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA USA 8 University of New Mexico Cancer Center, Albuquerque, NM USA 9 Bristol-Myers Squibb, Princeton, NJ USA 10 Dana-Farber Cancer Institute, Boston, MA USA 11 Current Address: KBP BioSciences, Princeton, NJ USA 16 8 2016 16 8 2016 2016 4 4420 5 2016 11 7 2016 © The Author(s). 2016\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\nIpilimumab (IPI), an anti-CTLA-4 antibody, and vemurafenib (VEM), a BRAF inhibitor, have distinct mechanisms of action and shared toxicities (e.g., skin, gastrointestinal [GI] and hepatobiliary disorders) that may preclude concomitant administration. Concurrent administration of IPI and VEM previously showed significant dose-limiting hepatotoxicity in advanced melanoma. This single-arm, open-label, phase II study evaluated a sequencing strategy with these two agents in previously untreated patients with BRAF-mutated advanced melanoma.\n\nMethods\nThis study was divided into two parts. During Part 1 (VEM1-IPI), patients received VEM 960 mg twice daily for 6 weeks followed by IPI 10 mg/kg every 3 weeks for 4 doses (induction), then every 12 weeks (maintenance) beginning at week 24 until disease progression or unacceptable toxicity. During Part 2 (VEM2), patients who progressed after IPI received VEM at their previously tolerated dose. The primary objective was to estimate the incidence of grade 3/4 drug-related skin adverse events (AEs) during VEM1-IPI.\n\nResults\nAll patients who were initially treated with VEM (n = 46) received IPI induction therapy; 8 received IPI maintenance and 19 were treated during VEM2. During VEM1-IPI, the incidence of grade 3/4 drug-related AEs associated with the skin, GI tract, and hepatobiliary system was 32.6 %, 21.7 %, and 4.3 %, respectively. There were no drug-related deaths. At a median follow-up of 15.3 months, median overall survival was 18.5 months. Median progression-free survival was 4.5 months.\n\nConclusions\nVEM (960 mg twice daily for 6 weeks) followed by IPI 10 mg/kg has a manageable safety profile. The benefits/risks of BRAF inhibitors followed by immunotherapy should be evaluated further in light of continuing developments in treatment options for metastatic melanoma.\n\nTrial registration\nClinicalTrials.gov identifier: NCT01673854 (CA184-240) Registered 24 August 2012\n\nKeywords\nVemurafenibIpilimumabMelanomaCTLA-4Immune checkpoint inhibitorBRAF inhibitorImmunotherapyTargeted agenthttp://dx.doi.org/http://dx.doi.org/10.13039/100002491Bristol-Myers Squibbissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nThe treatment landscape for metastatic melanoma has shifted dramatically in the past five years with the introduction of immune checkpoint inhibitors and targeted agents. In 2011, the anti-CTLA-4 antibody YERVOY® (ipilimumab, IPI; Bristol-Myers Squibb, New York, NY, USA) and BRAF inhibitor Zelboraf® (vemurafenib, VEM; Genentech, San Francisco, CA, USA) were approved for the treatment of metastatic melanoma, marking the first immune checkpoint inhibitor and the first targeted agent, respectively, to be approved for this indication.\n\nThe dynamics and durability of response observed with IPI and VEM differ markedly. IPI has demonstrated a durable survival benefit in ~20 % of patients, ~10 years from the initial treatment in a proportion of patients; however, IPI-induced tumor responses often require time to reach their full potential [1–5]. VEM can induce rapid and substantial responses in approximately 50 % of patients with advanced, BRAF-mutated melanoma [6, 7], but in most cases responses are not durable, as tumors develop resistance to BRAF inhibition due to activation of alternate signaling pathways [8, 9]. Patients may experience rapid disease progression once tumors bypass BRAF inhibition, often not allowing time for other therapeutic options to be considered.\n\nSeveral lines of evidence provide a rationale for combining an immune checkpoint inhibitor with a targeted agent to optimize patient outcomes (rapid response with VEM, and durability of response with IPI), while minimizing toxicity [10]. Tumor cell death mediated by inhibition of the MAPK pathway may lead to increased antigen presentation or cross-presentation to tumor-specific T cells [11]. Inhibition of the MAPK pathway has been shown to increase the expression of melanocyte differentiation antigens in melanoma cell lines and fresh tumor digests, conferring enhanced antigen-specific recognition by T lymphocytes [12]. In co-cultures of melanoma cell lines and human monocyte-derived dendritic cells, inhibition of BRAF and MEK restores compromised dendritic cell function [13].\n\nConcurrent administration of VEM and IPI was evaluated in a phase I study of patients with BRAF-mutated metastatic melanoma [14]. Patients in the first cohort (n = 6) received 960 mg VEM twice daily for 4 weeks, before starting concurrent IPI 3 mg/kg given every 3 weeks for four infusions; in the second cohort (n = 6), the dose of VEM was reduced to 720 mg twice daily. Four of six patients in the first cohort experienced grade 3 elevations in aminotransferase levels after the first infusion of VEM plus IPI. Among the first four patients treated in the second cohort, two patients experienced grade 3 elevations in aminotransferase levels after starting IPI. Given the hepatotoxicity observed with VEM plus IPI, the remaining two patients in the second cohort received VEM alone and the study was closed to further patient accrual. All hepatic adverse events (AEs) were asymptomatic and reversible with discontinuation of study therapy or administration of glucocorticoids. Two of six patients in the first cohort experienced grade 3 rash with VEM plus IPI.\n\nThe current study was designed to evaluate a sequencing strategy (VEM followed by IPI), in order to avoid the toxicities observed with concurrent administration. The rationale for this treatment sequence was that it could potentially delay or prevent the emergence of BRAF inhibitor resistance by initiating IPI before disease progression, and to optimize a potential immune-synergy by initiating IPI soon after BRAF-inhibitor induced T-cell infiltration.\n\nThis report focuses on patients who were treated with VEM followed by IPI during Part 1 of the study (VEM1-IPI). Data collected during Part 2 (subsequent VEM re-treatment, VEM2) are summarized in brief. Grade 3/4 skin AEs were the most frequent severe common toxicities shared by the two agents and the incidence of these events was therefore chosen as the primary endpoint. Grade 3/4 gastrointestinal and hepatobiliary AEs were evaluated as secondary endpoints.\n\nMethods\nPatients\nEligible patients had histologically confirmed unresectable stage III or IV malignant melanoma that harbored a BRAF V600 mutant. Patients had to be at least 18 years old with measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Prior systemic treatment for melanoma was not permitted. Patients with primary ocular melanoma, active autoimmune diseases, or symptomatic brain metastases requiring corticosteroid treatment were ineligible.\n\nAll patients provided written informed consent. The protocol was approved by the institutional review boards or ethics committees of the participating sites. The study was conducted in accordance with declaration of Helsinki with good clinical practice as defined by the International Conference on Harmonization.\n\nStudy design and treatment\nThis phase II, single-arm, open-label study (CA184-240, ClinicalTrials.gov identifier: NCT01673854) was carried out in two parts (Fig. 1a). During Part 1 (VEM1-IPI), patients received VEM 960 mg orally twice daily for 6 weeks. After a washout period of 3 to 10 days, patients were initiated on IPI induction at 10 mg/kg every 3 weeks for 4 doses. At week 24, patients received IPI maintenance at the dose of 10 mg/kg every 12 weeks until disease progression by modified World Health Organization (mWHO) criteria or unacceptable toxicity for a maximum treatment period of 3 years from the first dose. A higher than approved dose of IPI for advanced melanoma was selected for this study based on clinical data showing a greater mean rate of increase in absolute lymphocyte count and improved efficacy measures (e.g., BOR) with IPI 10 versus 3 mg/kg [15].Fig. 1 This study was divided into two parts: VEM1-IPI and VEM2. During VEM1-IPI, patients received VEM 960 mg twice daily for 6 weeks followed by IPI 10 mg/kg induction and maintenance therapy. During VEM2, patients who progressed after IPI received VEM at their previously tolerated dose (a). Among 70 patients who enrolled in this study, 46 were treated during VEM1 and continued to IPI induction. Eight patients received IPI maintenance therapy. Nineteen patients were treated during VEM2. Reasons for discontinuation of study drug are provided (b). AE = adverse event; BID = twice daily; IPI = ipilimumab; PO = by mouth; PD = progressive disease; Q3W = every 3 weeks; Q12W = every 12 weeks; VEM = vemurafenib\n\n\n\nDuring Part 2 (VEM2), patients without progression or unacceptable toxicity to VEM during Part 1 (VEM1-IPI) and who had discontinued IPI were re-treated with VEM at their previously tolerated dose. A minimum of 1-month washout period between IPI and treatment in VEM2 was required for patients who stopped IPI because of toxicity or reasons other than progression. Patients who proceeded to VEM2 after progression on IPI maintenance did not have any minimum washout requirement before re-initiating VEM. Treatment was continued until disease progression by WHO criteria or unacceptable toxicity. Tumor response was assessed by mWHO criteria after completion of VEM1-IPI induction and then every 12 weeks.\n\nStudy objectives\nThe primary objective was to estimate the incidence of grade 3/4 drug-related skin AEs during VEM1-IPI. Secondary objectives were to estimate the rates of grade 3/4 drug-related gastrointestinal (GI) and hepatobiliary AEs during VEM1-IPI. For both the primary and secondary objectives, analyses included events that occurred from the first dose of VEM1 to the last dose of IPI plus 90 days or to the first dose of VEM2, whichever occurred first. Worst grade drug-related skin, GI, and hepatobiliary AEs were taken into account.\n\nExploratory objectives included progression-free survival (PFS), best overall response (BOR), objective response rate (ORR), duration of response (DOR), duration of stable disease (DOSD), and safety during VEM1-IPI. PFS was defined as the time between the first dose date of VEM1 and the date of progressive disease by mWHO criteria or death, whichever occurred first. BOR analysis was defined over the VEM1-IPI period as a whole and compared the on-study tumor burden to the study baseline tumor assessment. ORR was defined as the number of patients who achieved a BOR of complete response (CR) or partial response (PR) divided by the total number of IPI-treated patients. DOR was assessed in patients who achieved a BOR of CR or PR, and was defined as the time between the date of confirmed response and the date of progressive disease or death, whichever occurred first. DOSD was defined as the time between the date of the first evaluable tumor assessment with at least SD and the date of progressive disease or death, whichever occurred first. Exploratory safety endpoints included AEs, serious adverse events (SAEs), drug-related AEs, and AEs leading to discontinuation. All AEs were coded using Medical Dictionary for Regulatory Activities (MedDRA) system organ classes and preferred terms, and were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0).\n\nAlthough this study was primarily focused on outcomes during VEM1-IPI, additional data during subsequent VEM re-treatment (VEM2) was also collected. All safety analyses performed during VEM1-IPI were also performed during VEM2, and included events from the first dose date of VEM2 to the last dose of VEM2 plus 14 days. ORR during VEM2 was also evaluated.\n\nAll treated patients were followed every 12 weeks for survival.\n\nStatistical analyses\nThe sample size for this study was not based on power calculation. It was estimated that approximately 45 eligible patients would be treated during VEM1. Allowing for a 10 % drop-out prior to IPI treatment, the number of patients with IPI was expected to be approximately 40. Assuming that the incidence of high-grade skin AEs was approximately 10 %, a sample size of 40 treated patients would provide two-sided exact 95 % confidence intervals (CIs) of 2.8 % to 23.7 %. Time-to-event endpoints (PFS, DOR, DOSD, and OS) were estimated using the Kaplan-Meier (KM) method. The estimate of median and two-sided 95 % CIs was calculated by the Brookmeyer and Crowley method. KM estimates of PFS rates and associated two-sided log-log transformation 95 % CIs were calculated at multiple time points, including 6 months and 1 year. For ORR, exact two-sided 95 % CIs were computed using the Clopper and Pearson method. For primary and secondary safety endpoints, exact two-sided 95 % CIs and point estimates were determined.\n\nResults\nPatients\nSeventy patients were enrolled between October 2012 and July 2014, and 46 were treated during VEM1-IPI (Fig. 1b). Patient demographic and baseline clinical characteristics during VEM1-IPI are summarized in Table 1. The mean age of patients was 55.0 years, and 80.4 % were male. Most patients (76.1 %) had an ECOG performance status of 0. At study entry, most patients had stage IV disease (82.6 %), M1c (52.2 %), and at least 5 disease sites involved (54.3 %).Table 1 Patient demographic and baseline clinical characteristics\n\nCharacteristic\tVEM1-IPI (n = 46)\t\nAge, years\t\t\n Mean (SD)\t55.0 (14.20)\t\nGender, n (%)\t\t\n Male\t37 (80.4)\t\nECOG performance status, n (%)\t\t\n 0\t35 (76.1)\t\n 1\t11 (23.9)\t\nDisease stage at study entry, n (%)\t\t\n III\t8 (17.4)\t\n IV\t38 (82.6)\t\nM-stage at study entry, n (%)\t\t\n M0\t6 (13.0)\t\n M1a\t8 (17.4)\t\n M1b\t8 (17.4)\t\n M1c\t24 (52.2)\t\nNumber of disease sites, n (%)\t\t\n 1\t2 (4.3)\t\n 2\t8 (17.4)\t\n 3\t7 (15.2)\t\n 4\t4 (8.7)\t\n ≥ 5\t25 (54.3)\t\n\nECOG Eastern Cooperative Oncology Group, IPI ipilimumab, SD standard deviation, VEM vemurafenib\n\n\n\nDrug exposure\nAll 46 patients treated with VEM during VEM1 continued to IPI induction (Fig. 1b). The median number of doses administered during IPI induction was 4; 24 patients (52.2 %) received all 4 doses, 8 (17.4 %) received 3 doses, 8 (17.4 %) received 2 doses, and 6 (13.0 %) received 1 dose. Eight patients (17.4 %) received IPI maintenance therapy. The median number of doses administered during IPI maintenance was 3; 1 patient each received 5, 6, or 7 doses; 3 patients received 3 doses and 2 patients received 1 dose. Ten patients (21.7 %) required at least one IPI dose delay, and 6 (13.0 %) needed at least one IPI infusion interruption. At the time of this analysis, all 46 patients had discontinued study treatment: 27 during IPI treatment and 19 during VEM2 treatment (Fig. 1b). Reasons for discontinuation of study drugs are provided in Fig. 1b.\n\nSafety\nDuring VEM1-IPI, 15 of 46 patients (32.6 %) experienced 1 or more grade 3/4 drug-related skin AEs (e.g., rash, erythema, pruritus) (Table 2). Grade 3/4 drug-related GI AEs occurred in 10 of 46 patients (21.7 %); diarrhea was the most common (n = 5, 10.9 %). Only 2 of 46 patients (4.3 %) experienced grade 3/4 drug-related hepatobiliary toxicity: hepatitis (n = 1, 2.2 %) and hyperbilirubinemia (n = 1, 2.2 %).Table 2 Drug-related grade 3/4 skin, gastrointestinal, and hepatobiliary AEs during VEM1-IPI by investigator-reported preferred term\n\nAE Organ Category, n (%)a\n\tVEM1-IPI (n = 46)\t\nSkin\t15 (32.6)\t\n Rash\t9 (19.6)\t\n Erythema\t2 (4.3)\t\n Exfoliative rash\t2 (4.3)\t\n Pruritus\t2 (4.3)\t\n Rash generalized\t2 (4.3)\t\n Rash maculo-papular\t1 (2.2)\t\nGastrointestinal disorders\t10 (21.7)\t\n Diarrhea\t5 (10.9)\t\n Colitis\t2 (4.3)\t\n Nausea\t2 (4.3)\t\n Abdominal pain\t1 (2.2)\t\n Autoimmune colitis\t1 (2.2)\t\n Vomiting\t1 (2.2)\t\nHepatobiliary disorders\t2 (4.3)\t\n Hepatitis\t1 (2.2)\t\n Hyperbilirubinemia\t1 (2.2)\t\n\nAE adverse event, IPI ipilimumab, VEM vemurafenib\n\n\naPatients may have experienced more than 1 event\n\n\n\nOverall during VEM1-IPI, 43 of 46 (93.5 %) patients reported a drug-related AE of any grade (Table 3). All 43 patients had 1 or more drug-related AEs that were consistent with an immune phenomenon. Grade 3/4 drug-related AEs were reported in 30 patients (65.2 %). Drug-related serious adverse events (SAEs) of any grade were noted in 18 patients (39.1 %). The only grade 3/4 drug-related SAE observed in 3 or more patients was squamous cell carcinoma (n = 3, grade 3 events).Table 3 Drug-related AEs during VEM1-IPI\n\nEvent, n (%)a\n\tVEM1-IPI (n = 46)\t\n\tAny Grade\tGrade 3\tGrade 4\t\nAny drug-related AE\t43 (93.5)\t27 (58.7)\t3 (6.5)\t\nAEs occurring in ≥ 3 patientsb\n\t\t\t\t\n Rash\t28 (60.9)\t9 (19.6)\t0 (0)\t\n Diarrhea\t17 (37.0)\t5 (10.9)\t0 (0)\t\n AST increased\t9 (19.6)\t3 (6.5)\t1 (2.2)\t\n ALT increased\t8 (17.4)\t4 (8.7)\t0 (0)\t\n Squamous cell carcinomac\n\t3 (6.5)\t3 (6.5)\t0 (0)\t\nAny drug-related serious AEs\t18 (39.1)\t15 (32.6)\t2 (4.3)\t\nAEs leading to discontinuation of treatment\t16 (34.8)\t9 (19.6)\t1 (2.2)\t\n\nAE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, IPI ipilimumab, VEM vemurafenib\n\n\naPatients may have experienced more than 1 event\n\n\nbOnly toxicities that reached Grade 3/4 in severity in ≥ 3 patients are presented\n\n\ncSquamous cell carcinoma was classified as a serious adverse event (SAE) and was the only SAE that was observed in 3 or more patients (n = 3, grade 3 events)\n\n\n\nDrug-related AEs of any grade leading to discontinuation of treatment during VEM1-IPI were most frequently seen as GI disorders (21.7 %), including colitis and diarrhea (6.5 % each), nausea and vomiting (4.3 % each); all other system-organ events leading to discontinuation were each reported in only 1 patient.\n\nDuring VEM2, drug-related AEs of any grade were observed in 10 of 19 patients (52.6 %). Five patients (26.3 %) experienced a grade 3 drug-related AE during VEM2.\n\nTwenty-four patients (52.2 %) died during this study due to disease (n = 22) or other/unknown factors (n = 2). There were no drug-related deaths.\n\nEfficacy\nDuring VEM1-IPI, the BOR rate was 32.6 % (Table 4). The median duration of response was 23.1 months (95 % CI: 5.03–not evaluable), and the median duration of stable disease was 5.2 months (95 % CI: 3.98–14.75) (Table 4, Fig. 2). The BOR rate during VEM2 was 36.8 %. The median PFS during VEM1-IPI was 4.5 months (95 % CI: 4.17–6.57) (Fig. 3a). At a median follow-up of 15.3 months, the median OS was 18.5 months (95 % CI: 11.96–not evaluable) (Fig. 3b).Table 4 Efficacy results during VEM1-IPI\n\n\tResult\t\nBest overall response, n (%)\t\t\n Complete response\t2 (4.3)\t\n Partial response\t13 (28.3)\t\n Stable disease\t5 (10.9)\t\n Progressive disease\t11 (23.9)\t\n Unknowna\n\t15 (32.6)\t\nBest overall response rate, % (95 % CI)\t32.6 (19.5–48.0)\t\nMedian duration of response, mo (95 % CI)\t23.1 (5.03–NE)\t\nMedian duration of stable disease, mo (95 % CI)\t5.2 (3.98–14.75)\t\n\nCI confidence interval, IPI ipilimumab, mo month, NE not evaluable, VEM vemurafenib\n\n\naResponse could not be determined due to missing assessment, image quality, etc\n\nFig. 2 Kaplan-Meier curves for DOR (a) and DOSD (b) during VEM1-IPI. The median DOR was 23.1 months (95 % CI: 5.03–not evaluable), and the median DOSD was 5.2 months (95 % CI: 3.98–14.75)\n\nFig. 3 Kaplan-Meier curves for PFS during VEM1-IPI (a) and OS (b). The median PFS was 4.5 months (95 % CI: 4.17–6.57). At a median follow-up of 15.3 months, the median OS was 18.5 months (95 % CI: 11.96–not evaluable)\n\n\n\nDiscussion\nThis phase II, single-arm, open-label study showed that VEM (960 mg twice daily for 6 weeks) followed by IPI 10 mg/kg can be administered safely in patients with previously untreated BRAF-mutated metastatic melanoma. Although 65.2 % of the patients experienced a grade 3/4 drug-related AE, no drug-related deaths occurred. During VEM1-IPI, grade 3/4 drug-related skin AEs were observed in 32.6 % of patients, which is higher than that reported with IPI 10 mg/kg alone (grade 3/4 immune-related skin AEs: 4.2 % in the phase II study CA184-022 and 3.2 % in the phase II study CA184-008) or VEM monotherapy (grade 3 rash: 8 % in the phase III study BRIM-3) [6, 15, 16]. Interestingly, the incidence of grade 3 squamous cell carcinoma in this study (6.5 % based on NCI CTCAE v3.0) was lower than that reported with VEM monotherapy (12 % based on NCI CTCAE v4.0), which is possibly due to the shorter duration of VEM therapy (6 weeks) in our study [6]. Alternatively, this may suggest a role for the immune response in the development of secondary squamous cell carcinomas in light of the possible etiologies of their development via HRAS mutations in keratinocytes [17]. The incidence of drug-related grade 3/4 diarrhea (10.9 %) and colitis (4.3 %) reported here is similar to that observed with IPI 10 mg/kg alone (CA184-022: 14.1 % and 2.8 %, respectively) [18]. In contrast to the high hepatotoxicity noted with concurrent administration of VEM and IPI (4 of 6 patients [66.7 %] treated with VEM 960 mg/kg in cohort 1) [14], only 2 of 46 patients (4.3 %) experienced grade 3/4 hepatotoxicity with this VEM/IPI sequencing regimen (Table 2), suggesting that sequential administration of VEM and IPI results in a better toxicity profile than concurrent administration.\n\nThe BOR observed during VEM1-IPI was 32.6 %, which is higher than that reported with IPI 10 mg/kg alone (11.1 % in CA184-022 and 5.8 % in CA184-008) [15, 16], and lower than that reported with VEM monotherapy (ORR: 57 % in BRIM-3) [19]. The response observed and reported in this study was captured at the end of completion of 4 doses of induction therapy with IPI and therefore does not necessarily reflect best response to VEM monotherapy at the end of the initial 6-week treatment. Some of the patients with rapidly progressive disease could potentially have had an increase in their tumor burden while receiving IPI prior to the first response evaluation of the study. During VEM1-IPI, the median duration of response was 23.1 months, and the median duration of stable disease was 5.2 months. The median duration of response was 19.3 months in the phase III study CA184-024, which evaluated IPI 10 mg/kg in combination with dacarbazine in patients with unknown BRAF mutation status [4], and was 6.7 months with VEM in the BRIM-2 study [7]. The BOR was 36.8 % during VEM2, showing ongoing sensitivity to BRAF inhibition.\n\nThe landscape of therapeutic options for advanced melanoma continues to evolve rapidly. Combinations of BRAF plus MEK inhibitors (e.g., dabrafenib plus trametinib, as well as vemurafenib plus cobimetinib) have shown an overall response rate of 66–70 % in patients with BRAF-mutated advanced melanoma [20–22] and are now approved for this indication by the US FDA.\n\nSeveral studies of PD-1 inhibition alone or in combination with IPI have included treatment-naïve patients with BRAF-mutated advanced melanoma who could have been eligible for our study. The ORR observed with PD-1 inhibition alone (i.e., nivolumab [NIVO] or pembrolizumab) is in the range of 33–37 %, while the combination of NIVO plus IPI elicited an ORR of 52–67 % [23–26]. NIVO and pembrolizumab as monotherapy and NIVO in combination with IPI are now approved treatments for advanced melanoma. It is important to keep the above data in mind to contextualize this study in current clinical practice.\n\nAlthough a number of very effective agents are now available for advanced melanoma, the best dosing schedules, combinations or sequencing are still not known and remain the focus of active investigation. As an example, a phase II, randomized study (CheckMate 064) showed consistent improvement in efficacy outcomes with NIVO followed by IPI versus IPI followed by NIVO (e.g., confirmed ORR at week 25: 41.2 % versus 20.0 %, respectively) [27]. The pattern of AEs reported in CheckMate 064 was similar to that previously reported with either agent, alone or in combination, whereas the frequency of AEs was consistent with previous reports for NIVO plus IPI [23, 24].\n\nThe sequencing strategy of targeted therapy followed by immune-modulation, demonstrated in this study with VEM followed by IPI, serves as one of the links in our efforts to understand how best to use these agents. Additional understanding of the immune-modulatory effects of BRAF as well as MEK inhibition in the tumor microenvironment is warranted. MEK inhibition may influence the activity of certain subsets of effector lymphocytes. BRAF inhibition with VEM may also activate lymphocytes via the paradoxical activation of MAPK in BRAF wild-type cells and contribute not only to some of the side effects observed with the combination of immunotherapy, but also to improved antitumor activity and clinical outcomes. This study sets the stage for further investigation of BRAF plus MEK inhibition followed by PD-1 with or without CTLA-4 inhibition for select groups of patients who have high tumor burden or rapidly progressive symptomatic disease, which will be borne out in the phase III ECOG study (NCT02224781) currently underway to evaluate dabrafenib plus trametinib followed by IPI plus NIVO at progression compared with IPI plus NIVO followed by dabrafenib plus trametinib at progression in patients with BRAF V600-mutant advanced melanoma.\n\nRegardless of recent developments exploring multiple sequential combinations, further investigation of the potential of BRAF inhibition combined with immune checkpoint inhibition, especially the PD-1 pathway, may be worthwhile. Our study showed that the sequential combination of VEM and IPI had manageable safety and that tumors remain sensitive to BRAF inhibition after progressing on immunotherapy with IPI.\n\nConclusions\nWe show that VEM (960 mg twice daily for 6 weeks) followed by IPI 10 mg/kg has a manageable safety profile. Although the combination of BRAF plus MEK inhibition and NIVO plus IPI immune checkpoint inhibition is more commonly used today than VEM or IPI monotherapy to treat advanced melanoma, this study shows that IPI has efficacy after treatment with VEM in patients with BRAF-mutated melanoma and that tumors remain sensitive to VEM re-treatment after progressing on IPI. In addition, because VEM and IPI are the major drivers of the AE profile associated with combination regimens (e.g., AE profile of NIVO plus IPI is primarily driven by IPI), evaluation of each agent alone may be informative regarding the safety profile of combination therapy when used in a sequential regimen. The benefits/risks of BRAF inhibitors followed by immunotherapy should be evaluated further in light of continuing developments in treatment options for metastatic melanoma.\n\nAbbreviations\nAE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; BOR, best overall response; CA, California; CI, confidence interval; CTLA-4, cytotoxic T-lymphocyte antigen 4; DOR, duration of response; DOSD, duration of stable disease; ECOG, Eastern Cooperative Oncology Group; FDA, Food and Drug Administration; GI, gastrointestinal; HR, hazard ratio; IPI, ipilimumab; KM, Kaplan-Meier; mo, month; mWHO, modified World Health Organization; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; NE, not evaluable; NIVO, nivolumab; NY, New York; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-1, programmed death receptor-1; PFS, progression-free survival; PO, by mouth; Q12W, every 12 weeks; Q3W, every 3 weeks; SAE, serious adverse event; SD, standard deviation; USA, United States of America; VEM, vemurafenib; VEM1-IPI, vemurafenib followed by ipilimumab treatment; VEM2, vemurafenib re-treatment\n\nProfessional medical writing and editorial assistance were provided by Jennifer DiNieri, PhD and Cara Hunsberger, MS of StemScientific, an Ashfield Company, funded by Bristol-Myers Squibb.\n\nFunding\nBristol-Myers Squibb Co.\n\nAvailability of data and materials\nData are available upon request for academic researchers.\n\nAuthors’ contributions\nAA and DHL collaborated in conception and design of this analysis. DHL, SST, MFS, BZ, FSH, and TG collected and assembled the data. DHL, AKSS, SJO, BZ, SF, FSH, HBK, and TG participated in data analysis and interpretation. AKSS, SJO, and TG assisted with provision of study material or patients. All authors helped to draft the manuscript. All authors approved the final version.\n\nCompeting interests\nAA is a paid consultant/advisor for Bristol-Myers Squibb and Merck. He has participated in speakers’ bureaus for Bristol-Myers Squibb, Merck, and Pfizer. AA has also received research funding from Bristol-Myers Squibb, Merck, Prometheus, and Argos. DHL has received honoraria, as well as travel, accommodations, and expenses from Genentech. He has also received research funding from Amgen, Bristol-Myers Squibb, and Merck. AKSS has received research funding from Bristol-Myers Squibb, Merck, GlaxoSmithKline, and Genentech. HBK is a paid consultant/advisor for and has received honoraria and research funding from Bristol-Myers Squibb. He has also participated in speakers’ bureaus for Bristol-Myers Squibb. TG has participated in speakers’ bureaus for Novartis, Bristol-Myers Squibb, and Boehringer Ingelheim. SST is a paid consultant/advisor for Bristol-Myers Squibb and Ipsen. He has received honoraria, as well as travel, accommodations, and expenses from Bristol-Myers Squibb, Ipsen, and Novartis. SST has also participated in speakers’ bureaus for Bristol-Myers Squibb, Ipsen and Novartis. SJO is a paid consultant/advisor for Bristol-Myers Squibb. He has also received honoraria, as well as travel, accommodations, and expenses from Bristol-Myers Squibb. BZ is a former employee of Bristol-Myers Squibb and has stock or other ownership in this company. SF is an employee of Bristol-Myers Squibb and has stock or other ownership in this company. FSH is a non-paid consultant/advisor for Bristol-Myers Squibb and has received research funding from Bristol-Myers Squibb on behalf of his institution. He also reports a patent pending (immune target) on behalf of his institution. MFS has no financial competing interests. No non-financial competing interests exist for any of the authors.\n\nConsent for publication\nNot applicable.\n\nEthics approval and consent to participate\nAll patients provided written informed consent. The protocol was approved by the institutional review boards or ethics committees of the participating sites. A list of specific ethical bodies for study CA184-240 is available upon request. The study was conducted in accordance with declaration of Helsinki with good clinical practice as defined by the International Conference on Harmonization.\n\nPrior presentation\nAmerican Society of Clinical Oncology 2015 Annual Meeting; May 29–June 2, 2015; Chicago, IL, USA; Poster presentation (abstract number: 9032, poster board number: 275).\n==== Refs\nReferences\n1. Hodi FS O’Day SJ McDermott DF Weber RW Sosman JA Haanen JB Improved survival with ipilimumab in patients with metastatic melanoma N Engl J Med 2010 363 711 23 10.1056/NEJMoa1003466 20525992 \n2. Lebbé C Weber JS Maio M Neyns B Harmankaya K Hamid O Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies Ann Oncol 2014 25 2277 84 10.1093/annonc/mdu441 25210016 \n3. Maio M Grob JJ Aamdal S Bondarenko I Robert C Thomas L Five-year survival rates for treatment-naïve patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial J Clin Oncol 2015 33 1191 6 10.1200/JCO.2014.56.6018 25713437 \n4. Robert C Thomas L Bondarenko I O’Day S Weber J Garbe C Ipilimumab plus dacarbazine for previously untreated metastatic melanoma N Engl J Med 2011 364 2517 26 10.1056/NEJMoa1104621 21639810 \n5. Schadendorf D Hodi FS Robert C Weber JS Margolin K Hamid O Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma J Clin Oncol 2015 33 1889 94 10.1200/JCO.2014.56.2736 25667295 \n6. Chapman PB Hauschild A Robert C Haanen JB Ascierto P Larkin J Improved survival with vemurafenib in melanoma with BRAF V600E mutation N Engl J Med 2011 364 2507 16 10.1056/NEJMoa1103782 21639808 \n7. Sosman JA Kim KB Schuchter L Gonzalez R Pavlick AC Weber JS Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib N Engl J Med 2012 366 707 14 10.1056/NEJMoa1112302 22356324 \n8. Spagnolo F Ghiorzo P Queirolo P Overcoming resistance to BRAF inhibition in BRAF-mutated metastatic melanoma Oncotarget 2014 5 10206 21 10.18632/oncotarget.2602 25344914 \n9. Wagle N Emery C Berger MF Davis MJ Sawyer A Pochanard P Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling J Clin Oncol 2011 29 3085 96 10.1200/JCO.2010.33.2312 21383288 \n10. Luke JJ Is there an optimal intersection for targeted and immunotherapy treatments for melanoma? Am J Hematol Oncol 2015 11 34 8 \n11. Hong DS Vence L Falchook G Radvanyi LG Liu C Goodman V BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency Clin Cancer Res 2012 18 2326 35 10.1158/1078-0432.CCR-11-2515 22355009 \n12. Boni A Cogdill AP Dang P Udayakumar D Njauw CN Sloss CM Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function Cancer Res 2010 70 5213 9 10.1158/0008-5472.CAN-10-0118 20551059 \n13. Ott PA Henry T Baranda SJ Frleta D Manches O Bogunovic D Inhibition of both BRAF and MEK in BRAF(V600E) mutant melanoma restores compromised dendritic cell (DC) function while having differential direct effects on DC properties Cancer Immunol Immunother 2013 62 811 22 10.1007/s00262-012-1389-z 23306863 \n14. Ribas A Hodi FS Callahan M Konto C Wolchok J Hepatotoxicity with combination of vemurafenib and ipilimumab N Engl J Med 2013 368 1365 6 10.1056/NEJMc1302338 23550685 \n15. Wolchok JD Neyns B Linette G Negrier S Lutzky J Thomas L Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study Lancet Oncol 2010 11 155 64 10.1016/S1470-2045(09)70334-1 20004617 \n16. O’Day SJ Maio M Chiarion-Sileni V Gajewski TF Pehamberger H Bondarenko IN Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study Ann Oncol 2010 21 1712 7 10.1093/annonc/mdq013 20147741 \n17. Ratushny V Gober MD Hick R Ridky TW Seykora JT From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma J Clin Invest 2012 122 464 72 10.1172/JCI57415 22293185 \n18. Wolchok JD Hoos A O’Day S Weber JS Hamid O Lebbé C Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria Clin Cancer Res 2009 15 7412 20 10.1158/1078-0432.CCR-09-1624 19934295 \n19. Chapman PB, Hauschild A, Robert C, Larkin JMG, Haanen JBA, Ribas A, et al. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. J Clin Oncol. 2012;30(Suppl). abstract 8502.\n20. Long GV Stroyakovskiy D Gogas H Levchenko E de Braud F Larkin J Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial Lancet 2015 386 444 51 10.1016/S0140-6736(15)60898-4 26037941 \n21. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroyakovskiy D, et al. Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib and trametinib with vemurafenib as first-line therapy in patients with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Presented at the European Cancer Congress; Vienna, Austria; September 28, 2015: abstract 3301.\n22. Larkin J, Yan Y, McArthur GA, Ascierto PA, Liszkay G, Maio M, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol. 2015;33(Suppl): abstract 9006.\n23. Postow MA Chesney J Pavlick AC Robert C Grossmann K McDermott D Nivolumab and ipilimumab versus ipilimumab in untreated melanoma N Engl J Med 2015 372 2006 7 10.1056/NEJMoa1414428 25891304 \n24. Larkin J Chiarion-Sileni V Gonzalez R Grob JJ Cowey CL Lao CD Combined nivolumab and ipilimumab or monotherapy in untreated melanoma N Engl J Med 2015 373 23 34 10.1056/NEJMoa1504030 26027431 \n25. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Efficacy and safety in key patient subgroups of nivolumab alone or combined with ipilimumab versus ipilimumab alone in treatment-naïve patients with advanced melanoma (CheckMate 067). Presented at the 40th Annual Meeting of the European Society for Medical Oncology; Vienna, Austria; September 25–29, 2015: abstract 3303.\n26. Robert C Schachter J Long GV Arance A Grob JJ Mortier L, et al, and KEYNOTE-006 investigators: pembrolizumab versus ipilimumab in advanced melanoma N Engl J Med 2015 372 2521 32 10.1056/NEJMoa1503093 25891173 \n27. Weber JS, Gibney G, Sullivan RJ, Sosman JA, Slingluff CL Jr, Lawrence DP, et al. 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. 2016; doi:10.1016/S1470-2045(16)30126-7.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2051-1426",
"issue": "4()",
"journal": "Journal for immunotherapy of cancer",
"keywords": "BRAF inhibitor; CTLA-4; Immune checkpoint inhibitor; Immunotherapy; Ipilimumab; Melanoma; Targeted agent; Vemurafenib",
"medline_ta": "J Immunother Cancer",
"mesh_terms": null,
"nlm_unique_id": "101620585",
"other_id": null,
"pages": "44",
"pmc": null,
"pmid": "27532019",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "25210016;20004617;20551059;22356324;19934295;27269740;25891304;22355009;23306863;26037941;25667295;25344914;20525992;21383288;21639810;25891173;21639808;23550685;25713437;20147741;26027431;22293185",
"title": "Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma.",
"title_normalized": "phase ii study of vemurafenib followed by ipilimumab in patients with previously untreated braf mutated metastatic melanoma"
} | [
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"companynumb": "US-ROCHE-1578952",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "5",
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"activesubstancename": "IPILIMUMAB"
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{
"abstract": "Background: Tuberculosis (TB) is considered to be an adverse effect of treatment with immune checkpoint inhibitors. Methodology & results: Our case was a 75-year-old woman diagnosed with unresectable stage III non-small-cell lung cancer. After radical chemoradiotherapy was completed, durvalumab was initiated as a consolidation therapy. However, since chest CT showed appearances of infiltration shadows scattered in the periphery of the lungs after five doses of immunotherapy, duruvalumab was discontinued. 6 weeks later, the patient was aware of intermittent fever. Chest CT scan showed the appearance of a tree-in-bud pattern in the right lung. Acid-fast bacilli stain of sputum was positive and the PCR test was positive for Mycobacterium tuberculosis. Conclusion: Duruvalumab as PD-L1 blockade may activate TB.",
"affiliations": "Department of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan.;Department of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan.;Department of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan.;Department of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan.;Department of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan.;Department of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan.",
"authors": "Kato|Yasuhiro|Y|;Watanabe|Yasutaka|Y|;Yamane|Yuki|Y|;Mizutani|Hideaki|H|;Kurimoto|Futoshi|F|;Sakai|Hiroshi|H|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; C000613593:durvalumab",
"country": "England",
"delete": false,
"doi": "10.2217/imt-2020-0061",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1750-743X",
"issue": "12(6)",
"journal": "Immunotherapy",
"keywords": "IGRA; LTBI; NSCLC; PD-L1 blockade; TB; chemoradiotherapy; durvalumab; immune checkpoint inhibitor; irAE; pulmonary TB",
"medline_ta": "Immunotherapy",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; D002289:Carcinoma, Non-Small-Cell Lung; D059248:Chemoradiotherapy; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms; D009169:Mycobacterium tuberculosis; D009367:Neoplasm Staging; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "101485158",
"other_id": null,
"pages": "373-378",
"pmc": null,
"pmid": "32314636",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reactivation of TB during administration of durvalumab after chemoradiotherapy for non-small-cell lung cancer: a case report.",
"title_normalized": "reactivation of tb during administration of durvalumab after chemoradiotherapy for non small cell lung cancer a case report"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1952406",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "Methemoglobinemia occurs when the heme moiety of hemoglobin (Hb) is oxidized from the ferrous to ferric state, leading to impairments in oxygen transport and delivery. Methemoglobinemia is rare in pediatric patients but has been described in the setting of congenital abnormalities in the Hb structure, inherited enzyme deficiencies, oxidative Hb injury in response to illness, and oxidative Hb injury due to toxicants. We present a 1-week-old infant born with a cervical lymphangioma who developed persistent desaturations that were unresponsive to oxygen after sclerotherapy with doxycycline. Arterial blood gas revealed a high Pao2 despite low saturations being found on pulse oximetry and a methemoglobin level that was found to be elevated. Further sclerotherapy was discontinued, the saturations eventually normalized, and the methemoglobin level decreased. This is a novel report of sclerotherapy with doxycycline associated with the development of methemoglobinemia.",
"affiliations": "Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and.;Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and.;Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and.;Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and.;Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and.;St Louis Children's Hospital, St Louis, Missouri.",
"authors": "Coughlin|Katherine|K|;Flibotte|John|J|;Cahill|Anne Marie|AM|;Osterhoudt|Kevin|K|;Hedrick|Holly|H|;Vrecenak|Jesse|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004318:Doxycycline",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2018-1642",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "143(2)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000900:Anti-Bacterial Agents; D004318:Doxycycline; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008708:Methemoglobinemia; D015911:Sclerotherapy",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30655334",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methemoglobinemia in an Infant After Sclerotherapy With High-Dose Doxycycline.",
"title_normalized": "methemoglobinemia in an infant after sclerotherapy with high dose doxycycline"
} | [
{
"companynumb": "US-CHARTWELL PHARMA-2062103",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE HYCLATE"
},
"drugadditional": "... |
{
"abstract": "OBJECTIVE\nTo evaluate the feasibility, toxicity, and efficacy of single-agent monoclonal antibody therapy targeting the human epidermal growth factor receptor 2 (HER2)/neu receptor in ovarian and primary peritoneal carcinoma.\n\n\nMETHODS\nEligible patients had measurable persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with 2+ or 3+ HER2 overexpression documented by immunohistochemistry. Intravenous trastuzumab was administered initially at a dose of 4 mg/kg, then weekly at 2 mg/kg. Patients without progressive disease or excessive toxicity could continue treatment indefinitely. Those with stable or responding disease at 8 weeks were offered treatment at a higher weekly dose (4 mg/kg) at time of progression. Patient sera were analyzed for the presence of the soluble extracellular domain of HER2, host antibodies against trastuzumab, and trastuzumab pharmacokinetics.\n\n\nRESULTS\nA total of 837 tumor samples were screened for HER2 expression, and 95 patients (11.4%) exhibited the requisite 2+/3+ expression level. Forty-five patients, all of whom received prior chemotherapy, were entered, and 41 were deemed eligible and assessable. There were only mild expected toxicities and no treatment-related deaths. Although an elevated level of the soluble extracellular domain of HER2 was detected in eight of 24 patients, serum HER2 was not associated with clinical outcome. There was no evidence of host antitrastuzumab antibody formation. Serum concentrations of trastuzumab gradually increased with continued therapy. An overall response rate of 7.3% included one complete and two partial responses. Median treatment duration was 8 weeks (range, 2 to 104 weeks), and median progression-free interval was 2.0 months.\n\n\nCONCLUSIONS\nThe clinical value of single-agent trastuzumab in recurrent ovarian cancer is limited by the low frequency of HER2 overexpression and low rate of objective response among patients with HER2 overexpression.",
"affiliations": "Division of Medical Science, Fox Chase Cancer Center, Rockledge, PA, USA. ma_bookman@fccc.edu",
"authors": "Bookman|Michael A|MA|;Darcy|Kathleen M|KM|;Clarke-Pearson|Daniel|D|;Boothby|Richard A|RA|;Horowitz|Ira R|IR|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2003.10.104",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "21(2)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D018262:Adenocarcinoma, Clear Cell; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018269:Carcinoma, Endometrioid; D018284:Cystadenocarcinoma, Serous; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D010534:Peritoneal Neoplasms; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "283-90",
"pmc": null,
"pmid": "12525520",
"pubdate": "2003-01-15",
"publication_types": "D016430:Clinical Trial; D017427:Clinical Trial, Phase II; D023362:Evaluation Study; D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group.",
"title_normalized": "evaluation of monoclonal humanized anti her2 antibody trastuzumab in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of her2 a phase ii trial of the gynecologic oncology group"
} | [
{
"companynumb": "US-ROCHE-1855378",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "The purpose of this study was to evaluate the effect of treating ocular surface disease (OSD) in patients with medically uncontrolled primary open-angle glaucoma (POAG) associated with OSD.\n\n\n\nWe compiled a retrospective observational case series of 10 patients with POAG that remained uncontrolled with topical treatments and who were referred for filtering glaucoma surgery. All patients underwent a complete assessment of their glaucoma and ocular surface for both eyes. The main treatments were change of topical antiglaucoma medications to preservative-free equivalents, removal of allergenic treatments or those identified as causing side effects, switch to another therapeutic class with the same efficacy but with a better safety profile and treatment of OSD.\n\n\n\nAfter a minimum follow-up of 6 months, we observed improved ocular surface in all patients, associated with an intraocular pressure (IOP) decrease or stabilization even if some antiglaucoma medications were removed. The mean IOP significantly decreased from 23.75±9.98 mm Hg to 15.15±4.75 mm Hg (-36.2%; P=0.0001). The mean number of IOP-lowering medications was 3.7±1.06 at presentation and 2.8±0.63 after treatment (P=0.01). The Oxford score also decreased from a mean 1.7±0.67 to 0.4±0.51 (-76.5%; P<0.001). For 2 patients, IOP was not sufficiently reduced after treatment and they finally underwent filtering surgery.\n\n\n\nThe prevalence of OSD in POAG patients is very high, particularly in patients with uncontrolled glaucoma with multiple topical medications. Careful management of the ocular surface associated with a reduction of the toxicity of eyedrops may result in improvement of ocular surface health and better IOP control.",
"affiliations": "Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital, DHU Sight Restore.;Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital, DHU Sight Restore.;Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital, DHU Sight Restore.;Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital, DHU Sight Restore.;Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital, DHU Sight Restore.;Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital, DHU Sight Restore.;Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital, DHU Sight Restore.",
"authors": "Dubrulle|Pierre|P|;Labbé|Antoine|A|;Brasnu|Emmanuelle|E|;Liang|Hong|H|;Hamard|Pascale|P|;Meziani|Lyes|L|;Baudouin|Christophe|C|",
"chemical_list": "D000959:Antihypertensive Agents; D009883:Ophthalmic Solutions; D011310:Preservatives, Pharmaceutical",
"country": "United States",
"delete": false,
"doi": "10.1097/IJG.0000000000001041",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1057-0829",
"issue": "27(12)",
"journal": "Journal of glaucoma",
"keywords": null,
"medline_ta": "J Glaucoma",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000959:Antihypertensive Agents; D003229:Conjunctival Diseases; D015352:Dry Eye Syndromes; D005260:Female; D018463:Filtering Surgery; D005902:Glaucoma, Open-Angle; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D009883:Ophthalmic Solutions; D011310:Preservatives, Pharmaceutical; D012189:Retrospective Studies; D014065:Tonometry, Ocular",
"nlm_unique_id": "9300903",
"other_id": null,
"pages": "1105-1111",
"pmc": null,
"pmid": "30489502",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Influence of Treating Ocular Surface Disease on Intraocular Pressure in Glaucoma Patients Intolerant to Their Topical Treatments: A Report of 10 Cases.",
"title_normalized": "influence of treating ocular surface disease on intraocular pressure in glaucoma patients intolerant to their topical treatments a report of 10 cases"
} | [
{
"companynumb": "FR-LANNETT COMPANY, INC.-FR-2019LAN000174",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NEOMYCIN SULFATE"
},
"drugadd... |
{
"abstract": "Aim: Glioblastoma multiforme (GBM) carries a dismal prognosis. Integrated proteogenomic analysis was performed to understand GBM pathophysiology. Patients & methods: 17 patient samples were analyzed for driver mutations, oncogenes, major pathway alterations and molecular changes at gene and protein level. Clinical, treatment and survival data were collected. Results: Significantly mutated genes included TP53, EGFR, PIK3R1, PTEN, NF1, RET and STAG2. EGFR mutations noted included EGFRvIII-expression, EGFR-L816Q missense mutation-exon 21 and EGFR fusion (FGFR3-TACC3). TP53 mutations were noticed in COSMIC hot-spot driver gene and accompany IDH1 and ATRX mutations suggesting low- to high-grade glioma transformation. Proteomics showed higher (53%) EGFR expression than genomic expression (23%). MGMT methylation was present in two-thirds of cases. Conclusion: This study identifies a distinct biological process that may characterize each GBM differently. Proteogenomic data identify potential therapeutic targets of GBM.",
"affiliations": "Saint Luke's Cancer Institute, University of Missouri, Kansas City, MO 64111, USA.;Saint Luke's Cancer Institute, University of Missouri, Kansas City, MO 64111, USA.;Saint Luke's Cancer Institute, University of Missouri, Kansas City, MO 64111, USA.;Saint Luke's Cancer Institute, University of Missouri, Kansas City, MO 64111, USA.;Saint Luke's Cancer Institute, University of Missouri, Kansas City, MO 64111, USA.",
"authors": "Asif|Samia|S|;Fatima|Rawish|R|;Krc|Rebecca|R|;Bennett|Joseph|J|;Raza|Shahzad|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/cns-2019-0003",
