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"abstract": "Progressive ventricular dysfunction is not uncommon in patients with univentricular hearts as they age. In the acute setting vasoactive support can be employed, but is not always sufficient and patients occasionally require mechanical support. We report the successful implantation and subsequent challenges of a percutaneous Abiomed Impella ventricular assist device as a rescue therapy for a 15-year old-patient with Fontan circulation and severe ventricular dysfunction after cardiac arrest.",
"affiliations": "1 Department of Pediatrics, Division of Cardiology, Medical University of South Carolina, Charleston, SC, USA.;1 Department of Pediatrics, Division of Cardiology, Medical University of South Carolina, Charleston, SC, USA.;2 Department of Surgery, Division of Pediatric Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC, USA.;1 Department of Pediatrics, Division of Cardiology, Medical University of South Carolina, Charleston, SC, USA.",
"authors": "Coffman|Zachary J|ZJ|;Bandisode|Varsha M|VM|;Kavarana|Minoo N|MN|;Buckley|Jason R|JR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2150135119847147",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2150-1351",
"issue": "10(4)",
"journal": "World journal for pediatric & congenital heart surgery",
"keywords": null,
"medline_ta": "World J Pediatr Congenit Heart Surg",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D004867:Equipment Design; D005260:Female; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome",
"nlm_unique_id": "101518415",
"other_id": null,
"pages": "518-519",
"pmc": null,
"pmid": "31307293",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Utilization of an Abiomed Impella Device as a Rescue Therapy for Acute Ventricular Failure in a Fontan Patient.",
"title_normalized": "utilization of an abiomed impella device as a rescue therapy for acute ventricular failure in a fontan patient"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0113227",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOPAMINE HYDROCHLORIDE"
},
"drugaddition... |
{
"abstract": "BACKGROUND\nThe visual prognosis of submacular hemorrhages caused by a retinal arterial macroaneurysm (RAM) is poor if left untreated. The use of recombinant tissue plasminogen activator (rtPA) has frequently been reported to displace submacular hemorrhages from the foveal area in patients with age-related macular degeneration. This study aims to investigate the results of displacement of recent-onset submacular hemorrhages due to RAM.\n\n\nMETHODS\nInstitutional retrospective interventional case series of 12 patients with macular hemorrhage due to RAM, who underwent pars plana vitrectomy (PPV); followed in 11 by submacular injection of rtPA and gas tamponade. The main outcome measures were displacement of the hemorrhage, complication rate, and visual acuity at 1 month after surgery and at the last follow-up visit.\n\n\nRESULTS\nOne month after surgery, the hemorrhage had been successfully displaced in ten out of 11 patients. In these ten patients, visual acuity (VA) increased by a mean of 1.2 logMAR at 1 month after surgery. At the last follow-up visit, the mean increase was 1.5 logMAR. Complications consisted of a vitreous hemorrhage and hyphema, retinal detachment, a new submacular hemorrhage, and vitreous hemorrhage after argon laser retinal photocoagulation of the RAM.\n\n\nCONCLUSIONS\nPPV with submacular rtPA and gas injection may successfully displace a recently developed submacular hemorrhage in patients with RAM, with a marked improvement in VA that is likely to be greater than if left untreated.",
"affiliations": "The Rotterdam Ophthalmic Institute, Schiedamse Vest 160-D, 3011 BH Rotterdam, The Netherlands. e.vanzeeburg@oogziekenhuis.nl",
"authors": "van Zeeburg|Elsbeth J T|EJ|;Cereda|Matteo G|MG|;van Meurs|Jan C|JC|",
"chemical_list": "D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D013459:Sulfur Hexafluoride",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00417-012-2116-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0721-832X",
"issue": "251(3)",
"journal": "Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie",
"keywords": null,
"medline_ta": "Graefes Arch Clin Exp Ophthalmol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000783:Aneurysm; D003131:Combined Modality Therapy; D058450:Endotamponade; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D017075:Laser Coagulation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011187:Posture; D011994:Recombinant Proteins; D012166:Retinal Hemorrhage; D012171:Retinal Vessels; D012189:Retrospective Studies; D013459:Sulfur Hexafluoride; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome; D014792:Visual Acuity; D014821:Vitrectomy",
"nlm_unique_id": "8205248",
"other_id": null,
"pages": "733-40",
"pmc": null,
"pmid": "22865261",
"pubdate": "2013-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21366180;19946027;7180915;10711904;17057793;19669780;16547320;11228297;21445629;9801038;10749314;18071732;10643313;20186279;16515019;17460587;8152762;11767030;3055391;17460594;17460588;15718829;9744368;20037915;20668667;18185138;2025175;15030802;10612511;9790631;10519583;1961614;20337300;12967867;15177972;7977569",
"title": "Recombinant tissue plasminogen activator, vitrectomy, and gas for recent submacular hemorrhage displacement due to retinal macroaneurysm.",
"title_normalized": "recombinant tissue plasminogen activator vitrectomy and gas for recent submacular hemorrhage displacement due to retinal macroaneurysm"
} | [
{
"companynumb": "NL-ROCHE-1151466",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "To compare the retinal toxicity due to hydroxychloroquine (HCQ) use in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) using multifocal electroretinography (mfERG), fundus autofluorescence (FAF) and optical coherence tomography (OCT).\n\n\n\nPatients who were using HCQ due to SLE and RA, and healthy subjects evaluated in this study. Central foveal thickness (CFT), inner-outer segment (IS-OS) junction irregularity, retinal nerve fiber layer thickness, mfERG and FAF measurements were performed to evaluate retinal toxicity.\n\n\n\nStudy included 35 eyes of 35 SLE patients, 40 eyes of 40 RA patients and 20 eyes of 20 healthy subjects. In SLE group, retinal abnormality was found in three eyes with mfERG, in one eye with FAF and in four eyes with OCT. In RA group, retinal abnormality was found in 10 eyes with mfERG, in five eyes with FAF and in nine eyes with OCT. A statistically significant difference was found with respect to mfERG between \"eyes with abnormal responses and without abnormal responses\" and \"eyes with abnormal responses and controls\" (p < 0.05). A statistically significant difference was found with respect to CFT between \"eyes with IS-OS junction irregularities and without IS-OS junction irregularities\" and \"eyes with/without IS-OS junction irregularities and controls\" (p < 0.05).\n\n\n\nThe use of HCQ seems to cause retinal toxicity more often in RA patients compared to SLE patients. For the early detection of retinal changes, OCT and mfERG can be used as screening tools due to their higher sensitivity rates compared to other tests.",
"affiliations": "Department of Ophthalmology, Ankara Training and Research Hospital, Sukriye, Ulucanlar St. No. 89, Altindag, 06340, Ankara, Turkey.;Department of Ophthalmology, Ankara Training and Research Hospital, Sukriye, Ulucanlar St. No. 89, Altindag, 06340, Ankara, Turkey. dryesilirmak@gmail.com.;Department of Ophthalmology, Ankara Training and Research Hospital, Sukriye, Ulucanlar St. No. 89, Altindag, 06340, Ankara, Turkey.;Department of Statistics, Gazi University Faculty of Sciences, Ankara, Turkey.;Department of Rheumatology, Ankara Training and Research Hospital, Ankara, Turkey.;Department of Ophthalmology, Ankara Training and Research Hospital, Sukriye, Ulucanlar St. No. 89, Altindag, 06340, Ankara, Turkey.",
"authors": "Telek|Hande Husniye|HH|;Yesilirmak|Nilufer|N|0000-0002-8632-2873;Sungur|Gulten|G|;Ozdemir|Yaprak|Y|;Yesil|Nesibe Karahan|NK|;Ornek|Firdevs|F|",
"chemical_list": "D018501:Antirheumatic Agents; D006886:Hydroxychloroquine",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10633-017-9607-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-4486",
"issue": "135(3)",
"journal": "Documenta ophthalmologica. Advances in ophthalmology",
"keywords": "Fundus autofluorescence; Hydroxychloroquine toxicity; Multifocal electroretinography; Optical coherence tomography; Rheumatoid arthritis; Systemic lupus erythematosus",
"medline_ta": "Doc Ophthalmol",
"mesh_terms": "D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D016022:Case-Control Studies; D004596:Electroretinography; D005260:Female; D005654:Fundus Oculi; D006801:Humans; D006886:Hydroxychloroquine; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012164:Retinal Diseases; D041623:Tomography, Optical Coherence",
"nlm_unique_id": "0370667",
"other_id": null,
"pages": "187-194",
"pmc": null,
"pmid": "28852896",
"pubdate": "2017-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "18465156;15249360;12757106;21060664;19692385;17562988;25408748;6703984;20693556;20533929;16804707;16877425;25884411;19373270;28962308;17336914;16310457;21292109;22457587;20535788;18997610;23710501;12867385;20126479",
"title": "Retinal toxicity related to hydroxychloroquine in patients with systemic lupus erythematosus and rheumatoid arthritis.",
"title_normalized": "retinal toxicity related to hydroxychloroquine in patients with systemic lupus erythematosus and rheumatoid arthritis"
} | [
{
"companynumb": "PHHY2018TR007458",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": "3",
... |
{
"abstract": "Purpose: Postural orthostatic tachycardia syndrome (POTS), an increasingly recognized dysautonomia, may affect as many as 3,000,000 Americans. Concurrently, prevalence estimates suggest 10% of individuals identify as lesbian, gay, bisexual, transgender, or questioning/queer. The preponderance of female POTS patients implies hormonal differences between natal sexes and their role in POTS. Transgender POTS patients using hormone therapies may offer further insight into the mechanism of POTS. There have been no previously published studies of transgender patients with POTS undergoing gender-affirming hormone therapy. Methods: We reviewed our electronic health record for clinical histories of transgender patients in our POTS Database. Results: Three patients who transitioned from female to male demonstrated clinical improvement of their POTS symptoms with the addition of testosterone therapy. Conclusion: We present our clinical experience of three transgender POTS patients who transitioned from female to male with hormone therapy, all of whom demonstrated clinical improvement with testosterone. This may give further insight into the pathophysiology of POTS. However, the authors do not endorse the use of hormone therapy as primary therapy for the symptoms of POTS.",
"affiliations": "Pediatric Cardiologist, Independent, Media, Pennsylvania.;Division of Adolescent Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Division of Radiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.",
"authors": "Boris|Jeffrey R|JR|;McClain|Zachary B R|ZBR|;Bernadzikowski|Thomas|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/trgh.2019.0041",
"fulltext": "\n==== Front\nTransgend HealthTransgend HealthtrghTransgender Health2380-193XMary Ann Liebert, Inc., publishers 140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA 3175463010.1089/trgh.2019.004110.1089/trgh.2019.0041Short ReportClinical Course of Transgender Adolescents with Complicated Postural Orthostatic Tachycardia Syndrome Undergoing Hormonal Therapy in Gender Transition: A Case Series Boris Jeffrey R. 1McClain Zachary B.R. 2,*Bernadzikowski Thomas 31 Pediatric Cardiologist, Independent, Media, Pennsylvania.2 Division of Adolescent Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.3 Division of Radiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.* Address correspondence to: Zachary B.R. McClain, MD, Division of Adolescent Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, 3401 Civic Center Boulevard, Philadelphia, PA 19104 mclainz@email.chop.edu20 11 2019 2019 20 11 2019 4 1 331 334 © Jeffrey R. Boris et al. 2019; Published by Mary Ann Liebert, Inc.2019This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nPurpose: Postural orthostatic tachycardia syndrome (POTS), an increasingly recognized dysautonomia, may affect as many as 3,000,000 Americans. Concurrently, prevalence estimates suggest 10% of individuals identify as lesbian, gay, bisexual, transgender, or questioning/queer. The preponderance of female POTS patients implies hormonal differences between natal sexes and their role in POTS. Transgender POTS patients using hormone therapies may offer further insight into the mechanism of POTS. There have been no previously published studies of transgender patients with POTS undergoing gender-affirming hormone therapy.\n\nMethods: We reviewed our electronic health record for clinical histories of transgender patients in our POTS Database.\n\nResults: Three patients who transitioned from female to male demonstrated clinical improvement of their POTS symptoms with the addition of testosterone therapy.\n\nConclusion: We present our clinical experience of three transgender POTS patients who transitioned from female to male with hormone therapy, all of whom demonstrated clinical improvement with testosterone. This may give further insight into the pathophysiology of POTS. However, the authors do not endorse the use of hormone therapy as primary therapy for the symptoms of POTS.\n\nKeywords\ndysautonomiaLGBT healthorthostatic intolerancetestosterone therapy\n==== Body\nIntroduction\nPostural orthostatic tachycardia syndrome (POTS), a dysautonomia that is increasingly being recognized and diagnosed, is thought to affect as many as 3,000,000 people in the United States.1,2 At the Children's Hospital of Philadelphia (CHOP) alone, nearly 950 pediatric patients through age 18 years were diagnosed from 2007 to 2018. Prior publications have reviewed demographics of this population of patients, including a 3.45:1 female to male ratio as well as an overwhelming preponderance of Caucasian patients.3,4 Concurrently, prevalence estimates show that ∼10% of individuals in the general population identify as lesbian, gay, bisexual, transgender or questioning/queer (LGBTQ).5 Caring for LGBTQ youth is a part of every general pediatric practice,6 and thus gender diverse and transgender adolescents may be of particular interest within this group of patients with POTS.\n\nIn the context of gender diverse or transgender youth, it is necessary to first understand the difference between natal sex and gender identity. An individual's natal sex is the sex identification assigned at birth. Natal sex is most frequently determined by external genitalia, but may also take into account chromosomes, reproductive organs, or hormone levels. Alternatively, an individual's gender identity is their internal sense of who they are. There is a wide range of gender identities, including female, male, a combination of both, somewhere in between, or neither. Individuals predominantly have a gender identity that matches their natal sex; cisgender is the term used to describe these individuals. For some individuals, their natal sex and gender identity do not align, and they are referred to as gender diverse or transgender.7 In the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), people whose sex designated at birth is contrary to the one with which they identify and is accompanied by distress or impairment from this incongruence, are diagnosed with gender dysphoria.8\n\nThere are little data regarding the role of hormones in the pathophysiology of POTS. The preponderance of female to male POTS patients raises questions regarding hormonal differences between natal sexes and the role these may play in how POTS is expressed clinically, with natal females possibly at greater risk or having more sensitivity to autonomic perturbations. Transgender POTS patients, especially those using hormone therapies in their transition, may offer further insight into the mechanism of POTS. There have been no previously published studies of transgender patients with POTS undergoing gender-affirming hormone therapy. The clinical experience of three transgender POTS patients in our patient population, all of whom were transitioning from female to male with hormone therapy, is presented in this study.\n\nCases\nPatient 1 is a natal female identifying as male (uses he/him/his pronouns) who was diagnosed with POTS in November 2014 at age 16 years. He had a 1 year history of dizziness and headaches, with subsequent onset of fatigue, cognitive dysfunction, insomnia (both in getting and staying asleep), early satiety, numbness, joint pain, heat and cold intolerance, exercise intolerance, dyspnea with activity, diaphoresis, palpitations, tachycardia, photophobia, and hyperacusis, and with the clinical findings of venous pooling, joint hypermobility, easy bruising, dislocation, and hyperelastic skin. Past medical history was notable for hypermobile Ehlers–Danlos syndrome, exercise-induced asthma, and overweight. At diagnosis, his medications included cyclobenzaprine, ibuprofen, and naproxen; he had allergies to latex, cetirizine, kiwi, and nuts. Family history was notable for Ehlers–Danlos syndrome in his mother, brother, maternal aunts, maternal uncles, and maternal cousins. On examination, resting blood pressure was 122/80 mmHg. On 10-min stand, heart rate persistently went from 95 to 135 beats per minute. He was noted to have joint hypermobility and venous pooling, but an otherwise normal examination and ECG. He was treated with cyproheptadine for headache prophylaxis, fludrocortisone for dizziness, and pregabalin for pain—his three worst symptoms. The headaches resolved, but his dizziness persisted, despite attempts at therapy with fludrocortisone, midodrine, and desmopressin. His pain did not respond to pregabalin or duloxetine. The pain was severe enough to prevent routine exercise to suppress POTS symptoms.\n\nHe was seen in the Gender and Sexuality Clinic at CHOP 1.5 years after his diagnosis of POTS. He was diagnosed with gender dysphoria, and started testosterone therapy for hormonal management of female to male gender-affirming therapy. Subsequent testosterone levels have been in the low-normal physiological male range. In November 2018, 4 years after diagnosis with POTS and 2 years after initiation of testosterone, he had no complaints of headaches or dizziness, and was off of all blood pressure supportive therapies. His blood pressure was elevated at 140/80 mmHg, and was treated with metoprolol. He continued to have pain, however, which was attributed to the joint hypermobility associated with Ehlers–Danlos syndrome.\n\nPatient 2 is a natal female identifying as male who was diagnosed with POTS in March 2017 at age 17 years. He had a 5 year history of dizziness with symptom onset after menarche, and with subsequent onset of blurry vision, syncope (numerous events), fatigue, cognitive dysfunction (improved with Strattera), insomnia (specifically getting to sleep, which improved with trazodone), headache, nausea, diarrhea, constipation, early satiety, abdominal pain, numbness, muscle pain, joint pain, heat intolerance, dyspnea with activity, chest pain, palpitations, tachycardia, photophobia, hyperacusis, and with the clinical findings of venous pooling, joint hypermobility, easy bruising, and hyperelastic skin. Past medical history was notable for attention deficit disorder with hyperactivity, bipolar disorder, exercise-induced asthma, hypermobile Ehlers–Danlos syndrome, and obsessive-compulsive disorder. At diagnosis, his medications included albuterol, quetiapine, atomoxetine, and trazodone. He had no allergies. Family history was notable for autistic spectrum disorder, but no other pertinent disorders. On examination, resting blood pressure was 116/65 mmHg, with heart rate persistently increasing from 70 to 105 on 10 min stand. Joint hypermobility and venous pooling were noted, with no other significant clinical findings. He was treated with cyproheptadine for headaches, fludrocortisone for dizziness, and pyridostigmine for early satiety—his three worst symptoms. He was also referred for physical therapy for education for joint protection and stabilization as well as for use of an exercise protocol for POTS. Headaches and early satiety improved with medical therapy, and he started routine exercise. Attempts to control dizziness were unsuccessful, despite therapy with fludrocortisone and desmopressin. Increased pyridostigmine dosing for persistent constipation led to muscle twitching, so the dose was reduced.\n\nHe was seen in the Gender and Sexuality Clinic in February 2019, 2 years after POTS diagnosis. He was subsequently diagnosed with gender dysphoria and started on testosterone therapy. In March 2019, resting blood pressure was 117/72 on low dose midodrine, with a heart rate increase from 72 to 102 beats per minute on 10 min stand. He also continued on cyproheptadine, pyridostigmine, and salt capsules for POTS therapy.\n\nPatient 3 is a natal female identifying as male who was diagnosed with POTS in July 2015 at age 16 years. He had a 10 year history of migraine, with subsequent onset of dizziness, blurred vision, fatigue, cognitive dysfunction, insomnia (both getting to and staying asleep), occasional nausea, early satiety, abdominal pain, numbness, muscle pain, joint pain, heat intolerance, cold intolerance, exercise intolerance, dyspnea with activity, diaphoresis, chest pain, palpitations, tachycardia, photophobia, and hyperacusis, and with the clinical finding of venous pooling. Past medical history was notable for migraine, anxiety disorder, obsessive-compulsive disorder, depression, Hashimoto's thyroiditis, bicuspid aortic valve with trivial aortic valve insufficiency and no stenosis, and juvenile idiopathic arthritis. Medications at diagnosis included albuterol, azelastine, diclofenac, fludrocortisone, fluoxetine, fluticasone/salmeterol, folic acid, gabapentin, levothyroxine, melatonin, methotrexate, salt tablets, ranitidine, tramadol, and zolmitriptan. He had no allergies. Family history was notable for fibromyalgia, but no other significant disorders. On examination, resting blood pressure was 104/72, with a persistent heart rate increase of 70–140 beats per minute on 10 min stand. Venous pooling was noted, but the remainder of the examination demonstrated no abnormalities. He was started on desmopressin for dizziness, lansoprazole for symptoms of gastroesophageal reflux, and methylphenidate for fatigue—his three worst symptoms. He also started exercising regularly with an exercise protocol for POTS. Dizziness was persistent, and required increased desmopressin and subsequent addition of midodrine. With regular exercise, symptoms improved. Stimulant therapy was subsequently discontinued in 2016. However, in February 2017, he sustained a concussion, which worsened symptoms of dizziness and fatigue, limiting his ability to exercise regularly.\n\nIn May 2017, he was seen in the Gender and Sexuality Clinic, was diagnosed with gender dysphoria, and started testosterone therapy. Subsequently, his symptoms associated with POTS, including dizziness, insomnia, fatigue, headache, and cognitive dysfunction, all significantly improved by report. Interestingly, he reported that when he had gaps in testosterone therapy, his POTS symptoms would return. In March 2019, resting blood pressure was 122/68 on midodrine and desmopressin as blood pressure supportive therapy. He was exercising regularly and had only rare dizziness with no complaints of palpitations, dyspnea, chest pain, or syncope. The therapeutic plan going forward included discontinuing the desmopressin. Testosterone levels were in the normal physiological male range subsequent to starting supplementation.\n\nConclusion\nPOTS is a dysautonomia that leads to multiple disabling symptoms. Pediatric patients with POTS often are not able to attend school or participate in typical activities of daily living.9 Although described >25 years ago,10 the pathophysiology of POTS remains undefined. There are data suggesting various triggers, such as infection and concussion,4 a high incidence of associated joint hypermobility,4,11,12 that autoantibodies are increasingly being found in association with POTS patients,13,14 and that natal females are more affected than natal males.15,16 However, none of these have been clearly demonstrated to be the singular etiology or a contributing factor to an abnormal pathway that leads to this disorder. Natal female sex preponderance in the disorder is yet another observation that may offer additional insight into how POTS symptoms manifest, and the potential effect of hormones. In this report, we discuss the clinical course of three transgender patients with POTS as natal females identifying as males who subsequently started testosterone for gender-affirming therapy. All three patients demonstrated apparent clinical improvement in their POTS symptoms with addition of supplemental testosterone. This improvement was independent of the use of medications to reduce their symptoms, and actually led to a reduction in the need for medications to control symptoms associated with POTS. Typical therapy for POTS includes high amounts of fluid and salt intake, exercise to suppress symptoms, and, as needed, medications to control symptoms so that patients can be functional and maintain the ability to exercise.17,18 Before initiation of hormone therapy, the symptoms associated with POTS in all three patients showed variable control, with overall improvement after addition of these interventions. However, these patients also demonstrated that symptom control drastically improved after testosterone was added. Notably, by patient report, when one of our patients would miss supplemental testosterone therapy, symptoms of POTS would subjectively worsen.\n\nSome caveats need to be understood in the interpretation of this case series. First, the patients' POTS symptoms were not evaluated with an objective measure of symptom severity, so all reports of symptomatology were subjective. Second, and more importantly, this case series is not a recommendation that patients with POTS should utilize male hormones to try to reduce symptoms. The reductions in symptomatology were unexpected additions to the primary therapeutic goal, namely hormonal gender-affirming therapy from female to male for these transgender adolescents. Certainly, hormone therapies, such as fludrocortisone18,19 and desmopressin,18,20 are used in treatment of the symptoms of POTS. These are not, however, gender-related therapies, nor do they have gender modifying effects. The recognition that male hormone therapy in these patients may have influenced the reduction of POTS symptoms supports the observation of natal female sex predominance in those patients who are symptomatic. It may be that females and males are actually affected more equally with the underlying pathophysiology, but that females demonstrate more severity of, or decreased relative tolerance to, symptoms. It also may be that natal females are more “susceptible” to the disease process that leads to POTS. Further attention should be given to LGBTQ patients who have concurrent POTS and use hormonal gender-affirming therapy, to try to further define if and how their symptoms of POTS improve with therapy.\n\nAcknowledgment\nThe authors thank Andrea Kennedy in the Cardiac Center of the Children's Hospital of Philadelphia for the creation of the POTS database.\n\nAuthor Disclosure Statement\nNo competing financial interests exist.\n\nFunding Information\nNo funding was received for this article.\n\n\nCite this article as: Boris JR, McClain ZBR, Bernadzikowski T (2019) Clinical course of transgender adolescents with complicated postural orthostatic tachycardia syndrome undergoing hormonal therapy in gender transition: a case series, Transgender Health 4:1, 331–334, DOI: 10.1089/trgh.2019.0041.\n\nAbbreviations Used\nCHOPChildren's Hospital of Philadelphia\n\nPOTSpostural orthostatic tachycardia syndrome\n==== Refs\nReferences\n1. \nRobertson D \nThe epidemic of orthostatic tachycardia and orthostatic intolerance . Am J Med Sci . 1999 ;317 :75 –77 10037110 \n2. \nMar PL , Raj SR \nNeuronal and hormonal perturbations in postural tachycardia syndrome . Front Physiol . 2014 ;5 :220 24982638 \n3. \nKanjwal K , Saeed B , Karabin B , et al. \nClinical presentation and management of patients with hyperadrenergic postural orthostatic tachycardia syndrome: a single center experience . Cardiol J . 2011 ;18 :527 –531 21947988 \n4. \nBoris JR , Bernadzikowski T \nDemographics of a large paediatric Postural Orthostatic Tachycardia Syndrome program . Cardiol Young . 2018 ;28 :668 –674 29357955 \n5. \nLGBT Stats . https://williamsinstitute.law.ucla.edu/lgbtstats (Last accessed 5 1 , 2019 )\n6. \nKann L , Kinchen S , Shanklin SL , et al. \nYouth risk behavior surveillance—United States, 2013 . MMWR Surveill Summ . 2014 ;63 (Suppl 4 ):1 –168 \n7. \nLevine DA Office Based Care for lesbian, gay, bisexual, transgender, and questioning youth . Pediatrics . 2013 ;132 :198 –203 23796746 \n8. \nAnxiety Disorders . In: American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders , 5th ed. Washington, DC : American Psychiatric Association , 2013 \n9. \nBoris JR \nPostural orthostatic tachycardia syndrome in children and adolescents . Auton Neurosci . 2018 ;215 :97 –101 29778304 \n10. \nSchondorf R , Low PA \nIdiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? \nNeurology . 1993 ;43 :132 –137 8423877 \n11. \nGazit Y , Nahir AM , Grahame R , Jacob G \nDysautonomia in the joint hypermobility syndrome . Am J Med . 2003 ;115 :33 –40 12867232 \n12. \nKanjwal K , Karabin B , Kanjwal Y , Grubb BP \nComparative clinical profile of postural orthostatic tachycardia patients with and without joint hypermobility syndrome . Indian Pacing Electrophysiol J . 2010 ;10 :173 –178 20376184 \n13. \nVernino S , Low PA , Fealey RD , et al. \nAutoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies . New Engl J Med . 2000 ;343 :847 –855 10995864 \n14. \nFedorowski A , Li H , Yu X , et al. \nAntiadrenergic autoimmunity in postural tachycardia syndrome . Europace . 2017 ;19 :1211 –1219 27702852 \n15. \nRaj SR \nThe Postural Tachycardia Syndrome (POTS): pathophysiology, diagnosis, and management . Indian Pacing Electrophysiol J . 2006 ;6 :84 –99 16943900 \n16. \nBurkhardt BEU , Fischer PR , Brands CK , et al. \nExercise performance in adolescents with autonomic dysfunction . J Pediatr . 2011 ;158 :15 –9 , 19.e1. 20813382 \n17. \nStewart JM , Boris JR , Chelimsky G , et al. \nPediatric disorders of orthostatic intolerance . Pediatrics . 2018 ;141 :e20171673 29222399 \n18. \nBoris JR , Bernadzikowski T \nUtilisation of medications to reduce symptoms in children with postural orthostatic tachycardia syndrome . Cardiol Young . 2018 ;28 :1386 –1392 30079848 \n19. \nFreitas J , Santos R , Azevedo E , et al. \nClinical improvement in patients with orthostatic intolerance after treatment with bisoprolol and fludrocortisone . Clin Auton Res . 2000 ;10 :293 –299 11198485 \n20. \nGachoka D , Kanjwal K , Karabin B , Grubb BP \nDesmopressin in the treatment of postural orthostatic tachycardia . J Innov Card Rhythm Management . 2015 ;6 :2222 –2226\n\n",
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"title": "Clinical Course of Transgender Adolescents with Complicated Postural Orthostatic Tachycardia Syndrome Undergoing Hormonal Therapy in Gender Transition: A Case Series.",
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"abstract": "Sexual dysfunctions in people with schizophrenia are more severe than in the general population and are an important element in the treatment of schizophrenia. The mechanism of sexual dysfunction in patients treated for schizophrenia may be related to the side effects of antipsychotic drugs (hyperprolactinemia, suppression of the reward system), but it may also be related to the pathogenesis of schizophrenia itself. The aim of the study was to present the possibility of using amantadine in the treatment of sexual dysfunction in schizophrenia without the concomitant hyperprolactinemia. In an open and naturalistic case series study, five men treated for schizophrenia in a stable mental state were described. All patients reported a prolonged lack of sexual desire and sexual activity prior to treatment with amantadine. After exclusion of hyperprolactinemia, patients received amantadine 100 mg in the evening. Sexual dysfunction was assessed using subscales of the 14-point Short Form of the Changes in Sexual Functioning Questionnaire (CSFQ-14). On subsequent visits after 1, 2 and 3 months of administration of amantadine, an improvement in sexual functioning was observed in all patients. Although this is only the preliminary report, amantadine may become a new indication for the treatment of sexual dysfunction in schizophrenia patients.",
"affiliations": "Clinic of Psychiatric Rehabilitation, Department of Psychiatry and Psychotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-635 Katowice, Poland.;Clinic of Psychiatric Rehabilitation, Department of Psychiatry and Psychotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-635 Katowice, Poland.;Clinic of Psychiatric Rehabilitation, Department of Psychiatry and Psychotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-635 Katowice, Poland.;Clinic of Psychiatric Rehabilitation, Department of Psychiatry and Psychotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-635 Katowice, Poland.;Institute of Psychology, University of Opole, 45-040 Opole, Poland.;Department of Histology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland.",
"authors": "Krzystanek|Marek|M|;Warchala|Anna|A|;Trędzbor|Beata|B|;Martyniak|Ewa|E|;Skałacka|Katarzyna|K|0000-0003-2188-7547;Pałasz|Artur|A|",
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"fulltext": "\n==== Front\nPharmaceuticals (Basel)\nPharmaceuticals (Basel)\npharmaceuticals\nPharmaceuticals\n1424-8247\nMDPI\n\n10.3390/ph14100947\npharmaceuticals-14-00947\nCommunication\nAmantadine in the Treatment of Sexual Inactivity in Schizophrenia Patients Taking Atypical Antipsychotics—The Pilot Case Series Study\nKrzystanek Marek 1*\nWarchala Anna 1\nTrędzbor Beata 1\nMartyniak Ewa 1\nhttps://orcid.org/0000-0003-2188-7547\nSkałacka Katarzyna 2\nPałasz Artur 3\nScarselli Marco Academic Editor\n1 Clinic of Psychiatric Rehabilitation, Department of Psychiatry and Psychotherapy, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-635 Katowice, Poland; awarchala@sum.edu.pl (A.W.); beataziarko@poczta.onet.pl (B.T.); emartyniak@sum.edu.pl (E.M.)\n2 Institute of Psychology, University of Opole, 45-040 Opole, Poland; katarzyna.skalacka@uni.opole.pl\n3 Department of Histology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland; artiassone@gmail.com\n* Correspondence: m.krzystanek@sum.edu.pl; Tel./Fax: +48-322059260\n22 9 2021\n10 2021\n14 10 94723 8 2021\n21 9 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSexual dysfunctions in people with schizophrenia are more severe than in the general population and are an important element in the treatment of schizophrenia. The mechanism of sexual dysfunction in patients treated for schizophrenia may be related to the side effects of antipsychotic drugs (hyperprolactinemia, suppression of the reward system), but it may also be related to the pathogenesis of schizophrenia itself. The aim of the study was to present the possibility of using amantadine in the treatment of sexual dysfunction in schizophrenia without the concomitant hyperprolactinemia. In an open and naturalistic case series study, five men treated for schizophrenia in a stable mental state were described. All patients reported a prolonged lack of sexual desire and sexual activity prior to treatment with amantadine. After exclusion of hyperprolactinemia, patients received amantadine 100 mg in the evening. Sexual dysfunction was assessed using subscales of the 14-point Short Form of the Changes in Sexual Functioning Questionnaire (CSFQ-14). On subsequent visits after 1, 2 and 3 months of administration of amantadine, an improvement in sexual functioning was observed in all patients. Although this is only the preliminary report, amantadine may become a new indication for the treatment of sexual dysfunction in schizophrenia patients.\n\namantadine\nsexual disfunctions\nsex drive\nlibido\nschizophrenia\nhyperprolactinemia\nantipsychotic drugs\natypical antipsychotics\n==== Body\npmc1. Introduction\n\nSexual dysfunctions in the schizophrenic population are more frequent and severe than in the healthy population [1,2]. For example, the prevalence of sexual dysfunctions in patients with schizophrenia treated with antipsychotics, depending on the study, concerns 44% [3], 50% [4] or 65% of patients [5], and even 82% in the group of men [6]. For these reasons, the treatment of sexual dysfunctions is a clinically important element in the comprehensive treatment of schizophrenia.\n\nThe pathogenesis of sexual dysfunction in schizophrenia is complex. They may be an adverse effect of antipsychotic drugs, but they may also be endogenous, related to the disease itself [7]. Antipsychotic drugs can cause sexual dysfunction by increasing the level of prolactin, on the other hand, the antidopaminergic mechanism of action of antipsychotic drugs itself may contribute to suppressing the reward system and reducing sexual desire. The mechanism of sexual dysfunction associated with the suppression of the mesocortical dopaminergic pathways is more likely in people treated with atypical antipsychotics, associated with a lower risk of hyperprolactinemia [8].\n\nThe routine therapeutic management in the treatment of sexual dysfunction in schizophrenia has so far included reducing the dose of the antipsychotic drug, switching to an atypical antipsychotic drug and psychotherapy, and in men adding a phosphodiesterase 5 inhibitor. Other substances that may have some efficacy in the treatment of sexual dysfunction in schizophrenia are bromocriptine [9,10], cabergoline [11], cyproheptadine [12], imipramine [13], shakuyaku-kanzo-to [14] and selegiline [15].\n\nOne of the therapeutic options in the treatment of sexual dysfunction in people with schizophrenia is also amantadine [16]. It has long been used in this indication for the treatment of sexual dysfunction associated with hyperprolactinemia side effects of antipsychotic medication [17]. Little is known about the possible use of the prodopaminergic effects of amantadine in patients treated for schizophrenia with sexual dysfunction without concomitant elevation of prolactin.\n\nAtypical antipsychotics act as more or less selective antagonists of dopamine receptors in the limbic structures. Amantadine in turn distinctly facilitates dopamine signaling by elevation of neurotransmitter level in the mesolimbic pathways via inhibition of dopamine transporter1 (DAT1). It can stimulate DAT-controlling presynaptic D2 receptors of ventral tegmental area (VTA) neurons and act as an D1 receptor agonist of the spiny nucleus accumbens neurons [18]. Long-term treatment with amantadine co-administered with imipramine resulted in up-regulation of D2 and D3 receptors in the rat brain [19].\n\nAmantadine also increases the L-DOPA decarboxylase (DCC) action, but it blocks monoamine oxidase B (MAO-B) activity in the presynaptic dopaminergic neuron [20]. Acting as a weak noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, amantadine silences receptor ion current and finally inhibit glutamate signaling [21]. This follows DAT1 blockage and increase in local dopamine concentration that plays an important role in the origin of the pharmacological effect [22]. The mechanisms of amantadine are summarized in Figure 1.\n\nSo far, there is only one report in the medical literature on the possibility of improving primary sexual dysfunctions in schizophrenia with amantadine [16]. This problem has not been studied for 23 years. Since the problem of the lack of desire and other sexual dysfunctions is common and requires new pharmacological methods to help patients, the authors decided to describe a series of cases of male patients diagnosed with schizophrenia, who were treated with amantadine due to complete loss of sexual desire and activity.\n\n2. Results\n\nAdding amantadine to antipsychotic treatment significantly improved sexual function in all CSFQ subscales in all patients. The greatest improvement was observed in the Desire/frequency subscale—patients had an average score 2.4 times higher than at the beginning of the treatment (F(2,8) = 105.41; p < 0.001; eta2 = 0.963). After 3 months of administration of amantadine, the Orgasm/completion subscale was also 1.7 times better (F(2,8) = 41.75; p < 0.001; eta2 = 0.913). The improvement in the other subscales was similar—patients achieved mean scores 1.2–1.3 times higher than the baseline values (for Desire/interest subscale: F(2,8) = 60.88; p < 0.001; eta2 = 0.938; for Arousal/excitement subscale F(2,8) = 70.58; p < 0.001; eta2 = 0.946). Figure 2 shows the mean scores of all patients on the CSFQ subscales in relation to the values obtained at Visit 1, and Table 1 presents the statistical significance of improvement between the first and the last visit. Additionally, Table 2 presents the results in individual subscales of the patients’ CSFQ scale at subsequent visits.\n\nAs the patients indicated the time before falling asleep as the time of planned sexual activity, all received amantadine in the evening. No worsening of schizophrenia symptoms and no significant side effects were observed in any of the patients. Two patients experienced an increase in time to fall asleep, which resolved after changing the time of administration of amantadine. Individual case reports are summarized below.\n\n2.1. Case 1\n\nCase 1 is a 42-year-old patient who has been treated for schizophrenia for 20 years. In the past, he had irregular intake of antipsychotics and treatment intolerance was the reason for withdrawing his medications. In 2015, he was given aripiprazole 15 mg for the first time, which he tolerated well. Initially, he took the form of long-acting injection, but decided that the oral form was better for him. In 2017, he complained of sexual dysfunction and asked to be prescribed a phosphodiesterase 5 inhibitor. In the interview, it turned out that the patient rarely thought about sex and did not want to engage in sexual activity, and that he did not (or did not notice) any erections not even related to sexual activity. The desire disorder had occurred before with treatment with other antipsychotics. When the patient stopped taking his previous antipsychotic drug and before starting aripiprazole, he was not sexually disturbed. The patient’s serum prolactin was within the normal range. The patient was offered to administer amantadine 100 mg in the evening. He returned after a month with improvement, reporting he thought about sex at least twice a week, began to feel pleasure and interest in watching short pornographic films, and that he began to feel little pleasure in having sexual fantasies. He became sexually active twice, in one case he easily obtained an erection and kept it until the end of intercourse. After another month, the patient reported that he thought about sex several times a week, continued to enjoy pornographic material, tried to engage in sexual activity at least twice a week, and in half of the cases he easily obtainobtains an erection and maintains it until the end of intercourse. The patient did not report problems with ejaculation and orgasm when he had full intercourse, and the quality of his orgasm increased with treatment. The results of each subscale of the CSFQ-14 are presented in Figure 2. There was no worsening of psychotic symptoms and sleep disturbances in the patient. The tolerance of amantadine was good.\n\n2.2. Case 2\n\nCase 2 is a 47-year-old patient who has been treated for schizophrenia for 15 years. He has been taking quetiapine 600 mg as prolonged-release tablets since 2012. During his visit in 2019, he mentioned that he generally felt sexually cold and that he had very rare relations with his wife, despite the fact that they are in a very close romantic relationship. The sexology interview revealed that the patient thought about sex very sporadically—about once a month, did not feel the desire to engage in sexual activity and had no erections apart from morning erections, but notices it on average once a month. The serum prolactin level was within the normal range. He was given 100 mg of amantadine which he was supposed to take in the evenings. On the next visit after a month, the patient stated that he thinks more about sex, about once a week wants to engage in sexual activity, and he had intercourse twice, in which he easily obtained an erection once that lasted throughout the intercourse. After 5 weeks, at the next visit, the patient reported an improvement in sexual activity. He fantasized about sex several times a week, had sexual intercourse (sometimes masturbation) 1–2 times a week, during which he was able to easily obtainobtain and maintain an erection. The patient claimed that every time he had an erection and managed to end the intercourse, he would ejaculate. On each subsequent visit, he reported an improvement in the pleasure associated with orgasm. The results of each subscale of the CSFQ-14 are presented in Figure 2. The patient tolerated amantadine well and did not report any adverse effects.\n\n2.3. Case 3\n\nCase 3 is a 33-year-old patient who has been treated for schizophrenia for 10 years. He takes aripiprazole at a dose of 15 mg and clozapine at a dose of 300 mg. He has been in stable remission for many years. In 2020, during a visit, he reported that he had met a girl but, even though he was attracted to her, he did not feel sexual desire towards her. He claimed that for several months he had not felt the desire to have sex and had not masturbated. He rarely fantasized sexually, tried to watch pornographic material sometimes, but did not enjoy it. He had erections in the morning several times a month, but was unable to obtain an erection on his own. Serum prolactin was within the normal range. He was offered to add amantadine 100 mg in the evening to his antipsychotic. After 5 weeks, on the next visit, he said that he had a much greater desire for sex and is trying to initiate sexual activity at least once a week. The frequency of fantasizing about sex did not increase, but he began to search for and enjoy watching pornographic material on the Internet. He had more frequent morning erections and with his partner he was able to obtain an erection more easily, which lasted during intercourse in half of the cases to the end. He was pleased with the orgasm. After 4 weeks, he stated that he was satisfied with the improvement, fantasized about sex more often and was sexually active more than twice a week, he enjoyed both viewing pornography and orgasm, he usually managed to obtain an erection and keep it until the end of intercourse. He did not complain about problems with ejaculation. The results of the individual CSFQ-14 subscales are presented in Figure 2. Due to occasional problems with falling asleep (he fell asleep 1–2 times a week 1–2 h later than before taking amantadine), the dose of amantadine was shifted to 4:00 p.m. On the third visit, he did not complain about any problems with falling asleep. In addition, the patient did not report any side effects of amantadine.\n\n2.4. Case 4\n\nCase 4 is a 31-year-old patient who has been treated for schizophrenia since 2013. He was in stable remission since 2016, when treated with aripiprazole 15 mg daily. Previously, he was taking medication irregularly. In 2018, he asked to talk about his sexuality. He admitted that he wanted to start a sex life with his girlfriend, but that he had not had a partner before. He admitted that despite a strong emotional relationship, he did not feel any desire towards his partner and did not feel sexual arousal. He had erections in the morning at least once a month. He rarely had sexual fantasies and did not watch pornographic material because he felt no interest. Serum prolactin level was within the normal range. He was offered to add amantadine 100 mg in the evening to his treatment. At the next visit after 5 weeks, he reported a change in his sexual activity. He spontaneously fantasized more often about sex with his partner, it gave him little pleasure. He attempted intercourse twice, the first time he ended the intercourse with an ejaculation, the second time he failed to obtain a sufficient erection. After a month, he reported an increase in the number of times he had intercourse; in most cases, he had no problems with obtaining and maintaining an erection and the intercourse used to end with ejaculation. He felt a little more pleasure in sex in general and a lot of pleasure in having an orgasm. The results of the individual CSFQ-14 subscales are shown in Figure 2. The patient tolerated amantadine well and did not report any adverse events.\n\n2.5. Case 5\n\nCase 5 is a 64-year-old patient who has been treated for schizophrenia from the age of 19. Since 2014, he has been in a stable remission on risperidone, initially 6 mg daily, and since 2018 on risperidone in the form of a long-acting injection 50 mg i.m. every 2 weeks. In 2019, he separated from his wife and met a new partner. At the visit, he said his sexuality “didn’t work.” Despite frequent thoughts about sex, he did not feel any desire to have intercourse and, despite attempts to break through, he did not have sex with the partner, despite the fact that they had known each other for over 3 months. He had occasional erections in the morning, but failed to obtain an erection either by viewing pornographic material or masturbating. In the serum prolactin test, the result was at the upper limit of the normal range (18 ng/mL). It has been proposed to add amantadine 100 mg in the evening to the treatment. After a month he came forward smiling and said that “something started”. Spontaneous sexual fantasies occurred, and he enjoyed browsing pornographic material on the Internet. He had intercourse about once a week, obtained an erection easily in half of the cases, and ended intercourse with a satisfying orgasm in half of the cases. He reported even greater improvement after the next month. He found it was easier to obtain an erection, he fantasized sexually every day, had more sexual intercourse, and had greater sexual desire. The results of the individual CSFQ-14 subscales are shown in Figure 2. At the second visit, the patient reported that he fell asleep almost every day 2–3 h later than before. The time to take amantadine was moved to 4 p.m. At visit 3, he reported occasional problems falling asleep—about once a week he fell asleep 1–2 h later than usual. He did not report any other adverse effects related to the initiation or continuation of treatment with amantadine.\n\n3. Discussion\n\nThe described study is the first clinical report in two decades concerning the possibility of treating drug-induced sexual disorders in schizophrenia with amantadine. A study by Valevsky et al., was, similar to our study, a short research report conducted on a small group of twelve men suffering from schizophrenia [16]. It was shown that amantadine administered for 6 weeks causes improvement in the field of desire, erection and sexual satisfaction. These results are consistent with the results of our report; however, the results presented now cover a longer period of observation.\n\nIn the described 3-month observation period, a constant improvement in sexual function was observed, the largest in terms of desire and orgasm. This suggests that people with schizophrenia treated with antipsychotic drugs can achieve greater improvements in sexual function along with the duration of treatment with amantadine. The shorter follow-up period in the study by Valevsky et al., may explain why no changes in ejaculatory function were observed in those patients—perhaps they would have occurred, as in this case series study after a longer treatment period.\n\nIn a study by Valevsky et al., no prolactin test was performed. It is, therefore, possible that the sexual dysfunctions observed at that time were caused by hyperprolactinemia. In this context, the case series study described here may be the first report on effective amantadine treatment for sexual problems in people with schizophrenia in whom sexual dysfunction is related to the suppression of the reward system by an antipsychotic drug. In such a model of the development of antipsychotic-drug-induced sexual dysfunctions, amantadine could play the role of a modulator, increasing dopaminergic firing in the structures of the reward system in the mesolimbic system, on which antidopaminergic drugs are active (Figure 3).\n\nThe presented case series does not prove that the mechanism of action of amantadine is as outlined above. The case series study was only a naturalistic study and was carried out without placebo control. For this reason, the results obtained by us should be interpreted with great caution as preliminary and requiring confirmation in a placebo study. On the other hand, amantadine in the described group of patients showed a spectacular effect, improving sexual dysfunctions in people with schizophrenia, whose sexual functioning was suppressed. For this reason, the demonstrated efficacy of treating sexual dysfunction with amantadine in patients with schizophrenia is a clinical rationale for research into a new indication for amantadine in the treatment of sexual dysfunctions in schizophrenia.\n\nSexual disturbances may also be an immanent feature of schizophrenia, unrelated to the action of antipsychotic drugs [7]. This is indicated by the results of the study by Dembler-Stamm et al. [2], in which, using the Derogatis Inventory for Sexual Function (DISF), a greater severity of sexual disorders was shown in four of the five DISF subscales: “sexual cognition and fantasy arousal,” “sexual behavior and experience,” “orgasm,” and “sexual drive and relationship.” The limitation of this study was, as in our study, the small number of respondents (n = 19, men = 17). The sexual dysfunction profile in the study by Dembler-Stamm et al., resembles the group of patients we described, but all of them were also taking atypical medication or antipsychotics.\n\nFrom this perspective, in patients treated for schizophrenia, endogenous sexual disorders and drug-induced disorders may overlap, and we have probably studied this group of patients. Amantadine, thanks to its mechanism of action, can correct both ways of sexual dysfunction, but to confirm this model, it would also be necessary to examine the effect of amantadine on sexual dysfunction in untreated patients with schizophrenia. This research problem may also be the subject of further research.\n\nIt is known that atypical antipsychotics differ in the incidence of sexual dysfunction [1]. Aripiprazole, administered as monotherapy in two of the patients described in our study, and quetiapine (Case 2) are among those antipsychotic drugs associated with the lowest risk of sexual dysfunction. However, as the described group shows, in selected patients, these disorders may be of significant intensity regardless of the type of antipsychotic. Therefore, in addition to considering the objective medical data from meta-analyzes when choosing a drug, a personalized approach is also needed [23] and in a situation where sexual dysfunctions occur even after the drug with a low risk of causing these problems, it is necessary to look for a solution to the patient’s problem, for example in the form of amantadine adding.\n\nIt is worth emphasizing the good tolerability of amantadine 100 mg in the described patients. This is especially meaningful in the context of potential concerns about the risk of the psychodysleptic effect of prodopaminergic drugs in schizophrenia. No worsening of schizophrenia symptoms was observed in any of the patients.\n\nThe limitation of the described study, apart from the number of patients, is also the gender of the patients—it only concerns men. Sexual dysfunctions in schizophrenia affect both women and men equally [7]; therefore, a study a similar study among women diagnosed with schizophrenia should be conducted.\n\n4. Materials and Methods\n\nThe study covered five cases of patients chronically treated for paranoid schizophrenia in remission, diagnosed on the basis of ICD-10 research criteria. The criteria for selecting the described cases into a series of cases were the lack of desire and sexual activity despite having a sexual partner, lasting at least 3 months, and the absence of hyperprolactinemia. All patients were in stable remission of schizophrenia for at least 6 months before starting treatment with amantadine. None of the patients underwent medical treatment due to accompanying physical illness. Plasma prolactin level testing was a routine diagnostic test to differentiate the cause of sexual dysfunction. Blood samples for laboratory testing of serum prolactin levels was drawn between 7–8 am on an empty stomach. Laboratory norm of prolactin for men was <20 ng/mL.\n\nThe sexual functioning and mental state were assessed every 4 weeks ± 1 week. Before starting amantadine, the mechanism of action of amantadine was explained to each patient and information on potential side effects was provided. Each patient consented to off-label treatment with amantadine.\n\nPatients received amantadine 100 mg per day at least 1 h before the scheduled time of sexual activity. The patients were informed that in the event of significant side effects or worsening of schizophrenia symptoms, they should discontinue amantadine and contact their physician. In addition to amantadine, patients continued the existing antipsychotic drug as the basic treatment for schizophrenia.\n\nA 14-point Short Form of the Changes in Sexual Functioning Questionnaire (CSFQ-14) [24,25] was used to assess sexual functions. As the patients did not report sexual activity prior to the administration of amantadine, the CSFQ subscales were used for the evaluation, which allows us to precisely assess which sexual functions are disturbed and their possible changes during amantadine treatment. Subscale scores were calculated by summing the values of selected CSFQ items: Desire/frequency subscale—items 2 + 3, Desire/interest subscale—4 + 5 + 6, Arousal/excitement subscale—7 + 8 + 9 and Orgasm/completion subscale—items 11 + 12 + 13. Before collecting the completed CSFQ, the doctor checked each time whether the patient had answered all the questions in the questionnaire.\n\nThe statistical analysis of obtained results was performed with the Student’s t-Test for paired data (for difference between the first and the last visit) and the nonparametric Friedman Test for repeated measures (for general effect). Descriptive statistics include mean values, confidence intervals for the subscales, and the amount of improvement expressed as a percentage.\n\n5. Conclusions\n\nAmantadine may become a new indication for the treatment of sexual dysfunction in schizophrenia without concomitant hyperprolactinemia in patients who take antipsychotic drugs. Due to the limitations of the study, this conclusion has preliminary character and needs to be validated in controlled clinical trials in a larger patient population.\n\n6. Patients\n\nThe retrospective case reports were used to prepare the publication. The data came from the outpatient clinic of one of the authors (M.K.). Patient data were anonymized for this report, making it impossible to identify them. The patients were informed about the mechanism of action for amantadine, potential side effects and the off-label use before taking the drug. Before the treatment, the patient consented to add-on treatment with amantadine.\n\nAuthor Contributions\n\nConceptualization, M.K; methodology, M.K. and K.S.; software, M.K., A.P. and K.S.; validation, M.K., A.W., B.T., K.S. and E.M.; formal analysis, A.W., B.T., K.S. and E.M.; data curation, A.W., B.T. and E.M.; writing—original draft preparation, M.K., A.W. and A.P.; writing—review and editing, M.K., A.P.; visualization, A.P. and M.K.; supervision, M.K. and A.P. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThe cost of the publication was covered by Medical University of Silesia in Katowice.\n\nInstitutional Review Board Statement\n\nAfter consulting with the Bioethics Committee of the Medical University of Silesia in Katowice ethical review and approval were waived because case reports do not require the approval of the bioethics committee.\n\nInformed Consent Statement\n\nAfter consulting with Bioethics Committee of the Medical University of Silesia in Katowice patient consent was waived because case reports do not require the approval of the bioethics committee.\n\nData Availability Statement\n\nData is contained within the article.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 A model of possible molecular mechanism of amantadine action at the level of brain dopaminergic signaling. Activation of presynaptic dopamine receptor D2 may reduce dopamine transporter 1 (DAT1) activity in response to high neurotransmitter and elevates dopamine level within synaptic cleft. D2 is a Gi-coupled receptor, its excitation causes an inhibition of the adenylyl cyclase (AC) activity, decreased cAMP production and finally silencing of protein kinase A (PKA)-dependent neuronal signaling pathway. Amantadine is also able to inhibit monoaminoxidase B (MAO-B) but it does support L-DOPA decar-boxylase (DCC) activity in the presynaptic neuron. DDC—L-DOPA decarboxylase; MAO-B—monoaminoxidase B; DAT—dopamine transporter; AC—adenyl cyclase; PKA—protein kinase A.\n\nFigure 2 Change in mean values (+SD) of the CSFQ subscales at Visit 2 and 3 versus the values obtained by patients (n = 5) at Visit 1. Results are expressed as a percentage of the values at Visit 1 treated as 100%.\n\nFigure 3 Hypothetical model of the mechanism of sexual functioning improvement by amantadine. The drug acts as a prodopaminergic modulator of the reward system (ventral tegmental area and nucleus accumbens), increasing the dopaminergic activation suppressed by antipsychotic therapy. DDC—L-DOPA decarboxylase; MAO-B—monoaminoxidase B; DAT—dopamine transporter; AC—adenyl cyclase; PKA—protein kinase A.\n\npharmaceuticals-14-00947-t001_Table 1 Table 1 Significance of the differences between the first and the last visit in CSFQ subscales.\n\nTitle\tΔ Mean\tSD\t95%CI\tt\tdf\tp\td\t\nDesire/frequency\t−4.80\t0.84\t(−0.84, −3.76)\t−12.83\t4\t0.001\t0.84\t\nDesire/interest\t−5.60\t1.52\t(−7.48, −3.72)\t−8.26\t4\t0.001\t1.52\t\nArousal/excitement\t−6.60\t1.52\t(−8.48, 4.72)\t−9.73\t4\t0.001\t1.52\t\nOrgasm/completion\t−7.20\t2.05\t(−9.74, −4.66)\t−7.86\t4\t0.001\t2.05\t\nNote: Δ Mean—difference in means between the last and the first visit; SD—standard deviation; 95%CI—95% confidence interval; t—Student’s t-Test for paired data; df—degree of freedom; p—significance; d—Cohen’s effect size.\n\npharmaceuticals-14-00947-t002_Table 2 Table 2 Results in individual subscales of the patients’ CSFQ scale at subsequent visits.\n\nVisit No\tSCFQ\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tMean [95%CI]\t\nVisit 1\tDesire/frequency\t2\t2\t2\t2\t2\t2.0 [2.0, 2.0]\t\nDesire/interest\t4\t4\t5\t4\t6\t4.6 [4.0, 5.4]\t\nArousal/excitement\t3\t4\t8\t4\t6\t5.0 [3.6, 6.6]\t\nOrgasm/completion\t3\t3\t7\t3\t5\t4.2 [3.0, 5.8]\t\nVisit 2\tDesire/frequency\t5\t6\t6\t5\t4\t5.2 [4.6, 5.8]\t\nDesire/interest\t8\t9\t9\t6\t11\t8.6 [7.0, 9.8]\t\nArousal/excitement\t9\t8\t11\t9\t10\t9.4 [8.6, 10.4]\t\nOrgasm/completion\t8\t7\t9\t8\t10\t8.4 [7.6, 9.4]\t\nVisit 3\tDesire/frequency\t7\t7\t8\t6\t6\t6.8 [6.2, 7.4]\t\nDesire/interest\t10\t10\t11\t7\t13\t10.2 [8.4, 11.8]\t\nArousal/excitement\t11\t12\t13\t11\t11\t11.6 [11.0, 12.4]\t\nOrgasm/completion\t11\t12\t12\t12\t10\t11.4 [10.6, 12.0]\t\nNote: 95%CI—95% confidence interval.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Serretti A. Chiesa A. A meta-analysis of sexual dysfunction in psychiatric patients taking antipsychotics Int. Clin. Psychopharmacol. 2011 26 130 140 10.1097/YIC.0b013e328341e434 21191308\n2. Dembler-Stamm T. Fiebig J. Heinz A. Gallinat J. Sexual Dysfunction in Unmedicated Patients with Schizophrenia and in Healthy Controls Pharmacopsychiatry 2018 51 251 256 10.1055/s-0044-100627 29378348\n3. Knegtering H. van der Moolen A.E. Castelein S. Kluiter H. van den Bosch R.J. What are the effects of antipsychotics on sexual dysfunctions and endocrine functioning? Psychoneuroendocrinology 2003 28 (Suppl. S2) 109 123 10.1016/S0306-4530(02)00130-0 12650685\n4. Montejo A.L. Montejo L. Navarro-Cremades F. Sexual side-effects of antidepressant and antipsychotic drugs Curr. Opin. Psychiatry 2015 28 418 423 10.1097/YCO.0000000000000198 26382168\n5. Raja M. Azzoni A. Sexual behavior and sexual problems among patients with severe chronic psychoses Eur. Psychiatry 2003 18 70 76 10.1016/S0924-9338(03)00009-9 12711402\n6. Macdonald S. Halliday J. MacEwan T. Sharkey V. Farrington S. Wall S. McCreadie R.G. Nithsdale Schizophrenia Surveys 24: Sexual dysfunction. Case-control study Br. J. Psychiatry 2003 182 50 56 10.1192/bjp.182.1.50 12509318\n7. Zhao S. Wang X. Qiang X. Wang H. He J. Shen M. Zheng C. Kang R. Is There an Association Between Schizophrenia and Sexual Dysfunction in Both Sexes? A Systematic Review and Meta-Analysis J. Sex. Med. 2020 17 1476 1488 10.1016/j.jsxm.2020.03.005 32299716\n8. De Berardis D. Fornaro M. Serroni N. Marini S. Piersanti M. Cavuto M. Valchera A. Mazza M. Girinelli G. Iasevoli F. Treatment of antipsychotic-induced hyperprolactinemia: An update on the role of the dopaminergic receptors D2 partial agonist aripiprazole Recent Pat. Endocr. Metab. Immune Drug Discov. 2014 8 30 37 10.2174/1872214807666131229125700 24372345\n9. Beau Y. Guillard P. Essai de traitement par la bromocriptine des effets secondaires endocriniens des traitements psychotropes. Trial therapy with bromocriptine of secondary endocrine effects after psychotropic treatment Ann. Med. Psychol. 1980 138 179 186\n10. Matsuoka I. Nakai T. Miyake M. Hirai M. Ikawa G. Effects of bromocriptine on neuroleptic-induced amenorrhea, galactorrhea and impotence Jpn. J. Psychiatry Neurol. 1986 40 639 646 10.1111/j.1440-1819.1986.tb03179.x 2885437\n11. Tollin S.R. Fallon E.F. Mikhail M. Goldstein H. Yung E. The utility of thyroid nuclear imaging and other studies in the detection and treatment of underlying thyroid abnormalities in patients with endogenous subclinical thyrotoxicosis Clin. Nucl. Med. 2000 25 341 347 10.1097/00003072-200005000-00004 10795691\n12. Jeffries J.J. Walker C. Cyproheptadine and drug-induced anorgasmia Can. J. Psychiatry 1987 32 79 10.1177/070674378703200123 2880654\n13. Aizenberg D. Zemishlany Z. Dorfman-Etrog P. Weizman A. Sexual dysfunction in male schizophrenic patients J. Clin. Psychiatry 1995 56 137 141 7713851\n14. Yamada K. Kanba S. Yagi G. Asai M. Herbal medicine (Shakuyaku-kanzo-to) in the treatment of risperidone-induced amenorrhea J. Clin. Psychopharmacol. 1999 19 380 381 10.1097/00004714-199908000-00018 10440470\n15. Angrist B. Gershon S. Sathananthan G. Walker R.W. Lopez-Ramos B. Mandel L.R. Vandenheuvel W.J. Dimethyltryptamine levels in blood of schizophrenic patients and control subjects Psychopharmacology 1976 47 29 32 10.1007/BF00428697 803203\n16. Valevski A. Modai I. Zbarski E. Zemishlany Z. Weizman A. Effect of amantadine on sexual dysfunction in neuroleptic-treated male schizophrenic patients Clin. Neuropharmacol. 1998 21 355 357 9844793\n17. Correa N. Opler L.A. Kay S.R. Birmaher B. Amantadine in the treatment of neuroendocrine side effects of neuroleptics J. Clin. Psychopharmacol. 1987 7 91 95 10.1097/00004714-198704000-00008 2884239\n18. Nikolaus S. Wittsack H.J. Beu M. Antke C. Hautzel H. Wickrath F. Müller-Lutz A. De Souza Silva M.A. Huston J.P. Antoch G. Amantadine enhances nigrostriatal and mesolimbic dopamine function in the rat brain in relation to motor and exploratory activity Pharmacol. Biochem. Behav. 2019 179 156 170 10.1016/j.pbb.2018.12.010 30639878\n19. Rogóz Z. Dlaboga D. Dziedzicka-Wasylewska M. Effect of combined treatment with imipramine and amantadine on the central dopamine D2 and D3 receptors in rats J. Physiol. Pharmacol. 2003 54 257 270 12832726\n20. Fisher A. Starr M.S. Opposite effects of glutamate antagonists and antiparkinsonian drugs on the activities of DOPA decarboxylase and 5-HTP decarboxylase in the rat brain Brain Res. 2000 868 268 274 10.1016/S0006-8993(00)02339-8 10854579\n21. Blanpied T.A. Clarke R.J. Johnson J.W. Amantadine inhibits NMDA receptors by accelerating channel closure during channel block J. Neurosci. 2005 25 3312 3322 10.1523/JNEUROSCI.4262-04.2005 15800186\n22. Huber T.J. Dietrich D.E. Emrich H.M. Possible use of amantadine in depression Pharmacopsychiatry 1999 32 47 55 10.1055/s-2007-979191 10333162\n23. Murawiec S. Krzystanek M. Symptom Cluster-Matching Antidepressant Treatment: A Case Series Pilot Study Pharmaceuticals 2021 14 526 10.3390/ph14060526 34072934\n24. Clayton A.H. McGarvey E.L. Clavet G.J. The Changes in Sexual Functioning Questionnaire (CSFQ): Development, reliability, and validity Psychopharmacol. Bull. 1997 33 731 745 9493486\n25. Keller A. McGarvey E.L. Clayton A.H. Reliability and construct validity of the Changes in Sexual Functioning Questionnaire short-form (CSFQ-14) J. Sex Marital Ther. 2006 32 43 52 10.1080/00926230500232909 16234225\n\n",
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"issue": "14(10)",
"journal": "Pharmaceuticals (Basel, Switzerland)",
"keywords": "amantadine; antipsychotic drugs; atypical antipsychotics; hyperprolactinemia; libido; schizophrenia; sex drive; sexual disfunctions",
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"pubdate": "2021-09-22",
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"title": "Amantadine in the Treatment of Sexual Inactivity in Schizophrenia Patients Taking Atypical Antipsychotics-The Pilot Case Series Study.",
"title_normalized": "amantadine in the treatment of sexual inactivity in schizophrenia patients taking atypical antipsychotics the pilot case series study"
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"abstract": "We present a rare documented case with consecutive hypo- and hyperthyroidism during fetal life. First, hypothyroidism was due to transplacental passage of antithyroid drugs. After the mother's thyroidectomy, fetal hyperthyroidism was due to transplacental passage of persistent anti-thyrotropin receptor antibodies. Fetal goiter disappeared after adjusting maternal treatment.",
"affiliations": "Department of Obstetrics and Gynecology FHU Prematurity Bichat Hospital Assistance publique-Hôpitaux de Paris Paris University Paris France.;Department of Obstetrics and Gynecology Assistance publique-Hôpitaux de Paris Bicêtre Hospital Le Kremlin-Bicêtre France.;Department of Obstetrics and Gynecology Assistance publique-Hôpitaux de Paris Bicêtre Hospital Le Kremlin-Bicêtre France.;Department of Endocrinology and Reproductive Medicine Bicêtre Hospital Le Kremlin-Bicêtre France.;Department of Obstetrics and Gynecology FHU Prematurity Bichat Hospital Assistance publique-Hôpitaux de Paris Paris University Paris France.",
"authors": "Didier-Mathon|Hortense|H|https://orcid.org/0000-0002-2206-8191;Bouchghoul|Hanane|H|https://orcid.org/0000-0002-8482-2815;Senat|Marie-Victoire|MV|;Young|Jacques|J|;Luton|Dominique|D|",
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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/ccr3.4012\nCCR34012\nCase Report\nCase Reports\nPrenatal management of fetal goiter alternating between hypothyroidism and hyperthyroidism in a mother with Graves’ disease\nDIDIER‐MATHON et al.\nDidier‐Mathon Hortense https://orcid.org/0000-0002-2206-8191\n1 Hortense.didier1@gmail.com\n\nBouchghoul Hanane https://orcid.org/0000-0002-8482-2815\n2\nSenat Marie‐Victoire 2\nYoung Jacques 3\nLuton Dominique 1 4\n1 Department of Obstetrics and Gynecology FHU Prematurity Bichat Hospital Assistance publique‐Hôpitaux de Paris Paris University Paris France\n2 Department of Obstetrics and Gynecology Assistance publique‐Hôpitaux de Paris Bicêtre Hospital Le Kremlin‐Bicêtre France\n3 Department of Endocrinology and Reproductive Medicine Bicêtre Hospital Le Kremlin‐Bicêtre France\n4 INSERM U1016 Institut IMAGINE Paris France\n* Correspondence\nHortense Didier‐Mathon, Department of Obstetrics and gynecology, Bichat Hospital, 46, rue Henri Huchard, 75018 Paris, France.\nEmail: Hortense.didier1@gmail.com\n\n04 3 2021\n4 2021\n9 4 10.1002/ccr3.v9.4 22812284\n17 2 2021\n24 12 2020\n22 2 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nWe present a rare documented case with consecutive hypo‐ and hyperthyroidism during fetal life. First, hypothyroidism was due to transplacental passage of antithyroid drugs. After the mother's thyroidectomy, fetal hyperthyroidism was due to transplacental passage of persistent anti‐thyrotropin receptor antibodies. Fetal goiter disappeared after adjusting maternal treatment.\n\nWe present a rare documented case with consecutive hypo‐ and hyperthyroidism during fetal life. First, hypothyroidism was due to transplacental passage of antithyroid drugs. After the mother's thyroidectomy, fetal hyperthyroidism was due to transplacental passage of persistent anti‐thyrotropin receptor antibodies. Fetal goiter disappeared after adjusting maternal treatment.\n\nendocrinology and metabolic disorders\nfetal goiter\nmaternal Grave's disease\nobstetrics and gynecology\nprenatal management\nsource-schema-version-number2.0\ncover-dateApril 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:27.04.2021\nDidier‐Mathon H , Bouchghoul H , Senat M‐V , Young J , Luton D . Prenatal management of fetal goiter alternating between hypothyroidism and hyperthyroidism in a mother with Graves’ disease. Clin Case Rep. 2021;9 :2281–2284. 10.1002/ccr3.4012\n==== Body\n1 INTRODUCTION\n\nGraves' disease is the most common cause of hyperthyroidism 1 and occurs in 0.1%‐0.4% of the pregnancies. 2 When it remains untreated, it can lead to materno‐fetal complications such as preeclampsia, preterm birth, placental abruption, miscarriage, and intrauterine fetal death due to cardiac failure. 3 It is also the most common cause of fetal goiter. Because of risks of fetal hyperthyroidism due to transplacental passage of antithyrotropin receptor antibodies (TRAb) and fetal hypothyroidism due to transplacental passage of antithyroid drugs (ATD), patients with Graves’ disease should be carefully monitored during pregnancy. We report here a case of management of a fetal goiter in which the mother had Graves’ disease. We documented a switch between fetal hypothyroidism and hyperthyroidism necessitating appropriate therapy.\n\n2 CASE PRESENTATION\n\nThe patient was a 37 years old Asian woman, fifth gravida, with only past history of Graves’ disease. Since the diagnosis after her third delivery, she underwent three recurrences. Because dysthyroidism was difficult to balance, a total thyroidectomy was scheduled but had to be delayed because of a new pregnancy.\n\nSince the beginning of the pregnancy, the disease was imbalanced with very high level of stimulating TRAbs (700 UI/L, NR: <1.6 UI/L), high level of f‐T4 (26 pmol/L, NR: 10.0‐22.5 pmol/L), and f‐T3 (27.6 pmol/L, NR: 3.1‐6.5 pmol/L) which necessitated the increase of propylthiouracil from 200 mg per to 300 mg a day since 16 weeks. The first‐trimester ultrasound showed no abnormalities, but a fetal goiter appeared at 18 weeks: Fetal thyroid was > 99 percentile with hyperextension of the neck. According to European Thyroid Association Guidelines, 4 the treatment was replaced by carbimazol 40 mg and soon after 60 mg a day. At 22 weeks and 2 days, ultrasound showed the persistence of fetal goiter with peripheral hypervascularization (shown in Figure 1A). A cordocentesis was performed at 22 weeks and 5 days diagnosing moderate fetal hypothyroidism with free thyroxin dosage (f‐T4) at 6.1 pmol/L (NR: 9.7‐16.4 pmol/L) and a TSH dosage of 0.15 mU/L (NR: 4‐13 mU/L). At that point lowering of carbimazol was considered but the mother clinical (bilateral exophthalmos, tachycardia and large vascular goiter) and biological state was so difficult to control that a total thyroidectomy was performed at 23 weeks and 3 days. The patient was then supplemented by levothyroxin 150 µg a day permitting the normalization of maternal thyroid function. Maternal TRAbs’ levels decreased to 153 UI/l. The monitoring of the fetal thyroid gland did not show a frank regression of its size. The following ultrasound showed the persistence of fetal goiter and fetal hyperthyroidism symptoms: tachycardia, central hypervascularization (shown in Figure 1B) of the thyroid, and accelerated skeletal maturation. As the carbimazol had been withdrawn since the mother's thyroidectomy, fetal hyperthyroidism was the obvious diagnosis; after multidisciplinary discussion, we preferred to establish the diagnosis by a fetal blood sample which confirmed, at 29 weeks and 3 days, hyperthyroidism with f‐T4 at 54.9 pmol/L (NR: 9.7‐16.4 pmol/L) and TSH < 0.01 mU/L (NR: 4‐13 mU/L), of note fetal TRAbs’ assays was at 34 UI/L. Levothyroxin was decreased at 100 µg a day and carbimazole was reintroduced with a daily dosage of 60 mg, gradually decreased to 20 mg. Fetal thyroid diameter progressively decreased until 32 weeks and 3 days when ultrasound examinations showed a normal thyroid size and normal heart beat until the end of pregnancy. It is interesting to note that fetal heart rate was normal on all ultrasound examination. Figure 2 shows evolution of fetal thyroid diameter and circumference and evolution of maternal dosage medication.\n\nFIGURE 1 A, Thyroid peripheral hypervascularization in an axial ultrasound section at 22 weeks B, Thyroid central hypervascularization in an axial ultrasound section at 28 weeks and 6 days\n\nFIGURE 2 A, Evolution of fetal thyroid diameter. B, Evolution of fetal thyroid circumference. C, Medication dosage of carbimazol (NMZ) and levothyroxine (L‐T4). FBS, fetal blood sample\n\nDelivery was induced because of fetal heart rate abnormalities at 37 weeks of gestation and 4 days. The patient gave birth to a girl, weighing 2830 g, measuring 48 cm, arterial pH was 7.34, and Apgar score was 10/10. Thyroid hormones of the newborn showed hypothyroxinemia (TSH was 2.64 mI/L, NR: 0.3‐7 mu/L, f‐T4 was 8.0 pmol/L, NR: 14‐35 pmol/L, and f‐T3 was 1.4, NR: 3.1‐6.5 pmol/L) at birth but she quickly developed hyperthyroidism at 6 days of life (TSH was 0.11 mI/L, NR: 0.3‐7 mu/L, f‐T4 was 44.2 pmol/L, NR: 14‐35 pmol/L, and f‐T3 was 13.6, NR: 3.1‐6.5 pmol/L). At that point, TRAbs were positive at 14.7 UI/L (NR < 1.6 U/L). A treatment was introduced at 8 days of life. It was stopped at 9 weeks of life, and the last control we know at 11 weeks of life showed normal thyroid function and normal clinical evolution.\n\n3 DISCUSSION\n\nFetal goiter is a rare condition that results of either fetal hypothyroidism or hyperthyroidism. It can cause several complications 5 and has several etiologies: congenital dyshormonogenesis, deficiency or excess of iodine or transplacental passage of maternal TRAb or ATD. 6 Maternal Graves’ disease accounts for more than 60% of fetal goiter. 7 The goiter itself can be responsible of tracheal and esophageal compression that leads to polyhydramnios, anasarca and, at the very last, cardiac insufficiency. In the most extreme cases, polyhydramnios leads to preterm birth and fetal cervical hyperextension causes dystocic labor and neonatal asphyxia. Fetal hyperthyroidism causes accelerated bone maturation, intrauterine growth restriction, cardiac insufficiency (leading to intrauterine fetal death), and craniostenosis. On the other hand, fetal hypothyroidism is often less severe and leads to delay of both bone maturation and potentially different degree of psychomotor development depending on maternal thyroidal status. 8\n\nGraves' disease is an autoimmune condition in which TRAb cross the placenta and bind to hormonal fetal receptors. A correlation between high level of TRAb and development of fetal hyperthyroidism symptoms has previously been demonstrated. 9 This is all the more likely in our case since TRAb were showed to be stimulating one (>1000%). Treatment is based on ATD (imidazole or thiouracil). 10 The strategy consisting in “combined” or “block‐replace” treatment is not recommended during pregnancy because the proportion of thyroxine crossing the placenta is lower than the ATDs’ leading therefore to a fetal hypothyroidism. Surgery is reserved for allergy to ATD or poor control of maternal hyperthyroidism. Thus, the balance between the risk of fetal hypothyroidism due to ATD placental passage and hyperthyroidism due to TRAb placental passage can be difficult to manage in Graves’ disease.\n\nThe presence of fetal goiter on ultrasound requires a precise diagnosis before introduction of any treatment. Indeed, it can be associated with hypothyroidism, hyperthyroidism, or more rarely euthyroid state. 11 Experienced physician can assume fetal thyroid hormone status by describing the appearance of fetal goiter (thyroid diameter and circumference, vascularization) and bone maturation at ultrasound examination. However, direct measure of fetal cordonal blood sample remains the gold standard diagnostic method in difficult cases, as recommended by the American Thyroid Association. 5 , 12 In our case, the first diagnosis of the fetal goiter was hypothyroidism due to relatively high dose of ATD in the mother; this was necessary due to maternal clinical and hormonal status. However, low dosage of TSH at that point was surprising. We supposed it was due to balancing between TRAb and ATD, resulting in changeover between fetal hypo and hyperthyroidism. Once the mother's disease was “cured” by thyroidectomy, a second problem arised in the fetus due to the only persistence of a significant TRAb level not counterbalanced by ATD; this led the fetus to switch from an hypo‐ to an hyperthyroid state. Challenge of our fetal medicine approach consisted in identifying this switch and choosing the good option, that is, reintroducing carbimazol with fine monitoring of the fetal thyroid gland. Previous study showed that one‐third of thyroidectomized patients have residual TRAb levels, 2 even though other series suggested that the activity of these antibodies is lower due to loss antigen stimulation. 13 , 14 Nevertheless, our patient kept significant levels of TRAb. This case is emblematic of fetal medicine challenge dealing with a fetus that experienced consecutive hypo‐ and hyperthyroidism with appropriate medical intervention.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTION\n\nHD‐M: wrote the original draft preparation; DL, HB, JY, M‐VS: wrote, reviewed, and edited; DL: involved in supervision.\n\nAll authors have read and agreed to the published version of the manuscript.\n\nETHICAL APPROVAL\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nACKNOWLEDGMENT\n\nPublished with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nAnonymized data will be shared on request from any qualified investigator.\n==== Refs\nREFERENCES\n\n1 Subekti I , Pramono LA . Current diagnosis and management of graves’ disease. Acta Med Indones. 2018;50 (2 ):177‐182.29950539\n2 Banigé M , Estellat C , Biran V , et al. Study of the factors leading to fetal and neonatal dysthyroidism in children of patients with Graves disease. J Endocr Soc. 2017;1 (6 ):751‐761.29130077\n3 Hirsch D , Levy S , Nadler V , Kopel V , Shainberg B , Toledano Y . Pregnancy outcomes in women with severe hypothyroidism. Eur J Endocrinol. 2013;169 (3 ):313‐320.23811188\n4 Kahaly GJ , Bartalena L , Hegedüs L , Leenhardt L , Poppe K , Pearce SH . 2018 European thyroid association guideline for the management of graves’ hyperthyroidism. Eur Thyroid J. 2018;7 (4 ):167‐186.30283735\n5 Huel C , Guibourdenche J , Vuillard E , et al. Use of ultrasound to distinguish between fetal hyperthyroidism and hypothyroidism on discovery of a goiter. Ultrasound Obstet Gynecol. 2009;33 (4 ):412‐420.19306478\n6 Hardley MT , Chon AH , Mestman J , Nguyen CT , Geffner ME , Chmait RH . Iodine‐induced fetal hypothyroidism: diagnosis and treatment with intra‐amniotic levothyroxine. Horm Res Paediatr. 2018;90 (6 ):419‐423.29791909\n7 Munoz JL , Kessler AA , Felig P , Curtis J , Evans MI . Sequential amniotic fluid thyroid hormone changes correlate with goiter shrinkage following in utero thyroxine therapy. Fetal Diagn Ther. 2016;39 (3 ):222‐227.26314950\n8 Rovet J , Ehrlich R , Sorbara D . Intellectual outcome in children with fetal hypothyroidism. J Pediatr. 1987;110 (5 ):700‐704.3572621\n9 McKenzie JM , Zakarija M . Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies. Thyroid. 1992;2 (2 ):155‐159.1356056\n10 Illouz F , Luton D , Polak M , Besançon A , Bournaud C . Graves’ disease and pregnancy. Ann Endocrinol (Paris). 2018;79 (6 ):636‐646.30224035\n11 Abuhamad AZ , Fisher DA , Warsof SL , et al. Antenatal diagnosis and treatment of fetal goitrous hypothyroidism: case report and review of the literature. Ultrasound Obstet Gynecol. 1995;6 (5 ):368‐371.8590211\n12 Alexander EK , Pearce EN , Brent GA , et al. 2017 Guidelines of the American thyroid association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27 (3 ):315‐389.28056690\n13 Early severe fetal Graves disease in a mother after thyroid ablation and thyroidectomy ‐ PubMed [Internet]. https://pubmed.ncbi.nlm.nih.gov/25710616/. Accessed Sep 9, 2020\n14 Luton D , Le Gac I , Vuillard E , et al. Management of Graves’ disease during pregnancy: the key role of fetal thyroid gland monitoring. J Clin Endocrinol Metab. 2005;90 (11 ):6093‐6098.16118343\n\n",
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"issue": "9(4)",
"journal": "Clinical case reports",
"keywords": "endocrinology and metabolic disorders; fetal goiter; maternal Grave's disease; obstetrics and gynecology; prenatal management",
"medline_ta": "Clin Case Rep",
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"pages": "2281-2284",
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"pmid": "33936679",
"pubdate": "2021-04",
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"title": "Prenatal management of fetal goiter alternating between hypothyroidism and hyperthyroidism in a mother with Graves' disease.",
"title_normalized": "prenatal management of fetal goiter alternating between hypothyroidism and hyperthyroidism in a mother with graves disease"
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"abstract": "We describe the case of a 23-month-old male infant with Epstein-Barr virus (EBV)-associated lymphoproliferative disorder, which mimicked the recurrence of EBV-associated hemophagocytic lymphohistiocytosis. Chemotherapy with dexamethasone, etoposide, and cyclosporine resolved fever, hepatosplenomegaly, and pancytopenia. However, on day 81 of illness, the patient developed similar symptoms. Plasma EBV-DNA levels markedly increased again, but no T-cell clonality was observed. B cells were identified to be infected with EBV. He was successfully treated with rituximab, dexamethasone and etoposide. When recurrence of EBV-associated hemophagocytic lymphohistiocytosis is suspected, performing tests to identify the infected cells will enable accurate understanding of the clinical condition, resulting in proper treatments.",
"affiliations": "Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City.;Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City.;Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City.;Department of Pediatrics, Shinshu University School of Medicine, Matsumoto.;Department of Advanced Medicine for Infections, National Center for Child Health and Development.;Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City.;Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City.;Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City.;Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City.",
"authors": "Yatsushiro|Yuki|Y|;Nishikawa|Takuro|T|;Saito|Aki|A|;Nakazawa|Yozo|Y|;Imadome|Ken-Ichi|KI|;Nakagawa|Shunsuke|S|;Kodama|Yuichi|Y|;Okamoto|Yasuhiro|Y|;Kanegane|Hirokazu|H|;Kawano|Yoshifumi|Y|",
"chemical_list": "D004279:DNA, Viral; D000069283:Rituximab; D005047:Etoposide; D003907:Dexamethasone",
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"issue": "41(1)",
"journal": "Journal of pediatric hematology/oncology",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001402:B-Lymphocytes; D004279:DNA, Viral; D003907:Dexamethasone; D020031:Epstein-Barr Virus Infections; D005047:Etoposide; D004854:Herpesvirus 4, Human; D006801:Humans; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic; D008232:Lymphoproliferative Disorders; D008297:Male; D000069283:Rituximab; D013601:T-Lymphocytes",
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"references": null,
"title": "Epstein-Barr Virus (EBV)-induced B-cell Lymphoproliferative Disorder Mimicking the Recurrence of EBV-associated Hemophagocytic Lymphohistiocytosis.",
"title_normalized": "epstein barr virus ebv induced b cell lymphoproliferative disorder mimicking the recurrence of ebv associated hemophagocytic lymphohistiocytosis"
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"abstract": "This report describes a patient with bilateral endogenous candida chorioretinitis. The patient had a 2-day history of bilateral blurred vision. Fundus photography revealed multiple chorioretinal infiltrations in both eyes and a parafoveal hemorrhage in the left eye. After 2 days, fundus examination showed an increased number of infiltrations and hemorrhages in both eyes and worsening vitreous inflammation. A large infiltrative intraretinal lesion and a retinal hemorrhage of the left eye were discovered on optical coherence tomography. Candida albicans was diagnosed from blood culture. The bilateral candida chorioretinitis had not responded to systemic or topical antifungal medication. The chorioretinitis was refractory to intravitreal amphotericin B as well. Intravitreal voriconazole injection in both eyes and intravitreal bevacizumab injection in the left eye were performed thereafter. The chorioretinal infiltrations and hemorrhages decreased in both eyes. Intravitreal voriconazole injection was effective in the treatment of intractable candida chorioretinitis.",
"affiliations": "Department of Ophthalmology, Sanggye Paik Hospital, Inje University of Korea College of Medicine, Seoul, Republic of Korea.;Department of Ophthalmology, Sanggye Paik Hospital, Inje University of Korea College of Medicine, Seoul, Republic of Korea.;Department of Ophthalmology, Sanggye Paik Hospital, Inje University of Korea College of Medicine, Seoul, Republic of Korea.;Department of Ophthalmology, Sanggye Paik Hospital, Inje University of Korea College of Medicine, Seoul, Republic of Korea.",
"authors": "Sim|Ha Eun|HE|;Kang|Min Ji|MJ|;Kim|Jae Suk|JS|;Hwang|Je Hyung|JH|",
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"fulltext": "\n==== Front\nCase Rep Ophthalmol\nCase Rep Ophthalmol\nCOP\nCase Reports in Ophthalmology\n1663-2699 S. 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\n10.1159/000508912\ncop-0011-0402\nCase Report\nIntravitreal Voriconazole for Treatment of Bilateral Endogenous Candida Chorioretinitis\nSim Ha Eun Kang Min Ji Kim Jae Suk Hwang Je Hyung * Department of Ophthalmology, Sanggye Paik Hospital, Inje University of Korea College of Medicine, Seoul, Republic of Korea\n*Je Hyung Hwang, Department of Ophthalmology, Inje University, Sanggye Paik Hospital, 1342 Dongil-ro, Nowon-gu, Seoul 139-707 (Republic of Korea), violentviolet15@daum.net\nMay-Aug 2020 \n5 8 2020 \n5 8 2020 \n11 2 402 410\n1 4 2020 25 5 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This 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.This report describes a patient with bilateral endogenous candida chorioretinitis. The patient had a 2-day history of bilateral blurred vision. Fundus photography revealed multiple chorioretinal infiltrations in both eyes and a parafoveal hemorrhage in the left eye. After 2 days, fundus examination showed an increased number of infiltrations and hemorrhages in both eyes and worsening vitreous inflammation. A large infiltrative intraretinal lesion and a retinal hemorrhage of the left eye were discovered on optical coherence tomography. Candida albicans was diagnosed from blood culture. The bilateral candida chorioretinitis had not responded to systemic or topical antifungal medication. The chorioretinitis was refractory to intravitreal amphotericin B as well. Intravitreal voriconazole injection in both eyes and intravitreal bevacizumab injection in the left eye were performed thereafter. The chorioretinal infiltrations and hemorrhages decreased in both eyes. Intravitreal voriconazole injection was effective in the treatment of intractable candida chorioretinitis.\n\nKeywords\nCandida chorioretinitisEndogenous chorioretinitisVoriconazole\n==== Body\nIntroduction\nImmunocompromised patients are at increased risk of fungal sepsis. Fungal dissemination to the organs occurs via hematogenous seeding and may include the retinal and choroidal capillaries in the eye. Candida species are the most common cause of endogenous fungal endophthalmitis [1]. A previous study described two main types of ocular candidiasis: endogenous endophthalmitis, which is characterized by vitritis and fluffy balls extending into the vitreous body, and candida chorioretinitis, in which the disease is restricted to the chorioretinal layer [2]. Ocular candidiasis can be treated by systemic or intravitreal injection of an antifungal agent. Voriconazole is a broad-spectrum antifungal agent that is derived from fluconazole and has been shown to achieve therapeutically significant concentrations in the vitreous body after oral administration [3]. Here we report a case of candida chorioretinitis that was unresponsive to oral voriconazole and intravitreal amphotericin B.\n\nCase Presentation\nA 62-year-old Korean woman was referred to our clinic with a 2-day history of bilateral blurred vision. She was receiving chemotherapy for anorectal cancer in the internal medicine department and intravenous fluconazole (10 mg/kg i.v. every 24 h × 24 days) to treat candidemia. Candida albicans was diagnosed from blood culture. Meningitis was not observed on neurological examination. Her past ophthalmic history was unremarkable.\n\nOn examination, her best-corrected distance visual acuity was 20/40 in the right eye and 20/200 in the left eye. Slit-lamp examination of the cornea and conjunctiva was unremarkable, and there was no active inflammation in the anterior chamber or neovascularization in the iris. Intraocular pressure was normal in both eyes. Fundus photography revealed multiple chorioretinal infiltrations in both eyes and a parafoveal hemorrhage in the left eye (Fig. 1). The patient's general condition was considered to be very poor, so we could not perform optical coherence tomography or fundus fluorescein angiography. Given the good intravitreal penetration of voriconazole [3], oral voriconazole was added to treat the candida chorioretinitis (400 mg every 12 h × 21 days). After 2 days of treatment with oral voriconazole, fundus examination showed an increased number of infiltrations and hemorrhages in both eyes and worsening vitreous inflammation. The parafoveal hemorrhage was increased in the left eye and the macula appeared to be elevated. The patient's general condition then deteriorated further and she was no longer able to visit our clinic. Therefore, a fundus examination was performed and bilateral intravitreal amphotericin B injections 0.1 mL (50 μg/mL) were administered while she was an inpatient in the internal medicine ward. Four days after the intravitreal injections, the patient's visual acuity decreased; at this time, her best-corrected distance visual acuity was 20/60 in the right eye and 2/100 in the left eye. On fundus examination, there were further infiltrations and hemorrhages in both eyes. The patient's general condition was improved (body temperature had normalized and WBC and inflammatory marker levels [ESR, CRP] had decreased on the blood tests), so we were able to perform optical coherence tomography, which revealed parafoveal hemorrhage in the left eye (Fig. 2). We administered intravitreal voriconazole injections 0.1 mL (100 μg/0.1 mL) bilaterally in the left eye. One week later, the chorioretinal infiltrations and hemorrhages were decreased in both eyes (Fig. 3). At the 1- and 3-month follow-up visits there was no recurrence of chorioretinitis (Fig. 4, 5).\n\nDiscussion and Conclusion\nThe risk factors for candidemia include long-term intravenous therapy, gastrointestinal surgery, trauma, indwelling bladder catheter, immunocompromised status, malignancy, and intravenous drug abuse. Our patient had three of these risk factors in the form of anorectal cancer, chemotherapy, and long-term intravenous therapy. For chemotherapy, a chemoport placed on October 31, 2017 via the right jugular vein was used; the patient received fourth-line chemotherapy with bevacizumab, 5-fluorouracil, leucovorin, and oxaliplatin. During follow-up, the patient developed fever and was thus hospitalized for fifth-line chemotherapy with bevacizumab, 5-fluorouracil, leucovorin, and oxaliplatin and the evaluation of fever. During hospitalization, candida bacteremia was confirmed in blood culture. Hence, the chemoport was removed and a peripherally inserted central catheter was inserted through the right basilic vein. Chorioretinitis has been reported to occur in 7.9–37% of patients with candidemia [4].\n\nFeman et al. [5] reported that inpatients were less likely to develop ocular candidiasis because of early diagnosis of candidemia and prompt systemic antifungal therapy. However, in our patient, early diagnosis of candidemia and intravenous fluconazole therapy did not prevent ocular candidiasis.\n\nIntravenous amphotericin has been recommended as a treatment for fluconazole-resistant C. albicans, C. krusei, and C. glabrata [6]. However, systemic amphotericin is not suitable for immunocompromised patients because of its poor intravitreal penetration and systemic side effects [7]. In our patient, intravenous fluconazole was effective for systemic candidemia and systemic amphotericin could not be used because of the patient's poor overall condition. Voriconazole is a broad-spectrum second-generation derivative of fluconazole that has 96% bioavailability and has been shown to reach therapeutically significant concentrations in the vitreous body after oral administration [3]. Biju et al. [1] reported that candida endophthalmitis could be treated successfully by oral administration of voriconazole, but this strategy was not effective in our patient. Intravitreal liposomal amphotericin B injection has been reported to be an effective treatment for endogenous candida endophthalmitis [8]. Voriconazole is cleared from the vitreous cavity within 24 h of injection, so multiple intravitreal injections are required to maintain therapeutic concentrations in the eye [8].\n\nConsidering the patient's generally poor condition, we opted to administer intravitreal amphotericin B instead of voriconazole to avoid the need for multiple intravitreal injections. In South Korea, voriconazole is only indicated in fungal infections that do not respond to amphotericin B or fluconazole. However, intravitreal amphotericin was not effective in our patient, whereas voriconazole was effective and did not require multiple injections.\n\nFurthermore, the peak, trough, and random serum levels of antifungal agents should be evaluated when using intravenous fluconazole. However, the patient was not evaluated for serum levels of the antifungal agents used because of issues related to medical insurance coverage and expenses, and her condition was clinically (fever, decreased WBC, decreased ESR and CRP) determined in the internal medicine department; this was a limitation of our study.\n\nTo our knowledge, this is the first report of endogenous candida chorioretinitis being treated successfully with a single intravitreal injection of voriconazole without vitrectomy.\n\nIn conclusion, intravitreal voriconazole could be considered as a first-line treatment for endogenous candida chorioretinitis, despite its short half-life in the vitreous cavity, in immunocompromised patients who do not respond to oral voriconazole or intravitreal amphotericin B.\n\nStatement of Ethics\nWritten informed consent for publication of this case report, including publication of images, was obtained from the patient.\n\nConflict of Interest Statement\nThe authors have no conflict of interest to declare.\n\nFunding Sources\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nAuthor Contributions\nSubstantial contributions to the conception or design of the work: H.E. Sim and J.H. Hwang. Acquisition of data: M.J. Kang and J.S. Kim. Drafting of the work: H.E. Sim and J.H. Hwang.\n\nFig. 1 Fundus photographs of the patient with multiple chorioretinal infiltrations in both eyes and a parafoveal hemorrhage in the left eye.\n\nFig. 2 Fundus photographs and optical coherence tomograms obtained 4 days after intravitreal injection of amphotericin B. There were increased multiple infiltrations and hemorrhages in both eyes.\n\nFig. 3 Fundus photographs and optical coherence tomograms obtained 1 week after bilateral intravitreal injections of voriconazole. There was a decrease in the chorioretinal infiltrations and hemorrhages in both eyes.\n\nFig. 4 Fundus photographs and optical coherence tomograms obtained 1 moth after bilateral intravitreal injections of voriconazole.\n\nFig. 5 Fundus photographs and optical coherence tomograms obtained 3 months after bilateral intravitreal injections of voriconazole.\n==== Refs\nReferences\n1 Biju R Sushil D Georgy NK Successful management of presumed Candida endogenous endophthalmitis with oral voriconazole Indian J Ophthalmol 2009 Jul-Aug 57 (4) 306 8 19574701 \n2 Rodríguez-Adrián LJ King RT Tamayo-Derat LG Miller JW Garcia CA Rex JH Retinal lesions as clues to disseminated bacterial and candidal infections: frequency, natural history, and etiology Medicine (Baltimore) 2003 5 82 (3) 187 202 12792305 \n3 Hariprasad SM Mieler WF Holz ER Gao H Kim JE Chi J Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans Arch Ophthalmol 2004 1 122 (1) 42 7 14718293 \n4 Parke DW 2nd Jones DB Gentry LO Endogenous endophthalmitis among patients with candidemia Ophthalmology 1982 7 89 (7) 789 96 6981788 \n5 Feman SS Nichols JC Chung SM Theobald TA Endophthalmitis in patients with disseminated fungal disease Trans Am Ophthalmol Soc 2002 100 67 70 12545679 \n6 Pappas PG Rex JH Sobel JD Filler SG Dismukes WE Walsh TJ Infectious Diseases Society of America Guidelines for treatment of candidiasis Clin Infect Dis 2004 1 38 (2) 161 89 14699449 \n7 O'Day DM Head WS Robinson RD Stern WH Freeman JM Intraocular penetration of systemically administered antifungal agents Curr Eye Res 1985 2 4 (2) 131 4 3987346 \n8 Bae JH Lee SC Intravitreal liposomal amphotericin B for treatment of endogenous candida endophthalmitis Jpn J Ophthalmol 2015 9 59 (5) 346 52 26215152\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "11(2)",
"journal": "Case reports in ophthalmology",
"keywords": "Candida chorioretinitis; Endogenous chorioretinitis; Voriconazole",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "402-410",
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"pubdate": "2020",
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"title": "Intravitreal Voriconazole for Treatment of Bilateral Endogenous Candida Chorioretinitis.",
"title_normalized": "intravitreal voriconazole for treatment of bilateral endogenous candida chorioretinitis"
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"abstract": "Advanced melanoma treatments often rely on immunotherapy or targeting mutations, with few treatment options for wild-type BRAF (BRAF-wt) melanoma. However, the mitogen-activated protein kinase pathway is activated in most melanoma, including BRAF-wt. We assessed whether inhibiting this pathway by adding kinase inhibitors trametinib or pazopanib to paclitaxel chemotherapy improved outcomes in patients with advanced BRAF-wt melanoma in a phase II, randomised and open-label trial.\n\n\n\nPatients were randomised (1 : 1 : 1) to paclitaxel alone or with trametinib or pazopanib. Paclitaxel was given for a maximum of six cycles, while 2 mg trametinib and 800 mg pazopanib were administered orally once daily until disease progression or unacceptable toxicity. Participants and investigators were unblinded. The primary end point was progression-free survival (PFS). Key secondary end points included overall survival (OS) and objective response rate (ORR).\n\n\n\nParticipants were randomised to paclitaxel alone (n = 38), paclitaxel and trametinib (n = 36), or paclitaxel and pazopanib (n = 37). Adding trametinib significantly improved 6-month PFS [time ratio (TR), 1.47; 90% confidence interval (CI) 1.08-2.01, P = 0.04] and ORR (42% versus 13%; P = 0.01) but had no effect on OS (P = 0.25). Adding pazopanib did not benefit 6-month PFS; (TR 1.36; 90% CI 0.96-1.93; P = 0.14), ORR, or OS. Toxicity increased in both combination arms.\n\n\n\nIn this phase II trial, adding trametinib to paclitaxel chemotherapy for BRAF-wt melanoma improved PFS and substantially increased ORR but did not impact OS.This study was registered with the EU Clinical Trials Register, EudraCT number 2011-002545-35, and with the ISRCTN registry, number 43327231.",
"affiliations": "Early Phase Clinical Trials Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; National Cancer Institute, Vilnius, Lithuania.;Department of Dermatology, University Hospital Essen, West German Cancer Centre, University Duisburg-Essen, Essen, Germany; The German Cancer Consortium, Essen, Germany.;Department of Dermatology, University Hospital Essen, West German Cancer Centre, University Duisburg-Essen, Essen, Germany; The German Cancer Consortium, Essen, Germany.;Department of Oncology, Sheffield Experimental Cancer Medicine Centre, Weston Park Hospital, Sheffield, UK.;Department of Oncology, Clatterbridge Cancer Centre, Wirral, UK.;Department of Oncology, Addenbrookes Hospital, Cambridge, UK.;Department of Oncology, Southampton General Hospital, Southampton, UK.;Department of Oncology, Freeman Hospital, Newcastle upon Tyne, UK.;Köln Universitätsklinik, Köln, Germany.;Oncology Clinical Trials Office, University of Oxford, Oxford, UK.;Oncology Clinical Trials Office, University of Oxford, Oxford, UK.;Centre for Statistics in Medicine, University of Oxford, Oxford, UK.;Centre for Statistics in Medicine, University of Oxford, Oxford, UK.;Early Phase Clinical Trials Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Department of Oncology, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. Electronic address: mark.middleton@oncology.ox.ac.uk.",
"authors": "Urbonas|V|V|;Schadendorf|D|D|;Zimmer|L|L|;Danson|S|S|;Marshall|E|E|;Corrie|P|P|;Wheater|M|M|;Plummer|E|E|;Mauch|C|C|;Scudder|C|C|;Goff|M|M|;Love|S B|SB|;Mohammed|S B|SB|;Middleton|M R|MR|",
"chemical_list": "D007191:Indazoles; D011728:Pyridones; D011743:Pyrimidines; D011744:Pyrimidinones; D013449:Sulfonamides; C560077:trametinib; C516667:pazopanib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D017239:Paclitaxel",
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"doi": "10.1093/annonc/mdy500",
"fulltext": "\n==== Front\nAnn OncolAnn. OncolannoncAnnals of Oncology0923-75341569-8041Oxford University Press 10.1093/annonc/mdy500mdy500Original ArticlesMelanomaPaclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF melanoma (PACMEL): a multicentre, open-label, randomised, controlled phase II trial Urbonas V 12Schadendorf D 34Zimmer L 34Danson S 5Marshall E 6Corrie P 7Wheater M 8Plummer E 9Mauch C 10Scudder C 11Goff M 11Love S B 12Mohammed S B 12Middleton M R 1131 Early Phase Clinical Trials Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK2 National Cancer Institute, Vilnius, Lithuania3 Department of Dermatology, University Hospital Essen, West German Cancer Centre, University Duisburg-Essen, Essen, Germany4 The German Cancer Consortium, Essen, Germany5 Department of Oncology, Sheffield Experimental Cancer Medicine Centre, Weston Park Hospital, Sheffield, UK6 Department of Oncology, Clatterbridge Cancer Centre, Wirral, UK7 Department of Oncology, Addenbrookes Hospital, Cambridge, UK8 Department of Oncology, Southampton General Hospital, Southampton, UK9 Department of Oncology, Freeman Hospital, Newcastle upon Tyne, UK10 Köln Universitätsklinik, Köln, Germany11 Oncology Clinical Trials Office, University of Oxford, Oxford, UK12 Centre for Statistics in Medicine, University of Oxford, Oxford, UK13 Department of Oncology, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UKCorrespondence to: Prof. Mark R. Middleton, Department of Oncology, University of Oxford, NIHR Oxford Biomedical Research Centre, Headington, Oxford OX3 7LE, UK. Tel: +44-1865-617331; E-mail: mark.middleton@oncology.ox.ac.uk2 2019 14 11 2018 14 11 2018 30 2 Cerebrospinal fluid cell-free tumour DNA as a liquid biopsy for brain tumours317 324 © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nBackground\nAdvanced melanoma treatments often rely on immunotherapy or targeting mutations, with few treatment options for wild-type BRAF (BRAF-wt) melanoma. However, the mitogen-activated protein kinase pathway is activated in most melanoma, including BRAF-wt. We assessed whether inhibiting this pathway by adding kinase inhibitors trametinib or pazopanib to paclitaxel chemotherapy improved outcomes in patients with advanced BRAF-wt melanoma in a phase II, randomised and open-label trial.\n\nPatients and methods\nPatients were randomised (1 : 1 : 1) to paclitaxel alone or with trametinib or pazopanib. Paclitaxel was given for a maximum of six cycles, while 2 mg trametinib and 800 mg pazopanib were administered orally once daily until disease progression or unacceptable toxicity. Participants and investigators were unblinded. The primary end point was progression-free survival (PFS). Key secondary end points included overall survival (OS) and objective response rate (ORR).\n\nResults\nParticipants were randomised to paclitaxel alone (n = 38), paclitaxel and trametinib (n = 36), or paclitaxel and pazopanib (n = 37). Adding trametinib significantly improved 6-month PFS [time ratio (TR), 1.47; 90% confidence interval (CI) 1.08–2.01, P = 0.04] and ORR (42% versus 13%; P = 0.01) but had no effect on OS (P = 0.25). Adding pazopanib did not benefit 6-month PFS; (TR 1.36; 90% CI 0.96–1.93; P = 0.14), ORR, or OS. Toxicity increased in both combination arms.\n\nConclusion\nIn this phase II trial, adding trametinib to paclitaxel chemotherapy for BRAF-wt melanoma improved PFS and substantially increased ORR but did not impact OS.\n\nThis study was registered with the EU Clinical Trials Register, EudraCT number 2011-002545-35, and with the ISRCTN registry, number 43327231.\n\nphase IImelanomaBRAF wild-typepazopanibtrametinibOncology Clinical Trials OfficeGlaxoSmithKline10.13039/100004330Novartis10.13039/100004336UK National Cancer Research NetworkCancer Research UK10.13039/501100000289C2195/A14189\n==== Body\nKey Message\nOur study indicates that addition of trametinib to paclitaxel chemotherapy was associated with an improvement in progression-free survival and increase in overall response rate in patients with BRAF wild-type melanoma. As in the NEMO study, comparing binimetinib with dacarbazine in NRAS mutant melanoma, this did not translate into an overall survival benefit. It appears that MEK inhibitors have some activity in BRAF-wt melanoma, but that this is not sustained.\n\n\n\n\nIntroduction\nAlthough substantial progress has been achieved in the management of unresectable and metastatic melanoma, it remains a fatal disease. Impressive anticancer activity has been shown by kinase inhibitors, which target aberrant signalling in the 50% of melanomas with BRAF mutations, and antibodies that bind to the immune checkpoints cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed death 1 (PD1) [1–3]. However, melanoma patients with wild-type BRAF (BRAF-wt) have fewer treatment choices, as they do not benefit from BRAF inhibitor therapy. \n\nExtracellular-signal-regulated kinase (ERK) is constitutively active in all melanoma, irrespective of its mutation status [4]. ERK is part of the mitogen-activated protein kinase (MAPK) pathway, which is activated by an upstream kinase called MAPK kinase, or MEK. Activating ERK through the MAPK pathway promotes melanoma cell growth and resistance to taxane chemotherapy, the latter by inhibiting apoptosis [5]. In pre-clinical BRAF-wt melanoma models, co-administering a taxane and a MEK inhibitor substantially induces tumour regression and apoptosis [6, 7]. A clinical trial of the taxane docetaxel with the MEK inhibitor selumetinib reported a higher response rate than with chemotherapy alone [8].\n\nPazopanib is an orally bioavailable, multi-target tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 (VEGFR1, 2, 3), platelet-derived growth receptors α and β (PDGFR α and β), and stem cell factor receptor (c-KIT). As well as its antiangiogenic effects, pazopanib inhibits MEK and ERK activation at clinically relevant doses [9]. Trametinib is a reversible, highly selective, allosteric inhibitor of MEK1/2 activation. Both pazopanib and trametinib can safely be given with weekly paclitaxel chemotherapy at the full monotherapy dose and showed promising activity in BRAF-wt melanoma in early clinical studies [10].\n\nWe therefore undertook the PACMEL phase II trial to better assess the benefits and safety of adding trametinib or pazopanib to paclitaxel chemotherapy in BRAF-wt unresectable or metastatic melanoma. \n\nMethods\nParticipants\nThis randomised, multicentre phase II trial was conducted in 26 centres in the UK and Germany. Participants were 18 years or older with measurable unresectable BRAF-wt stage 3 or 4 melanoma, an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1, and acceptable haematological, renal, and hepatic function. Patients were excluded if they had received a prior MEK inhibitor or taxane, had grade ≥2 peripheral neuropathy, had undergone recent systemic therapy or radiotherapy, or had a recent history of another active malignancy. Patients with mucosal or ocular melanoma or with ocular disease that predisposed them to central serous retinopathy or retinal vein occlusion were excluded.\n\nThe study protocol was approved by the independent ethics committee or independent review board at each study centre. All patients provided written consent to participate before screening procedures. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.\n\nStudy design and treatment\nPACMEL phase II was an open-label, multicentre, and randomised trial that evaluated paclitaxel in combination with trametinib or pazopanib. Eligible patients were randomised 1 : 1 : 1 to receive single-agent paclitaxel or paclitaxel combined with trametinib or pazopanib, stratifying for NRAS mutation status, lactate dehydrogenase level (LDH; elevated versus within normal limits), and prior therapy for metastatic melanoma (yes versus no), using minimisation with a random element of 0.8. Randomisation was administered by a central trials unit to maintain allocation concealment. Participants, investigators, and outcome assessors were unblinded to treatment allocation.\n\nPaclitaxel (80 mg/m2 in the single-agent paclitaxel and paclitaxel–trametinib arms, 65 mg/m2 in the paclitaxel–pazopanib arm) was administered intravenously on days 1, 8, and 15 of each cycle for up to a maximum of six cycles. Trametinib (2 mg, determined during PACMEL phase I) or pazopanib (800 mg) were administered orally once daily until disease progression or unacceptable toxicity. Dose reductions of paclitaxel, trametinib, and pazopanib were permitted for toxicity.\n\nEnd points\nThe primary end point was progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Secondary end points included overall survival (OS), objective response rate (ORR), 6-month progression-free percentage, safety, and tolerability. Adverse events (AEs) were graded according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03.\n\nAssessments\nAt screening, prospective participants gave a medical history and underwent a full physical examination; ophthalmological evaluation; pregnancy test; 12-lead ECG; echocardiography; computed tomography (CT) of the head, chest, abdomen, and pelvis; urinalysis; haematology; coagulation and blood chemistry testing; and NRAS and BRAF mutation assessment.\n\nParticipants underwent a targeted physical assessment, AE documentation, urinalysis, and full blood chemistry and haematology testing before each paclitaxel dosing. Participants on trametinib or pazopanib underwent echocardiography at baseline and weeks 4 and 12, then every 12 weeks whilst on treatment. All participants underwent repeat CT assessments at weeks 7, 15, and 23, then every 3 months until disease progression. All participants underwent additional ophthalmological examination as clinically indicated.\n\nStatistical analysis\nWe planned to recruit 120 patients, randomised 1 : 1 : 1 to allow independent comparison of each combination arm with single-agent paclitaxel. PFS analysis was planned after 58 events in each comparison, giving 80% power to detect a hazard ratio of 0.57, with a one-sided α level of 0.10. Recruitment was significantly slower than anticipated, allowing a revised minimum of 104 patients to deliver the required number of events. All statistical analyses were pre-specified in the statistical analysis plan that was signed off before the data analysis.\n\nAll efficacy analyses were carried out on an intention-to-treat basis, analysing all randomised patients according to the treatment arm to which they were randomised. Median follow-up time was calculated using the reverse Kaplan–Meier method. Patients who withdrew consent for further follow-up were censored at the time of withdrawal.\n\nPFS was defined as the time from the date of randomisation to the date of progression or death from any cause, whichever came first. PFS at 6 months was defined as the Kaplan–Meier estimate percentage of participants who were progression-free at 6 months, with a 90% confidence interval (CI). Participants without an event were censored at the time of their last assessment. OS was defined as the time from the date of randomisation to the date of death. Participants without an event were again censored at the date of their last visit. ORR was defined as the best overall response for each participant, portrayed as the proportion of participants achieving a complete or partial response out of all randomised participants.\n\nThe PFS and OS were compared between treatment arms using Cox regression analysis, adjusting for the stratification variables. The proportional hazard assumption was then checked using Schoenfeld residuals. If the assumption was not met, then the Cox regression results were not considered valid and were not to be reported. Instead, the analysis used an accelerated failure time (AFT) model as specified in the Statistical Analysis Plan [11] (supplementary Figure S1, available at Annals of Oncology online) AFT results are reported as a time ratio (TR) with 90% CI.\n\nThe ORR was compared between treatment groups using the χ2 test and odds ratios. Safety analyses were carried out on patients who received at least one treatment dose. AEs grade ≥3 and serious AEs (SAEs) between treatment groups were compared using the χ2 test.\n\nA sensitivity analysis was carried out on the per-protocol population to examine the robustness of the intention-to-treat analysis conclusions. A sub-group analysis was planned comparing outcomes in the NRAS mutant and wild-type subgroups.\n\nSTATA v14.1 (StataCorp, College Station, TX) was used in all analyses. All reported P-values are two-sided for the primary and secondary analyses.\n\nResults\nParticipants and treatment\nBetween April 2012 and March 2016, 382 patients were considered for the trial at 26 sites in the UK and Germany. We randomised 111 patients to treatment (paclitaxel, n = 38, paclitaxel–trametinib, n = 36, and paclitaxel–pazopanib, n = 37). Although smaller than the calculated sample size, this sample provided the required number of events to achieve the power calculated and all 111 were included in the efficacy and safety analyses (Figure 1). The most common reasons for non-participation were patients declining to participate (85 patients), melanoma with BRAF mutation (33 patients), evidence of brain metastases (33 patients), and uncontrolled co-morbidities (15 patients). Participant demographics and baseline clinical characteristics (Table 1) were well balanced across the three arms. Most (64%) of the patients were treatment-naïve.\nTable 1. Patient characteristics at baseline \n\nCharacteristics\tPaclitaxel (n = 38)\tPaclitaxel+trametinib (n = 36)\tPaclitaxel+pazopanib (n = 37)\t\nAge, years, median (range)\t64 (35–80)\t60 (27–80)\t66 (41–80)\t\nGender male, n (%)\t27 (71)\t23 (64)\t25 (68)\t\nEthnicity, n (%)\t\n White\t35 (92)\t33 (92)\t34 (92)\t\n Other ethnic groups\t2 (5)\t2 (6)\t2 (5)\t\n Not given\t1 (3)\t1 (3)\t1 (3)\t\nECOG performance score, n (%)\t\n 0\t21 (55)\t23 (64)\t25 (68)\t\n 1\t17 (45)\t13 (36)\t12 (32)\t\nDisease stage at entry, n (%)\t\n IV\t38 (100)\t34 (94)\t34 (92)\t\n Unresectable stage III\t0 (0)\t2 (6)\t3 (8)\t\nStratification variables, n (%)\t\n Prior therapy\t13 (34)\t12 (33)\t14 (38)\t\n LDH within normal range\t19 (50)\t18 (50)\t18 (49)\t\n NRAS mutant\t14 (37)\t14 (39)\t18 (49)\t\nn, number of patients in a group; LDH, lactate dehydrogenase; ECOG, Eastern Cooperative Oncology Group.\n\n\n\nFigure 1. CONSORT diagram. \n\nPaclitaxel was given for a median 3, 6, and 4 cycles as a single agent, with trametinib, and with pazopanib, respectively. Six cycles of paclitaxel treatment were completed by 19% of participants as a single agent, 42% in the paclitaxel–trametinib arm, and 20% in the paclitaxel–pazopanib arm. The main reasons for discontinuing paclitaxel treatment were progressive disease (62% single-agent paclitaxel, 49% paclitaxel–trametinib, and 43% paclitaxel–pazopanib) and toxicity (8% single-agent paclitaxel, 6% paclitaxel–trametinib, and 32% paclitaxel–pazopanib). The inhibitor agent was taken for more than 4 months by 17 (47%) participants on trametinib and 11 (30%) participants on pazopanib.\n\nEfficacy\nAfter 95 events, the median PFS was 3.4 months (90% CI 2.0–3.8) with paclitaxel alone, 5.2 months (90% CI 3.7–7.0) with paclitaxel and trametinib, and 5.3 months (90% CI 3.4–6.4) with paclitaxel and pazopanib (Table 2). There were more than 58 events in each of the pairwise comparisons, as required for the calculated power.\nTable 2. Summary of clinical outcomes by treatment arm\n\nEnd point\tPaclitaxel (n = 38)\tPaclitaxel+trametinib (n = 36)\tPaclitaxel+pazopanib (n = 37)\t\nProgression-free survival (months)\t\nMedian duration (90% CI)\t3.4 (2.0–3.8)\t5.2 (3.7–7.0)\t5.3 (3.4–6.4)\t\nTRa (90% CI)\t1.0\t1.47 (1.08–2.01) P = 0.04\t1.36 (0.96–1.93) P = 0.14\t\nProgression-free survival rate at 6 months\t\nPercentage (90% CI)\t27 (16–40)\t39 (26–52) P = 0.27\t41 (28–55) P = 0.18\t\nOverall survival (months)\t\nMedian duration (90% CI)\t10.8 (8.8–not reached)\t9.4 (8.3–13.5)\t11.6 (8.0–16.2)\t\nTR (90% CI)\t\t0.71 (0.44–1.11) P = 0.18\t0.87 (0.71–1.09) P = 0.34\t\nResponse to treatment\t\nComplete response\t2\t0\t0\t\nPartial response\t3\t15\t8\t\nStable disease\t13\t11\t16\t\nProgressive disease\t13\t6\t9\t\nNot evaluated\t7\t4\t4\t\nDuration of responseb (months)\t\nMedian duration (90% CI)\t3.8 (0.6–not reached)\t3.6 (1.9–6.6)\t4.6 (3.1–5.5)\t\nORRc, n (%)\t5 (13)\t15 (42) P = 0.01\t8 (22) P = 0.34\t\nOdds ratio (90% CI)\t1.0\t4.7 (1.7–13.2) P = 0.01\t1.82 (0.6–5.2) P = 0.34\t\nAll P-values reported are two-sided; P-value <0.1 was considered to be significant.\n\na As the Cox model did not fit, the accelerated failure time model was used, as required in the analysis plan, giving time ratios. A TR above 1 implies that the covariate prolongs the time to event.\n\nb Median duration of response from Kaplan–Meir graph of time from best overall response (whether complete or partial response) to relapse or death.\n\nc ORR, the best overall response for each patient portrayed as the proportion of achieving complete response or partial response out of patients randomised.\n\nCI, confidence interval; TR, time ratio; OR, odds ratio; n, number of patients in a group; ORR, objective response rate.\n\n\n\nA Cox regression was run for the PFS analysis and the proportional hazard assumption checked. As the assumption failed, Cox regression was not considered a valid method here and the results are not reported. Following the pre-specified statistical analysis plan, an AFT model was used instead to analyse PFS. PFS was significantly longer in the paclitaxel–trametinib arm than in single-agent paclitaxel (TR 1.47; 90% CI 1.08–2.01; two-sided P = 0.04). There was no difference in PFS between the paclitaxel–pazopanib and single-agent paclitaxel arms (TR 1.36; 90% CI 0.96–1.93; two-sided P = 0.14) (Figure 2A; Table 2).\n\n\nFigure 2. Kaplan–Meier curve for (A) progression-free survival and (B) overall survival with the time ratio (TR) calculated using a log-logistic accelerated failure time model.\n\nORR was significantly higher with paclitaxel and trametinib than with single-agent paclitaxel (42% versus 13%, two-sided P = 0.01), but paclitaxel and pazopanib showed no improvement over single-agent paclitaxel (22% versus 13%, two-sided P = 0.34) (Table 2).\n\nThe PFS rates at 6 months were 27%, 39%, and 41% in the single-agent paclitaxel, paclitaxel–trametinib, and paclitaxel–pazopanib groups, respectively. There was no significant difference in 6-month PFS rate between the paclitaxel–trametinib and single-agent paclitaxel arms (two-sided P = 0.27) or the paclitaxel–pazopanib and single-agent paclitaxel arms (two-sided P = 0.18).\n\nAfter a median follow-up of 25.9 months (90% CI 20.1–32.9) and 66 deaths, the median OS was 10.8 months (90% CI 8.8–not reached) in the paclitaxel group, 9.4 months (90% CI 8.3–13.5) in the paclitaxel–trametinib group and 11.6 months (90% CI 8.0–16.2) in the paclitaxel–pazopanib group (Table 2). Due to the AFT model being required for PFS, it was also used for the OS analysis. The OS was not significantly different between the paclitaxel–trametinib and single-agent paclitaxel arms (TR 0.71; 90% CI 0.44–1.11; two-sided P = 0.18) or paclitaxel–pazopanib and single-agent paclitaxel arms (TR 0.87; 90% CI 0.70–1.09; two-sided P = 0.34) (Figure 2B; Table 2).\n\nA sensitivity analysis repeating all tests using the per-protocol population gave broadly similar results to the intention-to-treat population, so is not reported in detail. As samples sizes were too small for the planned subgroup analysis comparing outcomes in NRAS mutant and wild-type, the results are not reported here.\n\nSafety\nAll of the 111 randomised participants who received treatment were included in the safety analysis. Almost all (109, 98%) experienced an AE. Rash was more prevalent in participants taking trametinib. Transaminitis and altered taste were more prevalent in those on pazopanib. Participants who were assigned targeted therapy experienced anorexia more frequently. Grade 3 or higher AEs were recorded in 9 (24%) of the 38 patients in the single-agent paclitaxel group, 27 (75%) of the 36 patients in the paclitaxel–trametinib group, and 29 (78%) of the 37 patients in the paclitaxel–pazopanib group (Table 3). Nineteen (54%) participants receiving paclitaxel–pazopanib stopped taking pazopanib due to toxicities, whereas 6 (18%) participants receiving paclitaxel–trametinib stopped taking trametinib.\nTable 3. Incidence of treatment-related adverse events\n\nAEs\tPaclitaxel (n = 38)\tPaclitaxel+trametinib (n = 36)\tPaclitaxel+pazopanib (n = 37)\t\n\tn (%)\t\nAny grade AEs\t36 (95)\t36 (100)\t37 (100)\t\nGrade ≥3 AEs\t9 (24)\t27 (75)\t29 (78)\t\nFatal AEs\t0 (0)\t1 (4)\t2 (5)\t\nAE per patient for AEs affecting 15 or more patientsa,b\tn (n of grade 3 or more)\t\nRash\t6 (0)\t35 (14)\t9 (0)\t\nALT increased\t1 (0)\t2 (0)\t12 (9)\t\nFatigue\t19 (1)\t24 (4)\t18 (3)\t\nDyspnoea\t8 (1)\t10 (1)\t8 (2)\t\nAbdominal pain\t7 (0)\t11 (1)\t14 (2)\t\nDiarrhoea\t17 (0)\t24 (2)\t20 (1)\t\nNausea\t11 (0)\t12 (0)\t16 (1)\t\nAnaemia\t3 (0)\t6 (2)\t8 (0)\t\nAlopecia\t17 (1)\t13 (0)\t13 (0)\t\nAnorexia\t6 (0)\t13 (0)\t11 (0)\t\nConstipation\t11 (0)\t13 (0)\t2 (0)\t\nDysgeusia\t3 (0)\t4 (0)\t12 (0)\t\nDyspepsia\t7 (0)\t4 (0)\t4 (0)\t\nEpistaxis\t4 (0)\t9 (0)\t6 (0)\t\nHeadache\t2 (0)\t6 (1)\t7 (0)\t\nVomiting\t6 (0)\t5 (0)\t9 (0)\t\nCough\t8 (0)\t5 (0)\t5 (0)\t\na The AE terms are ranked according to the highest frequency of grade ≥3.\n\nb In any one row, a patient appears only once whether they had one episode of the AE or many.\n\nAE, adverse events measured by Common Terminology Criteria for Adverse Events V4.03; ALT, alanine aminotransferase; n, number of patients in a group.\n\n\n\nSeventy-two serious AEs (SAEs) were reported in 47 patients. The incidence of SAEs was higher when paclitaxel was combined with trametinib (47%) or pazopanib (67%) than when given alone (13%). Deaths during study treatment or within 35 days of the last study medication were reported for two participants on paclitaxel and pazopanib and one participant taking paclitaxel and trametinib. One participant in the paclitaxel–pazopanib arm died of pneumonia that was likely to have been related to paclitaxel-induced myelosuppression. Another participant in the same group died of bowel perforation related to disease progression, however, we were unable to exclude a contribution from pazopanib. One patient in the paclitaxel–trametinib arm died due to disease progression.\n\nDiscussion\nAlthough patients with BRAF-mutant melanoma have access to effective targeted treatments, these do not yet exist for BRAF-wt melanoma. Effective treatment options are urgently needed for patients with BRAF-wt melanoma, particularly those with rapidly progressive disease.\n\nAs melanoma is almost always associated with an activated MAPK pathway, even in tumours not driven by BRAF mutation, MEK inhibition is a promising therapeutic strategy. However, the activity of MEK inhibitors in BRAF-mutant melanoma has not been replicated in other genotypes [12]. Binimetinib showed an ORR of 20% and a median PFS of 4 months in BRAF-wt NRAS-mutant melanoma patients in a phase II trial [13]. However, in the randomised, phase III NEMO trial, the median PFS was only 2.8 months, ORR was 15%, and OS was not statistically significantly different from that achieved with dacarbazine chemotherapy [14].\n\nOur study showed superior PFS for paclitaxel and trametinib compared with paclitaxel chemotherapy alone. These results were obtained even though half of the patients had elevated LDH and nearly 40% a mutation in tumour NRAS, both of which are associated with poor prognosis. The outcomes with paclitaxel alone were consistent with published data from larger studies, providing evidence that the improvements seen in PFS and ORR when trametinib was added cannot be explained by poor performance in the control arm [15, 16].\n\nHowever, the significant difference in PFS did not translate into an improvement in OS. This is consistent with the modest durability of responses in all three study arms, at around 4 months. Post-progression treatment with immunotherapy may also have influenced this outcome. Most of the participants had not received prior systemic therapy, as there was limited availability of checkpoint inhibitors early in the life of this trial. The NEMO trial and a study of docetaxel with or without selumetinib in NRAS-mutant non-small-cell lung cancer also found a PFS advantage that did not yield an OS benefit [17]. Thus, the biological effects of MEK inhibition may be rapidly overcome by BRAF-wt tumours, perhaps due to the loss of negative feedback mechanisms under MEK inhibition.\n\nThe median PFS observed at 5.2 months when combining paclitaxel and trametinib was superior to that observed with binimetinib alone in phase II and III (NEMO) melanoma trials [13, 14]. The patient populations in the current study and NEMO trial were different, as we included patients with neither NRAS- nor BRAF-mutant melanoma. However, PACMEL included a higher proportion of participants with elevated LDH. The MEK inhibitor-chemotherapy combination regimen’s tolerability was similar to that of binimetinib alone, with 6 of the 33 (18%) participants discontinuing treatment because of toxicity in our paclitaxel–trametinib arm, compared with 20% of binimetinib-treated patients in the NEMO study.\n\nThe improved outcomes in the paclitaxel–trametinib arm came at the cost of more AEs than when using paclitaxel alone, with 75% of patients experienced a grade 3 or higher toxicity. The paclitaxel pazopanib combination also caused grade 3 or 4 AEs in three quarters of patients and over half of the participants had to discontinue treatment, mainly due to hepatotoxicity.\n\nIn conclusion, the PACMEL phase II trial found that adding the MEK inhibitor trametinib to paclitaxel chemotherapy significantly improved PFS and ORR in patients with BRAF-wt melanoma, but did not impact OS.\n\nSupplementary Material\nSupplementary Data Click here for additional data file.\n\n Acknowledgements\nWe would like to acknowledge the patients participating in the PACMEL study, and the investigators and institutions involved in this study. MRM is supported by the Oxford NIHR Comprehensive Biomedical Research Centre. We acknowledge English language editing by Jennifer A. de Beyer. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.\n\nFunding\nThe study was conducted by the Oncology Clinical Trials Office (OCTO) and the University of Oxford, and supported by an educational grant from GlaxoSmithKline/Novartis. Support in kind was provided by the UK National Cancer Research Network after endorsement by Cancer Research UK (grant number C2195/A14189). \n\nDisclosure\nDS has received honoraria and he has been as a member of the speaker bureaus for GSK, Roche, BMS, Amgen, Novartis, Merck/MSD. He has received research funding from Merck. LZ has received honoraria and he has had a consulting/advisory role for Roche, BMS, MSD, Novartis. SD has received honoraria from Amgen, BMS. She has had a consulting/advisory role for Incanthera. She has received research funding from Roche, BMS, Astra Zeneca, Lilly, Boehinger Ingelheim. PC has had a consulting/advisory role for Incyte, Novartis, BMS, MSD. She has been as a member of the speaker bureau for Novartis, MSD. MRM has received honoraria/grants from Amgen, Roche, AstraZeneca, Novartis, BMS, Merck, Eisai, Rigontec, Bioline, Array Biopharma. He has received study/research funding from Millenium, Immunocore, BMS, Vertex, Eisai, Pfizer, Merck, Rigontec, Regeneron, TCBiopharma, Array Biopharma, Replimune, Novartis, Astellas. VU, EM, MW, EP, CM, CS, MG, SBL, and SBM have declared no conflicts of interest.\n==== Refs\nReferences\n1 \nHodi FS , O'Day SJ , McDermott DF \net al\nImproved survival with Ipilimumab in patients with metastatic melanoma . N Engl J Med 2010 ; 363 (8 ): 711 –723 .20525992 \n2 \nLong GV , Stroyakovskiy D , Gogas H \net al\nCombined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma . N Engl J Med 2014 ; 371 (20 ): 1877 –1888 .25265492 \n3 \nRobert C , Long GV , Brady B \net al\nNivolumab in previously untreated melanoma without BRAF mutation . N Engl J Med 2015 ; 372 (4 ): 320 –330 .25399552 \n4 \nKortylewski M , Heinrich PC , Kauffmann ME \net al\nMitogen-activated protein kinases control p27/Kip1 expression and growth of human melanoma cells . Biochem J 2001 ; 357 (Pt 1 ): 297 –303 .11415463 \n5 \nTan TT , Degenhardt K , Nelson DA \net al\nKey roles of BIM driven apoptosis in epithelial tumors and rational chemotherapy . Cancer Cell 2005 ; 7 (3 ): 227 –238 .15766661 \n6 \nMacKeigan JP , Collins TS , Ting JP. \nMEK inhibition enhances paclitaxel-induced tumor apoptosis . J Biol Chem 2000 ; 275 (50 ): 38953 –38956 .11038347 \n7 \nMcDaid HH , Horwitz SB. \nSelective potentiation of paclitaxel (taxol)-induced cell death by mitogen-activated protein kinase inhibition in human cancer cell lines . Mol Pharmacol 2001 ; 60 (2 ): 290 –301 .11455016 \n8 \nGupta A , Love S , Schuh A \net al\nDOC-MEK: a double blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma . Ann Oncol 2014 ; 25 (5 ): 968 –974 .24567366 \n9 \nGril B , Palmieri D , Qian Y \net al\nThe B-Raf status of tumor cells may be a significant determinant of both antitumor and anti-angiogenic effects of pazopanib in xenograft tumor models . PLoS One 2011 ; 6 (10 ): e25625 .21998674 \n10 \nKendra KL , Plummer R , Salgia R \net al\nA multicenter phase I study of pazopanib in combination with paclitaxel in first-line treatment of patients with advanced solid tumors . Mol Cancer Ther 2015 ; 14 (2 ): 461 –469 .25504632 \n11 \nBradburn MJ , Clark TG , Love SB \net al\nSurvival analysis part II: multivariate data analysis—an introduction to concepts and methods . Br J Cancer 2003 ; 89 (3 ): 431 –436 .12888808 \n12 \nFlaherty KT , Robert C , Hersey P \net al\nImproved survival with MEK inhibition in BRAF-mutated melanoma . N Engl J Med 2012 ; 367 (2 ): 107 –114 .22663011 \n13 \nAscierto PA , Schadendorf D , Berking C \net al\nMEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study . Lancet Oncol 2013 ; 14 (3 ): 249 –256 .23414587 \n14 \nDummer R , Schadendorf D , Ascierto PA \net al\nBinimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicenter, open-label, randomised, phase 3 trial . Lancet Oncology 2017 ; 18 (4 ): 435 –445 .28284557 \n15 \nRibas A , Puzanov I , Dummer R \net al\nPembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial . Lancet Oncol 2015 ; 16 (8 ): 908 –918 .26115796 \n16 \nWalker L , Schalch H , King DM \net al\nPhase II trial of weekly paclitaxel in patients with advanced melanoma . Melanoma Res 2005 ; 15 (5 ): 453 –459 .16179874 \n17 \nJanne PA , Shaw AT , Pereira JR \net al\nSelumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study . Lancet Oncol 2013 ; 14 (1 ): 38 –47 .23200175\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0923-7534",