"fulltext": "\n==== Front\nCNS OncolCNS OncolCNSCNS Oncology2045-09072045-0915Future Medicine Ltd London, UK 3129067910.2217/cns-2019-0003Research ArticleComparative proteogenomic characterization of glioblastoma Asif Samia *1Fatima Rawish 1Krc Rebecca 1Bennett Joseph 1Raza Shahzad 11 Saint Luke’s Cancer Institute, University of Missouri, Kansas City, MO 64111, USA* Author for correspondence: Tel.: +1 913 749 3467; samasif22@gmail.com10 7 2019 6 2019 10 7 2019 8 2 CNS3728 1 2019 21 5 2019 10 7 2019 © 2019 Samia Asif2019This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported LicenseAim:\nGlioblastoma multiforme (GBM) carries a dismal prognosis. Integrated proteogenomic analysis was performed to understand GBM pathophysiology.\n\nPatients & methods:\n17 patient samples were analyzed for driver mutations, oncogenes, major pathway alterations and molecular changes at gene and protein level. Clinical, treatment and survival data were collected.\n\nResults:\nSignificantly mutated genes included TP53, EGFR, PIK3R1, PTEN, NF1, RET and STAG2. EGFR mutations noted included EGFRvIII-expression, EGFR-L816Q missense mutation-exon 21 and EGFR fusion (FGFR3-TACC3). TP53 mutations were noticed in COSMIC hot-spot driver gene and accompany IDH1 and ATRX mutations suggesting low- to high-grade glioma transformation. Proteomics showed higher (53%) EGFR expression than genomic expression (23%). MGMT methylation was present in two-thirds of cases.\n\nConclusion:\nThis study identifies a distinct biological process that may characterize each GBM differently. Proteogenomic data identify potential therapeutic targets of GBM.\n\nKeywords: \ngenomicsglioblastomaproteomicssurvivaltemozolomide chemotherapy\n==== Body\nGlioblastoma multiforme (GBM) is the most common and aggressive brain tumor, with a median survival of 14–15 months [1]. GBM is primarily found in the brain, but it can also be found in other areas including the brain stem, cerebellum and spinal cord. A landmark Phase III study by Stupp et al. demonstrated that postsurgical radiotherapy with concomitant temozolomide (TMZ) chemotherapy (also known as the Stupp regimen) increases median survival by 2.5 months and results in a 37% reduction in death compared with radiotherapy treatment alone. This study also showed a direct relationship between methylation of the MGMT gene and TMZ response rate [2]. MGMT is a gene involved in the repair of highly mutagenic DNA changes. Thus, any damage to it leads to a cascade of uncontrolled mutations, which ultimately allows for subsequent targeting by alkylating agents like TMZ [3,4]. But despite these advancements in treatments and better characterization of the genomic landscape, GBM still carries a highly aggressive and catastrophic prognosis. This is largely due to the poorly understood pathophysiology of GBM, as well as the lack of identifiable biologic targets to guide new therapies. There remains an unmet need to further unravel the pathophysiology of GBM and identify new biologic targets.\n\nRecently, genomic profiling and The Cancer Genome Atlas project sequenced more than 600 genes from approximately 200 human samples [5]. GBM was also systematically studied by the Cancer Genome Atlas Research Network (TCGA) in detail. As a result of these studies, it was found that GBM has a complex genomic/proteomic signaling network, which is key to its rapid growth and differentiation. This network has the ability to adapt in response to certain targeted molecular treatments. Thus, the need for a comprehensive catalog of molecular alterations is of paramount importance. We hope that this understanding will help drive future investigations to further our understanding of GBM, as well as develop new patient-specific therapies [6].\n\nMethods\nPatients\nSamples were obtained from 17 consecutive, newly diagnosed and pathologically confirmed GBMs in patients seen during 2017–2018 at Saint Luke’s Hospital on the Plaza in Kansas City, MO, USA. Inclusion criteria were histopathologic confirmation of GBM, as well as the availability of proteomic and genomic analysis results. Patients without available genomic data were excluded. All patients in the sample had primary grade IV GBMs.\n\nAfter initial diagnosis, standard treatment was initiated. This included optimal surgical resection and subsequent adjuvant radiotherapy and chemotherapy (with TMZ) at a daily dose of 150–200 mg/m2 of body surface area for 5 days. This scheme was then repeated on a 28-day cycle [4]. Both clinical and diagnostic/radiological evaluation were subsequently used to determine disease progression as well as incidence of relapse. MRI of the brain before and after treatment was utilized in diagnostic evaluation and assessment of treatment response. The tumor samples utilized for proteogenomic analysis were those obtained at time of initial biopsy and diagnosis; no samples from recurrent tumors were analyzed.\n\nTumor specimens were collected surgically for all 17 patients with newly diagnosed GBM. For each patient, an initial sample for intraoperative frozen section was obtained. Subsequently, optimal tumor resection was performed. For patients undergoing total or near-total resection, tumor samples in their entirety were sectioned and reviewed for histopathology. For some patients, tissue samples were obtained as separate fragments. If complete or partial resection was not possible, core biopsies were obtained and then analyzed. Details regarding surgical practices utilized and tumor samples obtained have been included as Supplementary Table 1. Sections with histopathological confirmation of GBM were then sent for proteogenomic analysis.\n\nTumor cells for analysis were obtained through a pathologist-directed laser microdissection system by methods defined previously by Hembrough et al. [7]. Areas for microdissection were included in the original individual analysis report as an image. Analysis was performed using molecular fingerprinting by GPS Cancer™, NantWorks (CA, USA). DNA and RNA were extracted from preserved tissues. DNA sequencing libraries were prepared for each tumor sample and a matched-normal sample. Tumor versus matched-normal variant analysis was performed using NantOmics Contraster analysis pipeline to determine somatic and germline single nucleotide variants, insertions, deletions and identify highly amplified regions of the tumor genome. RNA-sequencing libraries were similarly prepared for the tumor sample. Sequencing using the Illumina platform in a NantOmics clinical laboratory improvement amendments and certified authorization profession-certified sequencing laboratory was performed. Quantitative proteomic analysis as well as genomic analysis was reported [8].\n\nMGMT methylation and other biomarkers (chemotherapy response markers, chemotherapy resistance markers, prognostic markers) were scanned from tumor and normal tissues using the laser microdissection system. Genomics were analyzed to look for alterations in known oncogenes, tumor-suppressor genes, potentially treatable genes, tumor mutation burden, variants and disruptive germline alterations (including frame-shifting, insertions, deletions, nonsense and missense). Gene type was obtained by using data from the COSMIC Cancer Gene Census. Clusters of mutations were discovered using OncodriveCLUST on the Five3 variant calls made on more than 5000 TCGA tumor exomes [9,10]. Secondary screening for cancer predisposition was completed according to ACMG’s recommendations for incidental findings [11]. Microsatellites consisting of homopolymer repeats were analyzed for a statistically significant increase in the number of length polymorphisms in tumor and normal sample to identify instability. The percentage of unstable loci is calculated for the tumor and matched-normal. The differential is then determined by subtracting the percentage of unstable loci in the normal sample from the percentage of unstable loci calculated in the tumor. A tumor is considered to demonstrate microsatellite instability when the differential exceeds the threshold. The number of length polymorphisms for each microsatellite locus was computed across approximately 5000 blood and solid normal exomes sequenced by TCGA comprising 18 different cancer types [12]. Loci covered by fewer than 30 reads were excluded from the analysis. Potential functional fusions were identified by using transcriptome aligned RNA sequencing data, using clusters of spanning reads between two transcripts where one of the transcripts belongs among the 74 commonly found genes in oncogenic fusions.\n\n‘My Cancer Genome’ is an online tool that considers disease-relevant human genes, drugs, drug–gene interactions and potential druggability, including 835 drug–gene interactions between 226 drugs and 169 target genes [13,14]. Our proteogenomic analysis utilized this resource and reported potentially activating alterations (missense mutations, in-frame deletions and amplifications) in this panel of 169 ‘druggable’ genes; a druggable or ‘treatable’ gene is defined as a gene against which at least one of 226 FDA approved or investigational drugs have demonstrated activity. This includes reporting the presence of genomics-based targets indicated on drug labels for 21 FDA-approved drugs [15,16]. Alterations that disrupt a gene were not considered treatable; as the genes must be functional for a drug to have an effect [10]. Variants produced from sequencing data of tumor sample (vs matched normal) were also scanned for evidence of resistance biomarkers for six drugs including cetuximab, dasatinib, imatinib mesylate, panitumumab, crizotinib and tamoxifen [16]. Known tumor genes were classified as tumor suppressors or oncogenes using data available from Cosmic Cancer Gene Census [14].\n\nData analysis\nRetrospective analysis of patients’ biomarkers, MGMT methylation, mutation burden, microsatellite instability and fusion findings were completed and then correlated to their respective ‘overall survival’ (OS). OS was defined as duration of survival after the initial diagnosis was made. ‘Progression-free survival’ (PFS) was defined as the time during and after treatment when the disease did not progress, or when death was caused by any other reason aside from the tumor itself. Alteration-driven treatment after thorough review from different literatures was provided to the appropriate patients and their responses were observed. Baseline demographic data including age at the time of diagnosis as well as gender was retrospectively collected from patients’ medical records.\n\nResults\nAs summarized in Tables 1 & 2, the dataset contains clinical and proteogenomic data from 17 patients. The same technological and laboratory modalities were utilized for each of these patients.\n\nTable 1. Patient characteristics (n = 17).\nAge at diagnosis:\n– Median\n– Minimum\n– Maximum\tYears:\n– 56\n– 20†\n– 72†\t\nGender:\n– Male\n– Female\tNumber of patients:\n– 8\n– 9\t\nOverall survival:\n– Minimum\n– Maximum\n– Range\tMonths:\n– 5\n– 28†\n– 23\t\nClinical status:\n– Living\n– Deceased\tNumber of patients\n– 13\n– 4\t\nNumber of relapses:\n– Zero\n– One\n– Two\tNumber of patients:\n– 12\n– 4\n– 1\t\nNo. of treatment lines:\n– One\n– Two\n– Three\tNumber of patients:\n– 12\n– 4\n– 1\t\nNo. receiving:\n– Temozolomide\n– Avastin\n– Irinotecan\n– Carboplatin\n– Lomustine\n– Radiotherapy\n– Surgical resection\tNumber of patients:\n– 17 (100)\n– 5 (29)\n– 4 (23.5)\n– 1 (0.06)\n– 1 (0.06)\n– 17 (100)\n– 17 (100)\t\nPatients with:\n– High mutation burden\n–TP53 mutation\n–EGFR mutation\n– Proteomic MGMT\n– Genetic cancer predisposition screen positive\tNumber of patients:\n– 1\n– 5 (29%)\n– 7 (41.2%)\n– 13 (76%)\n– 1 (MSH6, frameshift mutation)\t\n† Living.\n\nTable 2. Biomarkers and survival status of patients (n = 17).\nPatient number\tProteomic MGMT\tProteomic EGFR\tG-EGFR\tG-p53\tOS (months)\tCurrent status\t\n1\tPresent\t \tPresent\t \t7\tAlive\t\n2\tPresent\tPresent\t \t \t15\tAlive\t\n3\tPresent\t \t \tPresent\t8\tAlive\t\n4\tPresent\t \tPresent\t \t10\tAlive\t\n5\tPresent\t \t \tPresent\t11\tAlive\t\n6\t \t \tPresent\t \t10\tDeceased\t\n7\tPresent\t \tPresent\t \t11\tAlive\t\n8\t \t \t \tPresent\t28\tAlive\t\n9\tPresent\tPresent\t \t \t11\tAlive\t\n10\tPresent\tPresent\t \t \t11\tAlive\t\n11\tPresent\tPresent\tPresent\t \t12\tAlive\t\n12\tPresent\tPresent\t \t \t25\tAlive\t\n13\t \tPresent\t \tPresent\t5\tDeceased\t\n14\tPresent\tPresent\tPresent\t \t17\tDeceased\t\n15\tPresent\tPresent\t \tPresent\t10\tDeceased\t\n16\t \t \tPresent\t \t10\tAlive\t\n17\tPresent\tPresent\t \t \t8\tAlive\t\nAmplification and overexpression of the EGFR gene is a distinct feature of GBM, noticed in 40% of these tumors. Table shows discrepancy between frequency of proteomic expression (9/17) and genomic mutation of EGFR (7/17), with overlap between the two in only 2/17 cases. No clear relationship has been found between the p53 pathway with treatment and outcome of GBM.\n\nGBM: Glioblastoma multiforme; G-EGFR: Presence of EGFR mutation on genomic analysis; G-P53: Presence of TP53 mutation on genomic analysis; OS: Overall survival.\n\nPatient characteristics\n17 patients newly diagnosed with GBM were included in the study. Nine (n = 9) patients were females (53%). The median age was 56 (range 20–72 years). Clinical and demographic characteristics of the study population are summarized in Table 1.\n\nAll patients underwent surgical resection: 9/17 patients had gross total resection, 4/17 patients had near total or partial resection and the remaining 4/17 had biopsy samples taken either stereotactically or via Burr-hole. Despite standard therapy being given to all patients, 5/17 relapsed. Following relapse, four of these patients were then treated with second-line therapy with Avastin and Irinotecan. One patient was treated with TMZ and Avastin.\n\n13 out of 17 (76%) patients were alive at time of completion of this study. The median OS was found to be 12.29 months. Five months was the lowest survival observed. For this patient, genetic aberrations included: TP53 missense mutation, SPEN nonsense mutation and H3F3A missense mutation.\n\nGenomic alterations\nPathogenic gene mutations detected in study participants included TP53, EGFR, NOTCH1, RAD21 and SYNE1 (missense mutations); SPEN, DEPDC5, STAG2, TPR, USP9X, MAGED1, ARHGAP5, CTDNEP1, ARID1A and BCOR (nonsense mutations); PTEN and ATRX (frame-shift mutations); and PIK3R1, CHD8 and CSMD3 (in-frame deletions).\n\nLikely pathogenic mutations noted were IDH1, RET, PPP2R1A, PGM5, ZNF117, ACVR1, EPHA6, ZNF479, ZNF117, ZNF181, ZFP2, MS4A8, IL5RA, MKRN1, CD163, ATPB3, KLK8, COBLL1, CHD8, GRXCR1, ABCB1 and H3F3A (missense mutations); KIAA1109, NBPF1, AMBRA1, COL5A2 and RBM10 (splice site mutation) and CHD3 (in-frame deletion).\n\nKey tumor-suppressor genes detected included TP53, SPEN, FBXO11, ARID1A, PIK3R1, BCOR, NOTCH1, ATRX, PTEN, CDKN2A, NF1 STAG2, RB1 and RAD21. Known oncogenes identified included EGFR, RET, IDH1, SOX2, GNAS, H3F3A, ACVR1, PPP2R1A, RPL5 and ATP2B3. These findings are summarized in Table 3, which depicts major types of mutations for each of the 17 patients included in the study and whether these were pathogenic, likely pathogenic or of unknown clinical significance. It also identifies potential ‘treatable’ genes. Table 4 summarizes the frequency of major mutations seen and highlights the major pathways these genes are involved in. Such pathways may be altered as a result of these mutations.\n\nTable 3. Alterations in top-ranked known oncogenes, tumor suppressor genes and/or treatable genes detected for each of 17 samples.\nGenetic mutation\tPatient\t\n \t1\t2\t3\t4\t5\t6\t7\t8\t9\t10\t11\t12\t13\t14\t15\t16\t17\t\nNonsense\tARHGAP5‡\tSPEN‡\tARID1A‡\tDEPDC5‡\tGRHPR\tCTDNEP1‡\tUSP9X‡\tCOL3A1\tPDZD2\tRPS16\tTPR‡\tSTAG2‡\tKDM4E\tRAVER2\tOR52N1\tPCDH11X\tMAGED1‡\t\n \tMEGF8\t \tBCOR‡\tABCB1†\t \tKRT33B\tCDKN2A ‡\t \t \tKEL\tDNAH6\tPIEZ02\tRPL5\tSAGE1\t \tCHUK\tRAB5A\t\n \t \t \tDPT\tHYDIN\t \tVAT1L\tNF1‡\t \t \t \t \tNBPF15\t \tCOX6B2\t \tHMCN1\tZSWIM1\t\n \t \t \tARGFX\tMGME1\t \tHAPLN1\tTHSD7B\t \t \t \t \tTTC3\t \tUSP17L11\t \t \tELMOD3\t\n \t \t \tPDE4DIP\tHECW2\t \tPHF21A\tSCAF11\t \t \t \t \t \t \t \t \t \tCFTR\t\n \t \t \tRTKN\tSRGAP1\t \tMUC19\tRAPGEF\t \t \t \t \t \t \t \t \t \tCOL7A1\t\n \t \t \t \t \t \t \tJMJD4\t \t \t \t \t \t \t \t \t \tCOL9A1\t\n \t \t \t \t \t \t \tCEP83\t \t \t \t \t \t \t \t \t \t \t\n \t \t \t \t \t \t \tNT5DC1\t \t \t \t \t \t \t \t \t \t \t\n \t \t \t \t \t \t \tPHLDA2\t \t \t \t \t \t \t \t \t \t \t\nMissense\tGNAS†\tTP53‡\tACVR1†\tWDR90\tNOTCH1‡\tTP53†\tMS4A8†\tKLK8†\t1DH1†\tTP53†\tPIK3R1§\tEGFR‡\tPPPR2R1A†\tRAD21‡\tIDH1†\tSYNE1‡\tEGFRp.R324L‡\t\n \tZNF479†\tH3F3A†\tFAM47A\tABCA7\tEGFR§,†\tEPHA6†\tIL5RA†\tZNF181†\tTP53†\tPHLDA1\tNLGN1\tCHD8†\tEGFR§,†\tATP2B3†\tTP53†\tPGM5†\tEGFRp.G598V‡\t\n \tPOTEF\tPTPRK\tMAP3K4\tCDC42BPB\tFBX011\tKIAA1109†\tMKRN1†\tDCAF12L2\tPRKRIR\tTBX3\tFAM83A\tGRXCR1†\tEVPL\tRBBP6\tCD163†\tZNF117†\tEGFRp.R108K†\t\n \tTNFRSF10C\tFBX011\tBIRC6\tTNRC18\tZNF335\tRET§,†\tOR2T33\tMYLK4\tDFNA5\tKDM5C\tDHCR24\tKIAA0907\tNOTCH2\tWRN\tSCML4\tKMT2C\tEGFRp.T363A†\t\n \tDOCK2\tDLG2\tNR2E1\tRADIL\tSPATA2L\tNBPF1p.L943V†\tTMEM132D\tNAV1\tAQP5\tBCOR\tCOBLL1\tCD5L\tFAM47B\tMME\tCTDNEP1\tSRSF1\tZNF117\t\n \tADAMTS10\tCASR\tCSNK1A1\tLPAR1\tXKR7\tNBPF1p.N114S†\tRYR2\tMEN1\tZNF469\tOR2A25\tFAM72D\tPPM1K\tBLM\tZNF91\tSP7\tDOPEY1\tZFP2\t\n \tNUMA1\tANP32E\tBTD\tJAG2\tVWF\tAMBRA1†\tNETO1\tMUC7\tRRN3\tGPC3\tSIGLEC9\tTTC37\tKRT72\tCENPB\tCFH\tHNF4G\tOR2M7\t\n \tOGT\tUIMC1\tTPTE\tSLC39A12\tCD19p.R514C\tNBPF1p.S340F†\tZFHX3\tATRX\tATAD3B\tCOG1\tTSPAN8\tAQP10\tARAP3\tDCAF12L2\tTLR4\tHCN1\tSYNE1\t\n \tDACH1\tTMCC1\tDNAH5\tSIGLEC7\tPRR23A\tZNF91\tCPEB2\tGCNT1\tPCNT\tFLNA\tUGT2A2\tRB1\tZNF469\tNR4A3\tERCC6\tCDC27\tKCNK9\t\n \tCPNE7\tNOV\tBCAR3\tSPATA13\tSLC30A4\tLEPR.pF898L\t \tCOG3\tNCF1\tTRIM3\tAMPH\tRIMS2\tTBXAS1\tOPLAH\tGTF2B\tZNF705B\tHNF1A\t\n \tZNF91\tSH2D4B\tASCL1\tDOK5\tLOXL4\tLEPR.pH924P\t \tCACNA1C\tGPR12\tTRIM49B\tVCX3A\tF5\tLRWD1\tTARS\tGEM\tCNTNAP3\tCDH1\t\n \t \tMYO18B\tSALL3\tPADI6\tMCCp.G20S\tNPHS2\t \tSVILp.P809A\tSPOPL\tMAP1B\tDNAH14\tNIPBL\tCENPB\tRRN3\tPLEC\t \tZNF107\t\n \t \tTDRD6\tFGF2\tZNF92\tLHX5\tGOLGA6B\t \tSVILp.L948R\tDNAAF1\t \tPCDHB7\tKRT7\tFBXL18\tTUBA3D\tMETTL4\t \tDIP2C\t\n \t \tCEP290\tINO80D\tKCNH2\tSLC37A4\tDIDO1\t \tTMPRSS13\tSVOP\t \tLRP2\tTYW1B\tZNF831\tCROCC\tZNF257\t \tDNM2\t\n \t \tCYP7B1\tTRIM22\tSULT1A4\tMCCp.G23S\t \t \t \t \t \tPAXIP1\tMUC12\tLIN37\tFLG\tTBX22\t \t1L16\t\n \t \tTTN\t \t \tCD19p.G41A\t \t \t \t \t \tPTPRQ\tMCM2\tEXOC4\tGPAT2\tHERC2\t \tAOAH\t\n \t \tWSCD2\t \t \tNHSL1\t \t \t \t \t \tEEF2\tOR6B3\tCRNN\tZNF708\tDDY28\t \tPCDHA4\t\n \t \tTERF1\t \t \tGCNT2\t \t \t \t \t \tSVIL\tC5ORf60\tZAN\t \tLAMA3\t \t \t\n \t \tCACNB4\t \t \tRGP1\t \t \t \t \t \tBCR\t \tAQP1\t \tCTSG\t \t \t\n \t \tHOXA3\t \t \tZNF407\t \t \t \t \t \tBASP1\t \tANKS4B\t \tPDE6B\t \t \t\n \t \tGANC\t \t \tPER1\t \t \t \t \t \t \t \tTRAPPC10\t \tCNTNAP4\t \t \t\n \t \tCSMD1\t \t \t \t \t \t \t \t \t \t \t \t \tPHF20\t \t \t\nFrame shift\tNPAS2\tTRIM37\tDDX10\tFOXD1\tFOXD1\tCSMD3‡\tUSP3\tADAMTS7\tATRX‡\tPTEN‡\tPAPSS2\tPTEN‡\tHMCN2\t \tATRX‡\tLRRK1\t \t\n \t \tRAD51AP2\tSPATA31D1\tANKLE1\tSLC16A9\tCCDC121\tC3\t \tNKX2-2\tCDKN2A‡\tZZEF1\tWDHD1\t \t \t \tANAPC4\t \t\n \t \t \t \tNLRP5\t \tDYNC2H1\tTPI1\t \tTRIM64B\tVGLL3\t \tKHSRP\t \t \t \tCCDC65\t \t\n \t \t \t \t \t \tADAMTS7\t \t \tHGC6.3p. Q151Tfs†7\tGOLGA4\t \t \t \t \t \t \t \t\n \t \t \t \t \t \tNBPF12\t \t \tHGC6.3p. Q151Hfs†7\tPIGP\t \t \t \t \t \t \t \t\n \t \t \t \t \t \t \t \t \tGABRG2\tFOXD1\t \t \t \t \t \t \t \t\n \t \t \t \t \t \t \t \t \tSAA1\tMSI2\t \t \t \t \t \t \t \t\n \t \t \t \t \t \t \t \t \tSAA2-SAA4\tCRCP\t \t \t \t \t \t \t \t\nSplice site\tCOL5A2†\t \t \t \t \t \t \tCHD9\t \tLYPD4\t \t \t \t \t \tHELQ\tSTAG2‡\t\n \tRBM10†\t \t \t \t \t \t \tWDR45B\t \t \t \t \t \t \t \t \t \t\n \tARAP2\t \t \t \t \t \t \tLRRC37B\t \t \t \t \t \t \t \t \t \t\n \tEIF3J\t \t \t \t \t \t \t \t \t \t \t \t \t \t \t \t \t\n \tELAVL3\t \t \t \t \t \t \t \t \t \t \t \t \t \t \t \t \t\n \tTMEM150A\t \t \t \t \t \t \t \t \t \t \t \t \t \t \t \t \t\nAmplification\tEGFR\t \t \t \t \tGNAS\t \tEGFR\t \t \t \tEGFR§\t \t \t \t \t \t\n \tWBSCR17\t \t \t \t \tSOX2\t \t \t \t \t \t \t \t \t \t \t \t\nFusion\tEGFRvIII§\t \t \t \t \t \tFGFR3-TACC3\tEGFR-SEPT14\t \tNOTCH1-AGPAT2\t \t \t \t \t \tEGFRvIII§\t \t\n \t \t \t \t \t \t \t \t \t \tFGFR3-TACC3§\t \t \t \t \t \t \t \t\nTruncation\t \tSPEN\tARID1A\t \t \t \t \t \t \t \t \tPTEN\t \t \t \t \t \t\n \t \t \tBCOR\t \t \t \t \t \t \t \t \tSTAG2\t \t \t \t \t \t\nInframe deletion\t \t \tPIK3R1§\t \t \t \t \t \tKRTAP5-5\t \tGIGYF2\t \tNPIPB5\tCHD8‡\tPIK3R1§,‡\t \t \t\n \t \t \tZMIZ1\t \t \t \t \t \tMNX1\t \t \t \t \tCHD3†\t \t \t \t\nEach column depicts genetic mutation profile for individual patients with glioblastoma multiforme, classified by the type of mutation. Mutations are further classified as pathogenic or likely pathogenic, suggesting these mutations likely have a role in tumorigenesis. Availability of an FDA-approved or investigational drug targeting a potentially ‘treatable’ gene is also depicted.\n\n† Pathogenic.\n\n‡ Likely pathogenic.\n\n§ Treatable genes detected in this cohort.\n\nTable 4. Frequency of detected mutations in known tumor-suppressor genes and known oncogenes and RNA fusions along with potentially altered pathways.\nMutations\tFrequency\tPathway\t\nKnown tumor-suppressor genes:\n– TP53\n– PIK3R1\n– FBXO11\n– ATRX\n– CKDN2A\n– PTEN\n– TBX3\n– BCOR\n– STAG2\n– SPEN\n– ARID1A\n– RB1\n– NOTCH1\n– NOTCH2\n– NF1\n– MEN1\n– GPC3\n– KDM5C\n– BLM1\n– RAD21\n– KMT2C\t\n5/17\n3/17\n3/17\n3/17\n2/17\n2/17\n2/17\n2/17\n2/17\n1/17\n1/17\n1/17\n1/17\n1/17\n1/17\n1/17\n1/17\n1/17\n1/17\n1/17\n1/17\t\np53 pathway\nPI3K signaling\nUbiquitination\nGenome integrity\nRb pathway\nPI3K signaling\nTranscription repression\nTranscription corepression, BCL6 pathway\nCell division, chromatids separation\nDNA repair and mitosis\nChromatin remodeling\nRB pathway\nLigand-activated transcription\nTranscriptional coactivation\nMAPK signaling\nTranscription regulation\nWnt pathway\nTranscription regulation/chromatin remodeling\nDNA repair\nRB1 pathway\nTranscriptional coactivation\t\nKnown oncogenes:\n– EGFR\n– EGFR variant III (RNA fusion)\n– EGFR Amplification\n– EGFR p.L62R\n– EGFR (p.L861Q)\n– EGFR (p.N842K)\n– IDH1\n– RET\n– GNAS\n– PPP2R1A\n– SOX2\n– ACVR1\n– H3F3A\n– RPL5\n– ATP2B3\t\n7/17\n2/17\n3/17\n1/17\n1/17\n1/17\n2/17\n1/17\n1/17\n1/17\n1/17\n1/17\n1/17\n1/17\n1/17\t\n\nRTK signaling\nRTK signaling\nRTK signaling\nRTK signaling\nRTK signaling\nMetabolism\nMAPK and PI3K signaling\nGPCR pathways\nGSK3β, Akt and mTOR signaling\nTranscription regulation\nBMP/TGF-β signaling pathway\nPost-translational modification\nRibosomal formation\nCalcium transport\t\nRNA fusions:\n– EGFR variant III\n– FGFR3-TACC3\n– NOTCH1-AGPAT2\n– EGFR-SEPT14\t\n2/17\n2/17\n1/17\n1/17\t\nRTK signaling\nRTK signaling\nNotch signaling\nRTK signaling\t\nOthers:\n– High-tumor exonic mutational burden\n– MSH6 frameshift detected\n– MGMT methylation\n– Proteomic EGFR\t\n1/17\n1/17\n13/17\n9/17\t\nMismatch repair\nDNA repair\nDNA repair\nProteomic expression higher than genomic expression\t\nThe TP53 pathway was dysregulated in 5/17 patients (29%). One patient had p53 mutation in PI3K pathway. At the RNA level, p53 mutations were noticed in COSMIC hotspot driver gene and accompany IDH1 and ATRX mutations in two patients. This suggests the transformation from low- to high-grade glioma. Three patients had coexisting RET, SPEN and CDK2NA mutations, respectively, with a p53 mutation. In contrast to proteomic expression, we noticed significant heterogeneity of EGFR expression on genomic platform. EGFR alterations were noticed in 7/17 patients (41.2%). Two of them showed EGFR variant III fusion. These mutations were accompanied by DNA amplification with multiple mutation allele frequencies. One patient had L816Q EGFR missense mutation on exon 21 which is commonly seen in lung cancer patients, who respond specifically to EGFR inhibitors.\n\nTreatable genes were identified. Three out of 17 patients showed PIK3R1, 7/17 showed EGFR and 1/17 showed RET as treatable genes. These are summarized along with potential targeted therapeutic agents in Table 5.\n\nTable 5. Treatable genes detected and potential targeted therapy options.\nTreatable gene\tTargeted treatment\t\nPIK3R1:\t\n– p.T576del\tBKM120 (investigational drug)\t\n– p.G376R\t \t\n– p.R465del\t \t\nEGFR amplification\tVandetanib, gefitinib, erlotinib, cetuximab, panitumumab, afatinib (FDA approved for other indications)\nTXL647, MM151, SYM004, MEHD7945A, CO-1686, AZD8931, necitumumab, nimotuzumab, icotinib, dacomitinib (investigational)\t\nEGFR variant III (RNA fusion)\tDacomitinib, rindopepimut, aNK-EGFR\t\nEGFR p.L62R\tVandetanib, gefitinib, erlotinib, cetuximab, panitumumab, afatinib (FDA approved for other indications)\nNimotuzumab, icotinib, dacomitinib, AZD8931 (investigational)\t\nEGFR (p.L861Q)\tVandetanib, gefitinib, erlotinib, cetuximab, panitumumab, afatinib (FDA approved for other indications)\nTXL647, MM151, SYM004, MEHD7945A, CO-1686, AZD8931, Necitumumab, Nimotuzumab, Icotinib, Dacomitinib (investigational)\t\nEGFR (p.N842K)\tVandetanib, gefitinib, erlotinib, cetuximab, panitumumab, afatinib (FDA approved for other indications)\nNimotuzumab, icotinib, dacomitinib (investigational)\t\nRET (p.H840–841delinsQT)\tVandetanib, sunitinib, regorafenib, sorafenib, cabozantinib\t\nFDA: Food and Drug Administration.\n\nProteomic expression\nBiomarkers analyzed in this study included hENT1, ERCC1, TUBB3, MGMT, PDL1, EGFR, FGFR1234, HER3, AXL, IDO1 and RRM1 proteins. KRAS, p16 and tissue Ki-67 were also analyzed. Only a single patient demonstrated high mutation burden, and this patient is still currently alive with an overall survival of 8 months. 9 out of 17 patients had proteomic expression of EGFR out of which only two showed its coinciding genomic expression. Mutation burden was found to be low in all patients except for one. 13 out of 17 (76%) biopsies showed MGMT methylation. Table 6 provides a detailed proteomic profile that was available for 13/17 patients. This includes presence or absence of different biomarkers on analysis including chemotherapy response markers, chemotherapy resistance markers, prognostic markers and biomarkers against which FDA-approved drugs may be available (for GBM or non-GBM indications) or may currently be in clinical trial phase.\n\nTable 6. Proteomic landscape of patients with glioblastoma multiforme (n = 13/17).\n \tProteins\tPatient number (n = 13)\t\n \t \t1\t2\t3\t4\t5\t6\t7\t8\t9\t10\t11\t12\t13\t\nTargeted therapy response markers\tEGFR\tD†\tD\tD†\tD\tD\tD†\tD†\tD\tD†\tD†\tD\tD†\tD†\t\n \tALK\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\t\n \tAR\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\t\n \tHER2\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\t\n \tPDL1\tND\tND\tND\tND\tND\tND\tND\tND\tND\tD†\tND\tND\tND\t\n \tROS1\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\t\n \tRET\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\t\nChemotherapy response markers\thENT1\tD†\tND\tD†\tND\tD†\tND\tND\tND\tND\tD†\tND\tD\tD†\t\n \tFr-alpha\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\t\n \tTOPO1\tD\tD\tD\tD\tD\tD\tD\tD\tND\tND\tD\tND\tD\t\n \tTOPO2A\tND\tD\tND\tD\tND\tND\tND\tND\tND\tND\tND\tND\tND\t\n \tTYMP\tND\tND\tND\tND\tND\tND\tD\tND\tND\tD\tD\tD\tND\t\nChemotherapy-resistance markers\tMGMT\tD‡\tD‡\tND†\tND†\tND†\tND†\tND†\tND†\tND†\tND†\tND†\tND†\tND†\t\n \tERCC1\tND†\tD‡\tD‡\tND†\tND†\tND†\tND†\tND†\tD‡\tD‡\tD‡\tND†\tND†\t\n \tTUBB3\tD‡\tD‡\tD‡\tD‡\tD‡\tD‡\tD‡\tD‡\tD‡\tD‡\tD‡\tD‡\tD‡\t\n \tRRM1\tD\tD\tD\tND\tD\tND\tND\tND†\tD\tND†\tD\tD\tD‡\t\nClinical trial response markers\tFGFR-1234\tND\tD†\tND\tND\tND\tND\tND\tND\tND\tD†\tND\tND\tND\t\n \tHer3\tND\tD†\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\t\n \tAXL\tND\tND\tND\tND\tND\tND\tD†\tND\tND\tD†\tND\tND\tD†\t\n \tIDO1\tND\tND\tND\tND\tND\tND\tND\tD†\tND\tND\tND\tND\tND\t\n \tIGF1R\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\t\n \tMET\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\t\n \tMSLN\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\tND\t\nPrognostic markers\tKRAS\tD\tD\tND\tD\tD\tND\tND\tND\tND\tD\tD\tND\tND\t\nOther\tP16\tND\tND\tD\tND\tND\tND\tD\tND\tND\tND\tD\tND\tND\t\nPatients (n = 13/17). Table shows presence or absence of biomarkers on proteomic analysis that may indicate chemotherapy response or resistance, availability of targeted therapy or clinical trials. Biomarkers are further classified on the basis of whether their absence or presence is of clinical advantage.\n\n† Beneficial.\n\n‡ Unlikely beneficial, otherwise uncertain clinical significance.\n\nD: Detected; ND: Not detected.\n\nDiscussion\nUnderstanding the pathogenesis of GBM and its genomic landscape is paramount. This is especially true considering it is the most prevalent primary brain tumor in adults and carries a particularly malignant and aggressive course in the majority of cases. The current standard of care includes maximal surgical resection, radiation therapy and subsequent chemotherapy with an alkylating agent such as temozolomide. Despite this multidisciplinary treatment approach, median survival is still quite short at 14.6 months. This is a 3–4 months increase in median survival without any type of treatment [17,18].\n\nData obtained from proteomic and genomic analysis in this study, among others, have concluded that each tumor has its own individual pathophysiologic profile. The future in treatment methodology will include identification of aberrations at a cellular level, which can allow for targeted therapies based on each tumor’s particular proteogenomic identity. This has been accomplished to some degree in solid and hematologic malignancies, with directed treatment strategies against EGFR in non-small-cell lung cancer (NSCLC) and ERBB2 in breast cancer. However, this approach has not been successful in the treatment of GBM thus far.\n\nIn one study by Blumenthal et al., 13 patients with GBM were treated based on results of genome sequencing. This included the utilization of EGFR tyrosine kinase inhibitors (TKI) afatinib and erlotinib. The study also treated one patient who had CDK4/6 amplification with Palbociclib. However, despite genomic sequencing and the identification of targetable genes, no significant response to tailored therapy was noticed [19]. This study showed that our understanding and knowledge of the molecular pathogenesis of GBM remains very limited, highlighting a need to continue our research in this domain.\n\nOur study focused on identifying tumor heterogeneity at the cellular and molecular level for each of the 17 patients. Thus, by correlating their proteogenomic alterations with clinical course and radiographic disease advancement, we can understand how a particular tumor profile affects both prognosis and survival. Ultimately, the objective of research in the field of GBM aims to define the molecular basis of glioblastoma evolution, so that specific therapies may be developed and tailored to an individual’s treatment. Our study aimed to delineate the essential biomarkers that can affect clinical outcome. Of note, this study did not aim to correlate GBM phenotype and pathologic structure with its mutation profile.\n\nWhile tumor heterogeneity evidently exists between different individual patients, it is important to note that it also occurs within different areas of a single patient’s tumor. In a prior study comparing primary and recurrent samples of low-grade gliomas, it was seen that in 43% cases, half the mutations seen in the primary tumor were undetectable in recurrent samples [20]. In our study, proteogenomic analysis was obtained to identify biomarkers that are of prognostic and predictive significance. Prognostic biomarkers aid in providing a more complete clinical picture regarding the overall survival with and without standard treatment following initial diagnosis. Predictive biomarkers help understand the potential benefits of a specific therapeutic intervention. Clinical data evaluated in the study included survival status, overall survival, relapse-free survival, treatment provided, number of relapses and treatment offered following a relapse. This information is summarized in Table 2. Corresponding genetic biomarkers were reviewed to assess for both prognostic and predictive significance.\n\nThe first biomarker of interest is MGMT, a DNA repair protein coded for by the MGMT gene. Alkylating agents, such as TMZ, result in the alkylation of this gene at O6 position of guanine. Such alkylation results in double-stranded DNA breaks and ultimately ends with apoptosis of the tumor cell. This action is counteracted by the DNA repair effect of the MGMT protein, leading to a less effective response to treatment [21]. MGMT protein was detected in samples from 13 of the 17 patients (76%) included in the study.\n\nAmplification and overexpression of the EGFR gene is a distinct feature of GBM and is noticed in 40% of these tumors. On the other hand, it is rare in low-grade gliomas. There are two types of EGFR mutations: wild-type and EGFR variant III with the latter being the most common. EGFRvIII occurs due to deletion of exons 2 through 7 of the EGFR gene, resulting in an in-frame deletion in its extracellular domain [22]. Studies have shown EGFRvIII to be more tumorigenic than the wild-type form [23]. The EGFR regulates cell proliferation via signal transmission by binding EGF and TNF-α. EGFRvIII on stimulation results in the activation of intracellular pathways such as PTEN resulting in increased tumor proliferation and survival [24]. EGFRvIII variant is a potential target for chimeric antigen receptor T-cell (CAR-T) therapy [25]. CAR-T is a form of immunotherapy, which uses T lymphocytes that have been genetically altered, and allows for high binding affinity and specificity to tumor antigens. It is currently FDA approved for the treatment of acute childhood lymphoblastic lymphoma and B-cell non-Hodgkin’s lymphoma [26]. Of particular interest were mutations in the EGFR gene that have previously been reported in patients with lung adenocarcinoma and have had a promising response to anti-EGFR antibodies in those patients. Response to EGFRvIII inhibitors has been very low in GBM. This suggests that complex molecular pathways need to be targeted within the EGFR system. There are also additional challenges pertaining to pharmacokinetics as any drug-targeting GBM needs to be able to cross the blood–brain barrier and then, should be able to stay in the brain parenchyma long enough to fulfill its action [27]. There has been conflicting data regarding the response to Erlotinib (TKI) in patients with coexpression of EGFRvIII and PTEN [28,29]. The discordance observed in EGFR expression on genomic and proteomic analysis shows the complex relationship between signaling pathways and molecular alterations.\n\nTP53 is a tumor-suppressor gene that codes for a protein involved in the regulation of cell cycle, differentiation and death. Such mutations are more common in secondary GBM in comparison to primary GBM (65 vs 28%) [30]. Loss-of-function of normal p53 function from TP53/MDM2/MDM4/p14ARF alteration leads to clonal expansion of glioma cells [31]. Due to the incomplete understanding of its complexity, no clear relationship has yet been found between the p53 pathway and targetable treatments as well as outcomes of GBM [32].\n\nIDH gene codes for isocitrate dehydrogenase, an intramitochondrial enzyme with three intracellular forms: of these, the IDH1 enzyme is involved in the production of NADPH from oxidative decarboxylation of isocitrate. NADPH has a role in protecting cells from oxidative stressors and damage. Mutations in the IDH1 gene lead to increased tumor proliferation by activation of VEGF-mediated angiogenesis. In patients with GBM, the presence of these mutations has been noted to improve the intracellular response to TMZ when compared with individuals with the wild-type IDH1 gene [33]. In a prior genomic analysis, IDH1 gene mutations were detected in 12% of GBM tumors. It was also identified in more than 70% of patients with grade II and III astrocytomas and oligodendrogliomas, as well as in GBMs that develop from lower-grade lesions [34]. The presence of IDH1 mutation has been associated with improved OS when compared with IDH wild-type [34]. In addition, in comparison to IDH1 wild-type tumor, presence of IDH1 mutation is associated with longer time between diagnosis of low grade or anaplastic glioma and eventual progression to GBM (66 vs 16 months). With respect to IDH1 mutation’s role in recurrent GBM, however, prior studies have shown no significant difference in PFS and OS between IDH1 mutation and IDH1 wild-type tumors [35]. In our study, two patients were found to have an IDH1 mutation (variant p. R132H). These two patients currently have a PFS with TMZ at 11 and 28 months. Also, in each case, the tumor pathology revealed the presence of both astrocytoma and GBM.\n\nGenomic analysis also reveals potential targetable genes, as summarized in Table 5. EGFR amplification and EGFR variant III were detected, which may be sensitive to medications such as an NK-EGFR, dacomitinib and rindopepimut [36]. In fact, dacomitinib is a kinase inhibitor recently approved by the FDA for first-line treatment of metastatic NSCLC in patients with either an EGFR exon 19 deletion or an exon 21 L858R mutation. This supports the possibility that these same drugs could be utilized to target the EGFR mutations in GBM in future.\n\nProteomic analysis in one patient in our study group revealed the presence of TOPO1 and hENT1. TOPO1 is a potential targetable protein for treatment with irinotecan and topotecan. hENT1 protein is a possible target for treatment with gemcitabine [37]. After this patient relapsed within 13 months of standard therapy with TMZ, she was treated with irinotecan and demonstrated good response with PFS at 12 months after its initiation.\n\nAt this point, the eventual clinical significance of the results of our proteomic and genomic analysis is unclear. However, presently, since molecular therapies are being developed, any information regarding molecular profiling contributes to current efforts to develop therapy tailored against pathogenic molecular processes, even though it is too preliminary to assess definite impact.\n\nThe observations made in this study highlight the importance of tumor tissue analysis and increased research in the realm of molecular studies in GBM. Understanding these complex genetic pathways and how they interact will lead to the development of effective treatment strategies that can be tailored to specific patients based on the pathologic makeup of their cancer. It also reminds us of the limitations of the current TCGA data and that there is still much to understand about the pathogenesis of GBM. Hence, this study validates the need for further research to assist in mapping specific gene and protein changes, in order to organize a detailed landscape of this deadly tumor.\n\nConclusion\nProteogenomic analysis suggests that the presence of certain biological processes in each GBM will aid to classify them into groups with different biological thumbprints. Meticulous defining of aberrations at the cellular level can potentially enable for the development of targeted therapies based on an individual tumors’ ‘identity.’ Thus, proteogenomic data are paramount to identifying potential future therapeutic targets for GBM.\n\nFuture perspective\nThere have been many successes in defining molecular profiles of tumors in patients with NSCLC. This has subsequently led to identification of therapeutic targets, either at protein or gene level. These advances with NSCLC fuel hope for similar triumph to be achieved in the future for patients with GBM. As described by Lin et al., retrospective analysis showed that treatment of patients with EGFR-mutant metastatic lung adenocarcinoma with EGFR-TKI improved 5-year survival rates from less than 5% to as high as 14.6% [38]. This study also highlighted that certain proteogenomic attributes, such as the presence of an exon 19 deletion, were associated with improved outcomes in NSCLC patients. With continued investigations to extract clinically significant proteomic and genomic data, new diagnostic, prognostic and predictive biomarkers may be identified for GBM in the near future in addition to already known molecular markers such as EGFR, PIK3R1 and PTEN that will serve as targets for a novel generation of therapies against GBM. While limited therapeutic success has been achieved in trials that have used therapies against known oncogenic pathways thus far, as greater information is accumulated regarding GBM pathogenesis and classification of aberrant genes, we anticipate that development of therapies, such as targeted immunotherapies, will be developed over the next few years. Current genomic sequencing techniques allow for accumulation of large pools of data. If applied clinically, this information provides positive prospects to achieve better outcomes in patients with GBM. Given heterogeneity of GBM, it remains essential that all information gathered by a GBM analysis in individual studies is incorporated into our current available knowledge. This can then serve as a resource on which future studies can be built upon.\n\nSummary points\nGlioblastoma multiforme (GBM) is the most frequent primary brain tumor, which has an aggressive clinical course and extremely poor prognosis. Given limited success of the current standard of care that combines surgery, chemotherapy and radiation, the search for more effective therapies is critical. Thus, understanding the molecular pathogenesis of GBM, and classifying these data into a pool of organized information can allow for the development of novel treatment agents.\n\nProteogenomic analysis in our study revealed TP53, EGFR, PIK3R1, PTEN, NF1, RET and STAG2 as significantly mutated genes in these aggressive tumors.\n\nEGFR alterations seen included EGFRvIII expression, L816Q EGFR missense mutation on exon 21 and EGFR fusion (FGFR3-TACC3); all three are potential therapeutic targets of novel agents including EGFRvIII-specific dendritic cell vaccine, EGFR inhibitors and FGFR inhibitors.\n\nTP53 mutation was found in 30% of patients, including in COSMIC hotspot driver gene as well as accompanying IDH1 and ATRX mutations suggesting transformation from low- to high-grade glioma.\n\nOne patient had a high mutation burden, currently living after 12 months of diagnosis.\n\nProteomics showed significantly higher (n = 9, 53%) EGFR expression than genomic expression (53 vs 23%), suggesting tumor heterogeneity. 75% were methyl guanine methyl transferase-methylated, a predictive marker of response to temozolomide chemotherapy.\n\nAt this point, while the eventual clinical significance of the results of our proteomic and genomic analysis in unclear, any information regarding molecular profiling contributes to current efforts to develop therapy tailored against pathogenic molecular processes.\n\nFurther research is required to completely comprehend the specific genetic and protein changes underlying the development of GBM.\n\nSupplementary Material\nClick here for additional data file.\n\n Acknowledgments\nThe authors acknowledge NantOmics for providing proteogenomic laboratory analysis.\n\nSupplementary data\n\nTo view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/cns-2019-0003\n\nFinancial & competing interests disclosure\n\nThe author S Raza is a member of advisory board and speaker bureau for Amgen, Celgene, Takeda, Novartis and Janssen. The authors have no other 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 apart from those disclosed.\n\nNo writing assistance was utilized in the production of this manuscript.\n\nEthical conduct of research\n\nThe study was approved by Institutional Review Board at Saint Luke’s Health System (MO, USA) and was conducted according to ethical principles for research involving human subjects as stated in the Declaration of Helsinki.\n\nOpen access\n\nThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/\n==== Refs\nReferences\nPapers of special note have been highlighted as: • of interest; •• of considerable interest\n\n1. 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Blumenthal DT , Dvir A , Lossos A \n\nClinical utility and treatment outcome of comprehensive genomic profiling in high grade glioma patients . J. Neurooncol. \n 130 (1 ), 211 –219 (2016 ). 27531351 •• This is a prior study in which targeted therapy for GBM patients was clinically applied.\n\n\n20. Johnson BE , Mazor T , Hong C \n\nMutational analysis reveals the origin and therapy-driven evolution of recurrent glioma . Science. \n343 (6167 ), 189 –193 (2014 ). 24336570 • Describes the heterogeneity of GBM and helps highlight the complexity of defining proteogenomic landscape of GBM.\n\n\n21. Pegg AE \nRepair of O6-alkylguanine by alkyltransferases . Mutat. Res. Rev. Mutat. Res. \n462 (2–3 ), 83 –100 (2000 ). • Describes role of MGMT as a predictive marker.\n\n\n22. Hatanpaa KJ , Burma S , Zhao D , Habib AA \nEpidermal growth factor receptor in glioma: signal transduction, neuropathology, imaging, and radioresistance . Neoplasia. \n12 (9 ), 675 –684 (2015 ).\n23. 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Ohgaki H , Kleihues P \nGenetic alterations and signaling pathways in the evolution of gliomas . Cancer Sci. \n 100 (12 ), 2235 –2241 (2009 ).19737147 \n31. Tanaka S , Louis DN , Curry WT , Batchelor TT , Dietrich J \nDiagnostic and therapeutic avenues for glioblastoma: no longer a dead end? \nNat. Rev. Clin. Oncol. \n 10 (1 ), 14 (2013 ).23183634 \n32. Masui K , Cloughesy TF , Mischel PS \nMolecular pathology in adult high-grade gliomas: from molecular diagnostics to target therapies . Neuropathol. Appl. Neurobiol. \n 38 (3 ), 271 –291 (2012 ).22098029 \n33. Songtao Q , Lei Y , Si G \n\nIDH mutations predict longer survival and response to temozolomide in secondary glioblastoma . Cancer Sci. \n 103 (2 ), 269 –273 (2012 ).22034964 \n34. Yan H , Parsons DW , Jin G \n\nIDH1 and IDH2 mutations in gliomas . N. Engl. J. Med. \n 360 (8 ), 765 –773 (2009 ).19228619 \n35. Mandel JJ , Cachia D , Liu D \n\nImpact of IDH1 mutation status on outcome in clinical trials for recurrent glioblastoma . J. Neurooncol. \n129 (1 ), 147 –154 (2016 ).27270908 \n36. Zahonero C , Aguilera P , Ramirez-Castillejo C \n\nPreclinical test of dacomitinib, an irreversible EGFR inhibitor, confirms its effectiveness for glioblastoma . Mol. Cancer Ther. \n 14 (7 ), 1548 –1558 (2015 ).25939761 \n37. Gilbert DC , Chalmers AJ , El-Khamisy SF \nTopoisomerase i inhibition in colorectal cancer: biomarkers and therapeutic targets . Br. J. Cancer. \n 106 (1 ), 18 (2012 ).22108516 \n38. Lin JJ , Cardarella S , Lydon CA \n\nFive-year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs . J. Thorac. Oncol. \n11 (4 ), 556 –565 (2016 ). 26724471 • Delineates how targeted therapy can markedly change clinical outcomes, which is what we are trying to achieve.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2045-0907",
"issue": "8(2)",
"journal": "CNS oncology",
"keywords": "genomics; glioblastoma; proteomics; survival; temozolomide chemotherapy",
"medline_ta": "CNS Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D019175:DNA Methylation; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D000071696:Proteogenomics; D055815:Young Adult",
"nlm_unique_id": "101594668",
"other_id": null,
"pages": "CNS37",
"pmc": null,
"pmid": "31290679",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "18772396;24122041;27899578;18955445;30233192;27531351;27270908;25355519;20824044;11070098;19269895;25881042;19737147;22108516;28239999;24135276;24120142;26724471;25939761;24987110;22098029;19584260;10767620;28724573;22034964;26049819;29721196;22554165;23183634;8845302;23884480;19228619;16282176;15758009;24336570;27854360",
"title": "Comparative proteogenomic characterization of glioblastoma.",
"title_normalized": "comparative proteogenomic characterization of glioblastoma"
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"abstract": "A 32-year-old Caucasian male presented to the emergency department with a one-day history of acute severe bilateral lower limb weakness, three days after competing in a bodybuilding competition. He consumed large quantities of carbohydrate-rich foods following the competition. His past medical history was significant for anxiety, and family history was non-contributory. Examination was normal except for reduced power and hyporeflexia in both legs, despite his muscular physique. He was noted to have severe hypokalaemia (K+= 1.9 mmol/L). His thyroid function tests were consistent with thyrotoxicosis. He reported taking thyroxine and several other agents to facilitate muscle mass generation before the bodybuilding competition. His presentation was reminiscent of thyrotoxic periodic paralysis, albeit uncommon with Caucasian ethnicity. He also had transient hyperglycaemia at presentation with concomitant hyperinsulinaemia, which could be attributed to the carbohydrate load and may have exacerbated his hypokalaemia through a transcellular shift. Urine toxicology screen subsequently ruled out the use of diuretics but confirmed the presence of a long-acting beta agonist (clenbuterol) which, along with other substances, may have aggravated the hypokalaemia further. After 12 h of i.v. replacement, the potassium level normalised and leg weakness resolved. The patient agreed to stop taking thyroxine and beta agonists and was well during the clinic visit at one month follow-up. This case highlights the potential for thyrotoxicosis factitia to exacerbate hypokalaemia and muscle weakness from other causes in bodybuilders presenting with acute severe weakness, irrespective of ethnicity.\nIn patients presenting with muscle weakness and hypokalaemia, early consideration of thyrotoxicosis is essential, even in the absence of a past history of thyroid disease or specific symptoms of thyrotoxicosis, in order to allow prompt initiation of appropriate treatment and to prevent recurrence. Bodybuilders may constitute a uniquely 'at-risk' group for thyrotoxic periodic paralysis secondary to thyrotoxicosis factitia, especially where there is concomitant use of beta-adrenergic agonists, even in the absence of diuretic use. Although rare and usually described in patients of Asian or Polynesian ethnicity, this case highlights that thyrotoxic periodic paralysis secondary to thyrotoxicosis factitia can also occur in patients with Caucasian ethnicity. We speculate that consuming large quantities of carbohydrates may induce hyperinsulinaemia, which could theoretically contribute to worse hypokalaemia, though mechanistic studies would be needed to explore this further.",
"affiliations": "Centre for Diabetes, Endocrinology & Metabolism.;Centre for Diabetes, Endocrinology & Metabolism.;Department of Nephrology, Endocrinology & Metabolism.;Department of Nephrology, Endocrinology & Metabolism.;Department of Cardiology, Galway, Ireland.;Department of Clinical Biochemistry, Galway University Hospitals, Saolta University Healthcare Group, Galway, Ireland.;Centre for Diabetes, Endocrinology & Metabolism.",
"authors": "Bonnar|Clare E|CE|;Brazil|John F|JF|;Okiro|Julie O|JO|;Giblin|Louise|L|;Smyth|Yvonne|Y|;O'Shea|Paula M|PM|;Finucane|Francis M|FM|0000-0002-5374-7090",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case Rep\nEndocrinol Diabetes Metab Case Rep\nEDM\nEndocrinology, Diabetes & Metabolism Case Reports\n2052-0573\nBioscientifica Ltd Bristol\n\n34612209\n10.1530/EDM-21-0060\nEDM210060\nAdult\nMale\nWhite\nIreland\nThyroid\nThyroid\nGeneral Practice\nNephrology\nRadiology/Rheumatology\nUnique/Unexpected Symptoms or Presentations of a Disease\nUnique/Unexpected Symptoms or Presentations of a Disease\nMaking weight: acute muscle weakness and hypokalaemia exacerbated by thyrotoxicosis factitia in a bodybuilder\nC E Bonnar and others\nThyrotoxic hypokalaemia in a bodybuilder\nBonnar Clare E 1\nBrazil John F 1\nOkiro Julie O 2\nGiblin Louise 2\nSmyth Yvonne 3\nO’Shea Paula M 4\nhttp://orcid.org/0000-0002-5374-7090\nFinucane Francis M 1\n1 Centre for Diabetes, Endocrinology & Metabolism\n2 Department of Nephrology, Endocrinology & Metabolism\n3 Department of Cardiology, Galway, Ireland\n4 Department of Clinical Biochemistry, Galway University Hospitals, Saolta University Healthcare Group, Galway, Ireland\nCorrespondence should be addressed to F M Finucane Email francis.finucane@nuigalway.ie or francis@gmail.com\n17 9 2021\n2021\n2021 21-006006 9 2021\n17 9 2021\n© The authors\n2021\nThe authors\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..\nSummary\n\nA 32-year-old Caucasian male presented to the emergency department with a one-day history of acute severe bilateral lower limb weakness, three days after competing in a bodybuilding competition. He consumed large quantities of carbohydrate-rich foods following the competition. His past medical history was significant for anxiety, and family history was non-contributory. Examination was normal except for reduced power and hyporeflexia in both legs, despite his muscular physique. He was noted to have severe hypokalaemia (K+= 1.9 mmol/L). His thyroid function tests were consistent with thyrotoxicosis. He reported taking thyroxine and several other agents to facilitate muscle mass generation before the bodybuilding competition. His presentation was reminiscent of thyrotoxic periodic paralysis, albeit uncommon with Caucasian ethnicity. He also had transient hyperglycaemia at presentation with concomitant hyperinsulinaemia, which could be attributed to the carbohydrate load and may have exacerbated his hypokalaemia through a transcellular shift. Urine toxicology screen subsequently ruled out the use of diuretics but confirmed the presence of a long-acting beta agonist (clenbuterol) which, along with other substances, may have aggravated the hypokalaemia further. After 12 h of i.v. replacement, the potassium level normalised and leg weakness resolved. The patient agreed to stop taking thyroxine and beta agonists and was well during the clinic visit at one month follow-up. This case highlights the potential for thyrotoxicosis factitia to exacerbate hypokalaemia and muscle weakness from other causes in bodybuilders presenting with acute severe weakness, irrespective of ethnicity.\n\nLearning points\n\nIn patients presenting with muscle weakness and hypokalaemia, early consideration of thyrotoxicosis is essential, even in the absence of a past history of thyroid disease or specific symptoms of thyrotoxicosis, in order to allow prompt initiation of appropriate treatment and to prevent recurrence.\n\nBodybuilders may constitute a uniquely ‘at-risk’ group for thyrotoxic periodic paralysis secondary to thyrotoxicosis factitia, especially where there is concomitant use of beta-adrenergic agonists, even in the absence of diuretic use.\n\nAlthough rare and usually described in patients of Asian or Polynesian ethnicity, this case highlights that thyrotoxic periodic paralysis secondary to thyrotoxicosis factitia can also occur in patients with Caucasian ethnicity.\n\nWe speculate that consuming large quantities of carbohydrates may induce hyperinsulinaemia, which could theoretically contribute to worse hypokalaemia, though mechanistic studies would be needed to explore this further.\n\nPatient Demographics\n\nAdult\nMale\nWhite\nIreland\nClinical Overview\n\nThyroid\nThyroid\nRelated Disciplines\n\nGeneral Practice\nNephrology\nRadiology/Rheumatology\nPublication Details\n\nUnique/unexpected symptoms or presentations of a disease\nOctober\n2021\n==== Body\npmcBackground\n\nThyrotoxic periodic paralysis (TPP) is a rare endocrine emergency, first described in Japan in 1957 (1), which presents with a triad of thyrotoxicosis, hypokalaemia and muscle weakness (2). It is usually associated with underlying thyroid disease, most commonly Graves’ thyrotoxicosis (3). There is a male preponderance and patients invariably have a non-White ethnic background: In one single-centre study in the US describing 19 patients presenting with 24 episodes of TPP over 15 years, all were men, one was of Black African ethnicity and the rest were of Asian (Korean, Filipino, Hispanic and Vietnamese) ethnicity (4). Hypokalaemia and paralysis are thought to arise from over-stimulation of Na-K-ATPase, with potassium influx into the skeletal muscle leading to disruption of the functioning of the skeletal muscle-specific inward rectifying potassium channel and paradoxical depolarisation which in turn inactivates sodium channels, leading to paralysis (5). Although this overstimulation of Na-K-ATPase is driven by excess thyroid hormone, the clinical manifestations of thyrotoxicosis in these patients are often mild (3). Acute episodes of paralysis in TPP can by precipitated by the ingestion of large quantities of carbohydrates (4), probably due to further stimulation of potassium sequestration in skeletal muscle by insulin (5). Treatment of acute presentations of this rare and potentially fatal condition requires emergency measures to replace the depleted potassium and a high degree of clinical suspicion for underlying thyroid disease in patients presenting with weakness and hypokalaemia.\n\nCase presentation\n\nA 32-year-old male bodybuilder presented to our emergency department overnight, with a 24-h history of progressively worsening weakness in both legs and difficulty in walking. Two days previously, he had participated in an international bodybuilding competition, immediately after which he had consumed three very large carbohydrate-rich meals. There was no family or past medical history of note, except moderately severe anxiety of four years duration, which his general practitioner had attributed to thyroxine use. Thyrotoxicosis had been confirmed by his general practitioner with fully suppressed thyroid stimulating hormone (TSH) on two sets of thyroid function tests previously, but the patient continued to take thyroxine against medical advice, which he obtained through the internet. In addition, he reported taking growth hormone, anabolic steroids (including trenbolone, stanozolol, oxandrolone, mesterolone, fluoxymesterone and drostanolone), a long-acting β2-agonist (clenbuterol) and a non-steroidal aromatase inhibitor (letrozole), all sourced illicitly online. He was married with two children, did not drink or smoke and went to the gym every day to lift weights. On systems review, aside from anxiety and muscle weakness, he had no other symptoms of thyrotoxicosis. He had no sensory symptoms or urinary or faecal incontinence. He denied liquorice ingestion, tobacco-chewing, diuretic or laxative abuse.\n\nOn examination he was alert and oriented, with normal affect. He was apyrexial and haemodynamically stable. He had a notably muscular physique. Respiratory, cardiovascular and abdominal examinations were normal and there was no goitre or features of hyperthyroidism. Neurological examination of his cranial nerves and upper limbs was normal, but he had symmetrically reduced grade 3/5 power in the lower limbs (for each of hip, knee and ankle flexion and extension and hip adduction and abduction), with normal tone. He had diminished deep-tendon reflexes at the knees and ankles and bilateral flexor plantar responses.\n\nInvestigation\n\nInitial biochemical investigations revealed metabolic alkalosis and severe hypokalaemia, with normal magnesium, calcium and renal function (see Table 1). His 12-lead ECG showed low-voltage P- and T-waves, prominent U-waves and a prolonged QT interval of 520 ms. Creatine kinase was elevated, consistent with his increased muscle mass and recent participation in the bodybuilding competition. His troponin T was elevated at 32 ng/L (normal <14) and remained so throughout the admission, suggesting myocardial injury. His random plasma glucose at presentation was elevated at 18.2 mmol/L and he had '3+' glycosuria, but he had no osmotic symptoms and urine ketones were undetectable. A fasting plasma glucose of 7.4 mmol/L with a concomitant fasting plasma insulin of 276 pmol/L were consistent with hyperglycaemia secondary to insulin resistance. Thereafter, his glucose levels normalised quickly without specific treatment and his HbA1c was normal at 34 mmol/mol. He had a mild transaminitis consistent with non-alcoholic fatty liver disease. A urinary potassium was sent in order to calculate a transtubular potassium gradient, which was low (Table 2) excluding renal potassium loss in general and diuretic use in particular as a likely cause of hypokalaemia. His thyroid function tests confirmed thyrotoxicosis, with fully suppressed TSH, although his free thyroxine and tri-iodothyronine were not elevated. Serum cortisol, testosterone, androstenedione, dihydroepiandosterone, growth hormone and serum IGF-1 were all within normal reference ranges. However, luteinising- and follicle stimulating hormone levels were undetectable and oestradiol was elevated, consistent with androgen excess secondary to his illicit anabolic steroid use. A qualitative urine drug screen, using ultra-performance liquid chromatography 'time of flight' mass spectrometry (UPLC TOF MS) confirmed the absence of diuretics or laxatives (specifically Rhein, Danthron, Bisacodyl and Phenolphthalein) and the presence of two of the six reported anabolic steroids (trenbolone and oxandrolone) and clenbuterol. There was no evidence to suggest either anorexia nervosa, malnutrition or chronic alcoholism (where total body content of potassium is low due to reduced intake) as causes of hypokalaemia, or any skin conditions that would lead to excessive potassium loss. He had nothing in his history to suggest primary hyperaldosteronism – there was no hypertension or hypokalaemia at previous general practioner visits in the preceding four years. He was normotensive throughout his hospital stay. There was nothing to suggest secondary hyperaldosteronism – he was not dehydrated, and had normal renal function serum osmolality. There was no evidence of ingestion of fludrocortisone or amphotericin-B, liquorice or chewing tobacco (both of which contain carbenoxolone, an 11-betaHSD1 inhibitor), nor did he have features of Cushing’s syndrome. There was no family history of Barter’s or Gitelman’s syndromes, both of which usually present in childhood. The absence of hypokalaemia on blood tests in the preceding four years strongly refutes these diagnoses. Table 1 Initial biochemistry results at presentation.\n\nLaboratory test (units)\tResult\tReference range\t\n*pH\t7.53\t7.35–7.45\t\n*pCO2, kPa\t4.2\t4.6–6.0\t\n*HCO3−, mmol/L\t26.2\t19–24\t\n*Base excess, mmol/L\t4.0\t−2.0 to +3.0\t\nSodium, mmol/L\t141\t136–145\t\nPotassium, mmol/L\t1.9\t3.5–4.5\t\nPhosphate, mmol/L\t0.41\t0.87–1.45\t\nCorrected calcium, mmol/L\t2.24\t2.17–2.51\t\nMagnesium, mmol/L\t0.68\t0.65–1.05\t\nUrea, mmol/L\t4.6\t2.1–7.1\t\nCreatinine, µmol/L\t73\t64–104\t\nCreatine kinase, U/L\t3128\t39–308\t\nPlasma beta-hydroxybutyrate, mmol/L\t0.1\t\t\nAlanine aminotransferase, U/L\t249\t0–40\t\nAlkaline phosphatase, U/L\t144\t40–129\t\nGamma glutamyltransferase, U/L\t149\t10–71\t\n*Arterial blood gas results 3 h after initial presentation.\n\nTable 2 Endocrine and metabolic work-up after presentation.\n\nLaboratory test\tResult\tReference range\t\nThyroid stimulating hormone, mIU/L\t<0.02\t0.27–4.20\t\nFree thyroxine, pmol/L\t12.0\t10.5–22.0\t\nTri-iodothyronine, nmol/L\t1.02\t1.28–2.33\t\nFollicle stimulating hormone, IU/L\t<0.5\t1.5–12.4\t\nLuteinising hormone, IU/L\t<0.5\t1.7–8.6\t\nOestradiol, pmol/L\t224\t99–192\t\nTestosterone, nmol/L\t23.7\t9.9–27.8\t\nAndrostenedione, nmol/L\t2.7\t2.0–5.4\t\nDihydroepiandosterone, µmol/L\t3.6\t2.3–10.0\t\nSexhormone-binding globulin, nmol/L\t8.4\t14.5–48.4\t\nCortisol, nmol/L\t513\t166–507\t\nIGF-1, µg/L\t79\t71–241\t\nUrine potassium, mmol/L\t17\t\t\nUrine osmolality, mmol/kg\t587\t\t\nSerum potassium, mmol/L\t2.6\t3.5–4.5\t\nSerum osmolality, mmol/kg\t284\t275–299\t\nTrans-tubular potassium gradient\t2.84\t<3*\t\n*Appropriate in hypokalaemia.\n\nTreatment\n\nThe patient received i.v. fluids and potassium replacement, with serum pH and potassium levels returning to normal within 12 h. Because hypokalaemia was due to an intracellular shift of potassium rather than tissue potassium loss, we were mindful of the potential for rebound hyperkalaemia and with a cautious approach and frequent monitoring, the patient required a total of only 60 mmol potassium chloride to restore normokalaemia. The patient also received magnesium and phosphate replacement as well as prophylactic low-molecular weight heparin. He was advised to stop taking thyroxine, as well as the other illicit bodybuilding substances.\n\nOutcome and follow-up\n\nThe patient’s weakness resolved within hours of correction of his hypokalaemia. His neurological examination returned to normal. On the third day of his admission, his potassium remained normal and he was discharged home. One month later, he was followed-up in out-patients and reported stopping thyroid supplements. The echocardiogram results were normal except for mild septal hypokinesis, and a gadolinium-enhanced cardiac MRI scan showed reduced long axis motion consistent with early interstitial myocardial fibrosis from steroid use. His potassium and thyroid function tests were normal at that time. At two months post discharge, potassium and thyroid function tests remained normal, as were fasting glucose and insulin and HbA1c. His transaminitis had resolved and sex hormone-binding globulin (SHBG) had normalised, consistent with resolution of his liver steatosis. However, his total testosterone and oestradiol were elevated, consistent with ongoing anabolic steroid use, despite the medical advice to the contrary. He had no further episodes of limb weakness.\n\nDiscussion\n\nThis man’s presentation with acute severe leg weakness and hypokalaemia was reminiscent of TPP, albeit with Caucasian ethnicity and no apparent history of thyroid disease, until systems review at presentation noted the consumption of thyroid supplements and thyrotoxicosis factitia which had been diagnosed by his general practioner. A description of a similar presentation in a 27-year-old bodybuilder of Hispanic ethnicity published last year was only the eighth ever described of TPP secondary to thyrotoxicosis factitia (6) and we believe that ours is the first description in a patient of Caucasian ethnicity. Case series suggest that TPP is typically present in the third decade, over 95% of the time in males (2, 6), and is much more common in those of Asian ethnicity (7, 8). Our patient’s presentation was typical, with rapidly progressive symmetrical muscle weakness in both legs, without sensory symptoms or signs, or bowel or bladder dysfunction (6, 7). Rarely, respiratory muscle involvement or ventricular arrhythmias can also occur (7). Rapid recognition and treatment of TPP is crucial and affected patients may require high dependency or intensive care unit admission. Non-selective beta blockers such as propranolol may be helpful, but we did not use this given the patient’s relatively prompt improvement. In contrast to the more common condition of familial hypokalaemic periodic paralysis (FHPP, an autosomal dominant condition), the vast majority of TPP cases are sporadic, though a familial form also exists. Acute episodes of either sporadic or familial TPP are indistinguishable from those of FHPP, except that there is a higher propensity for arrhythmias, cardiac arrest and respiratory failure with the former (4). As in our case, clinical features of thyrotoxicosis may be subtle or absent in TPP (3). Unexpectedly, our patient did not have raised free thyroxine or tri-iodothyronine levels, which we would have anticipated given he had taken these agents 48 h prior to presentation. However, the presence of a fully suppressed TSH with a clear history of chronic exogenous thyroid hormone use was confirmatory of thyrotoxicosis.\n\nAcute hypokalaemia is the hallmark of TPP and its severity correlates with the degree of muscle weakness (5), which arises from myopathy rather than neurological dysfunction (8). Other causes of hypokalaemia such as laxative or diuretic use need to be excluded, even where thyrotoxicosis is present, before TPP can be diagnosed. In particular, diuretic use may be present in bodybuilders with TPP secondary to thyrotoxicosis factitia (6), but this would be expected to lead to much greater requirements for potassium replacement, as well as an elevated trans-tubular potassium gradient and a positive urinary diuretic screen, none of which were present in our patient. Our patient’s use of clenbuterol, a potent stimulator of the beta-2 adrenergic receptor is likely to have contributed to enhanced skeletal muscle Na-K-ATPase activation and further sequestration of potassium (9), precipitating his acute presentation. Clenbuterol may also have contributed to hypophosphataemia and thus worsened his rhabdomyolysis. Furthermore, he may have developed a refeeding syndrome after severe dietary restriction before the bodybuilding competition, followed by high carbohydrate intake, which would have led to insulin-mediated phosphate (as well as potassium) sequestration. Also, stanozolol use is the likely cause of his metabolic alkalosis and may have further aggravated his hypokalaemia (10). Acute attacks of TPP often occur when the patient is asleep or after carbohydrate-rich meals (4, 7), suggesting insulin may be an important contributor to intracellular potassium sequestration through its activation of Na-K-ATPase (5). We postulate that the significant carbohydrate binge and likely subsequent hyperinsulinemia aggravated our patient’s acute presentation with hypokalaemia and weakness. His suppressed SHBG at presentation was also suggestive of insulin resistance, particularly in the context of thyroxine use, which would be expected to raise SHBG. The higher incidence of TPP in men may be due to testosterone-mediated myoblast hypertrophy, with greater expression of Na-K-ATPase (4). This patient’s hypokalaemia and muscle weakness arose from a synergistic combination of exogenous thyroxine, stanazolol, clenbuterol, refeeding syndrome and anabolic steroids. The combined use of these agents by bodybuilders to gain muscle and lose fat represents a serious but underappreciated risk to health that outweighs any 'benefits' for body composition and bodybuilding competition.\n\nDeclaration of interest\n\nClare Bonnar, John Brazil, Julie Okiro, Yvonne Smyth, Louise Giblin and Paula O’Shea have no conflicts of interest to declare. Francis Finucane has (until 2017) received honoraria and travel grants and has served on advisory boards for Novo Nordisk, Eli Lilly, Ethicon, Pfizer Inc., Sanofi-Aventis, Astra Zeneca, Merck-Serono, Boehringer Ingelheim, Janssen, and Novartis in the past.\n\nFunding\n\nFrancis Finucane is funded by a Clinical Research Career Development Award from the Saolta University Health Care Group.\n\nPatient consent\n\nFully informed, written consent was obtained from the patient to describe their care and relevant investigations in this case report for consideration for publication in EDM.\n\nAuthor contribution statement\n\nClare Bonnar, John Brazil, Julie Okiro, Yvonne Smyth and Louise Giblin alllevel contributed to the clinical care of this patient and influenced management decisions, as well as drafting and revising the manuscript. Paula O’Shea supervised the laboratory analyses and their interpretation and revised the manuscript. Francis Finucane supervised the clinical care of the patient and the drafting and revision of the manuscript.\n==== Refs\nReferences\n\n1 Shizume K Shishiba Y Kuma K Noguchi S Tajiri J Ito K Noh JY . Comparison of the incidence of association of periodic paralysis and hyperthyroidism in Japan in 1957 and 1991. Endocrinologia Japonica 1992 39 315–318. (10.1507/endocrj1954.39.315)1425456\n2 Chang CC Cheng CJ Sung CC Chiueh TS Lee CH Chau T Lin SH . A 10-year analysis of thyrotoxic periodic paralysis in 135 patients: focus on symptomatology and precipitants. European Journal of Endocrinology 2013 169 529–536. (10.1530/EJE-13-0381)23939916\n3 Kung AW Clinical Review: Thyrotoxic periodic paralysis: a diagnostic challenge. Journal of Clinical Endocrinology and Metabolism 2006 91 2490–2495. (10.1210/jc.2006-0356)16608889\n4 Manoukian MA Foote JA Crapo LM . Clinical and metabolic features of thyrotoxic periodic paralysis in 24 episodes. Archives of Internal Medicine 1999 159 601–606. (10.1001/archinte.159.6.601)10090117\n5 Lin SH Huang CL . Mechanism of thyrotoxic periodic paralysis. Journal of the American Society of Nephrology 2012 23 985–988. (10.1681/ASN.2012010046)22460532\n6 Patel AJ Tejera S Klek SP Rothberger GD . Thyrotoxic periodic paralysis in a competitive bodybuilder with thyrotoxicosis factitia. AACE Clinical Case Reports 2020 6 e252–e256. (10.4158/ACCR-2020-0154)32984532\n7 Clarine LHS Hosein N . Thyrotoxic periodic paralysis: a review of cases in the last decade. AACE Clinical Case Reports 2015 1 e182–e186. (10.4158/EP14304.CR)\n8 Panikkath R Nugent K . I lost weight, but I became weak and cannot walk – a case of nutraceutical (T3)-induced thyrotoxic periodic paralysis. American Journal of Therapeutics 2014 21 e211–e214. (10.1097/MJT.0b013e318288a460)23567793\n9 MacLennan PA Edwards RH . Effects of clenbuterol and propranolol on muscle mass. Evidence that clenbuterol stimulates muscle beta-adrenoceptors to induce hypertrophy. Biochemical Journal 1989 264 573–579. (10.1042/bj2640573)\n10 Maini AA Maxwell-Scott H Marks DJ . Severe alkalosis and hypokalemia with stanozolol misuse. American Journal of Emergency Medicine 2014 32 196.e3–196. e4. (10.1016/j.ajem.2013.09.027)\n\n",
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"title": "Making weight: acute muscle weakness and hypokalaemia exacerbated by thyrotoxicosis factitia in a bodybuilder.",
"title_normalized": "making weight acute muscle weakness and hypokalaemia exacerbated by thyrotoxicosis factitia in a bodybuilder"
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"abstract": "BACKGROUND\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by an overwhelming cytokine response. Various treatment strategies have been attempted.\n\n\nRESULTS\nA 61-year-old man with heart transplantation in 2017 presented with fever, cough, and dyspnea, and was confirmed positive for coronavirus disease 2019 (COVID-19). Laboratory tests showed significant elevations in C-reactive protein and interleukin-6 (IL-6). Echocardiogram showed left ventricular ejection fraction 58% (with ejection fraction 57% 6 months prior). Given the lack of clear management guidelines, the patient was initially managed symptomatically. However, the patient subsequently had a rapid respiratory deterioration with worsening inflammatory markers on day 5 of admission. Tocilizumab (anti-IL-6R) was in low supply in the hospital. The patient was offered clazakizumab (anti-IL-6) for compassionate use. Patient received 25 mg intravenously × 1 dose. Within 24 hours, he showed significant improvement in symptoms, oxygen requirements, radiological findings, and inflammatory markers. There was a transient leukopenia that improved in 4 days. He was discharged home on day 11, with negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, development of positive serum COVID-19 IgG antibody, and he continued to do well on day 60, with no heart-related symptoms.\n\n\nCONCLUSIONS\nClazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19. Although not yet FDA approved, it is being investigated for treatment of renal antibody-mediated rejection. Clinical trials of clazakizumab for treatment of COVID-19 are underway worldwide.",
"affiliations": "Cedars-Sinai Smidt Heart Institute, Heart Transplant Program, Cedars Sinai Medical Center, Los Angeles, California.;Cedars-Sinai Smidt Heart Institute, Heart Transplant Program, Cedars Sinai Medical Center, Los Angeles, California. Electronic address: Lawrence.Czer@cshs.org.;Cedars-Sinai Smidt Heart Institute, Heart Transplant Program, Cedars Sinai Medical Center, Los Angeles, California.;Cedars-Sinai Smidt Heart Institute, Heart Transplant Program, Cedars Sinai Medical Center, Los Angeles, California.;Cedars-Sinai Smidt Heart Institute, Heart Transplant Program, Cedars Sinai Medical Center, Los Angeles, California.;Cedars-Sinai Smidt Heart Institute, Heart Transplant Program, Cedars Sinai Medical Center, Los Angeles, California.;Cedars-Sinai Smidt Heart Institute, Heart Transplant Program, Cedars Sinai Medical Center, Los Angeles, California.;Department of Medicine, William Beaumont Hospital, Royal Oak, Michigan.;Department of Pharmacy Services, Cedars Sinai Medical Center, Los Angeles, California.;Comprehensive Transplant Center, Transplant Immunotherapy Program, Cedars Sinai Medical Center, Los Angeles, California.;Comprehensive Transplant Center, Transplant Immunotherapy Program, Cedars Sinai Medical Center, Los Angeles, California.;Comprehensive Transplant Center, Transplant Immunotherapy Program, Cedars Sinai Medical Center, Los Angeles, California.;Division of Infectious Diseases, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California.;Comprehensive Transplant Center, Transplant Immunotherapy Program, Cedars Sinai Medical Center, Los Angeles, California.",
"authors": "Vaidya|Gaurang|G|;Czer|Lawrence S C|LSC|;Kobashigawa|Jon|J|;Kittleson|Michelle|M|;Patel|Jignesh|J|;Chang|David|D|;Kransdorf|Evan|E|;Shikhare|Anuja|A|;Tran|Hai|H|;Vo|Ashley|A|;Ammerman|Noriko|N|;Huang|Edmund|E|;Zabner|Rachel|R|;Jordan|Stanley|S|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C508603:IL6R protein, human; D019947:Receptors, Interleukin-6; C000604955:clazakizumab",
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"mesh_terms": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D019947:Receptors, Interleukin-6; D000086402:SARS-CoV-2",
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"references": "32376398;27547870;30635033;27059799;32428990;27049586;22679491;11053081",
"title": "Successful Treatment of Severe COVID-19 Pneumonia With Clazakizumab in a Heart Transplant Recipient: A Case Report.",
"title_normalized": "successful treatment of severe covid 19 pneumonia with clazakizumab in a heart transplant recipient a case report"
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"abstract": "Immune checkpoint blockade has shown anti-tumour activity and improved survival in advanced non-small cell lung cancer (NSCLC). A number of anti-PD-1/PD-L1 and CTLA-4 monoclonal antibody agents have been evaluated in metastatic non-small cell lung cancer. Nivolumab, pembrolizumab and atezolizumab are currently approved for use in clinical practice due to demonstrated improvement in response rate, overall survival (OS) and quality of life (QoL) over standard chemotherapy. We present a series of cases that highlight the clinical challenges that these novel agents present. A review of rare immune-related adverse events (AEs), optimal treatment duration and patient selection will be presented. This series will also address real-life clinical scenarios such as treatment re-challenge and management of immune-related AEs.",
"affiliations": "Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.",
"authors": "Tay|Rebecca|R|;Prelaj|Arsela|A|;Califano|Raffaele|R|",
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"title": "Immune checkpoint blockade for advanced non-small cell lung cancer: challenging clinical scenarios.",
"title_normalized": "immune checkpoint blockade for advanced non small cell lung cancer challenging clinical scenarios"
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"abstract": "Pyrethroids are broad-spectrum insecticides. Permethrin intoxication due to topical application has not been documented in humans. We report a 20-month-old infant who had used 5% permethrin lotion topically for scabies treatment. Approximately 60 mL (20 mL/day) was used and after the third application he developed agitation, nausea, vomiting, respiratory distress, tachycardia, and metabolic acidosis. His clinical symptoms and metabolic acidosis normalized within 20 hours. His follow-up was unremarkable. Toxicity of permethrin is rare, and although permethrin is a widely and safely used topical agent in the treatment of scabies and lice, inappropriate use may rarely cause toxicity. Moreover, in cases of unexplained metabolic acidosis, topically applied medications should be carefully investigated.",
"affiliations": "Department of Pediatrics, Medical Faculty, Abant Izzet Baysal University, Bolu, Turkey.",
"authors": "Goksugur|Sevil B|SB|;Karatas|Zehra|Z|;Goksugur|Nadir|N|;Bekdas|Mervan|M|;Demircioglu|Fatih|F|",
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"doi": "10.1111/pde.12473",
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"issn_linking": "0736-8046",
"issue": "32(1)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000138:Acidosis; D006801:Humans; D007223:Infant; D007306:Insecticides; D008297:Male; D026023:Permethrin; D012532:Scabies",
"nlm_unique_id": "8406799",
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"references": null,
"title": "Metabolic acidosis in an infant associated with permethrin toxicity.",
"title_normalized": "metabolic acidosis in an infant associated with permethrin toxicity"
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"abstract": "Urticarial vasculitis (UV) is a rare form of cutaneous leukocytoclastic vasculitis with persistent urticarial lesions. UV may be severe and refractory to standard treatment including antihistamines, anti-inflammatories, antimalarials, corticosteroids and immunosuppressants. Omalizumab, an anti-IgE antibody, is approved for chronic spontaneous urticaria. However, its benefit for UV remains controversial. We report, herein, three patients with normocomplementemic UV and angioedema. All patients were diagnosed with chronic urticaria preceding the presentation of painful urticarial plaques. The diagnosis of UV was confirmed by skin biopsy and/or direct immunofluorescence. All patients had none or minimal response to standard treatments. Initial omalizumab dosing of 150 mg was administered subcutaneously (SC), however, increment to 300 mg monthly was necessary in 2 patients to control the disease. All 3 patients remained in complete remission after minimum follow up period of 9 months. To conclude, omalizumab has shown to be beneficial for severe normocomplementemic UV in our series.",
"affiliations": "Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.",
"authors": "Rattananukrom|Teerapong|T|;Svetvilas|Pranee|P|;Chanprapaph|Kumutnart|K|",
"chemical_list": "D018926:Anti-Allergic Agents; D015415:Biomarkers; D000069444:Omalizumab",
"country": "Thailand",
"delete": false,
"doi": "10.12932/AP-050918-0402",
"fulltext": null,
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"issn_linking": "0125-877X",
"issue": "38(4)",
"journal": "Asian Pacific journal of allergy and immunology",
"keywords": null,
"medline_ta": "Asian Pac J Allergy Immunol",
"mesh_terms": "D018926:Anti-Allergic Agents; D015415:Biomarkers; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000069444:Omalizumab; D012867:Skin; D063189:Symptom Assessment; D016896:Treatment Outcome; D018366:Vasculitis, Leukocytoclastic, Cutaneous",
"nlm_unique_id": "8402034",
"other_id": null,
"pages": "286-289",
"pmc": null,
"pmid": "30660172",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Successful treatment of normocomplementemic urticarial vasculitis with omalizumab: A report of three cases and literature review.",
"title_normalized": "successful treatment of normocomplementemic urticarial vasculitis with omalizumab a report of three cases and literature review"
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"abstract": "Arterioportal shunt (APS) is an organic communication between the hepatic arterial system and the portal venous system. The APS is one of the major causes of transient hepatic attenuation differences on dynamic computed tomography (CT) or magnetic resonance imaging (MRI). This condition is usually associated with trauma, liver cirrhosis, and malignancies of the liver. However, there has been no report about oxaliplatin-induced APS. A 41-year-old male was diagnosed with Stage IIIB gastric cancer. The patient initially underwent neoadjuvant chemotherapy with capecitabine and oxaliplatin After 3 cycles of therapy, the mass had markedly decreased, and a total gastrectomy with splenectomy was performed. Since the malignancy was locally invasive, the patient was continued on the same regimen of the adjuvant chemotherapy. After 3 more cycles, a computed tomography revealed a 1 cm sized arterial-enhancing nodule in the right lobe of the liver. An MRI revealed an arterial enhancing lesion, and a positron emission tomography CT scan showed a hypermetabolic lesion in the same portion of the liver. We tried to perform a liver biopsy; however, an ultrasonography could not detect any mass. A presumptive diagnosis of an APS due to a recurred cancer was made. We found a similar but slightly different case report of an oxaliplatin-induced liver injury, mimicking a metastatic tumor on an MRI. Based on a prior report, the patient was continued on treatment with adjuvant chemotherapy following discontinuation of oxaliplatin. After 2 cycles, the arterial enhancing liver mass resolved, supporting the final diagnosis of an APS, related to oxaliplatin-induced sinusoidal injury. The patient has not experienced any a relapse after two years of additional follow up recurrent gastric cancer upon interpretation of multiple imaging modalities.",
"affiliations": "Department of Premedical Course, Chosun University School of Medicine, Gwangju 501-717, South Korea.;Department of Internal Medicine, Hemato-oncology, Chosun University Hospital, Gwangju 501-717, South Korea. sgpark@chosun.ac.kr.",
"authors": "Kim|Hong-Beum|HB|;Park|Sang-Gon|SG|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "United States",
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"doi": "10.3748/wjg.v23.i33.6187",
"fulltext": "\n==== Front\nWorld J GastroenterolWorld J. GastroenterolWJGWorld Journal of Gastroenterology1007-93272219-2840Baishideng Publishing Group Inc jWJG.v23.i33.pg618710.3748/wjg.v23.i33.6187Case ReportArterioportal shunt incidental to treatment with oxaliplatin that mimics recurrent gastric cancer Kim Hong-Beum Department of Premedical Course, Chosun University School of Medicine, Gwangju 501-717, South KoreaPark Sang-Gon Department of Internal Medicine, Hemato-oncology, Chosun University Hospital, Gwangju 501-717, South Korea. sgpark@chosun.ac.krSupported by: The National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, and Future Planning, No. NRF-2015R1A5A2009070; research fund from Chosun University, 2015.\n\nAuthor contributions: Kim HB were the major contributors in writing the manuscript; Park SG were involved in drafting, writing and editing the manuscript, and reviewed the manuscript as corresponding author; all authors read and approved the final manuscript.\n\nCorrespondence to: Sang-Gon Park, MD, PhD, Department of Internal Medicine, Hemato-oncology, Chosun University Hospital, 365 Pilmun-daero, Dong-gu, Gwangju 501-717, South Korea. sgpark@chosun.ac.kr\n\nTelephone: +82-62-2203984 Fax: +82-62-2349653\n\n7 9 2017 7 9 2017 23 33 6187 6193 15 3 2017 31 5 2017 12 7 2017 ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.2017This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.Arterioportal shunt (APS) is an organic communication between the hepatic arterial system and the portal venous system. The APS is one of the major causes of transient hepatic attenuation differences on dynamic computed tomography (CT) or magnetic resonance imaging (MRI). This condition is usually associated with trauma, liver cirrhosis, and malignancies of the liver. However, there has been no report about oxaliplatin-induced APS. A 41-year-old male was diagnosed with Stage IIIB gastric cancer. The patient initially underwent neoadjuvant chemotherapy with capecitabine and oxaliplatin After 3 cycles of therapy, the mass had markedly decreased, and a total gastrectomy with splenectomy was performed. Since the malignancy was locally invasive, the patient was continued on the same regimen of the adjuvant chemotherapy. After 3 more cycles, a computed tomography revealed a 1 cm sized arterial-enhancing nodule in the right lobe of the liver. An MRI revealed an arterial enhancing lesion, and a positron emission tomography CT scan showed a hypermetabolic lesion in the same portion of the liver. We tried to perform a liver biopsy; however, an ultrasonography could not detect any mass. A presumptive diagnosis of an APS due to a recurred cancer was made. We found a similar but slightly different case report of an oxaliplatin-induced liver injury, mimicking a metastatic tumor on an MRI. Based on a prior report, the patient was continued on treatment with adjuvant chemotherapy following discontinuation of oxaliplatin. After 2 cycles, the arterial enhancing liver mass resolved, supporting the final diagnosis of an APS, related to oxaliplatin-induced sinusoidal injury. The patient has not experienced any a relapse after two years of additional follow up recurrent gastric cancer upon interpretation of multiple imaging modalities.\n\nLiverArterioportal shuntRecurred cancerOxaliplatinTransient hepatic attenuation differences\n==== Body\nCore tip: Although there have been several recent reports about oxaliplatin-induced sinusoidal injury, this is first case report of a non-tumorous incidental arterioportal shunt following oxaliplatin chemotherapy. We made a presumptive diagnosis of an AP shunt mimicking a recurred gastric cancer, due to an oxaliplatin-induced transsinusoidal injury. This case is the first report of an oxaliplatin-induced incidental arterioportal shunt mimicking recurred gastric cancer on various images.\n\nINTRODUCTION\nTransient hepatic attenuation differences (THAD) lesions indicate areas of parenchymal enhancement, visible during the hepatic artery phase on a dynamic computed tomography (CT) or magnetic resonance imaging (MRI), and are thought to be a physiological phenomenon due to the dual hepatic blood supply. The arterioportal shunt (APS) is one of the most important THAD[1,2].\n\nAPS is an organic communication between the hepatic arterial system and the portal venous system, and is caused by the redistribution of arterial flow into a focal region of the portal venous flow. This condition is associated with hepatic tumors, trauma, intervention, liver cirrhosis and metastatic tumors[2-5].\n\nCASE REPORT\nA 41-year-old Korean man was admitted with a chief complaint of epigastric pain. The patient initially underwent an endoscopy, which revealed a 4 cm sized ulcerofungating mass in the gastric cardia and CLO test (Campylobacter-like organism test; Rapid urease test) was negative. Pathologic findings revealed poorly differentiated adenocarcinoma without intestinal metaplasia and a CT scan showed a bulky ulcerative mass with direct invasion of the pancreas, and the left diaphragm. Furthermore, there were multiple perigastric and upper aortic lymph node enlargements. Based on these findings, the patient was diagnosed with Stage IIIB gastric cancer (T4N2M0) (Figure 1A and B). He had a far advanced stage of gastric cancer; therefore, the patient underwent firstly a neoadjuvant chemotherapy with capecitabine and oxaliplatin. After 3 cycles of this therapy (#1-#3), the mass had markedly decreased and a total gastrectomy with splenectomy was performed (Figure 1C and D). Since this was a stage IIIB gastric cancer [T4bN0 (0/48) M0], the patient was continued on the same regimen as adjuvant chemotherapy\n\nFigure 1 On admission, computed tomography revealed a bulky ulcerative mass with direct invasion of pancreas and left diaphragm (A and B). After 3 cycle of neoadjuvant chemotherapy (capecitabine and oxaliplatin), the mass had markedly decrease (C and D).\n\nAfter another 3 cycles of therapy (#4-#6), a follow-up CT demonstrated an arterial enhancing mass like lesion in the peripheral portion of the right lobe of the liver (Figure 2).\n\nFigure 2 After total six cycle of chemotherapy (capecitabine and oxaliplatin), dynamic computed tomography showed an arterial enhanced mass like lesion. A: Pre-enhanced image; B: Arterial phase image; C: Portal phase image; D: Delayed phase image.\n\nWe presumed initially a new hepatocellular carcinoma or recurred gastric cancer, and we evaluated the arterial enhancing mass like lesion. He had a no history of hepatitis (hepatitis B and C) and he was social alcohol drinking. There was no proof of liver cirrhosis in CT, too. The test results showed HBsAg (-), HBsAb (+), and HCVAb (−) and tumor marker of hepatocellular carcinoma was under the normal range such as Alpha-fetoprotein (α-FP) of 2.2 ng/mL (normal; < 5 ng/mL) and protein induced by vitamin K absence-II of 23 mAU (0–39 mAU). CEA (Carcinoembryonic antigen) and CA 19-9 (carbohydrate antigen) were under the normal range, too. Various other image studies were done. An MRI showed the arterial enhancing lesion, and a PET CT scan showed a hypermetabolic lesion in that same portion of the liver (Figures 3 and 4). We tried to perform a pathological confirmation of the lesion through a liver biopsy. However, we could not obtain the tissue because no typical mass was detected on ultrasonography.\n\nFigure 3 Dynamic magnetic resonance imaging demonstrated an arterial enhance mass like lesion as same as computed tomography scan. A: Pre-enhanced image; B: Arterial phase image; C: Portal phase image; D: delayed phase image.\n\nFigure 4 This arterial enhances mass like lesion had a hypermetabolism in positron emission tomography computed tomography.\n\nIn summary, he had a no risk of hepatocellular carcinoma and normal range of tumor markers, and there was no mass in liver. He was initially far advanced stage of gastric cancer, and he was high risk subtype of recurrence. Base on the data, we assumed it might be an arterial-portal shunt in the liver. However, this phenomenon strongly indicated a recurred mass in the liver despite of no obvious proof of recurrence such as typical mass or elevated tumor marker (CEA, CA 19-9). After reviewing literature, we found a few case report of an oxaliplatin-induced liver injury, mimicking a metastatic tumor on an image, although it was a slightly different case (mainly colon cancer and different enhance pattern)[6-10].\n\nTherefore, we continued with the adjuvant chemotherapy, this time, eliminating oxaliplatin. After 2 cycles of capecitabine monotherapy, the arterial enhancing mass in the liver disappeared (Figure 5). We were able to confirm the diagnosis of an AV shunt due to oxaliplatin-induced sinusoidal injury, the patient has not relapsed in 2 years.\n\nFigure 5 After adjuvant chemotherapy without oxaliplatin, the arterial enhance lesion disappeared. A: PET CT; B: Arterial phase image; C: Portal phase image; D: Delayed phase image.\n\nDISCUSSION\nA unique feature of the liver’s blood supply system is its dual blood supply, which comes from the hepatic artery (25%) and the portal vein (75%). A perfusion gradient between the artery and portal vein under various conditions such as diminished blood flow through the portal vein can result in an increased attenuation or signal intensity difference during the early phases of a contrast-enhanced dynamic imaging of the liver. In most cases, this finding reflects an increased arterial blood flow, related to an APS. APSs tend to show an amorphous or nodular appearance in the peripheral portion of the liver. There are various causes of APS: hepatic neoplasms, hepatic trauma including interventional procedure, liver cirrhosis, inflammatory diseases, obstruction of the portal or hepatic vein due to various causes, external compression such as hepatic tumor (hepatocellullar carcinoma and cholangiocarcinoma, metastatic tumor, hematoma), or an internal obstruction (tumor thrombus, invasion of cancer). There are various routes, depending on each cause. These routes are transtumoral (through the tumor itself), transversal (due to portal vein tumor thrombosis), transplexal (peribiliary vascular plexus) and transsinusoidal (between microscopic hepatic arterioles and portal venules, distal to portal vein compression or thrombosis), each of which can occur alone or in combination with each other[2-5].\n\nHowever, our case was an incidental arterioportal shunt, mimicking a recurred gastric cancer, on various images (dynamic CT, MRI and PET). Actually, we are uncertain about why the arterial enhancing nodule (suspected APS) spontaneously disappeared. However, our patient had no history of liver cirrhosis, intervention of liver, or liver trauma (including trauma from surgery of the liver). Moreover, no typical mass was picked up by the sonography.\n\nOxaliplatin is platinum-based, and a third generation chemotherapeutic agent, administered to patients with gastric cancer, and colorectal cancer. It has comparably less toxic side effects than that of cisplatin. However, there are increasing numbers of reports indicating that oxaliplatin-based chemotherapy could cause damage to a non-tumor-bearing liver. Several reports have confirmed the association between hepatic sinusoidal injury and oxaliplatin. Oxaliplatin-induced hepatic sinusoidal injury can range from a mild sinusoidal dilatation to a hepatic sinusoidal obstruction syndrome. Clinical manifestations vary from asymptomatic to hepatomegaly, jaundice, and ascites. The oxaliplatin sinusoidal injury lesions appeared after the administration of oxaliplatin; however, most lesions disappeared after the cessation of oxaliplatin treatment[6-10].\n\nThe incidence of hepatic sinusoidal injury ranges between 19% and 54%. A retrospective study demonstrated that approximately half the patients who received preoperative chemotherapy with oxaliplatin developed some degree of hepatic sinusoidal dilation and microscopic hemorrhage related to damage to the hepatic sinusoidal endothelial cell barrier[11,12].\n\nOxaliplatin-induced liver damage is characterized histologically by sinusoidal dilatation and congestion outlined by atrophic hepatocyte and/or fibrosis and venular obstruction. An immunohistochemical study of cluster of differentiation 34 revealed a decrease in sinusoidal endothelial cells in this lesion. Such an injury often increases the porosity of the sinusoidal endothelium, and increases cellular fenestrations. This led to the obstruction of the sinusoids and interruption of the portal circulation, resulting in hepatic congestion and eventually elevated portal pressures. Finally, some advanced cases of oxaliplatin-induced sinusoidal injury, have induced veno-occlusive disease, sinusoidal obstruction and portal hypertension[13-15]. Among the pathogenesis of oxaliplatin-induced sinusoidal injury, hepatic congestion due to an obstruction of the sinusoids and an interruption of portal circulation is similar to APS, through a transsinusoidal route. It is thought that oxaliplatin-induced sinusoidal obliteration of peripheral hepatic venules could lead to a retrograde filling of small portal vein branches, by way of a trans-sinusoidal route[2-5].\n\nOur patient underwent splenectomy, and there might be a question that it may affect to oxaliplatin induced sinusoidal injury. However, we couldn’t find the relationship between splenectomy and oxaliplatin-induced sinusoidal injury or APS, and splenectomy was rather as option of treatment of hypersplenism from oxaliplatin-induced sinusoidal injury[16].\n\nIn conclusion, although we had no established evidence of a relationship between oxaliplatin and incidental APS, we concluded on the diagnosis because of the following reasons: Firstly, there was no reason lead to be APS such as trauma, intervention and liver cirrhosis. Secondly, the arterial enhancing lesion appeared after the administration of oxaliplatin and disappeared after the cessation of oxaliplatin. Thirdly, although no definitive mechanism exists for our case, oxaliplatin-induced sinusoidal injury has been identified, and this is enough evidence from literature, to support our case. To the best of our knowledge, this is the first case report of arterioportal shunt incidental to treatment with oxaliplatin that mimics recurrent gastric cancer upon interpretation of multiple imaging modalities.\n\nCOMMENTS\nCase characteristics\nAfter adjuvant chemotherapy with capecitabine and oxaliplatin in stage IIIb gastric cancer, a computed tomography revealed a 1 cm sized arterial-enhancing nodule in the liver.\n\nClinical diagnosis\nThe authors presumed initially a new hepatocellular carcinoma or recurred gastric cancer.\n\nDifferential diagnosis\nHepatocellular carcinoma, recurred gastric cancer, arterioportal shunt.\n\nLaboratory diagnosis\nVarious tumor marker were under the normal range.\n\nImaging diagnosis\nVarious imaging including dynamic computed tomography (CT), magnetic resonance imaging, and Positron emission tomography-CT showed an arterioportal shunt.\n\nPathological diagnosis\nThe authors could not obtain the tissue because no typical mass was detected on ultrasonography.\n\nTreatment\nThe patient was continued on treatment with adjuvant chemotherapy following discontinuation of oxaliplatin.\n\nRelated reports\nThere was no report of non-tumorous incidental Arterioportal shunt (APS) related to treatment with oxaliplatin.\n\nTerm explanation\nAPS is an organic communication between the hepatic arterial system and the portal venous system.\n\nExperiences and lessons\nThe authors want to share this case as rare condition of arterioportal shunt due to oxaliplatin induced sinusoidal injury.\n\nPeer-review\nThis is the first case report of arterioportal shunt incidental to treatment with oxaliplatin that mimics recurrent gastric cancer upon interpretation of multiple imaging modalities\n\nManuscript source: Unsolicited manuscript\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: South Korea\n\nPeer-review report classification\n\nGrade A (Excellent): A\n\nGrade B (Very good): B\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nInformed consent statement: Written informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nConflict-of-interest statement: The authors declare no conflict-of-interest.\n\nPeer-review started: March 16, 2017\n\nFirst decision: May 12, 2017\n\nArticle in press: July 12, 2017\n\nP- Reviewer: Koch TR, Nakano H, Tziomalos K S- Editor: Qi Y L- Editor: A E- Editor: Huang Y\n==== Refs\n1 Colagrande S Centi N Galdiero R Ragozzino A Transient hepatic intensity differences: part 1, Those associated with focal lesions AJR Am J Roentgenol 2007 188 154 159 17179358 \n2 Choi BI Lee KH Han JK Lee JM Hepatic arterioportal shunts: dynamic CT and MR features Korean J Radiol 2002 3 1 15 11919473 \n3 Ahn JH Yu JS Hwang SH Chung JJ Kim JH Kim KW Nontumorous arterioportal shunts in the liver: CT and MRI findings considering mechanisms and fate Eur Radiol 2010 20 385 394 19657644 \n4 Matsuo M Kanematsu M Kondo H Maeda S Goshima S Suenaga I Hoshi H Arterioportal shunts mimicking hepatic tumors with hyperintensity on T2-weighted MR images J Magn Reson Imaging 2002 15 330 333 11891979 \n5 Tian JL Zhang JS Hepatic perfusion disorders: etiopathogenesis and related diseases World J Gastroenterol 2006 12 3265 3270 16718850 \n6 Uchino K Fujisawa M Watanabe T Endo Y Nobuhisa T Matsumoto Y Kai K Sato S Notohara K Matsukawa A Oxaliplatin-induced liver injury mimicking metastatic tumor on images: a case report Jpn J Clin Oncol 2013 43 1034 1038 23958518 \n7 Choi JH Won YW Kim HS Oh YH Lim S Kim HJ Oxaliplatin-induced sinusoidal obstruction syndrome mimicking metastatic colon cancer in the liver Oncol Lett 2016 11 2861 2864 27073565 \n8 Arakawa Y Shimada M Utsunomya T Imura S Morine Y Ikemoto T Hanaoka J Sugimoto K Bando Y Oxaliplatin-related sinusoidal obstruction syndrome mimicking metastatic liver tumors Hepatol Res 2013 43 685 689 23730707 \n9 Lawal TO Farris AB El-Rayes BF Subramanian RM Kim HS Oxaliplatin-induced hepatoportal sclerosis, portal hypertension, and variceal bleeding successfully treated with transjugular intrahepatic portosystemic shunt Clin Colorectal Cancer 2012 11 224 227 22537609 \n10 Slade JH Alattar ML Fogelman DR Overman MJ Agarwal A Maru DM Coulson RL Charnsangavej C Vauthey JN Wolff RA Portal hypertension associated with oxaliplatin administration: clinical manifestations of hepatic sinusoidal injury Clin Colorectal Cancer 2009 8 225 230 19822514 \n11 Vauthey JN Pawlik TM Ribero D Wu TT Zorzi D Hoff PM Xiong HQ Eng C Lauwers GY Mino-Kenudson M Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases J Clin Oncol 2006 24 2065 2072 16648507 \n12 Rubbia-Brandt L Lauwers GY Wang H Majno PE Tanabe K Zhu AX Brezault C Soubrane O Abdalla EK Vauthey JN Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis Histopathology 2010 56 430 439 20459550 \n13 Robinson SM Mann J Vasilaki A Mathers J Burt AD Oakley F White SA Mann DA Pathogenesis of FOLFOX induced sinusoidal obstruction syndrome in a murine chemotherapy model J Hepatol 2013 59 318 326 23624001 \n14 Yeong ML Wakefield SJ Ford HC Hepatocyte membrane injury and bleb formation following low dose comfrey toxicity in rats Int J Exp Pathol 1993 74 211 217 8499322 \n15 Ryan P Nanji S Pollett A Moore M Moulton CA Gallinger S Guindi M Chemotherapy-induced liver injury in metastatic colorectal cancer: semiquantitative histologic analysis of 334 resected liver specimens shows that vascular injury but not steatohepatitis is associated with preoperative chemotherapy Am J Surg Pathol 2010 34 784 791 20421779 \n16 Litvak DA Malad S Wascher RA Markman M Niu J Laparoscopic Splenectomy in Colorectal Cancer Patients with Chemotherapy-Associated Thrombocytopenia due to Hypersplenism Case Rep Oncol 2012 5 601 607 23275773\n\n",
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"journal": "World journal of gastroenterology",
"keywords": "Arterioportal shunt; Liver; Oxaliplatin; Recurred cancer; Transient hepatic attenuation differences",
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"title": "Arterioportal shunt incidental to treatment with oxaliplatin that mimics recurrent gastric cancer.",
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"abstract": "Patients presenting with psychiatric symptoms, even in cases where there is no clear psychiatric history, are often labeled as having \"psychogenic\" symptoms or a psychosomatic reaction, and a tendency does exist to mislabel and/or misdiagnose certain patients in medical settings. The 3 cases presented in this issue of the Journal provide examples of patients presenting with psychotic or manic symptoms in the context of an underlying nonpsychiatric medical disorder. Kim and colleagues describe the case of a 65-year-old man with no psychiatric history who presented with acute visual hallucinations 1 day after starting omeprazole for gastroesophageal reflux. The visual hallucinations resolved immediately after the medication was stopped. Fipps and Rainey describe the case of a 74-year-old man with chronic generalized anxiety who presented with severe panic and suicidal thinking as well as refractory nausea that were unresponsive to benzodiazepine treatment and to a taper of the benzodiazepine. This patient was later found to have a subdural hematoma that was causing what had at first been suspected to be psychogenic nausea. Finally, Das and Brasseux present the case of a 23-year-old man hospitalized from jail who presented with manic symptoms; this patient was found to have had a traumatic brain injury 2 months earlier and, on brain imaging, was also found to have had a perinatal brain injury. The patient responded to mood stabilizers and the off-label use of memantine for his cognitive deficits. These 3 cases highlight the importance of obtaining a comprehensive neurological and medical history and, if indicated, workup, in cases involving patients with atypical presentations or nonresponse to traditional treatments.",
"affiliations": "GARAKANI: Department of Psychiatry and Behavioral Health, Greenwich Hospital, Greenwich, CT; Department of Psychiatry, Yale University School of Medicine, New Haven, CT.",
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"mesh_terms": "D000328:Adult; D000368:Aged; D001569:Benzodiazepines; D006801:Humans; D008297:Male; D001523:Mental Disorders; D055815:Young Adult",
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"title": "Commentary: Psychiatric Presentations of Nonpsychiatric Illness or Treatment.",
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"abstract": "Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is the most Serious Cutaneous Adverse Reaction (SCAR) often with a fatal outcome. Coronavirus Disease (COVID-19) is caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-COV2) and is an emergent pandemic for which no cure exist at the moment. Several drugs have been tried often with scant clinical evidence and safety.\nHere we report the case of 78-years-old woman with cardiometabolic syndrome and COVID-19. A multidrug regimen including others hydroxychloroquine, antibiotics, dexamethasone and paracetamol, low-molecular-weight-heparin and potassium canrenoate was started. After almost 3 weeks, the patient started to display a violaceous rash initially involving the flexural folds atypical targetoid lesions and showing a very fast extension, blister formation and skin detachments of approximately 70% of the total body surface area and mucous membranes involvement consistent with toxic epidermal necrolysis (TEN). The ALDEN algorithm was calculated inserting all drugs given to the patient in the 28 days preceding the onset of the skin manifestations. The highest score retrieved was for hydroxychloroquine. Other less suspicious drugs were piperacillin/tazobactam, ceftriaxone and levofloxacin.\nTo our knowledge, this is the first case of TEN in a patient suffering from COVID-19 probably associated with hydroxychloroquine. Given the activation of the immune system syndrome induced by the virus and the widespread off-label use of this drug, we suggest a careful monitoring of skin and mucous membranes in all COVID-19 positive patients treated with hydroxychloroquine in order to early detect early signs of toxicities.",
"affiliations": "Dipartimento di Area Medica, U.O. Medicina Interna, ASST Nord Milano, Ospedale Edoardo Bassini, Via Massimo Gorki 50, 20092 Cinisello Balsamo (MI), Italy.;Scuola di Specializzazione in Farmacia Ospedaliera, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milan, MI Italy.;Dipartimento di Area Medica, U.O. Medicina Interna, ASST Nord Milano, Ospedale Edoardo Bassini, Via Massimo Gorki 50, 20092 Cinisello Balsamo (MI), Italy.;Dipartimento di Area Medica, U.O. Medicina Interna, ASST Nord Milano, Ospedale Edoardo Bassini, Via Massimo Gorki 50, 20092 Cinisello Balsamo (MI), Italy.;U.O.C. Farmacia Interna, ASST Nord Milano, Ospedale Edoardo Bassini, Via Massimo Gorki 50, 20092 Cinisello Balsamo (MI), Italy.",
"authors": "Rossi|Carlo Maria|CM|;Beretta|Flavio Niccolò|FN|0000-0002-4214-6230;Traverso|Grazia|G|;Mancarella|Sandro|S|;Zenoni|Davide|D|",
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"doi": "10.1186/s12948-020-00133-6",
"fulltext": "\n==== Front\nClin Mol Allergy\nClin Mol Allergy\nClinical and Molecular Allergy : CMA\n1476-7961\nBioMed Central London\n\n133\n10.1186/s12948-020-00133-6\nCase Report\nA case report of toxic epidermal necrolysis (TEN) in a patient with COVID-19 treated with hydroxychloroquine: are these two partners in crime?\nRossi Carlo Maria carlomariarossi@hotmail.com\n\n1\nhttp://orcid.org/0000-0002-4214-6230\nBeretta Flavio Niccolò flavioniccolo.beretta@gmail.com\n\n2\nTraverso Grazia grazia.traverso@asst-nordmilano.it\n\n1\nMancarella Sandro sandro.mancarella@asst-nordmilano.it\n\n1\nZenoni Davide davide.zenoni@asst-nordmilano.it\n\n3\n1 grid.432778.d Dipartimento di Area Medica, U.O. Medicina Interna, ASST Nord Milano, Ospedale Edoardo Bassini, Via Massimo Gorki 50, 20092 Cinisello Balsamo (MI), Italy\n2 grid.4708.b 0000 0004 1757 2822 Scuola di Specializzazione in Farmacia Ospedaliera, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milan, MI Italy\n3 grid.432778.d U.O.C. Farmacia Interna, ASST Nord Milano, Ospedale Edoardo Bassini, Via Massimo Gorki 50, 20092 Cinisello Balsamo (MI), Italy\n6 10 2020\n6 10 2020\n2020\n18 1928 5 2020\n31 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\nStevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is the most Serious Cutaneous Adverse Reaction (SCAR) often with a fatal outcome. Coronavirus Disease (COVID-19) is caused by Severe Acute Respiratory Syndrome–Coronavirus—2 (SARS-COV2) and is an emergent pandemic for which no cure exist at the moment. Several drugs have been tried often with scant clinical evidence and safety.\n\nCase presentation\n\nHere we report the case of 78-years-old woman with cardiometabolic syndrome and COVID-19. A multidrug regimen including others hydroxychloroquine, antibiotics, dexamethasone and paracetamol, low-molecular-weight-heparin and potassium canrenoate was started. After almost 3 weeks, the patient started to display a violaceous rash initially involving the flexural folds atypical targetoid lesions and showing a very fast extension, blister formation and skin detachments of approximately 70% of the total body surface area and mucous membranes involvement consistent with toxic epidermal necrolysis (TEN). The ALDEN algorithm was calculated inserting all drugs given to the patient in the 28 days preceding the onset of the skin manifestations. The highest score retrieved was for hydroxychloroquine. Other less suspicious drugs were piperacillin/tazobactam, ceftriaxone and levofloxacin.\n\nConclusions\n\nTo our knowledge, this is the first case of TEN in a patient suffering from COVID-19 probably associated with hydroxychloroquine. Given the activation of the immune system syndrome induced by the virus and the widespread off-label use of this drug, we suggest a careful monitoring of skin and mucous membranes in all COVID-19 positive patients treated with hydroxychloroquine in order to early detect early signs of toxicities.\n\nKeywords\n\nCOVID 19\nSARS-CoV- 2\nToxic Epidermal Necrolysis (TEN)\nHydroxychloroquine\nSevere Cutaneous Adverse Reactions (SCAR)\nAdverse Drug Reaction (ADR)\nStevens–Johnson Syndrome (SJS)\nALDEN Algorithm\nSCORTEN Score\nPharmacovigilance\nissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\n\nToxic Epidermal Necrolysis (TEN) is a rare Serious Cutaneous Adverse Reaction (SCAR). It displays an acute onset and is characterized by erythematous or violaceous patches, atypical targetoid lesions, bullae, erosions and skin detachment. It differs from Stevens-Johnson Syndrome (SJS) only in the percentage of skin involvement, which in TEN is greater than 30% of the body surface [1]. Etiopathogenetically, it results from the combination of drug and host genetic factors (such as drug metabolism and T cell clonotypes) resulting in a delayed-type hypersensitivity reaction, where drug or drug-peptide complexes are recognized by T cell receptors [2].\n\nCoronavirus Disease (COVID-19) is caused by Severe Acute Respiratory Syndrome–Coronavirus—2 (SARS-CoV-2) and can be potentially fatal disease [3]. The most common symptoms at onset of COVID-19 illness are fever, cough, and fatigue, followed by dyspnea and diarrhea [4]. Lymphopenia, elevation of creatinine kinase (CK), lactate dehydrogenase (LDH) are also frequently observed. The lung involvement is frequently that of an interstitial pneumonia, COVID-19 later shows an over exuberant inflammatory response with a no correlation between viral load and the worsening of symptoms [5].\n\nAt the moment there is no effective cure for COVID-19, several drugs often in combination have been used, often with scant clinical evidence or conflicting results, with the aim of targeting the virus replication and/or the inflammatory process, such as anti-retrovirals, macrolides, hydroxychloroquine and monoclonal antibodies targeted on inflammatory cytokines [6–9]. There is limited data establishing their safety profile during SARS-CoV-2 infection.\n\nCase presentation\n\nHere we report the case of 78-year old woman with several comorbidities (hypertension, obesity, unstable angina, type 2 diabetes) admitted to our hospital for respiratory insufficiency with fever requiring non-invasive ventilation and a diagnosis of COVID-19 lung infection with bacterial superinfection was formulated given the radiological evidence of a bilateral interstitial pneumonia, the positivity of nasopharyngeal swab for SARS-CoV-2 and (Fig. 1). Lymphopenia (0.55 103/µL [1.00–4.00]), elevation of CK (252 U/L [24–170]) and LDH (407 U/L [30–250]) were also observed.Fig. 1 The X-ray shows bilateral and extensive interstitial infiltrates\n\nA multidrug regimen with hydroxychloroquine 200 mg twice a day, sodium enoxaparin and dexamethasone were started. Besides, an antibiotic treatment with ceftriaxone for 1 day, followed by piperacillin/tazobactam for 4 days was given. The patient was initially treated in a sub-intensive care unit and after the favorable clinical evolution was transferred to our general medicine division, 18 days after the admission. At the arrival in our unit, the patient started to display a violaceous erythematous rash mainly involving the flexural folds. The patient was still taking hydroxychloroquine, along with levofloxacin (started the day before); other drugs were reported in Table 1.Table 1 Calculation of the ALDEN score for each drug administrated during the hospitalization (chronic treatments were excluded) [10]\n\nDRUG\tALDEN score\tCausal link\t\nEnoxaparin\t−2\tVery unlikelya\t\nOseltamivir\t−2\tVery unlikely\t\nCeftriaxone\t+1\tUnlikely\t\nPotassium Canrenoate\t−3\tVery unlikely\t\nPantoprazole\t−2\tVery unlikelya\t\nHydroxychloroquine\t+4\tPossible\t\nPiperacillin/Tazobactam\t+1\tUnlikely\t\nDexamethasone\t0\tUnlikely\t\nLevofloxacin\t+1\tUnlikely\t\nParacetamol\t−1\tVery unlikelya\t\n < 0: very unlikely\n\n0–1: unlikely\n\n2–3: possible\n\n4–5: probable\n\n ≥ 6: very probable\n\nare-challenge without any adverse reactions. Score (−12; +10)\n\nThe rash presented in the course of 3 days a rapid extension with the involvement of the whole trunk and buttocks, reaching approximately 70% of the total body surface area, with the appearance of atypical targetoid lesions and the formation of blisters, with subsequent skin detachment (Figs. 2, 3 and 4). Nikolsky’s sign was present. A severe desquamation of the buccal and nasal mucosa was also observed. The patient referred severe skin pain requiring morphine. Blood tests did not show eosinophilia or alterations of liver and renal function tests.Fig. 2 The violaceous rash extension with atypical targetoid elements (at day 3 from clinical onset) is depicted in a. b shows the complete resolution (after 6 weeks)\n\nFig. 3 The extensive skin detachment is showed in a (at day 5) and its favorable evolution at 6 weeks in (b)\n\nFig. 4 The figure shows the extensive disepithelialization with subcutaneous oozing and bleeding\n\nA clinical diagnosis of toxic epidermal necrolysis (TEN) also confirmed by the dermatologist was formulated. Methylprednisone 1 mg/kg, as an intravenous bolus regiment was administred along with intravenous immunoglobulin (IVIG) 1 mg/kg for 3 days. Then oral prednisone 1 mg/kg daily was given and subsequently tapered in 1 month.\n\nTo identify the culprit drug, the ALDEN algorithm was calculated (Table 1) [10] (Additional file 1). The highest score retrieved was for hydroxychloroquine, with a possible correlation (+4 score). Other less suspicious drugs were piperacillin/tazobactam, ceftriaxone and levofloxacin. All suspected drugs according to the ALDEN algorithm were promptly stopped (Additional file 2).\n\nThe patient was cared for by the wound care service of the hospital with topical therapy, a marked improvement in the skin conditions was observed progressively over a period of 6 weeks, until the complete resolution (Figs. 2 and 3). Paracetamol, pantoprazole, enoxaparin were tolerated after the reaction, ruling out their correlation with the skin reaction.\n\nDue to the COVID-19 epidemic, no skin biopsies were technically feasible for logistical problems. However, the clinical manifestations were highly compelling for SJS/TEN. Other differential diagnosis included Drug-Reaction with Eosinophilia and Systemic Symptoms (DRESS), which was excluded given the absence of eosinophilia and internal organ involvement, Staphylococcal Scalded Skin Syndrome (SSSS), which is a pediatric form, and bullous dermatoses that were ruled out in our case given the minor mucous involvement and intense skin inflammation.\n\nDiscussion\n\nSJS/TEN is the most severe SCAR being associated with a high mortality rate [1]. It is a delayed reaction occurring after 4–28 days from drug exposure, therefore it is of paramount importance to acquire precise retrospective pharmacological information for a long period of time preceding the onset of skin manifestations.\n\nSTS/TEN has an approximate incidence of 1 or 2 cases/1,000,000 annually. It results from the clonal expansion of CD8 + cytotoxic T lymphocytes (CTLs) and Natural Killer cell (NK),which are major histo-compatibility complex (MHC)-restricted and induce epidermal apoptosis [1, 11, 12]. Recently, it has been shown that low molecular weight drugs can directly bind the T cell receptor (TCR) of T cells or the Human Leukocyte Antigen (HLA) of antigen-presenting cells [13–16].\n\nUsually implicated drugs are allopurinol, anticonvulsant drugs nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics such as cephalosporins, aminopenicillins and rarely macrolides, as shown in the EuroSCAR study, together with the REACT project and the regiSCAR project [17–21].\n\nThe ALDEN algorithm represents the gold standard tool in SJS/TEN to identify the culprit drug and to discriminate it from the “innocent” drugs which can be safely administered. It gives to each drug taken by patient a score, ranging from −12 to +10, which corresponds to the probability of having caused the reaction, ranging from very unlikely to very probable [10]. Besides, from a recent analysis a significant statistic for agreement (kappa 0.571) was found between ALDEN score for related-drugs (ALDEN ≥ 4) and lymphocyte transformation test (LTT) results performed after recovery [22].\n\nAccording to the ALDEN algorithm results, the most likely implicated drug in our case is hydroxychloroquine.\n\nHydroxychloroquine is an 4-aminoquinoline with a low molecular weight (333,9 Da) [23–26]. It has been used for decades to treat rheumatologic conditions (with a dose of 6 mg/kg) with a general good safety, even though in last years cases of skin reactions, also severe, have increasingly been reported [27].\n\nWe searched the Eudravigilance database and found 30 cases of TENs related to the use of hydroxychloroquine [28].\n\nHydroxychloroquine is being profusely used to treat SARS-CoV-2 infection with an unconventionally high dosage (from 200 mg twice a day to 200 mg three times a day, which is independent of body weight sometimes with a loading dose, due to its high volume of distribution).\n\nInterestingly, some new severe skin manifestation to hydroxychloroquine have also been reported during the treatment of SARS-CoV-2 positive patient [29–31].\n\nIn this instance, it is not to be discounted that a rare side effect, such as TEN, occurring with a not commonly associated drug, hydroxychloroquine, could have been favored by the particular immune stimulation induced by the virus SARS-CoV-2 [3]. SJS/TEN, and SCAR more generally, have been classically demonstrated to be associated with viral replication [11, 32–34].\n\nTo our knowledge, this is the first case of TEN in a COVID-19 positive patient.\n\nAnother salient aspect of the case is the favorable evolution of the patient given that this type of SCAR is typically associated with a bad prognosis [35–37], even more so because the patient displayed all the negative typical prognostic factors also for COVID-19 [38–41], indeed the calculation of the severity-of-illness score for toxic epidermal necrolysis (SCORTEN) in our patient led to an estimated mortality rate of 58.3% (CI 36,6 –77,59) (Table 2) [42, 43].Table 2 Calculation of the Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN) in our patient\n\nRisk factor\tScore\tPatient score\t\n0\t1\t\nAge\t< 40 years\t> 40 years\t1\t\nAssociated malignancy*\tNo\tYes\t0\t\nHeart rate (beats/min)\t< 120\t≥ 120\t1\t\nSerum urea (mg/dL) [mmol/L]\t≤ 28 [10]\t> 28 [10]\t1\t\nDetached or compromised body surface\t< 10%\t≥ 10%\t1\t\nSerum bicarbonate (mEq/L)\t≥ 20\t< 20\t0\t\nSerum glucose (mg/dL) [mmol/L]\t≤ 250 [14]\t> 250 [14]\t0\t\nTotal\t\t\t4\t\nMore risk factors result in a higher score and a higher mortality rate (%) as follows:\n\n0–1 = 3.2% (CI: 0.1-16.7)\n\n2 = 12.1% (CI: 5.4-22.5)\n\n3 = 35.5% (CI: 19.8-53.5)\n\n4 = 58.3% (CI: 36.6-77.9)\n\n≥5 = 90% (CI: 55.5-99.8)\n\n CI: Confidence Interval [42, 43]\n\naMalignancy: evolving cancer and hematological malignancies\n\nIt is possible that the prompt diagnosis of TEN, the suspension of all the suspected drugs (in particularly hydroxychloroquine) and the administration of steroid and IVIG, both targeting the inflammatory syndrome initially triggered by the virus, may have had contributed to a better prognosis, [1, 5].\n\nFurther studies are needed to assess the safety profile of hydroxychloroquine in patients with COVID-19.\n\nConclusion\n\nTo our knowledge, this is the first case of TEN associated with hydroxychloroquine in patient suffering from COVID-19. Given the widespread off-label use of this drug, the high degree of immune activation induced by the virus and the recent increase of hydroxychloroquine-related SCARs, we believe that it is necessary to adequately monitor the skin in all COVID-19 positive patients treated with hydroxychloroquine in order to early detect early signs of toxicities.\n\nSupplementary information\n\nAdditional file 1: Details regarding the calculation of the ALDEN score [10].\n\nAdditional file 2: Timing of the drugs administered to the patients regarding the calculation of the ALDEN score [10].\n\nAbbreviations\n\nCK Creatinine Kinase\n\nCOVID-19 COronaVIrus Disease 19\n\nCTLs Cytotoxic T Lymphocytes\n\nDRESS Drug Reaction with Eosinophilia and Systemic Symptoms\n\nHLA Human Leukocyte Antigen\n\nIVIG IntraVenous Immunoglobulin\n\nLDH Lactate Dehydrogenase\n\nLTT Lymphocyte Transformation Test\n\nMHC Major Histocompatibility Complex\n\nNK Natural Killer\n\nNSAIDs NonSteroidal Anti-Inflammatory Drugs\n\nSARS-CoV-2 Severe Acute Respiratory Syndrome– - Coronavirus—2\n\nSCAR Severe Cutaneous Adverse Reaction\n\nSCORTEN Severity-of-illness Score for Toxic Epidermal Necrolysis\n\nSSSS Staphylococcal Scalded Skin Syndrome\n\nSJS Stevens Johnson Syndrome\n\nTCR T-Cell Receptor\n\nTEN Toxic Epidermal Necrolysis\n\nSupplementary information\n\nSupplementary information accompanies this paper at 10.1186/s12948-020-00133-6.\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nCMR and FNB collected data. CMR and FNB wrote the draft paper and analyzed the data. CMR, GT and SM followed clinical course of the patient. DZ revised the draft paper. All authors read and approved the final manuscript.\n\nFunding\n\nThe authors declare that they have not received any funding.\n\nAvailability of data and materials\n\nNot applicable.\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nInformed consent to clinical data collection and publication was obtained from the patient.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\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. Harr T French LE Toxic epidermal necrolysis and Stevens-Johnson syndrome Orphanet J Rare Dis 2010 10.1186/1750-1172-5-39 21162721\n2. 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Impatto dell’epidemia covid-19 sulla mortalità totale della popolazione residente primo trimestre 2020. https://www.epicentro.iss.it/coronavirus/pdf/Rapporto_Istat_ISS.pdf. Accessed 15 May 2020.\n40. D. P. C. DipartimentoProtezione Civile. COVID-19: Monitoraggio della situazione. 2020. http://opendatadpc.maps.arcgis.com/apps/opsdashboard/index.html#/b0c68bce2cce478eaac82fe38d4138b1. Accessed 15 May 2020.\n41. Guan WJ Clinical characteristics of coronavirus disease 2019 in China N Engl J Med 2019 10.1056/NEJMoa2002032\n42. Guégan S Bastuji-Garin S Poszepczynska-Guigné E Roujeau JC Revuz J Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of epidermal necrolysis J Invest Dermatol 2006 10.1038/sj.jid.5700068 16374466\n43. Bastuji-Garin S Fouchard N Bertocchi M Roujeau JC Revuz J Wolkenstein P Scorten: a severity-of-illness score for toxic epidermal necrolysis J Invest Dermatol 2000 10.1046/j.1523-1747.2000.00061.x 10951229\n\n",