"issue": "30(2)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "BRAF wild-type; melanoma; pazopanib; phase II; trametinib",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007191:Indazoles; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009154:Mutation; D017239:Paclitaxel; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf; D011728:Pyridones; D011743:Pyrimidines; D011744:Pyrimidinones; D013449:Sulfonamides; D015996:Survival Rate",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "317-324",
"pmc": null,
"pmid": "30428063",
"pubdate": "2019-02-01",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "12888808;11038347;22663011;20525992;11455016;16179874;26115796;21998674;25504632;23200175;25399552;28284557;24567366;23414587;11415463;25265492;15766661",
"title": "Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF melanoma (PACMEL): a multicentre, open-label, randomised, controlled phase II trial.",
"title_normalized": "paclitaxel with or without trametinib or pazopanib in advanced wild type braf melanoma pacmel a multicentre open label randomised controlled phase ii trial"
} | [
{
"companynumb": "GB-PFIZER INC-2019231215",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "Alkylglycerol monooxygenase (AGMO) is the only enzyme known to cleave the O-alkyl bonds of ether lipids (alkylglycerols) which are essential components of cell membranes. A homozygous frameshift variant [p.(Glu324LysfsTer12)] in AGMO has recently been reported in two male siblings with syndromic microcephaly. In this study, we identified rare nonsense, in frame deletion, and missense biallelic variants in AGMO in two unrelated individuals with neurodevelopmental disabilities. We assessed the activity of seven disease associated AGMO variants including the four variants identified in our two affected individuals expressed in human embryonic kidney (HEK293T) cells. We demonstrated significantly diminished enzyme activity for all disease-associated variants, supporting the mechanism as decreased AGMO activity. Future mechanistic studies are necessary to understand how decreased AGMO activity leads to the neurologic manifestations.",
"affiliations": "Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.;Institute of Biological Chemistry, Biocenter, Center for Chemistry and Biomedicine (CCB), Medical University of Innsbruck, 6020, Innsbruck, Austria.;Department of Pediatrics, Ochsner Clinic, New Orleans, LA, 70394, USA.;Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.;Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.;Department of Anesthesiology and Critical Care Medicine, Medical University of Innsbruck, 6020, Innsbruck, Austria.;Institute of Biological Chemistry, Biocenter, Center for Chemistry and Biomedicine (CCB), Medical University of Innsbruck, 6020, Innsbruck, Austria. ernst.r.werner@i-med.ac.at.;Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA. wkc15@columbia.edu.",
"authors": "Okur|Volkan|V|;Watschinger|Katrin|K|;Niyazov|Dmitriy|D|;McCarrier|Julie|J|;Basel|Donald|D|;Hermann|Martin|M|;Werner|Ernst R|ER|;Chung|Wendy K|WK|",
"chemical_list": "D006899:Mixed Function Oxygenases; C020678:glyceryl-ether monooxygenase",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00439-019-02065-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-6717",
"issue": "138(11-12)",
"journal": "Human genetics",
"keywords": null,
"medline_ta": "Hum Genet",
"mesh_terms": "D000483:Alleles; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases; D009154:Mutation; D065886:Neurodevelopmental Disorders; D011379:Prognosis",
"nlm_unique_id": "7613873",
"other_id": null,
"pages": "1259-1266",
"pmc": null,
"pmid": "31555905",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25675482;23441072;17303893;20643956;25954001;28586473;25047030;28796901;22220568;29741738;27000257",
"title": "Biallelic variants in AGMO with diminished enzyme activity are associated with a neurodevelopmental disorder.",
"title_normalized": "biallelic variants in agmo with diminished enzyme activity are associated with a neurodevelopmental disorder"
} | [
{
"companynumb": "AT-TEVA-2020-AT-1178902",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": "1",
... |
{
"abstract": "To examine survival outcomes of women with recurrent cervical cancer who received salvage chemotherapy with modified dose-dense paclitaxel (MDDP) monotherapy (paclitaxel 80 mg/m, administered on day 1, 8, and 15 without day 22).\n\n\n\nA retrospective study was conducted to evaluate cause-specific survival after the first recurrence (SAR) of women with recurrent cervical cancer diagnosed between 2006 and 2014. Pooled analyses were performed to examine SAR in women who received MDDP monotherapy (n=17) for any treatment line, compared with those who received salvage chemotherapy with paclitaxel-doublet (n=18) and nonpaclitaxel regimens (n=52).\n\n\n\nIn the whole cohort, median SAR was 13.7 months including 63 (72.4%) events. MDDP monotherapy regimen was most commonly used in the second-line setting (35.3%) followed by the third/fourth lines (both, 23.5%). Among the women who received MDDP regimen, there were 6 (35.3%) women who received ≥6 cycles; there was 1 (5.9%) women who discontinued the regimen due to adverse effects (grade 3 transaminitis); regimen postponement was seen in 2 (1.4%) of 140 total cycles; and the response rate after the sixth cycle of this regimen was 29.4% (1 complete and 4 partial responses). On univariate analysis, MDDP usage had the highest 2-year SAR rate (MDDP 54.1%, paclitaxel-doublet 43.6%, and nonpaclitaxel regimens 28.1%; Ptrend=0.044). On multivariate analysis, MDDP monotherapy remained an independent prognostic factor for improved SAR compared with the nonpaclitaxel regimen (adjusted-hazard ratio, 0.50; 95% confidence interval, 0.26-0.95; P=0.036).\n\n\n\nOur results suggested that MDDP monotherapy is a tolerable and relatively effective regimen for recurrent cervical cancer.",
"affiliations": "Department of Obstetrics and Gynecology, Division of Gynecologic Oncology.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology.;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology.",
"authors": "Machida|Hiroko|H|;Moeini|Aida|A|;Ciccone|Marcia A|MA|;Mostofizadeh|Sayedamin|S|;Takiuchi|Tsuyoshi|T|;Brunette|Laurie L|LL|;Roman|Lynda D|LD|;Matsuo|Koji|K|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1097/COC.0000000000000394",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "41(9)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic; D002294:Carcinoma, Squamous Cell; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D011379:Prognosis; D012189:Retrospective Studies; D016879:Salvage Therapy; D015996:Survival Rate; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "851-860",
"pmc": null,
"pmid": "28763329",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19097774;21293244;22735789;15904950;22317951;23948349;23108141;24582486;25446609;11230468;26197856;19720909;8622025;16622463;9311440;25310856;12051877;9053486;19738606;26933849;23515621;7835768;21514632;16803500;2910782;10561341;25638326;12185296;26474517;14766258;17947786;25732161;1623479;16894366;17330854;15911865;10586332;21145100;24552320;10071264;1526855;23552805;18303437;26049123;16333028;19457937;19509587;19268342;26742998;27350404;15284262;19367689;17380438;22437870;10850285;25096168;10600285;3802384;20606531;10446995",
"title": "Efficacy of Modified Dose-dense Paclitaxel in Recurrent Cervical Cancer.",
"title_normalized": "efficacy of modified dose dense paclitaxel in recurrent cervical cancer"
} | [
{
"companynumb": "US-PFIZER INC-2017282710",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nIn the 1950s, a high-dose (40-70 mg/kg/day) of pyrazinamide (PZA), was reported to cause drug-induced liver injury (DILI) at an unacceptable frequency. It remains unclear whether adding PZA (Z) at the currently accepted low-dose (20-25 mg/kg/day) for two months to a regimen of isoniazid (H) + rifampicin (R) + ethambutol (E) actually increases the risk of DILI.\n\n\nMETHODS\nSmear-positive tuberculosis patients were treated with daily HRE or HRZE regimen under direct observation. We used three independent models. Model 1 was analyzed with a multivariate Cox-analysis using a pre-matched cohort. Next, propensity score matching was conducted using the nearest neighbor method with caliper of 0.03. Models 2 and 3 were analyzed by univariate and multivariate Cox-analyses, respectively, with the matched cohort. DILI was assessed based on the guidelines of the American Thoracic Society.\n\n\nRESULTS\nWe reviewed the records of 383 patents (male, n=260; female n=123; mean age, 64±20 years). Among these patients, 75 patients were treated with HRE and 308 were treated with HRZE. DILI occurred in the first two months in 24% (18/75) and 8% (24/308) of the HRE-treated and HRZE-treated cases, respectively. In all three of the models, DILI was less frequent in patients treated with the HRZE regimen: Model 1, HR of 0.30 (95% confidence interval (CI) 0.14-0.68, p=0.004); Model 2, HR of 0.37 (95%CI 0.14-0.96, p=0.041); and Model 3, HR of 0.34 (95%CI 0.12-0.94, p=0.038).\n\n\nCONCLUSIONS\nThe addition of the currently accepted low dose (20-25 mg/kg/day) of PZA to the HRE regimen did not increase the incidence of DILI during the first two months of treatment.",
"affiliations": "Department of Pulmonology, Yokohama City University Graduate School of Medicine, Japan.",
"authors": "Horita|Nobuyuki|N|;Miyazawa|Naoki|N|;Yoshiyama|Takashi|T|;Kojima|Ryota|R|;Ishigatsubo|Yoshiaki|Y|;Kaneko|Takeshi|T|",
"chemical_list": "D000995:Antitubercular Agents; D011718:Pyrazinamide",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.5533",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "54(18)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000995:Antitubercular Agents; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017410:Practice Guidelines as Topic; D057216:Propensity Score; D011718:Pyrazinamide; D016896:Treatment Outcome; D014376:Tuberculosis",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2315-20",
"pmc": null,
"pmid": "26370854",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Currently Used Low-Dose Pyrazinamide Does Not Increase Liver-Injury in the First Two Months of Tuberculosis Treatment.",
"title_normalized": "currently used low dose pyrazinamide does not increase liver injury in the first two months of tuberculosis treatment"
} | [
{
"companynumb": "JP-SA-2015SA145884",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional": null,
"dru... |
{
"abstract": "Neuroblastoma (NB) is the most common extra-cranial malignancy in preschool children. To portray the genetic landscape of an overly aggressive NB leading to a rapid clinical progression of the disease, tumor DNA collected pre- and post-treatment has been analyzed. Array comparative genomic hybridization (aCGH), whole-exome sequencing (WES), and pharmacogenetics approaches, respectively, have identified relevant copy number alterations (CNAs), single nucleotide variants (SNVs), and polymorphisms (SNPs) that were then combined into an integrated analysis. Spontaneously formed 3D tumoroids obtained from the recurrent mass have also been characterized. The results prove the power of combining CNAs, SNVs, and SNPs analyses to assess clonal evolution during the disease progression by evidencing multiple clones at disease onset and dynamic genomic alterations during therapy administration. The proposed molecular and cytogenetic integrated analysis empowers the disease follow-up and the prediction of tumor recurrence.",
"affiliations": "Laboratory of Target Discovery and Biology of Neuroblastoma, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, C.so Stati Uniti 4, 35127 Padova, Italy.;Bioinformatics Core Service, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, C.so Stati Uniti 4, 35127 Padova, Italy.;Laboratory of Target Discovery and Biology of Neuroblastoma, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, C.so Stati Uniti 4, 35127 Padova, Italy.;Laboratory of Target Discovery and Biology of Neuroblastoma, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, C.so Stati Uniti 4, 35127 Padova, Italy.;Advanced Diagnostics and Target Discovery in Rare Pediatric Solid Tumors, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, C.so Stati Uniti 4, 35127 Padova, Italy.;Pediatric Hematology, Oncology, and Stem Cell Transplant Center, Department of Woman's and Child's Health, University of Padova, Via Gustiniani 3, 35128 Padova, Italy.;Pediatric Hematology, Oncology, and Stem Cell Transplant Center, Department of Woman's and Child's Health, University of Padova, Via Gustiniani 3, 35128 Padova, Italy.;Clinical Genetics Unit, Department of Woman's and Child's Health, University of Padova, Via Gustiniani 3, 35128 Padova, Italy.;Clinical Genetics Unit, Department of Woman's and Child's Health, University of Padova, Via Gustiniani 3, 35128 Padova, Italy.;Pathology Department, Medical School, University of Valencia-INCLIVA, 46010 Valencia, Spain.;Pathology Department, Medical School, University of Valencia-INCLIVA, 46010 Valencia, Spain.;Pharmacogenetics Unit, Instituto Investigación Sanitaria La Fe and Department Pharmacology, University of Valencia, Avda. Fernando Abril Martorell 106, 46026 Valencia, Spain.;Pharmacogenetics Unit, Instituto Investigación Sanitaria La Fe and Department Pharmacology, University of Valencia, Avda. Fernando Abril Martorell 106, 46026 Valencia, Spain.;Pediatric Hematology, Oncology, and Stem Cell Transplant Center, Department of Woman's and Child's Health, University of Padova, Via Gustiniani 3, 35128 Padova, Italy.;Pediatric Hematology, Oncology, and Stem Cell Transplant Center, Department of Woman's and Child's Health, University of Padova, Via Gustiniani 3, 35128 Padova, Italy.;Laboratory of Target Discovery and Biology of Neuroblastoma, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, C.so Stati Uniti 4, 35127 Padova, Italy.",
"authors": "Corallo|Diana|D|;Zanon|Carlo|C|;Pantile|Marcella|M|;Tonini|Gian Paolo|GP|;Zin|Angelica|A|0000-0002-7104-273X;Francescato|Samuela|S|;Rossi|Bartolomeo|B|;Trevisson|Eva|E|0000-0002-5380-6265;Pinato|Claudia|C|;Monferrer|Ezequiel|E|;Noguera|Rosa|R|0000-0003-4546-7459;Aliño|Salvador F|SF|;Herrero|Maria Jose|MJ|0000-0002-6042-4185;Biffi|Alessandra|A|;Viscardi|Elisabetta|E|;Aveic|Sanja|S|0000-0002-3886-4360",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/cells10102695",
"fulltext": "\n==== Front\nCells\nCells\ncells\nCells\n2073-4409\nMDPI\n\n10.3390/cells10102695\ncells-10-02695\nCase Report\nIntegrated CGH/WES Analyses Advance Understanding of Aggressive Neuroblastoma Evolution: A Case Study\nCorallo Diana 1†\nZanon Carlo 2†\nPantile Marcella 1\nTonini Gian Paolo 1\nhttps://orcid.org/0000-0002-7104-273X\nZin Angelica 34\nFrancescato Samuela 4\nRossi Bartolomeo 4\nhttps://orcid.org/0000-0002-5380-6265\nTrevisson Eva 5\nPinato Claudia 5\nMonferrer Ezequiel 6\nhttps://orcid.org/0000-0003-4546-7459\nNoguera Rosa 6\nAliño Salvador F. 7\nhttps://orcid.org/0000-0002-6042-4185\nHerrero Maria Jose 7\nBiffi Alessandra 4\nViscardi Elisabetta 4\nhttps://orcid.org/0000-0002-3886-4360\nAveic Sanja 18*\nCarriero Maria Vincenza Academic Editor\n1 Laboratory of Target Discovery and Biology of Neuroblastoma, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, C.so Stati Uniti 4, 35127 Padova, Italy; d.corallo@irpcds.org (D.C.); m.pantile@irpcds.org (M.P.); gp.tonini@irpcds.org (G.P.T.)\n2 Bioinformatics Core Service, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, C.so Stati Uniti 4, 35127 Padova, Italy; c.zanon@irpcds.org\n3 Advanced Diagnostics and Target Discovery in Rare Pediatric Solid Tumors, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, C.so Stati Uniti 4, 35127 Padova, Italy; angelica.zin@unipd.it\n4 Pediatric Hematology, Oncology, and Stem Cell Transplant Center, Department of Woman’s and Child’s Health, University of Padova, Via Gustiniani 3, 35128 Padova, Italy; sam.francescato@gmail.com (S.F.); bart.rossi@gmail.com (B.R.); alessandra.biffi@unipd.it (A.B.); elisabetta.viscardi@unipd.it (E.V.)\n5 Clinical Genetics Unit, Department of Woman’s and Child’s Health, University of Padova, Via Gustiniani 3, 35128 Padova, Italy; eva.trevisson@unipd.it (E.T.); claudia.pinato@iov.veneto.it (C.P.)\n6 Pathology Department, Medical School, University of Valencia-INCLIVA, 46010 Valencia, Spain; ezequiel.mo.ga@gmail.com (E.M.); Rosa.Noguera@uv.es (R.N.)\n7 Pharmacogenetics Unit, Instituto Investigación Sanitaria La Fe and Department Pharmacology, University of Valencia, Avda. Fernando Abril Martorell 106, 46026 Valencia, Spain; alino@uv.es (S.F.A.); Maria.Jose.Herrero@uv.es (M.J.H.)\n8 Department of Dental Materials and Biomaterials Research, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany\n* Correspondence: s.aveic@irpcds.org; Tel.: +39-049-9640124\n† Equally contributing authors.\n\n09 10 2021\n10 2021\n10 10 269512 9 2021\n06 10 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nNeuroblastoma (NB) is the most common extra-cranial malignancy in preschool children. To portray the genetic landscape of an overly aggressive NB leading to a rapid clinical progression of the disease, tumor DNA collected pre- and post-treatment has been analyzed. Array comparative genomic hybridization (aCGH), whole-exome sequencing (WES), and pharmacogenetics approaches, respectively, have identified relevant copy number alterations (CNAs), single nucleotide variants (SNVs), and polymorphisms (SNPs) that were then combined into an integrated analysis. Spontaneously formed 3D tumoroids obtained from the recurrent mass have also been characterized. The results prove the power of combining CNAs, SNVs, and SNPs analyses to assess clonal evolution during the disease progression by evidencing multiple clones at disease onset and dynamic genomic alterations during therapy administration. The proposed molecular and cytogenetic integrated analysis empowers the disease follow-up and the prediction of tumor recurrence.\n\nNeuroblastoma\nrecurrent tumor\narray CGH\nclonal evolution\nwhole exome sequencing\n3D tumoroids\nsingle nucleotide variants\npharmacogenetics\n==== Body\npmc1. Introduction\n\nNeuroblastoma (NB) is an embryonal tumor of the developing sympathetic nervous system [1]. The primary tumors can show a broad spectrum of biological, genetic, and morphological characteristics that make NB one of the most heterogeneous malignancies in children [2]. A search for the genes involved in NB development has revealed a very low number of somatic mutations in primary tumors [3], while the exact cause of NB onset remains unknown. Nevertheless, next generation sequencing has increased the knowledge about NB heterogeneity, improved patients’ risk stratification, and opened new avenues for tailored therapies [4].\n\nOther events such as segmental (e.g., partial chromosome deletions, gains, and amplifications) and numerical (e.g., gain or loss of the entire chromosomes) chromosomal alterations (SCA and NCA, respectively) are closely associated with NB aggressiveness [5]. According to their detected cytogenetic abnormalities, their age at diagnosis, the tumor stage, and their histological characteristics, patients with NB can be stratified into high risk (HR, 50% of all cases), intermediate risk (IR), and low and very low risk (LR) groups [6]. Tumor characteristics strongly correlate with the type of chromosomal aberration, with the prevalence of SCA in HR, and NCA in LR and IR patients [7]. With a prevalence of around 20%, genomic amplification of the MYCN gene (MNA) is one of the most frequent SCAs [8], and the histopathologic evaluation of MYCN gene status provides the information required for both patient stratification and treatment protocol assignment [9].\n\nArray comparative genomic hybridization (aCGH) is a gold standard methodology for the analysis of chromosome integrity. Along with fluorescence in situ hybridization, aCGH analysis is a powerful tool for detecting genomic alterations [10]. In NB, allelic losses at chromosomes 1p, 3p, 4p, and 11q, and gains of chromosomes 1q, 2p, and 17q predict poor patient outcomes [11]. Concomitantly, immunohistochemistry (IHC) is a diagnostic tool used to target neural cell adhesion molecule (e.g., NCAM, or CD56) expressing NB cells [12], while CD133 has been associated with cancer stem cell phenotype and chemoresistance in MNA NB [13]. Along with the extracellular matrix (ECM) composition of NB tumors [14], CD133 is proposed as an additional factor that is able to delineate a group of patients with a very poor prognosis. All of these parameters define the clinical portrait of the patient and inevitably influence the incidence of relapses (5–15% in LR/IR cases; ≥50% in HR patients with an overall survival rate of <10%) [15].\n\nIn this study, we performed an integrated analysis of aCGH and whole-exome sequencing (WES) data on the genetic material obtained from a rapidly progressing form of NB tumor collected at different time points during the patient’s treatment. Pharmacogenetics was employed to analyze the germline single nucleotide polymorphisms (SNPs) in genes encoding metabolism-related enzymes and drug targets [16] while correlating them with the therapeutic efficacy of the administered drugs. Collectively, genomic, cytogenetic, pharmacogenetics, and biological information have been integrated to assess the molecular rationale for the observed clinical evolution of the analyzed NB and a rapid disease progression.\n\n2. Materials and Methods\n\n2.1. Patient Information, Tumor Sample Collection, and Primary Cells Maintenance\n\nThe informed consent approving the patient-derived material included in the study was obtained from the parents. The case study was conducted following the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Padua, Italy (Prot. n. 0009761). Malignant tissue samples were obtained by thru cut or after surgical removal and immediately processed according to the type of the study as schematically presented in Figure 1a. Single tumor cells were obtained from recurrent (REC) tumor material after mechanical dissociation and enzymatic digestion (30 min at 37 °C in the digestion medium composed of DMEM/F-12, DNAse (1 mg/mL; Sigma-Aldrich; Milan, Italy)) and collagenase/dispase (1 mg/mL, Roche; Indianapolis, IN, USA), passed through the cell strainer cap (BD Falcon, BD Biosciences; Heidelberg, Germany), and placed in serum-free KnockOut™ DMEM/F-12 medium (Gibco; Milan, Italy) supplemented with 1× B27, 1× N2, bFGF (20 ng/mL, all from Gibco; Milan, Italy), and EGF (20 ng/ml, Cell Guidance Systems; Cambridge, UK) growth factors. A density of 200,000 cells/mL was used for the sphere formation assay to assess the capacity of obtained tumor cells to self-renew after dissociating with TripLE (Gibco; Milan, Italy) [17]. Short-term primary cell cultures allowed for the selection of auto-formed spheroids that were subsequently grown for 30 days without biomimetic ECM support, and 30 days after embedding in Matrigel.\n\n2.2. Histological and Immunohistochemical Analyses\n\nThe tumoroids were fixed in 4% paraformaldehyde after 60 days of in vitro growth, embedded in paraffin, cut into 7 μm sections, and then subjected to hematoxylin and eosin (H&E) staining according to standard protocols [18]. Immunohistochemistry (IHC) analysis was performed with the following antibodies: mouse monoclonal anti-human CD56 (1:100, SC Biotechnology; Heidelberg, Germany); rabbit polyclonal anti-human CD133 (1:100, Novus Biologicals; Abingdon, UK); rabbit polyclonal anti-human TH (1:100, Cusabio; Houston, TX, USA); rabbit polyclonal anti-human Vitronectin (VT; 1:100, Abcam; Cambridge, UK); rabbit polyclonal anti-human MYCN (1:200, Cusabio; Houston, TX, USA). IHC stains were done manually after an antigen retrieval step (PT Link instrument, Agilent; Santa Clara, CA, USA). All images were acquired with a Zeiss Axio Observer microscope (Oberkochen, Germany).\n\n2.3. DNA Extraction, Library Construction, and WES\n\nGenomic DNA (gDNA) was extracted from peripheral blood lymphocytes (PBL) using a QIAmp DNA Mini Kit (Qiagen; Hilden, Germany), while the DNA from the primary tumor (PT), resected residual PT mass (RES), REC tumor, and REC-3D tumoroids were processed using spin filter columns (Invisorb® Spin Tissue Mini Kit, Stratec Molecular GmbH; Berlin, Germany) according to the manufacturers’ protocols. Total gDNA was quantified using a Qubit® dsDNA HS assay (Qubit® 2.0 Fluorometer, Life Technologies; Monza, Italy) and 150 ng were processed by the DNA fragmentation assay (Covaris Model M220, Woburn; MA, USA). The exome library was prepared with the SureSelectXT HS Target Enrichment System (Illumina Paired-End Multiplexed Sequencing Library), subsequently loaded onto an Illumina Next Seq 500/550 High Output Flow Cell Cartridge v2.5 (Illumina; San Diego, CA, USA), and processed with the Illumina Next Seq 500/550. The mean coverage of 100× for PBL and 360× for tumors allowed us to thoroughly explore the variants in malignant tissues. The most frequent ALK gene mutations (F1174L and R1275Q), and several randomly selected variants verified by WES, were additionally checked by Sanger sequencing using standard lab protocols [19]. Primers are listed in Supplementary Table S1.\n\n2.4. WES Analysis\n\nWES data fastq files were pre-processed with fastp v0.20.0 to remove low-quality stretches of bases at both ends of short reads and then aligned to the reference human genome (hg19) using bwa v0.7.12-r1039 with default options. Allele counts, base calling, and somatic mutation detection were performed using custom scripts based on Samtools v1.3.1. Candidate driver mutations and functional variants were identified using several functional prediction algorithms included in the Annovar software v2018Apr16 and then visually inspected with Samtools ‘tview’.\n\n2.5. aCGH Analysis\n\naCGH was performed on gDNA extracted from PBL, PT, REC, and REC-3D deriving tissue samples. gDNA integrity was additionally assessed on an Agilent 2100 bioanalyzer. aCGH was carried out using the SurePrint G3 Human CGH Microarray 8 × 60 K kit (approximately 60,000 oligonucleotide probes; median probe space 41 kb throughout the genome) (Agilent Technologies; Santa Clara, CA, USA). Control DNA (Promega; Madison, WI, USA) was used as the reference. The arrays were analyzed through an Agilent scanner (G2505C) and Feature Extraction software V.10.1.1.1. A graphical overview of the results was performed using the ‘base’ R statistical software package. DNA sequence information refers to the public UCSC database (Human Genome Browser, February 2009, assembly hg19 (NCBI Build 37.1)).\n\n2.6. Pharmacogenetics Study\n\nFor the pharmacogenetic study, 1000 µg of DNA was used to genotype all the SNPs included in Supplementary Table S2, in triplicate, using mass spectrometry with MassARRAY device (Agena Bioscience; San Diego, CA, USA) according to the manufacturer’s instructions. The genotyping service was carried out at CEGEN-PRB3-ISCIII. The design of the SNPs included in the panel, the risk assignment for each variant, and the results report are called the VIP Onco study, which is a registered innovation by ©Aliño SF, Herrero MJ Universitat de València/IIS La Fe/HUP La Fe. In brief, the SNPs included in the analysis were chosen according to their relationship with the efficacy and/or toxicity of the drugs most widely employed for pediatric solid tumors, based in PharmGKB (www.pharmgkb.org, accessed on 1 September 2019), drug regulatory agencies (mainly Food and Drug administration, FDA, and European Medicines Agency, EMA), and international pharmacogenetics implementation consortia (mainly Clinical Pharmacogenetics Implementation Consortium, CPIC, and Dutch Pharmacogenomics Working group, DPWG). Only those SNP–drug pairs with the highest levels of evidence were selected to be included in the panel.\n\n2.7. Statistical and Clonal Analysis\n\nThe statistical analyses and visualizations were performed with R statistical software v3.5.2: packages ‘base’ and ‘stats’ for the common statistical tests; ‘prcomp’ for Principal Component Analysis (PCA); ‘dbscan’ for cluster identification; ‘graphics’, ‘riverplot’ and ‘fishplot’ for clonal composition and evolution modeling; and visualization, ‘euler’, for Venn-Euler plot. Bedtools v.2.25.0 was used for mapping features on genomic intervals.\n\n3. Results\n\n3.1. Case Description\n\nA two-year-old child was hospitalized with symptoms of fever, stomach pain, and constipation. An abdominal mass of a hard consistency was revealed by palpation and magnetic resonance, and irregular margins were present at the left hemi-abdomen with extension up to 2–3 cm below the transverse umbilical line (Supplementary Figure S1a). The presence of a retroperitoneal primary mass (12 × 11 × 8.5 cm) containing inhomogeneous fat and calcifications zones resulted in the dislocation of the left kidney and aorta toward the right side. aCGH was performed on DNA extracted from the PT typifying a gain of 17q, a loss of 11q, while an MNA was not found (Supplementary Figure S1b). The former chromosomal alterations are recognized as a marker of poor prognosis in NB [20]. Histologically, the tumor was poorly differentiated with intense mitotic karyorrhexis index positivity. No metaiodobenzylguanidine uptake was reported and no sign of disseminated NB cells was observed in the bone marrow (BM) biopsy or BM aspirate (data not shown). An evaluation of other clinical parameters gave the following values: HVA/Cr (417 mmol/mol), VMA/Cr (208 mmol/L), elevated ferritin and NSE levels, and hypertension (180/90 mmHg). Based on the clinical and histological evaluation, the tumor was classified as L2 stage.\n\nDuring induction chemotherapy, the patient was treated with a rapid COJEC according to the Society For Pediatric Oncology European Neuroblastoma HR-NBL-1 protocol [21] that led to substantial tumor mass reduction and overall improvement of the clinical parameters and general patient’s condition. Subsequently, RES mass (post-COJEC) was collected for the analysis after surgical intervention, while the patient’s clinical and biological data advised the introduction of the European Low and Intermediate Risk Neuroblastoma Protocol (LINES; NCT01728155). After an excellent initial response to the administered therapy, rapid disease progression occurred leading to uncontrolled tumor growth and the patient’s demise. Considering the peculiarity of the clinical course of the disease, we investigated the genetic background that sustained poor response to adopted treatment and disease recurrence.\n\n3.1.1. The 3D In Vitro Study\n\nTo explore whether the aggressive malignant cell behavior was maintained in vitro, the tumor material obtained from the REC mass (post-LINES) was used for the cell expansion ex vivo (Figure 1a). The sphere formation assay sustained the intrinsic self-renewal property of the 3D structures and implied for cancer stem cells’ presence (Figure 1b). After three weeks of culture, pre-dissociated single cells maintained the capability to form spheroids spontaneously (Figure 1c), and during the following 30 days established compact 3D structures. To explore their invasive capacities, we embedded them in the biomimetic ECM (Figure 1d). Two days after the embedding, a clear invasive cell front developed around the spheroid body. Radially organized cell extrusions were formed progressively occupying the entire volume of free ECM and served as a leading trail for a single cell migration, corroborating their pro-invasive features (Supplementary Figure S1c). Such behavior led to the in vitro tumor outgrowth and the generation of thick tumoroid-like structures (named REC-3D) (Figure 1d). Histological evaluations of the tumor mass collected after 60 days of in vitro growth confirmed that the REC-3D tumoroids displayed features of poorly differentiated/differentiating neuroblasts (Figure 1e) with positive immunoreactivity for CD56, tyrosine hydroxylase (TH), and particularly for the CD133 stem cell marker (Figure 1f).\n\nMoreover, a high rate of accumulated intracellular VN abundantly expressed in the ECM of aggressive NB [22] was present, highlighting the pro-invasive capabilities of the tumor cells. Notably, positive immunoreactivity toward MYCN proteins was detected in the REC-3D tumoroids, implying its triggered MYCN overexpression during the therapy course. Intriguingly, accelerated in vitro growth of tumor cells anticipated the clinical manifestation of the disease progression.\n\n3.1.2. Genomic Analyses\n\nThe aCGH analysis showed that the genome of all the tested specimens shared some common events along with acquiring new alterations during the disease progression. Circulating tumor DNA of approximately 166bp length (data not shown) was not traced in PBL which showed a euploid profile (Supplementary Figure S1b). Diverse CNAs were detected in the DNA obtained from PT, REC, and REC-3D samples suggesting for the genome instability. Numerous chromosomes (3, 6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 20, and 22) were found altered in the PT and during the disease progression (such as losses: 3p, 6q, 11q, 22q, and gains: 7q, 15q, 17q) (Figure 2a). Among these alterations, a loss in 11q is particularly remarkable since it generated a nullisomy of ATM, a gene involved in DNA repair. The REC and REC-3D acquired a partial gain in 2p, affecting the regions including MYCN, and two atypical SCAs (loss of 3p and gain of 16q). The gain in 2p was confirmed by quantitative PCR (qPCR) analysis (Supplementary Table S1), thus explaining the observed MYCN protein overexpression (Figure 1f). Genome-wide CNA profiles showed a high correlation between REC and REC-3D, with both sharing key attributes with PT (Pearson correlation coefficient: 0.95; r2: 0.90), thus indicating that the tumoroid structures maintained the essential copy number features of the parental tumor but attained additional rearrangements such as 17p and 19 losses.\n\nTo pursue the possibility of an existent predisposition toward the observed modest efficacy of intensive chemotherapy and radiation, we performed a pharmacogenetics investigation detecting risk alleles in 23/61 SNPs related to drugs currently used in pediatric oncology (for a complete list of the SNPs, see Supplementary Table S2). Several SNPs in the PBL were potentially relevant for the final response to the COJEC and LINES protocols. The same SNPs were confirmed by WES analysis (bold capital letters; Table 1), thus reinforcing the possibility to evaluate the pharmacogenetics risk alleles in tumor-derived material.\n\nAn extended analysis on the RES and REC tumor material showed additional variations worsening the SNPs risk pattern. In addition, WES pointed out the risk alleles with frequencies of 5–10% possibly involved in defining the type of response to therapy (bold lowercase letters; Table 1). These findings imply a probable cumulative burden of the SNPs (Supplementary Table S3) that could lead to a limited response to therapy.\n\nTo assess the mutational profile of the malignant tissue, WES analysis was performed on DNA from PBL, PT, RES, REC, and REC-3D. A total of 30 somatic variants were identified, most of which were shared among tumor samples (Figure 2b): 11 in PT, 11 in RES, 22 in REC, and 29 in REC-3D (Tables S4 and S5). Twenty-two mutations were exonic (17 non-synonymous, five synonymous), seven intronic/intergenic, and one was confirmed in the 5′UTR. The most frequent ALK mutations (F1174L and R1275Q) were not found in any of the analyzed specimens (data not shown). Several heterozygous germline variants that showed frequency shifts among samples were validated by Sanger sequencing (Supplementary Table S1).\n\nBy applying the Uniform Manifold Approximation and Projection approach (UMAP) to CNAs identified by aCGH across PBL, PT, REC, and REC-3D (WES-derived segments are highly correlated with aCGH data, thus giving remarkably similar outcomes), we identified clusters of distinctive genomic segments (Figure 2c) with coordinated ploidy switches in recurrent samples (Figure 2d and Supplementary Figure S1d). The coordinated allele frequencies’ shifts in germline SNPs suggest their connection to CNAs fluctuations, envisaging a scenario with a selection of deleterious alleles upon numerical imbalances including those that are copy-neutral. This prompted us to attempt an integrated CNA–SNV modeling of the tumor clonal composition and dynamics considering the interplay between all the identified genomic alterations. By combining the inferred CNAs- and SNVs-derived clonal models, we obtained a synthesis of the possible mass composition and clonal evolution (Figure 2e and Supplementary Figure S1e) while taking into consideration the allele frequency changes of variants characterizing each evolving clone (Figure 2f). The synthetic model foresees the presence of six key clones, hereafter named after single genes harboring specific variants, including four nested ones originating in PT, three persisting in all tumor samples and characterized by variants in CDKN2A, ALDH18A1, and TGFBR3, respectively, while the fourth with a change in ALDH1B1 was not detected in REC-3D (Figure 2e). Then, two independent clones featuring somatic variants arose in the REC sample and propagated to REC-3D: one identified by a mutation in SMARCAL1 and nested in the TGFBR3 background, while the second harbored within the ALDH18A1 clone with mutations in the SWSAP1 gene (Figure 2e,f). Notably, the nonsynonymous rare germline alleles (minor allele frequencies ranging between 0.01% and 5%) in ALDH18A1 [23], CDKN2A [24], TGFBR3 [25], and ALDH1B1 genes had predicted unfavorable effects on protein function and were previously associated with NB, indicating a possible role for an underlying oligogenic mechanism [26]. Altogether, the combination of aCGH and WES data allowed the shortlisting of the putative causal variants required for clone selection within the tumor.\n\n4. Discussion\n\nThe therapeutic approaches currently used in the treatment of HR patients with NB unfortunately show limited effectiveness stemming from an insufficient understanding of the biology of the disease [27]. The huge heterogeneity among NB tumors demands a more accurate and detailed diagnosis able to identify smaller, more clinically homogeneous groups of patients or individuals so to tailor more specific and more effective therapeutic regimens.\n\nThe possibility of analyzing more specimens from the same patient during the disease course allows for a more complete follow-up of the clinical progression [28]. Advances made in the performing standards, and economically sustainable diagnostic analyses such as aCGH, allow for the detection of small chromosomal imbalances reaching a greater resolution when compared to cytogenetic analyses [29]. In our research, the analysis of aCGH data alone or in combination with the WES recognized a driver in chromosomal alterations spanning the time window between the diagnosis and disease recurrence. By considering the intermediate time points of the disease progression, and the 3D tumoroid structures spontaneously formed from a recurrent tumor mass, we were able to explore the NB clones and define the related dynamics of their evolution during the treatment. By unveiling the combinations of copy number imbalances in the PT, REC, and REC-3D ex vivo tumor material, while correlating them with germinal SNPs and somatic variants, we achieved new insights into the nature of developing tumor masses. Some of the reported genomic alterations were atypical (a loss of 3pq and gain of 16q), while others were already reported for their hazardous potentials such as the gain of 2p and the loss of 11q and 6q [30]. The loss of chromosome 11q harboring the ATM gene is frequently seen in tumors without MNA and is an unfavorable prognostic marker for the patients [20]. The recognition of novel alterations as strong clinical risk group classifiers is the key step toward developing new modes of targeted therapy. In the analyzed case, aCGH was instrumental in revealing the dynamics of the disease progression during therapy.\n\nBased on the aCGH/WES data, we discovered that most of the recurrent clones emerged early during the disease progression and persisted throughout the therapy treatment while being flanked by new somatic variants. The synchronous involvement of CNAs and germinal SNPs frequency fluctuations, including those which were copy-neutral and exceedingly rare, suggests an initial generation of clonal diversity that is mainly driven by imbalances affecting disadvantageous alleles. Such mechanisms could also explain part of the observed multidrug resistance, as the pharmacogenetics results strongly suggest. Additional newly arising somatic SNVs at relapse could have helped in determining the outcome. The most frequent mutations in the ALK gene were not found, excluding the genetic burden toward this tyrosine kinase. Pharmacogenetics analyses provided an advanced snapshot of the patient’s response to chemotherapy, suggesting the strong predictive potential of this method in clinical routine. The pharmacogenetics approach also revealed a particular result of interest: the patients bore the AA genotype at SNP rs1801133 in the MTHFR gene in the PBL sample but also in all the other specimens analyzed by WES. This variant has been previously linked with MNA [31], and although the actual causal link is not yet clear, it is remarkable that while this patient originally had a non-MNA primary tumor, after the chemotherapy resistance a gain of the 2p locus with MYCN gene also occurred.\n\nThe present study allowed us to better comprehend the genomic abnormalities that occurred during the disease progression. With more articulated aCGH analysis, we were also able to determine the clonal heterogeneity and to follow the ongoing evolution of the candidate genetic lesions during the patient’s cure. The high rate of chromosomal instability and the acquired mutations found in the recurrent mass correlated with an unfavorable clinical picture, with the observed rapid tumor progression, with the aggressiveness, and with the drug-resistant phenotypes [5]. In fact, the results of our study sustain the possibility of achieving an improved prognosis by more systematic genome analysis. Moreover, they affirm that we might be able to anticipate the disease progression by studying in vitro culture behavior and by longitudinally analyzing the DNA imbalances. The most intriguing feature of the 3D tumoroids was the observed burst of the in vitro growth that anticipated a dramatic escalation of the disease clinical presentation.\n\n5. Conclusions\n\nCollectively, we have showed that besides providing information on CNAs, aCGH may be instrumental, upon the integration with mutational information, in refining the clonal dynamics that allow for an improved disease progression monitoring.\n\nAcknowledgments\n\nThe authors would like to thank Fondazione Italiana per la Lotta al Neuroblastoma, Fondazione Umberto Veronesi, and Fondazione Città della Speranza for their support.\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/cells10102695/s1. Supplementary figure legends. Figure S1. Data summary. (a) Computed tomography (CT) images at the moment of diagnosis. Yellow circles indicate localized tumor mass on the dorsal and ventral sections of the CT scans. (b) aCGH profile of the PT at the moment of diagnosis and the corresponding PBL. (c) Invasive cell front developed around the spheroid body. Radially organized fibers that serve as a leading trail for a single cell migration are marked with white arrows. Scale bar, 100 µm. (d) Dot plot of the segmented log2r aCGH values in the REC vs. REC-3D samples (log2r scales at the bottom and left, ploidy scales at the top and right). Each segmented value is color-coded according to the CNAs derived UMAP clustering of Figure 2b. (e) aCGH whole-genome profiles of the PT, REC, and REC-3D tumor material. Chromosome names on top and log2 of tumor/normal signal intensities ratio on the Y-axis. Log2r values averaged across 50 kb overlapping windows are represented by black dots, while their segmented values represent CNAs derived UMAP clusters with the same color code used in Figure 2b. Supplementary Table Legends. Table S1. List of primers used in this paper for real-time qPCR and Sanger sequencing. Table S2. Pharmacogenetics analysis. Summary of the SNPs currently correlated with response to the most frequently used antineoplastic drugs (according to PharmGKB 1 and 2 levels of evidence in Clinical Annotations; Drug Labels; and Guidelines from Pharmacogenetics International Experts Consortia). Table S3. Cumulative effects of SNPs in tumor specimens. Protocols used to treat the patient are listed. Final genotype numbers are a sum of all risk genotypes found in the samples analyzed by WES. Brackets indicate that risk genotype was found in <5% of risk-related alleles. Table S4. WES data. Excel spreadsheet with summary information on somatic mutations identified by WES. Table S5. WES data. Excel spreadsheet with detailed information on germline variants identified by WES.\n\nClick here for additional data file.\n\nAuthor Contributions\n\nConceptualization, S.A.; methodology, M.P., D.C., A.Z., C.P. and M.J.H.; software, C.Z. and M.J.H.; validation, D.C., A.Z. and M.P.; formal analysis, C.Z., C.P., B.R. and E.T.; investigation, E.V.; resources, S.A., M.J.H., A.B., R.N. and E.M.; data curation S.F., E.V. and S.F.A.; writing—original draft preparation, S.A., C.Z. and D.C.; writing—review and editing, G.P.T., R.N., S.F., S.F.A., A.B. and E.V.; visualization, C.Z. and D.C.; supervision, S.A.; funding acquisition, S.A., M.J.H., R.N. and E.M. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research was funded by the following grants: Fundación Mutua Madrileña-Ayudas a la Investigación Científica en Salud 2016 and Asociación Pablo Ugarte (M.J.H); 20/11 FCR funded by Fondazione CARIPARO (S.A.); 2018/150 from the Asociación Fundación Española contra el Cáncer, JAP-AECC (E.M.); and PI20/01107 of the ISCIII (FIS) and FEDER (European Regional Development Fund) (R.N.).\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the “Progetti e Ricerca Clinica Azienda Ospedale” from the University of Padua (Prot. n. 0009761; 15/2/2021).\n\nInformed Consent Statement\n\nInformed consent was obtained from the parents of the patient prior to the study.\n\nData Availability Statement\n\nThe datasets generated during the study are available from the corresponding author upon request.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Tumor collection and immunophenotypic characterization. (a) Scheme of the tumor tissue processing for molecular biology analyses and ex vivo cell cultivation. (b) Three-step procedure of sphere formation assay. Bright field shows sphere formed upon single-cell plating. Scale bar, 500 µm. (c) Spontaneously formed spheroids in a petri dish (I and II, top panel) and their single view (white dashed insets). Higher magnifications of the formed 3D structures can be seen in the bottom panels ((a) and (b)). Scale bars, 500 μm. (d) Bright field images of the spontaneously formed spheroids embedded in Matrigel. A time-lapse image was performed until day 30 after embedding. Daily extension of cell invasion frontier from the tumoroid body edge was measured until day 4 (protrusion length is indicated in µm). Growth of the main tumoroid’s body was assessed until day 7 (total area intensity was measured with Fiji and is presented in Arbitrary Units). Scale bar, 500 μm. (e) Representative H&E staining of the paraffin-embedded tumoroids. Higher magnifications of different regions of the same tumoroid are indicated (black dashed insets). Scale bar, 200 μm. (f) Representative IHC stainings of the paraffin-embedded tumoroids. Sections were stained for CD56 (NCAM), TH (tyrosine hydroxylase), CD133 (prominin-1), Vitronectin (VN) and MYCN (N-myc) proteins. A stage IV, MYCN single copy NB primary tumor was used as a negative control for specific MYCN staining. Scale bar, 100 μm.\n\nFigure 2 Analysis of tumor specific genetic alterations during disease progression. (a) Whole-genome array comparative genomic hybridization (aCGH) profiles of the primary tumor biopsy (PT), recurrent disease (REC), and 3D tumoroids deriving from REC material (REC-3D). Chromosome names on top and log2 of tumor/normal signal intensities ratio on the Y-axis. Log2r values averaged across 50 kb overlapping windows are represented by black dots, while their segmented values represent gains (red), losses (green), and no change (blue). (b) Euler diagram indicates the number of somatic mutations identified in each sample (PT, RES, REC, and REC-3D). (c) UMAP clustering of segmented log2r values analyzed across PT, REC, and REC-3D samples. (d) Dot plot of the segmented log2r aCGH values in the PT vs. REC-3D samples (log2r scales at the bottom and left, ploidy scales at the top and right); each segmented value is color-coded according to the CNAs-derived UMAP clustering of panel b. (e) Fish plot of clonal analysis based on germinal and somatic SNVs (WES) stratified by the CNAs-derived (aCGH) UMAP clusters. The treatment scheme is emphasized on top along with the temporal window harboring the MYCN gain. Prominent genes were singled out to identify each evolving clone. (f) Allele frequency changes of variants characterizing each evolving clone across the analyzed samples.\n\ncells-10-02695-t001_Table 1 Table 1 SNPs correlated with drug resistance. The asterisk highlights drugs included in the treatment protocols adopted for the patient. Bold capital letters indicate the presence of the risk SNPs alleles found in the analyzed samples (a lowercase letter indicates the additional change of the allele observed by WES with the frequency <5%). Note: The genetic variants included in this study represent SNPs. The chosen SNPs and the recommendations provided are based on the highest scientific level of evidence (1 and 2) according to Pharmacogenetics Knowledge Base (PharmGKB), drug regulatory agencies (FDA, EMA), and international pharmacogenetics consortia (mainly CPIC and DPWG). (www.pharmgkb.org, accessed on 1 September 2019).\n\n\t\tGenotypes\tSNP Array\tWES\t\nDrug\tGene\tSNP\tNO\nRisk\tRisk\tPBL\tPBL\tPT\tRES\tREC\tREC-3D\t\nAzathioprine\tTPMT\trs1800462\tCC\tCG,GG\tCC\tCC\tCC\tCC\tCC\tCC\t\nTPMT\trs1800584\tCC\tCT,TT\tCC\tCC\tCC\tCC\tCC\tCC\t\nTPMT\trs1142345\tTT\tTC,CC\tTT\tTT\tTT\tTT\tTT\tTT\t\nTPMT\trs1800460\tCC\tCT,TT\tCC\tCC\tCC\tCC\tCC\tCC\t\nNUDT15\trs116855232\tCC\tCT,TT\tCC\tCC\tCC\tCC\tCC\tCC\t\nCarboplatin *\tERCC1\trs11615\tGG\tAG,AA\tAA\tAA\tAA\tAA\tAA\tAA\t\nERCC1\trs3212986\tAA\tAC,CC\tCC\t\t\t\t\t\t\nGSTP1\trs1695\tGG\tAG,AA\tAA\tAA\tAA\tAA\tAA\tAA\t\nMTHFR\trs1801133\tAA\tAG,GG\tAA\tAA\tAA\tAA\tAA\tAA\t\nNQO1\trs1800566\tGG\tAG,AA\tAG\t\t\t\t\t\t\nXRCC1\trs25487\tCC\tCT,TT\tCC\t\t\tCC\t\t\t\nCyclophosphamide *\tGSTP1\trs1695\tAA,AG\tGG\tAA\tAA\tAA\tAA\tAA\tAA\t\nSOD2\trs4880\tAA\tAG,GG\tGG\t\tGG\tGG\ta-GG\tGG\t\nTP53\trs1042522\tCC\tCG,GG\tCC\tCC-g\tCC-g\tCC-g\tCC-g\tCC-g\t\nCisplatin *\tERCC1\trs11615\tGG\tAG,AA\tAA\tAA\tAA\tAA\tAA\tAA\t\nERCC1\trs3212986\tAA\tAC,CC\tCC\t\t\t\t\t\t\nGSTP1\trs1695\tGG\tAG,AA\tAA\tAA\tAA\tAA\tAA\tAA\t\nMTHFR\trs1801133\tAA\tAG,GG\tAA\tAA\tAA\tAA\tAA\tAA\t\nNQO1\trs1800566\tGG\tAG,GG\tAG\t\t\t\t\t\t\nTP53\trs1042522\tCC\tCG,GG\tCC\tCC-g\tCC-g\tCC-g\tCC-g\tCC-g\t\nTPMT\trs1800462\tCC\tCG,GG\tCC\tCC\tCC\tCC\tCC\tCC\t\nTPMT\trs1800584\tCC\tCT,TT\tCC\tCC\tCC\tCC\tCC\tCC\t\nTPMT\trs1142345\tTT\tTC,CC\tTT\tTT\tTT\tTT\tTT\tTT\t\nTPMT\trs1800460\tCC\tCT,TT\tCC\tCC\tCC\tCC\tCC\tCC\t\nXRCC1\trs25487\tCC\tCT,TT\tCC\t\t\t\t\t\t\nXPC\trs2228001\tTT\tGT,GG\tTT\t\t\t\t\t\t\nDoxorubicin *\tNQO1\trs1800566\tGG\tAG,GG\tAG\t\t\t\t\t\t\nEtoposide *\tDYNC2H1\trs716274\tAA\tAG,GG\tAG\t\t\t\t\t\t\nOpioids\tABCB1\trs1045642\tAA,AG\tGG\tAG\tAG\tg-AG\tg-AG\tAG\tg-AG\t\nIrinotecan\tC8orf34\trs1517114\tGG\tCG,CC\tGG\t\t\t\t\t\t\nSEMA3C\trs7779029\tTT\tCT,CC\tTT\t\t\t\t\t\t\nUGT1A1\trs4148323\tGG\tGA,AA\tGG\tGG\tGG\tGG\tGG\tGG\t\nMercaptopurine\tTPMT\trs1800462\tCC\tCG,GG\tCC\tCC\tCC\tCC\tCC\tCC\t\nTPMT\trs1800584\tCC\tCT,TT\tCC\tCC\tCC\tCC\tCC\tCC\t\nTPMT\trs1142345\tTT\tTC,CC\tTT\tTT\tTT\tTT\tTT\tTT\t\nTPMT\trs1800460\tCC\tCT,TT\tCC\tCC\tCC\tCC\tCC\tCC\t\nNUDT15\trs116855232\tCC\tCT,TT\tCC\tCC\tCC\tCC\tCC\tCC\t\nMethotrexate\tABCB1\trs1045642\tGG\tAG,AA\tAG\tAG\tg-AG\tg-AG\tAG\tg-AG\t\nSLCO1B1\trs11045879\tCC\tCT,TT\tCT\t\t\t\t\t\t\nMTHFR\trs1801133\tGG\tAA,AG\tAA\t\tAA\tAA\tAA\tAA\t\nMTRR\trs1801394\tAA\tAG,GG\tGG\tGG\ta-GG\tGG\tGG\ta-GG\t\nATIC\trs4673993\tCC,CT\tTT\tCT\t\t\t\t\t\t\nOndansetron\tABCB1\trs1045642\tAA\tAG,GG\tAG\tAG\tg-AG\tg-AG\tAG\tg-AG\t\nThioguanine\tTPMT\trs1800462\tCC\tCG,GG\tCC\tCC\tCC\tCC\tCC\tCC\t\nTPMT\trs1800584\tCC\tCT,TT\tCC\tCC\tCC\tCC\tCC\tCC\t\nTPMT\trs1142345\tTT\tTC,CC\tTT\tTT\tTT\tTT\tTT\tTT\t\nTPMT\trs1800460\tCC\tCT,TT\tCC\tCC\tCC\tCC\tCC\tCC\t\nNUDT15\trs116855232\tCC\tCT,TT\tCC\tCC\tCC\tCC\tCC\tCC\t\nVincristine *\tCEP72\trs924607\tCC,CT\tTT\tCC\t\t\t\t\t\t\n*—drugs included in the protocols used for the patient’s cure.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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BMC Cancer 2017 17 20 10.1186/s12885-016-2986-6 28056863\n6. Sokol E. Desai A. The Evolution of Risk Classification for Neuroblastoma Children 2019 6 27 10.3390/children6020027\n7. Janoueix-Lerosey I. Schleiermacher G. Michels E. Mosseri V. Ribeiro A. Lequin D. Vermeulen J. Couturier J. Peuchmaur M. Valent A. Overall Genomic Pattern Is a Predictor of Outcome in Neuroblastoma J. Clin. Oncol. 2009 27 1026 1033 10.1200/JCO.2008.16.0630 19171713\n8. Monclair T. Brodeur G.M. Ambros P.F. Brisse H.J. Cecchetto G. Holmes K. Kaneko M. London W.B. Matthay K.K. Nuchtern J.G. The International Neuroblastoma Risk Group (INRG) Staging System: An INRG Task Force Report J. Clin. Oncol. 2009 27 298 303 10.1200/JCO.2008.16.6876 19047290\n9. Ambros I.M. Benard J. Boavida M. Bown N. Caron H. Combaret V. Couturier J. Darnfors C. Delattre O. Freeman-Edward J. Quality Assessment of Genetic Markers Used for Therapy Stratification J. Clin. Oncol. 2003 21 2077 2084 10.1200/JCO.2003.03.025 12775732\n10. Scaruffi P. Coco S. Cifuentes F. Albino D. Nair M. Defferrari R. Mazzocco K. Tonini G.P. Identification and characterization of DNA imbalances in neuroblastoma by high-resolution oligonucleotide array comparative genomic hybridization Cancer Genet. Cytogenet. 2007 177 20 29 10.1016/j.cancergencyto.2007.05.002 17693187\n11. Maris J.M. Weiss M.J. Guo C. Gerbing R.B. Stram D.O. White P.S. Hogarty M.D. Sulman E.P. Thompson P.M. Lukens J.N. Loss of Heterozygosity at 1p36 Independently Predicts for Disease Progression But Not Decreased Overall Survival Probability in Neuroblastoma Patients: A Children’s Cancer Group Study J. Clin. Oncol. 2000 18 1888 1899 10.1200/JCO.2000.18.9.1888 10784629\n12. Park S.-J. Park C.-J. Kim S. Jang S. Chi H.-S. Kim M.J. Im H.-J. Seo J.-J. Detection of Bone Marrow Metastases of Neuroblastoma With Immunohistochemical Staining of CD56, Chromogranin A, and Synaptophysin Appl. Immunohistochem. Mol. Morphol. 2010 18 348 352 10.1097/PAI.0b013e3181d2ed4c 20216406\n13. Zhong Z.-Y. Shi B.-J. Zhou H. Wang W.-B. CD133 expression and MYCN amplification induce chemoresistance and reduce average survival time in pediatric neuroblastoma J. Int. Med. Res. 2018 46 1209 1220 10.1177/0300060517732256 29322842\n14. Tadeo I. Berbegall A.P. Castel V. García-Miguel P. Callaghan R. Påhlman S. Navarro S. Noguera R. Extracellular matrix composition defines an ultra-high-risk group of neuroblastoma within the high-risk patient cohort Br. J. Cancer 2016 115 480 489 10.1038/bjc.2016.210 27415013\n15. London W.B. Castel V. Monclair T. Ambros P.F. Pearson A.D.J. Cohn S.L. Berthold F. Nakagawara A. Ladenstein R.L. Iehara T. Clinical and Biologic Features Predictive of Survival After Relapse of Neuroblastoma: A Report From the International Neuroblastoma Risk Group Project J. Clin. Oncol. 2011 29 3286 3292 10.1200/JCO.2010.34.3392 21768459\n16. Olivera G. Sendra L. Herrero M.J. Berlanga P. Gargallo P. Yáñez Y. Urtasun A. Font de Mora J. Castel V. Cañete A. 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The randomised induction for high-risk neuroblastoma comparing COJEC and N5-MSKCC regimens: Early results from the HR-NBL1.5/SIOPEN trial J. Clin. Oncol. 2018 36 10507 10.1200/JCO.2018.36.15_suppl.10507\n22. Burgos-Panadero R. Noguera I. Cañete A. Navarro S. Noguera R. Vitronectin as a molecular player of the tumor microenvironment in neuroblastoma BMC Cancer 2019 19 479 10.1186/s12885-019-5693-2 31117974\n23. Guo Y.-F. Duan J.-J. Wang J. Li L. Wang D. Liu X.-Z. Yang J. Zhang H.-R. Lv J. Yang Y.-J. Inhibition of the ALDH18A1-MYCN positive feedback loop attenuates MYCN -amplified neuroblastoma growth Sci. Transl. Med. 2020 12 eaax8694 10.1126/scitranslmed.aax8694 32075946\n24. Carr-Wilkinson J. O’Toole K. Wood K.M. Challen C.C. Baker A.G. Board J.R. Evans L. Cole M. Cheung N.-K.V. Boos J. High Frequency of p53/MDM2/p14ARF Pathway Abnormalities in Relapsed Neuroblastoma Clin. Cancer Res. 2010 16 1108 1118 10.1158/1078-0432.CCR-09-1865 20145180\n25. Iolascon A. Giordani L. Borriello A. Carbone R. Izzo A. Tonini G.P. Gambini C. Ragione F. Della Reduced expression of transforming growth factor-beta receptor type III in high stage neuroblastomas Br. J. Cancer 2000 82 1171 1176 10.1054/bjoc.1999.1058 10735501\n26. Longo L. Tonini G.P. Ceccherini I. Perri P. Oligogenic inheritance in neuroblastoma Cancer Lett. 2005 228 65 69 10.1016/j.canlet.2004.12.052 15923081\n27. Esposito M.R. Aveic S. Seydel A. Tonini G.P. Neuroblastoma treatment in the post-genomic era J. Biomed. Sci. 2017 24 14 10.1186/s12929-017-0319-y 28178969\n28. Manica M. Kim H.R. Mathis R. Chouvarine P. Rutishauser D. De Vargas Roditi L. Szalai B. Wagner U. Oehl K. Saba K. Inferring clonal composition from multiple tumor biopsies NPJ Syst. Biol. Appl. 2020 6 27 10.1038/s41540-020-00147-5 32843649\n29. Kjeldsen E. Oligo-based high-resolution aCGH analysis enhances routine cytogenetic diagnostics in haematological malignancies Cancer Genom. Proteom. 2015 12 301 337\n30. Depuydt P. Boeva V. Hocking T.D. Cannoodt R. Ambros I.M. Ambros P.F. Asgharzadeh S. Attiyeh E.F. Combaret V. Defferrari R. Genomic Amplifications and Distal 6q Loss: Novel Markers for Poor Survival in High-risk Neuroblastoma Patients JNCI J. Natl. Cancer Inst. 2018 110 1084 1093 10.1093/jnci/djy022 29514301\n31. Olivera G.G. Yáñez Y. Gargallo P. Sendra L. Aliño S.F. Segura V. Sanz M.Á. Cañete A. Castel V. Font De Mora J. MTHFR and VDR Polymorphisms Improve the Prognostic Value of MYCN Status on Overall Survival in Neuroblastoma Patients Int. J. Mol. Sci. 2020 21 2714 10.3390/ijms21082714 32295184\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2073-4409",
"issue": "10(10)",
"journal": "Cells",
"keywords": "3D tumoroids; Neuroblastoma; array CGH; clonal evolution; pharmacogenetics; recurrent tumor; single nucleotide variants; whole exome sequencing",
"medline_ta": "Cells",
"mesh_terms": null,
"nlm_unique_id": "101600052",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34685674",
"pubdate": "2021-10-09",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't; D016428:Journal Article",
"references": "19047290;23334666;26543079;27500184;30754710;31117974;32075946;17693187;28178969;27823645;12775732;19171713;32295184;29514301;20216406;29322842;10735501;26121087;27415013;32843649;271968;16306521;21768459;17586306;28056863;20145180;10784629;15923081",
"title": "Integrated CGH/WES Analyses Advance Understanding of Aggressive Neuroblastoma Evolution: A Case Study.",
"title_normalized": "integrated cgh wes analyses advance understanding of aggressive neuroblastoma evolution a case study"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-292256",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"dru... |
{
"abstract": "Tumors with anaplastic lymphoma kinase (ALK) fusion rearrangements, including non-small-cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. Although mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, because of lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germline FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Monotherapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 mo treatment, the residual primary tumor shrunk, was surgically removed, and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 mo treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.",
"affiliations": "Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.;Department of Pathology and Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.;Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.;Childhood Cancer Research Unit, Department of Women's and Children's Health, and Pediatric Oncology Program Karolinska University Hospital, Stockholm 17176, Sweden.;Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.;Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.;Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.;Institute of Molecular Biology, Umeå University, Umeå 90187, Sweden.;Childhood Cancer Research Unit, Department of Women's and Children's Health, and Pediatric Oncology Program Karolinska University Hospital, Stockholm 17176, Sweden.;Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17176, Sweden.;Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17176, Sweden.;Department of Radiology, Karolinska University Hospital, Stockholm 17176, Sweden.;Department of Pediatric Radiology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm 17176, Sweden.;Department of Pediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm 17176, Sweden.;Department of Pediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm 17176, Sweden.;Department of Pediatrics and Pathology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.;Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.;Department of Pathology and Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.;Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.;Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17176, Sweden.;Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.",
"authors": "Guan|Jikui|J|0000-0003-1723-0307;Fransson|Susanne|S|0000-0002-9713-3074;Siaw|Joachim Tetteh|JT|0000-0002-1286-4485;Treis|Diana|D|;Van den Eynden|Jimmy|J|0000-0003-0002-5614;Chand|Damini|D|;Umapathy|Ganesh|G|;Ruuth|Kristina|K|;Svenberg|Petter|P|;Wessman|Sandra|S|;Shamikh|Alia|A|;Jacobsson|Hans|H|;Gordon|Lena|L|;Stenman|Jakob|J|;Svensson|Pär-Johan|PJ|;Hansson|Magnus|M|;Larsson|Erik|E|;Martinsson|Tommy|T|0000-0002-9403-3123;Palmer|Ruth H|RH|0000-0002-2735-8470;Kogner|Per|P|0000-0002-2202-9694;Hallberg|Bengt|B|0000-0003-2032-2616",
"chemical_list": "C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013450:Sulfones; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C586847:ceritinib",
"country": "United States",
"delete": false,
"doi": "10.1101/mcs.a002550",
"fulltext": "\n==== Front\nCold Spring Harb Mol Case StudCold Spring Harb Mol Case StudcshmcscshmcscshmcsCold Spring Harbor Molecular Case Studies2373-2873Cold Spring Harbor Laboratory Press 10.1101/mcs.a002550MCS002550GuaResearch ArticleClinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib Clinical response to ceritinib in ALK-positive neuroblastomaClinical response to ceritinib in ALK-positive neuroblastomahttp://orcid.org/0000-0003-1723-0307Guan Jikui 1212http://orcid.org/0000-0002-9713-3074Fransson Susanne 312http://orcid.org/0000-0002-1286-4485Siaw Joachim Tetteh 112Treis Diana 412http://orcid.org/0000-0003-0002-5614Van den Eynden Jimmy 1Chand Damini 1Umapathy Ganesh 1Ruuth Kristina 5Svenberg Petter 4Wessman Sandra 67Shamikh Alia 67Jacobsson Hans 8Gordon Lena 9Stenman Jakob 10Svensson Pär-Johan 10Hansson Magnus 11Larsson Erik 1http://orcid.org/0000-0002-9403-3123Martinsson Tommy 3http://orcid.org/0000-0002-2735-8470Palmer Ruth H. 1http://orcid.org/0000-0002-2202-9694Kogner Per 67http://orcid.org/0000-0003-2032-2616Hallberg Bengt 11 Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden;2 Children's Hospital Affiliated to Zhengzhou University, 450018 Zhengzhou, China;3 Department of Pathology and Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden;4 Childhood Cancer Research Unit, Department of Women's and Children's Health, and Pediatric Oncology Program Karolinska University Hospital, Stockholm 17176, Sweden;5 Institute of Molecular Biology, Umeå University, Umeå 90187, Sweden;6 Department of Oncology-Pathology, Karolinska Institutet, Stockholm 17176, Sweden;7 Department of Clinical Pathology, Karolinska University Hospital, Stockholm 17176, Sweden;8 Department of Radiology, Karolinska University Hospital, Stockholm 17176, Sweden;9 Department of Pediatric Radiology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm 17176, Sweden;10 Department of Pediatric Surgery, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm 17176, Sweden;11 Department of Pediatrics and Pathology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden12 Co–first authors.\n\nCorresponding authors: bengt.hallberg@gu.se; ruth.palmer@gu.se; tommy.martinsson@gu.se; per.kogner@ki.se8 2018 4 4 a00255015 12 2017 13 4 2018 © 2018 Guan et al.; Published by Cold Spring Harbor Laboratory Press2018This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.Tumors with anaplastic lymphoma kinase (ALK) fusion rearrangements, including non-small-cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. Although mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, because of lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germline FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Monotherapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 mo treatment, the residual primary tumor shrunk, was surgically removed, and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 mo treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.\n\nabnormality of the enteric gangliaanaplastic large-cell lymphomaneuroblastomaSwedish Cancer Society 10.13039/501100002794TMCAN2015/794BHCAN15/775RHP CAN15/391PK CAN16/3625Swedish Childhood Cancer FoundationTM PR2016-0147BH 2015-802014-150RHP 2015-96PK PR2014-0084JG 2016-0011SF 15-0061DT 12-00912-002Swedish Research CouncilRHP 2015-04466BH 521-2012-2831TM 521-2014-3031PK 2014-3036Swedish Foundation for Strategic ResearchRB13-0204Göran Gustafsson FoundationRHP2016PhD-Student programNC2012-0026Post-doctoral Research Fellow PositionTJ2016-0088Research Assistant Fellowship14-0064Swedish Childhood Cancer FoundationCenter Léon Bérard laboratory (Lyon, France)\n==== Body\nINTRODUCTION\nAnaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) comprising an extracellular ligand-binding domain, a transmembrane domain and an intracellular tyrosine kinase domain (Iwahara et al. 1997; Morris et al. 1997). ALK was first described in 1994 as a fusion partner in the t(2;5) chromosomal translocation in anaplastic large cell lymphoma (ALCL) (Morris et al. 1994). Vertebrate ALK is activated by the recently described small secreted ALKAL (FAM150/AUG) ligands, which potently activate ALK signaling (Zhang et al. 2014; Guan et al. 2015; Reshetnyak et al. 2015; Mo et al. 2017; Fadeev et al. 2018). ALK activates multiple signaling pathways, such as the PI3K-AKT, CRKL-C3G, MEKK2/3-MEK5-ERK5, JAK-STAT, and MAPK pathways (Hallberg and Palmer 2016).\n\nMutation of full-length ALK has been well described in the neural crest derived pediatric cancer neuroblastoma (Carén et al. 2008; Chen et al. 2008; George et al. 2008; Janoueix-Lerosey et al. 2008; Mosse et al. 2008; Hallberg and Palmer 2013). Of the more than 35 mutations in ALK described, the majority are point mutations in the kinase domain, although deletions in the extracellular domain and translocations have also been reported (Okubo et al. 2012; Cazes et al. 2013; Hallberg and Palmer 2013; Bresler et al. 2014; Fransson et al. 2015). Within the kinase domain three hotspot residues, F1174, F1245, and R1275, represent most patient mutations (De Brouwer et al. 2010; Hallberg and Palmer 2013; Bresler et al. 2014). In addition to ALK mutations in treatment-naïve neuroblastoma, examination of ALK status in relapsed neuroblastoma samples has highlighted an increase in activating ALK mutations appearing later in the disease course (Martinsson et al. 2011; Schleiermacher et al. 2014; Eleveld et al. 2015).\n\nIn neuroblastoma, ALK signaling has been shown to act synergistically with MYCN to drive tumor development (Berry et al. 2012; Heukamp et al. 2012; Schonherr et al. 2012; Zhu et al. 2012; Cazes et al. 2014; Ueda et al. 2016), with combined occurrence of MYCN amplification and ALK mutations being associated with particularly bad prognosis (De Brouwer et al. 2010). ALK has led to the suggestion that inhibition of ALK with small molecule tyrosine kinase inhibitors (TKIs) may offer clinical benefit in neuroblastoma. The ALK TKI crizotinib was approved for clinical use in patients with ALK-positive non-small-cell lung cancer (NSCLC) in 2011 ([FDA] 26th of August 2011; Kwak et al. 2010), based on a robust response in this patient population. Although significant problems with resistance to ALK TKIs occur, a trial comparing crizotinib with chemotherapy concluded that crizotinib is superior in patients with previously treated, advanced ALK-positive NSCLC (Shaw et al. 2013). Similarly, treatment with crizotinib resulted in a strong response in a phase I crizotinib monotherapy trial of pediatric patients with ALK-fusion positive tumors, although patient responses in pediatric ALK mutant neuroblastoma were less encouraging (Mosse et al. 2013, 2017). It is not clear whether this relates to clinical factors unique to neuroblastoma or to issues of efficacy of inhibition of ALK by crizotinib. The clinical data thus far motivates exploration of alternative strategies in neuroblastoma, including ALK monotherapy with next-generation TKIs and combination strategies (Berry et al. 2012; Moore et al. 2014; Umapathy et al. 2014; Guan et al. 2016; Infarinato et al. 2016; Krytska et al. 2016).\n\nOther ALK TKIs include ceritinib, brigatinib, alectinib, and lorlatinib (Christensen et al. 2007; Katayama et al. 2011, 2015; Sakamoto et al. 2011; Marsilje et al. 2013; Chia et al. 2014; Johnson et al. 2014) (for the latest details of clinical trials using ALK TKIs, please see Clinicaltrials.gov). These ALK inhibitors bind slightly differently within the ATP-binding pocket of the ALK kinase domain, show varying abilities to cross the blood–brain barrier, and have differing profiles of inhibition for the wild-type ALK kinase domain compared with the various ALK kinase mutants. These properties have important implications for potential treatment of ALK-positive neuroblastoma in which ALK mutations are present in treatment-naïve tumors. Ceritinib gained U.S. Food and Drug Administration approval in 2014 following accelerated review for the treatment of patients with ALK-positive (ALK+) metastatic NSCLC who have progressed on, or are intolerant to, crizotinib ([FDA] 29th of April 2014; Shaw et al. 2014; [FDA] 26th of May 2017).\n\nHere we report the robust response of an ALK-positive neuroblastoma patient to ceritinib treatment. The patient received chemotherapy according to protocol after being diagnosed with high-risk neuroblastoma but displayed severe hematological failure early after initial treatment. This led to suspicion of Fanconi anemia (FA), which was confirmed by chromosomal breakage assessment and identification of FANCA gene mutations. FA is a rare recessive genetic disorder clinically characterized by congenital abnormalities and progressive bone marrow failure (Kutler et al. 2003b), although some patients may show only subtle symptoms or no phenotype at all (Neveling et al. 2009). FA is caused by mutations in one of at least 21 different FA genes encoding proteins that function in interstrand cross-link and double strand DNA repair (Mamrak et al. 2017). Because of the impaired DNA damage response, FA patients have significantly increased cancer susceptibility, particularly to acute myeloid leukemia, head and neck squamous cell carcinoma (Kutler et al. 2003a,b), and, more rarely, embryonic tumors such as Wilms tumor, hepatoblastoma, or neuroblastoma (Abbondanzo et al. 1986; Bissig et al. 2002; Berrebi et al. 2006; Kopic et al. 2011; Malric et al. 2015). The management of cancer in FA patients is challenging as defective DNA repair leads to hypersensitivity to both radiation and cross-linking agents such as mitomycin C and cisplatin with increased risk of developing severe toxicity (Walsh et al. 2017) (http://fanconi.org/explore/clinical-care-guidelines). In parallel to identification of FANCA gene mutations in this neuroblastoma patient, we also noted the presence of an ALK mutation at residue I1171.\n\nPreclinical analysis showed that the mutation of ALK-I1171 to threonine (T), which has not previously been reported in neuroblastoma, generates a potent gain-of-function mutant. PC12 cells expressing ALK-I1171T display ligand-independent activation of ALK, neurite outgrowth and activation of downstream signaling. In addition, ALK-I1171T drives foci formation in NIH3T3 cells. We were able to identify ceritinib as a next-generation ALK TKI that effectively inhibits ALK-I1171T in a preclinical setting, and based on these experimental data, the patient was treated with ceritinib. A dramatic response was observed and 7.5 mo after initiation of treatment, tumor material was surgically removed, exhibiting reduced Ki67 levels and up-regulation of markers of differentiation. Based on this case, we suggest that ceritinib presents a viable therapeutic option for patients with ALK-positive neuroblastoma.\n\nRESULTS\nPatient Presentation\nA 16-mo-old boy presenting with neurologic symptoms at the pediatric emergency unit was found to have metastatic neuroblastoma stage M (INRGSS) (Fig. 1). There was no previous family history of neuroblastoma. SNP-microarray analysis of genomic DNA from initial biopsy showed no MYCN-amplification but revealed several unfavorable segmental alterations (Fig. 2A). COJEC chemotherapy induction was started according to HR-NBL-1 SIOPEN (Ladenstein et al. 2017) and the patient received one A course (day 0; vincristine, carboplatin, etoposide), one B course (day 10; vincristine, cisplatin), and a partial C course (day 20; vincristine, etoposide, cyclophosphamide), before chemotherapy had to be discontinued because of severe bone marrow toxicity with anemia, neutropenia, and thrombocytopenia. For the ensuing 4 months, the patient was continuously hospitalized and suffered repeated episodes of septicemia, intestinal hemorrhage, and typhlitis as well as respiratory failure requiring intensive care. Because of the unusual severity of the toxicity, and also because the patient displayed moderate radial dysplasia with deviant thumbs bilaterally, suspicion of Fanconi anemia was raised. A clinical chromosome breakage assessment was found positive. A more detailed genomic analysis then revealed inherited mutations in the FANCA gene; one novel missense variant at genomic position Chr 16:89831348 (NM_000135.2; c.2728C>T, p.L910F) predicted to be deleterious and probably damaging by scale-invariant feature transform (SIFT) and PolyPhen-2 (PP2), respectively, and one splice site mutation at the acceptor site of intron 42 at genomic position Chr 16:89805118, (NM_000135.2; c.4261-2A>C) (Table 1; Fig. 2B). The L910F variant is not present in either ClinVar or HGMD and, to best of our knowledge, this is the first report of a L910F variant in association with FA. A third rare missense variant at Chr 16:89871709 (c.688G>A; p.V230I) was detected in the patient, although predicted to be benign by SIFT and PP2, indicating a nonpathogenic function. This is supported by a recent study showing that the V230I variant is localized to the nucleus and does not confer sensitivity to mitomycin C (Kimble et al. 2017). The fact that the child presents as a compound heterozygote for FANCA (p.L910F/c.4261-2A>C) is a likely cause for the above described toxicity (Table 1; Fig. 2B). Further use of chemotherapy, or irradiation, was advised against in this patient because of the DNA repair defects in Fanconi anemia. Because initial genomic analysis also identified an ALK-I1171T mutation in the patient (Table 1; Fig. 2C), ALK TKI therapy was considered and experimentally investigated preclinically for this patient.\n\nFigure 1. Patient tumor imaging. Disease at initial diagnosis and after targeted therapy in full clinical remission (A–D). (A) Whole-body MIBG-I123 scintigraphy showing extensive metastatic disease at diagnosis of high-risk neuroblastoma (upper panels). (Left panel) anterior view; (right panel) posterior view. Lower panels display head and neck region. (B) MIBG-scintigraphy after 21 mo of ceritinib therapy showing complete remission at all metastatic sites. (C) Brain CT scans at diagnosis showing a CNS metastasis (43 mm × 46.7 mm) posterior to the right orbit. (D) CT scans after 21 mo of ceritinib therapy showing complete metastatic response. (E–H) Primary tumor immediately before and after targeted therapy. (E) Magnetic resonance imaging (MRI) of primary abdominal tumor (indicated by arrows and measurements inserted) immediately before start of ceritinib targeted therapy (∼18.8 mL tumor volume), (F) MRI after 3 mo therapy (∼13.8 mL tumor volume), and (G) MRI after 6 mo therapy immediately prior to radical surgery (∼10.6 mL tumor volume). (H) Decrease of evaluable tumor volume after 3 and 6 mo of targeted therapy.\n\nFigure 2. Genomic analysis of the tumor sample. (A) Copy number profiling using Affymetrix HD SNP-microarray shows a genomic profile with 11q-deletion and 17q-gain indicative of high-risk neuroblastoma. (B) Two different likely pathogenic variants in the FANCA gene were detected through exome sequencing and confirmed in constitutional DNA of the patient. Read mapping is visualized in IGV. (C) Exome sequencing also detected a novel ALK I1171T mutation in the tumor that was confirmed to be somatic through Sanger sequencing. Electrophorogram of tumor in upper panel and from constitutional DNA in lower panel.\n\nTable 1. FANCA and ALK mutation details\n\nGene\tDescription\tSomatic\tCytoband\tPos (hg19/GRCh37)\tRef\tVar\tCoverage at mutation site\tVar allele fraction\tVariant function on protein\tChange cDNA/protein\tPredicted impact on protein function\tPresence public databases\t\nSIFT\tPP2\tLRT\tdbSNP(132)\t1000 Genome\tesp6500 all\tCosmic\tClinVar\tHGMD\t\nFANCA\tFanconi anemia group A protein\tNo\t16q24.3\tChr 16:89805118\tT\tG\t80×\t43%\tSplicing\tFANCA: NM_000135.2:exon43:c.4261-2A>C\t-\t-\t-\t-\t-\t-\t-\t-\tCS04812\t\nFANCA\tFanconi anemia group A protein\tNo\t16q24.3\tChr 16:89831348\tG\tA\t185×\t49%\tNonsynonymous SNV\tFANCA:NM_000135.2:exon28:c.C2728T:p.L910F\tDeleterious\tProbably damaging\tDeleterious\t-\t-\t-\t4483710\t-\t-\t\nFANCA\tFanconi anemia group A protein\tNo\t16q24.3\tChr 16:89871709\tC\tT\t81×\t62%\tNonsynonymous SNV\tFANCA:NM_000135.2:exon7:c.G688A:p.V230I\tNondeleterious\tBenign\tNeutral\trs144560850\t-\t0.000231\t-\t321366\t-\t\nALK\tALK tyrosine kinase receptor\tYes\t2p23.2\tChr 2:29445213\tA\tG\t83×\t40%\tNonsynonymous SNV\tALK:NM_004304.4:exon22:c.T3512C:p.I1171T\t-\tProbably damaging\tDeleterious\t-\t-\t-\t4381100\t-\t-\t\nVariant specific information including position, transcript-ID, coverage, and presence in publically available databases.\n\nALK-I1171T Is a Gain-of-Function ALK Mutation\nExome sequence analysis of a tumor biopsy sample revealed a heterozygous mutation of ALK (Chr 2:29445213) in exon 22; (NM_004304.4; c.3512T>C) leading to a missense mutation I117IT (Table 1; Fig. 2C). Sanger sequencing of tumor and patient's corresponding constitutional DNA indicated that the ALK variant was caused by a somatic event. I1171 is located in the ALK kinase domain in close proximity to F1174, one of the mutational hotspots of ALK in neuroblastoma that is localized in the αC-helix in the amino-terminal lobe of the kinase (Fig. 3A). Mutation of I1171 to either N/T or S has previously been described in ALK TKI-treated patients with ALK fusion-positive NSCLC (in the EML4-ALK and HIP1-ALK fusion proteins) (Katayama et al. 2014; Ou et al. 2014; Toyokawa et al. 2014), resulting in tumor resistance.\n\nFigure 3. Characterization of ALK-I1171T with cell culture systems. (A) Model of the ALK kinase domain (PDB #3LCS) using PyMol, which can be divided into the upper amino-terminal lobe and the lower carboxy-terminal lobe by the hinge region and ceritinib binding/ATP (red) binding pocket. Regulatory spine (R-spine) residues are shown in magenta. The spine is anchored in the αF-helix (D1311) and includes the DFG (F1271) and the HRD motif (H1247) of the C-lobe. R-spine residues in the amino-terminal lobe include the β4 strand (C1182) and the residue mutated in this patient in the αC-helix (I1171). Mutation of residue I1171 to threonine in PyMol, results in a small shift, which potentially drives a dynamic allostery that results in a gain-of-function ALK activity (upper insert: wild-type ALK kinase domain; lower insert: ALK-I1171T kinase domain). (B) ALK kinase activity and activation of downstream signaling pathways were visualized by western blot with antibodies against pALK (Y1604) and pERK1/2. Total ALK and pan-ERK were used as loading controls. Blots are representative of three independent experiments. (C) Neurite outgrowth of PC12 cells as a readout for ALK kinase activity was performed with wild-type ALK and ALK variants in the absence or presence of ALKAL1 ligand. Bars represent mean percentage ± STD of neurite-carrying cells among GFP-positive cells from three independent experiments. (D) Representative focus formation assays for NIH 3T3 cells transfected with wild-type ALK, ALK variants (ALK-I1171T and ALK-F1174L), or empty vector. (E) Inhibition profiling of ALK TKIs on ALK-I1171T. PC12 cells expressing ALK-I1171T were treated with serial dilution of ALK inhibitors as indicated. Phosphorylation of ALK was detected with pALK (Y1604) antibody and total ALK was used as loading control. (F) IC50 values of different ALK inhibitors were calculated with GraphPad Prism 6.0 by fitting data to a log (inhibitor concentration) versus normalized response (variable slope) equation and shown in the accompanying table. Values represent average ± STD from three independent experiments.\n\nThis is the first report of mutation of ALK-I1171T in neuroblastoma, although mutation of ALK-I1171N has been reported (Mosse et al. 2008; Bresler et al. 2014). Intriguingly, the residue I1171 contributes to the regulatory spine (Fig. 3A; Kornev and Taylor 2015), prompting us to experimentally validate its behavior in the context of the full-length ALK RTK. To evaluate the ALK-I1171T mutant we used a PC12 cell culture system for expression of either wild-type or ALK-I1171T. Wild-type ALK can be activated with the ALKAL1 ligand (FAM150A, AUGβ) (Guan et al. 2015; Reshetnyak et al. 2015), leading to extensive tyrosine phosphorylation of the receptor and activation of downstream targets, such as ERK1/2 (Fig. 3B). In contrast to wild-type ALK, we observed ligand-independent auto-trans-phosphorylation of the ALK-I1171T mutant together with activation of the downstream target ERK1/2 (Fig. 3B).\n\nWe next investigated whether the ALK-I1171T mutant was capable of stimulating neurite outgrowth in the PC12 cell line. PC12 cells are a clonal rat adrenal pheochromocytoma cell line with enteric cell origin, which differentiate and extend neurites upon extended ERK1/2 stimulation (Cowley et al. 1994). We and others have previously shown that activation of ALK triggers differentiation of PC12 cells into sympathetic-like neurons, a process characterized by extension of neurites (Fig. 3C; Motegi et al. 2004; Schonherr et al. 2011). Expression of wild-type ALK mediates only a low level of neurite outgrowth in this assay (Fig. 3C). In contrast, expression of the ALK-I1171T mutant results in robust neurite outgrowth to a level similar to that observed for the well characterized ALK-F1174L mutant used as positive control.\n\nFinally, we investigated whether the human ALK-I1171T mutant displays transforming potential in NIH3T3 cells. Expression of either the positive control human ALK-F1174L or the ALK-I1171T mutant led to formation of foci of transformed cells over the background monolayer (Fig. 3D), whereas expression of the wild-type human ALK receptor was unable to mediate foci formation. Thus, ALK-I1171T exhibits intrinsic transforming activity in a focus formation assay, in addition to ligand-independent activation of downstream targets and neurite outgrowth.\n\nCeritinib Abrogates Growth in ALK-Addicted Neuroblastoma Cell Lines\nCeritinib is a small molecule ALK TKI that has been extensively explored for ALK-positive NSCLC and is FDA approved for clinical use in that setting. It has not yet been reported as being used clinically in the context of ALK mutations in neuroblastoma. Previous analysis of the I1171T mutation in NSCLC (arising in response to sequential crizotinib and alectinib treatment) noted that the I1171 mutation is relatively insensitive to inhibition by crizotinib and alectinib but was still sensitive to other ALK TKIs such as TAE684 and ceritinib (Katayama et al. 2014). We therefore assembled a panel of neuroblastoma cell lines harboring either mutated or wild-type ALK in combination with other genetic aberrations, CLB-GE, CLB-GA, CLB-BAR, CLB-PE, IMR32, Kelly, SK-N-AS, SK-N-DZ, and SK-N-BE (Table 2) to examine the effect of ceritinib on ALK activity and cell proliferation in a neuroblastoma setting (Kohl et al. 1984; Combaret et al. 1995; Schleiermacher et al. 2003; Cazes et al. 2013; Fransson et al. 2015; Umapathy et al. 2017). In this analysis we also compared the ability of ceritinib to inhibit proliferation of neuroblastoma cells with the well-characterized clinical ALK TKI crizotinib (Christensen et al. 2007), treating cells with increasing doses of either crizotinib or ceritinib. Proliferation of ALK-addicted cell lines such as CLB-BAR, CLB-GE, CLB-GA, and Kelly was inhibited in a dose-dependent manner by both crizotinib and ceritinib (Table 2). Of the neuroblastoma cell lines tested, growth of CLB-BAR and CLB-GE was inhibited in a manner similar to that previously shown for crizotinib (Schonherr et al. 2012), although the observed IC50 values differ up to twofold. IC50 values were similar for both ceritinib and crizotinib in CLB-GA and Kelly cells with values of ∼110 and 330 nM, respectively (Table 2). Importantly, we did not observe inhibition of proliferation in non-ALK-addicted cell lines such as CLB-PE, SK-N-AS, SK-N-BE, and SK-N-DZ, which carry other driver mutations. IMR32 cells, which express wild-type ALK and respond to stimulation with ALKAL ligands (Guan et al. 2015), are more sensitive to crizotinib than ceritinib, although IC50 values are high, more than 350 nM (Table 2). Thus, these preclinical results show that although activity of the ALK-dependent neuroblastoma cells tested here is inhibited by crizotinib, treatment with ceritinib has greater efficacy.\n\nTable 2. Indicated neuroblastoma cell lines were treated with increasing doses of either ceritinib or crizotinib for 72 h and cell viability was assessed by resazurin assay\n\nCell line\tALK status\tMYCN status\tIC50 nM (ceritinib)\tIC50 nM (crizotinib)\t\nCLB-GE\tF1174V, A\tA\t131.3 ± 24\t233.7 ± 18\t\nCLB-BAR\tg-o-f Δexon 4-12\tA\t36.1 ± 6.2\t54.9 ± 20\t\nKELLY\tF1174L, A\tA\t328.9 ± 36\t333.3 ± 78\t\nCLB-GAR\tR1275Q\tNA\t102.3 ± 16\t119.3 ± 45\t\nIMR32\twt\tA\t>500\t348.7 ± 45\t\nSK-N-BE\twt, NA\tA\t>1500\t>1000\t\nSK-N-DZ\twt\tA\t>800\t>4000\t\nSK-N-AS\twt, NA\tNA\t>3000\t353.0 ± 27\t\nCLB-PE\twt\tA\t>15000\t>4000\t\nNA, nonamplified; A, amplified; g-o-f Δexon 4-11, gain-of-function deletion of exons in the extracellular domain of ALK; wt, wild-type.\n\nCeritinib Effectively Inhibits the Crizotinib-Resistant ALK-I1171T Mutant in PC12 Cells\nTo determine which ALK TKI would be suitable in this clinical case we examined the ability of different ALK inhibitors to abrogate ALK-I1171T activity. As readout for ALK activity we used phosphorylation of ALK Y1604, which reflects ALK activation, in PC12 cells (Chand et al. 2013). PC12 cells expressing ALK-I1171T were treated with serial dilution of the ALK inhibitors crizotinib, ceritinib, lorlatinib, and brigatinib, and Y1604 phosphorylation levels were quantified. We observed that full-length ALK-I1171T was more resistant to crizotinib than other inhibitors as measured by Y1604 phosphorylation (Fig. 3E). The IC50 of crizotinib for ALK-I1171T in this analysis was 193 ± 57 nM, approximately 11 times that of ceritinib for ALK-I1171T (Fig. 3F). The next-generation ALK TKIs also showed strong anti-ALK-I1171T activity. The observed IC50 values of ALK-I1171T for brigatinib and lorlatinib were in a similar range (6.8–7.5 nM), approximately 1/28th of the crizotinib IC50 for ALK-I1171T (Fig. 3F). Taken together, our results indicate that ceritinib as well as the third-generation TKIs lorlatinib and brigatinib represent experimentally well-supported choices for treatment of tumor(s) harboring the ALK-I1171T mutation.\n\nTo extend our analysis we examined the activity of ceritinib to inhibit a range of gain-of-function ALK variants expressed in PC12 cells, using ALK Y1604 phosphorylation as readout (Supplemental Fig. S2; includes all loading ALK control blots for this experiment). In this analysis crizotinib abrogates wild-type ALK phosphorylation with an IC50 of ∼18 nM, which is similar to earlier reports (Schonherr et al. 2011; Siaw et al. 2016). In comparison, ceritinib blocks ALK Y1604 phosphorylation with a threefold lower IC50 level, of ∼5 nM. The IC50 values for crizotinib inhibition of ALK Y1604 phosphorylation of the various ALK mutations tested here are similar to earlier reports, highlighting a requirement for higher crizotinib dosage for effective inhibition of ALK-I1171N (Table 3; Schonherr et al. 2011; Guan et al. 2016; Siaw et al. 2016). ALK-G1269A has only been described in EML4-ALK fusions arising in NSCLC patients that have developed resistance to ALK TKI treatment (Doebele et al. 2012), but is included here as reference in the context of full-length ALK.\n\nTable 3. IC50 values for inhibition of ALK Y1604 phosphorylation by ceritinib or crizotinib in PC12 cells\n\nALK mutation\tCeritinib (IC50 nM)\tNormalized to IC50 of wt\tCrizotinib (IC50 nM)\tNormalized to IC50 of WT\tFold change\t\nwt\t5.3 ± 0.2\t1.0\t17.8 ± 0.2\t1\t3.4\t\nG1128A\t19.8 ± 3.5\t3.7\t22.2 ± 3.4\t1.2\t1.1\t\nI1171N\t46.6 ± 16\t8.8\t139.5 ± 13.8\t7.8\t3.0\t\nF1174L\t16.9 ± 8\t3.2\t29.9 ± 4.8\t1.7\t1.8\t\nR1192P\t26.1 ± 1.2\t4.9\t28.1 ± 7.5\t1.6\t1.1\t\nF1245C\t24.6 ± 6.4\t4.6\t37.5 ± 7.7\t2.1\t1.5\t\nG1269A\t28.9 ± 3.6\t5.5\t113.5 ± 8.5\t6.4\t3.9\t\nR1275Q\t10.8 ± 3.5\t2.0\t30.3 ± 0.9\t1.7\t2.8\t\nY1278S\t20.5 ± 0.1\t3.9\t69.5 ± 0.03\t3.9\t3.4\t\nIC50 values were determined by quantification of Y1604 phosphorylation from the immunoblots in Supplemental Figure 1. Values represent mean ± SD from at least two independent experiments.\n\nOur extensive examination of the inhibition profiles of both crizotinib and ceritinib on the different ALK mutations reveals one important exception—ALK-I1171T. We observe that inhibition of ALK-I1171T by ceritinib exhibits an IC50 value (17.4 ± 3.1 nM; Fig. 3F) that is not too far from that of wild-type ALK (5.3 ± 0.2 nM) (Table 3). This is in stark contrast to the ALK-I1171N mutation at the same residue, which displays resistance to both ceritinib (46.6 ± 0.16 nM) and crizotinib (139.5 ± 13.8 nM) when compared with wild-type ALK (Table 3). In summary, ceritinib was active in a range comparable to crizotinib as measured by inhibition of ALK phosphorylation/activation in PC12 cells with one exception, the ALK-I1171T mutant which was insensitive to crizotinib but efficiently inhibited by ceritinib.\n\nPhosphoproteomic Profiling of Ceritinib in Different Neuroblastoma Cell Lines\nPhosphoproteomic profiling has clinical value because it can be translated into prognostic biomarkers, which can be used to identify functional downstream targets as combinatorial treatment target options together with ceritinib. Here we determined the difference in the phosphoproteomic patterns upon treatment with ceritinib in ALK-addicted (CLB-BAR and CLB-GE) neuroblastoma cell lines with that of a non-ALK-addicted (SK-N-AS) neuroblastoma cell line (Fig. 4A). The CLB-BAR and CLB-GE cell lines harbor activating ALK mutations, are ALK/MYCN amplified, lack p53/RAS mutations, and display high levels of NF1 (Umapathy et al. 2017). The SK-N-AS cell line harbors an activating mutation in the NRAS gene and exhibits down-regulated NF1 expression leading to an activation of the RAS-MAPK pathway. SK-N-AS has a 11q deletion, is non-MYCN-amplified, has no p53/ALK mutations, and has undetectable levels of ALK protein (Umapathy et al. 2017). SK-N-AS was used as a control cell line for off-target effects of the inhibitors used, because ALK protein is undetectable in this cell line with no MYCN amplification.\n\nFigure 4. Ceritinib phosphoproteomic profile in neuroblastoma cell lines. (A) Three neuroblastoma cell lines (CLB-BAR, CLB-GE, and SK-N-AS) were cultured in control conditions or in the presence of ceritinib. Cells were harvested for tyrosine and serine/threonine phosphoproteomic analysis after 60 min. The pie chart indicates the number of targeted sites. (B) Overview of all ALK tyrosine phosphorylation sites with log2 fold change values (FC; treated/untreated) in CLB-BAR and CLB-GE. Note that no signal was measured in SK-N-AS cells, reflecting the known absent expression of ALK. (C) Log2 FC values of all analyzed phosphosites indicating the number of proteins found to contain phosphorylated (red) or dephosphorylated (green) sites for the three cell lines analyzed. Dotted lines indicate thresholds to determine differential phosphorylation. (D) Venn diagrams show the correlation between phosphorylated (red) and dephosphorylated (green) proteins in the different cell lines. Sixty proteins were found to be dephosphorylated upon ceritinib treatment in the ALK-addicted CLB-BAR and CLB-GE lines but not in the SK-N-AS cell line. (E) These proteins were mapped to the InWeb_ InBioMap protein–protein interaction network. For visualization purposes, only direct interactions between the identified proteins are shown. Node sizes are proportional to the number of connections, whereas node colors indicate different log2 FC values as indicated in the color scale legend on the top left. (F) Reactome gene set enrichment analysis on all 60 proteins that were identified to be dephosphorylated. The 10 most significantly enriched pathways are shown and ranked on FDR values.\n\nTo identify sites with altered phosphorylation associated with ALK activity, we utilized an immunoaffinity-coupled LC-MS/MS approach by treating neuroblastoma cell lines with ceritinib. Prior to MS, lysates were examined for ALK, ERK, and AKT activity, which have previously been shown to be reduced upon ALK TKI treatment for 1 h (Supplemental Fig. S3). We observed reduced phosphorylation levels of ALK and ERK in response to ceritinib, validating response to inhibitor treatment (Supplemental Fig. S3). Phosphoproteomic analysis of neuroblastoma cell lines (CLB-BAR, CLB-GE, and SK-N-AS) identified 2223 phosphothreonine sites, 2583 phosphotyrosine sites, and 5013 phosphoserine residue sites in 3345 different proteins (Fig. 4A). All previously observed 11 ALK phosphotyrosine sites were identified and showed drastically reduced phosphorylation signals in both ALK-addicted neuroblastoma cell lines (i.e., CLB-BAR and CLB-GE) after ceritinib treatment. The strongest dephosphorylation signals were measured at ALK tyrosine sites 1096, 1278, 1282, and 1283 (Fig. 4B). The latter three sites were previously reported as important residues in the ALK activation loop (Donella-Deana et al. 2005; Rush et al. 2005; Rikova et al. 2007; Tartari et al. 2008; Wang et al. 2010; Sattu et al. 2013; Guan et al. 2017). As expected, no phosphorylation signal was observed in the control SK-N-AS cell line. Furthermore, this strong dephosphorylation response was only observed for ALK and not for any other RTK (Supplemental Fig. S4). In CLB-BAR, 182 proteins were dephosphorylated and 52 proteins were phosphorylated upon treatment with ceritinib (Fig. 4C). Similarly, in CLB-GE, 200 proteins were dephosphorylated and 120 proteins were phosphorylated (Fig. 4C). Treatment with ceritinib in SK-N-AS revealed only 35 proteins that were dephosphorylated and 20 proteins that were phosphorylated. Few similarities were found between the RAS-addicted SK-N-AS cell line and the ALK-addicted CLB-BAR/GE cell lines and, although phosphorylation responses were specific between all cell lines with little overlap, 60 proteins were dephosphorylated in both CLB-BAR and CLB-GE but not in SK-N-AS (Fig. 4D; Supplemental Table S1). Assuming that these 60 proteins represent the most specific response to ceritinib, they were used for further analysis. To illustrate downstream phosphorylation targets of ALK signaling activity that are inhibited upon treatment with ceritinib in ALK-addicted neuroblastoma cells, we mapped the dephosphorylated proteins to a protein–protein interaction network (Fig. 4E). This network analysis highlighted FRS2, IRS2, ERK1/2, AKT family members, SHC family members, SOS1, and GAB1/2 as key components of the underlying signaling pathways. Many of these proteins are known to be active in insulin, NGF, and FGFR receptor signaling pathways, as confirmed by a gene set enrichment analysis (Fig. 4F). Similar results were found when independently focusing on the 182 and 200 dephosphorylated proteins of the CLB-BAR and CLB-GE cell lines respectively (Supplemental Figs. S5, S6).\n\nPatient Response to Ceritinib\nBased on the experimental data presented here that indicated a potentially poor response to crizotinib, as well as evidence for FA prohibiting use of conventional chemotherapy or irradiation, the patient was started on ceritinib monotherapy as soon as severe acute toxicity had subsided (initiated 9.5 mo after diagnosis, indicated by *; Fig. 5A). Initial dosage was 225 mg once daily (450 mg/m2 body surface area) for a period of 10.5 mo, after which dosage was increased to 540 mg/m2 body surface area. Hematological counts were stabilized at normal levels (Fig. 5A). After the first 4-wk cycle, elevated urinary catecholamines had decreased to levels below the upper reference limit (Fig. 5B). Other than mild gastrointestinal side effects, no toxicity was observed, and the child was able to lead a normal life (Kim et al. 2016). After 6.5 mo of ceritinib treatment, the primary tumor had decreased in size (−43.6% according to MRI with volumetric measurements; Fig. 1) and the remaining CNS metastasis showed response by MRI (Supplemental Fig. S1), although not as sensitive as CT scans performed at diagnosis and after 21 mo of treatment showing complete metastatic remission (Fig. 1). The remaining primary was radically removed surgically together with the left adrenal gland at 7.5 mo from start of ceritinib treatment. The tumor was subjected to immunohistochemical analysis with both proliferation and differentiation markers. The treated tumor displayed a large proportion of calcification and nonmalignant stroma, reduced cell proliferation as measured by Ki-67 positivity (5% vs. 27% before treatment), and hallmarks of differentiation as assessed with NB84 and NFP (Fig. 6). The overall morphology of the primary tumor indicated differentiation in response to treatment, resembling a ganglioneuroblastoma, and was rich in schwannian stroma containing scattered foci of tumor cells of varying degrees of maturation to ganglion cells. Complete clinical evaluation with CT and MRI 1 yr after surgery and 21 mo after initiation of ceritinib treatment showed no residual tumor in the abdomen and complete resolution of metastases at all sites (Fig. 1). MIBG-I123 scintigraphy showed normal findings, indicating completely resolved tumor activity (Fig. 1B). After 34 mo of continuous ceritinib treatment, the child is in continuous complete remission (Park et al. 2017).\n\nFigure 5. Hematological counts and catecholamine metabolites in urine. (A) After conventional high-risk neuroblastoma chemotherapy was started, the patient suffered severe bone marrow toxicity with protracted anemia and thrombocytopenia requiring frequent transfusions (each peak indicates posttransfusion measurement). When hematological counts stabilized, ceritinib treatment could be started (*). Hemoglobin and platelet counts remained stable during TKI treatment, allowing for surgery (#) with radical removal of the differentiated and calcified decreased primary tumor. (B) Catecholamine metabolites (dopamine in black, homovanillic acid [HVA] in red, and vanillylmandelic acid [VMA] in green) as neuroblastoma markers in the patient's urine (molar concentrations/creatinine concentration). During ceritinib therapy (*), elevated urine catecholamine metabolites returned to normal (below respective dashed line), indicating a biologically inactive residual tumor. At surgery (#) normal levels had been reached.\n\nFigure 6. Immunohistochemical analysis of tumor material. Tumor sample taken in November 2014 was stroma-poor, comprising of small, round, primitive-appearing cells positive for the Ki-67 proliferation marker in up to 27%. Postceritinib treatment resected tumor displayed few Ki-67 positive cells and increased expression of NB84 and NFP, which are markers for differentiated neuroblastoma.\n\nDISCUSSION\nHere we report the case of a metastatic high-risk neuroblastoma that was treated according to HR_NBL-1 SIOPEN protocol and developed severe toxicity including protracted neutropenia, anemia, and thrombocytopenia that required intensive clinical care for 4 mo. During this time genetic analyses revealed inherited biallelic sequence variants in FANCA. This confirmed the initial suspicion of FA as likely cause of the observed toxicity and a potential contributing factor to tumor development. Genomic analysis also detected a somatic ALK-I1171T mutation that has not previously been described in neuroblastoma. This presented a clinical option to treat the child, whose FA status precluded further chemotherapy or irradiation, with targeted inhibition of ALK. Therefore an extensive preclinical experimental investigation of the ALK-I1171T mutant was performed.\n\nALK-I1171T exhibits robust gain-of-function activity in several different systems, such as triggering neurite outgrowth in PC12 cells, activation of validated downstream ALK targets, and transformation competence in NIH 3T3 cells. A critical part of this investigation was defining the sensitivity of ALK-I1171T to available ALK TKIs, including crizotinib, ceritinib, brigatinib, and lorlatinib. Of these, the next-generation inhibitors ceritinib, brigatinib, and lorlatinib, which have been explored in preclinical neuroblastoma models (Guan et al. 2016; Wood et al. 2016), were effective in inhibition. Most importantly, crizotinib was a very poor inhibitor of ALK-I1171T activity and does not efficiently cross the blood–brain barrier. This is in agreement with data from NSCLC patients, where resistance mutations in ALK fusions have been reported at I1171 (Katayama et al. 2014; Ou et al. 2014, 2015; Toyokawa et al. 2014). We also performed a preclinical LC-MS/MS analysis of ceritinib activity in neuroblastoma confirming a strong dephosphorylation response at all tyrosine residues that are known to be involved in the ALK activation loop, but not in any other RTK, indicating the specificity of the response. The downstream signaling response included FRS2, ERK1/2, AKT family members, SHC family members, and GAB1/2 among others and was similar to insulin, NGF, and FGFR signaling pathways. Based on the collective preclinical information, the child was included in the compassionate use individual patient program for ceritinib.\n\nThe patient responded strongly to ceritinib with minimal side effects allowing the child to lead a normal life. To date, the patient is in complete clinical remission after continuous ceritinib monotherapy treatment for 34 mo. It is unclear to what extent the efficacy of ceritinib treatment may have been influenced by the initial chemotherapy treatment, which induced partial remission. One possibility that should be considered is that the initial chemotherapy treatment sensitized the tumor to the subsequent ALK TKI treatment. A preclinical report investigating combination of crizotinib with commonly used chemotherapy showed synergistic cytotoxicity and increased apoptosis in neuroblastoma cell lines with ALK aberrations, supporting this scenario (Krytska et al. 2016). However, it is important to note that at initiation of ceritinib treatment the patient displayed significant active disease, as shown by persistent elevated urine catecholamine markers, metastatic disease, and remaining primary tumor tissue, which all responded strongly and rapidly to ALK TKI therapy with finally complete clinical remission at all sites.\n\nIn conclusion, we have shown the importance of comprehensive genetic profiling combined with preclinical investigation, which was conducted during a forced drug holiday of a neuroblastoma patient later discovered to present with FA caused by FANCA mutations and an ALK mutation. A compassionate use protocol with ceritinib has shown a clear benefit for the patient who is in complete clinical remission with clearance of all metastatic sites 34 mo from start of targeted ceritinib treatment. After the initial 7.5 mo of treatment with ceritinib, the primary tumor had decreased in size and was removed surgically. The removed tumor displayed a large amount of calcification and nonmalignant stroma, reduced proliferation index, and hallmarks of differentiation. Here we show that monotherapy with next-generation ALK TKIs can be effective against metastatic high-risk neuroblastoma carrying an activating ALK mutation, confirming ceritinib as a viable therapeutic option for ALK-positive neuroblastoma patients.\n\nMETHODS\nPatient\nA 16-mo-old boy presented at the pediatric emergency unit with neurologic symptoms including facial palsy, impaired balance, and strabismus. There was no past medical history of note except for examination by a hand surgeon and a dysmelia team because of slightly deviant thumbs, which had been present since birth. At the emergency visit, exophthalmus and an abdominal mass were also noted, and imaging using MIBG scintigraphy, CT scans, and MRI revealed a metastatic neuroblastoma with metastases in bone, lungs, and intracranially (Fig. 1; Supplemental Fig. S1) but with no neuroblastoma detected in the bone marrow. Biological workup of the diagnostic biopsy showed a number of unfavorable chromosomal aberrations, including 11q loss, 17q gain, 2q loss, 4p loss,7q, and 9q gain (Fig. 2). Treatment was initiated according to the high-risk neuroblastoma protocol HR-NBL-1 SIOPEN (Ladenstein et al. 2017) (ethical permit 02-294). In response to this treatment, the patient developed protracted neutropenia, anemia, and thrombocytopenia, necessitating repeated transfusions of erythrocytes and platelets for almost 6 mo (Fig. 5). Furthermore the patient experienced repeated episodes of severe septicemia and typhlitis requiring intensive care. Based on the suspicion of underlying FA (Walsh et al. 2017), chromosomal breakage assessment was perfomed and found positive. Further genomic analysis revealed inherited germline mutations in the FANCA gene, confirming FA diagnosis (Table 1; Fig. 2B). Detailed genomic analysis further identified a somatic ALK-I1171T mutation in the patient, raising the possibility of ALK TKI treatment (Fig. 2C; Table 1). Following preclinical investigation of the ALK-I1171T mutation, a clinical multidisciplinary conference, an Institutional Ethical Board meeting, and a Clinical Ethical Board meeting endorsed application for a Medical Products Agency (MPA) license (according to LVFS 2008:1). In addition, written informed consent from the patient's guardians was obtained and the patient was included in the Novartis compassionate use Individual Patient Program for ceritinib (CLDK378A2003M). Sampling and analyses of tumor tissues and linkage to clinical information were performed according to the ethical permit 2009/1369-31/1. Written informed consent was obtained from the patient's guardians allowing scientific research publication.\n\nImmunohistochemistry\nStaining for NB84 (Novocastra, NCL-NB84), NF (DAKO, 2F11), and Ki-67 (DAKO, MIB-1) was performed using a DAKO Autostainer. Slides were rehydrated with Xylene followed by a series of alcohol dilutions and a rinse in buffer (DAKO 8007). PTLINK (DAKO) was used for enzyme antigen retrieval. Endogenous enzyme block was performed for 5 min with EnVision FLEX Peroxidase-Blocking Reagent (DAKO). The antibodies (diluted at DAKO Company) were incubated for 20 min at room temperature. After a 5-min rinse in buffer, the labeled polymer, EnVision FLEX/HRP (DAKO), was applied and incubated for 20 min with two additional rinses before the slides were incubated with substrate-chromogen, Substrate Working Solution (DAKO), for 10 min. Slides were ultimately rinsed and counterstained in EnVision FLEX Hematoxylin prior to mounting.\n\nGenomics Profile with SNP Array\nMicroarray analyses of DNA from the tumor samples were performed using Affymetrix Human Cytoscan High Density arrays essentially as described earlier (Fransson et al. 2016). For primary data analysis, the GDAS software (Affymetrix) was used, whereas genomic profiles were generated using CNAG (Copy Number Analyzer for AffymetrixGeneChip Mapping arrays) version 3.3 (Genome Laboratory, Tokyo University; http://www.genome.umin.jp; 11).\n\nDetection of ALK Mutation with Massive Parallel DNA Sequencing\nDNA was extracted from tumor sample using standard procedures and evaluated through fluorometric quantitation and DNA integrity assessment on Agilent Tapestation (Agilent) prior to exome sequencing. Exome sequencing was performed at GATC (GATC) through paired-end sequencing (101 bp read length) on Illumina platforms after enrichment with Agilent SureSelect Human All Exon v5 enrichment kit giving an average coverage of 85× (sequencing details are supplied in Supplemental Information file “Exome sequencing”). Alignment against hg19 was performed using BWA with GATK local realignment followed by SNV calling using SNPeff and Annovar annotation. Visualization of mapped reads and manual QC of called variants was done through IGV (Robinson et al. 2011). Only variants located at regions covered by at least 10 unique reads were kept. A systematic filtering approach was used to identify critical variants by removal of common variants (e.g., showing an allele frequency of >0.005 in the 1000 Genomes or exome variant server) as well as excluding all synonymous variants or variants in noncoding regions except those affecting canonical splice sites. PolyPhen-2 (PP2) and SIFT were used for prediction of functional relevance of called SNVs. Sanger sequencing of the patient's constitutional and tumor DNA verified presence of a somatic ALK mutation in the tumor. Sanger sequencing of ALK exons was performed as described previously (Carén et al. 2008). All genomic positions are specified according hg19/GRCh37.\n\nGeneration of Human ALK Mutant Constructs in PC12 Cells\nThe ALK-I1171T mutation was generated based on pcDNA3-ALK-WT (NM_004304.3) by Eurofins Genomics. ALK-F1174L has been described previously (Martinsson et al. 2011). All mutations generated in the kinase domain were confirmed by sequencing from both directions.\n\nNeurite Outgrowth Assay\nPC12 (2 × 106) cells were cotransfected with 0.5 µg of empty pcDNA3 vector, pcDNA3-ALK-WT, pcDNA3-ALK-I1171T, or pcDNA3-ALK-F1174L, respectively, together with 0.5 µg of pEGFP-N1 (Clonetech) as indicated by electroporation using Amaxa electroporator (Amaxa Biosystems) and Ingenio electroporation solution (Mirus Bio LCC). After electroporation, cells were kept in minimum essential medium (MEM) supplemented with 7% horse serum and 3% fetal bovine serum and seeded into 24-well plates. For samples stimulated with ALK ligand, purified ALKAL1 (FAM150A) protein was added to the well with a final concentration of 1 µg/ml (Guan et al. 2015). After 48 h of incubation, the fraction of green fluorescent protein (GFP)-positive and neurite-carrying cells versus GFP-positive cells was observed under a Zeiss Axiovert 40 CFL microscope. To be judged as a neurite-carrying cell, the neurite of the cell should be at least twice the diameter of a normal cell body. Experiments were performed in triplicate, and each sample within an experiment was performed in triplicate.\n\nTransformation Assay\nNIH 3T3 cells (5 × 104) were seeded into collagen-coated 12-well plates and transfected with 0.55 µg of pcDNA3 vector, pcDNA3-ALK-WT, pcDNA3-ALK-I1171T, or pcDNA3-ALK-F1174L, respectively, using Lipofectamine 2000 according to the manufacturer's protocol (Invitrogen). Twenty-four hours later, three-fifths of the cells from each well were transferred to wells in six-well plates and kept in DMEM supplemented with 10% FBS and 0.5 mg/ml G418 until the cells reached confluence. Thereafter, cells were kept in DMEM supplemented with 5% FBS and 0.25 mg/ml G418 for another 10 d, with replacement of medium every second day. Plates were washed with PBS and air-dried, and fixed with methanol for 20 min, and cells were stained with 0.2% crystal violet in 20% ethanol for 20 min, followed by three short rinses in water.\n\nCell Culture, Viability, Lysis, and Immunoblotting\nCell viability was assessed as relative redox metabolic activity using aresazurin-based assay. Cell lines used were CLB-BAR, CLB-GE, CLB-GA, Kelly, SK-N-AS, SK-N-BE, SK-N-DZ, IMR32, and CLB-PE neuroblastoma cells (Umapathy et al. 2017). Cells (4 × 104) were plated on collagen-coated 48-well plates and treated with either ceritinib or crizotinib with indicated concentrations. Cell viability was determined after 72 h with 55 µM resazurin (Sigma-Aldrich). After 3 h at 37°C, the amount of metabolized resazurin was analyzed as relative fluorescence with an Infinit200 plate reader (TEKAN). Results were from one of three representative experiments, with each experiment being performed in triplicate. GraphPad Prism 6.0 was used to calculate IC50 values by fitting data to a log (inhibitor concentration) versus normalized response (variable slope) equation.\n\nPC12 cells were transfected with 0.5 µg of empty pcDNA3 vector, pcDNA3-ALK-WT, or pcDNA3-ALK variants as specified, respectively by electroporation as described above. Cells were serum-starved for 36 h before lysis. For samples stimulated with ALK ligand, they were treated with 1 µg/ml of purified ALKAL1 protein for 30 min prior to lysis. Cells were washed twice with ice-cold PBS prior to harvest in lysis buffer (25 mmol/L Tris-Cl, pH7.5, 150 mmol/L NaCl, 1% (v/v) Triton X-100, 1 mmol/L DTT, protease inhibitor cocktail tablet [Roche]). Cell lysates were cleared by centrifugation at 14,000 rpm for 15 min at 4°C. Samples were boiled in 1× SDS sample buffer and analyzed by immunoblotting. Primary antibodies used for immunoblotting were: anti-pan-ERK (1:10,000), purchased from BD Transduction Laboratories, anti-pALK (Y1604) and anti-pERK1/2 (T202/Y204) from Cell Signaling Technology. Monoclonal antibody 135 (anti-ALK) was produced in the Hallberg laboratory against the extracellular domain of ALK as described (Moog-Lutz et al. 2005; Schonherr et al. 2012). Horseradish peroxidase–conjugated secondary antibodies goat anti-rabbit IgG and goat anti-mouse IgG (1:5,000) were from Thermo Scientific.\n\nALK Inhibitor Profiles on ALK Variants\nPC12 cells (2 × 106) were transfected with 1.0 µg of pcDNA3-ALK-WT, or pcDNA3-ALK variants as described (Guan et al. 2016; Siaw et al. 2016). Cells from three electroporations were pooled together, mixed, and equally seeded into nine wells of one 24-well plate. After 24–36 h culture, cells were treated with serial dilutions of the indicated inhibitors for 1 h before lysis. Cells were washed with cold 1× PBS and lysed with 1× SDS sample buffer and samples were boiled for 5 min at 95°C. Phospho-ALK (Y1604) antibody was used to detect ALK phosphorylation, and ALK mAb135 was used to detect total ALK. The intensity of pALK (Y1604) and total ALK bands was quantified with Image Studio Lite 3.1 software. Data were normalized to the 0 nM inhibitor samples. GraphPad Prism 6.0 was used to calculate IC50 values by fitting data to a log (inhibitor concentration) versus normalized response (variable slope) equation.\n\nPhosphoproteomics\nTyrosine and serine/threonine phosphorylation profiling of neuroblastoma cells (CLB-BAR, CLB-GE, and SK-N-AS) in the presence or absence of ceritinib (200 nM for 60 min) was undertaken by immunoaffinity purification with P-Tyr-100 or P-Ser/Thr-antibodies accordingly (Cell Signaling Technology). Cells were lysed in lysis buffer (20 mM Hepes pH 8.0, 9 M UREA, 1 mM sodium orthovanadate, 2.5 mM sodium pyrophosphate and 1 mM β-glycerol-phosphate) and ∼20 mg protein per sample subjected to LC-MS/MS. This was performed as previously described (Sattu et al. 2013). Phosphorylation responses were quantified for each site (tyrosine, serine, or threonine) under analysis as log2 fold change (FC) values of ceritinib treated/untreated control counts. If a specific site was measured in multiple peptides, its median log2 FC value was used for analysis. Protein sites were considered differentially phosphorylated when their absolute log2 FC values were >1.5. A gene set enrichment analysis (GSEA) was performed using Fisher's exact test and false discovery rate correction using the Benjamini–Hochberg method (Benjamini and Hochberg 1995). Reactome pathway information was downloaded from the Molecular Signatures Database v5.2 (Subramanian et al. 2005). The differentially phosphorylated proteins were mapped to the InWeb_InBioMap protein–protein interaction (PPI) network (Li et al. 2017). For the analysis of related TRKs, a list of 40 different TRKs was downloaded from HGNC (Gray et al. 2015).\n\nADDITIONAL INFORMATION\nData Deposition and Access\nThe detected DNA variants in FANCA and ALK have been submitted to ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) and can be found under accession numbers SCV000777897–SCV000777901. Raw sequencing data could not be deposited because of lack of patient consent.\n\nEthics Statement\nTreatment was initiated according HR-NBL-1 SIOPEN protocol (permit 02-294). A Clinical Ethical Board meeting and an endorsed license application from the MPA license (according to LVFS 2008:1) supported LDK378 compassionate use. Written informed consent from the patient's guardians was obtained and the patient was included in the Novartis compassionate use program for ceritinib (CLDK378A2003M). Tumor analyses and linkage to clinical information were performed according to the ethical permit 2009/1369-31/1. Written informed consent was obtained from the patient's guardians allowing the scientific research publication and are filed with the case notes.\n\nAcknowledgments\nThis work has been supported by grants from the Swedish Cancer Society (TMCAN2015/794; BHCAN15/775; RHP CAN15/391; PK CAN16/3625), the Swedish Childhood Cancer Foundation (TM PR2016-0147; BH 2015-80, and 2014-150; RHP 2015-96; PK PR2014-0084; JG 2016-0011; SF 15-0061; DT 12-009 and 12-002), the Swedish Research Council (RHP 2015-04466; BH 521-2012-2831; TM 521-2014-3031; PK 2014-3036); the Swedish Foundation for Strategic Research (RB13-0204, www.nnbcr.se), and the Göran Gustafsson Foundation (RHP2016). D.T. was supported by a PhD-Student program (NC2012-0026), J.G. was supported by a Post-doctoral Research Fellow Position (TJ2016-0088), and S.F. was supported by a Research Assistant Fellowship (14-0064), by the Swedish Childhood Cancer Foundation. The CLB-BAR, CLB-GE, CLB-GA, and CLB-PE cell lines used in this study were kindly provided by Valérie Combaret under an MTA agreement with the Center Léon Bérard laboratory (Lyon, France). Novartis supplied ceritinib free of charge within the compassionate use program “Ceritinib IPP for ALK-Positive IMT, ALCL, and Neuroblastoma Pediatric Patients.”\n\nCompeting Interest Statement\nThe authors have declared no competing interest.\n\nReferees\nRogier Versteeg\n\nAnonymous\n\nSupplementary Material\nSupplemental Material\n [Supplemental material is available for this article.]\n==== Refs\nREFERENCES\nAbbondanzo \nSL , Manz \nHJ , Klappenbach \nRS , Gootenberg \nJE . 1986 \nHepatocellular carcinoma in an 11-year-old girl with Fanconi's anemia. 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FEBS J \n280 : 5269 –5282 .23889739 \nSchleiermacher \nG , Janoueix-Lerosey \nI , Combaret \nV , Derre \nJ , Couturier \nJ , Aurias \nA , Delattre \nO . 2003 \nCombined 24-color karyotyping and comparative genomic hybridization analysis indicates predominant rearrangements of early replicating chromosome regions in neuroblastoma . Cancer Genet Cytogenet \n141 : 32 –42 .12581896 \nSchleiermacher \nG , Javanmardi \nN , Bernard \nV , Leroy \nQ , Cappo \nJ , Rio Frio \nT , Pierron \nG , Lapouble \nE , Combaret \nV , Speleman \nF , \n2014 \nEmergence of new ALK mutations at relapse of neuroblastoma . J Clin Oncol \n32 : 2727 –2734 .25071110 \nSchonherr \nC , Ruuth \nK , Yamazaki \nY , Eriksson \nT , Christensen \nJ , Palmer \nRH , Hallberg \nB . 2011 \nActivating ALK mutations found in neuroblastoma are inhibited by Crizotinib and NVP-TAE684 . Biochem J \n440 : 405 –413 .21838707 \nSchonherr \nC , Ruuth \nK , Kamaraj \nS , Wang \nCL , Yang \nHL , Combaret \nV , Djos \nA , Martinsson \nT , Christensen \nJG , Palmer \nRH , \n2012 \nAnaplastic lymphoma kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells . Oncogene \n31 : 5193 –5200 .22286764 \nShaw \nAT , Kim \nDW , Nakagawa \nK , Seto \nT , Crino \nL , Ahn \nMJ , De Pas \nT , Besse \nB , Solomon \nBJ , Blackhall \nF , \n2013 \nCrizotinib versus chemotherapy in advanced ALK-positive lung cancer . N Engl J Med \n368 : 2385 –2394 .23724913 \nShaw \nAT , Kim \nDW , Mehra \nR , Tan \nDS , Felip \nE , Chow \nLQ , Camidge \nDR , Vansteenkiste \nJ , Sharma \nS , De Pas \nT , \n2014 \nCeritinib in ALK-rearranged non-small-cell lung cancer . N Engl J Med \n370 : 1189 –1197 .24670165 \nSiaw \nJT , Wan \nH , Pfeifer \nK , Rivera \nVM , Guan \nJ , Palmer \nRH , Hallberg \nB . 2016 \nBrigatinib, an anaplastic lymphoma kinase inhibitor, abrogates activity and growth in ALK-positive neuroblastoma cells, Drosophila and mice . Oncotarget \n7 : 29011 –29022 .27049722 \nSubramanian \nA , Tamayo \nP , Mootha \nVK , Mukherjee \nS , Ebert \nBL , Gillette \nMA , Paulovich \nA , Pomeroy \nSL , Golub \nTR , Lander \nES , \n2005 \nGene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles . Proc Natl Acad Sci \n102 : 15545 –15550 .16199517 \nTartari \nCJ , Gunby \nRH , Coluccia \nAM , Sottocornola \nR , Cimbro \nB , Scapozza \nL , Donella-Deana \nA , Pinna \nLA , Gambacorti-Passerini \nC . 2008 \nCharacterization of some molecular mechanisms governing autoactivation of the catalytic domain of the anaplastic lymphoma kinase . J Biol Chem \n283 : 3743 –3750 .18070884 \nToyokawa \nG , Hirai \nF , Inamasu \nE , Yoshida \nT , Nosaki \nK , Takenaka \nT , Yamaguchi \nM , Seto \nT , Takenoyama \nM , Ichinose \nY . 2014 \nSecondary mutations at I1171 in the ALK gene confer resistance to both crizotinib and alectinib . J Thorac Oncol \n9 : e86 –e87 .25393798 \nUeda \nT , Nakata \nY , Yamasaki \nN , Oda \nH , Sentani \nK , Kanai \nA , Onishi \nN , Ikeda \nK , Sera \nY , Honda \nZI , \n2016 \nALK(R1275Q) perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN . Oncogene \n35 : 4447 –4458 .26829053 \nUmapathy \nG , El Wakil \nA , Witek \nB , Chesler \nL , Danielson \nL , Deng \nX , Gray \nNS , Johansson \nM , Kvarnbrink \nS , Ruuth \nK , \n2014 \nThe kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma . Sci Signal \n7 : ra102 .25351247 \nUmapathy \nG , Guan \nJ , Gustafsson \nDE , Javanmardi \nN , Cervantes-Madrid \nD , Djos \nA , Martinsson \nT , Palmer \nRH , Hallberg \nB . 2017 \nMEK inhibitor trametinib does not prevent the growth of anaplastic lymphoma kinase (ALK)-addicted neuroblastomas . Sci Signal \n10 : eaam7550 .29184034 \nWalsh \nMF , Chang \nVY , Kohlmann \nWK , Scott \nHS , Cunniff \nC , Bourdeaut \nF , Molenaar \nJJ , Porter \nCC , Sandlund \nJT , Plon \nSE , \n2017 \nRecommendations for childhood cancer screening and surveillance in DNA repair disorders . Clin Cancer Res \n23 : e23 –e31 .28572264 \nWang \nP , Wu \nF , Zhang \nJ , McMullen \nT , Young \nLC , Ingham \nRJ , Li \nL , Lai \nR . 2010 \nSerine phosphorylation of NPM-ALK, which is dependent on the auto-activation of the kinase activation loop, contributes to its oncogenic potential . Carcinogenesis \n32 : 146 –153 .21045017 \nWood \nAC , Krytska \nK , Ryles \nHT , Infarinato \nNR , Sano \nR , Hansel \nTD , Hart \nLS , King \nFJ , Smith \nTR , Ainscow \nE , \n2016 \nDual ALK and CDK4/6 inhibition demonstrates synergy against neuroblastoma . Clin Cancer Res \n23 : 2856 –2868 .27986745 \nZhang \nH , Pao \nLI , Zhou \nA , Brace \nAD , Halenbeck \nR , Hsu \nAW , Bray \nTL , Hestir \nK , Bosch \nE , Lee \nE , \n2014 \nDeorphanization of the human leukocyte tyrosine kinase (LTK) receptor by a signaling screen of the extracellular proteome . Proc Natl Acad Sci \n111 : 15741 –15745 .25331893 \nZhu \nS , Lee \nJS , Guo \nF , Shin \nJ , Perez-Atayde \nAR , Kutok \nJL , Rodig \nSJ , Neuberg \nDS , Helman \nD , Feng \nH , \n2012 \nActivated ALK collaborates with MYCN in neuroblastoma pathogenesis . Cancer Cell \n21 : 362 –373 .22439933\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2373-2873",
"issue": "4(4)",
"journal": "Cold Spring Harbor molecular case studies",
"keywords": "abnormality of the enteric ganglia; anaplastic large-cell lymphoma; neuroblastoma",
"medline_ta": "Cold Spring Harb Mol Case Stud",
"mesh_terms": "D016475:3T3 Cells; D000293:Adolescent; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001932:Brain Neoplasms; D005199:Fanconi Anemia; D052217:Fanconi Anemia Complementation Group A Protein; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D009447:Neuroblastoma; D016716:PC12 Cells; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051381:Rats; D013450:Sulfones",
"nlm_unique_id": "101660017",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29907598",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15938644;25228590;15592455;16199517;24819116;21575866;22439933;18083107;28572264;27483357;26418745;8122112;28259608;25429239;21045017;25228534;25393796;18923524;29317532;25517749;15886198;18089725;22249260;22764207;12525204;25071110;25331893;23742252;22789543;23104988;7911739;25351247;29084134;26630010;12581896;28787259;22235099;26554404;16410081;26973324;6505694;28471719;9174053;15226403;18923525;7705946;27986745;20719933;18070884;27049722;25381700;18990089;18923523;27892958;21221095;21059859;19464302;24060861;23724913;26829053;23598171;21138478;27760710;24670165;9053841;27573755;22286764;20979469;12393516;21502504;29184034;3026193;21838707;26438783;26794043;25251827;25736571;25361968;29078341;26481499;23889739;23139213;12395380;24811913;25979929;29098742;26121087;18724359;25393798",
"title": "Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib.",
"title_normalized": "clinical response of the novel activating alk i1171t mutation in neuroblastoma to the alk inhibitor ceritinib"
} | [
{
"companynumb": "SE-PFIZER INC-2018251283",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": null... |
{
"abstract": "Anlotinib is a multi-target tyrosine kinase inhibitor and has been approved for the treatment of patients with advanced non-small cell lung cancer. The most common adverse events of this treatment include hypertension, fatigue, thyroid-stimulating hormone elevation, hypertriglyceridemia, hand-foot syndrome and hypercholesterolemia. The present study reported the case of a 69-year-old man with squamous cell lung cancer that experienced disease progression following first-line and second-line chemotherapy. Subsequently, anlotinib was administered as a third-line therapy. Following the second cycle of oral targeted therapy, the patient was admitted to the hospital with a one-week history of chest tightnesss, shortness of breath and cough blood-stained sputum and necrosis. Computed tomography scan showed: Bronchopleural fistula (BPF) complicating lung cancer. However, symptoms were not relieved following anti-infective treatment and the patient subsequently died of respiratory failure. To the best of our knowledge, this is the first case of bronchopleural fistula associated with the use of anlotinib in a patient with squamous cell lung cancer.",
"affiliations": "Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China.;Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China.;Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China.;Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China.;Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China.;Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China.;Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China.;Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China.",
"authors": "Li|Dan|D|;Wei|Guoli|G|;Li|Lingchang|L|;Ma|Jun|J|;Huang|Xiaofei|X|;Qin|Fengxia|F|;Gong|Zhen|Z|;Huo|Jiege|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2019.1939",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "11(6)",
"journal": "Molecular and clinical oncology",
"keywords": "anlotinib; bronchopleural fistula; squamous cell lung cancer; tyrosine kinase inhibitor",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "595-598",
"pmc": null,
"pmid": "31798876",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": "27063612;20204363;30098152;23617826;28727865;26598747;30755242;31183998;26728673;26426663;22906119;30578392;29027099;18467733;29454091;21030401;24743204;30996564;22833836;30766754;29895706;29446853;30207593",
"title": "Bronchopleural fistula in squamous cell lung cancer following anlotinib treatment: A case report.",
"title_normalized": "bronchopleural fistula in squamous cell lung cancer following anlotinib treatment a case report"
} | [
{
"companynumb": "CN-ACCORD-194380",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NEDAPLATIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Observational studies have already reported the risk of serious infections in RA treated with tocilizumab, but in limited samples. The aim of this study was to investigate the predictive risk factors for serious infections in the largest European registry of patients treated with tocilizumab for RA.\n\n\n\nA total of 1491 RA patients included in the French REGistry-RoAcTEmra were analysed to calculate the incidence rate of first serious infections rate after initiation of tocilizumab. To identify independent factors associated with serious infections, a Cox model was performed.\n\n\n\nAmong the 1491 patients, average age 56.6 (13.6) years, 125 serious infections occurred in 122 patients (incidence rate of serious infection: 4.7/100 patient-years). Univariate analysis identified initial ACPA positivity as the only factor associated with a lower risk of serious infection [hazard ratio (HR) = 0.56, 95% CI: 0.36, 0.88]. Other factors significantly associated with a higher risk of serious infections were DAS28, concomitant Leflunomide (LEF) treatment, and absolute neutrophil count (ANC) at baseline. Initial ANC above 5.0 × 109/l (HR = 1.94, 95% CI: 1.32, 2.85; P < 0.001), negative ACPA (HR = 1.79, 95% CI: 1.15, 2.78; P = 0.012) at baseline and concomitant LEF treatment (LEF alone vs no treatment, HR = 2.18, 95% CI: 1.22, 3.88; P = 0.009) remained significantly associated with first serious infections in multivariate analysis after imputation for missing data.\n\n\n\nThe rate of first serious infections in current practice is similar to that reported in clinical trials. High ANC (above 5.0 × 109 at baseline), negative ACPA and concomitant therapy with LEF are predictive factors of serious infection, requiring in this case a tighter surveillance.",
"affiliations": "Department of Rheumatology, Teaching Hospital Lapeyronie, University of Montpellier, Montpellier.;Department of Rheumatology, Teaching Hospital Purpan, and University of Paul Sabatier, Toulouse.;Centre de Recherche en Epidémiologie et Statistiques, INSERM U1153, Centre d'Épidémiologie Clinique, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris (AP-HP), Descartes University, Paris.;Department of Rheumatology, Hospital Le Mans, Le Mans.;Department of Rheumatology, Teaching Hospital, and University of Lille 2, Lille.;Department of Rheumatology, Hospital Orléans, Orléans.;Department of Rheumatology, Teaching Hospital Lapeyronie, University of Montpellier, Montpellier.;Department of Rheumatology, Teaching Hospital, University of Strasbourg, Strasbourg.;Department of Rheumatology, Teaching Hospital Pellegrin, University of Bordeaux, Bordeaux.;Department of Rheumatology, Teaching Hospital, University of Clermont-Ferrand, Clermont-Ferrand.;Department of Rheumatology, Teaching Hospital, University of Rouen, Inserm 905, Rouen.;Department of Rheumatology, Teaching Hospital Cochin, University of Paris Descartes, Paris.;Department of Rheumatology, Teaching Hospital, University of Brest, Brest.;Department of Rheumatology, Hôpitaux Universitaires, and University of Paris Sud U1184, Center of Immunology of Viral Infections, Auto-immune Diseases, Paris, France.;Centre de Recherche en Epidémiologie et Statistiques, INSERM U1153, Centre d'Épidémiologie Clinique, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris (AP-HP), Descartes University, Paris.;Department of Rheumatology, Teaching Hospital, University of Strasbourg, Strasbourg.",