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"journal": "Clinical and molecular allergy : CMA",
"keywords": "ALDEN Algorithm; Adverse Drug Reaction (ADR); COVID 19; Hydroxychloroquine; Pharmacovigilance; SARS-CoV- 2; SCORTEN Score; Severe Cutaneous Adverse Reactions (SCAR); Stevens–Johnson Syndrome (SJS); Toxic Epidermal Necrolysis (TEN)",
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"title": "A case report of toxic epidermal necrolysis (TEN) in a patient with COVID-19 treated with hydroxychloroquine: are these two partners in crime?",
"title_normalized": "a case report of toxic epidermal necrolysis ten in a patient with covid 19 treated with hydroxychloroquine are these two partners in crime"
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"abstract": "Pulmonary hypertension (PH) after heart transplantation (HT) is associated to right ventricular (RV) dysfunction and increased morbidity and mortality. We present our experience with bosentan for the treatment of PH after HT.\n\n\n\nA retrospective evaluation of patients with PH receiving bosentan post-transplant was performed. Pulmonary hemodynamics before and after bosentan (BG) and clinical outcomes were assessed and compared to a historical control group (CG) not receiving bosentan.\n\n\n\nBetween 2013 and 2016, 21 patients were treated post-transplant with bosentan. Twenty-four hours after bosentan initiation, there were significant decreases in systolic (42.5 ± 8 to 38.1 ± 8 mm Hg, P = 0.015), diastolic (21.4 ± 4 to 17.8 ± 6 mm Hg, P = 0.008) and mean (29.6 ± 5 to 25 ± 6 mm Hg, P = 0.001) pulmonary artery pressures (PAP), transpulmonary gradient (13.1 ± 3 to 9.7 ± 4 mm Hg, P < 0.001), diastolic gradient (5.2 ± 4 to 2.3 ± 3 mm Hg, P = 0.001) and pulmonary vascular resistance (PVR) (2.2 ± 1 to 1.6 ± 1WU, P = 0.015). This effect was maintained at day 3. Compared with CG, BG showed significantly more decrease in PVR (0.7 ± 0.9 vs 0.3 ± 1.7WU, P = 0.025) and mean PAP (4.6 ± 5.2 vs 1.5 ± 4.4 mm Hg, P = 0.040). RV function 7 days post-transplant was significantly better in BG compared to CG, P = 0.004. There were not clinically significant interactions between bosentan and immunosuppressive treatment.\n\n\n\nBosentan, initiated early post-transplant, was associated with a significant decrease in PVR. Bosentan was well tolerated and did not interact with immunosuppressive treatment.",
"affiliations": "Heart Failure and Heart Transplantation Unit, Cardiovascular Institute, Hospital Clinic, Barcelona, Spain.;Heart Failure and Heart Transplantation Unit, Cardiovascular Institute, Hospital Clinic, Barcelona, Spain.;Heart Failure and Heart Transplantation Unit, Cardiovascular Institute, Hospital Clinic, Barcelona, Spain.;Heart Failure and Heart Transplantation Unit, Cardiovascular Institute, Hospital Clinic, Barcelona, Spain.;Heart Failure and Heart Transplantation Unit, Cardiovascular Institute, Hospital Clinic, Barcelona, Spain.;Medical Statistics Core Facility, August Pi and Sunyer Biomedical Research Institute (IDIBAPS), Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.;Heart Failure and Heart Transplantation Unit, Cardiovascular Institute, Hospital Clinic, Barcelona, Spain.",
"authors": "Santiago-Vacas|Evelyn|E|;Farrero|Marta|M|0000-0002-2404-8821;Ivey-Miranda|Juan B|JB|;Castel|Maria Ángeles|MÁ|;García-Álvarez|Ana|A|;Rios|José|J|;Perez-Villa|Felix|F|0000-0001-9244-938X",
"chemical_list": "D000959:Antihypertensive Agents; D000077300:Bosentan",
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"keywords": "bosentan; heart transplant; pulmonary hypertension; right ventricular dysfunction",
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"mesh_terms": "D000959:Antihypertensive Agents; D000077300:Bosentan; D019468:Disease Management; D005260:Female; D005500:Follow-Up Studies; D016027:Heart Transplantation; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D018497:Ventricular Dysfunction, Right",
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"title": "Initial experience with bosentan for the management of pulmonary hypertension after heart transplantation.",
"title_normalized": "initial experience with bosentan for the management of pulmonary hypertension after heart transplantation"
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"abstract": "OBJECTIVE\nThe aim of the study was to describe the successful treatment of delirium with electroconvulsive therapy (ECT).\n\n\nMETHODS\nThe method of the study was a case report.\n\n\nRESULTS\nA 75-year-old man, with a recently diagnosed carcinoma of the parotid gland, was admitted with a fluctuating psychiatric syndrome. Delirium was diagnosed, although an acute underlying somatic cause could not be readily established. Antipsychotics and benzodiazepines were not effective. After 7 sessions of ECT, all symptoms ceased. This enabled him to receive radiotherapy for his tumor and enjoy a good quality of life for the remaining 8 months of his life.\n\n\nCONCLUSIONS\nElectroconvulsive therapy is not only a powerful treatment for catatonia, neuroleptic malignant syndrome, and delirious mania but also for the most commonly occurring fluctuating psychiatric syndrome--delirium.",
"affiliations": "From the *Department of Psychiatry, Rijnstate Hospital, Arnhem; †Department of Old Age Psychiatry, Pro Persona, Wolfheze; and ‡University Center of Psychiatry and Interdisciplinary Center for Psychopathology of Emotion Regulation, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.",
"authors": "van den Berg|Karen S|KS|;Marijnissen|Radboud M|RM|;van Waarde|Jeroen A|JA|",
"chemical_list": "D014150:Antipsychotic Agents",
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"mesh_terms": "D000368:Aged; D014150:Antipsychotic Agents; D002100:Cachexia; D003693:Delirium; D004565:Electroconvulsive Therapy; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D010259:Paranoid Disorders; D010307:Parotid Neoplasms; D011788:Quality of Life; D016896:Treatment Outcome",
"nlm_unique_id": "9808943",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Electroconvulsive Therapy as a Powerful Treatment for Delirium: A Case Report.",
"title_normalized": "electroconvulsive therapy as a powerful treatment for delirium a case report"
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"abstract": "The systemic toxicity of lidocaine is an extremely rare complication of thyroid RFA procedure, and it can be life-threatening. The quick recognization of its symptoms and intravenous use of lipid emulsion are essential to preventing mortality.",
"affiliations": "Center of Endocrinology and Diabetes Family Hospital Da Nang Vietnam.;Center of Endocrinology and Diabetes Family Hospital Da Nang Vietnam.;Center of Endocrinology and Diabetes Family Hospital Da Nang Vietnam.;Department of Internal Medicine Hue University of Medicine and Pharmacy Hue University Hue City Vietnam.",
"authors": "Nguyen|Van Bang|VB|https://orcid.org/0000-0003-2488-3496;Nguyen|Van Vy Hau|VVH|;Tuyen|Linh Pham Nguyen|LPN|;Le|Chi Van|CV|https://orcid.org/0000-0001-5595-044X",
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"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4910\nCCR34910\nCase Report\nCase Report\nLidocaine‐induced systemic toxicity complicating radiofrequency ablation of benign thyroid nodule procedure: A case report and review of literature\nNGUYEN et al.\nNguyen Van Bang https://orcid.org/0000-0003-2488-3496\n1\nNguyen Van Vy Hau 1\nTuyen Linh Pham Nguyen 1\nLe Chi Van https://orcid.org/0000-0001-5595-044X\n2 lvanchi@hueuni.edu.vn\n\n1 Center of Endocrinology and Diabetes Family Hospital Da Nang Vietnam\n2 Department of Internal Medicine Hue University of Medicine and Pharmacy Hue University Hue City Vietnam\n* Correspondence\nChi Van Le, Department of Internal Medicine, Hue University of Medicine and Pharmacy, Hue University, No. 06 Ngo Quyen Str., Hue city, Vietnam.\nEmail: lvanchi@hueuni.edu.vn\n\n10 10 2021\n10 2021\n9 10 10.1002/ccr3.v9.10 e0491026 8 2021\n20 9 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nThe systemic toxicity of lidocaine is an extremely rare complication of thyroid RFA procedure, and it can be life‐threatening. The quick recognization of its symptoms and intravenous use of lipid emulsion are essential to preventing mortality.\n\nThe systemic toxicity of lidocaine is an extremely rare complication of thyroid RFA procedure, and it can be life‐threatening. The quick recognization of its symptoms and intravenous use of lipid emulsion are essential to preventing mortality.\n\ncase report\nlidocaine‐induced systemic toxicity\nradiofrequency ablation\nthyroid nodules\nsource-schema-version-number2.0\ncover-dateOctober 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.8 mode:remove_FC converted:10.10.2021\nNguyen VB , Nguyen VVH , Tuyen LPN , Le CV . Lidocaine‐induced systemic toxicity complicating radiofrequency ablation of benign thyroid nodule procedure: A case report and review of literature. Clin Case Rep. 2021;9 :e04910. 10.1002/ccr3.4910\n\nFunding information\n\nNot applicable\n==== Body\npmc1 INTRODUCTION\n\nThis study describes a patient with lidocaine‐induced systemic toxicity during radiofrequency ablation of benign thyroid nodule procedure. The quick symptom recognization and intravenous lipid emulsion treatment are cornerstone to prevent mortality. This report emphasizes and discusses an extremely rare complication of thyroid RFA procedure.\n\nIn recent years, radiofrequency ablation (RFA) has been emerging as one of the treatments of thyroid nodule(s). Theoretically, the RFA procedure usually used 2 basic techniques including the moving‐shot technique and the trans‐isthmic approach with the guidance of ultrasonography (US) after local anesthesia with 2% lidocaine at the needle‐puncture site and thyroid capsule. 1 , 2 To relieve pain, this procedure required a large amount of 2% lidocaine which could reach 25 ml in volume. 3\n\nSystemic toxicity from using lidocaine, particularly in RFA procedure, is extremely scarce, but can reduce the effectiveness of treatment and even be potentially life‐threatening due to its toxic manifestations to the central nervous system (CNS) and cardiovascular system (CVS). 3 , 4 , 5 To the best of our knowledge, there are few reports of lidocaine‐induced systemic toxicity during thyroid RFA procedure in the literature. This report aims to describe a case of lidocaine‐induced systemic toxicity in a healthy 48‐year‐old female who underwent an RFA procedure for benign thyroid nodule at an outpatient clinic and to raise awareness among endocrinologists/surgeons/radiologists using RFA for the treatment of thyroid nodule(s) to identify and manage patients with lidocaine toxicity.\n\n2 CASE PRESENTATION\n\nA 48‐year‐old South African woman presented with a left neck mass for 1 year with cosmetic concerns and no compressive symptoms. She reported no significant history of cardiovascular disease, and no history of food or drug allergies. No family history of any thyroid diseases and any allergies was reported. She was admitted to the hospital for a tentative thyroid radiofrequency ablation.\n\nHer body mass index was 24.5 kg/m2 (weight 66.7 kg; height 165 cm), and her blood pressure, heartbeat, SpO2, and body temperature were normal (113/71 mmHg, 70 beats/min, 96%, and 37.2°C, respectively). On physical examination, there was a soft mass in the left thyroid lobe, which was moving on swallowing (Figure 1A). Her report was no compressive symptoms, with a symptom score of 5/10 on a visual analog scale and a cosmetic score of ¾. The physical examination of heart, lung, abdomen, and CNS was normal.\n\nFIGURE 1 A 48‐year‐old South African woman presented with a left neck mass. (A) A soft mass in the left thyroid lobe, which was moving on swallowing (yellow arrow). (B) A single, mixed echogenicity mass on the left thyroid lobe, with no calcification, no vascularity, and no lymph node involvement. (C) Injecting 10ml of 2% lidocaine at the peri‐thyroidal area under ultrasound guidance (red arrow)\n\nBefore the procedure, thyroid function tests (FT4, thyrotropin) and other tests (CBC, liver, and renal function tests, prothrombin time) were normal with serum FT4 1.16 ng/dl (normal range [NR] 0.93–2.22); thyrotropin 4.17 microUI/ml (NR 0.27–4.2); prothrombin time 111%, and INR 1.0. Her chest X‐ray showed no abnormal findings. ECG showed normal sinus rhythm at a rate of 73 bpm. The thyroid ultrasonography showed a single, mixed echogenicity mass (cystic part of 50%) on the left thyroid lobe, with no calcification, no vascularity, and no lymph node involvement (Figure 1B). Nodule volume was 6.2 ml (W × H × D: 22.8 × 20.1 × 25.7 mm). 2 separate FNAs of the thyroid nodule revealed a colloid nodular hyperplasia with hyperplastic thyrocytes and fluid colloid (Bethesda II) affirmed the diagnosis of the large benign thyroid nodule. Because of her fear of surgery complications, we proposed RFA of the nodule.\n\nIn a preliminary assessment, a procedure safety checklist (medical conditions, drugs using, allergies) and written informed consent for the procedure (efficacy, possible complications) were obtained. The emergency drug box (including methylprednisolone, epinephrine, diphenhydramine, and lipofundin 20% (lipid emulsion)) and the vital signs monitor machine were routinely prepared. The patient underwent an intravenous infusion in 500 ml of 0.9% saline during and after thyroid RFA. In the RFA procedure, after finishing skin sterilization and careful local anesthesia with 10 ml of 2% lidocaine at the needle‐puncture site and peri‐thyroidal area under ultrasound guidance (Figure 1C), complete fluid aspiration was performed before ablating the nodule and its vascularity via the trans‐isthmic approach and the moving‐shot technique.\n\nAfter 15 min of ablation, the patient started feeling circumoral numbness, dizziness, nausea, and blurred vision. Her skin became cold, and no rash appeared. Shortly, she was hypotensive, bradycardia, and hypoxia with a blood pressure of 80/60 mmHg, a heartbeat of 34 bpm, and SpO2 of 74%. The ablation procedure was aborted immediately. Emergency management was rapidly started including “call help” with red code, nasal cannula oxygen therapy to maintain SpO2 of 100%, monitor the cardiovascular system, and support the patient with keeping rapid intravenous fluids flow (0.9% saline). At the same time, we administrated of lipid emulsion therapy (lipofundin 20%) in different intravenous way: first, intravenous bolus 1.5 ml/kg over 1–2 min (100 ml) and then intravenous infusion 0.25 ml/kg/min (~17 ml/min). The normal sinus rhythm and blood pressure were restored within 5 min of intravenous lipid injection with 60 bpm and 110/80 mmHg. Her mental status became stable. The total used volume of lipofundin 20% was 500 ml. The patient was subsequently transferred to our intensive care unit for follow‐up and supportive treatment. She was discharged 12 h later.\n\n3 DISCUSSION AND CONCLUSIONS\n\nRFA has been worldwide used for thyroid nodules treatment with high feasibility of performing in an outpatient room. 6 , 7 For pain relief while ablating procedure, this therapy requires local anesthesia by injecting a high volume of lidocaine 1% or 2% lidocaine at the needle‐puncture site and peri‐thyroidal area under ultrasound guidance.\n\nLidocaine, which has been used as a local anesthetic medication in almost all medical specialties since its advent in 1948, causes transient blockade of sensory and motor when being injected in closeness to neural tissue. 8 , 9 In RFA for thyroid nodules, lidocaine is recommended using from the Korean Society of Thyroid Radiology. 1 , 10 Its mechanism is to close voltage‐gated Na+ channels inside the cell, inhibiting the next channel activation and interrupting the large transient Na+ flow associated with membrane depolarization. 11 , 12 The total rate of lidocaine‐induced systemic toxicity ranges from 1:10,000 (epidurals anesthesia) to 1:2000 (peripheral nerve blocks). 4 Because electrophysiological changes affect earlier CNS than the CVS, neurological symptoms including dizziness, tinnitus, and perioral numbness usually manifest. 4 , 13\n\nPhysicians need to limit the total dose given as low as possible to minimize its systemic toxicity. Lidocaine toxicity was well correlated with the total dose (usually 4.5 mg/kg) and the rate of absorption, which depends on the blood supply of that tissue. 14 , 15 , 16 However, lidocaine toxicity may occur even at a lower dose in case of alpha‐1‐acid glycoprotein and albumin deficiencies.\n\nIt has been discussed in literature that circumoral numbness, tongue paresthesia, and dizziness are early symptoms. Blurred vision and tinnitus may be sensory manifestations. The next neurological symptoms include nervousness, restlessness, agitation, and paranoia, which may develop into seizures. Unconsciousness and coma can occur if lidocaine is largely overdosed. Adverse effects of relative lidocaine overdoses are hypotension and bradycardia which sometimes happen during local anesthesia near the CNS. 14 , 15 Thus, the diagnosis of lidocaine‐induced systemic toxicity is based on clinical symptoms. Considering this complication is based on important factors such as the site of injection, dose, and the timing. It is important to notice that even low doses may cause CNS toxicity if injected directly into an artery accidentally.\n\nUnder ultrasound guidance, lidocaine was injected at the needle‐puncture site and peri‐thyroidal area for pain relief during RFA procedure. Having a rich blood supply and locating near CNS, the thyroid gland increases the rate of lidocaine absorption and toxicity. 17 In our case, the total amount of lidocaine used for this patient of 66.7 kg accounted for only 10 ml 2% lidocaine (200 mg) during the procedure, which could not be considered an overdose with respect to the weight (2.99 mg/kg).\n\nOther factors leading to hypotension and bradycardia in our patient were the thermal injuries of the vagus nerve and anaphylaxis. Our patient had the early symptoms of lidocaine toxicity such as circumoral numbness, dizziness, nausea, and blurred vision before developing hypotension and bradycardia. Thus, heat‐induced injury of the vagus nerve can be excluded. Allergic reactions to lidocaine are extremely rare compared to the ester‐type local anesthetics, because of its class of the local amide anesthetics. 16 Our patient fully recovered after administrating lipid emulsion therapy (lipofundin 20%) and was discharged after 12 h. 18 , 19\n\nReviewing cases with lidocaine toxicity in radiofrequency ablation of thyroid nodule procedure in the literature, keywords including “lidocaine toxicity”, “thyroid”, “radiofrequency ablation”, “case report” were used to search for reported cases on Google Scholar, only one case was reported by Cherry Kim and her colleagues (its percentage of 0.1%). In Kim's report, lidocaine toxicity developed immediately post‐ablation with transient mild mental confusion and was attributed to overdose with respect to the weight. The patient fully recovered within 20 min. 3\n\nFrom our case and literature review, to avoid lidocaine toxicity in RFA of thyroid nodule, first, physicians must obtain written informed consent and procedure safety checklist (medical conditions, drugs using, allergies). Second, doctors document the amount of lidocaine used during the RFA procedure or can combine epinephrine with lidocaine to prolong nerve block and increase the maximum dose. 16 Third, any changes in neurologic signs or symptoms should be considered as a possible manifestation of lidocaine toxicity in the procedure. Finally, lipid emulsion is one of the important drug in the emergency drug box. 14 , 15 , 18 , 19\n\nIn conclusion, the systemic toxicity of lidocaine is one of the thyroid RFA procedure complications and it can be life‐threatening. The quick recognization of its symptoms and intravenous use of lipid emulsion are essential to preventing mortality.\n\nCONFLICTS OF INTEREST\n\nConflict of interest relevant to this article was not reported.\n\nAUTHOR CONTRIBUTIONS\n\nAll authors contributed to data analysis, drafting, or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.\n\nCONSENT\n\nWritten informed consent form was given to patient.\n\nACKNOWLEDGEMENT\n\nThe authors would like to thank the patient who agreed to participate in this study and Danang Family hospital for financial support.\n\nDATA AVAILABILITY STATEMENT\n\nAvailability of data and materials supporting our findings will be shared upon request.\n==== Refs\nREFERENCES\n\n1 Kim J‐H , Baek JH , Lim HK , Na DG . Summary of the 2017 thyroid radiofrequency ablation guideline and comparison with the 2012 guideline. Ultrasonography. 2019;38 (2 ):125‐134.30458605\n2 Baek JH , Lee JH , Valcavi R , Pacella CM , Rhim H , Na DG . Thermal ablation for benign thyroid nodules: radiofrequency and laser. Korean J Radiol. 2011;12 (5 ):525‐540.21927553\n3 Kim C , Lee JH , Choi YJ , Kim WB , Sung TY , Baek JH . Complications encountered in ultrasonography‐guided radiofrequency ablation of benign thyroid nodules and recurrent thyroid cancers. Eur Radiol. 2017;27 (8 ):3128‐3137.27975148\n4 Torp KD , Metheny E , Simon LV . Lidocaine Toxicity, in StatPearls. StatPearls Publishing; 2021 Jan‐. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482479/\n5 Liew J , Lundblad J , Obley A . Local anesthetic systemic toxicity complicating thyroid biopsy. Cureus. 2017;9 (12 ):e1955.29487769\n6 Park HS , Baek JH , Park AW , Chung SR , Choi YJ , Lee JH . Thyroid radiofrequency ablation: updates on innovative devices and techniques. Korean J Radiol. 2017;18 (4 ):615‐623.28670156\n7 Tufano RP , Pace‐Asciak P , Russell JO , et al. Update of radiofrequency ablation for treating benign and malignant thyroid nodules. The Future is Now. Front Endocrinol (Lausanne). 2021;12 :698689.34248853\n8 Catterall WA , Mackie K , Local anesthetics . Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 12th ed. McGraw‐Hill, Medical Publishing Division; 2011:565‐582.\n9 Aronson J . Local anesthetics, in Side Effects of Drugs Annual. Elsevier; 1994:141‐149.\n10 Shin JH , Baek JH , Chung J , et al. Ultrasonography diagnosis and imaging‐based management of thyroid nodules: revised Korean Society of Thyroid Radiology consensus statement and recommendations. Korean J Radiol. 2016;17 (3 ):370‐395.27134526\n11 Jimenez‐Kairuz A , Allemandi D , Manzo RH . Mechanism of lidocaine release from carbomer–lidocaine hydrogels. J Pharm Sci. 2002;91 (1 ):267‐272.11782916\n12 Courtney KR . Mechanism of frequency‐dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J Pharmacol Exp Ther. 1975;195 (2 ):225‐236.1081138\n13 Sharma S , Bhardwaj G , Bhatnagar V . Successful resuscitation after cardiac arrest in a patient presenting with local anesthetic systemic toxicity. Bali J Anesthesiol. 2020;4 (6 ):71.\n14 Neal JM , Woodward CM , Harrison TK . The American Society of Regional Anesthesia and Pain Medicine checklist for managing local anesthetic systemic toxicity: 2017 version. Reg Anesth Pain Med. 2018;43 (2 ):150‐153.29356775\n15 Picard J , Ward SC , Zumpe R , Meek T , Barlow J , Harrop‐Griffiths W . Guidelines and the adoption of ‘lipid rescue’therapy for local anaesthetic toxicity. Anaesthesia. 2009;64 (2 ):122‐125.19143686\n16 Nord‐Norge R , Lidocaine‐maximum dose.\n17 Allen E , Fingeret A . Anatomy, Head and Neck, Thyroid. StatPearls [Internet]; 2020.\n18 Litz RJ , Roessel T , Heller AR , Stehr SN . Reversal of central nervous system and cardiac toxicity after local anesthetic intoxication by lipid emulsion injection. Anest Analg. 2008;106 (5 ):1575‐1577.\n19 Weinberg G , Ripper R , Feinstein DL , Hoffman W Lipid emulsion infusion rescues dogs from bupivacaine‐induced cardiac toxicity. Reg Anesth Pain Med. 2003;28 (3 ):198‐202.12772136\n\n",
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"title": "Lidocaine-induced systemic toxicity complicating radiofrequency ablation of benign thyroid nodule procedure: A case report and review of literature.",
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"abstract": "OBJECTIVE\nWe sought to assess the safety and tolerability of 3 calcitonin gene-related peptide (CGRP) monoclonal antibodies in patients with chronic migraine who have failed multiple classes of migraine preventive therapies.\n\n\nBACKGROUND\nCGRP is an important neuromodulator implicated in the pathogenesis of migraine. They are approved for the treatment of episodic and chronic migraine. In current clinical practice, CGRP monoclonal antibodies are used in patients who have failed multiple preventive agents, but safety, tolerability, and efficacy have not been well described in real-world populations outside of clinical trials.\n\n\nMETHODS\nThis was a single-center, observational, retrospective study in adults with chronic migraine treated with a CGRP monoclonal antibody between May 1, 2018 and September 30, 2019. Charts were reviewed at 0, 3, and 6 months after treatment.\n\n\nRESULTS\nFrom May 1, 2018 to September 30, 2019, 77 patients with chronic migraine were prescribed 90 treatment trials of a CGRP monoclonal antibody. Patients reported adverse outcomes in 2/5 (40.0%) with erenumab 70 mg, 32/46 (69.6%) with erenumab 140 mg, 8/16 (50.0%) with fremanezumab, and 15/23 (65.2%) with galcanezumab. The most frequent adverse effects were constipation and injection site reactions. Adverse effects leading to discontinuation were reported as follows: erenumab 70 mg 1/5 (20.0%), erenumab 140 mg 10/46 (22.7%), fremanezumab 1/16 (6.3%), and galcanezumab 1/23 (4.3%), with 13/90 (14.4%) discontinuation rate overall. The most frequent reasons for discontinuation were lack of improvement in 17/90 (18.9%) and constipation in 4/90 (4.4%). A 50% or greater reduction in the number of severe headache days per month was achieved for 32/66 (48.5%) at 3 months and 17/48 (35.4%) at 6 months.\n\n\nCONCLUSIONS\nIn patients with chronic migraine, the 3 CGRP monoclonal antibodies were well tolerated, and reduced the number of severe headache days.",
"affiliations": "Department of Neurology, University at Buffalo, State University of New York, Buffalo, NY, USA.;Department of Neurology, University at Buffalo, State University of New York, Buffalo, NY, USA.;Department of Neurology, University at Buffalo, State University of New York, Buffalo, NY, USA.",
"authors": "Alex|Ashley|A|;Vaughn|Caila|C|;Rayhill|Melissa|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000604315:fremanezumab; C000628360:galcanezumab; C000605816:erenumab; D015740:Calcitonin Gene-Related Peptide",
"country": "United States",
"delete": false,
"doi": "10.1111/head.13956",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-8748",
"issue": "60(10)",
"journal": "Headache",
"keywords": "chronic migraine; erenumab; fremanezumab; galcanezumab; headache; preventive therapy",
"medline_ta": "Headache",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015740:Calcitonin Gene-Related Peptide; D002908:Chronic Disease; D003248:Constipation; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D000075662:Injection Site Reaction; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "2985091R",
"other_id": null,
"pages": "2454-2462",
"pmc": null,
"pmid": "32969035",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Safety and Tolerability of 3 CGRP Monoclonal Antibodies in Practice: A Retrospective Cohort Study.",
"title_normalized": "safety and tolerability of 3 cgrp monoclonal antibodies in practice a retrospective cohort study"
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"abstract": "Post-traumatic defects of the distal third of the leg often require skipping a few steps of the well-established reconstructive ladder, due to the limited local reliable reconstructive options. In rare cases, the reconstructive plan and flap choice may encounter challenges when the patient has psychiatric illness affecting compliance with postoperative care. We describe a case of a patient with severe intellectual disability and an open fracture of the distal lower limb. After fracture management and debridement of devitalized tissues, the resultant soft tissue defect was covered with a free gracilis flap. On postoperative day 7, the patient ripped out the newly transplanted flap. The flap was too traumatized for salvage, so a contralateral free gracilis muscle flap was used. The patient showed good aesthetic and functional outcomes at a 1-year follow-up. When planning the postoperative management of patients with psychiatric illness, less complex and more robust procedures may be preferred over a long and complex surgical reconstruction requiring good compliance with postoperative care. The medical team should be aware of the risk of postoperative collapse, focus on the prevention of pain, and be wary of drug interactions. Whenever necessary, free tissue transfer should be performed despite potential compliance issues.",
"affiliations": "Department of Plastic, Reconstructive and Hand Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.;Canniesburn Plastic Surgery Unit, Glasgow Royal Infirmary, Glasgow, UK.;Department of Plastic, Reconstructive and Hand Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.;Department of Plastic, Reconstructive and Hand Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.;Department of Plastic, Reconstructive and Hand Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.",
"authors": "Schaffer|Clara|C|;Hart|Andrew|A|;Watfa|William|W|;Raffoul|Wassim|W|;di Summa|Pietro Giovanni|PG|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5999/aps.2018.01039",
"fulltext": "\n==== Front\nArch Plast SurgArch Plast SurgAPSArchives of Plastic Surgery2234-61632234-6171Korean Society of Plastic and Reconstructive Surgeons 10.5999/aps.2018.01039aps-2018-01039Case ReportLate avulsion of a free flap in a patient with severe psychiatric illness: Establishing a successful salvage strategy http://orcid.org/0000-0001-7230-4984Schaffer Clara 1Hart Andrew 2http://orcid.org/0000-0002-5951-9443Watfa William 1http://orcid.org/0000-0002-3524-0077Raffoul Wassim 1di Summa Pietro Giovanni 12\n1 Department of Plastic, Reconstructive and Hand Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland\n2 Canniesburn Plastic Surgery Unit, Glasgow Royal Infirmary, Glasgow, UKCorrespondence: Pietro Giovanni di Summa Department of Plastic, Reconstructive and Hand Surgery, University Hospital of Lausanne (CHUV), Rue du Bugnon 46, Lausanne 1005, Switzerland Tel: +41-21-314-2525 Fax: +41-21-314-2530 E-mail: pietro.di-summa@chuv.chThis article was presented at the European Federation Societies of Microsurgery Congress on May 5–8, 2018, in Belgrade, Serbia.\n\n11 2019 20 4 2019 46 6 589 593 27 7 2018 14 1 2019 1 2 2019 Copyright © 2019 The Korean Society of Plastic and Reconstructive Surgeons2019This 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 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Post-traumatic defects of the distal third of the leg often require skipping a few steps of the well-established reconstructive ladder, due to the limited local reliable reconstructive options. In rare cases, the reconstructive plan and flap choice may encounter challenges when the patient has psychiatric illness affecting compliance with postoperative care. We describe a case of a patient with severe intellectual disability and an open fracture of the distal lower limb. After fracture management and debridement of devitalized tissues, the resultant soft tissue defect was covered with a free gracilis flap. On postoperative day 7, the patient ripped out the newly transplanted flap. The flap was too traumatized for salvage, so a contralateral free gracilis muscle flap was used. The patient showed good aesthetic and functional outcomes at a 1-year follow-up. When planning the postoperative management of patients with psychiatric illness, less complex and more robust procedures may be preferred over a long and complex surgical reconstruction requiring good compliance with postoperative care. The medical team should be aware of the risk of postoperative collapse, focus on the prevention of pain, and be wary of drug interactions. Whenever necessary, free tissue transfer should be performed despite potential compliance issues.\n\nFree tissue flapLower extremityMental disorderReconstruction\n==== Body\nINTRODUCTION\nPost-traumatic lower limb reconstruction represents a challenge in plastic surgery. The initial management includes extensive debridement of devitalized tissue, as well as reduction and stabilization of fractures if needed. Flap reconstruction is commonly required, with options including a local/propeller flap, a pedicled flap, or a free flap. However, defects of the distal third of the leg often require skipping a few steps of the well-established reconstructive ladder. This is due to the limited local reliable reconstructive options for this area, leading to a lower threshold for free tissue transfer [1]. The most commonly used muscular free flaps for the distal limb include gracilis and latissimus dorsi myocutaneous or muscle flaps, which can potentially cover defects of all sizes. Among the variety of perforator flaps, the anterolateral thigh flap probably represents the most versatile option due to potential uses of its multiple components. The choice of a flap depends on the defect characteristics, the reconstructive needs (function, sensitivity, and aesthetics), and the experience of the surgeon.\n\nHowever, the reconstructive plan and flap choice may encounter challenges if the patient has a psychiatric disorder. Severe intellectual disability is associated with twice as many complications after surgery as in the general population [2]. However, little is known about the postoperative course of patients with learning disabilities or psychiatric disorders after reconstructive surgery procedures, particularly free flap surgery. Guidelines for the pre- and postoperative management of these patients are lacking. The literature contains case reports of patients suffering from psychosis, schizophrenia, and other neuropsychological disorders who required free flap surgery, mainly following hand self-amputation [3]. Other studies have focused on the postoperative course of patients experiencing alcohol withdrawal syndrome after oncologic surgery [4-6]. Few cases of microsurgical free tissue transfer in patients with intellectual disability have described [7].\n\nIn this report, we present our experience with a patient suffering from intellectual disability, who presented with an open fracture of the distal third of the leg, requiring fracture stabilization followed by soft tissue coverage with a contralateral free gracilis muscle flap. The postoperative self-inflicted flap avulsion due to psychiatric deterioration required emergent hemostasis and a secondary reconstructive procedure, using a free gracilis muscle flap harvested from the right leg. The patient’s postoperative course was uneventful, and the secondary procedure resulted in successful long-term coverage.\n\nCASE\nA 48-year-old male patient with known severe autism and learning disability with psychotic traits, living in a care institution, fell out of the window of his room from a 3-m height, apparently without suicidal intent. He was found with a Gustilo-Anderson IIIB fracture on the right tibia. After antibiotic prophylaxis with intravenous amoxicillin and clavulanic acid, emergency reduction and stabilization of the fracture with a tibiocalcaneal external fixator (Orthofix; Orthofix Holdings Inc., Bussolengo, Italy) was performed. Unfortunately, the patient developed cutaneous necrosis of the surgical site, which required repeated surgical debridement and replacement of the external fixator material on postoperative days (POD) 9, 11, and 21. The last procedure allowed definitive tibial osteosynthesis. The resultant pyramidshaped soft tissue defect (8×14 cm) was covered with a left free gracilis muscle flap, and anastomosed in a termino-lateral manner to the posterior tibial artery and in a termino-terminal manner with one of the posterior tibial venae comitantes. The muscle flap was then covered with a split-thickness skin graft (Fig. 1). The flap was monitored hourly during the first 24 hours, and strict bed rest with slight limb elevation was prescribed. Surveillance intervals were progressively increased on POD2 and POD3 to four times/day. Despite the difficulty in adequately communicating flap care needs to the patient, he complied with splint immobilization and bedrest for the first 6 days.\n\nOn POD7, during the night, the patient removed the splint and ripped out the newly transplanted flap from his right leg, without a specific reason, with consequent bleeding from the posterior tibial artery at the level of the anastomosis, requiring emergency hemostasis overnight. Due to severe damage to the flap, it was impossible to re-anastomose (Fig. 2), and the defect was temporarily covered with Epigard (Biovision, Ilmenau, Germany). Postoperatively, the patient remained sedated and placed under continuous surveillance in the intermediate care unit. On the next day, operatory wound revision revealed the posterior tibial artery to be thrombosed but continous, and a second posterior tibial vena comitans was intact. After resecting the thrombosed and traumatized area of the artery, a second free gracilis muscle flap was raised and anastomosed in a termino-terminal manner to the posterior tibial artery and residual vena comitans. On this occasion, the flap was protected with a full-leg above-knee cast. He was again placed on bed rest, with a 24-hour nursing team surveillance. A psychiatric nurse and physician regularly visited the patient and counselled the medical team to adjust his antipsychotic medications (olanzapine and topiramate) and tranquilizer (lorazepam). The doses remained unchanged, but haloperidol and clomethiazole were added to prevent new acute schizophrenic episodes. Analgesic treatment, combining long-acting and short-acting oxycodone, was administered according to the level of pain, as assessed by the Faces Pain Scale. The patient did not develop further medical, flap-related, or psychiatric complications, and remained compliant for the rest of the hospital stay. He was transferred to his psychiatric institution 13 days after the last intervention. After 6 weeks, after radiography confirmed that adequate healing had occurred mobilization (partial load) was started with a physiotherapist. Full loading was allowed after 3 months.\n\nThe patient healed uneventfully, showing good aesthetic and functional outcomes at a 1-year follow-up (Fig. 3), with preserved mobility and no donor site complications.\n\nThe patient’s legal guardian provided informed consent, including permission for photographic and video documentation.\n\nDISCUSSION\nPatients with severe psychiatric conditions or learning disabilities are particularly vulnerable in the postoperative period. A previous study reported the outcomes of 38 patients with neuropsychological impairment and hand and facial traumatic injuries requiring free flap reconstruction, who underwent 40 microsurgical reconstructive procedures [7]; however, only three of those patients had severe psychiatric illness. The overall success rate (87.5%) was similar to that of the population at large. The reported relapse rate of the psychiatric disorders was 23.1%, but the flap-related complication and re-intervention rates were not stated. The main issue during hospitalization was poor compliance with postoperative immobilization. However, all flaps healed uneventfully. Psychiatric patients, and those with learning disabilities, often present with an altered perception of pain combined with a reduced ability to communicate symptoms [3]. Moreover, studies have raised awareness about interactions between antipsychotic, anesthetic, and analgesic medications due to enzymatic induction. In our case, even though the heavy daily antipsychotic treatment received by the patient (topiramate, olanzapine, and lorazepam) was never interrupted during the hospital stay, pharmacologic interactions between analgesic (oxycodone) and antipsychotic drugs may have decreased the effectiveness of both analgesics and neuroleptics. This phenomenon probably triggered pain or discomfort, along with psychiatric collapse, leading the patient to avulse his free flap in response.\n\nWhen planning the postoperative management of patients with severe psychiatric illness, a learning disability, or inability to communicate, the medical team should be aware of the risk of postoperative deterioration, especially after trauma, emergency procedures, or repeated general anesthesia. Reconstruction should not be withheld, especially if soft tissue coverage of fractures or prosthetic material is needed, but postoperative compliance and patient understanding should be factored into the selection of the reconstructive technique, even in the emergency setting, and the care plan and choice of dressings. If possible, single-stage, more robust procedures, such as local flaps, should be selected over complex surgical reconstructions requiring compliance with prolonged postoperative care regimens. Locoregional anesthesia and sedation should be considered instead of general anesthesia. Nonetheless, free tissue transfer should be performed when necessary, but postoperative care should be adjusted to increase flap protection and to minimize the opportunity for self-harm.\n\nThe team should focus on optimal pain management and preventing psychiatric deterioration, as well as closely observing for early signs of decompensation (restlessness, algetic face, apathy, and muteness). Daily antipsychotic medications must be continued with advice from a psychiatrist either to adapt the dose or to add other drugs, as in our case. A pharmacologist should provide counselling regarding drug interactions and dosage adjustment on a case-by-case basis. Periodic dosage of medications may be helpful for adapting the dosage, especially for olanzapine. Despite the risk of drug interactions, optimal analgesia is essential to maintain a steady psychiatric state. Pain control can be achieved by detecting any signs of discomfort using the Faces Pain Scale, rather than the usual self-reported pain level, and combining short- and long-acting analgesics. Restricting access to the flap with a full-leg cast may prevent injuries to the flap if psychiatric collapse occurs. A multidisciplinary team comprising psychiatric, surgical, pharmacology teams, including both physicians and nurses, is most suitable for managing communication issues and promoting adherence to postoperative recommendations [8].\n\nIf acute decompensation occurs despite preventive measures, rapid neuroleptic treatment should be administered and sedation (e.g., haloperidol) should be introduced, followed by continuous monitoring.\n\nBefore discharge, the patient’s medical prescriptions must be checked accurately. In this case, the oral antibiotic (rifampicin), a powerful inducer of cytochromes (CYP 2C9, 2C19, 2C8, and 3A4), was implicated in the inactivation of various drugs, potentially reducing the efficacy of antipsychotic and antalgic medications. Concomitant administration is not contraindicated, but close monitoring is warranted. Close biological follow-up (with a complete blood count, hepatic function, and renal function tested at least once a week) is advised. When the analgesic medication is discontinued, the doses of antipsychotic medications should be reduced according to preoperative standards, and the added drugs may be removed progressively. Postoperative surgical and psychiatric follow-up must be scheduled before discharge. Caregivers should be highly vigilant in recognizing signs of a recurrent delusional episode [9]. A rapid return to the patient’s usual surroundings and care structure is beneficial, suggesting that over-hospitalization may be deleterious rather than cautious.\n\nOn a more general level, outcomes after head and neck oncologic surgery and microsurgical tissue transfer have improved due to standardized care protocols and the early detection and treatment of patients presenting with postoperative alcohol withdrawal syndrome [10]. Patients with neuropsychological impairment should benefit from similar protocols. Further cases should be reported in order to assess flap-related and psychiatric outcomes in this particular population, and ultimately to provide clear preoperative management guidelines.\n\nNo potential conflict of interest relevant to this article was reported.\n\nEthical approval\n\nThe study was approved by the Institutional Review Board of Lausanne University Hospital and performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained.\n\nPatient consent\n\nPatient’s legal guardian provided written informed consent for the publication and the use of his images.\n\nAuthor contribution\n\nStudy concept and design: Watfa W, di Summa PG. Data acquisition: Schaffer C. Data analysis and interpretation: Schaffer C. Drafting of the manuscript: Schaffer C. Critical revision of the manuscript for important intellectual content: Hart A, Watfa W, di Summa PG, Raffoul W. Approval of final manuscript: all authors.\n\nFig. 1. Intraoperative images of the first reconstruction procedure\n(A) A free gracilis muscle flap harvested from the left thigh and the prepared posterior tibial recipient vessels (green arrows). (B) The flap was anastomosed in a termino-lateral manner to the posterior tibial artery (red arrow) and in a termino-terminal manner with one of the posterior tibial venae comitantes (blue arrow). (C) In setting of the muscular flap before split-thickness skin graft coverage.\n\nFig. 2. Self-inflicted injury to the free gracilis flap\n(A) Bedside wound status after the flap was ripped out by the patient. (B) A severely damaged flap that was impossible to re-anastomose.\n\nFig. 3. Aesthetic outcomes at a 1-year follow-up\n==== Refs\nREFERENCES\n1 Bennett N Choudhary S Why climb a ladder when you can take the elevator? Plast Reconstr Surg 2000 105 2266 10839429 \n2 Ailey SH Johnson TJ Fogg L Factors related to complications among adult patients with intellectual disabilities hospitalized at an academic medical center Intellect Dev Disabil 2015 53 114 9 25860449 \n3 Copeland LA Zeber JE Pugh MJ Postoperative complications in the seriously mentally ill: a systematic review of the literature Ann Surg 2008 248 31 8 18580204 \n4 Chang CC Kao HK Huang JJ Postoperative alcohol withdrawal syndrome and neuropsychological disorder in patients after head and neck cancer ablation followed by microsurgical free tissue transfer J Reconstr Microsurg 2013 29 131 6 23277407 \n5 Kuo YR Jeng SF Lin KM Microsurgical tissue transfers for head and neck reconstruction in patients with alcohol-induced mental disorder Ann Surg Oncol 2008 15 371 7 17973172 \n6 Ferrari S Copelli C Bianchi B Free flaps in elderly patients: outcomes and complications in head and neck reconstruction after oncological resection J Craniomaxillofac Surg 2013 41 167 71 22883078 \n7 Lin CH Wei FC Chen CT Microsurgical tissue transplantation or replantation in patients with psychoneurological impairment Plast Reconstr Surg 2001 108 1211 7 11604621 \n8 Abrams TE Vaughan-Sarrazin M Rosenthal GE Influence of psychiatric comorbidity on surgical mortality Arch Surg 2010 145 947 53 20956762 \n9 Strain JJ DeMuth GW Care of the psychotic self-amputee undergoing replantation Ann Surg 1983 197 210 4 6824374 \n10 Lansford CD Guerriero CH Kocan MJ Improved outcomes in patients with head and neck cancer using a standardized care protocol for postoperative alcohol withdrawal Arch Otolaryngol Head Neck Surg 2008 134 865 72 18711062\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2234-6163",
"issue": null,
"journal": "Archives of plastic surgery",
"keywords": "Free tissue flap; Lower extremity; Mental disorder; Reconstruction",
"medline_ta": "Arch Plast Surg",
"mesh_terms": null,
"nlm_unique_id": "101577999",
"other_id": null,
"pages": "589-593",
"pmc": null,
"pmid": "31006183",
"pubdate": "2019-04-20",
"publication_types": "D016428:Journal Article",
"references": "25860449;18711062;17973172;18580204;20956762;23277407;22883078;6824374;11604621;10839429",
"title": "Late avulsion of a free flap in a patient with severe psychiatric illness: Establishing a successful salvage strategy.",
"title_normalized": "late avulsion of a free flap in a patient with severe psychiatric illness establishing a successful salvage strategy"
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"abstract": "A 54-year-old diabetic female presented with orbital abscess and corneal infiltrate 3 days after deep posterior subtenon triamcinolone acetonide injection in her right eye. This was administered immediately after focal laser photocoagulation for diabetic macular edema. The orbital abscess and corneal infiltrate responded to systemic and topical antibiotics.",
"affiliations": "Department of Ophthalmology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Sukhija|Jaspreet|J|;Dogra|Mangat R|MR|;Ram|Jagat|J|;Ichhpujani|Parul|P|;Gupta|Amod|A|",
"chemical_list": "D000890:Anti-Infective Agents; D005938:Glucocorticoids; D014222:Triamcinolone Acetonide",
"country": "India",
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"fulltext": "\n==== Front\nIndian J OphthalmolIndian Journal of OphthalmologyIndian Journal of Ophthalmology0301-47381998-3689Medknow Publications India IndianJOphthalmol_2008_56_3_246_4037018417832 Brief CommunicationAcute orbital abscess complicating deep posterior subtenon triamcinolone injection Sukhija Jaspreet MDDogra Mangat R MDRam Jagat MDIchhpujani Parul MDGupta Amod MDDepartment of Ophthalmology, Post Graduate Institute of Medical\nEducation and Research, Chandigarh, IndiaCorrespondence to Dr. Jagat Ram, Department of Ophthalmology, Post\nGraduate Institute of Medical Education and Research, Chandigarh,\nIndia. Email: jagatrampgi@yahoo.co.inMay-Jun 2008 56 3 246 247 13 4 2007 04 9 2007 Copyright: © Indian Journal of Ophthalmology2008This is an \nopen-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, \nwhich permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly \ncited.A 54-year-old diabetic female presented with orbital abscess\nand corneal infiltrate 3 days after deep posterior subtenon\ntriamcinolone acetonide injection in her right eye. This was\nadministered immediately after focal laser photocoagulation for\ndiabetic macular edema. The orbital abscess and corneal infiltrate\nresponded to systemic and topical antibiotics.\n\nDiabetes mellitusorbital abscesssubtenon triamcinolone\n==== Body\nPosterior subtenon injections of corticosteroids have been\nwidely used for treatment of cystoid macular edema following\nuveitis and intraocular surgeries. They are increasingly used\nnowadays for the management of diabetic macular edema.1\nThe main advantage is maximum concentration at the macula\nwhich is the desired site of action with minimal side-effects.\nWe herein report of a case of orbital abscess following deep\nposterior subtenon triamcinolone injection.\n\nCase Report\nA 54-year-old female patient presented to us with pain,\nswelling of lids of the right eye (RE) associated with intense\nchemosis and congestion of the conjunctiva. She was a\nknown diabetic since 20 years and a hypertensive since\n15 years. She had received posterior subtenon triamcinolone\n20 mg injection with a 20-gauge veinflow canula in her RE\nimmediately following focal laser treatment 3 days back for\ndiabetic macular edema. At presentation her vision in RE was\nhand movement close to face (HMCF) and the same in the\nleft eye (LE). Intraocular pressure could not be measured in\nRE due to massive lid edema. It was recorded as 14 mmHg in\nLE. The RE revealed lid edema with erythema [Fig. 1A]. The\ntemperature of the overlying skin was raised but there was no\npalpable mass. The conjunctiva was congested and chemosed.\nExtraocular movements were limited in all directions of gaze\nin RE. In LE the movements were full in all directions. On\nforcibly lifting the upper lid of RE there was frank white\ntenacious discharge from the site of subtenon injection along\nwith necrosis of the surrounding conjunctiva and peripheral\ncorneal infiltrate [Fig. 1B]. Pupillary reaction was normal.\nPosterior segment examination showed proliferative diabetic\nretinopathy (PDR) with clinically significant macular edema\n(CSME) in both eyes.\n\nMicrobiological investigation of the discharge and infiltrate\nshowed the presence of gram-positive cocci in clusters but no\ngrowth was observed on culture. Her fasting blood sugar was\n284 mg% at presentation. Thereafter she was started on insulin\ninfusion along with intravenous ciprofloxacin 500 mg twice\ndaily, vancomycin 1 g twice a day and metrogyl 80 mg twice\ndaily along with topical moxifloxacin 0.3% six times a day and\natropine thrice a day. She had previously received injection\ncefazolin and ciprofloxacin elsewhere for 1 day. Computed\ntomography (CT) of head was consistent with diagnosis of\norbital abscess [Fig. 1C] with no involvement of optic nerve.\nThere was no evidence of intracranial involvement.\n\nOver the next 3 days there was very little improvement. At\nthis moment oral linazolid 500 mg twice a day was added to the\ndrug regimen suspecting methicillin and vancomycin-resistant\nStaphylococcus aureus. There was remarkable improvement in\nthe ensuing 48 h. Lid edema reduced considerably along with\ndecrease in conjunctival chemosis and congestion. Extraocular\nmovements improved and the discharge was seemingly much\nless than before. The above treatment continued for a period\nof 7 days. At 3 weeks follow-up all parameters were normal\nexcept for adjacent conjunctival and corneal scarring [Fig. 1D].\nVisual acuity improved to 20/200. There was no restriction of\nocular movements.\n\nDiscussion\nSubtenon injections of steroids are commonly used in\nthe treatment of macular edema associated with diabetes\nand uveitis. In general, patients with recalcitrant macular\nedema do not respond to focal laser treatment and require\nadjunctive subtenon injection of steroid. Complications\nthough rare include inadvertent intravascular injection,\nglobe perforation, cataract formation, ptosis, orbital fat\natrophy or allergic reaction.2 Bakri et al. injected posterior\nsubtenon triamcinolone in patients at least 3 months after\nlaser treatment with minimal side-effects.3 Transient rise in\nintraocular pressure was observed in three eyes and ptosis\nin two eyes. In another study by Javadzadeh et al., a similar\nprotocol for treating recalcitrant diabetic macular edema\nwas followed.1 Only two cases in their series developed\nfocal conjunctival necrosis over the site of injection. Orbital\ncellulitis has been seen after anterior subtenon injection of\nlocal anesthetic agent for cataract surgery.4 Recently, Oh et al.\nreported a case of periocular abscess which presented 1 month\nfollowing posterior subtenon injection of triamcinolone and\npanretinal photocoagulation.5\n\nAsymptomatic orbital abscess presenting 3 weeks following\nposterior subtenon injection of triamcinolone has been\nreported.6 However, acute orbital abscess is a previously\nunrecognized complication of this procedure. Our case\nhighlights the fact that posterior subtenon triamcinolone\ninjection should preferably be avoided at the same time as\nlaser photocoagulation. Coupling solution used during focal\nlaser treatment may have contaminated the conjunctival sac\ncausing localized infection. Uncontrolled diabetes may have\nalso contributed. It is well known that after posterior subtenon\ninjection of anesthetic solution, nearly 50% of the solute resides\nin the orbital tissues anterior to the globe equator.7 In such a\nsituation injection of deep posterior subtenon corticosteroid\nmay have created a similar tract for the infection to present as\nan orbital abscess.\n\nFigure 1A (A) Swelling and erythema of right lid at presentation\n\nFigure 1AFigure 1B (B) Note the area of corneal infiltrate alongwith conjunctival infection\nand discharge from the site of injection\n\nFigure 1BFigure 1C (C) CT scan of orbit shows proptosis, hypoechoic lesion with hyperechoic borders localized in\npreseptal tissues and anterior orbit with surrounding preseptal soft\ntissue swelling extending nasally and temporally\n\nFigure 1CFigure 1D (D) Right eye showing\narea of conjunctival scarring and adjacent corneal opacity at 3 weeks\nfollow-up\n\nFigure 1D\n==== Refs\n1 Javadzadeh A The effect of posterior subtenon methyllprednisolone\nacetate in refractory diabetic macular oedema: A prospective\nnon randomized interventional case series BMC Ophthalmol 2006 6 15 29 16595011 \n2 Dafflon ML Tran VT Guex-Crosier Y Herbort CP Posterior sub-\ntenon′s steroid injections for the treatment of posterior ocular\ninflammation: Indications, efficacy and side effects Graefes Arch Clin Exp Ophthamol 1999 237 289 95 \n3 Bakri SJ Kaiser PK Posterior subtenon triamcinolone acetonide\nfor refractory diabetic macular edema Am J Ophthalmol 2005 139 290 4 15733990 \n4 Dahlmann AH Appaswamy S Headon MP Orbital cellulitis\nfollowing sub-tenon′s anaesthesia Eye 2002 16 200 1 11988827 \n5 Oh IK Baek S Huh K Oh J Periocular abscess caused by\nPseudallescheria boydii after a posterior subtenon injection of\ntriamcinolone acetonide Graefes Arch Clin Exp Ophthalmol 2007 245 164 6 16612634 \n6 Engelman CG Palmer JD Jose S Orbital abscess following subtenon\ntriamcinolone injection Arch Ophthalmol 2004 122 654 5 15078688 \n7 Niemi-Murola L Krootila K Kivisaari R Kangasmaki A Kivisaari L Maunuksela EL Localization of local anesthetic\nsolution by magnetic resonance imaging Ophthalmology 2004 111 342 7 15019387\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0301-4738",
"issue": "56(3)",
"journal": "Indian journal of ophthalmology",
"keywords": null,
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D000038:Abscess; D000208:Acute Disease; D000890:Anti-Infective Agents; D003131:Combined Modality Therapy; D003238:Connective Tissue; D048909:Diabetes Complications; D003930:Diabetic Retinopathy; D004359:Drug Therapy, Combination; D015818:Eye Infections, Bacterial; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007267:Injections; D017075:Laser Coagulation; D008269:Macular Edema; D008875:Middle Aged; D009916:Orbital Diseases; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus; D014057:Tomography, X-Ray Computed; D014222:Triamcinolone Acetonide",
"nlm_unique_id": "0405376",
"other_id": null,
"pages": "246-7",
"pmc": null,
"pmid": "18417832",
"pubdate": "2008",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10208261;16595011;11988827;15078688;15733990;15019387;16612634",
"title": "Acute orbital abscess complicating deep posterior subtenon triamcinolone injection.",
"title_normalized": "acute orbital abscess complicating deep posterior subtenon triamcinolone injection"
} | [
{
"companynumb": "IN-G+W LABS-GW2016IN000130",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
"drugadditional"... |
{
"abstract": "Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, potentially life-threatening delayed drug-induced hypersensitivity reaction. The most frequently reported drugs causing DRESS are aromatic antiepileptic agents. Prompt withdrawal of the offending drug and administering systemic corticosteroids is the most widely accepted and used treatment. The treatment of severe DRESS not responsive to systemic corticosteroids is uncertain.\n\n\n\nThe objective of this study was to describe a case series of pediatric patients with DRESS who were treated successfully with intravenous immunoglobulins (IVIGs).\n\n\n\nA retrospective review of all children hospitalized in a tertiary care children's hospital with severe DRESS syndrome who received IVIG in addition to offending drug withdrawal and systemic corticosteroids during 1999-2017 is performed.\n\n\n\nSeven severe DRESS patients (4 males, age: 9.5 ± 5.7 years) are described. The offending drugs were antiepileptics in all but one case. Clinical findings included fever, rash, lymphadenopathy, dyspnea, anasarca, and hepatic involvement. After IVIG treatment (total dosage: 1-2 g/kg), fever resolved within a median time of 1 (range, 0-5) day, rash disappeared after 6.3 ± 1.6 days, and liver enzymes substantially improved after 3.8 ± 1.6 days. Patients were discharged 6.1 ± 2.7 days after IVIG commencement. There was no mortality.\n\n\n\nThe addition of IVIG in DRESS syndrome resistant to regular drug withdrawal and systemic corticosteroid therapy may hasten disease recovery.",
"affiliations": "Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Kipper Institute of Immunology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.;Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Pulmonology Institute, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Neurology Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.;Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: odedshv@clalit.org.il.",
"authors": "Marcus|Nufar|N|;Smuel|Keren|K|;Almog|Moran|M|;Prais|Dario|D|;Straussberg|Rachel|R|;Landau|Daniel|D|;Scheuerman|Oded|O|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D016756:Immunoglobulins, Intravenous",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaip.2017.10.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "6(4)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "DRESS syndrome; Intravenous immunoglobulins; Pediatric",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D016896:Treatment Outcome",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "1238-1242",
"pmc": null,
"pmid": "29198698",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Successful Intravenous Immunoglobulin Treatment in Pediatric Severe DRESS Syndrome.",
"title_normalized": "successful intravenous immunoglobulin treatment in pediatric severe dress syndrome"
} | [
{
"companynumb": "IL-TEVA-2018-IL-933857",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo observe the long term response to first-line antiretroviral therapy (ART) in HIV and hepatitis B virus (HBV) co-infected patients in Ghana and explore predictors of poor clinical outcomes.\n\n\nMETHODS\nRetrospective cohort study of hepatitis B surface antigen (HBsAg) positive and negative patients receiving predominantly NNRTI-based ART with lamivudine plus either zidovudine or stavudine for up to seven years. Cox proportional hazards and Kaplan Meier survival analyses compared clinical outcomes and identified baseline characteristics predictive of poor outcomes. A mixed effects model compared changes in CD4 counts.\n\n\nRESULTS\nA total of 299 HBsAg-positive and 1869 HBsAg-negative patients started ART between 2004 and 2008. Over a median 35 months of follow-up, HBsAg-positive patients were more likely to die or default care than HBsAg-negative patients, aHR 1.36 (95% CI, 1.03-1.80). HBsAg-positive patients were also more likely to develop Grade 3/4 hepatotoxicity than HBsAg-negative patients, HR 1.99 (1.16-3.40) on survival analysis. There was no significant difference in CD4 responses between HBsAg-positive and HBsAg-negative patients.\n\n\nCONCLUSIONS\nHBsAg-positive patients are at significantly increased risk of adverse clinical outcomes after starting ART. Further studies are warranted to evaluate whether these risks remain now that tenofovir is becoming routinely available in Ghana.",
"affiliations": "Komfo Anokye Teaching Hospital, Kumasi, Ghana; Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.;Wolfson Research Institute for Health and Wellbeing, Durham University, Stockton-on-Tees TS17 6BH, UK.;Komfo Anokye Teaching Hospital, Kumasi, Ghana; Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.;Institute of Global Health, University of Liverpool, L69 7BE, UK.;The James Cook University Hospital, Middlesbrough, TS4 3BW, UK. Electronic address: davidr.chadwick@stees.nhs.uk.",
"authors": "Sarfo|Fred Stephen|FS|;Kasim|Adetayo|A|;Phillips|Richard|R|;Geretti|Anna Maria|AM|;Chadwick|David R|DR|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-4453",
"issue": "69(5)",
"journal": "The Journal of infection",
"keywords": "Antiretroviral therapy; Clinical outcomes; HIV; Hepatitis B; Lamivudine",
"medline_ta": "J Infect",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D060085:Coinfection; D005260:Female; D005869:Ghana; D015658:HIV Infections; D006509:Hepatitis B; D006801:Humans; D008099:Liver; D008297:Male; D008875:Middle Aged; D013997:Time Factors",
"nlm_unique_id": "7908424",
"other_id": null,
"pages": "481-9",
"pmc": null,
"pmid": "24975175",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-term responses to first-line antiretroviral therapy in HIV and hepatitis B co-infection in Ghana.",
"title_normalized": "long term responses to first line antiretroviral therapy in hiv and hepatitis b co infection in ghana"
} | [
{
"companynumb": "GH-MYLANLABS-2016M1053161",
"fulfillexpeditecriteria": "1",
"occurcountry": "GH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHypoglycemia in a critical care setting is often multifactorial with iatrogenic insulin use, sulfonylurea (SU) use, sepsis, adrenal insufficiency and insulinoma among the common causes. Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by the presence of insulin-binding autoantibodies to the sulfhydryl group-containing agents. We report a case of methimazole-induced IAS managed in the intensive care unit.\n\n\nMETHODS\nA 76-year-old woman with a history of primary hyperthyroidism was sent from a nursing home for unresponsiveness. Vital signs were significant for hypotension (74/46) and low blood sugars. Fluid resuscitations with normal saline and 50% dextrose stabilized the blood pressure (BP) to 135/75 and her blood glucose to 264. Due to respiratory distress and septic appearance, she required emergency intubation. Nursing home medications were noted for methimazole and absence of any insulin or SU use. Empiric antibiotic treatment was started and fluid resuscitation was continued while home medications were held. Her laboratory values were significant for elevated creatinine, lactic acid, serum cortisol, C-peptide, and insulin. Her cultures, SU screen and computerized tomography (CT) scan were negative for significant findings. On day 2, in addition to 10% dextrose, octreotide was initiated for recurrent hypoglycemia. Her blood glucose (BG) continued to drop throughout the day for which she required glucagon support and a D20 infusion. By day 4, the rate of infusion was titrated up and her BG continued to drop to <60 mg/dl despite D20, octreotide and tube feeds with concentrated calories (1.5 cal/ml). Due to her declining health, her family endorsed palliative care and she was extubated. After day 11, her hypoglycemic episodes resolved and she remained endogenously euglycemic.\n\n\nCONCLUSIONS\nIAS is associated with methimazole use due to formation of autoantibodies to insulin after its interaction with Sulfhydryl (SH) group in methimazole. While IAS is a rare entity, it demands consideration in hypoglycemia in patients with autoimmune conditions.",
"affiliations": "Department of Medicine, University of Tennessee Health Science Center, Coleman Building, 956 Court Avenue, Suite H314, Memphis, TN 38163, USA.;Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.;Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.;Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.",
"authors": "Jain|Nidhi|N|;Savani|Malvi|M|;Agarwal|Manyoo|M|;Kadaria|Dipen|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2042018816658396",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2042-0188",
"issue": "7(4)",
"journal": "Therapeutic advances in endocrinology and metabolism",
"keywords": "drug reaction; insulin autoimmune syndrome; methimazole",
"medline_ta": "Ther Adv Endocrinol Metab",
"mesh_terms": null,
"nlm_unique_id": "101532143",
"other_id": null,
"pages": "178-81",
"pmc": null,
"pmid": "27540463",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "19440117;1605150;25289063;8710037;4676677;24711924;7859599;10411353;15901524;7647412;8064238;8325948;26315093;6138590;22759245;19070385",
"title": "Methimazole-induced insulin autoimmune syndrome.",
"title_normalized": "methimazole induced insulin autoimmune syndrome"
} | [
{
"companynumb": "US-APOTEX-2016AP010826",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHIMAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "Scarce literature exists regarding risk factors associated with postoperative acute kidney injury (AKI) after first-stage revision procedures. The purpose of this study was to determine risk factors for AKI and the efficacy of intra-articular antibiotics in infection eradication.\n\n\n\nWe retrospectively identified 247 patients who underwent a 2-stage revision procedure for the treatment of hip or knee periprosthetic joint infection. We applied previously published diagnostic criteria for AKI to determine its incidence and risk factors for its development.\n\n\n\nA 26% incidence of AKI was found after first-stage joint revision for infection. Higher body mass index (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.01-1.13; P = .02), lower baseline hemoglobin level (OR, 0.70; 95% CI, 0.51-0.96; P = .03), and existence of a comorbid condition (OR, 2.67; 95% CI, 1.26-5.64; P = .01) were significant risk factors for AKI. Neither a higher dose of vancomycin (OR, 0.99; 95% CI, 0.88-1.11; P = .83) nor tobramycin (OR, 0.89; 95% CI, 0.77-1.04; P = .15) used in the cement spacer increased the risk of AKI. Each unit increase in vancomycin dose in the cement spacer decreased the odds of failing to clear the infection at 1 and 2 years by a factor of 0.82 (95% CI, 0.70-0.95; P = .01).\n\n\n\nAKI after first-stage revision procedures for periprosthetic joint infection occurs more commonly than previously reported. Patients with identified risk factors should be managed carefully with attention paid to hemoglobin levels, to avoid AKI after this procedure. Further research is needed to determine the optimal local antibiotic type and dosing to maximize infection clearance and minimize potential side effects.",
"affiliations": "Department of Orthopedic Surgery, Center for Hip and Knee Replacement, Columbia University Medical Center at New York Presbyterian Hospital, New York, New York.;Department of Orthopedic Surgery, Center for Hip and Knee Replacement, Columbia University Medical Center at New York Presbyterian Hospital, New York, New York.;Department of Orthopedic Surgery, Center for Hip and Knee Replacement, Columbia University Medical Center at New York Presbyterian Hospital, New York, New York.;Department of Orthopedic Surgery, Center for Hip and Knee Replacement, Columbia University Medical Center at New York Presbyterian Hospital, New York, New York.;Department of Orthopaedic Surgery, Rothman Institute, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.",
"authors": "Geller|Jeffrey A|JA|;Cunn|Gregory|G|;Herschmiller|Thomas|T|;Murtaugh|Taylor|T|;Chen|Antonia|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin; D014031:Tobramycin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.arth.2017.04.054",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-5403",
"issue": "32(10)",
"journal": "The Journal of arthroplasty",
"keywords": "acute kidney injury; antibiotic spacer; periprosthetic joint infection; total joint arthroplasty; vancomycin",
"medline_ta": "J Arthroplasty",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D019645:Arthroplasty, Replacement, Knee; D005260:Female; D006801:Humans; D015994:Incidence; D007719:Knee Joint; D008297:Male; D008875:Middle Aged; D009518:New York; D016017:Odds Ratio; D016459:Prosthesis-Related Infections; D012086:Reoperation; D012189:Retrospective Studies; D012307:Risk Factors; D014031:Tobramycin; D014640:Vancomycin; D055815:Young Adult",
"nlm_unique_id": "8703515",
"other_id": null,
"pages": "3120-3125",
"pmc": null,
"pmid": "28578840",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Acute Kidney Injury After First-Stage Joint Revision for Infection: Risk Factors and the Impact of Antibiotic Dosing.",
"title_normalized": "acute kidney injury after first stage joint revision for infection risk factors and the impact of antibiotic dosing"
} | [
{
"companynumb": "PHHY2018US003882",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFAZOLIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "BACKGROUND\nDural venous sinus stenting (VSS) is an effective, durable treatment for patients with idiopathic intracranial hypertension (IIH) due to underlying venous sinus stenosis. However, the use of venous sinus stenting to treat IIH with acute vision loss has rarely been described.\n\n\nMETHODS\nA retrospective chart analysis identified patients who received VSS for fulminant IIH, defined as acute (< 8 weeks) visual field loss to within the central 5° and/or a decrease in visual acuity to less than or equal to 20/50 in either eye in the presence of papilledema.\n\n\nRESULTS\nTen patients were identified with average patient age of 31.0 years, and all except one were female. Mean body mass index was 41.2 kg/m2. All patients presented with vision loss and some with headache and tinnitus. The average trans-stenotic gradient pre-stenting was 28.7 mmHg (range 9-62 mmHg). All patients had diminished or resolved venous gradients immediately following the procedure. At mean follow-up of 60.5 weeks, 100% had improvements in papilledema, 80.0% had subjective vision improvement, 55.6% had headache improvement and 87.5% had tinnitus improvement. 90.0% had stable or improved visual acuity in both eyes with a mean post-stenting Snellen acuity of 20/30 and an average gain of 3 lines Snellen acuity post-stenting (95% confidence intervals 0.1185-0.4286, p = 0.0018). Two patients (20.0%) required further surgical treatment (cerebrospinal shunting and/or stenting) after their first stenting procedure.\n\n\nCONCLUSIONS\nThis series suggests that VSS is feasible in patients presenting with IIH and acute vision loss with a fairly low complication rate and satisfactory clinical outcomes.",
"affiliations": "Department of Neurological Surgery, Wake Forest Baptist Health, USA.;Department of Neurological Surgery, Wake Forest Baptist Health, USA.;Department of Ophthalmology, Wake Forest Baptist Health, USA.;Department of Neurological Surgery, Wake Forest Baptist Health, USA.;Department of Ophthalmology, Wake Forest Baptist Health, USA.;Department of Neurological Surgery, Wake Forest Baptist Health, USA.;Department of Neurological Surgery, Wake Forest Baptist Health, USA.",
"authors": "Zehri|Aqib H|AH|;Lee|Katriel E|KE|https://orcid.org/0000-0001-8367-4470;Kartchner|Jeff|J|;Arnel|Madison|M|;Martin|Timothy|T|https://orcid.org/0000-0001-7194-5560;Wolfe|Stacey Q|SQ|;Fargen|Kyle M|KM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/19714009211026923",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1971-4009",
"issue": null,
"journal": "The neuroradiology journal",
"keywords": "Venous sinus stenting; idiopathic intracranial hypertension; papilledema",
"medline_ta": "Neuroradiol J",
"mesh_terms": null,
"nlm_unique_id": "101295103",
"other_id": null,
"pages": "19714009211026923",
"pmc": null,
"pmid": "34224285",
"pubdate": "2021-07-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy of dural venous sinus stenting in treating idiopathic intracranial hypertension with acute vision loss.",
"title_normalized": "efficacy of dural venous sinus stenting in treating idiopathic intracranial hypertension with acute vision loss"
} | [
{
"companynumb": "US-BAYER-2022A029393",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Hyperammonemia has been associated with intracranial hypertension and mortality in patients with acute liver failure (ALF). We evaluated the effect of renal replacement therapy (RRT) on serum ammonia level and outcomes in ALF. This was a multicenter cohort study of consecutive ALF patients from the United States ALF Study Group registry between January 1998 and December 2016. First, we studied the association of ammonia with hepatic encephalopathy (HE) and 21-day transplant-free survival (TFS; n = 1,186). Second, we studied the effect of RRT on ammonia for the first 3 days post study admission (n = 340) and on 21-day TFS (n = 1,186). Higher admission (n = 1,186) median ammonia level was associated with grade 3-4 HE (116 vs. 83 μmol/L) and mortality at day 21 attributed to neurological (181 vs. 90 μmol/L) and all causes (114 vs. 83 μmol/L; P < 0.001 for all). Among 340 patients with serial ammonia levels, 61 (18%) were on continuous RRT (CRRT), 59 (17%) were on intermittent RRT (IRRT), and 220 (65%) received no RRT for the first 2 days. From days 1 to 3, median ammonia decreased by 38%, 23%, and 19% with CRRT, IRRT, and no RRT, respectively. Comparing to no RRT use, whereas ammonia reduction with CRRT was significant (P = 0.007), with IRRT it was not (P = 0.75). After adjusting for year of enrollment, age, etiology, and disease severity, whereas CRRT (odds ratio [OR], 0.47 [95% confidence interval {CI}, 0.26-0.82]) was associated with reduction in 21-day transplant-free all-cause mortality, IRRT (OR, 1.68 [95% CI, 1.04-2.72]) was associated with an increase. Conclusion: In a large cohort of ALF patients, hyperammonemia was associated with high-grade HE and worse 21-day TFS. CRRT was associated with a reduction in serum ammonia level and improvement of 21-day TFS. (Hepatology 2018;67:711-720).",
"affiliations": "Intensive Care Unit, Curry Cabral Hospital, Central Lisbon Hospital Center, Lisbon, Portugal.;Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.;Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX.;Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS.;Departments of Critical Care and Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Alberta, Canada.",
"authors": "Cardoso|Filipe S|FS|;Gottfried|Michelle|M|;Tujios|Shannan|S|;Olson|Jody C|JC|;Karvellas|Constantine J|CJ|0000-0002-1555-1089;|||",
"chemical_list": "D000641:Ammonia",
"country": "United States",
"delete": false,
"doi": "10.1002/hep.29488",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0270-9139",
"issue": "67(2)",
"journal": "Hepatology (Baltimore, Md.)",
"keywords": null,
"medline_ta": "Hepatology",
"mesh_terms": "D000328:Adult; D000641:Ammonia; D005260:Female; D006801:Humans; D017114:Liver Failure, Acute; D008297:Male; D008875:Middle Aged; D017582:Renal Replacement Therapy; D012189:Retrospective Studies",
"nlm_unique_id": "8302946",
"other_id": null,
"pages": "711-720",
"pmc": null,
"pmid": "28859230",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "24126646;23439263;8440100;17685471;17006913;22264279;21352532;24141714;12225610;12663235;16646985;20673233;16024550;23786538;26041966;10051463;24369077;25887923;8320931;8828772;25019700;27699760;26325537;20638564;23548002;12577144",
"title": "Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure.",
"title_normalized": "continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure"
} | [
{
"companynumb": "PT-JNJFOC-20180301596",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune dysregulation characterized by fever, hepatosplenomegaly, cytopenias, central nervous system disease, increased inflammatory markers, and hemophagocytosis. Currently, allogeneic hematopoietic stem cell transplantation is the only curative approach for patients with HLH, with reported survival ranging from 50% to 70% with myeloablative conditioning (MAC) regimens. However, donor availability and transplantation-related mortality associated with conventional MAC are major barriers to success. Unrelated umbilical cord blood transplantation (UCBT) provides a readily available alternative donor source for patients lacking matched related donors. Accordingly, we report the results of UCBT in 14 children treated between 1998 and 2016. All children received standard HLH chemotherapy before UCBT. The median age at diagnosis was 2.7 months (range, .8 to 10.4) and at transplantation was 7.5 months (range, 3.8 to 17). Ten patients received MAC with busulfan/cyclophosphamide/etoposide /antithymocyte globulin (ATG) (n = 5), busulfan/cyclophosphamide /ATG (n = 4), or busulfan /melphalan/ATG (n = 1). Four patients received reduced-toxicity conditioning (RTC) with alemtuzumab/fludarabine/melphalan/hydroxyurea ± thiotepa. Cord blood units were mismatched at either 1 (n = 9) or 2 (n = 5) loci and delivered a median total nucleated cell dose of 11.9 × 107/kg (range, 4.6 to 27.9) and CD34+ dose of 3.1 × 105/kg (range, 1.1 to 6.8). The cumulative incidence of neutrophil engraftment by day 42 was 78.6% (95% confidence interval [CI], 42.9% to 93.4%) with a median of 19 days (range, 13 to 27), and that for platelet (50,000) engraftment by day 100 was 64.3% (95% CI, 28.2% to 85.7%) with a median of 51 days (range, 31 to 94). Six patients developed either grade II (n = 5) or grade IV (n = 1) acute graft-versus-host disease (GVHD); no extensive chronic GVHD was seen. Ten patients (71.4%) are alive and well at a median of 11.2 years after transplantation (range, .85 to 18.25), 9 of whom maintain sustained full donor chimerism after a single UCBT, whereas 1 patient with autologous recovery after first UCBT with RTC has achieved full donor chimerism after a second UCBT with MAC. This series demonstrates that, in combination with standard HLH therapy, UCBT after MAC or RTC conditioning can provide long-term survival with durable complete donor chimerism comparable to that of conventional donors. UCBT should be considered for patients with HLH lacking a fully matched related or unrelated adult donor.",
"affiliations": "Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska.;Department of Pediatrics, Florida Hospital, Orlando, Florida.;Duke Translational Research Institute, Durham, North Carolina.;Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation, Duke University Medical Center, Durham, North Carolina.;Duke Translational Research Institute, Durham, North Carolina; Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation, Duke University Medical Center, Durham, North Carolina. Electronic address: suhag.parikh@duke.edu.",
"authors": "Patel|Sachit A|SA|;Allewelt|Heather A|HA|;Troy|Jesse D|JD|;Martin|Paul L|PL|;Driscoll|Timothy A|TA|;Prasad|Vinod K|VK|;Kurtzberg|Joanne|J|;Page|Kristin M|KM|;Parikh|Suhag H|SH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2017.06.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "23(10)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "HLH; Hemophagocytic lymphohistiocytosis; Pediatric; Stem cell transplantation; Umbilical cord blood transplantation",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D046528:Chimerism; D036101:Cord Blood Stem Cell Transplantation; D018572:Disease-Free Survival; D005312:Fetal Blood; D006085:Graft Survival; D006086:Graft vs Host Disease; D006801:Humans; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic; D019172:Transplantation Conditioning",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1722-1728",
"pmc": null,
"pmid": "28647558",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Durable Chimerism and Long-Term Survival after Unrelated Umbilical Cord Blood Transplantation for Pediatric Hemophagocytic Lymphohistiocytosis: A Single-Center Experience.",
"title_normalized": "durable chimerism and long term survival after unrelated umbilical cord blood transplantation for pediatric hemophagocytic lymphohistiocytosis a single center experience"
} | [
{
"companynumb": "US-TEVA-2018-US-921819",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
... |
{
"abstract": "The aim of the present study was to present a retrospective review of 42 metastatic colorectal cancer (mCRC) patients treated using the XELIRI regimen as second-line chemotherapy during the period between 2010 and 2012. Patients were treated with capecitabine, 1,600 (≥65 years) or 2,000 mg/m2 (<65 years), on days 1-15, 200 mg/m2 irinotecan (CPT-11) on day 1, with or without 7.5 mg/kg bevacizumab on day 1 and every 21 days. A total of 21 patients underwent XELIRI and 21 underwent XELIRI plus bevacizumab treatment. Fifteen patients received continuous administration of bevacizumab in the first- and second-line settings [bevacizumab beyond progression (BBP)+], whereas 27 patients did not receive the treatment (BBP-). Forty patients (95.2%), including all the patients in the BBP+ group, received sequentially administered XELOX and XELIRI regimens from the first- to the second-line setting. The disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events were compared between the BBP- and BBP+ groups. The median relative dose intensity was similar (93.9% for capecitabine and 96.3% for CPT-11 in the BBP- group vs. 94.8% for capecitabine and 91.5% for CPT-11 in the BBP+ group). The DCR was 25.9% in the BBP- and 66.6% in the BBP+ groups (P=0.020). The median PFS was 3.5 months in the BBP- and 7.2 months in the BBP+ groups (P=0.028). The BBP+ group exhibited a higher median OS time compared to the BBP- group (12.5 months in the BBP- group vs. not reached in the BBP+ group; P=0.0267). The most common grade 3/4 adverse event (n≥20) was hypertension observed in the BBP+ group [three patients (20%)]: these three patients were well-controlled with a single antihypertensive drug. Treatment with sequentially administered XELOX and XELIRI regimens did not aggravate adverse events in the 40 patients. The results showed that the XELIRI regimen, involving continuous treatment with bevacizumab, was well-tolerated and effective as a second-line chemotherapy and sequentially administering XELOX and XELIRI was feasible and manageable for patients with mCRC.",
"affiliations": "Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan.;Nerima-Hikarigaoka Hospital, Tokyo 179-0072, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan.",
"authors": "Suzuki|Koichi|K|;Takaharu|Kato|K|;Muto|Yuta|Y|;Ichida|Kosuke|K|;Fukui|Taro|T|;Takayama|Yuji|Y|;Tsujinaka|Shingo|S|;Sasaki|Junichi|J|;Horie|Hisanaga|H|;Kawamura|Yutaka J|YJ|;Konishi|Fumio|F|;Rikiyama|Toshiki|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2014.306",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "2(5)",
"journal": "Molecular and clinical oncology",
"keywords": "XELIRI; XELOX; bevacizumab; capecitabine; irinotecan; metastatic colorectal cancer",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "827-832",
"pmc": null,
"pmid": "25054053",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": "17558305;17008691;18640933;23352604;23463625;17947725;11156391;18421054;23168366;15007088",
"title": "XELIRI regimen plus continuous treatment with bevacizumab is well-tolerated and effective in metastatic colorectal cancer patients in a second-line setting involving the sequential administration of XELOX and XELIRI.",
"title_normalized": "xeliri regimen plus continuous treatment with bevacizumab is well tolerated and effective in metastatic colorectal cancer patients in a second line setting involving the sequential administration of xelox and xeliri"
} | [
{
"companynumb": "JP-ROCHE-1442858",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "OBJECTIVE\nHerpes simplex virus (HSV) encephalitis continues to be the most common form of sporadic lethal encephalitis worldwide. The wide spectrum of clinical presentations and laboratory findings often poses a diagnostic challenge for physicians which might delay administration of life-saving therapy with acyclovir. Atypical presentations of HSV encephalitis have become increasingly prevalent with better diagnostic techniques and have not been well studied.\n\n\nMETHODS\nWe retrospectively evaluated all consecutive PCR-proven HSV encephalitis cases treated at the Hospital of the Ludwig-Maximilians-University in Munich, Germany from January 1, 2013 to February 28, 2018.\n\n\nRESULTS\nWe included 18 patients with PCR-proven HSV encephalitis. The most common clinical features were altered mental status (77.8%), focal neurologic deficits (72.2%) and fever (72.2%). Remarkably, four of these patients (22.2%) had a normocellular cerebrospinal fluid (CSF) on admission. Electroencephalography and magnetic resonance imaging abnormalities were highly sensitive for HSV encephalitis independent of CSF cell count. Striking atypical findings on MRI were extensive global brain swelling and severe brainstem involvement in single patients. Of note, initial CT scans were normal in 11 out of 16 patients (68.8%). All patients were treated with acyclovir. Three patients still developed a clinical deterioration under therapy with acyclovir with one patient requiring decompressive craniotomy due to bilateral space-occupying temporal lobe hemorrhage. 94.4% of the patients survived but only 38.9% were discharged with a good clinical outcome (Glasgow Outcome Score = 5).\n\n\nCONCLUSIONS\nAtypical presentations of HSV encephalitis seem to be more common than previously thought and physicians should apply a high level of clinical suspicion and a low threshold to initiate life-saving acyclovir therapy in suspected cases.",
"affiliations": "Department of Neurology, Klinikum der Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany.;Department of Neurology, Klinikum der Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany.;Department of Neuroradiology, Klinikum der Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany.;Department of Neurology, Klinikum der Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany.;Department of Neurology, Klinikum der Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany.;Department of Neurology, Klinikum der Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany.;Department of Neurology, Klinikum der Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany. matthias.klein@med.uni-muenchen.de.",
"authors": "Bewersdorf|Jan Philipp|JP|;Koedel|Uwe|U|;Patzig|Maximilian|M|;Dimitriadis|Konstantinos|K|;Paerschke|Grit|G|;Pfister|Hans-Walter|HW|;Klein|Matthias|M|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-018-1257-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "47(2)",
"journal": "Infection",
"keywords": "Acyclovir; Encephalitis; Foscarnet; Herpes simplex virus (HSV); Neuroradiologic imaging; Normocellular",
"medline_ta": "Infection",
"mesh_terms": "D000212:Acyclovir; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents; D001921:Brain; D015331:Cohort Studies; D020803:Encephalitis, Herpes Simplex; D005260:Female; D005858:Germany; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D055815:Young Adult",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "267-273",
"pmc": null,
"pmid": "30506479",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": "10770879;19201192;195208;19581112;20121412;20952256;23136265;23861361;23886833;24582285;24768322;2544743;25637586;25956891;26096420;26387515;26879928;27171421;27185323;28090058;28419350;28627955;29057131;29249385;6877301",
"title": "Challenges in HSV encephalitis: normocellular CSF, unremarkable CCT, and atypical MRI findings.",
"title_normalized": "challenges in hsv encephalitis normocellular csf unremarkable cct and atypical mri findings"
} | [
{
"companynumb": "DE-GLAXOSMITHKLINE-DE2018GSK231591",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": "3",... |
{
"abstract": "Switch strategies based on rilpivirine/tenofovir/emtricitabine or on an integrase inhibitor (InSTI) plus tenofovir/emtricitabine have never been compared in randomized clinical trials. The main aim of the study was to investigate the durability of these two switch regimens in virologically suppressed, HIV-infected patients.\n\n\n\nRetrospective analysis of patients who started rilpivirine or an InSTI (both with tenofovir and emtricitabine) with <50 HIV-RNA copies/mL and had at least one HIV-RNA assessed while receiving the study regimen. Virological failure (VF) was defined as two consecutive measurements of HIV-RNA >50 copies/mL. Treatment failure (TF) was define as either VF or discontinuation of any drug of the regimen. Durability was assessed by the Kaplan-Meier method and compared by Log-rank test. Residual viremia was defined as any detectable HIV-RNA below 50 copies/mL, as assed by a real-time PCR assay.\n\n\n\nSix hundred seventy-five patients (466 switched to a rilpivirine-, 209 switched to an InSTI-based regimen [18% dolutegravir, 39% raltegravir, 43% elvitegravir/cobicistat] were included in the analysis. The median (interquartile range, IQR) follow-up in the rilpivirine and in the InSTI group was 16.7 (8.8-22.2) and 10.4 (5.4-19.6) months. The 1-year cumulative probabilities (95%CI) of VF and TF were 0.97% (0.36%-2.62%) and 9.73% (7.21%-13.06%) in the rilpivirine group and 1.83% (0.57%-5.77%) and 8.75% (5.25%-14.4%) in the InSTI group, with no difference between groups (p = 0.328 and 0.209 for VF and TF). The proportion of time spent with residual viremia was comparable in the two groups (9% [IQR 0.5%-49%] and 17% [IQR 0.5%-50%] in the rilpivirine and in the InSTI group, p = 0.087). By the multivariable Cox regression model, TF was independently associated with being on therapy with a protease inhibitor vs. a non-nucleoside reverse transcriptase inhibitor at switch (AHR = 0.52; 95%CI = 0.31-0.90; p = 0.018), baseline total/HDL-cholesterol ratio (AHR = 1.19 per 0.5-units increments; 95%CI = 1.06-1.34; p = 0.004), baseline estimated glomerular filtration rate (AHR = 0.78 per 10-units increments; 95%CI = 0.67-0.90; p = 0.001) and baseline hemoglobin (AHR = 0.78 per 1-unit increments; 95%CI = 0.64-0.94; p = 0.009), but not with treatment group (rilpivirine vs. InSTI).\n\n\n\nIn our clinical practice, the durability of the two regimens was comparable and both showed a very low probability of VF.",
"affiliations": "Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127, Milan, Italy. gianotti.nicola@hsr.it.;Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127, Milan, Italy.;Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127, Milan, Italy.;Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127, Milan, Italy.;Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127, Milan, Italy.;Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127, Milan, Italy.;Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127, Milan, Italy.;Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127, Milan, Italy.;Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127, Milan, Italy.;Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127, Milan, Italy.;Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127, Milan, Italy.",
"authors": "Gianotti|Nicola|N|0000-0002-7182-5080;Poli|Andrea|A|;Nozza|Silvia|S|;Galli|Laura|L|;Galizzi|Nadia|N|;Ripa|Marco|M|;Merli|Marco|M|;Carbone|Alessia|A|;Spagnuolo|Vincenzo|V|;Lazzarin|Adriano|A|;Castagna|Antonella|A|",
"chemical_list": "D019428:HIV Integrase Inhibitors; D000068698:Tenofovir; D000068696:Rilpivirine; D000068679:Emtricitabine",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-017-2831-9",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 283110.1186/s12879-017-2831-9Research ArticleDurability of switch regimens based on rilpivirine or on integrase inhibitors, both in association with tenofovir and emtricitabine, in HIV-infected, virologically suppressed patients http://orcid.org/0000-0002-7182-5080Gianotti Nicola +390226437906gianotti.nicola@hsr.it 1Poli Andrea poli.andrea@hsr.it 1Nozza Silvia nozza.silvia@hsr.it 1Galli Laura galli.laura@hsr.it 1Galizzi Nadia galizzi.nadia@hsr.it 12Ripa Marco ripa.marco@hsr.it 12Merli Marco merli.marco@hsr.it 1Carbone Alessia carbone.alessia@hsr.it 1Spagnuolo Vincenzo spagnuolo.vincenzo@hsr.it 12Lazzarin Adriano lazzarin.adriano@hsr.it 12Castagna Antonella castagna.antonella1@hsr.it 121 0000000417581884grid.18887.3eInfectious Diseases, San Raffaele Scientific Institute, Via Stamira d’Ancona 20, 20127 Milan, Italy 2 grid.15496.3fUniversità Vita-Salute San Raffaele, Milan, Italy 16 11 2017 16 11 2017 2017 17 72313 6 2017 12 11 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\nSwitch strategies based on rilpivirine/tenofovir/emtricitabine or on an integrase inhibitor (InSTI) plus tenofovir/emtricitabine have never been compared in randomized clinical trials. The main aim of the study was to investigate the durability of these two switch regimens in virologically suppressed, HIV-infected patients.\n\nMethods\nRetrospective analysis of patients who started rilpivirine or an InSTI (both with tenofovir and emtricitabine) with <50 HIV-RNA copies/mL and had at least one HIV-RNA assessed while receiving the study regimen. Virological failure (VF) was defined as two consecutive measurements of HIV-RNA >50 copies/mL. Treatment failure (TF) was define as either VF or discontinuation of any drug of the regimen. Durability was assessed by the Kaplan-Meier method and compared by Log-rank test. Residual viremia was defined as any detectable HIV-RNA below 50 copies/mL, as assed by a real-time PCR assay.\n\nResults\nSix hundred seventy-five patients (466 switched to a rilpivirine-, 209 switched to an InSTI-based regimen [18% dolutegravir, 39% raltegravir, 43% elvitegravir/cobicistat] were included in the analysis.\n\nThe median (interquartile range, IQR) follow-up in the rilpivirine and in the InSTI group was 16.7 (8.8–22.2) and 10.4 (5.4–19.6) months. The 1-year cumulative probabilities (95%CI) of VF and TF were 0.97% (0.36%–2.62%) and 9.73% (7.21%–13.06%) in the rilpivirine group and 1.83% (0.57%–5.77%) and 8.75% (5.25%–14.4%) in the InSTI group, with no difference between groups (p = 0.328 and 0.209 for VF and TF). The proportion of time spent with residual viremia was comparable in the two groups (9% [IQR 0.5%–49%] and 17% [IQR 0.5%–50%] in the rilpivirine and in the InSTI group, p = 0.087).\n\nBy the multivariable Cox regression model, TF was independently associated with being on therapy with a protease inhibitor vs. a non-nucleoside reverse transcriptase inhibitor at switch (AHR = 0.52; 95%CI = 0.31–0.90; p = 0.018), baseline total/HDL-cholesterol ratio (AHR = 1.19 per 0.5-units increments; 95%CI = 1.06–1.34; p = 0.004), baseline estimated glomerular filtration rate (AHR = 0.78 per 10-units increments; 95%CI = 0.67–0.90; p = 0.001) and baseline hemoglobin (AHR = 0.78 per 1-unit increments; 95%CI = 0.64–0.94; p = 0.009), but not with treatment group (rilpivirine vs. InSTI).\n\nConclusions\nIn our clinical practice, the durability of the two regimens was comparable and both showed a very low probability of VF.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12879-017-2831-9) contains supplementary material, which is available to authorized users.\n\nKeywords\nRilpivirineRaltegravirElvitegravir/cobicistatDolutegravirNon-nucleoside reverse transcriptase inhibitorsIntegrase inhibitorsSwitch regimenResidual viremiaVirological suppressionissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nRandomized clinical trials support the switch both to the fixed dose combination (FDC) of rilpivirine/tenofovir disoproxil fumarate/emtricitabine from a ritonavir-boosted protease inhibitor (PI/r) and to regimens based on integrase strand transfer inhibitors (InSTI) from any kind of antiretroviral therapy. In the SPIRIT Study switching from a regimen based on a PI/r to the FDC of rilpivirine/tenofovir/emtricitabine was not inferior to continuing the PI/r, with virological success in 93,7% and 89,9% of patients at 48 weeks [1]. Non-inferiority was shown also for switching from the FDC of efavirenz/tenofovir disoproxil fumarate/emtricitabine to rilpivirine/tenofovir alafenamide/emtricitabine [2], as well as for switching from a PI/r to raltegravir [3], from a regimen based on a non-nucleoside reverse transcriptase inhibitor (NNRTI) to the FDC of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate [4] or from any regimen to the FDC of dolutegravir/abacavir/lamivudine [5]. By contrast, in the STRATEGY-PI Study, switching from a PI/r to the FDC of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate was superior in terms of virological success (93,8% vs. 87,1%) and improved patients related outcomes [6], while switching from lopinavir/ritonavir to raltegravir (without changing the nucleoside backbone) was associated with a higher incidence of virological failure [7].\n\nHowever, these switch strategies have never been compared in randomized clinical trials and it is very unlikely that such a trial will be performed.\n\nThe aim of this study was two-fold: first, we aimed at identifying factors associated with the choice of a FDC of rilpivirine/tenofovir/emtricitabine vs. an InSTI-based switch regimen; secondly, we aimed at investigating the durability of rilpivirine/tenofovir/emtricitabine and of InSTI-based switch regimens (when associated to tenofovir disoproxil fumarate/emtricitabine, TDF/FTC) in virologically suppressed HIV-infected patients in clinical practice.\n\nMethods\nRetrospective cohort study on patients followed at the Infectious Diseases Department of the San Raffaele Scientific Hospital in Milan (Italy). Data recorded in the database of the Infectious Diseases Department of the San Raffaele Hospital (IDD-HSR) were used for the analyses. At their first visit in our clinic, subjects provide written informed consent to include their clinical and laboratory data in the IDD-HSR for scientific purposes. The study was approved by the ethics committee of the San Raffaele Scientific Institute.\n\nEligible patients were those who started rilpivirine or an InSTI (both along with TDF and FTC) with <50 HIV-RNA copies/mL and had at least one HIV-RNA assessed while receiving the study regimen. Patients who switched to one of the study regimens since 2008 (date of availability of raltegravir in Italy) were included in the analyses. Patients were followed up to virological failure (VF) or discontinuation of any drug or data freezing (8th September 2015), whichever occurred first.\n\nEstimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration Equation (CKD-EPI) [8] and the liver fibrosis FIB-4 index was calculated as described [9].\n\nHIV-RNA was quantified by using the kinetic PCR molecular system (kPCR, Versant HIV-1 RNA kPCR 1.0; Siemens HealthCare Diagnostics, Tarrytown, NY, USA) up to March 2014 and by using the Abbot Real-Time PCR (Abbott Molecular, Des Plaines, IL, USA) thereafter. The kPCR assay gives three possible outputs: (i) a quantitative result for HIV-RNA values of ≥37 copies/mL; (ii) a semiquantitative result (detectable below 37 copies/mL) when HIV RNA is detectable but not precisely quantifiable; (iii) a qualitative result (‘undetectable’) when no signal can be detected. The Abbot Real-Time PCR assay gives also three possible outputs: (i) a quantitative result for HIV RNA values of ≥40 copies/mL; (ii) a semiquantitative result (detectable below 40 copies/mL) when HIV RNA is detectable but not precisely quantifiable; (iii) a qualitative result (‘undetectable’) when no signal can be detected.\n\nVF was defined as two consecutive measurements of HIV-RNA >50 copies/mL or a single HIV-RNA >50 copies/mL followed by ART modification; an unconfirmed HIV-RNA >50 copies/mL (i.e. one measurement >50 copies/mL preceded and followed by a measurement <50 copies/mL), not followed by ART modification, was defined as viral blip. Residual viremia was defined as any detectable HIV-RNA below 50 copies/mL, as assed by Siemens kPCR or by Abbot Real-Time PCR.\n\nTime spent with residual viremia was calculated as a proportion of time with residual viremia on observed follow-up. If between 2 observation the viremia changed from undetectable to residual or vice-versa, the time spent considered in this interval was the half. The mathematical formula was: T%=∑i=1i=jti−ti−1attot⋅100 where t is the time length of interval i, j is the last observation and t\ntot is the patient’s cumulative follow-up. If, during the i\nth interval, viremia changed from undetectable to residual or vice-versa, then a = 2, else a = 1.\n\nTreatment failure (TF) was define as either VF or discontinuation (for any length) of any drug of the regimen, for any reason. Causes of change in the regimen were reviewed independently by two clinicians; discordances were discussed and reconciled.\n\nDescriptive data are expressed as median (interquatile range) of frequency (%), as appropriate.\n\nChi-square and Mann-Whitney tests were used to evaluate differences between the two groups for categorical and continuous variables respectively. Durability was assessed by the Kaplan-Meier curve and compared by Log-rank test. Multivariable logistic regression was used to identify predictors of opting for an InSTI- rather than a rilpivirine-based regimen and a multivariable Cox regression model was used to identify factors independently associated with TF.\n\nAll of the statistical tests were two-sided at 5% level, and were performed using SAS Software (release 9.2; SAS Institute).\n\nResults\nSix hundred seventy-five patients (466 switched to a rilpivirine-, 209 switched to an InSTI-based regimen [18% dolutegravir, 39% raltegravir, 43% elvitegravir/cobicistat]), on antiretroviral therapy since 6.6 [3.3–14.1] years and with HIV-RNA <50 copies/mL since 3.1 [1.1–5.6] years, were included in the analysis; their baseline characteristics are illustrated in Table 1 and in the Additional file 1: Table S1. Dolutegravir was used at a daily dose 50 mg in all cases, raltegravir at the standard dose of 400 mg twice daily and elvitegravir/cobicistat was always co-formulated with TDF/FTC).Table 1 Baseline characteristics\n\n\tOverall (n = 675)\tInSTI + TDF/FTC (n = 209)\tRPV/FTC/TDF (n = 466)\t\np-value\t\nAge (years)\n\t46.2 (39.9–51.6)\t48.7 (41.8–53.3)\t45.4 (39.2–50.7)\t0.0002\t\nMale gender\t578(86%)\t174(83%)\t404(87%)\t0.238\t\nHIV risk factor\t\t\t\t<0.0001\t\nMSM\t330(49%)\t78(37%)\t252(54%)\t\t\nHeterosexual\t134(20%)\t38(18%)\t96(21%)\t\t\nIDU\t88(13%)\t49(23%)\t39(8%)\t\t\nOther/Unknown\t123(18%)\t44(21%)\t79(17%)\t\t\nYears since HIV diagnosis\t10.3 (5.1–17.3)\t13.8 (6.6–22.5)\t9.1 (4.8–15.5)\t<0.0001\t\nHistory of AIDS defining events\t78(12%)\t26(12%)\t52(11%)\t0.696\t\nYears of ART\t6.6 (3.3–14.1)\t10.1 (4.0–16.8)\t5.7 (3.0–11.9)\t<0.0001\t\nNRTI-experience\t661(98%)\t206(99%)\t455(98%)\t0.567\t\nNNRTI-experience\t326 (48%)\t88 (42%)\t238 (51%)\t0.037\t\nPI-experience\t533 (79%)\t193 (92%)\t340 (73%)\t<0.0001\t\nYears with HIV-RNA <50copies/mL\t3.07 (1.07–5.62)\t2.96 (0.77–6.12)\t3.09 (1.25–5.46)\t0.493\t\nTime spent with residual viremia (%)\t47.8 (23.9–74.1)\t51.7 (22.1–74.2)\t46.4 (24.3–73.6)\t0.437\t\nHistory of failure to NRTIs\t130 (19%)\t70 (34%)\t60 (13%)\t<0.0001\t\nHistory of failure to NNRTIs\t32 (5%)\t22 (11%)\t10 (2%)\t<0.0001\t\nHistory of failure to PIs\t110 (16%)\t54 (26%)\t56 (12%)\t<0.0001\t\nType of treatment\t\t\t\t<0.0001\t\nPI-based\t438 (65%)\t172 (82%)\t266 (57%)\t\t\nNNRTI-based\t205 (30%)\t24 (12%)\t181 (39%)\t\t\nOther\t32 (5%)\t13 (6%)\t19 (4%)\t\t\nNadir CD4+ count (cell/μL)\n\t271 (160–384)\t228 (122–336)\t289 (205–397)\t<0.0001\t\nZenith HIV-RNA before starting ART (log\n10\ncopies/mL)\n\t4.85 (4.08–5.32)\t4.97 (4.11–5.40)\t4.80 (4.08–5.29)\t0.187\t\nCD4+ (cell/μL)\n\t679 (517–868)\t663 (451–854)\t687 (542–870)\t0.017\t\nHCV-Ab+\t159 (24%)\t82 (39%)\t77 (17%)\t<0.0001\t\nALP (U/L)\n\t87 (69–106)\t93 (73–110)\t86 (69–105)\t0.040\t\nALT (U/L)\n\t31 (22–47)\t34 (22–63)\t30 (22–43)\t0.001\t\nTotal bilirubin (mg/dL)\n\t0.57 (0.34–1.44)\t0.68 (0.41–1.71)\t0.50 (0.32–1.37)\t0.003\t\nFIB-4\t0.89 (0.65–1.27)\t1.08 (0.72–1.64)\t0.84 (0.61–1.12)\t<0.0001\t\neGFR (ml/min/1.73m\n2\n)\n\t104 (93–113)\t102 (90–111)\t105 (95–114)\t0.013\t\nProteinuria (mg/dL)\n\t5 (0–10)\t5 (0–10)\t5 (0–10)\t0.858\t\nTotal cholesterol (mg/dL)\n\t191 (162–219)\t191 (159–216)\t191 (164–222)\t0.168\t\nLDL cholesterol (mg/dL)\n\t119 (95–144)\t117 (91–145)\t120 (97–144)\t0.407\t\nHDL cholesterol (mg/dL)\n\t45 (38–55)\t42 (36–51)\t47 (40–58)\t<0.0001\t\nTotal/HDL cholesterol\t4.25 (3.37–5.18)\t4.56 (3.43–5.23)\t4.18 (3.36–5.07)\t0.045\t\nTriglycerides (mg/dL)\n\t122 (86–180)\t137 (98–215)\t117 (82–166)\t0.0002\t\nGlucose (mg/dL)\n\t85 (78–93)\t87 (80–96)\t84 (78–91)\t0.001\t\nHemoglobin (10\n9\n/L)\n\t15.1 (14.1–15.7)\t14.9 (14.1–15.7)\t15.1 (14.2–15.7)\t0.315\t\nPhosphate (mmol/L)\n\t0.98 (0.86–1.10)\t0.99 (0.85–1.13)\t0.98 (0.87–10.8)\t0.621\t\n\nALP Alkaline phosphatase, ALT Alanine aminotransferase, ART Antiretroviral therapy, eGFR Estimated glomerular filtration rate, FIB-4 Liver fibrosis-4 index, HCV-Ab Anti-hepatitis C antibodies, HDL High density lipoprotein, IDU Intravenous drug user, InSTI Integrase strand transfer inhibitor, LDL Low density lipoprotein, MSM Man who have sex with men, NNRTI Non-nucleoside reverse transcriptase inhibitor, NRTIs Nucleoside reverse transcriptase inhibitors, PI Protease inhibitor, RPV/FTC/TDF Rilpivirine/tenofovir disoproxil fumarate/emtricitabine, TDF/FTC Tenofovir disoproxil fumarate/emtricitabine\n\n\n\n\nAfter adjusting for age, gender, HIV risk factor, higher HIV-RNA value before starting ART, nadir and baseline CD4+ count, baseline triglycerides and cholesterol, history of failure to nucleoside reverse transcriptase inhibitors (NRTIs) or to non-NRTIs (NNRTIs), opting for an InSTI- rather than a rilpivirine-based regimen was more likely in subjects co-infected with HCV (OR = 2.16; 95%CI = 1.26–3.71; p = 0.015), with longer exposure to antiretroviral therapy (OR = 1.05 per year longer; 95%CI = 1.01–1.09; p = 0.042) and shorter time with undetectable viremia (OR = 0.93 per year longer; 95%CI = 0.86–0.99; p = 0.041), treated with protease inhibitors (PIs) vs NNRTIs (OR = 5.14; 95%CI = 3.09–8.95;p = 0.003), and treated with regimens not based on a PI/r and not based on a NNRTI vs those treated with NNRTIs (OR = 5.67; 95%CI = 2.22–14.38;p = 0.032).