"authors": "Morel|Jacques|J|;Constantin|Arnaud|A|;Baron|Gabriel|G|;Dernis|Emmanuelle|E|;Flipo|René Marc|RM|;Rist|Stéphanie|S|;Combe|Bernard|B|;Gottenberg|Jacques Eric|JE|;Schaeverbeke|Thierry|T|;Soubrier|Martin|M|;Vittecoq|Olivier|O|;Dougados|Maxime|M|;Saraux|Alain|A|;Mariette|Xavier|X|;Ravaud|Philippe|P|;Sibilia|Jean|J|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001323:Autoantibodies; D007555:Isoxazoles; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D000077339:Leflunomide; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/kex238",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "56(10)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "DMARDs; observational study; registry; rheumatoid arthritis; risk factors; safety; serious infection; steroids; tocilizumab; tolerance",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001323:Autoantibodies; D004359:Drug Therapy, Combination; D005260:Female; D005602:France; D006801:Humans; D015994:Incidence; D007555:Isoxazoles; D000077339:Leflunomide; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D009894:Opportunistic Infections; D010456:Peptides, Cyclic; D016016:Proportional Hazards Models; D012042:Registries; D012307:Risk Factors",
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "1746-1754",
"pmc": null,
"pmid": "28957557",
"pubdate": "2017-10-01",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Risk factors of serious infections in patients with rheumatoid arthritis treated with tocilizumab in the French Registry REGATE.",
"title_normalized": "risk factors of serious infections in patients with rheumatoid arthritis treated with tocilizumab in the french registry regate"
} | [
{
"companynumb": "FR-TEVA-2017-FR-829191",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOCILIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Thrombotic microangiopathy (TMA) is a frequent and severe complication in systemic lupus erythematosus (SLE). It is reported in almost 20-25% of renal biopsies of patients with lupus nephritis (LN) and is associated with a poor renal prognosis. We report the case of a patient suffering from an aggressive form of proliferative LN in association with thrombotic microangiopathy (TMA-LN), who was resistant to standard combined immunosuppressive treatment with corticosteroids and cyclophosphamide, as well as to plasma exchange (PEX). Eculizumab was given as a rescue therapy with an optimal clinical response. We performed a systematic review of the literature and identified 11 papers, published between 2011 and 2018, with a total of 20 patients, in which eculizumab was used, always as rescue therapy, to treat TMA-LN. All reported cases showed a positive clinical response to eculizumab with a high rate of remission. Even if sparse, available clinical cases and case series support the use of eculizumab in highly selected cases as rescue treatment for LN-TMA resistant to conventional combined immunosuppressive treatment.",
"affiliations": "UO Nefrologia e Dialisi, Ospedale San Giovanni di Dio, Usl Toscana Centro, Italy.;UO Nefrologia, AOU Parma, Azienda Ospedaliera-Universitaria Parma, Dipartimento Medicina e Chirurgia, Università di Parma, Parma, Italy.;UO Nefrologia, AOU Parma, Azienda Ospedaliera-Universitaria Parma, Dipartimento Medicina e Chirurgia, Università di Parma, Parma, Italy.;UO Nefrologia, AOU Parma, Azienda Ospedaliera-Universitaria Parma, Dipartimento Medicina e Chirurgia, Università di Parma, Parma, Italy.;UO Nefrologia, AOU Parma, Azienda Ospedaliera-Universitaria Parma, Dipartimento Medicina e Chirurgia, Università di Parma, Parma, Italy.;SOC Genetica Medica, Azienda Ospedaliera-Universitaria Meyer, Firenze, Dipartimento di Scienze Biomediche Sperimentali e Cliniche \"Mario Serio\", Università degli studi di Firenze, Firenze, Italy.;UO Nefrologia, AOU Parma, Azienda Ospedaliera-Universitaria Parma, Dipartimento Medicina e Chirurgia, Università di Parma, Parma, Italy.;UO Nefrologia, AOU Parma, Azienda Ospedaliera-Universitaria Parma, Dipartimento Medicina e Chirurgia, Università di Parma, Parma, Italy.",
"authors": "Fani|Filippo Maria|FM|;Patera|Annalisa|A|;Delsante|Marco|M|;Rossi|Giovanni Maria|GM|;Manenti|Lucio|L|;Landini|Samuela|S|;Regolisti|Giuseppe|G|;Fiaccadori|Enrico|E|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D051056:Complement Inactivating Agents; D007166:Immunosuppressive Agents; C481642:eculizumab",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0393-5590",
"issue": "37(3)",
"journal": "Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia",
"keywords": "Thrombotic microangiopathy; eculizumab; lupus nephritis; systemic lupus erythematosus",
"medline_ta": "G Ital Nefrol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D051056:Complement Inactivating Agents; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D008181:Lupus Nephritis; D008875:Middle Aged; D010951:Plasma Exchange; D016879:Salvage Therapy; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "9426434",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32530153",
"pubdate": "2020-06-10",
"publication_types": "D002363:Case Reports; D000078182:Systematic Review",
"references": null,
"title": "Eculizumab as rescue therapy for lupus nephritis-related thrombotic microangiopathy.",
"title_normalized": "eculizumab as rescue therapy for lupus nephritis related thrombotic microangiopathy"
} | [
{
"companynumb": "IT-ACCORD-229942",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drugadditional": null,
"... |
{
"abstract": "Chemotherapy-induced nausea and vomiting (CINV) is one of the most frequent adverse events compromising quality of life (QoL) in patients undergoing autologous stem cell transplantation (ASCT). However, CINV prophylaxis is still lacking uniformity for high-dose melphalan (HDM), which is used to condition patients with multiple myeloma (MM). Netupitant/palonosetron (NEPA) is administered with dexamethasone (DEXA) for CINV prevention in several chemotherapy regimens. Our study aims to assess the efficacy of NEPA, without DEXA, in preventing CINV in 106 adult patients with MM receiving HDM and ASCT. All patients had antiemetic prophylaxis with multiple doses of NEPA 1 h before the start of conditioning and after 72 h and 120 h. A complete response (CR) was observed in 99 (93%) patients at 120 h (overall phase). The percentage of patients with complete control was 93%. The CR rate during the acute phase was 94% (n = 100). During the delayed phase, the CR rate was 95% (n = 101). Grade 1 nausea and vomiting were experienced by 82% and 12% of the patients, respectively. Grade 2 nausea was reported in 18% and vomiting in 10% of patients. Our results showed, for the first time, that NEPA, without DEXA, was a well-tolerated and effective antiemetic option for MM patients receiving HDM followed by ASCT.",
"affiliations": "Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Medical Affairs Department, Italfarmaco SpA, Milan, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Catholic University of the Sacred Heart, Rome, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy.;Stem Cell Transplant and Cellular Therapies Unit, Hemato-Oncology and Radiotherapy Department, Grande Ospedale Metropolitano \"Bianchi-Melacrino-Morelli\", Viale Europa, 89133, Reggio Calabria, Italy. massimo.martino@ospedalerc.it.",
"authors": "Loteta|Barbara|B|;Paviglianiti|Annalisa|A|;Naso|Virginia|V|;Ferreri|Anna|A|;Moscato|Tiziana|T|;Console|Giuseppe|G|;Canale|Filippo Antonio|FA|;Irrera|Giuseppe|G|;Pugliese|Marta|M|;Di Costanzo|Antonella|A|;Provenzano|Pasquale Fabio|PF|;Loddo|Viviana|V|;Porto|Gaetana|G|;Cusumano|Giuseppa|G|;Russo|Letteria|L|;Meliambro|Nicola|N|;Romeo|Valentina|V|;Porcino|Domenico|D|;Gallo|Salvatore|S|;Gangemi|Tiziana|T|;Rossetti|Antonio Maria|AM|;Martino|Massimo|M|http://orcid.org/0000-0002-3987-419X",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-021-06472-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "30(1)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "ASCT; Chemotherapy-induced nausea and vomiting (CINV); High-dose melphalan; Multiple myeloma; Netupitant/palonosetron (NEPA)",
"medline_ta": "Support Care Cancer",
"mesh_terms": null,
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "585-591",
"pmc": null,
"pmid": "34347181",
"pubdate": "2022-01",
"publication_types": "D016428:Journal Article",
"references": "16434375;15352652",
"title": "Netupitant/palonosetron without dexamethasone for preventing nausea and vomiting in patients with multiple myeloma receiving high-dose melphalan for autologous stem cell transplantation: a single-center experience.",
"title_normalized": "netupitant palonosetron without dexamethasone for preventing nausea and vomiting in patients with multiple myeloma receiving high dose melphalan for autologous stem cell transplantation a single center experience"
} | [
{
"companynumb": "IT-AMGEN-ITASP2021207794",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
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"drugadditional": "3",
... |
{
"abstract": "A 65-year-old woman received bone marrow transplantation from an HLA-DRB1 one locus mismatched donor for high-risk myelodysplastic syndrome. On day 237 after transplantation, she developed recurrent acute gastrointestinal graft-versus-host disease and adenoviral hemorrhagic cystitis. Hence, the methylprednisolone (mPSL) dose was increased to 2 mg/kg, and mesenchymal stem cells were administered. After the dose was tapered, she developed high fever, gross hematuria, and progressive pancytopenia. Then, the serum LDH, ferritin, and hepatobiliary enzyme levels of the patient increased, and hemophagocytosis was observed based on bone marrow examination. The adenovirus DNA level in the plasma was 6.3×106 copies/ml on day 278, and the volume of cerebrospinal fluid increased. Hence, the patient was diagnosed with meningitis and disseminated adenovirus infection. On day 288, cidofovir was administered at a dose of 1 mg/kg three times a week for 8 doses. The mPSL dose was again increased to 2 mg/kg for the treatment of hemophagocytic syndrome. Then, the patient's symptoms gradually improved, and the adenovirus viral load became negative on day 369. Based on the clinical course of our patient, cidofovir is useful for severe adenovirus infection.",
"affiliations": "Department of Hematology, Oita City Medical Association's Almeida Memorial Hospital.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine.;Department of Hematology, Oita Prefectural Hospital.;Department of Hematology, Oita City Medical Association's Almeida Memorial Hospital.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine.;Department of Hematology, Oita Memorial Hospital.;Department of Hematology, Oita University Hospital.",
"authors": "Nagamatsu|Kentaro|K|;Takano|Kuniko|K|;Sakata|Masanori|M|;Yanai|Yuka|Y|;Katayama|Oju|O|;Honda|Shuhei|S|;Yoshida|Natsumi|N|;Kawano|Rie|R|;Imamura|Tomoyuki|T|;Ogata|Masao|M|",
"chemical_list": "D000998:Antiviral Agents; D000077404:Cidofovir",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.62.251",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "62(4)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Adenovirus; Cidofovir; Disseminated infection; Hemophagocytic syndrome",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000257:Adenoviridae Infections; D000368:Aged; D000998:Antiviral Agents; D000077404:Cidofovir; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D008581:Meningitis",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "251-256",
"pmc": null,
"pmid": "33967148",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment with cidofovir for disseminated adenovirus infection accompanied by hemophagocytic syndrome and meningitis in an allogeneic hematopoietic stem cell transplantation recipient.",
"title_normalized": "successful treatment with cidofovir for disseminated adenovirus infection accompanied by hemophagocytic syndrome and meningitis in an allogeneic hematopoietic stem cell transplantation recipient"
} | [
{
"companynumb": "JP-SAKK-2021SA172140AA",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Immune-related adverse events (irAEs) are a class-effect of checkpoint inhibitors (CIs). The development of a Bullous pemphigoid (BP)-like blistering disease, driven by autoantibodies against the hemidesmosomal protein BP180, is a potentially serious irAE whose incidence seems to be increasing. We therefore set out to characterize the clinical and (immuno)histopathological features and treatment responses of cases of BP which developed during or after CI therapy collated in six German tertiary referral centers between 2014 and 2018. We identified twelve cases of BP which emerged during and/or after CI therapy. The time interval between the initiation of CI therapy and the diagnosis of BP was 3-74 weeks (median: 23 weeks). Age at the time of diagnosis of BP varied between 62 and 80 years (median: 76 years). The clinical presentation of the patients was diverse but the severity was relatively mild when compared to that seen in most cases of spontaneous BP. Only four patients met all of the immunopathological criteria recommended in the European guidelines for the diagnosis of BP. Topical corticosteroid treatment was sufficient to achieve disease control in most patients. CI therapy could be continued in 8 out of 12 patients. In summary, our study indicates that cases of BP during or after CI therapy bear several peculiarities distinguishing them from spontaneous BP. Given the diversity of the clinical presentation of CI-induced BP the application of existing diagnostic algorithms developed for spontaneous BP can be utilized to uncover the frequency and features of CI-induced BP and to develop and optimize management algorithms.",
"affiliations": "Department of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, Germany.;Department of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, Germany.;Skin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Hannover, Germany.;Department of Dermatology, University Medical Center Mainz, Mainz, Germany.;Department of Dermatology, University Medical Center Mainz, Mainz, Germany.;Department of Dermatology, University Hospital Dresden, Dresden, Germany.;Department of Dermatology, University Hospital Dresden, Dresden, Germany.;Department of Dermatology, University of Gießen, Gießen, Germany.;Department of Dermatology, HELIOS Klinikum Erfurt, Erfurt, Germany.;Department of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, Germany.;Department of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, Germany.",
"authors": "Sadik|Christian D|CD|;Langan|Ewan A|EA|;Gutzmer|Ralf|R|;Fleischer|Maria Isabel|MI|;Loquai|Carmen|C|;Reinhardt|Lydia|L|;Meier|Friedegund|F|;Göppner|Daniela|D|;Herbst|Rudolf A|RA|;Zillikens|Detlef|D|;Terheyden|Patrick|P|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000074322:Antineoplastic Agents, Immunological; D000082082:Immune Checkpoint Inhibitors",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2020.588582",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2020.588582\nImmunology\nOriginal Research\nRetrospective Analysis of Checkpoint Inhibitor Therapy-Associated Cases of Bullous Pemphigoid From Six German Dermatology Centers\nSadik Christian D. 12*†\n\nLangan Ewan A. 13†\n\nGutzmer Ralf 4\nFleischer Maria Isabel 5\nLoquai Carmen 5\nReinhardt Lydia 6\nMeier Friedegund 6\nGöppner Daniela 7\nHerbst Rudolf A. 8\nZillikens Detlef 12\n\nTerheyden Patrick 1\n\n1Department of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, Germany\n2Center for Research on Inflammation of the Skin (CRIS), University of Lübeck, Lübeck, Germany\n3Dermatological Sciences, University of Manchester, Manchester, United Kingdom\n4Skin Cancer Center Hannover, Department of Dermatology, Hannover Medical School, Hannover, Germany\n5Department of Dermatology, University Medical Center Mainz, Mainz, Germany\n6Department of Dermatology, University Hospital Dresden, Dresden, Germany\n7Department of Dermatology, University of Gießen, Gießen, Germany\n8Department of Dermatology, HELIOS Klinikum Erfurt, Erfurt, Germany\nEdited by: Nobuo Kanazawa, Hyogo College of Medicine, Japan\n\nReviewed by: Jun Yamagami, Keio University Hospital, Japan; Takashi Hashimoto, Osaka City University, Japan\n\n*Correspondence: Christian D. Sadik, Christian.Sadik@uksh.de\nThis article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology\n\n†These authors have contributed equally to this work\n\n23 2 2021\n2020\n11 58858229 7 2020\n22 12 2020\nCopyright © 2021 Sadik, Langan, Gutzmer, Fleischer, Loquai, Reinhardt, Meier, Göppner, Herbst, Zillikens and Terheyden\n2021\nSadik, Langan, Gutzmer, Fleischer, Loquai, Reinhardt, Meier, Göppner, Herbst, Zillikens and Terheyden\nThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nImmune-related adverse events (irAEs) are a class-effect of checkpoint inhibitors (CIs). The development of a Bullous pemphigoid (BP)-like blistering disease, driven by autoantibodies against the hemidesmosomal protein BP180, is a potentially serious irAE whose incidence seems to be increasing. We therefore set out to characterize the clinical and (immuno)histopathological features and treatment responses of cases of BP which developed during or after CI therapy collated in six German tertiary referral centers between 2014 and 2018. We identified twelve cases of BP which emerged during and/or after CI therapy. The time interval between the initiation of CI therapy and the diagnosis of BP was 3–74 weeks (median: 23 weeks). Age at the time of diagnosis of BP varied between 62 and 80 years (median: 76 years). The clinical presentation of the patients was diverse but the severity was relatively mild when compared to that seen in most cases of spontaneous BP. Only four patients met all of the immunopathological criteria recommended in the European guidelines for the diagnosis of BP. Topical corticosteroid treatment was sufficient to achieve disease control in most patients. CI therapy could be continued in 8 out of 12 patients. In summary, our study indicates that cases of BP during or after CI therapy bear several peculiarities distinguishing them from spontaneous BP. Given the diversity of the clinical presentation of CI-induced BP the application of existing diagnostic algorithms developed for spontaneous BP can be utilized to uncover the frequency and features of CI-induced BP and to develop and optimize management algorithms.\n\ncheckpoint inhibitors\nautoimmunity\npemphigoid disease\nautoantibodies\npembrolizumab\nnivolumab\nPD-1 - PD-L1 axis\nipilimumab\nDeutsche Forschungsgemeinschaft10.13039/501100001659\n==== Body\nBackground\n\nCheckpoint inhibitors (CIs) constitute a new class of immunomodulatory drugs which block co-inhibitory signals on immune effector cells and result in the generation of potent T-cell mediated immune responses. Among the CIs which are currently licensed are monoclonal antibodies which target the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or the programmed cell death protein 1 (PD-1) pathway. For example, the first-in-class drug ipilimumab inhibits CTLA-4, nivolumab and pembrolizumab inhibit PD-1, and atezolizumab and durvalumab target the PD-1 ligand PD-L1 (1). The advent of checkpoint inhibitors has revolutionized the treatment of solid cancers. Initially licensed for the treatment of metastatic melanoma, CIs are employed in an ever increasing number of cancer entities, including Merkel cell carcinoma, head and neck squamous cell carcinoma, renal cell carcinoma, non-small cell lung cancer, urothelial bladder cancer, hepatocellular carcinoma, and Hodgkin’s lymphoma (1).\n\nGiven that the CTLA-4 and PD-1 pathways play a central role in regulating cellular immune responses, removal of this control mechanism can result in both generalized and tissue-specific inflammation. These inflammatory responses are collectively termed “immune-related adverse events” (irAEs), and include, but are not limited to, dermatitis, colitis, hypophysitis, hepatitis, and nephritis (1). The skin is the most frequently affected organ, with up to 50% of patients receiving CIs developing skin-related irAEs.\n\nThe clinical presentation of cutaneous irAEs is remarkably diverse. Commonly presenting with a non-specific maculopapular rash accompanied by pruritus, they may also present with lichenoid, eczematous, granulomatous, lupus-like, or erythema multiforme-like skin changes and/or vitiligo (2).\n\nMost intriguingly, there is a growing body of literature which reports the development of the antibody-driven autoimmune disease bullous pemphigoid (BP), the most common disease of the group of pemphigoid diseases, in the context of treatment with immune CI (2–8).\n\nThe hallmark of BP is the development of autoimmunity against type XVII collagen (BP180) (9). BP presents clinically with the development of widespread urticarial plaques (pre-bullous phase), which evolve into blisters and erosions (10, 11). However, non-bullous and atypical variants of BP also exist. In these variants, patients exhibit localized blister formation with minimal or absent inflammation of the surrounding skin. Additionally, BP may present with predominantly eczematous (including dyshidrosiform) and subacute prurigo-like skin changes (12). Indeed, BP may exist in the absence of skin changes, with the only symptom being widespread, intractable itch. Given the wide spectrum of clinical symptoms and signs in BP, the disease can neither be reliably diagnosed nor excluded based on the clinical presentation alone. The European Academy of Dermatology and Venereology (EADV) guidelines recommend that the diagnosis of BP should be based on both the clinical findings and (immuno)pathological investigations of the patient’s skin, both lesional and perilesional, and serum (12). Central to establishing the diagnosis of BP is the demonstration of linear depositions of autoantibodies, which are in most cases predominantly of the IgG immunoglobulin class, and/or of complement factor 3 (C3) at the dermal-epidermal junction (DEJ) of perilesional skin (12). As the deposition of autoantibodies and/or complement at the DEJ is the defining feature of all pemphigoid diseases and as the clinical features of BP may overlap with those of other pemphigoid diseases, the clear distinction of pemphigoid diseases requires the detection of autoantibodies in the serum and a determination of their antigen specificity. This is achieved by indirect immunofluorescence microscopy on NaCl-split human skin, which detects the presence of autoantibodies against proteins of the dermal-epidermal junction, and by ELISA biochip-based techniques, and/or immunoblot assays to pinpoint the antigen specificity of the autoantibodies. Serological examination alone is not sufficient to diagnose BP given that autoantibodies are reportedly undetectable in the serum of up to 20% of BP patients, but are present in the serum of 0.5% of healthy individuals (12, 13). Histopathologically, an early blister exhibits a subepidermal cleft combined with a dense dermal inflammatory infiltrate mainly consisting of eosinophils and neutrophils. However, the histopathological examination is also non-specific and is therefore not suitable alone to confirm the diagnosis (14).\n\nThe complexity and heterogeneity of both BP and cutaneous irAEs means that a comprehensive clinical, serological, and (immuno)histopathological work-up is central to correctly diagnosing suspected cases of BP during or after CI therapy. In the present study, we retrospectively profiled twelve cases of CI-associated BP diagnosed in six German Dermatology centres and contrasted their features with previously reported cases of both immune-checkpoint mediated and spontaneous BP.\n\nMethods\n\nWe systematically searched the clinical records of patients treated with CIs between 2014 and 2018 in six German Dermatology centres for the diagnosis of BP. The case notes of affected patients were then retrospectively analyzed to determine the salient clinical, histopathological, and immunopathological features. Histo- and immunopathological analyses were conducted by routine autoimmune and dermatohistopathology laboratories. Ethical approval was obtained from the University of Lübeck’s ethics committee 19-332A.\n\nResults\n\nWe identified 12 patients diagnosed with BP during immune CI therapy between 2014 and 2018. Seven patients were undergoing CI for metastatic cutaneous melanoma. The remaining patients were receiving CI therapy for metastatic uveal melanoma, metastatic melanoma of unknown primary, squamous cell carcinoma of the lung, and renal cell carcinoma (Table 1).\n\nTable 1 Clinical features of patients diagnosed with bullous pemphigoid (BP) under CI therapy.\n\nPat. No.\tSex/age at emergence of BP\tCancer\tTreatment\tTreatment response\tTime interval initiation of CI therapy—BP (weeks)\tClinical symptoms of BP\tOther irAEs\t\n1\tM/62\tAmelanotic melanoma\tP\tCR\t27\tSkin: scattered papules with central vesicles\nMucosa: vesicular lesions of the oral mucosa\t–\t\n2\tM/76\tRenal cell CA\tN\tSD\t19\tSkin: palmoplantar hyperkeratosis, polygonal papules and vesicles;\nMucosa: vesicular and white reticular lesions of the oral mucosa\t–\t\n3\tM/76\tMM\tP\tPR\t16\tSkin: large facial bullae, minimal pruritus\nMucosa: none\t–\t\n4\tM/62\tNM\tP\tPD\t8\tSkin: maculopapular erythema and bullae on the trunk\nMucosa: none\t–\t\n5\tM/78\tMM of unknown primary\tP\tCR\t74\tSkin: maculopapular erythema and bullae on the trunk\nMucosa: none\t–\t\n6\tM/70\tNM\tN\tCR\t69\tNo information available\t–\t\n7\tM/80\tSSM\tN\tPR\t3\tSkin: bullae and pruritus affecting the trunk and extremities\nMucosa: none\tMaculopapular rash on the trunk\t\n8\tF/73\tNot available\tP\tPR\t37\tSkin: single blister on the left thigh\nMucosa: none\tThyroiditis de Quervain\npruritus\t\n9\tF/76\tUveal melanoma\tN + I\tPD\t60\tSkin: pruritus, excoriations, later urticated plaques and blisters\nMucosa: none\t–\t\n10\tM/63\tSquamous cell CA of the lung\tN\tPD\t11\tSkin: erythematous plaques\nMucosa: none\t–\t\n11\tM/77\tMM\tN\tPD\t55\tSkin: erythematous plaques\nMucosa: none\tEncephalitis Grade 3\t\n12\tM/76\tMM\tN +/− Relatlimab\tPD\t60\tSkin: erythematous plaques and one blister\nMucosa: none\t–\t\nM, male; F, female; N, nivolumab; P, pembrolizumab; I, ipilimumab; CA, carcinoma, MM, malignant melanoma; NM, nodular melanoma; SSM, superficial spreading melanoma; CR, complete remission; PR, partial remission; PD, progressive disease; SD, stable disease.\n\nTen patients were males, two were females. The age at diagnosis of BP ranged between 62 and 80 years with a median age of 76 years (Figure 1). Five patients received pembrolizumab, six received nivolumab, and in one case the combination of nivolumab and ipilimumab was administered (Table 1). The median time interval from the initiation of CI therapy to the diagnosis of BP was 23 weeks and ranged between 3 and 74 weeks (Figure 1).\n\nFigure 1 Distribution of age and latency after the initiation of CI therapy to the diagnosis of bullous pemphigoid (BP). (A) Age of patients at the diagnosis of BP. (B) Time interval in weeks between the initiation of CI therapy and the diagnosis of BP. Results are presented as violin plot. Each dot represents one patient (n = 12). The red dashed line represents the median, the red dotted lines the 25 and 75% percentiles.\n\nThe clinical presentation of the 12 patients at the time of diagnosis of BP is detailed in Table 1, and illustrations of their clinical presentation are compiled in Figure 2.\n\nFigure 2 Examples of clinical manifestations of cases diagnosed as bullous pemphigoid (BP) under CI therapy. (A) Patient presenting with erythematous urticaria and tense blisters and erosions scattered over larger areas of the body, typical for classical BP. Patients presenting with (B) a single blister and (C) a single blister and erythematous urticaria. (D) Eczematous skin changes. (E) Oral mucosal erosions.\n\nNine patients developed vesico-bullous skin changes, but in two of these patients this comprised only a single blister (Table 1). Two patients exhibited urticarial plaques without blistering, the typical presentation of the pre-bullous state of BP (15). Two patients additionally developed vesicles affecting the oral mucosa; the only patients to exhibit involvement of the mucous membranes.\n\nDirect immunofluorescence (DIF) microscopy was only conducted in six of the patients. Linear IgG and C3 depositions were present in the skin biopsies from five patients, and only linear C3 deposition in one patient (Table 2). Indirect immunofluorescence (IIF) microscopy using monkey esophagus and/or salt-split human skin was performed in eleven patients. IgG antibodies were thereby detected in seven patients (Table 2). One of these patients additionally had low levels of IgA autoantibodies in the serum. Circulating IgA but not IgG antibodies, binding to the epidermal side of salt-split skin, were detected in one patient who presented with a single blister affecting the left thigh (Tables 1 and 2). IIF microscopy was negative in three patients (Table 2). The sera of nine patients were examined for anti-BP180 IgG by ELISA. Anti-BP180 IgG was detectable in four of these patients, and in another patient anti-LAD IgG was detected by immunoblot (Table 2). In the sera of two patients positive for anti-BP180 IgG, anti-BP230 IgG was additionally present. The histopathological findings were variable (Table 2), but the histopathological picture was often summarized as interface dermatitis.\n\nTable 2 Summary of immuno- and histopathology.\n\nPat. No.\tDIF\tIIF\tELISA\tHistopathology\t\n1\tn/p\tIgG: +\tBP180+\nBP230 +\tInterface dermatitis, focal epidermal necrosis\t\n2\tC3: +\tIgG: +\tBP180+\nBP230 +\tOrthohyperkeratosis, hypergranulosis, lichenoid interface dermatitis with a subepidermal, band-like lymphocytic infiltrate obscuring the DEJ\t\n3\tIgG: +\nC3: +\tIgG: +\tBP180: +\nBP230: −\tn/p\t\n4\tUnspecific IgG & C3 deposition\tIgG: +\tBP180: −\nBP230: −\tSubepidermal cleft, lymphohistiocytic infiltrate with single neutrophils and eosinophils\t\n5\tIgG: +\nC3: +\tIgG: (+)\tBP180: −\nBP230: −\tn/p\t\n6\tn/p\tIgG: −\tBP180: −\nBP230: −\tn/p\t\n7\tn/p\tIgG: +\tBP180: −\nBP230: n/p\tn/p\t\n8\tn/p\tIgA: + (DS)\tBP180: n/p\nBP230: n/p\tn/p\t\n9\tC3: +\tIgG: +\nIgA: (+)\tBP180: n/p\nBP230: n/p\tConsistent with cutaneous drug reaction or BP\t\n10\tn/p\tn/p\tBP180: +\nBP230: n/p\tSuperficial interface dermatitis with eosinophilia\t\n11\tn/p\tIgG: −\tBP180: n/p\nBP230: n/p\tFocal orthohyper- und parakeratosis, psoriasiform acanthosis, mixed inflammatory infiltrate including eosinophils\t\n12\tIgG: +\nC3: +\tIgG: −\tBP180: −\nBP230: −\n(*)LAD: +\tSpongiotic dermatitis, lymphohistiocytic infiltrate with eosinophils\t\nn/p, not performed; −, negative, +, positive; +, positive; (+), faintly positive; −, negative; DS, dermal side; (*), assayed by immunoblot.\n\nAfter the diagnosis of BP, CI therapy was permanently discontinued in four patients but switched or continued in the remaining eight patients (Table 3). The treatment of the skin lesions in the different centers in 11 cases included topical corticosteroids (classes II to IV according to Niedner’s classification) (Table 3). Three patients additionally required treatment with systemic corticosteroids, one of these patients also received three cycles of rituximab. Treatment resulted in a complete resolution of the skin findings in six patients and a partial resolution in the remaining six patients. Eleven patients remain alive, but one patient has subsequently died of metastatic melanoma.\n\nTable 3 Management and outcome of bullous pemphigoid (BP).\n\nPat. No.\tTreatment of BP\tOutcome of BP\tCI therapy\t\n1\tTopical clobetasol ointment 2x/day + prednisolone 1 mg/kg p.o. followed by a slow taper over the course of 3 months plus rituximab 375 mg/m² every 4 weeks; discontinuation after three doses due to CTCAE grade 3 thrombocytopenia\tMinor alleviation\tDiscontinued\t\n2\tPalmoplantar: topical clobetasol ointment 1x/day, later mometasone ointment 1x/day; oral mucosa: triamcinolone, dexpanthenol ointment, and mouthwash\tAlleviated but not completely resolved\tContinued\t\n3\tTopical corticosteroids\tAlleviated under continued topical corticosteroids but not resolved completely\tContinued\t\n4\tOral methylprednisolone\tResolved\tDiscontinued\t\n5\tTopical mometasone ointment\tResolved\tDiscontinued\t\n6\tTopical and systemic corticosteroids\tResolved\tSwitched to Pembrolizumab/discontinued\t\n7\tTopical corticosteroids\tOngoing\tContinued\t\n8\tTopical prednicarbate\tResolved\tContinued\t\n9\tTopical corticosteroids\nPrednisolone 15 mg/day p.o.\tResolved\tPaused\t\n10\tTopical clobetasol ointment 2x/day\tResolved\tContinued\t\n11\tTopical clobetasol ointment 2x/day\tOngoing\tDiscontinued\t\n12\tTopical clobetasol ointment 2x/day\tOngoing\tContinued\t\n\nDiscussion\n\nWe identified 12 patients who developed BP, while undergoing CI therapy for metastatic cancer, via a retrospective analysis of case notes at six Departments of Dermatology in Germany. Our analysis reveals that the minimal diagnostic requirements needed to confirm the presence of BP were not met in all cases, suggesting that diagnostic algorithms for BP have not been fully incorporated into routine clinical practice and testing for linear deposition of autoantibodies and/or C3 at the DEJ was not performed as standard.\n\nIn fact, linear depositions of autoantibodies or C3 at the DEJ were demonstrated in six out of twelve cases recorded as “BP during CI therapy.” It must be borne in mind that these minimal requirements do not allow a clear distinction between BP and other pemphigoid diseases such as the inflammatory variant of epidermolysis bullosa acquisita and anti-p200 pemphigoid, which cannot be clearly distinguished from BP by the clinical presentation alone. Given that linear deposition of autoantibodies at the DEJ is also present in epidermolysis bullosa acquisita and anti-p200 pemphigoid, the diagnosis of BP can only be confirmed by additionally detecting anti-BP180 IgG in the serum. This criterion was only met in four of our cases. The detection of linear depositions of IgG at the DEJ and the demonstration of anti-BP180 IgG antibodies in the serum was only met in three cases. The absence of confirmatory serum anti-BP180 IgG antibodies is a frequent finding in the hitherto reported cases of BP during CI therapy. Therefore, it is difficult to determine the true incidence and prevalence of BP during CI therapy. Nevertheless, a temporal relationship between the use of CI therapy and the development of BP and/or the development of BP during a re-challenge with CI therapy provide evidence for an irAE aetiology.\n\nGiven the complexity and clinical heterogeneity of BP as an autoimmune blistering dermatosis, let alone as an irAE, diagnostic algorithms for the accurate diagnosis of cutaneous irAEs under CI therapy are necessary not only to optimize CI therapy and improve the management of its side-effects, but also to gain new insight into the pathophysiology of autoimmune blistering diseases in general. We therefore suggest that in all cases of cutaneous irAEs under CI, including cases where severe pruritus is the only symptom, DIF microscopy for linear depositions of autoantibodies at the DEJ should be considered. If positive, serological analyses searching for autoantibodies against proteins of the dermal-epidermal adhesion complex should be conducted. The analyses should include IIF microscopy to screen for autoantibodies directed to proteins of the dermal-epidermal adhesion complex and should optimally be conducted on NaCl-split human skin because it, in contrast to the alternative substrate monkey esophagus, allows BP to be distinguished from epidermolysis bullosa acquisita and anti-p200 pemphigoid depending on where the antibodies bind. IIF microscopy should be followed by ELISA and immunoblotting analyses to precisely determine the antigen specificity of the autoantibodies. Employing this diagnostic algorithm may ensure the accurate determination of the frequency of pemphigoid diseases, possibly induced by CIs, and to pinpoint their specific features, central to improving the management of cutaneous irAEs. In fact, determination of the presence and serum concentration of autoantibodies directed to proteins of the dermal-epidermal adhesion complex could even be considered prior to the initiation of CI therapy. This may help to determine whether CI inhibition may promote the emergence of BP by facilitating the break of tolerance against proteins of the dermal-epidermal adhesion complex or by promoting the initiation of the effector phase in individuals in whom tolerance had already been broken before the administration of CIs. Ultimately, patient subgroups with increased susceptibility to BP under CI therapy could be identified to facilitate earlier recognition and treatment. Interestingly, it has recently been suggested that the development of skin autoantibodies may even be associated with improved response to CI therapy, albeit in lung cancer (16). Therefore, the detection of skin autoantibodies may actually provide additional prognostic information.\n\nFurthermore, it is worth bearing in mind that CI therapy has also been associated with the development of lichen planus pemphigoides (LPP) (17, 18). While the clinical presentation of LPP may mimic BP, a careful correlation of the clinical, histopathological, and immunopathological features usually permits differentiation between these two conditions.\n\nThe twelve cases of BP during CI therapy reported here were mild to moderate in their clinical severity. In contrast to spontaneous BP, the skin lesions were often restricted to single body areas and treatment with topical or oral corticosteroids alone was sufficient to achieve disease control in 11 patients. Topical therapy for spontaneous BP, according to the European guidelines, usually includes whole body treatment with superpotent corticosteroids twice daily (12). However, topical therapy alone is often not sufficient to control the disease and the addition of one or two systemic treatment options, including dapsone, azathioprine, mycophenolate mofetil, doxycycline, high-dose intravenous corticosteroid pulses, intravenous immunoglobulins, or rituximab is often necessary.\n\nIt is striking that no patient required the topical treatment regimen recommended by the European guidelines and that only one patient required systemic treatment with rituximab. Although rituximab has been highlighted in a recent case report to be effective in the treatment of CI-induced BP, in our patient the effect was poor, consistent with its limited efficacy in spontaneous BP (19).\n\nFurthermore, the histopathological analysis of lesional skin in our study, as well as in many case reports, revealed a minimal inflammatory infiltrate in the dermis. These features are reminiscent of the findings reported recently in BP induced by dipeptidyl peptidase IV inhibitors (“gliptins”) used in the treatment of diabetes (20–22), although a causal link between gliptin intake and BP has not yet been established. Similar to CI-associated disease, gliptin-associated cases tend to feature milder skin inflammation (22), and discontinuing gliptins does not lead to spontaneous reversal of disease as is the case for most other drug-induced cutaneous side-effects (20). Intriguingly, dipeptidyl peptidase IV (CD26) exerts diverse immunomodulatory roles, including regulatory functions in T cell activation similar to PD-1 and its ligands (23). It is therefore tempting to speculate that gliptins and CIs elicit BP by related molecular mechanisms.\n\nCollectively, our retrospective analysis reveals important differences between spontaneous BP and BP-induced during CI therapy. Firstly, BP during CI therapy was milder than as is case in spontaneous BP. Secondly, the immunopathological features of spontaneous BP were only confirmed in a minority of CI-induced cases. Whilst this may result from a lack of familiarity of the diagnostic algorithms for BP in oncology, it may also reflect a milder immune response to BP180 in IC-induced BP, potentially explaining the less severe phenotype. Consequently, the immunopathological analyses usually used for the diagnosis of BP may be not sensitive enough and, with respect to ELISA assays, the cut-lines defined for BP to distinguish pathological and non-pathological autoantibody levels may be not completely applicable to diagnose CI-induced BP. In line with this latter notion, it has recently been reported that levels of anti-BP180 IgG are often increased in patients under CI therapy but in the vast majority of cases still do not reach the defined cut-off lines between the pathological and non-pathological range. Furthermore, commercially available ELISAs for the detection of anti-BP180 IgG only detect autoantibodies directed to one or both terminal ends of the NC16A domain of BP180. It cannot be excluded that blistering disease induced by CI therapy results from the production of autoantibodies against other parts of the protein. Indeed, there are also reports of CI inducing rare BP variants, including anti-LAD-1 IgG-positive, anti-BP180 NC16A IgG-negative BP (24).\n\nPerhaps the most important question for the clinical management of CI-induced BP is whether CI therapy can be continued. Whilst the decision to continue IC therapy in patients with IC-induced BP should be made on an individual basis, carefully weighing up the risks and benefits, it is reassuring that treatment could be continued in a number of our patients. In fact, it is worth noting that similar to the case in IC-induced vitiligo (25, 26), IC-induced BP may be associated with improved treatment response and increased overall survival (27), although this remains to be confirmed in larger, prospective studies.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Ethics Committee of the University of Lübeck.\n\nAuthor Contributions\n\nCS, EAL, PT, RG, MF, CL, LR, FM, DG, RH, and DZ identified patients and characterized these cases. CS, EAL, and PT planned the study, analyzed the data, and wrote the paper. RG, MF, CL, LR, FM, DG, RH, and DZ revised the paper. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis research was supported by DFG funding for the Clinician Research Unit 303 Pemphigoid Diseases—Molecular Pathways and their therapeutic Potential and for the Excellence Cluster 2167 Precision Medicine in Chronic Inflammation.\n\nConflict of Interest\n\nDG reports personal fees and other from Pierre Fabre Pharma Gmbh, personal fees and other from Roche Pharma AG, personal fees and other from Bristol-Myers Squibb GmbH & Co. KGaA, personal fees and other from Novartis Pharma GmbH, personal fees and other from Sanofi-Aventis GmbH, during the conduct of the study; other from Amgen GmbH, other from Janssen-Cilag GmbH, other from Galderma Laberatorium GmbH, outside the submitted work. RG reports personal fees and non-financial support from BristolMyersSquibb, personal fees and non-financial support from Roche Pharma, grants, personal fees and non-financial support from Merck Serono, grants, personal fees and non-financial support from Amgen, personal fees and non-financial support from Pierre Fabre, grants, personal fees and non-financial support from Sanofi Regeneron, personal fees from MerckSharpDohme, grants, personal fees and non-financial support from Novartis, personal fees from Almirall Hermal, grants and personal fees from Pfizer, personal fees from SUN Pharma, personal fees from 4SC, grants from Johnson&Johnson outside the submitted work. RH reports personal fees from ROCHE, personal fees from BMS, personal fees from MSD, personal fees from Novartis, personal fees from Pierre-Fabre, outside the submitted work. EL reports personal fees and non-financial support from BristolMyersSquibb, personal fees and non-financial support from Novartis, Meeting and travel support from Curevac and advisory board fees from Sun Pharma. CL reports personal fees from BMS, personal fees from MSD, personal fees from Sanofi, personal fees from Novartis, personal fees from Roche, personal fees from Pierre Fabre, personal fees from Amgen, personal fees from Kyowa Kirin, personal fees from Biontech, personal fees from Almiral Hermal, personal fees from Sun Pharma, personal fees from Merck, outside the submitted work. PT: speaker´s honoraria from BMS, Novartis, MSD, Pierre-Fabre, CureVac and Roche, consultant´s honoraria from BMS, Novartis, Pierre-Fabre, Merck Serono, Sanofi und Roche and travel support fom BMS, Pierre-Fabre and Roche.\n\nThe remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n\n1 Callahan MK Postow MA Wolchok JD . Targeting T Cell Co-receptors for Cancer Therapy. Immunity (2016) 44 (5 ):1069–78. 10.1016/j.immuni.2016.04.023\n2 Sibaud V . Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy. Am J Clin Dermatol (2018) 19 (3 ):345–61. 10.1007/s40257-017-0336-3\n3 Siegel J Totonchy M Damsky W Berk-Krauss J Castiglione F Jr. Sznol M . Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol (2018) 79 (6 ):1081–8. 10.1016/j.jaad.2018.07.008\n4 Sun CW Grossman SK Aphale A Hsu S . Pembrolizumab-induced bullous pemphigoid. JAAD Case Rep (2019) 5 (4 ):362–4. 10.1016/j.jdcr.2019.02.008\n5 Heinzerling L de Toni EN Schett G Hundorfean G Zimmer L . Checkpoint Inhibitors. Dtsch Arztebl Int (2019) 116 (8 ):119–26. 10.3238/arztebl.2019.0119\n6 Jour G Glitza IC Ellis RM Torres-Cabala CA Tetzlaff MT Li JY . Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions. J Cutan Pathol (2016) 43 (8 ):688–96. 10.1111/cup.12717\n7 Hirotsu K Chiou AS Chiang A Kim J Kwong BY Pugliese S . Localized bullous pemphigoid in a melanoma patient with dual exposure to PD-1 checkpoint inhibition and radiation therapy. JAAD Case Rep (2017) 3 (5 ):404–6. 10.1016/j.jdcr.2017.06.004\n8 Thomsen K Diernaes J Ollegaard TH Spaun E Vestergaard C . Bullous Pemphigoid as an Adverse Reaction to Pembrolizumab: Two Case Reports. Case Rep Dermatol (2018) 10 (2 ):154–7. 10.1159/000489661\n9 Sadik CD Schmidt E Zillikens D Hashimoto T . Recent progresses and perspectives in autoimmune bullous diseases. J Allergy Clin Immunol (2020) 145 (4 ):1145–7. 10.1016/j.jaci.2020.02.020\n10 Sadik CD Schmidt E . Resolution in bullous pemphigoid. Semin Immunopathol (2019) 41 (6 ):645–54. 10.1007/s00281-019-00759-y\n11 Egami S Yamagami J Amagai M . Autoimmune bullous skin diseases, pemphigus and pemphigoid. J Allergy Clin Immunol (2020) 145 (4 ):1031–47. 10.1016/j.jaci.2020.02.013\n12 Feliciani C Joly P Jonkman MF Zambruno G Zillikens D Ioannides D . Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology. Br J Dermatol (2015) 172 (4 ):867–77. 10.1111/bjd.13717\n13 Prussmann W Prussmann J Koga H Recke A Iwata H Juhl D . Prevalence of pemphigus and pemphigoid autoantibodies in the general population. Orphanet J Rare Dis (2015) 10 :63. 10.1186/s13023-015-0278-x 25971981\n14 Schmidt E Zillikens D . Pemphigoid diseases. Lancet (2013) 381 (9863 ):320–32. 10.1016/S0140-6736(12)61140-4\n15 Sadik CD Lima AL Zillikens D . Pemphigoid gestationis: Toward a better understanding of the etiopathogenesis. Clin Dermatol (2016) 34 (3 ):378–82. 10.1016/j.clindermatol.2016.02.010\n16 Ali OH Bomze D Ring S Berner F Fassler M Diem S . BP180-specific IgG is associated with skin adverse events, therapy response and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors. J Am Acad Dermatol (2020) 82 (4 ):854–61. 10.1016/j.jaad.2019.08.045\n17 Strickley JD Vence LM Burton SK Callen JP . Nivolumab-induced lichen planus pemphigoides. Cutis (2019) 103 (4 ):224–6.\n18 Sato Y Fujimura T Mizuashi M Aiba S . Lichen planus pemphigoides developing from patient with non-small-cell lung cancer treated with nivolumab. J Dermatol (2019) 46 (10 ):e374–e5. 10.1111/1346-8138.14906\n19 Lamberts A Euverman HI Terra JB Jonkman MF Horvath B . Effectiveness and Safety of Rituximab in Recalcitrant Pemphigoid Diseases. Front Immunol (2018) 9 :248. 10.3389/fimmu.2018.00248 29520266\n20 Plaquevent M Tetart F Fardet L Ingen-Housz-Oro S Valeyrie-Allanore L Bernard P . Higher Frequency of Dipeptidyl Peptidase-4 Inhibitor Intake in Bullous Pemphigoid Patients than in the French General Population. J Invest Dermatol (2019) 139 (4 ):835–41. 10.1016/j.jid.2018.10.045\n21 Varpuluoma O Forsti AK Jokelainen J Turpeinen M Timonen M Huilaja L . Vildagliptin Significantly Increases the Risk of Bullous Pemphigoid: A Finnish Nationwide Registry Study. J Invest Dermatol (2018) 138 (7 ):1659–61. 10.1016/j.jid.2018.01.027\n22 Tasanen K Varpuluoma O Nishie W . Dipeptidyl Peptidase-4 Inhibitor-Associated Bullous Pemphigoid. Front Immunol (2019) 10 :1238. 10.3389/fimmu.2019.01238 31275298\n23 Zhao Y . CD26 in autoimmune diseases: The other side of “moonlight protein”. Int Immunopharmacol (2019) 75 :105757. 10.1016/j.intimp.2019.105757 31357088\n24 Sadik CD Langan EA Gratz V Zillikens D Terheyden P . Checkpoint Inhibition May Trigger the Rare Variant of Anti-LAD-1 IgG-Positive, Anti-BP180 NC16A IgG-Negative Bullous Pemphigoid. Front Immunol (2019) 10 :1934. 10.3389/fimmu.2019.01934 31474998\n25 Hua C Boussemart L Mateus C Routier E Boutros C Cazenave H . Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab. JAMA Dermatol (2016) 152 (1 ):45–51. 10.1001/jamadermatol.2015.2707 26501224\n26 Sanlorenzo M Vujic I Daud A Algazi A Gubens M Luna SA . Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression. JAMA Dermatol (2015) 151 (11 ):1206–12. 10.1001/jamadermatol.2015.1916\n27 Nelson CA Singer S Chen T Puleo AE Lian CG Wei EX . Bullous pemphigoid after anti-PD-1 therapy: a retrospective case-control study evaluating impact on tumor response and survival outcomes. J Am Acad Dermatol (2019) 103 (4 ):224–6. 10.1016/j.jaad.2019.12.068\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "11()",
"journal": "Frontiers in immunology",
"keywords": "PD-1 - PD-L1 axis; autoantibodies; autoimmunity; checkpoint inhibitors; ipilimumab; nivolumab; pembrolizumab; pemphigoid disease",
"medline_ta": "Front Immunol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D003880:Dermatology; D005260:Female; D005858:Germany; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D010391:Pemphigoid, Bullous; D012189:Retrospective Studies",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "588582",
"pmc": null,
"pmid": "33708189",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "29520266;26501224;27192570;26222619;27086658;25971981;29256113;31474998;31449902;31008169;31062404;30543900;31357088;29427585;32272983;30940340;31931083;28884139;25827742;31732776;27265076;23237497;31116807;31275298;32272980;30025829;30022934",
"title": "Retrospective Analysis of Checkpoint Inhibitor Therapy-Associated Cases of Bullous Pemphigoid From Six German Dermatology Centers.",
"title_normalized": "retrospective analysis of checkpoint inhibitor therapy associated cases of bullous pemphigoid from six german dermatology centers"
} | [
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"companynumb": "DE-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-030148",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
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"abstract": "We report on a patient with postsurgical cystoid macular edema (CME) after phacoemulsification and multifocal intraocular lens (MIOL) implantation. At first, there was a very good reaction to intravitreal triamcinolone, inducing complete regression of the edema without increasing intraocular pressure (IOP). One year later the patient suffered from retinal detachment and was treated with vitrectomy, laser, and gas tamponade. Afterward, he developed macular pucker with edema. After surgical treatment with pucker peeling and intravitreal triamcinolone, the patient showed a steroid response and an increase IOP. Postoperatively, there was a recurrence of CME. A coincidental administration of a steroid injection intramuscularly by the general practitioner achieved a prompt reduction of the CME without increasing IOP. This case shows that an initially good reaction to triamcinolone without increasing IOP does not rule out a future steroid response, and that a potential treatment option for CME in patients with a known steroid response could consist of intramuscularly injected steroids.",
"affiliations": "Knappschaftsaugenklinik Sulzbach, An der Klinik 10, 66280, Sulzbach, Deutschland. anna.seuthe@googlemail.com.;Knappschaftsaugenklinik Sulzbach, An der Klinik 10, 66280, Sulzbach, Deutschland.;Knappschaftsaugenklinik Sulzbach, An der Klinik 10, 66280, Sulzbach, Deutschland.",
"authors": "Seuthe|A-M|AM|;Szurman|P|P|;Boden|K T|KT|",
"chemical_list": "D003692:Delayed-Action Preparations; D014221:Triamcinolone; C011175:betamethasone-17,21-dipropionate; D001623:Betamethasone",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00347-016-0425-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-293X",
"issue": "114(11)",
"journal": "Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft",
"keywords": "Intramuscular steroid application; Intraocular pressure increase; Postoperative cystoid macular edema; Steroid response; Triamcinolone",
"medline_ta": "Ophthalmologe",
"mesh_terms": "D001623:Betamethasone; D003692:Delayed-Action Preparations; D006801:Humans; D007273:Injections, Intramuscular; D007910:Lenses, Intraocular; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D018918:Phacoemulsification; D011183:Postoperative Complications; D012008:Recurrence; D012086:Reoperation; D012163:Retinal Detachment; D041623:Tomography, Optical Coherence; D014221:Triamcinolone; D014821:Vitrectomy",
"nlm_unique_id": "9206148",
"other_id": null,
"pages": "1034-1037",
"pmc": null,
"pmid": "28004156",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18204501;21921587;19268890;23264331;26879555;26664246;16395193;21187730;23264866;25646032",
"title": "Intramuscular depot steroids : Possible treatment of postsurgical cystoid macula edema with steroid response?",
"title_normalized": "intramuscular depot steroids possible treatment of postsurgical cystoid macula edema with steroid response"
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{
"companynumb": "DE-MYLANLABS-2018M1090944",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "BETAMETHASONE DIPROPIONATE\\BETAMETHASONE SODIUM PHOSPHATE"
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{
"abstract": "Skeletal dysplasias are a complex group of more than 350 disorders with phenotypic and genotypic heterogeneity affecting bone and cartilage growth. We studied a 2-year-old girl and her 21-year-old mother with disproportionate short stature. In addition to typical features of hypochondroplasia found in both patients, the child had deformities of the extremity bones, metaphyseal flares, and bilateral transverse (Bowdler) fibular spurs with overlying skin dimples detected at birth. Intravenous pamidronate was started in the child since the age of 17 days, and then every two months. Exome sequencing revealed that the girl was heterozygous for a missense mutation (c.1651A>G, p.Ile538Val) in exon 13 of FGFR3, a known mutation for hypochondroplasia, inherited from her mother. Interestingly, the child also harbored compound heterozygous missense mutations in exon 12 of ALPL, c.1460C>T (p.Ala487Val) inherited from her mother and c.1479C>A (p.Asn493Lys) inherited from her healthy father. The former mutation was previously reported in perinatal hypophosphatasia while the latter was novel. Constantly reduced serum alkaline phosphatase levels including the one before the pamidronate administration and a substantially elevated level of plasma pyridoxal 5'-phosphate detected at age 28 months supported the diagnosis of hypophosphatasia. After a definite diagnosis was achieved, pamidronate was withdrawn at the age of 28 months. No adverse events were observed during pamidronate therapy. In conclusion, we describe a unique case with monoallelic FGFR3 and biallelic ALPL mutations leading to features of both hypochondroplasia and hypophosphatasia.",
"affiliations": "Craniofacial Genetics and Stem Cells Research Group, Faculty of Dentistry, Department of Physiology, Chulalongkorn University, Bangkok, Thailand.;Center of Excellence for Medical Genetics, Faculty of Medicine, Department of Pediatrics, Chulalongkorn University, Bangkok, Thailand.;Center of Excellence for Medical Genetics, Faculty of Medicine, Department of Pediatrics, Chulalongkorn University, Bangkok, Thailand.;Center of Excellence for Medical Genetics, Faculty of Medicine, Department of Pediatrics, Chulalongkorn University, Bangkok, Thailand.",
"authors": "Porntaveetus|Thantrira|T|;Srichomthong|Chalurmpon|C|;Suphapeetiporn|Kanya|K|http://orcid.org/0000-0001-5679-7547;Shotelersuk|Vorasuk|V|",
"chemical_list": "C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; C548267:ALPL protein, human; D000469:Alkaline Phosphatase",
"country": "United States",
"delete": false,
"doi": "10.1002/ajmg.a.38370",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4825",
"issue": "173(10)",
"journal": "American journal of medical genetics. Part A",
"keywords": "dento-osseous; dual diagnosis; exome sequencing; metabolic bone disease; two mendelian diseases",
"medline_ta": "Am J Med Genet A",
"mesh_terms": "D000469:Alkaline Phosphatase; D000483:Alleles; D001842:Bone and Bones; D002648:Child; D004392:Dwarfism; D005260:Female; D006801:Humans; D007014:Hypophosphatasia; D017880:Limb Deformities, Congenital; D008141:Lordosis; D009154:Mutation; D051498:Receptor, Fibroblast Growth Factor, Type 3; D013785:Thailand",
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "2747-2752",
"pmc": null,
"pmid": "28763161",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Monoallelic FGFR3 and Biallelic ALPL mutations in a Thai girl with hypochondroplasia and hypophosphatasia.",
"title_normalized": "monoallelic fgfr3 and biallelic alpl mutations in a thai girl with hypochondroplasia and hypophosphatasia"
} | [
{
"companynumb": "TH-MYLANLABS-2017M1066838",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PAMIDRONATE DISODIUM"
},
"drugadditional": "3... |
{
"abstract": "5F-MDMB-PICA has been detected in products sold on the internet as well as in biological samples since 2016. It is associated with serious adverse health and behavioral effects and even death. Herein we report on twelve cases with proven 5F-MDMB-PICA consumption, including three fatalities, four cases of driving under the influence of drugs and five other criminal acts. In these cases, 5F-MDMB-PICA was detected in postmortem blood or serum. Concentrations ranged from 0.1-16ng/mL. In some blood (serum) and urine samples, the hydrolysis metabolite of 5F-MDMB-PICA (M12) could also be detected. In this case series, co-consumption with other drugs occurred in 9 of 12 cases, most commonly alcohol, cannabis and other contemporary SCs. In five cases, 4F-MDMB-BINACA was also detected. The described cases demonstrate various adverse effects that might be associated with 5F-MDMB-PICA. Observed physical adverse effects were mainly balance deficiencies and ocular effects such as reddened conjunctivae, glassy eyes and delayed or unresponsive pupil light reactions. Observed mental and behavioral effects were mainly changing moods, aggression, confusion, erratic behavior, mental leaps, disorientation, slowed reaction, logorrhea and slurred speech. Due to the fast changing market of synthetic cannabinoids, data on such new appearing substances are basically scarce. Because of the limited number of studies on pharmacological properties of synthetic cannabinoids, reports of findings in human samples along with corresponding case history descriptions can be valuable for the interpretation of upcoming routine cases.",
"affiliations": "Institute of Forensic Medicine, Forensic Toxicology, Johannes Gutenberg University Mainz, Mainz, Germany. Electronic address: kleis@uni-mainz.de.;Institute of Forensic Medicine, Forensic Toxicology, Johannes Gutenberg University Mainz, Mainz, Germany.;Institute of Forensic Medicine, Forensic Toxicology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Hermann Staudinger Graduate School, University of Freiburg, Freiburg, Germany.;Institute of Forensic Medicine, Forensic Toxicology, Johannes Gutenberg University Mainz, Mainz, Germany.;Institute of Forensic Medicine, Forensic Toxicology, Johannes Gutenberg University Mainz, Mainz, Germany.;Institute of Forensic Medicine, Forensic Toxicology, Johannes Gutenberg University Mainz, Mainz, Germany.;Institute of Forensic Medicine, Forensic Toxicology, Johannes Gutenberg University Mainz, Mainz, Germany.",
"authors": "Kleis|J|J|;Germerott|T|T|;Halter|S|S|;Héroux|V|V|;Roehrich|J|J|;Schwarz|C S|CS|;Hess|C|C|",
"chemical_list": "C000710668:5F-MDMB-PICA; D002186:Cannabinoids; D013287:Illicit Drugs",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2020.110410",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "314()",
"journal": "Forensic science international",
"keywords": "5F-MDMB-PICA; DUID; High resolution mass spectrometry; Intoxication; Post mortem; Synthetic cannabinoids",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D000374:Aggression; D002186:Cannabinoids; D002853:Chromatography, Liquid; D003221:Confusion; D003228:Conjunctiva; D003415:Crime; D000066448:Driving Under the Influence; D005260:Female; D006801:Humans; D013287:Illicit Drugs; D057230:Limit of Detection; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D015394:Molecular Structure; D019964:Mood Disorders; D004856:Postural Balance; D011681:Pupil Disorders; D012678:Sensation Disorders; D052616:Solid Phase Extraction; D019966:Substance-Related Disorders",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "110410",
"pmc": null,
"pmid": "32683270",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The synthetic cannabinoid 5F-MDMB-PICA: A case series.",
"title_normalized": "the synthetic cannabinoid 5f mdmb pica a case series"
} | [
{
"companynumb": "DE-JNJFOC-20200843832",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXEPIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nThe main clinical manifestations of autoimmune thyroid diseases are Graves' disease (GD) and Hashimoto's thyroiditis (HT). Graves' disease is the cause of most cases of hyperthyroidism in childhood. Indications for radical therapy (surgery or 131I treatment) in children are still a matter of discussion, as sustained (sometimes very long) remission of GD is possible, while the radical therapy almost always leads to hypothyroidism. Spontaneous evolution from GD with hyperthyroidism to HT with hypothyroidism may also be observed.\n\n\nOBJECTIVE\nThe aim of the study was to analyze the clinical course of 6 cases of hyperthyroid girls with GD in whom a normalization of previously increased autoantibodies against thyrotropin (TSH) receptor (anti-TSHR) was observed together with a significant increase in autoantibodies against thyroid peroxidase (anti-TPO) and thyroglobulin (anti-Tg), with concomitant hypo- or euthyroidism but no recurrence of hyperthyroidism.\n\n\nMETHODS\nPatients' age at diagnosis ranged from 5.0 to 16.5 years. Two (2) patients had Turner syndrome, another one (1), diabetic, was on insulin therapy.\n\n\nRESULTS\nIn all the girls, antithyroid drugs were administered and euthyroid state was achieved during the first 2.0-3.5 months of the treatment. Mild side effects were observed in only one case. The therapy was continued up to 1.5-4.0 years. Relapses during the therapy were observed in 2 cases. Up to now, no relapses have been observed for 0.5-7.5 years since the therapy withdrawal in 5 patients (1 patient was lost to follow-up), 2 patients are currently treated with levothyroxine due to hypothyroidism.\n\n\nCONCLUSIONS\nIt seems that the prolonged pharmacotherapy with antithyroid drugs, followed by observation after remission of hyperthyroidism, may be an appropriate therapeutic option at least in some children with GD as they can be cured without radical therapy and the potential risks of such treatment.",
"affiliations": "Department of Endocrinology and Metabolic Diseases, Polish Mother's Memorial Hospital - Research Institute, Lodz, Poland.;Department of Endocrinology and Metabolic Diseases, Polish Mother's Memorial Hospital - Research Institute, Lodz, Poland.;Department of Endocrinology and Metabolic Diseases, Polish Mother's Memorial Hospital - Research Institute, Lodz, Poland.;Department of Endocrinology and Metabolic Diseases, Polish Mother's Memorial Hospital - Research Institute, Lodz, Poland.;Department of Endocrinology and Metabolic Diseases, Polish Mother's Memorial Hospital - Research Institute, Lodz, Poland.",
"authors": "Smyczńyska|Joanna|J|;Cyniak-Magierska|Anna|A|;Stasiak|Magdalena|M|;Karbownik-Lewińska|Małgorzata|M|;Lewiński|Andrzej|A|",
"chemical_list": "D013956:Antithyroid Agents; D001323:Autoantibodies; D011989:Receptors, Thyrotropin; D008713:Methimazole; D011441:Propylthiouracil; D013972:Thyrotropin",
"country": "Sweden",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-780X",
"issue": "35(5)",
"journal": "Neuro endocrinology letters",
"keywords": null,
"medline_ta": "Neuro Endocrinol Lett",
"mesh_terms": "D000293:Adolescent; D013956:Antithyroid Agents; D001323:Autoantibodies; D002648:Child; D002675:Child, Preschool; D005260:Female; D006111:Graves Disease; D050031:Hashimoto Disease; D006801:Humans; D007037:Hypothyroidism; D008297:Male; D008713:Methimazole; D011441:Propylthiouracil; D011989:Receptors, Thyrotropin; D012074:Remission Induction; D013972:Thyrotropin",
"nlm_unique_id": "8008373",
"other_id": null,
"pages": "335-41",
"pmc": null,
"pmid": "25275265",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Persistent remission of Graves` disease or evolution from Graves' disease to Hashimoto's thyroiditis in childhood - a report of 6 cases and clinical implications.",
"title_normalized": "persistent remission of graves disease or evolution from graves disease to hashimoto s thyroiditis in childhood a report of 6 cases and clinical implications"
} | [
{
"companynumb": "PHHY2015PL080884",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHIMAZOLE"
},
"drugadditional": null,
"dru... |
{
"abstract": "There are only a few cases found in literature regarding air embolism in endoscopic procedures, especially in connection to endoscopic retrograde cholangiopancreatography (ERCP). We are presenting a case of a 56-year-old female patient who suffered from non-Hodgkin lymphoma located in her right groin. She was also diagnosed with choledocholithiasis and underwent ERCP to remove the gallstones. Immediately after the procedure she went into sudden cardiac arrest and subsequently died, despite all of our efforts. We reviewed literature in order to identify possible causes of death because fatal outcome following an uneventful and successful procedure was not expected. It is important to bear in mind all possible complications of ERCP. Our focus during the literature search was on air embolism.",
"affiliations": "From the Department of Internal Medicine, Division of Gastroenterology (GH, DS); Department of Surgery, Division of Digestive Surgery (MZ); and Department of Anaesthesiology, Clinical Hospital Centre Rijeka, 51000 Rijeka, Croatia (MM).",
"authors": "Hauser|Goran|G|;Milosevic|Marko|M|;Zelić|Marko|M|;Stimac|Davor|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000000235",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2550108710.1097/MD.0000000000000235002354500ArticleClinical Case ReportSudden Death After Endoscopic Retrograde Cholangiopancreatography (ERCP)—Case Report and Literature Review Hauser Goran MD, PhDMilosevic Marko MDZelić Marko MD, PhDStimac Davor MD, PhDNzeako. Ugo From the Department of Internal Medicine, Division of Gastroenterology (GH, DS); Department of Surgery, Division of Digestive Surgery (MZ); and Department of Anaesthesiology, Clinical Hospital Centre Rijeka, 51000 Rijeka, Croatia (MM).Correspondence: Goran Hauser, Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre Rijeka, 51000 Rijeka, Croatia (e-mail: goran.hauser@medri.uniri.hr).12 2014 12 12 2014 93 27 e23518 8 2014 2 10 2014 9 10 2014 Copyright © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins2014This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nThere are only a few cases found in literature regarding air embolism in endoscopic procedures, especially in connection to endoscopic retrograde cholangiopancreatography (ERCP). We are presenting a case of a 56-year-old female patient who suffered from non-Hodgkin lymphoma located in her right groin. She was also diagnosed with choledocholithiasis and underwent ERCP to remove the gallstones. Immediately after the procedure she went into sudden cardiac arrest and subsequently died, despite all of our efforts. We reviewed literature in order to identify possible causes of death because fatal outcome following an uneventful and successful procedure was not expected. It is important to bear in mind all possible complications of ERCP. Our focus during the literature search was on air embolism.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nEndoscopic retrograde cholangiopancreatography (ERCP) is a widely used procedure to both diagnose and treat diseases of the pancreatobiliary tree, with over 500,000 ERCP procedures performed annually in the USA alone.1 Although this procedure is complex and requires great skill, it is performed routinely on a daily basis. Because of its complexity it carries some risks of complications. Most common complications of endoscopic retrograde cholangiopancreatography are hemorrhage, pancreatitis, cholangitis and perforation.2 Other, less common, complications include cardiac arrest, air in hepatic veins, cerebral air embolism and paradoxical air embolism.3 We are presenting a case of a 56-year-old female with sudden cardiac arrest and subsequent death of unknown etiology. Specificity of this case is in the fact that a patient underwent a routine endoscopic procedure and died. Especially if we take into consideration it was during the procedure, but after it had finished uneventfully. Due to many controversies in this field, we reviewed recent literature in order to detect possible causes of preventable death.\n\nCASE REPORT\nA 56-year-old female patient with localized non-Hodgkin lymphoma was referred to a gastroenterologist prior to scheduled chemotherapy due to cholestatic profile in laboratory findings. She was completely asymptomatic, but transabdominal ultrasound revealed chronic cholecystitis with extremely dilated (>20 mm) common bile duct (CBD) filled with gallstones. Electrocardiogram obtained 2 days before the procedure was normal. Next day she was scheduled for ERCP. In conscious sedation with pethidine (1 mg/ kg i.v.) and midazolam (5 mg i.v.), and premedication with 20 mg i.v. of hyoscine butylbromide (Buscopan) in left lateral position we performed ERCP.\n\nAfter easy cannulation with sphincterotome and guide wire (Cook Fusion Omni-Tome with FSW-35 guide wire) we injected a bolus (10 ml) of iohexol (Omnipaque) contrast solution. X-ray confirmed multiple choledocholitihiasis with extremely dilated CBD (Figure 1). We proceeded with sphincterotomy, which caused spontaneous propulsion of stones. After that we extracted residual stones with a balloon extractor (Cook Fusion Extraction balloon), all together more than 30. During the whole procedure patient was monitored and we recorded no disturbances in cardiac rhythm, blood pressure or oxygen saturation. After we removed the scope patient was awake and we explained to her what we have done.\n\nFIGURE 1 Multiple choledocholithiasis.\n\nSeveral minutes after that, while the patient was still connected to the monitor, we registered alarm due to ventricular fibrillation. Immediately we proceeded with cardiopulmonary reanimation (CPR) according to recent guidelines for Advanced Life Support.4 It includes defibrillations, orotracheal intubation and chest compressions. After the third defibrillation, rhythm changed to pulseless electrical activity. Despite prolonged CPR (50 min), the patient died. Autopsy was performed on the next day and it found no obvious cause of sudden death. There were no signs of duodenal wall perforation, myocardial lesions or pulmonary embolism. We suggest that a possible reason of cardiorespiratory arrest could be air embolism of the heart, due to the fact that during autopsy the heart was dissected in a traditional fashion. Any residual air in the heart would then be released into atmosphere upon dissection.\n\nDISCUSSION\nEndoscopic retrograde cholangiopancreatography is a well-established procedure in gastrointestinal medicine used to diagnose and treat many diseases, such as choledocholithiasis or neoplastic lesions of the pancreatobiliary system. Beside the gastrointestinal and pancreatic complications, cardiopulmonary complications of ERCP are also possible and occur in 1% of cases. These include arrhythmias, hypoxemia and transitory myocardial ischemia.3,5\n\nCardiopulmonary and neurological adverse events can occur due to a rare, but potentially fatal complication of ERCP—air embolism. It can lead to hypotension, right heart failure, cardiovascular collapse and even cardiac arrest. Pulmonary manifestations of air embolism can include dyspnea, tachypnea, decrease in end-tidal carbon dioxide (EtCO2) concentration, hypoxia, cyanosis, and respiratory failure. Neurological deterioration can be presented as dilated pupil(s), failure to regain consciousness after anesthesia or loss of consciousness, altered mental status, hemiparesis, cerebral edema, etc.6\n\nThis complication is often neglected and less considered during ERCP. First documented case of air embolism in gastrointestinal endoscopy was described by Lowdon and Tidmore in 1988.7 In their report a 5-week-old infant who had biliary atresia due to a previous Kasai procedure died during endoscopy. Autopsy showed presence of air in the right atrium and ventricle and in the area of porta hepatis. However, the infant had a patent foramen ovale and air present in his coronary arteries. Lowdon and Tidmore suggested that air was insufflated across the hepatic tissue into the large hepatic vein, and the patient's heart condition helped development of systemic embolism.\n\nIn 2013, Donepudi et al8 conducted a systematic review of the risk factors, clinical presentation and management of air embolism in gastrointestinal endoscopy. They found 26 cases of air embolism as a complication of ERCP to date. Almost half of these cases, 12 of them to be precise, ended fatally. Air embolism can occur during any endoscopical intervention in gastroenterology, although most commonly it occurs during ERCP. Air embolism as a complication of ERCP was first noted in 1997 by Kennedy et al.9 In their case report, a 63-year-old woman underwent ERCP due to choledocholithiasis. She developed cardiorespiratory arrest due to hepatic venous air embolism. Another case of air embolism during ERCP was described by Mohammedi et al.10 A 27-year-old man with a post-traumatic hepatic injury had to have ERCP to determine the location of the leakage of bile. While sphincterotomy was done, a massive air embolism occurred. Luckily, the patient survived. They suggested that insufflated air caused air embolism via damaged hepatic veins.\n\nGeneral consensus about how air embolism occurs is that the air which is insufflated passes intramurally into the portal venous system via duodenal vein radicles which are cut transversely during the procedure. Presence of a biliary-venous fistula or shunt eases the occurrence of air embolism. Other underlying conditions such as previous procedures of the bile duct system, trauma to the liver, gastrointestinal fistulas and inflammations can facilitate air embolism development.8,10\n\nSiddiqui et al11 reported a case of a fatal air embolism in a 43-year-old female patient after percutaneous liver biopsy and ERCP.\n\nA hypothesis in another air embolism case was made by Stabile et al.12 They described a fatal massive paradoxical cerebral embolism in a patient who didn’t have a patent foramen ovale or other septal defects. They proposed that in case of massive air embolism presence, pulmonary circulation could not be capable of filtering all the venous gas, so it could build up on the arterial side and cause ischemia of a certain organ.\n\nKatzgraber et al13 reported a case of air embolism in a 56-year-old man who had a gastroscopy because of gastric ulcer. During the procedure he went into cardiac arrest and died. During autopsy air was found in his right ventricle, and also an open vessel at the base of the ulcer. It is notable that air was insufflated at high volumes during the procedure being the possible and likely cause of air embolism.\n\nFinsterer et al14 conducted a Medline search in order to provide an overview of current knowledge of pathophysiology, diagnosis, management and prognosis of air embolism during ERCP. They found 18 reports about 19 patients concerning their field of interest. In 14 cases air embolism after ERCP occurred; 8 patients suffered cerebral air embolism and 6 of them ending fatally. According to authors, all these cases were presumed to have air entering blood vessels through portal or hepatic veins. They concluded that in case that patient does not wake up after the procedure, air embolism should be taken into consideration and all of therapeutic measures provided.\n\nSeveral other case reports describe air embolism during endoscopy procedures. Some patients survived due to recognition of symptoms and swift initialization of treatment like in the case report by Goins et al.15 They reported a case of a 72-year-old woman undergoing ERCP because of cholangiocarcinoma. During the procedure she developed pulseless electrical activity and went into cardiac arrest due to a massive air embolus in her right heart. Transesophageal echo found 30 ml of air in her right ventricle. Pulmonary artery catheter was inserted and air was aspired saving the patient's life. They suggest that an injury of a small vessel had occurred and allowed air to pass into the veins which then travelled up to the right heart.\n\nCha et al16 described a case of massive fatal embolism during ERCP. A 50-year-old female went into cardiac arrest during the procedure. Air embolism originated either from a biliary-venous fistula forming due to tissue damage caused by insufflation pressure, or from the previously existent choledochoduodenostomy which could allow easier access for the endoscope and therefore let more air to be insufflated. Another similar case was reported by Bisceglia et al.17 A 78-year-old man underwent ERCP for recurrent cholangitis due to gallstones and went into cardiac arrest. Autopsy revealed massive pulmonary and cerebral air embolism, and a spontaneous duodenobiliary fistula which was the entering point for the embolus which then penetrated the intrahepatic veins already weakened due to his disease.\n\nOther case reports suggest cerebral complications due to paradoxical air embolism. Rangappa et al18 presented a case of a 50-year-old woman undergoing ERCP due to suspected choledocholithiasis, who suffered a fatal cerebral air embolism. After the procedure the patient was unresponsive with her gaze deviating to the right. CT of her head showed air embolism in her right hemisphere with tonsilar herniation and diffused cerebral edema. During autopsy her heart was placed underwater which showed air in the right atrium. Cause of death was brain edema due to paradoxical air embolism caused by injury of blood vessels at the site of sphincterotomy. Nayagam et al19 reported a case of a 56-year-old man who died during ERCP due to cerebral ischemia caused by venous and arterial air embolism. Furthermore, Lopez et al20 presented a case of a 61-year-old woman who died of pneumocephalus and ischemic infarction of the right hemisphere. She underwent esophagogastroduodenoscopy due to hematemesis caused by esophageal varices. The patient developed hypotension and was unresponsive. Brain death was declared 24 hours post admission. Another patient suffered from systemic air embolism that presented with deterioration of neurological state. Bechi et al21 described a case of a complete neurological recovery in a 79-year-old female patient who developed systemic air embolism during endoscopic sphincterotomy and gallstone removal. They provided only conservative treatment: 100% oxygen, head down position, lateral position and fluid resuscitation.\n\nIn a report by Mellado et al22 a 52-year-old woman with ovarian cancer suffered from a severe deterioration of her consciousness. A CT scan was made with findings of multiple air embolism areas between the anterior and middle right cerebral arteries. Patient died after 48 hours. Argüelles et al23 reported a case of patient who died due to a cerebral artery embolism during ERCP as he developed a severe ishemic brain injury. Another case of cerebral air embolism is described by Laan et al.24 A patient had his gastric-mediastinal fistula evaluated following subtotal oesophagectomy and gastric tube reconstruction due to oesophageal cancer. Air embolism developed causing acute left sided hemiparesis. Hyperbaric oxygen was administered, and the patient almost fully recovered.\n\nMost recent case of air embolism during ERCP has been published in 2014. Painter et al25 described a case report about a 76-year-old female patient who underwent ERCP to remove a biliary stent and have a lithotripsy. They noted acute drop in end-tidal CO2 with cardiorespiratory arrest soon after. They immediately started with advanced cardiac life support and a transesophageal echo was done proving pulmonary embolism. Thrombolytic therapy was administered and the patient was discharged with oral warfarin therapy.\n\nAll of the summarized cases describe patients undergoing ERCP and dying from fatal air embolism occurring either in the brain or in the heart.\n\nWe can see that air embolism is caused either by high air insuflation pressure or by invasive procedures (ie, sphincterotomy), which can damage the integrity of gastrointestinal structures. Additional risk factor is an existent biliary-hepato-venous fistula or an open/injured blood vessel, as they can provide access to the bloodstream. Air embolism is difficult to recognize, and physicians should be aware of it as an ERCP complication. If a patient suddenly becomes hypoxic, bradycardic, hypotensive, or neurogically decompensated we should always take air embolism into consideration. Transesophageal echocardiography is useful in finding gas in the heart.16 Management of air embolism should start by positioning the patient in the Trendelenburg position. Furthermore, hyperbaric oxygen is the therapy of choice. It reduces the gas bubbles’ volume and allows them to dissolve more easily. It also decreases cerebral edema due to hyperoxic vasoconstriction and prevents reperfusion injury by preventing leukocyte aggregation.18 Also if necessary, central venous catheter can be of great use, as it can aspirate excess of air from the heart.15\n\nCONCLUSIONS\nIn our case, sudden cardiac death was unexpected and cause of it unknown. According to known similar cases, we can only suggest that the death of our patient was caused by air embolism. Risk factors for air embolism such as previous procedures of the bile duct system, abdominal trauma or digestive system inflamation should always be considered. Some preventive measures can also be used. For example, using CO2 as the insufflating agent instead of air lowers the possibility of embolism, due to easier absorption. End-tidal CO2 monitoring is also useful and important. It is a simple, cheap and an effective method. Although prevention of air embolism during ERCP is not difficult, constant education and sharing experiences can teach us to quickly recognize the symptoms of air embolism which is important for the treatment to be successful.\n\nAbbreviations: CBD = common bile duct, CPR = cardiopulmonary reanimation, CT = computed tomography, ECG = electrocardiogram, EtCO2 = end-tidal carbon dioxide, ERCP = endoscopic retrograde cholangiopancreatography.\n\nThe authors have no funding or conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Silviera ML Seamon MJ Porshinsky B \nComplications related to endoscopic retrograde cholangiopancreatography: a comprehensive clinical review . J Gastrointest Liver Dis \n2009 ; 18 :73 –82 .\n2. Dumonceau JM Andriulli A Deviere J \nEuropean Society of Gastrointestinal Endoscopy (ESGE) guideline: prophylaxis of post-ERCP pancreatitis . Endoscopy \n2010 ; 42 :503 –515 .20506068 \n3. Complications of ERCP . Am Soc Gastrointest Endosc \n2012 ; 75 :467 –473 . http://www.asge.org/assets/0/71542/71544/076fbf43-9959-4859-8286-bc62fec2b5dc.pdf\n4. Deakin CD Nolan JP Soar J \nEuropean Resuscitation Council Guidelines for Resuscitation 2010 Section 4. Adult advanced life support . Resuscitation \n2010 ; 81 :1305 –1352 .20956049 \n5. Christensen M Milland T Rasmussen V \nECG changes during endoscopic retrograde cholangiopancreatography and coronary artery disease . Scand J Gastroenterol \n2005 ; 40 :713 –720 .16036532 \n6. Mirski MA Lele AV Fitzsimmons L \nDiagnosis and treatment of vascular air embolism . Anesthesiology \n2007 ; 106 :164 –177 .17197859 \n7. Lowdon JD Tidmore TL Jr \nFatal air embolism after gastrointestinal endoscopy . Anesthesiology \n1988 ; 69 :622 –623 .3177925 \n8. Donepudi S Chavalitdhamrong D Pu L \nAir embolism complicating gastrointestinal endoscopy . World J Gastrointest Endosc \n2013 ; 5 :359 –365 .23951390 \n9. Kennedy C Larvin M Linsell J \nFatal hepatic air embolism following ERCP . Gastrointest Endosc \n1997 ; 45 :187 –188 .9041008 \n10. Mohammedi I Ber C Peguet O \nCardiac air embolism after endoscopic retrograde cholangipancreatography in a patient with blunt hepatic trauma . J Trauma \n2002 ; 53 :1170 –1172 .12478046 \n11. Siddiqui J Jaffe PE Aziz K \nFatal air and bile embolism after percutaneous liver biopsy and ERCP . Gastrointest Endosc \n2005 ; 61 :153 –157 .15672079 \n12. Stabile L Cigada M Stillittano D \nFatal cerebral air embolism after endoscopic retrograde cholangiopancreatography . Acta Anaesthesiol Scand \n2006 ; 50 :648 –649 .16643257 \n13. Katzgraber F Glenewinkel F Fischler S \nMechanism of fatal air embolism after gastrointestinal endoscopy . Int J Legal Med \n1998 ; 111 :154 –156 .9587799 \n14. Finsterer J Stöllberger C Bastovansky A \nCardiac and cerebral air embolism from endoscopic retrograde cholangiopancreatography . Eur J Gastroenterol Hepatol \n2010 ; 22 :1157 –1162 .20555267 \n15. Goins KM May JM Hucklenbruch KE \nUnexpected cardiovascular collapse from massive air embolism during endoscopic retrograde cholangiopancreatography . Acta Anaesthesiol Scand \n2010 ; 54 :385 –388 .19878099 \n16. Cha ST Kwon CI Seon HG \nFatal biliary-systemic air embolism during endoscopic retrograde cholangiopancreatography: a case with multifocal liver abscesses and choledochoduodenostomy . Yonsei Med J \n2010 ; 51 :287 –290 .20191026 \n17. Bisceglia M Simeone A Forlano R \nFatal venous air embolism durign endoscopic retrograde cholangiopancreatography . Adv Anat Pathol \n2009 ; 16 :255 –262 .19546613 \n18. Rangappa P Uhde B Byard RW \nFatal cerebral arterial gas embolism after endoscopic retrograde cholangiopancreatography . Indian J Crit Care Med \n2009 ; 13 :108 –112 .19881196 \n19. Nayagam J Ho KM Liang J \nFatal systemic air embolism during endoscopic retrograde cholangio-pancreatography . Anaesth Intensive Care \n2004 ; 32 :260 –264 .15957727 \n20. Lopez JC Perez X Esteve F \nCerebral air embolism during upper endoscopy . Endoscopy \n2010 ; 42 :E41 .20073014 \n21. Bechi A Nucera MP Olivotto I \nComplete neurological recovery after systemic air embolism during endoscopic retrograde cholangiopancreatography . Minerva Anestesiol \n2012 ; 78 :622 –625 .22240610 \n22. Mellado TP Constanzo PF Miguel PJF \nIshemic brain infarction after an air embolism. Case report . Rev Med Chil \n2005 ; 133 :453 –456 .15953953 \n23. Argüelles García B García Blanco A Meilán Martínez A \nCerebral artery air embolism secondary to endoscopic retrograde cholangiopancreatography . Gastroenterol Hepatol \n2009 ; 32 :614 –617 .19664852 \n24. ter Laan M Totte E van Hulst RA \nCerebral gas embolism due to upper gastrointestinal endoscopy . Eur J Gastroenterol Hepatol \n2009 ; 21 :833 –835 .19357524 \n25. Painter NP Kumar PA Arora H \nAcute pulmonary embolism during e endoscopic retrograde cholangiopancreatography . Ann Card Anaesth \n2014 ; 17 :145 –147 .24732617\n\n",
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"mesh_terms": "D002760:Cholangiopancreatography, Endoscopic Retrograde; D003645:Death, Sudden; D005260:Female; D006801:Humans; D008875:Middle Aged",
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"title": "Sudden death after endoscopic retrograde cholangiopancreatography (ERCP)--case report and literature review.",
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"abstract": "BACKGROUND\nThe growth in the use of anti-tumor necrosis factor α (TNF-α) agents for treatment of inflammatory conditions has led to increased recognition of the side effects associated with this class of drugs.\n\n\nMETHODS\nWe report a case of a patient who developed erythema multiforme (EM) major with characteristic oral and cutaneous lesions following treatment with the anti-TNF-α medication infliximab therapy for Crohn's disease (CD).\n\n\nCONCLUSIONS\nTo our knowledge, this is the first reported case of infliximab-induced EM secondary to the treatment of CD. It is important for dental clinicians evaluating patients using anti-TNF-α agents to be aware of this possible complication.",
"affiliations": "National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA. dean.edwards@nih.gov",
"authors": "Edwards|Dean|D|;Boritz|Eli|E|;Cowen|Edward W|EW|;Brown|Ronald S|RS|",
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"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D003424:Crohn Disease; D004892:Erythema Multiforme; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D019226:Oral Ulcer",
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"title": "Erythema multiforme major following treatment with infliximab.",
"title_normalized": "erythema multiforme major following treatment with infliximab"
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"abstract": "Denosumab is a humanized monoclonal antibody that binds RANKL to inhibit osteoclast activity. It is indicated for the prevention of skeletal-related events (SRE) in patients with solid tumors who have bone metastasis and in patients with multiple myeloma. Hypocalcemia is one of the known side effects of denosumab, which can be prevented with calcium supplementation. We present a case of a 72-year-old male with diagnosed metastatic prostate cancer who had received one dose of denosumab 10 days prior to presentation with fatigue, insomnia, and somnolence. His labs showed severe (Grade 4) hypocalcemia, which improved with intravenous calcium supplementation. This case highlights a known but life-threatening side effect of denosumab and the potential need for prolonged calcium monitoring in patients placed on the drug.",
"affiliations": "Internal Medicine, Bassett Medical Center, Cooperstown, USA.;Internal Medicine, Bassett Medical Center, Cooperstown, USA.;Hematology / Oncology, Bassett Medical Center, Cooperstown, USA.;Hematology / Oncology, Bassett Medical Center, Cooperstown, USA.",
"authors": "Gouli|Sugam|S|;Wang|Jimmy|J|;Patel|Anush|A|;Allerton|Jeffery|J|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.17046\nEndocrinology/Diabetes/Metabolism\nOncology\nHypocalcemia in a Patient With Metastatic Prostate Cancer From Denosumab Treatment\nMuacevic Alexander\nAdler John R\nGouli Sugam 1\nWang Jimmy 1\nPatel Anush 2\nAllerton Jeffery 2\n1 Internal Medicine, Bassett Medical Center, Cooperstown, USA\n2 Hematology / Oncology, Bassett Medical Center, Cooperstown, USA\nSugam Gouli goulisugam@gmail.com\n10 8 2021\n8 2021\n13 8 e1704610 8 2021\nCopyright © 2021, Gouli et al.\n2021\nGouli 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/64660-hypocalcemia-in-a-patient-with-metastatic-prostate-cancer-from-denosumab-treatment\nDenosumab is a humanized monoclonal antibody that binds RANKL to inhibit osteoclast activity. It is indicated for the prevention of skeletal-related events (SRE) in patients with solid tumors who have bone metastasis and in patients with multiple myeloma. Hypocalcemia is one of the known side effects of denosumab, which can be prevented with calcium supplementation.\n\nWe present a case of a 72-year-old male with diagnosed metastatic prostate cancer who had received one dose of denosumab 10 days prior to presentation with fatigue, insomnia, and somnolence. His labs showed severe (Grade 4) hypocalcemia, which improved with intravenous calcium supplementation. This case highlights a known but life-threatening side effect of denosumab and the potential need for prolonged calcium monitoring in patients placed on the drug.\n\nhypocalcemia\ndenosumab\nprostate cancer\nsre\nsuper scan\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\npmcIntroduction\n\nDenosumab is a human monoclonal antibody that acts by inhibiting the receptor activator of nuclear factor-kB ligand (RANKL) and is commonly used to prevent skeletal-related events (SRE) in patients with metastatic solid tumors and multiple myeloma. Denosumab has been proven to be more effective than zoledronic acid in preventing skeletal-related events in patients with metastatic prostate cancer. Hypocalcemia is one of the side effects of denosumab, which can also be seen in metastatic prostate cancer. Although often mild and transient, hypocalcemia can lead to significant morbidity or even mortality. Careful monitoring of calcium levels is required in patients with metastatic prostate cancer getting denosumab.\n\nCase presentation\n\nA 72-year-old male who was recently diagnosed with metastatic prostate cancer presented with fatigue, insomnia with daytime somnolence. The patient’s metastatic prostate cancer was Gleason score (5+5=10) with extensive bone metastasis. His bone scan was described as a “super scan” (Figure 1) due to the intense and extensive radiopharmaceutical uptake. He received one dose of denosumab and leuprolide/docetaxel 10 days prior to his admission. Upon physical examination, he appeared fatigued but still alert and oriented. Neurological examination showed 4/5 strength and decreased reflexes in all four extremities, without Chvostek sign, clonus, or asterixis. His initial laboratory testing showed new hypocalcemia 2.6mg/dl ionized (normal range 4.65 to 5.2 mg/dl), hypophosphatemia 1.4 mg/dl (normal range 2.5-4.5 mg/dl), and neutropenia absolute neutrophil count (ANC) 790 cell/ul. Parathyroid hormone was elevated at 1140 pg/ml (normal range 14 to 65 pg/ml) and total vitamin D was as low as 13 ng/ml (normal range 20-40 ng/ml). The patient was started on calcium gluconate infusion (13 g/day), oral calcium carbonate 500mg twice a day, and oral calcitriol 0.25 mcg daily. Calcium gluconate infusion was stopped after four days as calcium was gradually increasing, and the patient was continued on oral calcium. A few days after the discontinuation of IV calcium, the ionized calcium level gradually decreased to 2.9 mg/dl, necessitating switching oral calcitriol to IV calcitriol 4 µg daily for three days with ionized calcium level improving to 4.1 mg/dl. The patient was discharged with oral calcitriol 0.75 mg BID, oral calcium carbonate 2g BID, and vitamin D 50,000 Units weekly. Three days after discharge, ionized calcium level was found to be slightly decreased to 3.8 mg/dl and oral calcium carbonate was increased to 2g TID. Ionized calcium was rechecked 10 days after discharge and increased to 4.2 mg/dl (Figure 2).\n\nFigure 1 Shows “super scan” in technetium-99m (Tc-99m) methylene diphosphonate (MDP) whole body scan scan of the patient\n\nSuper scan is a diffusely increased radioisotope uptake in the bones with absent or faint renal and soft tissue activity on a Tc-99m MDP labeled bone scan.\n\nFigure 2 Ionized calcium level (mg/dl) after calcium supplementation in patients with hypocalcemia\n\nDiscussion\n\nProstate cancer is the second most common cancer (13.5% ) in men and among the leading causes of death in men (6.7%) [1]. Prostate cancer may be asymptomatic at the early stage and generally has an indolent course. However, in a more advanced state, it commonly metastasizes to the bones, leading to complications like pathologic fractures, spinal cord compression, and bone pain, collectively referred to as skeletal-related events [2]. The axial skeleton is the most common site for metastasis [2]. Multiple post-mortem studies in animals and humans have shown venous blood from the breasts and pelvis flowed through the vertebral-venous plexus that extends throughout the epidural and peri-vertebral veins, which partly explains the metastasis of prostate cancer to the axial skeleton [3].\n\nMedications indicated for the prevention of skeletal-related events are anti-resorptive bone-modifying agents like bisphosphonates and denosumab [4]. Denosumab is a human monoclonal antibody used for skeletal-related events (SRE) in postmenopausal women who are at risk of osteoporosis and in patients with bony metastases of solid tumor. Denosumab binds to RANKL and prevents its binding to the RANK receptor; thus, limiting excessive bone resorption and decreasing the fracture risk.\n\nThe FREEDOM trial showed that denosumab reduced the fracture risk in postmenopausal women by 2.3% in the denosumab group compared to 7.2% in the placebo group (CI 0.26 to 0.41; P<0.001) and did not increase the risk of adverse events in patients with glomerular filtration rate (GFR)>=30 [5]. It has also shown improved efficacy, better tolerability, and is convenient to administer as compared to bisphosphonates (another group of drugs used to reduce fracture risks) [6].\n\nOur search showed that numerous studies have been conducted to compare denosumab and zoledronic acid regarding their ability to delay skeletal-related events and onset of bone metastasis, as shown in Table 1.\n\nTable 1 Studies comparing denosumab vs zoledronic acid\n\nRCT: randomized control trial; SRE: skeletal-related events\n\nColumn 1\tColumn 2\tColumn 3\t\nType of study\tAuthor\tResults\t\nRCT\tLipton et al.\tDelay in first SRE (HR 0.82, CI 0.71-0.95,p =0.01), median time: unknown in denosumab vs 26.4 months in zoledronic acid [7].\t\nRCT\tFizazi et al.\tDelay in first SRE (HR 0.82, CI 0.71-0.95, p<=0.01), median time: 20.7 months in denosumab vs 17.1 months in zoledronic acid [8].\t\nmeta-analysis\tChen C et al.\tDelay in first SRE (HR = 0.86; 95% CI, 0.80–0.93; P = 0.0001), no difference in overall survival [9].\t\nmeta-analysis\tZheng G et al.\tDelay in first SRE (OR =0.82; 95% CI, 0.75-0.89; P < 0.01), no difference in overall survival [10].\t\nmeta-analysis\tHayes et al.\tDelay onset of bone metastasis in non-metastatic prostate cancer (RR 0.83, CI 0.73-0.95; P <0.01) [11].\t\n\nStudies have shown that denosumab has a higher risk of hypocalcemia compared to zoledronic acid. Lik-Hui et al. mentioned in their review article that all-grade hypocalcemia in patients was (9.6%-13%) in multiple RCTs, (14%-39.6%) in observational studies with denosumab [12]. Other studies have shown similar results in a decrease in SRE and increased risk of hypocalcemia [13-14]. Most studies have shown hypocalcemia within a one-week and one-month period [15-17]. Few patients have hypocalcemia of grade 4 (<6 mg/dl) while others have a high incidence of hypocalcemia grades 1-3 [17-18]. This study showed that the incidence of denosumab-associated hypocalcemia was 14% (95% CI 9.1-20.7) within six months of treatment despite the use of appropriate calcium/cholecalciferol supplementation [19].\n\nHypocalcemia itself is also a rare phenomenon in cancer metastasis. Riancho et al. showed that about 75% of cases of hypocalcemia in cancer metastasis were from prostate cancer metastasis [20]. Prostate cancer metastasis is an osteoblastic, process and the influx of calcium into bone due to increased bone formation causes hypocalcemia [21]. The incidence of denosumab-induced hypocalcemia is high in dialysis patients as shown by this study that found it to be 42% [22].\n\nIntravenous calcium treatment is required for patients with serum calcium < 7.6 mg/dl (1.9 mmol/L) and/or symptomatic hypocalcemia. The guideline suggests 10-20 ml of 10% calcium gluconate in 50-100 ml of 5% dextrose intravenous (IV) over 10 min with ECG monitoring and repeating until the patient is asymptomatic. This should be followed up by diluting 100 ml of 10% calcium gluconate (10 vials) in 1 L of normal saline or 5% dextrose and infuse at 50-100 ml/h. The rate of infusion should be titrated to achieve normocalcemia [23]. Also, oral calcium, vitamin D, and calcitriol should be given concurrently. Concurrent hypomagnesemia and hypophosphatemia should be treated as well. In patients on denosumab who took supplements of >= 600 mg calcium and 400 IU vitamin D daily, risks of vertebral facture and hypocalcemia were decreased during three years [24].\n\nConclusions\n\nSkeletal-related events like pathologic fractures, spinal cord compression, and bone pain are common in metastatic prostate cancer. Denosumab is a bone-protective agent used for the prevention of SREs in prostate cancer. Denosumab can cause hypocalcemia within one week to one month of its administration and may require hospital admission. Patients receiving denosumab should be on calcium + vitamin D supplementation prior to receiving this agent and maintained on supplementation with dosing adjustments based on laboratory parameters. Hypocalcemia can be treated by intravenous calcium or oral calcium, vitamin D, and calcitriol.\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 Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A 394 424 68 2018 30207593\n2 Management of skeletal-related events in patients with advanced prostate cancer and bone metastases: Incorporating new agents into clinical practice Can Urol Assoc J So A Chin J Fleshner N Saad F 465 470 6 2012 https://pubmed.ncbi.nlm.nih.gov/23282666/ 23282666\n3 The role of the vertebral veins in metastatic processes Ann Intern Med Batson OV 38 45 16 1942 https://doi.org/10.7326/0003-4819-16-1-38\n4 Revisiting the role of bone-modifying agents in the management of metastatic prostate cancer Asia Pac J Clin Oncol Cheung FY 13 15 14 Suppl 5 2018 https://doi.org/10.1111/ajco.13061 30489032\n5 Denosumab for prevention of fractures in postmenopausal women with osteoporosis N Engl J Med Cummings SR San Martin J McClung MR 756 765 361 2009 19671655\n6 Role of denosumab in the management of skeletal complications in patients with bone metastases from solid tumors Biologics Brown-Glaberman U Stopeck AT 89 99 6 2012 22532777\n7 Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials Eur J Cancer Lipton A Fizazi K Stopeck AT 3082 3092 48 2012 https://doi.org/10.1016/j.ejca.2012.08.002 22975218\n8 Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study Lancet Fizazi K Carducci M Smith M 813 822 377 2011 https://doi.org/10.1016/S0140-6736(10)62344-6 21353695\n9 Denosumab versus zoledronic acid in the prevention of skeletal-related events in vulnerable cancer patients: a meta-analysis of randomized, controlled trials Clin Ther Chen C Li R Yang T 1494 1507 42 2020 32718784\n10 Meta-analysis comparing denosumab and zoledronic acid for treatment of bone metastases in patients with advanced solid tumours Eur J Cancer Care (Engl) Zheng GZ Chang B Lin FX 0 26 2017\n11 Osteoclast inhibitors to prevent bone metastases in men with high-risk, non-metastatic prostate cancer: a systematic review and meta-analysis PLoS One Hayes AR Brungs D Pavlakis N 0 13 2018 https://doi.org/10.1371/journal.pone.0191455\n12 Hypocalcaemia following denosumab in prostate cancer: a clinical review Clin Endocrinol (Oxf) Lau LH Cliff ER Wong V 495 502 92 2020 32017154\n13 Denosumab for treatment of bone metastases secondary to solid tumours: systematic review and network meta-analysis Eur J Cancer Ford JA Jones R Elders A 416 430 49 2013 https://doi.org/10.1016/j.ejca.2012.07.016 22906748\n14 Incidence and risk of denosumab-related hypocalcemia in cancer patients: a systematic review and pooled analysis of randomized controlled studies Curr Med Res Opin Qi WX Lin F He AN Tang LN Shen Z Yao Y 1067 1073 29 2013 https://doi.org/10.1185/03007995.2013.813840 23745518\n15 Risk factors for hypocalcemia following treatment with denosumab in patients with bone metastases from prostate cancer J Clin Trials Koguchi D Satoh T Tsumura H 1 7 6 2016\n16 Severe hypocalcemia associated with denosumab in metastatic castration-resistant prostate cancer: risk factors and precautions for treating physicians Clin Genitourin Cancer Autio KA Farooki A Glezerman IG 0 9 13 2015\n17 The effects of denosumab on calcium profiles in advanced cancer patients with bone metastases Support Care Cancer Lechner B DeAngelis C Jamal N 1765 1771 22 2014 24515277\n18 Incidence of hypocalcemia in patients receiving denosumab for prevention of skeletal-related events in bone metastasis J Oncol Pharm Pract Yerram P Kansagra S Abdelghany O 179 184 23 2017 https://doi.org/10.1177/1078155216628325 26830549\n19 Denosumab-associated hypocalcaemia: incidence, severity and patient characteristics in a tertiary hospital setting Pharmacoepidemiol Drug Saf Huynh AL Baker ST Stewardson AJ Johnson DF 1274 1278 25 2016 https://doi.org/10.1002/pds.4045 27255807\n20 The clinical spectrum of hypocalcaemia associated with bone metastases J Intern Med Riancho JA Arjona R Valle R Sanz J González-Macías J 449 452 226 1989 https://doi.org/10.1111/j.1365-2796.1989.tb01423.x 2489231\n21 Severe hypocalcaemia associated with extensive osteoblastic metastases in a patient with prostate cancer Neth J Med Fokkema MI De Heide LJ Van Schelven WD 34 37 63 2005 https://njmonline.nl/getpdf.php?t=a&id=281 15719851\n22 Hypocalcemia and bone mineral density changes following denosumab treatment in end-stage renal disease patients: a meta-analysis of observational studies Osteoporos Int Thongprayoon C Acharya P Acharya C 1737 1745 29 2018 https://doi.org/10.1007/s00198-018-4533-6 29713798\n23 Society for Endocrinology Endocrine Emergency Guidance: emergency management of acute hypocalcaemia in adult patients Endocr Connect Turner J Gittoes N Selby P 0 8 5 2016\n24 Three-year denosumab treatment in postmenopausal Japanese women and men with osteoporosis: results from a 1-year open-label extension of the Denosumab Fracture Intervention Randomized Placebo Controlled Trial (DIRECT) Osteoporos Int Sugimoto T Matsumoto T Hosoi T 765 774 26 2015 https://doi.org/10.1007/s00198-014-2964-2 25403903\n\n",
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"title": "Hypocalcemia in a Patient With Metastatic Prostate Cancer From Denosumab Treatment.",
"title_normalized": "hypocalcemia in a patient with metastatic prostate cancer from denosumab treatment"
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"abstract": "Tracheoesophageal fistula is a challenging anomaly with a rare prevalence with symptoms mainly respiratory, sometimes digestive. We present a rare case of oesophageal atresia with distal Tracheoesophageal fistula in a female child whose mother presented with severe oligohydramnios on ultrasonography with intrauterine growth retardation before cesarean section. After the birth of preterm and very low birth weight neonate, we initially diagnosed as respiratory distress syndrome with a club foot. However, we diagnosed oesophageal atresia with distal Tracheoesophageal fistula on the 2nd day as nasogastric tube insertion was failed beyond 10cm and confirmed by X-ray with a rubber catheter. Right thoracotomy with ligation of the fistula with end to end anastomosis was performed successfully without complications. Breastfeeding initiated and the child discharged after she started gaining weight. Early post-operation complication (anastomotic stricture) was noticed after 2 weeks; however, corrected with endoscopic balloon dilatation. Currently, the child is healthy weighing 10kgs at 18 months of age.",
"affiliations": "Department of Surgery, Patan Academy of Health Sciences, Lagankhel, Lalitpur, Nepal.;Laligurans Hospital, Talchhikhel-14, Lalitpur, Nepal.;Department of Pediatrics, Patan Academy of Health Sciences, Lagankhel, Lalitpur, Nepal.;Department of Surgery, Patan Academy of Health Sciences, Lagankhel, Lalitpur, Nepal.;Laligurans Hospital, Talchhikhel-14, Lalitpur, Nepal.",
"authors": "Maharjan|Anu|A|;Sharma|Amit Kumar|AK|;Kansakar|Prerana|P|;K C|Samyukta|S|;Singh|Yogendra|Y|",
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"doi": "10.31729/jnma.5207",
"fulltext": "\n==== Front\nJNMA J Nepal Med Assoc\nJNMA J Nepal Med Assoc\nJ Nepal Med Assoc\nJNMA\nJNMA: Journal of the Nepal Medical Association\n0028-2715\n1815-672X\nJournal of the Nepal Medical Association\n\n10.31729/jnma.5207\nCase Report\nCongenital Tracheoesophageal Fistula in Very Low Birth Weight Preterm Neonate with an Oligohydramnios as a Rare Presentation: A Case Report\nMaharjan Anu 1\nSharma Amit Kumar 2\nKansakar Prerana 3\nK.C Samyukta 1\nSingh Yogendra 2\n1 Department of Surgery, Patan Academy of Health Sciences, Lagankhel, Lalitpur, Nepal\n2 Laligurans Hospital, Talchhikhel-14, Lalitpur, Nepal\n3 Department of Pediatrics, Patan Academy of Health Sciences, Lagankhel, Lalitpur, Nepal\nCorrespondence: Dr. Anu Maharjan, Department of Surgery (Pediatric), Patan Academy of Health Sciences, Lagankhel, Lalitpur, Nepal. Email: anumaharjan@pahs.edu.np. Phone: +9779841225822.\n12 2020\n31 12 2020\n58 232 10751079\n© The Author(s) 2018.\n2018\nThis is an Open-Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nABSTRACT\n\nTracheoesophageal fistula is a challenging anomaly with a rare prevalence with symptoms mainly respiratory, sometimes digestive. We present a rare case of oesophageal atresia with distal Tracheoesophageal fistula in a female child whose mother presented with severe oligohydramnios on ultrasonography with intrauterine growth retardation before caesarean section. After the birth of preterm and very low birth weight neonate, we initially diagnosed as respiratory distress syndrome with club foot. However, we diagnosed oesophageal atresia with distal Tracheoesophageal fistula on 2nd day as nasogastric tube insertion was failed beyond 10cm and confirmed by X-ray with rubber catheter. Right thoracotomy with ligation of the fistula with end to end anastomosis was performed successfully without complications. Breastfeeding initiated and the child discharged after she started gaining weight. Early post-operation complication (anastomotic stricture) was noticed after 2 weeks; however, corrected with endoscopic balloon dilatation. Currently, the child is healthy weighing 10kgs at 18 months age.\n\nKeywords\n\nCongenital tracheoesophageal fistula\noligohydramnios\npreterm baby\nvery low birth weight\ncase report\n==== Body\nINTRODUCTION\n\nTracheoesophageal fistula (TEF) is a birth defect with an abnormal communication between the trachea and the oesophagus.1 This rare condition affects one child in 2500-4500 live births.2 Type C is the most common among 5 types of TEF, depending upon the location of atresia and associated fistula.3 The hallmarks of TEF is copious salivation associated with choking, coughing, vomiting, and cyanosis with the onset of feeding.1,2\n\nWe present a case of oesophageal atresia (EA) with distal TEF in a female infant delivered at 31 weeks of gestation with very low birth weight whose pre-delivery USG showed severe oligohydramnios with IUGR.\n\nCASE REPORT\n\nA 24 years old primigravida who had previous normal antenatal (ANC) visit along with USG at 17 weeks showed single live fetus at 16 weeks of gestation (WOG) without any gross fetal anomalies at Darchula district hospital, presented with the chief complaints of pain abdomen and per vaginal leaking for 1 day at 31 weeks of gestation in the same hospital and was referred initially to nearby tertiary care Seti Zonal Hospital. Further, she was referred to our centre (Patan Academy of Health Sciences). Repeat USG was done at 31 weeks which revealed severe oligohydramnios with amniotic fluid index (AFI) 1.5cm and intrauterine growth retardation (IUGR) with the expected fetal weight of 1365 grams only. Emergency lower segment caesarean section was performed with prior administration of 2 doses of dexamethasone (12mg) and prophylactic antibiotics to the mother. A female baby was born with a birth weight of 1.2 kilograms and was immediately transferred to the neonatal intensive care unit (NICU) due to respiratory distress. There was no gross congenital anomaly (no murmur) noted except the club foot. She was managed conservatively with intravenous fluids, antibiotics and non-invasive ventilation (Continuous positive airway pressure (CPAP) at 6 centimetre water) with an initial diagnosis of respiratory distress syndrome with a pre-term baby with very low birth weight. Further, NG tube insertion was tried but failed to pass beyond 10 cm for feeding purpose. Therefore, a red rubber catheter was inserted and a chest X-ray (Figure 1)\n\nFigure 1 X-ray showing red rubber tube not passing beyond 10 cm and gastric distension indicating oesophageal atresia with tracheoesophageal fistula.\n\nFigure 2 2A- White arrow showing Azygos vein before ligation, 2B- White arrow showing ligated fistula and black arrow shows distal esophagus, 2C- Arrow shows proximal esophagus with feeding tube, 2D- Arrow showing end to end esophageal anastomosis.\n\nwas performed which demonstrated EA with TEF. Eventually, surgical correction was planned with all the pre-operative evaluation done to rule out other associated anomalies and complications. Right thoracotomy with ligation of the fistula with end to end anastomosis was performed without any perioperative complications (Figure 2A, 2B, 2C, 2D).\n\nAdditionally, a prophylactic chest tube was kept in situ and the NG tube was fixed. Furthermore, post-operatively continuous monitoring of vitals, haemoglobin, electrolytes, nasogastric and chest tube care, antibiotics coverage (Piperacillin-tazobactam + Metronidazole), and maintaining neutral neck position were done. Repeat chest X-ray on the first post-operative day (POD) showed atelectasis of the left lung and chest tube in situ on right (Figure 3A). NG feeding was started on the second post-operative day and endotracheal tube extubated on day three. Initially kept on RAM cannula and then on continuous positive airway pressure (CPAP). There was no collection in the chest drain. The upper gastrointestinal study was carried out on the 7th POD which was inconclusive with right-sided pneumonia. Antibiotics upgraded to Meropenem and Colistin. Fluoroscopic evaluations on 9th POD demonstrated patent oesophageal lumen with dye in the stomach without tracheal and mediastineal spillage and normal expansion of the bilateral lungs field (Figure 3B). Therefore, oral feeding (as tolerated) started on the same day followed by oro-gastric feeding; however, sucking reflex was absent. The chest tube was removed on the 10th POD. Complete breastfeeding commenced on 21st day and transferred to the children ward and subsequently discharged at weight 1900gm. The patient came on emergency after 2 weeks with complaints of choking, chest X-ray done which revealed oesophageal stricture which is one of the early post-surgical complications (Figure 3C). The oesophageal stricture was endoscopically managed with balloon dilatation. She is under regular follow-up and since has been uneventful. Her current weight is 10 kg at 18 months of age.\n\nFigure 3 (A) Post-operative X-ray showing atelectasis of left lung and chest tube in right lung. (B) Fluoroscopic evaluation demonstrating patent oesophagus without mediastinal spillage of dye and bilateral normal expansion of lungs field. (C) X-ray demonstrating proximal oesophageal dilatation revealing post-surgical oesophageal stricture.\n\nDISCUSSION\n\nTracheo-oesophageal fistula is an abnormal communication between the trachea and the oesophagus.1,4 A rare clinical condition but a challenging congenital anomaly which was first reported in 1697 by Thomas Gibson, has always made managing this condition to be very much strenuous.2,4 The abnormality is itself a huge challenge, as a rule, comes in association with one other abnormality (VACTREL: vertebral defects, anorectal malformation, cardiac defects, TEF, renal anomalies, and limb abnormalities).1 These abnormalities can be explained as in Table 1. The TEF classification is determined by the location of the oesophageal atresia and the presence of any associated fistula to the trachea.2 Five different variants have been clinically described, the first described by Vogt in 1929, and modified by Gross in 1953. Thus, two classifications are used today which includes: (i) EA with distal TEF (85%, Vogt IIIb, Gross C), (ii) Isolated EA without TEF (8%, Vogt II, Gross A), (iii) TEF without atresia or H-type TEF (4%, Gross E), (iv) EA with proximal TEF (3%, Vogt III, Gross B), and (v) EA with proximal and distal TEF (< 1%, Vogt IIIa, Gross).2,4\n\nTEF presents in a new-born by copious salivation associated with choking, coughing, vomiting, and cyanosis during the onset of feeding.1 The presentation may vary depending upon the presence or absence of EA. New-borns with EA present immediately after birth with excessive secretions that cause drooling, choking, respiratory distress, and feeding inability. Gastric distension is a common complication of a fistula between the trachea and the distal oesophagus. In EA subsequent inability to swallow typically cause polyhydramnios in utero, a common finding on antenatal USG scanning.1,2 However, in our case, the mother presented with oligohydramnios which led our doubts overshadowed towards correct diagnosis and hence, following the scan done at 31st weeks of gestation a diagnosis of oligohydramnios with intrauterine growth retardation was made. A very low birth weight infant with the birth weight of 1.2 kgs delivered via a caesarean section without gross anomaly except for club foot. Additionally, there was no excessive secretions. This contrasts with the typical presentation of esophageal atresia. One reason behind the cause of severe oligohydramnios in our case after reviewing the history again could be per vaginal leaking of amniotic fluid. Prenatal diagnosis with USG scans can be helpful when a scan in a mother with polyhydramnios shows the absence of a stomach or a small stomach.1 Routine USG scans done between 16-20 weeks of pregnancy can aid the diagnosis but the findings are not specific, are subjective and occasionally transient. This might be due to the reason that polyhydraminos is only diagnostic if TEF is associated with EA. MRI can be complementary to USG as it can be highly predictive although questions have been raised over the feasibility and cost.1,2 After birth, if EA is suspected, a radiopaque 8 French (in preterm infants) or 10 French (in term infants) NG or feeding tube should be passed. In patients with atresia, the NG tube coils at 10 to 12 cm.5 After passing the tube, chest radiographs (postero-anterior and lateral views) including the entire abdomen should be obtained to confirm the position of the tube.1,2,4 In patients with EA, the air in the stomach confirms the presence of a fistula. In our case, as she was delivered pre-term and had very low birth weight, she had a higher risk of developing respiratory distress and so was admitted in NICU (Neo-Natal Intensive Care Unit) and started on intravenous fluids, antibiotics and non-invasive ventilation with a diagnosis of acute respiratory distress syndrome. This misled us to establish the correct diagnosis. However, when a NG tube was inserted in the NICU for the purpose of feeding, the tube could not be inserted; additionally, continuous frothy secretion was noticed only after that point. This gave a clue to us to suspect TEF and hence, a red rubber tube was inserted and a chest x-ray was performed.\n\nFollowing multiple innovative ways aimed at the correction, it was 1941 when a successful surgical correction was performed by Cameron Haight.2 Earlier to this many attempts were made and many surgical procedures tried which failed and this proves how difficult the procedure can be.4 The survival rate of such cases which was once hopeless has improved and reached 100%.5 For successful management care and precision has to be given since the time of diagnosis and needs special pre-operative, intra-operative and post-operative care and management.5 An open surgery which includes thoracotomy with end to end anastomosis of the esophagus with correction of fistula has been reducing the mortality rate of the patients diagnosed with this challenging condition.2 Currently various endoscopic and other surgical techniques are being tried in various hospitals with some promising outcomes.2,6 In cases of neonates with very low birth weight and extremely low birth weight primary repair of EA and closure of a TEF seems to be a better option amongst the open surgical procedure and has proven to enhance the better outcome than the staged repair;7 however controversies exist here as well.8 In our case, we performed right thoracotomy with ligation of the fistula with end to end anastomosis without any peri-operative complications. Many surgeons prefer stage repair in VLBW neonate over primary repair; however, here we performed primary repair as patient was from remote region with low socio-economic condition leading to refusal for stage repair or follow ups.\n\nComplications are mostly post-operative and include anastomotic leak (10-20%), anastomotic strictures (30-40%) as in our case which was managed with balloon dilatation, recurrent TEF (5-14%), tracheomalacia (10%), gastroesophageal reflux (40%), and respiratory infections.1,2,4 The prognosis may be influenced by the presence of major anomalies such as cardiac malformation, renal deformity, external risk factorssepsis, respiratory failure; it is also influenced by the neonatal caregivers.9 Undoubtedly, any efforts to reduce the incidence of the external risk factors may decrease the mortality rate.\n\nThe early diagnosis of the case, within 2 days of delivery despite normal antenatal check-up, and the most successfully performed surgery, good post-operative NICU care without any intra or post-surgical complication, are the prime strength of our study. Very low birth weight and prematurity were some of the worth considering factors in the case of our patient as both of them have been taken as factors that adversely affect the outcome;9 however, we were lucky enough and our patient proved herself a survivor. Spitz classification deals with classification and survival based on weight.1,2 This classification states that the survival rate of infants below 1.5 kgs of birth weight without any major cardiac anomaly to be between 59-82%.4 Despite our strengths, we were unable to diagnose this anomaly during pre-delivery (LSCS) USG scanning and the child, unfortunately, developed an early complication as oesophageal stricture; however, oesophageal stricture was successfully managed endoscopically with balloon dilatation.\n\nAlthough TEF is uncommon in newborn babies, it is wise to USG screening during the antenatal check-up and if doubtful, MRI. Sometimes, they may present with an atypical presentation like in our case with oligohydramnios. Early diagnosis and good care to prevent external risk factors and ultimately surgical correction provide a good prognosis unless the absence of major organ anomalies.\n\nACKNOWLEDGEMENTS\n\nWe want to thank Dr. Ramesh Rana, Laligurash hospital, Lalitpur, and also want to thank Prof Dr. Sanjay Paudyal, and Dr. Niraj Giri, Department of Surgery, Patan Academy of Health Science, Lagankhel, Lalitpur for the support and guidance.\n\nConsent:\n\nJNMA Case Report Consent Form was signed by the patient and the original article is attached with the patient's chart.\n\nConflict of Interest\n\nNone.\n==== Refs\nREFERENCES\n\n1. Lee S Basic Knowledge of Tracheoesophageal Fistula and Esophageal Atresia Adv Neonatal Care 2 2018 18 1 14 21 10.1097/ANC.0000000000000464 29373345\n2. Pinheiro PFM Simões e Silva AC Pereira RM Current knowledge on esophageal atresia World J Gastroenterol 2012 18 28 3662 72 10.3748/wjg.v18.i28.3662 22851858\n3. Lal DR Gadepalli SK Downard CD Ostlie DJ Minneci PC Swedler RM et al Perioperative management and outcomes of esophageal atresia and tracheoesophageal fistula J Pediatr Surg. Aug 2017 52 8 1245 51 10.1016/j.jpedsurg.2016.11.046 27993359\n4. Spitz L Oesophageal atresia Orphanet J Rare Dis 2007 2 24 24 10.1186/1750-1172-2-24 17498283\n5. Alberti D Boroni G Corasaniti L Torri F Esophageal atresia: pre and post-operative management J Matern Fetal Neonatal Med 10 2011 24 Suppl 1 4 6 10.3109/14767058.2011.607558 21942581\n6. Ramai D Alexis Bivona William Latson Andrew Ofosu Emmanuel Ofori Madhavi Reddy et al Endoscopic management of tracheoesophageal fistulas Ann Gastroenterol Jan-Feb 2019 32 1 24 9 30598588\n7. Hannon EJ Billington J Kiely EM Agostino Pierro Lewis Spitz Kate Cross et al Oesophageal atresia is correctable and survivable in infants less than 1 kg Pediatr Surg Int 2016 32 6 571 6 10.1007/s00383-015-3851-4 27090660\n8. Petrosyan M Estrada J Hunter C Russell Woo James Stein Henri R Ford et al Esophageal atresia/tracheoesophageal fistula in very low-birth-weight neonates: improved outcomes with staged repair J Pediatr Surg 12 2009 44 12 2278 81 10.1016/j.jpedsurg.2009.07.047 20006009\n9. Li XW Jiang YJ Wang XQ Yu JL Li LQ A scoring system to predict mortality in infants with esophageal atresia: A case-control study Medicine (Baltimore) 8 2017 96 32 e7755 10.1097/MD.0000000000007755 28796065\n\n",
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"issue": "58(232)",
"journal": "JNMA; journal of the Nepal Medical Association",
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"medline_ta": "JNMA J Nepal Med Assoc",
"mesh_terms": "D002585:Cesarean Section; D002648:Child; D004933:Esophageal Atresia; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D019102:Infant, Very Low Birth Weight; D016104:Oligohydramnios; D011247:Pregnancy; D014138:Tracheoesophageal Fistula",
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"pubdate": "2020-12-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29373345;28796065;22851858;21942581;27993359;17498283;20006009;27090660;30598588",
"title": "Congenital Tracheoesophageal Fistula in Very Low Birth Weight Preterm Neonate with an Oligohydramnios as a Rare Presentation: A Case Report.",
"title_normalized": "congenital tracheoesophageal fistula in very low birth weight preterm neonate with an oligohydramnios as a rare presentation a case report"
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"abstract": "A 57-year-old woman diagnosed with primary melanoma was managed with a wide variety of treatments over 18 years. Given her long history of disease, the array of therapies she has received range from those no longer recommended to those recently approved. This case highlights the extraordinary rate at which both the medical and surgical melanoma treatment landscape has evolved, alongside how professional consensus has changed over the past two decades. It also demonstrates the innovation and collaboration required between the patient and the multidisciplinary team, as well as how external factors such as national guidelines, eligibility for clinical trials and drug funding in the National Health Service (NHS) alter a management plan, presenting yet another set of challenges when managing cancer patients in the modern era.",
"affiliations": "University of Cambridge School of Clinical Medicine, Cambridge, UK garance.biosseduplan@addenbrookes.nhs.uk.;Department of Plastic and Reconstructive Surgery, Addenbrooke's Hospital, Cambridge, UK.;Department of Plastic and Reconstructive Surgery, Addenbrooke's Hospital, Cambridge, UK.;Department of Oncology, Addenbrooke's Hospital, Cambridge, UK.",
"authors": "Biosse-Duplan|Garance|G|http://orcid.org/0000-0002-6685-8574;Murphy|Suzanne|S|;Durrani|Amer|A|;Corrie|Pippa|P|",