\n\nThe median (interquartile range, IQR) follow-up in the rilpivirine and in the InSTI group was 16.7 (8.8–22.2) and 10.4 (5.4–19.6) months. Four (0.9%) and three (1.4%) patients showed VF at 1 year in the rilpivirine and in the InSTI group; cumulatively, 12 patients (8 [1.7%] in the rilpivirine and 4 [1.9%] in the InSTI group) showed VF during follow-up: their characteristics at VF are detailed in Table 2. TFs at 1 year were 38 (8.2%) and 14 (6.7%) in the rilpivirine and in the InSTI group. The 1-year cumulative probabilities (95%CI) of VF and TF were 0.97% (0.36%–2.62%) and 9.73% (7.21%–13.06%) in the rilpivirine group and 1.83% (0.57%–5.77%) and 8.75% (5.25%–14.4%) in the InSTI group, with no difference between groups (p = 0.328 and 0.209 for VF and TF; Fig. 1, panel A and B).Table 2 Patients’ characteristics at virological failure\n\nPatient ID\tPrevious resistance mutations\tNadir CD4+ (cells/μL)\tHIV-RNA zenith (copies/mL)\tCD4 + (cells/μL) at baseline\tHIV-RNA at baseline\t3rd drug\tCD4 + (cells/μL) at failure\tHIV-RNA (copies/mL) at failure\tHistory of NRTI failure\tHistory of NNRTI failure\tHistory of PI failure\tNRTI mutations\tNNRTI mutations\tPI mutations\tInSTI mutations\t\n1412\tN/A\t258\t500.000\t675\tUndetectable\tRPV\t691\t69\tYes\tNo\tYes\tNone\tNone\tNone\tNone\t\n1428\tN/A\t200\t1.400.000\t700\tResidual viremia\tRAL\t356\t11.236\tYes\tYes\tYes\tM41 L, M184 V, L210 W, T215Y\tK103 N, V108I\tNone\tN155H\t\n2718\tN/A\t245\t350.000\t922\tUndetectable\tRPV\t660\t27.823\tNo\tNo\tNo\tM41 L, K65R, D67N, M184 V\tY181V\tM46I\tNone\t\n4418\tN/A\t229\t751.000\t674\tResidual viremia\tRPV\t578\t4.737\tNo\tNo\tNo\tA62V, K65R, M184 V\tV106I, E138K, H221Y\tNone\tN/A\t\n5443\tN/A\t113\t1.978.100\t694\tResidual viremia\tRPV\t648\t367\tNo\tNo\tNo\tN/A\tN/A\tN/A\tN/A\t\n5799\tN/A\t324\t70.000\t653\tResidual viremia\tRAL\t594\t138\tYes\tNo\tNo\tN/A\tN/A\tN/A\tNone\t\n5967\tN/A\t182\t78,674\t1166\tUndetectable\tRPV\t1083\t326\tNo\tNo\tNo\tD67N, K70R, M184 V, T215I, K219E\tL100I, K103 N, V179 T\tNone\tNone\t\n6264\tN/A\t374\t570\t904\tResidual viremia\tRAL\t697\t216\tNo\tNo\tNo\tN/A\tN/A\tN/A\tN/A\t\n7165\tNone\t488\t1.492.000\t995\tUndetectable\tRPV\t1224\t181\tNo\tNo\tNo\tN/A\tN/A\tN/A\tN/A\t\n8270\tNone\t108\t374.400\t444\tUndetectable\tRPV\t598\t89\tYes\tNo\tYes\tN/A\tN/A\tN/A\tN/A\t\n9037\tNone\t283\t46.291\t921\tUndetectable\tRPV\t1067\t104\tNo\tNo\tNo\tN/A\tN/A\tN/A\tN/A\t\n9827\tN/A\t95\t279\t113\tResidual viremia\tEVG/COBI\t174\t52\tNo\tNo\tNo\tN/A\tN/A\tN/A\tNone\t\n\nEVG/COBI Elvitegravir/cobicistat, InSTI Integrase strand transfer inhibitor, N/A Not available, NNRTI Non-nucleoside reverse transcriptase inhibitor, NRTIs Nucleoside reverse transcriptase inhibitors, PI Protease inhibitor, RAL Raltegravir, RPV Rilpivirine\n\n\nFig. 1 Cumulative probabilities of virological failure (Panel a) and of treatment failure (Panel b) after switch to a rilpivirine- and or to an integrase inhibitor (InSTI)-based regimen. RPV: rilpivirine; InSTI: integrase strand transfer inhibitor; FTC: emtricitabine; TDF: ftenofovir disoproxil fumarate\n\n\n\n\nThe incidence rate (IR) (95%CI) of viral blips was 4.46 (3.07–6.27) and 4.48 (2.51–7.40) per 1000 person months of follow-up in the rilpivirine and in the InSTI group (p = 0.988).\n\nThe proportion of time spent with residual viremia was comparable in the two groups (9% [IQR 0.5%–49%] and 17% [IQR 0.5%–50%] in the rilpivirine and in the InSTI group, p = 0.087).\n\nOverall, 62/466 (13.3%) and 41/209 (19.6%) patients in the rilpivirine and in the InSTI group discontinued at least one drug of the regimen for any reason. Discontinuations were due to toxicity in 34 (7%) and in 17 (8%) patients in the rilpivirine and in the InSTI group. Of the 51 discontinuations occurred because of toxicity, 28 (55%) were deemed tenofovir toxicity (15 [3.2%] and 13 [6.2%] in the rilpivirine and in the InSTI group); other leading causes of discontinuation were non-tenofovir related toxicity or untoward drug interactions (19 [4.1%] and 4 [1.9%] in the rilpivirine and in the InSTI group) and treatment simplification (none and 12 [5.7%] in the rilpivirine and in the InSTI group).\n\nNon-tenofovir related toxicities leading to discontinuation were: liver toxicity in 9 (2%), gastrointestinal toxicity in 5 (1%), central nervous system toxicity in 4 (1%) and undefined toxicity in one further patient in the rilpivirine group, liver toxicity in 1 (<1%) and central nervous system toxicity in 1 (<1%) in the InSTI group. Three (1.5%) patients in the InSTI group discontinued for untoward drug interactions.\n\nOf note, discontinuations occurred in 37/82 (45%) patients who started raltegravir; 27 of these 37 patients (73%) discontinued only raltegravir; the main reason for raltegravir discontinuation was treatment simplification (12/27 [44%]).\n\nBy the multivariable Cox regression model, TF was independently associated with being on therapy with a PI vs. a NNRTI at switch (AHR = 0.52; 95%CI = 0.31–0.90; p = 0.018), baseline total/HDL-cholesterol ratio (AHR = 1.19 per 0.5-units increments; 95%CI = 1.06–1.34; p = 0.004), baseline eGFR (AHR = 0.78 per 10-units increments; 95%CI = 0.67–0.90; p = 0.001) and baseline hemoglobin (AHR = 0.78 per 1-unit increments; 95%CI = 0.64–0.94; p = 0.009), whereas treatment group (rilpivirine vs. InSTI), HCV-coinfection, nadir and baseline CD4+ cell count, time with HIV-RNA <50 copies/mL, time spent with residual viremia, years of antiretroviral therapy, failure to NRTIs, failure to NNRTIs, failure to PIs, triglycerides and FIB-4 were not. No violation of the proportional hazard assumption was detected using graphical representation (Log-log plot).\n\nDiscussion\nIn this non-randomized study, the efficacy of switching to a FDC of rilpivirine/tenofovir disoproxil fumarate/emtricitabine was similar to that of switching to an InSTI plus tenofovir disoproxil fumarate/emtricitabine-based regimen: both the virological outcomes and treatment discontinuations were similar. As regards to virological outcomes, not only the cumulative risk of virological failure was very low and similar for both regimens, but also the incidence of viral blips and the exposure to residual viremia during follow-up were not statistically different. This suggest that both of these types of switch regimen can be safely used in clinical practice.\n\nHowever, among patients switched to InSTI, most discontinuation occurred in those switched to raltegravir: this suggests clinician should preferentially switch patients virologically suppressed to a once-daily regimen.\n\nA lower risk of failure was observed in patients switched from PIs: our hypothesis is that patients switched from a PI to a PI-sparing regimen have a greater improvement in symptoms than those switched from NNRTI to another NNRTI or to a InSTI-based regimen. Indeed, the only switch study in which the superiority of the switch strategy was demonstrated was the STRATEGY-PI [6]: in this randomized clinical trial, patients who underwent treatment switch to a FDC of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine had a significant improvement in several PI-related symptoms (mainly gastrointestinal). On the contrary, in studies with comparable design, switching from a NNRTI to a FDC of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine was not superior to continuing the NNRTI [4], as well as switching from a FDC of efavirenz/tenofovir disoproxil fumarate/emtricitabine to rilpivirine/tenofovir alafenamide/emtricitabine did not resulted superior to continuing efavirenz/tenofovir disoproxil fumarate/emtricitabine [2].\n\nAlthough nonspecific, hemoglobin is a marker of the general health status; it has been also associated with mortality in HIV-infected patients [10]: thus, it not surprising that in our analysis it was independently associated with TF, as it is conceivable that patients with a worse general health status are more prone to interrupt or change drugs for toxicity issues. Patients with a higher baseline total/HDL-cholesterol ratio are those with greater metabolic problems: it is likely that, in these cases, treatment was then further modified, in the attempt of normalizing the dyslipidemia. The greater risk of TF in patients with lower eGFR value is consistent with the observation that a major cause of TF in our study was toxicity due to TDF.\n\nOverall, the results of our study confirm, in a large, unselected population, the safety and the efficacy of switch regimens based on either rilpivirine or InSTI demonstrated in randomized clinical trials [1–6], thus providing useful data for clinical decision making.\n\nWith this study, we also aimed at identifying clinical reasons for opting for an InSTI- rather than a rilpivirine-based switch strategy in everyday clinical practice; this because there are no data from randomized clinical trials guiding clinicians in this decision and the results from switch trials do not clear indicate which is the best switching strategy. The results of our analysis showed that we preferentially opted for InSTI in patients with HCV co-infection, a longer ART duration, a shorter time of HIV suppression, an ongoing treatment with PIs. Possible drivers of these preferences are likely related to the common belief that NNRTIs entail greater liver toxicity (at least among persons co-infected with HCV) [11–13], to the results of the STRATEGY-PI study (which showed the superiority of this strategy compared to continuing on a PI) [6] and to the belief that InSTI are more potent than NNRTIs, thus favoring this strategy in patients a shorter time of viral suppression when a decision on whether or not switching has to be taken.\n\nMajor limitations of this study are the lack of randomization and the fact that the patients switched to rilpivirine/tenofovir disoproxil fumarate/emtricitabine were different from those switched to an InSTI in many baseline clinical features; however, after adjustment for these differences, the multivariable analysis confirmed that switching to a regimen rather than the other was not independently associated to TF.\n\nConclusions\nIn our clinical practice, the durability of switch regimens based on rilpivirine and on InSTI (along with TDF and FTC) was comparable and both showed a very low probability of VF.\n\nAdditional file\n\nAdditional file 1: Specific PIs and NNRTIs ongoing at baseline. (DOCX 12 kb)\n\n\n\n\nAbbreviations\nAHRAdjuster hazard ratio\n\nALPAlkaline phosphatase\n\nALTAlanine aminotransferase\n\nARTAntiretroviral therapy\n\nASTAspartate aminotransferase\n\nCIConfidence interval\n\nCKD-EPIChronic Kidney Disease Epidemiology Collaboration Equation\n\neGFREstimated glomerular filtration rate\n\nEVG/COBIElvitegravir/cobicistat\n\nFDCFixed dose combination\n\nFIB-4Liver fibrosis-4 index\n\nHCV-AbAnti-hepatitis C antibodies\n\nHDLHigh density lipoprotein\n\nIDD-HSRInfectious Diseases Department San Raffaele Hospital\n\nIDUIntravenous drug user\n\nInSTIIntegrase strand transfer inhibitor\n\nIQRInterquartile range\n\nIRIncidence rate\n\nLDLLow density lipoprotein\n\nMSMMan who have sex with men\n\nN/ANot available\n\nNNRTINon-nucleoside reverse transcriptase inhibitor\n\nNRTIsNucleoside reverse transcriptase inhibitors\n\nOROdds ratio\n\nPCRPolymerase chain reaction\n\nPIProtease inhibitor\n\nPI/rRitonavir-boosted protease inhibitor\n\nRALRaltegravir\n\nRPVRilpivirine\n\nRPV/FTC/TDFRilpivirine/tenofovir disoproxil fumarate/emtricitabine\n\nTDF/FTCTenofovir disoproxil fumarate/emtricitabine\n\nTFTreatment failure\n\nVFVirological failure\n\nWork presented in part at the 20th international workshop on HIV observational databases, 7th – 9th April 2016, Budapest, Hungary, abstract number 109 and at the VIII Italian conference on AIDS and antiviral research, Milano, Italy, 6th – 8th June 2016, abstract number OC 75.\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s12879-017-2831-9) contains supplementary material, which is available to authorized users.\n\nAcknowledgements\nNone to declare.\n\nFunding\nThis study did not receive specific funding: data were collected as part of the routine clinical activity.\n\nAvailability of data and materials\nThe datasets analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nNG1 conceived the study, collected data and wrote the manuscript. AP and LG performed the statistical analyses and contributed to the writing of the manuscript. SN, NG2, MR, MM, AC1, VS, AL and AC2 collected data and contributed to the writing of the manuscript. All authors have read and approved the manuscript.\n\nEthics approval and consent to participate\nThis study was approved by the ethics committee of the San Raffaele Scientific Institute; the patients provided written informed consent for scientific analysis of their clinical and laboratory data.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nNicola Gianotti has been advisor for Gilead Sciences, AbbVie and Janssen-Cilag and has received speakers’ honoraria from Gilead Sciences, ViiV, Bristol-Myers Squibb, Merck Sharp and Dohme, Roche, AbbVie, Boehringer Ingelheim, and Janssen-Cilag and is a member of the editorial board of BMC Infectious Diseases; Adriano Lazzarin has been advisor for and has received speakers’ honoraria from Bristol-Myers Squibb, ViiV AbbVie, GILEAD, Janssen-Cilag, Mylan; Vincenzo Spagnuolo as received speakers’ honoraria from Gilead Sciences, Merck Sharp and Dohme and ViiV. Andrea Poli, Laura Galli, Silvia Nozza, Marco Merli, Nadia Galizzi, Marco Ripa, Alessia Carbone and Antonella Castagna have no potential conflict of interest to declare.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Palella FJ Jr Fisher M Tebas P Gazzard B Ruane P Van Lunzen J Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants AIDS 2014 28 335 344 10.1097/QAD.0000000000000087 24670520 \n2. DeJesus E Ramgopal M Crofoot G Ruane P LaMarca A Mills A Martorell CT de Wet J Stellbrink HJ Molina JM Post FA Valero IP Porter D Liu Y Cheng A Quirk E SenGupta D Cao H Switching from efavirenz, emtricitabine, and tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study Lancet HIV 2017 4 e205 e213 10.1016/S2352-3018(17)30032-2 28259776 \n3. Martínez E Larrousse M Llibre JM Gutiérrez F Saumoy M Antela A Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study AIDS 2010 24 1697 1707 10.1097/QAD.0b013e32833a608a 20467288 \n4. Pozniak A Markowitz M Mills A Stellbrink HJ Antela A Domingo P Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGY-NNRTI): 48 week results of a randomised, open-label, phase 3b non-inferiority trial Lancet Infect Dis 2014 14 590 599 10.1016/S1473-3099(14)70796-0 24908550 \n5. Trottier B, Lake JE, Logue K, Brinson C, Santiago L, Brennan C, Koteff JA, Wynne B, Hopking J, Granier C, Aboud M. Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed patients (STRIIVING): a 48-week, randomized, non-inferiority, open-label, phase IIIb study. Antivir Ther. 2017. doi:10.3851/IMP3166 [Epub ahead of print].\n6. Arribas JR Pialoux G Gathe J Di Perri G Reynes J Tebas P Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial Lancet Infect Dis 2014 14 581 589 10.1016/S1473-3099(14)70782-0 24908551 \n7. Eron JJ Young B Cooper DA Youle M Dejesus E Andrade-Villanueva J Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials Lancet 2010 375 396 407 10.1016/S0140-6736(09)62041-9 20074791 \n8. Levey AS Stevens LA Schmid CH Zhang YL Castro AF 3rd Feldman HI A new equation to estimate glomerular filtration rate Ann Intern Med 2009 150 604 612 10.7326/0003-4819-150-9-200905050-00006 19414839 \n9. Sterling RK Lissen E Clumeck N Sola R Correa MC Montaner J Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection Hepatology 2006 43 1317 1325 10.1002/hep.21178 16729309 \n10. Tate JP Justice AC Hughes MD Bonnet F Reiss P Mocroft A An internationally generalizable risk index for mortality after one year of antiretroviral therapy AIDS 2013 27 563 572 10.1097/QAD.0b013e32835b8c7f 23095314 \n11. Servoss JC Kitch DW Andersen JW Reisler RB Chung RT Robbins GK Predictors of antiretroviral-related hepatotoxicity in the adult AIDS clinical trial group (1989-1999) J Acquir Immune Defic Syndr 2006 43 320 323 10.1097/01.qai.0000243054.58074.59 16967041 \n12. Brück S Witte S Brust J Schuster D Mosthaf F Procaccianti M Hepatotoxicity in patients prescribed efavirenz or nevirapine Eur J Med Res 2008 13 343 348 18700192 \n13. Soriano V Puoti M Garcia-Gascó P Rockstroh JK Benhamou Y Barreiro P Antiretroviral drugs and liver injury AIDS 2008 22 1 13 10.1097/QAD.0b013e3282f0e2fd 18090386\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "17(1)",
"journal": "BMC infectious diseases",
"keywords": "Dolutegravir; Elvitegravir/cobicistat; Integrase inhibitors; Non-nucleoside reverse transcriptase inhibitors; Raltegravir; Residual viremia; Rilpivirine; Switch regimen; Virological suppression",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000328:Adult; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005260:Female; D005919:Glomerular Filtration Rate; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D000068696:Rilpivirine; D000068698:Tenofovir; D016896:Treatment Outcome",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "723",
"pmc": null,
"pmid": "29145807",
"pubdate": "2017-11-16",
"publication_types": "D016428:Journal Article",
"references": "18700192;20467288;24670520;19414839;16729309;18090386;23095314;28259776;24908551;20074791;24908550;16967041;28401876",
"title": "Durability of switch regimens based on rilpivirine or on integrase inhibitors, both in association with tenofovir and emtricitabine, in HIV-infected, virologically suppressed patients.",
"title_normalized": "durability of switch regimens based on rilpivirine or on integrase inhibitors both in association with tenofovir and emtricitabine in hiv infected virologically suppressed patients"
} | [
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"companynumb": "IT-GILEAD-2017-0310869",
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"occurcountry": "IT",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EMTRICITABINE\\RILPIVIRINE\\TENOFOVIR DISOPROXIL FUMARATE"
... |
{
"abstract": "OBJECTIVE\nTo investigate aspects of juvenile dermatomyositis (DM), including disease characteristics and treatment, through a national multicenter registry.\n\n\nMETHODS\nSubjects meeting the modified Bohan and Peter criteria for definite juvenile DM were analyzed from the cross-sectional Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry between 2010 and 2012 from 55 US pediatric rheumatology centers. Demographics, disease characteristics, diagnostic assessments, and medication exposure data were collected at enrollment.\n\n\nRESULTS\nA total of 384 subjects met the criteria for analysis. At enrollment, the median Childhood Myositis Assessment Scale score was 51 (interquartile range [IQR] 46-52), the median Childhood Health Assessment Questionnaire score was 0 (IQR 0-0.5), and the median physician and subject global assessment scores were 1 (IQR 0-2) and 1 (IQR 0-3), respectively, out of a maximum of 10. Of the diagnostic assessments, magnetic resonance imaging was more likely than electromyography or muscle biopsy to show abnormalities. A total of 329 subjects had ≥2 diagnostic studies performed, and >34% of these subjects reported ≥1 negative study. Ninety-five percent had been treated with corticosteroids and 92% with methotrexate, suggesting that these medications were almost universally prescribed for juvenile DM in the US.\n\n\nCONCLUSIONS\nIn 2 years, the ongoing CARRA Registry has collected clinical data on 384 children with juvenile DM and has the potential to become one of the largest juvenile DM cohorts in the world. More research is needed about prognostic factors in juvenile DM, and differences in therapy based on manifestations of disease need to be explored by practitioners. This registry provides the infrastructure needed to advance clinical and translational research and represents a major step toward improving outcomes of children with juvenile DM.",
"affiliations": "Rainbow Babies and Children's Hospital, Cleveland, Ohio.",
"authors": "Robinson|Angela Byun|AB|;Hoeltzel|Mark F|MF|;Wahezi|Dawn M|DM|;Becker|Mara L|ML|;Kessler|Elizabeth A|EA|;Schmeling|Heinrike|H|;Carrasco|Ruy|R|;Huber|Adam M|AM|;Feldman|Brian M|BM|;Reed|Ann M|AM|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/acr.22142",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2151-464X",
"issue": "66(3)",
"journal": "Arthritis care & research",
"keywords": null,
"medline_ta": "Arthritis Care Res (Hoboken)",
"mesh_terms": "D000293:Adolescent; D002648:Child; D003430:Cross-Sectional Studies; D003882:Dermatomyositis; D005260:Female; D006801:Humans; D008297:Male; D012042:Registries; D012219:Rheumatology",
"nlm_unique_id": "101518086",
"other_id": null,
"pages": "404-10",
"pmc": null,
"pmid": "23983017",
"pubdate": "2014-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "7986222;20191521;22674907;5015065;16467366;16567354;15818654;1575785;11510308;20595275;14145026;14100086;21345298;22526832;11196524;12794783;20191492;10524696;9632086;1089199",
"title": "Clinical characteristics of children with juvenile dermatomyositis: the Childhood Arthritis and Rheumatology Research Alliance Registry.",
"title_normalized": "clinical characteristics of children with juvenile dermatomyositis the childhood arthritis and rheumatology research alliance registry"
} | [
{
"companynumb": "US-JNJFOC-20140316686",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Black tongue is a rare, benign, self-limiting disorder caused by certain conditions and some medications. We report the first case of a child diagnosed with black tongue associated with ranitidine use. We report our case to emphasize the rare side effect of this frequently used drug. Health care professionals should be aware of the likelihood of ranitidine-induced black tongue in clinical practice.",
"affiliations": "Department of Pediatrics, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Pediatrics, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Pediatrics, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.;Department of Pediatrics, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.",
"authors": "Akcaboy|Meltem|M|http://orcid.org/0000-0002-0862-3961;Sahin|Sanliay|S|;Zorlu|Pelin|P|;Şenel|Saliha|S|",
"chemical_list": "D006635:Histamine H2 Antagonists; D011899:Ranitidine",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13309",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "34(6)",
"journal": "Pediatric dermatology",
"keywords": "black tongue; children; ranitidine",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D002675:Child, Preschool; D005260:Female; D006635:Histamine H2 Antagonists; D006801:Humans; D011899:Ranitidine; D014059:Tongue; D014064:Tongue, Hairy; D028761:Withholding Treatment",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e334-e336",
"pmc": null,
"pmid": "28967681",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ranitidine-induced black tongue: A case report.",
"title_normalized": "ranitidine induced black tongue a case report"
} | [
{
"companynumb": "TR-LANNETT COMPANY, INC.-TR-2018LAN000038",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RANITIDINE HYDROCHLORIDE"
},
... |
{
"abstract": "To examine the safety of an agonist-type treatment, lisdexamfetamine (LDX), at 250 mg/day among adults with methamphetamine (MA) dependence.\n\n\n\nA dose-escalating, phase-2, open-label, single-group study of oral LDX at two Australian drug treatment services.\n\n\n\nThe study was conducted at two Australian stimulant use disorder treatment clinics.\n\n\n\nThere were 16 participants: at least 18 years old, MA dependent for at least the preceding 2 years using ICD-10 criteria, reporting use of MA on at least 14 of the preceding 28 days.\n\n\n\nDaily, supervised LDX of 100-250 mg, single-blinded to dose, ascending-descending regimen over 8 weeks (100-250 mg over 4 weeks; followed by 4-week dose reduction regimen, 250-100 mg). Participants were followed through to week 12.\n\n\n\nPrimary outcomes were safety, drug tolerability and regimen completion at the end of week 4. Participants were followed to week 12. Secondary outcomes included: change in MA use; craving; withdrawal; severity of dependence; risk behaviour; change in other substance use; medication acceptability; potential for non-prescription use; adherence and neurocognitive functioning.\n\n\n\nFourteen of 16 participants (87.5%) completed escalation to 250 mg/day. Two participants withdrew from the trial in the first week: one relocated away from the study site, the other self-withdrew due to a possible, known side effect of LDX (agitation). There was one serious adverse event of suicidal ideation which resolved. All other adverse events were mild or moderate in severity and known side effects of LDX. No participant was withdrawn due to adverse events. MA use decreased from a median of 21 days (IQR: 16-23) to 13 days (IQR: 11-17) over the 4-week escalation period (p=0.013).\n\n\n\nLDX at a dose of up to 250 mg/day was safe and well tolerated by study participants, warranting larger trials as a pharmacotherapy for MA dependence.\n\n\n\nACTRN12615000391572.",
"affiliations": "Alcohol and Drug Service, St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia nadine.ezard@svha.org.au.;Alcohol and Drug Service, St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia.;Drug and Alcohol Clinical Research and Improvement Network, C/O South East Sydney Local Health District, Sydney, New South Wales, Australia.;School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia.;Centre for Applied Medical Research, St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia.;Centre for Applied Medical Research, St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia.;Alcohol and Drug Service, St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia.;Drug and Alcohol Clinical Research and Improvement Network, C/O South East Sydney Local Health District, Sydney, New South Wales, Australia.",
"authors": "Ezard|Nadine|N|0000-0002-7495-8305;Clifford|Brendan|B|;Dunlop|Adrian|A|;Bruno|Raimondo|R|;Carr|Andrew|A|;Liu|Zhixin|Z|0000-0003-3337-0692;Siefried|Krista J|KJ|0000-0002-6534-3325;Lintzeris|Nicholas|N|",
"chemical_list": "D000697:Central Nervous System Stimulants; D008694:Methamphetamine; D000069478:Lisdexamfetamine Dimesylate",
"country": "England",
"delete": false,
"doi": "10.1136/bmjopen-2020-044696",
"fulltext": "\n==== Front\nBMJ Open\nBMJ Open\nbmjopen\nbmjopen\nBMJ Open\n2044-6055\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n34006547\nbmjopen-2020-044696\n10.1136/bmjopen-2020-044696\nAddiction\n1506\n1681\nOriginal researchSafety and tolerability of oral lisdexamfetamine in adults with methamphetamine dependence: a phase-2 dose-escalation study\nhttp://orcid.org/0000-0002-7495-8305\nEzard Nadine 1234\nClifford Brendan 15\nDunlop Adrian 467\nBruno Raimondo 8\nCarr Andrew 9\nhttp://orcid.org/0000-0003-3337-0692\nLiu Zhixin 910\nhttp://orcid.org/0000-0002-6534-3325\nSiefried Krista J 123\nLintzeris Nicholas 41112\n1 Alcohol and Drug Service, St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia\n2 National Centre for Clinical Research on Emerging Drugs, C/O University of New South Wales Faculty of Medicine, Sydney, New South Wales, Australia\n3 National Drug and Alcohol Research Centre, University of New South Wales Faculty of Medicine, Sydney, New South Wales, Australia\n4 Drug and Alcohol Clinical Research and Improvement Network, C/O South East Sydney Local Health District, Sydney, New South Wales, Australia\n5 Susan Wakil School of Nursing & Midwifery, The University of Sydney, Sydney, New South Wales, Australia\n6 Drug and Alcohol Clinical Services, Hunter New England Local Health District, Newcastle, New South Wales, Australia\n7 School of Medicine and Public Health, University of Newcastle Faculty of Health, Callaghan, New South Wales, Australia\n8 School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania, Australia\n9 Centre for Applied Medical Research, St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia\n10 Mark Wainwright Analytical Centre, University of New South Wales, Sydney, New South Wales, Australia\n11 Division of Addiction Medicine, The University of Sydney Faculty of Medicine and Health, Sydney, New South Wales, Australia\n12 The Langton Centre, South East Sydney Local Health District, Sydney, New South Wales, Australia\nCorrespondence to Dr Nadine Ezard; nadine.ezard@svha.org.au\n2021\n18 5 2021\n11 5 e04469614 9 2020\n12 4 2021\n16 4 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nObjectives\n\nTo examine the safety of an agonist-type treatment, lisdexamfetamine (LDX), at 250 mg/day among adults with methamphetamine (MA) dependence.\n\nDesign\n\nA dose-escalating, phase-2, open-label, single-group study of oral LDX at two Australian drug treatment services.\n\nSetting\n\nThe study was conducted at two Australian stimulant use disorder treatment clinics.\n\nParticipants\n\nThere were 16 participants: at least 18 years old, MA dependent for at least the preceding 2 years using ICD-10 criteria, reporting use of MA on at least 14 of the preceding 28 days.\n\nInterventions\n\nDaily, supervised LDX of 100–250 mg, single-blinded to dose, ascending-descending regimen over 8 weeks (100–250 mg over 4 weeks; followed by 4-week dose reduction regimen, 250–100 mg). Participants were followed through to week 12.\n\nOutcomes\n\nPrimary outcomes were safety, drug tolerability and regimen completion at the end of week 4. Participants were followed to week 12. Secondary outcomes included: change in MA use; craving; withdrawal; severity of dependence; risk behaviour; change in other substance use; medication acceptability; potential for non-prescription use; adherence and neurocognitive functioning.\n\nResults\n\nFourteen of 16 participants (87.5%) completed escalation to 250 mg/day. Two participants withdrew from the trial in the first week: one relocated away from the study site, the other self-withdrew due to a possible, known side effect of LDX (agitation). There was one serious adverse event of suicidal ideation which resolved. All other adverse events were mild or moderate in severity and known side effects of LDX. No participant was withdrawn due to adverse events. MA use decreased from a median of 21 days (IQR: 16–23) to 13 days (IQR: 11–17) over the 4-week escalation period (p=0.013).\n\nConclusions\n\nLDX at a dose of up to 250 mg/day was safe and well tolerated by study participants, warranting larger trials as a pharmacotherapy for MA dependence.\n\nTrial registration number\n\nACTRN12615000391572.\n\nsubstance misuse\nclinical pharmacology\nclinical trials\nSt Vincent's Hospital, Sydney none provided by funder http://dx.doi.org/10.13039/100010635 Hunter New England Local Health District none provided by funder St Vincent's Curran Foundation, Sydney none provided by funder special-featureunlocked\n==== Body\nStrengths and limitations of this study\n\nThis study is the first to demonstrate the safety, tolerability and acceptability of higher doses of lisdexamfetamine (LDX) in people with methamphetamine (MA) dependence than those currently approved in the treatment attention deficit/hyperactivity disorder and binge eating disorder.\n\nThere are currently no pharmacotherapies approved for the treatment of MA dependence, research into medication options could provide a complementary adjunct to the success of psychosocial therapies.\n\nThis pilot study demonstrated the safety and tolerability of LDX in this population, which may encourage further larger scale trials of LDX as a pharmacotherapy for MA dependence.\n\nThe small sample size and short duration of treatment is typical of pilot safety studies, limiting the clinical extrapolation of findings.\n\nThe study is not powered to explore efficacy of LDX and this precludes more sophisticated statistical analysis.\n\nIntroduction\n\nAmphetamine-type stimulants, including methamphetamine (MA), make up the second most commonly used illicit drug class. An estimated 29 million people used amphetamines in 2019,1 with 7 million estimated to be dependent.2 Poor health outcomes are seen particularly among people who use MA several times a week,3 including psychosis, depression, anxiety, bloodborne virus transmission, sexually transmitted infections, and cardio/cerebral vascular events.4 5\n\nCurrently, treatment for MA dependence is based on psychological therapies such as cognitive–behavioural therapy.6 7 Psychological therapies are labour-intensive and predicated on high levels of attendance and participation by patients. No pharmacotherapy has yet achieved comparable efficacy, and there are as yet none licensed for the treatment of MA dependence. Though agonist therapies show some promise,8 their efficacy for treatment of MA dependence is uncertain, with one systematic review showing no benefit over placebo, although limitations in retention and power of published studies were noted.9 Dexamphetamine, an MA agonist, has similar neurochemical and behavioural effects to MA,10 and has been used off-label for both amphetamine and MA dependence in the UK11 12 and Australia.13\n\nLisdexamfetamine (LDX) is a pharmacologically inactive prodrug of dexamphetamine approved for the treatment of attention deficit/hyperactivity disorder (ADHD) in Australia, Brazil (in children only), Canada, several European countries, the UK and the USA14 and more recently for binge eating disorder (BED) in Australia and the USA. Potential advantages of LDX over immediate release dexamphetamine include once-daily dosing, a slower onset, lower peak concentration, longer duration of action and lower abuse potential.15 LDX presents a candidate pharmacotherapy for MA dependence.\n\nThere are no clinical trial data on the effectiveness of LDX for the treatment of MA dependence. Chronic use of high doses of MA may lead to physiological adaptation so that a dose higher than the licenced therapeutic range of medication is required.9 For the treatment of ADHD and BED in stimulant-naïve populations, LDX is licensed for doses ranging from 30 to 70 mg/day. A previous study of dexamphetamine has trialled doses up to 110 mg for this population without serious adverse events (SAEs),16 which is approximate to 275 mg of LDX using a mole weight equivalent of 100 mg LDX to 40 mg dexamphetamine.17 The highest dose for which safety data of LDX are available is 250 mg/day, equivalent to 100 mg dexamphetamine, tolerated in a safety and pharmacokinetic study of LDX in non-MA dependent volunteers18 and in participants with clinically stable schizophrenia adherent to antipsychotic pharmacotherapy.19\n\nThis study aimed to determine the safety of LDX in people with MA dependence, at doses higher than those currently approved for the treatment of ADHD and BED. The primary objectives of the study were to describe the safety, tolerability and regimen completion of ascending doses of LDX in adults with MA dependence. Secondary objectives included measures of efficacy, drug-liking and neurocognition.\n\nMethods\n\nTrial design\n\nA phase-2, open-label, single-group trial was undertaken at two stimulant use disorder treatment outpatient clinics in New South Wales, Australia.20 All participants provided written, informed consent prior to undergoing study assessments. An independent data safety and monitoring board reviewed safety data during and at completion of the study.\n\nPatient and public involvement\n\nThe original idea for the study was proposed by a patient at the St Vincent’s Hospital Outpatient Stimulant TreatmentProgramme.\n\nRecruitment and enrolment\n\nNotices were displayed at clinics at both sites, as well as at other drug and alcohol services, associated community organisations, and local general practice clinics. Interested individuals either approached or were referred to a research nurse who undertook a standardised prescreening. If basic inclusion criteria and no exclusion criteria were met, potential participants attended a screening visit with a site principal investigator.\n\nParticipants\n\nEligible participants were at least 18 years of age who had been dependent on MA for at least the preceding 2 years, determined by an addiction medicine physician (AD and NE) using International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) criteria.21 Inclusion additionally required reported use of MA on 14 days or more of the previous 28 days at the time of screening, confirmed by two urine samples positive for MA 1 week apart. Patients who had used dexamphetamine in the previous 4 weeks were excluded, as were those with known sensitivity or previous adverse reaction to LDX or prescribed drugs which may interact with LDX (venlafaxine, desvenlafaxine, monoamine oxidase inhibitors), known contraindications to LDX (severe and symptomatic peripheral vascular disease or Raynaud’s phenomenon, significant prior or symptomatic cardiovascular disease, moderate to severe hypertension, glaucoma, phaeochromocytoma, hyperthyroidism, motor and phonic tics, Tourette’s syndrome, high suicide risk, voicing suicidal ideation, active psychosis, severe agitation or unstable use of alcohol or drugs other than MA as assessed by a specialist in addiction medicine22). Patients with well-controlled mild to moderate hypertension on a single antihypertensive agent were permitted, and those with a history of psychosis were permitted on review by a psychiatrist. Pregnant or breastfeeding women and women not willing to avoid becoming pregnant during the study were also excluded.\n\nStudy procedures\n\nAt the screening visit, informed consent was obtained as well as a detailed medical and substance use history, physical and mental state examinations, an ECG and a urine human chorionic gonadotrophin test (for women of childbearing potential) to verify eligibility.\n\nAll participants were commenced on a dose escalation regimen of supervised daily dispensing of ascending doses of LDX from 100 to 250 mg over 4 weeks, followed by a 4-week dose reduction regimen from 250 to 100mg, and attended a follow-up visit 4 weeks after ceasing the study drug (see figure 1).\n\nFigure 1 Study participant flow chart. LDX, lisdexamfetamine; MA, methamphetamine.\n\nFive capsules were dispensed to each participant daily, with the number containing active study drug or placebo varying with the dose phase to maintain blinding. Both participants and dispensing nurses were aware of dose escalation and reduction, and of the dose range (100–250 mg), but they were blinded to the time points at which the doses changed. Participants received each dose for 7 days, based on the data that steady state for LDX is achieved after 5 days,23 and were reviewed by a medical officer weekly.\n\nParticipants not already engaged with psychological therapy were offered concurrent standard of care weekly counselling, although attendance was not mandatory. Participants were offered supermarket vouchers with a value of $A80 at the end of each of six visits: baseline; weeks 1–4 (escalation phase); and follow-up (week 12) (total possible value of $A480).\n\nCriteria for withdrawing participants were: resting heart rate greater than 120 beats per minute (BPM) for more than 60 min; hypertension (two consecutive readings within 1 hour of each other where the systolic blood pressure (SBP) was greater than 160 mm Hg, or the diastolic blood pressure (DBP) greater than 100 mm Hg); clinically significant psychosis; or significant or SAE related to the study drug. Other withdrawal criteria were diversion of study medication, missing more than one planned medical review and missing three or more doses of study drug over a 7-day period. Full details of the study protocol were published prior to study completion.20\n\nOutcome measures\n\nThe primary outcomes of the study were the safety, tolerability and regimen completion of ascending doses of LDX in adults with MA dependence.\n\nSafety was assessed with a number of measures. Blood pressure, pulse and temperature were recorded daily. Participants were assessed weekly by a physician and had treatment emergent adverse events (TEAEs) recorded. TEAEs were volunteered by the participants during or between visits, as well through physical examination, laboratory test or other assessments. Severity of TEAEs was determined by a site principal investigator (both addiction medicine specialists). Severity of symptoms was graded as mild if they caused no or minimal interference with usual social and function activities and required no intervention. Moderate TEAEs were those which caused greater than minimal interference with usual social and functional activities, requiring only minimal intervention. Severe TEAEs were classified as those which resulted in an inability to perform usual social and functional activities and medically significant events which required intervention. SAEs were medically significant events that were; fatal or life-threatening; resulted in persistent or significant disability or incapacity; or required unplanned inpatient hospitalisation. The Psychosis and Hostility items of the Brief Psychiatric Rating Scale (BPRS)24 were administered weekly. The Insomnia Severity Index,25 Patient Health Questionnaire 9 (PHQ9)26 and the Generalised Anxiety Disorder 7 (GAD7) scale27 were administered every 2 weeks and at follow-up, measuring insomnia, depression and anxiety, respectively. The PHQ1528 was administered to assess for changes to somatic symptoms and weight in kilograms measured every 4 weeks. ECGs were recorded at Baseline and at weeks 2 and 4.\n\nTolerability of LDX was assessed by the side-effects item of the Treatment Satisfaction Questionnaire for Medication (TSQM),29 administered weekly from week 1, and at follow-up.\n\nRegimen completion was defined as the proportion of participants enrolled who completed the escalation phase to the end of week 4, at which point they would have received at least 5 days of 250 mg of LDX.\n\nSecondary outcomes were: efficacy measures; change in other substance use; medication acceptability; potential for non-prescription use; adherence and neurocognitive functioning. Efficacy measures comprised changes in MA use (self-reported and urine screen), withdrawal, craving, severity of dependence, HIV transmission risk and criminal behaviours as well as participant-reported effectiveness measures. MA and other substance use was recorded weekly with a validated self-report tool, the Time Line Follow Back Questionnaire.30 31 Urine samples were obtained weekly, and tested for the presence of MA. Craving and withdrawal were measured weekly from Baseline and at Follow-up. Craving was measured with a single item 0–100 Visual Analogue Scale (VAS)32 and withdrawal with the Amphetamine Withdrawal Scale.33 Severity of dependence was measured with the Severity of Dependence Scale34 at Baseline, week 8 and follow-up. The HIV risk behaviour and crime sections of the Opiate Treatment Index35 were completed at baseline, weeks 4 and 8, and at follow-up. The TSQM Questionnaire29 was administered weekly from week 1 and at Follow-up to measure self-rated medication effectiveness, convenience and global satisfaction. Potential for non-prescription drug use was measured weekly from baseline to week 4 using the Drug Effects Questionnaire 5 (DEQ5),36 the Acute Subjective Response to Substances questionnaire for amphetamines,37 a VAS to measure similarity to MA, and asking participants what price they would pay for the drug (PWP).38\n\nGeneral cognition was assessed using the Wechsler test of adult reading39 and the Montreal Cognitive Assessment40 at Baseline. Paper-based neurocognitive tests were administered at baseline, week 2, week 4 and at follow-up 4 weeks after drug discontinuation assessing switching (Trail making test41 42), working memory (Digit-sequencing43) and verbal learning and memory (Rey Auditory Verbal Learning Task, RAVLT44). Electronic neurocognitive testing was conducted using the Penscreen Six software45 on an Android 7 tablet assessing: processing speed (Digit-symbol test43), sustained attention (Rapid Visual Information Processing, RVIP), attention/focus (Arrow flankers46) and inhibition (go/no-go46) weekly from Baseline until week 4 and at follow-up.47\n\nStatistical analysis\n\nAdverse events were described by the proportion of participants who experienced TEAE by type, severity and dose. Non-parametric tests of paired data (Wilcoxon signed rank test) were performed for measures taken at the beginning of week 1 (baseline), and compared with those taken at the primary endpoint, the end of week 4 (at presumed steady state of 250 mg/day of LDX). Mixed models for repeated measures (MMRM) were performed for primary cardiovascular (SBP, DBP and heart rate) and neurocognitive outcomes. MMRM analyses makes use of all available data and is reliable for effect estimates under missing at random assumption. The secondary outcomes of dose adequacy, medication acceptability and potential for non-prescription use are described using median scores and IQRs at each dose. Missing urine drug results are assumed positive for MA. As per protocol, change in days of MA use were analysed separately for participants who partook in at least four sessions of counselling over the 8-week trial period. Other secondary outcomes were tested for statistical significance with Wilcoxon rank-sum test for non-parametric data.\n\nResults\n\nStudy sample\n\nOf the 68 potential participants prescreened for the study, 16 were enrolled and commenced on the LDX regimen (figure 1) between June 2015 and December 2016. Mean age of the 16 participants was 41 years (SD 6.7), and 75.0% (n=12) were male. Participants had a mean of 12 years (SD 8.4) problematic MA use and had used MA a mean of 21 days (SD 5.4) of the previous 28. Other sample demographics at study enrolment are provided in table 1.\n\nTable 1 Sample characteristics at enrolment\n\nDemographics\tAll (n=16)\nn (% (unless otherwise indicated))\t\nMean age (SD)\t41 (6.7)\t\nGender\t\t\n Cis-male\t12 (75.0)\t\n Cis-female\t4 (25.0)\t\nAboriginal/Torres Strait Islander\t2 (12.5)\t\nSexual Identity\t\t\n Heterosexual\t9 (56.3)\t\n Gay or lesbian\t3 (18.8)\t\n Bisexual\t3 (18.8)\t\n Something else\t1 (6.3)\t\nMedical history\t\t\nHIV infection\t3 (18.8)\t\nHepatitis C virus (HCV) infection\t5 (31.3)\t\nSelf-reported history of childhood ADHD diagnosis\t2 (12.5)\t\nWender Utah Rating Scale* >46\t7 (43.8)\t\nCurrent opioid agonist therapy\t2 (12.5)\t\nConcomitant psychiatric medication\t2 (12.5)\t\nOther substance use (prior 28 days)\t\t\n Tobacco\t10 (62.5)\t\n Cannabis\t5 (31.3)\t\n Gamma hydroxybutyrate (GHB)\t4 (25.0)\t\n Alcohol\t3 (18.8)\t\n Opioids (oxycodone/heroin)\t2 (12.5)\t\nMethamphetamine use\tMean (SD)\t\nAge at first use (years)\t22 (9.0)\t\nYears of self-reported problematic use\t12 (8.4)\t\nDays use of previous 28\t21 (5.4)\t\nReported injecting MA in past 28 days n (%)\t12 (69.0)\t\nNeurocognition\tMean (SD)\t\nMontreal cognitive assessment (MoCA)\t26 (2.6)\t\n MoCA <26, n (%)\t8 (50.0)\t\nWechser Test of Adult Reading (Estimated Wechsler Adult Intelligence Scale -III IQ)\t105 (11.4)\t\n*Score >46 considered positive for the retrospective assessment of the presence of symptoms of ADHD in childhood\n\nADHD, attention deficit/hyperactivity disorder; MA, methamphetamine.\n\nPrimary outcomes\n\nRegimen completion\n\nFourteen (87.5%) participants achieved each of the doses of 100 mg, 150 mg, 200 mg and the primary endpoint of 250 mg at the end of 4 weeks. Ten participants (62.5%) completed 8 weeks of study drug and 12 (75.0%) were followed up 4 weeks after the last dose.\n\nTwo participants (12.5%) withdrew prior to the primary endpoint at the end of Week 4. One participant stopped presenting to the clinic after 5 days of 100 mg LDX in week 1. The participant declined to attend for further follow-up but responded by text message: ‘I’m OK pills made me angry and not nice feeling don’t won’t [sic] to continue’. The other participant withdrew in week 1 due to relocation away from study site.\n\nFour participants (25.0%) were withdrawn due to non-adherence (missing three doses in a 5-day period after the escalation regimen was completed) after reaching the primary endpoint but prior to study completion: one (6.3%) in week 6 (at the 200 mg dose); two (12.5%) in week 7 (150 mg dose) and one (6.3%) in week 8 (100mg dose) (see figure 1).\n\nAdverse events\n\nNo participant was withdrawn due to TEAEs. The proportion of participants experiencing TEAEs by dose, week and severity are shown in figure 2.\n\nFigure 2 Proportion of participants experiencing adverse events by dose, week, and severity. TEAE, treatment emergent adverse event.\n\nDaily measurements of tympanic temperature were within normal range. There was one (6.3%) SAE of suicidal ideation requiring hospitalisation, deemed possibly study drug related and classified as severe. This SAE occurred on the final day of the de-escalation regimen. The participant had a prior history of self-harm, which had not been disclosed during screening. The SAE resolved following a 7-day admission in a short stay psychiatric emergency care centre during which time atomoxetine was commenced. There were three moderate TEAEs (18.8% of participants who received at least one dose of study drug): irritability (week 1, 100 mg); viral respiratory illness (week 7, 150 mg de-escalation phase) and an episode of hypomania during the follow-up period (4 weeks after LDX cessation). All were determined to be possibly study related. An additional eight (50.0%) participants experienced at least one mild TEAE. TEAEs occurring in at least two participants throughout the 12-week study are shown in table 2.\n\nTable 2 Adverse events reported by at least two participants at any time (baseline to week 12)\n\nAdverse event category\tn (%)\t\nAgitation/irritability\t4* (25.0)\t\nCardiovascular\t2 (12.5)\t\nGastrointestinal\t4 (25.0)\t\nHeadache\t3 (18.8)\t\nLoss of appetite\t2 (12.5)\t\nMuscular tension/jaw clenching\t3 (18.8)\t\nPain\t3 (18.8)\t\nPsychiatric\t2† (12.5)\t\nRespiratory complaints\t3 (18.8)\t\nSkin/soft tissue/mucosal infections\t5 (31.3)\t\nSleep disturbances\t2 (12.5)\t\nn=number of people reporting AE, %=of total sample (n=16).\n\n*Including one participant in Week one who was subsequently withdrawn due to lack of adherence to protocol (missed three doses).\n\n†Including one participant meeting definition of a serious adverse event (admission to hospital).\n\nNo clinically significant hostility or psychosis was detected using the relevant BPRS items.24 No participant met the study protocol discontinuation parameters for elevated SBP or experienced a treatment-limiting adverse cardiovascular event. One participant had a single DBP reading of 101 mm Hg and heart rate of 134 bpm after 5 days of 100 mg LDX. Another participant had a single pulse reading of 124 bpm during week 3 (after 5 days of 200 mg LDX), assessed to be not clinically significant. Participants’ mean change in SBP over the escalation regimen (baseline to end of week 4) was +3.4 mm Hg (range −21.0 to +27.0, SD 14.6), mean change in DBP was −0.4 mm Hg (range −22.0 to +24.0, SD 14.5), and mean change in heart rate was 7.3 bpm (range −17.0 to +37.0, SD 13.4). Individual-level change for cardiovascular outcomes are shown in figure 3. No clinically significant ECG changes were detected at week 4 following dose escalation to 250 mg.\n\nFigure 3 Change in cardiovascular parameters. Grey: individual measures; black—mean; error bars—95% CI. BPM, beats per minute.\n\nPost hoc analysis did not detect significant correlation between frequency of MA use on enrolment and change in blood pressure (SBP: r=0.04, p=0.88; DBP: r=0.16, p=0.57). MMRM demonstrated no significant overall difference across the five time-points in either SBP (F4 39 =1.43, p=0.241), DBP (F4 35 =0.07, p=0.990) or HR (F4 35 =1.30, p=0.288), all measured at peak LDX concentrations (4 hours postdose) over the course of the escalation regimen, the multiple comparison of each post-baseline measure vs baseline are summarised in table 3.\n\nTable 3 Cardiovascular safety parameters (n=16)\n\n \tBL to week 1: estimate (SE) p value*\tBL to week 2: estimate (SE) p value*\tBL to week 3: estimate (SE) p value*\tBL to week 4: estimate (SE) p value*\t\nUnadjusted\t\n SBP (4 hours postdose)\t5.5 (3.4) p=0.00.370\t−1.6 (3.5) p=0.985\t2.7 (3.6) p=0.919\t3.3 (3.8) p=0.853\t\n DBP (4 hours postdose)\t−0.8 (2.9) p=0.998\t0.9 (3.1) p=0.998\t0.1 (3.1) p=1\t−0.7 (3.4) p=0.999\t\n HR (4 hours postdose)\t4.2 (2.9) p=0.497\t3.0 (3.1) p=0.810\t6.6 (3.1) p=0.162\t6.2 (3.4) p=0.271\t\nAdjusted (for: age; sex at birth; baseline methamphetamine use (days))\t\n SBP (4 hours postdose)\t5.8 (3.4) p=0.321\t−1.7 (3.5) p=0.981\t2.5 (3.5) p=0.928\t3.2 (3.7) p=0.863\t\n DBP (4 hours postdose)\t−0.3 (2.9) p=1\t0.3 (3.1) p=1\t−0.5 (3.1) p=1\t−1.4 (3.4) p=0.990\t\n HR (4 hours postdose)\t4.1 (2.9) p=0.514\t2.9 (3.1) p=0.817\t6.6 (3.1) p=0.165\t6.2 (3.4) p=0.271\t\nAll analyses use mixed models for repeated measures.\n\n*Sidak correction for multiple comparisons (four pairs) applied.\n\nBL, baseline; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure.\n\nStudy drug tolerability\n\nParticipant-rated treatment tolerability of LDX using the TSQM side effects item29 was high, with no significant difference detected (z=−0.639, p=0.524) between the lowest dose at week 1 and the highest escalated dose at the end of week 4 (table 4).\n\nTable 4 Outcomes\n\n\tAll enrolled\n(n=16)\tCompleted week 4 (n=14)\tCompleted week 4 (n=14)\tMean difference (95%CI)\tP value*\tCompleted week 8\n(n=10)\tFollowed up\nweek 12\n(n=12)\t\nBaseline\tBaseline\tWeek 4\t\nPrimary outcomes\t\t\t\t\t\t\nSBP mm Hg (median (IQR])\t119 (101–136)\t119 (103–130)\t123 (112–130)\t3.4 (-5.0 to 11.9)\t0.327\t124 (118–130)\t129 (106–131)\t\nDBP mm Hg (median (IQR))\t77 (65–90)\t77 (65–89)\t74 (67–85)\t−0.4 (-8.8 to 8.0)\t0.975\t78 (76–82)\t80 (72–83)\t\nHeart rate bpm (median (IQR))\t90 (76–96)\t89 (73–93)\t90 (76–103)\t7.3 (-0.4 to 15.0)\t0.059\t81 (75–91)\t82 (77–83)\t\nWeight (kg) (median (IQR))\t73 (68–82)\t73 (68–76)\t74 (69–83)\t0.9 (0.1 to 1.8)\t0.024\t–\t73 (67–80)\t\nInsomnia (ISI) (median (IQR))\t11 (5–15)\t10 (5–13)\t7 (3–9)\t−3.3 (-6.0 to 0.5)\t0.027\t9 (1–14)\t7 (3–10)\t\nPhysical health (PHQ15) (median (IQR))\t8 (5–10)\t7 (5–9)\t6 (3–8)\t−2.1 (-3.2 to -0.9)\t0.004\t7 (3–10)\t5 (2–9)\t\nDepression (PHQ9) (median (IQR))\t11 (7–14)\t11 (7–14)\t4 (3–9)\t−4.6 (-7.0 to -2.1)\t0.002\t8 (6–10)\t9 (8–11)\t\nAnxiety (GAD7) (median (IQR))\t9 (5–11)\t9 (5–10)\t4 (1–9)\t−3.9 (-7.3 to -0.6)\t0.009\t6 (1–8)\t7 (4–10)\t\nTSQM—tolerability (median (IQR))\t100 (86–100)\t100 (88–100)\t100 (98–100)\t2.4 (-5.2 to 10.0)\t0.524\t100 (84–100)\t100 (89–100)\t\nSecondary outcomes\t\t\t\t\t\t\nMethamphetamine use (days out of last 28) (median (IQR))\t21 (16–23)\t21 (18–26)\t13 (11–17)\t\t0.013\t11 (2–13)\t13 (9–19)\t\nUrine drug screen for MA (n (%) negative)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t–\t–\t3 (18.8%)\t1 (6.3%)\t\nCravings (VAS) (median (IQR))\t64 (20–85)\t64 (23–82)\t31 (12–52)\t−25.9 (-47.3 to -4.6)\t0.035\t40 (22–67)\t42 (22–87)\t\nWithdrawal (AWQ) (median (IQR))\t16 (9–18)\t16 (10–18)\t12 (7–18)\t−1.4 (-4.5 to 1.8)\t0.307\t9 (7–22)\t13 (11–20)\t\nMedication efficacy (TSQM) (median (IQR))\t50 (37–68)†\t50 (39–67)†\t64 (50–79)\t12.4 (3.8 to 21.0)\t0.021\t69 (58–82)\t80 (63–83)\t\nMedication convenience (TSQM) (median (IQR))\t78 (61–83)†\t78 (67–83)†\t83 (56–100)\t0.2 (-9.4 to 9.7)\t0.608\t78 (63–83)\t61 (56–78)\t\nMedication global satisfaction (TSQM) (Median (IQR))\t64 (48–87)†\t64 (50–86)†\t71(63-88)\t7.6 (-0.9 to 16.2)\t0.073\t75 (66–79)\t79 (71–100)\t\nCrime (OTI) (median (IQR))\t2 (0–5)\t3 (0–7)\t0 (0–2)\t−1.7 (-3.3 to 0.0)\t0.042\t–\t0 (0–0)\t\nHIV risk behaviour (OTI) (median (IQR))\t11 (7–14)\t10 (7–12)\t9 (5–14)\t−1.2 (-3.7 to 1.3)\t0.327\t–\t10 (8–17)\t\nSeverity of Dependence Scale (median (IQR))\t11 (8–12)\t11 (8–12)\t–\t−0.3 (-1.6 to 1.0)\t–\t11 (10–12)\t11 (9–12)\t\nDrug liking\t\t\t\t\t\t\n Price Would Pay ($A) (median (IQR))\t8 (0–33)\t5 (0–20)\t5 (0–30)\t13.8 (−17.1 to 44.7)\t0.416\t–\t–\t\n ASRS (median (IQR))\t3 (2–7)\t3 (3–7)\t3 (3–7)\t0.1 (−1.7 to 1.9)\t0.811\t\t\t\n Similarity to MA (median (IQR))\t22 (8–52)\t17 (8–45)\t20 (5–57)\t10.5 (−11.3 to 32.2)\t0.241\t–\t–\t\n DEQ5 ‘Feel’ item (median (IQR))\t15 (8–46)\t15 (7–46)\t26 (13–45)\t9.5 (−2.3 to 21.4)\t0.221\t–\t–\t\n DEQ5 ‘More’ item (median (IQR))\t48 (17–85)\t48 (13–80)\t49 (9–86)\t−3.5 (−30.8 to 23.9)\t0.421\t–\t–\t\n DEQ5 ‘High’ item (median (IQR))\t9 (2–35)\t9 (2–24)\t28 (5–48)\t13.5 (3.4 to 23.6)\t0.009\t–\t–\t\n DEQ5 ‘Like’ item (median (IQR))\t40 (11–58)\t40 (11–45)\t47 (20–62)\t14.7 (−4.9 to 34.3)\t0.208\t–\t–\t\n DEQ5 ‘Dislike’ item (median (IQR))\t4 (0–12)\t5 (1–12)\t2 (2–28)\t6.5 (−9.5 to 22.6)\t0.916\t–\t–\t\n*Based on Wilcoxon signed-rank test; bold values denote statistical significance at the p <0.05 level.