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"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\nbcr-2021-246070\n10.1136/bcr-2021-246070\nCase Report\n1506\n1333\n285\n1349\n625\n1560\n1313\n1492\nEvolving treatment landscape: 18 years of managing melanoma in a single patient\nhttp://orcid.org/0000-0002-6685-8574\nBiosse-Duplan Garance 1\nMurphy Suzanne 2\nDurrani Amer 2\nCorrie Pippa 3\n1 University of Cambridge School of Clinical Medicine, Cambridge, UK\n2 Department of Plastic and Reconstructive Surgery, Addenbrooke's Hospital, Cambridge, UK\n3 Department of Oncology, Addenbrooke's Hospital, Cambridge, UK\nCorrespondence to Garance Biosse-Duplan; garance.biosseduplan@addenbrookes.nhs.uk\n2021\n2 11 2021\n2 11 2021\n14 11 e24607019 10 2021\n© BMJ Publishing Group Limited 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 and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nA 57-year-old woman diagnosed with primary melanoma was managed with a wide variety of treatments over 18 years. Given her long history of disease, the array of therapies she has received range from those no longer recommended to those recently approved. This case highlights the extraordinary rate at which both the medical and surgical melanoma treatment landscape has evolved, alongside how professional consensus has changed over the past two decades. It also demonstrates the innovation and collaboration required between the patient and the multidisciplinary team, as well as how external factors such as national guidelines, eligibility for clinical trials and drug funding in the National Health Service (NHS) alter a management plan, presenting yet another set of challenges when managing cancer patients in the modern era.\n\nskin cancer\nsurgical oncology\ncancer intervention\nmalignant disease and immunosuppression\nhealthcare improvement and patient safety\nspecial-featureunlocked\n==== Body\npmcBackground\n\nMelanoma is a public health concern, with incidence increasing faster than any other type of cancer, affecting both men and women of all ages.1 Melanoma is the most lethal form of skin cancer however, the overall 5-year survival rate has increased dramatically from 52% to 90% since the 1970s, while 10-year survival has also almost doubled over the same time period.2 The vast majority of people diagnosed with melanoma present with a pigmented lesion and much of the survival gains have been due to earlier diagnosis and intervention with surgical resection. Improving outcomes for patients with advanced melanoma has proved far more challenging, with life expectancy remaining under 1 year for most people well into the 21st century.\n\nThe melanoma treatment landscape has undergone constant and dynamic evolution over the last 20 years,3 as historic approaches were learnt from and replaced, while new knowledge and interventions have emerged. Translation of basic and clinical research into changing practice requires significant collaboration from multiple stakeholders involved in healthcare, including pharma, regulators, commissioners, doctors and not least the patients themselves. The most noteworthy gain has been the rapid introduction of several new systemic therapies shown for the first time to improve survival of metastatic melanoma patients into routine clinical practice, which has tripled life expectancy in the last decade, now offering potential for cure in some cases.\n\nWe report a patient originally diagnosed with primary melanoma 18 years ago, whose treatment history is a reflection of how rapidly the treatment landscape has changed in both surgery and drug therapy. The case further demonstrates the innovation and collaboration between the patient and healthcare professionals needed to manage multiple challenges that arise along the patient journey.\n\nCase presentation\n\nA 57-year-old Caucasian woman was originally diagnosed with an acral lentiginous melanoma on the left heel (Breslow thickness 5.2 mm) while living in Spain in December 2003, which was removed surgically. The initial surgery was followed by a wide local excision and an immediate elective left inguinal lymph node dissection. She received standard high-dose adjuvant interferon over the following year.4\n\nIn January 2007, multiple subcutaneous intransit metastases occurred, which were resected from her left leg. However, they reoccurred and became too numerous for further surgical clearance, so she was treated with combination chemotherapy comprising cisplatin, vinblastine and dacarbazine. The disease responded well to chemotherapy and was kept under control for several years.\n\nIn July 2011, a routine surveillance CT scan identified liver and lung metastases. She returned to the UK, where her tumour was tested for the presence of and confirmed to harbour a BRAFV600 gene mutation. She enrolled in a clinical trial testing a novel combined BRAF-MEK inhibitor drug. The disease regressed on treatment, which was continued for 12 months despite some unpleasant but non-life-threatening side effects. However, in 2012, a restaging scan confirmed enlarging liver metastases, so the trial drug was halted. At this time, a new immune checkpoint inhibitor antibody targeting the CTLA-4 T cell receptor, called ipilimumab, had just been approved for use by the National Institute for Health and Care Excellence (NICE) following international randomised clinical trials which reported overall survival benefit from systemic therapy for the first time ever in metastatic melanoma patients.5 The patient was treated with ipilimumab, given over a 12-week period. Despite risk of complex immune-related side effects, she tolerated it well and she achieved a durable response, lasting 2 years (figure 1).\n\nFigure 1 CT scans show low volume liver metastases prior to starting ipilimumab (A) and after 2 years on the drug (B). They remained unchanged.\n\nDuring 2014, the patient developed multiple small soft tissue metastases, which were visible and palpable in various parts of her body, including limbs, groins, axillae and posterior chest wall. As there was no new visceral disease at this time, the larger tumours were managed by surgical resection. In 2015, NICE approved a second immune checkpoint inhibitor, pembrolizumab, which blocks the T cell PD-1 receptor and had been shown to have both superior efficacy and better side effect profile compared with ipilimumab.6 A CT scan in December 2015 showed disease progression involving major organs, so the patient began treatment with pembrolizumab in January 2016. The liver and lung metastases were stabilised and she continued on immunotherapy for the next 18 months. During this time, further soft tissue metastases occurred, which were either surgically excised, or palliated with external beam radiotherapy. In 2017, she also underwent electrochemotherapy to manage particularly problematic large volume, painful chest wall soft tissue disease (figure 2) which had not responded to radiotherapy, to good effect and palliation of symptoms.\n\nFigure 2 Electrochemotherapy to a posterior chest wall melanoma metastasis generated tumour regression 7 weeks after treatment.\n\nUnfortunately, in July 2017, the patient developed immunotherapy-related colitis and the pembrolizumab was halted. Once recovered, because it was known that her melanoma harboured a BRAFV600 mutation, she was started on the BRAF inhibitor, dabrafenib, which had been approved by NICE in 2014.7 Her remaining disease responded well, with partial resolution of some soft tissue and visceral metastases (figure 3). New randomised trials reported that combining the MEK inhibitor, trametinib, with dabrafenib, offered greater survival benefit compared with dabrafenib alone, so when NICE approved the combination regimen 5 months later in early 2018, trametinib was added to her treatment regimen.8 She went on to achieve an almost complete response on this combination regimen. However, drug treatment was interrupted 6 months later due to intolerable side effects, including uveitis, arthralgia and severe fatigue. In the absence of BRAF inhibition, more subcutaneous metastases recurred, so she was restarted on a modified dose of dabrafenib monotherapy taken intermittently, which she was able to tolerate and kept her disease under control.9\n\nFigure 3 CT scans show a partial response of left buttock soft tissue metastasis (labelled) to dabrafenib before starting (A) and 8 weeks after being on dabrafenib treatment (B).\n\nA timeline summarising the patient’s treatment alongside key practice-changing events in melanoma management is provided in figure 4.\n\nFigure 4 Timeline showing key interventions during the patient pathway (above the timeline) and the availability of standards of care associated with NICE guidelines (below the timeline). Note, access to dacarbazine and IFN alpha predate NICE. IFN, interferon; LN, lymph node; RAF/MEKi, RAF/MEK protein kinase inhibitor; ECT, electrochemotherapy\n\nOutcome and follow up\n\nIn February 2020, while still continuing in response on intermittent dabrafenib dosing, the patient suffered a debilitating ischaemic stroke, which was unrelated to melanoma. After a period of partial recovery, she restarted dabrafenib, which enabled her to live alongside her disease and maintain a good quality of life despite gradual loss of disease control, with multiple metastases evident on imaging in February 2021. She stopped treatment completely in March 2021 and was admitted for end-of-life hospice care in July 2021.\n\nDiscussion\n\nThis case demonstrates the rapid pace at which the melanoma treatment landscape has advanced, particularly during the last decade. With 5-year and 10-year survival rates increasing, metastatic melanoma is becoming a chronic disease rather than a death sentence, so awareness of the increasing treatment options at our disposal is all the more important.\n\nWhen our patient was first diagnosed, surgery was the only treatment for melanoma known to improve survival. Adjuvant interferon was approved for use in the USA, but with uncertain benefits alongside significant toxicity.10 11 Dacarbazine was used to treat metastatic disease, offering a modest response rate only and median overall survival of patients diagnosed with advanced melanoma was around 8 months. In the early 21st century, huge progress in our understanding of cancer at the molecular level led to a revolution of mechanism-driven anticancer therapies being developed. This approach has been particularly successful in melanoma, now with two major new forms of systemic therapy established as standard of care: immune checkpoint inhibitor antibodies (eg, pembrolizumab, nivolumab and ipilimumab), as well as small molecule inhibitors of the BRAF-MEK signalling pathway (eg, vemurafenib, dabrafenib and trametinib) for those 50% of patients with BRAF mutant melanoma. Modern systemic therapy has extended median overall survival of metastatic melanoma to beyond 3 years, with many patients entering long term remission, some of whom may yet be considered cured.3\n\nWith new treatments come new challenges, including how best to sequence and combine different classes of anticancer drugs, as well as how to manage complex toxicities entirely different to those associated with traditional cytotoxic chemotherapy. Of note, while BRAF-targeted therapies tend to generate relatively minor but chronic side effects, immune-related toxicities can be both life-threatening and life-changing. Immune-mediated inflammation may require hospitalisation and support by intensivists across multiple specialties, while some data are emerging which links severe toxicity to a greater chance of treatment response.12 13 There is a pressing need to educate non-oncologists regarding this new class of anticancer drugs which are being used to treat increasing numbers of cancer types. Importantly, we also have yet to assess the impact on these new agents in long-term survivors.\n\nIn recent years, both immune checkpoint inhibitors and BRAF targeted therapy have been tested as adjuvant therapy and have been shown to halve the rate of recurrence when given to patients with high risk resected melanoma for up to 1 year after their surgery.8 14–16 Thus the historical use of adjuvant interferon can finally be put to bed.\n\nDespite the excitement around novel systemic therapies, the mainstay of treatment for most patients diagnosed with melanoma remains primary surgical resection. Management of regional lymph nodes has evolved over the last decade. As was standard practice in the late 20th century, our patient had an immediate inguinal lymph node dissection at the time of primary melanoma resection, aimed at preventing disease spread. Regional lymph node clearance is associated with significant morbidity, including potentially debilitating lymphoedema of the affected limb. A randomised trial failed to show any survival gain with this approach,17 which led to the practice being abandoned in the 21st century. On the other hand, techniques to identify the sentinel lymph node were developed and sentinel lymph node biopsy (SLNB) has been adopted into routine clinical practice.18 SLNB provides a key pathological staging tool, but the question whether removal of the sentinel node offered therapeutic benefit has been the subject of great debate. SLNB positive patients were previously offered completion lymph node dissection (CLND), but three landmark trials have now convincingly shown no melanoma-specific survival benefit of full lymph node clearance.19–21 Therefore, this practice has now stopped. Instead, modern melanoma surgeons play an increasing role supporting management of metastatic melanoma patients. CLND is indicated for patients presenting with palpable regional lymph nodes. Furthermore, as demonstrated by our patient, differential response to systemic therapy is often seen, with some metastases becoming resistant while others are kept in check. Surgeons assist in removing isolated drug-resistant lesions alongside systemic therapy maintenance. Electrochemotherapy, which our patient received in 2017, was approved by NICE in 201322 as an additional innovative intervention available for controlling limited metastatic melanoma where surgery is not practical.\n\nOur case demonstrates how an individual patient diagnosed with melanoma was able to gain benefit from a series of new interventions that became available during the course of her 18-year illness. Alongside her treatment, she was able to maintain a good quality of life, her own expressed wish was to become a grandmother and she achieved and enjoyed this to the full. Her disease was managed through a multidisciplinary team (MDT) of specialists working to good effect. The MDT was able to take advantage of effective international research and clinical trials, as well as guidance from national regulators and commissioners who took bold decisions at the time to provide patients with significant unmet need access to high cost drugs, based on sound health economic assessments confirming their cost-effectiveness.\n\nPatient’s perspective\n\nDuring my long and varied ‘assault’ on my disease, I always felt that every day of my survival, was 1 day closer to the eventual discovery through constant research of a cure. I felt many times that I was living with a chronic disease when receiving a new drug or therapy, and enjoyed a useful and good quality of life for much of the time. A minor but important point to my own well-being is that I have never worried about what tomorrow may or may not bring, and only put my energies into what challenges today presents.\n\nLearning points\n\nThe melanoma treatment landscape of melanoma has been radically transformed this century and particularly over the last decade.\n\nThe impact of both new non-surgical therapies and surgical interventions has extended life expectancy with improved quality of life at all stages of disease.\n\nLong-term benefits of adjuvant systemic therapy suggest recurrence rates can be halved, while some metastatic melanoma patients are likely being cured.\n\nOptimal care requires a well-informed, multidisciplinary team to co-ordinate individual patient management.\n\nThe authors would like to thank Ms Victoria McMorran for her invaluable role in the patient’s care.\n\nEthics statements\n\nPatient consent for publication\n\nConsent obtained directly from patient(s)\n\nContributors: Conceptualised and supervised by AD. The patient was under care of PC, AD and SM. Report was written by GB-D, with invaluable help from PC and SM.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 Common cancer sites — cancer STAT facts. Available: https://seer.cancer.gov/statfacts/html/common.html [Accessed 20 Jul 2021].\n2 Melanoma skin cancer survival statistics [Internet]. Cancer Research UK, 2015. Available: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/melanoma-skin-cancer/survival [Accessed 15 Jan 2021].\n3 Curti BD, Faries MB. Recent advances in the treatment of melanoma. Longo dl, editor. N Engl J Med 2021;384 :2229–40.34107182\n4 Kirkwood JM, Manola J, Ibrahim J, et al . A pooled analysis of eastern cooperative Oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 2004;10 :1670–7. 10.1158/1078-0432.CCR-1103-3 15014018\n5 National Institute for Health and Care Excellence. Ipilimumab for previously treated advanced unresectable or metastatic melanoma (Technology appraisal guidance [TA268]), 2012. Available: https://www.nice.org.uk/guidance/ta268\n6 National Institute for Health and Care Excellence. Pembrolizumab for treating advanced melanoma after disease progression with ipilimumab (Technology appraisal guidance [TA357]), 2015. Available: https://www.nice.org.uk/guidance/ta357\n7 National Institute for Health and Care Excellence. Dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma (Technology appraisal guidance [TA321]), 2014. Available: https://www.nice.org.uk/guidance/ta321\n8 National Institute for Health and Care Excellence. Dabrafenib with trametinib for adjuvant treatment of resected BRAF V600 mutation-positive melanoma (Technology appraisal guidance [TA544]), 2018. Available: https://www.nice.org.uk/guidance/ta544\n9 Dooley AJ, Gupta A, Bhattacharyya M, et al . Intermittent dosing with vemurafenib in BRAF V600E-mutant melanoma: review of a case series. Ther Adv Med Oncol 2014;6 :262–6. 10.1177/1758834014548187 25364391\n10 Cole BF, Gelber RD, Kirkwood JM, et al . Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an eastern cooperative Oncology Group study. J Clin Oncol 1996;14 :2666–73. 10.1200/JCO.1996.14.10.2666 8874325\n11 Tarhini AA. The current state of adjuvant therapy of melanoma. Lancet Oncol 2020;21 :1394–5. 10.1016/S1470-2045(20)30544-1 32961120\n12 Das S, Johnson DB. Immune-Related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer 2019;7 :306. 10.1186/s40425-019-0805-8 31730012\n13 Dimitriou F, Staeger R, Ak M, et al . Frequency, treatment and outcome of immune-related toxicities in patients with Immune-Checkpoint inhibitors for advanced melanoma: results from an institutional database analysis. Cancers 2021;13 :2931. 10.3390/cancers13122931 34208218\n14 National Institute for Health and Care Excellence. Pembrolizumab for advanced melanoma not previously treated with ipilimumab (Technology appraisal guidance [TA366]), 2015. Available: https://www.nice.org.uk/guidance/ta366\n15 National Institute for Health and Care Excellence. Nivolumab for treating advanced (unresectable or metastatic) melanoma (Technology appraisal guidance [TA384]), 2016. Available: https://www.nice.org.uk/guidance/ta384\n16 National Institute for Health and Care Excellence. Systemic anticancer therapies for stage IV melanoma (NICE pathways), 2021. Available: https://pathways.nice.org.uk/pathways/melanoma\n17 Cascinelli N, Morabito A, Santinami M, et al . Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. The Lancet 1998;351 :793–6. 10.1016/S0140-6736(97)08260-3\n18 Morton DL, Thompson JF, Essner R, et al . Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma. Ann Surg 1999;230 :453. 10.1097/00000658-199910000-00001 10522715\n19 Morton DL, Elashoff R, Hoekstra HJ. Sentinel-Node biopsy or nodal observation in melanoma. n engl j med 2006;11 .\n20 Leiter U, Stadler R, Mauch C, et al . Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol 2016;17 :757–67. 10.1016/S1470-2045(16)00141-8 27161539\n21 Faries MB, Thompson JF, Cochran AJ, et al . Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med 2017;376 :2211–22. 10.1056/NEJMoa1613210 28591523\n22 National Institute for Health and Care Excellence. Electrochemotherapy for metastases in the skin from tumours of non-skin origin and melanoma (Interventional procedures guidance [IPG446]), 2013. Available: https://www.nice.org.uk/guidance/ipg446\n\n",
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"keywords": "cancer intervention; healthcare improvement and patient safety; malignant disease and immunosuppression; skin cancer; surgical oncology",
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"mesh_terms": "D005260:Female; D006801:Humans; D008545:Melanoma; D008875:Middle Aged; D013222:State Medicine",
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"title": "Evolving treatment landscape: 18 years of managing melanoma in a single patient.",
"title_normalized": "evolving treatment landscape 18 years of managing melanoma in a single patient"
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"abstract": "To investigate the incidence and characteristics of breast cancer in transgender people in the Netherlands compared with the general Dutch population.\n\n\n\nRetrospective, nationwide cohort study.\n\n\n\nSpecialised tertiary gender clinic in Amsterdam, the Netherlands.\n\n\n\n2260 adult trans women (male sex assigned at birth, female gender identity) and 1229 adult trans men (female sex assigned at birth, male gender identity) who received gender affirming hormone treatment.\n\n\n\nIncidence and characteristics (eg, histology, hormone receptor status) of breast cancer in transgender people.\n\n\n\nThe total person time in this cohort was 33 991 years for trans women and 14 883 years for trans men. In the 2260 trans women in the cohort, 15 cases of invasive breast cancer were identified (median duration of hormone treatment 18 years, range 7-37 years). This was 46-fold higher than in cisgender men (standardised incidence ratio 46.7, 95% confidence interval 27.2 to 75.4) but lower than in cisgender women (0.3, 0.2 to 0.4). Most tumours were of ductal origin and oestrogen and progesterone receptor positive, and 8.3% were human epidermal growth factor 2 (HER2) positive. In 1229 trans men, four cases of invasive breast cancer were identified (median duration of hormone treatment 15 years, range 2-17 years). This was lower than expected compared with cisgender women (standardised incidence ratio 0.2, 95% confidence interval 0.1 to 0.5).\n\n\n\nThis study showed an increased risk of breast cancer in trans women compared with cisgender men, and a lower risk in trans men compared with cisgender women. In trans women, the risk of breast cancer increased during a relatively short duration of hormone treatment and the characteristics of the breast cancer resembled a more female pattern. These results suggest that breast cancer screening guidelines for cisgender people are sufficient for transgender people using hormone treatment.",
"affiliations": "Centre of Expertise on Gender Dysphoria, Amsterdam UMC, VU University Medical Centre, Amsterdam, Netherlands.;Centre of Expertise on Gender Dysphoria, Amsterdam UMC, VU University Medical Centre, Amsterdam, Netherlands.;Centre of Expertise on Gender Dysphoria, Amsterdam UMC, VU University Medical Centre, Amsterdam, Netherlands.;Department of Clinical Genetics, Amsterdam UMC, VU University Medical Centre, Amsterdam, Netherlands.;Department of Clinical Genetics, Netherlands Cancer Institute, Amsterdam, Netherlands.;Centre of Expertise on Gender Dysphoria, Amsterdam UMC, VU University Medical Centre, Amsterdam, Netherlands.;Department of Pathology, Amsterdam UMC, VU University Medical Centre, Amsterdam, Netherlands.;Department of Oncology, Amsterdam UMC, VU University Medical Centre, Amsterdam, Netherlands.;Centre of Expertise on Gender Dysphoria, Amsterdam UMC, VU University Medical Centre, Amsterdam, Netherlands m.denheijer@vumc.nl.",
"authors": "de Blok|Christel J M|CJM|;Wiepjes|Chantal M|CM|;Nota|Nienke M|NM|;van Engelen|Klaartje|K|;Adank|Muriel A|MA|;Dreijerink|Koen M A|KMA|;Barbé|Ellis|E|;Konings|Inge R H M|IRHM|;den Heijer|Martin|M|0000-0003-3620-5617",
"chemical_list": "D000726:Androgen Antagonists; D004967:Estrogens; D013739:Testosterone",
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"doi": "10.1136/bmj.l1652",
"fulltext": "\n==== Front\nBMJBMJBMJ-UKbmjThe BMJ0959-81381756-1833BMJ Publishing Group Ltd. debc04742510.1136/bmj.l1652ResearchBreast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands de Blok Christel J M PhD candidate1 2Wiepjes Chantal M PhD candidate1 2Nota Nienke M PhD candidate1 2van Engelen Klaartje clinical geneticist3Adank Muriel A clinical geneticist4Dreijerink Koen M A endocrinologist1 2Barbé Ellis pathologist5Konings Inge R H M medical oncologist6http://orcid.org/0000-0003-3620-5617den Heijer Martin professor in endocrinology and head of division1 2\n1 Centre of Expertise on Gender Dysphoria, Amsterdam UMC, VU University Medical Centre, Amsterdam, Netherlands\n2 Department of Endocrinology, Amsterdam UMC, VU University Medical Centre, Amsterdam, Netherlands\n3 Department of Clinical Genetics, Amsterdam UMC, VU University Medical Centre, Amsterdam, Netherlands\n4 Department of Clinical Genetics, Netherlands Cancer Institute, Amsterdam, Netherlands\n5 Department of Pathology, Amsterdam UMC, VU University Medical Centre, Amsterdam, Netherlands\n6 Department of Oncology, Amsterdam UMC, VU University Medical Centre, Amsterdam, NetherlandsCorrespondence to: M den Heijer, Department of Internal Medicine, Section Endocrinology, Amsterdam UMC, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, Netherlands m.denheijer@vumc.nl2019 14 5 2019 365 l165227 3 2019 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions2019BMJThis 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 and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.Abstract\nObjective\nTo investigate the incidence and characteristics of breast cancer in transgender people in the Netherlands compared with the general Dutch population.\n\nDesign\nRetrospective, nationwide cohort study.\n\nSetting\nSpecialised tertiary gender clinic in Amsterdam, the Netherlands.\n\nParticipants\n2260 adult trans women (male sex assigned at birth, female gender identity) and 1229 adult trans men (female sex assigned at birth, male gender identity) who received gender affirming hormone treatment.\n\nMain outcome measures\nIncidence and characteristics (eg, histology, hormone receptor status) of breast cancer in transgender people.\n\nResults\nThe total person time in this cohort was 33 991 years for trans women and 14 883 years for trans men. In the 2260 trans women in the cohort, 15 cases of invasive breast cancer were identified (median duration of hormone treatment 18 years, range 7-37 years). This was 46-fold higher than in cisgender men (standardised incidence ratio 46.7, 95% confidence interval 27.2 to 75.4) but lower than in cisgender women (0.3, 0.2 to 0.4). Most tumours were of ductal origin and oestrogen and progesterone receptor positive, and 8.3% were human epidermal growth factor 2 (HER2) positive. In 1229 trans men, four cases of invasive breast cancer were identified (median duration of hormone treatment 15 years, range 2-17 years). This was lower than expected compared with cisgender women (standardised incidence ratio 0.2, 95% confidence interval 0.1 to 0.5).\n\nConclusions\nThis study showed an increased risk of breast cancer in trans women compared with cisgender men, and a lower risk in trans men compared with cisgender women. In trans women, the risk of breast cancer increased during a relatively short duration of hormone treatment and the characteristics of the breast cancer resembled a more female pattern. These results suggest that breast cancer screening guidelines for cisgender people are sufficient for transgender people using hormone treatment.\n==== Body\nIntroduction\nBreast cancer is the most common malignancy in females,1 but it is rare in males. The lifetime risk in the general female population is 12% and in the general male population is 0.1%.2 Several risk factors have been identified for breast cancer, including advancing age, genetics (eg, BReast CAncer 1/2 mutations (BRCA1/2)), family history, overweight or obesity, breast density, tobacco use, alcohol use, and null parity in females.3\n4 The molecular pathogenesis of breast cancer differs between sexes.5 For instance, cancers positive for human epidermal growth factor receptor 2 (HER2) are rare in males (1.7%), whereas 6-12% of the breast cancers in females express HER2.5\n6\n7\n\n\nTransgender people experience an incongruence between the sex assigned to them at birth and their experienced or expressed gender. In the Netherlands, an estimated one in 2800 birth assigned males and one in 5200 birth assigned females identify themselves as transgender.8 However, a substantial increase in the number of referrals for psychological counselling, for endocrine or surgical treatment, or a combination of those has been seen over the past 10 years.8 Transgender people can receive gender affirming hormones (sex steroids) to reduce psychological distress and to induce desired physical changes, such as for body hair and body composition.9\n10 In trans women (male sex assigned at birth, female gender identity), treatment usually consists of antiandrogens and oestrogens. In trans men (female sex assigned at birth, male gender identity), treatment usually consists of testosterone. Besides gender affirming hormone treatment, transgender people might also want surgical transition, which can consist of breast augmentation and orchiectomy or vaginoplasty in trans women and subcutaneous mastectomy and uterus extirpation or oophorectomy, or both, and phalloplasty in trans men. Subcutaneous mastectomy in trans men is often subtotal to obtain an aesthetic masculine thorax.\n\nWhether (exogenous) sex steroids influence breast cancer risk and pathogenesis in transgender people is not fully understood. It is known that sex steroids induce changes in breast tissue.2\n11 During female puberty and in trans women receiving hormone treatment, mammary development includes duct and lobule formation and an increase in deposition of fat in the breasts.2 Some structural changes occur in breast tissue under the influence of testosterone, such as an increase in fibrous tissue2\n11 and the up regulation of potential oncogenes.12 Large prospective studies have shown that hormone replacement therapy increases the risk of breast cancer in cisgender postmenopausal women,13\n14\n15 in particular in those using both oestrogens and progestogens, which could suggest an increased breast cancer risk in trans women receiving hormone treatment compared with cisgender men.\n\nCurrently, information about the risk of breast cancer in transgender people is limited. To date, 22 cases of breast cancer in trans women and 20 cases in trans men have been published.16\n17\n18\n19 However, reliable estimations of the risk in transgender people are lacking because of the heterogeneity in the population and study cohorts.20\n\n\nTo gain more insight into the risk of breast cancer in transgender people receiving hormone treatment and the influence of (exogenous) sex steroids on the development of breast cancer, we investigated the incidence and characteristics of breast cancer in a well documented cohort of transgender people receiving hormone treatment in the Netherlands, compared with the general Dutch population.\n\nMethods\nStudy population\nFor this retrospective cohort study, we identified all transgender people who visited the gender clinic of the VU University Medical Centre Amsterdam between 1972 and January 2016 for either psychological, endocrine, or surgical treatment. More than 95% of transgender people in the Netherlands receive healthcare at our centre.8 People were excluded from analyses if they never used hormone treatment or the start date was unknown, they were younger than 18 years at the time of the study, or they used alternating oestrogen and testosterone during the follow-up time because of regret about their transition. As data on breast cancer diagnosis were retrieved from the Nationwide Network and Registry of Histopathology and Cytopathology in the Netherlands (PALGA), which covers all pathology diagnoses since 1991,21 we also excluded those whose last visit to our gender identity clinic was before 1991.\n\nMost trans women were treated with a combination of antiandrogens and oestrogens. Antiandrogen treatment usually consisted of cyproterone acetate (a progestogenic antiandrogen, 10 to 100 mg daily) or spironolactone (100 to 200 mg daily), and treatment was often stopped after orchiectomy. Oestrogen was prescribed as ethinylestradiol (25 to 100 µg daily), conjugated oestrogens (0.625 to 1.25 mg daily), estradiol patches (50 to 150 µg/24 hours twice weekly), estradiol implants (20 mg every 3 to 6 months), estradiol injections (10 to 100 mg every 2 to 4 weeks), estradiol valerate (2 to 6 mg daily), or estradiol gel (0.75 to 3.0 mg daily). In recent years, mainly estradiol valerate, estradiol patches, or estradiol gel have been used. Trans men were treated with either testosterone gel (20 to 100 mg daily), intramuscular testosterone esters (150 to 250 mg every 2 to 3 weeks), or oral or intramuscular testosterone undecanoate (orally: 40 to 160 mg daily, intramuscularly: 1000 mg every 10 to 14 weeks). Trans men who experienced persistent menstrual blood loss during testosterone treatment were in some cases treated with additional progestogens such as lynestrenol (5 to 10 mg daily). People who started hormone treatment younger than 18 years often received only gonadotrophin releasing hormone agonists before the addition of oestrogen or testosterone treatment.\n\nData collection\nAfter inclusion of eligible people, we collected data about age at start of hormone treatment, type of treatment, gender affirming surgery, and medical history. Subsequently, the data were linked to PALGA and Statistics Netherlands (CBS). We retrieved data on year of breast cancer diagnosis and breast cancer histology from PALGA. To adequately calculate the follow-up time, we retrieved data on mortality from Statistics Netherlands.\n\nStatistical analysis\nData from trans women and trans men were analysed separately. Baseline data are presented as means with standard deviations for normally distributed data, and medians with interquartile ranges, ranges, or both for non-normally distributed data. For those people who had started hormone treatment before treatment at our clinic, we used the first known start date of the treatment to calculate the most accurate duration. To calculate standardised incidence ratios, we determined the number of observed breast cancer cases in this cohort. Person time was calculated as the number of years from the first known start date of hormone treatment to the first terminating event: breast cancer diagnosis, death, or end of study period (31 August 2017). The number of expected cases were calculated using age matched incidence rates for cisgender men and women from the Netherlands Comprehensive Cancer Organisation (IKNL).22 We calculated the number of expected cases for the whole study population and for the age categories younger than 30 years, 30 to 50 years, and older than 50 years. Finally, standardised incidence ratios with 95% confidence intervals were calculated with a mid-P exact test. Mean oestradiol and testosterone concentrations for each participant were calculated by averaging the results from the measurements performed during hormone treatment.\n\nAnalyses were carried out using STATA statistical software, version 14.1 (Statacorp, College Station, TX) and OpenEpi version 3.01 (www.OpenEpi.com).\n\nPatient and public involvement\nOwing to the design of this study, there was no patient or public involvement. The results of this paper will be shared with the public through our institutions’ website and during an open science evening at our centre, which is intended for transgender people, their friends and family, and other interested people.\n\nResults\nOf 6793 transgender people identified, 4432 were birth assigned males and 2361 were birth assigned females. After exclusions, 2260 trans women and 1229 trans men were included in this study (fig 1). The median age at start of hormone treatment in trans women was 31 years (interquartile range 23-41 years) and in trans men was 23 (interquartile range 19-31) years. The median person time in trans women was 13 (interquartile range 5-23, range 0-63) years and in trans men was 8 years (interquartile range 3-20, range 0-47) years. The total person time was 33 991 years and 14 883 years, respectively. Table 1 shows the baseline characteristics of the study cohort.\n\nFig 1 Study flowchart\n\nTable 1 Baseline characteristics of study cohort. Values are medians (interquartile ranges) unless stated otherwise\n\nCharacteristics\tOverall (n=3489)\tTrans women (n=2260)\tTrans men (n=1229)\t\nAge (years)\t47 (31-57)\t51 (38-60)\t39 (26-51)\t\nAge at start of hormone treatment (years)\t28 (21-38)\t31 (23-41)\t23 (19-31)\t\n% (No) white\t96.5* (2509)\t96.7† (1579)\t96.3‡ (930)\t\n% (No) ever smokers*\t38.9 (1356)\t39.1 (884)\t38.4 (472)\t\nBMI§\t22.9 (20.5-26.2)\t22.7 (20.4-25.6)\t23.2 (20.7-27.3)\t\n% (No) gonadectomy\t-\t68.9 (1556)\t68.5 (842)\t\nOestradiol levels (pmol/L)\t-\t217¶ (129-335)\t125** (78-176)\t\nTestosterone levels (nmol/L)\t-\t1.3†† (0.8-1.3)\t23.3‡‡ (15.9-35.2)\t\nPerson time (years)\t12 (4-22)\t13 (5-23)\t8 (3-20)\t\nTotal person time (years)\t48 874\t33 991\t14 883\t\nData available for *2599 people, †1633 people, ‡966 people, §2201 people, ¶1521 people, ††1334 people, **919 people, ‡‡924 people of cohort.\n\nIn 17 of the 2260 trans women, a total of 18 cases of breast cancer (15 invasive and three non-invasive) were diagnosed after a median 18 (interquartile range 12-27, range 7-37) years of hormone treatment. The median age at diagnosis was 50 (interquartile range 43-55) years. The breast cancers were mostly tumours of ductal origin (67%, n=10/15). The oestrogen receptor was positive in 83% (n=10/12) of the tumours, the progesterone receptor was positive in 67% (n=8/12), and HER2 was positive in 8% (n=1/12). In trans women with breast cancer the median oestradiol level was 236 pmol/L (range 20-492 pmol/L) and the median testosterone level was 1.3 nmol/L (range 0.8-1.3 nmol/L), both comparable with the median levels in the whole cohort of trans women (table 1). Table 2 shows the standardised incidence ratios. A higher overall risk of breast cancer was found (standardised incidence ratio 46.7, 95% confidence interval 27.2 to 75.4) compared with Dutch cisgender men. A lower overall risk of breast cancer was found compared with Dutch cisgender women (0.3, 0.2 to 0.4).\n\nTable 2 Standardised incidence ratios of 18 cases of breast cancer (15 invasive and three non-invasive) in 17 trans women and four cases of invasive breast cancer in four trans men\n\nVariables\tObserved cases\tExpected cases\tStandardised incidence ratio (95% CI)\tExpected cases\tStandardised incidence ratio (95% CI)\t\n\t\tReference: incidence ratio in cisgender men\tReference: incidence ratio in cisgender women\t\n\nTrans women (n=2260)\n\t\nInvasive\t15\t0.32\t46.7 (27.2 to 75.4)\t59.95\t0.3 (0.2 to 0.4)\t\nAge (years):\t\t\t\t\t\t\n <30\t0\t0.00\t-\t0.14\t-\t\n 30-50\t9\t0.01\t659.4 (321.6 to 1210.0)\t9.16\t1.0 (0.5 to 1.8)\t\n >50\t6\t0.31\t19.5 (7.9 to 40.6)\t50.65\t0.1 (0.1 to 0.3)\t\nNon-invasive\t3\t0.03\t96.1 (24.5 to 261.6)\t12.10\t0.3 (0.1 to 0.7)\t\nAge (years):\t\t\t\t\t\t\n <30\t0\t0.00\t-\t0.01\t-\t\n 30-50\t1\t0.00\t5288.0 (264.6 to 26 080.0)\t1.25\t0.8 (0.0 to 4.0)\t\n >50\t2\t0.03\t64.5 (10.8 to 213.0)\t10.83\t0.2 (0.0 to 0.6)\t\n\nTrans men (n=1229)\n\t\nInvasive\t4\t0.07\t58.9 (18.7 to 142.2)\t18.54\t0.2 (0.1 to 0.5)\t\nAge (years):\t\t\t\t\t\t\n <30\t0\t0.00\t-\t0.14\t-\t\n 30-50\t2\t0.01\t282.3 (47.3 to 932.5)\t4.78\t0.4 (0.1 to 1.4)\t\n >50\t2\t0.06\t32.9 (5.5 to 108.8)\t13.62\t0.2 (0.0 to 0.5)\t\nNon-invasive\t0\t0.01\t-\t3.55\t-\t\nIn four of 1229 trans men, four cases of invasive breast cancer were diagnosed at a median age of 47 (range 35-59) years and after a median 15 (range 2-17) years of hormone treatment, but no cases of non-invasive breast cancer. Three of the four cases of breast cancer were of ductal origin. Two cases were oestrogen and progesterone receptor positive, one was HER2 positive, and one was androgen receptor positive. Three of the four cases of breast cancer were diagnosed several years after subcutaneous mastectomy, the other at the time of mastectomy. The median oestradiol level in trans men with breast cancer was 116 pmol/L (range 60-191 pmol/L), comparable with the median level in the whole cohort of trans men. The mean testosterone level in trans men with breast cancer was lower than the median level in the whole cohort (13.2 nmol/L (range 12.8-16.0 nmol/L) v 23.3 (15.9-35.2) nmol/L, respectively). With an overall standardised incidence ratio of 0.2 (95% confidence interval 0.1 to 0.5) in trans men, the risk of breast cancer was lower compared with Dutch cisgender women. Compared with Dutch cisgender men, trans men had a higher overall risk of breast cancer (58.9, 18.7 to 142.2). Table 2 shows the standardised incidence ratios.\n\nWe were unable to perform analyses on different types of hormone treatment, because treatment was often changed over the follow-up period or there was too little variation in treatment regimen (this was particularly the case for antiandrogen treatment).\n\nDiscussion\nThis study found an increased risk of breast cancer in trans women in the Netherlands compared with Dutch cisgender men. In both trans women and trans men, the risk of breast cancer was lower than in Dutch cisgender women. This suggests that hormone treatment alters the risk of breast cancer in transgender people compared with initial risk based on their birth assigned sex. The median age at breast cancer diagnosis was 52 years in trans women and 46 years in trans men, both lower than the average age of 61 years in Dutch cisgender women. HER2 receptor status in trans women was higher than expected in male breast cancer.\n\nComparison with other studies\nThe overall incidence of breast cancer for trans women and trans men combined in the current study was 43.0 per 100 000 person years, which is higher than the numbers found in two previous studies (20.0 per 100 000 person years and 4.5 per 100 000 person years).23\n24 Both studies concluded that the risk of breast cancer in transgender people is comparable to the risk in cisgender men. The incidence in the first of the studies, however, was 31.4 per 100 000 person years in people who underwent hormone treatment, which is in line with our results. In the other study, the breast cancer risk could have been underestimated because of technical limitations resulting in overestimation of the total follow-up time and not including people who underwent treatment for breast cancer in other hospitals. We addressed these limitations in our study. None of the reported cases in this study have been previously published.\n\nIn accordance with previous studies, we observed a younger age at time of breast cancer diagnosis in transgender people compared with cisgender women.25 Moreover, the exposure to hormone treatment before breast cancer diagnosis was relatively short in trans women, at a median of 18 years, suggesting a rapid development of breast tumours in a subset of people. This observation could be explained by genetic susceptibility. Genetics data were available for one trans woman who is a carrier of a BRCA 1 germ line mutation. Another explanation might be the presence of undiagnosed hormone sensitive cancer before treatment, which could become apparent when stimulated by hormones. In trans women, most breast tumours were of the luminal type, suggesting that the tumours are driven in a cell autonomous fashion by the growth stimulatory actions of oestrogens as well as the progestogenic characteristics of the predominantly used antiandrogen cyproterone acetate. As androgens are known to inhibit the progression of luminal breast cancer, antiandrogenic treatment and orchiectomy might have contributed to tumour initiation in the affected people.26\n\n\nBreast cancer screening advise\nCurrent recommendations suggest that trans women and trans men who have not undergone mastectomy should be biennially screened with mammography from the age of 50 years and if they are using hormone treatment for more than five years.27\n28\n29 After subcutaneous mastectomy, monitoring of trans men with mammography is not considered feasible owing to the minimal residual breast tissue, and therefore self examination is advised, although there is no evidence for effectiveness.2\n27\n29 The absolute risk of breast cancer in transgender people is still low in this study, and, more importantly, is not increased compared with cisgender women. We believe therefore that awareness in both doctors and transgender people30 is of more importance than the start of screening at a younger age or intensifying available screening, even though the median age at diagnosis in the current study was lower than in cisgender women. Besides, discontinuation of hormone treatment in older transgender people can be considered, which might from then decrease the risk of breast cancer.31 Trans women and trans men who have not had a mastectomy are advised to undergo the same intensified breast surveillance as their close female relatives if the risk of breast cancer is increased because of a familial predisposition. It is important to remember that transgender people who changed their legal sex might not be automatically invited for population based screenings, including breast cancer screening.\n\nStrengths and limitations of this study\nThis study provides novel insights into the risk of breast cancer in transgender people. The reported risk in the current study is higher than estimates from previous studies, possibly related to cohort size and data quality, including the use of a national pathology database. Furthermore, this study included people with a wide range of ages. This study does, however, have some limitations. Owing to the retrospective design of the study, information about hormone use, family history, genetic mutations, benign breast lesions and breast density, tobacco and alcohol use, and body mass index is missing or incomplete. Although these risk factors for breast cancer should not be underestimated, the most important difference between transgender people and cisgender men and women is the use of hormone treatment. It would be interesting to study these risk factors in more detail, to investigate whether certain factors determine the observed increased risk in trans women. The study participants with breast cancer did not necessarily undergo treatment in our centre, and thus detailed data about type and outcome of the treatment are lacking in most of the cases. Although this would be interesting to study in more detail, it was not the purpose of this study. It would be worthwhile for future studies to investigate whether treatment outcomes of breast cancer in trans women are comparable to those of cisgender women.\n\nConclusions\nThis large nationwide cohort study in the Netherlands showed an increased risk of breast cancer in trans women compared with cisgender men. The risk in trans women is still lower than in Dutch cisgender women and resembles a more female type of breast cancer and hormone receptor status. In trans men, a lower risk compared with Dutch cisgender women was observed. Based on this study, we conclude that the absolute overall risk of breast cancer in transgender people remains low and therefore it seems sufficient for transgender people using hormone treatment to follow screening guidelines as for cisgender people. As the risk of breast cancer in trans women increased during a relatively short duration of hormone treatment, it would be worthwhile for future studies to investigate in more detail the cause of breast cancer in transgender people receiving hormone treatment.\n\nWhat is already known on this topic\nTransgender people, defined as an incongruence between sex assigned at birth and experienced gender, can receive gender affirming hormone treatment (sex steroids) to induce desired physical changes\n\nWhether (exogenous) sex steroids influence breast cancer risk and pathogenesis in transgender people is not fully understood\n\nCurrently, information about the risk of breast cancer in transgender people is limited\n\nWhat this study adds\nAn increased risk of breast cancer was observed in trans women (male sex assigned at birth, female gender identity) compared with cisgender men, and a lower risk in trans men (female sex assigned at birth, male gender identity) compared with cisgender women\n\nA striking finding was that in trans women the risk of breast cancer increased in a relatively short time\n\nThe absolute risk of breast cancer in transgender people remains low, and therefore following breast cancer screening guidelines for cisgender people seems sufficient for transgender people using hormone treatment\n\nContributors: CdB, CW, NN, and MdH designed the study. CdB, CW, NN, KvE, EB, and MdH collected the data. CdB, CW, and NN analysed the data. CdB, CW, NN, KvE, MA, KD, EB, IK, and MdH interpreted the data. CdB drafted the manuscript. CdB, CW, NN, KvE, MA, KD, EB, IK, and MdH revised the manuscript and approved the final version. CdB and MdH are the guarantors. This manuscript is an honest, accurate, and transparent account of the study being reported and no important aspects of the study have been omitted. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.\n\nFunding: None.\n\nCompeting interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.\n\nEthical approval: This study was reviewed by the ethical review board of the VU University Medical Centre Amsterdam. It was determined that the Medical Research Involving Human Subjects Act (WMO) does not apply to this study, and necessity for informed consent was waived. All data were processed anonymously.\n\nData sharing: Statistics Netherlands prohibit data sharing at an individual level to guarantee the anonymity of the people in its databases.\n\nTransparency: The lead authors (CdB and MdH) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.\n==== Refs\n1 \nColeman C \nEarly Detection and Screening for Breast Cancer . Semin Oncol Nurs \n2017 ;33 :141 -55 . 10.1016/j.soncn.2017.02.009 . \n28365057 \n2 \nSonnenblick EB Shah AD Goldstein Z Reisman T \nBreast Imaging of Transgender Individuals: A Review . Curr Radiol Rep \n2018 ;6 :1 . 10.1007/s40134-018-0260-1 . \n29392096 \n3 \nMattingly AE Kiluk JV Lee MC \nClinical considerations of risk, incidence, and outcomes of breast cancer in sexual minorities . Cancer Control \n2016 ;23 :373 -82 . 10.1177/107327481602300408 \n27842326 \n4 \nJohansen Taber KA Morisy LR Osbahr AJ 3rdDickinson BD \nMale breast cancer: risk factors, diagnosis, and management (Review) \n[Review] . Oncol Rep \n2010 ;24 :1115 -20 . 10.3892/or_00000962 . \n20878100 \n5 \nFentiman IS \nThe biology of male breast cancer . Breast \n2018 ;38 :132 -5 . 10.1016/j.breast.2018.01.001 . \n29316513 \n6 Lakhani SR, Ellis IO, Schnitt SJ, et al. WHO Classification of Tumours of the Breast, 4th edn.\n7 \nvan Dooijeweert C Deckers IAG Baas IO van der Wall E van Diest PJ \nHormone- and HER2-receptor assessment in 33,046 breast cancer patients: a nationwide comparison of positivity rates between pathology laboratories in the Netherlands . Breast Cancer Res Treat \n2019 ; published online 1 Mar. 10.1007/s10549-019-05180-5 . \n30825048 \n8 \nWiepjes CM Nota NM de Blok CJM \nThe Amsterdam Cohort of Gender Dysphoria Study (1972-2015): Trends in Prevalence, Treatment, and Regrets . J Sex Med \n2018 ;15 :582 -90 . 10.1016/j.jsxm.2018.01.016 . \n29463477 \n9 \nThe World Professional Association of Transgender Health \nStandards of care for the health of transsexual, transgender, and gender nonconforming people. Version 7. \nWPATH , 2012 .\n10 \nde Blok CJM Klaver M Wiepjes CM \nBreast Development in Transwomen After 1 Year of Cross-Sex Hormone Therapy: Results of a Prospective Multicenter Study . J Clin Endocrinol Metab \n2018 ;103 :532 -8 . 10.1210/jc.2017-01927 . \n29165635 \n11 \nGrynberg M Fanchin R Dubost G \nHistology of genital tract and breast tissue after long-term testosterone administration in a female-to-male transsexual population . Reprod Biomed Online \n2010 ;20 :553 -8 . 10.1016/j.rbmo.2009.12.021 . \n20122869 \n12 \nMillican-Slater R Good R Nash C \nAdding value to rare tissue samples donated to biobanks: characterisation of breast tissue and primary cell cultures obtained from a female-to-male transgender patient . Cell Tissue Bank \n2015 ;16 :27 -34 . 10.1007/s10561-014-9444-y . \n24715474 \n13 \nBeral V Million Women Study Collaborators \nBreast cancer and hormone-replacement therapy in the Million Women Study . Lancet \n2003 ;362 :419 -27 . 10.1016/S0140-6736(03)14596-5 . \n12927427 \n14 \nColditz GA Hankinson SE Hunter DJ \nThe use of estrogens and progestins and the risk of breast cancer in postmenopausal women . N Engl J Med \n1995 ;332 :1589 -93 . 10.1056/NEJM199506153322401 \n7753136 \n15 \nRossouw JE Anderson GL Prentice RL Writing Group for the Women’s Health Initiative Investigators \nRisks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial . JAMA \n2002 ;288 :321 -33 . 10.1001/jama.288.3.321 \n12117397 \n16 \nJoint R Chen ZE Cameron S \nBreast and reproductive cancers in the transgender population: a systematic review . BJOG \n2018 ;125 :1505 -12 . 10.1111/1471-0528.15258 . \n29706033 \n17 \nHartley RL Stone JP Temple-Oberle C \nBreast cancer in transgender patients: A systematic review. Part 1: Male to female . Eur J Surg Oncol \n2018 ;44 :1455 -62 .\n30087072 \n18 \nBarghouthi N Turner J Perini J \nBreast Cancer Development in a Transgender Male Receiving Testosterone Therapy . Case Rep Endocrinol \n2018 ;2018 :3652602 .\n30693115 \n19 \nEismann J Heng YJ Fleischmann-Rose K \nInterdisciplinary Management of Transgender Individuals at Risk for Breast Cancer: Case Reports and Review of the Literature . Clin Breast Cancer \n2019 ;19 :e12 -9 .\n30527351 \n20 \nBraun H Nash R Tangpricha V Brockman J Ward K Goodman M \nCancer in Transgender People: Evidence and Methodological Considerations . Epidemiol Rev \n2017 ;39 :93 -107 . 10.1093/epirev/mxw003 . \n28486701 \n21 \nCasparie M Tiebosch ATMG Burger G \nPathology databanking and biobanking in The Netherlands, a central role for PALGA, the nationwide histopathology and cytopathology data network and archive . Cell Oncol \n2007 ;29 :19 -24 .\n17429138 \n22 the Netherlands Comprehensive Cancer Organisation (IKNL). Dutch cancer figures. www.cijfersoverkanker.nl/selecties/dataset_1/img5b30c289b4687?language=en [updated 2 Feb 2018. accessed 15 May 2018].\n23 \nGooren LJ van Trotsenburg MA Giltay EJ van Diest PJ \nBreast cancer development in transsexual subjects receiving cross-sex hormone treatment . J Sex Med \n2013 ;10 :3129 -34 . 10.1111/jsm.12319 . \n24010586 \n24 \nBrown GR Jones KT \nIncidence of breast cancer in a cohort of 5,135 transgender veterans . Breast Cancer Res Treat \n2015 ;149 :191 -8 . 10.1007/s10549-014-3213-2 . \n25428790 \n25 \nMaglione KD Margolies L Jaffer S \nBreast cancer in male-to-female transsexuals: use of breast imaging for detection . AJR Am J Roentgenol \n2014 ;203 :W735 -40 . 10.2214/AJR.14.12723 . \n25415740 \n26 \nChia K O’Brien M Brown M Lim E \nTargeting the androgen receptor in breast cancer . Curr Oncol Rep \n2015 ;17 :4 . 10.1007/s11912-014-0427-8 . \n25665553 \n27 \nDeutsch MB Radix A Wesp L \nBreast Cancer Screening, Management, and a Review of Case Study Literature in Transgender Populations . Semin Reprod Med \n2017 ;35 :434 -41 . 10.1055/s-0037-1606103 . \n29073682 \n28 \nImborek KL Graf EM McCune K \nPreventive Health for Transgender Men and Women . Semin Reprod Med \n2017 ;35 :426 -33 . 10.1055/s-0037-1604457 . \n29073681 \n29 \nPhillips J Fein-Zachary VJ Mehta TS Littlehale N Venkataraman S Slanetz PJ \nBreast imaging in the transgender patient . AJR Am J Roentgenol \n2014 ;202 :1149 -56 . 10.2214/AJR.13.10810 \n24758673 \n30 \nDhand A Dhaliwal G \nExamining patient conceptions: a case of metastatic breast cancer in an African American male to female transgender patient . J Gen Intern Med \n2010 ;25 :158 -61 . 10.1007/s11606-009-1159-6 . \n19898907 \n31 \nSattari M \nBreast cancer in male-to-female transgender patients: a case for caution . Clin Breast Cancer \n2015 ;15 :e67 -9 . 10.1016/j.clbc.2014.08.004 . \n25445423\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0959-8138",
"issue": "365()",
"journal": "BMJ (Clinical research ed.)",
"keywords": null,
"medline_ta": "BMJ",
"mesh_terms": "D000328:Adult; D000726:Androgen Antagonists; D001943:Breast Neoplasms; D018567:Breast Neoplasms, Male; D004967:Estrogens; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D009426:Netherlands; D012189:Retrospective Studies; D012307:Risk Factors; D013739:Testosterone; D014189:Transsexualism; D055815:Young Adult",
"nlm_unique_id": "8900488",
"other_id": null,
"pages": "l1652",
"pmc": null,
"pmid": "31088823",
"pubdate": "2019-05-14",
"publication_types": "D016428:Journal Article",
"references": "12117397;12927427;17429138;19898907;20122869;20878100;24010586;24715474;24758673;25415740;25428790;25445423;25665553;27842326;28365057;28486701;29073681;29073682;29165635;29316513;29392096;29463477;29706033;30087072;30527351;30693115;30825048;7753136",
"title": "Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands.",
"title_normalized": "breast cancer risk in transgender people receiving hormone treatment nationwide cohort study in the netherlands"
} | [
{
"companynumb": "NL-ENDO PHARMACEUTICALS INC-2020-005523",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TESTOSTERONE UNDECANOATE"
},
"d... |
{
"abstract": "A 69-year-old woman undergoing treatment for hypertension and epilepsy was scheduled to undergo cataract surgery. All preoperative examination results were within normal limits. Despite being tense, she walked to the operating room. Approximately 2 minutes after an intravenous line was established by an anesthesia resident, severe hypoxia and bradycardia developed, and she lost consciousness. Cardiopulmonary resuscitation was initiated immediately, and after 1 minute, she regained consciousness, and her breathing and circulation recovered. After admission to the intensive care unit, emergency coronary angiography was performed. The blood flow in all the coronary arteries was normal. However, a decrease in the apical left ventricular wall motion and an increase in the basal wall motion were observed. Based on these findings, Takotsubo cardiomyopathy was diagnosed. The wall motion gradually improved and the patient was discharged from the hospital on postoperative day 15. The respiratory depression and bradycardia were thought to be due to an inadvertent bolus of remifentanil. We surmised that the patient had received a slight amount of retained medication when the anesthesia resident established the intravenous line, which caused severe respiratory depression. It is important to note that adverse effects such as severe respiratory depression and bradycardia can be caused by even small doses of remifentanil.",
"affiliations": "Department of Anesthesiology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Electronic address: yukof@nms.ac.jp.;Department of Anesthesiology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.;Department of Anesthesiology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.;Intensive Care Unit, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.;Department of Anesthesiology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.",
"authors": "Furuichi|Yuko|Y|;Hamada|Ayaka|A|;Nakazato|Keiko|K|;Kobayashi|Katsuya|K|;Sakamoto|Atsuhiro|A|",
"chemical_list": "D000701:Analgesics, Opioid; D010880:Piperidines; D014662:Vasoconstrictor Agents; D000077208:Remifentanil; D004837:Epinephrine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jclinane.2016.08.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0952-8180",
"issue": "35()",
"journal": "Journal of clinical anesthesia",
"keywords": "Anesthesia induction; Bradycardia; Remifentanil; Respiratory depression; Takotsubo cardiomyopathy; β-Blocker",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000368:Aged; D000701:Analgesics, Opioid; D000768:Anesthesia, General; D001919:Bradycardia; D016887:Cardiopulmonary Resuscitation; D002387:Cataract Extraction; D017023:Coronary Angiography; D004562:Electrocardiography; D004827:Epilepsy; D004837:Epinephrine; D005260:Female; D006801:Humans; D006973:Hypertension; D010880:Piperidines; D000077208:Remifentanil; D012131:Respiratory Insufficiency; D054549:Takotsubo Cardiomyopathy; D014662:Vasoconstrictor Agents",
"nlm_unique_id": "8812166",
"other_id": null,
"pages": "275-277",
"pmc": null,
"pmid": "27871542",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe respiratory depression and bradycardia before induction of anesthesia and onset of Takotsubo cardiomyopathy after cardiopulmonary resuscitation.",
"title_normalized": "severe respiratory depression and bradycardia before induction of anesthesia and onset of takotsubo cardiomyopathy after cardiopulmonary resuscitation"
} | [
{
"companynumb": "JP-SA-2017SA042034",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nCardio-pulmonary exercise testing (CPET) is frequently used to assess aerobic capacity, to evaluate respiratory tolerance and to provide prognostic information. Therefore, CPET is often incorporated in the preoperative assessment of cancer patients. This clinical case report presents the preoperative assessment of a patient before thoracic surgery, in whom an important decrease of aerobic capacity was noted, possibly because of muscular toxicity linked to chemotherapy.\n\n\nMETHODS\nThis clinical case concerns a fit, 66-year-old man with a large cell carcinoma of the bronchus. He had received 2 cycles of adjuvant chemotherapy. Subsequently, a left pneumonectomy had been proposed and preoperative assessment performed. CPET showed no further increase in oxygen uptake after the first ventilatory threshold, in spite of increases in carbon dioxide output, minute ventilation and heart rate. Moreover, maximal oxygen uptake was low and there was a decrease of oxygen pulse at maximal effort.\n\n\nCONCLUSIONS\nWe suggest that the limitation of effort was due to a limitation of muscular oxygen extraction, which could be explained by possible muscular toxicity due to chemotherapy.",
"affiliations": "Unité de physiologie respiratoire et sportive, hôpitaux de Rouen, CHU, hôpitaux de Rouen, CHU, 1, rue de Germont, 76031 Rouen, France. Electronic address: secqama@gmail.com.;UFR STAPS, CETAPS, EA3832, université de Rouen, 76130 Mont-Saint-Aignan, France. Electronic address: jeremy.coquart@yahoo.com.;Unité de physiologie respiratoire et sportive, hôpitaux de Rouen, CHU, hôpitaux de Rouen, CHU, 1, rue de Germont, 76031 Rouen, France.;Service de chirurgie thoracique, clinique du Cèdre, 76230 Bois-Guillaume, France.;Cabinet de pneumologie, 76140 Le Petit-Quevilly, France.;Service de cancérologie, clinique Saint-Hilaire, 76000 Rouen, France.;Service de cardiologie, hôpitaux de Rouen, CHU, 76031 Rouen, France.;Unité de physiologie respiratoire et sportive, hôpitaux de Rouen, CHU, hôpitaux de Rouen, CHU, 1, rue de Germont, 76031 Rouen, France.;Unité de physiologie respiratoire et sportive, hôpitaux de Rouen, CHU, hôpitaux de Rouen, CHU, 1, rue de Germont, 76031 Rouen, France.;Unité de physiologie respiratoire et sportive, hôpitaux de Rouen, CHU, hôpitaux de Rouen, CHU, 1, rue de Germont, 76031 Rouen, France.;Unité de physiologie respiratoire et sportive, hôpitaux de Rouen, CHU, hôpitaux de Rouen, CHU, 1, rue de Germont, 76031 Rouen, France.;Unité de physiologie respiratoire et sportive, hôpitaux de Rouen, CHU, hôpitaux de Rouen, CHU, 1, rue de Germont, 76031 Rouen, France.",
"authors": "Secq|A|A|;Coquart|J|J|;Prum|G|G|;Dujon|A|A|;Madru|B|B|;Radji|A|A|;Stepowski|D|D|;Netchitailo|M|M|;Maure|D|D|;Molina|A|A|;Boutry|A|A|;Debeaumont|D|D|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "France",
"delete": false,
"doi": "10.1016/j.rmr.2018.11.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0761-8425",
"issue": "36(3)",
"journal": "Revue des maladies respiratoires",
"keywords": "Aerobic capacity; Aptitude aérobie; Arterio-venous oxygen difference; Cancer; Différence artérioveineuse en oxygène; Limitation périphérique musculaire; Muscular limitation",
"medline_ta": "Rev Mal Respir",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D000072599:Cardiorespiratory Fitness; D017024:Chemotherapy, Adjuvant; D005080:Exercise Test; D017079:Exercise Tolerance; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009135:Muscular Diseases; D010101:Oxygen Consumption; D011013:Pneumonectomy",
"nlm_unique_id": "8408032",
"other_id": null,
"pages": "364-368",
"pmc": null,
"pmid": "30902442",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Assessment of muscular toxicity due to chemotherapy by cardio-pulmonary exercise testing.",
"title_normalized": "assessment of muscular toxicity due to chemotherapy by cardio pulmonary exercise testing"
} | [
{
"companynumb": "FR-FRESENIUS KABI-FK201905152",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Mycophenolate mofetil (MMF) is the standard treatment for lupus nephritis. In Japan, it was approved for lupus nephritis in 2015. We investigated its real-world safety and effectiveness in Japanese patients with systemic lupus erythematosus (SLE).\nWe analyzed the continuation rate, adverse events, and reasons for discontinuation of MMF in Japanese patients with SLE in a retrospective single-center study. We included 119 patients who received MMF from 31 July 2015 to 31 May 2019. To compare demographic and clinical characteristics between groups, the Mann-Whitney U-test was used for nonnormally distributed variables. Categorical variables were compared using Fisher's exact test. Kaplan-Meier curves were plotted for the discontinuation rate of MMF.\nPatients consisted of 18 males and 101 females. Thirty-five patients discontinued MMF. The cumulative discontinuation rate was 42.4%. Twenty-nine patients discontinued MMF due to adverse events, and six patients discontinued MMF due to remission of SLE or desire for childbearing. At the time of the last observation, the lupus low disease activity state achievement rate was significantly lower in patients who experienced adverse events than those who did not (64% vs. 35%, P = 0.009). We examined the concentration of mycophenolate acid (trough level) in stored frozen serum in 11 patients. Two patients had irreversible complications due to viral meningitis; their trough mycophenolate acid concentrations were 8.3 and 6.3 μg/mL, respectively.\nAlthough MMF may be effective in Japanese patients with SLE, physicians should pay attention to infections in patients with high mycophenolate acid concentrations.",
"affiliations": "Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.;Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.;Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.;Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.",
"authors": "Abe|Yoshiyuki|Y|https://orcid.org/0000-0002-1014-2868;Tada|Kurisu|K|;Yamaji|Ken|K|;Tamura|Naoto|N|",
"chemical_list": "D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.1155/2021/8630596",
"fulltext": "\n==== Front\nBiomed Res Int\nBiomed Res Int\nBMRI\nBioMed Research International\n2314-6133 2314-6141 Hindawi \n\n10.1155/2021/8630596\nResearch Article\nReal-World Experience of Safety of Mycophenolate Mofetil in 119 Japanese Patients with Systemic Lupus Erythematosus: A Retrospective Single-Center Study\nhttps://orcid.org/0000-0002-1014-2868Abe Yoshiyuki yo-abe@juntendo.ac.jp Tada Kurisu Yamaji Ken Tamura Naoto Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan\nAcademic Editor: Vinod Chandran\n\n\n2021 \n23 1 2021 \n2021 86305962 8 2020 11 1 2021 15 1 2021 Copyright © 2021 Yoshiyuki Abe et al.2021This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Objectives\n Mycophenolate mofetil (MMF) is the standard treatment for lupus nephritis. In Japan, it was approved for lupus nephritis in 2015. We investigated its real-world safety and effectiveness in Japanese patients with systemic lupus erythematosus (SLE). \n\nMethods\n We analyzed the continuation rate, adverse events, and reasons for discontinuation of MMF in Japanese patients with SLE in a retrospective single-center study. We included 119 patients who received MMF from 31 July 2015 to 31 May 2019. To compare demographic and clinical characteristics between groups, the Mann–Whitney U-test was used for nonnormally distributed variables. Categorical variables were compared using Fisher's exact test. Kaplan–Meier curves were plotted for the discontinuation rate of MMF. \n\nResults\n Patients consisted of 18 males and 101 females. Thirty-five patients discontinued MMF. The cumulative discontinuation rate was 42.4%. Twenty-nine patients discontinued MMF due to adverse events, and six patients discontinued MMF due to remission of SLE or desire for childbearing. At the time of the last observation, the lupus low disease activity state achievement rate was significantly lower in patients who experienced adverse events than those who did not (64% vs. 35%, P = 0.009). We examined the concentration of mycophenolate acid (trough level) in stored frozen serum in 11 patients. Two patients had irreversible complications due to viral meningitis; their trough mycophenolate acid concentrations were 8.3 and 6.3 μg/mL, respectively. \n\nConclusions\n Although MMF may be effective in Japanese patients with SLE, physicians should pay attention to infections in patients with high mycophenolate acid concentrations.\n\nChugai Pharmaceutical Co., Ltd\n==== Body\n1. Introduction\nMycophenolate mofetil (MMF) is an immunosuppressant that was approved for the prevention of transplant rejection in 1992 [1]. MMF is an ester of mycophenolate acid (MPA), the active metabolite. Since MPA inhibits de novo purine synthesis, on which only lymphocytes depend, MPA has specific antiproliferative effects [2]. The MMF is used as an immunosuppressant to treat rheumatic diseases, especially lupus nephritis [3, 4]. The American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) published guidelines for lupus nephritis in 2012 in which they recommended that MMF and cyclophosphamide should be considered equivalent for patients with International Society of Nephrology class III/IV lupus nephritis [5–7]. MMF is currently an important treatment for systemic lupus erythematosus (SLE).\n\nMMF often causes adverse events. Typical adverse events include infections, upper gastrointestinal symptoms, and diarrhea [5]. ACR guidelines recommend that “Asians compared to non-Asians might require lower doses of MMF for similar efficacy” [7–9]. Previous Japanese studies have reported MMF doses of almost 1,000–2,000 mg/day/person for lupus nephritis [10–14]. In this single-center retrospective study, we evaluated medication continuation, adverse events, and reasons for discontinuation of MMF in 119 patients with SLE.\n\n2. Patients and Methods\n2.1. Patients\nThis retrospective single-center observational study included 173 patients who received MMF treatment from 31 July 2015 to 31 May 2019 at Juntendo University Hospital. MMF was approved for SLE on 31 July 2015 in Japan. We ultimately analyzed 119 of the initial 173 patients. We excluded 54 patients because 8 patients started MMF before 31 July 2015, 20 patients had been treated with MMF at another hospital, and 26 patients were treated with MMF for other rheumatic diseases. All 119 patients were diagnosed with SLE according to the 1997 ACR SLE classification criteria [15]. There was no standardized treatment regimen in this retrospective observational study; MMF treatment was determined by each patient's physician. The ethics committee of Juntendo University Hospital approved this study (approval number 19-054). Patients could opt out of the study through the hospital's website.\n\n2.2. Clinical Evaluations and Outcomes\nClinical data, including patient demographics, clinical manifestations, laboratory data, outcomes, adverse events, and reasons for MMF discontinuation, were obtained from medical records. We analyzed clinical manifestations from any point in time. Laboratory data were from the time of MMF initiation. Treatments included all therapies received by patients at the time of MMF initiation and history of treatments before starting MMF. The primary outcome was the rate of MMF continuation. Secondary outcomes were adverse events associated with MMF, reasons for MMF discontinuation, MMF dose during the last observation period, and prevalence of the lupus low disease activity state (LLDAS) during the last observation period [16]. In this study, a major SLE flare was defined as British Isles Lupus Assessment Group Index category A disease [17].\n\n2.3. Measurement of Serum MPA Levels\nSerum MPA levels were measured retrospectively with frozen serum. We stored surplus serum after clinical laboratory testing for retrospective testing (Juntendo University Hospital ethics committee approval number 334). All measurements were performed using the enzyme multiplied immunoassay technique on serum samples collected when the MMF dose had been stable for more than a week. In order to collect serum at precisely 12 hours after administration to assess trough levels, only serum samples from hospitalized patients with confirmed blood collection times were selected.\n\n2.4. Statistical Analysis\nTo compare demographic and clinical characteristics between groups, the Mann–Whitney U-test was used for nonnormally distributed variables. Categorical variables were compared using Fisher's exact test. Spearman's correlation coefficients were calculated. Kaplan–Meier curves were plotted for the discontinuation rate of MMF. Data are presented as medians (interquartile range (IQR)). Analyses were performed using SPSS version 23.0 software (SPSS, Armonk, NY) with P < 0.05 considered to be statistically significant.\n\n3. Results\nThe median observation period was 16 (5–33) months. Patients consisted of 18 males and 101 females. The median age was 38 (31–46) years, and the median duration of SLE was 138 (39–242) months. Ninety-six patients received MMF as induction therapy and 23 patients received MMF as maintenance therapy. MMF was used for the following reasons: lupus nephritis (70 patients), serological abnormality (24 patients), change from another immunosuppressant (10 patients), rash (8 patients), neuropsychiatric manifestation (3 patients), cytopenia (2 patients), and arthritis (2 patients). Thirty-five patients discontinued MMF. The cumulative discontinuation rate was 42.4%. Twenty-nine of 35 patients discontinued MMF because of adverse events and six patients discontinued due to SLE remission or desire for childbearing. The reasons for discontinuation were as follows: infection (11 patients), nausea or diarrhea (9 patients), SLE exacerbation (3 patients), SLE remission (3 patients), desire for childbearing (3 patients), cytopenia (2 patients), and renal dysfunction, liver dysfunction, alopecia, and rash (1 patient each) (Figure 1(a)). For all adverse events, infection and SLE exacerbation were differentiated from general adverse events. Nausea or diarrhea, cytopenia, renal dysfunction, liver dysfunction, alopecia, and rash were distinguished from adverse effects of MMF. Table 1 shows the background characteristics, laboratory test findings, treatments, and outcomes in all patients and by adverse event status. The group with adverse events had lower hemoglobin, as well as higher alanine aminotransferase (ALT) and blood urea nitrogen (BUN) levels. At the last observation, the LLDAS achievement rate was significantly lower in the adverse event group than in the no-adverse event group (64% vs. 35%; P = 0.009). Supplemental Table 1 shows the comparison between patients who received MMF as induction therapy versus maintenance therapy. The induction therapy group had lower concentrations of complement and higher anti-deoxyribonucleic acid (DNA) antibody titers and glucocorticoid (GC) dose at the start of MMF therapy. Supplemental Tables 2 and 3 show the comparison between patients with general adverse events versus adverse effects associated with MMF. Among patients with general adverse events, serum aspartate aminotransferase levels were higher. There were no significant differences in other variables.\n\nAt the time of LLDAS achievement, patients in the no-AE and AE groups had a mean daily GC dose of 7.0 (6.0–7.0) mg and 7.0 (7.0–7.13) mg (P = 0.27), respectively. The proportion of patients using MMF in the two groups was 93% and 0% (not applicable), respectively. The proportion of patients using tacrolimus in the two groups was 46% and 20% (P = 0.17), respectively. There was one patient treated with azathioprine in the no-AE group and one patient treated with belimumab in the AE group.\n\n\nFigure 1(b) shows the Kaplan-Meier curve for the overall MMF discontinuation rate. Figure 1(c) shows the Kaplan-Meier curve for the MMF discontinuation rate due to adverse events. Fifty-five percent of adverse events occurred in the first 2 months after the start of MMF therapy, and 79% occurred in the first 6 months. Figure 1(d) shows the MMF dose at the last observation. The median MMF dose at the last observation was 1,000 (1,000–1,500) mg.\n\nSeven severe infections occurred, consisting of two cases of varicella-zoster virus (VZV) meningitis, and one case each of disseminated VZV, urosepsis, osteomyelitis of the mandible, necrotizing fasciitis, and multiple subcutaneous abscesses. The GC dose in each patient at the time of infection was 60 mg, 55 mg, 55 mg, 35 mg, 30 mg, 28 mg, and 14 mg daily, respectively. One patient with disseminated VZV died during the observation period. There were four mild infections consisting of upper respiratory infections and mycobacterial dermatitis. Supplemental Table 4 shows the details of immunosuppressive therapies and outcomes in each patient.\n\nWe examined serum trough MPA concentrations (Table 2) in our patients' surplus frozen serum samples, which were stored as a general practice. All 11 patients received MMF as induction therapy. Reliable trough levels could only be measured in 11 samples. It was not possible to measure trough levels in the other samples because the timing of blood collection and oral MMF administration was uncertain. Two patients who had irreversible brain damage due to viral meningitis had MPA concentrations of 8.3 and 6.3 μg/mL, respectively.\n\n4. Discussion\nWe analyzed 119 patients with SLE treated with MMF. The overall discontinuation rate was 42.4%, the adverse event-related discontinuation rate was 34.0%, and there were 29 adverse events. Although the most reason for discontinuation was 11 infection, we considered that it was also influenced by the high median GC of 20 (10–40) mg/dL. These findings correspond to real-world safety data for MMF in Japanese patients with SLE.\n\nThe effectiveness of MMF for patients with SLE was also revealed in our study. The LLDAS achievement rate was 57%. Several patients were still tapering from GCs at the last observation, so the prevalence of LLDAS might have been higher if the observation period was extended. However, the interpretation of these results was limited due to the lack of standard therapeutic regimens and uniform follow-up duration. The no-AE group had a significantly higher LLDAS achievement rate, which might indicate the effectiveness of MMF in Japanese patients with SLE.\n\nWe analyzed the safety of MMF in Japanese patients with SLE. Life-threatening adverse events included seven severe infections. In order to use MMF safely, we consider it necessary to analyze factors that might predict adverse events. The analysis showed that lower hemoglobin, higher BUN, and use of other immunosuppressants are associated with adverse events. However, anemia was not associated with serum MPA levels in a previous report [18]. These results may not reflect renal dysfunction, because only BUN was associated with adverse events, not creatinine, and eGFR. Unfortunately, these results may include confounding factors because hemoglobin, BUN, and use of other immunosuppressants are correlated with each other and other factors. Focusing on the trends of higher anti-DNA antibodies, proteinuria, SLE disease activity index, and lower complement concentrations instead of anemia and BUN suggests that the AE group may have more active SLE. However, no statistical differences were observed; these findings should be verified in a larger study. We found MPA levels of 8.3 and 6.3 μg/mL, respectively, in two patients with VZV meningitis. MMF was associated with increased susceptibility to VZV infection in previous studies on kidney transplantation [19, 20] and SLE [21, 22]. There is a Japanese case report of SLE and fatal VZV infection [23]. Physicians should be aware of the risk of viral infections such as VZV in patients with SLE taking MMF.\n\nIn this study, the median dose of MMF at the last observation was 1,000 mg, reflecting physicians' real-world choices for SLE maintenance therapy in Japan. EULAR recommends 3,000 mg of MMF for induction therapy and 2,000 mg of MMF for maintenance remission therapy in non-Asian patients with SLE and 2,000 mg of MMF for induction therapy in Asian patients with SLE. Because GCs interfere with MPA bioavailability, patients had higher MPA concentrations while being tapered off GCs after induction therapy than during induction therapy [24].\n\nThe usefulness of therapeutic drug monitoring for MPA in patients with SLE is controversial. Several studies on SLE reported that the concentration of MPA is associated with therapeutic effect and adverse events [25–27], only therapeutic effects [28–36], or neither [13]. Higher MPA concentration is associated with effectiveness in lupus nephritis during therapy to induce remission. Actual mean daily MMF doses were appropriate 1,500–2,000 mg [13, 27–29, 31, 32]. In these studies, the mean predose MPA concentration was between 1.7 and 2.5 μg/mL. Higher MPA concentration during maintenance therapy is associated with favorable outcomes [13, 25–27, 31, 33–36]. The mean daily MMF dose was 1,900–2,000 mg, and the mean predose MPA concentration was between 1.7 and 4.2 μg/mL. Trough levels did not correspond to the area under the blood concentration-time curve in patients with SLE [13, 25]. We could not conclude that therapeutic drug monitoring was useful. Further evaluation is needed.\n\nA noteworthy point of our study was that MPA levels were measured retrospectively. If we had confirmed high serum MPA levels during treatment, we may have reduced the dose of MMF. Due to the difficulties in reliably measuring trough levels in a retrospective study, serum trough MPA levels could only be examined in 11 patients. This was the major limitation of our study.\n\n5. Conclusion\nWe evaluated the rate of MMF continuation and reasons for MMF discontinuation in Japanese patients with SLE. High serum MPA levels may be associated with severe infections in Japanese patients with SLE. Although MMF may be effective in Japanese patients with SLE, physicians should pay attention to infections in patients with high MPA concentrations.\n\nAcknowledgments\nThe authors would like to thank Dr. Yuki Asai for assistance with data collection. NT has received research grants from Chugai Pharmaceutical Co., Ltd.\n\nData Availability\nThe data used to support the findings of this study are available from the corresponding author upon request.\n\nConflicts of Interest\nYA, KT, and KY have no conflicts of interest to declare.\n\nSupplementary Materials\nSupplementary Materials Supplementary Table 1: characteristics of patients taking MMF as induction versus maintenance therapy. Supplementary Table 2: characteristics of patients with had general AEs versus adverse effects associated with MMF. Supplementary Table 3: patient characteristics by reason for MMF discontinuation. Supplementary Table 4: characteristics of patients who discontinued MMF due to severe infection.\n\nClick here for additional data file.\n\n Figure 1 Details about MMF use. (a) Distribution of reasons for MMF discontinuation. (b) The Kaplan-Meier curve for MMF discontinuation. (c) The Kaplan-Meier curve for MMF discontinuation due to adverse events. (d) MMF dose at last observation. MMF: mycophenolate mofetil.\n\nTable 1 Characteristics of patients in the AE and no-AE groups.\n\n\tOverall\tNo-AE group\tAE group\t\nP value\t\n\nN = 119\t\nn = 90\t\nn = 29\t\nAge at start of MMF therapy, median (IQR)\t38 (31–46)\t39 (31–46)\t33 (29–45)\t0.20\t\nFemale sex, n (%)\t101 (85)\t74 (82)\t27 (93)\t0.23\t\nBody weight (kg), median (IQR)\t55 (48–63)\t57 (48–64)\t54 (46–62)\t0.23\t\nDuration of SLE, months, median (IQR)\t138 (39–242)\t133 (40–227)\t160 (23–262)\t0.68\t\nMMF started as induction therapy, n (%)\t96 (81)\t72 (81)\t24 (83)\t1.00\t\nMalar rash, n (%)\t62 (52)\t51 (57)\t11 (38)\t0.09\t\nDiscoid rash, n (%)\t23 (20)\t16 (18)\t7 (24)\t0.59\t\nPhotosensitivity, n (%)\t31 (26)\t21 (24)\t10 (35)\t0.15\t\nOral ulcers, n (%)\t31 (27)\t20 (23)\t11 (38)\t0.33\t\nArthritis, n (%)\t75 (64)\t54 (61)\t21 (72)\t0.28\t\nSerositis, n (%)\t28 (24)\t23 (26)\t5 (17)\t0.45\t\nRenal disorder, n (%)\t81 (68)\t62 (69)\t19 (66)\t0.82\t\nNeurologic disorder, n (%)\t9 (8)\t6 (7)\t3 (10)\t0.69\t\nHematologic disorder, n (%)\t89 (75)\t68 (76)\t21 (72)\t0.8\t\nImmunologic disorder, n (%)\t118 (99)\t89 (99)\t29 (100)\t1.00\t\nAntinuclear antibody, n (%)\t119 (100)\t90 (100)\t29 (100)\tN/A\t\nSLEDAI at start of MMF therapy, median (IQR)\t6 (4–10)\t6 (4–10)\t8 (4–13)\t0.14\t\nNumber of SLE flare-ups, median (IQR)\t1 (1–3)\t2 (1–2)\t1 (0–3)\t0.30\t\nWBC count (/μL), median (IQR)\t6,600 (4,500–7,900)\t6,100 (4,400–7,600)\t7,000 (5,800–9,500)\t0.07\t\nLymphocytes (/μL), median (IQR)\t1,001 (598–1,335)\t925 (544–1,326)\t1,039 (619–1,404)\t0.41\t\nHemoglobin (g/dL), median (IQR)\t11.8 (10.6–13.1)\t12.1 (11.1–13.2)\t11.2 (10–12.3)\t0.014∗\t\nPlatelets (104/μL), median (IQR)\t23.3 (18.6–28.8)\t23.6 (19.3–28)\t22.4 (17.8–30.7)\t0.91\t\nAST (U/L), median (IQR)\t19 (15–24)\t18 (15–24)\t19 (15–25)\t0.67\t\nALT (U/L), median (IQR)\t18 (12–28)\t16 (11–25)\t25 (15–34)\t0.011\t\nAlbumin (g/dL), median (IQR)\t3.5 (3–3.9)\t3.6 (3.1–3.9)\t3.2 (2.6–3.8)\t0.06\t\nBUN (mg/dL), median (IQR)\t15 (11–20)\t14 (10–19)\t18 (14–27)\t0.006∗∗\t\nCreatinine (mg/dL), median (IQR)\t0.62 (0.49–0.83)\t0.62 (0.49–0.78)\t0.57 (0.48–0.99)\t0.48\t\neGFR (mL/min/1.73 m2), median (IQR)\t91 (67–115)\t92 (70–115)\t89 (46–124)\t0.63\t\nCH50 (U/mL), median (IQR)\t28 (20–38)\t29 (21–39)\t25 (16–37)\t0.33\t\nC3 (mg/dL), median (IQR)\t66 (48–84)\t69 (52–85)\t61 (44–83)\t0.38\t\nC4 (mg/dL), median (IQR)\t11 (7–18)\t12 (7–19)\t10 (5–17)\t0.31\t\nIgG (mg/dL), median (IQR)\t1,220 (914–1,455)\t1,243 (943–1,431)\t1,151 (597–1,718)\t0.59\t\nAnti-DNA antibody (RIA) (IU/mL), median (IQR)\t11 (0–62)\t7 (0–50)\t30 (5–188)\t0.053\t\nAnti-U1-RNP antibody, positivity, n (%)\t43 (36)\t34 (38)\t9 (31)\t0.52\t\nAnti-Sm antibody, positivity, n (%)\t16 (14)\t14 (16)\t2 (7)\t0.35\t\nAnti-CL antibody, positivity, n (%)\t26 (22)\t22 (25)\t4 (14)\t0.30\t\nAnti-CLβ2GP1 antibody, positivity, n (%)\t13 (11)\t9 (10)\t4 (14)\t1.00\t\nLupus anticoagulant, median (IQR)\t0.9 (0.9–1)\t1 (0.9–1)\t0.9 (0.8–1)\t0.51\t\nProteinuria (g/day), median (IQR)\t0.6 (0–2.3)\t0.5 (0–2.1)\t0.7 (0–2.5)\t0.46\t\nHematuria, positivity, n (%)\t38 (33)\t28 (33)\t10 (35)\t1.00\t\nGC dose at start of MMF therapy (mg/day), median (IQR)\t20 (10–40)\t19 (10–36)\t28 (12–55)\t0.07\t\nOverall maximum GC dose (mg/day), median (IQR)\t50 (40–60)\t50 (40–60)\t50 (40–60)\t0.93\t\nLLDAS at last observation, n (%)\t67 (57)\t57 (64)\t10 (35)\t0.009∗∗\t\nAE: adverse event; MMF: mycophenolate mofetil; IQR: interquartile range; SLE: systemic lupus erythematosus; SLEDAI: SLE disease activity index; WBC: white blood cell; AST: aspartate aminotransferase; ALT: alanine aminotransferase; BUN: blood urea nitrogen; eGFR: estimated glomerular filtration rate; IgG: immunoglobulin G; DNA: deoxyribonucleic acid; RIA: radioimmunoassay; U1RNP: U1-ribonucleoprotein; Sm: Smith; CL: cardiolipin; CLβ 2GP1: cardiolipin β2-glycoprotein I; GC: glucocorticoid; LLDAS: lupus low disease activity state. ∗P < 0.05. ∗∗P < 0.01.\n\nTable 2 Characteristics of patients with measured MPA trough levels.\n\nPatient\tAge at start of MMF therapy (years)\tSex\tDuration of MMF therapy (month)\tMMF trough level (μg/mL)\tMMF dose (mg/day)\tSLEDAI at start of MMF therapy\tOutcome of MMF\tAdverse event\tAchievement of LLDAS\t\n1\t32\tMale\t5\t8.5\t2,000\t14\tWithdrawal\tRenal dysfunction\tNo\t\n2\t43\tFemale\t16\t8.3\t2,000\t12\tWithdrawal\tInfection (VZV meningitis)\tYes\t\n3\t38\tFemale\t1\t7.3\t1,500\t18\tDose decrease\t\tNo\t\n4\t43\tFemale\t2\t6.7\t2,000\t14\tWithdrawal\tCytopenia\tNo\t\n5\t46\tMale\t20\t6.6\t2,000\t6\tDose decrease\t\tYes\t\n6\t32\tFemale\t4\t6.3\t2,000\t14\tWithdrawal\tInfection (VZV meningitis)\tNo\t\n7\t32\tFemale\t2\t5.3\t1,500\t16\tDose decrease\t\tNo\t\n8\t18\tFemale\t12\t4.7\t2,000\t12\tDose decrease\t\tNo\t\n9\t38\tFemale\t11\t4\t1,000\t9\tContinue\t\tNo\t\n10\t23\tFemale\t3\t3.5\t2,000\t8\tWithdrawal\tAlopecia\tYes\t\n11\t23\tFemale\t1\t3.1\t2,000\t20\tWithdrawal\tCytopenia\tNo\t\nMPA: mycophenolate acid; MMF: mycophenolate mofetil; SLEDAI: systemic lupus erythematosus disease activity index; LLDAS: lupus low disease activity state.\n==== Refs\n1 Sollinger H. W. Belzer F. O. Deierhoi M. H. RS-61443 (mycophenolate mofetil). A multicenter study for refractory kidney transplant rejection Annals of Surgery 1992 216 4 513 518 10.1097/00000658-199210000-00014 2-s2.0-0026787479 1417199 \n2 Lipsky J. J. Mycophenolate mofetil The Lancet 1996 348 9038 1357 1359 10.1016/s0140-6736(96)10310-x 2-s2.0-0030590745 \n3 Dooley M. A. Cosio F. G. Nachman P. H. Mycophenolate mofetil therapy in lupus nephritis: clinical observations Journal of the American Society of Nephrology 1999 10 4 833 839 10203368 \n4 Gaubitz M. Schorat A. Schottel H. Kern P. Domschke W. Mycophenolate mofetil for the treatment of systemic lupus erythematosus: an open pilot trial Lupus 1999 8 9 731 736 10.1191/096120399678840927 2-s2.0-0032704059 10602445 \n5 Ginzler E. M. Dooley M. A. Aranow C. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis The New England Journal of Medicine 2005 353 21 2219 2228 10.1056/NEJMoa043731 2-s2.0-28144433147 16306519 \n6 Bertsias G. K. Tektonidou M. Amoura Z. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis Annals of the Rheumatic Diseases 2012 71 11 1771 1782 10.1136/annrheumdis-2012-201940 2-s2.0-84867401561 22851469 \n7 Hahn B. H. McMahon M. Wilkinson A. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis Arthritis Care & Research 2012 64 6 797 808 10.1002/acr.21664 2-s2.0-84863226066 22556106 \n8 Touma Z. Gladman D. D. Urowitz M. B. Beyene J. Uleryk E. M. Shah P. S. Mycophenolate mofetil for induction treatment of lupus nephritis: a systematic review and metaanalysis The Journal of Rheumatology 2011 38 1 69 78 10.3899/jrheum.100130 2-s2.0-78650881053 20952473 \n9 Weng M. Y. Weng C. T. Liu M. F. The efficacy of low-dose mycophenolate mofetil for treatment of lupus nephritis in Taiwanese patients with systemic lupus erythematosus Clinical Rheumatology 2010 29 7 771 775 10.1007/s10067-010-1403-9 2-s2.0-77956262334 20195879 \n10 Hara R. Miyazawa H. Nishimura K. A national survey on current use of mycophenolate mofetil for childhood-onset systemic lupus erythematosus in Japan Modern Rheumatology 2015 25 6 858 864 10.3109/14397595.2015.1077555 2-s2.0-84947046175 26215483 \n11 Ikeuchi H. Hiromura K. Takahashi S. Efficacy and safety of multi-target therapy using a combination of tacrolimus, mycophenolate mofetil and a steroid in patients with active lupus nephritis Modern Rheumatology 2014 24 4 618 625 10.3109/14397595.2013.844397 2-s2.0-84903696731 24252014 \n12 Onishi A. Sugiyama D. Tsuji G. Mycophenolate mofetil versus intravenous cyclophosphamide for induction treatment of proliferative lupus nephritis in a Japanese population: a retrospective study Modern Rheumatology 2014 23 1 89 96 10.3109/s10165-012-0634-9 \n13 Katsuno T. Ozaki T. Ozeki T. Investigation on the benefits of mycophenolate mofetil and therapeutic drug monitoring in the treatment of Japanese patients with lupus nephritis Clinical and Experimental Nephrology 2018 22 6 1341 1350 10.1007/s10157-018-1590-2 2-s2.0-85047249864 29796823 \n14 Kawazoe M. Kaneko K. Yamada Z. Efficacy of mycophenolate mofetil in Japanese patients with systemic lupus erythematosus Clinical Rheumatology 2019 38 6 1571 1578 10.1007/s10067-019-04473-w 2-s2.0-85061733311 30778862 \n15 Hochberg M. C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus Arthritis and Rheumatism 1997 40 9 p. 1725 10.1002/art.1780400928 2-s2.0-0031229830 9324032 \n16 Franklyn K. Lau C. S. Navarra S. V. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS) Annals of the Rheumatic Diseases 2016 75 9 1615 1621 10.1136/annrheumdis-2015-207726 2-s2.0-84951816992 26458737 \n17 Isenberg D. A. Gordon C. From BILAG to BLIPS--disease activity assessment in lupus past, present and future Lupus 2000 9 9 651 654 10.1191/096120300672904669 2-s2.0-17744370325 11199918 \n18 Langman L. J. LeGatt D. F. Yatscoff R. W. Blood distribution of mycophenolic acid Therapeutic Drug Monitoring 1994 16 6 602 607 10.1097/00007691-199412000-00012 2-s2.0-0027944882 7878701 \n19 Lauzurica R. Bayés B. Frías C. Disseminated varicella infection in adult renal allograft recipients: role of mycophenolate mofetil Transplantation Proceedings 2003 35 5 1758 1759 10.1016/S0041-1345(03)00684-5 2-s2.0-0041831288 12962784 \n20 Rothwell W. S. Gloor J. M. Morgenstern B. Z. Milliner D. S. Disseminated varicella infection in pediatric renal transplant recipients treated with mycophenolate mofetil Transplantation 1999 68 1 158 161 10.1097/00007890-199907150-00030 2-s2.0-0033565532 10428286 \n21 Chakravarty E. F. Michaud K. Katz R. Wolfe F. Increased incidence of herpes zoster among patients with systemic lupus erythematosus Lupus 2013 22 3 238 244 10.1177/0961203312470186 2-s2.0-84874435498 23257402 \n22 Rondaan C. de Haan A. Horst G. Altered cellular and humoral immunity to varicella-zoster virus in patients with autoimmune diseases Arthritis & Rhematology 2014 66 11 3122 3128 10.1002/art.38804 2-s2.0-84920052630 25223407 \n23 Habuka M. Wada Y. Kurosawa Y. Fatal visceral disseminated varicella zoster infection during initial remission induction therapy in a patient with lupus nephritis and rheumatoid arthritis-possible association with mycophenolate mofetil and high-dose glucocorticoid therapy: a case report BMC Research Notes 2018 11 1 p. 165 10.1186/s13104-018-3271-3 2-s2.0-85042933950 29506558 \n24 Cattaneo D. Perico N. Gaspari F. Gotti E. Remuzzi G. Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation Kidney International 2002 62 3 1060 1067 10.1046/j.1523-1755.2002.00531.x 2-s2.0-0036424769 12164891 \n25 Pourafshar N. Karimi A. Wen X. The utility of trough mycophenolic acid levels for the management of lupus nephritis Nephrology, Dialysis, Transplantation 2019 34 1 83 89 10.1093/ndt/gfy026 2-s2.0-85056445656 29548021 \n26 Zabotti A. Baraldo M. Quartuccio L. Sacco S. De Marchi G. De Vita S. Optimizing the dose of mycophenolate mofetil for the maintenance treatment of lupus nephritis by therapeutic drug monitoring Clinical Rheumatology 2015 34 1 171 174 10.1007/s10067-014-2786-9 2-s2.0-84930396144 25249327 \n27 Alexander S. Fleming D. H. Mathew B. S. Pharmacokinetics of concentration-controlled mycophenolate mofetil in proliferative lupus nephritis: an observational cohort study Therapeutic Drug Monitoring 2014 36 4 423 432 10.1097/FTD.0000000000000031 2-s2.0-84904571620 25014074 \n28 Lertdumrongluk P. Somparn P. Kittanamongkolchai W. Traitanon O. Vadcharavivad S. Avihingsanon Y. Pharmacokinetics of mycophenolic acid in severe lupus nephritis Kidney International 2010 78 4 389 395 10.1038/ki.2010.170 2-s2.0-77955174768 20531457 \n29 Pawinski T. Therapeutic drug monitoring of mycophenolic acid: a potential treatment for lupus nephritis Kidney International 2010 78 4 335 336 10.1038/ki.2010.181 2-s2.0-77955134607 20671734 \n30 van Gelder T. Berden J. H. Berger S. P. To TDM or not to TDM in lupus nephritis patients treated with MMF? Nephrology, Dialysis, Transplantation 2015 30 4 560 564 10.1093/ndt/gfu184 2-s2.0-84926680548 \n31 Kittanamongkolchai W. Rukrung C. Supasiri T. Therapeutic drug monitoring of mycophenolate mofetil for the treatment of severely active lupus nephritis Lupus 2013 22 7 727 732 10.1177/0961203313486949 2-s2.0-84879238114 23651860 \n32 Kiyokawa T. Hanaoka H. Iida H. High plasma mycophenolate acid concentration in the early phase of induction therapy predicts good renal outcome in lupus nephritis Modern Rheumatology 2020 30 3 517 524 10.1080/14397595.2019.1623435 2-s2.0-85067579890 31135249 \n33 Luszczynska P. Pawinski T. Kunicki P. K. Durlik M. Augustyniak-Bartosik H. Hurkacz M. Pharmacokinetics of free and total mycophenolic acid in adult lupus nephritis patients-implications for therapeutic drug monitoring European Journal of Clinical Pharmacology 2019 75 3 371 379 10.1007/s00228-018-2599-x 2-s2.0-85056467018 30430214 \n34 Neumann I. Fuhrmann H. Fang I. F. Jaeger A. Bayer P. Kovarik J. Association between mycophenolic acid 12-h trough levels and clinical endpoints in patients with autoimmune disease on mycophenolate mofetil Nephrology, Dialysis, Transplantation 2008 23 11 3514 3520 10.1093/ndt/gfn360 2-s2.0-54149103127 \n35 Daleboudt G. M. N. Reinders M. E. J. Hartigh J. . Concentration-controlled treatment of lupus nephritis with mycophenolate mofetil Lupus 2013 22 2 171 179 10.1177/0961203312469261 2-s2.0-84872546074 23257398 \n36 Zahr N. Arnaud L. Marquet P. Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetil Arthritis and Rheumatism 2010 62 7 2047 2054 10.1002/art.27495 2-s2.0-77954234138 20506558\n\n",
"fulltext_license": "CC BY",
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"issue": "2021()",
"journal": "BioMed research international",
"keywords": null,
"medline_ta": "Biomed Res Int",
"mesh_terms": "D000328:Adult; D064420:Drug-Related Side Effects and Adverse Reactions; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007564:Japan; D053208:Kaplan-Meier Estimate; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101600173",
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"pages": "8630596",
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"pmid": "33564682",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "20531457;12164891;25249327;22851469;22556106;29548021;30430214;20671734;1417199;29506558;25014074;12962784;29796823;23257398;20952473;20195879;16306519;20506558;25223407;7878701;31135249;26215483;30778862;10428286;11199918;9324032;23651860;23257402;10602445;8918281;26458737;18586766;24252014;24811231;22447557;10203368",
"title": "Real-World Experience of Safety of Mycophenolate Mofetil in 119 Japanese Patients with Systemic Lupus Erythematosus: A Retrospective Single-Center Study.",
"title_normalized": "real world experience of safety of mycophenolate mofetil in 119 japanese patients with systemic lupus erythematosus a retrospective single center study"
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"abstract": "BACKGROUND\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous reactions. There is scant literature on the characteristics and causes of these conditions in Kenyatta National Hospital.\n\n\nOBJECTIVE\nThe aim of this study was to determine the prevalence, risk factors, and etiologies of SJS/TEN among patients admitted to Kenyatta National Hospital.\n\n\nMETHODS\nA retrospective cross-sectional study was done to find the characteristics and causes of severe cutaneous reactions among patients admitted to Kenyatta National Hospital. Universal sampling was employed, whereby all 115 patients with severe cutaneous reactions between June 2006 and June 2016 were studied. Information collected included participants' sociodemographic variables, clinical characteristics of the disease, and the possible triggers. Data were analyzed using STATA version 13 at p ≤ 0.05.\n\n\nRESULTS\nThe mean age of patients was 31 years (±20). Low case numbers precluded statistically significant results; however, females represented 59.1% of patients, and 46.1% of patients were diagnosed between the ages of 21 and 40 years. SJS occurred in 47% of patients followed by TEN in 33.9% and SJS/TEN overlap in 19.1%. Drugs were determined to be the causative agent in 94.8% of the severe cutaneous reactions followed by infectious agents at 5.2%, principally HIV, herpes simplex virus 1, and mycoplasma. The most common drugs implicated were sulfonamides (26.1%) and nevirapine (15.7%).\n\n\nCONCLUSIONS\nNumerically, SJS was the most common subtype of SJS/TEN in Kenyatta National Hospital and was usually attributed to use of drugs, especially sulfonamides. Severe cutaneous reactions were observed more frequently in females and in patients aged between 21 and 40 years, indicating that emphasizing surveillance and medication counselling in these patient populations could be beneficial.",
"affiliations": "Ministry of Health, Karatina Sub-County Referral Hospital, P.O. Box 133-10101, Karatina, Kenya. kariuki.kenneth@gmail.com.;Department of Pharmaceutics and Pharmacy Practice, School of Pharmacy, University of Nairobi, P.O. Box 19676-00202, Nairobi, Kenya.;Department of Pharmaceutics and Pharmacy Practice, School of Pharmacy, University of Nairobi, P.O. Box 19676-00202, Nairobi, Kenya.",
"authors": "Irungu|Kenneth|K|;Nyamu|David|D|;Opanga|Sylvia|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40801-017-0105-x",
"fulltext": "\n==== Front\nDrugs Real World OutcomesDrugs Real World OutcomesDrugs - Real World Outcomes2199-11542198-9788Springer International Publishing Cham 10510.1007/s40801-017-0105-xOriginal Research ArticleCharacterization of Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis Among Patients Admitted to Kenyatta National Hospital: A Retrospective Cross-Sectional Study Irungu Kenneth kariuki.kenneth@gmail.com 1Nyamu David 2Opanga Sylvia 21 grid.415727.2Ministry of Health, Karatina Sub-County Referral Hospital, P.O. Box 133-10101, Karatina, Kenya 2 0000 0001 2019 0495grid.10604.33Department of Pharmaceutics and Pharmacy Practice, School of Pharmacy, University of Nairobi, P.O. Box 19676-00202, Nairobi, Kenya 11 4 2017 11 4 2017 6 2017 4 2 79 85 © The Author(s) 2017\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\nStevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous reactions. There is scant literature on the characteristics and causes of these conditions in Kenyatta National Hospital.\n\nObjective\nThe aim of this study was to determine the prevalence, risk factors, and etiologies of SJS/TEN among patients admitted to Kenyatta National Hospital.\n\nMethods\nA retrospective cross-sectional study was done to find the characteristics and causes of severe cutaneous reactions among patients admitted to Kenyatta National Hospital. Universal sampling was employed, whereby all 115 patients with severe cutaneous reactions between June 2006 and June 2016 were studied. Information collected included participants’ sociodemographic variables, clinical characteristics of the disease, and the possible triggers. Data were analyzed using STATA version 13 at p ≤ 0.05.\n\nResults\nThe mean age of patients was 31 years (±20). Low case numbers precluded statistically significant results; however, females represented 59.1% of patients, and 46.1% of patients were diagnosed between the ages of 21 and 40 years. SJS occurred in 47% of patients followed by TEN in 33.9% and SJS/TEN overlap in 19.1%. Drugs were determined to be the causative agent in 94.8% of the severe cutaneous reactions followed by infectious agents at 5.2%, principally HIV, herpes simplex virus 1, and mycoplasma. The most common drugs implicated were sulfonamides (26.1%) and nevirapine (15.7%).\n\nConclusion\nNumerically, SJS was the most common subtype of SJS/TEN in Kenyatta National Hospital and was usually attributed to use of drugs, especially sulfonamides. Severe cutaneous reactions were observed more frequently in females and in patients aged between 21 and 40 years, indicating that emphasizing surveillance and medication counselling in these patient populations could be beneficial.\n\nissue-copyright-statement© The Author(s) 2017\n==== Body\nKey Points\n\nMost of the drugs implicated in causing Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) were low-cost antibiotics commonly prescribed in our setting and drugs for treating HIV, malaria, and TB (infections which are common in our population), thus putting many people at risk of SJS/TEN.\t\nAll patients of all ages should be informed of the symptoms of SJS/TEN and closely monitored for these when starting new medications, especially sulfonamide drugs.\t\n\n\n\nIntroduction\nStevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe bullous skin reactions considered medical emergencies due to their high mortality rate [1]. They are characterized by mucocutaneous tenderness, erythema, hemorrhagic erosions, and necrotic epidermal detachment [1]. They are both rare with SJS and TEN having a global incidence of 1–6 and 0.4–1.2 cases per million person years, respectively [2]. Cutaneous drug reactions have a prevalence of 8.259% and these reactions range from urticaria and erythema to SJS and TEN [3].\n\nThe average age groups for TEN and SJS in West Germany have been documented as 63 and 25 years, respectively. Women in this region are at a higher risk for TEN than men at a ratio of 2:1, while the converse is true for SJS [4]. In Japan, the average ages for TEN and SJS were observed to be 56.6 and 55.1 years, respectively, with women being more predisposed to SJS than men at a ratio of 1:0.7. There was an equal sex ratio for TEN [5]. In a West African study, the average age group for both SJS and TEN was found to be 32.3 years with a female:male ratio of 1:0.6 [6]. Genetic factors also play a role, with human leukocyte antigens being implicated in SJS and TEN in patients of Asian ancestry. In addition, a slow N-acetylation phenotype predisposes to sulfonamide reactions [7].\n\nStudies have revealed that 80% of the SJS/TEN cases are caused by drugs, mostly antibacterial sulfonamides, β-lactams, and also nevirapine [8]. The risk increases when there is co-infection with either mycoplasma pneumonia, herpes simplex virus 1 (HSV-1) or HIV virus, which are also independent etiologies for SJS/TEN [8].\n\nThere is scant published local data on the possible causes for SJS and TEN. The main objective of this study was to characterize SJS/TEN and identify their etiologies in Kenyatta National Hospital (KNH).\n\nMethodology\nThe study design was a retrospective cross-sectional study in the KNH medical records department. Patients who met the inclusion criteria (children and adults who were diagnosed and treated for SJS/TEN at KNH from June 2006 to June 2016) were included in the study. One hundred and fifteen patients met the criteria. In order to identify these patients, files of SJS/TEN patients were retrieved using the International Classification of Diseases–Adapted Coding Modification 10 (ICDA-10) for L51.1 (SJS) and L51.2 (TEN). Only 89 patient files were obtained using this method. A further search for ICDA-10 skin diagnoses with bullous dermatologic erythematous conditions not otherwise specified (L51.9) yielded 26 more patients. Further review of the excluded files yielded no more SJS/TEN patient files. For a patient to be diagnosed as having SJS they must have had symptoms of acute erythematous mucosal and skin erosions or bullae which are target-like in appearance extending to <10% of the body surface area. For SJS/TEN overlap the patient should have had similar lesions covering 10–30% of the body surface area and for TEN they should have had extensive epidermal detachment of >30% body surface area in addition to the above symptoms. Patient medication histories and a short time lapse from intake of the drug to development of symptoms (2–14 days) confirmed the drugs as causative agents while the history of other illness confirmed, without intake of anti-retrovirals, HIV as the etiology. Furthermore, a Naranjo algorithm was used to determine causality of adverse drug reaction as had been indicated in the file [9]. Mycoplasma pneumonia was determined through laboratory tests and HSV-1 was determined through physical examination by a dermatologist.\n\nPre-designed data collection forms were used to abstract participants’ socio-demographics, disease characteristics, subtype of the disease, and causative drugs. Twenty of the SJS/TEN patients’ medical files were randomly picked and data abstracted by an independent reviewer on separate data collection forms for comparison with our investigators’ forms. Discrepancies were sorted out by consensus. A database was created using MS Excel version 2007 software. This was exported to STATA software version 13 for analysis.\n\nPrevalence of the subtypes SJS, TEN, and SJS/TEN overlap was determined. The mean and median age of the disease at diagnosis were computed. Percentages were calculated for all of the patient characteristics and the causative agents. Inferential data analysis was done using the Chi-square test to compare for differences across causative agents and patient characteristics using STATA software version 13 (Statacorp, 4905 Lakeway Drive College Station, Texas 77845 USA: licensed to Major Nyamai University of Nairobi). The level of significance was set at 0.05 and p values ≤0.05 were considered statistically significant.\n\nResults\nOf the 115 patients, the majority (68) was female. The mean and median ages were 31 (±20) and 32 (12–42) years, respectively. More patients were aged 21–40 years (53) than younger or older (33 and 29, respectively) (Table 1).Table 1 Socio-demographic characteristics of the study participants\n\nCharacteristic\t\nn (%)\t\nAge category\t\n Mean age, years (SD)\t31 (±20)\t\n Median age, years (range)\t32 (12–42)\t\n 21–40 years\t53 (46.1)\t\n 41-60 years\t22 (19.1)\t\n >60 years\t7 (6.1)\t\nSex\t\n Male\t47 (40.9)\t\n Female\t68 (59.1)\t\nOccupation\t\n Salaried\t24 (21.1)\t\n Self-employed\t35 (30.7)\t\n Unemployed\t55 (48.3)\t\nEducation level\t\n Non-formal\t25 (23.2)\t\n Primary\t43 (39.8)\t\n Secondary\t30 (27.8)\t\n College/university\t10 (9.3)\t\nYear of diagnosis\t\n 2006–2009\t17 (14.9)\t\n 2010–2013\t42 (36.5)\t\n 2014–2016\t56 (48.7)\t\nResidence\t\n Nairobi\t27 (23.5)\t\n Central\t24 (20.9)\t\n Eastern\t21 (18.3)\t\n Nyanza\t14 (12.2)\t\n Rift Valley\t13 (11.3)\t\n Western\t12 (10.4)\t\n North Eastern\t3 (2.6)\t\n Coast\t1 (0.9)\t\n\n\n\nRelative Frequency of Various Disease Subtypes Across the Study Population\nWhile insufficient cases were recorded to reach statistical significance, SJS was observed most frequently, occurring in 54 patients followed by TEN (n = 39) and SJS/TEN (n = 22). Among the total number of patients with severe cutaneous reactions, only 24 had a severity-of-illness score (SCORTEN) calculated, as shown in Table 2.Table 2 Disease characteristics of the study population\n\nCharacteristic\t\nn (%)\t\nSubclass of the disease (n = 115)\t\n SJS\t54 (47.0)\t\n SJS/TEN overlap\t22 (19.1)\t\n TEN\t39 (33.9)\t\nSCORTEN\t\n 1\t5 (20.8)\t\n 2\t11 (45.8)\t\n 3\t5 (20.8)\t\n 4\t2 (8.3)\t\n 6\t1 (4.2)\t\nMethod of diagnosis (n = 115)\t\n Histopathological\t2 (1.7)\t\n Clinical\t113 (98.3)\t\nOrigin of the skin reaction (n = 115)\t\n Home\t105 (91.3)\t\n Hospital\t10 (8.7)\t\nFamily history (n = 115)\t\n Positive\t2 (1.7)\t\n Negative\t113 (98.3)\t\nMedian latency time from exposure to drug to onset of symptoms\t4 days (range 2–14)\t\n\nSJS Stevens–Johnson syndrome, TEN toxic epidermal necrolysis\n\n\n\n\nIn keeping with total cases in 21- to 40-year-olds being more frequent than in other age groups, there were greater numbers of cases of each subtype within this age group than in other age brackets (see Table 4). Numerically, more cases of SJS and TEN occurred in females and more cases of SJS/TEN overlap occurred in males (Table 4).\n\nRelative Frequency of Exposure to Agents Known to Cause SJS/TEN in the Study Population\nOne hundred and nine (94.8%) of the SJS/TEN cases were thought to be caused by use of drugs. Twelve (10.4%) of the patients in the study had SJS/TEN attributable to intake of more than one drug. The remaining six cases of SJS/TEN were thought to be caused by infectious agents, namely HIV (n = 4), HSV1 (n = 1), and mycoplasma pneumonia (n = 1).\n\nAs seen in Table 3, use of sulfonamides accounted for the highest number of cases at 25 (22.9%), followed by nevirapine at 18 (16.5%), ciprofloxacin at 13 (11.9%), and penicillins at 8 (7.3%). Other drugs implicated included metronidazole (n = 3), lamotrigine (n = 1), phenobarbitone (n = 1), efavirenz (n = 2), meloxicam (n = 1), hydrochlorothiazide (n = 1), paracetamol (n = 2), allopurinol (n = 1), rifampicin/isoniazid/pyrazinamide/ethambutol (n = 3), quinine (n = 2), magnesium sulphate (n = 1), griseofulvin (n = 1), streptomycin (n = 1), herbal medication (n = 2),oral polio vaccine (n = 1), and unknown medication (n = 11).Table 3 Probable causative agent of SJS/TEN in Kenyatta Hospital patients where a drug was suspected (N = 109)\n\nDrug\tSJS/TEN cases attributable to drug, n (%)\t\nSulfamethoxazole/trimethoprim\t25 (22.9)\t\nNevirapine\t18 (16.5)\t\nCiprofloxacin\t13 (11.9)\t\nPenicillins\t8 (7.3)\t\nCephalosporins\t6 (5.5)\t\nArtemether/lumefantrine\t6 (5.5)\t\nSulfadoxine/pyrimethamine\t5 (4.6)\t\nCarbamazepine\t5 (4.6)\t\nOthers\t23 (21.1)\t\nTotal\t109 (100)\t\n\nSJS Stevens–Johnson syndrome, TEN toxic epidermal necrolysis\n\n\n\n\nAssociation Between Demographic Characteristics and Development of Various Disease Subtypes\nTable 4 compares the demographic characteristics and development of disease subtypes. There were no statistically significant associations between patient’s age, gender, and education level on the development of various disease subclasses.Table 4 Relationship between demographics and SJS/TEN disease subtype\n\nDemographic characteristic\tDisease subclass\t\np value\t\nSJS\n\nn (%)\tSJS/TEN\n\nn (%)\tTEN\n\nn (%)\t\nAge category (years)\t\n 0–20\t15 (13)\t6 (5.2)\t12 (10.4)\t\t\n 21–40\t29 (25.2)\t8 (7)\t16 (13.9)\t0.547\t\n 41–60\t8 (7)\t5 (4.3)\t9 (7.8)\t\t\n >60\t2 (1.7)\t3 (2.6)\t2 (1.7)\t\t\nSex\t\n Male\t19 (16.5)\t12 (10.4)\t16 (13.9)\t\t\n Female\t35 (30.4)\t10 (8.7)\t23 (20)\t0.313\t\nOccupation\t\n Salaried\t8 (7.0)\t6 (5.2)\t10 (8.7)\t\t\n Self-employed\t18 (15.7)\t6 (5.2)\t11 (9.6)\t0.634\t\n Unemployed\t28 (24.3)\t9 (7.8)\t18 (15.7)\t\t\nEducation level\t\n Non-formal\t11 (9.6)\t4 (3.5)\t10 (8.7)\t\t\n Primary\t23 (20)\t6 (5.2)\t14 (12.2)\t\t\n Secondary\t11 (9.6)\t8 (7)\t11 (9.6)\t0.154\t\n College/university\t7 (6.1)\t3 (2.6)\t0 (0)\t\t\n\nSJS Stevens–Johnson syndrome, TEN toxic epidermal necrolysis\n\n\n\n\nAssociation Between the Prevalence of Various Drugs Implicated in Causation of Disorders and Development of Disease Subtypes\nTable 5 shows the association between the prevalence of various drugs implicated in causation of disorders and development of disease subtypes. Notably, most of the drugs implicated in causing SJS/TEN disease subtypes were antibiotics and drugs used in the treatment of HIV and malaria.Table 5 Relationship between frequency of drugs being implicated in SJS/TEN causation and disease subtypes\n\nDrug\tSJS\n\nn (%)\tSJS/TEN overlap\n\nn (%)\tTEN\n\nn (%)\t\np value\t\nSulfonamides\t16 (13.9)\t7 (6.1)\t15 (13)\t0.657\t\nNevirapine\t10 (8.7)\t4 (3.5)\t4 (3.5)\t0.496\t\nCiprofloxacin\t4 (3.5)\t2 (1.7)\t7 (6.1)\t0.311\t\nUnknown drug\t6 (5.2)\t1 (0.9)\t4 (3.5)\t0.839\t\nβ-Lactam antibioticsa\n\t7 (6.1)\t3 (2.6)\t4 (3.5)\t0.869\t\nArtemether/lumefantrine\t1 (0.9)\t5 (4.3)\t0 (0)\t0.001\t\nCarbamazepine\t4 (3.5)\t0 (0)\t1 (0.9)\t0.126\t\n\nSJS Stevens–Johnson syndrome, TEN toxic epidermal necrolysis\n\n\naβ-Lactam antibiotics—penicillins and cephalosporins\n\n\n\n\nDiscussion\nThere were a total of 115 patients treated for severe cutaneous reactions over a period of 10 years, representing a prevalence of 11 cases per year. This result mirrors the scarcity of this serious toxidermia observed in other studies [1, 2, 4]. While cases were too infrequent for comparisons to reach statistical significance, 59.1% of cases were in women, while 40.9% were in men. This female predominance is similar to findings from other studies done by Saka et al. [6] and Chan [10]. Numerically, there were more females than males with SJS and TEN disease subtypes at 30.4 versus 16.5% and 20.0 versus 13.9%, respectively. This trend has been seen in another study, where more females had SJS and TEN disease subtypes at 28.2 versus 16.2% and 29.1 versus 26.5%, respectively [11]. There were, however, no statistically significant associations between patients’ sex on the development of various disease subclasses.\n\nThe largest number of patients was those aged between 21 and 40 years (46.1%), compared with 0–20 years (28.7%), 41–60 years (19.1%), or >60 years (6.1%). There were also more patients in this age category across the various disease subtypes, a finding that was replicated in the study by Saka et al. [6]. This does not match all-cause age distribution for patients at the hospital, so could possibly be attributed to frequent self-prescribing of medicine in this age group. Our results on the most prevalent age group conflict with other studies that show most patients being elderly and attributing this to reduced drug clearance, or to most patients being children because of poor immune status. For instance, one study [10] found more SJS/TEN patients in the <5-years-old category, attributing it to viral causes that are more prevalent in this age group, while some findings in West Germany found more TEN in patients aged above 63 years [4].\n\nNearly half of the patients were seen in the last 2 years because of improved referral systems from different health facilities and reception to our study site. These were put in place by the public health administration that facilitated more patients reaching our study site. Kenyatta National Hospital is the largest referral center in East Africa. The site was appropriate because it is the largest public hospital that provides specialized medical management and treatment services for all conditions and for all ages, both children and adults. It is also the facility with the top medical experts in the country, including dermatologists who are involved in the management of SJS/TEN, hence justifying the referrals to the hospital. SJS/TEN patients from all over the country are also referred here because management of this condition can be appropriately carried out in either the critical care unit or the burns unit if necessary.\n\nNairobi and Central provinces contributed the highest percentage of patients at 23.5 and 20.9%, respectively. This could be attributable to the proximity of the provinces to the study site and as such most patients were referred for further management owing to the life-threatening nature of the toxidermia.\n\nMore patients were also less educated (63.0%), and a high percentage were unemployed (48.3%).These are factors that affect proper medication use and good access to safe efficacious medications [12].\n\nThe causative agents of SJS/TEN were determined by checking the original patient medical files since it was a retrospective study. These were considered accurate due to the following reasons: the drugs implicated in our study were consistent with those in other studies. For other drugs like anti-tuberculosis drugs and anti-malarials there is literature implicating them to cause SJS/TEN [6]. There was a reasonable time lapse between exposure to the drugs and development of symptoms. All our patients during their stay at the hospital had been reviewed by teams of dermatologists and medical experts whose acumen we thought was adequate to have determined the causative agents. Also, during data collection, the medical files had been reviewed by two independent reviewers to ascertain that information obtained from the files was accurate.\n\nOur study revealed the probable causes of SJS/TEN to be mostly drugs, accounting for over 90%. Twelve of our patients had SJS/TEN attributable to use of more than one drug. For each of these drugs, a probability of causality of 0.5 was assigned and the latency period for onset of symptoms was determined from intake of the first drug. The median latency for development of symptoms after exposure to the drugs was 4 days with a range of 2–14 days, matching other studies [7, 13]. This is consistent with the latency period for type IV hypersensitivity reaction mediated by T lymphocytes, the reaction responsible for causing SJS/TEN [2, 7]. The high prevalence of probable drug causes correlates with studies by Roujeau et al. [1], Haddad et al. [14], and Levi et al. [15]. HIV as a cause accounted for 3.5% of the cases and in a regional study by Saka et al., an association was found between HIV and SJS/TEN [6]. HSV-1 and mycoplasma pneumonia were also confirmed to be associated with SJS/TEN as in other studies [16, 17]. Of particular importance is the fact that the drugs mostly implicated to cause SJS/TEN in our study are antibiotics, anti-retrovirals, anti-tuberculosis drugs, and anti-malarials. All of these are commonly used locally, due to the high prevalence of relevant infectious diseases in this region, suggesting that many people are at risk of SJS/TEN because of using these drugs. While anti-retrovirals and anti-tuberculosis drugs are used more frequently in patients aged 21–40 years, antibiotics and anti-malarials are more frequently used in patients aged 0–20 years [18, 19]. As such, the region’s unique prescribing patterns likely do not account for the prevalence of SJS/TEN in patients aged 21–40 years as opposed to different age groups, as observed in some other studies [4, 10].\n\nMost of the severe cutaneous reactions were attributed to sulfonamides (27.5%) followed by ciprofloxacin (11.9%), penicillins (7.3%), and cephalosporins. The multi-centric European study by Roujeau et al. found a significant association between SJS/TEN and antibacterial sulfonamides, aminopenicillins, and quinolones [1]. Nevirapine use was also implicated at 16.5%, as was found by Mockenhaupt et al. in the EuroScar study [20].\n\nRoujeau et al. implicated anticonvulsant medications carbamazepine, phenobarbitone, and phenytoin to cause SJS/TEN, but this did not match our study [1].This could have been due to a lower prevalence of convulsive disorders in our population or differences in study methodologies. This could also be because of genetic differences between our population and the Western and Asian countries. Mockenhaupt et al. had also found significant association between SJS/TEN and lamotrigine, whereas we found only one case linked to its use in our study [20]. This could be attributed to the infrequent use of this drug among the local population since it is not in our treatment guidelines as first-line management of seizures [21].\n\nAnti-tuberculosis medications and antimalarial drugs were notably missing as probable causes of SJS/TEN in the studies done in Europe and Asia, but have featured in our study and also in a multicentric study done by Saka et al. in West Africa [6]. This could be explained by the high prevalence of tuberculosis and malaria in Africa as compared with the other two continents.\n\nHerbal medications sought from traditional healers may have unknown ingredients owing to adulteration and undocumented phytochemical extracts. These herbal medications have been shown to cause SJS/TEN [6] and in our study they were implicated in two cases. This was minimal considering the rampant use of herbal medicines locally. We attributed this to under-reporting of their use by patients to clinicians.\n\nThere is a paucity of published data on associations between metronidazole and SJS/TEN. However, in our study it accounted for two cases. This prevalence was low because local anecdotal information on the association between metronidazole and SJS/TEN is high and may have alerted clinicians on its use. Other drugs implicated in our study and not in previous research included magnesium sulfate and griseofulvin. However, it was observed that the patient who reacted to magnesium sulfate had been receiving penicillins earlier, which might have been a confounder. It was also observed that the patient who reacted to griseofulvin had been taking sulfonamides, a possible confounder.\n\nThere was a high number of SJS/TEN cases (n = 11) caused by unidentified drugs. It was observed that these had been prescribed from far-flung hospitals and no records were available to identify them.\n\nStudy Limitations\nInformation bias arose since the cases were already classified as SJS or TEN according to the medical records. We relied on reported data and the verification was difficult because some of these patients may have suffered from other skin illnesses. This bias was minimized by using a standardized data collection tool that indicated the symptoms required for diagnosis of SJS/TEN. Additionally, twenty random medical files were selected, reviewed, and data extracted to a separate data collection tool by an independent dermatology resident who was not affiliated to the study. Comparisons were made for the two data sets and differences sorted out by consensus. There was also a small sample size which we tried to increase by going back in time over 10 years.\n\nConclusion and Recommendation\nSJS/TEN are rare severe cutaneous reactions and the most frequently observed disease subtype in our study was SJS. Women and persons aged 21–40 years were the most affected groups within our study population, and drugs, especially sulfur-based medications, were deemed to be the causative agent in over 90% of the cases. The findings suggest that clinicians should be aware of the side effects of sulfur-based drugs for effective pharmacovigilance among patients who have these medicines prescribed for them. Due to the severity of SJS/TEN, all patients of all age groups taking new medications should undergo close drug monitoring and, based on our study results, this is especially important for women aged 21–40 years. Further studies are warranted in greater sample sizes across Kenya, comparing patient characteristics with the general population, in order to reach statistical significance and to determine any other predisposing factors to SJS/TEN.\n\nAcknowledgements\nWe thank the following for their support: Dr Peter Karimi, Dr Eric Guantai, Samantha Irungu, and the Kenyatta National Hospital medical records staff.\n\nAuthor’s Contributions\nAll authors were involved in drafting the protocol and the interpretation of results. Data were extracted from patient files by KI. Data analysis was carried out by KI with the help of DG and a biostatistician. All authors were involved in the drafting and approval of the final review, with KI being the coordinating author. All authors read and approved the final manuscript.\n\nCompliance with Ethical Standards\nFunding for the study\nThis study was funded by the authors.\n\nConflict of interest\nKenneth Irungu declares no conflict of interest, David Nyamu declares no conflict of interest, Sylvia Opanga declares no conflict of interest.\n\nEthical clearance\nEthical approval was sought from the Kenyatta National Hospital/University of Nairobi Ethics and Research committee (KNH/UON-ERC) and approval (Ref: KNH-ERC/A/119) was granted on 4th April 2016.\n==== Refs\nReferences\n1. Roujeau J Kelly J Naldi L Rzany B Stern R Anderson T Medication use and the risk of Stevens–Johnson syndrome or toxic epidermal necrolysis N Engl J Med 1995 333 1600 1607 10.1056/NEJM199512143332404 7477195 \n2. Harr T French L Toxic epidermal necrolysis and Stevens–Johnson syndrome Orphanet J Rare Dis 2010 5 39 10.1186/1750-1172-5-39 21162721 \n3. Patel T Thakkah S Sharmar D Cutaneous adverse drug reactions in Indian population: a systematic review Indian Dermatol Online J 2014 5 76 86 10.4103/2229-5178.146165 \n4. Schopf E Stuhmer A Rzany B Victor N Zentgraf R Kapp J Toxic epidermal necrolysis and Stevens–Johnson syndrome: an epidemiologic study from West Germany Arch Dermatol 1991 127 839 842 10.1001/archderm.1991.01680050083008 2036029 \n5. Yamane Y Matsukura S Watanabe Y Yamaguchi Y Retrospective analysis of Stevens Johnson syndrome and toxic epidermal necrolysis in 87 Japanese patients: treatment and outcome Allergol Int 2016 65 74 81 10.1016/j.alit.2015.09.001 26666483 \n6. Saka B Barro-traore F Atadokpe FA Niamba PA Ade H Pitche VP Tropical medicine rounds Stevens–Johnson syndrome and toxic epidermal necrolysis in sub-Saharan Africa: a multicentric study in four countries Int J Dermatol 2013 52 575 579 10.1111/j.1365-4632.2012.05743.x 23330601 \n7. Clinard V. Drug-induced skin disorders. In: US Pharmacist. 2012. https://www.uspharmacist.com/article/drug-induced-skin-disorders. Accessed 10 Dec 2015.\n8. Roujeau J Stern R Severe adverse cutaneous reactions to drugs N Engl J Med 1994 331 1272 1285 10.1056/NEJM199411103311906 7794310 \n9. Naranjo C Busto U Sellers E Sandor P Ruiz I Roberts E A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508 \n10. Chan H-L The incidence of erythema multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis Arch Dermatol Am Med Assoc 1990 126 43 10.1001/archderm.1990.01670250049006 \n11. Yamane Y Aihara M Ikezawa Z Analysis of Stevens–Johnson syndrome and toxic epidermal necrolysis in Japan from 2000 to 2006 Allergol Int 2007 56 419 425 10.2332/allergolint.O-07-483 17713361 \n12. Kizito M. Assessment of the patient factors impacting on oral anticoagulation therapy among adult outpatients at Kenyatta national hospital. [MPharm Thesis]. University of Nairobi, 2015.\n13. Bastuji-garin S Rzany B Stern RS Shear NH Naldi L Roujeau J Clinical classification of cases of toxic epidermal necrolysis, Stevens–Johnson syndrome, and erythema multiforme Arch Dermatol 1993 129 92 96 10.1001/archderm.1993.01680220104023 8420497 \n14. Haddad C Sidoroff A Kardaun SH Mockenhaupt M Creamer D Dunant A Stevens–Johnson syndrome/toxic epidermal necrolysis: are drug dictionaries correctly informing physicians regarding the risk? Drug Saf 2013 36 681 686 10.1007/s40264-013-0070-6 23743691 \n15. Levi N Bastuji-Garin S Mockenhaupt M Roujeau J-C Flahault A Kelly JP Medications as risk factors of Stevens–Johnson syndrome and toxic epidermal necrolysis in children: a pooled analysis Pediatrics 2009 123 297 304 10.1542/peds.2008-1923 \n16. Sontheimer R Garibaldi R Gerald G Krueger M Stevens–Johnson syndrome associated with Mycoplasma pneumoniae infections Arch Dermatol 1978 114 241 244 10.1001/archderm.1978.01640140059014 629550 \n17. Garcia-Doval I LeCleach L Bocquet H Otero X Roujeau J-C Toxic epidermal necrolysis and Stevens–Johnson syndrome Arch Dermatol Am Med Assoc 2000 136 323 327 \n18. Kilmarx PH Global epidemiology of HIV Curr Opin I HIV AIDS 2009 4 240 246 10.1097/COH.0b013e32832c06db 19532059 \n19. Malaria Control Programme Epidemiology of malaria in Kenya Afr J Med Pract 1994 1 5 6 12287810 \n20. Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, et al. Stevens–Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Investig Dermatol. The Society for Investigative Dermatology, Inc. 2008;128:35–44.\n21. Wafula E Abinya N Karanja J Kaseje D Musoke R Clinical guidelines for management and referral of common conditions at levels 4–6 hospitals 2009 Nairobi Ministry of Medical Services and Ministry of Public Health and Sanitation\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2198-9788",
"issue": "4(2)",
"journal": "Drugs - real world outcomes",
"keywords": null,
"medline_ta": "Drugs Real World Outcomes",
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"pages": "79-85",
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"pmid": "28401493",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": "10724193;23743691;23330601;19153164;2036029;8420497;21162721;629550;7477195;2404462;19532059;17713361;7249508;26666483;12287810;17805350;25593813;7794310",
"title": "Characterization of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Among Patients Admitted to Kenyatta National Hospital: A Retrospective Cross-Sectional Study.",
"title_normalized": "characterization of stevens johnson syndrome and toxic epidermal necrolysis among patients admitted to kenyatta national hospital a retrospective cross sectional study"
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"abstract": "Regorafenib has been demonstrated to prolong survival in patients with metastatic colorectal cancer refractory to standard chemotherapy. However, overall survival is limited to 2.5 months. The present report describes a unique case of metastatic colon cancer, which showed a complete response to regorafenib. A 54-year-old woman was diagnosed with right colon cancer obstruction with peritoneal seeding. The patient underwent laparoscopic right hemicolectomy, and the pathology was T4aN2bM1, moderately differentiated adenocarcinoma with high microsatellite instability (MSI-H) and wild-type KRAS/NRAS. The first-line chemotherapy was fluorouracil, leucovorin and irinotecan with cetuximab. After 12 cycles, recurrence at the anastomotic site was identified. The patient underwent palliative colectomy, and superior mesenteric artery (SMA) lymph node metastases were evident. The patient received second-line chemotherapy of fluorouracil, leucovorin and oxaliplatin with bevacizumab. Progression of metastasis to the right common iliac lymph nodes was detected after only four cycles of therapy. Thereafter, the patient received regorafenib as third-line therapy, starting with 160 mg for two cycles and reducing the dose thereafter, for a total of 17 cycles. The previously confirmed SMA lymph node metastasis had disappeared after the seventh cycle, and the right common iliac lymph node metastasis was not visible on CT after the 16th cycle. The patient decided to terminate regorafenib and has not experienced recurrence 2 years since treatment cessation. This is the first report of refractory metastatic colon cancer with MSI-H showing a complete response to regorafenib. Further studies are required to investigate the efficacy of regorafenib in refractory metastatic colon cancer with MSI-H and to elucidate the mechanism of remission.",
"affiliations": "Department of Surgery, Inje University, College of Medicine, Busan Paik Hospital, Busan 47392, Republic of Korea.;Department of Surgery, Inje University, College of Medicine, Busan Paik Hospital, Busan 47392, Republic of Korea.;Department of Surgery, Inje University, College of Medicine, Busan Paik Hospital, Busan 47392, Republic of Korea.;Department of Pathology, Inje University, College of Medicine, Busan Paik Hospital, Busan 47392, Republic of Korea.;Department of Radiology, Inje University, College of Medicine, Busan Paik Hospital, Busan 47392, Republic of Korea.;Department of Nuclear Medicine, Inje University, College of Medicine, Busan Paik Hospital, Busan 47392, Republic of Korea.;Department of Surgery, Inje University, College of Medicine, Busan Paik Hospital, Busan 47392, Republic of Korea.",
"authors": "Baik|Hyungjoo|H|;Lee|Hee Ju|HJ|;Park|Jueun|J|;Park|Ha Young|HY|;Park|Jinyoung|J|;Lee|Sunseong|S|;Bae|Ki Beom|KB|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2021.2405",
"fulltext": "\n==== Front\nMol Clin Oncol\nMol Clin Oncol\nMCO\nMolecular and Clinical Oncology\n2049-9450\n2049-9469\nD.A. Spandidos\n\nMCO-0-0-02405\n10.3892/mco.2021.2405\nArticles\nComplete response of MSI-high metastatic colon cancer following treatment with regorafenib: A case report\nBaik Hyungjoo 1\nLee Hee Ju 1\nPark Jueun 1\nPark Ha Young 2\nPark Jinyoung 3\nLee Sunseong 4\nBae Ki Beom 1\n1 Department of Surgery, Inje University, College of Medicine, Busan Paik Hospital, Busan 47392, Republic of Korea\n2 Department of Pathology, Inje University, College of Medicine, Busan Paik Hospital, Busan 47392, Republic of Korea\n3 Department of Radiology, Inje University, College of Medicine, Busan Paik Hospital, Busan 47392, Republic of Korea\n4 Department of Nuclear Medicine, Inje University, College of Medicine, Busan Paik Hospital, Busan 47392, Republic of Korea\nCorrespondence to: Dr Ki Beom Bae, Department of Surgery, Inje University, College of Medicine, Busan Paik Hospital, Bokji-ro 75, Busangjin, Busan 47392, Republic of Korea bkbsur@yahoo.co.kr; bkbsur@hanmail.net\n11 2021\n24 9 2021\n24 9 2021\n15 5 24312 2 2021\n06 8 2021\nCopyright: © Baik et al.\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.\nRegorafenib has been demonstrated to prolong survival in patients with metastatic colorectal cancer refractory to standard chemotherapy. However, overall survival is limited to 2.5 months. The present report describes a unique case of metastatic colon cancer, which showed a complete response to regorafenib. A 54-year-old woman was diagnosed with right colon cancer obstruction with peritoneal seeding. The patient underwent laparoscopic right hemicolectomy, and the pathology was T4aN2bM1, moderately differentiated adenocarcinoma with high microsatellite instability (MSI-H) and wild-type KRAS/NRAS. The first-line chemotherapy was fluorouracil, leucovorin and irinotecan with cetuximab. After 12 cycles, recurrence at the anastomotic site was identified. The patient underwent palliative colectomy, and superior mesenteric artery (SMA) lymph node metastases were evident. The patient received second-line chemotherapy of fluorouracil, leucovorin and oxaliplatin with bevacizumab. Progression of metastasis to the right common iliac lymph nodes was detected after only four cycles of therapy. Thereafter, the patient received regorafenib as third-line therapy, starting with 160 mg for two cycles and reducing the dose thereafter, for a total of 17 cycles. The previously confirmed SMA lymph node metastasis had disappeared after the seventh cycle, and the right common iliac lymph node metastasis was not visible on CT after the 16th cycle. The patient decided to terminate regorafenib and has not experienced recurrence 2 years since treatment cessation. This is the first report of refractory metastatic colon cancer with MSI-H showing a complete response to regorafenib. Further studies are required to investigate the efficacy of regorafenib in refractory metastatic colon cancer with MSI-H and to elucidate the mechanism of remission.\n\ncolon cancer\nstage IV\ncomplete response\nregorafenib\nhigh microsatellite instability\nFunding: The present study was supported by the 2015 Inje University Busan Paik Hospital Research Grant (Busan Paik-2015).\n==== Body\npmcIntroduction\n\nRegorafenib is a novel oral multikinase inhibitor that has shown antitumor activity in various gastrointestinal cancers, including colorectal cancer and gastrointestinal stromal tumor (1). The CORRECT and CONCUR trials have been significant benchmarks in the management of metastatic colorectal cancer (mCRC), demonstrating that regorafenib can slow disease progression and increase the median overall survival (OS) in patients with mCRC (2,3). Those double-blind phase 3 studies showed that the addition of regorafenib to best supportive care prolongs the median OS by up to 2.5 months and progression-free survival (PFS) by up to 1.5 months compared with the addition of placebo in patients with mCRC who had progressed after standard therapy failure. Although disease control [partial response (PR) plus stable disease] was achieved in 51% of the patients, only 4% showed a PR, and none showed a complete response (CR). Yoshino et al (4) recently reported a case of mCRC that responded well to regorafenib, resulting in a 2-year-long therapy with a PR. Here, we report the very first case of mCRC that was refractory to conventional chemotherapy such as fluorouracil, leucovorin and irinotecan (FOLFIRI) with cetuximab and fluorouracil, leucovorin and oxaliplatin (FOLFOX) with bevacizumab, but showed a CR to regorafenib. Our patient was a MSI-H, right sided advanced colon cancer patient who had extensive sunlight exposure to her torso. We believe these factors may have contributed to the patient's excellent response to regorafenib, resulting in a prolonged state of CR even after treatment cessation. The mechanism behind CR should be further elucidated in future studies; for now, we have suggested some possible theories.\n\nCase report\n\nA 54-year-old woman with abdominal pain and nausea was diagnosed with hepatic flexure colon cancer obstruction with peritoneal seeding in March 2016 (Fig. 1). The patient underwent palliative laparoscopic right hemicolectomy due to obstruction signs, with pathologic report of T4aN2bM1 moderately differentiated adenocarcinoma with lymphovascular invasion and perineural invasion. The tumor also had epidermal growth factor (EGFR) positivity, high microsatellite instability (MSI-H), wild-type KRAS/NRAS, and safety proximal and distal margins of 7 and 11 cm, respectively. The peritoneal seeding mass was partially removed for biopsy confirmation, which revealed pathologically metastatic adenocarcinoma (Fig. 2). Shortly after palliative laparoscopic right hemicolectomy, the patient received 12 cycles of FOLFIRI with cetuximab. After the 12th cycle, local anastomosis site recurrence and pericolic lymph node metastasis were observed (Fig. 3). In October 2016, the patient underwent palliative colectomy with lymph node dissection, which revealed 10/18 positive lymph nodes. During surgery, SMA lymph node metastasis was evident, which was confirmed by selective lymph node retrieval and permanent biopsy. Metal clips were placed in the area of lymph node metastasis for follow-up. Following recovery, the patient received second-line chemotherapy consisting of FOLFOX with bevacizumab. Progression of metastasis to the right iliac lymph nodes was detected in January 2017 after only four cycles of FOLFOX with bevacizumab (Fig. 4). Thereafter, the patient received regorafenib, starting with 160 mg for two cycles, which was quickly reduced to 120 mg for five cycles according to the Common Terminology Criteria for Adverse Events (CTCAE version 5) indicating grade 3 palmar-plantar erythrodysesthesia syndrome (5). Symptoms were partially alleviated after dose reduction, but because grade 2 palmar-plantar erythrodysesthesia syndrome persisted, the patient requested a further dose reduction; therefore, she received 80 mg of regorafenib during cycles 8-12. After the seventh cycle, the previously confirmed SMA lymph node metastasis had disappeared on computed tomography (CT) (Fig. 5A). From cycle 13 to 17, the patient requested a further dose reduction to 40 mg due to general weakness. The right common iliac lymph node metastasis was no longer visible on CT after the cycle 16 (Fig. 5B). The patient decided to terminate chemotherapy and has not experienced recurrence at 2 years since treatment cessation. The clinical effect of regorafenib monotherapy was classified as a CR according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1(6). CT was used for periodic screening, and 18F-fluorodeoxyglucose positron emission tomography (PET)-CT was used to confirm the CR (Fig. 6). The levels of two tumor markers, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9, were higher during chemotherapy, but decreased during regorafenib treatment and became within normal range at the time of termination (3.05 ng/ml and 7.35 U/ml, respectively) (Fig. 7). The patient did not suffer from any adverse events aside from palmar-plantar erythrodysesthesia syndrome and mild fatigue. While the patient underwent regorafenib monotherapy, she exposed herself to extensive sunlight for at least 1 h per day (Fig. 8). The patient's vitamin D ((1α25-(OH)2Vitamin D3) level was not recorded during therapy but was much higher (68.49 pg/ml) than the normal range (19.6-54.3 pg/ml) after CR achievement, without any supplements.\n\nDiscussion\n\nPrior to the introduction of regorafenib for mCRC treatment, patients who were not responsive to conventional palliative chemotherapy basically had no other treatment option. However, the CORRECT and CONCUR trials showed that both the PFS and OS of mCRC patients were prolonged following regorafenib treatment, compared with the placebo groups (P<0.0001 and P=0.0016), with a high disease control rate of up to 51% (2,3). Unfortunately, no patients in either study showed a CR, and only a few previously reported cases indicated radiological responses (4,7). More recent studies of regorafenib have reported similar results, with no patients showing a CR and only a few showing a PR (0-3%) (8,9). Our patient, who initially had MSI-high, right-sided colon cancer with peritoneal carcinomatosis, progressed to SMA and paraaortic lymph node metastases despite conventional chemotherapy. Progression led to cessation of chemotherapy and administration of regorafenib, which resulted in a CR according to both radiological studies and serum tumor marker levels, consistent with the RECIST criteria. Furthermore, the patient has not experienced recurrence at 2 years since cessation of regorafenib. The CEA level was initially normal but increased dramatically due to diffuse paraaortic lymph node metastasis and then approached the normal range soon after the patient started regorafenib, remaining normal even after treatment cessation. However, the CA 19-9 level appeared to be the more sensitive marker in this patient, showing significant elevation at the time of cancer progression. Despite first- and second-line chemotherapy and targeted therapy, the CA 19-9 level continued to increase with cancer progression and only gradually decreased during regorafenib treatment (Fig. 7).\n\nTo our knowledge, this is the first case of a CR in a patient with mCRC treated with regorafenib; only a handful of other gastrointestinal cancer cases have shown a CR following regorafenib treatment. Notably, the patient's cancer not only stopped progressing but completely regressed. We hypothesize the following reasons for the sudden disappearance of the previously chemotherapy-resistant tumor following regorafenib treatment. MSI-high tumors have a high mutational burden, which increases the likelihood of tumor exposure to the innate immune system (10,11). High MSI is also an effective biomarker of the response to immune-check inhibitor (ICI) in colon cancer, compared with the previously established marker PD-1. Thus, the mutational burden appears to be a more significant factor in immune system escape compared with PD-1; consequently, high MSI is an important surrogate marker (12,13). Increased antitumor immunity is among the pharmacologic traits of regorafenib (14,15), which inhibits CSF1R, a tyrosine kinase receptor involved in macrophage proliferation. CSF1R inhibition by regorafenib may reduce the recruitment of tumor-associated macrophages to the tumor bed, limiting their function, as demonstrated in a model of highly aggressive murine CT26 metastatic colon cancer (16,17). Regorafenib also increases cytotoxic T cells and inhibits the MAPK and JAK1/2-STAT axis, thereby attenuating IFNγ-induced PD-L1 and IDO1 expression and inducing immune cell attacks (18). The REGONIVO study reported steady tumor regression after treatment with a combination of regorafenib and ICI (19). Based on these studies, increased tumor recognition after regorafenib treatment and decreased tumor immune system escape after ICI treatment appear very promising. Therefore, we suggest that the increased tumor burden due to MSI-H status led to elevated tumor antigenicity, along with enhanced tumor recognition of the immune cells, by regorafenib in our patient, thereby inducing remission. However, this hypothesis should be further evaluated in larger sample sizes.\n\nAnother factor that may have influenced our patient's outcome is that she exposed her torso to sunlight for at least 1 h per day (Fig. 8). Her vitamin D level was higher than the of normal range at the time of the CR, although we did not record her initial vitamin D level. The patient took no vitamin D supplements or injections; therefore we infer that her high vitamin D level was due solely to the direct absorption of sunlight. Recent studies investigating the relationship between vitamin D and cytotoxic T cells that attack cancer suggested that an increased vitamin D level may promote CD8+ T cell tumor infiltration, which would result in a lower tumor burden. Karkeni et al (20) have reported that vitamin D supplements contributed to significant increases in CD8+ T cell recruitment to the tumor site and CD8+ T cell activation compared with the control. We cautiously infer that vitamin D synthesized by sunshine may have played a role in activating cytotoxic T cells, which contributed to the patient's CR. This theory should be explored in both laboratory and clinical trials.\n\nOur patient had a right-sided tumor harboring wild-type RAS. In their CORRELATE study, Ducreux et al (21) showed similar OS and PFS after regorafenib treatment between left- and right-sided mCRC patients; however, Yoon et al (9) found that left-sided primary tumors were associated with improved outcomes, including PFS, after treatment in their multivariate analysis (2.6 vs. 1.9 months, P=0.04). The role of the RAS mutation status remains controversial; in the CORRECT study, no relationship was detected between the KRAS mutation status and outcomes following regorafenib treatment, whereas in the REBECCA study, mutations were found to be a prognostic factor for poor survival (2,22). Further studies are essential to confirm whether these factors influence the outcomes of regorafenib treatment.\n\nAs suggested by Yoshino et al (4), we stopped regorafenib treatment after the 17th cycle due to the lack of remnant tumor evident on both CT and PET-CT. Remarkably, the patient has not experienced recurrence 2 years since treatment cessation; no similar findings have been reported previously. Although the regorafenib dose had to be reduced due to palmar-plantar erythrodysesthesia syndrome, there were no other severe side effects such as liver function deterioration or hypertension. Notably, the dose reduction did not appear to diminish the antitumor effect of regorafenib; however, further studies are needed for confirmation.\n\nIn summary, this case study suggests that the high mutational burden carried by MSI-H tumor acts as a neoantigen in the innate immune system, and that regorafenib plays an additional role in enhancing tumor antigen recognition by immune cells. An increased vitamin D level via extensive sunlight exposure may also have encouraged cytotoxic T cell recruitment and activation to the tumor microenvironment. All of these factors appear to have contributed to the patient's CR. However, well-designed preclinical and clinical studies are required to demonstrate the mechanism behind this response.\n\nIn conclusion, this case report presents the first patient with MSI-H mCRC to achieve a CR to regorafenib treatment after failure of conventional palliative chemotherapy. The mechanism behind this response requires further evaluation in larger studies, to identify which mCRC patients are most likely to benefit from regorafenib.\n\nAcknowledgements\n\nNot applicable.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors' contributions\n\nHB was involved in manuscript writing and acquisition of data. HJL wrote the manuscript. JuP designed the study and gathered patient information. HYP was involved in pathology review and case review. JiP was involved in image (CT) review. SL was involved in image (PET) review. KBB was involved in conception of the case report and analysis of the case. HB and KBB confirm the authenticity of all the raw data. HB, HJL and KBB have reviewed all the raw data separately, and have confirmed that the results are correctly described. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\n\nThis type of study does not require ethics approval due to its retrospective nature. The patient consented to the treatment.\n\nPatient consent for publication\n\nInformed oral consent was obtained from the patient.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nFigure 1 Preoperative images. (A) Colonoscopy findings of the obstructive cancer. (B) Abdominopelvic CT images of ascending colon cancer obstruction (arrow) with pericolic lymph node enlargement (arrowheads). (C) Positron emission tomography-CT images.\n\nFigure 2 Intraoperative and pathologic findings. (A) Laparoscopic view of the exophytic primary tumor. (B) Pathologic findings of the primary tumor showing fused/cribriform glands and extracellular mucin pools (H&E staining; magnification, x200). (C) Laparoscopic view of pericolic lymph node enlargement. (D) Pathologic findings of the metastatic tumor in pericolic lymph node (H&E staining; magnification, x200). (E) Laparoscopic view of peritoneal seeding. (F) Pathologic findings of peritoneal seeding (H&E staining; magnification, x200).\n\nFigure 3 Local recurrence after 12 cycles of fluorouracil, leucovorin and irinotecan plus cetuximab. (A) Recurrence at the anastomosis site confirmed by colonoscopy. (B) Recurrence at the anastomosis site (arrow) with pericolic lymph node enlargement (arrowhead) on abdominopelvic CT images. (C) Positron emission tomography-CT images showing high fluorodeoxyglucose uptake at the anastomosis site. (D) Pathologic evidence of a locally recurrent tumor showing histologic features similar to those of the primary tumor (H&E staining; magnification, x200). H&E staining of a metastatic tumor in the superior mesenteric artery lymph node at (E) low power (magnification, x12.5) and (F) high power (magnification, x200).\n\nFigure 4 Distant lymph node metastasis after anastomosis site colectomy and lymphadenectomy followed by four cycles of fluorouracil, leucovorin and oxaliplatin plus bevacizumab (pre-regorafenib). (A) APCT showing superior mesenteric artery lymph node metastasis with clip marking (arrow). (B) APCT showing right common iliac lymph node metastasis (arrow). (C) Positron emission tomography-CT showing multifocal lymph node metastasis. APCT, abdominopelvic CT.\n\nFigure 5 Responses to regorafenib. (A) Disappearance of the superior mesenteric artery lymph node (with clips) but persistence of the right iliac lymph node metastasis after seven cycles of regorafenib. (B) Disappearance of the right iliac lymph node metastasis along with other lymph node metastases after 16 cylces of regorafenib. A complete response was observed.\n\nFigure 6 The complete response persisting at 2 years after cessation of regorafenib treatment. Lack of recurrence was indicated by (A) abdominopelvic CT and confirmed by (B) positron emission tomography-CT.\n\nFigure 7 CEA and CA 19-9 levels of the patient throughout the treatment duration. Recurrence was accompanied by elevated CEA or CA 19-9 levels. CA 19-9 appeared to be the more sensitive marker in this patient. FOLFIRI, fluorouracil, leucovorin and irinotecan; FOLFOX, fluorouracil, leucovorin and oxaliplatin; preop, preoperative; postop, postoperative; mo, months.\n\nFigure 8 Patient's tanned skin due to extensive sunlight exposure of the torso and limbs.\n==== Refs\nReferences\n\n1 Wilhelm SM Dumas J Adnane L Lynch M Carter CA Schütz G Thierauch KH Zopf D Regorafenib (BAY 73-4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity Int J Cancer 129 245 255 2011 10.1002/ijc.25864 21170960\n2 Grothey A Van Cutsem E Sobrero A Siena S Falcone A Ychou M Humblet Y Bouché O Mineur L Barone C Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial Lancet 381 303 312 2013 10.1016/S0140-6736(12)61900-X 23177514\n3 Li J Qin S Xu R Yau TC Ma B Pan H Xu J Bai Y Chi Y Wang L Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): A randomised, double-blind, placebo-controlled, phase 3 trial Lancet Oncol 16 619 629 2015 10.1016/S1470-2045(15)70156-7 25981818\n4 Yoshino K Manaka D Kudo R Kanai S Mitsuoka E Kanto S Hamasu S Konishi S Nishitai R Metastatic colorectal cancer responsive to regorafenib for 2 years: A case report J Med Case Rep 11 227 2017 10.1186/s13256-017-1366-4 28818109\n5 U.S. Department of Health and Human Services: Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0. U.S. Department of Health and Human Services, Washington, DC, 2017. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf.\n6 Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R Dancey J Arbuck S Gwyther S Mooney M New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) Eur J Cancer 45 228 247 2009 10.1016/j.ejca.2008.10.026 19097774\n7 Kawasaki K Hamamoto Y Adachi M Kanai T Takaishi H Early tumor cavitation with regorafenib in metastatic colorectal cancer: A case report Oncol Lett 11 231 233 2016 10.3892/ol.2015.3905 26870193\n8 Moriwaki T Fukuoka S Taniguchi H Takashima A Kumekawa Y Kajiwara T Yamazaki K Esaki T Makiyama C Denda T Propensity score analysis of regorafenib versus trifluridine/tipiracil in patients with metastatic colorectal cancer refractory to standard chemotherapy (REGOTAS): A Japanese society for cancer of the colon and rectum multicenter observational study Oncologist 23 7 15 2018 10.1634/theoncologist.2017-0275 28894015\n9 Yoon SE Lee SJ Lee J Park SH Park JO Lim HY Kang WK Park YS Kim ST The impact of primary tumor sidedness on the effect of regorafenib in refractory metastatic colorectal cancer J Cancer 10 1611 1615 2019 10.7150/jca.29106 31205516\n10 Schrock AB Ouyang C Sandhu J Sokol E Jin D Ross JS Miller VA Lim D Amanam I Chao J Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer Ann Oncol 30 1096 1103 2019 10.1093/annonc/mdz134 31038663\n11 Mandal R Samstein RM Lee KW Havel JJ Wang H Krishna C Sabio EY Makarov V Kuo F Blecua P Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response Science 364 485 491 2019 10.1126/science.aau0447 31048490\n12 Innocenti F Ou FS Qu X Zemla TJ Niedzwiecki D Tam R Mahajan S Goldberg RM Bertagnolli MM Blanke CD Mutational analysis of patients with colorectal cancer in CALGB/SWOG 80405 identifies new roles of microsatellite instability and tumor mutational burden for patient outcome J Clin Oncol 37 1217 1227 2019 10.1200/JCO.18.01798 30865548\n13 André T Shiu KK Kim TW Jensen BV Jensen LH Punt C Smith D Garcia-Carbonero R Benavides M Gibbs P Pembrolizumab in microsatellite-instability-high advanced colorectal cancer N Engl J Med 383 2207 2218 2020 10.1056/NEJMoa2017699 33264544\n14 Grothey A Prager G Yoshino T The mechanism of action of regorafenib in colorectal cancer: A guide for the community physician Clin Adv Hematol Oncol 12 (Suppl 17) S1 S19 2019 32720931\n15 Arai H Battaglin F Wang J Lo JH Soni S Zhang W Lenz HJ Molecular insight of regorafenib treatment for colorectal cancer Cancer Treat Rev 81 101912 2019 10.1016/j.ctrv.2019.101912 31715423\n16 Abou-Elkacem L Arns S Brix G Gremse F Zopf D Kiessling F Lederle W Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model Mol Cancer Ther 12 1322 1331 2013 10.1158/1535-7163.MCT-12-1162 23619301\n17 Cannarile MA Weisser M Jacob W Jegg AM Ries CH Rüttinger D Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy J Immunother Cancer 5 53 2017 10.1186/s40425-017-0257-y 28716061\n18 Wu RY Kong PF Xia LP Huang Y Li ZL Tang YY Chen YH Li X Senthilkumar R Zhang HL Regorafenib promotes antitumor immunity via inhibiting PD-L1 and IDO1 expression in melanoma Clin Cancer Res 25 4530 4541 2019 10.1158/1078-0432.CCR-18-2840 30940655\n19 Fukuoka S Hara H Takahashi N Kojima T Kawazoe A Asayama M Yoshii T Kotani D Tamura H Mikamoto Y Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: An open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603) J Clin Oncol 38 2053 2061 2020 10.1200/JCO.19.03296 32343640\n20 Karkeni E Morin SO Tayeh BB Goubard A Josselin E Castellano R Fauriat C Guittard G Olive D Nunès JA Vitamin D controls tumor growth and CD8+ T cell infiltration in breast cancer Front Immunol 10 1307 2019 10.3389/fimmu.2019.01307 31244851\n21 Ducreux M Petersen LN Öhler L Bergamo F Metges JP de Groot JW Wang JY Paredes BC Dochy E Fiala-Buskies S Safety and effectiveness of regorafenib in patients with metastatic colorectal cancer in routine clinical practice in the prospective, observational CORRELATE study Eur J Cancer 123 146 154 2019 10.1016/j.ejca.2019.09.015 31698328\n22 Adenis A de la Fouchardiere C Paule B Burtin P Tougeron D Wallet J Dourthe LM Etienne PL Mineur L Clisant S Survival, safety, and prognostic factors for outcome with regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: Results from a multicenter study (REBECCA) nested within a compassionate use program BMC Cancer 16 412 2016 10.1186/s12885-016-2440-9 27389564\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2049-9450",
"issue": "15(5)",
"journal": "Molecular and clinical oncology",
"keywords": "colon cancer; complete response; high microsatellite instability; regorafenib; stage IV",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "243",
"pmc": null,
"pmid": "34650810",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": "19097774;31038663;31244851;26870193;31205516;21170960;23619301;31715423;27389564;31048490;28818109;31698328;33264544;23177514;28716061;25981818;30865548;30940655;28894015;32720931;32343640",
"title": "Complete response of MSI-high metastatic colon cancer following treatment with regorafenib: A case report.",
"title_normalized": "complete response of msi high metastatic colon cancer following treatment with regorafenib a case report"
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"companynumb": "KR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-318368",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
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{
"abstract": "BACKGROUND\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) form a spectrum of a rare and life-threatening cutaneous drug reaction. SJS/TEN in pregnancy poses largely unknown risk factors and outcomes for both the mother and foetus compared to the general population.\n\n\nMETHODS\nWe conducted a study of consecutive pregnant women admitted to single tertiary referral centre in South Africa with SJS/TEN over a 3 year period. They were all managed by the same medical team using the same protocols. We evaluated their underlying illnesses, offending drugs and the course of pregnancy and outcomes to determine factors influencing maternal and foetal outcomes.\n\n\nRESULTS\nWe identified twenty-two women who developed SJS/TEN while pregnant, all of them HIV-infected. Their median age was 29 years. The majority 16/22 (73%) had SJS, the milder variant of the disease affecting < 10% body surface area. Nevirapine was the offending drug in 21/22 (95%) cases. All 22 of the mothers survived with 3/22 (14%) developing postpartum sepsis. Pregnancy outcomes were known in 18/22 women and 9/18 (50%) babies were delivered by caesarean section. There were 2 foetal deaths at 21 and 31 weeks respectively and both were associated with post-partum sepsis. Postnatal complications occurred in 5 cases, 3 involving the respiratory system and the other two being low birth weight deliveries. Eight placentae and one foetus were sent for histology and none showed macroscopic or microscopic features of SJS/TEN. On follow-up, only 12/20 children were tested for HIV at 6 weeks post-delivery and none of them were HIV-infected. All had received prophylactic ARVs including nevirapine.\n\n\nCONCLUSIONS\nTEN, the severe form of the disease, was associated with poorer foetal outcomes. SJS/TEN-associated mortality is not increased in HIV-infected pregnant women. Maternal SJS/TEN does not seem to commonly manifest in the foetus.",
"affiliations": "Division of Dermatology, Department of Medicine, University of Cape Town, Cape Town, South Africa.;Division of Dermatology, Department of Medicine, University of Cape Town, Cape Town, South Africa.;Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.;Department of Obstetrics and Gynaecology, University of Cape Town, Cape Town, South Africa.;Division of Dermatology, Department of Medicine, University of Cape Town, Cape Town, South Africa.",
"authors": "Knight|Lauren|L|;Todd|Gail|G|;Muloiwa|Rudzani|R|;Matjila|Mushi|M|;Lehloenya|Rannakoe J|RJ|",
"chemical_list": "D019380:Anti-HIV Agents; D019829:Nevirapine",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0135501",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2626765910.1371/journal.pone.0135501PONE-D-14-51782Research ArticleStevens Johnson Syndrome and Toxic Epidermal Necrolysis: Maternal and Foetal Outcomes in Twenty-Two Consecutive Pregnant HIV Infected Women Pregnancy Outcomes in 22 HIV Infected Women with SJS/TENKnight Lauren \n1\nTodd Gail \n1\nMuloiwa Rudzani \n2\nMatjila Mushi \n3\nLehloenya Rannakoe J. \n1\n*\n1 \nDivision of Dermatology, Department of Medicine, University of Cape Town, Cape Town, South Africa\n\n2 \nDepartment of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa\n\n3 \nDepartment of Obstetrics and Gynaecology, University of Cape Town, Cape Town, South Africa\nGutman Julie Editor\nCenters for Disease Control and Prevention, UNITED STATES\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: GT RJL LK. Performed the experiments: GT LK MM RJL. Analyzed the data: RM GT LK RJL. Contributed reagents/materials/analysis tools: RM. Wrote the paper: LK RJL GT RM MM.\n\n* E-mail: rannakoe.lehloenya@uct.ac.za12 8 2015 2015 10 8 e013550127 11 2014 22 7 2015 © 2015 Knight et al2015Knight 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 properly credited.Introduction\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) form a spectrum of a rare and life-threatening cutaneous drug reaction. SJS/TEN in pregnancy poses largely unknown risk factors and outcomes for both the mother and foetus compared to the general population.\n\nMethods\nWe conducted a study of consecutive pregnant women admitted to single tertiary referral centre in South Africa with SJS/TEN over a 3 year period. They were all managed by the same medical team using the same protocols. We evaluated their underlying illnesses, offending drugs and the course of pregnancy and outcomes to determine factors influencing maternal and foetal outcomes.\n\nResults\nWe identified twenty-two women who developed SJS/TEN while pregnant, all of them HIV-infected. Their median age was 29 years. The majority 16/22 (73%) had SJS, the milder variant of the disease affecting < 10% body surface area. Nevirapine was the offending drug in 21/22 (95%) cases. All 22 of the mothers survived with 3/22 (14%) developing postpartum sepsis. Pregnancy outcomes were known in 18/22 women and 9/18 (50%) babies were delivered by caesarean section. There were 2 foetal deaths at 21 and 31 weeks respectively and both were associated with post-partum sepsis. Postnatal complications occurred in 5 cases, 3 involving the respiratory system and the other two being low birth weight deliveries. Eight placentae and one foetus were sent for histology and none showed macroscopic or microscopic features of SJS/TEN. On follow-up, only 12/20 children were tested for HIV at 6 weeks post-delivery and none of them were HIV-infected. All had received prophylactic ARVs including nevirapine.\n\nConclusions\nTEN, the severe form of the disease, was associated with poorer foetal outcomes. SJS/TEN-associated mortality is not increased in HIV-infected pregnant women. Maternal SJS/TEN does not seem to commonly manifest in the foetus.\n\nThe authors received no specific funding for this work. Data AvailabilityAll relevant data are within the paper and its tables.Data Availability\nAll relevant data are within the paper and its tables.\n==== Body\nIntroduction\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare life-threatening cutaneous drug reactions, with skin and mucous membrane involvement that are considered a spectrum of the same disease. In SJS, there is <10% of epidermal detachment and in TEN there is >30% with SJS/TEN overlap lying between these two extremes.[1] The incidence of SJS/TEN is approximately 0,05–2 cases/million per year for the general population, in developed countries where the data is available. In patients with AIDS the incidence is estimated to be 1 to 2 per 1000 individuals.[2] The disease is associated with significant morbidity and mortality. In larger published series of patients, mortality has been reported to be between 4 and 60%, while long-term sequelae is as high as 50% in children and more than 80% in adults.[3–7][8–10]\n\nVarious risk factors for the development of SJS/TEN have been reported, including HIV infection, some HLA alleles, collagen vascular disease and age.[2,5,11] Sekula and colleagues conducted a survival analysis of a cohort of patients with SJS/TEN which validated the parameters of SCORTEN, a prognostic score for in-hospital mortality.[12] The score is based on seven risk indicators, these being: (1) age more than 40 years, (2) recent or current malignancy, (3) tachycardia more than 120 per minute, (4) blistering more than 10% of total affected body surface area, (5) serum urea more than 10 mmol/L, (6) bicarbonate less than 20 mmol/L, and (7) serum glucose more than 250 mg/dL.[13] In addition, the authors found that a recent infection was an independent predictor of mortality.[12] None of the patients evaluated in the survival analysis was reported to be pregnant. There is paucity of robust data relating to predictors of maternal and foetal outcomes in pregnant women who develop SJS/TEN. Almost all of the reported cases are single cases.[14]-\n\n\nPregnant women who develop SJS/TEN are a unique subset, possibly with different risk factors and outcomes for both the mother and the foetus compared to the general population. SJS/TEN can simultaneously affect the mother and the foetus and in the literature there are at least 5 such reported cases[15]. In pregnancy, low maternal body weight, high nevirapine (NVP) plasma levels and CD4 counts of greater than 250 cells/μl have been associated with an increase in the incidence of SJS/TEN[16]. Dube et al, in a matched case control study found that pregnancy itself increased the risk of developing SJS by 14 fold when HIV-infected women used NVP based regimens in pregnancy (OR14.28, p = 0.006, 95% CI 1.54–131.82).[16] In reviewed literature, a high survival rate is suggested for both the mother and fetus. Based on the current limited data, it seems mortality in pregnancy-associated SJS/TEN is lower than the general population. In pregnancy, the most significant effect of SJS/TEN on the unborn foetus has been shown to be an increased risk of premature birth due to foetal distress.[14] What is not clear is if this increased risk is as a result of underlying maternal illness, fever or placental insufficiency. There also seems to be a relationship between severity of the disease and premature birth, likely attributed to foetal stress as a result of maternal disease.[9] However, it is unclear what percentage of maternal body surface area needs to be denuded for the risk to become significant.\n\nSJS/TEN is associated with mucosal surface necrosis and this is a major cause of long-term sequalae. Niemeijer et al reported genital involvement in 70% of patients which included; mucosal erosions, ulcerations and purulent blood-stained vaginal discharge. Mucosal lesions can persist for weeks to months and up to 28% of patients could suffer long term sequelae. These include vaginal adhesions and stenosis, vaginal and vulval adenosis, endometriosis and telangiectasia. Sequelae may result in painful intercourse, difficult conception and infertility[17]. In pregnancy this may interfere with normal delivery.[14]\n\nThe impact of HIV infection on maternal and foetal outcomes in pregnant women with SJS/TEN is largely unknown. It is well established that the HIV infected population has a higher predisposition to SJS/TEN.[2,8] In an attempt to answer some of these questions we conducted a review of clinical data and records of pregnant patients admitted to a single tertiary referral centre in South Africa with SJS/TEN and managed by the same group of dermatologists using the same protocols. We followed-up those who had delivered outside of the tertiary hospital by retrieving their records from secondary and primary level delivery facilities or contacting them physically and/or telephonically.\n\nMethods\nStudy setting\nThe study population comprised of patients admitted with SJS/TEN to a tertiary referral hospital in Cape Town, South Africa. The hospital is one of two tertiary referral centres serving the population of Cape Town (approximately 3.7 million) including primary health care clinics, district and secondary hospitals[18]. The study was approved by the Faculty of Health Sciences Human Research Ethics Committee of the University of Cape Town (HREC Ref 124/2013) and conducted within the provisions of the World Medical Association Declaration of Helsinki.[19] The pregnant women were part of a prospective study on SJS/TEN effects on the foetus, new born and placenta (REC REF 81/2010). The placentas were collected post-delivery and sent for histology and the new-borns were examined for skin and mucosal anomalies. The women were also part of a prospective study of the long term mucosal sequelae of SJS/TEN (REC REF 82/2010). All patients gave consent for their data and information to be included prospectively in the RegiSCAR international registry for severe cutaneous adverse reactions to drugs (REC REF 424/2009). Additional information was obtained retrospectively from patient records and personal interviews where necessary. Signed informed consent was given by all women recruited into the prospective studies.\n\nParticipants and data extraction\nWe reviewed clinical records and study data of all pregnant patients admitted with SJS, TEN and SJS/TEN overlap to the dermatology ward from 1st January 2009 to 31st December 2012. Patients were admitted to a general dermatology ward managed by experienced nursing staff and dermatologists in conjunction with obstetricians and gynaecologists where necessary. Patient management followed our standard protocol which is mainly supportive including fluid resuscitation, enteral nutritional support, daily baths with antiseptic solution, topical care of mucosa including eyes, mouth and genitalia and sterile non-adherent dressings. No physical debridement was performed and we avoided urinary catheters and intravenous lines unless intravenous antibiotics or urgent resuscitation was necessary. We avoided the use of antibiotics unless there was clinical or laboratory indication for their initiation. No prophylactic antibiotics, systemic steroids, intravenous immunoglobulin, cyclosporine or other specific therapeutic medications were administered to any of the patients. Anticoagulation was only administered to patients who were completely bed-bound for more than 7 consecutive days.\n\nThe following data parameters were extracted from the clinical records: age; HIV status; CD4 count; co-morbidities; gestation of pregnancy; medication used in the preceding 8 weeks; interval between the first symptoms of SJS/TEN and admission to our centre; classification as SJS, SJS/TEN overlap and TEN; vital signs; clinical management before and during admission to hospital; results of bacterial cultures; length of stay in hospital and the final outcome of both mother and child.\n\nSampling and definitions\nWhere possible attempts to recover placentae at the time of delivery were made. These were collected in buffered formaline and sent for routine H&E staining. All placentas were reviewed by a single experienced pathologist as per our protocol.\n\nData management and statistical analysis\nData was entered into a Microsoft Excel database. Continuous variables were described using medians and ranges or medians and interquartile ranges while categorical variables were summarized as proportions and percentages. No inferential statistics or hypothesis testing was undertaken as the small size of the sample did not allow for a meaningful analysis.\n\nResults\nWe identified twenty-two women (21 black African women and 1 woman of mixed ancestry) who developed SJS/TEN while pregnant and their baseline characteristics are summarised in Table 1. Their median age was 29 years (range 23–36) and all of the twenty-two were HIV-infected on antiretriviral therapy (ARV) with a median CD4 count of 316 (IQR 224,360). Apart from HIV, 3 participants had other pre-existing co-morbidities on admission namely; two cases of pre-eclampsia and a case of pneumonia. Eight of the twenty-two were primigravidas. SJS was diagnosed in 16/22 (73%) cases, TEN in 5/22 (23%) and SJS/TEN overlap in a single case. Seventeen of the twenty-two (77%) had genital erosions on admission and 2/17 (12%) of the cases had unspecified vaginal discharge. The median time between onset of symptoms and admission to hospital was four days (IQR 3,6). Nevirapine was the offending drug in 21/22 (95%) cases while efavirenz was implicated in a single case. Causality was decided clinically with reference to recently introduced drugs and experience and knowledge of the most likely offending agent. In all cases the ARVs given prophylactically to prevent HIV transmission to the child were the most recently introduced medications. Nevirapine regimes were used for all women except one where efavirenz was substituted for nevirapine. Onset of SJS/TEN symptoms was temporally related to the introduction of nevirapine (mean 16 days from nevirapine introduction) or to an increase in dose from 100mg to 200mg daily after 2 weeks of treatment (mean 4 days from increased nevirapine dose). In order to prevent the development of HIV resistance only nevirapine was stopped in suspected cases while the other ARVs were continued at full doses to cover the withdrawal tail of nevirapine excretion. In the case of efavirenz, all ARVs were stopped and on complete resolution of SJS/TEN the ARVs were restarted and efavirenz substituted with alluvia. Causality was thus determined by the temporal relationship to SJS/TEN and healing on withdrawal of the suspected offender despite continuation of all other medication.\n\n10.1371/journal.pone.0135501.t001Table 1 Baseline characteristics and description of pregnancy and outcomes of 22 HIV positive participants who developed SJS/TEN during pregnancy.\nPatient\tAge (years)\tCD4 value\tDiagnosis\tMucosal involvement\tPast Obstetric History\tGestation at time of SJS/TEN (weeks+days)\tGestation at outcome (weeks+days)\tMode of delivery\tBirth weight (grams)\tPlacental weight (grams)\tApgar 1min\tApgar 5min\t\n1\t37\t360\tSJS\tEye, oral, genital\tG3P2\t20 + 6\t37 + 2\tNVD\t1950\t450\t9\t10\t\n2\t24\t887\tSJS\tEye\tG2P1\t36\t39 + 5\tNVD\t3415\t480\t8\t9\t\n3\t34\t110\tSJS\tEye, oral\tG2P1\t37 +\t41 + 2\tC/S for high VL\t3610\t625\t7\t10\t\n4\t33\t133\tSJS\tEye,oral, geital\tG2P0E1\t29 + 3\t39 + 3\tNVD\t3410\t635\t9\t10\t\n5\t28\t340\tSJS\tEye, oral\tG2P0M1\t23 + 2\t41\tC/S\t2565\t350\t9\t10\t\n6\t32\t1213\tSJS\tEye,oral\tG1P0\t13\tunknown\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\t\n7\t36\t26\tSJS\tOral, genital\tG3P2-1\t24\t31\tNVD for IUD\t580\t170\t0\t0\t\n8\t33\t236\tSJS\tEye, oral, genital\tG3P1M1\t32 + 6\t35 +\tC/S for pre-eclampsia\t2330\t450\t9\t10\t\n9\t30\tunknown\tSJS\tEye,oral\tG1P0\t34\tunknown\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\t\n10\t26\t162\tTEN\tEye, oral, genital\tG2P1\t32\t34 + 2\tC/S for foetal distress\t1760\tUnknown\t0\t8\t\n11\t25\t521\tTEN\tEye, oral\tG1P0\t8\tunknown\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\t\n12\t28\t622\tSJS\tEye, oral, genital\tG1P0\t25\t40 +\tNVD\tUnknown\tUnknown\tUnknown\tUnknown\t\n13\t30\t712\tTEN\tEye, oral\tG4P2M1\t36 + 2\t36 + 3\tC/S for foetal distress\t2230\t430\t9\t10\t\n14\t24\t203\tSJS\tEye, oral, genital\tG1P0\t29 + 3\t38 + 2\tC/S for high VL\t3040\t425\t7\t10\t\n15\t23\t224\tSJS\tEye, oral\tG2P1-1\t14 +\t39 +\tC/S for foetal distress\t2960\t630\t9\t10\t\n16\t34\t291\tSJS\tEye, oral, genital\tG3P2\t23\t39\tNVD\t3200\t715\t9\t10\t\n17\t28\t242\tSJS/TEN\tEye, oral, genital\tG1P0\t27 +\tunknown\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\t\n18\t33\t349\tSJS\tEye, oral\tG2P1\t11\t38 +\tC/S for foetal distress\t2520\t450\t8\t9\t\n19\t27\t348\tSJS\tEye, oral, genital\tG1P0\t16\t38\tNVD\tUnknown\tUnknown\tUnknown\tUnknown\t\n20\t28\t228\tSJS\tEye\tG2P1\t15 + 3\t39 +\tNVD\t3255\t855\t9\t10\t\n21\t30\t342\tTEN\tEye, genital\tG2P1\t21\t21 +\tMiscarriage\t330\t100\t0\t0\t\n22\t26\t345\tTEN\tEye, oral genital\tG1P0\t28 + 6\t39 + 2\tC/S for foetal distress\t2540\t380\t5\t9\t\nKey: G:gravidity, P:parity, M:miscarriage, NVD: normal vertex delivery, C/S: casaerian section, VL: viral\n\nDuring hospitalization for SJS/TEN, deranged laboratory parameters (2xupper limit of normal) were reported in 7/22 (32%) and the most common was elevation of transaminases in four cases. One case each had elevated creatinine and alkaline phosphatase as well as a case of thrombocytopenia. Therapeutic systemic antibiotics were initiated in 13/22 cases, ten of these on clinical suspicion of bacterial systemic infection, which included temperature of >38°, tachycardia, offensive lochia, and three on confirmed positive bacterial cultures. The blood cultures grew Klebsiella pneumoniae,methycillin-susceptible Staphylococcus aureus (S.aureus) and methycillin-resistant S. aureus respectively. All the twenty two cases survived and were discharged home following recovery or delivery. No cases required admission to an intensive care unit (ICU). All cases were competently managed in an isolated side ward in the dermatology unit by a team of experienced nurses supported by a team of specialists. Management was based on the standardised unit protocol which dictates that all patients are monitored several times a day for sepsis, systemic involvement and metabolic imbalances. Three of the twenty-two (14%) developed post-partum sepsis (Table 2). The offending organism was known in only one patient, a case of methycillin-resistant S. aureus. Both cases of foetal death, one being a vertex delivery following an induction of labour and the other a miscarriage due to chorioamnionitis, were amongst the three that developed postpartum sepsis. The other case of post partum sepsis occurred after caesarean section delivery for foetal distress. Postpartum sepsis occurred a median of 17 days (range 12–29) after the initial presentation with SJS/TEN. Two of the three cases of post-partum sepsis occurred in women with SJS and the other in a woman with TEN. Only one of the cases had TEN at the time of delivery and sepsis, with the other 2 having recovered from their CADR before delivery. There were five reported cases of long-term sequelae associated with SJS/TEN in the study population, namely two cases of dyspareunia and two ophthalmological complications (Table 2). A fifth case was identified retrospectively as having a complication in her subsequent pregnancy in which she suffered 3rd degree tears of the vagina.\n\n10.1371/journal.pone.0135501.t002Table 2 Baseline characteristics, offending agents and description of pregnancy with outcomes and complications of 22 HIV positive participants who developed SJS/TEN in pregnancy.\nPt\tAge (yrs)\tCD4\tVL\tCADR\tDrug\tDays to CADR\tDays to admission\tCo-morbidity\tGA (weeks)\tU/S\tAntibiotics\tAntibiotic indication\tSeptic\tPregnancy outcome\tFoetal complications\tAntenatal Complications\tMaternal Complications\tChild’s 6 week HIV PCR\t\n\n1\n\t37\t360\tLDL\tSJS\tNVP\t15\t4\tNone\t20+6\tN\tCef\tclinical\tno\tAlive, NVD, IOL for IUGR\tIUGR\tIUGR Chronic diarrhoea\tEye problems\tNeg\t\n\n2\n\t24\t887\t<40\tSJS\tEFV\t17\t9\tNone\t36\tN\t0\t0\tyes\tAlive, NVD\tnone\tNone\tNone\tNeg\t\n\n3\n\t34\t110\t1260\tSJS\tNVP\t15\t10\tNone\t37+1\tN\tCotrimox; Metroni\tclinical\tyes\tAlive, C/S for high VL\tnone\tNone\tNone\tNeg\t\n\n4\n\t33\t133\t<40\tSJS\tNVP\t22\t4\tNone\t29+3\tN\t0\t0\tyes\tAlive, NVD\tnone\tNone\tNone\tneg\t\n\n5\n\t28\t340\t<40\tSJS\tNVP\t19\t3\tNone\t23+2\tN\t0\t0\tno\tAlive, C/S\tnone\tNone\tNone\tUNK\t\n\n6\n\t32\t1213\tLDL\tSJS\tNVP\t15\t2\tPneumonia\t13\tND\tAmoxyl\tclinical\tno\tAlive, UNK\tUNK\tUNK\tUNK\tUNK\t\n\n7\n\t36\t26\tUNK \tSJS\tNVP\t8\t6\tNone\t24\tN\t0\t0\tyes\tDead, NVD, IOL for IUD\tIUD\tHerpes Simplex\tPostpartum Sepsis\tN/A\t\n\n8\n\t33\t236\tLDL\tSJS\tNVP\t10\t4\tpre-eclampsia\t32+6\tN\tClinda\tclinical\tno\tAlive, C/S for preeclampsia\tnone\tPre-eclampsia\tUNK\tNeg\t\n\n9\n\t30\tUNK\tUNK \tSJS\tNVP\t26\t1\tNone\t34\tND\tAmoxyl, Augmentin\tLRTI\tno\tUNK\tUNK\tUNK\tUNK\tUNK\t\n\n10\n\t26\t162\tUNK \tTEN\tNVP\t14\t7\tNone\t32\tN\tAmpi, Metroni, Erta, Amik\tclinical; LRTI; URTI\tno\tAlive, C/S for foetal distress\tBirth asphyxia LBW\tRLL pneumonia\tUNK\tNeg\t\n\n11\n\t25\t521\tUNK \tTEN\tNVP\t13\t3\tNone\t8\tND\tCef, Erythro, Augmentin,Amoxyl\tclinical\tno\tUNK\tUNK\tUNK\tUNK\tUNK\t\n\n12\n\t28\t622\tUNK \tSJS\tNVP\t22\t6\tNone\t25\tND\t0\t0\tno\tAlive, NVD\tnone\tUNK\tDyspareunia\tNeg\t\n\n13\n\t30\t712\tLDL\tTEN\tNVP\tUNK\t3\tNone\tPost-partum\tN\tClinda\tclinical\tno\tAlive, C/S for foetal distress\tcongenital pneumonia\tnone\tUNK\tNeg\t\n\n14\n\t24\t203\t<40\tSJS\tNVP\t15\t4\tNone\t29+3\tN\tAmpi, Cef\tclinical\tno\tAlive C/S for high VL\tnone\tLiver impairment\tUNK\tNeg\t\n\n15\n\t23\t224\tLDL\tSJS\tNVP\t18\t7\tNone\t14+1\tN\t0\t0\tno\tAlive C/S for foetal distress\tFailed IOL\tnone\tPostpartum sepsis\tUNK\t\n\n16\n\t34\t291\tUNK \tSJS\tNVP\t24\t3\tNone\t23\tND\tClinda\tclinical\tno\tAlive, NVD\tnone\tNone\tNone\tNeg\t\n\n17\n\t28\t242\tLDL\tSJS/TEN\tNVP\t19\t1\tNone\t27+1\tN\t0\t0\tno\tUNK\tUNK\tUNK\tUNK\tUNK\t\n\n18\n\t33\t349\t1.54\tSJS\tNVP\t14\t10\tNone\t11\tN\t0\t0\tno\tAlive C/S for foetal distress\trespiratory distress\tPre-eclampsia\tEye problems\tUNK\t\n\n19\n\t27\t348\tUNK \tSJS\tNVP\t12\t2\tNone\t16\tND\t0\t0\tno\tAlive, NVD\tNone\tUNK\tNone\tNeg\t\n\n20\n\t28\t228\t<40\tSJS\tNVP\t18\t4\tNone\t15+3\tN\t0\t0\tno\tAlive, NVD\tNone\tNone\tNone\tNeg\t\n\n21\n\t30\t342\tUNK\tTEN\tNVP\t1\t5\tNone\t21\tIUD\tVanco\t3\tno\tmiscarriage, medical TOP\tmiscarriage\tChorio-amnionitis\tPostpartum sepsis\tN/A\t\nKey: Amik: amikacin, Ampi: ampicillin, CADR: cutaneous adverse drug reaction, Cef: ceftriaxone, Clinda: clindamycin, Cotrimox: cotrimoxazole, C/S: caesarean section, EFV: efavirenz, Erta: ertapenem, Erythro: erythromycin, GA: gestational age, IOL: induction of labour, IUD: intra-uterine death, IUGR: intra-uterine growth restriction, LDL: lower than detectable limit, LRTI: lower respiratory tract infection, Metroni: metronidazole, N: normal, ND: not done, Neg: negative, NVP: Nevirapine, NVD: normal vertex delivery, RLL: right lower lobe, UNK: unknown, UTI: urinary tract infection, Vanco: vancomycin\n\nOutcomes of the pregnancy were known in 18/22 women. Seven of the eighteen pregnancies (39%) had a normal vertex delivery while 9/18 (50%) patients were delivered by caesarean section. Two of the eighteen pregnancies (11%) resulted in intrauterine deaths (Tables 1 and 2). Six of the nine caesarean sections were emergencies, the indications being foetal distress in three cases, increased maternal viral load in two cases and a case of worsening pre-eclampsia. The two foetal deaths were a second trimester miscarriage at 148 days (21+1 weeks) and the other an intrauterine foetal death at 217days (31 weeks). Both had non-viable birthweights of 330g and 580g respectively. The placenta to birthweight ratios were both 0.3, well within normal limits. The median gestation at delivery of the live births was 274 days (39weeks) (IQR: 265, 277) and the median birth weight was 2763g (IQR: 2378, 3241). Placental weights were available for 13/18 (72%) of the cases and the median placenta to foetal weight ratio was 0.18 (range 0.14–0.26) (Table 1). Apgar scores were available for 14/18 (78%) live births. The one minute score was 9 in 8/14 cases (57%), 8 in 2/14 (14%), 7 in 2/14 (14%) and 5 and 0 in 1/14 case each. At five minutes the Apgar scores were 10 for 10/14 (71%), 9 for 3/14 and 8 for single case. There were complications in 5/16 (31%) of the live deliveries. Three of the cases involved the respiratory system, namely birth asphyxia and congenital pneumonia. The other two cases were low birth weight babies weighing 1760g and 1950g respectively. Two of the five live birth complications occurred in mothers who had experienced TEN (2 and 15 days after the CADR). Three were associated with mothers who had had SJS. These complications however occurred more than 6weeks after the CADR (6weeks, 4months and 6months). Eight placentae and one foetus were sent for macroscopic and histological evaluation. No abnormalities of the placental surface, membranes, vasculature and chorionic villi were detected. The foetus showed no macroscopic or microscopic features of SJS/TEN.\n\nAll new-borns received prophylactic ARVs (nevirapine) until HIV status confirmation at 6 weeks post-delivery without incident. On follow-up, results of 6week HIV PCRs were only available for twelve of the twenty children. None of them were HIV-infected. Maternal CD4 counts at the time of pregnancy were available for ten of these twelve women, with the median being 262 cells/mm3 (IQR: 210,391). Viral loads were available for eight of the mothers of the children who were known to have been tested (Table 2). Seven of the mothers were adequately supressed, 4 <40 copies/ml in four and lower than the detectable limit in three. Two women were delivered by caesarean section for high maternal viral load, one with a viral load of 1260 copies/ml and the other with a presumed high viral load due to late start of ARV therapy but no viral load was documented prior to caesarean section.\n\nDiscussion\nIn this series of 22 consecutive women who developed SJS/TEN during their pregnancy, to our knowledge the largest published single centre experience, our main findings were: a) SJS/TEN-associated mortality is not increased in HIV-infected pregnant women b) maternal SJS/TEN does not manifest in the foetus c) SJS/TEN in pregnancy is not associated with intra-uterine HIV transmission.\n\nIt is well established that the incidence of SJS/TEN is increased in HIV-infected persons, however it is not clear if SJS/TEN-associated mortality is higher in this population. A literature review by Struck and colleagues suggested a high survival rate for the mother (24/28 survived, 1/28 died, 3/28 unknown outcome). Foetal survival was not as high (22/28 survived, 5/28 died, 1/28 unknown outcome).[14] Among our participants, maternal mortality was zero and none of the women required ICU admission. The zero maternal mortality was due to dedicated intensive nursing and supportive care without use of any immunomodulatory therapies. Foetal mortality was 2/18 (11%) documented pregnancy outcomes, marginally better than the 5/27 (19%) reported in the review. Our maternal and foetal mortality figures confirm and strengthen those reported in Struck and colleagues review as we report consecutive cases treated at a single centre following a standard treatment protocol. Due to the rarity of the disease and the small study population, it is difficult to quantify mortality associated with SJS/TEN in pregnant predominantly HIV-infected women. In our experience mortality was zero, with further possible explanations being that pregnant women have fewer co-morbidities and as a result are on less concomitant medications and they are younger. All were below the age of 40 years in our series, an age that is considered a low risk factor for mortality according to SCORTEN.[13] This is supported by comparison with larger reported series which showed comparatively lower mortality in children and younger cohorts. [5,8,12,20–26]\n\nThere have been previous reports of SJS/TEN manifesting in both the mother and the foetus when the disease occurs during pregnancy.[15] In our series of 22 consecutive patients none of the foetuses, both intrauterine deaths and live births, showed clinical features of SJS/TEN. This, taken together with existing English literature of only 1 published cases of mother and child being affected, suggests that foetal manifestation of SJS/TEN are rare during pregnancy.[15] Placenta-to-birth weight ratio (PWR) is variable and depends on numerous factors including race, gestational age, anaemia, maternal body mass, age, smoking and presence of pregnancy-related pathology.[27,28] PWR has been shown to be predictive of obstetrical outcomes as well as perinatal morbidity and mortality. PWR can be thought of as a balance between foetal and placental growth.[29] In this cohort of pregnant women the median PWR was within the normal ranges reported in the literature (mean 0.2 SD = 0.044, minimum 0.023, maximum 1.17).[29] A total of 8/22 placentas were examined histologically and no abnormalities were found. However, these histology findings should be interpreted with caution due to a significant possibility of a sampling error in assessing histological sections of such a large tissue mass. Despite this, it seems that SJS/TEN, although a severe maternal disease, does not have a significant impact on PWR and the physical structure of the placenta. The possible explanations include the relatively short duration of the SJS/TEN; onset of the disease late in pregnancy when the disease is less likely to have a sustained impact on PWR; and confinement of SJS/TEN to the mother, without direct involvement of the placenta and foetus. Larger studies, stratifying the study population based on the above-mentioned parameters, are needed to clarify the impact of SJS/TEN on PWR.\n\nA recent report of an uneventful normal vaginal delivery after a well monitored pregnancy following recovery from SJS highlights the importance of genital care in SJS/TEN.[30] In our cohort, none of the women developed clinically detectable labial, vulvar or vaginal adhesions on pelvic examination. This is likely to be a result of our routine practice of four times a day Sitz baths with separation and lubrication of apposed eroded mucosa surfaces in patients with genital lesions. Vaginal stenosis and labial synechiae result from adhesions of apposing denuded mucosal surfaces which results in fibrosis. Before this practice we had encountered a few cases of vaginal stenosis and fibrosis of the labia. No formal examination of the genito-urinary tract were performed on these patients, thus it is still possible we missed these well established sequelae of SJS/TEN, particularly in the cases delivered by caesarian section for foetal distress or other indications.[30–32]\n\nNevirapine was the most common offending drug in 21 of the 22 cases. The use of nevirapine in prevention of mother to child transmission of HIV (PMTCT) regimens during the study period was the major contributor to the higher incidence of nevirapine-associated SJS/TEN in this population. We expect a significant drop in the incidence of SJS/TEN with elimination of nevirapine from the ARV protocols that have recently been introduced in South Africa.\n\nAs a result of the small number of TEN cases and loss to follow up of these cases we could not establish that TEN, the more severe form of the disease, is associated with poorer foetal outcomes. Larger studies involving multiple centres are required to determine if severity of SJS/TEN impacts maternal and/or foetal outcomes in pregnant women.\n\nThere are several limitations to our study. Some of the patients delivered in secondary hospitals hence the loss to follow up and missing data. Another limitation of the study as with others on this subject is the small number of subjects in the study population precluding a meaningful statistical analysis. However, all the patients were consecutive and managed at a single center during the acute stage of SJS/TEN using similar protocols allowing for a cohesive assessment of the data.\n\nSummary\nWe describe clinical characteristics and outcomes of SJS/TEN in a series of consecutive HIV-infected pregnant women. We found that maternal mortality was not increased, probably lower, in this population compared to the general population. SJS/TEN did not affect the placenta and foetus directly. SJS/TEN did not increase the risk of HIV transmission to the foetus in mothers on ARV prophylaxis.\n==== Refs\nReferences\n1 \nRoujeau JC (1997 ) Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme . J Dermatol \n24 : 726 –729 .\n9433029 \n2 \nDodiuk-Gad RP , Laws PM , Shear NH (2014 ) Epidemiology of severe drug hypersensitivity . Semin Cutan Med Surg \n33 : 2 –9 .\n25037253 \n3 \nGeorge SM , Harrison DA , Welch CA , Nolan KM , Friedmann PS (2008 ) Dermatological conditions in intensive care: a secondary analysis of the Intensive Care National Audit and Research Centre (ICNARC) Case Mix Programme database . Crit Care 12 Suppl \n1 : S1 .\n4 \nRevuz J , Penso D , Roujeau JC , Guillaume JC , Payne CR , Wechsler J , et al (1987 ) Toxic epidermal necrolysis. Clinical findings and prognosis factors in 87 patients . Arch Dermatol \n123 : 1160 –1165 .\n3632000 \n5 \nSaka B , Barro-Traore F , Atadokpede FA , Kobangue L , Niamba PA , Adegbidi H , et al (2013 ) Stevens-Johnson syndrome and toxic epidermal necrolysis in sub-Saharan Africa: a multicentric study in four countries . Int J Dermatol \n52 : 575 –579 . 10.1111/j.1365-4632.2012.05743.x \n23330601 \n6 \nLimpawattana P , Choonhakarn C , Kongbunkiat K (2014 ) Clinical profiles of Stevens-Johnson syndrome among Thai patients . J Dermatol \n41 : 634 –637 . 10.1111/1346-8138.12499 \n24815085 \n7 \nKourouma S , Sangare A , Kaloga M , Kouassi I , Ecra E , Gbery I , et al (2014 ) [Stevens-Johnson syndrome and toxic epidermal necrolysis: retrospective study of 185 cases in Abidjan (Cote d'Ivoire) ]. Med Sante Trop \n24 : 94 –98 . 10.1684/mst.2013.0272 \n24736218 \n8 \nFinkelstein Y , Soon GS , Acuna P , George M , Pope E , Ito S , et al (2011 ) Recurrence and outcomes of Stevens-Johnson syndrome and toxic epidermal necrolysis in children . Pediatrics \n128 : 723 –728 . 10.1542/peds.2010-3322 \n21890829 \n9 \nFellahi A , Zouhair K , Amraoui A , Benchikhi H (2011 ) [Stevens-Johnson and Lyell syndromes: mucocutaneous and ocular sequels in 43 cases ]. Ann Dermatol Venereol \n138 : 88 –92 . 10.1016/j.annder.2010.10.029 \n21333817 \n10 \nOplatek A , Brown K , Sen S , Halerz M , Supple K , Gamelli RL (2006 ) Long-term follow-up of patients treated for toxic epidermal necrolysis . J Burn Care Res \n27 : 26 –33 .\n16566534 \n11 \nChung WH , Hung SI , Hong HS , Hsih MS , Yang LC , Ho HC , et al (2004 ) Medical genetics: a marker for Stevens-Johnson syndrome . Nature \n428 : 486 \n15057820 \n12 \nSekula P , Dunant A , Mockenhaupt M , Naldi L , Bouwes Bavinck JN , Halevy S , et al (2013 ) Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis . J Invest Dermatol \n133 : 1197 –1204 . 10.1038/jid.2012.510 \n23389396 \n13 \nBastuji-Garin S , Fouchard N , Bertocchi M , Roujeau JC , Revuz J , Wolkenstein P (2000 ) SCORTEN: a severity-of-illness score for toxic epidermal necrolysis . J Invest Dermatol \n115 : 149 –153 .\n10951229 \n14 \nStruck MF , Illert T , Liss Y , Bosbach ID , Reichelt B , Steen M (2010 ) Toxic epidermal necrolysis in pregnancy: case report and review of the literature . J Burn Care Res \n31 : 816 –821 . 10.1097/BCR.0b013e3181eed441 \n20671561 \n15 \nRodriguez G , Trent JT , Mirzabeigi M , Zaulyanov L , Bruce J , Vincek V (2006 ) Toxic epidermal necrolysis in a mother and fetus . J Am Acad Dermatol \n55 : S96 –98 .\n17052547 \n16 \nDube N , Adewusi E , Summers R (2013 ) Risk of nevirapine-associated Stevens-Johnson syndrome among HIV-infected pregnant women: the Medunsa National Pharmacovigilance Centre, 2007–2012 . S Afr Med J \n103 : 322 –325 .\n23971123 \n17 \nNiemeijer IC , van Praag MC , van Gemund N (2009 ) Relevance and consequences of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in gynecology . Arch Gynecol Obstet \n280 : 851 –854 . 10.1007/s00404-009-1008-1 \n19277691 \n18 Statistics South Africa (2011) Midyear population estimates.\n19 \nWorld Medical A (2013 ) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects . JAMA \n310 : 2191 –2194 . 10.1001/jama.2013.281053 \n24141714 \n20 \nKannenberg SM , Jordaan HF , Koegelenberg CF , Von Groote-Bidlingmaier F , Visser WI (2012 ) Toxic epidermal necrolysis and Stevens-Johnson syndrome in South Africa: a 3-year prospective study . QJM \n105 : 839 –846 . 10.1093/qjmed/hcs078 \n22543685 \n21 \nWetter DA , Camilleri MJ (2010 ) Clinical, etiologic, and histopathologic features of Stevens-Johnson syndrome during an 8-year period at Mayo Clinic . Mayo Clin Proc \n85 : 131 –138 . 10.4065/mcp.2009.0379 \n20118388 \n22 \nSaka B , Kombate K , Mouhari-Toure A , Akakpo S , Tchangai-Walla K , Pitche P (2010 ) [Stevens-Johnson syndrome and toxic epidermal necrolysis in a teaching hospital in Lome, Togo: retrospective study of 89 cases ]. Med Trop (Mars) \n70 : 255 –258 .20734593 \n23 \nKoh MJ , Tay YK (2010 ) Stevens-Johnson syndrome and toxic epidermal necrolysis in Asian children . J Am Acad Dermatol \n62 : 54 –60 . 10.1016/j.jaad.2009.06.085 \n19811851 \n24 \nMittmann N , Knowles SR , Koo M , Shear NH , Rachlis A , Rourke SB (2012 ) Incidence of toxic epidermal necrolysis and Stevens-Johnson Syndrome in an HIV cohort: an observational, retrospective case series study . Am J Clin Dermatol \n13 : 49 –54 . 10.2165/11593240-000000000-00000 \n22145749 \n25 \nKnight L , Muloiwa R , Dlamini S , Lehloenya RJ (2014 ) Factors associated with increased mortality in a predominantly HIV-infected population with Stevens Johnson syndrome and toxic epidermal necrolysis . PLoS One \n9 : e93543 \n10.1371/journal.pone.0093543 \n24695805 \n26 \nGarcia-Doval I , LeCleach L , Bocquet H , Otero XL , Roujeau JC (2000 ) Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? \nArch Dermatol \n136 : 323 –327 .\n10724193 \n27 \nPerry IJ , Beevers DG , Whincup PH , Bareford D (1995 ) Predictors of ratio of placental weight to fetal weight in multiethnic community . BMJ \n310 : 436 –439 .\n7873949 \n28 \nWilliams LA , Evans SF , Newnham JP (1997 ) Prospective cohort study of factors influencing the relative weights of the placenta and the newborn infant . BMJ \n314 : 1864 –1868 .\n9224128 \n29 \nMacdonald EM , Koval JJ , Natale R , Regnault T , Campbell MK (2014 ) Population-based placental weight ratio distributions . Int J Pediatr \n2014 : 291846 \n10.1155/2014/291846 \n24895497 \n30 \nKratzert K , Marks F , Antoine C , Brescia RJ , Parodneck L , Young BK (1988 ) Pregnancy post-Stevens-Johnson syndrome: case report and review of the literature . Obstet Gynecol \n72 : 447 –450 .\n3043292 \n31 \nPliskow S (2013 ) Severe gynecologic sequelae of Stevens-Johnson syndrome and toxic epidermal necrolysis caused by ibuprofen: a case report . J Reprod Med \n58 : 354 –356 .\n23947089 \n32 \nRowan DM , Jones RW , Oakley A , de Silva H (2010 ) Vaginal stenosis after toxic epidermal necrolysis . J Low Genit Tract Dis \n14 : 390 –392 . 10.1097/LGT.0b013e3181ddf5da \n20885170\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "10(8)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D019380:Anti-HIV Agents; D005260:Female; D005333:Fetus; D015658:HIV Infections; D006801:Humans; D019829:Nevirapine; D011247:Pregnancy; D011256:Pregnancy Outcome; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0135501",
"pmc": null,
"pmid": "26267659",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "24736218;10724193;17052547;24695805;19811851;23330601;9433029;3632000;25037253;23971123;19105799;16566534;15057820;21333817;9224128;3043292;20885170;20671561;19277691;20118388;10951229;24141714;20734593;7873949;23389396;22543685;21890829;24815085;24895497;23947089;22145749",
"title": "Stevens Johnson Syndrome and Toxic Epidermal Necrolysis: Maternal and Foetal Outcomes in Twenty-Two Consecutive Pregnant HIV Infected Women.",
"title_normalized": "stevens johnson syndrome and toxic epidermal necrolysis maternal and foetal outcomes in twenty two consecutive pregnant hiv infected women"
} | [
{
"companynumb": "ZA-PRINSTON PHARMACEUTICAL INC.-2015PRN00120",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
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"drugaddit... |
{
"abstract": "There is no global consensus on the optimal management of bone metastases (BMs) in neuroendocrine neoplasms (NENs).\n\n\n\nTo review current management and outcomes of patients with BMs in NENs, in order to identify areas for improvement.\n\n\n\nA retrospective study of all patients with NENs, except Grade 3 lung NENs (April 2002 to March 2018) was conducted. Baseline characteristics, nature of BMs, treatment received and overall survival (OS) were evaluated. Statistical analyses were performed using SPSS version 23.0/STATA v12.\n\n\n\nOf 1,212 patients, 85 (7%) had BMs; median age 58 years. The majority had a gastro-entero-pancreatic primary (49%, n = 42) followed by lung (25%, n = 21), unknown primary (20%, n = 17), and \"others\" (6%, n = 5). Two-thirds (n = 57) had G1-2 neuroendocrine tumours, and 41% (n = 35) had functional tumours. Overall, 28% (n = 24) presented with synchronous BMs at first NEN diagnosis, and 55% (n = 47) developed BMs at the same time as other distant metastases. For the subpopulation of patients in whom BMs developed metachronously to other distant metastases (45%, n = 38), median time to development of BMs was 14.0 months. BMs were \"widespread\" in 61% (n = 52). Although only 22% (n = 19) reported symptoms at initial diagnosis of BMs, most (78%) developed symptoms at some time during the follow-up period (pain/hypercalcaemia 64%, skeletal-related events 20%). BMs were mainly managed with analgesia (44%, n = 37). Radiotherapy and bisphosphonates were used in 34% (n = 29) and 22% (n = 19) respectively. Surgery was rarely performed (2%, n = 2). Median OS from identification of BMs was 31.0, and 18.9 months from development of BMs-related symptoms.\n\n\n\nIn this cohort study, most patients with BMs developed symptoms. The utility of radiotherapy and/or bisphosphonates should be prospectively and systematically explored further for its potential impact on patients' quality of life and survival outcomes.",
"affiliations": "Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom, angela.lamarca@christie.nhs.uk.",
"authors": "Lim|Kok Haw Jonathan|KHJ|;Raja|Hussain|H|;D'Arienzo|Paolo|P|;Barriuso|Jorge|J|;McNamara|Mairéad G|MG|;Hubner|Richard A|RA|;Mansoor|Wasat|W|;Valle|Juan W|JW|;Lamarca|Angela|A|",
"chemical_list": "D004164:Diphosphonates",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000504256",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3835",
"issue": "110(7-8)",
"journal": "Neuroendocrinology",
"keywords": "Bisphosphonates; Bone metastases; Hypercalcaemia; Palliative radiotherapy; Skeletal-related events; Survival",
"medline_ta": "Neuroendocrinology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms; D015331:Cohort Studies; D003695:Delivery of Health Care; D004164:Diphosphonates; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009382:Neoplasms, Unknown Primary; D018358:Neuroendocrine Tumors; D010166:Palliative Care; D010818:Practice Patterns, Physicians'; D011379:Prognosis; D058996:Quality Improvement; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D006113:United Kingdom",
"nlm_unique_id": "0035665",
"other_id": null,
"pages": "688-696",
"pmc": null,
"pmid": "31639796",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Identification of Areas for Improvement in the Management of Bone Metastases in Patients with Neuroendocrine Neoplasms.",
"title_normalized": "identification of areas for improvement in the management of bone metastases in patients with neuroendocrine neoplasms"
} | [
{
"companynumb": "GB-AMGEN-GBRSP2020127609",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Atypical anti-glomerular basement membrane (GBM) nephritis is a rare variant of the classical anti-GBM antibody disease. Patients present with an undetectable anti-GBM antibody but show linear glomerular basement membrane staining for immunoglobulin. We present a 69-year-old man who underwent a living-donor kidney transplant. The aetiology of the renal failure was a focal segmental glomerulonephritis-like lesion resistant to immunosuppressive therapy. A renal graft biopsy revealed diffuse endocapillary hypercellularity, and mild mesangiolysis with linear GBM staining for IgG. The patient was diagnosed with atypical anti-GBM nephritis since the patient tested negative for circulating anti-GBM antibodies. Treatment involved intravenous methylprednisolone, plasma exchange, and rituximab administration. Protocol graft biopsy performed 1 year after the renal transplant showed a focal segmental glomerulonephritis-like lesion possibly progressing from endocapillary hypercellularity and mesangiolysis. These findings were similar to his native kidney biopsy findings. Although classical recurrent anti-GBM nephritis is rare when a renal transplant is performed after decreased disease activity, this case was considered as a case of recurrent atypical anti-GBM nephritis after renal transplant.",
"affiliations": "Department of Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan, isobe58@hama-med.ac.jp.;Department of Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan.;Department of Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan.;Department of Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan.;Department of Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan.;Department of Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan.;Department of Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan.;Department of Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan.;Department of Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan.;Department of Kidney Disease Center, Nagoya Daini Red Cross Hospital, Nagoya, Japan.",
"authors": "Isobe|Shinsuke|S|;Tomosugi|Toshihide|T|;Futamura|Kenta|K|;Okada|Manabu|M|;Hiramitsu|Takahisa|T|;Tsujita|Makoto|M|;Narumi|Shunji|S|;Goto|Norihiko|N|;Takeda|Asami|A|;Watarai|Yoshihiko|Y|",
"chemical_list": "D001323:Autoantibodies; C051951:antiglomerular basement membrane antibody",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000511625",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1660-8151",
"issue": "144 Suppl 1()",
"journal": "Nephron",
"keywords": "Anti-GBM antibody disease; Atypical anti-GBM nephritis; De novo glomerulonephritis; Focal segmental glomerulosclerosis; Kidney transplantation",
"medline_ta": "Nephron",
"mesh_terms": "D000368:Aged; D019867:Anti-Glomerular Basement Membrane Disease; D001323:Autoantibodies; D001706:Biopsy; D006801:Humans; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D009393:Nephritis; D011183:Postoperative Complications; D012008:Recurrence",
"nlm_unique_id": "0331777",
"other_id": null,
"pages": "49-53",
"pmc": null,
"pmid": "33238273",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A Case of Recurrent Atypical Anti-Glomerular Basement Membrane Nephritis Suspicion after Renal Transplantation.",
"title_normalized": "a case of recurrent atypical anti glomerular basement membrane nephritis suspicion after renal transplantation"
} | [
{
"companynumb": "JP-MYLANLABS-2021M1013855",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIZORIBINE"
},
"drugadditional": "3",
... |
{
"abstract": "Bleeding occurs with some regularity at the end of life. Patients often endure fatigue, weakness, pain, dyspnea and anxiety. These symptoms are magnified in visually apparent bleeds. Management can be particularly challenging as we attempt to balance therapies with goals of care. Children are at risk for such complications and symptoms; providers must ensure comfort for both the patient and family.\nA 7-year-old male with recurrent, refractory Burkitt lymphoma was frequently hospitalized for palliative chemotherapy and disease complications. On his final admission, he experienced gross hemoptysis and hematemesis: he was short of breath, fatigued and anxious due to his blood loss. His and his family's angst were heightened by \"seeing\" his bleed. Potential, especially invasive, treatments were limited by our goals to promote comfort, limit interventions, maintain alertness, poor intravenous access and a small bowel obstruction. Nebulized vasopressin, 10 units in 4ml of normal saline given over 10 minutes provided JC with needed relief. His bleeding remitted and he tolerated its administration.\nThere are many treatments for hemorrhage; however, given the challenges of goals of care, administration, side-effects and tolerability, further investigation into nebulized vasopressin as a potential therapy for hemoptysis and hematemesis at the end-of-life is warranted.",
"affiliations": "Division of General Internal Medicine and Geriatrics, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.;Division of General Internal Medicine and Geriatrics, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.",
"authors": "Dulin|Jennifer D|JD|https://orcid.org/0000-0003-4793-4401;Coyne|Patrick J|PJ|",
"chemical_list": "D014662:Vasoconstrictor Agents; D014667:Vasopressins",
"country": "United States",
"delete": false,
"doi": "10.1177/0825859719883844",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0825-8597",
"issue": "35(2)",
"journal": "Journal of palliative care",
"keywords": "hematemesis; hemoptysis; nebulized; palliative; pediatric; vasopressin",
"medline_ta": "J Palliat Care",
"mesh_terms": "D000280:Administration, Inhalation; D002051:Burkitt Lymphoma; D002648:Child; D017809:Fatal Outcome; D006396:Hematemesis; D006469:Hemoptysis; D006801:Humans; D008297:Male; D010166:Palliative Care; D014662:Vasoconstrictor Agents; D014667:Vasopressins",
"nlm_unique_id": "8610345",
"other_id": null,
"pages": "71-74",
"pmc": null,
"pmid": "31680640",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nebulized Vasopressin for the Control of Hematemesis and Hemoptysis in a Child With Recurrent, Refractory Stage III Burkitt Lymphoma.",
"title_normalized": "nebulized vasopressin for the control of hematemesis and hemoptysis in a child with recurrent refractory stage iii burkitt lymphoma"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-286728",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"d... |
{
"abstract": "Acute mucocutaneous methotrexate toxicity is not classically associated with prominent tissue eosinophilia. We present a case of acute methotrexate toxicity associated with pancytopenia and mucocutaneous erosion with interface dermatitis and numerous eosinophils. A 79-year-old male, with a history of psoriasis vulgaris on methotrexate therapy, presented with blisters of the oral mucosa, groin, sacrum, and extremities after daily consumption of methotrexate. Examination revealed blisters and erosions localized to psoriatic plaques, the perineum, and the oral mucosa. Laboratory evaluation demonstrated pancytopenia, megaloblastic anemia, and elevated liver function tests. A skin biopsy of an eroded plaque revealed psoriasiform epidermal hyperplasia with epidermal erosion, parakeratosis, and loss of the granular cell layer. There was an underlying band-like lymphoid infiltrate with interface dermatitis, dyskeratotic keratinocytes, and numerous eosinophils. Direct immunofluorescence studies were negative for the deposition of immunoreactants. Methotrexate was held, and the patient received leucovorin resulting in improvement of blood counts and cutaneous lesions. The histopathologic changes associated with acute mucocutaneous toxicity have been described as pauci-inflammatory erosions associated with dyskeratotic keratinocytes to interface dermatitis with necrotic keratinocytes and occasionally associated eosinophils. Although these changes are most often superimposed on psoriatic plaques, they have been reported to occur on normal skin. Therefore, the differential diagnosis may include lichen planus, a lichenoid drug eruption, or a fixed drug eruption, and given the presence of mucosal ulceration, incipient pemphigus vulgaris or paraneoplastic pemphigus vulgaris. This case illustrates that acute mucocutaneous methotrexate toxicity may be associated with both interface dermatitis and numerous eosinophils.",
"affiliations": "Department of Dermatology, University of Iowa Hospital and Clinics, Iowa City, IA 52242, USA. nkanyezi-ferguson@uiowa.edu",
"authors": "Ferguson|Nkanyezi N|NN|;Asarch|Adam|A|;VanBeek|Marta|M|;Swick|Brian L|BL|",
"chemical_list": "D003879:Dermatologic Agents; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0b013e31827b7674",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "35(4)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D003879:Dermatologic Agents; D003937:Diagnosis, Differential; D003875:Drug Eruptions; D004802:Eosinophilia; D006801:Humans; D008297:Male; D008727:Methotrexate; D008856:Microscopy, Fluorescence; D009061:Mouth Mucosa; D010198:Pancytopenia; D011237:Predictive Value of Tests; D011565:Psoriasis; D012867:Skin",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "e63-6",
"pmc": null,
"pmid": "23221488",
"pubdate": "2013-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute mucocutaneous methotrexate toxicity associated with interface dermatitis and numerous eosinophils.",
"title_normalized": "acute mucocutaneous methotrexate toxicity associated with interface dermatitis and numerous eosinophils"
} | [
{
"companynumb": "US-ACCORD-105375",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nImmune reconstitution inflammatory syndrome (IRIS) related to tuberculosis (TB) is an exacerbation of an inflammatory response that most often occurs in HIV-infected patients but it has also been observed in non-HIV immunocompromised hosts. We describe two cases of TB associated IRIS with CNS involvement, one in a patient diagnosed with HIV infection and the other in a patient with immunosuppression due to anti tumor necrosis factor treatment. CASE REPORT; The first case was a 40-year-old man, newly diagnosed with HIV infection, who developed right hemiplegia and expressive aphasia. Lumbar puncture and MRI sustained the diagnosis of TB meningoencephalitis. He initially improved understandard antituberculous therapy (ATT). After 6 weeks of ATT antiretroviral treatment (ART) was initiated and one week later the patient experienced worsening of his symptoms (left hemiparesis and mixed aphasia), of CSF and MRI changes. He improved after he was starting on corticosteroids in tapering doses, with clinical deterioration at lower doses over a 5-month period. The second case was a 56-year-old male, treated for 3 years with Infliximab for ankylosing spondylitis. He was diagnosed with disseminated TB (CNS tuberculomas and pulmonary TB), histological and bacteriological confirmed the diagnosis. His neurological symptoms improved after starting ATT but after 2 weeks of therapy he presented with diplopia and generalized tonic-clonic seizures. These symptoms improved only after corticosteroids were added (tapering doses during the next 6 months).\n\n\nCONCLUSIONS\nTB-associated IRIS with CNS involvement is potentially life threatening. Corticosteroids should be used to control the IRIS symptoms in those patients. The dosing and duration should be tailored to each patient.",
"affiliations": null,
"authors": "Manea|Eliza|E|;Munteanu|Daniela|D|;Jipa|Raluca|R|;Moroti|Ruxandra|R|;Arama|Victoria|V|;Diaconu|Ioan-Alexandru|IA|;Hristea|Adriana|A|",
"chemical_list": "D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D005938:Glucocorticoids",
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2067-2993",
"issue": "64(4)",
"journal": "Pneumologia (Bucharest, Romania)",
"keywords": null,
"medline_ta": "Pneumologia",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D004359:Drug Therapy, Combination; D005938:Glucocorticoids; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013167:Spondylitis, Ankylosing; D016896:Treatment Outcome; D020306:Tuberculosis, Central Nervous System",
"nlm_unique_id": "100941067",
"other_id": null,
"pages": "32-6",
"pmc": null,
"pmid": "27451593",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Immune reconstitution inflammatory syndrome in central nervous system tuberculosis.",
"title_normalized": "immune reconstitution inflammatory syndrome in central nervous system tuberculosis"
} | [
{
"companynumb": "RO-JNJFOC-20160802624",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Phlegmonous gastritis (PG) is a nonspecific suppurative inflammation disease arising from the submucosal layer, and extending to the full thickness of the stomach. We herein report on a case of acute PG which was diagnosed with abdominal ultrasonography. A 64-year-old man presented at a hospital after having recently undergone pacemaker implantation for the treatment of complete atrioventricular block. He was admitted as an emergency due to a fever of 39 degrees C. He showed anorexia, epigastralgia, vomiting of coffee-ground emesis on the second hospital day, and abdominal ultrasonography (AUS) performed on the third hospital day showed the disappearance of the normal laminated structure and hypoechoic thickening of the stomach walls. Upper gastrointestinal endoscopy revealed significant hyperplasia of the stomach walls, an erythrogenic mucosa, and poor extension. On the fourth hospital day, computed tomography revealed concentric thickening of the stomach walls. Streptococcus pyogenes was cultured from his blood sample. Based on those findings, the patient was diagnosed as having acute phlegmonous gastritis. His clinical symptoms improved and the abnormal ultrasonographic examination findings thereafter returned to normal following the administration of antibiotics. PG should therefore be included in the differential diagnosis when encountering patients with acute abdomen. We experienced a rare case of acute phlegmonous gastritis and AUS was useful for making an early diagnosis.",
"affiliations": null,
"authors": "Odai|Tsuyoshi|T|;Hibino|Takenori|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.11150/kansenshogakuzasshi.90.113",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0387-5911",
"issue": "90(2)",
"journal": "Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases",
"keywords": null,
"medline_ta": "Kansenshogaku Zasshi",
"mesh_terms": "D000005:Abdomen; D000208:Acute Disease; D002481:Cellulitis; D005756:Gastritis; D006801:Humans; D008297:Male; D008875:Middle Aged; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography",
"nlm_unique_id": "0236671",
"other_id": null,
"pages": "113-9",
"pmc": null,
"pmid": "27197437",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The Abdominal Ultrasonographic Appearance of Acute Phlegmonous Gastritis.",
"title_normalized": "the abdominal ultrasonographic appearance of acute phlegmonous gastritis"
} | [
{
"companynumb": "JP-BAYER-2016-113266",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "A woman in her mid-50s contacted her social worker and expressed intent to commit suicide by ingesting prescription medications. On arrival of emergency responders, the patient was found unconscious with an empty bottle of amitriptyline. Time of ingestion was estimated using the social worker's contact with local authorities. The patient's presentation at the emergency department (ED) exemplified tricyclic antidepressant toxidrome with a poor prognosis, based on measurable criteria and physical findings. Respiratory and cardiovascular collapse was managed emergently. Haemodynamic status and EKG findings responded in a stepwise fashion with therapy in the ED and intensive care unit. Full clinical recovery took 7 days, and the patient was subsequently transferred to an in-patient psychiatric facility for further evaluation. Eight days later, she was discharged home with no neurological sequelae.",
"affiliations": "Emergency Medicine Residency Program-Baton Rouge, Louisiana State University Health Sciences Center School of Medicine in New Orleans, Baton Rouge, Louisiana, USA.;Emergency Medicine Residency Program-Baton Rouge, Louisiana State University Health Sciences Center School of Medicine in New Orleans, Baton Rouge, Louisiana, USA.;Emergency Medicine Residency Program-Baton Rouge, Louisiana State University Health Sciences Center School of Medicine in New Orleans, Baton Rouge, Louisiana, USA.",
"authors": "Clark|Simon|S|;Catt|Jerry W|JW|;Caffery|Terrell|T|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D000639:Amitriptyline",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000639:Amitriptyline; D000929:Antidepressive Agents, Tricyclic; D005260:Female; D006801:Humans; D008875:Middle Aged; D013406:Suicide, Attempted",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26468220",
"pubdate": "2015-10-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24505046;9377889;21436332;15533027;22226400;3706169;17695569;16390222;23699975;12974977;19698905;17200994",
"title": "Rapid diagnosis and treatment of severe tricyclic antidepressant toxicity.",
"title_normalized": "rapid diagnosis and treatment of severe tricyclic antidepressant toxicity"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-108267",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMITRIPTYLINE"
},
"d... |
{
"abstract": ": Due to their ease of use, the direct oral anticoagulants (DOACs) are an attractive treatment option for cancer-associated venous thromboembolism (VTE) and have been readily adopted by many clinicians. A recent published study comparing a DOAC (edoxaban) to the current standard-of-care low molecular weight heparin dalteparin for the treatment of cancer-associated thrombosis showed that edoxaban was noninferior to dalteparin for recurrent VTE, but the risk of major bleeding was higher. We present three patients with high-risk gastrointestinal malignancies complicated by cancer-associated VTE with progression of thrombosis while treated with the oral direct Xa inhibitor rivaroxaban. Upon switching therapy to low molecular weight heparin, we found that these patients had clinical and radiologic improvement of VTE. More studies are needed to evaluate the efficacy of rivaroxaban in high-risk gastrointestinal-VTE. We suggest that in some patients, DOACs may not be sufficient for the treatment of VTEs related to high-risk gastrointestinal malignancies.",
"affiliations": "Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, USA.",
"authors": "Choe|Hannah K|HK|;De Sancho|Maria T|MT|;Kim|Sunnie S|SS|;Dai|Tong|T|;Shah|Manish A|MA|",
"chemical_list": "D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; D000069552:Rivaroxaban",
"country": "England",
"delete": false,
"doi": "10.1097/MBC.0000000000000704",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0957-5235",
"issue": "29(2)",
"journal": "Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis",
"keywords": null,
"medline_ta": "Blood Coagul Fibrinolysis",
"mesh_terms": "D000368:Aged; D065427:Factor Xa Inhibitors; D005260:Female; D005770:Gastrointestinal Neoplasms; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D008297:Male; D008875:Middle Aged; D000069552:Rivaroxaban; D054556:Venous Thromboembolism",
"nlm_unique_id": "9102551",
"other_id": null,
"pages": "227-230",
"pmc": null,
"pmid": "29389673",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Low molecular weight heparin versus rivaroxaban in the treatment of venous thromboembolism in gastrointestinal malignancies.",
"title_normalized": "low molecular weight heparin versus rivaroxaban in the treatment of venous thromboembolism in gastrointestinal malignancies"
} | [
{
"companynumb": "US-JNJFOC-20180313688",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": "1",
... |
{
"abstract": "Takotsubo cardiomyopathy typically presents in menopausal women following episodes of intense physical or mental stress. To our knowledge, the literature contains only two documented cases of Takotsubo cardiomyopathy arising following a suicide attempt, neither of which involved pharmaceutical poisoning. Here, however, we document the case of a young male patient with borderline personality disorder and a clinical and angiographic presentation compatible with Takotsubo cardiomyopathy arising following a suicide attempt by voluntary drug intoxication (risperidone, barbiturates, and benzodiazepine). The potential pathophysiological mechanisms behind this unusual clinical picture are discussed.",
"affiliations": "Department of Cardiology, Vigevano Hospital, Corso Milano 19, 27029 Vigevano, Italy.",
"authors": "Romanò|Massimo|M|;Zorzoli|Federica|F|;Bertona|Roberta|R|;Villani|Rosvaldo|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2013/946378",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIM.MEDICINECase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2013/946378Case ReportTakotsubo Cardiomyopathy as an Early Complication of Drug-Induced Suicide Attempt Romanò Massimo *Zorzoli Federica Bertona Roberta Villani Rosvaldo Department of Cardiology, Vigevano Hospital, Corso Milano 19, 27029 Vigevano, Italy*Massimo Romanò: max.romano51@gmail.comAcademic Editor: Tian Po Oei\n\n2013 14 11 2013 2013 94637828 7 2013 16 9 2013 Copyright © 2013 Massimo Romanò et al.2013This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Takotsubo cardiomyopathy typically presents in menopausal women following episodes of intense physical or mental stress. To our knowledge, the literature contains only two documented cases of Takotsubo cardiomyopathy arising following a suicide attempt, neither of which involved pharmaceutical poisoning. Here, however, we document the case of a young male patient with borderline personality disorder and a clinical and angiographic presentation compatible with Takotsubo cardiomyopathy arising following a suicide attempt by voluntary drug intoxication (risperidone, barbiturates, and benzodiazepine). The potential pathophysiological mechanisms behind this unusual clinical picture are discussed.\n==== Body\n1. Introduction\nTakotsubo syndrome, or stress-induced cardiomyopathy, manifests as a transitory dysfunction of the left ventricle, whose characteristic angiographic appearance is known as apical ballooning. It mimics the symptoms and electrocardiographic appearance of acute myocardial infarction, generally with ST segment elevation but without any significant signs of coronary lesions under angiography. Its pathogenesis is probably secondary to a damage to the myocytes mediated by the catecholamines and microvascular dysfunction [1].\n\nOver recent years, increasing numbers of cases, arising in various circumstances of physical or mental stress, have been described in the literature. Nonetheless, only two reported cases brought on following a suicide attempt have been documented, one following the consumption of herbicide [2] and the other by hanging [3]. To our knowledge, this is the first reported case of Takotsubo cardiomyopathy arising following a suicide attempt by ingestion of psychotropic drugs. \n\n2. Case Report\nA 40-year-old male with type 2 diabetes mellitus and obesity (110 kg, 172 cm, and BMI 37.2) who underwent a biliodigestive bypass in 2011 was brought in a comatose state to our accident and emergency department by the emergency services. This followed a suicide attempt, attested to by a note addressed to family members, by ingestion of phenobarbital, risperidone, lorazepam, clotiazepam, and bisoprolol. The patient was already known to the mental health services as a sufferer of borderline personality disorder and was being treated with 5 mg/day olanzapine.\n\nTests conducted on the patient in accident and emergency confirmed the comatose state, Glasgow Coma Scale 5, and revealed an arterial pressure of 110/80 mmHg, heart rate 80 bpm, and oxygen saturation at 94%, with an oxygen mask set at 6 L/min. Arterial blood gas analysis showed respiratory acidosis, and the patient was fitted with a nasogastric tube and orotracheal intubation. ECG showed anterolateral ST elevation (Figure 1), while an echocardiogram showed normal ventricular chamber dimensions, apical akinesis, and a slight overall reduction in contractile function of the left ventricle (ejection fraction 0.50). The patient therefore underwent emergency coronary angiogram, which revealed normal coronary arteries (Figure 2). Left ventriculography confirmed the marked apical hypokinesis (Figure 3).\n\nThe patient, still on mechanical ventilation, was moved to our intensive care unit, where his haemodynamic status remained stable. Toxicological examination revealed high serum concentrations of phenobarbital (50 mcg/mL, normal values 10–40 mcg/L) and risperidone (149 mcg/mL, normal values < 100 mcg/mL), and concentrations of lorazepam and clotiazepam within the normal range. Myocardial damage markers were not significantly elevated (troponin T Hs 15 pg/mL, normal values < 11 pg/mL). \n\nThe patient was treated with ramipril by the oral route, starting on 5 mg/day and rising incrementally up to 10 mg/day. Treatment was completed with bisoprolol at 1.25 mg/day, together with aspirin 100 mg and enoxaparin 6000 U twice daily.\n\nOn the third day, the breathing tube was removed and the haemodynamic status remained stable at AP 140/80 mmHg, heart rate 74/bpm. The patient was therefore transferred to our Intensive Coronary Care Unit, where he recovered with no complications, and his electrocardiogram returned to normal (Figure 4). \n\nEchocardiography performed on the sixth day of hospitalization showed that the segmental kinesis had returned to normal, with ejection fraction 0.70. On the seventh day, the patient was transferred to the psychiatric unit, from which he was discharged after 10 days. \n\n3. Discussion\nTakotsubo syndrome was first described by Sato et al. in 1990 [4], who named it after the morphology, peculiar to this condition, of the left ventricle, whose apex takes on the appearance of a balloon with a narrow neck, a shape reminiscent of the basket used by Japanese fishermen to catch octopi. Over the years, cases of stress-induced dysfunction of the left ventricle with alterations in the kinesis of the anterolateral segments but normal contractile apex have also been described [5]. \n\nAccording to a large survey in the USA [6], the prevalence of Takotsubo cardiomyopathy was 0.02% of all hospital admissions in the USA in 2008. The majority of these cases were seen in middle-aged women with a history of smoking, excess alcohol consumption, states of anxiety, and hyperlipidaemia. The in-hospital mortality is reported as roughly 4.2% [7]. \n\nThe pathophysiological mechanisms behind Takotsubo syndrome are still the object of discussion, although a multifactorial origin is the most popular theory. That being said, alterations in the coronary microcirculation, vasospasm, neurogenic stunning caused by acute autonomic dysfunction, and catecholaminergic cardiotoxicity have all been implicated [8–11]. This latter hypothesis is supported by cases of left ventricular dysfunction in patients with pheochromocytoma [10], but not all studies have shown high blood levels of noradrenaline. It is therefore possible that the density and activity of beta-adrenergic receptors play a role in the left ventricular dysfunction. \n\nNumerous studies have also shown correlations between several psychiatric illnesses and a high incidence of cardiovascular events [11]. In particular, psychiatric disturbances associated with anxiety and posttraumatic stress seem to have a greater correlation with cardiovascular events than depressive disorders. A higher-than-normal incidence of cardiovascular events has also been correlated with personality disorders [12], like the borderline patient described here, a 40-year-old male receiving neuroleptic treatment. It is likely that common underlying pathophysiological mechanisms such as sympathetic nervous system alterations, reduced heart rate variability, altered platelet function and an increase in pro-inflammatory processes play a role in Takotsubo onset. Furthermore, the catecholaminergic system is also the most affected following exposure to trauma [13].\n\nIt has been observed, in a large retrospective study of Takotsubo syndrome patients, a higher prevalence of depression, compared with a group of patients with acute anterior myocardial infarction [14]. Nevertheless, 4 cases of Takotsubo syndrome associated with an exacerbation of psychiatric illness have been described in the literature, all in women aged between 53 and 67 years. Respectively, these women had a diagnosis of Alzheimer's with psychotic features, adjustment disorder, major depressive disorder, and type 1 bipolar disorder [15]. \n\nThere are, however, only two previous cases of Takotsubo syndrome arising following a suicide attempt reported in the literature, one by glufosinate ammonium herbicide intoxication [2] and the second by hanging [3]. We hypothesize that in our patient, the only known documented case arising following attempted suicide by psychiatric drug ingestion, Takotsubo cardiomyopathy may have been triggered by an exacerbation of his psychiatric illness, which features high baseline levels of catecholamines that could have been further elevated by the stress experienced during the suicide attempt.\n\nConflict of Interests\nThe authors declare no conflicts of interests.\n\nAcknowledgment\n The authors kindly thank the patient, Mr. M. N., for his permission to report this clinical case. \n\nFigure 1 ECG on admission, showing anterolateral ST segment elevation.\n\nFigure 2 Left (a) and right (b) coronary arteries, without significant coronary lesions.\n\nFigure 3 Left ventriculography in diastole (a) and systole (b), showing the apical hypokinesis.\n\nFigure 4 ECG at discharge, showing normal ST segment.\n==== Refs\n1 Milinis K Fisher M Takotsubo cardiomyopathy: pathophysiology and treatment Postgraduate Medical Journal 2012 88 530 538 22647668 \n2 Keichiro T Manabu I Masayuki S Takotsubo cardiomyopathy as a delayed complication with a herbicide containing glufosinate ammonium in a suicide attempt: a case report Case Reports in Medicine 2012 2012 3 pages 630468 \n3 Gnanavelu G Sathiakumar DBD Reversible left ventricular dysfunction in suicidal hanging Journal of Association of Physicians of India 2008 56 545 546 2-s2.0-48849092754 18846910 \n4 Sato H Tateishi H Uchida T Kodama K Haze K Hori M Tako-tsubo-like left ventricular dysfunction due to multivessel coronary spasm Clinical Aspect of Myocardial Injury: From Ischemia to Heart Failure 1990 Tokyo, Japan Kagakuhyoronsha Publishing 56 64 \n5 Mazzarotto P Stecconi P Gemelli F Azzarito M Farnetti F A case of ballooning syndrome with atypical anterior localization Italian Heart Journal 2005 6 11 730 734 2-s2.0-33644809314 16318248 \n6 Deshmukh A Kumar G Pant S Prevalence of Takotsubo cardiomyopathy in the United States The American Heart Journal 2012 164 66 71 22795284 \n7 Brinjikji W El-Sayed AM Salka S In-hospital mortality among patients with takotsubo cardiomyopathy: a study of the National Inpatient Sample 2008 to 2009 The American Heart Journal 2012 164 215 221 22877807 \n8 Nishikawa S Ito K Adachi Y Katoh S Azuma A Matsubara H Ampulla (“Takotsubo”) cardiomyopathy of both ventricles: evaluation of microcirculation disturbance using 99mTc-tetrofosmin myocardial single photon emission computed tomography and Doppler guide wire Circulation Journal 2004 68 11 1076 1080 2-s2.0-9144269748 15502391 \n9 Wittstein IS Thiemann DR Lima JAC Neurohumoral features of myocardial stunning due to sudden emotional stress The New England Journal of Medicine 2005 352 6 539 548 2-s2.0-13444293219 15703419 \n10 Ganguly PK Beamish RE Dhalla NS Catecholamine cardiotoxicity in pheochromocytoma The American Heart Journal 1989 117 6 1399 1400 2-s2.0-0024686870 2729074 \n11 Kapfhammer H-P The relationship between depression, anxiety and heart disease: a psychosomatic challenge Psychiatria Danubina 2011 23 4 412 424 2-s2.0-82155191312 22075746 \n12 Newcomer JW Hennekens CH Severe mental illness and risk of cardiovascular disease Journal of the American Medical Association 2007 298 15 1794 1796 2-s2.0-35348960372 17940236 \n13 Southwick SM Krystal JH Morgan CA Abnormal noradrenergic function in posttraumatic stress disorder Archives of General Psychiatry 1993 50 4 266 274 2-s2.0-0027447306 8466387 \n14 Mudd JO Navin KK Hunter CC Patients with stress-induced (Takotsubo) cardiomyopathy have an increased prevalence of mood disorders and antidepressant use compared to patients with acute myocardial infarction Journal of Cardiac Failure 2007 13, article S176 supplement 6 \n15 Corrigan FE III Kimmel MC Jayaram G Four cases of takotsubo cardiomyopathy linked with exacerbations of psychiatric illness Innovations in Clinical Neuroscience 2011 8 7 50 53 2-s2.0-80052040683\n\n",
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"abstract": "Peripheral nerve blocks are often used for foot and ankle surgery. The occurrence of persistent neurological symptoms thereafter is very rare. Preventive strategies pose no guarantee and uncovering true etiology is often complicated. We discuss a case in which a young, healthy patient developed nerve damage after an uneventful popliteal block and cheilectomy. Nerve conduction studies revealed axonal injury in the distribution area of the sciatic nerve. The neurological symptoms persisted for more than 12 months, emotionally affecting the patient greatly. Patients will primarily report to the orthopedic surgeon, for whom cooperation with anaesthesia and neurology is of importance. Anesthetic involvement probably improves patient satisfaction during complication management.",
"affiliations": "Department of Anesthesia, Maxima Medical Centre, Veldhoven, Netherlands.;Department of Neurology, Maxima Medical Centre, Veldhoven, Netherlands.;Department of Anesthesia, Maxima Medical Centre, Veldhoven, Netherlands.",
"authors": "Kuijpers|Y A M|YAM|https://orcid.org/0000-0002-9297-6443;Setz|J M|JM|;Khemlani-Houthoff|K|K|",
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"fulltext": "\n==== Front\nCase Rep Anesthesiol\nCase Rep Anesthesiol\nCRIA\nCase Reports in Anesthesiology\n2090-6382\n2090-6390\nHindawi\n\n10.1155/2021/9942195\nCase Report\nAxonal Injury with Persistent Neuropathy following Popliteal Nerve Block for Cheilectomy Surgery\nhttps://orcid.org/0000-0002-9297-6443\nKuijpers Y. A. M. yvettekuijpers@gmail.com\n1\nSetz J. M. 2\nKhemlani-Houthoff K. 1\n1Department of Anesthesia, Maxima Medical Centre, Veldhoven, Netherlands\n2Department of Neurology, Maxima Medical Centre, Veldhoven, Netherlands\nAcademic Editor: Alparslan Apan\n\n2021\n5 7 2021\n2021 99421958 3 2021\n25 6 2021\nCopyright © 2021 Y. A. M. Kuijpers et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nPeripheral nerve blocks are often used for foot and ankle surgery. The occurrence of persistent neurological symptoms thereafter is very rare. Preventive strategies pose no guarantee and uncovering true etiology is often complicated. We discuss a case in which a young, healthy patient developed nerve damage after an uneventful popliteal block and cheilectomy. Nerve conduction studies revealed axonal injury in the distribution area of the sciatic nerve. The neurological symptoms persisted for more than 12 months, emotionally affecting the patient greatly. Patients will primarily report to the orthopedic surgeon, for whom cooperation with anaesthesia and neurology is of importance. Anesthetic involvement probably improves patient satisfaction during complication management.\n\nMaxima Medical Centre\n==== Body\n1. Introduction\n\nFoot and ankle surgery is often accompanied by peripheral nerve blocks (PNBs) for perioperative pain management. Long-term peripheral nerve injury (PNI) is an uncommon complication, but could be reported at postoperative check-up at the orthopedic outpatient clinic. Depending on definitions, the incidence for neurologic symptoms >6 months ranges from 0 to 0.7%, specifically for popliteal nerve blocks [1, 2]. Available literature states that perioperative nerve damage has a multifactorial etiology, with only one-third of the PNI actually associated with PNBs. For educational purposes, we describe a case in which postoperative neurological symptoms developed due to axonal injury. Additional literature on etiology, preoperative preventive strategies, and postoperative diagnostics is discussed. Most importantly, we emphasize the importance of a multidisciplinary approach, timely consulting the anaesthesiologist and neurologist in the postoperative course. The patient had provided written consent for the publication of the case.\n\n2. Case Description\n\nA woman in her late thirties, presented to the orthopedic outpatient clinic. Her history revealed a right-sided ankle trauma 5 years ago and a pulmonary embolism/deep venous thrombosis (DVT) while on oral contraceptives 17 years ago. Current consultation was for right-sided hallux rigidus, with metatarsophalangeal joint osteoarthritis. A cheilectomy was planned. She was considered ASA II status and currently did not use any medication. The anesthetic plan consisted of general anaesthesia combined with a popliteal nerve block for postoperative pain relief. Informed consent was obtained. Preoperatively, the patient underwent ultrasound guided, with use of a neurostimulator (0.5 mA, 0.3 ms, 2 Hz), single-shot popliteal block. No sedatives were administered. A 22 G Braun Stimuplex® Ultra 360® with a 30-degree angled needle tip was used. The procedure was executed by an anaesthesiologist in training under direct supervision of an experienced consultant anaesthesiologist. A total of 20 cc ropivacaine 0.75% without additives was injected perineural with subjectively low injection pressure. Injection was nonpainful. The procedure was unremarkable and the nerve block spread accordingly. General anaesthesia was induced with sufentanil and propofol. After induction, dexamethasone (8 mg) and granisetron (1 mg) were administered. Placement of a supraglottic airway device was uneventful and anaesthesia was maintained with sevoflurane. During surgery, the patient was in supine position with a tourniquet around the right upper leg at a pressure of 250 mmHg for 18 minutes. Mean arterial pressure always exceeded 70 mmHg, without the use of vasopressor agents. The cheilectomy procedure went surgically uneventful.\n\nEight days after surgery, the patient had persistent numbness and paresthesia of the foot, initially attributed to postoperative hematoma and swelling. After two weeks of progressive complaints, the neurologist was consulted. Physical examination revealed hypesthesia in the toes, ball, and lateral part of the foot and lateral part of the lower leg. Theoretically, the area is related to the superficial peroneal, tibial, and sural nerve. Loss of motor function was not objectified, although subjective weakness of toe-extension existed. Additionally, she mentioned an invalidating painful cramping of the calf musculature during physical activity. Postoperative PNI after PNB was suspected and nerve conduction studies and electromyography (EMG) were conducted. This revealed absent sensory conduction of the superficial peroneal nerve on the right side. Conduction velocity of the right sural nerve was normal. Compound muscle action potential amplitudes of the right extensor digitorum brevis muscle were decreased, with also denervation potentials seen during myography. The amplitudes of the right abductor hallucis brevis muscle were also decreased. Therefore, the conclusion of the EMG was a partial sciatic nerve neuropathy with axonal injury. Three months after surgery, the patient still experienced complaints and was emotionally affected by the series of events, filing an informal complaint towards the anaesthesia department. It was at this point that the anaesthesiologist, involved in the case, was informed. During follow-up at 5 and 10 months after surgery, the EMG showed recovery and also clinical recovery was present. Despite improvements 12 months after surgery, the patient received continued counseling from a physical therapist, still reporting daily complaints associated to the nerve damage.\n\n3. Discussion\n\nLong-term peripheral nerve injury (PNI) is an uncommon complication, with an aforementioned incidence of 0–0.7% for popliteal nerve blocks. The benefits of nerve blocks for perioperative pain management in bone and joint surgery are therefore greater than the risks. A divergent postoperative course would present during postoperative check-ups at the orthopedic outpatient clinic, outside of the anaesthesiologist's view. However, the impact on patients, if PNI does occur, might be enormous as it was for our patient. Patients might impute their symptoms to the PNB, although literature implies multifactorial etiology. Anesthesiologists should be able to provide explanation, based on current knowledge, and guide the patient postoperatively. If association of neurologic symptoms with a conducted PNB is likely, several pathogenic pathways such as mechanical, chemical, pressure, or vascular damage might contribute [3, 4]. Chemical damage is proven for all local anesthetics (LA), as they show cytotoxicity in vitro and in vivo, inducing histological damage and metabolic alterations, resulting in cell death and apoptosis. This is thought to be a consequence of prolonged intracellular Ca2+ concentrations [3]. The clinical symptoms of neurotoxicity can vary from neurological deficits to neuropathic pain and may be observed for months after initial injury. Concentration, duration of exposure, and location of deposit influence the extent of toxic damage [3]. Besides neurotoxicity, vascular compromise can induce nerve ischemia. Especially after intraneural injection, sustained high intraneural pressures can exceed capillary occlusion pressures of the vasa nervorum [4]. However, when LA was applied topically on the exposed sciatic nerve in rats, all showed vasoconstrictive properties, with ropivacaine showing the greatest decrease in neuronal blood flow [5].\n\nAnesthesiologists use multiple measures to try to prevent nerve injury. The purpose of these measures is avoidance of intraneural (and especially intrafascicular) injection, leading to axonal injury. Objectifying needle-tip placement is herein the subject of interest. Neurostimulation is often used to assess needle-to-nerve contact although correlated sensitivity is low [6]. Additional ultrasound guidance has advantages for needle localization and reduces the risk of systemic LA toxicity during PNB procedures. However, based on historical cohorts, it does not reduce the risk of persistent long-term PNI compared to neurostimulator-based nerve localization alone [7]. Moreover, ultrasound might identify intraneural needle placement, but cannot distinguish between extra- and intrafascicular needle placement. Clinically, intrafascicular injection can induce high injection pressures. Subjective pressure estimation is proven to be unreliable, but there are several, simple and more advanced, methods to objectify injection pressures. Evidence suggests that opening pressures <15 PSI correlate with extrafascicular needle position. However, no evidence to date has proven rigorous reduction of PNI [8]. When accidental intraneural needle placement occurs, a high gauge, short beveled needle significantly reduces the risk of perforation of fascicles. In our case, a 22 G and 30-degree angled needle tip was considered safe [9]. The occurrence of nerve damage is not predictable. Even intentional intraneural injection did not result in higher incidences of PNI [10]. Clinically uneventful procedures simply do not imply uneventful recovery, and vice versa. With the current knowledge and materials, it might be a difficult undertaking, if not impossible, to decrease the incidence of PNI even more by only operator chariness. Unfortunately, since persistent neurological injury after PNB is rare, generating sufficient scientific evidence to resolve this question will be challenging. When postoperative PNI is suspected, nerve conduction studies are the cornerstone of diagnosing nerve damage [11]. It can be helpful, but it cannot prove etiology. For example, when routinely performing EMG after intentional intraneural injection during PNB, electrophysiologic abnormalities indicating some degree of axonal damage were found in 100% of nonsymptomatic patients [10]. Moreover, EMG cannot differ between a singular lesion proximal and two distinct lesions more distally, when not anticipated for. For our patient, symptoms in the distribution area of the superficial peroneal nerve were clinically most evident and were the main finding on EMG. This may be independent of the PNB. The aforementioned painful cramps in the calf were not explained by EMG. Furthermore, EMG cannot always differ in timing of lesions, which could be of importance since prior ipsilateral ankle trauma and DVT might have influenced distal nerve integrity. Factors such as the PNB, use of a tourniquet, and direct surgical damage might have contributed as a “second hit.” It should be noted that nerve injury is also the most common complication associated with the use of a tourniquet. The pathophysiology remains unclear, but it is likely that mechanical compression and neural ischemia are both involved [4]. As mentioned above, neural ischemia may also be caused by intraneural LA deposition and vasoconstrictive properties of LA. A combination of these mechanisms might conceivably influence the adequate reperfusion after tourniquet deflation.\n\nWhen performing EMG early (7 days to 3 weeks) after suspected injury, signs of acute denervation may be visible suggesting recent damage [10]. EMG performed later will mostly show reinnervation signs. In the current case, the anaesthesia department was consulted quite late in the course of the case. Benefit of earlier consultation might be found in advice for testing specific locations of possible nerve damage, timing, and the precise clinical question. The anaesthesiologist should therefore be familiar with the possibilities and value of nerve conduction studies [11]. Nerve injury had a major impact on the patient in the current case and emotions such as sadness and anger occurred. Explanation and patient support by anaesthesia might help patients feel heard and taken seriously and provide understanding, even though actual causality may not be present. Unfortunately, anesthesiologists probably often miss out on (temporary) neurological symptoms after surgery.\n\n4. Conclusion\n\nAlthough long-term PNI is an uncommon complication, it can have devastating consequences for the patient. Anesthesiologists take multiple measures to avoid PNI. Postoperative communication between the anaesthesiologist, orthopedic surgeon, and neurologist is important to start the appropriate diagnostic pathway when PNI is suspected. This may also contribute to the patient feeling heard and taken seriously, based on open communication. Postoperative check-up is done by orthopedic colleagues and we would like to address the importance of timely consultation of the anaesthesiologist, especially for patient satisfaction.\n\nAcknowledgments\n\nThe authors wish to thank Dr. P. Meijer for his constructive criticism of the manuscript. Funding was performed through the personal budget granted on employment within the Maxima Medical Centre.\n\nConflicts of Interest\n\nThe authors declare no conflicts of interest.\n==== Refs\n1 Neal J. M. Barrington M. J. Brull R. The second ASRA practice advisory on neurologic complications associated with regional anesthesia and pain medicine Regional Anesthesia and Pain Medicine 2015 40 5 401 430 10.1097/aap.0000000000000286 2-s2.0-84940661235 26288034\n2 Anderson J. G. Bohay D. R. Maskill J. D. Complications after popliteal block for foot and ankle surgery Foot & Ankle International 2015 36 10 1138 1143 10.1177/1071100715589741 2-s2.0-84942870637 26109605\n3 Sondekoppam R. V. Tsui B. C. H. Factors associated with risk of neurologic complications after peripheral nerve blocks Anesthesia & Analgesia 2017 124 2 645 660 10.1213/ane.0000000000001804 2-s2.0-85008601712 28067709\n4 Brull R. Hadzic A. Reina M. A. Barrington M. J. Pathophysiology and etiology of nerve injury following peripheral nerve blockade Regional Anesthesia and Pain Medicine 2015 40 5 479 490 10.1097/aap.0000000000000125 2-s2.0-84940656879 25974275\n5 Bouaziz H. Iohom G. Estébe J.-P. Campana W. M. Myers R. R. Effects of levobupivacaine and ropivacaine on rat sciatic nerve blood flow British Journal of Anaesthesia 2005 95 5 696 700 10.1093/bja/aei242 2-s2.0-27744529939 16183680\n6 Wiesmann T. Bornträger A. Vassiliou T. Minimal current intensity to elicit an evoked motor response cannot discern between needle-nerve contact and intraneural needle insertion Anesthesia & Analgesia 2014 118 3 681 686 10.1213/ane.0b013e3182a94454 2-s2.0-84896729477 24284806\n7 Neal J. M. Ultrasound-guided regional anesthesia and patient safety Regional Anesthesia and Pain Medicine 2016 41 2 195 204 10.1097/aap.0000000000000295 2-s2.0-84959327036 26695877\n8 Rambhia M. Gadsden J. Pressure monitoring: the evidence so far Best Practice & Research Clinical Anaesthesiology 2019 33 1 47 56 10.1016/j.bpa.2019.03.001 2-s2.0-85064510221 31272653\n9 Sala-Blanch X. Ribalta T. Rivas E. Structural injury to the human sciatic nerve after intraneural needle insertion Regional Anesthesia and Pain Medicine 2009 34 3 201 205 10.1097/aap.0b013e31819a2795 2-s2.0-70349232477 19587616\n10 Cappelleri G. Cedrati V. L. E. Fedele L. L. Effects of the intraneural and subparaneural ultrasound-guided popliteal sciatic nerve block Regional Anesthesia and Pain Medicine 2016 41 4 430 437 10.1097/aap.0000000000000413 2-s2.0-84976320546 27281720\n11 Borgeat A. Aguirre J. Assessment and treatment of postblock neurologic injury Anesthesiology Clinics 2011 29 2 243 256 10.1016/j.anclin.2011.04.004 2-s2.0-79956359967 21620341\n\n",
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"title": "Axonal Injury with Persistent Neuropathy following Popliteal Nerve Block for Cheilectomy Surgery.",
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"abstract": "Cerebral hyperperfusion syndrome (CHS) is increasingly recognized as an uncommon, but serious, complication subsequent to carotid artery stenting (CAS) and carotid endarterectomy (CEA). The onset of CHS generally occurs within two weeks of CEA and CAS, and a delay in the onset of CHS of over one week after CAS is quite rare. We describe a patient who developed CHS three weeks after CAS with status epilepticus.",
"affiliations": "Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.;Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.;Department of Radiology, College of Medicine, Hanyang University, Seoul, Korea.;Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.",
"authors": "Oh|Seong-Il|SI|;Lee|Seok-Joon|SJ|;Lee|Young Jun|YJ|;Kim|Hee-Jin|HJ|",
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"fulltext": "\n==== Front\nJ Korean Neurosurg SocJ Korean Neurosurg SocJKNSJournal of Korean Neurosurgical Society2005-37111598-7876The Korean Neurosurgical Society 10.3340/jkns.2014.56.5.441Case ReportDelayed Cerebral Hyperperfusion Syndrome Three Weeks after Carotid Artery Stenting Presenting as Status Epilepticus Oh Seong-il M.D.1*†Lee Seok-joon M.D.1*Lee Young Jun M.D.2Kim Hee-Jin M.D.11 Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.2 Department of Radiology, College of Medicine, Hanyang University, Seoul, Korea.Address for reprints : Hee-Jin Kim, M.D. Department of Neurology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-792, Korea. Tel: +82-2-2290-8368, Fax: +82-2-2299-2391, hyumcbrain@hanyang.ac.kr*These outhors contributed equally to this work.\n\n†Move to : Department of Neurology, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.\n\n11 2014 30 11 2014 56 5 441 443 26 6 2013 03 12 2013 28 2 2014 Copyright © 2014 The Korean Neurosurgical Society2014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Cerebral hyperperfusion syndrome (CHS) is increasingly recognized as an uncommon, but serious, complication subsequent to carotid artery stenting (CAS) and carotid endarterectomy (CEA). The onset of CHS generally occurs within two weeks of CEA and CAS, and a delay in the onset of CHS of over one week after CAS is quite rare. We describe a patient who developed CHS three weeks after CAS with status epilepticus.\n\nCerebral hyperperfusion syndromeCarotid artery stentingCarotid artery stenosisStatus epilepticusHanyang UniversityHY-2009-C\n==== Body\nINTRODUCTION\nCerebral hyperperfusion syndrome (CHS) is a dangerous complications following carotid endarterectomy (CEA) or carotid artery stenting (CAS)3,4,7,11). CHS following CEA or CAS is characterized by unilateral headache, seizure, focal neurologic defects, and intracerebral hemorrhage in most severe form6,9). Little is known about the exact cause of CHS; however, a deterioration in cerebrovascular autoregulation seems to increase regional cerebral blood and lead to CHS1).\n\nRate of occurrence of CHS after CAS is reported to be 0.4% to 3%1,8,9). Previous studies found that CHS mostly occurs within one week after CAS6,9). Although there are a few reports of CHS occurring from three weeks to four weeks after CEA, a delay in onset of over one week is very rare6). Risk factors for CHS are known diabetes mellitus, old age, recent contralateral CEA, post-interventional hypertension, contralateral carotid occlusion, intra-interventional ischemia, and administration of anticoagulants or antiplatelet agents.\n\nWe describe a case of delayed CHS, presenting as status epilepticus, three weeks after CAS in a high risk patient.\n\nCASE REPORT\nA 67-year-old woman was admitted for evaluation of an incidental finding of carotid bruit on physical examination. She had been treated for hypertension and diabetes mellitus for 10 years. On admission, her blood pressure was 140/100 mg. On neurological examination, she was normal. Magnetic resonance imaging (MRI) revealed multiple old infarctions in the bilateral parieto-occipital junctions and right internal border zone area. MR angiography revealed occlusion of the right proximal internal carotid artery (ICA), and severe stenosis of the left proximal ICA and orifices of both vertebral arteries (VA). Digital subtraction angiography demonstrated total occlusion of the right proximal ICA, 73% stenosis of the left proximal ICA and more than 70% stenosis of both VA orifices (Fig. 1A). The patient was pre-treated with aspirin and clopidogrel for 5 days before undergoing stenting at the left proximal ICA and right VA orifices via a transfemoral approach under local anesthesia (Fig. 1B). There was no transient hypotension or bradycardia during the periprocedural period. Anti-hypertensive drugs including a calcium channel blocker (CCB) were administered to maintain systolic blood pressure below 140 mm Hg. After close observation for one week, she was discharged without any complications.\n\nThree weeks after CAS, the patient presented to the emergency room with generalized tonic-clonic seizure for 40 minutes and stuporous mentality. Blood pressure had risen to 190/110 mm Hg. On neurologic examination, the withdrawal response in the right extremities was decreased, but there was hyper-reflexia in all the extremities, with pathologic plantar reflexes bilaterally. Brain MRI showed high signal intensities in the left hemispheric white matter on FLAIR, without diffusion restriction, pointing to vasogenic edema (Fig. 2A, B, C). Neck computed tomography angiography revealed no significant stenosis in the previously stented vessel. Slower waves were recorded on the left than on the right hemisphere on electroencephalograms, and there was no epileptiform discharge. Thees findings were compatible with CHS presenting vasogenic edematous change with symptomatic epilepsy. After administration of antiepileptics and antihypertensives, the deteriorated mentality recovered slowly and seizures ceased. The weakness of the right extremities recovered gradually from the sixth hospital day.\n\nThe patient's blood pressure was controlled by high dose intravenous labetalol and losartan/hydrochlorothiazide. Follow-up MRI of two weeks after CHS showed resolution of the vasogenic edema (Fig. 2D, E, F). Perfusion CT was performed at the time of symptom development and 24 days after CHS, when the state of the CHS had improved. It revealed a higher cerebral blood volume (CBV) in both hemispheres at the onset than 24 days after CHS. The CBV returned to normal within 4 weeks (Fig. 3) and the patient recovered without any neurological abnormality. Blood pressure was normalized by the prescribed drugs and the seizure was stabilized with valproic acid and levetiracetam.\n\nDISCUSSION\nThere have been a few reports of CHS after CEA, but it has rarely been described after CAS6). The pathophysiology of CHS after CAS remains unclear, but there are several possible mechanisms. Firstly, prolonged hypoperfusion may lead to abnormality of cerebral vascular autoregulation8). Secondly, transient bradycardia and hypotension due to damage to the carotid artery baroreceptor can often occur during CAS, and can result in further ischemic injury to damaged brains9). Thirdly, systemic hypertension secondary to CAS can result in intense cerebral blood flow1,6).\n\nThe most important issue in this case is differentiation between CHS and seizure due to a periprocedural thromboembolism. We performed perfusion CT at the time of symptom development and 24 days after CHS when the CHS had improved. In the perfusion CT, greater CBV was observed in both hemispheres at the onset of the CHS than 24 days after the CHS. Periprocedural thromboembolism is a common adverse effect of CAS and a risk factor for CHS. If the patient had presented with seizure due to a periprocedural embolism, the features of the perfusion CT scan might have been different. The most common post-ictal perfusion abnormality is decreased cerebral blood flow and cerebral blood volume2). CT perfusion revealed a reduced time-to-peak and mean-transient-time and increased cerebral blood volume and cerebral blood flow in the CHS10). The perfusion CT scan was compatible with CHS, and the patient had no neurological deficit or clinical symptoms related to the CHS, based on the results of blood pressure measurements over the 2 weeks after the CHS. Although we did not perform a special evaluation, the possibility of a diagnosis of periprocedural thromboembolism or other adverse effect seemed to be low. Also, the large lesion and generalized clinical symptoms were more likely to be related to CHS than to a thromboembolism.\n\nIn the present case, the occurrence of CHS was associated with multiple risk factors including ipsilateral occlusion, contralateral stenosis, poor collateral circulation, old age, long-standing hypertension, and administration of antiplatelet agents9,13). Although the patient had potential risk factors for CHS, the latter could have been due to some other mechanism. One might the usage of CCB, which could induce cerebral vasodilation5,12). Another might be associated with the unstable status of preprocedural cerebrovascular reactivity in patients with various predisposing factors11), or the unknown status of postprocedural cerebrovascular autoregulation11).\n\nCONCLUSION\nThis case suggests that we should take into careful consideration all periprocedural risk factors for CHS. In addition, it suggests that delayed onset of CHS may occasionally present with status epilepticus. After CAS, clinicians should observe patients who have undergone CAS and have high risk factors for at least two or three weeks.\n\nAcknowledgements\nThis study was supported by the cluster research fund of Hanyang University (HY-2009-C).\n\nFig. 1 Pre-stenting cerebral angiography shows the narrow left proximal internal carotid artery (ICA) (A) and post-stenting cerebral angiography shows the widened left ICA stenosis (B).\n\nFig. 2 Postprocedural magnetic resonance imaging three weeks (A, B, and C) and five weeks (D, E, and F) after carotid artery stenting. The signal abnormality on the fluid-attenuated inversion recovery image at three weeks (A) was markedly improved at five weeks (D). The diffusion weighted images and apparent diffusion coefficient map images shown were improved compared to the previous MR images.\n\nFig. 3 Perfusion CT shows that cerebral blood volume at the time of the development of the cerebral hyperperfusion syndrome (CHS) (A) is higher than at 24 days after CHS with improvement (B) in both hemispheres.\n==== Refs\n1 Abou-Chebl A Yadav JS Reginelli JP Bajzer C Bhatt D Krieger DW Intracranial hemorrhage and hyperperfusion syndrome following carotid artery stenting : risk factors, prevention, and treatment J Am Coll Cardiol 2004 43 1596 1601 15120817 \n2 Gelfand JM Wintermark M Josephson SA Cerebral perfusion-CT patterns following seizure Eur J Neurol 2010 17 594 601 19968701 \n3 Ho DS Wang Y Chui M Ho SL Cheung RT Epileptic seizures attributed to cerebral hyperperfusion after percutaneous transluminal angioplasty and stenting of the internal carotid artery Cerebrovasc Dis 2000 10 374 379 10971023 \n4 Kim DE Choi SM Yoon W Kim BC Hyperperfusion syndrome after carotid stent-supported angioplasty in patients with autonomic dysfunction J Korean Neurosurg Soc 2012 52 476 479 23323169 \n5 Kuriyama Y Hashimoto H Nagatsuka K Sawada T Omae T Effects of dihydropyridines on cerebral blood vessels J Hypertens Suppl 1993 11 S9 S12 8169383 \n6 Lieb M Shah U Hines GL Cerebral hyperperfusion syndrome after carotid intervention : a review Cardiol Rev 2012 20 84 89 22183061 \n7 McCabe DJ Brown MM Clifton A Fatal cerebral reperfusion hemorrhage after carotid stenting Stroke 1999 30 2483 2486 10548688 \n8 Moulakakis KG Mylonas SN Sfyroeras GS Andrikopoulos V Hyperperfusion syndrome after carotid revascularization J Vasc Surg 2009 49 1060 1068 19249185 \n9 Ogasawara K Sakai N Kuroiwa T Hosoda K Iihara K Toyoda K Intracranial hemorrhage associated with cerebral hyperperfusion syndrome following carotid endarterectomy and carotid artery stenting : retrospective review of 4494 patients J Neurosurg 2007 107 1130 1136 18077950 \n10 Schoknecht K Gabi S Ifergane G Friedman A Shelef I Detection of cerebral hyperperfusion syndrome after carotid endarterectomy with CT Perfusion J Neuroimaging 2012 [Epub ahead of print] \n11 Sundt TM Jr Sharbrough FW Piepgras DG Kearns TP Messick JM Jr O'Fallon WM Correlation of cerebral blood flow and electroencephalographic changes during carotid endarterectomy : with results of surgery and hemodynamics of cerebral ischemia Mayo Clin Proc 1981 56 533 543 7266064 \n12 Tietjen CS Hurn PD Ulatowski JA Kirsch JR Treatment modalities for hypertensive patients with intracranial pathology : options and risks Crit Care Med 1996 24 311 322 8605807 \n13 van Mook WN Rennenberg RJ Schurink GW van Oostenbrugge RJ Mess WH Hofman PA Cerebral hyperperfusion syndrome Lancet Neurol 2005 4 877 888 16297845\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "56(5)",
"journal": "Journal of Korean Neurosurgical Society",
"keywords": "Carotid artery stenosis; Carotid artery stenting; Cerebral hyperperfusion syndrome; Status epilepticus",
"medline_ta": "J Korean Neurosurg Soc",
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"title": "Delayed cerebral hyperperfusion syndrome three weeks after carotid artery stenting presenting as status epilepticus.",
"title_normalized": "delayed cerebral hyperperfusion syndrome three weeks after carotid artery stenting presenting as status epilepticus"
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"abstract": "Allogeneic stem cell transplantation is potentially curative, but associated with post-transplantation complications, including cytomegalovirus (CMV) infections. An effective immune response requires T cells recognizing CMV epitopes via their T cell receptors (TCRs). Little is known about the TCR repertoire, in particular the TCR-α repertoire and its clinical relevance in patients following stem cell transplantation. Using next-generation sequencing we examined the TCR-α repertoire of CD8(+) T cells and CMV-specific CD8(+) T cells in four patients. Additionally, we performed single-cell TCR-αβ sequencing of CMV-specific CD8(+) T cells. The TCR-α composition of human leucocyte antigen (HLA)-A*0201 CMVpp65- and CMVIE -specific T cells was oligoclonal and defined by few dominant clonotypes. Frequencies of single clonotypes reached up to 11% of all CD8(+) T cells and half of the total CD8(+) T cell repertoire was dominated by few CMV-reactive clonotypes. Some TCR-α clonotypes were shared between patients. Gene expression of the circulating CMV-specific CD8(+) T cells was consistent with chronically activated effector memory T cells. The CD8(+) T cell response to CMV reactivation resulted in an expansion of a few TCR-α clonotypes to dominate the CD8(+) repertoires. These results warrant further larger studies to define the ability of oligoclonally expanded T cell clones to achieve an effective anti-viral T cell response in this setting.",
"affiliations": "Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus.;DFG Research Center for Regenerative Therapies Dresden, Dresden, Germany.;Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus.;Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus.;Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus.;Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus.;DFG Research Center for Regenerative Therapies Dresden, Dresden, Germany.;DFG Research Center for Regenerative Therapies Dresden, Dresden, Germany.;DFG Research Center for Regenerative Therapies Dresden, Dresden, Germany.;DFG Research Center for Regenerative Therapies Dresden, Dresden, Germany.;DFG Research Center for Regenerative Therapies Dresden, Dresden, Germany.;DKMS Clinical Trials Unit, Dresden, Germany.;DFG Research Center for Regenerative Therapies Dresden, Dresden, Germany.;Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus.;Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus.;Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus.;DFG Research Center for Regenerative Therapies Dresden, Dresden, Germany.",
"authors": "Link|C S|CS|;Eugster|A|A|;Heidenreich|F|F|;Rücker-Braun|E|E|;Schmiedgen|M|M|;Oelschlägel|U|U|;Kühn|D|D|;Dietz|S|S|;Fuchs|Y|Y|;Dahl|A|A|;Domingues|A M J|AM|;Klesse|C|C|;Schmitz|M|M|;Ehninger|G|G|;Bornhäuser|M|M|;Schetelig|J|J|;Bonifacio|E|E|",
"chemical_list": "D000956:Antigens, Viral; D000939:Epitopes; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta",
"country": "England",
"delete": false,
"doi": "10.1111/cei.12770",
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"issn_linking": "0009-9104",
"issue": "184(3)",
"journal": "Clinical and experimental immunology",
"keywords": "CMV; T cell receptor alpha; T cell receptor repertoire; allogeneic transplantation; next-generation sequencing",
"medline_ta": "Clin Exp Immunol",
"mesh_terms": "D000368:Aged; D000595:Amino Acid Sequence; D000956:Antigens, Viral; D018414:CD8-Positive T-Lymphocytes; D002999:Clone Cells; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D000939:Epitopes; D005260:Female; D005786:Gene Expression Regulation; D015789:HLA-A2 Antigen; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007156:Immunologic Memory; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D016693:Receptors, Antigen, T-Cell, alpha-beta; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D059010:Single-Cell Analysis; D014184:Transplantation, Homologous",
"nlm_unique_id": "0057202",
"other_id": null,
"pages": "389-402",
"pmc": null,
"pmid": "26800118",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21540462;25852054;24239865;10037822;24778446;22160050;25728493;22517587;18238896;25430567;19403059;23744585;25452035;23652802;25445637;24391640;15172442;12576317;25898052;18978023;16237109;18590456;14671648;25681349;23656731;17709536;21236396;17391521;23313705;23933763;24020931;23435170;16287711;19776383;18802479;22491952",
"title": "Abundant cytomegalovirus (CMV) reactive clonotypes in the CD8(+) T cell receptor alpha repertoire following allogeneic transplantation.",
"title_normalized": "abundant cytomegalovirus cmv reactive clonotypes in the cd8 t cell receptor alpha repertoire following allogeneic transplantation"
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"abstract": "To determine preliminary outcomes of a treatment for refractory pediatric migraine that integrates outpatient dihydroergotamine (DHE) infusion with interdisciplinary adjunctive care.\n\n\n\nLimited data are available to inform treatment of refractory migraine in children. Intravenous DHE therapy has shown promise but has been implemented in costly inpatient settings and in isolation of nonpharmacological strategies shown to enhance analgesia and functional improvement.\n\n\n\nWe conducted a retrospective chart review of 36 patients ages 11-18 with refractory migraine who underwent a pilot treatment program in an outpatient neurology clinic. The treatment integrated up to 5 days of outpatient DHE infusion with adjunctive nonpharmacological care (pain coping skills training, massage, aromatherapy, and school reintegration support). Changes in headache, healthcare utilization, and functional limitations were assessed as indicators of treatment response through 3-month follow-up.\n\n\n\nOn average, headache intensity declined (M = 5.8 ± 2.5 to M = 2.4 ± 2.7; P < .0001) during the treatment period and remained statistically significantly improved through 3-month follow-up. Headache frequency decreased by a mean of 1.5 days per week (M = 6.7 ± 1.0 vs M = 5.2 ± 2.7, P = .012) through 3-month follow-up, with a 27% reduction (from 0.91 to 0.66) in the proportion of patients reporting a continuous headache (P = .009). Over this same follow-up period, there was a reduction in school days missed per month (median [25th, 75th percentile]: 4.5 [0, 21.0] vs 0 [0.0, 0.5]). There also were reductions in headache-related visits per month to the emergency department and medical providers. Adverse effects were common but typically minor and transient.\n\n\n\nCombining outpatient DHE infusion with interdisciplinary adjunctive care has promise as an effective treatment option for adolescents with refractory migraine.",
"affiliations": "Division of Developmental and Behavioral Sciences, Children's Mercy Hospital, Kansas City, MO, USA.;University of Missouri Kansas City School of Medicine, Kansas City, MO, USA.;University of Missouri Kansas City School of Medicine, Kansas City, MO, USA.;Division of Neurology, Children's Mercy Hospital, Kansas City, MO, USA.;Division of Neurology, Children's Mercy Hospital, Kansas City, MO, USA.",
"authors": "Connelly|Mark|M|0000-0001-8157-8901;Sekhon|Subhjit|S|;Stephens|Dane|D|;Boorigie|Madeline|M|;Bickel|Jennifer|J|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D004087:Dihydroergotamine",
"country": "United States",
"delete": false,
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"issue": "60(1)",
"journal": "Headache",
"keywords": "dihydroergotamine; interdisciplinary; nonpharmacological treatment; pediatric; refractory migraine",
"medline_ta": "Headache",
"mesh_terms": "D000293:Adolescent; D000553:Ambulatory Care; D018712:Analgesics, Non-Narcotic; D019341:Aromatherapy; D002648:Child; D002985:Clinical Protocols; D003131:Combined Modality Therapy; D004087:Dihydroergotamine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008405:Massage; D008881:Migraine Disorders; D017063:Outcome Assessment, Health Care; D010044:Outpatient Clinics, Hospital; D010865:Pilot Projects; D011613:Psychotherapy; D012189:Retrospective Studies; D012574:Schools; D012944:Social Support",
"nlm_unique_id": "2985091R",
"other_id": null,
"pages": "101-109",
"pmc": null,
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"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Enhancing Outpatient Dihydroergotamine Infusion With Interdisciplinary Care to Treat Refractory Pediatric Migraine: Preliminary Outcomes From the Comprehensive Aggressive Migraine Protocol (\"CAMP\").",
"title_normalized": "enhancing outpatient dihydroergotamine infusion with interdisciplinary care to treat refractory pediatric migraine preliminary outcomes from the comprehensive aggressive migraine protocol camp"