\n\n†Measured at week 1.\n\nASRS, Acute Subjective Response to Substances; AWS, Amphetamine Withdrawal Scale; DBP, diastolic blood pressure; DEQ 5, Drug Effects Questionnaire 5; GAD 7, Generalised Anxiety Disorder 7; ISI, Insomnia Severity Index; MA, methamphetamine; OTI, Opiate Treatment Index; PHQ9, Patient Health Questionnaire 9; SBP, systolic blood pressure; TSQM, Treatment Satisfaction Questionnaire for Medication; VAS, Visual Analogue Scale.\n\nSecondary outcomes\n\nSecondary outcomes are provided in table 4. Days of MA use decreased significantly over the 4 weeks escalation regimen from a median of 21 (IQR: 16–23) to 13 days (IQR: 11–17) of the previous 28 days (z=−2.485, p=0.013). Individual level data of MA use are given in figure 4.\n\nFigure 4 Change in days of methamphetamine use. Grey: individual measures; black—mean; error bars—95% CI.\n\nParticipants who had attended four or more sessions of counselling (n=9) during the 8-week period had a mean decrease of 5.8 days (95% CI: −10.8 to −0.7, p=0.038). Those who attended fewer than four sessions (n=7), had a mean decrease of 4.0 days (95% CI:−11 to 3, p=0.144). All urine drug screens provided during the escalation phase (weeks 1–4) were positive for MA. A post hoc analysis showed three participants achieved two consecutive weeks of self-reported abstinence during the 8 weeks of LDX administration. There was a significant decrease in craving from a median of 64 mm (IQR: 20–85) to 31 mm (z=−2.105, p=0.035) on a VAS. Five (36%) of the participants reported slight increase in the frequency of other substance use over the 4 weeks (alcohol, tobacco, gamma-hydroxybutyrate, heroin), with four (29%) of these having a concurrent reduction in MA use. Self-reported medication efficacy using the TSQM was rated significantly higher at the end of week 4 than at week 1 (z=−2.301, p=0.021). Adherence to study medication was maintained from week 2 to week 5, with no participants missing more than 2 days of study medication in a 7-day period. There was an indication of improvement among participants in sleep quality, physical and mental health measures, and weight over the 4-week period. The ‘high’ item of the DEQ-5 questionnaire increased from a median score of 9 (IQR: 2–35) to 28 (IQR: 5–48) (z=−2.622, p=0.009). Other non-significant changes are reported in table 4.\n\nAll analyses use MMRM; Adjusted for: sex at birth; Wender-Utah ADHD score; WTAR performance and baseline days MA use; RAVLT % retained is RAVLT Trial 6 (delay) as a proportion of words recalled at Trial 5.\n\nLarge magnitude improvements in focused attention (Hedges’ g=1.59 at peak dose) and inhibitory control (Hedges’ g=1.12 at peak dose) were seen over the course of the trial and were maximal at 200 mg and above. Moderate magnitude but non-significant improvements were apparent on measures of processing speed and sustained attention (Hedges’ g>0.6 at peak dose for Digit Symbol, Trails A, RVIP). No meaningful changes were observed in working memory, learning, retention and switching (Hedges’ g<0.4 at peak for all) (table 5).\n\nTable 5 Cognitive effects of lisdexamfetamine (n=16)\n\nDomain\tMeasure\tOverall effect\tBL to 100 mg:\nEstimate (SE)\nSidak-adj\np value\tBL to 150 mg:\nEstimate (SE)\nSidak-adj p value\tBL to 200 mg:\nEstimate (SE)\nSidak-adj p value\tBL to 250 mg:\nEstimate (SE)\nSidak-adj p value\tBL to FU:\nestimate (SE)\nSidak-adj p value\t\nUnadjusted\t \t \t \t \t \t \t\n Processing speed\tTrail making test (A)\tF(3, 11)=4.80, p=0.022\t \t1.8 (1.9) p=0.931\t \t6.4 (1.9) p=0.017\t3.8 (2.4) p=0.577\t\n Processing speed\tDigit symbol RT\tF(5, 16)=3.43, p=0.026\t237.3 (135.8) p=0.795\t366.1 (150.4) p=0.300\t313.6 (137.5) p=0.425\t345.0 (136.7) p=0.289\t317.9 (140.0) p=0.423\t\n Attention\tFlankers RT\tF(5, 38)=9.07, p<0.001\t27.8 (13.5) p=0.496\t44.4 (14.0) p=0.035\t50.1 (12.5) p=0.010\t58.3 (12.5) p<0.001\t16.6 (17.1) p=0.998\t\n Attention\tFlankers Per cent Correct\tF(5, 29)=2.18, p=0.084\t0.5 (0.2) p=0.188\t0.2 (0.3) p=0.999\t0.5 (0.2) p=0.085\t0.3 (0.2) p=0.768\t0.2 (0.3) p=0.999\t\n Sustained attention\tRVIP Reaction Time (RT)\tF(5, 16)=3.26, p=0.032\t28.3 (25.5) p=0.992\t70.1 (19.5) p=0.031\t58.9 (22.2) p=0.189\t60.7 (18.1) p=0.058\t73.3 (25.2) p=0.153\t\n Sustained attention\tRVIP Per cent Correct\tF(5, 14)=5.42, p=0.011\t0.4 (1.2) p=0.999\t3.2 (1.0) p=0.061\t3.9 (1.1) p=0.019\t2.8 (1.2) p=0.332\t2.9 (1.2) p=0.262\t\n Working memory\tDigit Sequencing Span\tF(3, 12)=1.79, p=0.202\t \t1.2 (0.6) p=0.377\t \t0.3 (0.5) p=0.980\t0.9 (0.5) p=0.510\t\n Immediate memory\tRAVLT Trial 1\tF(3, 11)=0.55, p=0.660\t \t0.3 (0.6) p=0.998\t \t0.6 (0.5) p=0.791\t0.5 (0.6) p=0.978\t\n Learning\tRAVLT Trials 1–5\tF(3,13)=3.01, p=0.068\t \t4.1 (3.2) p=0.783\t \t1.9 (3.1) p=0.990\t7.0 (2.4) p=0.125\t\n Retention\tRAVLT % Retained\tF(3, 18)=0.52, p=0.677\t \t−0.6 (10.3) p=0.999\t \t4.3 (8.5) p=0.997\t−4.4 (10.6) p=0.999\t\n Switching\tTrail making test (B)\tF(3, 13)=5.18, p=0.015\t \t5.2 (8.9) p=0.993\t \t7.9 (7.6) p=0.892\t18.0 (6.2) p=0.029\t\n Inhibition\tGo-NoGo False Positives\tF(5, 21)=6.53, p=0.001\t2.3 (0.6) p=0.015\t2.4 (0.7) p=0.016\t2.6 (0.9) p=0.097\t2.9 (0.5) p=0.001\t3.0 (0.6) p=0.001\t\nAdjusted\t \t \t \t \t \t \t\n Processing speed\tTrail making test (A)\tF(3,10)=2.91 p=0.090\t \t0.1 (2.4) p=0.999\t \t5.6 (2.6) p=0.240\t4.2 (3.5) p=0.840\t\n Processing speed\tDigit Symbol RT\tF(5, 12)=2.08 p=0.141\t322.5 (157.3) p=0.599\t414.7 (177.6) p=0.362\t383.9 (163.1) p=0.382\t383.9 (163.1) p=0.263\t394.7 (169.0) p=0.399\t\n Attention\tFlankers RT\tF(5, 40)=9.13 p<0.001\t34.3 (14.0) p=0.227\t51.3 (14.7) p=0.013\t60.5 (15.3) p=0.002\t68.8 (13.9), p<0.001\t24.1 (18.0) p=0.956\t\n Attention\tFlankers Per cent Correct\tF(5, 30)=1.22 p=0.323\t0.3 (0.2) p=0.727\t0.1 (0.3) p=0.999\t0.3 (0.2) p=0.863\t0.1 (0.2) p=0.999\t0.1 (0.3) p=0.999\t\n Sustained attention\tRVIP RT\tF(5, 15)=2.07 p=0.125\t10.2 (30.7) p=0.999\t54.6 (24.2) p=0.431\t48.6 (31.0) p=0.876\t48.3 (24.5) p=0.631\t23.2 (25.6) p=0.999\t\n Sustained attention\tRVIP Per cent Correct\tF(5, 11)=2.37 p=0.105\t−0.1 (1.5) p=0.932\t2.6 (1.3) p=0.055\t3.4 (1.4) p=0.025\t2.9 (1.6) p=0.081\t2.6 (1.7) p=0.131\t\n Working memory\tDigit Sequencing Span\tF(3, 11)=0.93 p=0.461\t \t1.3 (0.8) p=0.517\t \t0.5 (0.6) p=0.970\t0.4 (0.8) p=0.998\t\n Immediate memory\tRAVLT Trial 1\tF(3, 9)=0.87 p=0.872\t \t0.2 (0.8) p=0.999\t \t0.2 (0.6) p=0.999\t0.7 (0.9) p=0.969\t\n Learning\tRAVLT Trials 1–5\tF(3, 13)=4.46 p=0.024\t \t5.9 (4.3) p=0.722\t \t3.0 (4.2) p=0.982\t11.2 (3.1) p=0.088\t\n Retention\tRAVLT % Retained\tF(3, 13)=0.03 p=0.994\t \t−2.9 (12.3) p=0.999\t \t−0.7 (9.9) p=0.999\t0.5 (13.9) p=0.999\t\n Switching\tTrail making test (B)\tF(3, 14)=2.97 p=0.067\t \t8.1 (10.8) p=0.976\t \t16.2 (9.5) p=0.486\t22.2 (7.9)\np=0.068\t\n Inhibition\tGo-NoGo False Positives\tF(5, 18)=5.04 p=0.005\t2.1 (0.7) p=0.114\t1.6 (0.8) p=0.579\t2.9 (1.1) p=0.208\t2.8 (0.7), p=0.010\t3.1 (0.7) p=0.008\t\nBold values denote statistical significance at the p<0.05 level.\n\nDiscussion\n\nPrincipal findings and comparison with other studies\n\nWe found that dose escalation of LDX over 4 weeks to a maximum of 250 mg/day appeared to be safe in people who use MA frequently (at least 14 out of the previous 28 days).\n\nThe physiological effects of LDX were not treatment-limiting in this sample. Cardiovascular changes were mild, with no significant change in blood pressure, and similarly mild (though trending towards significant) changes in heart rate at the completion of the escalation to 250 mg. This contrasts with a study among stimulant-naive populations where single sequential doses up to 250 mg per day observed dose-dependent adverse changes in blood pressure, with more than half of their participants (11 of 20) withdrawn due to meeting blood pressure endpoints.17 These findings were not observed in a study of up to 250 mg LDX daily among people with stable schizophrenia treated with antipsychotic medication, which may attenuate the pressor effects of LDX.19 In our study, tolerance to the pressor effects may result from chronic stimulant exposure among MA dependent participants,48 though the small study sample prevents any conclusions on inverse correlation between frequency of MA use prior to enrolment and change in blood pressure.\n\nOne SAE was reported by a participant, suicidal ideation on the last day of the 8 weeks LDX administration period, which required hospitalisation. One participant withdrew from the study due to feelings of anger and hostility. This occurred at the lowest dose (100 mg) during week 1, likely related to the drug rather than to the dose. While no clinically significant results were obtained with the BPRS, these events suggest it would be prudent to closely monitor patients’ mental state receiving higher doses of LDX, as well as comprehensive treatment planning when the drug is ceased. The slight increase in other substance use over the escalation period suggests that this should also be monitored during periods of LDX administration.\n\nOther TEAEs reported during the study likely to be drug related were known side effects of LDX (agitation, headache, loose stool, decreased appetite and jaw clenching). Other measures of general health (weight, PHQ-15, PHQ-9, GAD-7) either improved or showed no deterioration, and participant subjective rating of side effects (TSQM-side effects) show high participant tolerability of LDX at all doses. These findings support the feasibility and acceptability of LDX as a possible pharmacotherapy for MA dependence.\n\nA reduction in self-reported MA use was significantly associated with LDX administration, indicating possible efficacy as a treatment for MA dependence. In addition, three participants achieved two consecutive weeks of self-reported MA cessation by the end of the 8 weeks of LDX administration. There was also a significant decrease in MA craving, as well as subjective rating of drug efficacy, supporting the utility of larger trials of LDX for this population. Although the reimbursement may have contributed an incentivising effect, the high proportion of participants (n=14 (87.5%)) to complete the protocol to the highest dose is promising, given typically low recruitment and retention in studies among this population.8\n\nLDX is theorised to have lower propensity for non-prescription use, having a slower onset of action than similar agonist formulations such as dexamphetamine and methylphenidate.49 50 Studies show lower drug-liking for LDX compared with other stimulant medications for doses up to 100 mg.51 In this study, the DEQ-5 item ‘Do you feel high?’, increased from 9 mm at baseline but remained low at 29 mm at 250 mg/day LDX on a 100 mm VAS, a clinically insignificant finding. PWP remained consistent at AUD $5 across dose ranges, and other changes in the drug liking effects were not significant. This indicates that LDX may have less potential for non-prescription use than other candidate agonists. Concurrent use of other substances should also be monitored in future trials of LDX, given that a small increase in other substance use was noted by participants.\n\nNeurocognitive data showed no safety concerns and promising efficacy signals. Although interpretation is necessarily limited by the lack of a comparison group, there were moderate to large magnitude improvements in processing speed, focused attention, sustained attention and inhibitory control. No meaningful changes in measures of working memory, learning, retention and switching were seen. General improvements on speeded tasks may be due to the stimulant effects of LDX, as improvements were dose dependent. The improvement of both speed and accuracy may reflect task learning due to repeated administration of neurocognitive assessments; and/or stabilisation of cognitive performance with chronic/tonic stimulant use compared with phasic/intermittent illicit stimulant use, (most participants continued illicit stimulant use throughout). Should LDX enhance cognition, this may have additional benefits in treatment adherence and functional outcomes. Task learning effects and associations between cognition and functional outcomes can be assessed in randomised controlled trial settings.\n\nLimitations of the study\n\nThe small sample size and short duration of treatment is typical of pilot safety studies; but the study is not powered to explore efficacy and this precludes more sophisticated statistical analysis. The lack of a control group also limits generalisability of secondary efficacy measures. Though blinded to dose escalation, the study was open label and so the participants may be subject to expectation effects. The maximum dose tested with the protocol was chosen on the basis of equivalence of doses of dexamphetamine used in agonist maintenance therapy in this population.16 Although we tested 250 mg, this was not dose-limiting. Higher rates of MA cessation could be obtained by a period of longer than 2 weeks at the highest dose of 250 mg LDX; and higher doses could be explored.\n\nFuture research\n\nFurther studies of longer duration with larger sample sizes are required. Our group is currently conducting a multicentre, randomised, controlled trial to assess efficacy (ACTRN12617000657325).52\n\nFor people with MA dependence, this study is the first to demonstrate the safety, tolerability and acceptability of higher doses of LDX than used for ADHD. Findings suggest the feasibility of larger scale studies to determine the efficacy of LDX for this indication.\n\nSupplementary Material\n\nReviewer comments\n\nAuthor's manuscript\n\nThe authors would like to express their gratitude to the study participants. We would like to thank Duncan Graham, medical writer, for support in editing and finalising the manuscript. We would also thank the study nurses and research assistants involved (Elaine Murray and Melissa Jackson at HNELHD, and Tamara Gradden and Alex Bissaker at SVHS), the nursing and counselling staff at each of the clinical sites, Robyn Richardson at SVHS for her assistance with the protocol and Michelle Hall for project management at HNELHD.\n\nData availability statement\n\nData are available on reasonable request. The datasets generated and/or analysed during the current study are not publicly available due to the small sample size but are available from the corresponding author on reasonable request.\n\nEthics statements\n\nPatient consent for publication\n\nNot required.\n\nEthics approval\n\nEthical approval was granted by the St Vincent’s Hospital Human Research Ethics Committee for both study sites (HREC/14/SVH/202).\n\nContributors: NE, BC, AD, RB, AC, KJS and NL designed the study. NE, BC and KJS drafted the manuscript. BC and ZL undertook statistical analyses. NE and AD were site leads. All authors critically revised and approved the final manuscript.\n\nFunding: This study was undertaken with the support of: the St Vincent’s Curran Foundation, Sydney; St. Vincent’s Hospital, Sydney; and Hunter New England Local Health District.\n\nCompeting interests: NE and AC are employed by St Vincent’s Hospital Sydney, a public health service funded by the NSW Ministry of Health. BC is employed by St Vincent’s Health Australia and has no conflicts to declare. AD is employed by Hunter New England Local Health District, a public health service funded by NSW Health and reports research and travel support from Braeburn/Camurus, research support from Indivior, and has served on an advisory board for Mundipharma, all for unrelated work. RB has received investigator-initiated untied educational grants from Reckitt Benckiser/Indivior for the development of an opioid-related behaviour scale and a study of opioid substitution therapy uptake among chronic non-cancer pain patients. RB has received an untied educational grant from Mundipharma for a postmarketing study of reformulated oxycodone. AC has received research funding from Bristol-Myers Squibb, Gilead Sciences, and ViiV Healthcare; lecture and travel sponsorships from Gilead Sciences and ViiV Healthcare; and has served on advisory boards for Gilead Sciences, MSD and ViiV Healthcare, all of which are unrelated to this present study. ZL is employed by UNSW and has no competing interests to declare. KJS is employed by UNSW and has received unrelated travel sponsorship from Gilead Sciences. NL is employed by South East Sydney Local Health District, a public health service funded by the NSW Ministry of Health; he has received research funding from Camurus, and has served on Advisory Boards for Mundipharma, Camurus and Indivior for work unrelated to this study.\n\nPatient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 United Nationa Office on Drugs and Crime (UNODC). World drug report 2019 (United nations publication, sales No. E.19.XI.8. Vienna, Austria, 2020.\n2 Farrell M, Martin NK, Stockings E, et al . Responding to global stimulant use: challenges and opportunities. Lancet 2019;394 :1652–67. 10.1016/S0140-6736(19)32230-5 31668409\n3 Hillhouse MP, Marinelli-Casey P, Gonzales R, et al . 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"keywords": "clinical pharmacology; clinical trials; substance misuse",
"medline_ta": "BMJ Open",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D019969:Amphetamine-Related Disorders; D001315:Australia; D000697:Central Nervous System Stimulants; D004311:Double-Blind Method; D006801:Humans; D000069478:Lisdexamfetamine Dimesylate; D008694:Methamphetamine; D016896:Treatment Outcome",
"nlm_unique_id": "101552874",
"other_id": null,
"pages": "e044696",
"pmc": null,
"pmid": "34006547",
"pubdate": "2021-05-18",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "29291509;23539642;29461134;30030312;22796358;16203381;17493057;24327450;11914441;21072503;23996457;11672492;20201847;16717171;11448083;10197890;25310201;18368606;32185696;7795497;20650520;14987333;22998781;18021493;5554941;27905916;13263471;31668409;19329547;15817019;20173084;16203496;23271193;11438246;24951855;11556941;19839966;18368613",
"title": "Safety and tolerability of oral lisdexamfetamine in adults with methamphetamine dependence: a phase-2 dose-escalation study.",
"title_normalized": "safety and tolerability of oral lisdexamfetamine in adults with methamphetamine dependence a phase 2 dose escalation study"
} | [
{
"companynumb": "AU-TAKEDA-2021TUS034006",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LISDEXAMFETAMINE DIMESYLATE"
},
"drugadditional... |
{
"abstract": "Warfarin overdose with unmeasurable values of the prothrombin time (PT-INR) is a significant problem in the preoperative preparation of the patient for acute invasive surgery. In contrast to conventional blood clotting assays, rotational thromboelastometry (ROTEM) evaluates the coagulation profile of the whole blood and provides a more complex view of the coagulation status of the patient. Thromboelastometry results are available within about 10 minutes and help us to provide targeted \"bedside\" therapy of coagulopathy in a bleeding patient. In our case report we describe a case of a patient with warfarin overdose and unmeasurable PT-INR values. The patient was indicated for urgent gastroscopy because of haematemesis and abdominal surgery because of ileus. Haematemesis was stopped by ROTEM targeted treatment of coagulopathy and the operation was performed without bleeding complications with normal ROTEM despite the prolongation of PT-INR to 1.8. Finally, we would like to say that ROTEM method can be used for rapid management of warfarin-induced coagulopathy and that surgery may be performed safely without any correction of PT-INR in case of normal ROTEM.\n\n\nBACKGROUND\nprothrombin time - bleeding - surgery thromboelastometry (ROTEM) warfarin.",
"affiliations": null,
"authors": "Durila|M|M|;Schützner|J|J|;Vymazal|T|T|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "Czech Republic",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0035-9351",
"issue": "95(8)",
"journal": "Rozhledy v chirurgii : mesicnik Ceskoslovenske chirurgicke spolecnosti",
"keywords": null,
"medline_ta": "Rozhl Chir",
"mesh_terms": "D000925:Anticoagulants; D005773:Gastroscopy; D006396:Hematemesis; D006801:Humans; D045823:Ileus; D011300:Preoperative Care; D013916:Thrombelastography; D014859:Warfarin",
"nlm_unique_id": "9815441",
"other_id": null,
"pages": "329-32",
"pmc": null,
"pmid": "27650566",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The role of rotational thromboelastometry (ROTEM) in the perioperative period in a warfarinized patient (case report).",
"title_normalized": "the role of rotational thromboelastometry rotem in the perioperative period in a warfarinized patient case report"
} | [
{
"companynumb": "CZ-MYLANLABS-2018M1029413",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nLow-dose, weekly cisplatin (40 mg/m2) regimens are currently utilized at Eskenazi Health in Indianapolis, Indiana for the treatment of head and neck cancer due to enhanced tolerability. This retrospective analysis analyzes the incidence, severity, and risk factors for AKI in patients who received this regimen.\n\n\nMETHODS\nA retrospective chart review was conducted including patients with head and neck cancer treated with weekly, low dose cisplatin (40 mg/m2) with concurrent radiotherapy (RT). From this criteria, 22 patients were identified and included in the final analysis. AKI was defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.\n\n\nRESULTS\nOf the 22 patients included, 12 (54.5%) experienced AKI, with 10 patients (45.5%) experiencing grade 1 AKI and 2 patients (9.1%) experiencing grade 2 AKI. Six patients (27.3%) required dose adjustments or delays due to renal adverse events, all of which had initial cisplatin total weekly doses of >70 mg. Those receiving a total weekly cisplatin dose of >70 mg were found to have a higher risk of developing an episode of AKI compared to the group receiving <70 mg (p = 0.029).\n\n\nCONCLUSIONS\nThis analysis showed patients receiving weekly doses >70 mg of cisplatin as their initial treatment dose for head and neck cancer were more likely to experience AKI. There are inconsistencies in the frequency of AKI in our study compared to published literature; however, this comparison is difficult due to the small sample size of our trial. This demonstrates the need for further investigation into the issue.",
"affiliations": "Purdue University College of Pharmacy Nursing and Health Sciences, West Lafayette, IN, USA.;Butler University College of Pharmacy and Health Sciences, Thorntown, IN, USA.;Eskenazi Health, Indianapolis, IN, USA.;Department of Pharmacy Practice, Purdue University, Indianapolis, IN, USA.",
"authors": "Dierckes|Stephen J|SJ|https://orcid.org/0000-0001-5388-9710;Ragsdale|Morgan E|ME|;Macik|Monica R|MR|;Weddle|Kellie J|KJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1078155220978454",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": null,
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "acute kidney injury; adverse drug events; cisplatin; head and neck cancer; radiotherapy",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1078155220978454",
"pmc": null,
"pmid": "33302822",
"pubdate": "2020-12-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Retrospective analysis of the incidence and severity of acute kidney injury (AKI) in patients with head and neck cancer receiving weekly cisplatin with radiotherapy (RAISe-AKI).",
"title_normalized": "retrospective analysis of the incidence and severity of acute kidney injury aki in patients with head and neck cancer receiving weekly cisplatin with radiotherapy raise aki"
} | [
{
"companynumb": "US-TEVA-2022-US-2023727",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo describe a case of corneal toxicity after migration of a dexamethasone implant into the anterior chamber.\n\n\nMETHODS\nA 62-year-old man with aphakia and a history of vitrectomy received a dexamethasone implant for a refractory Irvine-Gass syndrome. Thirty days later, the implant migrated into the anterior chamber causing endothelial contact with secondary corneal oedema that justified the removal of the implant without resolution of the oedema.\n\n\nCONCLUSIONS\nClinical tolerability to dislocated implant is poor in cases with pre-existing corneal oedema, and because of this, it must be removed early. In cases of aphakia and vitrectomy, the increased risk of Ozurdex(®) dislocation justifies performing a prior endothelial count.",
"affiliations": "Servicio de Oftalmología, Complejo Hospitalario Universitario Insular Materno Infantil, de Las Palmas de Gran Canaria, España. Electronic address: laura_bernal15@hotmail.com.;Servicio de Oftalmología, Complejo Hospitalario Universitario Insular Materno Infantil, de Las Palmas de Gran Canaria, España.",
"authors": "Bernal|L|L|;Estévez|B|B|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D004343:Drug Implants; D003907:Dexamethasone",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0365-6691",
"issue": "91(6)",
"journal": "Archivos de la Sociedad Espanola de Oftalmologia",
"keywords": "Corneal oedema; Dexamethasone implant; Edema de córnea; Implante de dexametasona; Migración en cámara anterior; Migration into anterior chamber; Ozurdex(®)",
"medline_ta": "Arch Soc Esp Oftalmol",
"mesh_terms": "D060433:Administration, Ophthalmic; D000867:Anterior Chamber; D000893:Anti-Inflammatory Agents; D001035:Aphakia; D002452:Cell Count; D015715:Corneal Edema; D003907:Dexamethasone; D004343:Drug Implants; D004728:Endothelium, Corneal; D005119:Extravasation of Diagnostic and Therapeutic Materials; D058447:Eye Pain; D005548:Foreign-Body Migration; D005901:Glaucoma; D006801:Humans; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D014821:Vitrectomy",
"nlm_unique_id": "1304603",
"other_id": null,
"pages": "292-4",
"pmc": null,
"pmid": "26922138",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Corneal toxicity after Ozurdex(®) migration into anterior chamber.",
"title_normalized": "corneal toxicity after ozurdex migration into anterior chamber"
} | [
{
"companynumb": "ES-ALLERGAN-1650753US",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "2",
... |
{
"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening systemic disease, characterized by overwhelming stimulation of the immune system and categorized as primary or secondary types. Occasionally, acute liver failure (ALF) may dominate the clinical presentation. Given the systemic nature of HLH and risk of recurrence, HLH is considered by many a contraindication to liver transplantation (LT). The aim of this study is to review our single-center experience with LT in children with secondary HLH and ALF (HLH-ALF). This is a cross-sectional, retrospective study of children with secondary HLH-ALF that underwent LT in 2005-2014. Of 246 LTs, 9 patients (3 males; median age, 5 years; range, 0.7-15.4 years) underwent LT for secondary HLH-ALF. Disease progression was rapid with median 14 days (range, 6-27 days) between first symptoms and LT. Low fibrinogen/high triglycerides, elevated ferritin, hemophagocytosis on liver biopsy, and soluble interleukin 2 receptor levels were the most commonly fulfilled diagnostic criteria; HLH genetic studies were negative in all patients. Immunosuppressive therapy after LT included corticosteroids adjusted to HLH treatment protocol and tacrolimus. Thymoglobulin (n = 5), etoposide (n = 4), and alemtuzumab (n = 2) were used in cases of recurrence. Five (56%) patients experienced HLH recurrence, 1 requiring repeat LT, and 3 died. Overall graft and patient survival were 60% and 67%, respectively. Six patients are alive and well at a median of 24 months (range, 15-72 months) after transplantation. In conclusion, LT can be beneficial in selected patients with secondary HLH-ALF and can restore good health in an otherwise lethal condition. Liver Transplantation 22 1245-1253 2016 AASLD.",
"affiliations": "Division of Gastroenterology, Hepatology and Nutrition, University of Toronto, Toronto, Ontario, Canada.;Paediatric Gastroenterology, Hepatology and Nutrition, University of Toronto, Toronto, Ontario, Canada.;Haematology and Oncology, University of Toronto, Toronto, Ontario, Canada.;Haematology and Oncology, University of Toronto, Toronto, Ontario, Canada.;General Surgery, University of Toronto, Toronto, Ontario, Canada.;Transplant and Regenerative Medicine Centre, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.;Transplant and Regenerative Medicine Centre, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.;Transplant and Regenerative Medicine Centre, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.;Transplant and Regenerative Medicine Centre, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.;Pathology, University of Toronto, Toronto, Ontario, Canada.;Paediatric Gastroenterology, Hepatology and Nutrition, University of Toronto, Toronto, Ontario, Canada.;Paediatric Gastroenterology, Hepatology and Nutrition, University of Toronto, Toronto, Ontario, Canada.;Transplant and Regenerative Medicine Centre, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.;Paediatric Gastroenterology, Hepatology and Nutrition, University of Toronto, Toronto, Ontario, Canada.;Paediatric Gastroenterology, Hepatology and Nutrition, University of Toronto, Toronto, Ontario, Canada.",
"authors": "Amir|Achiya Z|AZ|;Ling|Simon C|SC|;Naqvi|Ahmed|A|;Weitzman|Sheila|S|;Fecteau|Annie|A|;Grant|David|D|;Ghanekar|Anand|A|;Cattral|Mark|M|;Nalli|Nadya|N|;Cutz|Ernest|E|;Kamath|Binita|B|;Jones|Nicola|N|;De Angelis|Maria|M|;Ng|Vicky|V|;Avitzur|Yaron|Y|",
"chemical_list": "D007166:Immunosuppressive Agents; D014280:Triglycerides; D005340:Fibrinogen; D005293:Ferritins",
"country": "United States",
"delete": false,
"doi": "10.1002/lt.24485",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-6465",
"issue": "22(9)",
"journal": "Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society",
"keywords": null,
"medline_ta": "Liver Transpl",
"mesh_terms": "D000293:Adolescent; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005293:Ferritins; D005340:Fibrinogen; D006084:Graft Rejection; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007223:Infant; D008099:Liver; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D035583:Rare Diseases; D012008:Recurrence; D012189:Retrospective Studies; D015996:Survival Rate; D061665:Time-to-Treatment; D016896:Treatment Outcome; D014280:Triglycerides",
"nlm_unique_id": "100909185",
"other_id": null,
"pages": "1245-53",
"pmc": null,
"pmid": "27216884",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Liver transplantation for children with acute liver failure associated with secondary hemophagocytic lymphohistiocytosis.",
"title_normalized": "liver transplantation for children with acute liver failure associated with secondary hemophagocytic lymphohistiocytosis"
} | [
{
"companynumb": "CA-PFIZER INC-2018372413",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "In the first case, the AA and glucose were infused through a perinatal port system into the umbilical vein at 30 weeks' gestation due to severe IUGR. The patient received daily hyperbaric oxygenation (HBO, 100% O2 ) with 1.4 atmospheres absolute for 50 min for 7 days. At 31+4 weeks' gestation, the patient gave birth spontaneously to a newborn weighing 1378 g, pH 7.33, APGAR score 4/6/intubation. In follow-up examinations at 5 years of age, the boy was doing well without any neurological disturbance or developmental delay. In the second case, the patient presented at 25/5 weeks' gestation suffering from severe IUGR received HBO and maternal AA infusions. The cardiotocography was monitored continuously during HBO treatment. The short-time variations improved during HBO from 2.9 to 9 msec. The patient developed pathologic CTG and uterine contractions 1 day later and gave birth to a hypotrophic newborn weighing 420 g. After initial adequate stabilization, the extremely preterm newborn unfortunately died 6 days later. Fetal nutrition combined with HBO is technically possible and may allow the prolongation of the pregnancy. Fetal-specific amino-acid composition would facilitate the treatment options of IUGR fetuses and extremely preterm newborn.",
"affiliations": "Center of Fetal Surgery, University Clinic of Obstetrics and Fetal Medicine, University Medical Center Halle (Saale), Martin Luther University Halle-Wittenberg, Halle, Germany.;Saling Institute of Perinatal Medicine, Berlin, Germany.;National Research Center for Mother and Child Health, Nazarbayev University, Astana, Republic of Kazakhstan.;Center of HBO, University Clinic of Anesthesiology, University Medical Center Halle (Saale), Martin Luther University Halle-Wittenberg, Halle, Germany.;Institute of Physiology, Martin Luther University Halle-Wittenberg, Halle, Germany.;Center of Fetal Surgery, University Clinic of Obstetrics and Fetal Medicine, University Medical Center Halle (Saale), Martin Luther University Halle-Wittenberg, Halle, Germany.",
"authors": "Tchirikov|Michael|M|0000-0001-7638-0730;Saling|Erich|E|;Bapayeva|Gauri|G|;Bucher|Michael|M|;Thews|Oliver|O|;Seliger|Gregor|G|",
"chemical_list": "D000596:Amino Acids; D005947:Glucose",
"country": "United States",
"delete": false,
"doi": "10.14814/phy2.13589",
"fulltext": "\n==== Front\nPhysiol RepPhysiol Rep10.1002/(ISSN)2051-817XPHY2physreportsPhysiological Reports2051-817XJohn Wiley and Sons Inc. Hoboken 10.14814/phy2.13589PHY213589Reproductive Conditions, Disorders and TreatmentsMaternal, Fetal and Neonatal PhysiologyDevelopment and RegenerationNutritionMetabolism and RegulationCase ReportCase ReportsHyperbaric oxygenation and glucose/amino acids substitution in human severe placental insufficiency M. Tchirikov et al.Tchirikov Michael http://orcid.org/0000-0001-7638-0730michael.tchirikov@uk-halle.de \n1\nSaling Erich \n2\nBapayeva Gauri \n3\nBucher Michael \n4\nThews Oliver \n5\nSeliger Gregor \n1\n\n1 \nCenter of Fetal Surgery\nUniversity Clinic of Obstetrics and Fetal Medicine\nUniversity Medical Center Halle (Saale)\nMartin Luther University Halle‐Wittenberg\nHalle\nGermany\n\n2 \nSaling Institute of Perinatal Medicine\nBerlin\nGermany\n\n3 \nNational Research Center for Mother and Child Health\nNazarbayev University\nAstana\nRepublic of Kazakhstan\n\n4 \nCenter of HBO\nUniversity Clinic of Anesthesiology\nUniversity Medical Center Halle (Saale)\nMartin Luther University Halle‐Wittenberg\nHalle\nGermany\n\n5 \nInstitute of Physiology\nMartin Luther University Halle‐Wittenberg\nHalle\nGermany\n* Correspondence\n\nMichael Tchirikov, Center of Fetal Surgery, University Clinic of Obstetrics and Prenatal Medicine, University Hospital Halle (Saale), Martin Luther University Halle‐Wittenberg, Ernst‐Grube Strasse 40, 06120 Halle (Saale), Germany.\n\nTel: +49 345 557 3250\n\nFax: +49 345 557 3251\n\nE‐mail: michael.tchirikov@uk-halle.de\n13 3 2018 3 2018 6 5 10.1002/phy2.2018.6.issue-5e1358927 9 2017 08 12 2017 18 12 2017 © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nIn the first case, the AA and glucose were infused through a perinatal port system into the umbilical vein at 30 weeks' gestation due to severe IUGR. The patient received daily hyperbaric oxygenation (HBO, 100% O2) with 1.4 atmospheres absolute for 50 min for 7 days. At 31+4 weeks' gestation, the patient gave birth spontaneously to a newborn weighing 1378 g, pH 7.33, APGAR score 4/6/intubation. In follow‐up examinations at 5 years of age, the boy was doing well without any neurological disturbance or developmental delay. In the second case, the patient presented at 25/5 weeks' gestation suffering from severe IUGR received HBO and maternal AA infusions. The cardiotocography was monitored continuously during HBO treatment. The short‐time variations improved during HBO from 2.9 to 9 msec. The patient developed pathologic CTG and uterine contractions 1 day later and gave birth to a hypotrophic newborn weighing 420 g. After initial adequate stabilization, the extremely preterm newborn unfortunately died 6 days later. Fetal nutrition combined with HBO is technically possible and may allow the prolongation of the pregnancy. Fetal‐specific amino‐acid composition would facilitate the treatment options of IUGR fetuses and extremely preterm newborn.\n\nAmino acidscordocentesisfetal growth restrictionHBOhyperbaric oxygenationintrauterine treatmentintravenous infusionIUGRplacental insufficiencyport implantation source-schema-version-number2.0component-idphy213589cover-dateMarch 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:13.03.2018\n\n\nM. \nTchirikov \n, \nE. \nSaling \n, \nG. \nBapayeva \n, \nM. \nBucher \n, \nO. \nThews \n, \nG. \nSeliger \n. Hyperbaric oxygenation and glucose/amino acids substitution in human severe placental insufficiency . Physiol Rep , 6 (5 ), 2018 , e13589, https://doi.org/10.14814/phy2.13589\n\n\n\n\nFunding Information\n\n\nNo funding information provided.\n==== Body\nIntroduction\nSevere intrauterine growth restriction (IUGR), caused by placental insufficiency, is a serious prenatal condition (Haram et al. 2006; Nardozza et al. 2017; Tang et al. 2017). It is often associated with arterial and venous blood flow redistribution which maintains the delivery of oxygenated blood to the brain, or the “brain sparing effect”, and the reduction in the placental arterial blood supply to the fetal liver due to increased shunting through the ductus venosus (Arbeille et al. 1987; Tchirikov et al. 1998, 2006; Cahill et al. 2014). However, a reduced liver blood supply could worsen fetal growth (Tchirikov et al. 2001, 2002, 2006). This reduction in blood flow resistance in the cerebral arteries is associated with significantly increased risk of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis and death (Flood et al. 2014). Placental insufficiency is responsible for about 40% of all stillbirths (Mongelli and Gardosi 2000; Platt 2014). The long‐term neurocognitive deficits of IUGR include poor executive functioning, cognitive inflexibility with poor creativity and language problems (Figueras et al. 2011).\n\nTreatment options for IUGR are limited and usually necessitate an early delivery (Haram et al. 2006; Mandruzzato et al. 2008; Thorne et al. 2014). There is evidence that the active placental transport of amino acids, glucose, and oxygen from the mother to the fetus is reduced in IUGR fetuses (Cetin et al. 1990, 1992; Rizzo et al. 1995; Jansson et al. 2002; Benirschke et al. 2013). Fetal amino acid and glucose supplementation combined with hyperbaric oxygenation (HBO) could lead to improved fetal growth, and prolonged pregnancy (Xiao et al. 2006; Shyu et al. 2008; Wu 2009; Tchirikov et al. 2010a, 2017).\n\nPreviously, we observed inadequate improvement in IUGR fetuses at a gestational age below 28 weeks’ gestation, using intraumbilical amino acid/glucose supplementations via a port system (Tchirikov et al. 2010b). We hypothesized that the additional nutrient load of IUGR fetuses could lead to lactic acidosis, which subsequently led us to use of HBO. HBO can increase oxygen diffusion in the placenta improving energy metabolism in the fetus. In this report, we describe in detail the treatment options of severe IUGR human fetuses with pronounced placental insufficiency and brain sparing, using the combination of HBO with the long‐term administration of nutrients directly into the umbilical vein via a subcutaneously implanted intraumbilical perinatal port system, or transplacental fetal supply.\n\nCase 1\nA 22‐year‐old second gravida, first para patient was referred to the clinic at 30 weeks’ gestation because of severe IUGR and preeclampsia. Three years earlier, the patient had a preterm delivery by C‐section because of severe preeclampsia and brain sparing. The patient did not have any other relevant history (e.g., smoking, etc.). On admission, the patient did not have any complaints. Patient monitoring included the evaluation of a multi‐vessel Doppler examination of the pulsatility index (PI) in the umbilical artery (UA), middle cerebral artery (MCA), uterine arteries (Ut.A), ductus venosus (DV), and CTG. All data were compared with published, standardized references for various Doppler parameters used in ultrasound software (Viewpoint, GE).\n\nThe estimated fetal weight was 1022 g (<3rd percentile), with a reduced amount of amniotic fluid (AFI 8.9 cm) (Voluson E8 Expert, GE, Milwaukee, WI). The Dopper parameters reflected placental insufficiency and brain sparing (Table 1). The patient received antihypertensive therapy with methyldopa 250 mg given orally, 4 times daily, and a prophylaxis for the respiratory distress syndrome (RDS) of dexamethasone. It was possible to stabilize the arterial pressure below 140/90 mmHg. The patient was informed about the study on amino acid supplementation via a subcutaneously implanted port system combined with hyperbaric oxygenation. The protocol for the port implantation was approved by the institutional review board and the invasive procedures were performed with written informed consent by the patient.\n\nTable 1 Ultrasound, Doppler and CTG examinations before and after HBO treatment\n\nParameter\tCase 1 before HBO 30 WG\tCase 1 after 5 HBOs 31 WG\tCase 1 after 7 HBOs 31+2 WG\tCase 2 before HBO 25 WG\tCase 2 immediately after HBO\t\nFetal weight\t1022 g\t–\t1378 g\t470 g\t–\t\nUt. A.‐PI\t0.79/1.97\t0.81/2.04\t0.68/1.64\t2.9/3.3\t1.9/2.05\t\nUA‐PI\t2.99\t1.4\t3.5\t3.27\t3.0\t\nMCA‐PI\t0.99\t1\t1.14\t1.12\t0.93\t\nDV‐PI\t0.55\t–\t–\t0.4\t1.0\t\nCTG‐STV\t10.2 msec\t9.8 msec\t–\t3.9 msec\t9 msec\t\nPI, pulsatility index; UA, umbilical artery; MCA, middle cerebral artery; Ut.A, the uterine arteries; DV, ductus venosus; CTG, cardiotocography; STV, short time variation; WG, weeks’ gestation.\n\nJohn Wiley & Sons, LtdAt 30+1 weeks’ gestation, the port implantation was performed under local anesthesia without any complications (Tchirikov et al. 2017). For the ultrasound‐guided puncture of the umbilical vein, we used an 18‐gauge needle (Echotip® Disposable Trocar Needle, COOK Medical, Spencer, IN) and the catheter was inserted transplacentally into the umbilical vein and then connected to the port capsule (Fig. 1) (Tchirikov et al. 2017).\n\nFigure 1 Amino acid and glucose supplementation via a subcutaneously implanted intraumbilical port system. (A) Connection of the port catheter to the port chamber in preparation for transplantation. (B) The situation after port implantation. The 25‐gauge port needle was used to enter the port system. The port system is connected to the pump containing amino acid and glucose solutions (with permission of J Perinatal Med (Tchirikov et al. 2017).\n\nThe 25‐gauge port needle was changed every 3 days. The pH in the umbilical vein was 7.43. Amino acids (4 mL/day, Aminoven infant 10%, Fresenius Kabi GmbH, Bad Homburg, Germany) and 10% glucose (20 mL/day) were infused with a constant rate of 1.0 mL/h for 9 days. The patient received daily HBO (100% O2) with 1.4 atmospheres absolute (ATA) for 50 min for 7 days (Baromed, Perry Baromedical Corporation, Florida). One week later, the resistance to the blood flow in the UA was measured to be slightly improved (Table 1). At 31+4 weeks’ gestation, the patient gave birth spontaneously to a preterm newborn weighing 1378 g, with a length 34 cm, pH 7.33, APGAR score 4/6/intubation. The port system was removed under local anesthesia. The pathological examination reported a small, insufficient placenta with infarcts and calcifications. The position of the catheter was found to be optimal without any local hemorrhage (Fig. \n1). Four days postdelivery, the patient was discharged from the hospital in a healthy condition without any further treatment, and the baby was discharged 3 weeks later. In follow‐up examinations at 5 years of age, the boy was doing well, but the speech development was delayed without any other neurological disturbance.\n\nCase 2\nA 30‐year‐old third gravida, null para patient was referred to our clinic at 25/0 weeks’ gestation because of severe IUGR with brain sparing and preeclampsia. The patient had indicated two previous miscarriages at 9 and 10 weeks’ gestation. The patient was diagnosed 2 years’ previously with systemic lupus erythematosus (SLE), which had been treated with hydroxychlorochine 200 mg/day and prednisolone 5 mg/day. On admission, the fetal weight was estimated to be 470 g (<3rd percentile), and clinical observation included anhydramnios, zero diastolic blood flow in the UA, with strong pulsation of UV (Fig. 2), brain sparing and the notching of both Ut.A and normal DV blood flow profile (Table 1, Viewpoint E10 Expert, GE).\n\nFigure 2 Doppler profiles of the umbilical artery and vein. Note the pulsation of the UV.\n\nThe TORCH test was negative. The monitored RR rate was stabilized below 160/100 mmHg. The patient had a proteinuria >3 g/day. The patient received RDS prophylaxis with 12 mg i.v. betamethasone (two applications over 24 h), 2 L infusion therapy, Aminovent Infant 10% 40 mL/h i.v. with 10% glucose, O2 3 L/min therapy, and an s.c. thrombosis prophylaxis.\n\nThe patient was informed about the experimental treatment and the possible potential for HBO and amino acid supplementation. However, the direct intraumbilical administration of AA, using the perinatal port system was not offered because an amino acid solution corresponding to fetal AA concentrations was not available (Tchirikov et al. 2017). Our previous prospective study indicated the intraumbilical delivery of a commercial AA formula known to deviate from fetal AA proportions is not effective in severe IUGR fetuses with brain sparing below 28 weeks’ gestation (Tchirikov et al. 2017). We obtained the informed written consent of the patient and approval from the University Ethics Committee for HBO‐only treatment.\n\nThe Ethics Committee stipulated the continuous monitoring of the mother and fetus during HBO. While the mother could be sufficiently monitored inside the HBO chamber, the standard equipment had no capabilities for fetal monitoring. For this reason, our engineer modified the HBO chamber by affixing an ECG‐cable (Monica®), which enabled sufficient fetal heart rate and ECG monitoring throughout the entire HBO treatment. The patient received HBO (Sayers/Hebold, Cuxhaven, Germany) with 1.4 atmospheres absolute for 50 min, the maximum transcutaneous oxygen – tcpO2 was measured as 723 mmHg (Fig 3).\n\nFigure 3 The HBO process. The patient received HBO (Sayers/Hebold, Cuxhaven, Germany) with 1.4 atmospheres absolute for 50 min, maximum transcutaneous oxygen – tcpO2 was measured 723 mmHg. Fetal monitoring was performed using a Monica ECG tool affixed to the HBO chamber.\n\nDuring HBO treatment, the patient complained of uterine contractions, which could be treated with i.v. tocolysis, using 25 μg fenoterol hydrobromide (Partusisten®, Boehringer Ingelheim Pharma KG, Ingelheim, Germany). The Doppler parameter did not change in response to HBO (before/after HBO (Table 1), although the cCTG improved sufficiently, increasing the STV from <2.9 to 9 msec (Fig. 3). One day later, the patient was delivered by cesarean section because of fetal late decelerations. The newborn weighed 420 g, APGAR 3/8/8, art. pH 7.12 and BE – 8.5 mmol/L was intubated and transferred to the neonatal ICU for high flow oxygen/NO treatment and surfactant applications. After an initial adequate stabilization, the newborn unfortunately developed a pulmonary bleed on the 4th postnatal day, with subsequent hypotonia, anuria, leucopenia and thrombocytopenia, and died 6 days later. The pathological examination reported a placenta (11 × 8.7 cm area), weighing 86 g, with large necrotic areas, fibrosis, and calcifications.\n\nDiscussion\nIUGR is one of the major causes of preterm delivery, which itself is associated with an increase in perinatal mortality and morbidity, in addition to fetal under‐nutrition and chronic hypoxia (Haram et al. 2006; Goldenberg et al. 2008). The WHO defines preterm delivery as a global problem. The survival rate of extreme preterm infants (<28 weeks gestation) is still low, with 40% dying by the age of 5 years (WHO) (March of Dimes, PMNCH 2012). Fetuses with IUGR have a higher rate of mortality [OR 8.3] as well as perinatal complications [OR 31.6] (Beckerath et al. 2013). The long‐term impacts of extreme preterm birth include: impairment of vision, hearing and executive functions, developmental delay, psychiatric and behavioral problems, cardiovascular and pulmonary diseases, and resulting socioeconomic burdens (March of Dimes, PMNCH 2012; Beckerath et al. 2013; Figueras et al. 2011; Howson et al. 2013; Platt 2014).\n\nThe etiology of IUGR is multifactorial and may be subdivided into maternal causes such as hypertension, diabetes, severe heart‐, autoimmune‐, renal‐ or other systemic‐diseases, nicotine and drug abuse, nutritional disorders, fetal causes, like chromosomal abnormalities, mosaicism and genetic syndromes, infections and metabolism‐disorders, and causes involving uteroplacental vascular insufficiency (Nardozza et al. 2017). The placenta is an essential organ for the transfer of nutrients and gases from the mother to fetus and for the elimination of products resulting from fetal metabolism. The interaction between the maternal and fetal circulations in the placenta is fundamental for the adequate exchange of nutrients and oxygen. Because of the presence of paternal antigens, the fetus and the fetal part of the placenta represent an allograft to maternal tissues (Nardozza et al. 2017). The inadequate trophoblast invasion of the myometrial portion of the spiral arteries, the reduced synthesis of nitric oxide and endothelial adhesion molecules in extravillous trophoblast lead to an increased vasoconstricting agent activity, a resistance to blood flow and a resultant decreased nutrition and oxygen transport of the intervillous space (Grati et al. 2017; Nardozza et al. 2017; Tang et al. 2017).\n\nDuring sustained hypoxia, fetal growth is slow, although oxygen consumption may be unaltered when corrected for fetal mass (Carter 2015). The increased anaerobic metabolism of glucose in the placenta could spare oxygen for the fetus but could reduce its supply of substrate and thereby limits fetal growth (Carter 2015). The mechanisms leading to neuronal injury in the IUGR neonatal brain are complex and not well understood. The brain sparing of IUGR fetuses is associated with changes in neurotransmitter profiles (Garcia‐Contreras et al. 2017). Neuroinflammation elevated production of proinflammatory cytokines and tumor necrosis factor‐α (Wixey et al. 2017). IUGR has been linked to reductions in overall brain volumes, with regional changes in gray and white matter volumes (Padilla et al. 2011), significantly thinner insular cortical thickness, and a smaller insular cortical volume than controls (Egana‐Ugrinovic et al. 2014).\n\nAs a consequence of irreversible placental pathology, treatment options for IUGR with placental insufficiency remain extremely limited (Haram et al. 2006; Benirschke et al. 2013; Thorne et al. 2014). A number of changes in the activity of amino acid transporters have been identified in the IUGR placenta (Pardi et al. 2002). In IUGR pregnancies, the maternal concentration of most amino acids is significantly higher than in normal pregnancies, which determines a significant increase in total nitrogen by approximately 18%. This observation coupled with lower fetal amino acid concentrations in IUGR fetuses, leads to significantly lower fetal‐maternal amino acid concentration differences in IUGR pregnancies (Cetin et al. 1992; Pardi et al. 2002). The active placental transport of amino acids, glucose and oxygen from the mother to the fetus is reduced due to the altered angiogenesis of placental tissue, disturbed syncytio‐ and cytotrophoblast development, proliferation, and trophoblast invasion (Cetin et al. 1992; Jansson et al. 2002; Benirschke et al. 2013). It is impossible for any treatment of IUGR to replace an organ as complex as the human placenta. However, a partial therapeutic solution to IUGR could be the supply of growth‐restricted fetuses with amino acids and glucose under HBO conditions. This could lead to improved fetal growth and prolong pregnancy (Tchirikov et al. 2010a, 2017). Paz et al. (2001) were able to demonstrate that full‐term infants with fetal growth restriction are not at increased risk for low intelligence scores at the age 17.\n\nThe intrauterine application of amino acids and glucose into the amniotic fluid for the treatment of IUGR human fetuses was first developed and introduced by Saling and his coworkers in the 1970s (Dudenhausen et al. 1972; Saling 1972, 1987). Intraamniotic amino acid application increased the amino acid concentration in fetal plasma but the increased risk of amnion infection syndrome thwarted the use of this method (Saling 1987).\n\nWe used the perinatal port system for the long‐term administration of nutrients into the umbilical vein of the first patient without any complications. In our previous study, we reported that intraumbilical supplementation, using a commercial amino acid solution via a port system did not lead to a sufficient weight gain in extremely preterm IUGR fetuses (Tchirikov et al. 2017). We hypothesized that the additional nutrient load of IUGR fetuses could lead to lactic acidosis. On the other hand, commercial amino acid solutions significantly deviate from the amino acid proportions in normal fetal plasma (Fig. 4) (Economides et al. 1989; Cetin et al. 1990, 1992), which could worsen the amino acid imbalance of IUGR fetuses (Fig. 4). The commercial AA solution used did not contain aspartic acid, glutamic acid or ornithine. Furthermore, the solution had fourfold lower relative concentrations of lysine and threonine and 25‐fold lower relative concentration of taurine, compared to the physiologic AA proportions in the plasma of extreme preterm fetuses. For these reasons, we did not use the intraumbilical port system to treat the second patient who presented at 25 weeks’ gestation.\n\nFigure 4 The amino acid concentrations of the commercial amino acid solution vs. amino acid concentrations observed in very preterm human fetuses under physiologic conditions. The commercial amino acid solution used was Aminoven infant 10% (Fresenius Kabi GmbH, Bad Homburg, Germany). The required amino acids’ (AA) concentration related to plasma AA concentration of human fetuses under physiological conditions was calculated as AA = fetal AA concentrations (mean) × 500 (Economides et al. 1989; Cetin et al. 1990, 1992; Tchirikov et al. 2017). The commercial AA solution did not contain aspartic acid, glutamic acid and ornithine. Furthermore, this solution had fourfold lower relative concentrations of lysine, and threonine, and 25‐fold lower relative concentration of taurine, compared to the physiologic AA proportions in the plasma of extreme preterm fetuses.\n\nHyperbaric oxygen (HBO) therapy is defined by the Undersea and Hyperbaric Medical Society (UHMS) as a treatment in which a patient intermittently breathes 100% oxygen under a pressure that is greater than the pressure at sea level [a pressure greater than 1 atmosphere absolute (ATA)]. HBO has been shown to be a potent means of increasing the oxygen content of blood and has been advocated for the treatment of various ailments, including air embolism, carbon monoxide poisoning, wound healing, and ischemic stroke affecting the expression of the endothelial adhesion molecules, NO production, NOS expression, cellular energetics, lipid peroxidation, and microvascular blood flow. (Buras 2000; Calvert et al. 2007). HBO with a significantly higher pressure is used as a standard procedure during pregnancy as a therapeutic option in patients with carbon monoxide intoxication (Kao and Nañagas 2004). Wattel et al. (2013) did not find any deviations in psychomotor or height/weight criteria of children following HBO treatment for carbon monoxide (CO) poisoning during pregnancy.\n\nWe used HBO with only 1.4 atmospheres absolute for 50 min (real time of 75 min with HBO initiation and completion). Modern HBO treatment is a relatively safe method. Analysis of 1.5 million HBO treatments by Jokinen‐Gordon et al. (2017), found that only 0.68% of treatments were associated with an adverse event. Barotrauma and confinement anxiety were the most frequently reported events. Similarly, Hadanny et al. (2016) reported a complication rate of 0.72% when analyzing the adverse effects of HBO on 2334 patients. Long et al. (2017) found that the HBO therapy is safe and effective for the treatment of sleep disorders in children with cerebral palsy.