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"abstract": "Monoclonal antibodies constitute a potent and broadly tolerable drug class, representing for some conditions the first newly approved treatment in years. As such, many are afforded \"fast-track\" or \"breakthrough therapy\" designations by the U.S. Food and Drug Administration, leading to provisional approval before Phase III clinical trials are reported. Although these drugs are usually safe, some patients experience life-threatening complications-myositis and encephalitis have led to permanent or temporary recalls. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a hypersensitivity condition easily missed due to its long incubation period and nonspecific presentation. This minireview is primarily intended as an abbreviated guide for practitioners who may be using these powerful treatments.\nWe searched PubMed using a string of symptoms consistent with DRESS syndrome and monoclonal antibodies approved by the FDA since 2015. Then, we excluded studies reporting dermatological complications of reactivation of nonherpetic infection, immunodeficiency-related infection, or reactions to the injection site or infusion. We searched for and accessed prior reviews and background studies via PubMed, Mendeley, and Google Scholar.\nTwo cases of DRESS syndrome were identified in the literature, both the result of treatment with daclizumab. There was one additional case of encephalitis without cutaneous symptoms caused by daclizumab. Drug-induced hypersensitivity dermatitis was reported following treatment with nivolumab and two cases of combination treatment with ipilimumab and either nivolumab or durvalumab produced maculopapular rash and bullae in the first patient and lichenoid dermatitis and blisters in the second patient.\nDaclizumab was the only recently approved monoclonal antibody associated with DRESS syndrome as such. Limitations in the diagnostic reliability of DRESS syndrome as a clinical entity and the lack of negative clinical trial reporting suggest enhanced vigilance on the part of clinicians and regulators may be warranted.",
"affiliations": "Università degli Studi di Pavia Facoltà di Medicina e Chirurgia, Piazza Volontari del Sangue Pal. Avis, Pavia (PV), 27100, Italy.;Università degli Studi di Pavia Facoltà di Medicina e Chirurgia, Piazza Volontari del Sangue Pal. Avis, Pavia (PV), 27100, Italy.;Università degli Studi di Pavia Facoltà di Medicina e Chirurgia, Piazza Volontari del Sangue Pal. Avis, Pavia (PV), 27100, Italy.",
"authors": "Di Palma-Grisi|James C|JC|https://orcid.org/0000-0001-6826-5572;Vijayagopal|Kesav|K|https://orcid.org/0000-0003-3351-6882;Muslimani|Muhammad A|MA|https://orcid.org/0000-0002-0926-5457",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2019/7595706",
"fulltext": "\n==== Front\nAutoimmune DisAutoimmune DisADAutoimmune Diseases2090-04222090-0430Hindawi 10.1155/2019/7595706Review ArticleCase Reports of DRESS Syndrome and Symptoms Consistent with DRESS Syndrome Following Treatment with Recently Marketed Monoclonal Antibodies https://orcid.org/0000-0001-6826-5572Di Palma-Grisi James C. james.dipalma-grisi01@universitadipavia.ithttps://orcid.org/0000-0003-3351-6882Vijayagopal Kesav https://orcid.org/0000-0002-0926-5457Muslimani Muhammad A. Università degli Studi di Pavia Facoltà di Medicina e Chirurgia, Piazza Volontari del Sangue Pal. Avis, Pavia (PV), 27100, ItalyAcademic Editor: Rizgar Mageed\n\n2019 9 6 2019 2019 75957061 4 2019 14 5 2019 28 5 2019 Copyright © 2019 James C. Di Palma-Grisi et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\n Monoclonal antibodies constitute a potent and broadly tolerable drug class, representing for some conditions the first newly approved treatment in years. As such, many are afforded “fast-track” or “breakthrough therapy” designations by the U.S. Food and Drug Administration, leading to provisional approval before Phase III clinical trials are reported. Although these drugs are usually safe, some patients experience life-threatening complications—myositis and encephalitis have led to permanent or temporary recalls. Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a hypersensitivity condition easily missed due to its long incubation period and nonspecific presentation. This minireview is primarily intended as an abbreviated guide for practitioners who may be using these powerful treatments.\n\n Methodology\n We searched PubMed using a string of symptoms consistent with DRESS syndrome and monoclonal antibodies approved by the FDA since 2015. Then, we excluded studies reporting dermatological complications of reactivation of nonherpetic infection, immunodeficiency-related infection, or reactions to the injection site or infusion. We searched for and accessed prior reviews and background studies via PubMed, Mendeley, and Google Scholar.\n\n Results\n Two cases of DRESS syndrome were identified in the literature, both the result of treatment with daclizumab. There was one additional case of encephalitis without cutaneous symptoms caused by daclizumab. Drug-induced hypersensitivity dermatitis was reported following treatment with nivolumab and two cases of combination treatment with ipilimumab and either nivolumab or durvalumab produced maculopapular rash and bullae in the first patient and lichenoid dermatitis and blisters in the second patient.\n\n Conclusions\n Daclizumab was the only recently approved monoclonal antibody associated with DRESS syndrome as such. Limitations in the diagnostic reliability of DRESS syndrome as a clinical entity and the lack of negative clinical trial reporting suggest enhanced vigilance on the part of clinicians and regulators may be warranted.\n==== Body\n1. Introduction\nMonoclonal antibodies are specific and effective treatments for immune system dysfunction, skin diseases, cancers and other conditions [1]. They can be synthesized as chimeric, humanized, or fully human antibodies—although fully human antibodies convey the least immunogenicity, adalimumab is capable of provoking antidrug antibody responses in some patients with rheumatoid arthritis [2]. Classical hypersensitivity reactions to monoclonal antibody therapy are broadly similar to those of other drugs. Manifestations of hypersensitivity reactions typically occur within six hours of drug administration and include cutaneous, cardiovascular, respiratory, gastrointestinal, and neurological changes [3].\n\nDelayed hypersensitivity reactions include DRESS syndrome, Stevens-Johnson syndrome, vasculitis, and maculopapular eruptions, among other conditions [4]. Once the disease process has begun, patients typically develop pyrexia, diffuse rash, pruritis and papular, pustular, or vesicular erythema. Hematologic manifestations include lymphadenopathy, thrombocytopenia, and lymphocytosis, while eosinophilia is not universally present, a finding that has contributed to the multiple naming practices for the disease, such as “drug-induced hypersensitivity syndrome” [5].\n\nGenetic factors appear to play a role and both diuretics and anticonvulsants appear particularly likely to cause DRESS syndrome. The mainstay of treatment is discontinuation of the offending drug and systemic glucocorticoids, although treatment may be confounded by multiple relapses after discontinuation [6]. The incubation period of DRESS syndrome is two to eight weeks, and the emergence of symptoms is thought to be connected to reactivation of latent human herpesvirus 6, although the exact mechanism behind this reactivation is unclear [7]. One proposed etiology is that the offending drugs or metabolites contribute to T-cell activation and viral reactivation [8].\n\nAmong monoclonal antibodies, a handful has been reported to cause DRESS syndrome, including several recently approved biologic agents. One reported case presented with widespread maculopapular exanthem and lymphadenopathy 54 days after treatment of basal cell carcinoma with vismodegib (approved 2012)—lymph node biopsy showed marked eosinophilic infiltrate in the absence of cancer cells [9]. A retrospective cohort study of patients treated with vemurafenib, a BRAF inhibitor, found among 131 patients, one case of DRESS syndrome, leading to permanent discontinuation of treatment [10]. Another case of DRESS syndrome occurred in a patient treated with sorafenib (approved 2013) for hepatocellular carcinoma, in which the authors report skin eruptions, eosinophilia, and both liver and kidney involvement [11].\n\nDaclizumab, a monoclonal antibody approved on a “first in class” designation, indicating a novel mechanism of action, was voluntarily and permanently recalled in March 2018 due to multiple reports of encephalitis (FDA). Daclizumab was designed first as prophylaxis for acute organ rejection but was later repurposed as a treatment for relapsing multiple sclerosis. Its hepatotoxicity led to a “black box” warning label from the FDA. In the course of postmarketing pharmacovigilance, the European Medicines Agency (EMA) found that multiple patients developed eosinophilia, skin rash, and involvement of other organs or multiorgan failure suspected to be secondary to immunomodulation. These cases were only retroactively recognized to be DRESS syndrome [12]. More recent reports describe patients with symptoms overlapping meningoencephalitis and DRESS syndrome criteria [13].\n\nIpilimumab is a model drug approved in 2011 to inactivate cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a discovery whose importance was recognized by a Nobel prize in 2018. Yet the cutaneous manifestations of checkpoint inhibitors are varied and occasionally life-threatening. DRESS syndrome is one of the many adverse reactions associated with ipilimumab. Nivolumab and pembrolizumab target programmed cell death-1 (PD-1) and are known to cause adverse cutaneous reactions occurring later in treatment than CTLA-4 cutaneous reactions. Atezolizumab targets the PD-1 ligand (PD-L1) and causes similar cutaneous side effects as PD-1 inhibitors, but combination therapy presents a statistically significant increase in severe complications [14].\n\nThe risks of missing this clinical constellation are salient—the object of this mini-review is to assess the most recently FDA-approved monoclonal antibodies for cutaneous symptoms consistent with DRESS syndrome. Case studies offer detailed clinical pictures in which the presence or absence of DRESS syndrome can be relatively cleanly ruled in or out, while clinical trials offer aggregate data to assess the proportion of patients that develop symptoms consistent with DRESS syndrome.\n\n2. Methods\nStudies were included by searching PubMed using the following string: (dress OR erythema OR pruritus OR rash OR urticaria OR eruption) AND (secukinumab OR dinutuximab OR alirocumab OR evolocumab OR idarucizumab OR mepolizumab OR daratumumab OR necitumumab OR elotuzumab OR obiltoxaximab OR ixekizumab OR reslizumab OR atezolizumab OR daclizumab OR olaratumab OR bezlotoxumab OR brodalumab OR avelumab OR ocrelizumab OR dupilumab OR durvalumab OR sarilumab OR guselkumab OR “inotuzumab ozogamicin” OR benralizumab OR emicizumab OR ibalizumab OR tildrakizumab OR burosumab OR erenumab OR mogamulizumab OR lanadelumab OR “moxetumomab pasudotox” OR fremanezumab OR galcanezumab OR cemiplimab OR emapalumab OR ravulizumab OR caplacizumab). Studies were then excluded by agreement between all three authors if they did not include either (a) case studies of or (b) rates of dermatological adverse effects of a recently approved biologic. Studies reporting dermatological manifestations of (a) reactivation of suspected latent infection, (b) immunodeficiency-related infection, (c) only injection-site or infusion reactions fitting the search criteria, (d) cases identified as Stevens-Johnson syndrome or toxic epidermal necrolysis, or (e) cases reporting only pooled adverse effects were also then excluded. Prior reviews and background studies were searched via PubMed, Mendeley, and Google Scholar.\n\n3. Syndromic Cutaneous Reactions\nTotal results by case report are arranged in Table 1. We found two cases of DRESS syndrome frankly identified as such in the literature, both as a result of daclizumab treatment of relapsing multiple sclerosis. In both cases, the syndrome was treated with high dose corticosteroids followed by plasmapheresis, but one case worsened and cyclophosphamide and rituximab were used in management [15]. There was also one case of drug-induced hypersensitivity dermatitis following treatment of metaplastic squamous cell carcinoma of the lung with nivolumab. This patient developed vesicles and bullae over 30% of his skin, which biopsy determined to be subepidermal bullous dermatitis with eosinophils. In the same case series, combination treatment with ipilimumab and nivolumab preceded a maculopapular rash and pruritis, followed a month later by bullae without mucosal involvement. A third patient treated with ipilimumab and durvalumab developed lichenoid dermatitis and pruritic, fluid-filled blisters on her foot, and a central pruritic rash [16]. There was another case of pruritus and erythematous macules and papules two months following treatment with durvalumab and tremelimumab, a combination checkpoint inhibitor regimen [17].\n\n4. Nonsyndromic Cutaneous Reactions\nReports of nonsyndromic cutaneous reactions were also found following treatment with a handful of other recently approved monoclonal antibodies. Treatment with ixekizumab, an IL-17 blocker used to treat psoriasis, preceded new psoriasiform eruptions [18] in one patient, photosensitive cutaneous eruptions [19] in another, and lentiginous eruption [20] in a third patient. Treatment with secukinumab, an IL-17A blocker for treating psoriasis and ankylosing spondylitis, preceded one case of pemphigus [21] and another case of severe, ulcerative lichenoid mucositis [22]. Treatment with dupilumab, an IL-4 receptor blocker used to treat eczema, preceded three cases of erythema, pruritus, and widespread skin peeling [23]. Lastly, treatment with brodalumab preceded psoriaform hyperplasia and pustular lesions [24].\n\n5. Discussion\nDRESS syndrome is one distinct, severe, and idiosyncratic drug reaction that is more relevant than ever due to the rapid advancements in the production of novel biologics and their widespread implementation in the treatment of rheumatic, immunologic, and neoplastic diseases. Fortunately, DRESS syndrome is a rare condition, but the difficulty in diagnosing leads to an even lower rate of identification and reporting. Severe cutaneous reactions of any type reported in clinical trials are very rare, and the only reported cases of DRESS syndrome were in clinical trials of daclizumab [25]. DRESS syndrome poses risks of chronic sequelae and even fatality, which are further complicated by a prolonged latency period. The main challenge is to recognize the pathology for what it is, as most clinicians lack familiarity with the condition due to its very low incidence, its high variability among ethnicities, and the variations of its clinical presentation secondary to which organs are affected [26, 27]. While fever, rash, and eosinophilia are essential features for the diagnosis of this syndrome, some of the atypical features are dysphagia, agranulocytosis, and chylous ascites. The European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples (RegiSCAR) criteria is widely used to make a diagnosis. RegiSCAR inclusion criteria for potential DRESS syndrome cases require at least 3 out of the following 4 signs: fever above 38°C, enlarged lymph nodes at a minimum of two sites, involvement of at least one internal organ, or blood count abnormalities [28]. Managing this syndrome mainly requires early removal of the causative agent and treatment with antihistamines and emollients in the mild form, corticosteroids in the moderate form, and plasmapheresis in the severe form [29].\n\nClinical manifestations are considered a hypersensitivity reaction to drugs when specific circulating antibodies and/or specifically sensitized lymphocytes are present. Pseudoallergic reactions on the other hand occur when manifestations similar to those of a hypersensitivity reaction are observed in the absence of immunological specificity [30, 31]. Although this pathophysiological classification is generally useful, it does not adequately allow inferring, based on clinical symptoms, in which immune mechanism is involved, as occurring in toxic epidermal necrolysis, Stevens-Johnson syndrome, and DRESS syndrome [32]. The available drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivities include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity regardless of the involved drug, as well as the diverse pathological mechanisms involved, makes diagnosis and management more challenging [33].\n\nIn nonclinical toxicity studies, type I hypersensitivity reactions are often observed following administration of biologics [34]. Type I reactions are mediated by specific IgE antibodies associated with mast cells and basophils, and their clinical manifestations may include anaphylaxis or urticaria/angioedema. Another mechanism suspected to be a potential consequence of immunostimulation by biologics is through the occurrence of more frequent hypersensitivity reactions to unrelated allergens [35]. Eosinophilic activation as well as activation of the inflammatory cascade in DRESS syndrome may be induced by interleukin-5 release from drug-specific T-cells [36]. A challenge remains to identify the optimal balance between dosage, benefits, and side effects, which could sometimes be more serious than the treated disease. Latent hypersensitivity reactions and viral reactivations in susceptible populations should warrant a thorough revision of the safety profiles of culprit biologics.\n\nIn contrast to an overall low incidence in clinical trials, there is a plethora of documented cases of severe cutaneous reactions, mimicking those encompassed by the clinical picture of DRESS syndrome, as a result of treatment with various biologics. Revising the literature, it is observed that some biologics caused hypersensitivity reactions independent of the dose and the duration of the therapy. Other biologics caused hypersensitivity reactions that seem to correlate with the dose, total number of cycles, and/or spacing between cycles (e.g., dinutuximab, necitumumab, and ixekizumab). Interestingly the hypersensitivities accompanying mogamulizumab-kpkc administration were all categorized as acute infusion reactions. The only incidence where DRESS was namely reported is in 0.1% of patients receiving 150mg of subcutaneous daclizumab every 4 weeks for 96 weeks. The reported overall cutaneous adverse events were significantly high for necitumumab. Molecularly, necitumumab's large paratope cavities are speculated to make it less susceptible to resistance through EGFR epitope mutation [37], a characteristic which could theoretically be a contributing factor to latent cutaneous adverse effects. In treatment with daclizumab, observed cutaneous adverse events are likely related to the immunomodulatory effects it exerts on innate lymphoid cells, including natural killer cells [38]. Identifying the mechanisms by which each biologic produces these severe side effects is crucial to generating appropriate countermeasures, including allergic prescreening, prophylactic regimens, pharmacovigilance, early-response drugs, and supportive care measures.\n\nWhile multiple studies have estimated the mortality rate of DRESS syndrome to be approximately 10%, the severity and extent of cutaneous involvement do not always correlate with the extent of internal organ involvement [39, 40]. The underreported incidents of DRESS syndrome complication may arise from a primary failure to recognize its syndromic appearance and to correlate it to biologic administration, especially in cases when the latter had been discontinued. Given the difficulties encountered while attempting to diagnose DRESS syndrome, it is justifiable to have doubts as to whether all cases consistent in clinical review were properly identified as DRESS syndrome. It is a valid assumption that a group of relevant cutaneous symptoms reported individually amounts to an acceptable diagnosis of DRESS syndrome. Most notably the timing of the manifestations is critical for the correct diagnosis [41]. Nonetheless all confirmed cases of hypersensitivity reactions should be reported in detail, as postmarketing surveillance and risk minimization requirements for biologics are set in place to ensure that long-term, real-world safety data are collected to assess biologics in clinical practice [42].\n\nThe diagnostic tools, including skin testing and in vitro testing, to evaluate for immediate hypersensitivity reactions remain insufficient [43]. Santiago et al. resorted to evaluating the safety and efficacy of patch testing in DRESS syndrome, thus attempting to identify a drug-dependent delayed hypersensitivity mechanism, but its application remains limited to DRESS syndrome induced by antiepileptic drugs [44]. Genotyping for HLA markers can be used as a screening tool before prescribing such potent drugs and can therefore prevent or at least mitigate DRESS syndrome in specific populations [45].\n\n6. Conclusion\nDRESS syndrome as such is very rare, but may be significantly underreported due to its complicated presentation. Given that the evidence for hypersensitivity reactions and immune dysregulation from biologics is not lacking, allergists, immunologists, and dermatologists should be involved in managing these patients to achieve optimal care. Certain genetic markers have high sensitivity and specificity, providing a plausible basis for the future development of tests to identify individuals at risk for biologic hypersensitivity.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nTable 1 Full results of the case study screen organized by reporter and monoclonal antibody.\n\nReporter\tMonoclonal Antibody\tCutaneous Adverse Effect\t\nRauer et. al.\tDaclizumab\tDRESS syndrome\t\n\n\n\t\n \tDaclizumab\tDRESS syndrome\t\n\n\n\t\nNaidoo et. al.\tNivolumab\tDrug-induced hypersensitivity dermatitis\t\n\n\n\t\n \tIpilimumab/Nivolumab\tMaculopapular rash, vesicles, erosions\t\n\n\n\t\n \tIpilimumab/Durvalumab\tLichenoid dermatitis, blisters, exanthema\t\n\n\n\t\nFontecilla et. al.\tDurvalumab/Tremelimumab\tEpidermal necrolysis, eosinophilic infiltrate\t\n\n\n\t\nOiwa et. al.\tIxekizumab\tPsoriasiform eruptions\t\n\n\n\t\nAnthony et. al.\tIxekizumab\tPruritic, photosensitive plaques\t\n\n\n\t\nMaria et. al.\tIxekizumab\tLentiginous eruption\t\n\n\n\t\nHayashida et. al.\tSecukinumab\tPemphigus vulgaris\t\n\n\n\t\nThompson et. al.\tSecukinumab\tUlcerative lichenoid mucositis\t\n\n\n\t\nAl Hammadi & Parmar\tDupilumab\tErythema, pruritus and diffuse skin peeling\t\n\n\n\t\nTakahashi et. al.\tBrodalumab\tPalmar pustular eruption\n==== Refs\n1 Harding F. A. Stickler M. M. Razo J. DuBridge R. B. The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions mAbs 2010 2 3 256 265 10.4161/mabs.2.3.11641 2-s2.0-77953658260 20400861 \n2 Radstake T. R. D. J. Svenson M. Eijsbouts A. M. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis Annals of the Rheumatic Diseases 2009 68 11 1739 1745 10.1136/ard.2008.092833 2-s2.0-70449725246 19019895 \n3 Brennan P. J. Rodriguez Bouza T. Hsu F. I. Sloane D. E. Castells M. C. Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment The Journal of Allergy and Clinical Immunology 2009 124 6 1259 1266 10.1016/j.jaci.2009.09.009 19910036 \n4 Gelincik A. Demir S. Şen F. Interleukin-10 is increased in successful drug desensitization regardless of the hypersensitivity reaction type Asia Pacific Allergy 2019 9 1, article no. e9 10.5415/apallergy.2019.9.e9 \n5 Peyriere H. Dereure O. Breton H. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? British Journal of Dermatology 2006 155 2 422 428 10.1111/j.1365-2133.2006.07284.x 16882184 \n6 Walsh S. A. Creamer D. Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking Clinical and Experimental Dermatology 2011 36 1 6 11 10.1111/j.1365-2230.2010.03967.x 2-s2.0-78650162681 21143513 \n7 Descamps V. Valance A. Edlinger C. Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms Archives of Dermatology 2001 137 3 301 304 11255328 \n8 Cho Y. Yang C. Chu C. Drug reaction with eosinophilia and systemic symptoms (DRESS): an interplay among drugs, viruses, and immune system International Journal of Molecular Sciences 2017 18 6 p. 1243 10.3390/ijms18061243 \n9 Thomas C. L. Arasaratnam M. Carlos G. Drug reaction with eosinophilia and systemic symptoms in metastatic basal cell carcinoma treated with vismodegib Australasian Journal of Dermatology 2017 58 1 69 70 2-s2.0-85012134628 10.1111/ajd.12472 \n10 Peuvrel L. Quéreux G. Saint-Jean M. Profile of vemurafenib-induced severe skin toxicities Journal of the European Academy of Dermatology and Venereology 2016 30 2 250 257 10.1111/jdv.13443 26524690 \n11 Kim Y. H. Bagot M. Pinter-Brown L. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial The Lancet Oncology 2018 19 9 1192 1204 30100375 \n12 Avasarala J. DRESS syndrome and daclizumab failure—were potentially dangerous signs missed in clinical trials? Drug Target Insights 2018 12 1177392818785136 10.1177/1177392818785136 \n13 Stork L. Brück W. von Gottberg P. Severe meningo-/encephalitis after daclizumab therapy for multiple sclerosis Multiple Sclerosis Journal 2019 10.1177/1352458518819098 \n14 Collins L. K. Chapman M. S. Carter J. B. Samie F. H. Cutaneous adverse effects of the immune checkpoint inhibitors Current Problems in Cancer 2017 41 2 125 128 2-s2.0-85012941098 10.1016/j.currproblcancer.2016.12.001 28190531 \n15 Rauer S. Stork L. Urbach H. Drug reaction with eosinophilia and systemic symptoms after daclizumab therapy Neurology 2018 91 4 e359 e363 10.1212/WNL.0000000000005854 29934423 \n16 Naidoo J. Schindler K. Querfeld C. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1 Cancer Immunology Research 2016 4 5 383 390 2-s2.0-84976354836 10.1158/2326-6066.CIR-15-0123 26928461 \n17 Fontecilla Natalia M. Khanna T. Bayan C. Y. Bullous pemphigoid associated with a new combination checkpoint inhibitor immunotherapy Journal of Drugs in Dermatology 2019 18 1 103 104 30681807 \n18 Oiwa T. Fujita M. Takase S. A case of ixekizumab-induced psoriasiform eruption Acta Dermato-Venereologica 2019 99 4 446 447 10.2340/00015555-3138 30723870 \n19 Anthony E. Rajgopal Bala H. Goh M. S. Balta S. Foley P. Ixekizumab-treatment-emergent photosensitive cutaneous eruption Australasian Journal of Dermatology 2018 59 4 e284 e286 10.1111/ajd.12811 29566260 \n20 María P. S. Valenzuela F. Morales C. De la Fuente R. Cullen R. Lentiginous eruption in resolving psoriasis plaques during treatment with ixekizumab: A case report and review of the literature Dermatology Reports 2017 9 2 43 45 2-s2.0-85039156681 \n21 Hayashida M. Z. Pinheiro J. R. S. Enokihara M. M. S. E. S. Vasconcellos M. R. D. A. Biologic therapy-induced pemphigus Anais Brasileiros de Dermatologia 2017 92 4 591 593 2-s2.0-85029876467 10.1590/abd1806-4841.20176481 28954128 \n22 Thompson J. M. Cohen L. M. Yang C. S. Kroumpouzos G. Severe, ulcerative, lichenoid mucositis associated with secukinumab JAAD Case Reports 2016 2 5 384 386 2-s2.0-84990064321 10.1016/j.jdcr.2016.07.009 27752531 \n23 Al Hammadi A. Parmar N. V. Erythema, pruritus, and diffuse peeling of skin during dupilumab therapy for atopic dermatitis in three adults International Journal of Dermatology 2018 58 1 e14 e15 10.1111/ijd.14296 30390308 \n24 Takahashi H. Sato K. Takagi A. Iizuka H. Brodalumab-induced palmar pustular eruption and joint swelling accompanied by muscle pains in two cases of psoriasis The Journal of Dermatology 2018 45 11 e325 e326 2-s2.0-85047491242 10.1111/1346-8138.14463 29767849 \n25 Krueger J. G. Kircik L. Hougeir F. Cutaneous adverse events in the randomized, double-blind, active-comparator DECIDE study of daclizumab high-yield process versus intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis Advances in Therapy 2016 33 7 1231 1245 10.1007/s12325-016-0353-2 2-s2.0-84973109385 27251051 \n26 Corneli H. M. DRESS syndrome: drug reaction with eosinophilia and systemic symptoms Pediatric Emergency Care 2017 33 7 499 502 10.1097/PEC.0000000000001188 2-s2.0-85024123117 28665896 \n27 Sarajärvi P. Kubin M. Tasanen K. Huilaja L. How to identify DRESS, drug reaction with eosinophilia and systemic symptoms? Duodecim 2017 133 1 43 51 29199808 \n28 Kardaun S. H. Sidoroff A. Valeyrie-Allanore L. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? British Journal of Dermatology 2007 156 3 609 611 10.1111/j.1365-2133.2006.07704.x 2-s2.0-33846997845 17300272 \n29 Behera S. K. Das S. Xavier A. S. Selvarajan S. DRESS syndrome: a detailed insight Hospital Practice 2018 46 3 152 162 10.1080/21548331.2018.1451205 29519170 \n30 Vervloet D. Durham S. Adverse reactions to drugs BMJ 1998 316 7143 p. 1511 2-s2.0-0032537307 10.1136/bmj.316.7143.1511 9582146 \n31 Tevrizian AT J. L. Ávila P. Parslow T. G. Stites D. P. Terr A. I. Imboden J. B. Drug allergy Medical Immunology 2001 10th New York, NY, USA McGraw Hill 294 400 \n32 Nagao-Dias A. T. Barros-Nunes P. Coelho H. L. L. Solé D. Allergic drug reactions Jornal de Pediatria 2004 80 4 259 266 2-s2.0-16644384289 10.2223/1198 15309226 \n33 Chen C.-B. Abe R. Pan R.-Y. An updated review of the molecular mechanisms in drug hypersensitivity Journal of Immunology Research 2018 2018 22 6431694 10.1155/2018/6431694 \n34 Leach M. W. Rottman J. B. Hock M. B. Finco D. Rojko J. L. Beyer J. C. Immunogenicity/Hypersensitivity of Biologics Toxicologic Pathology 2014 42 1 293 300 10.1177/0192623313510987 24240973 \n35 Descotes J. Gouraud A. Clinical immunotoxicity of therapeutic proteins Expert Opinion on Drug Metabolism & Toxicology 2008 4 12 1537 1549 2-s2.0-58149191484 10.1517/17425250802525496 19040329 \n36 Choquet-Kastylevsky G. Intrator L. Chenal C. Bocquet H. Revuz J. Roujeau J.-C. Increased levels of interleukin 5 are associated with the generation of eosinophilia in drug-induced hypersensitivity syndrome British Journal of Dermatology 1998 139 6 1026 1032 2-s2.0-0032420752 10.1046/j.1365-2133.1998.02559.x 9990366 \n37 Bagchi A. Haidar J. N. Eastman S. W. Molecular basis for necitumumab inhibition of EGFR variants associated with acquired cetuximab resistance Molecular Cancer Therapeutics 2018 17 2 521 531 10.1158/1535-7163.MCT-17-0575 29158469 \n38 Cortese I. Ohayon J. Fenton K. Cutaneous adverse events in multiple sclerosis patients treated with daclizumab Neurology 2016 86 9 847 855 2-s2.0-84959496129 10.1212/WNL.0000000000002417 26843560 \n39 Eshki M. Allanore L. Musette P. Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of unpredictable multiorgan failure JAMA Dermatology 2009 145 1 67 72 10.1001/archderm.145.1.67 2-s2.0-58849091724 \n40 Seth D. Kamat D. Montejo J. DRESS syndrome: A practical approach for primary care practitioners Clinical Pediatrics 2008 47 9 947 952 2-s2.0-53249134745 10.1177/0009922808320703 18648083 \n41 Descamps V. Ranger-Rogez S. DRESS syndrome Joint Bone Spine 2014 81 1 15 21 2-s2.0-84893747138 10.1016/j.jbspin.2013.05.002 23816504 \n42 Uhlig T. Goll G. L. Reviewing the evidence for biosimilars: key insights, lessons learned and future horizons Rheumatology 2017 56 49 62 10.1093/rheumatology/kex276 \n43 Patel S. V. Khan D. A. Adverse reactions to biologic therapy Immunology and Allergy Clinics of North America 2017 37 2 397 412 10.1016/j.iac.2017.01.012 28366484 \n44 Santiago F. Gonçalo M. Vieira R. Coelho S. Figueiredo A. Epicutaneous patch testing in drug hypersensitivity syndrome (DRESS) Contact Dermatitis 2010 62 1 47 53 2-s2.0-74949129204 10.1111/j.1600-0536.2009.01659.x 20136879 \n45 Choudry S. McLeod M. Romanelli P. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome Journal of Clinical and Aesthetic Dermatology 2013 6 6 31 37 23882307\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-0430",
"issue": "2019()",
"journal": "Autoimmune diseases",
"keywords": null,
"medline_ta": "Autoimmune Dis",
"mesh_terms": null,
"nlm_unique_id": "101546750",
"other_id": null,
"pages": "7595706",
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"pmid": "31308976",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D016454:Review",
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"title": "Case Reports of DRESS Syndrome and Symptoms Consistent with DRESS Syndrome Following Treatment with Recently Marketed Monoclonal Antibodies.",
"title_normalized": "case reports of dress syndrome and symptoms consistent with dress syndrome following treatment with recently marketed monoclonal antibodies"
} | [
{
"companynumb": "US-ASTRAZENECA-2018SE88902",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstance": {
"activesubstancename": "DURVALUMAB"
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{
"abstract": "We report a 10-year-old patient with haemophilia A developing anaphylaxis to recombinant factor VIII (octocog alfa). Allergic reactions, and especially anaphylactic events, are rare in patients with haemophilia A. The nature of these reactions is not fully understood. Here, we demonstrate a type I hypersensitivity reaction using sodium dodecyl sulfate-polyacrylamide gel electrophoresis immunoblotting assay. This test revealed itself as an essential diagnostic tool, as it allowed us to choose an alternative treatment (moroctocog alfa). Its safety was later confirmed by an uneventful challenge test.",
"affiliations": "Pediatric Department, Hospital Pediátrico de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Haematology Department, Hospital Pediátrico de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Pediatric Department, Hospital Pediátrico de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Application Lab, R&D Department, Roxall Group, Bilbao, Spain.",
"authors": "Pires|Sofia|S|http://orcid.org/0000-0002-7621-5732;Sevivas|Teresa|T|;Loureiro|Carla Chaves|CC|http://orcid.org/0000-0002-6326-8173;Bartholomé|Borja|B|",
"chemical_list": "C427184:recombinant factor VIII SQ; D005169:Factor VIII",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227426",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "11(1)",
"journal": "BMJ case reports",
"keywords": "paediatrics (drugs and medicines); unwanted effects/adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000707:Anaphylaxis; D002648:Child; D005169:Factor VIII; D005383:Finger Injuries; D006406:Hematoma; D006467:Hemophilia A; D006801:Humans; D008297:Male; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30567269",
"pubdate": "2018-12-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9461372;10215966;25929310;8623140;10919414;6160766;19486169;17212734;519841",
"title": "Anaphylaxis after treatment with recombinant factor VIII: investigation and therapeutic challenge.",
"title_normalized": "anaphylaxis after treatment with recombinant factor viii investigation and therapeutic challenge"
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"abstract": "Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a newer and effective therapeutic option approved for patients with relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Acute kidney injury is a complication of CAR T-cell therapy that can result in kidney failure. In most cases, it is thought to be related to hemodynamic changes due to cytokine release syndrome. Kidney biopsy in this clinical scenario is usually not performed. We report on a kidney transplant recipient in his 40s who developed a posttransplant lymphoproliferative disorder of B-cell origin refractory to conventional treatments and received anti-CD19 CAR T-cell therapy as compassionate treatment. Beginning on day 12 after CAR T-cell infusion, in the absence of clinical symptoms, a progressive decline in estimated glomerular filtration rate of the kidney graft occurred. A subsequent allograft biopsy showed mild tubulointerstitial lymphocyte infiltrates, falling into a Banff borderline-changes category and resembling an acute immunoallergic tubulointerstitial nephritis. Neither CAR T cells nor lymphomatous B cells were detected within the graft cellular infiltrates, suggesting an indirect mechanism of kidney injury. Although kidney graft function partially recovered after steroid therapy, the posttransplant lymphoproliferative disorder progressed and the patient died 7 months later.",
"affiliations": "Nephrology Department, Bellvitge University Hospital-Hospitale, Barcelona, Spain.;Institut de Investigació Biomedica de Bellvitge (IDIBELL)-Hospitalet, Barcelona, Spain.;Institut de Investigació Biomedica de Bellvitge (IDIBELL)-Hospitalet, Barcelona, Spain.;Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA.;IHC/ISH Oncology Precision Medicine, Novartis Group, Cambridge, MA.;IHC/ISH Oncology Precision Medicine, Novartis Group, Cambridge, MA.;Pathology Department, Bellvitge University Hospital-Hospitalet, Barcelona, Spain.;Nephrology Department, Bellvitge University Hospital-Hospitale, Barcelona, Spain.;Nephrology Department, Bellvitge University Hospital-Hospitale, Barcelona, Spain.;Nephrology Department, Bellvitge University Hospital-Hospitale, Barcelona, Spain.;Pathology Department, Bellvitge University Hospital-Hospitalet, Barcelona, Spain.;Nephrology Department, Bellvitge University Hospital-Hospitale, Barcelona, Spain.;Nephrology Department, Bellvitge University Hospital-Hospitale, Barcelona, Spain.;Nephrology Department, Bellvitge University Hospital-Hospitale, Barcelona, Spain.;Institut de Investigació Biomedica de Bellvitge (IDIBELL)-Hospitalet, Barcelona, Spain.;Nephrology Department, Bellvitge University Hospital-Hospitale, Barcelona, Spain.",
"authors": "Melilli|Edoardo|E|;Mussetti|Alberto|A|;Linares|Gabriela Sanz|GS|;Ruella|Marco|M|;La Salette|Charette|C|;Savchenko|Alexandre|A|;Taco|Maria Del Rosario|MDR|;Montero|Nuria|N|;Grinyo|Josep|J|;Fava|Alex|A|;Gomà|Montse|M|;Meneghini|Maria|M|;Manonelles|Anna|A|;Cruzado|Josepmaria|J|;Sureda|Ana|A|;Bestard|Oriol|O|",
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"doi": "10.1016/j.xkme.2021.03.011",
"fulltext": "\n==== Front\nKidney Med\nKidney Med\nKidney Medicine\n2590-0595\nElsevier\n\nS2590-0595(21)00101-1\n10.1016/j.xkme.2021.03.011\nCase Report\nAcute Kidney Injury Following Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphoma in a Kidney Transplant Recipient\nMelilli Edoardo emelilli@bellvitgehospital.cat\n12∗\nMussetti Alberto 23\nLinares Gabriela Sanz 23\nRuella Marco 45\nLa Salette Charette 6\nSavchenko Alexandre 6\nTaco Maria del Rosario 7\nMontero Nuria 1\nGrinyo Josep 1\nFava Alex 1\nGomà Montse 7\nMeneghini Maria 1\nManonelles Anna 1\nCruzado Josepmaria 1\nSureda Ana 23\nBestard Oriol 12\n1 Nephrology Department, Bellvitge University Hospital–Hospitale, Barcelona, Spain\n2 Institut de Investigació Biomedica de Bellvitge (IDIBELL)–Hospitalet, Barcelona, Spain\n3 Clinical Hematology Department, Institut Català d'Oncologia–Hospitalet, Barcelona, Spain\n4 Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA\n5 Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA\n6 IHC/ISH Oncology Precision Medicine, Novartis Group, Cambridge, MA\n7 Pathology Department, Bellvitge University Hospital–Hospitalet, Barcelona, Spain\n∗ Address for Correspondence: Edoardo Melilli, MD, PhD, Nephrology Department, Bellvitge University Hospital, Feixa llarga s/n 08907, L’Hospitalet de Llobregat, Barcelona, Spain. emelilli@bellvitgehospital.cat\n28 5 2021\nJul-Aug 2021\n28 5 2021\n3 4 665668\n© 2021 The Authors\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/).\nAnti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a newer and effective therapeutic option approved for patients with relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Acute kidney injury is a complication of CAR T-cell therapy that can result in kidney failure. In most cases, it is thought to be related to hemodynamic changes due to cytokine release syndrome. Kidney biopsy in this clinical scenario is usually not performed. We report on a kidney transplant recipient in his 40s who developed a posttransplant lymphoproliferative disorder of B-cell origin refractory to conventional treatments and received anti-CD19 CAR T-cell therapy as compassionate treatment. Beginning on day 12 after CAR T-cell infusion, in the absence of clinical symptoms, a progressive decline in estimated glomerular filtration rate of the kidney graft occurred. A subsequent allograft biopsy showed mild tubulointerstitial lymphocyte infiltrates, falling into a Banff borderline-changes category and resembling an acute immunoallergic tubulointerstitial nephritis. Neither CAR T cells nor lymphomatous B cells were detected within the graft cellular infiltrates, suggesting an indirect mechanism of kidney injury. Although kidney graft function partially recovered after steroid therapy, the posttransplant lymphoproliferative disorder progressed and the patient died 7 months later.\n\nIndex Words\n\nPTLD\nposttransplant lymphoproliferative disorder\nkidney transplant\nT-cell therapy\nB-cell lymphoma\n==== Body\nIntroduction\n\nPosttransplant lymphoproliferative disorder represents a rare but serious complication after organ transplantation.1 Treatment includes reduction or withdrawal of immunosuppression followed by rituximab with or without chemotherapy.2,3 Transplant recipients who fail to respond or relapse after conventional treatments have a poor prognosis.4 Chimeric antigen receptor (CAR) T cells directed against CD19 surface antigen represent a recent type of autologous adoptive transfer cell therapy currently approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma and other hematologic malignancies.5, 6, 7, 8 Apart from cytokine release syndrome and neurotoxicity,9,10 other adverse events have been described, including acute kidney injury (AKI) and electrolyte level abnormalities.11 Recently, several solid-organ transplant recipients treated with CAR T-cell therapy were reported.12 We describe the case of a kidney transplant recipient who developed severe AKI after CAR T-cell therapy. A kidney biopsy was performed, helping clarify the pathogenesis of this unique case.\n\nCase report\n\nA kidney transplant recipient in his 40s was diagnosed with monomorphic type B-cell posttransplant lymphoproliferative disorder approximately 18 years after transplantation; induction therapy included basiliximab. He had a large abdominal mass and supraclavicular lymphadenopathy but no additional organ involvement was detected with staging positron emission tomography computed tomography. He was classified with Ann Arbor stage IVB disease, with an international prognostic score of 2. Histologic characterization of malignant cells showed the following: CD20+, CD79+, CD10+, bcl6+, bcl2+, p53+, c-myc+, CD3−, and CD5−. Additionally, Epstein-Barr virus–encoded small RNA and human herpesvirus-8 were negative. Fluorescence in situ hybridization was positive for BCL2 but negative for either BCL6 or c-MYC. Ki67 expression was >80%.\n\nImmunosuppression was reduced, with tacrolimus switched to everolimus and mycophenolate mofetil dose decreased to 50%. Four weekly infusions of rituximab were administered. Due to disease progression, he subsequently received 3 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) immunochemotherapy. Everolimus was reduced to 50% and mycophenolate mofetil therapy was discontinued. Due to disease persistence, intensification treatment with 2 cycles of R-GDP (rituximab, gemcitabine, dexamethasone, and cisplatin) immunochemotherapy was administered and, with the exception of 5 mg of prednisone daily, immunosuppression was discontinued. Autologous hematopoietic stem cell transplantation consolidation was performed but relapse was observed in positron emission tomography computed tomography performed 3 months after autologous hematopoietic stem cell transplantation.\n\nApproximately 28 months after the initial diagnosis, the patient received lymphodepletion chemotherapy with intravenous fludarabine and intravenous cyclophosphamide for 3 days, followed by CAR T-cell therapy (tisagenlecleucel) infusion. The patient developed grade 3 neutropenia without significant acute complications. Baseline creatinine level was 1.5 mg/dL. At day 12 after CAR T-cell infusion, serum creatinine and C-reactive protein levels began to increase, without relevant symptoms and without oliguria (Fig 1). Neither cytokine release syndrome nor immune effector cell–associated neurotoxicity syndrome were observed. All potentially nephrotoxic drugs (omeprazole and acyclovir) were stopped. Proteinuria was protein excretion of 0.4 g/d, and sediment showed mild leukocyturia with no erythrocytes. Myoglobin and creatine kinase levels were within the normal range. Polymerase chain reaction for cytomegalovirus was negative. Doppler ultrasound showed a mild increase in kidney echogenicity, with normal resistive index and no sign of obstruction. Calculated panel-reactive antibody level at the time of biopsy was 39% for the presence of alloantibodies against class II, without donor-specific antibodies.Figure 1 (A) C-Reactive protein and (B) creatinine level evolution during follow-up. Abbreviation: CAR-T, chimeric antigen receptor T-cell.\n\nOn day 21 after CAR T-cell therapy administration, serum creatinine level had increased to 6 mg/dL and a kidney biopsy was performed; C-reactive protein level was 43 mg/dL at that time. The biopsy showed interstitial fibroedema with moderate mononuclear infiltrates and patchy tubular injury with epithelial thinning, coarse cytoplasmic vacuolization, and mild isolated tubulitis. Arteriolar changes were prominent and demonstrated periodic acid–Schiff–positive hyaline deposits deep in muscle layers. Glomeruli were unremarkable. C4d and immunoglobulins were negative on direct immunofluorescence. Immunohistochemical staining for simian virus 40 was negative. Banff classification was compatible with borderline changes not grading 1A acute cellular rejection (Fig S1). The presumptive diagnosis was acute borderline changes in the context of mild alloimmune rejection versus acute immunoallergic interstitial nephritis.\n\nWe next aimed to characterize the origin of the lymphocytic infiltrate in the kidney biopsy. As shown in Fig 2, lymphocytic infiltrate was comprised exclusively of CD3+ lymphocytes, with no CD19+ cells. RNA-scope, a technique used to evaluate the expression of the gene encoding the engineered CAR, did not show evidence of CAR T-cell–19 infiltration in the kidney. Aiming to reduce lymphocytic infiltrates but also preserve CAR T-cell function, prednisone was initiated at a dose of 1 mg/kg per day.13 Kidney allograft function partially recovered, reaching a nadir of 3.17 mg/dL after 60 days (Fig 2), whereas proteinuria was unchanged. Prednisone dosage was progressively tapered to 10 mg per day by 40 days after the kidney biopsy. At 30 and 60 days following CAR T-cell therapy, peripheral-blood CD19+ B-cell counts were undetectable. The patient died approximately 3 years after the initial posttransplant lymphoproliferative disorder diagnosis due to progression of the malignancy.Figure 2 (A) Absence of chimeric antigen receptor (CAR) T cells using RNA scope in situ hybridization. (B) Presence of CD3 cells in kidney tissue. (C) Absence of CD19 cells.\n\nDiscussion\n\nTo our knowledge, this is the first report of a kidney biopsy performed in a kidney transplant recipient treated with anti-CD19 CAR T-cell therapy. The main acute treatment-related toxicity was KDIGO (Kidney Disease: Improving Global Outcomes) stage III AKI14 that partially recovered with steroid therapy. AKI has been reported in 19% to 30% of patients undergoing CAR T-cell therapy.12,15 The occurrence of AKI after CAR T-cell therapy is thought to be functional, secondary to arterial hypotension in the context of cytokine release syndrome. Nonetheless, more severe AKI episodes are likely due to the persistence of severe hemodynamic alterations leading to acute tubular necrosis,16 but none of these studies provided data on the histopathology of the kidney injury.\n\nRecently, a study reported that among patients with B-cell lymphoproliferative disorders and kidney lymphoma infiltration, AKI was common.17 This observation raises the concern that CAR T-cell therapy might damage the kidney by recognizing kidney tissue–resident B cells. In our case, we did not observe B-cell infiltration in the kidney on a kidney biopsy performed 3 weeks after CAR T-cell therapy infusion. Importantly, no CAR19 RNA was detected, thereby excluding the presence of CAR T-cells in the kidney allograft at the time of the kidney biopsy. Findings observed in the graft histology could have been promoted by a CAR T-cell–induced systemic inflammatory status, thus explaining the resemblance to an acute immunoallergic tubulointerstitial nephritis. Alternatively, biopsy findings could reflect an alloimmune response stimulated by cognate T cell with endogenous lymphocyte inducing an acute cellular rejection. We decided to use steroids to manage this complication, observing partial recovery of graft function that was sufficient to prevent dialysis therapy and potentially preserve CAR T-cell function, as demonstrated by the absence of peripheral-blood CD19+ cells.18 Although proton pump inhibitor use has been associated with AKI in patients treated by immune-checkpoint inhibitors19 through a second-hit mechanism, no similar data have been reported with CAR T-cell therapy, suggesting that proton pump inhibitor use was not likely the cause of AKI.\n\nIn conclusion, although there was no evidence of damage mediated by direct infiltration of CAR T-cells in the kidney, our case suggests that this new therapy could generate kidney graft failure through an indirect inflammatory and/or immune-mediated mechanism, stressing the central role of the kidney biopsy to guide therapy.\n\nSupplementary Material\n\nSupplementary File (PDF)\n\nFigure S1.\n\nArticle Information\n\nAuthors’ Full Names and Academic Degrees\n\nEdoardo Melilli, MD, PhD, Alberto Mussetti, MD, Gabriela Sanz Linares, MD, Marco Ruella, MD, PhD, Charette La Salette, PhD, Alexandre Savchenko, PhD, Maria del Rosario Taco, MD, Nuria Montero, MD, PhD, Josep Grinyo, MD, PhD, Alex Fava, MD, Montse Gomà, MD, Maria Meneghini, MD, Anna Manonelles, MD, PhD, Josepmaria Cruzado, MD, PhD, Ana Sureda, MD, PhD, and Oriol Bestard, MD, PhD.\n\nAuthors’ Contributions\n\nDrs Melilli and Mussetti contributed equally to this work.\n\nSupport\n\nWe thank CERCA Program/Generalitat de Catalunya and the ISCIII RETICS RedinRen RD16/0009/0003 for institutional support.\n\nFinancial Disclosure\n\nDr Mussetti received research funding from Gilead and honoraria for lectures from Novartis. Dr Melilli received research funding from Chiesi and honoraria for lectures from Novartis, Astellas, and Menarini. Dr Ruella has intellectual property in the field of CART immunotherapy that is licensed to Novartis and Tmunity and managed by the University of Pennsylvania and received honoraria and consulting fees by AbClon, BMS, and Nanostring.\n\nAcknowledgements\n\nWe are grateful to the patient and his family; during the course of the disease and after the patient’s death, they always granted permission to share the patient’s history with the scientific community. We thank Novartis Precision Medicine for collaboration in the renal biopsy analysis and imaging.\n\nPatient Protections\n\nThe authors declare that they have obtained consent from a relative with appropriate authority for publication of the information about the patient that appears within this Case Report and any associated supplementary material.\n\nPeer Review\n\nReceived December 10, 2020, as a submission to the expedited consideration track with 2 external peer reviews. Direct editorial input from an Associate Editor and the Editor-in-Chief. Accepted in revised form March 14, 2021.\n\nComplete author and article information provided before references.\n\nSupplementary File (PDF)\n\nFigure S1. Hematoxylin and eosin stain of kidney tissue. Banff score was compatible with borderline changes (g0, i1-2, ti1-2, i-IFTA1-2, t1, v 0, ptc0, ah3, aah3, cg0, ci0, ct0, cv0, and mm0).\n==== Refs\nReferences\n\n1 Opelz G. Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report Am J Transplant 4 2004 222 230 14974943\n2 Vikas R. Dharnidharka D. Comprehensive review of post-organ transplant hematologic cancers Am J Transplant 18 3 2018 537 549 29178667\n3 Dierickx D. Habermann T. Post-transplantation lymphoproliferative disorders in adults N Engl J Med 378 6 2018 549 562 29414277\n4 González-Barca E. Capote F.J. Gómez-Codina J. Long-term follow-up of a prospective phase 2 clinical trial of extended treatment with rituximab in patients with B cell post-transplant lymphoproliferative disease and validation in real world patients Ann Hematol 100 4 2021 1023 1029 32367180\n5 Maude S.L. Laetsch T.W. Buechner J. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia N Engl J Med 378 5 2018 439 448 29385370\n6 Locke F. Ghobadi A. Jacobson C.A. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial Lancet Oncol 20 1 2019 31 42 30518502\n7 Schuster S.J. Bishop M. Tam C. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma N Engl J Med 380 2019 45 56 30501490\n8 Wang M. Munoz J. Goy A. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma N Engl J Med 382 2020 1331 1342 32242358\n9 Neelapu S. Tummala S. Kebriae P. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities Nat Rev Clin Oncol 15 1 2018 47 62 28925994\n10 Brudno J. Kochenderfer J.K. Chimeric antigen receptor T-cell therapies for lymphoma Nat Rev Clin Oncol 15 1 2018 31 46 28857075\n11 Gupta S. Seethapathy H. Strohbehn I.A. Acute kidney injury and electrolyte abnormalities after chimeric antigen receptor T-cell (CAR-T) therapy for diffuse large B-cell lymphoma Am J Kidney Dis 76 1 2020 63 71 31973908\n12 Krishnamoorthy S. Ghobadi A. Delos Santos R. CAR-T therapy in solid organ transplant recipients with treatment refractory post transplant lymphoproliferative disorder Am J Transplant 21 2 2021 809 814 33089906\n13 Bassil C. Khimani F. Immunotherapy use in kidney transplant recipients: immune checkpoint inhibitors and CAR-T cell therapy J Onconephrol 4 3 2020 165 170\n14 Aspelin P. Barsoum R.S. Burdmann E.A. KDIGO clinical practice guideline for acute kidney injury Accessed January 3, 2021 https://kdigo.org/wpcontent/uploads/2016/10/KDIGO-2012-AKI-Guideline-English.pdf\n15 Gutgarts V. Jain T. Zheng J. Acute kidney injury after CAR-T cell therapy: low incidence and rapid recovery Biol Blood Marrow Transplant 26 6 2020 1071 1076 32088364\n16 Jhaveri K.D. Rosner M.H. Chimeric antigen receptor T cell therapy and the kidney: what the nephrologist needs to know Clin J Am Soc Nephrol 13 5 2018 796 798 29523675\n17 Javaugue V. Debiais-Delpech C. Nouvier M. Clinicopathological spectrum of renal parenchymal involvement in B-cell lymphoproliferative disorders Kidney Int 96 1 2019 94 103 30987838\n18 Liu S. Deng B. Yin Z. Corticosteroids do not influence the efficacy and kinetics of CAR-T cells for B-cell acute lymphoblastic leukemia Blood Cancer J 10 2 2020 15 32029707\n19 Seethapathy H. Zhao S. Chute D. The incidence, causes, and risk factors of acute kidney injury in patients receiving immune checkpoint inhibitors Clin J Am Soc Nephrol 14 12 2019 1692 1700 31672794\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2590-0595",
"issue": "3(4)",
"journal": "Kidney medicine",
"keywords": "B-cell lymphoma; PTLD; T-cell therapy; kidney transplant; posttransplant lymphoproliferative disorder",
"medline_ta": "Kidney Med",
"mesh_terms": null,
"nlm_unique_id": "101756300",
"other_id": null,
"pages": "665-668",
"pmc": null,
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"references": "29385370;29414277;29523675;28857075;31973908;32029707;30501490;32088364;28925994;32367180;32242358;30518502;33089906;31672794;29178667;14974943;30987838",
"title": "Acute Kidney Injury Following Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphoma in a Kidney Transplant Recipient.",
"title_normalized": "acute kidney injury following chimeric antigen receptor t cell therapy for b cell lymphoma in a kidney transplant recipient"
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"abstract": "There are only three cases in the literature that describe development of neurosarcoidosis in a patient who is on tumour necrosis factor α inhibitors. We describe a case of a 33-year-old woman with a history of juvenile rheumatoid arthritis and refractory uveitis (with previous treatment trials of adalimumab, infliximab, mycophenolate, methotrexate) who had been stable for 2 years on etanercept. She was diagnosed with biopsy-proven systemic sarcoidosis with meningeal and parenchymal neurosarcoidosis. She was switched to infliximab and methotrexate, with clinical and imaging improvements. This is a case that demonstrates the difficulty of choosing tumour necrosis factor α (TNF-α) inhibitors when treating patients with multiple clinical autoimmune entities. It is also a case where a change in the mechanism of TNF-α inhibition pathway can still be used to treat refractory sarcoidoisis and rheumatoid arthritis. It is still unclear what the exact difference between the TNF-α blockers and their neurological complications is, and who the patients at risk of developing neurological complications are.",
"affiliations": "Department of Neurology, University of Massachusetts School of Medicine, Worcester, Massachusetts, USA.;Department of Neurology, University of Massachusetts School of Medicine, Worcester, Massachusetts, USA.;Department of Neurology, University of Massachusetts School of Medicine, Worcester, Massachusetts, USA.;Department of Neurology, University of Massachusetts School of Medicine, Worcester, Massachusetts, USA.",
"authors": "Berrios|Idanis|I|;Jun-O'Connell|Adalia|A|;Ghiran|Sorina|S|;Ionete|Carolina|C|",
"chemical_list": "D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068800:Etanercept; D008727:Methotrexate",
"country": "England",
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"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D001171:Arthritis, Juvenile; D002493:Central Nervous System Diseases; D003072:Cognition Disorders; D000068800:Etanercept; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008727:Methotrexate; D012507:Sarcoidosis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D014605:Uveitis",
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"title": "A case of neurosarcoidosis secondary to treatment of etanercept and review of the literature.",
"title_normalized": "a case of neurosarcoidosis secondary to treatment of etanercept and review of the literature"
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"abstract": "Ethnic evaluation of the pharmacokinetics and safety of new drugs is required in Japan before implementing bridging or joining global studies. As therapeutic monoclonal antibodies (mAbs) show limited ethnic differences, their pharmacokinetics and safety in Japanese individuals could be estimated from prior non-Japanese studies. Therefore, there is potential to re-evaluate the development program for mAbs in Japan. We reviewed the pharmacokinetics of mAbs approved in Japan. Although some differences had been observed in pharmacokinetics of mAbs between Japanese and non-Japanese populations (mainly Caucasians), these differences were attributed to differences of body weight and/or antigen levels. Moreover, the influential factors can be estimated without conducting regional pharmacokinetic/safety studies. The pharmacokinetics of some mAbs is presumably non-linear and show differences between healthy volunteers and patients because of differences in antigen levels. However, for 10/24 mAbs approved in Japan, Japanese healthy volunteer studies were conducted before the patient studies. Additionally, for the mAbs that showed ethnic differences in pharmacokinetics, the doses selected in subsequent patient studies were the same as the doses approved in the United States. In this review, we discuss new drug development strategies in various regions, and assess the need for regional pharmacokinetics/safety studies before joining global studies.",
"affiliations": "Laboratory of Clinical Pharmacology, Yokohama College of Pharmacy, Yokohama, Japan.;Discovery Medicine & Clinical Pharmacology, Research & Development, Bristol-Myers Squibb, Princeton, NJ, USA.;Department of Drug Development and Regulatory Science, Keio University Graduate School of Pharmaceutical Science, Tokyo, Japan.;Clinical Research Planning Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.;Clinical Research Planning Department, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.;Clinical Sciences, Bayer Pharma AG, Berlin, Germany.;Department of Drug Development and Regulatory Science, Keio University Graduate School of Pharmaceutical Science, Tokyo, Japan.;DMCP, Clinical Research, Bristol-Myers K.K., Tokyo, Japan.",
"authors": "Chiba|Koji|K|;Yoshitsugu|Hiroyuki|H|;Kyosaka|Yuto|Y|;Iida|Satofumi|S|;Yoneyama|Koichiro|K|;Tanigawa|Takahiko|T|;Fukushima|Takashi|T|;Hiraoka|Masaki|M|",
"chemical_list": "D000911:Antibodies, Monoclonal",
"country": "England",
"delete": false,
"doi": "10.1002/jcph.231",
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"issn_linking": "0091-2700",
"issue": "54(5)",
"journal": "Journal of clinical pharmacology",
"keywords": "Japan; monoclonal antibody preparations; regulatory affairs",
"medline_ta": "J Clin Pharmacol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D017321:Clinical Trials, Phase I as Topic; D017277:Drug Approval; D005006:Ethnicity; D006801:Humans; D007564:Japan",
"nlm_unique_id": "0366372",
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"title": "A comprehensive review of the pharmacokinetics of approved therapeutic monoclonal antibodies in Japan: Are Japanese phase I studies still needed?",
"title_normalized": "a comprehensive review of the pharmacokinetics of approved therapeutic monoclonal antibodies in japan are japanese phase i studies still needed"
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"abstract": "Factor VII (FVII) deficiency is the most prevalent rare bleeding disorder in the USA and affects approximately 1 out of every 500,000 people. Warfarin inhibits the synthesis of FVII, in addition to other clotting factors. Warfarin is contraindicated in patients with bleeding tendencies or blood dyscrasias; therefore, the literature regarding the use of warfarin in FVII deficiency is very limited. We report a successful re-challenge of warfarin therapy in a patient with FVII deficiency. A 70-year-old woman with FVII deficiency experienced a significant decrease in FVII activity and subsequent vaginal bleeding roughly 5 weeks after starting warfarin for atrial fibrillation. The patient was switched to aspirin therapy. Nearly 4 years later, warfarin therapy was re-attempted by a different haematologist. After 9 months, FVII activity remained in an acceptable range and no bleeding events had occurred. In addition, once the maintenance dose was established, the international normalized ratio remained within the goal range (1.5-2.0) for the majority of assessments. Regarding future considerations, we hypothesize that anticoagulants that do not directly affect FVII, such as the direct oral anticoagulants, would carry less risk of bleeding complications and therefore may be safer alternatives to warfarin to reduce the risk of thromboembolic stroke in patients with atrial fibrillation and FVII deficiency.",
"affiliations": "Advocate Medical Group, Chicago, IL, USA. eric.paulus@advocatehealth.com.;Midwestern University Chicago College of Pharmacy, 555 31st Street, Downers Grove, IL, 60515, USA.;Midwestern University Chicago College of Pharmacy, 555 31st Street, Downers Grove, IL, 60515, USA.;Midwestern University Chicago College of Pharmacy, 555 31st Street, Downers Grove, IL, 60515, USA.",
"authors": "Paulus|Eric|E|;Komperda|Kathy|K|;Park|Gabriel|G|;Fusco|Julie|J|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.1007/s40800-016-0031-y",
"fulltext": "\n==== Front\nDrug Saf Case RepDrug Saf Case RepDrug Safety - Case Reports2199-11622198-977XSpringer International Publishing Cham 277476883110.1007/s40800-016-0031-yCase ReportAnticoagulation Therapy Considerations in Factor VII Deficiency Paulus Eric +1-312-8085585eric.paulus@advocatehealth.comejpaulus@gmail.com 1Komperda Kathy 2Park Gabriel 2Fusco Julie 21 Advocate Medical Group, Chicago, IL USA 2 Midwestern University Chicago College of Pharmacy, 555 31st Street, Downers Grove, IL 60515 USA 8 8 2016 8 8 2016 12 2016 3 8© 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.Factor VII (FVII) deficiency is the most prevalent rare bleeding disorder in the USA and affects approximately 1 out of every 500,000 people. Warfarin inhibits the synthesis of FVII, in addition to other clotting factors. Warfarin is contraindicated in patients with bleeding tendencies or blood dyscrasias; therefore, the literature regarding the use of warfarin in FVII deficiency is very limited. We report a successful re-challenge of warfarin therapy in a patient with FVII deficiency. A 70-year-old woman with FVII deficiency experienced a significant decrease in FVII activity and subsequent vaginal bleeding roughly 5 weeks after starting warfarin for atrial fibrillation. The patient was switched to aspirin therapy. Nearly 4 years later, warfarin therapy was re-attempted by a different haematologist. After 9 months, FVII activity remained in an acceptable range and no bleeding events had occurred. In addition, once the maintenance dose was established, the international normalized ratio remained within the goal range (1.5–2.0) for the majority of assessments. Regarding future considerations, we hypothesize that anticoagulants that do not directly affect FVII, such as the direct oral anticoagulants, would carry less risk of bleeding complications and therefore may be safer alternatives to warfarin to reduce the risk of thromboembolic stroke in patients with atrial fibrillation and FVII deficiency.\n\nissue-copyright-statement© The Author(s) 2016\n==== Body\nKey Points\n\nWe observed a successful re-challenge of warfarin therapy in a patient with atrial fibrillation and factor VII (FVII) deficiency.\t\nChallenges with using warfarin therapy in FVII deficiency include lack of a defined optimal target international normalized ratio range and a poor correlation between the degree of FVII deficiency and bleeding risk.\t\nWe hypothesize anticoagulants which do not directly affect FVII, such as the direct oral anticoagulants, may carry less risk of bleeding complications than warfarin to reduce the risk of thromboembolic stroke in patients with atrial fibrillation and FVII deficiency.\t\n\n\n\nIntroduction\nThe coagulation pathway is a complex system and is an essential part of haemostasis [1]. It involves a number of enzymatic steps, which activate circulating clotting factors, ultimately leading to clot formation (see Fig. 1). Coagulation is typically initiated through the extrinsic pathway when tissue injury exposes tissue factor. Circulating factor VII (FVII) binds to tissue factor, and the resulting complex becomes activated FVII (FVIIa). FVIIa then directly catalyses the conversion of factor X to factor Xa (FXa) in the common pathway and indirectly via the activation of factor IX to factor IXa. While the extrinsic pathway initiates haemostasis, sustained haemostasis is dependent upon the continued and amplified procoagulant action of the intrinsic pathway, which involves factors VIII, IX, XI and XII [2, 3].Fig. 1 Effects of multiple anticoagulant medications on the coagulation cascade\n\n\n\n\nGiven the complex nature of the coagulation pathway, one can appreciate the complexity of coagulation disorders. Classical bleeding disorders include haemophilia A and B; however, a number of rare bleeding disorders (RBDs) exist [4]. RBDs represent only about 3–5 % of inherited coagulation deficiencies and include deficiencies in fibrinogen; factors II, V, V + VIII, VII, X and XIII; and a combination of the vitamin K-dependent factors [5]. The most prevalent RBD is FVII deficiency, which affects approximately 1 out of every 500,000 people in the USA, and the prevalence varies in other countries [6]. FVII deficiency is an autosomal-recessive bleeding disorder. The hallmark of FVII deficiency is a prolonged prothrombin time (PT) and an elevated international normalized ratio (INR) in the setting of normal liver function and a normal activated partial thromboplastin time (aPTT) [7].\n\nManaging an FVII-deficient patient presents several challenges. First, FVII can potentially exist in several different forms, and measuring FVII is further complicated by the many different assays available [8–10]. For the purposes of this article, FVII is reported as FVII coagulation activity (FVIIc), expressed as a percentage, with normal activity being 50–150 %. Our institution utilized a one-step clotting assay, with the result being normalized to determine the percentage activity. Second, determining disease severity on the basis of FVIIc is also difficult, as there is a poor correlation between FVIIc and bleeding risk, as some patients with moderate to severe deficiency may remain asymptomatic, while others with mild deficiency may experience major bleeding events [11]. Disease severity may be better classified on the basis of the location and frequency of bleeding events [7, 12]. A recent retrospective analysis of 83 patients with FVII deficiency undergoing surgical procedures recommended using FVII levels, the bleeding history and the type of surgery to help estimate bleeding risk and guide perioperative management [13]. Lastly, gene analysis is also difficult to interpret, as there are over 130 known mutations, with many still lacking defined phenotypic characteristics [11]. Progress is being made as national and international registries for RBDs continue to provide information about FVII deficiency.\n\nAlthough RBDs inherently limit coagulation and may predispose patients to bleeding, patients with FVII deficiency may still require anticoagulation therapy if indicated. A case series analysed thromboembolic events in patients with FVII deficiency and concluded that those with mild FVII deficiency should not be precluded from receiving antithrombotic prophylaxis [14]. Historically, warfarin has been the initial treatment of choice in this limited patient population. Warfarin works by blocking the regeneration of vitamin K epoxide, thus inhibiting the synthesis of vitamin K-dependent clotting factors II, VII, IX and X, as well as the anticoagulant proteins C and S. There is evidence to suggest that not all of the vitamin K-dependent clotting factors are affected equally by warfarin, with FVII and factor IX being suppressed to a greater degree than factors II and X [15]. The PT is used to monitor warfarin therapy and is converted to an INR for standardization. The PT reflects the functionality of several different clotting factors, including the vitamin K-dependent clotting factors; however, a prolonged PT is not seen until one of the clotting factors has decreased to <30–40 % [16]. For conventional patients who are stable on warfarin therapy, the INR should accurately represent variations in coagulation factor activities [17]. However, in the presence of FVII deficiency, the INR may not as accurately represent the degree of coagulation ability, given the inherent decrease of FVII in this RBD. Monitoring treatment through FVII activity may also prove to be difficult, as the minimal levels needed to sustain haemostasis are not well established [7]. There is limited published literature to guide anticoagulation therapy and monitoring in this population due to the rare nature of the disorder.\n\nThree case reports involving the use of vitamin K antagonists for atrial fibrillation in patients with FVII deficiency have been published:The first case was a 50-year-old male with a prolonged PT and an INR of 1.5 at baseline [18]. He developed an INR of 19.6 after four doses of warfarin 5 mg, which prompted discontinuation. Two weeks later, laboratory analysis revealed an FVIIc of 43 %, which led to the diagnosis of mild FVII deficiency. Warfarin was re-started at a higher INR goal of 2.5–3.5 to ensure adequate anticoagulation in the presence of an elevated baseline INR. After 18 months, no bleeding or thrombotic events were reported, despite the INR being in the therapeutic range only 32 % of the time.\n\nThe second case was a 77-year-old female [19]. She developed an INR of 6.0 after two doses of warfarin 10 mg, which prompted discontinuation. Thirteen days later, her INR was 2.2. Warfarin was re-started, and over the next few months, the patient’s INR ranged from 2.2 to 3.8 with doses ranging from 0.5 to 4 mg weekly. When warfarin was withheld for 2 weeks and the patient’s INR remained elevated at 3.5, she was evaluated for an RBD. Laboratory analysis revealed an FVIIc of 14 %. It was concluded that the risks with warfarin outweighed the benefits, and the patient was switched to aspirin.\n\nThe third case was an 80-year-old male with a baseline INR of 2.1 and an FVIIc of 10 % [20]. His INR goal was set at 2.5–3.0. While his INR was within the goal range, his FVIIc decreased to 5 % (equal to a 50 % decrease from baseline), whereas none of the other vitamin K-dependent clotting factors decreased more than 30 % in comparison with baseline. Given the risk of bleeding and perceived inadequate anticoagulant effect, warfarin was discontinued, and enoxaparin (a low molecular weight heparin [LMWH]) was initiated, which was monitored using anti-FXa activity. The patient received enoxaparin for 3 months without any bleeding symptoms before undergoing successful cardioversion.\n\n\n\n\nIn summary, although none of these patients developed major bleeding symptoms with vitamin K antagonist therapy, all encountered challenges with monitoring and accurate assessment of the anticoagulant effect. Such challenges lead to uncertainties in how to implement anticoagulation therapy in patients with this RBD, as further highlighted by the case summary below.\n\nCase Report\nA 70-year-old African American female with atrial fibrillation was referred to haematology in 2010 for evaluation of a mildly prolonged PT with persistent vaginal bleeding. Laboratory test results revealed a decreased FVIIc of 33 % (reference 50–150 %), and FVII deficiency was diagnosed. The patient underwent endometrial cryotherapy, and after 4 months without recurrent vaginal bleeding, haematology cleared the patient to start warfarin therapy, with an INR goal of 2.0–3.0. Haematology recommended discontinuing warfarin if FVIIc decreased to 10 % or less. The patient’s baseline INR was 1.4, and warfarin was conservatively started at 2 mg daily. The INR remained at 1.4 for the first 4 weeks of therapy, despite gradual dose increases. Nearly 6 weeks into therapy, the patient made a dosing error, which caused her INR to increase to 2.5. She developed recurrent vaginal bleeding, and her FVIIc was found to be 10 %, which prompted warfarin discontinuation. She was switched to aspirin 81 mg daily.\n\nIn 2014, she was evaluated by a different haematologist. Her FVIIc was 44 %, with a baseline INR of 1.2. It was decided to re-attempt warfarin therapy with a lower INR goal of 1.5–2.0, as the risks of stroke without anticoagulation seemed to outweigh the risks of bleeding with anticoagulation. The patient’s risk factors for stroke had not changed since her initial warfarin course. Haematology recommended discontinuing warfarin if FVIIc decreased to <15% or if the patient developed any clinical signs of bleeding. A total weekly dose of 40 mg was found to maintain her INR in the range of 1.6–1.8. The FVIIc varied between 24 and 28 % during the first 6 months of warfarin therapy. During the seventh month, the patient’s FVIIc decreased to 15 %, with a corresponding increase in her INR to 2.4, despite no change in her weekly dose. The patient denied any signs of bleeding during this second treatment course. Her weekly doses, INR results and FVIIc results are shown in Table 1.Table 1 Case patient dose, international normalized ratio (INR) and factor VII coagulation activity (FVIIc) results\n\nDate\tDose (mg/week)\tINR\tFVIIc (%)\tComments\t\nSeptember 27, 2010\tNone\t1.3\t33\tFirst haematology consultation\t\nApril 11, 2011\tNone\t1.4\t–\tWarfarin 2 mg daily started—1st attempt\t\nMay 5, 2011\t24\t1.4\t37\t\t\nMay 23, 2011\t56\t2.5\t10\tDose error, recurrent vaginal bleeding, warfarin discontinued\t\nMarch 26, 2014\tNone\t1.2\t44\tSecond haematology consultation\t\nJune 19, 2014\tNone\t1.2\t–\tWarfarin 2 mg daily started—2nd attempt\t\nAugust 11, 2014\t32\t1.4\t24\t\t\nOctober 7, 2014\t40\t1.7\t28\t\t\nDecember 11, 2014\t40\t1.7\t32\t\t\nJanuary 27, 2015\t40\t2.4\t15\tNo signs/symptoms of bleeding, warfarin dose decreased to 38 mg/week\t\nMarch 3, 2015\t38\t1.6\t30\t\t\n\n\n\nDiscussion\nOur case report describes a successful re-challenge of warfarin therapy in a patient with FVII deficiency. However, we must recognize the varying degrees of FVIIc and the corresponding bleeding risk among patients with FVII deficiency. When our case is compared with the two patient cases that required vitamin K antagonist discontinuation, our patient had a more mild FVII deficiency and maintained higher FVIIc activity during anticoagulation therapy. For patients with lower FVIIc at baseline or who experience bleeding events or significant decreases in FVIIc with warfarin therapy, alternative therapies could be considered.\n\nOur patient was initially treated with warfarin in 2011. At that time, evidence-based practice guidelines recommended long-term antithrombotic therapy with either warfarin or aspirin, since the patient had only one major risk factor—hypertension [21, 22]. In 2014, however, updated guidelines now favoured anticoagulation therapy for our patient, despite no change in her risk factors [23, 24]. The American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) 2014 guidelines recommend using the CHA2DS2-VASc scoring system to assess stroke risk. The CHA2DS2-VASc score for our patient was 3, due to hypertension, female sex, and age ≥65 years. For scores ≥2, anticoagulation therapy is recommended (warfarin: level of evidence—A; dabigatran, rivaroxaban, apixaban: level of evidence—B) [24]. These changes in treatment guidelines are significant for our patient, as aspirin is no longer considered an acceptable treatment option on the basis of her risk factors.\n\nThe new agents mentioned above represent a new group of anticoagulants known as direct oral anticoagulants (DOACs). This group currently includes direct thrombin (factor II [FII]) inhibitors (dabigatran) and direct FXa inhibitors (rivaroxaban, apixaban and edoxaban). The mechanisms by which both classes of agents act target a clotting factor only in the common pathway of the coagulation cascade, independent from FVII. Laboratory analysis has shown that these agents do not inhibit FVII [25, 26]. In contrast, warfarin inhibits FVII in the extrinsic pathway. Clinical studies have shown dabigatran, rivaroxaban, apixaban and edoxaban to be comparably safe and effective in comparison with warfarin therapy for the treatment of atrial fibrillation, although patients with FVII deficiency and other RBDs were excluded from the trials [27–30]. However, because these agents provide therapeutic anticoagulation by targeting clotting factors below FVII in the clotting cascade (Fig. 1) and do not directly affect FVII activity, they may theoretically carry less bleeding risk than warfarin in patients with FVII deficiency.\n\nThis suggestion to choose an anticoagulant that does not affect FVII activity is supported by the case report [20] in 2009, which emphasized heparin use in patients with FVII deficiency. In that case, LMWH was safely tolerated throughout the duration of maintenance therapy. However, at that time, the DOACs were not approved or available for use. Interestingly, the DOACs have mechanisms of action similar to those of heparin, targeting FXa and/or FII. While heparin remains a viable option, it must be administered parenterally, which is a disadvantage in comparison with orally administered medications. One important difference between LMWH and the DOACs is the ability to monitor the anticoagulant effect beyond the FVIIc activity assay, as LMWH can be monitored using anti-Xa levels, which correlate with the actual bleeding risk. This ability (not requirement) to monitor the anticoagulant effect may serve as an advantage in this population at higher risk of bleeding, as it gives the clinician a method to objectively assess the degree of anticoagulation being provided. The DOACs rivaroxaban, apixaban and edoxaban are FXa inhibitors and, although anti-Xa level monitoring is not performed clinically, it would seem reasonable that it could be utilized with these agents as well [31]. Lastly, the initial lack of antidotes or reversal agents for the DOAC class was considered to be a disadvantage but, recently, highly specific reversal agents have been developed and studied with positive results in clinical trials [32, 33]. Before reversal agents were available, a subgroup analysis from the ROCKET-AF trial of 779 patients who experienced major bleeding revealed no differences in outcomes in patients treated with rivaroxaban versus warfarin, including death (20.4 vs 26.1 %; hazard ratio 0.69, 95 % confidence interval 0.46–1.04). There was also less use of prothrombin complex concentrate (PCC) and significantly less use of fresh frozen plasma (FFP) with rivaroxaban compared with warfarin [34]. This information supports the consideration of DOACs as a potential alternative to vitamin K antagonists, even in unique and high-risk patient situations.\n\nConclusion\nWarfarin has been the treatment of choice for thromboembolic conditions for multiple decades, but the data are limited in patients with RBDs. We have described a successful re-challenge of warfarin therapy in a patient with FVII deficiency. However, compared with our patient case, patients with more severe FVII deficiency at baseline or those who experience lower levels of FVII activity during warfarin therapy may not observe the same positive response. The emergence of the DOAC group of anticoagulants has provided more options for clinicians when treating patients with RBDs in the outpatient setting. Based on their mechanisms of action in relation to the coagulation cascade, it would seem DOACs could potentially be safer alternatives to warfarin for patients with FVII deficiency by providing similarly therapeutic anticoagulation with less bleeding risk. Future studies would be helpful to evaluate the safety and effectiveness of DOAC therapy in patients with FVII deficiency. However, because of the rare nature of the disorder, it is not feasible to conduct prospective, randomized studies. Large clinical trials of anticoagulants typically exclude patients with FVII deficiency and other RBDs, although this would be an excellent way to obtain more data. It is imperative for clinicians to publish case reports and other retrospective data to guide future therapy in this population.\n\nEric Paulus, Kathy Komperda, Gabriel Park and Julie Fusco declare they have no conflict(s) of interest. No financial support was received for the preparation of this manuscript.\n\nCompliance with Ethical Standards\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent may be requested for review from the corresponding author.\n\nFunding\nThe authors received no sources of funding that require acknowledgment.\n==== Refs\nReferences\n1. 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Lapecorella M Marian G Factor VII deficiency: defining the clinical picture and optimizing therapeutic options Haemophilia 2008 14 1170 1175 10.1111/j.1365-2516.2008.01844.x 19141157 \n8. Fair DS Quantitation of factor VII in the plasma of normal and warfarin-treated individuals by radioimmunoassay Blood 1983 62 784 791 6882924 \n9. Morrissey JH Macik BG Neuenschwander PF Comp PC Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation Blood. 1993 81 734 744 8427965 \n10. Goudemand J Caron C Dreyfus M Sie P Standardization of factor VII/activated factor VII measurement in plasma of patients treated with recombinant factor activated VII Blood Coagul Fibrinolysis 2003 14 505 511 10.1097/00001721-200307000-00013 12851539 \n11. Peyvandi F Bolton-Maggs PHB Batorova A Rare bleeding disorders Haemophilia 2012 18 148 153 10.1111/j.1365-2516.2012.02841.x 22726099 \n12. 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Christensen TD Jensen C Larsen TB Christiansen K Sorensen B Thrombin generation and coagulation factor activities: evaluation and comparison with the international normalized ratio Blood Coagul Fibrinolysis. 2009 20 358 365 10.1097/MBC.0b013e32832aa68c 19417631 \n18. Davidson SJ Turner N Tillyer L Anticoagulation of a patient with hypertrophic cardiomyopathy and factor VII deficiency Blood Coagul Fibrinolysis 2010 21 707 708 10.1097/MBC.0b013e32833e47ad 20885134 \n19. Baltodano LE Mungall DR Watson DD Management of a patient with atrial fibrillation and factor VII deficiency Ann Pharmacother 1998 32 1251 1252 10.1345/aph.17447 9825099 \n20. Arellano-Rodrigo E Gironella M Nicolau I Clinical management of thrombosis in inherited factor VII deficiency: a description of two cases Thromb Haemost 2009 101 402 404 19190828 \n21. 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January CT Wann LS Alpert JS 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary Circulation 2014 64 2246 2280 \n25. Perzborn E Strassburger J Wilmen A In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct factor Xa inhibitor J Thromb Haemost 2005 3 514 521 10.1111/j.1538-7836.2005.01166.x 15748242 \n26. Pinto DJ Orwat MJ Koch S Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydo-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa J Med Chem 2007 50 5339 5356 10.1021/jm070245n 17914785 \n27. Connolly SJ Ezekowitz MD Yusuf S Dabigatran versus warfarin in patients with atrial fibrillation N Engl J Med 2009 361 1139 1151 10.1056/NEJMoa0905561 19717844 \n28. 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Piccini JP Garg J Patel MR Management of major bleeding events in patients treated with rivaroxaban vs warfarin: results from the ROCKET-AF trial Eur Heart J 2014 35 1873 1880 10.1093/eurheartj/ehu083 24658769\n\n",
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"title": "Anticoagulation Therapy Considerations in Factor VII Deficiency.",
"title_normalized": "anticoagulation therapy considerations in factor vii deficiency"
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"abstract": "The novel coronavirus SARS-CoV-2 is known to cause hypoxemia and acute respiratory distress syndrome (ARDS) in a significant portion of those with severe disease. Survivors of critical illness and ARDS often experience neurocognitive impairment but, to date, there is scant literature correlating radiographic hypoxic brain injury to hypoxemia related to ARDS. In this case series, we describe three cases of hypoxic brain injury seen on magnetic resonance imaging (MRI) in patients with hypoxemia secondary to COVID-19-related ARDS. The lack of severe observed hypoxemia in two of the cases suggests that unrecognized or asymptomatic hypoxemia may play a role in hypoxic brain injury related to COVID-19.",
"affiliations": "Department of Neurology, Rush University Medical Center, Chicago, IL 60612, USA. Electronic address: Caitlin_A_Radnis@rush.edu.;Department of Neurology, Rush University Medical Center, Chicago, IL 60612, USA.;Department of Diagnostic Radiology and Nuclear Medicine, Rush University Medical Center, Chicago, IL 60612, USA.;Department of Neurology, Rush University Medical Center, Chicago, IL 60612, USA.;Department of Neurology, Rush University Medical Center, Chicago, IL 60612, USA.;Department of Neurology, Rush University Medical Center, Chicago, IL 60612, USA.",
"authors": "Radnis|Caitlin|C|;Qiu|Sunny|S|;Jhaveri|Miral|M|;Da Silva|Ivan|I|;Szewka|Aimee|A|;Koffman|Lauren|L|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jns.2020.117119",
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"issn_linking": "0022-510X",
"issue": "418()",
"journal": "Journal of the neurological sciences",
"keywords": "Acute respiratory distress syndrome; Brain MRI; COVID-19; Hypoxic-ischemic encephalopathy",
"medline_ta": "J Neurol Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D000086382:COVID-19; D015897:Comorbidity; D005260:Female; D006801:Humans; D000860:Hypoxia; D007087:Illinois; D008279:Magnetic Resonance Imaging; D008297:Male; D009422:Nervous System Diseases; D058873:Pandemics; D012189:Retrospective Studies; D000086402:SARS-CoV-2",
"nlm_unique_id": "0375403",
"other_id": null,
"pages": "117119",
"pmc": null,
"pmid": "32957036",
"pubdate": "2020-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31718695;10793162;32169119;32123994;32109013;32298250;29907163;20130355;20473145;32527843;24088092;29135617;10390379;15542793;18191684;22710202;28235962;32255761;26191390;16537268;22926653;21470008;30592986;32530583;22492988;16963688",
"title": "Radiographic and clinical neurologic manifestations of COVID-19 related hypoxemia.",
"title_normalized": "radiographic and clinical neurologic manifestations of covid 19 related hypoxemia"
} | [
{
"companynumb": "US-UCBSA-2020040422",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nThe treatment of Ewing Sarcoma family of tumors is multimodal, both in children and adults. Axial location and metastases are classic prognostic factors. However, the worse prognosis in older patients is more controversial.\n\n\nMETHODS\nRetrospective analysis was performed of pediatric and adult patients treated with the 2001 SEOP protocol: 6 cycles of VIDE chemotherapy (CT). If no progression was observed, local (surgery and/or radiotherapy) and consolidation treatments were performed adjusted to prognosis: 8 cycles of VAC in standard-risk patients or 1 cycle of VAC and high-dose CT and autologous transplant in the case of increased risk.We analyzed induction CT toxicity, type of consolidation treatment, and disease-free (DFS) and overall (OS) survival by the Kaplan-Meier method, with a log-rank analysis of prognostic factors with regard to OS.\n\n\nRESULTS\nThirty-six patients were analyzed (2003 to 2011). Sixty percent were male, with a median age of 16 years (range, 7 to 57 y). The most frequent location was axial (43%), followed by extremities (34%), extraosseous (18%), and ribs (9%). Fifty-four percent of patients had metastases, of which, 58% were pulmonary.The median follow-up period was 36 months (5 to 101 mo). Median DFS was 25 months (16 to 34 mo) and median OS 29 months (19 to 40 mo), with a 3-year OS of 40%. Median OS from progression was 7 months (0.4 to 15 mo). Age <15 years and normal lactate dehydrogenase levels were associated with prolonged OS.\n\n\nCONCLUSIONS\nInduction CT with the VIDE regimen was feasible in most patients, with a low risk for early progression. Hematological toxicity was substantial but manageable. Adult patients had a worse prognosis. Survival after progression was dismal.",
"affiliations": "*Medical Oncology Department †Pediatric Oncology Department, University Hospital La Fe, Valencia, Spain.",
"authors": "Diaz-Beveridge|Robert|R|;Lorente|David|D|;Torres|Barbara|B|;Cañete|Adela|A|;Rodrigo|Esteban|E|;Bruixola|Gema|G|;Berlanga|Pablo|P|;Reche|Encarnacion|E|;Montalar|Joaquin|J|;Verdeguer|Amparo|A|;Aparicio|Jorge|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000339",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "37(5)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D002648:Child; D003131:Combined Modality Therapy; D060830:Consolidation Chemotherapy; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D019637:Orthopedic Procedures; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D012512:Sarcoma, Ewing; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e278-84",
"pmc": null,
"pmid": "25929608",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Multimodality Treatment of Pediatric and Adult Patients With Ewing Sarcoma: A Single-institution Experience.",
"title_normalized": "multimodality treatment of pediatric and adult patients with ewing sarcoma a single institution experience"
} | [
{
"companynumb": "ES-BAXTER-2016BAX010889",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "We herein report two patients with dementia with Lewy bodies (DLB) presenting characteristic symptoms suggestive of the behavioural variant of frontotemporal dementia (bvFTD). Patient 1 presented behavioural and personality changes from the onset, such as restlessness, compulsive behaviours, and stereotypical speech. A neuroimaging study showed preferential frontal involvement, and this patient fulfilled the diagnostic criteria for bvFTD. However, 123 I-metaiodobenzylguanidine cardiac scintigraphy revealed a markedly lowered uptake, suggesting the diagnosis of possible DLB. Patient 2 fulfilled the criteria for probable DLB, but later presented bvFTD-like symptoms similar to those in patient 1. These patients suggest that DLB can be a candidate for differential diagnosis of bvFTD in the clinical setting.",
"affiliations": "Kawasaki Memorial Hospital, Kawasaki-city, Japan.;Kawasaki Memorial Hospital, Kawasaki-city, Japan.",
"authors": "Nagahama|Yasuhiro|Y|https://orcid.org/0000-0001-9876-3820;Fukui|Toshiya|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/psyg.12405",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-3500",
"issue": "19(5)",
"journal": "Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society",
"keywords": "behavioral symptoms; frontal cortex; frontotemporal dementia; lewy body disease",
"medline_ta": "Psychogeriatrics",
"mesh_terms": "D000368:Aged; D003937:Diagnosis, Differential; D005260:Female; D057180:Frontotemporal Dementia; D006801:Humans; D020961:Lewy Body Disease",
"nlm_unique_id": "101230058",
"other_id": null,
"pages": "505-509",
"pmc": null,
"pmid": "30729636",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Dementia with Lewy bodies presenting as frontotemporal dementia phenotype.",
"title_normalized": "dementia with lewy bodies presenting as frontotemporal dementia phenotype"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-223210",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMANTADINE HYDROCHLORIDE"
},
... |
{
"abstract": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 19 (COVID-19) pandemic, which is deeply affecting the whole world. In this new case for the scientific world, scientists are investigating the etiopathogenesis of viral infection-induced damage and have started to focus on the short and long-term immune system effects and alterations after SARS-CoV-2 infection. The case is here reported of a 53-year-old female patient with acute monoarthritis after SARS-CoV-2 infection, who responded adequately to 150 mg/day diclofenac treatment, and the available case reports are comprehensively reviewed. With the focus on arthritis after SARS-CoV2 infection, which emerges as a new pathological condition associated with COVID-19, it was aimed to examine the possible immunological mechanisms of post-COVID-19 arthritis based on the current data on SARS-CoV-2 and the known pathogenetic background of viral arthritis.",
"affiliations": "Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Kahramanmaraş Sütçü İmam University, Kahramanmaraş, Turkey. bfk2701@hotmail.com.;Physiotherapy and Rehabilitation Application and Research Center, Hasan Kalyoncu University, Gaziantep, Turkey.",
"authors": "Kocyigit|Burhan Fatih|BF|http://orcid.org/0000-0002-6065-8002;Akyol|Ahmet|A|http://orcid.org/0000-0002-8953-5196",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-021-04998-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "41(11)",
"journal": "Rheumatology international",
"keywords": "Acute arthritis; COVID-19; Reactive arthritis; SARS-CoV-2; Viral arthritis",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D000328:Adult; D000368:Aged; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016918:Arthritis, Reactive; D000086382:COVID-19; D004008:Diclofenac; D005260:Female; D006801:Humans; D008875:Middle Aged; D000086402:SARS-CoV-2",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "2031-2039",
"pmc": null,
"pmid": "34550429",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "33515320;32202240;32277367;33388969;22811010;32474885;7402632;34196842;23783643;33939015;33733315;33978818;24418301;21800117;33653867;33874649;32652541;32694352;33409010;33420769;32763956;32753423;33587197;32826276;33615130;32923288;33979033;34130744;28321226;32666137;16455584;32292901;33014690;25870477;25199646;32495226;16432687;29139030;15550534;29065931",
"title": "Reactive arthritis after COVID-19: a case-based review.",
"title_normalized": "reactive arthritis after covid 19 a case based review"
} | [
{
"companynumb": "TR-LUPIN PHARMACEUTICALS INC.-2021-24084",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugad... |
{
"abstract": "We hypothesized that ofatumumab with sequential methylprednisolone - alemtuzumab would be an effective and tolerable regimen for patients with high-risk chronic lymphocytic leukemia (CLL) with TP53 dysfunction. Thirty CLL patients with TP53 dysfunction (15 treatment naive (TN), 15 relapsed/refractory (R/R)) were enrolled in this phase II study. Therapy included ofatumumab with methylprednisolone for 2-4 monthly cycles, then ofatumumab with alemtuzumab for 4-24 weeks, then allogeneic transplantation or maintenance. The rate of overall response, complete response, marrow minimal residual disease (MRD) negativity, 3-year progression-free survival and overall survival were 80, 13, 80, 53, and 66%, respectively, in TN patients and 68, 0, 54, 25, and 53%, respectively, in R/R patients. Notable grade 3/4 toxicities included neutropenia and infection in 43 and 40% of patients, respectively. At median follow-up of 45 months, 13 patients died, and 10 patients are alive posttransplant. Overall, we observed high rates of MRD-negativity and acceptable tolerability in high-risk CLL.",
"affiliations": "a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.;b Biostatistics and Computational Biology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.;a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.;a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.;a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.;a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.;a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.;a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.;a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.;a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.;c Department of Medical Oncology , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA.;a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.;a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.;a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.;a Departments of Medical Oncology , Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA.",
"authors": "Davids|Matthew S|MS|;Kim|Haesook T|HT|;Yu|Lijian|L|;De Maeyer|Guadalupe|G|;McDonough|Mikaela|M|;Vartanov|Alexander R|AR|;Langey|Rachael|R|;Fernandes|Stacey M|SM|;Hellman|Jeffrey M|JM|;Francoeur|Karen|K|;Arnason|Jon|J|;Jacobsen|Eric D|ED|;LaCasce|Ann S|AS|;Fisher|David C|DC|;Brown|Jennifer R|JR|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000074323:Alemtuzumab; C527517:ofatumumab; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2018.1519814",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "60(5)",
"journal": "Leukemia & lymphoma",
"keywords": "CLL; MRD; TP53; alloHSCT; deletion 17p",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17; D003131:Combined Modality Therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008775:Methylprednisolone; D011379:Prognosis; D017384:Sequence Deletion; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1312-1315",
"pmc": null,
"pmid": "30322319",
"pubdate": "2019-05",
"publication_types": "D016422:Letter; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ofatumumab plus high dose methylprednisolone followed by ofatumumab plus alemtuzumab to achieve maximal cytoreduction prior to allogeneic transplantation for 17p deleted or TP53 mutated chronic lymphocytic leukemia.",
"title_normalized": "ofatumumab plus high dose methylprednisolone followed by ofatumumab plus alemtuzumab to achieve maximal cytoreduction prior to allogeneic transplantation for 17p deleted or tp53 mutated chronic lymphocytic leukemia"
} | [
{
"companynumb": "US-PFIZER INC-2018427637",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "The plasma cell dyscrasias (PCDs) include a number of entities such as multiple myeloma, primary amyloidosis, and monoclonal immunoglobulin deposition disease. Hematopoietic cell transplant (HCT) is the only cure for a variety of hematologic and oncologic diseases. Clinically significant renal impairment is a common feature in plasma cell myeloma, affecting 20% to 55% of patients at initial diagnosis; 2% to 3% of patients present with failure sufficiently severe to require hemodialysis. This circumstance is associated with a high early mortality. The necessity for immunosuppression after HCT could complicate its management and may precipitate the development of complications. In some patients an effective alternative could be kidney transplant (KT); however, the presence of 2 transplants will require optimal adjustment of immunosuppression and management of complications. At present, there are few published cases of KT after HCT, and the experience of managing 2 transplants is limited. We would like to describe our experience with 4 patients who had a PCD and initially received HCT and received subsequent KT. In our experience the progress and outcome of KT after HCT were optimal. We would like to address that a higher incidence of cytopenia associated with the combination of immunosuppression (lenalidomide, tacrolimus, mycophenolate, etc.) and other drugs (ie, valganciclovir) should be considered together with an increased risk of opportunistic infections and PCD relapse.",
"affiliations": "Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain. Electronic address: vdpimentel.ull@hotmail.com.;Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.;Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.;Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.;Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.;Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.;Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.;Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.;Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.",
"authors": "Domínguez-Pimentel|V|V|;Rodríguez-Muñoz|A|A|;Froment-Brum|M|M|;Reguera-Carmona|M J|MJ|;Jarque-López|A|A|;García-García|P|P|;Rivero-González|A|A|;Luis-Rodríguez|D|D|;Macía|M|M|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.10.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "51(2)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010265:Paraproteinemias; D051437:Renal Insufficiency",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "383-385",
"pmc": null,
"pmid": "30879547",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Kidney Transplantation After Hematopoietic Cell Transplantation in Plasma Cell Dyscrasias: Case Reports.",
"title_normalized": "kidney transplantation after hematopoietic cell transplantation in plasma cell dyscrasias case reports"
} | [
{
"companynumb": "ES-MYLANLABS-2019M1094457",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Current discourses about the causes of the overdose crisis largely focus on the harmful effects of drugs. Prior research, however, indicates that drug use experience is shaped by complex interactions of drugs with physiological and mental \"sets\" of people who use drugs and the wider social and physical \"setting.\" Zinberg's \"drug, set, and setting\" theoretical framework was applied to identify patterns in circumstances leading up to women's overdose.\n\n\n\nIn-depth semi-structured interviews were conducted with 29 opioid-injecting street-involved women, clients of a Philadelphia harm reduction program. Qualitative analysis with deductive and inductive coding was utilized to examine transcripts for theory-driven and emerging themes.\n\n\n\nTen out of 29 women attributed their overdose to \"drugs,\" reporting the unpredictable quality of street opioids, concurrent use of benzodiazepines, or chasing the \"high.\" Thirteen women reported \"set\" as a type of circumstance where their emotional states were affected by a \"good\" or \"bad\" day, leading them to unusual drug consumption practices. Six women described \"setting\" type of circumstances where their overdose was preceded by a recent change in context, such as release from prison, which prompted unsafe drug use to address physiological or psychological dependence on drugs.\n\n\n\nWhile all overdoses result from the pharmacological action of drugs, some overdoses were triggered by circumstances occurring in women's set or setting. Overdose prevention policies should embrace not only individual-level behavioral interventions, but also structural measures to address stress, social isolation, and risky drug use contexts that plague the lives of street-involved women who inject opioids.",
"affiliations": "Department of Community Health and Prevention, Dornsife School of Public Health, Drexel University, 3215 Market St, Philadelphia, PA 19104, USA. Electronic address: ja633@drexel.edu.;Department of Community Health and Prevention, Dornsife School of Public Health, Drexel University, 3215 Market St, Philadelphia, PA 19104, USA.;Prevention Point Philadelphia, 2913 Kensington Ave, Philadelphia, PA 19134, USA.;Department of Community Health and Prevention, Dornsife School of Public Health, Drexel University, 3215 Market St, Philadelphia, PA 19104, USA.",
"authors": "Ataiants|Janna|J|;Roth|Alexis M|AM|;Mazzella|Silvana|S|;Lankenau|Stephen E|SE|",
"chemical_list": "D000701:Analgesics, Opioid; D004364:Pharmaceutical Preparations",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.drugpo.2020.102691",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0955-3959",
"issue": "78()",
"journal": "The International journal on drug policy",
"keywords": "Circumstances; Drug; Injection; Opioids; Overdose; Set; Setting; Women",
"medline_ta": "Int J Drug Policy",
"mesh_terms": "D000701:Analgesics, Opioid; D062787:Drug Overdose; D005260:Female; D006801:Humans; D004364:Pharmaceutical Preparations; D015143:Philadelphia; D015819:Substance Abuse, Intravenous",
"nlm_unique_id": "9014759",
"other_id": null,
"pages": "102691",
"pmc": null,
"pmid": "32086154",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "16685288;26202771;29598858;16840107;29754032;19634955;15847621;23318302;18941540;30707673;24364027;28319291;24189594;21090958;26868674;28735776;30646080;12791797;27770541;23820967;17280803;22980450;15246182;29095804;16002023;22081835;23313145;29502564;20022184;29801458;19147339;17215533;26642424;15679746;27364392;12663840;21497898;19232832;28859052;30064061;25213747;28355456;12144602;30629574;30075401;25151334;29267060;21696913;12088097;10551667",
"title": "Circumstances of overdose among street-involved, opioid-injecting women: Drug, set, and setting.",
"title_normalized": "circumstances of overdose among street involved opioid injecting women drug set and setting"
} | [
{
"companynumb": "US-PFIZER INC-2020165442",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALPRAZOLAM"
},
"drugadditional": "3",
... |
{
"abstract": "There are limited clinical data regarding prolonged-release tacrolimus (PR-T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR-T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate-release tacrolimus (IR-T), on a 1:1 mg total-daily-dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy-confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole-blood trough levels (target 3.5-15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6-17.7% of patients across follow-up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug-related treatment-emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR-T to PR-T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.",
"affiliations": "Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.;Pediatric Hepatology Unit, APHP-Hôpital Universitaire Necker, Paris, France.;The Liver Unit, Birmingham Women's & Children's Hospital, Birmingham, UK.;Pediatric Cardiology Unit, APHP-Hôpital Universitaire Necker, Paris, France.;Department of Pediatric Nephrology, NIHR/Wellcome Trust Manchester Clinical Research Facility, Manchester Academic Health Science Centre, Royal Manchester Children's Hospital, University of Manchester, Manchester, UK.;Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Pediatrics, Second School of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.;Department of Nephrology, Rheumatology, and Dermatology, Center for Rare Diseases, Civil Hospice of Lyon, 'Woman-Mother-Child' Hospital, Bron Cedex, France.;Pediatric Hepatology, Gastroenterology and Transplantation, Civil Hospice of Lyon, Lyon, France.;Department of Pediatrics, ISMETT-IRCCS, Palermo, Italy.;Department of Pediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany.;Pediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy.;Department of Pediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.;Unité de Chirurgie et Transplantation Pédiatrique, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;BENKAZ Consulting Ltd, Cambridge, UK.;Astellas Pharma Europe Ltd, Chertsey, UK.",
"authors": "Rubik|Jacek|J|;Debray|Dominique|D|https://orcid.org/0000-0002-0345-963X;Kelly|Deirdre|D|;Iserin|Franck|F|;Webb|Nicholas J A|NJA|;Czubkowski|Piotr|P|;Vondrak|Karel|K|;Sellier-Leclerc|Anne-Laure|AL|;Rivet|Christine|C|;Riva|Silvia|S|;Tönshoff|Burkhard|B|;D'Antiga|Lorenzo|L|https://orcid.org/0000-0001-7150-3148;Marks|Stephen D|SD|https://orcid.org/0000-0001-9850-8352;Reding|Raymond|R|;Kazeem|Gbenga|G|;Undre|Nasrullah|N|https://orcid.org/0000-0001-7294-7883",
"chemical_list": "D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1111/tri.13479",
"fulltext": "\n==== Front\nTranspl IntTranspl. Int10.1111/(ISSN)1432-2277TRITransplant International0934-08741432-2277John Wiley and Sons Inc. Hoboken 10.1111/tri.13479TRI13479Original ArticleClinical ResearchEfficacy and safety of prolonged‐release tacrolimus in stable pediatric allograft recipients converted from immediate‐release tacrolimus – a Phase 2, open‐label, single‐arm, one‐way crossover study Tacrolimus in pediatric transplant recipientsRubik et al.Rubik Jacek \n1\nDebray Dominique https://orcid.org/0000-0002-0345-963X\n2\nKelly Deirdre \n3\nIserin Franck \n4\nWebb Nicholas J. A. \n5\nCzubkowski Piotr \n6\nVondrak Karel \n7\nSellier‐Leclerc Anne‐Laure \n8\nRivet Christine \n9\nRiva Silvia \n10\nTönshoff Burkhard \n11\nD'Antiga Lorenzo https://orcid.org/0000-0001-7150-3148\n12\nMarks Stephen D. https://orcid.org/0000-0001-9850-8352\n13\nReding Raymond \n14\nKazeem Gbenga \n15\n\n16\nUndre Nasrullah https://orcid.org/0000-0001-7294-7883\n16\nnas.undre@astellas.com \n1 \nDepartment of Nephrology, Kidney Transplantation and Hypertension\nThe Children's Memorial Health Institute\nWarsaw\nPoland\n\n2 \nPediatric Hepatology Unit\nAPHP‐Hôpital Universitaire Necker\nParis\nFrance\n\n3 \nThe Liver Unit\nBirmingham Women's & Children's Hospital\nBirmingham\nUK\n\n4 \nPediatric Cardiology Unit\nAPHP‐Hôpital Universitaire Necker\nParis\nFrance\n\n5 \nDepartment of Pediatric Nephrology\nNIHR/Wellcome Trust Manchester Clinical Research Facility\nManchester Academic Health Science Centre\nRoyal Manchester Children's Hospital\nUniversity of Manchester\nManchester\nUK\n\n6 \nDepartment of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics\nThe Children's Memorial Health Institute\nWarsaw\nPoland\n\n7 \nDepartment of Pediatrics\nSecond School of Medicine\nUniversity Hospital Motol\nCharles University\nPrague\nCzech Republic\n\n8 \nDepartment of Nephrology, Rheumatology, and Dermatology\nCenter for Rare Diseases\nCivil Hospice of Lyon\n‘Woman‐Mother‐Child’ Hospital\nBron Cedex\nFrance\n\n9 \nPediatric Hepatology, Gastroenterology and Transplantation\nCivil Hospice of Lyon\nLyon\nFrance\n\n10 \nDepartment of Pediatrics\nISMETT–IRCCS\nPalermo\nItaly\n\n11 \nDepartment of Pediatrics I\nUniversity Children's Hospital Heidelberg\nHeidelberg\nGermany\n\n12 \nPediatric Hepatology, Gastroenterology and Transplantation\nHospital Papa Giovanni XXIII\nBergamo\nItaly\n\n13 \nDepartment of Pediatric Nephrology\nGreat Ormond Street Hospital for Children\nNHS Foundation Trust\nLondon\nUK\n\n14 \nUnité de Chirurgie et Transplantation Pédiatrique\nCliniques Universitaires Saint-Luc\nUniversité Catholique de Louvain\nBrussels\nBelgium\n\n15 \nBENKAZ Consulting Ltd\nCambridge\nUK\n\n16 \nAstellas Pharma Europe Ltd\nChertsey\nUK\n* Correspondence\n\nDr. Nasrullah Undre, Astellas Pharma Global Development, 2000 Hillswood Drive, Chertsey, Surrey KT16 0RS, UK.\n\nTel.: +44 203 379 8000;\n\nfax: +44 203 379 8315;\n\ne‐mail: nas.undre@astellas.com\n27 8 2019 11 2019 32 11 10.1111/tri.v32.111182 1193 20 12 2018 21 1 2019 11 7 2019 © 2019 Astellas Pharma Europe. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOTThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Summary\nThere are limited clinical data regarding prolonged‐release tacrolimus (PR‐T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR‐T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate‐release tacrolimus (IR‐T), on a 1:1 mg total‐daily‐dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy‐confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole‐blood trough levels (target 3.5–15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6–17.7% of patients across follow‐up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug‐related treatment‐emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR‐T to PR‐T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.\n\ncalcineurin inhibitor: tacrolimusclinical trialheart (allograft) function/dysfunctionimmunosuppressantkidney (allograft) function/dysfunctionliver (allograft) function/dysfunctionAstellas Pharma Europe 10.13039/501100006044NIHR Manchester Clinical Research Facility 10.13039/100006662 source-schema-version-number2.0cover-dateNovember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.1 mode:remove_FC converted:13.11.2019\n==== Body\nIntroduction\nTacrolimus is the most frequently used immunosuppressive therapy following organ transplantation, with over 95% of pediatric kidney and liver transplant recipients in North America receiving tacrolimus‐based regimens following transplantation in 2016 1, 2. Tacrolimus is available as an immediate‐release formulation (capsules and granules), administered twice‐daily, and as a prolonged‐release formulation (capsules), administered once daily. Immediate‐release tacrolimus is licensed to prevent allograft rejection in both adult and pediatric kidney, liver, and heart transplant recipients 3. The prolonged‐release formulation is currently licensed for use in adult and pediatric kidney transplant recipients in the United States 4, and in adult kidney and liver transplant recipients in Europe 5.\n\nHigh intrapatient variability in tacrolimus exposure and poor adherence to immunosuppressive therapy have been associated with an increased risk of graft loss and rejection post‐transplantation 6, 7, 8, 9. However, some studies in stable adult transplant recipients have shown that conversion from twice‐daily, immediate‐release to once‐daily, prolonged‐release tacrolimus may reduce intrapatient variability in tacrolimus exposure and increase medication adherence, thereby, potentially improving transplant outcomes 10, 11, 12, 13.\n\nEvidence from clinical studies suggests that prolonged‐release tacrolimus is effective and well tolerated in adult transplant recipients converted from the immediate‐release formulation 10, 14, 15. From the small number of published studies, efficacy and safety outcomes in pediatric kidney and liver transplant recipients converted from immediate‐ to prolonged‐release tacrolimus were generally comparable to those in adult transplant patients 16, 17, 18, 19, 20, 21. Indeed, Heffron et al. 16 found no episodes of acute rejection (AR), graft loss, or death in an open‐label study of 18 stable pediatric liver transplant recipients over a 1‐year period after conversion from immediate‐ to prolonged‐release tacrolimus. Furthermore, there were no severe drug‐related adverse events (AEs) and no significant changes in renal function reported in a 1‐year follow‐up open‐label study of 21 pediatric kidney transplant recipients following conversion from immediate‐ to prolonged‐release tacrolimus 21.\n\nClinical experience with prolonged‐release tacrolimus is limited in pediatric solid organ transplant recipients and reported data are generally from small patient numbers 16, 17, 18, 19, 20, 21. Therefore, we undertook this study to assess the pharmacokinetics, efficacy, and safety of prolonged‐release tacrolimus over a 1‐year period in a large cohort of pediatric kidney, liver, and heart transplant recipients following conversion from immediate‐release tacrolimus. Results from the pharmacokinetics evaluation are reported elsewhere 22.\n\nPatients and methods\nStudy design and patients\nThis was a Phase 2, open‐label, single‐arm, one‐way crossover study in stable pediatric transplant recipients converted from immediate‐release tacrolimus (Prograf®; Astellas Pharma Ltd, Chertsey, UK) to prolonged‐release tacrolimus (Advagraf®; Astellas Pharma Europe BV, Leiden, the Netherlands; ClinicalTrials.gov NCT01294020). The study was conducted at 14 centers in seven European countries between June 2011 and October 2015. Ethics Committee approval was obtained for each participating center, and the study was carried out in accordance with Good Clinical Practice, the International Council for Harmonisation guidelines, and the Declaration of Helsinki. All patients or their guardians provided written informed consent.\n\nPatients were eligible for inclusion in the study if they were aged ≥5 and ≤16 years, had received a kidney, liver, or heart transplant ≥6 months prior to the study, were maintained on an immediate‐release tacrolimus‐based regimen for ≥3 months before the study, and were able to swallow intact tacrolimus capsules. Patients were required to have whole‐blood tacrolimus trough levels in the range 3.5–15.0 ng/ml on two or more occasions ≥6 days apart, and within 30 days prior to Day 1 of the study (the first day of study drug treatment). Key exclusion criteria were a multi‐organ transplant, a rejection episode within 3 months, or within 6 months if anti‐lymphocyte antibody therapy was required, or two or more rejection episodes within 12 months prior to the study. Patients were excluded if they were receiving rapamycin, everolimus, or mycophenolic acid (Myfortic; Novartis Pharmaceuticals UK Ltd, Camberley, Surrey, UK). Use of substances known to interfere with tacrolimus metabolism was not permitted during the 28 days pre‐transplantation or the 28 days post‐transplantation.\n\nAll eligible patients entered a 30‐day screening period (Day −30 to Day −1) during which they continued to receive their routine, twice‐daily, immediate‐release tacrolimus‐based regimen. On Days 1–7, patients received twice‐daily, immediate‐release tacrolimus orally, at the same dose as during the screening period. On Day 8, all patients were converted on a 1:1 mg total‐daily‐dose basis from twice‐daily immediate‐release tacrolimus to once‐daily, prolonged‐release tacrolimus, and continued to receive prolonged‐release tacrolimus to Week 54. Dose adjustments for clinical reasons were permitted at any time during the study, and adjustments to maintain target whole‐blood tacrolimus trough levels within the range 3.5–15 ng/ml 5 were permitted after Day 15 based on the clinical practice protocol at each center. Patients could maintain their pre‐enrollment treatment with steroids, azathioprine, or mycophenolate mofetil (CellCept; Roche Pharma AG, Grenzach‐Wyhlen, Germany) throughout the study period, but dose adjustment was not permitted until after Day 15. Concomitant medications included prescribed and over‐the‐counter drugs, taken from the start of the 30‐day screening period to the end‐of‐study visit.\n\nThe initial pharmacokinetic assessment was undertaken from Day −30 to Day −15 (part A) 22, and the efficacy, safety, tacrolimus daily dose, and blood trough levels were assessed from Week 2 to Week 54 (part B; assessments at Weeks 2, 6, 10, 14, 28, 42, and 54; Fig. 1).\n\nFigure 1 Study design. aDuring the screening period, patients received their routine twice‐daily, immediate‐release tacrolimus‐based immunosuppressive regimen. After the initial pharmacokinetic assessment (Day −30 to Day 15; part A), patients were administered a prolonged‐release tacrolimus‐based immunosuppressive regimen for 52 additional weeks (part B). Part B follow‐up visits occurred at 6, 10, 14, 28, 42, and 54 weeks.\n\nEndpoints and variables\nEfficacy endpoints included the number of AR and biopsy‐confirmed AR (BCAR) episodes, patient and graft survival, and efficacy failure (a composite of death, graft loss, BCAR, and unknown outcome). Graft loss was defined as retransplantation, death, graft nephrectomy, or dialysis ongoing at the end of the study or at study discontinuation (in kidney transplant recipients). For the composite endpoint, a patient was considered to have an unknown outcome if they did not have the event of interest (death, graft loss or BCAR), did not have a study assessment within 30 days prior to the target day of analysis, and had no further assessments thereafter. Other endpoints included tacrolimus total daily dose and number of dose adjustments, tacrolimus whole‐blood trough levels (monitored using local assay methods, e.g., IMX®, EMIT® or high‐performance liquid chromatography/tandem mass spectrometry), and the proportion of patients within the recommended target trough level range (3.5–15 ng/ml). Renal function was assessed using the estimated glomerular filtration rate (eGFR), calculated with the Schwartz equation 23.\n\nTreatment‐emergent AEs (TEAEs), vital signs, and clinical laboratory variables were also recorded. A serious TEAE was defined as a TEAE that in the opinion of the investigator resulted in one of the following outcomes: (i) death; (ii) a life‐threatening adverse event; (iii) inpatient hospitalization or prolongation of existing hospitalization (for >24 h); (iv) persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; and (v) a congenital anomaly/birth defect. TEAEs were graded mild, moderate, or severe according to the Common Terminology Criteria for Adverse Events 24.\n\nStatistical analysis\nThe planned study sample size of 72 patients (24 patients for each organ type) provided a power of 97% to assess similarity of tacrolimus exposure in the pharmacokinetic evaluation 22. A separate power calculation was not undertaken for the efficacy and safety assessments, and the analysis was descriptive. The full‐analysis set (FAS) included all patients who received at least one dose of study drug. Efficacy and safety analyses were performed on the modified FAS (mFAS), which included all patients who received at least one dose of prolonged‐release tacrolimus. Patients who were lost to follow‐up or alive at the end of the study (Week 54) were censored in survival analyses.\n\nDescriptive statistics were reported for continuous variables. All analyses were stratified by organ type; however, no statistical comparisons were made between different organ transplant groups. The last observation on or before the day that prolonged‐release tacrolimus treatment was initiated was considered the baseline for prolonged‐release tacrolimus efficacy and safety outcomes. SAS® version 9.3 or higher was used for data processing, summarization and analyses.\n\nResults\nStudy population\nOf 113 patients who were screened, 81 were enrolled, received immediate‐release tacrolimus and were included in the FAS. Two liver transplant recipients did not receive prolonged‐release tacrolimus; therefore, the mFAS comprised 79 patients (kidney transplant, n = 48; liver transplant, n = 29; heart transplant, n = 2; Fig. 2). Three patients discontinued prolonged‐release tacrolimus treatment: two due to AEs and one patient withdrew consent. Overall, 76 patients completed the 12‐month efficacy and safety study.\n\nFigure 2 Patient flow through the study. AE, adverse event; FAS, full‐analysis set; mFAS, modified full‐analysis set.\n\nPatient baseline demographics and characteristics are presented in Table 1. In the mFAS, most patients were Caucasian (93%) and over half were male (57%). Overall, the mean ± standard deviation (SD) age was 11.6 ± 2.8 years (range, 5–16 years); 41.8% of patients were children (aged 2–11 years) and 58.2% were adolescents (aged 12–16 years). There was wide variation in weight and height due to the age range of the patients; mean ± SD weight and height were 43.0 ± 16.6 kg and 144.8 ± 17.5 cm, respectively.\n\nTable 1 Patient baseline demographics and characteristics for the overall population and stratified by organ type (mFAS)\n\nParameter\tKidney transplant (n = 48)\tLiver transplant (n = 29)\tHeart transplant (n = 2)\tOverall (n = 79)\t\nAge, years\t\nMean ± SD\t11.0 ± 3.0\t12.4 ± 2.3\t13.5 ± 0.7\t11.6 ± 2.8\t\nMedian\t11.5\t13.0\t13.5\t12.0\t\nMinimum, maximum\t5, 16\t7, 16\t13, 14\t5, 16\t\nAge category, n (%)\t\n≥2 to ≤11 years (children)\t24 (50.0)\t9 (31.0)\t0\t33 (41.8)\t\n≥12 to ≤16 years (adolescents)\t24 (50.0)\t20 (69.0)\t2 (100.0)\t46 (58.2)\t\nSex, n (%)\t\nMale\t29 (60.4)\t15 (51.7)\t1 (50.0)\t45 (57.0)\t\nRace, n (%)\t\nCaucasian\t37 (92.5)\t16 (94.1)\t0\t53 (93.0)\t\nAsian\t2 (5.0)\t0\t0\t2 (3.5)\t\nOther\t1 (2.5)\t1 (5.9)\t0\t2 (3.5)\t\nMissing*\n\t8\t12\t2\t22*\n\t\nWeight, kg\t\nMean ± SD\t40.5 ± 19.2\t45.9 ± 10.3\t62.0 ± 0\t43.0 ± 16.6\t\nMedian\t35.1\t47.4\t62.0\t41.0\t\nMinimum, maximum\t17, 109\t29, 66\t62, 62\t17, 109\t\nHeight, cm\t\nMean ± SD\t139.2 ± 18.3\t153.2 ± 12.4\t158.5 ± 8.6\t144.8 ± 17.5\t\nMedian\t137.8\t155.2\t158.5\t146.5\t\nMinimum, maximum\t103, 181\t130, 174\t152, 165\t103, 181\t\nmFAS, modified full‐analysis set; SD, standard deviation.\n\n*Data on race were not collected from French patients as this was not permitted in France.\n\nJohn Wiley & Sons, LtdTacrolimus dose and whole‐blood trough levels\nThe mean ± SD duration of prolonged‐release tacrolimus exposure was 361.0 ± 53.3 days in the overall patient population and was similar for the kidney and liver transplant recipients (368.5 ± 14.8 and 360.6 ± 54.0 days, respectively). Overall, 88.6% of patients received prolonged‐release tacrolimus for between 253 and 378 days.\n\nMean tacrolimus total daily dose (Fig. 3a) and blood trough levels (Fig. 3b) remained stable during the 12‐month period following conversion from immediate‐ to prolonged‐release tacrolimus. The overall mean ± SD daily dose of prolonged‐release tacrolimus was 0.097 ± 0.053 mg/kg at Week 2 and 0.088 ± 0.046 mg/kg at Week 54. The mean ± SD dose was numerically higher for kidney transplant recipients (Week 2: 0.112 ± 0.057 mg/kg; Week 54: 0.100 ± 0.049 mg/kg) than for liver transplant recipients (Week 2: 0.074 ± 0.036 mg/kg; Week 54: 0.070 ± 0.031 mg/kg) throughout the 12‐month follow‐up period (Fig. 3a), in line with lower mean tacrolimus trough levels in liver transplant recipients (Fig. 3b).\n\nFigure 3 Mean ± SD tacrolimus (a) weight‐adjusted daily dose and (b) blood trough levels following conversion to prolonged‐release tacrolimus for the overall pediatric transplant population and stratified by organ type (mFAS). Note: One of two heart transplant patients withdrew at an early stage in the study. The data for the remaining heart transplant recipient are not presented separately, but are included in the overall population. mFAS, modified full‐analysis set; SD, standard deviation.\n\nThroughout the study period, mean tacrolimus trough levels remained within the target range of 3.5–15 ng/ml for both kidney and liver transplant recipients. At Day 14, 14 patients (17.7%) had trough levels below 3.5 ng/ml, and across follow‐up visits from Week 6 to Week 54, below target trough levels were observed in 7.6–11.4% of patients. None of the patients had trough levels above 15 ng/ml. At Week 2, the mean ± SD tacrolimus trough levels were 5.07 ± 1.87 ng/ml for the overall transplant population, 5.57 ± 1.72 ng/ml for the kidney transplant group, and 4.07 ± 1.40 ng/ml for the liver transplant group. Tacrolimus trough levels were stable during the follow‐up period, and levels were similar to Week 2 at Week 54 (overall: 5.16 ± 2.06; kidney: 5.56 ± 1.54; liver: 4.00 ± 1.52 ng/ml; Fig. 3b).\n\nTacrolimus dose adjustments were made based on individual centers’ clinical practice protocol, and to maintain the patient at the target trough level. Overall, 52/79 (65.8%) patients had a dose adjustment during the study. At Week 6, 12.7% of patients had an increased dose, and 7.6% had a decreased dose (Fig. 4). At Week 54, just 5.1% of patients had a dose adjustment, with similar numbers receiving increased and decreased dosages (2.5% and 3.8%, respectively; Fig. 4). Concomitant mycophenolate mofetil, prednisone, prednisolone, and azathioprine were continued in 49.4%, 38.0%, 17.7%, and 12.7% of patients, respectively.\n\nFigure 4 Patients, as a percentage of the study population, requiring dose adjustments at study Week 6 and study Week 54, for the overall pediatric transplant population and kidney and liver transplant patients (mFAS). Note: One of two heart transplant patients withdrew at an early stage in the study. The data for the remaining heart transplant recipient are not presented separately, but are included in the overall population; this patient had no changes in dosage at either Week 6 or Week 54; Week 6 is from Day 19 to 56 and Week 54 (end of study) from Day 337; mFAS, modified full‐analysis set.\n\nRejection episodes, graft and patient survival\nTwo transplant recipients (2.5%, both kidney) had AR episodes (Table 2), both considered as a serious TEAE of moderate severity. In one patient, a BCAR episode (an acute T‐cell‐mediated rejection and acute antibody‐mediated rejection) occurred on Day 281 and was resistant to corticosteroid treatment. The patient discontinued prolonged‐release tacrolimus and was withdrawn from the study. The rejection episode resolved after further treatment with methylprednisolone, anti‐thymocyte immunoglobulin and rituximab. The AR episode in the second patient on Day 145 was not confirmed by biopsy and was treated with corticosteroids and plasmapheresis. Following further treatment with intravenous immunoglobulins, intravenous methylprednisolone, and oral prednisone, the AR episode resolved with sequelae (elevated serum creatinine levels). There were no episodes of graft loss or deaths during the follow‐up period (Table 2).\n\nTable 2 Efficacy outcomes for the overall population and stratified by organ type (mFAS)\n\nParameter\tPatients, n (%)\t\nKidney transplant (n = 48)\tLiver transplant (n = 29)\tHeart transplant (n = 2)\tOverall (n = 79)\t\nAll ARs\t2 (4.2)\t0\t0\t2 (2.5)\t\nBCAR\t1 (2.1)\t0\t0\t1 (1.3)\t\nNon‐BCAR\t1 (2.1)\t0\t0\t1 (1.3)\t\nAny ARs\t2 (4.2)\t0\t0\t2 (2.5)\t\nCorticosteroid‐sensitive AR\t1 (2.1)\t0\t0\t1 (1.3)\t\nCorticosteroid‐resistant AR\t1 (2.1)*\n\t0\t0\t1 (1.3)\t\nResolved with further treatment\t2 (4.2)\t0\t0\t1 (1.3)\t\nAll BCARs\t1 (2.1)\t0\t0\t1 (1.3)\t\nCorticosteroid‐sensitive AR\t0\t0\t0\t0\t\nCorticosteroid‐resistant AR\t1 (2.1)\t0\t0\t1 (1.3)\t\nResolved with further treatment\t1 (2.1)\t0\t0\t1 (1.3)\t\nEfficacy failure†\n\t1 (2.1)\t1 (3.4)\t1 (50.0)\t3 (3.8)\t\nDeath\t0\t0\t0\t0\t\nGraft loss\t0\t0\t0\t0\t\nBCAR, n (%)\t1 (2.1)‡\n\t0\t0\t1 (1.3)\t\nUnknown outcome§, n (%)\t0\t1 (3.4)\t1 (50.0)\t2 (2.5)\t\nAR, acute rejection; BCAR, biopsy‐confirmed acute rejection; mFAS, modified full‐analysis set; SAE, serious adverse event.\n\n*This patient was withdrawn from the study.\n\n\n†Composite of subcategories shown.\n\n\n‡Moderate SAE (corticosteroid‐resistant BCAR in a kidney transplant recipient; the patient discontinued from the study and the event resolved after treatment with methylprednisolone, anti‐thymocyte immunoglobulin, and rituximab).\n\n\n§A patient was considered to have an unknown outcome if he/she did not have the event of interest (death, graft loss, BCAR) and did not have a study assessment within 30 days prior to the target day of analysis, and had no further assessments thereafter.\n\nJohn Wiley & Sons, LtdEfficacy failure\nOverall, three transplant recipients (3/79, 3.8%) had composite efficacy failure (Table 2). One kidney transplant recipient had a BCAR episode on Day 281 (discussed above); one liver transplant recipient had an AE (diarrhea) on Day 90 that led to study withdrawal. A heart transplant recipient withdrew consent and discontinued the study on Day 14.\n\nRenal function\nRenal function, as assessed by mean ± SD eGFR, was relatively stable during the study period in kidney transplant recipients: 112.1 ± 31.0 ml/min/1.73 m2 at Week 2 and 101.8 ± 28.2 ml/min/1.73 m2 at Week 54 (Fig. 5).\n\nFigure 5 Renal function over time in kidney and liver transplant patients (mFAS). eGFR was calculated using the Schwartz equation. eGFR, estimated glomerular filtration rate; mFAS, modified full‐analysis set; SD, standard deviation.\n\nSafety\nNo new safety signals for prolonged‐release tacrolimus were identified during the course of this study. Overall, 282 TEAEs were reported in 84.8% (67/79) of patients; serious TEAEs occurred in 24.1% (19/79) of patients (Table 3\n). The most common TEAEs were diarrhea (13.9%), headache (13.9%), and cough (11.4%). TEAEs were mild in 56.7% and severe in 7.6% of patients.\n\nTable 3 Overview of TEAEs for overall population and stratified by organ type (mFAS)\n\nParameter\tPatients, n (%)\t\nKidney transplant (n = 48)\tLiver transplant (n = 29)\tOverall (n = 79)\t\nTEAEs\t39 (81.3)\t27 (93.1)\t67 (84.8)\t\nDrug‐related TEAEs*\n\t24 (50.0)\t4 (13.8)\t28 (35.4)\t\nSerious TEAEs\t15 (31.3)\t4 (13.8)\t19 (24.1)\t\nDrug‐related serious TEAEs*\n\t9 (18.8)\t1 (3.4)\t10 (12.7)\t\nTEAEs leading to permanent discontinuation\t0\t1 (3.4)†\n\t1 (1.3)\t\nmFAS, modified full‐analysis set; TEAE, treatment‐emergent adverse event.\n\nData for the heart transplant recipient (n = 1) are not presented separately, but are included in the overall population.\n\n*Possible or probable, as assessed by the investigator, or records where relationship is missing.\n\n\n†Drug‐related TEAE (diarrhea).\n\nJohn Wiley & Sons, LtdOverall, 28 patients (28/79, 35.4%) had drug‐related TEAEs, of whom 10 (10/79, 12.7%) had drug‐related serious TEAEs. All drug‐related TEAEs subsequently resolved. Overall, infections and infestations were the most common class of drug‐related TEAE (18/79, 22.8%) (Table 4). Most drug‐related TEAEs were mild in severity.\n\nTable 4 Drug‐related TEAEs by system organ class and preferred term (mFAS)\n\nSystem organ class (≥5% overall) preferred term\tPatients, n (%)\t\nKidney transplant (n = 48)\tLiver transplant (n = 29)\tOverall (n = 79)\t\nOverall\t24 (50.0)\t4 (13.8)\t28 (35.4)\t\nGastrointestinal disorders\t4 (8.3)\t1 (3.4)\t5 (6.3)\t\nDiarrhea\t2 (4.2)\t1 (3.4)\t3 (3.8)\t\nVomiting\t1 (2.1)\t1 (3.4)\t2 (2.5)\t\nEnterocolitis\t1 (2.1)\t0\t1 (1.3)\t\nNausea\t0\t1 (3.4)\t1 (1.3)\t\nInfections and infestations\t17 (35.4)\t1 (3.4)\t18 (22.8)\t\nAcute sinusitis\t2 (4.2)\t0\t2 (2.5)\t\nCytomegalovirus infection\t1 (2.1)\t0\t1 (1.3)\t\nEscherichia urinary tract infection\t2 (4.2)\t0\t2 (2.5)\t\nGastroenteritis\t2 (4.2)\t0\t2 (2.5)\t\nLiver abscess\t0\t1 (3.4)\t1 (1.3)\t\nNasopharyngitis\t0\t1 (3.4)\t1 (1.3)\t\nOral fungal infection\t1 (2.1)\t0\t1 (1.3)\t\nOral herpes\t3 (6.3)\t0\t3 (3.8)\t\nPharyngitis\t2 (4.2)\t0\t2 (2.5)\t\nPneumonia\t1 (2.1)\t0\t1 (1.3)\t\nScarlet fever\t1 (2.1)\t0\t1 (1.3)\t\nSuperinfection bacterial\t1 (2.1)\t0\t1 (1.3)\t\nTracheobronchitis mycoplasmal\t1 (2.1)\t0\t1 (1.3)\t\nUpper respiratory tract infection\t2 (4.2)\t0\t2 (2.5)\t\nUrinary tract infection\t1 (2.1)\t0\t1 (1.3)\t\nViral upper respiratory tract infection\t1 (2.1)\t0\t1 (1.3)\t\nInvestigations\t6 (12.5)\t1 (3.4)\t7 (8.9)\t\nAspartate aminotransferase increased\t0\t1 (3.4)\t1 (1.3)\t\nBlood creatinine increased\t2 (4.2)\t0\t2 (2.5)\t\nBlood iron decreased\t1 (2.1)\t0\t1 (1.3)\t\nBlood pressure increased\t1 (2.1)\t0\t1 (1.3)\t\nC‐reactive protein increased\t1 (2.1)\t0\t1 (1.3)\t\nImmunosuppressant drug level decreased\t1 (2.1)\t0\t1 (1.3)\t\nImmunosuppressant drug level increased\t1 (2.1)\t0\t1 (1.3)\t\nmFAS, modified full‐analysis set; TEAE, treatment‐emergent adverse event.\n\nData for the heart transplant recipient (n = 1) are not presented separately, but are included in the overall population.\n\nJohn Wiley & Sons, LtdLaboratory and vital signs\nNo unusual laboratory test results or vital signs were observed in patients during the course of this study. Results from laboratory evaluations and vital signs were comparable in the liver and kidney transplant recipients. Overall, 12 patients (8/48 kidney and 4/29 liver transplant recipients) had potentially clinically significant increases in hematocrit, hemoglobin levels, leukocyte counts, and platelet counts. Overall, 15 patients (11/48 kidney and 4/29 liver transplant recipients) had potentially clinically significant biochemistry test results. The most common changes from baseline were reductions in total bilirubin and high‐density lipoprotein levels.\n\nDiscussion\nDuring this prospective, open‐label study, mean tacrolimus whole‐blood trough levels were stable up to 1 year following conversion from immediate‐release to prolonged‐release tacrolimus and were in the target range for most patients. There were just two ARs in kidney transplant recipients and no deaths or graft loss during the study. Importantly, no new safety signals were identified for prolonged‐release tacrolimus in this pediatric population.\n\nIn the companion pharmacokinetics paper based on the same patient cohort, we recently demonstrated that following conversion from immediate‐ to prolonged‐release tacrolimus (1:1 mg), the mean systemic exposure to tacrolimus (AUC0–24) under steady‐state conditions (after 7 days on the same dose) and the linear relationship between AUC0‐24 and C24 were similar for the two formulations (rho, 0.89 and 0.84, respectively) 22. This indicated that stable pediatric transplant recipients can be converted from immediate‐release to prolonged‐release tacrolimus on a 1:1 mg total‐daily‐dose basis, in line with previous reports 14, 15, 16, 19. In the present study, mean ± SD trough levels prior to conversion were 5.80 ± 1.73 ng/ml. Following conversion, tacrolimus exposure remained stable, with observed trough levels at Week 2 of 5.07 ± 1.87 ng/ml and Week 54 of 5.16 ± 2.06 ng/ml. The tacrolimus trough levels observed in our study were comparable with that observed in a study of 11 pediatric kidney transplant recipients (preconversion: 6.2 ± 2.0 ng/ml; 1 year postconversion: 6.5 ± 0.9 ng/ml) 19, and 18 pediatric liver transplant recipients: (4.9 ± 2.4–5.9 ± 2.7 ng/ml during the first year following conversion) 16.\n\nWhile mean exposure to tacrolimus was stable in pediatric transplant recipients converted from immediate‐ to prolonged‐release tacrolimus, almost two‐thirds of patients (65.8%) had dose adjustments during the study. It is noteworthy that although no patients had tacrolimus trough levels above the target range, six patients (7.6%) at Week 6 and three patients (3.8%) at Week 54 were administered a decreased tacrolimus dose. These dose adjustments were tailored to the specific clinical characteristics of individual patients (including concomitant immunosuppressive medications used, time post‐transplantation, growth‐related changes in body weight and age‐related changes in tacrolimus clearance), according to the clinical practice protocol at each center.\n\nTacrolimus has a narrow therapeutic index and, therefore, exposure to the drug should be maintained within a tightly defined target range on an individual patient basis, as underexposure is associated with poor transplant outcomes 25, 26, while overexposure can cause drug‐related adverse effects and toxicity 27. During the study, 7.6–17.7% of all transplant recipients across visits had individual tacrolimus trough levels less than 3.5 ng/ml.\n\nIn this study, only two (2.5%) kidney transplant recipients experienced AR, and there were no deaths or graft losses. These data are aligned with previous reports of pediatric kidney and liver transplant recipients converted from immediate‐ to prolonged‐release tacrolimus, in whom ARs were very low, or absent, over follow‐up periods ranging from 6 months to 5 years 16, 17, 18, 19, 20, 21. For example, in a study of 11 pediatric stable kidney transplant recipients converted from immediate‐ to prolonged‐release tacrolimus, there were two BCAR episodes in one patient during the 1‐year follow‐up period 19. Furthermore, a study of 55 Spanish pediatric liver transplant recipients reported no graft losses or patient deaths over a mean postconversion follow‐up time of 5.2 ± 2.4 years 17.\n\nWe found that renal function was stable in both kidney and liver transplant recipients after conversion from immediate‐ to prolonged‐release tacrolimus, in accordance with previous studies 15, 17, 18, 20, 21. Collectively, the efficacy data presented here suggest that conversion from immediate‐ to prolonged‐release tacrolimus is associated with a very low AR rate over 1 year in solid organ transplant recipients.\n\nProlonged‐release tacrolimus was generally well tolerated during our study and no new safety signals were identified in this pediatric population. Although approximately one‐third of patients experienced drug‐related TEAEs following conversion from immediate‐ to prolonged‐release tacrolimus, most were mild in severity, and all resolved. Similar results have been seen in previous studies of pediatric kidney and liver transplant recipients converted from immediate‐ to prolonged‐release tacrolimus 16, 17, 18, 19, 20, 21.\n\nThis study had several limitations, including the absence of a control group to act as a comparator. In addition, since the patient population was predominantly Caucasian (93%), the results of the study may not be applicable to the general population due to differences in the pharmacokinetic profile and metabolism of tacrolimus between races. For example, African Americans exhibit 20–50% lower bioavailability and higher clearance of tacrolimus compared with Caucasians 28, 29, and therefore require 1.5‐ to 2‐times higher tacrolimus doses to achieve equivalent target trough concentrations 30, 31, 32, 33, 34. The study was only powered to compare the pharmacokinetics of immediate‐ and prolonged‐release tacrolimus; therefore, it was not possible to assess the statistical significance of differences in efficacy and safety between the different organ transplant groups. Furthermore, as only two heart transplant recipients were enrolled in this study, and one of these patients subsequently withdrew at an early stage, it was not possible to assess the efficacy and safety of conversion from immediate‐ to prolonged‐release tacrolimus in this transplant group. Clearance of prolonged‐release tacrolimus has been shown to be higher in younger patients aged <5 years (even if they are able to swallow the capsules intact), which can necessitate twice‐daily treatment with tacrolimus 35. Patients enrolled in this study were ≥5 years, and therefore conclusions drawn about efficacy and safety may not be applicable to younger children. Additionally, there is limited information regarding an appropriate dose in these patients. Per‐protocol biopsies were not performed in this study, so smoldering (sub‐clinical) rejection, an important pathogenesis in chronic antibody‐mediated rejection 36, could not be detected. Further limitations are that neither medication adherence nor donor‐specific antibodies were evaluated in the present study.\n\nIn conclusion, our data suggest that conversion from twice‐daily, immediate‐release to once‐daily, prolonged‐release tacrolimus on a 1:1 mg total‐daily‐dose basis is effective over 1 year postconversion in pediatric transplant recipients. Prolonged‐release tacrolimus was generally well tolerated and no new safety signals were identified in this pediatric population. Tacrolimus dose adjustments may be required to maintain stable postconversion target tacrolimus blood trough levels, thereby highlighting the importance of therapeutic drug monitoring in pediatric transplant recipients following conversion from immediate‐ to prolonged‐release tacrolimus.\n\nAuthorship\nJR, DD, DK, FI, NJAW, PC, KV, ASL, CR, SR, BT, LD, SDM and RR: performed research and collected data. GK: analyzed the data. NU: designed the study, and all authors reviewed and approved the manuscript.\n\nFunding\nThis study was supported by the NIHR Manchester Clinical Research Facility and was sponsored by Astellas Pharma Europe Ltd.\n\nConflict of interest\nJR, DK, PC, KV, ASL, CR and LD report nonfinancial support from Astellas, during the conduct of the study. DD and FI report nonfinancial, and other support from Astellas, during the conduct of the study, and other support from Astellas, outside the submitted work. NJAW, SR and RR report nonfinancial, and other support from Astellas, during the conduct of the study. BT reports nonfinancial, and other support from Astellas, during the conduct of the study; grants and other support from Astellas and Novartis, outside the submitted work; and other support from Bristol‐Myers Squibb and Roche, outside the submitted work. SDM reports grants, other, and nonfinancial support from Astellas, during the conduct of the study, and grants from Novartis, outside the submitted work. GK reports nonfinancial, and other support from Astellas, during the conduct of the study, and is a consulting statistician working on behalf of Astellas. NU reports nonfinancial, and other support from Astellas, during the conduct of the study, and is an employee of Astellas. Medical writing support in the development of this manuscript was provided by Cello Health MedErgy, funded by Astellas Pharma, Inc.\n\nData statement\nAccess to anonymized individual participant level data collected during the trial, in addition to supporting clinical documentation, is planned for trials conducted with approved product indications and formulations, as well as compounds terminated during development. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on http://www.clinicalstudydatarequest.com. Study‐related supporting documentation is redacted and provided if available, such as the protocol and amendments, statistical analysis plan and clinical study report. Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data. Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.\n\nAcknowledgements\nAmy MacLucas and James Wallis from Cello Health MedErgy assisted in drafting the initial version of the manuscript under the direction of the authors, and provided editorial support throughout its development. Editorial support was funded by Astellas Pharma, Inc.\n==== Refs\nReferences\n1 \n\nKim \nWR \n, \nLake \nJR \n, \nSmith \nJM \n, et al\nOPTN/SRTR 2016 annual data report: liver . Am J Transplant \n2018 ; 18 : 172 .29292603 \n2 \n\nHart \nA \n, \nSmith \nJM \n, \nSkeans \nMA \n, et al\nOPTN/SRTR 2016 annual data report: kidney . Am J Transplant \n2018 ; 18 : 18 .29292608 \n3 \nAstellas Pharma Europe Ltd \n. Prograf 0.5 mg, 1 mg, 5 mg hard capsules summary of product characteristics . https://www.medicines.org.uk/emc/product/6720. Accessed April 17, 2019.\n4 \nUS Food and Drug Administration \n. Astagraf XL prescribing information . https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204096s005lbl.pdf. Accessed February 14, 2019.\n5 \nAstellas Pharma Europe Ltd \n. Advagraf 0.5 mg, 1 mg, 3 mg and 5 mg prolonged‐release hard capsules summary of product characteristics . https://www.medicines.org.uk/emc/product/345/smpc. Accessed February 20, 2019.\n6 \n\nButler \nJA \n, \nRoderick \nP \n, \nMullee \nM \n, et al\nFrequency and impact of nonadherence to immunosuppressants after renal transplantation: a systematic review . Transplantation \n2004 ; 77 : 769 .15021846 \n7 \n\nShemesh \nE \n, \nDuncan \nS \n, \nAnand \nR \n, et al\nTrajectory of adherence behavior in pediatric and adolescent liver transplant recipients: the medication adherence in children who had a liver transplant cohort . Liver Transpl \n2018 ; 24 : 80 .28779546 \n8 \n\nChisholm‐Burns \nMA \n, \nSpivey \nCA \n, \nRehfeld \nR \n, et al\nImmunosuppressant therapy adherence and graft failure among pediatric renal transplant recipients . Am J Transplant \n2009 ; 9 : 2497 .19681814 \n9 \n\nBorra \nLC \n, \nRoodnat \nJI \n, \nKal \nJA \n, et al\nHigh within‐patient variability in the clearance of tacrolimus is a risk factor for poor long‐term outcome after kidney transplantation . Nephrol Dial Transplant \n2010 ; 25 : 2757 .20190242 \n10 \n\nBeckebaum \nS \n, \nIacob \nS \n, \nSweid \nD \n, et al\nEfficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice‐daily tacrolimus‐based regimen to once‐daily tacrolimus extended‐release formulation . Transpl Int \n2011 ; 24 : 666 .21466596 \n11 \n\nEberlin \nM \n, \nOtto \nG \n, \nKrämer \nI \n. Increased medication compliance of liver transplant patients switched from a twice‐daily to a once‐daily tacrolimus‐based immunosuppressive regimen . Transplant Proc \n2013 ; 45 : 2314 .23726723 \n12 \n\nKuypers \nDR \n, \nPeeters \nPC \n, \nSennesael \nJJ \n, et al\nImproved adherence to tacrolimus once‐daily formulation in renal recipients: a randomized controlled trial using electronic monitoring . Transplantation \n2013 ; 95 : 333 .23263559 \n13 \n\nKurnatowska \nI \n, \nKrawczyk \nJ \n, \nOleksik \nT \n, et al\nTacrolimus dose and blood concentration variability in kidney transplant recipients undergoing conversion from twice daily to once daily modified release tacrolimus . Transplant Proc \n2011 ; 43 : 2954 .21996199 \n14 \n\nAlloway \nR \n, \nSteinberg \nS \n, \nKhalil \nK \n, et al\nConversion of stable kidney transplant recipients from a twice daily Prograf‐based regimen to a once daily modified release tacrolimus‐based regimen . Transplant Proc \n2005 ; 37 : 867 .15848559 \n15 \n\nFlorman \nS \n, \nAlloway \nR \n, \nKalayoglu \nM \n, et al\nConversion of stable liver transplant recipients from a twice‐daily Prograf‐based regimen to a once‐daily modified release tacrolimus‐based regimen . Transplant Proc \n2005 ; 37 : 1211 .15848672 \n16 \n\nHeffron \nTG \n, \nPescovitz \nMD \n, \nFlorman \nS \n, et al\nOnce‐daily tacrolimus extended‐release formulation: 1‐year postconversion in stable pediatric liver transplant recipients . Am J Transplant \n2007 ; 7 : 1609 .17511684 \n17 \n\nQuintero \nJ \n, \nJuampérez \nJ \n, \nOrtega \nJ \n, et al\nConversion from twice‐daily to once‐daily tacrolimus formulation in pediatric liver transplant recipients – a long‐term prospective study . Transpl Int \n2018 ; 31 : 38 .28833714 \n18 \n\nCarcas‐Sansuán \nAJ \n, \nHierro \nL \n, \nAlmeida‐Paulo \nGN \n, et al\nConversion from Prograf to Advagraf in adolescents with stable liver transplants: comparative pharmacokinetics and 1‐year follow‐up . Liver Transplant \n2013 ; 19 : 1151 .\n19 \n\nPape \nL \n, \nHeidotting \nN \n, \nAhlenstiel \nT \n. Once‐daily tacrolimus extended‐release formulation: 1 year after conversion in stable pediatric kidney transplant recipients . Int J Nephrol \n2011 ; 2011 : 126251 .21647310 \n20 \n\nMin \nSI \n, \nHa \nJ \n, \nKang \nHG \n, et al\nConversion of twice‐daily tacrolimus to once‐daily tacrolimus formulation in stable pediatric kidney transplant recipients: pharmacokinetics and efficacy . Am J Transplant \n2013 ; 13 : 2191 .23734831 \n21 \n\nCarcas‐Sansuán \nAJ \n, \nEspinosa‐Román \nL \n, \nAlmeida‐Paulo \nGN \n, et al\nConversion from Prograf to Advagraf in stable paediatric renal transplant patients and 1‐year follow‐up . Pediatr Nephrol \n2014 ; 29 : 117 .23907143 \n22 \n\nRubik \nJ \n, \nDebray \nD \n, \nIserin \nF \n, et al\nComparative pharmacokinetics of tacrolimus in stable pediatric allograft recipients converted from immediate‐release tacrolimus to prolonged‐release tacrolimus formulation . Pediatr Transplant \n2019 ; 23 : e13391 .30932313 \n23 \n\nSchwartz \nGJ \n, \nHaycock \nGB \n, \nEdelmann \nCM \nJr.\n, et al\nA simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine . Pediatrics \n1976 ; 58 : 259 .951142 \n24 \nUS National Institutes of Health \n. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 . https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Published 2010. Accessed April 17, 2019.\n25 \n\nSellarés \nJ \n, \nde Freitas \nDG \n, \nMengel \nM \n, et al\nUnderstanding the causes of kidney transplant failure: the dominant role of antibody‐mediated rejection and nonadherence . Am J Transplant \n2012 ; 12 : 388 .22081892 \n26 \n\nWiebe \nC \n, \nGibson \nIW \n, \nBlydt‐Hansen \nTD \n, et al\nRates and determinants of progression to graft failure in kidney allograft recipients with de novo donor‐specific antibody . Am J Transplant \n2015 ; 15 : 2921 .26096305 \n27 \n\nKuypers \nDR \n, \nClaes \nK \n, \nEvenepoel \nP \n, et al\nClinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long‐term pharmacokinetics in de novo renal allograft recipients . Clin Pharmacol Ther \n2004 ; 75 : 434 .15116056 \n28 \n\nDirks \nNL \n, \nHuth \nB \n, \nYates \nCR \n, et al\nPharmacokinetics of immunosuppressants: a perspective on ethnic differences . Int J Clin Pharmacol Ther \n2004 ; 42 : 701 .15624287 \n29 \n\nMancinelli \nLM \n, \nFrassetto \nL \n, \nFloren \nLC \n, et al\nThe pharmacokinetics and metabolic dispostion of tacrolimus: a comparison across ethnic groups . Clin Pharmacol Ther \n2001 ; 69 : 24 .11180035 \n30 \n\nAndrews \nLM \n, \nDe Winter \nBC \n, \nVan Gelder \nT \n, et al\nConsideration of the ethnic prevalence of genotypes in the clinical use of tacrolimus . Pharmacogenomics \n2016 ; 17 : 1737 .27790923 \n31 \n\nLaftavi \nMR \n, \nPankewycz \nO \n, \nPatel \nS \n, et al\nAfrican American renal transplant recipients (RTR) require higher tacrolimus doses to achieve target levels compared to white RTR: does clotrimazole help? \nTransplant Proc \n2013 ; 45 : 3498 .24314941 \n32 \n\nNarayanan \nM \n, \nPankewycz \nO \n, \nEl‐Ghoroury \nM \n, et al\nOutcomes in African American kidney transplant patients receiving tacrolimus and mycophenolic acid immunosuppression . Transplantation \n2013 ; 95 : 566 .23423268 \n33 \n\nBeermann \nKJ \n, \nEllis \nMJ \n, \nSudan \nDL \n, et al\nTacrolimus dose requirements in African‐American and Caucasian kidney transplant recipients on mycophenolate and prednisone . Clin Transplant \n2014 ; 28 : 762 .24754564 \n34 \n\nVadivel \nN \n, \nGarg \nA \n, \nHolt \nDW \n, et al\nTacrolimus dose in black renal transplant recipients . Transplantation \n2007 ; 83 : 997 .17460575 \n35 \n\nKim \nJS \n, \nAviles \nDH \n, \nSilverstein \nDM \n, et al\nEffect of age, ethnicity, and glucocorticoid use on tacrolimus pharmacokinetics in pediatric renal transplant patients . Pediatr Transplant \n2005 ; 9 : 162 .15787787 \n36 \n\nZhang \nR \n. Donor‐specific antibodies in kidney transplant recipients . Clin J Am Soc Nephrol \n2018 ; 13 : 182 .28446536\n\n",
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"issue": "32(11)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": "calcineurin inhibitor: tacrolimus; clinical trial; heart (allograft) function/dysfunction; immunosuppressant; kidney (allograft) function/dysfunction; liver (allograft) function/dysfunction",
"medline_ta": "Transpl Int",
"mesh_terms": "D000293:Adolescent; D064591:Allografts; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D005260:Female; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D061214:Patient Safety; D011446:Prospective Studies; D016559:Tacrolimus; D066027:Transplant Recipients; D016896:Treatment Outcome",
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"pages": "1182-1193",
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"pmid": "31325368",
"pubdate": "2019-11",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "11180035;28779546;27790923;23423268;17511684;22081892;15624287;28833714;23894093;23263559;23726723;30932313;29292603;28446536;20190242;17460575;24754564;951142;15787787;23734831;26096305;15021846;24314941;21996199;29292608;23907143;15848672;15848559;21466596;21647310;15116056;19681814",
"title": "Efficacy and safety of prolonged-release tacrolimus in stable pediatric allograft recipients converted from immediate-release tacrolimus - a Phase 2, open-label, single-arm, one-way crossover study.",
"title_normalized": "efficacy and safety of prolonged release tacrolimus in stable pediatric allograft recipients converted from immediate release tacrolimus a phase 2 open label single arm one way crossover study"
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"abstract": "Early recognition of trimethoprim and sulfonamide-induced aseptic meningitis is important because drug cessation leads to rapid clinical improvement. We present clinical and laboratory findings in two typical cases. In both cases, MRI revealed previously undescribed diffuse white matter abnormalities that resolved within a few months. These MRI findings are important because they may aid in early diagnosis of this condition in the appropriate clinical setting. In addition, the white matter abnormalities suggest an encephalitic component in addition to the meningitis.",
"affiliations": "Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.",
"authors": "Blumenfeld|H|H|;Cha|J H|JH|;Cudkowicz|M E|ME|",
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"doi": "10.1212/wnl.46.2.556",
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"mesh_terms": "D000328:Adult; D000890:Anti-Infective Agents; D000892:Anti-Infective Agents, Urinary; D001921:Brain; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D004917:Erythromycin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008590:Meningoencephalitis; D013444:Sulfisoxazole; D013997:Time Factors; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Trimethoprim and sulfonamide-associated meningoencephalitis with MRI correlates.",
"title_normalized": "trimethoprim and sulfonamide associated meningoencephalitis with mri correlates"
} | [
{
"companynumb": "US-PFIZER INC-2020259315",
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"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
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{
"abstract": "Newer techniques that have found a place in cancer management in adults are offered far less commonly in pediatric patients. We present a case of a patient with recurrent Wilms' tumor managed with a novel combination of cytoreductive surgery, intraperitoneal brachytherapy, and subsequent hyperthermic intraperitoneal chemotherapy. Each stage presents challenges that the pediatric anesthetist is unlikely to have faced before. Such cases require flexibility and thorough planning to manage the combination of major surgery, remote anesthesia with brachytherapy and hyperthermic chemotherapy with its potential for metabolic derangement, significant fluid shifts, analgesic care, and potential exposure of staff to cytotoxic agents. Comprehensive care can be offered in pediatric centers.",
"affiliations": "Department of Anaesthesia, The Children's Hospital at Westmead, Sydney, Australia.;Department of Anaesthesia, Middlemore Hospital, Auckland, New Zealand.;Department of Anaesthesia, The Children's Hospital at Westmead, Sydney, Australia.;Department of Anaesthesia, The Children's Hospital at Westmead, Sydney, Australia.;Department of Anaesthesia, The Children's Hospital at Westmead, Sydney, Australia.",
"authors": "Weatherall|Andrew D|AD|;Bennett|Tristan R|TR|;Lovell|Mark|M|;Fung|Winnie|W|;de Lima|Jonathan|J|",
"chemical_list": "D008738:Methyl Ethers; D000077149:Sevoflurane; D005283:Fentanyl; D015742:Propofol",
"country": "France",
"delete": false,
"doi": "10.1111/pan.13094",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1155-5645",
"issue": "27(4)",
"journal": "Paediatric anaesthesia",
"keywords": "anesthesia; brachytherapy; cytoreduction surgical procedures; hyperthermic intraperitoneal chemotherapy; pediatrics",
"medline_ta": "Paediatr Anaesth",
"mesh_terms": "D000293:Adolescent; D000768:Anesthesia, General; D001918:Brachytherapy; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D005283:Fentanyl; D006801:Humans; D006979:Hyperthermia, Induced; D007268:Injections, Epidural; D007668:Kidney; D007680:Kidney Neoplasms; D008297:Male; D008738:Methyl Ethers; D009364:Neoplasm Recurrence, Local; D010537:Peritoneum; D015742:Propofol; D000077149:Sevoflurane; D016896:Treatment Outcome; D009396:Wilms Tumor",
"nlm_unique_id": "9206575",
"other_id": null,
"pages": "338-345",
"pmc": null,
"pmid": "28211128",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Staged intraperitoneal brachytherapy and hyperthermic intraperitoneal chemotherapy in an adolescent: novel anesthetic challenges for pediatric anesthetists.",
"title_normalized": "staged intraperitoneal brachytherapy and hyperthermic intraperitoneal chemotherapy in an adolescent novel anesthetic challenges for pediatric anesthetists"
} | [
{
"companynumb": "AU-ACCORD-052639",
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"drug": [
{
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"drugadministrationroute": "048",
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{
"abstract": "The Food and Drug Administration (FDA) had approved fingolimod usage for multiple sclerosis in 2010. Melanoma after the usage of fingolimod immunomodulation was reported rarely in clinical trials, and only two case reports exist in the published literature, both occurring in Europe. Most of the incidences reported in clinical trials were in-situ, whereas both case reports were of malignant melanoma. Fingolimod has been found to inhibit metastatic melanoma growth in a mouse model that depends on vascular endothelial growth factor (VEGF)-induced angiogenesis for metastasis. However, there are numerous pathways of angiogenesis and tumour growth found in vivo by which melanoma can expand that do not mandate VEGF. We report a case of superficial spreading malignant melanoma occurring after fingolimod therapy in the USA.",
"affiliations": "Department of Dermatology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA.;Department of Dermatology, St. Louis University, St. Louis, Missouri, USA.",
"authors": "Robinson|Christopher Lee|CL|;Guo|Mary|M|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-217885",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D008545:Melanoma; D008875:Middle Aged; D009103:Multiple Sclerosis; D012878:Skin Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28003234",
"pubdate": "2016-12-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16397235;16971719;20089952;20089954;21844470;24685276;25533302;26577239;26827074;27285567",
"title": "Fingolimod (Gilenya) and melanoma.",
"title_normalized": "fingolimod gilenya and melanoma"
} | [
{
"companynumb": "PHHY2017US000676",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INTERFERON BETA-1A"
},
"drugadditional": "1",
... |
{
"abstract": "A number of treatment options have been used over the years in short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) with variable results. The most common preventive treatments include carbamazepine, lamotrigine, indomethacin, gabapentin and topiramate. Ketamine is being increasingly used in the treatment of neuropathic pain. The parentral formulations are generally used as oral preparations have poor bioavailability. Recently, ketamine lozenges have been shown to have sufficiently high bioavailability to support their use as a preventive treatment in a number of conditions causing intractable neuropathic pain. We report a 58-year-old man whose symptoms of SUNCT were not responsive to conventional preventive treatments but responded well to a subcutaneous, sub-anaesthetic ketamine infusion and subsequently, sublingual ketamine lozenges.",
"affiliations": "Pain Management Centre, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.",
"authors": "Aggarwal|Arun|A|",
"chemical_list": "D000701:Analgesics, Opioid; D000778:Anesthetics, Dissociative; D007649:Ketamine",
"country": "India",
"delete": false,
"doi": "10.4103/0970-258X.275347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0970-258X",
"issue": "32(2)",
"journal": "The National medical journal of India",
"keywords": null,
"medline_ta": "Natl Med J India",
"mesh_terms": "D000286:Administration, Sublingual; D000701:Analgesics, Opioid; D000778:Anesthetics, Dissociative; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006801:Humans; D055104:Infusions, Subcutaneous; D007649:Ketamine; D008297:Male; D008875:Middle Aged; D050798:SUNCT Syndrome; D016896:Treatment Outcome",
"nlm_unique_id": "8809315",
"other_id": null,
"pages": "86-87",
"pmc": null,
"pmid": "31939403",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ketamine as a potential option in the treatment of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.",
"title_normalized": "ketamine as a potential option in the treatment of short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing"
} | [
{
"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-239614",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drug... |
{
"abstract": "A 30-year-old man with acquired aplastic anemia underwent an HLA-identical bone marrow transplant. He developed a grade III acute graft versus host disease (GVHD) refractory to various lines of treatment. On post-transplant day 196, he was diagnosed with stem cell transplantation-associated thrombotic micro-angiopathy (HSCT-TMA) and he received treatment with eculizumab 900 mg iv weekly for 4 doses followed by a single dose of 1200 mg 2 weeks later. After the first dose of eculizumab, the patient ceased to require transfusions and a progressive improvement in analytical parameters for microangiopathy was observed until their complete normalization. Coinciding with the improved of HSCT-TMA, the patient presented a clear response to his acute GVHD with disappearance of the diarrhea and bilirubin normalization. He was discharged eight weeks after the start of treatment. Unfortunately, one month later, the patient was readmitted for a GVHD relapse and he died two weeks later by an acute respiratory distress syndrome. In our case, the rapid clinical and analytical response to early treatment with eculizumab supports the implication of the complement in HSCT-TMA and suggests that the drug has a beneficial effect when used as coadjuvant therapy in acute GVHD.",
"affiliations": "Department of Hematology, Hospital Universitario Puerta de Hierro Majadahonda , Madrid, Spain.;Department of Hematology, Hospital Universitario Puerta de Hierro Majadahonda , Madrid, Spain.;Department of Hematology, Hospital Universitario Puerta de Hierro Majadahonda , Madrid, Spain.;Department of Hematology, Hospital Universitario Puerta de Hierro Majadahonda , Madrid, Spain.",
"authors": "Fernández|Cristina|C|;Lario|Ana|A|;Forés|Rafael|R|;Cabrera|Rafael|R|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/hr.2015.6107",
"fulltext": "\n==== Front\nHematol RepHematol RepHRHematology Reports2038-83222038-8330PAGEPress Publications, Pavia, Italy 10.4081/hr.2015.6107Case ReportEculizumab Treatment in a Patient with Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy and Steroid-Refractory Acute Graft Versus Host Disease Fernández Cristina Lario Ana Forés Rafael Cabrera Rafael Department of Hematology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, SpainServicio de Hematología y Hemoterapia, Hospital Puerta de Hierro, calle Joaquín Rodrigo 2, Majadahonda, 28222 Madrid, Spain. +34.91.191.6811;+34.91.191.7809 - +34.91.191.7862. rafael.fores@salud.madrid.orgContributions: the authors contributed equally.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n09 12 2015 23 11 2015 7 4 610709 7 2015 16 10 2015 20 10 2015 ©Copyright C. Fernández et al.2015Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.A 30-year-old man with acquired aplastic anemia underwent an HLA-identical bone marrow transplant. He developed a grade III acute graft versus host disease (GVHD) refractory to various lines of treatment. On post-transplant day 196, he was diagnosed with stem cell transplantation-associated thrombotic micro-angiopathy (HSCT-TMA) and he received treatment with eculizumab 900 mg iv weekly for 4 doses followed by a single dose of 1200 mg 2 weeks later. After the first dose of eculizumab, the patient ceased to require transfusions and a progressive improvement in analytical parameters for microangiopathy was observed until their complete normalization. Coinciding with the improved of HSCT-TMA, the patient presented a clear response to his acute GVHD with disappearance of the diarrhea and bilirubin normalization. He was discharged eight weeks after the start of treatment. Unfortunately, one month later, the patient was readmitted for a GVHD relapse and he died two weeks later by an acute respiratory distress syndrome. In our case, the rapid clinical and analytical response to early treatment with eculizumab supports the implication of the complement in HSCT-TMA and suggests that the drug has a beneficial effect when used as coadjuvant therapy in acute GVHD.\n\nKey words\nEculizumabthrombotic microangiopathyacute graft versus host disease\n==== Body\nIntroduction\nAn article recently published demonstrated the efficacy of eculizumab in the treatment of children with severe hematopoietic stem cell transplantation-associated thrombotic micro-angiopathy (HSCT-TMA).1 We report the case of an adult with HSCT-TMA successfully treated with eculizumab.\n\nHSCT-TMA is a rare but very serious complication of allogeneic hematopoietic progenitor stem cell transplantation. Several factors have been implicated in the endothelial damage which leads to HSCT-TMA: calcineurin inhibitors, acute graft versus host disease (GVHD) and cytomegalovirus (CMV) infection; however, in recent years another mechanism has been described in which complement deregulation plays an important role. Therefore complement-modulating therapies are beginning to gain ground in the treatment of this complication.2,3\n\nCase Report\nWe report the case of a 30-year-old man, diagnosed with very serious acquired bone marrow aplasia in July 2014. He underwent progenitor stem cell transplantation of bone marrow from his HLA-identical sister in July 2014. The conditioning regimen consisted of cyclophosphamide (30 mg/kg/day, −7 to −4), fludarabine (30 mg/m2/day, −5 to −2) and antithymocyte globulin (2.5 mg/kg/day, −3 to −1). GVHD prophylaxis was performed with tacrolimus and methotrexate. On post-transplant day 47, the patient developed acute cutaneous and liver GVHD (grade II) which initially responded to treatment with corticosteroids and etanercept. The patient was readmitted on post-transplant day 116 with diarrhea and hyperbilirubinemia (1.7 mg/dL, normal values 0.3-1.1 mg/dL) and colonoscopy confirmed the existence of acute intestinal GVHD. After the diagnosis of acute grade III GVHD, which was refractory to steroids, he sequentially received various lines of treatment (corticosteroids, mesenchymal stromal cells and sirolimus) without any response.\n\nOn post-transplant day 189, the patient developed severe bloody diarrhea (up to 3000 mL/day) followed by persistent rectal bleeding that required intense transfusional support and treatment with activated Factor VII (5 mg/2 h × 6 doses). A new colonoscopy was performed and the colonic mucosa biopsy confirmed worsening of the intestinal GVHD without histological evidence of HSCT-TMA (Figure 1).4 Biochemistry showed LDH 765 IU/L (normal values 230-460 IU/L), total bilirubin 0.7 mg/dL (normal values 0.3-1.1 mg/dL), hemoglobin 8.5 g/dL, platelets 42×109/L and normal coagulation tests. Treatment was then initiated with one dose of pentostatin (4 mg/m2 iv) and alemtuzumab (20 mg sc 3 times/week for 2 weeks).\n\nOne week after the administration of pentostatin, and with persistent gastrointestinal bleeding, biochemistry showed hyperbilirubinemia (total bilirubin 6.4 mg/dL, direct bilirubin 5.5 mg/dL, normal values 0.0-0.5 mg/dL) and elevated LDH (2700 IU/L). The blood count revealed profound anemia (up to 6.8 g Hb/dL), reticulocytosis (0.3×109/L), thrombocytopenia 39×109/L and the presence of numerous schistocytes in blood smear (6%). Other laboratory findings were: negative direct Coombs test, undetectable haptoglobin, proteinuria (30 mg/dL), normal ADAMST13 activity (94%) and normal complement proteins (C3 and C4). These results led to the diagnosis of HSCT-TMA.5\n\nThe patient had no neurological symptoms or renal failure. PCR for both CMV and Epstein Barr virus were negative. On the day that the patient was diagnosed with HSCT-TMA, treatment was initiated with eculizumab 900 mg iv weekly for 4 doses followed by a single maintenance dose of 1200 mg 2 weeks later. After the first dose of eculizumab, the patient ceased to require transfusions and a progressive improvement in analytical parameters for microangiopathy was observed until their complete normalization after 7 weeks (Hb 11.4 g/dL, platelets 164×109/L, no schistocytes, bilirubin 0.8 mg/dL and 450 LDH IU/L). CH50 determinations showed complement activity inhibition after each dose had been administered. Coinciding with the improved of HSCT-TMA, the patient presented a clear response to his acute GVHD with disappearance of the diarrhea and bilirubin normalization (Figure 2), although it has not been documented histologically. He was discharged eight weeks after the start of treatment (post-transplant day 257). Unfortunately, one month later, the patient was readmitted by diarrhea; a new colonoscopy showed intestinal GVHD relapse. The patient died two weeks after admission because of acute respiratory distress syndrome of unknown cause, with diffuse bilateral infiltrates, cardiomegaly and right pleural effusion in chest CT.\n\nDiscussion and Conclusions\nThe treatment for HSCT-TMA is not well-defined. Plasma exchange, defibrotide, rituximab and basiliximab have been used with variable response rates. We started eculizumab instead of plasma exchange for the poor results of this treatment in HSCT-TMA cases associated with acute GVHD.6,7 In our case, the rapid clinical and analytical response to early treatment with eculizumab (a humanized monoclonal antibody against complement fraction 5) supports the implication of the complement in its pathophysiology. The drug was well tolerated without any side effects. The rapid response of a severe, refractory GVHD is noteworthy and suggests that the drug has a beneficial effect when used as coadjuvant therapy in this situation. More cases and studies would be required to confirm these data.\n\nAcknowledgments\nThe authors wish to thank Martin Hadley-Adams for translating the manuscript.\n\nFigure 1. A) Colon biopsy with acute graft versus host disease (GVHD); B) colonic mucosa with apoptotic bodies in crypts (GVHD).\n\nFigure 2. Levels of diarrhea (mL), bilirubin (mg/dL), platelets (×109) and LDH (IU/dL) after transplantation.\n==== Refs\nReferences\n1. Jodele S Fukuda T Vinks A \nEculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy . Biol Blood Marrow Transplant \n2014 ;20 :518 -25 .24370861 \n2. Okano M Sakata N Ueda S Takemura T. \nRecovery from life-threatening transplantation-associated thrombotic microangiopathy using eculizumab in a patient with very severe aplastic anemia . Bone Marrow Transplant \n2014 ;49 :1116 -8 .24820211 \n3. Peffault de Latour R Xhaard A Fremeaux-Bacchi V \nSuccessful use of eculizumab in a patient with post-transplant thrombotic microangiopathy . Br J Haematol \n2013 ;161 :279 -80 .23294015 \n4. Inamoto Y Ito M Suzuki R \nClinicopathological manifestations and treatment of intestinal transplant-associated microangiopathy . Bone Marrow Transplant \n2009 ;44 :43 -9 .19139727 \n5. Jodele S Davies SM Lane A \nDiagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults . Blood \n2014 ;124 :645 -53 .24876561 \n6. Llamas P Romero R Cabrera R \nManagement of thrombotic microangiopathy following allogeneic transplantation: what is the role of plasma exchange? \nBone Marrow Transplant \n1997 ;20 :305 -6 .9285545 \n7. Kennedy GA Kearey N Bleakley S \nTransplantation-associated thrombotic microangiopathy: effect of concomitant GVHD on efficacy of therapeutic plasma exchange . Bone Marrow Transplant \n2010 ;45 :699 -704 .19767787\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2038-8322",
"issue": "7(4)",
"journal": "Hematology reports",
"keywords": "Eculizumab; acute graft versus host disease; thrombotic microangiopathy",
"medline_ta": "Hematol Rep",
"mesh_terms": null,
"nlm_unique_id": "101556723",
"other_id": null,
"pages": "6107",
"pmc": null,
"pmid": "26734129",
"pubdate": "2015-11-23",
"publication_types": "D002363:Case Reports",
"references": "24370861;24820211;19139727;23294015;24876561;19767787;9285545",
"title": "Eculizumab Treatment in a Patient with Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy and Steroid-Refractory Acute Graft Versus Host Disease.",
"title_normalized": "eculizumab treatment in a patient with hematopoietic stem cell transplantation associated thrombotic microangiopathy and steroid refractory acute graft versus host disease"
} | [
{
"companynumb": "ES-SA-2015SA222947",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
"drugadditi... |
{
"abstract": "BACKGROUND\nPreliminary evidence indicates that the addition of low-dose total body irradiation (TBI) (2-4 Gy) to reduced intensity conditioning may reduce the rate of relapse in allogeneic stem cell transplants. In very high-risk patients receiving combination haploidentical single-unit cord blood transplants, we have added 4 Gy TBI to the widely used fludarabine, melphalan conditioning regimen, in hopes of reducing relapse and decreasing graft rejection.\n\n\nMETHODS\nWe retrospectively reviewed the posttransplant outcomes of patients who underwent haplocord stem cell transplant between May 2013 and March 2015 and who received fludarabine 30 mg/m day (D)-7 to -3, melphalan 140 mg/m D-2, and 2 Gy TBI D-4 and -3.\n\n\nRESULTS\nAll 25 patients achieved primary neutrophil engraftment after a median of 12 days. The median time to platelet engraftment was 27 days. The cumulative incidence of nonrelapse mortality was 16% by D+100 and 33% by 1 year. The cumulative incidence of grade III to IV acute graft-versus-host disease was 36% by D+100. The CIR was 13% by D+100 and 29% by 1 year. The estimated 1-year overall survival and progression-free survival were 40% and 37%, respectively. In a subgroup analysis, we compared the outcome of 13 acute myeloid leukemia patients receiving this conditioning regimen with age and disease risk index-matched acute myeloid leukemia patients receiving fludarabine-melphalan without TBI. The TBI group had lower incidence of relapse at 1 year (15% vs 54%, P = 0.05).\n\n\nCONCLUSIONS\nOverall, combination fludarabine-melphalan with low-dose TBI after haplocord stem cell transplant assures good engraftment and leads to acceptable toxicity and disease control in the setting of high risk, heavily pretreated patients. These findings warrant further investigation at a larger-scale, prospective level.",
"affiliations": "1 Department of Hematology/Oncology, Weill Cornell Medicine, New York, NY. 2 Department of Radiation Oncology, Weill Cornell Medicine, New York, NY.",
"authors": "Choe|Hannah K|HK|;Gergis|Usama|U|;Mayer|Sebastian A|SA|;Nagar|Himanshu|H|;Phillips|Adrienne A|AA|;Shore|Tsiporah B|TB|;Smith|Michael J|MJ|;van Besien|Koen|K|",
"chemical_list": "D019653:Myeloablative Agonists; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000001538",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "101(1)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000328:Adult; D000368:Aged; D036101:Cord Blood Stem Cell Transplantation; D018572:Disease-Free Survival; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D019653:Myeloablative Agonists; D011829:Radiation Dosage; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D019172:Transplantation Conditioning; D016896:Treatment Outcome; D014740:Vidarabine; D014916:Whole-Body Irradiation; D055815:Young Adult",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "e34-e38",
"pmc": null,
"pmid": "27764032",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Addition of Low-Dose Total Body Irradiation to Fludarabine and Melphalan Conditioning in Haplocord Transplantation for High-Risk Hematological Malignancies.",
"title_normalized": "the addition of low dose total body irradiation to fludarabine and melphalan conditioning in haplocord transplantation for high risk hematological malignancies"
} | [
{
"companynumb": "US-PFIZER INC-2020228765",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
"drug... |
{
"abstract": "Isoniazid-resistant rifampicin-susceptible (HRRS) tuberculosis (TB) is the most prevalent form of drug-resistant TB globally, and may be a risk factor for poor outcomes, but has been poorly described in children.\n\n\n\nTo characterise the clinical presentation, treatment, and clinical and microbiological outcomes among children with culture-confirmed HRRS TB.\n\n\n\nRetrospective hospital-based cohort study.\n\n\n\nOf the 72 children included in the study, the median age was 50.1 months (IQR 21.5-102.5); 42% were male. Forty-four (51%) had a potential source case; only 13 were confirmed HRRS TB. Of 66 tested, 12 (17%) were human immunodeficiency virus (HIV) infected, and 36 (60%) of the 60 with pulmonary TB (PTB) had severe disease. Seventy children had treatment data; the median total duration of treatment was 11.3 months (IQR 9-12.3); 25 (36%) initiated treatment with a three-drug intensive phase; 52 (74%) received a fluoroquinolone. Of 63 children with known outcomes, 55 (88%) had a favourable outcome, 1 died and 3 had treatment failure. Ten had positive follow-up cultures at ⩾2 months after starting treatment. Older age (P = 0.008), previous anti-tuberculosis treatment (P = 0.023) and severe PTB (P = 0.018) were associated with failure to culture-convert at ⩾2 months.\n\n\n\nAlthough overall outcomes were good, prolonged culture positivity and cases of treatment failure emphasise the need for additional attention to the management of children with HRRS TB.",
"affiliations": "Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.;Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.;Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.;Brewelskloof Hospital, Western Cape Government Department of Health, Worcester, South Africa.;Department of Paediatrics, Imperial College London, London, UK.;Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.;Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.;Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.",
"authors": "Garcia-Prats|A J|AJ|;du Plessis|L|L|;Draper|H R|HR|;Burger|A|A|;Seddon|J A|JA|;Zimri|K|K|;Hesseling|A C|AC|;Schaaf|H S|HS|",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid; D012293:Rifampin",
"country": "France",
"delete": false,
"doi": "10.5588/ijtld.16.0293",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1027-3719",
"issue": "20(11)",
"journal": "The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease",
"keywords": null,
"medline_ta": "Int J Tuberc Lung Dis",
"mesh_terms": "D000995:Antitubercular Agents; D002648:Child; D002675:Child, Preschool; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections; D006801:Humans; D007223:Infant; D007538:Isoniazid; D008297:Male; D012189:Retrospective Studies; D012293:Rifampin; D012307:Risk Factors; D013019:South Africa; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "9706389",
"other_id": null,
"pages": "1469-1476",
"pmc": null,
"pmid": "27776587",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Outcome of culture-confirmed isoniazid-resistant rifampicin-susceptible tuberculosis in children.",
"title_normalized": "outcome of culture confirmed isoniazid resistant rifampicin susceptible tuberculosis in children"
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"companynumb": "ZA-SA-2016SA209604",
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"abstract": "Chronic bisphosphonate therapy is associated with atypical fractures of the subtrochanteric and proximal femoral diaphyseal regions. Various radiologic imaging signs can identify bisphosphonate-associated stress fractures before they progress to complete fractures. Identifying patients who are at risk and modifying treatment can prevent these fractures from occurring. We present a case study of a patient taking bisphosphonate with 2 years of chronic pain, and characteristic clinical signs of bisphosphonate-associated incomplete stress fractures that went untreated until the patient suffered from a right subtrochanteric complete fracture. Our goal is to make physicians aware of the signs of insufficiency fractures associated with chronic bisphosphonate therapy such that appropriate clinical decisions are made to optimize the quality of patient care.",
"affiliations": "From Wayne State University School of Medicine (WS), Detroit, MI; Department of Orthopedic Surgery (DM), St John Providence Health System, Southfield, MI; School of Medicine (SM), Mercer University, Macon, GA. wshaikh@med.wayne.edu.;From Wayne State University School of Medicine (WS), Detroit, MI; Department of Orthopedic Surgery (DM), St John Providence Health System, Southfield, MI; School of Medicine (SM), Mercer University, Macon, GA.;From Wayne State University School of Medicine (WS), Detroit, MI; Department of Orthopedic Surgery (DM), St John Providence Health System, Southfield, MI; School of Medicine (SM), Mercer University, Macon, GA.",
"authors": "Shaikh|Wassi|W|;Morris|Dan|D|;Morris|Sean|S|",
"chemical_list": "D000924:Anticholesteremic Agents; D050071:Bone Density Conservation Agents; D019821:Simvastatin; D019386:Alendronate",
"country": "United States",
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"doi": "10.3122/jabfm.2016.03.150242",
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"issn_linking": "1557-2625",
"issue": "29(3)",
"journal": "Journal of the American Board of Family Medicine : JABFM",
"keywords": "Bisphosphonates; Case Reports; Orthopedics; Radiology; Subtrochanteric Fractures",
"medline_ta": "J Am Board Fam Med",
"mesh_terms": "D000368:Aged; D019386:Alendronate; D000924:Anticholesteremic Agents; D050071:Bone Density Conservation Agents; D003937:Diagnosis, Differential; D005260:Female; D015775:Fractures, Stress; D006620:Hip Fractures; D006801:Humans; D006937:Hypercholesterolemia; D019637:Orthopedic Procedures; D010024:Osteoporosis; D010146:Pain; D010147:Pain Measurement; D065286:Prophylactic Surgical Procedures; D011859:Radiography; D011877:Radionuclide Imaging; D019821:Simvastatin; D013997:Time Factors",
"nlm_unique_id": "101256526",
"other_id": null,
"pages": "404-7",
"pmc": null,
"pmid": "27170798",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Signs of Insufficiency Fractures Overlooked in a Patient Receiving Chronic Bisphosphonate Therapy.",
"title_normalized": "signs of insufficiency fractures overlooked in a patient receiving chronic bisphosphonate therapy"
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"abstract": "A 70-year-old hypertensive man was prescribed telmisartan for control of blood pressure. He concurrently took over-the-counter diclofenac for back pain. Few days later, he presented to the casualty after syncopal episodes. He was found to have acute kidney injury and elevated potassium of 6.6 mmol/L with junctional bradycardia on electrocardiogram (ECG). Medical measures were instituted for hyperkalemia and sinus rhythm was restored, but peaked T waves were still present in the precordial leads. Hemodialysis was done, and antihypertensive therapy was changed on discharge.",
"affiliations": "General Medicine, Government Medical College and Hospital, Chandigarh, IND.;General Medicine, Government Medical College and Hospital, Chandigarh, IND.;General Medicine, Government Medical College and Hospital, Chandigarh, IND.;General Medicine, Government Medical College and Hospital, Chandigarh, IND.",
"authors": "Gaba|Saurabh|S|;Jesrani|Gautam|G|;Gupta|Samiksha|S|;Gupta|Monica|M|",
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"doi": "10.7759/cureus.9858",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.9858\nCardiology\nEmergency Medicine\nInternal Medicine\nAcute Kidney Injury and Hyperkalemia With Precarious Electrocardiographic Changes Caused by Concurrent Use of Telmisartan and Diclofenac\nMuacevic Alexander Adler John R Gaba Saurabh 1 Jesrani Gautam 1 Gupta Samiksha 1 Gupta Monica 1 \n1 \nGeneral Medicine, Government Medical College and Hospital, Chandigarh, IND \n\nGautam Jesrani jesranigautam@gmail.com\n18 8 2020 \n8 2020 \n12 8 e985810 8 2020 18 8 2020 Copyright © 2020, Gaba et al.2020Gaba et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/39286-acute-kidney-injury-and-hyperkalemia-with-precarious-electrocardiographic-changes-caused-by-concurrent-use-of-telmisartan-and-diclofenacA 70-year-old hypertensive man was prescribed telmisartan for control of blood pressure. He concurrently took over-the-counter diclofenac for back pain. Few days later, he presented to the casualty after syncopal episodes. He was found to have acute kidney injury and elevated potassium of 6.6 mmol/L with junctional bradycardia on electrocardiogram (ECG). Medical measures were instituted for hyperkalemia and sinus rhythm was restored, but peaked T waves were still present in the precordial leads. Hemodialysis was done, and antihypertensive therapy was changed on discharge.\n\nakiacute kidney injurytelmisartandiclofenacdrug induceddialysishyperkalemiaecgThe 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\nHyperkalemia is a medical emergency due to its potential to cause life-threatening arrhythmias. The risk depends on the potassium level and the time period over which it develops [1]. The etiologic factors are diverse and include renal failure, drugs, states of increased cell turnover and certain endocrine disturbances. Herein, a case of hyperkalemia resulting from concurrent use of telmisartan and diclofenac leading to a catastrophic clinical scenario is presented.\n\nCase presentation\nA 70-year-old male was prescribed telmisartan 40 mg a day to achieve the target blood pressure (BP), since his BP was not well controlled on amlodipine that he had been taking for the previous few months. He had no other significant past medical history. His serum creatinine and potassium, measured a few weeks earlier, were 1.3 mg/dL and 4.1 mmol/L, respectively. After starting telmisartan, he also took over-the-counter diclofenac 50 mg, up to three tablets a day, for his back pain. He presented to the casualty after a week on experiencing two syncopal episodes while sitting. They were not accompanied by chest pain, palpitations or breathlessness. There was no history of fever, diarrhea, vomiting, limb weakness or convulsions. On presentation, he had BP of 80/40 mmHg and pulse of 20 beats per minute. His electrocardiogram (ECG) showed junctional bradycardia (Figures 1, 2).\n\nFigure 1 The initial electrocardiogram showing junctional bradycardia. \nThe QRS complexes (yellow arrows) are narrow (<120 ms). The P waves are retrograde as they occur after the QRS complex. They are either upright (black arrows) or inverted (red arrows).\n\nFigure 2 Enlarged complexes from the initial electrocardiogram showing junctional bradycardia. \nThe retrograde P waves are inverted (red arrow) in lead II and upright (black arrow) in lead aVR.\n\nThe cardiology team was informed and preparations were made for temporary pacemaker placement. Meanwhile, a sample was sent for venous blood gas analysis for quick assessment of electrolytes. The potassium was found to be elevated to 6.6 mmol/L. The patient was administered intravenous calcium gluconate and dextrose with insulin, and nebulization was done with salbutamol. Within seconds, sinus rhythm was restored, albeit with peaked T waves (Figure 3). \n\nFigure 3 The electrocardiogram showing sinus rhythm with peaked T waves (black arrows) after institution of medical measures for control of hyperkalemia. \nOne session of hemodialysis was done, and the clinical course was uneventful thereafter. Telmisartan was substituted with hydrochlorthiazide. The serum creatinine and potassium values are mentioned in Table 1. No abnormality was found on urinalysis and ultrasound of the kidneys. \n\nTable 1 Trend of creatinine and potassium during the hospital stay.\nInvestigation\tDay 1 (before hemodialysis)\tDay 1 (after hemodialysis)\tDay 6\t\nCreatinine (mg/dL)\t2.9\t1.7\t1.6\t\nPotassium (mmol/L)\t6.6\t4.0\t3.7\t\nDiscussion\nThe serum potassium levels are tightly regulated in the range of 3.5-5.5 mmol/L by a complex interplay of urinary excretion, gastrointestinal loss, transcelluar shifts and dietary intake. The causes of hyperkalemia are mentioned in Table 2 [2,3]. In addition, pseudohyperkalemia can occur due to the release of potassium from cells in the presence of hemolysis, traumatic venipuncture, prolonged clenching of fist or when the vial with blood sample is shaken.\n\nTable 2 Etiology of hyperkalemia. \nACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; NSAID, non-steroidal anti-inflammatory drug.\n\nCategory\tCauses\t\nDecreased renal loss\tAcute kidney injury, chronic kidney disease, type IV renal tubular acidosis, adrenal insufficiency, drugs (ACEI, ARB, NSAID, heparin, cyclosporin, tacrolimus, spironolactone, eplerenone)\t\nIncreased load\tHigh potassium diet, hemolysis, tumor lysis syndrome, rhabdomyolysis, blood transfusions, gastrointestinal hemorrhage \t\nExtracellular shift\tDrugs (digoxin, non-selective beta blockers), hyperglycemia, hyperkalemic periodic paralysis, strenuous exercise\t\nAngiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) decrease angiotensin II-mediated constriction of the efferent arterioles in renal glomeruli, leading to reduced glomerular filtration rate (GFR) [4]. In some patients, acute kidney injury (AKI) can be precipitated. Patients with a pre-existing renal disease, renovascular disease or dehydration are more susceptible. Apart from being related to AKI, hyperkalemia can also occur secondary to decreased aldosterone level and retention of potassium in the distal renal tubules. It is recommended to monitor potassium levels after starting ACEI/ARB or after increasing their dose. Conversely, non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin-mediated dilatation of afferent arterioles, predisposing the patient to AKI [5]. AKI can also result from NSAID-induced tubulointerstitial nephritis. The concurrent use of these drugs, as in the patient under consideration in this report, places the patient at a very high risk of AKI and hyperkalemia.\n\nPostassium plays a key role in cardiac impulse generation and propagation. Hyperkalemia leads to decrease in the myocyte resting membrane potential, prolongation of membrane depolarization time and shortening of the repolarization time [6]. These electrophysiological perturbations result in characteristic ECG changes (Table 3) [7]. However, the relationship between potassium level and ECG finding is not uniform, and the sequential changes may not necessarily be seen at the levels mentioned. Acute rises in potassium produce more pronounced ECG changes. Fatal rhythms like ventricular tachycardia, ventricular fibrillation, complete heart block and asystole can occur precipitously, giving little time for treatment. In a study, 54% of the patients with serum potassium more than 6 mmol/L did not have the specific ECG changes consistent with hyperkalemia [8]. Cases with potassium more than 8 mmol/L without the typical ECG changes have also been reported. One of the earliest and easily identifiable sign of hyperkalemia is the presence of peaked T waves in precordial leads (V2-V4) and limb leads (II and III). They have a narrow base, in contrast to the broad-based peaked T waves seen in early myocardial infarction [7].\n\nTable 3 The electrocardiographic findings in hyperkalemia.\nPotassium level (mmol/L)\tECG finding\t\n5.5–6.5\tPeaked T waves, short PR interval, short QT interval, sinus tachycardia or bradycardia\t\n6.5–8.0\tWide QRS complex, prolonged PR interval, sinus tachycardia or bradycardia, heart blocks\t\n8.0–9.0\tWide QRS complex, absent P waves (mimicking ventricular tachycardia), heart blocks, ventricular tachycardia\t\n>9.0\tJunctional rhythm, blending of P and T waves with the wide QRS complex (sine wave pattern), ventricular tachycardia, ventricular fibrillation, asystole\t\nThe treatment of hyperkalemia is straightforward and very effective. In most of the cases, immediate correction assumes importance over addressing the underlying cause. The myocyte electrophysiological changes can be temporarily antagonized by administration of intravenous 10% calcium gluconate over three minutes under continuous cardiac monitoring [9]. Its action starts within a minute and lasts for an hour. Immediate reduction in serum potassium level is achieved by promoting its influx into cells by salbutamol nebulization and intravenous insulin [10]. Typically, 10 units of regular insulin are given in 25% or 50% dextrose solution. If blood glucose is more than 250 mg/dL, then dextrose is not needed. Both salbutamol and insulin work by potentiating the action of sodium-potassium adenosine triphosphatase (Na/K-ATPase) pump. The effect of insulin is much more potent and clinically important than salbutamol, and it can lower serum potassium by 1 mmol/L within 30 minutes [11]. The reduction is temporary as total body potassium is not altered. Mild reduction over several hours can also be achieved by bicarbonate infusion, but its use is restricted to patients with acidemia [12]. Finally, the fastest and most effective to reduce total body potassium is hemodialysis. For patients with life-threatening arrhythmias, early hemodialysis is essential to avoid cardiac arrest. The medical measures should always be instituted first as access to hemodialysis can take time [9]. The role of ion-exchange resins, such as sodium polystyrene sulfonate and patiromer, in emergency setting is limited as they take several hours or days to produce effect. They enhance potassium elimination by gastrointestinal route and are used in conjunction with laxatives to prevent constipation [9].\n\nThe common causes of junctional rhythm include sick sinus syndrome, coronary artery disease, drugs (antiarrhythmics, beta blockers, digoxin), hypoxia, ischemic heart disease and hyperkalemia [13]. It can also occur in athletes due to increased vagal tone. Treatment is not always required and depends on the underlying morbidity, heart rate and evidence of cardiac decompensation. The modalities include withdrawal of the implicated drug, correction of potassium, reversal of hypoxia, management of ischemic heart disease and placement of a permanent cardiac pacemaker.\n\nConclusions\nThis case emphasizes the hazards of concurrent use of drugs having potential to cause AKI and hyperkalemia. The patient took an over-the-counter NSAID, without knowledge of his physician, in addition to an ARB that was prescribed to him. This led to hyperkalemia with dangerous ECG changes that necessitated urgent hemodialysis.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 How dangerous is hyperkalemia? J Am Soc Nephrol Montford JR Linas S 3155 3165 28 2017 28778861 \n2 Disorders of potassium homeostasis. Hypokalemia and hyperkalemia Crit Care Clin Gennari FJ 273 288 18 2002 12053834 \n3 Drug-induced hyperkalemia: old culprits and new offenders Am J Med Perazella MA 307 314 109 2000 10996582 \n4 Overview of the angiotensin-converting-enzyme inhibitors Am J Health Syst Pharm Piepho RW 0 57 2000 \n5 Pathophysiological aspects of nephropathy caused by non-steroidal anti-inflammatory drugs. (Article in En, Portuguese) J Bras Nefrol Lucas GNC Leitão ACC Alencar RL Xavier RMF Daher EF Silva Junior GBD 124 130 41 2019 30281062 \n6 Clinical disorders of potassium homeostasis. Hyperkalemia and hypokalemia Vet Clin North Am Small Anim Pract Phillips SL Polzin DJ 545 564 28 1998 9597714 \n7 Hyperkalemia, cardiac conduction, and the electrocardiogram: a review Am Heart J Ettinger PO Regan TJ Oldewurtel HA 360 371 88 1974 4604546 \n8 Severe hyperkalemia with minimal electrocardiographic manifestations: a report of seven cases J Electrocardiol Martinez-Vea A Bardají A Garcia C Oliver JA 45 49 32 1999 10037088 \n9 Therapeutic approach to hyperkalemia Nephron Kim HJ Han SW 33 40 92 2002 12401936 \n10 Albuterol and insulin for treatment of hyperkalemia in hemodialysis patients Kidney Int Allon M Copkney C 869 872 38 1990 2266671 \n11 Management of hyperkalemia in dialysis patients Semin Dial Putcha N Allon M 431 439 20 2007 17897250 \n12 Effect of prolonged bicarbonate administration on plasma potassium in terminal renal failure Kidney Int Blumberg A Weidmann P Ferrari P 369 374 41 1992 1552710 \n13 Junctional Rhythm 8 2020 Hafeez Y Grossman SA Treasure Island, FL StatPearls Publishing 2020 https://www.ncbi.nlm.nih.gov/books/NBK507715/\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(8)",
"journal": "Cureus",
"keywords": "acute kidney injury; aki; dialysis; diclofenac; drug induced; ecg; hyperkalemia; telmisartan",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e9858",
"pmc": null,
"pmid": "32963900",
"pubdate": "2020-08-18",
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"title": "Acute Kidney Injury and Hyperkalemia With Precarious Electrocardiographic Changes Caused by Concurrent Use of Telmisartan and Diclofenac.",
"title_normalized": "acute kidney injury and hyperkalemia with precarious electrocardiographic changes caused by concurrent use of telmisartan and diclofenac"
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"abstract": "Prolongation of the QT interval associated with ventricular arrhythmias has been the most common cause of the restriction or withdrawal of drugs from the market in the past 10 years. Methadone, a synthetic opioid that is increasingly used for the management of chronic pain, has recently been implicated in the development of the prolonged QT syndrome. We present a case report of a patient who developed a prolonged QT while being treated with oral methadone for a chronic pain syndrome. Of particular interest in this patient is the fluctuation of the QT interval at a stable dose of methadone, suggesting that a single normal electrocardiogram (ECG) does not guarantee that the patient is not at risk of ventricular arrhythmias. After reviewing the current literature, we suggest that there is no dose of methadone that may be considered to be completely safe. Other risk factors for prolonged QT interval such as underlying cardiac abnormalities, electrolyte disturbances, and concurrent medications should be sought, and all patients should be monitored with serial ECGs even when methadone doses remain stable.",
"affiliations": "Department of Anesthesiology and Perioperative Medicine, University of Western Ontario, St. Joseph's Health Care Center, London, Ontario, Canada.",
"authors": "Ower|Katherine|K|;Morley-Forster|Patricia|P|;Moulin|Dwight|D|",
"chemical_list": "D000701:Analgesics, Opioid; D008691:Methadone",
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"issn_linking": "1551-7489",
"issue": "1(2)",
"journal": "Journal of opioid management",
"keywords": null,
"medline_ta": "J Opioid Manag",
"mesh_terms": "D000701:Analgesics, Opioid; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008133:Long QT Syndrome; D008691:Methadone; D008875:Middle Aged; D012019:Reflex Sympathetic Dystrophy",
"nlm_unique_id": "101234523",
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"pages": "73-6",
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"references": null,
"title": "Fluctuating QTc interval in an asymptomatic patient treated with methadone for chronic pain.",
"title_normalized": "fluctuating qtc interval in an asymptomatic patient treated with methadone for chronic pain"
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"abstract": "Congenital teratoma is a rare condition and is a germ cell tumor composed of elements from one or more of the embryonic germ layers and contain tissues usually foreign to the anatomic site of origin. We report a case of a neck tumor diagnosed during pregnancy, initially thought to be a goiter. After birth the neck mass kept growing until it compressed the trachea and produced respiratory failure. The infant had a difficult tracheal intubation because of the compressing mass. The staff decided to surgically remove the neck mass. After that, the infant became eupneic. The histological analysis showed a mature teratoma with no atypias.",
"affiliations": "Pediatric Intensive Care Unit, Santa Catarina Hospital, São Paulo, 01310-000, Brazil.;Pediatric Surgery Group, Santa Catarina Hospital, São Paulo, 01310-000, Brazil.;Pediatric Endocrinology Group, Santa Catarina Hospital, São Paulo, 01310-000, Brazil.;Pediatric Oncology Group, Santa Catarina Hospital, São Paulo, 01310-000, Brazil.;Pediatric Intensive Care Unit, Santa Catarina Hospital, São Paulo, 01310-000, Brazil.;Pediatric Intensive Care Unit, Santa Catarina Hospital, São Paulo, 01310-000, Brazil.;Pediatric Intensive Care Unit, Santa Catarina Hospital, São Paulo, 01310-000, Brazil.;Pediatric Intensive Care Unit, Santa Catarina Hospital, São Paulo, 01310-000, Brazil.",
"authors": "Colleti Junior|Jose|J|;Tannuri|Uenis|U|;Monti Lora|Felipe|F|;Armelin Benites|Eliana Carla|EC|;Koga|Walter|W|;Honda Imamura|Janete|J|;Rute Moutinho|Patricia|P|;Brunow de Carvalho|Werther|W|",
"chemical_list": null,
"country": "England",
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"doi": "10.12688/f1000research.6589.2",
"fulltext": "\n==== Front\nF1000ResF1000ResF1000ResearchF1000Research2046-1402F1000Research London, UK 2666470410.12688/f1000research.6589.2Case ReportArticlesHead & Neck CancersPediatric OncologyPregnancy, Labor, Delivery & Postpartum CareCase Report: Severe acute respiratory distress by tracheal obstruction due to a congenital thyroid teratoma. [version 2; referees: 1 approved\n\nColleti Junior Jose a1Tannuri Uenis 2Monti Lora Felipe 3Armelin Benites Eliana Carla 4Koga Walter 1Honda Imamura Janete 1Rute Moutinho Patricia 1Brunow de Carvalho Werther 1\n1 Pediatric Intensive Care Unit, Santa Catarina Hospital, São Paulo, 01310-000, Brazil\n2 Pediatric Surgery Group, Santa Catarina Hospital, São Paulo, 01310-000, Brazil\n3 Pediatric Endocrinology Group, Santa Catarina Hospital, São Paulo, 01310-000, Brazil\n4 Pediatric Oncology Group, Santa Catarina Hospital, São Paulo, 01310-000, Brazila colleti@gmail.comJCJ drafted the first manuscript. UT is the pediatric surgeon and helped with the decision of resecting the tumor. FML did the endocrinological research and helped with the draft. ECB is from the pediatric oncology team and helped with the diagnosis and the draft. WK, JHI and PRM contributed to treating the patient. WBC revised and edited the manuscript. All authors have read and approved the content of the final manuscript.\n\n\nCompeting interests: The authors declare that they have no competing interests.\n\n23 7 2015 2015 4 15920 7 2015 Copyright: © 2015 Colleti Junior J et al.2015This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Congenital teratoma is a rare condition and is a germ cell tumor composed of elements from one or more of the embryonic germ layers and contain tissues usually foreign to the anatomic site of origin. We report a case of a neck tumor diagnosed during pregnancy, initially thought to be a goiter. After birth the neck mass kept growing until it compressed the trachea and produced respiratory failure. The infant had a difficult tracheal intubation because of the compressing mass. The staff decided to surgically remove the neck mass. After that, the infant became eupneic. The histological analysis showed a mature teratoma with no atypias.\n\nthyroid teratomapediatric neck masspediatric respiratory distresshypothyroidismchildren case reportThe author(s) declared that no grants were involved in supporting this work.Revised Amendments from Version 1\nThis new version of the manuscript corrects one author name (Eliana Carla Armelin Benites) and removes from the title \"case report and literature review\", since it is redundant, as it is already at the beginning of the title.\n==== Body\nIntroduction\nCongenital thyroid teratoma is a rare condition\n1,\n2. We report a case of an infant with a neck mass diagnosed by ultrasound during pregnancy which was initially supposed to be a congenital goiter. Two doses of levothyroxine were administered into the amniotic fluid. The goiter kept growing after birth until it caused severe respiratory distress by compressing the trachea, necessitating immediate tracheal intubation. The tumor was surgically resected and the patient went eupneic for the first time in his life. The histological analysis demonstrated a mature teratoma with no atypias. Thyroid hormone substitute therapy was started and the infant is thriving well.\n\nCase report\nA 2-months-and-20-days-old Brazilian white male infant weighing 4.2 kg was admitted to the pediatric intensive care unit of our hospital (Santa Catarina Hospital, São Paulo, Brazil) in acute respiratory distress and was immediately intubated and placed in mechanical ventilation.\n\nFrom a routine ultrasound during pregnancy, the fetus had been diagnosed with a cervical mass, considered initially to be a goiter (\nFigure 1) by doctors at another institution. Family history of the mother uncovered a cousin with hypothyroidism. The mother was previously healthy, but after diagnosis of the cervical mass of the fetus, she was tested for thyroid hormones and had hypothyroidism diagnosed during pregnancy (TSH: 5.0 mUI/mL – normal: 0.2 to 3.0 mUI/mL; free T4: 0.7 ng/dL – normal: 0. To 1.3 ng/dL; antithyroglobulin antibodies: 65 U/mL – normal: inferior to 60 U/mL and thyroid antiperoxidase antibodies: 166 UI/mL – normal: inferior to 9 UI/mL). Two single doses of 200µg of levothyroxine were administered into the amniotic fluid, one during the 28th and one during the 31st week of pregnancy, in order to treat the supposed fetal thyroid hormone deficiency. Chorioamnionitis appeared after the second levothyroxine administration which triggered a premature cesarean birth which was undertaken in the other hospital. The premature newborn had sepsis due to maternal infection (chorioamnionitis) and remained in mechanical ventilation for 10 days. After tracheal extubation, he remained in nasal continuous positive airway pressure (CPAPn) for 7 more days, and after that was kept on oxygen therapy for 10 days. He was discharged from the hospital 50 days after birth, still presenting with a laryngeal stridor that was attributed to tracheal malacia by the doctors that initially treated the patient.\n\nFigure 1. Prenatal ultrasound showing the neck mass.\nAfter hospital discharge, he was observed by a pediatric endocrinologist who started research on thyroid disorders. Meanwhile, the infant maintained a euthyroid state, receiving no treatment, waiting for more investigation on the cause of the neck mass. However, the cervical mass kept visibly growing, was palpable and the infant presented a laryngeal stridor that was still attributed, by the pediatrician who followed the infant, to laryngomalacia. In the few days preceding hospitalization at our institution, the infant became increasingly dispneic each day, as related by his mother. One day, after choking and vomiting during breastfeeding he became hypotonic and went into acute respiratory distress.\n\nHe was admitted to our pediatric intensive care unit 25 days after he had been discharged from the other hospital, and was immediately intubated. An X-ray showed a small amount of interstitial infiltrate, compatible with aspiration pneumonia. However, the respiratory distress was attributed mainly to an upper airway obstruction. It was difficult to tracheally intubate the infant; only an uncuffed 2.5 mm endotracheal tube (ETT) was able to be inserted into the trachea and it was difficult to place this in the right position. The X-ray after intubation showed the ETT in a high position and the trachea displaced to the right (\nFigure 2). Magnetic resonance imaging (MRI) revealed the extent of the cervical mass and its compression on the trachea, and the latter’s subsequent displacement (\nFigure 3a and 3b).\n\nFigure 2. Endotracheal tube displaced to the right position.\nFigure 3. \na. Sagittal MRI (T2) of the neck showing the teratoma.\nb. Axial MRI (T2) of the neck showing the teratoma and the tracheal displacement.\n\nMeanwhile, we started investigation into the cause of the neck mass and performed blood tests on the infant: thyroid hormones were in the normal range (free thyroxine (T4): 1.3 ng/dL and thyroid-stimulating hormone (TSH): 4.7 ng/dL). Calcitonin levels, for investigations into potential malignance, were normal (calcitonin: 21 pg/mL), as was the alpha-fetoprotein: 505 µg/L.\n\nWe decided to remove the cervical mass, since it was causing the tracheal obstruction. The surgery lasted 35 minutes and was uneventful. The mass was well circumscribed and could be easily dissected, weighed 20 grams and measured 33×61×45 mm\nFigure 4. The infant returned from surgery in good condition. A bronchoscopy was performed the next day after surgery, during tracheal extubation, which revealed no malacia or any other disorders on the trachea or the upper respiratory tract. The patient has been eupneic since then. The histological analysis revealed a mature teratoma with no atypias or signs of malignancy.\n\nFigure 4. The resected benign teratoma.\nLevothyroxine was started (25µg, once a day) as thyroid hormone substitute therapy and the infant is thriving well according to the pediatric endocrinologist that continues following the patient.\n\nDiscussion\nTeratomas originate from multipotent primitive germ cells and result in different tissues, diverging from the anatomical site of origin\n2,\n3. They are most common during early childhood and the most common location is the sacrococcygeal region in children and the gonadal region in adults\n2–\n4. The frequency of these embryonic tumours is about 1:20,000–40,000 live births. However, only 1.5% to 5.5% of all pediatric teratomas are placed in the neck region. These tumours are usually solitary, with no other associated congenital malformations or chromosomal abnormalities\n4. Although 95% of all teratomas are benign, the cervical teratomas if not properly treated, lead to death in 80% of the cases due to obstructive respiratory distress\n3–\n5.\n\nIn this case, the acute clinical presentation of the neck mass with severe respiratory distress, needing ready intervention and immediate tracheal intubation should alert all pediatricians to the risk of these neck masses, and consider it as a potentially fatal case. In the presented case, surgical removal of the neck mass was both diagnostic and therapeutic.\n\nConclusion\nThyroid teratoma is rare in infants, it is usually benign, and can cause airway compression depending on the site and size of the mass. The likelihood of a malignant thyroid teratoma is low in infants, however it could be fatal by causing upper airway obstruction. Therefore, surgical resection is required both for diagnosis and treatment. If the surgical removal is a success, the long-term outcome and quality of life should be good\n5.\n\nConsent\nWritten informed consent was obtained from parents of 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 of this journal.\n\n10.5256/f1000research.7320.r10593Referee response for version 2 Garros Daniel 1Referee\n1 Pediatric Intensive Care Unit, Stollery Children’s Hospital, Edmonton, AB, Canada\nCompeting interests: No competing interests were disclosed.\n\n30 9 2015 Version 2recommendationapprove-with-reservationsThe authors describe an interesting case, with a positive outcome despite some delay in diagnosis.\n\nThe title and the description of the case are all well written.\n\nHowever, the\ndiscussion and the conclusion require more work. This case brings up an important and not so rare clinical scenario in Paediatric Critical Care, i.e. the difficulties inherent to extrinsic airway compression by a tumour. The authors, on their discussion, should take advantage of this case and discuss the approach to airway extrinsic compression, the use of extra-corporeal life support (ECLS) as a back-up plan, who should be present in such situations (ENT, anaesthesia), etc… The clinician could barely secure the child’s airway, and the child survived and was able to have the teratoma resected. But it could have been a disastrous outcome. There are protocols for such scenarios, and they should be mentioned and described for the reader to be prepared when facing with similar situations\n\nI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.\n\n10.5256/f1000research.7320.r9516Referee response for version 2 Eulógio Martinez Francisco 1RefereeGonçalves-Ferri Walusa Assad 1Co-referee\n1 Department of Pediatrics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil\nCompeting interests: No competing interests were disclosed.\n\n25 8 2015 Version 2recommendationapproveColetti\net al described in a case report of severe acute respiratory distress by tracheal obstruction due to congenital thyroid teratoma. This case report adds knowledge to the literature, not only by tumor description, but also the clinical management of the case.\n\nTumor description is interesting, however I believe that the authors should also discuss in this article the clinical management of malacia in premature, since this is very common in neonatal clinic. I believe that this discussion would make the most interesting article and is also an opportunity to develop the discussion of the article, which I believe is short. For this reason there are some points which need to be considered and are necessary clarifications\n\nAdd data:\nThe patient was born with what gestational age?\n\nAfter birth was not performed control with imaging for the mass?\n\nWhat are the results of thyroid hormones tests after birth?\n\nThe staff investigated other causes for laryngeal stridor before discharge?\n\nSuggestions:\n\nThe discussion could discuss the differential diagnosis of stridor. The staff not investigated a patient with stridor, attributing the malacia. Many patients in neonatology have stridor and I believe that this article could show that there is need for investigation in stridor, because sometimes the differential diagnosis can be serious pathologies.\n\nCase reports are interesting, but I believe it should have a good discussion of the various aspects involved in the pathology, in which case I would like that you develop the discussion and mainly develop the discussion about the differential diagnosis.\n\nWe have read this submission. We believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\nColleti Junior Jose Hospital Santa Catarina, Brazil\nCompeting interests: I declare no competing interests to disclose.\n\n10 9 2015 I would like to thank Dr Martinez and colleague for the remarks and suggestions above.\n\nAnswering the questions regarding this case report:\nThe patient was born with 31 weeks of gestational age, immediately after the second administration of levothyroxine in the amniotic fluid due to a chorioamnionitis.\n\nAfter birth new imaging control was done in the previous hospital and in our medical center (figure 3).\n\nAfter first hospital discharge, the patient was followed by a pediatric endocrinologist who asked for thyroid hormone tests which resulted normal for the age (TSH=1.8 mUI/mL – normal: 0.8 to 6.0 mUI/mL; free T4: 0.9 ng/dL – normal= 0.7 to 1.5 ng/dL).\n\nSince the patient was born in other hospital we could not know if the staff did any other investigation for other causes of laryngeal stridor. In our medical center, the patient was admitted in a critical clinical status and the surgery was promptly performed.\n\nI hope I have clarified your doubts and concerns about this case report. Thank you for the review.\n==== Refs\n1 \nOak CY Kim HK Yoon TM :\nBenign teratoma of the thyroid gland. \nEndocrinol Metab (Seoul). \n2013 ;28 (2 ):144 –8 .\n10.3803/EnM.2013.28.2.144 \n\n24396669 \n2 \nHasiotou M Vakaki M Pitsoulakis G :\nCongenital cervical teratomas. \nInt J Pediatr Otorhinolaryngol. \n2004 ;68 (9 ):1133 –9 .\n10.1016/j.ijporl.2004.04.018 \n15302143 \n3 \nFichera S Hackett H Secola R :\nPerinatal germ cell tumors: a case report of a cervical teratoma. \nAdv Neonatal Care. \n2010 ;10 (3 ):133 –9 .\n10.1097/ANC.0b013e3181dd6d25 \n20505423 \n4 \nKocarslan S Dorterler ME Koçarslan A :\nAsymptomatic cervical mature teratoma in a child: an unusual presentation. \nJ Clin Diagn Res. \n2015 ;9 (2 ):EL01 –2 .\n10.7860/JCDR/2015/11090.5568 \n\n25859464 \n5 \nSheikh F Akinkuotu A Olutoye OO :\nPrenatally diagnosed neck masses: long-term outcomes and quality of life. \nJ Pediatr Surg. \n2015 ;50 (7 ):1210 –3 .\n10.1016/j.jpedsurg.2015.02.035 \n25863543\n\n",
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"abstract": "A 62-year-old woman with a history of end-stage renal disease on haemodialysis, essential hypertension and type 2 diabetes mellitus was diagnosed with sepsis and placed on 600 mg oral linezolid every 12 hours and 1 g intravenous ceftriaxone every 24 hours. Blood cultures grew Streptococcus dysgalactiae, and she was switched to intravenous ceftriaxone 2 g daily. Platelet counts slowly trended down after starting ceftriaxone reaching 5 K/μL on day 12 of treatment. Ceftriaxone was discontinued and heparin-induced thrombocytopaenia was ruled out. She was switched to vancomycin and her platelet count improved. Given the temporal relationship between changing platelet counts and starting and discontinuing ceftriaxone, a diagnosis of drug-induced thrombocytopaenia was made.",
"affiliations": "School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA aishwaryasharma97@gmail.com.;Internal Medicine, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA.;Internal Medicine, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA.;Internal Medicine, Sanford Medical Center Fargo, Fargo, North Dakota, USA.",
"authors": "Sharma|Aishwarya|A|;Mannuru|Devendranath|D|;Matta|Abhishek|A|http://orcid.org/0000-0001-7824-8055;Kaushal|Amit|A|",
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"abstract": "BACKGROUND\nHepatocellular carcinoma (HCC) is a highly invasive cancer associated with high mortality rates. Although sorafenib is currently recommended as standard treatment for advanced HCC, its treatment efficacy is limited. Effective treatments for patients with advanced HCC that progresses on or after sorafenib treatment or patients who are intolerant of sorafenib remain an unmet medical need.\nWe report an advanced HCC patient with many lung metastases who failed sorafenib treatment.\nSorafenib refractory HCC patient with a large number of lung metastases.\n\n\nMETHODS\nThe apatinib alone was used as second line therapy.\n\n\nRESULTS\nThe patient achieved partial response (PR) soon after the treatment, which was maintained for approximately 1 year. During the entire process, the lung metastases continued to diminish. Finally, only a few lesions remained LESSONS:: Apatinib alone may be a good second-line therapy for advanced HCC patients who are refractory to sorafenib. However, further investigation in future prospective clinical studies is warranted.",
"affiliations": "Department of Medical Oncology, West China Hospital, Sichuan University Department of Medical Oncology, The People's Hospital of Ganzi Tibetan Autonomous Prefecture, Sichuan, P.R. China.",
"authors": "Zhu|Hong|H|;Ma|Xiaojun|X|;Zhao|Yaqin|Y|;Duo|Ji|J|",
"chemical_list": "D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; C553458:apatinib; D000077157:Sorafenib",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29924049MD-D-18-0157710.1097/MD.0000000000011214112145700Research ArticleClinical Case ReportThe excellent antitumor effect of apatinib alone as second-line therapy in a patient with sorafenib-refractory hepatocellular carcinoma A case reportZhu Hong MDabMa Xiaojun MSbZhao Yaqin MDaDuo Ji MDb∗NA. a Department of Medical Oncology, West China Hospital, Sichuan Universityb Department of Medical Oncology, The People's Hospital of Ganzi Tibetan Autonomous Prefecture, Sichuan, P.R. China.∗ Correspondence: Ji Duo, Department of Medical Oncology, The People's Hospital of Ganzi Tibetan Autonomous Prefecture, Ganzi 626000, Sichuan, P.R. China (e-mail: 1667832924@qq.com).6 2018 22 6 2018 97 25 e112147 3 2018 31 5 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nHepatocellular carcinoma (HCC) is a highly invasive cancer associated with high mortality rates. Although sorafenib is currently recommended as standard treatment for advanced HCC, its treatment efficacy is limited. Effective treatments for patients with advanced HCC that progresses on or after sorafenib treatment or patients who are intolerant of sorafenib remain an unmet medical need.\n\nPatient concerns:\nWe report an advanced HCC patient with many lung metastases who failed sorafenib treatment.\n\nDiagnoses:\nSorafenib refractory HCC patient with a large number of lung metastases.\n\nInterventions:\nThe apatinib alone was used as second line therapy.\n\nOutcomes:\nThe patient achieved partial response (PR) soon after the treatment, which was maintained for approximately 1 year. During the entire process, the lung metastases continued to diminish. Finally, only a few lesions remained\n\nLessons:\nApatinib alone may be a good second-line therapy for advanced HCC patients who are refractory to sorafenib. However, further investigation in future prospective clinical studies is warranted.\n\nKeywords\napatinibhepatocellular carcinomasecond-line therapysorafenib refractoryOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nHepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third most common cause of cancer-related death.[1] Patients often present with unresectable, recurrent, or metastatic HCC, for which chemotherapy has been shown to be ineffective.[2,3] Sorafenib is currently acknowledged as a standard therapy for advanced HCC, but its efficacy is very limited, especially in Asian populations, extending overall survival only 2.3 months.[3] Effective treatments for patients with advanced HCC that progresses on or after sorafenib treatment or patients who are intolerant of sorafenib remain an unmet medical need.[4]\n\nApatinib is a small-molecule tyrosine kinase inhibitor that selectively binds to vascular endothelial growth factor (VEGF) receptor 2, resulting in a decrease in VEGF-mediated endothelial cell migration, proliferation, and tumor microvascular density.[5,6] It has been recommended as a third-line treatment for metastatic gastric cancer patients.[6] However, there have been very few reports evaluating its efficacy and safety in patients with HCC. In addition, in past reports apatinib has always been combined with transcatheter arterial chemoembolization (TACE) or radiotherapy.[7–9] We report here a case of advanced sorafenib-refractory HCC with many lung metastases treated with apatinib alone as second-line therapy showing an excellent effect in our hospital. This report was approved by the West China Hospital institutional review board, and the patient provided written informed consent.\n\n2 Case presentation\nA 43-year-old man was brought to the outpatient department of our hospital with symptoms of cough and hemoptysis 2.5 years ago. HCC with lung metastases was first diagnosed at his local hospital in April 2015. He had a history of hepatitis B infection and liver cirrhosis for 13 years. The patient also had a history of hypertension and diabetes for 4 years. At the time of his visit, he was taking nifedipine 30 mg daily and irbesartan 150 mg twice daily for hypertension and entecavir 0.5 mg daily for hepatitis B. He also received insulin 14 IU twice daily for diabetes. A liver puncture biopsy confirmed the diagnosis of HCC. The patient then began taking sorafenib 400 mg twice a day. In addition, he underwent TACE twice (in April and June 2015). Computed tomography (CT) at our hospital (September 18, 2015) showed a large number of lung metastases (Figs. 1A, 2A, 3A, and 4A) and 3 liver masses with lipiodol deposition (Fig. 5A). His alpha fetoprotein (AFP) level was 183.50 ng/mL. The evaluation indicated progression disease (PD) because there were many new and enlarged lung metastases compared with the CT images from his local hospital in April 2015. Therefore, treatment with apatinib was suggested, and the patient began to take apatinib 750 mg once daily and stopped sorafenib on September 23, 2015. The patient received no other treatment. Three months later (December 23, 2015), a CT evaluation showed an excellent effect. The lung metastases had diminished remarkably, and a few metastases had disappeared (Figs. 1B, 2B, 3B, and 4B). The liver masses were almost the same (Fig. 5B). The evaluation indicated partial response (PR). His AFP level was decreased to 59.00 ng/mL. The patient continued to take apatinib. The CT evaluation on April 12 (Figs. 1C, 2C, 3C, and 4C) and November 18, 2016 (Figs. 1D, 2D, 3D, and 4D) showed that the lung metastases had continued to diminish and many lung metastases disappeared. The masses in the liver remained the same (Fig. 5C, D). Therefore, the tumor evaluation showed continued PR for approximately 1 year. The patient's AFP level was 70.09 ng/mL. However, this patient got a serious lung infection on January 10, 2017 and died on January 15, 2017.\n\nFigure 1 A, The lung metastases before the apatinib treatment (September 18, 2015). B, The lung metastases 3 months after the apatinib treatment (December 23, 2015). C, The lung metastases 7 months after the apatinib treatment (April 12, 2016). D, The lung metastases 14 months after the apatinib treatment (November 18, 2016).\n\nFigure 2 A, The lung metastases before the apatinib treatment (September 18, 2015). B, The lung metastases 3 months after the apatinib treatment (December 23, 2015). C, The lung metastases 7 months after the apatinib treatment (April 12, 2016). D, The lung metastases 14 months after the apatinib treatment (November 18, 2016).\n\nFigure 3 A, The lung metastases before the apatinib treatment (September 18, 2015). B, The lung metastases 3 months after the apatinib treatment (December 23, 2015). C, The lung metastases 7 months after the apatinib treatment (April 12, 2016). D, The lung metastases 14 months after the apatinib treatment (November 18, 2016).\n\nFigure 4 A, The lung metastases before the apatinib treatment (September 18, 2015). B, The lung metastases 3 months after the apatinib treatment (December 23, 2015). C, The lung metastases 7 months after the apatinib treatment (April 12, 2016). D, The lung metastases 14 months after the apatinib treatment (November 18, 2016).\n\nFigure 5 A, The liver mass before the apatinib treatment (September 18, 2015). B, The liver mass 3 months after the apatinib treatment (December 23, 2015). C, The liver mass 7 months after the apatinib treatment (April 12, 2016). D, The liver mass 14 months after the apatinib treatment (November 18, 2016).\n\nDuring the treatment process, the patient experienced grade 3 hypertension, grade 2 hand-foot syndrome, grade 3 proteinuria, and grade 2 thrombocytopenia. Nevertheless, the symptoms relieved soon after the appropriate treatments were administered. The cough and hemoptysis continued after the apatinib treatment, but they were mild and could be controlled by hemostatic therapy.\n\n3 Discussion\nHCC is a leading cause of death in Eastern countries, where hepatitis B and C viruses are prevalent.[3] A minority of patients are diagnosed with resectable HCC, whereas approximately 70% to 85% of HCC patients have locally advanced unresectable or metastatic disease at diagnosis.[1,2] Advanced HCC carries a poor prognosis, and systemic therapy with cytotoxic agents provides a marginal benefit.[10]\n\nHCC is featured by vascular recruitment and rich in vascular vessels always leads to early recurrence after surgical operation.[10–12] Sorafenib, a multikinase inhibitor that targets multiple signaling pathways, including VEGF signaling, is the only systemic agent to demonstrate an overall survival benefit as first-line therapy in advanced HCC.[2,3] However, disease control with sorafenib is short lived.[3,4] Therefore, there is an unmet need for effective systemic therapies for HCC, particularly after treatment with sorafenib.\n\nIn this report, the patient used sorafenib for 5 months. However, there were many new metastases of the lung, and the previous lesions of the lung grew. Therefore, the patient experienced disease progression soon after the first-line treatment. It was thought that the patient would die in a short time. As there was no standard treatment after sorafenib, apatinib was suggested. Surprisingly, he came to our hospital 3 months later. The CT results showed the lung metastases had diminished remarkably and a few metastases disappeared (PR). Furthermore, the PR state continued for approximately 1 year. At his last follow-up visit (November 18, 2016), most of the lung metastases had disappeared with several small lesions remaining and the patient had a very good performance status. Regretfully, he died of a lung infection <2 months later.\n\nApatinib, a new antiangiogenesis small-molecule oral agent, has been recommended for patients with advanced or metastatic gastric cancer for whom 2 or more lines of chemotherapy have failed.[5,6] It has not been reported for other cancers in clinical trials, except for some case reports. Kou et al[13] reported treatment of a patient with HCC using a combination of apatinib and TACE followed by oxaliplatin-based chemotherapy; the patient's progression-free survival (PFS) time was 8 months. Liu et al[9] reported a retrospective study involving 19 patients with HCC treated with apatinib and TACE, with a median PFS time of 8.1 months. In addition, the apatinib was used as first-line treatment in these 2 reports.[9,13] In the present case report, the apatinib was used alone as second-line treatment in a patient with sorafenib-resistant HCC and many lung metastases. Nevertheless, the patient showed PR 3 months after the treatment, and the PR state continued for approximately 1 year. During the entire process, the lung metastases continued to diminish. Finally, only very few lesions remained. If the patient had not gotten a lung infection, he would have had a much longer PFS time. The adverse effects were tolerable and were easily relieved by appropriate treatments.\n\n4 Conclusion\nApatinib alone as second-line treatment of a patient with HCC and many lung metastases who failed treatment with sorafenib showed an excellent antitumor effect. Most of the lung metastases diminished with only a few lesions left. The patient achieved PR soon after the treatment, which lasted for approximately 1 year. Apatinib alone may be a good choice for the second-line treatment of HCC when sorafenib fails; however, further investigation in future prospective clinical studies is warranted.\n\nAuthor contributions\nConceptualization: Ji Duo.\n\nData curation: Hong Zhu, Xiaojun Ma.\n\nFormal analysis: Hong Zhu, Ji Duo.\n\nInvestigation: Hong Zhu, Xiaojun Ma, Yaqin Zhao.\n\nResources: Hong Zhu.\n\nSupervision: Ji Duo.\n\nWriting – original draft: Hong Zhu, Xiaojun Ma, Yaqin Zhao.\n\nWriting – review and editing: Hong Zhu, Ji Duo.\n\nAbbreviations: AFP = alpha fetoprotein, CT = computed tomography, HCC = hepatocellular carcinoma, PD = progression disease, PFS = progression-free survival, PR = partial response, TACE = transcatheter arterial chemoembolization, VEGF = vascular endothelial growth factor.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Altekruse SF McGlynn KA Reichman ME \nHepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005 . J Clin Oncol \n2009 ;27 :1485 –91 .19224838 \n[2] Llovet JM Ricci S Mazzaferro V \nSorafenib in advanced hepatocellular carcinoma . N Engl J Med \n2008 ;359 :378 –90 .18650514 \n[3] Cheng AL Kang YK Chen Z \nEfficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial . Lancet Oncol \n2009 ;10 :25 –34 .19095497 \n[4] Bruix J Qin S Merle P \nRegorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial . Lancet \n2017 ;389 :56 –66 .27932229 \n[5] Li J Qin S Xu J \nApatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial . J Clin Oncol \n2013 ;31 :3219 –25 .23918952 \n[6] Li J Qin S Xu J \nRandomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction . J Clin Oncol \n2016 ;34 :1448 –54 .26884585 \n[7] Zhu H Zhao Y Wang X \nThe radiosensitive effect of apatinib for hepatocellular carcinoma patient with big paraspinal metastasis: a case report . Medicine \n2018 ;97 :e9598 .29480860 \n[8] Lu W Jin XL Yang C \nComparison of efficacy between TACE combined with apatinib and TACE alone in the treatment of intermediate and advanced hepatocellular carcinoma: a single-center randomized controlled trial . Cancer Biol Ther \n2017 ;18 :433 –8 .28548587 \n[9] Liu C Xing W Si T \nEfficacy and safety of apatinib combined with transarterial chemoembolization for hepatocellular carcinoma with portal venous tumor thrombus: a retrospective study . Oncotarget \n2017 ;8 :100734 –45 .29246017 \n[10] Burroughs A Hochhauser D Meyer T \nSystemic treatment and liver transplantation for hepatocellular carcinoma: two ends of the therapeutic spectrum . Lancet Oncol \n2004 ;5 :409 –18 .15231247 \n[11] Cheng AL Kang YK Lin DY \nSunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial . J Clin Oncol \n2013 ;31 :4067 –75 .24081937 \n[12] Poon RT Ng IO Lau C \nTumor microvessel density as a predictor of recurrence after resection of hepatocellular carcinoma: a prospective study . J Clin Oncol \n2002 ;20 :1775 –85 .11919234 \n[13] Kou P Zhang Y Shao W \nSignificant efficacy and well safety of apatinib in an advanced liver cancer patient: a case report and literature review . Oncotarget \n2017 ;8 :20510 –5 .28103584\n\n",
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"mesh_terms": "D000328:Adult; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D008113:Liver Neoplasms; D008168:Lung; D008175:Lung Neoplasms; D008297:Male; D009362:Neoplasm Metastasis; D009536:Niacinamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000077157:Sorafenib; D014057:Tomography, X-Ray Computed",
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"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "The excellent antitumor effect of apatinib alone as second-line therapy in a patient with sorafenib-refractory hepatocellular carcinoma: A case report.",
"title_normalized": "the excellent antitumor effect of apatinib alone as second line therapy in a patient with sorafenib refractory hepatocellular carcinoma a case report"
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"abstract": "BACKGROUND\nAsymptomatic, isolated, and thin-walled cystic lung cancer with extensive extrapulmonary metastasis is rare, and the risk of pulmonary cyst developing into lung cancer is poorly understood. The efficacy of apatinib for end-stage pulmonary adenosquamous carcinoma has not been clarified yet.\nWe herein report a rare case of primary lung cancer that appeared as an isolated thin-walled cystic lesion on computed tomography (CT) image, who was initially misdiagnosed as having pulmonary cyst empirically.\nFluorine-18-fluorodeoxyglucose-positron emission tomography and CT-guided liver biopsy of the patient revealed extra-pulmonary metastasis of lung cancer.\n\n\nMETHODS\nEight cycles of cisplatin-based chemotherapy were administered, followed by oral apatinib for 6 months. Thereafter, best supportive care was given for this patient.\n\n\nRESULTS\nThe pulmonary cystic lesion indicated stable disease through the therapy, but the hepatic tumors were progressed gradually after anticancer treatment. The patient died 16 months after the correct diagnosis.\n\n\nCONCLUSIONS\nSolitary thin-walled cystic lung cancer should be kept in mind during the differential diagnosis of pulmonary cavitary lesions. Chest CT alone is insufficient for surveillance of these cystic diseases. Timely biopsy and resection are essential to avoid delayed management. Besides, apatinib may play a role in the treatment of end-stage pulmonary adenosquamous carcinoma.",
"affiliations": "Thoracic Oncology Center.;Thoracic Oncology Center.;Thoracic Oncology Center.;Thoracic Oncology Center.;Thoracic Oncology Center.;Department of Respiratory Medicine, Xuzhou Central Hospital of Southeast University, Xuzhou, China.",
"authors": "Wang|Xiang|X|;Tao|Yun-Xia|YX|;Zhang|Miao|M|;Wu|Wen-Bin|WB|;Yang|Dun-Peng|DP|;Wang|Min|M|",
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"country": "United States",
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"doi": "10.1097/MD.0000000000012950",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30412112MD-D-18-0262110.1097/MD.0000000000012950129505700Research ArticleClinical Case ReportSolitary thin-walled cystic lung cancer with extensive extrapulmonary metastasis A case report and review of the literatureWang Xiang MDaTao Yun-Xia MDaZhang Miao MDaWu Wen-Bin PhDaYang Dun-Peng MDaWang Min MDb∗NA. a Thoracic Oncology Centerb Department of Respiratory Medicine, Xuzhou Central Hospital of Southeast University, Xuzhou, China.∗ Correspondence: Min Wang, Department of Respiratory Medicine, Xuzhou Central Hospital Affiliated to Southeast University, 199 Jiefang South Road, Xuzhou 221009, China (e-mail: wangmindoc@qq.com).10 2018 26 10 2018 97 43 e1295011 4 2018 28 9 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nAsymptomatic, isolated, and thin-walled cystic lung cancer with extensive extrapulmonary metastasis is rare, and the risk of pulmonary cyst developing into lung cancer is poorly understood. The efficacy of apatinib for end-stage pulmonary adenosquamous carcinoma has not been clarified yet.\n\nPatient concerns:\nWe herein report a rare case of primary lung cancer that appeared as an isolated thin-walled cystic lesion on computed tomography (CT) image, who was initially misdiagnosed as having pulmonary cyst empirically.\n\nDiagnoses:\nFluorine-18-fluorodeoxyglucose-positron emission tomography and CT-guided liver biopsy of the patient revealed extra-pulmonary metastasis of lung cancer.\n\nInterventions:\nEight cycles of cisplatin-based chemotherapy were administered, followed by oral apatinib for 6 months. Thereafter, best supportive care was given for this patient.\n\nOutcomes:\nThe pulmonary cystic lesion indicated stable disease through the therapy, but the hepatic tumors were progressed gradually after anticancer treatment. The patient died 16 months after the correct diagnosis.\n\nLessons:\nSolitary thin-walled cystic lung cancer should be kept in mind during the differential diagnosis of pulmonary cavitary lesions. Chest CT alone is insufficient for surveillance of these cystic diseases. Timely biopsy and resection are essential to avoid delayed management. Besides, apatinib may play a role in the treatment of end-stage pulmonary adenosquamous carcinoma.\n\nKeywords\napatinibbevacizumabcavitarycysticlung cancerthin-walledOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThe knowledge about the clinical features of thin-walled cavitary lung cancer is limited for its rarity. It is characterized by cystic malignancy with a wall of ≤4 mm thick, along with at least 75% of the circumference of the lesion.[1] Early lung cancers with cystic airspaces are increasingly being recognized as a cause of delayed diagnoses[2] because solitary thin-walled cavitary lung cancers mimic benign emphysematous diseases, which could be a pitfall in differential diagnosis.[3] In general, the prognosis of patients with cavitary adenocarcinoma is unfavorable.[4]\n\nThe initial presentation of solitary thin-walled cavity lung cancer varies. It is sometimes difficult to obtain pathological diagnosis from thin-walled cavitary lesions by percutaneous biopsy. The differential diagnosis of benign diseases and malignancies is essential for treatment,[5] besides, solitary thin-walled cavity lung cancer is easily to be neglected by pitfalls in computed tomography (CT) diagnosis. The patients of this kind would take the risk of delayed treatment because it might disseminate without noticeable manifestations. Therefore, a minimally invasive surgery could be considered for patients with high-risk factors for lung cancer.\n\nTreatment options for patients with advanced lung cancer that is resistant to conventional chemotherapy are limited. Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2, is an orally bioavailable agent for a variety of solid tumors. It has shown a survival benefit in non-small cell lung cancer (NSCLC) in a phase II trial.[6] The efficacy of apatinib for end-stage pulmonary adenosquamous carcinoma has not been clarified yet.\n\nHerein, a rare case of solitary cystic lung cancer with extensive extrapulmonary metastasis is presented, who has missed a timely operation because of the initial misdiagnosis. Related literature is reviewed, with the aim to promote the identification of solitary thin-walled cavitary lung cancer.\n\n2 Case presentation\nA 63-year-old man was admitted to our hospital on June 6th, 2016, because of lower back pain for a month, without fever, cough, hemoptysis, hoarseness, or obvious loss of weight. He had no alcohol or tobacco history before admission. His family and social histories were unremarkable. The patient was initially diagnosed as asymptomatic pulmonary cyst empirically on November 11th, 2015 during health examination, as his chest CT indicated an isolated thin-walled cystic lesion measuring 1.5 cm in diameter in the left upper lung (Fig. 1). Whole-body CT scan, biopsy, or thoracoscopic resection of the lesion was not performed, and he was advised to take periodic examination by the clinicians in the local hospital.\n\nFigure 1 Lung-window computed tomographic image of the patient indicated an isolated thin-walled cystic lesion in left upper lobe (arrow) on November 11th, 2015.\n\nHis thorough physical examination on admission showed nothing abnormal. Further tests were performed step by step for differential diagnosis. Routine serum tumor markers of carcinoembryonic antigen, cytokeratin 19 fragment, squamous cell carcinoma, neuron-specific enolase, alpha fetal protein, serum ferritin, carbohydrate antigens (CA) such as CA242, CA72–4, CA153, CA125. and CA19–9 were all in normal range. Subsequently, radiological examinations were carried out for a definite diagnosis. His chest and abdomen CT revealed a morphologically solitary, thin-walled cavitary lesion, measuring 1.6 cm in diameter, along with several hepatic masses (Fig. 2). The cystic lesion was suspicious of malignancy,because the wall was slightly thickened unevenly comparing with the imaging findings (Fig. 1) nearly half a year ago.\n\nFigure 2 Computed tomography revealed an isolated pulmonary thin-walled cystic lesion (A) and irregular liver masses (B) on June 6th, 2016. Liver biopsy displayed atypical malignant cells (C), and it was pathologically confirmed as pulmonary sarcomatoid carcinoma (D), by hematoxylin and eosin staining (×200).\n\nTherefore, positron emission tomography-computed tomography (PET-CT) was performed, which indicated a solitary thin-walled pulmonary cystic lesion, several hepatic masses, intramuscular and osteolytic damages, and enlarged mediastinal lymph nodes with hyper-metabolic features. These lesions demonstrated significantly abnormal uptake of fluorine-18-fluorodeoxyglucose (FDG) (Fig. 3). The isolated thin-walled cavitary lesion showed a maximum standard uptake values (SUVmax) of 4.3. Similarly, SUVmax of the masses located in left hepatic lobe, the right scapula, pelvis, and sacrum was 5.6 and 11.3, respectively. The SUVmax of right paratracheal, aortopulmonary, and hilar lymph nodes was 8.4. These lesions were strongly suspicious of malignancy. Then CT-guided percutaneous liver biopsy was performed, which showed aggregation of atypical malignant cells, in accordance with lung cancer (Fig. 2C and D). His Eastern Cooperative Oncology Group (ECOG) score was 1. Based on the above findings, his diagnosis was corrected as stage IV pulmonary adenosquamous carcinoma according to the 7th edition of the TNM staging system for lung cancer.\n\nFigure 3 Positron emission tomography-computed tomography of the patient showed a small pulmonary cystic lesion, multiple hepatic masses, intramuscular and osteolytic damages (arrow) on June 6th, 2016, with abnormal uptake of Fluorine-18-fluorodeoxyglucose.\n\nSubsequently, the patient received 4 cycles of pemetrexed (500 mg/m2 of body surface area) plus cisplatin (75 mg/m2 of body surface area), followed by 4 cycles of concurrent gemcitabine (1000 mg/m2, day 1 and day 8) plus cisplatin (75 mg/m2) and bevacizumab (Avastin, Roche Pharma [Schweiz] Ltd., 10 mg/kg of body weight). Meanwhile, zoledronic acid (4 mg at a time) was administered every 21 days along with the chemotherapy. During the treatment, whole-body CT and bone emission computed tomography scan were carried out every 2 to 3 months. The pulmonary cystic lesion indicated stable disease, whereas the hepatic lesions were slightly enlarged after the chemotherapy, as shown by whole-body CT. One month later, he had been recovered from chemotherapy-related thrombocytopenia and fatigue. Then his ECOG score was 2. Oral apatinib (425 mg per day) was given as third-line therapy for 3 months, followed by leukopenia, thrombocytopenia, and cough, which could be controlled by medication. Thereafter, the dosage of apatinib was decreased to 200 mg/day for another 3 months.\n\nThe pulmonary cystic lesion maintained stable disease, whereas the hepatic lesions were enlarged and disseminated (progressive disease) as indicated by radiography 15 months after the treatment. Further therapeutic regime was suspended because of concomitant apatinib-related side effects, including discontinuous rhinorrhagia, leukopenia, thrombocytopenia, albuminuria, and fatigue. And his ECOG score was 3 at that time. Therefore, best supportive care was given with the aim to alleviate his suffering, and further laboratory or imaging examinations were no longer performed. His treatment process was depicted in Figure 4. He died of multiple organ failure nearly a month later.\n\nFigure 4 The schematic illustration of therapeutic regimen of the patient. AP = pemetrexed + cisplatin, Bev = bevacizumab, GP = gemcitabine + cisplatin.\n\n3 Discussion\nIn the era of precision medicine, a timely and accurate diagnosis is the most important premise. Patients with both pulmonary bulla and lung cancer have poor prognosis because they always receive treatment when the tumor is at an advanced stage. Moreover, cavitary tumors tend to be associated with a worse prognosis as compared with noncavitary adenocarcinoma.[4] The features of cystic airspaces include emphysematous bullae, congenital or fibrotic cysts, subpleural blebs, bronchiectatic airways, and distended distal airspaces.[2] However, the prevalence and risk of pulmonary cyst developing into lung cancer are still poorly understood. The patient in our report was misdiagnosed as solitary pulomonary cyst because of lacking knowledge of solitary thin-walled cystic lung cancer. Unfortunately, he missed a timely surgery half a year before his admission, which might deliver a better prognosis for him before the extensive metastasis. Herein, there are several issues about thin-walled cystic lung cancer that are urgently needed to be elucidated.\n\nFirst, thorough workup for etiologies of cavitary lung lesions is needed to decrease missed and delayed diagnosis. Individuals with chronic obstructive pulmonary disease and emphysema might have a higher frequency of lung cancer.[7,8] Evidence suggests that emphysema is an independent risk factor for lung cancer, and it may be a contributing factor to the development of malignancy.[9] The bronchial wall damage leads to the formation of valves and cavity,[10] and cystic airspaces preceded by nodules can evolve into lung cancer.[11] An isolated cystic airspace with progressive wall thickening over time should raise the suspicion of lung cancer.[12] Location in the periphery of the upper lobes, emphysema, additional cystic lesions or ground-glass nodules, lymphadenopathy, and previous lung cancer should further increase suspicion.[11] A report of 26 cases shows that, in the cystic lesions with initially uniformly thin wall of approximately 1 mm, nodules have been emerged 12 to 118 months (median, 35 months) after the initial CT scan.[12] Another report shows that the median time between the first observation of a cystic airspace and lung cancer diagnosis is 25.5 months.[11] Thus, cystic airspaces with wall thickening and/or associated nodules of any attenuation warrant regular surveillance.\n\nSecond, cystic airspaces may be formed after obstruction of the small airways, lepidic growth of adenocarcinoma in emphysema, cystification of tumor because of degeneration, or adenocarcinoma growing along the wall of a preexisting bulla.[11] Cavitary lung nodules could be caused by primary pulmonary cancer, metastatic pulmonary cancer, pulmonary abscess, tuberculosis, fungal infection, infected bulla, coccidioidomycosis, and septic emboli, but the differential diagnosis is sometimes difficult.[13] Furthermore, the notch and irregular internal wall are more frequent in malignant cavitary nodules, whereas a linear margin, presence of satellite nodule, bronchial wall thickening, consolidation, and ground-glass attenuation are more frequent in benign nodules.[13]\n\nSpecifically, thick-walled cavities (cavity wall thickness >4 mm) are formed as a result of vascular necrosis and destruction of the pulmonary alveoli by excessive mucus through a check-valve mechanism,[14–16] whereas thin-walled cavitary (cavity wall thickness ≤4 mm) lung metastasis can occasionally result from drainage of necrotizing tumor cells via a peripheral bronchus.[17] The thick-walled lung adenocarcinoma patients have a higher frequency of solid predominant tumors, hematogenous metastasis, large-vessel and lymphatic invasion, and necrosis, whereas the lepidic and papillary predominant patterns are more common in the thin-walled patients.[18] Meanwhile, patients with thick-walled cavitary adenocarcinomas have significantly higher incidence of postoperative recurrence and shorter survival, as compared with thin-walled cases, with similar frequency of EGFR and KRAS mutations in both groups.[18] However, the patient in this report with single thin-walled cycstic lung cancer demonstrates extensive hematogenous metastasis, large-vessel and lymphatic invasion, which is inconsistent with the previous reports.\n\nPreviously reported cases of thin-walled cystic lung cancer include adenocarcinomas, bronchioalveolar carcinoma,[19,20] squamous cell carcinoma, adenosquamous cell carcinoma,[15] and solitary metastasis of extra-pulmonary tumors.[17] Spontaneous formation of cavity in metastatic lung lesions is rare.[21] Percutaneous needle washing and aspiration of cavitary lesions for cytological examination may be useful for diagnosis.[22] Radiological features including single thin-walled cavity accompanied by uneven thickening of the cavity wall or wall nodules, increased SUV by FDG-PET, and compartments in the cavity on CT images probably indicate lung cancer.[10] However, FDG-PET is useful for workup of lesions with a solid component >8 mm.[11] Progressive wall thickening or appearance/increase of a nodule inside or outside a cystic airspace should raise suspicion of lung cancer irrespective of FDG uptake.[23] Pericystic cancers are reported to be morphologically classified into 4 types as shown in CT images: solid nodule protruding externally (type I) or internally (type II) from the cyst wall, circumferential thickening of the cyst wall (type III), and tissue intermixed within clusters of cysts (type IV).[2] Type I and IV cystic lung cancers are more likely to be misdiagnosed as benign lesions, whereas types II and III cases could easily be confused with inflammation.[2] The case in our report could be classified as type I according to this classification system.\n\nThird, malignancy in cystic lesions may be because of ventilation, clearance, and deposition of carcinogens.[12] Tumor metastasis is an inefficient process, and the major sites of non-small cell lung cancer (NSCLC) metastasis are brain, bone, adrenal gland, and the liver.[24,25] In addition to biopsy, circulating tumor cells (CTCs) or tumour DNA (ctDNA) obtained from peripheral blood may be another diagnostic tool for morphologically atypical lung cancer.[26] Besides, human epidermal growth factor receptor 2, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, and epidermal growth factor receptor mutation status might be detected in CTCs.[27] Lung cancer screen for patients with a giant bulla is necessary. However, it is difficult to obtain sufficient material from thin-walled cavitary lesions by fine needle biopsy; therefore, a timely resection of the bulla is reasonable to avoid delayed diagnosis of coexisting cancer and bulla, especially for patients with high-risk factors for lung cancer.\n\nSimilar reports of solitary thin-walled cavity lung cancer are collected (Table 1),[3,5,11,12,18,22,23,28,29] which indicates that distant metastasis may occur when the solitary thin-walled cystic lesion remains unchanged or changed slightly. A few of these collected cases demonstrates distal metastasis with single small thin-walled cystic lung cancer. Therefore, chest CT for annual screening is insufficient because distal dissemination of the malignancy could be asymptomatic. Whole-body CT or FDG-PET is necessary, although PET is not covered by the health insurance in China. Thus, the role of thoracoscopic surgery as a minimally invasive approach is truly indispensable.\n\nTable 1 A collection of reports of solitary thin-walled cavity lung cancer.\n\nFinally, the prognosis for patients with progressive or relapsed NSCLC remains poor, regardless of the progress in anticancer agents. First-line therapy is platinum-based regimens, whereas second-line therapies include docetaxel, pemetrexed, and erlotinib. Treatment options for patients who have failed to conventional chemotherapy are limited, and apatinib is considered to be third-line therapy and beyond for NSCLC patients.[30] There has been little progress in targeted therapies for adenosquamous carcinoma, and genetic profiling may facilitate the personalized treatments.[31] Bevacizumab and apatinib inhibit the angiogenesis in malignant tumors, and anti-angiogenesis therapy is a major option for stage IV non-squamous NSCLC patients.[32] As for the patient in this report, apatinib had been administered as third-line therapy for 6 months. Although it demonstrated satisfactory efficacy, many noticeable side effects were also inevitable, which made the patient suffered. The patient in this report survived only 16 months after his corrected diagnosis. More effective target therapeutic agents with decreased adverse reactions are still urgently needed.\n\n4 Conclusion\nIn summary, asymptomatic solitary thin-walled cystic lung cancer should be kept in mind during the differential diagnosis of cavitary lesions, and chest CT alone is inadequate for surveillance of these patients. Thoracoscopic resection could be considered if whole-body CT scan excludes metastasis. A combination of chemotherapy and target therapy is somewhat effective for patients with advanced lung cancer.\n\nAuthor contributions\nData curation: Xiang Wang, Yun-Xia Tao, Miao Zhang, Wen-Bin Wu.\n\nFormal analysis: Yun-Xia Tao.\n\nMethodology: Xiang Wang, Yun-Xia Tao, Dun-Peng Yang.\n\nResources: Miao Zhang, Wen-Bin Wu.\n\nValidation: Xiang Wang, Min Wang, Dun-Peng Yang.\n\nVisualization: Wen-Bin Wu.\n\nWriting – original draft: Xiang Wang, Min Wang.\n\nWriting – review & editing: Miao Zhang, Min Wang, Wen-Bin Wu, Dun-Peng Yang.\n\nAbbreviations: CA = carbohydrate antigens, CT = computed tomography, CTCs = circulating tumour cells, ECT = emission computed tomography, FDG = fluorodeoxyglucose, MRI = magnetic resonance images, NSCLC = Non-small cell lung cancer, PET = positron emission tomography, SD = stable disease, SUVmax = maximum standard uptake values, VEGF = vascular endothelial growth factor.\n\nXW and Y-XT are co-first authors.\n\nXW, R-RL, W-BW, and MW planned the article and contributed to discussion, follow up and reviewing the article. Y-MW, MZ, D-PY, and Y-XT participated in study design, data collection and writing the article.\n\nInformed consent: Written informed consent was obtained from the patient for publication of this case report and any accompanying images, and it was approved by the Institutional Review Board of Xuzhou Central Hospital.\n\nFunding: This study is supported by Projects of medical and health technology development program in Zhejiang province (No.2018243718), Jiangsu Province Innovative and Entrepreneurial Talent Introduction Plan (Wenbin Wu and Xiaodong Wu, 2016), and Xuzhou City Science and Technology Project (No.KC16SH102).\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n[1] Guo J Liang C Chu X \n[Thin-walled cystic lung cancer: an analysis of 24 cases and review of literatures] . Zhongguo Fei Ai Za Zhi \n2014 ;17 :553–6 .25034586 \n[2] Sheard S Moser J Sayer C \nLung cancers associated with cystic airspaces: underrecognized features of early disease . Radiographics \n2018 ;38 :704–17 .29652577 \n[3] Iwata T Nishiyama N Nagano K \nSquamous cell carcinoma presenting as a solitary growing cyst in lung: a diagnostic pitfall in daily clinical practice . Ann Thorac Cardiovasc Surg \n2009 ;15 :174–7 .19597393 \n[4] Watanabe Y Kusumoto M Yoshida A \nSurgically resected solitary cavitary lung adenocarcinoma: association between clinical, pathologic, and radiologic findings and prognosis . Ann Thorac Surg \n2015 ;99 :968–74 .25620598 \n[5] Xue XY Liu YX Wang KF \nComputed tomography for the diagnosis of solitary thin-walled cavity lung cancer . Clin Respir J \n2015 ;9 :392–8 .24931383 \n[6] Scott AJ Messersmith WA Jimeno A \nApatinib: a promising oral antiangiogenic agent in the treatment of multiple solid tumors . Drugs Today (Barc) \n2015 ;51 :223–9 .26020064 \n[7] Stoloff IL Kanofsky P Magilner L \nThe risk of lung cancer in males with bullous disease of the lung . Arch Environ Health \n1971 ;22 :163–7 .5539979 \n[8] Lee G Walser TC Dubinett SM \nChronic inflammation, chronic obstructive pulmonary disease, and lung cancer . Curr Opin Pulm Med \n2009 ;15 :303–7 .19417670 \n[9] de Torres JP Bastarrika G Wisnivesky JP \nAssessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest . Chest \n2007 ;132 :1932–8 .18079226 \n[10] Qi Y Zhang Q Huang Y \nManifestations and pathological features of solitary thin-walled cavity lung cancer observed by CT and PET/CT imaging . Oncol Lett \n2014 ;8 :285–90 .24959262 \n[11] Fintelmann FJ Brinkmann JK Jeck WR \nLung cancers associated with cystic airspaces: natural history, pathologic correlation, and mutational analysis . J Thorac Imaging \n2017 ;32 :176–88 .28338535 \n[12] Farooqi AO Cham M Zhang L \nLung cancer associated with cystic airspaces . AJR Am J Roentgenol \n2012 ;199 :781–6 .22997368 \n[13] Honda O Tsubamoto M Inoue A \nPulmonary cavitary nodules on computed tomography: differentiation of malignancy and benignancy . J Comput Assist Tomogr \n2007 ;31 :943–9 .18043361 \n[14] Isobe K Hata Y Iwata M \n[An autopsied case of mucinous bronchioloalveolar carcinoma associated with multiple thin-walled cavities] . Nihon Kokyuki Gakkai Zasshi \n2009 ;47 :512–7 .19601529 \n[15] Sugimoto Y Semba H Fujii S \n[Clinical analysis of primary lung cancer with a thin-walled cavity to explain the mechanism of thin-walled cavity formation] . Nihon Kokyuki Gakkai Zasshi \n2007 ;45 :460–4 .17644941 \n[16] Soo Chang S Go T Yokomise H \n[Adenocarcinoma with cavity formation caused by check valve mechanism] . Kyobu Geka \n2014 ;67 :399–402 .24917288 \n[17] Nomori H Kobayashi R Morinaga S \nSolitary, thin-walled cavitary lung metastasis of osteogenic sarcoma . Scand J Thorac Cardiovasc Surg \n1995 ;29 :95–6 .8643935 \n[18] Watanabe Y Kusumoto M Yoshida A \nCavity wall thickness in solitary cavitary lung adenocarcinomas is a prognostic indicator . Ann Thorac Surg \n2016 ;102 :1863–71 .27663793 \n[19] Weisbrod GL Towers MJ Chamberlain DW \nThin-walled cystic lesions in bronchioalveolar carcinoma . Radiology \n1992 ;185 :401–5 .1329140 \n[20] Sabloff BS Wistuba II Erasmus JJ \nCystic bronchioloalveolar cell carcinoma . J Thorac Imaging \n2005 ;20 :110–4 .15818211 \n[21] Raissouni S Ghizlane R Mouzount H \nUnusual case of cavitary lung metastasis from squamous cell carcinoma of the uterine cervix . Pan Afr Med J \n2013 ;14 :37.23560120 \n[22] Nakahara Y Mochiduki Y Miyamoto Y \nPercutaneous needle washing for the diagnosis of pulmonary thin-walled cavitary lesions filled with air . Intern Med \n2007 ;46 :1089–94 .17634705 \n[23] Mascalchi M Attina D Bertelli E \nLung cancer associated with cystic airspaces . J Comput Assist Tomogr \n2015 ;39 :102–8 .25279848 \n[24] Wood SL Pernemalm M Crosbie PA \nThe role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets . Cancer Treat Rev \n2014 ;40 :558–66 .24176790 \n[25] Popper HH \nProgression and metastasis of lung cancer . Cancer Metastasis Rev \n2016 ;35 :75–91 .27018053 \n[26] Rothwell DG Smith N Morris D \nGenetic profiling of tumours using both circulating free DNA and circulating tumour cells isolated from the same preserved whole blood sample . Mol Oncol \n2016 ;10 :566–74 .26639657 \n[27] O’Flaherty JD Gray S Richard D \nCirculating tumour cells, their role in metastasis and their clinical utility in lung cancer . Lung Cancer \n2012 ;76 :19–25 .22209049 \n[28] Jakopovic M Slobodnjak Z Krizanac S \nLarge cell carcinoma arising in bronchogenic cyst . J Thorac Cardiovasc Surg \n2005 ;130 :610–2 .16077456 \n[29] Ji Young P Taehoon L Hong Yeul L \nA case of lung squamous cell carcinoma mimicking benign solitary cyst . J Lung Cancer \n2012 ;11 :108–10 .\n[30] Langer CJ Mok T Postmus PE \nTargeted agents in the third-/fourth-line treatment of patients with advanced (stage III/IV) non-small cell lung cancer (NSCLC) . Cancer Treat Rev \n2013 ;39 :252–60 .22703830 \n[31] Kenmotsu H Serizawa M Koh Y \nProspective genetic profiling of squamous cell lung cancer and adenosquamous carcinoma in Japanese patients by multitarget assays . BMC Cancer \n2014 ;14 :78.24512546 \n[32] Greillier L Tomasini P Barlesi F \nBevacizumab in the treatment of nonsquamous non-small cell lung cancer: clinical trial evidence and experience . Ther Adv Respir Dis \n2016 ;10 :485–91 .27340254\n\n",
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"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D018196:Carcinoma, Adenosquamous; D057210:Delayed Diagnosis; D017809:Fatal Outcome; D006801:Humans; D008113:Liver Neoplasms; D017116:Low Back Pain; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D014057:Tomography, X-Ray Computed; D051598:Whole Body Imaging",
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"title": "Solitary thin-walled cystic lung cancer with extensive extrapulmonary metastasis: A case report and review of the literature.",
"title_normalized": "solitary thin walled cystic lung cancer with extensive extrapulmonary metastasis a case report and review of the literature"
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"abstract": "Inhibitors of tumor necrosis factor-alpha (anti-TNF-alpha) are widely used in different medical specialties. The main adverse effect of these agents is the increased risk of infection. We report the case of a 30-year-old man with ankylosing spondylitis who had begun receiving golimumab two weeks earlier. He presented with a 10-day history of salmon-colored lesions on trunk, palms and soles. The clinical suspicion was secondary syphilis. Treponemal and nontreponemal tests confirmed the diagnosis of syphilis. Lumbar puncture was also performed, although there was no neurological involvement, to rule out neurosyphilis. Cases of syphilis in patients in treatment with TNF-alpha inhibitors are uncommon in the literature and there are no established protocols.",
"affiliations": "Servicio de Dermatología, Hospital Universitari Sagrat Cor, Barcelona, España. Electronic address: anaiglesiasplaza@gmail.com.;Servicio de Dermatología, Hospital Universitari Sagrat Cor, Barcelona, España.;Servicio de Dermatología, Hospital Universitari Sagrat Cor, Barcelona, España.;Servicio de Reumatología, Hospital Universitari Sagrat Cor, Barcelona, España.;Servicio de Dermatología, Hospital Universitari Sagrat Cor, Barcelona, España.",
"authors": "Iglesias-Plaza|Ana|A|;Iglesias-Sancho|Maribel|M|;Quintana-Codina|Mónica|M|;García-Miguel|Javier|J|;Salleras-Redonnet|Montse|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; C529000:golimumab",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.reuma.2017.12.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2173-5743",
"issue": "15(6)",
"journal": "Reumatologia clinica",
"keywords": "Factor de necrosis tumoral alfa; Infección; Infection; Syphilis; Sífilis; Tumor necrosis factor-alpha",
"medline_ta": "Reumatol Clin (Engl Ed)",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D006801:Humans; D008297:Male; D013167:Spondylitis, Ankylosing; D013587:Syphilis; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101717526",
"other_id": null,
"pages": "e108-e110",
"pmc": null,
"pmid": "29398464",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Syphilis in the Setting of Anti-tumor Necrosis Factor Alpha Therapy.",
"title_normalized": "syphilis in the setting of anti tumor necrosis factor alpha therapy"
} | [
{
"companynumb": "ES-JNJFOC-20180214729",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GOLIMUMAB"
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"drugadditional": "3",
"d... |
{
"abstract": "BACKGROUND\nChimeric antigen receptor T (CAR-T) cells targeting B-cell maturation antigen (BCMA) have been used in the treatment of relapsed and refractory multiple myeloma (RRMM). The response rate and the depth of responses induced by anti-BCMA CAR-T cells are impressive. However, despite this, remissions are not sustained, and the majority of patients eventually relapse.\nTwo patients with multiple myeloma (MM) were selected to enroll in a phase I study involving anti-BCMA CAR-T cells (ChiCTR-OPC-16009113) because they did not have the good effect after traditional treatment. One is a 48-year-old male patient who received a diagnosis of IgG lambda MM in June 2015, he has received 4 cycles of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and obtained a complete response (CR). Approximately 11 months later, the disease progressed. Subsequent treatment included regimens incorporating liposomal doxorubicin, bortezomib, and dexamethasone (3 cycles); the response was poor, and the disease kept progressing. Another 65-year-old female patient received a diagnosis of IgG lambda MM in September 2016, she has received induction therapy with 1 cycle of bortezomib and dexamethasone (VD) and 4 cycles of lenalidomide and dexamethasone, the response was poor.\n\n\nMETHODS\nBoth patients were diagnosed with RRMM according to the International Myeloma Working Group criteria.\n\n\nMETHODS\nBoth patients received infusions of anti-BCMA CAR-T cells following an induction chemotherapy regimen of cyclophosphamide and fludarabine.\n\n\nRESULTS\nBoth of them achieved a stringent CR at the 30th day with minimal residual disease-negative bone marrow by flow cytometry and serum monoclonal protein was undetectable at 4 and 10 months after cell transfusion. The CR has persisted in the 2 patients for >36 months.\n\n\nCONCLUSIONS\nOur findings demonstrate the anti-BCMA CAR-T cell treatment is a feasible therapeutic option for patients with RRMM. Fewer early lines of treatment may be beneficial to maintain the efficacy of CAR-T cells.\n\n\nBACKGROUND\nChiCTR-OPC-16009113.",
"affiliations": "Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China.",
"authors": "Xu|Jinhuan|J|;Ming|Xi|X|;Wang|Chunyan|C|;Xu|Bi|B|;Xiao|Yi|Y|",