\n\nThe second patient reacted with increased uterine contractions to the HBO. The possible constricting influence of HBO onto arterial vessels is common (Thews and Vaupel 2016; van der Bel et al. 2017). We have not registered any increased uterine contraction of pregnant patients with carbon monoxide intoxication treated with HBO in our medical center till now. van Hoesen et al. (1989) described also a good tolerance of HBO in pregnant patients.\n\nThe influence of HBO on tissues and metabolic and regeneration processes remains controversial. Oxidative stress, an imbalance between free radical generation and antioxidant defense, is recognized as a key factor in the pathogenesis of adverse pregnancy outcomes (Sultana et al. 2017). Exposure to HBO could increase the formation of oxygen radical species and reduce antioxidant enzyme activity, causing lipid peroxidation and DNA damage (Chavko and Harabin 1996; Gröger et al. 2009; Michalski et al. 2011; Simsek et al. 2011; Yuan et al. 2011; Schmale et al. 2012; Wixey et al. 2017). Yuan et al. (2011) demonstrated limited DNA damage in response to HBO with 2.2 ATA in human umbilical cord endothelial cells. In opposition to this finding, Migita et al. (2016) demonstrated that HBO (>2 atmospheres absolute) suppressed apoptosis, which caused inflammation after renal ischemia/reperfusion, and promoted tubular cell regeneration. Zeng et al. (2012) found that HBO preconditioning could significantly increase the level of the cortical neurons’ peroxisome proliferator‐activated receptor‐γ mRNA, playing a central role in the regulation of apoptosis and oxidative stress.\n\nHuang et al. (2016) who applied HBO 1 h/day × 3 days at 2 ATA were able to demonstrate in a rat model that HBO significantly decreased MRI‐identified abnormalities and tissue histopathology after repetitive mild traumatic brain injury. Yu et al. (2015) demonstrated that early HBO (2 ATA for 1 h) after CMA occlusion could have protective effects on brain tissue after cerebral ischemia, possibly via the inhibition of tumor necrosis factor‐alpha and phospho‐protein kinase C‐alpha. Wei et al. (2015) suggested that HBO promotes neural stem cell proliferation and protects learning and memory abilities in neonatal hypoxic‐ischemic brain damage. Chen et al. (2016) demonstrated that HBO enhances antioxidant capacity and reduces the ultrastructural damage induced by hypoxic‐ischemia, which may improve synaptic reconstruction and alleviate immature brain damage to promote the habilitation of brain function.\n\nShyu et al. (2008) showed that HBO can induce the expression of a placental growth factor in human bone marrow‐derived mesenchymal stem cells, which may play an important role in HBO‐induced vasculogenesis. The combination of HBO with glutamine substitution was effective in reducing neuronal apoptosis, increasing serum prealbumin concentration and improving neurological function following traumatic brain injury (Fu et al. 2014). The use of HBO has been recently described in artificial uterus system and the placenta supporting oxygen supply of very preterm neonate in parallel to ECMO equipment (Tchirikov 2017).\n\nIn conclusion, the combination of HBO and intraumbilical amino acid and glucose supplementations via a port system or transplacental supply, offer a treatment option in the development of placenta substitution in cases with severe IUGR. We believe that the reestablishment of fetal physiological concentrations of amino acids, glucose, trace elements, hormones, growth factors, vitamins, and oxygen in IUGR fetuses, using HBO and a placental by‐pass of these substances via an intraumbilical port system could improve neonatal outcomes and IUGR‐altered fetal programing.\n\nConflict of Interest\nThe authors do not have any conflicts of interest or financial disclosure.\n==== Refs\nReferences\n\n\nArbeille , P. \n, \nA. \nRoncin \n, \nM. \nBerson \n, \nF. \nPatat \n, and \nL. \nPourcelot \n. 1987 \nExploration of the fetal cerebral blood flow by duplex Doppler‐linear array system in normal and pathological pregnancies . Ultrasound Med. Biol. \n13 :329 –337 .3303590 \n\n\nvon Beckerath , A. K. \n, \nM. \nKollmann \n, \nC. \nRotky‐Fast \n, \nE. \nKarpf \n, \nU. \nLang \n, and \nP. \nKlaritsch \n. 2013 \nPerinatal complications and long‐term neurodevelopmental outcome of infants with intrauterine growth restriction . Am. J. 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World Health Organization , Geneva Online verfügbar unter http://www.who.int/pmnch/media/news/2012/201204_borntoosoon-report.pdf.\n\n\nMichalski , D. \n, \nW. \nHartig \n, \nD. \nSchneider \n, and \nC. \nHobohm \n. 2011 \nUse of normobaric and hyperbaric oxygen in acute focal cerebral ischemia ‐ a preclinical and clinical review . Acta Neurol. Scand. \n123 :85 –97 . https://doi.org/10.1111/j.1600-0404.2010.01363.x.20456243 \n\n\nMigita , H. \n, \nS. \nYoshitake \n, \nY. \nTange \n, \nN. \nChoijookhuu \n, and \nY. \nHishikawa \n. 2016 \nHyperbaric oxygen therapy suppresses apoptosis and promotes renal tubular regeneration after renal ischemia/reperfusion injury in rats . Nephro‐Urol. Mon. \n8 :e34421 \nhttps://doi.org/10.5812/numonthly.34421.\n\n\nMongelli , M. \n, and \nJ. \nGardosi \n. 2000 \nFetal growth . Curr. Opin. Obstet. Gynecol. \n12 :111 –115 .10813572 \n\n\nNardozza , L. M. M. \n, \nA. C. R. \nCaetano \n, \nA. C. P. \nZamarian \n, \nJ. B. \nMazzola \n, \nC. P. \nSilva \n, \nV. M. G. \nMarçal \n, et al. 2017 \nFetal growth restriction: current knowledge . Arch. Gynecol. Obstet. \n295 :1061 –1077 . https://doi.org/10.1007/s00404-017-4341-9.28285426 \n\n\nPadilla , N. \n, \nC. \nFalcón \n, \nM. \nSanz‐Cortés \n, \nF. \nFigueras \n, \nN. \nBargallo \n, \nF. \nCrispi \n, et al. 2011 \nDifferential effects of intrauterine growth restriction on brain structure and development in preterm infants: a magnetic resonance imaging study . Brain Res. \n1382 :98 –108 . https://doi.org/10.1016/j.brainres.2011.01.032.21255560 \n\n\nPardi , G. \n, \nA. M. \nMarconi \n, and \nI. \nCetin \n. 2002 \nPlacental‐fetal interrelationship in IUGR fetuses—a review . Placenta \n23 :S136 –S141 . https://doi.org/10.1053/plac.2002.0802.11978072 \n\n\nPaz , I. \n, \nA. \nLaor \n, \nR. \nGale \n, \nS. \nHarlap \n, \nD. K. \nStevenson \n, and \nD. S. \nSeidman \n. 2001 \nTerm infants with fetal growth restriction are not at increased risk for low intelligence scores at age 17 years . J. Pediat. \n138 :87 –91 . https://doi.org/10.1067/mpd.2001.110131.11148518 \n\n\nPlatt , M. J. \n\n2014 \nOutcomes in preterm infants . Public health \n128 :399 –403 . https://doi.org/10.1016/j.puhe.2014.03.010.24794180 \n\n\nRizzo , G. \n, \nA. \nCapponi \n, \nD. \nArduini \n, and \nC. \nRomanini \n. 1995 \nThe value of fetal arterial, cardiac and venous flows in predicting pH and blood gases measured in umbilical blood at cordocentesis in growth retarded fetuses . Br. J. Obstet. Gynaecol. \n102 :963 –969 .8652487 \n\n\nSaling , E \n. 1972 \nPerinatale Medizin . Georg Thieme Verlag , 3 Bände .\n\n\nSaling , E. \n\n1987 \nVersuch einer neuen kompensatorischen Versorgung des hypotrophen Feten . Geburtshilfe Frauenheilkd. \n47 :90 –92 . https://doi.org/10.1055/s-2008-1035781.3106133 \n\n\nSchmale , M. \n, \nA. \nFichtner \n, \nC. \nPohl \n, \nE. \nJohn \n, and \nM. \nBucher \n. 2012 \nHyperbare Oxygenation bei nekrotisierenden Weichteilinfektionen: Pro . Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen \n83 :973 –979 . https://doi.org/10.1007/s00104-012-2283-0.23108429 \n\n\nShyu , K. G. \n, \nH. F. \nHung \n, \nB. W. \nWang \n, and \nH. \nChang \n. 2008 \nHyperbaric oxygen induces placental growth factor expression in bone marrow‐derived mesenchymal stem cells . Life Sci. \n83 :65 –73 . https://doi.org/10.1016/j.lfs.2008.05.005.18558410 \n\n\nSimsek , K. \n, \nH. \nAy \n, \nT. \nTopal \n, \nM. \nOzler \n, \nB. \nUysal \n, \nE. \nUcar \n, et al. 2011 \nLong‐term exposure to repetitive hyperbaric oxygen results in cumulative oxidative stress in rat lung tissue . Inhalation Toxicol. \n23 :166 –172 . https://doi.org/10.3109/08958378.2011.558528.\n\n\nSultana , Z. \n, \nK. \nMaiti \n, \nJ. \nAitken \n, \nJ. \nMorris \n, \nL. \nDedman \n, and \nR. \nSmith \n. 2017 \nOxidative stress, placental ageing‐related pathologies and adverse pregnancy outcomes . Am. J. Reprod. Immunol. \n77 :1 –10 . https://doi.org/10.1111/aji.12653.\n\n\nTang , L. \n, \nG. \nHe \n, \nX. \nLiu \n, and \nW. \nXu \n. 2017 \nProgress in the understanding of the etiology and predictability of fetal growth restriction . Reproduction \n153 :R227 –R240 . https://doi.org/10.1530/rep-16-0287.28476912 \n\n\nTchirikov , M \n. 2017 \nKünstliches Gebärmuttersystem und Plazenta . Angemeldet durch Universitätsklinikum Halle (Saale), Deutschland am 21.03.2017. Anmeldenr: 513976. Veröffentlichungsnr: PCT/EP2017/056704.\n\n\nTchirikov , M. \n, \nC. \nRybakowski \n, \nB. \nHuneke \n, and \nH. J. \nSchroder \n. 1998 \nBlood flow through the ductus venosus in singleton and multifetal pregnancies and in fetuses with intrauterine growth retardation . Am. J. Obstet. Gynecol. \n178 :943 –949 .9609564 \n\n\nTchirikov , M. \n, \nS. \nKertschanska \n, and \nH. J. \nSchroder \n. 2001 \nObstruction of ductus venosus stimulates cell proliferation in organs of fetal sheep . Placenta \n22 :24 –31 . https://doi.org/10.1053/plac.2000.0585.11162349 \n\n\nTchirikov , M. \n, \nS. \nKertschanska \n, \nH. J. \nStürenberg \n, and \nH. J. \nSchröder \n. 2002 \nLiver blood perfusion as a possible instrument for fetal growth regulation . Placenta \n23 :S153 –S158 . https://doi.org/10.1053/plac.2002.0810.11978076 \n\n\nTchirikov , M. \n, \nH. J. \nSchroder \n, and \nK. \nHecher \n. 2006 \nDuctus venosus shunting in the fetal venous circulation: regulatory mechanisms, diagnostic methods and medical importance . Ultrasound Obstet. Gynecol. \n27 :452 –461 . https://doi.org/10.1002/uog.2747.16565980 \n\n\nTchirikov , M. \n, \nO. \nKharkevich \n, \nJ. \nSteetskamp \n, \nM. \nBeluga \n, and \nM. \nStrohner \n. 2010a \nTreatment of growth‐restricted human fetuses with amino acids and glucose supplementation through a chronic fetal intravascular perinatal port system . Eur. Surg. Res. \n45 :45 –49 . https://doi.org/10.1159/000318859\n20733317 \n\n\nTchirikov , M. \n, \nJ. \nSteetskamp \n, \nM. \nHohmann \n, and \nH. \nKoelbl \n. 2010b \nLong‐term amnioinfusion through a subcutaneously implanted amniotic fluid replacement port system for treatment of PPROM in humans . Eur. J. Obstet. Gynecol. Reprod. Biol. \n152 :30 –33 . https://doi.org/10.1016/j.ejogrb.2010.04.023.20488612 \n\n\nTchirikov , M. \n, \nZ. S. \nZhumadilov \n, \nG. \nBapayeva \n, \nM. \nBergner \n, and \nM. \nEntezami \n. 2017 \nThe effect of intraumbilical fetal nutrition via a subcutaneously implanted port system on amino acid concentration by severe IUGR human fetuses . J. Perinat. Med. \n45 :227 –236 . https://doi.org/10.1515/jpm-2016-0155.27533115 \n\n\nThews , O. \n, and \nP. \nVaupel \n. 2016 \nTemporal changes in tumor oxygenation and perfusion upon normo‐and hyperbaric inspiratory hyperoxia . Strahlenther. Onkol. \n192 :174 –181 . https://doi.org/10.1007/s00066-015-0916-1.26501141 \n\n\nThorne , J. \n, \nP. \nDowney \n, and \nE. E. \nMooney \n. 2014 \nPlacental pathology associated with small for gestational age infants . Ir. Med. J. \n107 :249 –250 .25282971 \n\n\nWattel , F. \n, \nD. \nMathieu \n, and \nM. \nMathieu‐Nolf \n. 2013 \nDevenir des enfants intoxiqués au monoxyde de carbone en période fœtale et traités par oxygénothérapie hyperbare—Étude d'une cohorte constituée sur 25 ans de 1983 à 2008 . Bull. Acad. Med. \n197 :677 –697 .\n\n\nWei , L. \n, \nJ. \nWang \n, \nY. \nCao \n, \nQ. \nRen \n, \nL. \nZhao \n, \nX. \nLi \n, et al. 2015 \nHyperbaric oxygenation promotes neural stem cell proliferation and protects the learning and memory ability in neonatal hypoxic‐ischemic brain damage . Int. J. Clin. Exp. Pathol. \n8 :1752 .25973064 \n\n\nWixey , J. A. \n, \nK. K. \nChand \n, \nP. B. \nColditz \n, and \nS. T. \nBjorkman \n. 2017 \nNeuroinflammation in intrauterine growth restriction . Placenta \n54 :117 –124 . https://doi.org/10.1016/j.placenta.2016.11.012.27916232 \n\n\nWu , Guoyao \n. 2009 \nAmino acids: metabolism, functions, and nutrition . Amino Acids \n37 :1 –17 . https://doi.org/10.1007/s00726-009-0269-0.19301095 \n\n\nXiao , X. M. \n, \nZ. H. \nYe \n, \nY. \nLong \n, and \nS. L. \nChen \n. 2006 \nThe effects of hyperbaric oxygen treatment on lipid peroxidation of pregnant rabbits and their fetus during late pregnancy . Undersea Hyperb. Med. \n33 :299 –303 .17004417 \n\n\nYu , M. \n, \nY. \nXue \n, \nW. \nLiang \n, \nY. \nZhang \n, and \nZ. \nZhang \n. 2015 \nProtection mechanism of early hyperbaric oxygen therapy in rats with permanent cerebral ischemia . J. Phys. Ther. Sci. \n27 :3271 –3274 . https://doi.org/10.1589/jpts.27.3271.26644690 \n\n\nYuan , J. \n, \nR. D. \nHandy \n, \nA. J. \nMoody \n, \nG. \nSmerdon \n, and \nP. \nBryson \n. 2011 \nLimited DNA damage in human endothelial cells after hyperbaric oxygen treatment and protection from subsequent hydrogen peroxide exposure . Biochem. Biophys. Acta. \n1810 :526 –531 . https://doi.org/10.1016/j.bbagen.2011.02.007.21371529 \n\n\nZeng , Y. \n, \nK. \nXie \n, \nH. \nDong \n, \nH. \nZhang \n, \nF. \nWang \n, \nY. \nLi \n, et al. 2012 \nHyperbaric oxygen preconditioning protects cortical neurons against oxygen‐glucose deprivation injury: role of peroxisome proliferator‐activated receptor‐gamma . Brain Res. \n1452 :140 –150 .22444276\n\n",
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"title": "Hyperbaric oxygenation and glucose/amino acids substitution in human severe placental insufficiency.",
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"abstract": "A variety of medications, most notably tricyclic antidepressants, and other antidepressants including venlafaxine have been reported to have triggered manic episodes in patients with bipolar disorder. The synthetic opioid tramadol has also been associated with mania activation. This report describes an unusual case of tramadol-associated mania in a patient without a charted diagnosis of bipolar disorder. However, she had a history of two prior episodes of mania following administration of tramadol that were also believed to be related to medication-induced mood disorder rather than underlying bipolar disorder. We hypothesize that tramadol-associated mania may have an underlying mechanism involving monoamine neurotransmission and increased oxidative stress.",
"affiliations": "Department of Medicine, University of California at Los Angeles, Los Angeles, California.;Department of Psychiatry, School of Medicine, Saint Louis University, St. Louis, Missouri.;BCPP, School of Pharmacy, Southern Illinois University at Edwardsville, Edwardsville, Illinois.;Forensic Psychiatry Division, Department of Psychiatry, School of Medicine, Saint Louis University, St. Louis, Missouri.",
"authors": "Nimah|Jamaluddin|J|;Chen|Alexander|A|;Gable|Kelly N|KN|;Felthous|Alan R|AR|",
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"abstract": "Osteonecrosis (ON), a significant complication following treatment of acute lymphoblastic leukemia (ALL), has a profound impact on quality of life of ALL survivors. We studied incidence and outcome of ON in patients treated on or according to Australian and New Zealand Children's Haematology/ Oncology Group (ANZCHOG) study 8 at The Children's Hospital at Westmead. The study involved retrospective chart review of the patients. ON was defined by development of symptoms and confirmed by magnetic resonance imaging. From 2002-2011, 251 patients (143M, 108F, 59 Standard Risk (SR), 159 Medium Risk (MR) 5 High Risk (HR), and 28 Very high risk (VHR)) were treated according to study 8. Eighteen (7M, 11F, 2 SR, 12 MR, 4 VHR) patients developed ON (7.2%). Median age at diagnosis was 13.05 years(4.3-16.7). Incidence of ON in patients > 10 years at diagnosis was 29%. Six out of 18 patients developed ON after allogeneic stem cell transplantation. Median time from diagnosis to the development of ON following chemotherapy for ALL was 1.15 years (range 0.25-2.12). Most patients were treated with intravenous Zoledronic acid. At last follow-up, three patients had undergone arthroplasty, two patients were symptom free, and the remaining 13 patients reported persistent pain with activity. A majority of patients with ON of the hips had radiological progression. Overall, 7% of patients with ALL developed ON. Age >10 years was the most important risk factor. At last follow-up, 70% of patients had persistent symptoms. Although Zoledronic acid improved pain, most patients with ON of the hips had radiological progression.",
"affiliations": "Department of Oncology, The Children's Hospital at Westmead, Sydney, Australia.;Department of Oncology, The Children's Hospital at Westmead, Sydney, Australia.;Department Orthopaedics, The Children's Hospital at Westmead, Sydney, Australia.;Department of Endocrinology, The Children's Hospital at Westmead, Sydney, Australia.",
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"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 10.1002/cam4.645CAM4645Original ResearchCancer PreventionOriginal ResearchIncidence and outcome of osteonecrosis in children and adolescents after intensive therapy for acute lymphoblastic leukemia (ALL) Padhye Bhavna \n1\nDalla‐Pozza Luciano \n1\nLittle David \n2\nMunns Craig \n3\n1 Department of OncologyThe Children's Hospital at WestmeadSydneyAustralia2 Department OrthopaedicsThe Children's Hospital at WestmeadSydneyAustralia3 Department of EndocrinologyThe Children's Hospital at WestmeadSydneyAustralia* Correspondence\n\nDr Bhavna Padhye MBBS, FRACP, Department of Oncology, The Children's Hospital at Westmead, Sydney, Australia. Tel: +61 2 9845 0000; Fax: +61 2 98452171; E‐mail: bhavna.padhye@health.nsw.gov.au\n20 1 2016 5 2016 5 5 10.1002/cam4.2016.5.issue-5960 967 10 12 2015 14 12 2015 27 12 2015 © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nOsteonecrosis (ON), a significant complication following treatment of acute lymphoblastic leukemia (ALL), has a profound impact on quality of life of ALL survivors. We studied incidence and outcome of ON in patients treated on or according to Australian and New Zealand Children's Haematology/ Oncology Group (ANZCHOG) study 8 at The Children's Hospital at Westmead. The study involved retrospective chart review of the patients. ON was defined by development of symptoms and confirmed by magnetic resonance imaging. From 2002–2011, 251 patients (143M, 108F, 59 Standard Risk (SR), 159 Medium Risk (MR) 5 High Risk (HR), and 28 Very high risk (VHR)) were treated according to study 8. Eighteen (7M, 11F, 2 SR, 12 MR, 4 VHR) patients developed ON (7.2%). Median age at diagnosis was 13.05 years(4.3–16.7). Incidence of ON in patients > 10 years at diagnosis was 29%. Six out of 18 patients developed ON after allogeneic stem cell transplantation. Median time from diagnosis to the development of ON following chemotherapy for ALL was 1.15 years (range 0.25–2.12). Most patients were treated with intravenous Zoledronic acid. At last follow‐up, three patients had undergone arthroplasty, two patients were symptom free, and the remaining 13 patients reported persistent pain with activity. A majority of patients with ON of the hips had radiological progression. Overall, 7% of patients with ALL developed ON. Age >10 years was the most important risk factor. At last follow‐up, 70% of patients had persistent symptoms. Although Zoledronic acid improved pain, most patients with ON of the hips had radiological progression.\n\nALLosteonecrosisoutcome source-schema-version-number2.0component-idcam4645cover-dateMay 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.8.9 mode:remove_FC converted:12.05.2016\n\nCancer Medicine \n2016 ; 5 (5 ): 960 –967 \n\n\n\nThis study was approved by Sydney Children's Hospital Network Human Research Ethics Committee.\n==== Body\nIntroduction\nAs survival rates for childhood acute lymphoblastic leukemia (ALL) improve, awareness, treatment, and prevention of adverse effects becomes increasingly important 1, 2 Osteonecrosis (ON) is a well‐recognized complication of chemotherapy in children and adolescents with ALL and it significantly impacts on the long‐term quality of life. The Childhood Cancer Survivor Study has compared the rate of self‐reported ON in cancer survivors with the rate observed in a sibling comparison group. The rate ratio was 6.5 in patients with ALL treated with chemotherapy, 11.2 in chemotherapy‐treated patients with acute myeloid leukemia (AML), and 59.2 for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) recipients for leukemia 3. Glucocorticoid use (prednisolone and dexamethasone) has been implicated as a major etiological factor in the development of ON in this patient group. Other risk factors include age >10 years, female sex, Caucasian race, and higher body mass index 4, 5, 6, 7, 8. Some ALL treatment regimens have a much higher frequency of ON than others, suggesting that some nonglucocorticoid drugs (e.g., Asparaginase and methotrexate) may modify the risk of osteonecrosis 9.\n\nIn addition genetic factors have a role in predisposing individuals to ON. Multiple candidate genes studies and GWAS have indicated several polymorphisms in genes putatively related to the development of ON such as SERPINE1, VDR, CYP3A4, ACP1, and SH3YL1\n4, 10, 11, 12, 13.\n\nWe studied incidence and outcome of ON in patients with ALL treated in a single institution on the Australian and New Zealand Children's Haematology Oncology group (ANZCHOG) ALL Study 8 (ANZCHOG Study 8) protocol at The Children's Hospital at Westmead, Sydney, Australia.\n\nPatients and Methods\nStudy population and treatment\nFrom 2002–2011, 251 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma were enrolled and treated on (Patients with ALL) or according to (patients with lymphoblastic lymphoma) the ANZCHOG study 8. (The ANZCHOG ALL8 trial is registered on the Australian and New Zealand clinical Trials registry as ACTRN12607000302459 http://www.anzctr.org.au/trial_view.)\n\nPatients on this trial were stratified into risk groups using minimal residual disease (MRD) levels at day 33 and day 79 together with other biological and clinical risk factors 14. Patients were divided into standard, medium, high, and very high‐risk groups. The very high‐risk (VHR) group was defined as patients with one or more of following factors: high levels of MRD at day 79, prednisolone poor response (PPR), and T‐cell ALL or white cell count (WCC) > 100 × 109/L, BCR‐ABL1 positive ALL or positive for the MLL t (4, 11) translocation, not in morphological remission at day 33, M2 bone marrow at day 15 .The high‐risk (HR) group had all of the following features: MRD <10−3 at day 79, PPR (absence of T‐cell ALL, t (9, 22) and t (4, 11), morphological remission at day 33. The standard‐risk group (SR) had no high‐risk features and were MRD negative at both day 33 and day 79 using two MRD markers with a minimum sensitivity of 10−4. The medium‐risk (MR) group were patients not qualifying for either standard or high risk. The stratification was the same as AEIOPBFM ALL‐2000 and there were no randomizations in the protocol 15. SR and MR patients were treated uniformly according to the common control arm in BFM ALL‐2000. High‐risk patients were assigned to treatment with novel high‐risk chemotherapy blocks 16.\n\nOf 251 patients, 48 patients underwent stem cell transplantation. Following completion of treatment, all patients were followed up in oncology clinic and then referred to long‐term follow‐up unit to monitor for late side effects of treatment.\n\nOsteonecrosis\nRetrospective chart analysis was undertaken to identify patients with ON. For patients receiving chemotherapy only, ON was defined by development of pain in bones/joints while on treatment or within 1 year of completion of treatment and confirmed by magnetic resonance imaging (MRI). X‐rays of the affected joints were performed at baseline and then 3–6 monthly as clinically indicated. Hip X‐rays were scored using the Association Research Circulation Osseous (ARCO) international classification of ON 17. Similar scoring system was used for knee and ankle ON. Stage I—abnormal MRI or bone scan but normal X‐ray, stage II—abnormal X‐ray showing sclerosis but no collapse, stage III—early collapse or deformity and stage IV—joint destruction.\n\nAll patients were seen by orthopedic surgeons and treatment included analgesia, periods of nonweight bearing, bisphosphonates, and surgical procedures including joint replacement in some patients.\n\nFor outcome assessment, clinical symptoms and radiological findings (X‐ray and or MRI) at the last follow‐up were recorded. Based on last follow‐up, patients were classified symptomatically as being pain free, having mild to moderate pain without restricting activities and having pain restricting activities and hence undergone joint replacement surgery.\n\nResults\nPatients\nFrom 2002 to 2011, 251 (143 males and 108 females) patients were treated for ALL/lymphoblastic lymphoma as per ANZCHOG study 8 at The Children's Hospital at Westmead. Fifty‐five (22%) patients were over 10 years at diagnosis. The numbers in each risk stratification grouping was as follows: SR 59, MR 159, HR 5, and VHR 29. Of 251 patients, 48 patients underwent stem cell transplantation either in first remission (n = 21) or following relapse (n = 24) or for therapy‐related acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) (n = 3).\n\nIncidence of osteonecrosis\nEighteen patients developed ON (Overall incidence 7%).Incidence of ON in females was 11.2% and that in males was 5.2% (P = 0.12). Incidence of ON in patients older than 10 years at diagnosis is 29%. Median age at diagnosis of patients who developed ON was 13.05 years (4.3–16.7). Age more than 10 years is a significant risk factor for development of ON (P < 0.00001, Chi ‐squared test).\n\nAccording to treatment group, 3.4% patients in SR, 7.5% in MR, and 13.8% in VHR group developed ON. Three out of four VHR patients with ON underwent stem cell transplantation and required post‐transplant GVHD therapy. No patient in HR group developed ON. Six patients developed ON following allogeneic stem cell transplant (12.5%).\n\nMedian time from diagnosis to the development of ON following chemotherapy for ALL was 1.15 years (range 0.25–2.12). Most patients who developed ON following stem cell transplantation (SCT) developed it within 1 year of SCT. There was no difference in the incidence of ON between patients with T‐cell ALL and Pre‐B ALL.\n\nChemotherapy and exposure to steroids\nAll patients underwent uniform induction therapy with prednisolone, vincristine, asparaginase, daunorubicin, and intrathecal methotrexate. SR, MR, and HR patients not undergoing SCT had reinduction course with dexamethasone. Cumulative steroid exposure for this group of patients was 3413 mg/m2. (1 mg dexamethasone = 6.67 mg prednisolone)30. All SR and MR patients received 4 courses of high‐dose methotrexate during protocol M. HR and VHR patients received 3–6 blocks of intensive therapy consisting of varying drugs. VHR patients underwent allogeneic BMT if there was a suitable donor available. Maintenance therapy consisted of daily 6‐mercaptopurine and weekly oral methotrexate to complete 2 years of therapy from diagnosis. As most of the patients developed symptomatic ON after completion of protocol 2 (reinduction), steroid dose was not modified.\n\nStem cell transplant\nSix patients developed ON following allogeneic SCT. Two patients underwent transplant in first remission for VHR disease and four patients underwent transplant following relapse of ALL. All four patients received steroid containing reinduction treatment prior to transplant. All patients received total body radiation as part of conditioning for transplant. Five out of six patients developed acute graft versus host disease (aGvHD) post‐transplant requiring steroid therapy.\n\nFeatures of osteonecrosis\nAll patients presented with pain in the joints while on chemotherapy or soon after finishing intensive phase of chemotherapy. Pain in the hips or knees was the most common complaint (88%). Diagnosis of osteonecrosis was confirmed after evaluating bone scans, MRI, and X‐rays of the affected joint. Most patients had involvement of multiple joints and lower limb joint were involved in all patients except one who had isolated shoulder involvement. At diagnosis of ON, X‐rays of affected joints in 15/18 patients (83%) showed minimal (ARCO II) or no change (ARCO I). Remaining three patients showed evidence of joint deformity (ARCO III) on initial X‐ray. No patient presented with joint collapse at initial diagnosis (Table 1).\n\nTable 1 Features of osteonecrosis and outcome\n\nPatient Gender/Age (years)\tRisk group and treatment\tJoint involved – most symptomatic joint underlined\tRadiological grading of most symptomatic joint at diagnosis (ARCO)\tRadiological grading of most symptomatic joint on latest radiograph (ARCO)\tFinal clinical outcome at last follow‐upa\n\t\n1. M/12.5\tMR\t\nKnees\n\tII\tII\t1\t\n2.F/14.5\tMR\t\nHips\n\tI\tIII\t3\t\n3.F/13.2\tMR\tKnees\tII\tIII\t2\t\n4.M/13.9\tMR\t\nKnees, Hips\tII\tII\t2\t\n5.M/14\tMR\t\nKnees, L elbow\tIII\tIV\t2\t\n6.F/16.7\tSR\tHips, knees, L ankle\tI\tI\t2\t\n7.F/10.6\tVHR\tShoulders, Hips, Knees, R ankle\n\tII\tII\t1\t\n8.F/12.9\tMR\tKnee\tIII\tIII\t2\t\n9.F/11.6\tMR\t\nHips, Knees\tIII\tIII\t2\t\n10.F/8.4\tSR\tKnees, Ankles\n\tII\tII\t2\t\n11.F/11.3\tVHR SCT in first remission\t\nHips, knees\tI\tIV\t2\t\n12.M/15.2\tVHR SCT in first remission\tKnees, ankles, shoulders\n\tI\tII\t2\t\n13.M/4.3\tMR SCT following relapse\tAnkle\tII\tII\t2\t\n14.F/16.4\tMR SCT following Relapse\tShoulder\tII\tII\t2\t\n15.F/10.6\tMR SCT following relapse\tShoulders, Knees, Hips, L Ankle\tII\tIV\t3\t\n16.F/13.3\tMR SCT following relapse\t\nHips\n\tII\tIV\t2 (Dead)\t\n17.M/14.6\tMR SCT following relapse\tKnees, Ankles\n\tI\tII\t2 (Dead)\t\n18.M/12.1\tVHR SCT therapy‐related MDS/AML\t\nHips, Knees, Ankles\tI\tIV\t3(Dead)\t\nAML, acute myeloid leukemia; ARCO, Association Research Circulation Osseous; VHR, very high risk; MDS, myelodysplastic syndrome; MR, medium risk; SCT, stem cell transplantation; SR; standard risk\n\na 1 = pain free, 2 = having mild to moderate pain not restricting activities, and 3 = having pain restricting activities and hence undergone joint replacement surgery.\n\nJohn Wiley & Sons, LtdSteroid therapy was modified in only one patient after diagnosis of ON. This patient, who developed ON early during therapy, received intermittent dexamethasone (7 days on and 7 days off) rather than the protocol specified continuous 21 day dexamethasone during reinduction. All other patients completed planned treatment with steroids.\n\nTreatment of osteonecrosis\nAll patients were reviewed and managed by a single orthopedic surgeon. Therapy consisted of nonweight bearing for a variable period of time. Pain was managed with oral analgesia in consultation with Pain and Palliative care services at the hospital. Following review by a pediatric endocrinologist, all except two patients were treated with intravenous Zoledronic acid (ZA). One of the two patients had abnormal renal function and the other had isolated involvement of shoulder joint. Prior to treatment with ZA, all children were evaluated by a pediatric dentist and any necessary dental work was performed before commencing ZA treatment. ZA was administered 0.025 mg/kg/dose at 12 weekly interval diluted in 50 mL of 0.9% Nail infused over 30 min. Median number of ZA doses per patient was 6 (range 2–8). Most common side effect of ZA infusion was acute flu‐like symptoms after first dose .No patient developed significant hypocalcemia (<2 mmol/L). Bone mineral density and bone turnover were monitored at regular intervals.\n\n\nOutcome of osteonecrosis\n\n(Table 1) At diagnosis, 6 of 18 patients had predominant involvement of hip joints. All these patients progressed to ARCO stage III or IV at last follow‐up despite treatment and three have undergone joint replacement surgery for increasing pain. One other patient died prior to planned surgical intervention. Two other patients report mild moderate pain and radiologically show deformed joint potentially requiring future hip replacement.\n\nSix patients had predominant involvement of knee joints at diagnosis. At last follow‐up, one patient is pain free. Radiologically, three patients have minimal or no joint destruction and three patients have evidence of joint deformity. No patient has undergone joint replacement surgery. One patient has undergone arthroscopy for removal of foreign bodies from the joint and other has undergone patella chondroplasty.\n\nFour patients had predominant involvement of ankle joints at diagnosis. At last follow‐up, all patients report mild pain in the joint and radiologically show sclerosis but no joint collapse (ARCO II).\n\nTwo patients had predominant involvement of shoulder, including one with isolated shoulder involvement who was not treated with ZA. At last follow‐up, both patients have mild to moderate pain and evidence of sclerosis on the radiographs. (ARCO II).\n\nDiscussion\nThe incidence of symptomatic osteonecrosis for children with ALL or lymphoblastic lymphoma treated as per on ANZCHOG study 8 is 7% for the whole group and 29% for children more than 10 years at diagnosis. Study 8 included prednisolone 60 mg/m2/day for 28 days (tapered over 9 days) during induction and dexamethasone 10 mg/m2/day for 21 continuous days (tapered over 9 days) during reinduction. There were no steroid pulses during maintenance.\n\nStudy 8 treatment protocol was similar to BFM 95 and BFM 2000, but the incidence of ON was significantly greater in Study 8. A possible explanation for this is better reporting and completeness of the data as this is single‐institution study. Burger et al. reported incidence of ON based on spontaneous reporting to the study center and via questionnaire, from all 64 participating centers for patients treated according to BFM 95 protocol (n = 1951). The overall 5‐year cumulative incidence for ON is 1.8%. The incidence increased significantly with age, however, with patients >10 years having an incidence of 8.9% and patients >15 years an incidence of 16.7% 16. The successor trial BFM 2000 study collected data on ON prospectively, incidence of ON in patients >10 years of age was 18.4% for females and 7.6% for males. The authors concluded that as the control treatment arms of the two trials were quite similar and the randomized treatment modifications in ALL‐BFM 2000 had no influence on the ON rate, the higher incidence may be attributed to the prospective data collection in this study and possibly to a higher attention to these complications by the attending doctors 18.\n\nThe reported incidence of osteonecrosis in the literature is variable. 7, 8, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 It is difficult to compare the incidence due to definitions of ON, differences in the treatment protocol, and glucocorticoid use (prednisolone vs. dexamethasone, continuous vs. discontinuous steroids, intensity of other drugs, e.g., asparaginase and cumulative dose of steroids including pulses during maintenance) and retrospective nature of most studies. In a prospective study at St. Jude's Children's Hospital and Research Centre (SJCHRC), the cumulative incidence of any versus symptomatic ON was 71.8% versus 17.6%, respectively. Of those patients older than 10 years of age, 44.6% developed symptomatic osteonecrosis compared with 10% in younger patients[12].\n\nGlucocorticoids (prednisolone and dexamethasone) appear to be the main etiological factors for development of ON. It is reported that dexamethasone, especially when administered continuously, is more toxic to bones as compared to prednisolone, although there are conflicting reports in the literature. 29, 30 Other drugs like asparaginase can influence steroid exposure and hence indirectly affect incidence of ON 31. Genetic polymorphisms in many genes including SERPINE1, VDR, CYP3A4, PAI 1, and ACP 1 are reported to be associated with ON. A recent meta‐analysis of genetic risk factors for glucocorticoid‐induced osteonecrosis concluded that PAI‐1 4G/5G and ABCB1 C3435T polymorphisms are risk factors for ON 32. Other risk factors include age >10 years, female sex, Caucasian race, higher body mass index, low albumin, and high cholesterol. In our study, age was most significant risk factor for development of ON.\n\nThe natural history of ON in the pediatric population and the factors that predict long‐term outcome are not well defined. Older age at diagnosis, pain at presentation, area of involvement (>30%), and lesions close to articular surface has been associated with joint collapse and need for arthroplasty. A recent study at SJCHRC described utility of early screening MRI for extensive hip osteonecrosis in pediatric ALL patients more than 10 years of age at diagnosis. On the basis of prospectively acquired protocol‐driven MRI of the hips obtained after standardized exposure to glucocorticoids, they found osteonecrosis in 17.1% of patients within 1 year of starting glucocorticoids and in 21.7% of patients by the end of ALL therapy, such that 79% of patients who would ultimately develop osteonecrosis did so within 1 year of starting glucocorticoids 33. In our study, the median time for diagnosis of symptomatic ON for chemotherapy patients was 1.15 years. Patients who developed ON following allogeneic SCT developed it within 1 year of transplant and majority of these patients (5/6) had developed acute graft versus host disease requiring prednisolone for treatment. We do not know if these patients had developed asymptomatic changes of ON prior to SCT. It is currently unknown if medical intervention at an earlier stage would improve joint outcome. Also, there is no consensus about how best to manage glucocorticoid therapy in patients who develop ON. The underlying diagnosis, phase of treatment, severity of the disease, and severity of joint involvement needs to be considered. For patients with joints that have already sustained grade III or IV damage, it is unlikely that discontinuation of steroids will change natural history of ON. In our study group, as the majority of patients were diagnosed after reinduction phase, glucocorticoid therapy was unaltered in all but one patient (who received discontinuous dexamethasone).\n\nThe only strategy proven in a randomized controlled trial to reduce the development of symptomatic ON is avoidance of prolonged, continuous exposure to dexamethasone. In the Children's Cancer Group 1961 trial in high‐risk ALL, 823 patients of age 10–21 years at diagnosis who had a rapid early response to induction chemotherapy were randomly assigned to receive dexamethasone 10 mg/m2 per day on days 0 through 20 of delayed intensification versus 10 mg/m2 per day on days 0 through 6 and 14 through 20. The cumulative incidence of symptomatic osteonecrosis at any site was 17% in patients treated with 21 days of continuous dexamethasone, but only 8.7% in those treated with the interrupted schedule (hazard ratio, 2.1; P < 0 .001) 34.\n\nCurrent treatment for ON includes analgesia, limited weight bearing and various surgical procedures including joint replacement. A number of medical therapies have also been undertaken, with variable and inconsistent results including hyperbaric oxygen, nifedipine, prostaglandin infusions, low‐molecular weight heparin, and statins. Few pediatric studies have reported use of bisphosphonates for chemotherapy‐related ON. In an observational study of 17 children with ON as a complication of chemotherapy for leukemia, improvements in the pain scores, analgesic requirement, and function were found in the nine patients who received bisphosphonate therapy while seven of eight patients who did not receive therapy showed clinical deterioration 35.\n\nAnother small study of childhood leukemic patients found a reduction in pain and increased mobility in four of the six patients treated with Pamidronate for 2 years; however, three of the six patients had a progression and required hip replacement 36. In our study, Zoledronic acid treatment improved pain in most patients. We also noted that patients who had predominant involvement of knees, ankles, or shoulder joint tended to stabilize after initiating treatment with ZA. All patients with predominant hip joint involvement showed radiological progression. It is currently unknown if there are differences in the natural history of hip and other joint ON. In addition, small lesions could improve spontaneously which makes evaluation of effectiveness of any nonsurgical intervention difficult. Patients who have grade III or IV joints at the end of treatment are more likely to develop early osteoarthritis and require joint replacement in early adult life. The relative risk of joint replacement in long‐term survivors of child hood cancer, as compared with siblings is 54 (95% CI 7.6–386.3) 37. A major concern with replacing joints in young patients is the durability of current prostheses and the probable need for replacement after 10–15 years.\n\nAs the outcome of ON with current medical therapies, especially involving hip joints is poor, future studies are needed to identify patients at high risk of this complications and possible intervention to change the natural history. All studies have identified age more than 10 years as a risk factor, if genetic markers described in the literature are confirmed a more targeted approach for screening and early intervention could be developed. One potential but likely reason for relative poor effectiveness of ZA in preventing joint collapse following ON is poor distribution to necrotic bone. Animal studies performed at our institution have shown that prophylactic administration of ZA improves femoral head architecture in rat models of ON 38, 39. While this strategy would not prevent the development of ON, this is an attractive strategy to prevent joint collapse and destruction of an effected in children and adolescents at high risk of chemotherapy‐related ON, without compromising the intensity of chemotherapy.\n\nConflict of Interest\nNo conflict of interest.\n\nAcknowledgments\nNil.\n==== Refs\nReferences\n1 \n\nHunger , S. P. \n, \nX. \nLu \n, \nM. \nDevidas \n, \nB. M. \nCamitta \n, \nP. S. \nGaynon \n, \nN. 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H. \nvan der Velden \n, et al. 2013 \nHigh‐risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation . Leukemia \n27 :1497 –1503 .23407458 \n17 \n\nSteinberg , M. E. \n, and \nD. R. \nSteinberg \n. 2004 \nClassification systems for osteonecrosis: an overview . Orthop. Clin. North Am. \n35 :273 –283 .15271535 \n18 \n\nA. Möricke , M. Zimmermann. \n, \nA. \nSchrauder \n, \nM. \nStanulla \n, \nH. \nSchmid \n, \nR. \nFengler \n, \nM. \nFrühwald \n, et al. 2008 \nNo influence on the incidence of osteonecrosis when dexamethasone replaces prednisone during induction treatment for childhood ALL: results of trial ALL‐BFM 2000 . Blood :112 :899 .\n19 \n\nBürger , B. \n, \nR. \nBeier \n, \nM. \nZimmermann \n, \nJ. D. \nBeck \n, \nA. \nReiter \n, and \nM. \nSchrappe \n. 2005 \nOsteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)—Experiences from trial ALL‐BFM 95 . Pediatr. Blood Cancer \n44 :220 –225 .15514916 \n20 \n\nWei , S. Y. \n, \nA. N. \nEsmail \n, \nN. \nBunin \n, and \nJ. P. \nDormans \n. 2000 \nAvascular necrosis in children with acute lymphoblastic leukemia . J. Pediatr. Orthop. \n20 :331 –335 .10823600 \n21 \n\nStrauss , A. J. \n, \nJ. T. \nSu \n, \nV. M. \nDalton \n, \nR. D. \nGelber \n, \nS. E. \nSallan \n, and \nL. B. \nSilverman \n. 2001 \nBony morbidity in children treated for acute lymphoblastic leukemia . J. Clin. Oncol. \n19 :3066 –3072 .11408503 \n22 \n\nAricò , M. \n, \nM. F. \nBoccalatte \n, \nD. \nSilvestri \n, \nE. \nBarisone \n, \nC. \nMessina \n, \nR. \nChiesa \n, et al. ,Associazione Italiana di Ematologia ed Oncologia Pediatrica \n.2003 \nOsteonecrosis: an emerging complication of intensive chemotherapy for childhood acute lymphoblastic leukemia . Haematologica \n88 :747 –753 .12857552 \n23 \n\nElmantaser , M. \n, \nG. \nStewart \n, \nD. \nYoung \n, \nR. \nDuncan \n, \nB. \nGibson \n, and \nS. F. \nAhmed \n. 2010 \nSkeletal morbidity in children receiving chemotherapy for acute lymphoblastic leukaemia . Arch. Dis. Child. \n95 :805 –809 .20576660 \n24 \n\nMitchell , C. D. \n, \nS. M. \nRichards \n, \nS. E. \nKinsey \n, \nJ. \nLilleyman \n, \nA. \nVora \n, and \nT. O. \nEden \n. 2005 \nMedical Research Council Childhood Leukaemia Working Party Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial . Br. J. Haematol. \n129 :734 –745 .15952999 \n25 \n\nMattano , L. A. \nJr\n, \nJ. B. \nNachman \n, \nM. \nDevidas \n, \nN. \nWinick \n, \nE. \nRaetz \n, \nW. L. \nCarroll \n, et al. 2008 \nIncreased incidence of osteonecrosis (ON) with a dexamethasone (DEX) induction for high risk acute lymphoblastic leukemia (HR‐ALL): a report from the Children's Oncology Group (COG) . Blood \n112 :898 .\n26 \n\nVora , A. \n, \nR. \nWade \n, \nC. \nMitchell \n, \nN. \nGoulden \n, and \nS. \nRichards \n. 2008 \nIncidence and outcome of osteonecrosis in children and young adults with acute lymphoblastic leukaemia treated on a dexamethasone containing protocol: results of the Medical Research Council UK trial ALL 2003 . Blood \n112 :910 .\n27 \n\nVrooman , Lynda. M. \n, \nDonna. S. \nNeuberg \n, \nKristen. E. \nStevenson \n, \nJeffrey. G. \nSupko \n, \nStephen. E. \nSallan \n, and \nLewis. B. \nSilverman \n. 2009 \nDexamethasone and individualized Asparaginase dosing are each associated with superior event‐free survival in childhood acute lymphoblastic leukemia: results from DFCI‐ALL Consortium protocol 00‐01 . Blood \n114 :321 .\n28 \n\nte Winkel , M. L. \n, \nR. \nPieters \n, \nW. C. \nHop \n, \nH. A. \nde Groot‐Kruseman \n, \nM. H. \nLequin \n, \nI. M. \nvan der Sluis \n, et al. 2011 \nProspective study on incidence, risk factors, and long‐term outcome of osteonecrosis in pediatric acute lymphoblastic leukemia . J. Clin. Oncol. \n29 :4143 –4150 .21947829 \n29 \n\nMcNeer , J. L. \n, and \nJ. B. \nNachman \n. 2010 \nThe optimal use of steroids in paediatric acute lymphoblastic leukaemia: no easy answers . Br. J. Haematol. \n149 :638 –652 .20408842 \n30 \n\nInaba , H. \n\n2010 \nPui CH Glucocorticoid use in acute lymphoblastic leukaemia Lancet Oncol . 11 :1096 –1106 .20947430 \n31 \n\nLiu , C. \n, \nJ. D. \nKawedia \n, \nC. \nCheng \n, \nD. \nPei \n, \nC. A. \nFernandez \n, \nX. \nCai \n, et al. 2012 \nClinical utility and implications of asparaginase antibodies in acute lymphoblastic leukemia . Leukemia \n26 :2303 –2309 .22484422 \n32 \n\nGong , L. L. \n, \nL. H. \nFang \n, \nH. Y. \nWang \n, \nJ. H. \nPeng \n, \nK. \nSi \n, \nJ. \nZhu \n, et al. 2013 \nGenetic risk factors for glucocorticoid‐induced osteonecrosis: a meta‐analysis . Steroids \n78 :401 –408 .23357434 \n33 \n\nKaste , S. C. \n, \nD. \nPei \n, \nC. \nCheng \n, \nM. D. \nNeel \n, \nW. P. \nBowman \n, \nR. C. \nRibeiro \n, et al. 2015 \nUtility of early screening magnetic resonance imaging for extensive hip osteonecrosis in pediatric patients treated with glucocorticoids . J. Clin. Oncol. \n33 :610 –615 .25605853 \n34 \n\nMattano , L. A. \nJr\n, \nM. \nDevidas \n, \nJ. B. \nNachman \n, \nH. N. \nSather \n, \nS. P. \nHunger \n, \nP. G. \nSteinherz \n, et al. 2012 \nSeibel NL; Children's Oncology Group. Effect of alternate‐week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG‐1961 randomised cohort trial . Lancet Oncol \n13 :906 –915 .22901620 \n35 \n\nKotecha , R. S. \n, \nN. \nPowers \n, \nS. J. \nLee \n, \nK. J. \nMurray \n, \nT. \nCarter \n, and \nC. \nCole \n. 2010 \nUse of bisphosphonates for the treatment of osteonecrosis as a complication of therapy for childhood acute lymphoblastic leukaemia (ALL) . Pediatr. Blood Cancer \n54 :934 –940 .20127847 \n36 \n\nNguyen , T. \n, and \nM. R. \nZacharin \n. 2006 \nPamidronate treatment of steroid associated osteonecrosis in young patients treated for acute lymphoblastic leukaemia—two‐year outcomes . J. Pediatr. Endocrinol. Metab. \n19 :161 –167 .16562590 \n37 \n\nOeffinger , K. C. \n, \nA. C. \nMertens \n, \nC. A. \nSklar \n, \nT. \nKawashima \n, \nM. M. \nHudson \n, \nA. T. \nMeadows \n, et al. , Childhood Cancer Survivor Study \n.2006 \nChronic health conditions in adult survivors of childhood cancer . N. Engl. J. Med. \n355 :1572 –1582 .17035650 \n38 \n\nLittle , D. G. \n, \nM. \nMcDonald \n, \nI. T. \nSharpe \n, \nR. \nPeat \n, \nP. Williams \n, and \nT. \nMcEvoy \n. 2005 \nZoledronic acid improves femoral head sphericity in a rat model of perthes disease . J. Orthop. Res. \n23 :862 –868 .16023001 \n39 \n\nLittle , D. G. \n, \nR. A. \nPeat \n, \nA. \nMcevoy \n, \nP. R. \nWilliams \n, \nE. J. \nSmith \n, and \nP. A. \nBaldock \n. 2003 \nZoledronic acid treatment results in retention of femoral head structure after traumatic osteonecrosis in young Wistar rats . J. Bone Miner. Res. \n18 :2016 –2022 .14606515\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "5(5)",
"journal": "Cancer medicine",
"keywords": "ALL; osteonecrosis; outcome",
"medline_ta": "Cancer Med",
"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D000971:Antineoplastic Combined Chemotherapy Protocols; D050071:Bone Density Conservation Agents; D002648:Child; D002675:Child, Preschool; D004164:Diphosphonates; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids; D006801:Humans; D007093:Imidazoles; D015994:Incidence; D008279:Magnetic Resonance Imaging; D008297:Male; D018365:Neoplasm, Residual; D010020:Osteonecrosis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012189:Retrospective Studies; D012307:Risk Factors; D033581:Stem Cell Transplantation; D000077211:Zoledronic Acid",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "960-7",
"pmc": null,
"pmid": "26792372",
"pubdate": "2016-05",
"publication_types": "D018848:Controlled Clinical Trial; D016428:Journal Article",
"references": "23953334;12857552;15514916;22901620;10823600;14606515;20576660;20947430;22412151;18285546;22484422;17989709;23407458;17035650;20408842;25605853;26792372;18565890;18239620;21947829;15459215;15271535;15952999;18421047;24146872;16562590;23357434;11417473;16023001;10986059;21148812;26265699;20127847;11408503;12768474;17442991",
"title": "Incidence and outcome of osteonecrosis in children and adolescents after intensive therapy for acute lymphoblastic leukemia (ALL).",
"title_normalized": "incidence and outcome of osteonecrosis in children and adolescents after intensive therapy for acute lymphoblastic leukemia all"
} | [
{
"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-164814",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"d... |
{
"abstract": "Low-molecular-weight heparins, such as enoxaparin, are often used to treat thrombosis in infants. We present 4 infants with diffuse brain injury who developed cerebral venous sinus thrombosis or deep vein thrombosis and were treated with enoxaparin. These infants subsequently developed subdural hemorrhages, and enoxaparin was stopped. In 3 cases, the subdural hemorrhages were found on routine surveillance brain MRI, and in 1 case imaging was urgently obtained because of focal seizures. Two patients needed urgent neurosurgical intervention, and all subdural hemorrhages improved or resolved on follow-up imaging. Each infant developed severe neurologic deficits, probably from the coexisting diffuse brain injury rather than from the subdural hemorrhages themselves. The risk of intracranial hemorrhage from enoxaparin may be accentuated in patients with diffuse brain injury, and careful consideration should be given before treatment in this population.",
"affiliations": "Divisions of Pediatric Neurology, louisdan@med.umich.edu.;Pediatric Hematology/Oncology, and.;Divisions of Pediatric Neurology.;Divisions of Pediatric Neurology.;Divisions of Pediatric Neurology.;Neonatology, Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.;Divisions of Pediatric Neurology.",
"authors": "Dang|Louis T|LT|;Shavit|Jordan A|JA|;Singh|Rani K|RK|;Joshi|Sucheta M|SM|;Leber|Steven M|SM|;Barks|John D E|JD|;Shellhaas|Renée A|RA|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2013-3029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "134(3)",
"journal": "Pediatrics",
"keywords": "anticoagulants; brain hypoxia–ischemia; cerebral hemorrhage; encephalomalacia; enoxaparin; infant; intracranial sinus thrombosis; subdural hematoma; venous thrombosis",
"medline_ta": "Pediatrics",
"mesh_terms": "D001284:Atrophy; D002540:Cerebral Cortex; D005260:Female; D005343:Fibrinolytic Agents; D006408:Hematoma, Subdural; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "e889-93",
"pmc": null,
"pmid": "25113301",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Subdural hemorrhages associated with antithrombotic therapy in infants with cerebral atrophy.",
"title_normalized": "subdural hemorrhages associated with antithrombotic therapy in infants with cerebral atrophy"
} | [
{
"companynumb": "US-UCBSA-2015010946",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "Several studies support the notion that the kinase inhibitor Imatinib mesylate exerts off-target effects on cells of the immune system. After our first report of continuous daily oral administration in subjects with relapsed/refractory neuroblastoma (NB, EudraCT: 2005-005778-63), here we update the clinical information and report additional information on potential surrogate markers for prediction of efficacy. Peripheral blood (PB) samples collected at study entry and after the first and second cycle of Imatinib mesylate treatment were tested for IFN-γ, TNF-α, TGF-β, IL-10, CXCL12 and soluble (s) B7-H6 plasma levels. In addition, paired PB and bone marrow (BM) samples collected at study entry and after the second Imatinib cycle were evaluated for CXCL12, CXCR4 and NKp30 isoform mRNA levels. Correlation between each parameter level and response/outcome was then evaluated. Out of the six subjects still alive at the time of the first report, thee died after additional therapy, two for NB progression and one for a second malignancy. Three are presently alive and cured from NB at 10 years after the first Imatinib cycle. Of these, one achieved complete response (CR) during Imatinib treatment and never relapsed, one had a local relapse removed by surgery and the third received TVD as rescue therapy. Response and outcome were associated with low Imatinib exposure, whereas none of the tested immunological and molecular parameters was predictive of response/outcome. However, after Imatinib treatment NKp30 isoform mRNA levels significantly increase in BM samples, indicating that Imatinib mesylate exerted an off-target effect on NK cells in vivo. Imatinib mesylate efficacy in relapsed/refractory NB has been confirmed at a longer follow-up, supporting its inclusion in new Phase II trials for these subjects, that should envisage collection of samples to evaluate the predictive power of other potential surrogate markers of efficacy.",
"affiliations": "Experimental Therapy in Oncology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Pediatric Oncology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy.;Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy.;Epidemiology and Biostatistics Section, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Università della Campania \"L.Vanvitelli\", Napoli, Italy.;Department of Hematology-Oncology, IRCCS Ospedale Bambino Gesù, Rome, Italy.;Pediatric Oncology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy.;Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy.;Experimental Therapy in Oncology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Experimental Therapy in Oncology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.",
"authors": "Morandi|Fabio|F|0000-0002-2849-7595;Amoroso|Loredana|L|0000-0003-1950-4754;Dondero|Alessandra|A|0000-0001-7340-8478;Castriconi|Roberta|R|0000-0003-2806-1115;Parodi|Stefano|S|0000-0002-9193-1622;Luksch|Roberto|R|0000-0002-7203-4176;Casale|Fiorina|F|0000-0001-6917-0743;Castellano|Aurora|A|;Garaventa|Alberto|A|0000-0002-5368-6363;Moretta|Alessandro|A|;Bottino|Cristina|C|0000-0001-6695-1739;Ponzoni|Mirco|M|0000-0002-6164-4286;Corrias|Maria Valeria|MV|0000-0002-7316-0772",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/2162402X.2018.1468953",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2162-4011",
"issue": "7(9)",
"journal": "Oncoimmunology",
"keywords": "NK cells; cytokines; imatinib mesylate; neuroblastoma; pharmacokinetics",
"medline_ta": "Oncoimmunology",
"mesh_terms": null,
"nlm_unique_id": "101570526",
"other_id": null,
"pages": "e1468953",
"pmc": null,
"pmid": "30357053",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19616426;15286804;23396605;24361820;24575100;27555472;19351841;11846609;2702835;25877893;28324923;26137398;28604107;8589229;28818704;28701512;21552268;21768459;21994039;28197361;27830764;24021349;28906153",
"title": "Updated clinical and biological information from the two-stage phase II study of imatinib mesylate in subjects with relapsed/refractory neuroblastoma.",
"title_normalized": "updated clinical and biological information from the two stage phase ii study of imatinib mesylate in subjects with relapsed refractory neuroblastoma"
} | [
{
"companynumb": "IT-MYLANLABS-2019M1022439",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": "3",
... |
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