"chemical_list": "D053301:B-Cell Maturation Antigen; D000076962:Receptors, Chimeric Antigen; C086966:TNFRSF17 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000025784",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\n33950974\nMD-D-20-12918\n10.1097/MD.0000000000025784\n25784\n3700\nResearch Article\nClinical Case Report\nLong event-free survival after anti-BCMA CAR-T cell treatment for relapsed and refractory multiple myeloma patients\nTwo case reports\nXu Jinhuan MD\nMing Xi MM\nWang Chunyan MM\nXu Bi MD\nXiao Yi MD ∗\nSaranathan. Maya\nDepartment of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China.\n∗ Correspondence: Yi Xiao, Department of Hematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology & Immunotherapy Research Center for Hematologic Diseases of Hubei Province, 1095 Jie-Fang Avenue, Wuhan, Hubei 430030, P. R. China (e-mail: yixiao@tjh.tjmu.edu.cn).\n07 5 2021\n07 5 2021\n100 18 e2578419 1 2021\n10 4 2021\n15 4 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nIntroduction:\n\nChimeric antigen receptor T (CAR-T) cells targeting B-cell maturation antigen (BCMA) have been used in the treatment of relapsed and refractory multiple myeloma (RRMM). The response rate and the depth of responses induced by anti-BCMA CAR-T cells are impressive. However, despite this, remissions are not sustained, and the majority of patients eventually relapse.\n\nPatient concerns:\n\nTwo patients with multiple myeloma (MM) were selected to enroll in a phase I study involving anti-BCMA CAR-T cells (ChiCTR-OPC-16009113) because they did not have the good effect after traditional treatment. One is a 48-year-old male patient who received a diagnosis of IgG lambda MM in June 2015, he has received 4 cycles of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and obtained a complete response (CR). Approximately 11 months later, the disease progressed. Subsequent treatment included regimens incorporating liposomal doxorubicin, bortezomib, and dexamethasone (3 cycles); the response was poor, and the disease kept progressing. Another 65-year-old female patient received a diagnosis of IgG lambda MM in September 2016, she has received induction therapy with 1 cycle of bortezomib and dexamethasone (VD) and 4 cycles of lenalidomide and dexamethasone, the response was poor.\n\nDiagnosis:\n\nBoth patients were diagnosed with RRMM according to the International Myeloma Working Group criteria.\n\nInterventions:\n\nBoth patients received infusions of anti-BCMA CAR-T cells following an induction chemotherapy regimen of cyclophosphamide and fludarabine.\n\nOutcomes:\n\nBoth of them achieved a stringent CR at the 30th day with minimal residual disease-negative bone marrow by flow cytometry and serum monoclonal protein was undetectable at 4 and 10 months after cell transfusion. The CR has persisted in the 2 patients for >36 months.\n\nConclusions:\n\nOur findings demonstrate the anti-BCMA CAR-T cell treatment is a feasible therapeutic option for patients with RRMM. Fewer early lines of treatment may be beneficial to maintain the efficacy of CAR-T cells.\n\nTrial registration:\n\nChiCTR-OPC-16009113.\n\nKeywords\n\nB-cell maturation antigen\nchimeric antigen receptor T cells\ncomplete response\nrelapsed and refractory multiple myeloma\nthe National Science Foundation of China81400147 Jinhuan Xuthe National Science Foundation of China81873446 Yi XiaoOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nChimeric antigen receptor T (CAR-T) cell therapy targeting B-cell maturation antigen (BCMA) produced unprecedented results in heavily pretreated relapsed and/or refractory multiple myeloma (MM). Data on >300 patients with MM treated with anti-BCMA-directed CAR-T cells are available, and these numbers are rapidly increasing. Coming from different T-cell products used in different patients and settings, the response rates and depth of responses induced by anti-BCMA CAR-T cells are impressive. However, despite this, remissions are not sustained, and the majority of patients eventually relapse.[1] So far, the longest median event-free survival (EFS) reported in the literature was 15 months.[1,2] In this report, 2 patients with RRMM treated with infusions of anti-BCMA CAR-T cells had an ongoing stringent complete response (CR) for >36 months with minimal residual disease (MRD)-negative bone marrow as determined by flow cytometry, which may continue for a longer period of time. We analyzed the possible mechanisms for the continuous remission with combining the published literature.\n\n2 Case presentation\n\n2.1 Case 1\n\nA 48-year-old male patient received a diagnosis of stage IIIA (Durie-Salmon standard) IgG lambda MM in June 2015, after presenting with anemia and multiple bone lesions. He received induction therapy with 4 cycles of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and obtained a CR. However, he did not undergo further consolidation and maintenance treatment. Approximately 11 months later (September 2016), the disease relapsed, 3% of his bone marrow cells were plasma cells, and monoclonal protein was detectable in his serum and urine. Subsequent treatment included regimens incorporating liposomal doxorubicin, bortezomib, and dexamethasone (3 cycles). According to the International Myeloma Working Group response criteria,[3] the response was poor, and the disease kept progressing. The patient refused to use other new drugs for treatment. In May 2017, after the failure of 2 previous lines of treatment, the patient was enrolled in a phase I clinical trial involving anti-BCMA CAR-T cell therapy. Before anti-BCMA CAR-T cell infusion, a bone marrow biopsy showed 3.5% myeloma involvement. CD38 and BCMA coexpression was revealed by flow cytometry (Fig. 2C). The treatment protocol and anti-BCMA CAR-T cell preparation (Supplemental Method) were the same as in our previous report.[4] The patient was given fludarabine 25 mg/m2 and cyclophosphamide 20 mg/kg for 3 days (days −4 to −2) for lymphodepletion. Anti-BCMA CAR-T cells were infused on successive 3-day periods from day 0 (June 13, 2017), the effective anti-BCMA CAR-T cells totaled 10.5 × 106/kg (Fig. 1A). One day after the completion of anti-BCMA CAR-T cell infusion, he became febrile. The patient was febrile for 4 days, with a maximum temperature of 38.3°C (Fig. 2a). The serum interleukin (IL)-6 and C-reactive protein (CRP) levels were elevated and peaked respectively on the 6th and 7th day postinfusion, which was also the time where toxicity culminated (Fig. 2A). Pancytopenia was observed but not central nervous system (CNS) toxicities. White blood cells and neutrophils returned to normal on the 9th day after infusion. No infusion of red blood cells or platelets was required during the entire treatment period. All coagulation and biochemistry parameters were normal over the whole treatment period. He experienced grade 1 cytokine-release syndrome (CRS). At the 7th day after anti-BCMA CAR-T cell infusion, we noted a striking decrease in serum monoclonal protein levels (Fig. 2B); 1 month later, multicolor flow cytometry did not detect MM cells for the plasma cell marker CD38 staining in the bone marrow (Fig. 2D), which confirmed a stringent CR. Normal plasma cells were also absent from the bone marrow 1 month after anti-BCMA CAR-T cell infusion. Serum monoclonal protein became undetectable 10 months postinfusion and remained undetectable until now (Fig. 2B). So far, the response to CAR-T cell infusion was still stringent CR at 37 months with MRD-negative bone marrow as determined by flow cytometry without any anti-myeloma treatment.\n\nFigure 1 Protocol of anti-B-cell maturation antigen CAR-T cell infusions following chemotherapy. A protocol of CAR-T cell infusion in combination with chemotherapy. Chemotherapy included fludarabine and cyclophosphamide. CAR-T cells were infused at a total dose of 10.5 × 106/kg for 3 days (A, Case 1) and 24.7 × 106/kg for 4 days (B, Case 2). CAR-T = chimeric antigen receptor T.\n\nFigure 2 Measures of multiple myeloma burden and clinical responses to infusions of anti-BCMA chimeric antigen receptor T (CAR-T) cells of case 1. (A) A total of 72 hours after CAR-BCMA infusion, the patient became febrile. She was febrile for 4 days. The plot shows the maximum temperature for each day. The levels of IL-6 and CRP were elevated. (B) Panel B shows the trend in IgG and M spike concentrations after treatment with anti-BCMA CAR-T cell infusion. (C) Bone marrow cells were 0.94% plasma cells as shown by CD38 staining at 13 days before the anti-BCMA CAR-T cell infusion. BCMA expression per flow cytometry showed uniform BCMA expression on CD38-positive malignant plasma cells before the anti-BCMA CAR-T cell infusion. (D) No plasma cells were found among the bone marrow cells on day 30 after anti-BCMA CAR-T cell infusion. BCMA = B-cell maturation antigen, CRP = C-reactive protein, IL = interleukin, SSC-A = side scatter area.\n\n2.2 Case 2\n\nAnother 65-year-old female patient received a diagnosis of stage IIA (Durie-Salmon standard) IgG lambda MM in September 2016, after presenting with anemia and multiple bone lesions. A bone marrow biopsy showed 36% myeloma involvement. Risk factors were noted, including P53 deletion, RB1 gene deletion, MAF gene deletion, and positive IgH/CCND1 fusion gene. She received induction therapy with 1 cycle of bortezomib and dexamethasone (VD). The patient developed severe diarrhea, fatigue, numbness of the limbs, and was unable to walk independently. After giving anti-diarrhea medication, correcting electrolyte disturbances and nutritional nerve treatment, diarrhea and fatigue improved significantly, but the numbness did not abate. There was a high possibility of nerve damage caused by bortezomib, and subsequent treatment included regimens incorporating lenalidomide and dexamethasone (TD 4 cycles). Although the numbness improved significantly, according to International Myeloma Working Group response criteria,[3] the patient's disease remained stable. In August 2017, the patient was enrolled in the aforementioned clinical trial and received anti-BCMA CAR-T cell treatment. Before anti-BCMA CAR-T cell infusion, a bone marrow biopsy showed 6% myeloma involvement, and CD138 and BCMA coexpression was revealed by flow cytometry (Fig. 3C). The treatment protocol was the same as that in patient 1; the effective cells totaled 24.7 × 106/kg (Fig. 1B). Six hours after the second infusion, she developed fever (38°C, peaked at 40.1°C on the next day), and lasted for 14 days) that was associated with elevated serum IL-6 and CRP levels. The peak of serum IL-6 (35 times higher than baseline) was detected on the second-day postinfusion, which was just the time where toxicity culminated (Fig. 3A). After the third reinfusion, this patient also had grade 1 delirium without other neurologic toxicities, which was treated with dexamethasone, diazepam, and mannitol. Neurological symptoms were relieved, and there was no long-term neurological dysfunction. Pancytopenia was observed, and the white blood cells and neutrophils returned to normal 11 days after the infusion. All coagulation and biochemistry parameters were normal over the whole treatment period. She experienced grade 1 cytokine-release syndrome and grade 1 central nervous system toxicities. Bone marrow MM cells were not detected by multicolor flow cytometry with CD138 staining 30 days after CAR-T cell infusion (Fig. 3D). Serum monoclonal protein became undetectable at 4 months postinfusion and remained undetectable until now (Fig. 3B). She also had an ongoing stringent CR at 36 months with MRD-negative bone marrow, as determined by flow cytometry, without any anti-myeloma treatment.\n\nFigure 3 Measures of multiple myeloma burden and clinical responses to infusions of anti-BCMA chimeric antigen receptor T (CAR-T) cells of case 2. (A) A total of 4 hours after the second day of CAR-BCMA infusion, the patient became febrile. She was febrile for 13 days. The plot shows the maximum temperature for each day. The levels of IL-6 and CRP were elevated. (B) Panel B shows the trend in IgG and M spike concentrations after treatment with anti-BCMA CAR-T cell infusion. (C) Bone marrow cells contained 1.75% plasma cells as shown by CD38 staining at 10 days before the anti-BCMA CAR-T cell infusion. BCMA expression per flow cytometry showed uniform BCMA expression on CD38-positive malignant plasma cells before the anti-BCMA CAR-T cell infusion. (D) No plasma cells were found among the bone marrow cells on day 30 after anti-BCMA CAR-T cell infusion. BCMA = B-cell maturation antigen, CRP = C-reactive protein, IL = interleukin, SSC-A = side scatter area.\n\n3 Discussion\n\nThe 2 patients with RRMM achieved stringent CR after the infusion of anti-BCMA CAR-T cells, with an EFS duration of >36 months, without any anti-myeloma treatment, that is likely to continue. So far, the longest median progression-free survival reported in the literature was 15 months.[1,2] Anti-BCMA CAR-T cell therapies have shown impressive anti-myeloma activities, but relapse is still inevitable in most patients. The underlying mechanisms of relapse in patients with MM treated with anti-BCMA CAR-T cells may be due to T cell-related, tumor-related, and microenvironmental factors.[1] The treatment efficacy was found to mainly correlate with the dose of CAR+ T cells infused and the degree of in vivo expansion after CAR-T cells therapy in MM.[5–7]\n\nOur patients achieved longer EFS, which may be related to several factors. First, they had fewer early lines of treatment, causing less damage to T cell function. Published data have shown that the number of median prior lines of treatment in all RRMM patients exceeded 3 before they were treated with anti-BCMA CAR-T cells,[1] whereas our 2 patients received only 2 previous lines of treatment. Research has shown that cancer and its treatment can hamper T cell fitness,[7] and starting the manufacturing process from fitter T cells may prolong in vivo CAR-T cell persistence, possibly limiting BCMA+ relapses.[1] In addition, in patients with MM who receive fewer early treatments, the number of early memory T cells may be higher.[8] There is initial evidence that there is a preferential transduction of the CAR in early memory cells (eg, P-Bcma-101).[9] In all current clinical studies of anti-BCMA CAR-T cell therapy for RRMM, the one with the fewest median previous treatment lines obtained the highest CR rate (74%) and the longest median EFS (15 months).[1,2] Second, lymphodepleted chemotherapy was more intense, although lymphodepletion was not necessary to obtain responses and CAR-T expansion. Lymphodepleted patients showed better CAR-T cell kinetics and outcomes.[6] The lack of competition by other lymphocytes allows CAR-T cell expansion and persistence.[10] In a recent report, a higher intensity of fludarabine-cyclophosphamide lymphodepletion correlated with the progression-free survival of non-Hodgkin lymphoma patients treated with anti-CD19 CAR-T cells.[11] Shi et al[12] investigated that more intense lymphodepletion protocols may support better CAR-T cell expansion. The combination of cyclophosphamide and fludarabine was used to deplete lymphocytes in our study, the dosage was higher than that in other studies, and the peripheral lymphocyte count of the 2 patients was very low (0.11 × 109 cells/L and 0.16 × 109 cells/L, respectively) before infusion, which provides better conditions for the proliferation of anti-BCMA CAR-T cells. Third, compared with other patients, larger doses of anti-BCMA CAR-T cells were infused into the 2 patients. According to reports in the literature, multiple studies have shown that the amount of cells infused was positively correlated with the therapeutic effect.[5,6] Finally, the low tumor burden of the 2 patients may be beneficial to their outcomes, although no studies have shown that the treatment efficacy of anti-BCMA CAR-T cells was related to MM tumor burden. Another study has shown that the treatment efficacy of CAR19/22 T cell cocktail therapy in patients with refractory/relapsed B cell malignancies was found to correlate with tumor burden.[13] These are speculations combined with findings from the literature, and the exact mechanism needs further basic and clinical research.\n\nAt present, most patients have undergone at least 3 lines of previous treatment before anti-BCMA CAR-T cells treatment, with a maximum of 29 lines.[1] Heavily pretreated patients are usually multidrug refractory and show aggressive patterns of relapse. In this context, clinical deterioration may preclude the actual CAR-T cell infusion.[6] Ongoing trials are looking at the efficacy of CAR-T cell therapy in earlier lines of treatment,[1] which is given as second-line treatment in high-risk patients who have had either early relapse or suboptimal responses to first-line therapy. CAR-T cell therapy allows some patients treatment-free intervals, when they often enjoy a high quality of life without therapy-related toxicities. We look forward to more patients with RRMM, like our 2 patients, achieving longer EFS with CAR-T cell treatment.\n\nAcknowledgments\n\nThe authors thank all members of the study team, the patient, and their family, and Wuhan Bio-Raid Biotechnology Co., LTD.\n\nAuthor contributions\n\nJ.X analyzed the data and wrote the manuscript. XM and BX Took care of the patient, C.W conducted the flow cytometry. YX revised the manuscript and was in charge of the final approval of the manuscript. J.X, XM and YX performed the experiments. YX conceived and designed the study. All authors read and approved the final manuscript.\n\nConceptualization: Jinhuan Xu, Yi Xiao.\n\nData curation: Jinhuan Xu, Xi Ming, Chunyan Wang.\n\nFormal analysis: Xi Ming.\n\nFunding acquisition: Jinhuan Xu, Yi Xiao.\n\nInvestigation: Xi Ming, Chunyan Wang.\n\nProject administration: Jinhuan Xu, Chunyan Wang, Bi Xu, Yi Xiao.\n\nSupervision: Bi Xu.\n\nVisualization: Xi Ming, Bi Xu.\n\nWriting – review & editing: Jinhuan Xu.\n\nSupplementary Material\n\nSupplemental Digital Content\n\nAbbreviations: BCMA = B-cell maturation antigen, CAR = chimeric antigen receptor, CR = complete remission, EFS = event-free survival, MM = multiple myeloma, MRD = minimal residual disease, RRMM = relapsed/refractory multiple myeloma.\n\nHow to cite this article: Xu J, Ming X, Wang C, Xu B, Xiao Y. Long event-free survival after anti-BCMA CAR-T cell treatment for relapsed and refractory multiple myeloma patients: Two case reports. Medicine. 2021;100:18(e25784).\n\nFunding: This article is supported by grants from the National Science Foundation of China (Grant No. Grant No. 81400147 &81873446),\n\nAvailability of data and materials: The datasets supporting the conclusions of this article are included within the article and additional files.\n\nEthics approval and consent to participate: This study was approved by the Medical ethics committee of the Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (TJ-IRB20160315). The patients gave their written informed consent in accordance with the Declaration of Helsinki. This study is registered at www.chictr.org.cn as ChiCTR-OPC-16009113.\n\nConsent for publication: The authors have obtained consent to publish from the participants to report individual patient data.\n\nThe authors report no conflicts of interest.\n\nThe datasets generated during and/or analyzed during the present study are available from the corresponding author on reasonable request.\n\nSupplemental digital content is available for this article.\n==== Refs\nReferences\n\n[1] D’Agostino M Raje N . Anti-BCMA CAR T-cell therapy in multiple myeloma: can we do better? Leukemia 2020;34 :21–34.31780814\n[2] Zhao W-H Liu J Wang B-Y . A phase 1, open-label study of LCAR-B38 M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. J Hematol Oncol 2018;11 :141.30572922\n[3] Durie BG Harousseau JL Miguel JS . International uniform response criteria for multiple myeloma. Leukemia 2006;20 :1467–73.16855634\n[4] Xu J Wang Q Xu H . Anti-BCMA CAR-T cells for treatment of plasma cell dyscrasia: case report on POEMS syndrome and multiple myeloma. J Hematol Oncol 2018;11 :128.30348186\n[5] Brudno JN Maric I Hartman SD . T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poorprognosis relapsed multiple myeloma. J Clin Oncol 2018;36 :2267–80.29812997\n[6] Raje N Berdeja J Lin Y . Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med 2019;380 :1726–37.31042825\n[7] Das RK Vernau L Grupp SA . Naïve T-cell deficits at diagnosis and after chemotherapy impair cell therapy potential in pediatric cancers. Cancer Discov 2019;9 :492–9.30630850\n[8] Dancy E Garfall AL Cohen AD . Clinical predictors of T cell fitness for CAR T cell manufacturing and efficacy in multiple myeloma. Blood 2018;132 :1886.\n[9] Gregory T Cohen AD Costello CL . Efficacy. and safety of P-Bcma-101 CAR-T cells in patients with relapsed/refractory (r/r) multiple myeloma (MM). Blood 2018;132 :1012.\n[10] McLellan AD Ali Hosseini Rad SM . Chimeric antigen receptor T cell persistence. and memory cell formation. Immunol Cell Biol 2019;97 :664–74.31009109\n[11] Hirayama AV Gauthier J Hay KA . The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells. Blood 2019;133 :1876–87.30782611\n[12] Shi X Yan L Shang J . Tandom autologous transplantation and combined infusion of CD19 and Bcma-specific chimeric antigen receptor T cells for high risk MM: initial safety and efficacy report from a clinical pilot study. Blood 2018;132 :1009.\n[13] Wang N Hu X Cao W . Efficacy and safety of CAR19/22 T-cell cocktail therapy in patients with refractory/relapsed B-cell malignancies. Blood 2020;135 :17–27.31697824\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "100(18)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D053301:B-Cell Maturation Antigen; D001853:Bone Marrow; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009364:Neoplasm Recurrence, Local; D000076962:Receptors, Chimeric Antigen; D016896:Treatment Outcome",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e25784",
"pmc": null,
"pmid": "33950974",
"pubdate": "2021-05-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30348186;30782611;31009109;31042825;30630850;31780814;31697824;30572922;29812997;16855634",
"title": "Long event-free survival after anti-BCMA CAR-T cell treatment for relapsed and refractory multiple myeloma patients: Two case reports.",
"title_normalized": "long event free survival after anti bcma car t cell treatment for relapsed and refractory multiple myeloma patients two case reports"
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"companynumb": "CN-TAKEDA-2021TUS030915",
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{
"abstract": "BACKGROUND\nWe aimed to investigate whether patient self-evaluated symptoms transmitted via Internet is feasible between planned visits to provide an early management of fever and neutropenia induced by chemotherapy, and if it can reduce hospitalizations for severe neutropenia.\n\n\nMETHODS\nPatients who received a chemotherapy regimen with an overall risk of febrile neutropenia ≥ 20% had to report daily temperature between physician planned visits using a web application. Fever and clinical signs of seriousness were reported to the physician (if some criteria were fulfilled in a specific algorithm) via automatic email notifications by the web application. Patients could be hospitalized quickly or could take over at home, make blood count, and take predefined oral antibiotics if indicated. Primary outcome was patient's compliance and satisfaction. The number and the cost of hospitalization were also assessed and compared with an historical cohort of patients with similar clinical conditions and treatment.\n\n\nRESULTS\nAmong the 41 patients included, 36 (87.8%) used the web application with 88% of daily compliance and 90% (28/33) of satisfaction. One patient (2.7%) had planned hospitalization after the web application alert. In the historical cohort, the rate of unplanned hospitalization for febrile neutropenia was 17% (6 patients) and 2.7% (1 patient) in users of the web application cohort. The cumulative cost of hospitalization for neutropenia was USD 28,827 in the historical cohort and USD 6563 in the web application cohort.\n\n\nCONCLUSIONS\nWeb-mediated follow-up of febrile neutropenia is feasible. It led to high patient satisfaction, high compliance, and a possible reduction of the number and the cost of hospitalizations.",
"affiliations": "Institut Inter-régional de Cancérologie Jean Bernard, 9 rue Beauverger, Le Mans, France. f.denis@cjb72.org.;Institut Inter-régional de Cancérologie Jean Bernard, 9 rue Beauverger, Le Mans, France.;Institut Inter-régional de Cancérologie Jean Bernard, 9 rue Beauverger, Le Mans, France.;Institut Inter-régional de Cancérologie Jean Bernard, 9 rue Beauverger, Le Mans, France.;Institut de Cancérologie de l'Ouest Paul Papin, 15 rue A Boquel, 49100, Angers, France.;Institut Inter-régional de Cancérologie Jean Bernard, 9 rue Beauverger, Le Mans, France.",
"authors": "Denis|Fabrice|F|http://orcid.org/0000-0002-2190-7782;Voog|Eric|E|;Pointreau|Yoann|Y|;Bourgeois|Hugues|H|;Seegers|Valérie|V|;Le Du|Katell|K|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-018-4505-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "27(6)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Chemotherapy; Clinical trial; Neutropenia; e-health",
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D064147:Febrile Neutropenia; D005260:Female; D006801:Humans; D020407:Internet; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D057566:Self Report; D017216:Telemedicine; D055815:Young Adult",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "2189-2194",
"pmc": null,
"pmid": "30306327",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "15908666;16575919;17634496;21258094;22511682;23995815;24414998;25800768;25811297;26644527;27233367;28423407;28437150",
"title": "Prospective study of a web-mediated management of febrile neutropenia related to chemotherapy (Bioconnect).",
"title_normalized": "prospective study of a web mediated management of febrile neutropenia related to chemotherapy bioconnect"
} | [
{
"companynumb": "FR-JNJFOC-20190541279",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"d... |
{
"abstract": "A regimen of escalating doses of thalidomide, in combination with bortezomib and high-dose melphalan (mel/vel/thal), was evaluated as a conditioning regimen for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) patients with a prior transplant who had relapsed or achieved less than a complete remission following a prior ASCT. Thalidomide was dose escalated starting from 600 mg to 1000 mg on days -5 to -1 in a 3 × 3 design, bortezomib was administered at 1.6 mg/m2 intravenously on days -4 and -1 and melphalan 200 mg/m2 was administered on day -2. No dose-limiting toxicity was seen in the phase I portion of the trial. An additional 20 patients were enrolled at the maximum tolerated dose of thalidomide of 1000 mg daily. The overall response rate was 69% with 38% complete remission. Median PFS and OS were 9.3 and 65.4 months, respectively, with a median follow-up of 17.8 months. The most common grade 3-4 adverse events (AEs) were neutropenic fever (58.6%), mucositis (6.9%), and diarrhea (6.9%). Serious AEs included somnolence (13.8%) and tumor lysis syndrome (3.4%). The addition of high-dose thalidomide to bortezomib and melphalan as conditioning for salvage ASCT was well tolerated and was an effective conditioning regimen.",
"affiliations": "John Theurer Cancer Center at Hackensack Meridian, Seton Hall University School of Medicine, Hackensack, NJ, USA. Noa.Biran@hackensackmeridian.org.;John Theurer Cancer Center at Hackensack Meridian, Seton Hall University School of Medicine, Hackensack, NJ, USA.;John Theurer Cancer Center at Hackensack Meridian, Seton Hall University School of Medicine, Hackensack, NJ, USA.;University of Minnesota School of Medicine, Minneapolis, MN, USA.;John Theurer Cancer Center at Hackensack Meridian, Seton Hall University School of Medicine, Hackensack, NJ, USA.;Novant Health, Charlotte, NC, USA.;Icahn School of Medicine at Mount Sinai, New York, NY, USA.;John Theurer Cancer Center at Hackensack Meridian, Seton Hall University School of Medicine, Hackensack, NJ, USA.;John Theurer Cancer Center at Hackensack Meridian, Seton Hall University School of Medicine, Hackensack, NJ, USA.",
"authors": "Biran|Noa|N|;Rowley|Scott D|SD|;Vesole|David H|DH|;Zhang|Shijia|S|0000-0002-7423-9255;Donato|Michele L|ML|;Skarbnik|Alan P|AP|;Richter|Joshua|J|;Pecora|Andrew|A|;Siegel|David S|DS|",
"chemical_list": "D013792:Thalidomide; D000069286:Bortezomib; D008558:Melphalan",
"country": "England",
"delete": false,
"doi": "10.1038/s41409-019-0534-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "54(11)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D064592:Autografts; D000069286:Bortezomib; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D015996:Survival Rate; D013792:Thalidomide; D019172:Transplantation Conditioning",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "1881-1891",
"pmc": null,
"pmid": "31101891",
"pubdate": "2019-11",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "A phase I/II study of escalating doses of thalidomide in conjunction with bortezomib and high-dose melphalan as a conditioning regimen for autologous stem cell transplantation in patients with multiple myeloma.",
"title_normalized": "a phase i ii study of escalating doses of thalidomide in conjunction with bortezomib and high dose melphalan as a conditioning regimen for autologous stem cell transplantation in patients with multiple myeloma"
} | [
{
"companynumb": "US-TAKEDA-2019TUS032913",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Metronidazole can produce neurological complications although it is not a common scenario. We present a case where a patient developed features of encephalopathy following prolonged metronidazole intake. Magnetic resonance imaging (MRI) brain showed abnormal signal intensity involving both dentate nuclei of cerebellum and splenium of corpus callosum. The diagnosis of metronidazole toxicity was made by the MRI findings and supported clinically.",
"affiliations": "Department of General Medicine, IPGMER, Kolkata, West Bengal, India. subratachakrabarti2011@gmail.com.",
"authors": "Chakrabarti|Subrata|S|;Pan|Koushik|K|",
"chemical_list": "D000890:Anti-Infective Agents; D008795:Metronidazole",
"country": "New Zealand",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-8446",
"issue": "127(1393)",
"journal": "The New Zealand medical journal",
"keywords": null,
"medline_ta": "N Z Med J",
"mesh_terms": "D000328:Adult; D000890:Anti-Infective Agents; D001927:Brain Diseases; D003937:Diagnosis, Differential; D003967:Diarrhea; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008795:Metronidazole; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0401067",
"other_id": null,
"pages": "120-2",
"pmc": null,
"pmid": "24816962",
"pubdate": "2014-05-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metronidazole-induced encephalopathy: an uncommon scenario.",
"title_normalized": "metronidazole induced encephalopathy an uncommon scenario"
} | [
{
"companynumb": "IN-BAUSCH-SYM-2014-23176",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Azacitidine has become an available therapy for high-risk myelodysplastic syndromes. Infectious complications (IC) may impede the success of therapy. Since most patients are managed in an outpatient setting, often with low level of clinical and microbiological documentation, the impact of IC remains unclear. We retrospectively evaluated the clinical course of 77 patients with MDS treated with azacitidine between 2004 and 2015 (median age 69 years). Clinical workup included severity and type of IC, days in the hospital and with antimicrobial therapy, response to azacitidine, and overall survival (OS). In total, 614 azacitidine cycles were administered, 81 cycles with at least one IC. The median number of administered cycles was 6 (range 1-43). Median OS after the start of azacitidine was 17 months (range 1-103). Infection rates were higher in the first 3 cycles with bacterial infections leading. The better patients' hematological response to azacitidine with less IC occurred, and fewer days with antimicrobial treatment were needed. Compared to progressive disease, stable disease made no significant improvement in occurrence of IC and days in the hospital. Older age was associated with more IC and longer time in the hospital. Comorbidities or IPSS-R had no influence on IC. The incidence of IC correlated with hematological response and age. Stable disease led to longer OS, but incidence of IC was comparable to progressive disease and survival seemed to be bought by a considerable number of IC. IC rates were highest in the first 3 cycles. We recommend response evaluation after 4-6 cycles.",
"affiliations": "Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany. Anna.Schuck@med.uni-duesseldorf.de.;Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.;Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.;Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.;Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.;Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.;Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.;Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.;Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Moorenstraße 5, 40225, Düsseldorf, Germany.",
"authors": "Schuck|Anna|A|;Goette|Marie-Christine|MC|;Neukirchen|Judith|J|;Kuendgen|Andrea|A|;Gattermann|Norbert|N|;Schroeder|Thomas|T|;Kobbe|Guido|G|;Germing|Ulrich|U|;Haas|Rainer|R|",
"chemical_list": "D000890:Anti-Infective Agents; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-017-3001-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "96(7)",
"journal": "Annals of hematology",
"keywords": "Azacitidine; Clinical course; Infectious complications; Myelodysplastic syndromes",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000890:Anti-Infective Agents; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D001424:Bacterial Infections; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D017063:Outcome Assessment, Health Care; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1097-1104",
"pmc": null,
"pmid": "28474144",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A retrospective study evaluating the impact of infectious complications during azacitidine treatment.",
"title_normalized": "a retrospective study evaluating the impact of infectious complications during azacitidine treatment"
} | [
{
"companynumb": "DE-CELGENEUS-DEU-20170503346",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "Hypogonadism is a known late effect of cancer treatment. Hypogonadism requires replacement of sex steroids to ensure appropriate development of secondary sex characteristics, growth, and other beneficial health effects. We present a cancer survivor with hypogonadotropic hypogonadism and gender dysphoria. The patient received gender affirming care in our gender clinic with a multidisciplinary team that included an endocrinologist. This is not an isolated case at our institution. Survivorship oncologists must include a discussion about gender concurrently with conversations about survivors' development of puberty. Conversations should start early to ensure appropriate referrals and gender affirming hormone replacement.",
"affiliations": "Department of Hematology/Oncology, Seattle Children's Hospital, Seattle, Washington.;Department of Endocrinology, Seattle Children's Hospital, Seattle, Washington.;Department of Gender Clinic, Seattle Children's Hospital, Seattle, Washington.;Department of Endocrinology, Seattle Children's Hospital, Seattle, Washington.",
"authors": "Barthel|Erin M|EM|;Werny|David M|DM|;Hayden|Lara L|LL|;Salehi|Parisa|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/jayao.2019.0070",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2156-5333",
"issue": "9(1)",
"journal": "Journal of adolescent and young adult oncology",
"keywords": "gender; gender dysphoria; gender identity; hormone; hypogonadism; survivor",
"medline_ta": "J Adolesc Young Adult Oncol",
"mesh_terms": "D000293:Adolescent; D000073116:Cancer Survivors; D020249:Hormone Replacement Therapy; D006801:Humans; D007006:Hypogonadism; D008297:Male; D009369:Neoplasms",
"nlm_unique_id": "101543508",
"other_id": null,
"pages": "128-131",
"pmc": null,
"pmid": "31580768",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gender Affirming Hormone Replacement for the Adolescent and Young Adult Cancer Survivor with Hypogonadism.",
"title_normalized": "gender affirming hormone replacement for the adolescent and young adult cancer survivor with hypogonadism"
} | [
{
"companynumb": "US-TEVA-2020-US-1208952",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Primary myelofibrosis is a clonal disease of chronic myeloproliferative neoplasm, and is a progressive clinical course with short median survival of less than 5 years after diagnosis. Leukemic transformation occurs in 8-23 % of myelofibrosis patients, and survival is about 3 months after transformation to leukemia. Thalidomide, an oral immunomodulatory drug, has been used effectively in the treatment of primary myelofibrosis, in which some patients could become transfusion independent, and showed improvement in thrombocytopenia and reduction in spleen size. Here, we report a patient with primary myelofibrosis with leukemic transformation who survived for more than 6 years with thalidomide monotherapy. Thalidomide may be beneficial for some myelofibrosis patients with leukemic transformation for whom intensive chemotherapy is not indicated.",
"affiliations": "Department of Laboratory Medicine, Division of Clinical Pathology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.",
"authors": "Huang|Wei-Han|WH|;Li|Ming-Shing|MS|;Chu|Sung-Chao|SC|;Wang|Tso-Fu|TF|;Kao|Ruey-Ho|RH|;Wu|Yi-Feng|YF|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D007166:Immunosuppressive Agents; D013792:Thalidomide",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-013-1478-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "99(2)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D020533:Angiogenesis Inhibitors; D001853:Bone Marrow; D002471:Cell Transformation, Neoplastic; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007166:Immunosuppressive Agents; D015470:Leukemia, Myeloid, Acute; D008297:Male; D055728:Primary Myelofibrosis; D012074:Remission Induction; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "188-92",
"pmc": null,
"pmid": "24307514",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18508796;11372731;11972510;16990762;14560783;17460705;15388582;11815715;2042444;23391517;17230228;19141119;8704209;18404742;9488952;11417486;7513432;11071630;9301478;12517815;3050294;10561375;16826578;620081;16583431;14752066",
"title": "Thalidomide treatment in a myelofibrosis patient with leukemia transformation.",
"title_normalized": "thalidomide treatment in a myelofibrosis patient with leukemia transformation"
} | [
{
"companynumb": "TW-FRESENIUS KABI-FK201504809",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MITOXANTRONE HYDROCHLORIDE"
},
"drugaddi... |
{
"abstract": "In this report, we present a case of acquired copper deficiency which initially presented as progressive pain and numbness in the patient's lower extremities. The acquired copper deficiency is attributed to a previous bariatric surgery exacerbated by zinc toxicity. A 42-year-old female with a past medical history of type 2 diabetes mellitus, anemia, hypertension, bipolar disorder, attention deficit disorder, pulmonary embolus, fibromyalgia, migraine headaches, and chronic pain as well as a remote past surgical history of gastric bypass procedure presented with progressive pain and numbness in her lower extremities. The patient reported chronic use of zinc supplements. Clinical evaluation revealed abnormal neurologic exam consistent with a myeloneuropathy and anemia. A cervical spine MRI showed increased signal intensity primarily affecting the posterior columns from C2-C6. Laboratory studies confirmed low copper, low ceruloplasmin, and elevated zinc levels. This case is an example of acquired copper deficiency due to previous bariatric surgery exacerbated by zinc ingestion. With an increased prevalence of bariatric surgery, it is important to monitor patients postoperatively for neurologic symptoms potentially due to copper deficiency.",
"affiliations": "University of South Dakota Sanford School of Medicine.;Regional Health Neurology and Rehabilitation, Rapid City, South Dakota.",
"authors": "Draine|Jillian|J|;Simmons|Matthew|M|",
"chemical_list": "D003300:Copper; D015032:Zinc",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0038-3317",
"issue": "73(4)",
"journal": "South Dakota medicine : the journal of the South Dakota State Medical Association",
"keywords": null,
"medline_ta": "S D Med",
"mesh_terms": "D000328:Adult; D050110:Bariatric Surgery; D003300:Copper; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D009422:Nervous System Diseases; D009460:Neurologic Examination; D015032:Zinc",
"nlm_unique_id": "101265265",
"other_id": null,
"pages": "178-180",
"pmc": null,
"pmid": "32445306",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Copper Deficiency Myeloneuropathy Precipitated by Zinc Ingestion and Bariatric Surgery.",
"title_normalized": "a case of copper deficiency myeloneuropathy precipitated by zinc ingestion and bariatric surgery"
} | [
{
"companynumb": "US-TEVA-2020-US-1839611",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPHETAMINE\\DEXTROAMPHETAMINE"
},
"drugadditio... |
{
"abstract": "Acute graft-vs-host disease (aGVHD) is a rare but deadly complication after liver transplantation (LT). It occurs when donor immunocompetent cells transplanted with the liver allograft repopulate and recognize recipient antigens as foreign and mount an alloreactive response. aGVHD patients can present with skin rash, fever, diarrhea, and pancytopenia. These nonspecific symptoms are usually misleading, delaying the diagnosis of aGVHD. Here, we present a patient who developed severe aGVHD after LT, with neurogenic symptoms as the first manifestation. Symptoms including fever, skin rash, diarrhea, and pancytopenia appeared several days later. A skin biopsy revealed dermal lymphocyte infiltration. A bone marrow chimerism test showed 99.87% liver donor cells. The patient was treated with high doses of methylprednisolone (360 mg a day), Rabbit anti-T lymphocyte immunoglobulin (300 mg per day), and antithymocyte globulin (40 mg per day). Unfortunately, the patient died of multiple organ failure at 47 days after transplantation. To our knowledge, this is the first case of aGVHD after LT with neurogenic symptoms as the single primary manifestation and also with the highest level of donor cells (>99%) in bone marrow chimerism test ever reported.",
"affiliations": "Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China.;Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China.;Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China.;Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China.;Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China.;Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China.;Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, China. Electronic address: liangtingbo@zju.edu.cn.",
"authors": "Chen|W|W|;Ma|T|T|;Bai|X|X|;Zhang|X|X|;Li|G|G|;Lao|M|M|;Liang|T|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.05.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "50(10)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000208:Acute Disease; D003221:Confusion; D017809:Fatal Outcome; D006086:Graft vs Host Disease; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D014202:Tremor",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "4028-4032",
"pmc": null,
"pmid": "30577308",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Graft-vs-Host Disease After Liver Transplantation in a Patient Presenting With Neurogenic Symptoms as the Single Primary Manifestation: A Case Report.",
"title_normalized": "acute graft vs host disease after liver transplantation in a patient presenting with neurogenic symptoms as the single primary manifestation a case report"
} | [
{
"companynumb": "CN-SAKK-2018SA394315AA",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "2",
... |
{
"abstract": "A 64-year-old Japanese woman with diabetes mellitus was admitted for hypoglycemia. Her diabetes had been under good control with glimepiride, voglibose, exenatide, and metformin for a few years. Although overt proteinuria was observed, the serum creatinine values were within normal range during the routine outpatient follow-up. Hypoglycemic attack caused by glimepiride and loss of appetite by urinary tract infection were diagnosed. Then, metformin-associated lactic acidosis with acute renal failure caused by dehydration was detected.\n\n\n\nHer condition was improved by continuous veno-venous hemodiafiltration and hemodialysis, known to be useful to remove metformin.\n\n\n\nWe reported a case of metformin-associated lactic acidosis with hypoglycemia during routine treatment of diabetes that was successfully rescued by early renal replacement therapy.",
"affiliations": "Department of Diabetes, Metabolism and Endocrinology Mie University Graduate School of Medicine Tsu Japan.;Department of Diabetes and Endocrinology Mie University Hospital Tsu Japan.;Department of Diabetes and Endocrinology Mie University Hospital Tsu Japan.;Department of Diabetes and Endocrinology Mie University Hospital Tsu Japan.;Department of Diabetes and Endocrinology Mie University Hospital Tsu Japan.;Department of Diabetes, Metabolism and Endocrinology Mie University Graduate School of Medicine Tsu Japan.;Department of Immunology Mie University Graduate School of Medicine Tsu Japan.;Department of Diabetes and Endocrinology Mie University Hospital Tsu Japan.;Department of Diabetes and Endocrinology Mie University Hospital Tsu Japan.;Department of Cardiology and Nephrology Mie University Graduate School of Medicine Tsu Japan.;Department of Diabetes, Metabolism and Endocrinology Mie University Graduate School of Medicine Tsu Japan.;Department of Immunology Mie University Graduate School of Medicine Tsu Japan.;Department of Cardiology and Nephrology Mie University Graduate School of Medicine Tsu Japan.;Department of Gastroenterology and Hepatology Mie University Graduate School of Medicine Tsu Japan.",
"authors": "Nishihama|Kota|K|;Maki|Kanako|K|;Okano|Yuko|Y|;Hashimoto|Rei|R|;Hotta|Yasuhiro|Y|;Uemura|Mei|M|;Yasuma|Taro|T|;Suzuki|Toshinari|T|;Hayashi|Toyomi|T|;Ishikawa|Eiji|E|;Yano|Yutaka|Y|;Gabazza|Esteban C|EC|;Ito|Masaaki|M|;Takei|Yoshiyuki|Y|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1002/ams2.233",
"fulltext": "\n==== Front\nAcute Med SurgAcute Med Surg10.1002/(ISSN)2052-8817AMS2Acute Medicine & Surgery2052-8817John Wiley and Sons Inc. Hoboken 10.1002/ams2.233AMS2233Case ReportCase ReportsA case of type 2 diabetes mellitus with metformin‐associated lactic acidosis initially presenting the appearance of a sulfonylurea‐related hypoglycemic attack K. Nishihama et al.Nishihama Kota kn2480@gmail.com \n1\nMaki Kanako \n2\nOkano Yuko \n2\nHashimoto Rei \n2\nHotta Yasuhiro \n2\nUemura Mei \n1\nYasuma Taro \n3\nSuzuki Toshinari \n2\nHayashi Toyomi \n2\nIshikawa Eiji \n4\nYano Yutaka \n1\nGabazza Esteban C. \n3\nIto Masaaki \n4\nTakei Yoshiyuki \n5\n\n1 \nDepartment of Diabetes, Metabolism and Endocrinology\nMie University Graduate School of Medicine\nTsu\nJapan\n\n2 \nDepartment of Diabetes and Endocrinology\nMie University Hospital\nTsu\nJapan\n\n3 \nDepartment of Immunology\nMie University Graduate School of Medicine\nTsu\nJapan\n\n4 \nDepartment of Cardiology and Nephrology\nMie University Graduate School of Medicine\nTsu\nJapan\n\n5 \nDepartment of Gastroenterology and Hepatology\nMie University Graduate School of Medicine\nTsu\nJapan\n* Corresponding: Kota Nishihama, MD, Department of Diabetes, Metabolism and Endocrinology, Mie University Graduate School of Medicine, 2‐174 Edobashi, Tsu, Mie 514‐8507, Japan. E‐mail: kn2480@gmail.com.03 8 2016 1 2017 4 1 10.1002/ams2.2017.4.issue-1123 126 22 11 2015 28 6 2016 © 2016 The Authors Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Case\nA 64‐year‐old Japanese woman with diabetes mellitus was admitted for hypoglycemia. Her diabetes had been under good control with glimepiride, voglibose, exenatide, and metformin for a few years. Although overt proteinuria was observed, the serum creatinine values were within normal range during the routine outpatient follow‐up. Hypoglycemic attack caused by glimepiride and loss of appetite by urinary tract infection were diagnosed. Then, metformin‐associated lactic acidosis with acute renal failure caused by dehydration was detected.\n\nOutcome\nHer condition was improved by continuous veno‐venous hemodiafiltration and hemodialysis, known to be useful to remove metformin.\n\nConclusion\nWe reported a case of metformin‐associated lactic acidosis with hypoglycemia during routine treatment of diabetes that was successfully rescued by early renal replacement therapy.\n\nDiabetes mellitushemodialysishypoglycemialactic acidosismetformin source-schema-version-number2.0component-idams2233cover-dateJanuary 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.1 mode:remove_FC converted:02.11.2017[The copyright line for this article was changed on 28 October 2016 after original online publication]\n==== Body\nIntroduction\nMetformin is an antidiabetic agent of the biguanide family used as a first choice medication for type 2 diabetes mellitus. Metformin‐associated lactic acidosis (MALA) is a severe adverse effect of metformin with a mortality rate of 50%.1 Metformin‐associated lactic acidosis may occur with hypoglycemia of 12.2%.2 Here, we report a case of type 2 diabetic mellitus with MALA treated with four hypoglycemic agents, including metformin. Severe hypoglycemia with rapidly progressive lactic acidosis was observed and the patient recovered with continuous veno‐venous hemodiafiltration (CVVHDF) and hemodialysis.\n\nCase\nThe patient was a 64‐year‐old Japanese woman with a 20‐year history of type 2 diabetes mellitus complicated with hypertension, dyslipidemia, and incomplete right paresis caused by cerebral infarction. She had diabetic nephropathy with overt proteinuria and proliferative retinopathy. She has been treated with the following medications: metformin 2,250 mg/day, glimepiride 1 mg/day, voglibose 0.9 mg/day, exenatide 20 μg/day, candesartan 8 mg/day, olmesartan 20 mg/day, amlodipine 5 mg/day, rosuvastatin 2.5 mg/day, tocopherol 600 mg/day, and polaprezinc 150 mg/day. Seven days before admission, her glycated hemoglobin was 5.6% (NGSP), serum creatinine was 0.76 mg/dL, and urinary protein was 1.85 g/g creatinine. She was admitted to Mie University Hospital (Tsu, Japan) because of general fatigue and bilateral leg edema. She complained of mild fever, fatigue, anorexia, and leg edema from 1 week before admission, and the symptoms were getting progressively worse. She was taking metformin and glimepiride until the evening of the day before her hospital visit. The clinical findings on examination were as follows: height, 155 cm; body weight, 77.2 kg; Glasgow Coma Scale, 15; blood pressure, 116/51 mmHg; heart rate, 90 b.p.m.; respiratory rate, 18 breaths/min; body temperature, 36.3°C; and peripheral oxygen saturation (SpO2), 84% (room air). Physical examination showed right costovertebral angle tenderness and bilateral leg pitting edema with tenderness. Laboratory data disclosed a blood glucose level of 42 mg/dL measured with a portable device and then confirmed by an analysis performed at the laboratory of Mie University Hospital; there was also severe renal dysfunction, high levels of C‐reactive protein, and leukocytosis (Table 1). Arterial blood gas analysis showed metabolic acidosis and increased blood lactic acid level. Urinalysis and urinary sediment suggested urinary tract infection (urine culture positive for Escherichia coli). Computed tomography revealed bilateral leg edema. The diagnoses on admission were hypoglycemia, lactic acidosis, urinary tract infection, and dehydration with peripheral circulatory failure‐associated acute renal injury.\n\nTable 1 Laboratory data on admission of a 64‐year‐old woman with type 2 diabetes mellitus and metformin‐associated lactic acidosis\n\nBlood cell count\tBiochemical examination\tArterial blood gas analysis (room air)\t\nWhite blood cells\t16,790/μL\tHbA1c\t6.2%\tpH\t7.182\t\nRed blood cells\t326 × 104/μL\tGlucose\t29 mg/dL\tpCO2\n\t41.9 mmHg\t\nHemoglobin\t9.1 g/dL\tTotal protein\t5.7 g/dL\tpO2\n\t67.5 mmHg\t\nHematocrit\t28.6%\tAlbumin\t3.0 g/dL\tHCO3\n−\n\t15.3 mmol/L\t\nMCV\t87.7 fl\tBUN\t54 mg/dL\tBase excess\t−12.5 mmol/L\t\nMCH\t27.9 pg\tCreatinine\t4.4 mg/dL\tAnion gap\t19.6 mmol/L\t\nPlatelets\t40.4 × 104/μL\tUric acid\t9.2 mg/dL\tLactic acid†\n\t10.3 mmol/L\t\n\t\tNa\t135 mEq/L\t\t\t\nUrinalysis\t\tK\t5.7 mEq/L\tPharmacologic concentration\t\nSpecific gravity\t1.011\tCl\t100 mEq/L\tMetformin\t31.1 μg/mL\t\npH\t5.0\tCa\t8.1 mg/dL\t\t\t\nGlucose\t(−)\tP\t7.7 mg/dL\tInsulin secretion\t\nProtein\t(+)\tAST\t13 U/L\tSerum C‐peptide‡\n\t4.5 ng/mL\t\nKetone body\t(−)\tALT\t7 U/L\tGlucose‡\n\t95 mg/dL\t\nBlood\t(2+)\tLDH\t201 U/L\t\t\t\n\t\tγ‐GTP\t18 U/L\t\t\t\nUrine sediment\t\tALP\t327 U/L\t\t\t\nRed blood cells\t1–4/HPF\tT‐Bil\t0.2 mg/dL\t\t\t\nWhite blood cells\t≥100/HPF\tCRP\t33.76 mg/dL\t\t\t\nBacteria§\n\t(3+)\t\t\t\t\t\n†Normal range of blood lactate level, 0.9–1.7 mmol/L. ‡Measured 7 days before admission (random blood glucose). §Urine culture isolated Escherichia coli. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; Cl, chloride; CRP, C‐reactive protein; γ‐GTP, γ‐glutamyl transferase; HbA1c, glycated hemoglobin; HPF, high power field; K, potassium; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; Na, sodium; P, phosphorus; T‐Bil, total bilirubin.\n\nJohn Wiley & Sons, LtdAfter admission, the patient was treated with i.v. fluid, bicarbonate, and ceftriaxone. However, despite i.v. fluid (2,000 mL/8 h) and bicarbonate therapy, no improvement in lactic acidosis or oliguria was observed. Therefore, the patient was first treated with CVVHDF. Her condition improved after 16 h of CVVHDF, and hemodialysis were subsequently undertaken for 3 h. These treatments improved lactic acidosis, renal function, and the acid‐based disturbance (Fig. 1). The plasma metformin concentration on admission was 31.1 μg/mL, which is approximately 10‐fold higher than the concentration observed in patients taking regular doses (850 mg) of metformin.3 After recovery from MALA and urinary tract infection, the patient was discharged on day 30 with the therapeutic indication of insulin glargine (10 units/day) and vildagliptin (50 mg/day).\n\nFigure 1 Clinical course after admission of a 64‐year‐old woman with type 2 diabetes mellitus and metformin‐associated lactic acidosis. Blood lactic acid level, acidosis, and serum creatinine level were ameliorated by renal replacement therapy. CLDM, clindamycin; CTRX, ceftriaxone; CVVHDF, continuous veno‐venous hemodiafiltration; DBP, diastolic blood pressure; HD, hemodialysis; SBP, systolic blood pressure.\n\nDiscussion\nMetformi‐associatedlactic acidosis is a rare but a life‐threatening adverse effect of metformin; the reported mortality rate of MALA is approximately 50%.1 A recent report suggested that the risk of MALA was significantly associated with impaired renal function and high dosage of metformin.4 Prescribing information for metformin also warns that renal insufficiency, dehydration, and hypoxemia may cause MALA.3 The mechanism of MALA is still not clear. It is assumed that metformin induces lactic acid accumulation by an intracellular shift in oxidation‐reduction reactions from aerobic to anaerobic metabolism. Accumulation of lactic acid reduces intracellular pH that inhibits pyruvate carboxylase and dehydrogenase, leading to increased lactic acid accumulation.5 Disturbed insulin secretion and action may worsen this pathological state.\n\nThis case presented many risk factors for MALA. The high blood levels of metformin observed in the current case could be explained by the high dose of metformin and possible overestimation of the patient's renal function based on the serum creatinine level, because of muscular atrophy following cerebral infarction and hemiparesis. Although the body weight of the patient was high, she had multiple comorbidities including diabetes, hypertension, dyslipidemia, and stroke that were probably associated with sarcopenic obesity.6 The angiotensin II receptor antagonist that the patient was receiving may explain the deterioration in renal dysfunction during dehydration. Hypoxia is an aggravating factor of MALA that may be caused by impaired ventilation due to obesity‐associated glossoptosis. In addition, decreased oral intake and continuous use of oral hypoglycemic agents may cause hypoglycemia. Hypoglycemia raises the level of blood lactic acid by increasing blood epinephrine levels7 and glycogenolysis in skeletal muscles.8 Therefore, it is conceivable that MALA had a progressive clinical course due to complicated hypoglycemia.\n\nIn general, MALA is treated by hemodialysis and bicarbonate. Hemodialysis is very useful to remove metformin because of low molecular weight, lack of protein binding, high water solubility, and broad tissue distribution of metformin. Previous reports suggested that hemodialysis improves acid–base imbalance and it is considered the most effective treatment for patients with severe MALA.5, 9, 10 Suggested criteria for implementation of renal replacement therapy in patients with MALA are severe acidosis (pH < 7.1), poor response to standard treatment, and renal insufficiency.9\n\n\nBased on the patient's poor response to initial therapy, we started renal replacement therapy. As her blood pressure was 20% lower than usual, we used CVVHDF to perform dialysis with low blood pressure. The therapy was then changed to hemodialysis in order to increase the removal efficiency of metformin, and after the blood pressure of the patient improved with CVVHDF for 16 h (Fig. 1). After this, the urine volume gradually increased and lactic acidosis was ameliorated by hemodialysis. A previous report has questioned the usefulness of continuous veno‐venous hemofiltration for MALA,11 however, we think that the quick change from CVVHDF to hemodialysis, which has higher removal efficiency, led to the rescue of this patient.\n\nIn conclusion, this is a well‐detailed report of MALA with hypoglycemia during routine treatment of diabetes, rescued by the combined therapy of CVVHDF and hemodialysis. We should take into consideration the diagnosis of MALA when we have a patient treated with metformin, even if the patient shows the appearance of common hypoglycemic attack. Once the diagnosis of MALA is confirmed, renal replacement therapy should be considered as soon as possible. Early diagnosis of MALA and renal replacement therapy is important to rescue MALA patients with sulfonylurea‐related hypoglycemic attack.\n\nConflict of Interest\nNone.\n==== Refs\nReferences\n1 \n\nFriesecke \nS \n, \nAbel \nP \n, \nRoser \nM \n, \nFelix \nSB \n, \nRunge \nS \n. Outcome of severe lactic acidosis associated with metformin accumulation . Crit. Care \n2010 ; 14 : R226 .21171991 \n2 \n\nRenda \nF \n, \nMura \nP \n, \nFinco \nG \n, \nFerrazin \nF \n, \nPani \nL \n, \nLandoni \nG \n. Metformin‐associated lactic acidosis requiring hospitalization. A national 10 year survey and a systematic literature review . Eur. Rev. Med. Pharmacol. Sci. \n2013 ; 17 (Suppl 1 ): 45 –9 .\n3 \nGlucophage‐prescribing information . Bristol‐Mayers Squibb, Princeton, NJ 08543, USA, 2009 .\n4 \n\nEppenga \nWL \n, \nLalmohamed \nA \n, \nGeerts \nAF \n\net al\nRisk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population‐based cohort study . Diabetes Care \n2014 ; 37 : 2218 –24 .24842984 \n5 \n\nKopec \nKT \n, \nKowalski \nMJ \n. Metformin‐associated lactic acidosis (MALA): case files of the Einstein Medical Center medical toxicology fellowship . J. Med. Toxicol. \n2013 ; 9 : 61 –6 .23233435 \n6 \n\nHwang \nB \n, \nLim \nJY \n, \nLee \nJ \n, \nChoi \nNK \n, \nAhn \nYO \n, \nPark \nBJ \n. Prevalence rate and associated factors of sarcopenic obesity in Korean elderly population . J. Korean Med. Sci. \n2012 ; 27 : 748 –55 .22787369 \n7 \n\nDisalvo \nRJ \n, \nBloom \nWL \n, \nBrust \nAA \n, \nFerguson \nRW \n, \nFerris \nEB \n. A comparison of the metabolic and circulatory effects of epinephrine, nor‐epinephrine and insulin hypoglycemia with observations on the influence of autonomic blocking agents . J. Clin. Invest. \n1956 ; 35 : 568 –77 .13319492 \n8 \n\nLaurent \nD \n, \nPetersen \nKF \n, \nRussell \nRR \n, \nCline \nGW \n, \nShulman \nGI \n. Effect of epinephrine on muscle glycogenolysis and insulin‐stimulated muscle glycogen synthesis in humans . Am. J. Physiol. \n1998 ; 274 : E130 –8 .9458758 \n9 \n\nNguyen \nHL \n, \nConcepcion \nL \n. Metformin intoxication requiring dialysis . Hemodial. Int. \n2011 ; 15 (Suppl 1 ): S68 –71 .22093605 \n10 \n\nPeters \nN \n, \nJay \nN \n, \nBarraud \nD \n\net al\nMetformin‐associated lactic acidosis in an intensive care unit . Crit. Care \n2008 ; 12 : R149 .19036140 \n11 \n\nArroyo \nAM \n, \nWalroth \nTA \n, \nMowry \nJB \n, \nKao \nLW \n. The MALAdy of metformin poisoning: is CVVH the cure? \nAm. J .Ther. \n2010 ; 17 : 96 –100 .19433973\n\n",
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"issue": "4(1)",
"journal": "Acute medicine & surgery",
"keywords": "Diabetes mellitus; hemodialysis; hypoglycemia; lactic acidosis; metformin",
"medline_ta": "Acute Med Surg",
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"pages": "123-126",
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"pubdate": "2017-01",
"publication_types": "D002363:Case Reports",
"references": "9458758;13319492;21171991;22787369;22093605;23436666;24842984;23233435;19433973;19036140",
"title": "A case of type 2 diabetes mellitus with metformin-associated lactic acidosis initially presenting the appearance of a sulfonylurea-related hypoglycemic attack.",
"title_normalized": "a case of type 2 diabetes mellitus with metformin associated lactic acidosis initially presenting the appearance of a sulfonylurea related hypoglycemic attack"
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"abstract": "Cryptococcosis is an opportunistic infection caused by the encapsulated yeast Cryptococcus neoformans and most remarkably manifests in HIV-infected individuals, especially in the settings of very low CD4 count. Development of cryptococcosis in HIV-uninfected individuals is exceedingly rare and usually signifies a marked immunodeficiency. Cryptococcosis in association with myasthenia gravis or thymoma has been previously documented in only very few cases in the literature.\n\n\n\nWe reported a complicated case of severe cutaneous cryptococcosis in a 39-year-old Vietnamese male patient with myasthenia gravis on long-term immunosuppressive therapy. The patient presented with a five month history of recurrent and progressive skin lesions that later on progressed into cryptococcal meningitis.\n\n\n\nThrough this case, we aimed to emphasize the importance of including cutaneous cryptococcosis in the differential diagnosis of cutaneous lesions in patients on chronic immunosuppressive therapy. The cutaneous manifestations of cryptococcosis can be the first clue for a disseminated disease, which makes early recognition crucial and life-saving.",
"affiliations": "Department of Infectious Diseases, University of Medicine and Pharmacy at Ho Chi Minh City , Ho Chi Minh city, Vietnam. camhuong37@yahoo.com.;Faculty of Medicine, University of Jordan, Amman, Jordan.;Department of Infectious Diseases, University of Medicine and Pharmacy at Ho Chi Minh City , Ho Chi Minh city, Vietnam.;Department of Infectious Diseases, University of Medicine and Pharmacy at Ho Chi Minh City , Ho Chi Minh city, Vietnam.;Dermatology and Venereology Department, Tanta University Hospital, Tanta, Egypt.;Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt.;Ho Chi Minh City Hospital of Dermatology-Venereology, Ho Chi Minh City, Vietnam.;The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.;The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.;Department of Infectious Diseases, University of Medicine and Pharmacy at Ho Chi Minh City , Ho Chi Minh city, Vietnam.;Department of Neurology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam.;Department of Dermatology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam. vanthetrungdhyd@yahoo.com.",
"authors": "Huong|Nguyen Thi Cam|NTC|;Altibi|Ahmed M A|AMA|;Hoa|Nguyen My|NM|;Tuan|Le Anh|LA|;Salman|Samar|S|;Morsy|Sara|S|;Lien|Nguyen Thi Bich|NTB|;Truong|Nguyen Thanh|NT|;Mai|Nguyen Thi Hoang|NTH|;Hoa|Pham Thi Le|PTL|;Thang|Nguyen Ba|NB|;Trung|Van The|VT|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "England",
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"doi": "10.1186/s12879-017-2415-8",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 241510.1186/s12879-017-2415-8Case ReportProgressive cutaneous Cryptococcosis complicated with meningitis in a myasthenia gravis patient on long-term immunosuppressive therapy – a case report Huong Nguyen Thi Cam camhuong37@yahoo.com 16Altibi Ahmed M. A. ahmed.mt@outlook.com 2Hoa Nguyen My myhoa163@gmail.com 16Tuan Le Anh tuanlee2511@gmail.com 16Salman Samar Samarsalman26@gmail.com 3Morsy Sara saram.morsy@yahoo.com 4Lien Nguyen Thi Bich bichlienbvdl@yahoo.com 5Truong Nguyen Thanh bsthanhtruong@gmail.com 6Mai Nguyen Thi Hoang mainth@oucru.org 86Hoa Pham Thi Le hoaph59@gmail.com 16Thang Nguyen Ba thang.nb@umc.edu.vn 9Trung Van The vanthetrungdhyd@yahoo.com 71 0000 0004 0468 9247grid.413054.7Department of Infectious Diseases, University of Medicine and Pharmacy at Ho Chi Minh City , Ho Chi Minh city, Vietnam 2 0000 0001 2174 4509grid.9670.8Faculty of Medicine, University of Jordan, Amman, Jordan 3 grid.479691.4Dermatology and Venereology Department, Tanta University Hospital, Tanta, Egypt 4 0000 0000 9477 7793grid.412258.8Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt 5 Ho Chi Minh City Hospital of Dermatology-Venereology, Ho Chi Minh City, Vietnam 6 grid.414273.7The Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 7 0000 0004 0468 9247grid.413054.7Department of Dermatology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam 8 0000 0004 0429 6814grid.412433.3Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam 9 0000 0004 0468 9247grid.413054.7Department of Neurology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam 26 4 2017 26 4 2017 2017 17 31119 2 2017 21 4 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\nCryptococcosis is an opportunistic infection caused by the encapsulated yeast Cryptococcus neoformans and most remarkably manifests in HIV-infected individuals, especially in the settings of very low CD4 count. Development of cryptococcosis in HIV-uninfected individuals is exceedingly rare and usually signifies a marked immunodeficiency. Cryptococcosis in association with myasthenia gravis or thymoma has been previously documented in only very few cases in the literature.\n\nCase presentation\nWe reported a complicated case of severe cutaneous cryptococcosis in a 39-year-old Vietnamese male patient with myasthenia gravis on long-term immunosuppressive therapy. The patient presented with a five month history of recurrent and progressive skin lesions that later on progressed into cryptococcal meningitis.\n\nConclusion\nThrough this case, we aimed to emphasize the importance of including cutaneous cryptococcosis in the differential diagnosis of cutaneous lesions in patients on chronic immunosuppressive therapy. The cutaneous manifestations of cryptococcosis can be the first clue for a disseminated disease, which makes early recognition crucial and life-saving.\n\nKeywords\nCryptococcusCutaneous CryptococcosisCryptococcus meningitisMyasthenia gravisissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nCryptococcosis is an infection caused by two species of the encapsulated yeast Cryptococcus: Cryptococcus neoformans (C. neoformans) and Cryptococcus gatti (C. gatti). C. neoformans is a rare opportunistic infection that is typically reported causing disease in immunocompromised patients, while C. gatti is an endemic infection in the tropical parts of the continent of Africa and Australia and is capable of causing disease in non-immunocompromised individuals.\n\nCryptococcosis, caused by C. neoformans, was known for a long time as an opportunistic infection that occurs exclusively in patients with HIV. Nowadays, many case-studies proved that this pathogen can cause disease in immunocompetent patients as well [1–3] and can also be fatal in patients without known immunosuppression history [3].\n\nThe pathogen can cause a wide range of diseases, ranging from isolated cutaneous cryptococcosis to fatal meningoencephalitis and disseminated disease affecting lungs, lymph nodes, skin, and brain [2]. It is transmitted to humans primarily by inhalation of the fungus present in the soil contaminated with avian excreta or decaying wood in the hollows of trees [4]. Other rare methods of transmission have been reported, including organ transplantation and from contact with birds [5, 6].\n\nAlthough it is well-known for causing meningoencephalitis, pulmonary and cutaneous cryptococcosis were reported in many cases. Cutaneous cryptococcosis is present in 5 % of patients with meningoencephalitis with increasing prevalence in patients with organ transplantation and disseminated disease [7]. However, this is not always the case, cutaneous cryptococcosis has been recently reported in patients with no signs of systemic infection and can present solely as localized cutaneous lesions with positive cultures for Cryptococcus species [7]. This predominantly cutaneous presentation is reported in both immunocompetent and immunocompromised patients [1].\n\nCryptococcosis is also reported in immunocompromised HIV-uninfected patients. This includes patients with organ transplantation, prolonged corticosteroids or immunosuppressive therapy. Cryptococcosis has also been rarely reported in myasthenia gravis (MG) patients.\n\nMG is an autoimmune disease with auto-antibodies that attack specific receptors located on the surface of muscle cells preventing acetylcholine from binding to them, and thus, preventing the muscle from responding to the nerve signal. That is why although treatment with anticholinesterase agents produce some benefit, the prognosis remains poor. More recently, with the use of immunosuppressive therapy or surgical removal of thymus gland the general outlook for MG has improved dramatically [8]. Generalized immune suppression from the MG treatment compromises the immune system as a whole with increased susceptibility to infections, including opportunistic infections, and neoplasia [9–11]. Here, we reported a complicated case of a predominantly cutaneous cryptococcosis that progressed later to meningitis in a myasthenia gravis patient on chronic immunosuppressive therapy.\n\nCase presentation\nA 39-year-old Vietnamese male presented with a five month history (from June to November 2016) of recurrent and progressive skin lesion. Initially, the patient had painless papules distributed at multiple locations, including the chest, arms, hands, thighs, and feet. The papules then progressed into nodules, which later on expanded, ulcerated and became painful.\n\nAt the age of 27, the patient was diagnosed with myasthenia gravis (MG), was treated with prednisolone and pyridostigmine since August 2004 and had surgical removal of thymus gland on November 2004. The regimen for his MG from 2010 to 2016 was methyl prednisolone and periodically combined with IMDH inhibitors (mycophenolate or azathioprine) based on his weakness. The starting dose on September 2010 were azathioprine 100 mg/day and methyl prednisolone 48 mg/day. These doses were adjusted afterwards under the consultance of his doctor for 2 years and he did self adjusted later by his objective feeling of weakness. At the time of admission, he was under azathioprine 50 mg/day and methyl prednisolone 16 mg/day.\n\nThe patient was also diagnosed with type II diabetes one month after his first eruption (July 2016). Since then, his blood glucose level has been monitored and controlled by dietary modification, his periodically HbA1C were under 6%. From June to September 2016, the patient had completed twelve weeks of directly-acting antivirals (DAAs) for his chronic hepatitis C and he had gained virologic response (HCV RNA negative after 3 months of stop treatment).\n\nAdditionally, he had been diagnosed with TB pneumonia at the Pham Ngoc Thach Hospital which is one of the top ranked TB centers in Vietnam for his cough, hemoptysis, shortness of breath, prolonged fever with body temperature from 38 °C - 39 °C, abnormal chest X ray and the Acid-fast bacilli positivity of the sputum. He was started on anti-tuberculosis regimen (2RHZE/4RHE) since September 2016. The regimen consisted of rifampin, isoniazid, pyrazinamide and ethambutol for two months, then withdrawn pyrazinamide for the next four months. His symptoms and chest X ray improved after two weeks of RHZE treatment. He was still on the last week of the first 2RHZE at the time of admission.\n\nThe chronological order of the patient’s medical history is shown in Fig. 1.Fig. 1 Chronological order of the patient’s medical history\n\n\n\n\nIt is worth mentioning that the patient had been breeding birds and had close contact with them for the past three years. He had no history of skin trauma within 1 month before the outbreak of painless papules.\n\nOn admission, the patient’s main complaints were mild fever, painful and persistent skin lesions with painful and swollen left knee that made him unable to stand or walk. For the past few days, he also had headache that was dull in nature, extended from anterior to posterior and was worse in the afternoon. He also had 5–6 bowel movements/day with loose stool. He did not have symptoms of cough and short breaths during this illness.\n\nHe looked thin, pale, anemic, and was only able to sit with support. His temperature was 38.5 °C. He had no neck stiffness, no hepatosplenomegaly or lymphadenopathy. His left leg had intense inflammation (red, swollen, hot, and tender) that resembled cellulitis.\n\nHe also had multiple ulcers on his body. The 10 × 15 cm ulcer on his left chest (Fig. 2) was deep with visible capillaries at the base, purulent and bleeding. A group of skin lesions 5 × 10 cm was seen on his right arm (Fig. 3). There were multiples papules, which some of them progressed into nodules and ulcers (Fig. 3). The largest and deepest ulcer (15 × 20 cm) was on his right thigh (Fig. 4). It was necrotic, purulent, bleeding, and had visible capillaries and small bullous with cloudy fluid in the margins. The presentation of the ulcerative skin lesions simulated Pyoderma gangrenosum.Fig. 2 Large, deep, ulcers on the left chest at 1st day of admission. Cryptococcus neoformans was detected upon culturing fluids expressed from these ulcers\n\n\nFig. 3 The cutaneous lesions at 1st day of admission: right arm (left) and left leg (right)\n\n\nFig. 4 Ulcers on the right thigh at day 11 after admission. The ulcers were deep and with pus and bled when it was cleaned by nurse\n\n\n\n\nOn complete blood count, the patient was found to have low hemoglobin (7.6 g/dL) and low red blood cells (RBC) count (2.64 M/mL). The white blood cells (WBC) and platelets counts were within the normal ranges. The first blood culture was negative. HIV testing was negative while his CD4 count was remarkably low (236 cells/mL). The MRI of the head did not reveal any lesions in the brain and the chest X-Ray was normal.\n\nThe fluids from his bullous skin lesions were collected for microbiology stain and culture. These results came back negative for bacteria. Despite the negative culture, the patient was treated empirically with a combination of meropenem and vancomycin for fourteen days. During the time under antibiotics, the patient was still fever. The headache and skin lesions and were not improved.\n\nThe skin biopsy of the chest and leg ulcers was performed subsequently. The histopathological results detected the spores of cryptococcosis inside the macrophages (Figs. 5 and 6).Fig. 5 \na and b. Light microscopic view (HE ×200 and HE ×400) of ulcer tissue from chest and leg shows loss of the epidermis and some portions of the dermis and subcutaneous fat. Lymphocyte and macrophages infiltrates with neutrophiles. c and d: The dermal infiltrates consisted of lymphocytes (↑) and a few monocytes-macrophages ; and numerous neutrophils created sporadic focal abscesses\n\n\nFig. 6 \na and b. PAS-stained (PAS ×400 & PAS ×1000) showing numerous Cryptococcal spores inside macrophages (←) that stain positive with PAS. Ziehl-Neelson stain was negative for acid-fast bacilli\n\n\n\n\n\nThe patient underwent a lumbar puncture at admission. The cerebral spinal fluid opening pressure was 9 cm H20 and all the opening pressures afterwards were normal. The analysis of the cerebral spinal fluid (CSF) detected elevated protein levels (1.61 g/L), mildly decreased glucose level (2.14 mmol/L, serum glucose: 4.84 mmol/L), lactate of 3.76 mmol/L and a white cell count of 112 cells/μL with neutrophilic predominance (78%). Lateral flow assay (LFA) test of the CSF was positive for cryptococcal antigen. The CSF cultures, however, were negative for both bacteria and fungi. Hence, the second culture of the smear of the skin ulcers was performed and was positive for C. neoformans and negative for bacteria.\n\nSubsequently, the patient was started on amphotericin B (1 mg/kg/day) and fluconazole (800 mg/day) firstly in parallel with methyl prednisolone, azathioprine, pyridostigmine and anti-tuberculosis regimen. As planned, amphotericin B and fluconazole would be continued for 28 day. Fluconazole, for consolidation, would be continued for 11 months later.\n\nThe fever subsided after 4 days of treatment with amphotericin B and fluconazole but the patient still complained a severe headache. The neurologist considered the immune suppression effect of azathioprine, the stable status of MG and the low CD4 cell count and decided stopping azathioprine and lowered the methyl prednisolone dose to 4 mg/day for better control of Cryptococcal infection. The patient’s hypokalemia, attributed to amphotericin B, was also corrected via oral potassium replacement.\n\nA dramatic clinical and microbiologic improvement was observed after 11 days of treatment: the anemic status improved with hemoglobin level increasing to 9.0 g/dL without RBC transfusion, the headache subsided, the meningeal signs disappeared and the patient became afebrile. The ulcers became smaller, with no exudates, granulated and improved quickly. The culture of skin ulcers on day 10 post-treatment was negative for both bacteria and fungi.\n\nOn day 14 of treatment, the WBC count of the CSF dropped to 19 cells/mL and the LFA test became negative; the glucose level was 3.53 mmol/L (serum glucose: 10.87 mmol/L) and the protein remained high (1.66 g/L).\n\nOn day 28 of treatment, the WBC count of the CSF was 12 cells/mL, the protein was 1.34 g/L, the glucose was 2.82 mmol/L (serum glucose: 6.02 mmol/L). The lactate level dropped to 2.48 mmol/L but the LFA test was positive again although the fungus culture was still negative in the CSF. The skin ulcer cultures were negative also for both bacteria and fungi.\n\nAfter 28 days of treatment, amphotericin B was stopped and fluconazole (1000 mg) was consolidated until 12 months of treatment as recommended. We used a high dose of fluconazole because the patient was using rifamycin (anti-tuberculosis) which is known to reduce the level of fluconazole.\n\nThe patient was finally discharged on day 32. He had also been advised to avoid contact with birds. The cutaneous lesions on the day of discharge are shown on (Fig. 7). The patient will be re-examined every two months during the time of fluconazole maintenance.Fig. 7 Cutaneous lesions at the day of discharge: Left chest (middle), right thigh (left) and right knee (right): these lesions were reduced in size compared to initial lesions\n\n\n\n\nDiscussion\nCryptococcosis in HIV-uninfected patients almost always develops in the setting of immunocompromised status, such as patient with organ transplant, with malignancies or on chronic immunosuppressive treatment (e.g., corticosteroids) [12]. The development of cutaneous cryptococcosis is exceedingly rare in HIV-uninfected population.\n\nHere, our patient has multiple risk factors. He has been on prolonged immunosuppressive therapy and had a low CD4+ cell count (236 cells/mL). Additionally, he had also been diagnosed with diabetes mellitus which is considered a clue for immune dysfunction [13]. Moreover, the patient also had tuberculosis, which most likely resulted from reactivation of a latent infection, another warning for weakening of the immune system. All of these coexisting factors in this patient revealed a high susceptibility to opportunistic agents such as Cryptococcus neoformans.\n\nOur patient had a prolonged course of cutaneous lesions (more than 5 months) before the final diagnoses was figured out. This can be justified by the great variation in cutaneous cryptococcus presentations and the rarity of this kind of infection in HIV-uninfected patients.\n\nAdditionally, in our case the initial bacterial culture of the fluid from the skin lesions was negative. Nevertheless, by the time of histopathological detecting of spores from the ulcer, the repeated culture of the smear from skin lesion for both fungal and bacteria was also positive for Cryptococcus. This adds to the complexity of making the diagnosis and provides an additional evidence that histopathology has a core role in making a rapid diagnosis of the disease – as many times the culture fails to flourish the pathogen [14]. The culture of the bullous fluid or smears from the ulcers was more sensitive for bacterial pathogens, but less helpful for fungal pathogens, especially when suspected fungal pathogens were not specifically notified by the clinician.\n\nFrom this case, we recommended physicians to perform a culture for yeast in all skin lesions in immunosuppressed patients or to perform a Lateral Flow Assay (LFA). The cryptococcal antigen LFA is a rapid, very sensitive, easy-to-perform assay with a demonstrated usefulness as a point-of-care assay for diagnosing cryptococcosis in resource-limited countries. The availability of this assay in remote locations could have a meaningful impact on early diagnosis of cryptococcosis [15].\n\nDespite being reported many times in the literature, arguments continue on the existence of primary cutaneous cryptococcosis versus cutaneous cryptococcosis being only secondary to hematogenous dissemination [16].\n\nThe patient had no history of skin trauma but he had bred birds many months in the past. He could had skin cuts once or several times without his notification. We could not precisely conclude whether he was acquired the cryptococcus through skin lesion or through respiratory aspiration of Cryptococcal spores. However, in case of aspiration the chronological sequence should be: firstly presentation of lung infection with respiratory symptoms and signs, bacteremia later, and lastly meningitis or skin appearances. His true progression was reversed with the skin ulcer were found several months in advance, the meningeal affect (headache, fever) progressed much later after the presentation of skin lesions, and the lung was not been affected at the time of menigitis. Therefore, the patient should be a case of primary cutaneous Cryptococosis, circulatory disseminated and secondary menigitis.\n\nIt is worth mentioning that, similar to our case, systemic or disseminated infections can firstly present solely with skin lesions and later progress to involve other organs such as the meninges [17]. Hence, a high index of suspicion is required to reach to an early diagnosis.\n\nThe treatment recommendation for HIV-uninfected patients who are diagnosed with cryptococcal meningoencephalitis is to give induction therapy with amphotericin B for 2–4 weeks followed by consolidation with fluconazole (400–800 mg/day) for 12 months [12]. In our case, however, after induction with Amphotericin B, we adjusted the dose of fluconazole into 900–1000 mg/day as the patient was receiving rifampicin which is known to reduce the blood level of fluconazole [18].\n\nIn case of cryptococcosis persisted during treatment or recurred after sufficient therapy, then we should consider antifungal resistance, relapse or immune reconstitution inflammatory syndrome. Resistance, that comes if we never achieve CSF sterility, could occur with low dose of fluconazole, especially if it is used as a monotherapy. We could deal with relapse by re-induction therapy with amphotericin at high doses (1 mg/kg/day) for at least seven days and fluconazole dose could be increased up to 1200 mg/day [19]. On the other hand, sudden onset deterioration with worsening meningitis symptoms along with CSF sterility or stable titers of cryptococcal antigen support the diagnosis of immune reconstitution inflammatory syndrome [20].\n\nThis is not the first case in literature to report cryptococcosis in patients with MG [8–11, 21–23]. And although not surprising in a MG patient on chronic immunosuppression, this is only the eighth case reporting on such association. Infections in previously reported cases were in the forms of meningitis in three cases [8, 9, 11], prostatic abscess in one case [21], prosthetic joint infection in one case [22], cryptococcal cellulitis [10] in one case and disseminated cryptococcal infection in one case [23].\n\nHowever, despite the fact that patients with diseases of the lymphatic systems are prone to fungal infections [11], this simultaneous occurrence of cryptococcosis and MG could be only a pure coincidence and directly attributed to the steroids-induced immunosuppression status.\n\nConclusion\nThis case is an opportunity to emphasize on the importance of including cutaneous cryptococcosis in the differential diagnosis of cutaneous lesions in patients on chronic immunosuppressive therapy, especially if the skin lesions are resistant to empiric antibiotic treatment. The cutaneous manifestations of cryptococcosis can be the first clue for a disseminated disease, which makes early recognition crucial and life-saving.\n\nAbbreviations\nC. gatti\nCryptococcus gatti\n\n\nC. neoformans\nCryptococcus neoformans.\n\n\nCSFCerebral spinal fluid.\n\nDAAsDirectly-acting antivirals.\n\nLFALateral flow assay.\n\nMGMyasthenia gravis.\n\nRBCRed blood cells.\n\nWBCWhite blood cells.\n\nAcknowledgment\nNot applicable.\n\nFunding\nThe authors declare that they have no funding source.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contribution\nAll authors have read and approved the final manuscript. All authors (NTCH, NMH, LAT, NTBL, NTT, NTHM, AMAA, SM, SS, NBT, VTT and PTLH) helped on the diagnosis, data collection and scientific writing.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nEthics approval and consent to participate\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. Also a statement for ethical approval was obtained from ethical committee of Hospital for Tropical Diseases. A copy of the written consent from the patient and a statement of ethical approval is available for reviewing by the Editor of the journal.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Christianson JC Engber W Andes D Primary cutaneous cryptococcosis in immunocompetent and immunocompromised hosts Med Mycol 2003 41 3 177 188 10.1080/1369378031000137224 12964709 \n2. Murakami Y Oki M Saka H Kajikawa S Murakami A Ishida A Disseminated cryptococcosis presenting as mediastinal and hilar lymphadenopathy in an immunocompetent patient Respirology Case Reports 2016 4 4 10.1002/rcr2.167 27512567 \n3. Raberahona M, Rakotoarivelo RA, Randriamampionona N, Rakotomalala AF, Razafinambinintsoa T, Bénet T, Vanhems P, Randria MJDD, Cornet M, Rakoto-Andrianarivelo M: Rapid Fatal Outcome of Cryptococcal Meningoencephalitis in a Non-HIV Immunocompromised Patient with a Low Fluconazole Susceptibility Isolate: A Case Report from Madagascar Case Reports in Infectious Diseases 2016, 2016: ID 3492504, 10.1155/2016/3492504.\n4. Chowdhary A Rhandhawa HS Prakash A Meis JF Environmental prevalence of Cryptococcus neoformans and Cryptococcus gattii in India: an update Crit Rev Microbiol 2012 38 1 1 16 10.3109/1040841X.2011.606426 22133016 \n5. Baddley JW. Schain dc Fau - Gupte AA, Gupte aa Fau - Lodhi SA, Lodhi Sa Fau - Kayler LK, Kayler Lk Fau - Frade JP, Frade Jp Fau - Lockhart SR, Lockhart Sr Fau - Chiller T, Chiller T Fau - Bynon JS, Jr., Bynon Js Jr Fau - bower WA, bower WA: transmission of Cryptococcus neoformans by organ transplantation. Clin Infect Dis. 2011;52:e94–8.\n6. Lagrou K. Van Eldere J Fau - Keuleers S, Keuleers S Fau - Hagen F, Hagen F Fau - Merckx R, Merckx R Fau - Verhaegen J, Verhaegen J Fau - Peetermans WE, Peetermans we Fau - Boekhout T, Boekhout T: zoonotic transmission of Cryptococcus neoformans from a magpie to an immunocompetent patient. Journal of Internal of Medicine. 2005;257(4):385–8.\n7. Neuville S Dromer F Morin O Dupont B Ronin O Lortholary O French Cryptococcosis study G: primary cutaneous Cryptococcosis: a distinct clinical entity Clin Infect Dis 2003 36 3 337 347 10.1086/345956 12539076 \n8. Schmidt S Padberg F Late onset immunodeficiency in a patient with recurrent thymic carcinoma and myasthenia gravis J Neurol Sci 1998 157 2 201 205 10.1016/S0022-510X(98)00085-9 9619646 \n9. Lorenzoni PJ Scola RH Kay CS Almeida SM Muro MD Burigo IP Carraro H Jr Werneck LC Myasthenia gravis complicated with cryptococcal meningitis after thymectomy and long-term immunosuppressive therapy Arq Neuropsiquiatr 2011 69 2b 410 411 10.1590/S0004-282X2011000300031 21625779 \n10. Lafleur L Beaty S Colome-Grimmer MI LaForte RA Dotson AD Cryptococcal cellulitis in a patient on prednisone monotherapy for myasthenia gravis Cutis 2004 74 3 165 170 15499758 \n11. Rowland LP Griffiths CO Kabat EA Myasthenia gravis, thymoma and cryptococcal meningitis N Engl J Med 1965 273 12 620 627 10.1056/NEJM196509162731202 5826424 \n12. Pappas PG Cryptococcal infections in non-Hiv-infected patients Trans Am Clin Climatol Assoc 2013 124 61 79 23874010 \n13. Geerlings SE Hoepelman AI Immune dysfunction in patients with diabetes mellitus (DM) FEMS Immunol Med Microbiol 1999 26 3–4 259 265 10.1111/j.1574-695X.1999.tb01397.x 10575137 \n14. Gonzalez Santiago TM Pritt B Gibson LE Comfere NI Diagnosis of deep cutaneous fungal infections: correlation between skin tissue culture and histopathology J Am Acad Dermatol 2014 71 2 293 301 10.1016/j.jaad.2014.03.042 24836547 \n15. Lindsley MD Mekha N Baggett HC Surinthong Y Autthateinchai R Sawatwong P Harris JR Park BJ Chiller T Balajee SA Evaluation of a newly developed lateral flow immunoassay for the diagnosis of cryptococcosis Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2011 53 4 321 325 10.1093/cid/cir379 21810743 \n16. Neuville S Dromer F Morin O Dupont B Ronin O Lortholary O Group FCS Primary cutaneous cryptococcosis: a distinct clinical entity Clin Infect Dis 2003 36 3 337 347 10.1086/345956 12539076 \n17. Nascimento E Bonifacio da Silva ME, Martinez R, von Zeska Kress MR: primary cutaneous cryptococcosis in an immunocompetent patient due to Cryptococcus gattii molecular type VGI in Brazil: a case report and review of literature Mycoses 2014 57 7 442 447 10.1111/myc.12176 24612099 \n18. Ayudhya DPN Thanompuangseree N Tansuphaswadikul S Effect of rifampicin on the pharmacokinetics of fluconazole in patients with AIDS Clin Pharmacokinet 2004 43 11 725 732 10.2165/00003088-200443110-00003 15301576 \n19. Musubire AK, Boulware DR, Meya DB, Rhein J. Diagnosis and Management of Cryptococcal Relapse. Journal of AIDS & clinical research. Suppl. 2013;3(3):S3–003.\n20. Boulware DR Bonham SC Meya DB Wiesner DL Park GS Kambugu A Janoff EN Bohjanen PR Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome The Journal of infectious diseases 2010 202 6 962 970 10.1086/655785 20677939 \n21. Yip SK Cheng C Wong MY Tan BH Sim CS Lim SH Cryptococcal prostatic abscess in an immunocompromised patient: a case report and review of the literature Ann Acad Med Singap 1998 27 6 873 876 10101568 \n22. Shah NB Shoham S Nayak S Cryptococcus neoformans Prosthetic joint infection: case report and review of the literature Mycopathologia 2015 179 3–4 275 278 10.1007/s11046-014-9847-0 25524725 \n23. Narayanan S Banerjee C Holt PA Cryptococcal immune reconstitution syndrome during steroid withdrawal treated with hydroxychloroquine Int J Infect Dis 2011 15 1 e70 e73 10.1016/j.ijid.2010.09.006 21094071\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "17(1)",
"journal": "BMC infectious diseases",
"keywords": "Cryptococcus; Cryptococcus meningitis; Cutaneous Cryptococcosis; Myasthenia gravis",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000328:Adult; D003453:Cryptococcosis; D003455:Cryptococcus neoformans; D003881:Dermatomycoses; D003937:Diagnosis, Differential; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D016919:Meningitis, Cryptococcal; D009157:Myasthenia Gravis; D009894:Opportunistic Infections",
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"pages": "311",
"pmc": null,
"pmid": "28446137",
"pubdate": "2017-04-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21810743;9619646;25524725;12539076;15301576;10575137;24836547;24371542;21094071;20677939;12964709;15788009;21220771;28078149;23874010;27512567;10101568;22133016;21625779;5826424;24612099;15499758",
"title": "Progressive cutaneous Cryptococcosis complicated with meningitis in a myasthenia gravis patient on long-term immunosuppressive therapy - a case report.",
"title_normalized": "progressive cutaneous cryptococcosis complicated with meningitis in a myasthenia gravis patient on long term immunosuppressive therapy a case report"
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"abstract": "Dual antiplatelet therapy (DAPT) is the cornerstone treatment of acute myocardial infarction (AMI).\n\n\n\nThe present study aimed to investigate the efficacy and safety of triple antiplatelet therapy (TAPT) in elderly female patients with diabetes and ST segment elevation myocardial infarction (STEMI), who had undergone percutaneous coronary intervention (PCI).\n\n\n\nWe designed a randomized, single-blind study. Control group A (97 elderly male patients with diabetes and STEMI, whose CRUSADE scores were < 30) received aspirin, ticagrelor, and tirofiban. A total of 162 elderly female patients with diabetes and STEMI were randomly divided into two groups according to CRUSADE score. Group B (69 patients with CRUSADE score > 31) received aspirin and ticagrelor. Group C (93 patients with CRUSADE score < 30) received aspirin, ticagrelor and tirofiban. P values < 0.05 were considered statistically significant.\n\n\n\nCompared to the findings in group A, post-PCI Thrombolysis in Myocardial Infarction (TIMI) grade 3 blood flow and TIMI myocardial perfusion grade 3 were significantly less prevalent in group B (p < 0.05). When compared to groups A and C, the incidence of major adverse complications was significantly higher in group B (p < 0.05).\n\n\n\nTAPT could effectively reduce the incidence of major complications in elderly female patients with diabetes and STEMI. However, close attention should be paid to hemorrhage in patients receiving TAPT. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0).",
"affiliations": "Affiliated People's Hospital of Zhengzhou,The Second School of Clinical Medicine,Southern Medical University, Zhengzhou - China.;Shenqiu County Hospital of Traditional Chinese Medicine, Shenqiu - China.;Affiliated People's Hospital of Zhengzhou,The Second School of Clinical Medicine,Southern Medical University, Zhengzhou - China.;Affiliated People's Hospital of Zhengzhou,The Second School of Clinical Medicine,Southern Medical University, Zhengzhou - China.;Affiliated People's Hospital of Zhengzhou,The Second School of Clinical Medicine,Southern Medical University, Zhengzhou - China.;Affiliated People's Hospital of Zhengzhou,The Second School of Clinical Medicine,Southern Medical University, Zhengzhou - China.",
"authors": "Liu|Yang|Y|;Gao|Yanyan|Y|;Liu|Hengliang|H|0000-0001-8400-8242;Chen|Qi|Q|;Ji|Jinrui|J|;Jia|Kailong|K|",
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"fulltext": "\n==== Front\nArq Bras Cardiol\nArq Bras Cardiol\nabc\nArquivos Brasileiros de Cardiologia\n0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC \n\n33470329\nabc.20190442\n10.36660/abc.20190442\nArtigo Original\nEfeitos Terapêuticos da Tripla Antiagregação Plaquetária em Pacientes Femininas Idosas com Diabetes e Infarto Agudo do Miocárdio\nLiu Yang 1 Gao Yanyan 2 https://orcid.org/0000-0001-8400-8242Liu Hengliang 1 Chen Qi 1 Ji Jinrui 1 Jia Kailong 1 \n1 \nAffiliated People’s Hospital of Zhengzhou\nThe Second School of Clinical Medicine\nSouthern Medical University\nZhengzhou\nChina\nAffiliated People’s Hospital of Zhengzhou,The Second School of Clinical Medicine,Southern Medical University, Zhengzhou - China\n\n\n2 \nShenqiu County Hospital of Traditional Chinese Medicine\nShenqiu\nChina\nShenqiu County Hospital of Traditional Chinese Medicine, Shenqiu - China\n\n Correspondência: Hengliang Liu • Zhengzhou People’s Hospital, Southern Medical University - No.33, huanghe road, jinshui district Zhengzhou 450003 – China E-mail:\nlhldoc@163.comContribuição dos Autores\n\nConcepção e desenho da pesquisa: Liu Y, Chen Q, Ji J, Jia K; Obtenção de dados: Liu Y, Gao Y, Liu H, Chen Q, Ji J, Jia K; Análise e interpretação dos dados: Liu H, Ji J, Jia K; Análise estatística: Liu Y, Gao Y, Chen Q; Obtenção de financiamento: Gao Y, Liu H; Redação do manuscrito: Liu Y, Liu H; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Liu H.\n\nPotencial Conflito de Interesses\n\nDeclaro não haver conflito de interesses pertinentes.\n\n\n13 1 2021 \n2 2021 \n116 2 229 235\n03 7 2019 09 12 2019 27 12 2019 This 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 original work is properly cited. Resumo\nFundamento\n A dupla antiagregação plaquetária (DAP) é o tratamento fundamental do infarto agudo do miocárdio (IAM).\n\nObjetivo\n O presente estudo visou investigar a eficácia e a segurança da tripla antiagregação plaquetária (TAP) em pacientes femininas idosas com diabetes e infarto agudo do miocárdio com supradesnível do segmento ST (IAMCSST), que foram submetidas à intervenção coronária percutânea ICP.\n\nMétodos\n Trata-se se de um estudo randomizado e mono-cego. O grupo controle A (97 pacientes idosos do sexo masculino com diabetes e STEMI, cujos escores CRUSADE foram < 30) recebeu aspirina, ticagrelor e tirofibana. Um total de 162 pacientes femininas idosas com diabetes e IAMCSST foram divididas aleatoriamente em dois grupos de acordo com o escore CRUSADE. O grupo B (69 pacientes com escore CRUSADE > 31) recebeu aspirina e ticagrelor. O grupo C (93 pacientes com escore CRUSADE < 30) recebeu aspirina, ticagrelor e tirofibana. Valores de p < 0,05 foram considerados estatisticamente significativos.\n\nResultados\n Após a PCI, o fluxo sanguíneo grau 3\nThrombolysis in Myocardial Infarction\n(TIMI) e a perfusão miocárdica TIMI grau 3 foram significativamente menos prevalentes no grupo B, em comparação com o grupo A (p < 0,05). Quando comparada aos grupos A e C, a incidência de complicações adversas maiores foi significativamente maior no grupo B (p < 0,05).\n\nConclusão\n A TAP pode efetivamente reduzir a incidência de complicações maiores em pacientes idosas com diabetes e IAMCSST. No entanto, atenção cuidadosa deve ser dada à hemorragia em pacientes que recebem TAP. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)\n\nAgregação PlaquetariaAcidente Vascular CerebralMulherIdosoDiabetes MellitusInfarto do MiocárdioIntervenção Coronária Percutânea/métodos\n==== Body\nIntrodução\nA dupla antiagregação plaquetária (DAP) é um tratamento fundamental do infarto agudo do miocárdio (IAM). Em comparação com o clopidogrel, o efeito inibitório do ticagrelor nas plaquetas no DAPT é rápido e potente, com inibição dupla e combinação reversível. Além disso, pode dilatar as artérias coronárias e é recomendado pelas diretrizes.1 No entanto, estudos têm demonstrado que o ticagrelor e o clopidogrel podem aumentar significativamente o risco de hemorragia, em comparação com o uso isolado do clopidogrel.2\n\nA incidência de fluxo sanguíneo lento, não-refluxo e complicações trombóticas em pacientes do sexo feminino com diabetes e IAM é maior do que em pacientes sem diabetes ou em pacientes do sexo masculino com diabetes e IAM que estão recebendo DAP.3\n-\n5 Os inibidores dos receptores da glicoproteína IIb/IIIa, em adição à DAP, podem efetivamente reduzir o aparecimento de complicações, tais como fluxo sanguíneo lento, não-refluxo, trombose aguda e subaguda e eventos cardíacos adversos maiores (ECAM).6\n-\n9 Porém, ainda não se sabe se a combinação de medicamentos da tripla antiagregação plaquetária (TAP), especialmente o ticagrelor, aumentaria o risco de hemorragia. A questão urgente no tratamento de IAM é como equilibrar o risco de eventos isquêmicos e de complicações hemorrágicas. Em relação à DAP (aspirina e ticagrelor), o presente estudo teve como objetivo investigar a eficácia e segurança a curto prazo da TAP (aspirina, ticagrelor e tirofibana), em mulheres idosas com diabetes e IAM.\n\nMateriais e Métodos\nParticipantes e Agrupamento\nEste estudo foi realizado em dois centros, no Hospital Popular de Zhengzhou da Universidade Médica do Sul e no Hospital de Medicina Tradicional Chinesa do Condado de Shenqiu, ambos na província de Henan. Foram incluídas pacientes femininas idosas com diabetes e infarto agudo do miocárdio com supradesnível do segmento ST (IAMCSST), internadas na unidade coronariana e que receberam intervenção coronária percutânea (ICP) de janeiro de 2013 a dezembro de 2018. O estudo foi randomizado e mono-cego. O sangue foi coletado imediatamente após a admissão. Foi calculado o escore\nCan Rapid Risk Stratification of UnsTabela Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines\n(CRUSADE)10 dos pacientes de acordo com hematócrito, taxa de depuração da creatinina, frequência cardíaca, pressão arterial, existência de insuficiência cardíaca, diabetes mellitus e doenças vasculares anteriores. Trata-se de um estudo prospectivo. De acordo com o escore CRUSADE, as pacientes foram divididas aleatoriamente em dois grupos: grupo B (pontuação maior que 30) e grupo C (pontuação menor que 30). A DAP (aspirina e ticagrelor) foi administrada às pacientes do grupo B e a TAP (aspirina, ticagrelor e tirofibana) foi administrada às pacientes do grupo C. Pacientes idosos do sexo masculino com diabetes e IAMCSST, que receberam ICP de emergência durante o mesmo período de hospitalização, foram alocados ao grupo A (grupo controle) e receberam a mesma terapia medicamentosa que os pacientes do grupo C. O diagnóstico de IAMCSST foi de acordo com as diretrizes da Sociedade Europeia de Cardiologia11 e o diagnóstico de diabetes mellitus foi de acordo com os critérios da Organização Mundial de Sáude.12 Foram aplicados os seguintes critérios de inclusão: (1) pacientes com início de IAMCSST em ≤ 12 hours, (2) pacientes com diagnóstico conhecido de diabetes mellitus, (3) pacientes que concordaram em receber ICP de emergência e DAP ou TAP e (4) pacientes com idade entre 60 e 79 anos. Os critérios de exclusão foram os seguintes: (1) pacientes com início de IAMCSST > 12 horas, (2) pacientes com pressão arterial ≥ 180/110 mmHg, (3) pacientes com dissecção aórtica suspeita, (4) pacientes com ICP recuperada após trombólise para IAMCSST, (5) pacientes com histórico de hemorragia cerebral e acidente vascular cerebral isquêmico em um ano, (6) pacientes com insuficiência hepática e/ou renal grave e (7) pacientes com histórico de doenças hemorrágicas.9 O presente estudo está de acordo com as normas de ética médica. Com a aprovação do Comitê de Ética do Hospital Popular de Zhengzhou, todos os tratamentos foram realizados com o consentimento esclarecido dos pacientes ou de seus familiares.9\n\nIntervenção Coronária Percutânea de Emergência\nFoi registrado eletrocardiograma de dezoito derivações imediatamente após a admissão e os sinais vitais foram verificados. Imediatamente após a admissão, foi coletado o sangue para análise de enzimas cardíacas, troponina e outros itens bioquímicos e de rotina relacionados. Além disso, foram administrados 100 mg de aspirina (Bayer, Alemanha; 100 mg/comprimido) e 180 mg de ticagrelor (Belinda Tabelats, Astra Zeneca; 90 mg/comprimido) por via oral aos pacientes nos três grupos. Foram realizadas angiografia coronária e ICP de emergência. Quando trombos foram encontrados, foi utilizado um cateter de aspiração de trombo para aspirá-los (10 pacientes, 6 pacientes e 9 pacientes nos grupos A, B e C, respectivamente). Foi injetado cloridrato de tirofibana (10 µg/kg) na artéria coronária nos pacientes dos grupos A e C. Após a ICP, 0,075 µg/kg·min de cloridrato de tirofibana foi bombeado continuamente na veia durante 24 horas 7. Foram usados stents farmacológicos em todos os pacientes. Apenas o vaso culpado foi tratado durante a emergência. Quando um vaso não culpado precisava de tratamento, foi realizada ICP seletiva 10 a 14 dias depois. Adicionalmente, 100 mg/d de aspirina e 90 mg/d de ticagrelor foram administrados duas vezes por via oral continuamente em pacientes nos três grupos. Posteriormente, a DAP foi aplicada durante pelo menos 12 meses. Além disso, bloqueadores do receptor, estatinas, agentes hipoglicêmicos e inibidores da enzima de conversão da angiotensina foram administrados continuamente.9\n\nCritérios de Observação\nForam coletados e contados os dados para tempo primeiro contato médico-balão, tempo porta-balão, idade, sexo, frequência cardíaca, pressão sistólica, creatinina sérica, classificação Killip da função cardíaca, enzimas miocárdicas, troponina, hematócrito, histórico de doença vascular ou diabetes mellitus e a existência de parada cardíaca. Os escores GRACE13 e CRUSADE integral10 foram calculados com base nesses dados. Foi calculado o SYNTAX integral14 de acordo com as características patológicas da angiografia coronária. Subsequentemente, foram determinadas as características do vaso culpado e foram registrados os dados do diâmetro e do comprimento dos stents. Por exemplo, se mais de dois stents eram necessários para mais de dois vasos culpados, o comprimento dos stents separados era somado para obter o comprimento. Se a lesão-alvo foi mais comprida e mais de dois stents foram colocados em série, 4 mm eram subtraídos do comprimento total. O diâmetro e o comprimento dos stents para cirurgia secundária seletiva de vasos não culpados não foram incluídos. Foram registrados os dados de tempo de internação hospitalar e eventos adversos, incluindo ICP seletiva durante a hospitalização, angina pectoris pós-infarto, re-infarto durante a hospitalização, trombose aguda e subaguda do stent, arritmia grave (taquicardia ventricular persistente, fibrilação ventricular, fibrilação atrial ou flutter atrial hemodinamicamente instável recém-emergido e bloqueio atrioventricular de alto grau, excluindo arritmia de reperfusão durante a ICP), função cardíaca acima de Killip grau III, choque cardiogênico e mortalidade em 30 dias7\n-\n9 dos pacientes dos três grupos. A classificação de sangramento\nThrombolysis in Myocardial Infarction\n(TIMI) foi registrada da maneira seguinte: (1) hemorragia grave: hemorragia intracraniana ou sangramento clinicamente visível (incluindo diagnóstico por imagem), diminuição da hemoglobina ≥ 5 g/dl e diminuição do hematócrito ≥ 15%); (2) hemorragia moderada: sangramento clinicamente visível (incluindo diagnóstico por imagem), diminuição da hemoglobina entre 3 e 5 g/dl, sangramento leve; (3) hemorragia leve: sangramento clinicamente visível (incluindo diagnóstico por imagem), com diminuição da hemoglobina < 3 g/dl.7\n-\n9\n,\n15 Também foram registrados o grau de fluxo sanguíneo TIMI e o grau de perfusão miocárdica TIMI (TMPG) dos vasos relacionados ao infarto após a ICP.7\n-\n9\n,\n15\n\nMétodos Estatísticos\nFoi usado o software SPSS 17.0 para análise estatística de todos os dados. Os dados de medição, expressos como média ± desvio padrão, apresentaram distribuição normal de acordo com o teste de Kolmogorov-Smirnov. A comparação entre os dois grupos foi realizada pelo teste t de Student não pareado. Os dados de contagem foram expressos em números de casos (razão de constituintes), e a comparação entre os dois grupos foi realizada pelo teste do qui-quadrado. ANOVA de uma via foi utilizada para comparar os três grupos e p < 0,05 foi considerado estatisticamente significativo.9\n\nResultados\nCaracterísticas Clínicas\nO grupo A (97 pacientes diabéticos do sexo masculino com IAMCSST; idade média: 65,9 ± 9,2 anos), que foi o grupo controle, apresentou escore CRUSADE de baixo risco (inferior a 30). O grupo B (69 pacientes do sexo feminino; idade média: 65,27 ± 9,8 anos) apresentou escore CRUSADE de risco moderado e acima de moderado (superior a 31). O grupo C (93 pacientes do sexo feminino; idade média: 64,8 ± 7,2 anos) apresentou escores CRUSADE de baixo risco (escore inferior a 30). Não houve diferenças estatisticamente significativas em relação a idade, tempo primeiro contato médico-balão, tempo porta-balão, hipertensão, hiperlipidemia, índice de massa corporal, história prévia de ICP, histórico familiar de doença cardíaca coronária e pontuação GRACE entre os três grupos (p\n > \n0,05,\nTabela 1\n).\n\n\nTabela 1 – Comparação das características clínicas gerais entre os três grupos\nGrupo\tMasculino (aspirina + ticagrelor + tirofibana) (Grupo A, 97 casos)\tFeminino (aspirina + ticagrelor) (Grupo B, 69 casos)\tFeminino (aspirina + ticagrelor + tirofibana) (Grupo C, 93 casos)\tp\t\nIdade (anos)\t65,9±9,2\t65,27±9,8\t64,8±7,2\t0,824\t\nSexo (masculino/feminino)\t97/0\t0/69\t0/93\t0,000\t\nHistórico de doença do trato digestivo [n(%)]\t5(5,15)\t3(4,35)\t4(4,3)\t0,953\t\nTabagismo [n(%)]\t22(22,68)\t2(2,9)a\t3(3,23)a\t0,000\t\nEtilismo [n(%)]\t37(38,14)\t7(10,14)\t13(13,98)\t0,000\t\nFEVE < 40%[n(%)]\t9(9,28)\t6(8,7)\t8(8,6)\t0,985\t\nUso de varfarina [n(%)]\t2(2,06)\t1(1,45)\t2(2,15)\t0,943\t\nIBP combinados [n(%)]\t6(6,19)\t3(4,35)\t7(7,53)\t0,257\t\nTempo PCM-B\t124,3±67,2\t132,5±71,3\t128,5±82,6\t0,797\t\nTempo P-B\t65,6±21,4\t71,3±26,9\t62,6±27,2\t0,892\t\nHipertensão [n(%)]\t57(58,77)\t37(53,62)\t55(59,14)\t0,745\t\nHiperlipidemia [n(%)]\t49(50,52)\t36(52,17)\t48(51,62)\t0,976\t\nIMC (kg/m2)\t32,46±4,65\t30,13±5,26\t29,99±6,31\t0,823\t\nCreatinina sérica (mmol/L)\t83,29±9,7\t96,,32±10,07a\t83,46±12,35b\t0,012\t\nHistórico de ICP [n(%)]\t4(4,12)\t2(2,90)\t6(6,46)\t0,543\t\nAngina pré-infarto [n(%)]\t19(19,59)\t2(2,90)a\t4(4,30)a\t0,000\t\nHistórico familiar de doença cardíaca coronária [n(%)]\t5(5,15)\t3(4,35)\t5(5,38)\t0,954\t\nEscore GRACE \t \t \t \t \t\nRisco baixo (< 85)[n(%)]\t9(9,28)\t8(11,59)\t9(9,68)\t0,526\t\nRisco médio (85 to 133)[n(%)]\t17(17,53)\t12(17,39)\t15(16,13)\t0,963\t\nRisco alto (>133)[n(%)]\t71(73,20)\t49(71,01)\t69(74,19)\t0,902\t\nEscore CRUSADE \t \t \t \t \t\nRisco extremamente baixo (1-20 )[n(%)]\t37(38,14)\t0(0)a\t42(45,16)b\t0,000\t\nRisco baixo (21-30)[n(%)]\t60(61,86)\t0(0)a\t51(54,84)b\t0,000\t\nRisco médio (31-40)[n(%)]\t0(0)\t32(46,38)a\t0(0)b\t0,000\t\nRisco alto (41-50)[n(%)]\t0(0)\t24(34,78)a\t0(0)b\t0,016\t\nRisco extremamente alto (>51)[n(%)]\t0(0)\t13(18,84)a\t0(0)b\t0,000\t\n\nFEVE: fração de ejeção do ventrículo esquerdo; IBP: inibidores da bomba de prótons; ICP: intervenção coronária percutânea; IMC: índice de massa corporal; P-B: porta-balão; PCM-B: primeiro contato médico-balão. Nota: a: p < 0,05 em comparação com o grupo A; b: p < 0,05 em comparação com o grupo B.\n\n\n\n\n\nCaracterísticas das Lesões da Artéria Coronária\nNão foram observadas diferenças significativas ao comparar o número de lesões em três artérias coronárias entre os três grupos. No entanto, em comparação com o grupo A, o diâmetro de stent implantado nos grupos B e C foi significativamente menor (p < 0,05). Além disso, o fluxo sanguíneo TIMI grau 3 e o TMPG grau 3 após a ICP foram significativamente menos prevalentes no grupo B do que nos grupos A e C (p\n < \n0,05,\nTabela 2\n).\n\n\nTabela 2 – Comparação das características das lesões da artéria coronária entre os três grupos (número de casos, %)\nCaracterísticas das lesões\tMasculino (aspirina + ticagrelor + tirofibana) (Grupo A, 97 casos)\tFeminino (aspirina + ticagrelor) (Grupo B, 69 casos)\tFeminino (aspirina + ticagrelor + tirofibana) (Grupo C, 93 casos)\tp\t\nLesão de ramo único\t9(9,28)\t6(8,70)\t8(8,60)\t0,992\t\nLesão de ramo duplo\t11(11,34)\t7(10,14)\t9(9,68)\t0,946\t\nLesão de ramo triplo\t77(79,38)\t56(81,16)\t75(80,65)\t0,956\t\nComplicado com lesão principal esquerda\t6(6,19)\t3(4,35)\t6(6,45)\t0,867\t\nEscore SYNTAX\t22,21±6,18\t21,75±8,57\t22,31±7,27\t0,863\t\nICP vaso-alvo Ramo descendente anterior esquerdo\t51(52,58)\t36(52,17)\t49(52,69)\t0,998\t\nRamo circunflexo direito\t14(14,43)\t11(15,94)\t8(8,60)\t0,314\t\nArtéria coronária direita\t32(32,99)\t22(31,88)\t36(38,71)\t0,564\t\nDiâmetro dos stents (mm, x±s)\t3,01±0,33\t2,69±0,27a\t2,70±0,39a\t0,046\t\nComprimento dos stents (mm, x±s)\t28,29±3,74\t27,36±5,13\t28,12±5,07\t0,783\t\nClassificação TIMI pré-operativa\t \t \t \t \t\nGrau 0\t95(97,94)\t68(98,55)\t92(98,92)\t0,857\t\nGrau 1 ou 2\t2(2,06)\t1(1,45)\t1(1,08)\t0,957\t\nGrau 3\t0\t0\t0\t \t\nClassificação TIMI pós-operativa\t \t \t \t \t\nGraus 0 a 2\t2(2,06)c\t10(14,49)ac\t4(4,30)bc\t0,003\t\nGrau 3\t95(97,94)c\t59(85,51)ac\t89(95,70)bc\t0,003\t\nClassificação TMPG pré-operativa\t \t \t \t \t\nGraus 0 a 2\t97(100)\t69(100)\t93(100)\t \t\nGrau 3\t0\t0\t0\t \t\nClassificação TMPG pós-operativa\t \t \t \t \t\nGraus 0 a 2\t6(6,19)\t20(28,99)ad\t14(15,05 )abd\t0,0003\t\nGrau 3\t91(93,81)d\t49(71,01)ad\t79(84,95)abd\t0,0001\t\n\nICP: intervenção coronária percutânea. Nota: a: p < 0,05 em comparação com o grupo A; b: p < 0,05 em comparação com o grupo B; c: comparações com TIMI pré-operatório intra-grupo do mesmo grau, p < 0,05; d: comparações com TMPG pré-operatório intra-grupo do mesmo grau, p < 0,05.\n\n\n\n\n\nTempo de Internação Hospitalar, Características da ICP e Incidência de Complicações\nO tempo médio de internação hospitalar foi significativamente mais alto no grupo B que nos grupos A e C (p\n < \n0,05). Além disso, o grupo B teve 14 casos de angina pectoris pós-infarto, enquanto os outros dois grupos tiveram 5 casos cada. Ocorreram 9 casos de arritmia grave no grupo B, o que foi maior do que nos outros dois grupos (2 casos no grupo A e 3 casos no grupo C). Houve 14 casos de insuficiência cardíaca, choque cardiogênico e mortalidade em 30 dias no grupo B, o que foi maior do que nos grupos A e C (5 e 4 casos, respectivamente). Além disso, a incidência de ICP seletiva, re-infarto e trombose de stent durante a internação hospitalar foi significativamente mais alta no grupo B, em comparação com o grupo A (p\n < \n0,05). No grupo B, ocorreram 14 casos de angina pectoris pós-infarto, 7 casos de re-infarto e 3 casos de trombose de stent. Em adição a isso, a incidência total de hemorragia e a incidência de hemorragia moderada foram significativamente maiores no grupo C, quando comparados aos grupos A e B (p\n < \n0,05,\nTabela 3\n). Houve 8 casos de hemorragia moderada no grupo C, enquanto os grupos A e B tiveram 1 caso cada.\n\n\nTabela 3 – Comparação de tempo de internação hospitalar, características da ICP e incidência de complicações nos três grupos\nItem\tMasculino (aspirina + ticagrelor + tirofibana) (Grupo A, 97 casos)\tFeminino (aspirina + ticagrelor) (Grupo B, 69 casos)\tFeminino (aspirina + ticagrelor + tirofibana) (Grupo C,93 casos)\tp\t\nTempo médio de internação hospitalar (dias)\t7,8±1,5\t11,2±3,3a\t8,3±1,9ab\t0,042\t\nCirurgia secundária seletiva [n(%)]\t12(12,37)\t19(27,54)a\t9(20,93)\t0,047\t\nAngina pectoris pós-infarto [n(%)]\t5(5,05)\t14(19,72)a\t5(5,38)b\t0,001\t\nRe-infarto [n(%)]\t0(0)\t7(10,14)a\t6(6,45)\t0,009\t\nTrombose de stent [n(%)]\t0(0)\t3(4,35)a\t1(1,08)\t0,073\t\nArritmia grave [n(%)]\t2(2,06)\t9(13,04)a\t3(3,23)b\t0,004\t\nFunção cardíaca acima de Killip grau III [n(%)]\t2(2,60)\t14(20,29)a\t8(8,60)ab\t0,0001\t\nChoque cardiogênico pós-operatório [n(%)]\t0(0)\t5(7,25)a\t1(1,08)b\t0,006\t\nMortalidade em 30 dias [n(%)]\t0(0)\t4(5,80)a\t1(1,08)\t0,004\t\nHemorragia total [n(%)]\t7(7,22)\t6(8,70)\t20(21,98)ab\t0,005\t\nHemorragia grave\t0(0)\t0(0)\t1(1,08)\t0,408\t\nHemorragia moderada\t1(1,03)\t1(1,45)\t8(8,60)ab\t0,012\t\nHemorragia leve\t6(6,19)\t5(7,25)\t11(11,83)\t0,344\t\n\na: p < 0,05 em comparação com o grupo A; b: p < 0,05 em comparação com o grupo B.\n\n\n\n\n\nDiscussão\nMais de 50% das mortes cardiovasculares ocorrem em mulheres. Independentemente dos resultados positivos da fisiopatologia, queixas, sintomas, sinais e resultados dos exames auxiliares, ou dos efeitos terapêuticos de curto e longo prazo, as pacientes do sexo feminino apresentam as suas particularidades.16\n,\n17 A ICP oportuna em pacientes do sexo feminino com síndrome coronariana aguda pode efetivamente reduzir a incidência de ECAM.9\n,\n15\n,\n17\n,\n18 No entanto, as mulheres, especialmente as idosas, geralmente não apresentam dor torácica típica durante um ataque isquêmico, o que pode atrasar o diagnóstico e o tratamento. No presente estudo, a incidência de angina pectoris antes do infarto foi significativamente menor nas mulheres em comparação com os homens. Além disso, sintomas não específicos, bem como desconforto pós-esternal, aperto no peito, falta de ar, náusea, vômito e fadiga, foram mais comuns em mulheres com IAM. Em adição a isso, a sensibilidade e a especificidade do eletrocardiograma e do eletrocardiograma de exercício no diagnóstico de doença cardíaca coronária são menores em mulheres. A falta de sintomas específicos e as alterações eletrocardiográficas correspondentes no quadro fisiopatológico de isquemia e a falta de medicamentos e intervenções no estilo de vida oportunas e necessárias, mesmo em condições críticas, como oclusão vascular completa ou subtotal, frequentemente levam a consulta tardia, perdendo a fase mais tratável e resultando em falta de intervenção precoce, como a ICP de emergência; isto é uma das principais causas da maior incidência de complicações e mortalidade em pacientes do sexo feminino com IAM.17\n,\n18\n\nA diabetes mellitus é uma condição isócrita de doença cardíaca coronária. Os efeitos terapêuticos dos medicamentos antiplaquetários em pacientes com diabetes são piores do que em pacientes sem diabetes. Além disso, a incidência de fluxo sanguíneo lento e não-refluxo após a ICP de emergência e as ECAM são significativamente maiores do que em pacientes sem diabetes.7\n-\n9\n,\n15 Isto sugere que uma terapia de antiagregação plaquetária intensificada é necessária para pacientes com diabetes. Diabetes mellitus é um dos fatores de risco mais importantes para pacientes com síndrome coronariana aguda, independentemente de o escore GRACE ser usado para avaliar eventos isquêmicos ou o escore CRUSADE ser usado para predizer o risco de sangramento. A DAP é o tratamento fundamental para a prevenção de isquemia e trombose após a ICP.19 Após receber a DAP, alguns pacientes ainda apresentam complicações graves de trombose, especialmente pacientes do sexo feminino com diabetes e pacientes idosos com diabetes. Os inibidores do receptor IIb/IIIa, em adição à DAP, podem efetivamente reduzir a ocorrência de fluxo sanguíneo lento e não-refluxo, a incidência de trombose aguda e subaguda e a ocorrência de ECAM.7\n-\n9\n-\n15 No entanto, não houve diferenças significativas em relação às características gerais, às características da lesão coronariana e aos escores GRACE entre os três grupos do presente estudo. Esses resultados revelaram que a TAP foi significativamente superior à DAP na redução de eventos relacionados à isquemia, como a incidência de angina pectoris pós-infarto, arritmia grave, insuficiência cardíaca, choque cardiogênico e mortalidade em 30 dias, em pacientes idosos de ambos os sexos com diabetes e IAMCSST, quando comparados a mulheres com diabetes e IAMCSST que receberam DAP. Além disso, em comparação com as pacientes que receberam DAP, a permanência hospitalar média foi menor naqueles que receberam a TAP. Em adição a isso, a incidência de ICP seletiva, re-infarto e trombose de stent em pacientes idosos masculinos com diabetes e IAMCSST que receberam TAP foi significativamente menor, quando comparada com as pacientes femininas idosas com diabetes e IAMCSST que receberam a DAP. Isso sugere que a TAP poderia efetivamente reduzir o início de eventos isquêmicos em pacientes idosos com diabetes e IAMCSST. Além disso, os pacientes do sexo masculino se beneficiam mais do que os do sexo feminino.\n\nO escore CRUSADE é um índice importante para avaliar o risco de hemorragia 10. A idade avançada, a presença de diabetes mellitus e o sexo feminino são todos fatores de risco importantes para a hemorragia. Devido ao forte efeito antiplaquetário da tirofibana e à aplicação combinada de ticagrelor, as complicações hemorrágicas sempre foram motivo de preocupação por parte dos médicos cardiovasculares.3\n,\n7\n-\n9\n,\n15 Atenção especial deve ser dada à aplicação de DAP e TAP para minimizar a ocorrência de complicações hemorrágicas. A DAP tem sido aplicada apenas para pacientes femininas idosas com IAMCSST, cujo escore CRUSADE estava acima do risco médio, enquanto a TAP foi aplicada para pacientes com escores CRUSADE de baixo risco. Esses resultados revelaram que a incidência total de hemorragia e a incidência de hemorragia moderada em pacientes idosas com diabetes após a TAP foi significativamente maior, quando comparada àquela de pacientes do sexo feminino com risco relativamente alto de hemorragia e pacientes idosos do sexo masculino com diabetes recebendo TAP. Isto indicou que o risco de hemorragia é maior para pacientes femininas idosas com diabetes e IAMCSST. Vale ressaltar que existem condições fisiopatológicas especiais na terapia antiplaquetária para pacientes idosas com diabetes e IAMCSST, que são diferentes das do sexo masculino. Ao prevenir eventos causados por isquemia, atenção especial deve ser dada ao aumento do risco de hemorragia.\n\nLimitações do Estudo\nO estudo comparou apenas pacientes femininas idosas com diabetes que receberam DAP e TAP e não incluiu pacientes do sexo masculino recebendo DAP como controle. Além disso, o tamanho da amostra era pequeno e houve falta de acompanhamento a longo prazo. A equipe de autores está conduzindo pesquisas adicionais para resolver essas limitações.\n\nConclusão\nO presente estudo mostrou que a incidência de complicações em mulheres idosas com diabetes e IAMCSST que receberam TAP após ICP foi significativamente menor do que em pacientes que receberam DAP. No entanto, a incidência de hemorragia nas pacientes femininas que receberam TAP foi significativamente maior, quando comparada aos pacientes masculinos que receberam TAP e às pacientes femininas que receberam DAP.\n\nVinculação Acadêmica\n\nNão há vinculação deste estudo a programas de pós-graduação.\n\n\nFontes de Financiamento\n. O presente estudo não teve fontes de financiamento externas.\n\nOriginal Article\nTherapeutic Effects of Triple Antiplatelet Therapy in Elderly Female Patients with Diabetes and Acute Myocardial Infarction\nLiu Yang 1 Gao Yanyan 2 https://orcid.org/0000-0001-8400-8242Liu Hengliang 1 Chen Qi 1 Ji Jinrui 1 Jia Kailong 1 \n1 \nChina\nAffiliated People’s Hospital of Zhengzhou,The Second School of Clinical Medicine,Southern Medical University, Zhengzhou - China\n\n\n2 \nChina\nShenqiu County Hospital of Traditional Chinese Medicine, Shenqiu - China\n\nMailing Address: Hengliang Liu\n• Zhengzhou People’s Hospital, Southern Medical University - No.33, huanghe road, jinshui district Zhengzhou 450003 – China E-mail: lhldoc@163.comAuthor Contributions\n\nConception and design of the research: Liu Y, Chen Q, Ji J, Jia K; Acquisition of data: Liu Y, Gao Y, Liu H, Chen Q, Ji J, Jia K; Analysis and interpretation of the data: Liu H, Ji J, Jia K; Statistical analysis: Liu Y, Gao Y, Chen Q; Obtaining financing: Gao Y, Liu H; Writing of the manuscript: Liu Y, Liu H; Critical revision of the manuscript for intellectual content: Liu H.\n\nPotential Conflict of Interest\n\nNo potential conflict of interest relevant to this article was reported.\n\n\nAbstract\nBackground\nDual antiplatelet therapy (DAPT) is the cornerstone treatment of acute myocardial infarction (AMI).\n\nObjective\nThe present study aimed to investigate the efficacy and safety of triple antiplatelet therapy (TAPT) in elderly female patients with diabetes and ST segment elevation myocardial infarction (STEMI), who had undergone percutaneous coronary intervention (PCI).\n\nMethods\nWe designed a randomized, single-blind study. Control group A (97 elderly male patients with diabetes and STEMI, whose CRUSADE scores were < 30) received aspirin, ticagrelor, and tirofiban. A total of 162 elderly female patients with diabetes and STEMI were randomly divided into two groups according to CRUSADE score. Group B (69 patients with CRUSADE score > 31) received aspirin and ticagrelor. Group C (93 patients with CRUSADE score < 30) received aspirin, ticagrelor and tirofiban. P values < 0.05 were considered statistically significant.\n\nResults\nCompared to the findings in group A, post-PCI Thrombolysis in Myocardial Infarction (TIMI) grade 3 blood flow and TIMI myocardial perfusion grade 3 were significantly less prevalent in group B (p < 0.05). When compared to groups A and C, the incidence of major adverse complications was significantly higher in group B (p < 0.05).\n\nConclusion\nTAPT could effectively reduce the incidence of major complications in elderly female patients with diabetes and STEMI. However, close attention should be paid to hemorrhage in patients receiving TAPT. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)\n\nPlatelet AggregationStrokeWomanAgingDiabetes MellitusMyocardial InfarctionPercutaneous Coronary Intervention/methodsIntroduction\nDual antiplatelet therapy (DAPT) is a cornerstone in the treatment of acute myocardial infarction (AMI). Compared with clopidogrel, the inhibitory effect of ticagrelor on platelets in DAPT is rapid and potent, with dual-inhibition and reversible combination. Furthermore, it can dilate coronary arteries, and it is recommended by guidelines.1However, studies have shown that ticagrelor and clopidogrel might significantly increase the risk of hemorrhage, compared with clopidogrel.2\n\nThe incidence of slow blood flow, no-reflow, and thrombotic complications in female patients with diabetes and AMI is higher than in patients without diabetes or in male patients with diabetes and AMI who are receiving DAPT.3\n-\n5Glycoprotein IIb/IIIa receptor inhibitors, in addition to DAPT, can effectively reduce the onset of complications, such as slow blood flow, no reflow, acute and subacute thrombosis, and major adverse cardiac events (MACE).6\n-\n9However, it remains unknown whether the combination of triple antiplatelet therapy (TAPT) drugs, especially ticagrelor, would increase the risk of hemorrhage. The urgent issue in the treatment of AMI is how to balance the risk of ischemic events and hemorrhagic complications. In relation to DAPT (aspirin and ticagrelor), the present study aimed to investigate the short-term efficacy and safety of TAPT (aspirin, ticagrelor, and tirofiban) in elderly female patients with diabetes and AMI.\n\nMaterials and Methods\nSubjects and Grouping\nThis study was conducted in two centers, Zhengzhou People’s Hospital of Southern Medical University and Shenqiu County Hospital of Traditional Chinese Medicine, both in the Henan province. Elderly female patients with diabetes and STEMI, who were admitted to the coronary care unit and who received emergency percutaneous coronary intervention (PCI) treatment from January 2013 to December 2018, were included into this study. This study was randomized and single-blinded. Blood was drawn immediately after admission. The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) score10was calculated according to patients’ hematocrit, creatinine clearance rate, heart rate, blood pressure, existence of heart failure, diabetes mellitus, and previous vascular diseases. This was a prospective study. According to CRUSADE score, patients were randomly divided into the following two groups: group B (score higher than 30) and group C (score lower than 30). DAPT (aspirin and ticagrelor) was given to the patients in group B, and TAPT (aspirin, ticagrelor, and tirofiban) was given to the patients in group C. Elderly male patients with diabetes and STEMI, who received emergency PCI during the same period of hospitalization, were assigned to group A (control group), and they received the same drug therapy as the patients in group C. Diagnosis of STEMI was in accordance with the European Society of Cardiology guidelines,11and diagnosis of diabetes mellitus was in accordance with the World Health Organization criteria.12The inclusion criteria were as follows: (1) patients with the onset of STEMI at ≤ 12 hours, (2) patients with known diagnosis of diabetes mellitus, (3) patients who agreed to receive emergency PCI and DAPT or TAPT, and (4) patients between the ages of 60 and 79 years old. The exclusion criteria were as follows: (1) patients with the onset of STEMI at > 12 hours, (2) patients with blood pressure ≥ 180/110 mmHg, (3) patients with suspected aortic dissection, (4) patients with retrieved PCI after thrombolysis for STEMI, (5) patients with a history of cerebral hemorrhage and ischemic stroke within one year, (6) patients with severe hepatic and/or renal insufficiency, and (7) patients with a history of hemorrhagic diseases.9The present study conforms to the standards of medical ethics. With the approval of the Ethics Committee of Zhengzhou People’s Hospital, all treatments were performed with the informed consent of patients or their families.9\n\nEmergency Percutaneous Coronary Intervention\nEighteen-lead electrocardiogram was recorded immediately after admission, and vital signs were checked. Blood was drawn immediately after admission for assay of cardiac enzymes, troponin, and other related biochemical and routine testing items. In addition, 100 mg of aspirin (Bayer, Germany; 100 mg/tablet) and 180 mg of ticagrelor (Belinda Tablets, Astra Zeneca; 90 mg/tablet) were orally administered to patients in these three groups. Emergency coronary angiography and PCI were performed. If thrombi were found, a thrombus aspiration catheter was used to aspirate them (10 patients, 6 patients and 9 patients in groups A, B, and C, respectively). Tirofiban hydrochloride (10 µg/kg) was injected into the coronary artery in patients in groups A and C. After PCI, 0.075 µg/kg·min of tirofiban hydrochloride was continuously pumped into the vein for 24 hours7. Drug-eluting stents were used for all patients. Merely the culprit vessel was treated during the emergency. If a non-culprit vessel needed to be treated, selected PCI was performed 10 to 14 days later. In addition, 100 mg/d of aspirin and 90 mg/d of ticagrelor were given twice orally and continuously in patients in all three groups. Subsequently, DAPT was applied for at least 12 months. Furthermore, -receptor blockers, statins, hypoglycemic agents, and angiotensin converting enzyme inhibitors were continuously administered.9\n\nObservation Criteria\nThe data for first-medical-contact-to-balloon time, door-to-balloon time, age, sex, heart rate, systolic pressure, serum creatinine, Killip classification of cardiac function, myocardial enzymes, troponin, hematocrit, past history of vascular disease and diabetes mellitus, and the existence of cardiac arrest were collected and counted. The GRACE scores13and CRUSADE integral10were calculated based on the above data. The SYNTAX integral14was calculated according to the pathological characteristics of coronary angiography. Subsequently, the characteristics of the culprit vessel were determined. Data for diameter and length of stents were recorded. For instance, if more than two stents were needed for more than two culprit vessels, the length of the separate stents was added to obtain the length of stent. If the target lesion was longer and more than two stents were placed in series, the total length of the stent was subtracted by 4 mm. The diameter and length of stents for selective secondary surgery of non-culprit vessels were not included. Data were also recorded for length of stay and adverse events, including selective PCI during hospitalization, post-infarction angina pectoris, re-infarction during hospitalization, acute and sub-acute thrombosis in the stent, severe arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, newly emerged hemodynamically unstable atrial fibrillation or atrial flutter, and high grade atrioventricular block, excluding reperfusion arrhythmia during PCI), cardiac function above Killip grade III, cardiogenic shock, and 30-day mortality7\n-\n9of patients in these three groups. The Thrombolysis in Myocardial Infarction (TIMI) bleeding classification was recorded as follows: (1) severe hemorrhage: intracranial hemorrhage or clinically visible bleeding (including imaging diagnosis), decreased hemoglobin of ≥ 5 g/dl and decreased hematocrit by ≥ 15%); (2) moderate hemorrhage: clinically visible bleeding (including imaging diagnosis), decreased hemoglobin between 3 and 5 g/dl, slight bleeding; (3): mild hemorrhage: clinically visible bleeding (including imaging diagnosis), with decreased hemoglobin < 3 g/dl.7\n-\n9\n,\n15TIMI blood flow grading and TIMI myocardial perfusion grade (TMPG) of the infarction-related vessels after PCI were also recorded.7\n-\n9\n,\n15\n\nStatistical Methods\nSPSS 17.0 software was used for statistical analysis of all data. The measurement data were expressed as mean ± standard deviation. They presented a normal distribution according to Kolmogorov-Smirnov test, and the comparison between the two groups was conducted by unpaired Student’s t test. The count data was expressed as the number of cases (constituent ratio), and the comparison between the two groups was performed by chi-squared test. One-way ANOVA was employed to compare these three groups, and p < 0.05 was considered statistically significant.9\n\nResults\nClinical Characteristics\nGroup A (97 male patients with diabetes and STEMI; mean age: 65.9 ± 9.2 years), which was the control group, had low risk CRUSADE scores (less than 30). Group B (69 female patients; mean age: 65.27 ± 9.8 years) had moderate and above moderate risk CRUSADE scores (higher than 31). Group C (93 female patients; mean age: 64.8 ± 7.2 years) had low risk CRUSADE scores (lower than 30). There were no statistically significant differences in age, first-medical-contact-to-balloon time, door-to-balloon time, hypertension, hyperlipidemia, body mass index, previous history of PCI, family history of coronary heart disease, and GRACE score among the three groups (p\n>\n0.05,\nTable 1\n).\n\n\nTable 1 – Comparison of the general clinical characteristics among the three groups\nGroup\tMale (aspirin + ticagrelor + tirofiban) (Group A, 97 cases)\tFemale (aspirin + ticagrelor) (Group B, 69 cases)\tFemale (aspirin + ticagrelor + tirofiban) (Group C, 93 cases)\tp\t\nAge (years)\t65.9±9.2\t65.27±9.8\t64.8±7.2\t0.824\t\nSex (male/female)\t97/0\t0/69\t0/93\t0.000\t\nHistory of digestive tract disease [n(%)]\t5(5.15)\t3(4.35)\t4(4.3)\t0.953\t\nSmoking [n(%)]\t22(22.68)\t2(2.9)a\t3(3.23)a\t0.000\t\nAlcohol consumption [n(%)]\t37(38.14)\t7(10.14)\t13(13.98)\t0.000\t\nLVEF < 40%[n(%)]\t9(9.28)\t6(8.7)\t8(8.6)\t0.985\t\nWarfarin use [n(%)]\t2(2.06)\t1(1.45)\t2(2.15)\t0.943\t\nCombined PPI [n(%)]\t6(6.19)\t3(4.35)\t7(7.53)\t0.257\t\nFMC-to-B time\t124.3±67.2\t132.5±71.3\t128.5±82.6\t0.797\t\nD-to-B time\t65.6±21.4\t71.3±26.9\t62.6±27.2\t0.892\t\nHypertension [n(%)]\t57(58.77)\t37(53,62)\t55(59.14)\t0.745\t\nHyperlipidemia [n(%)]\t49(50.52)\t36(52.17)\t48(51.62)\t0.976\t\nBMI (kg/m2)\t32.46±4.65\t30.13±5.26\t29.99±6.31\t0.823\t\nSerum creatinine (mmol/L)\t83.29±9.7\t96..32±10.07a\t83.46±12.35b\t0.012\t\nHistory of PCI [n(%)]\t4(4.12)\t2(2.90)\t6(6.46)\t0.543\t\nPre-infarction angina [n(%)]\t19(19.59)\t2(2.90)a\t4(4.30)a\t0.000\t\nFamily history of coronary heart disease [n(%)]\t5(5.15)\t3(4.35)\t5(5.38)\t0.954\t\nGRACE score\t \t \t \t \t\nLow risk (< 85)[n(%)]\t9(9.28)\t8(11.59)\t9(9.68)\t0.526\t\nMiddle risk (85 to 133)[n(%)]\t17(17.53)\t12(17.39)\t15(16.13)\t0.963\t\nHigh risk (>133)[n(%)]\t71(73.20)\t49(71.01)\t69(74.19)\t0.902\t\nCRUSADE score\t \t \t \t \t\nExtremely low risk (1-20 )[n(%)]\t37(38.14)\t0(0)a\t42(45.16)b\t0.000\t\nLow risk (21-30)[n(%)]\t60(61.86)\t0(0)a\t51(54.84)b\t0.000\t\nMiddle risk (31-40)[n(%)]\t0(0)\t32(46.38)a\t0(0)b\t0.000\t\nHigh risk (41-50)[n(%)]\t0(0)\t24(34.78)a\t0(0)b\t0.016\t\nExtremely high risk (>51)[n(%)]\t0(0)\t13(18.84)a\t0(0)b\t0.000\t\n\nBMI: body mass index; D-to-B: door-to-balloon; FMC-to-B: first-medical-contact-to-balloon; LVEF: left ventricular ejection fraction; PCI: percutaneous coronary intervention; PPI: proton pump inhibitors. Note:a: p < 0.05 compared with group A;b: p < 0.05 compared with group B.\n\n\n\n\n\nCharacteristics of Coronary Artery Lesions\nNo significant differences were observed when comparing the number of lesions in three coronary arteries among the three groups. However, compared to group A, the diameter of the implanted stent in groups B and C was significantly smaller (p\n<\n0.05). In addition, TIMI grade 3 blood flow and TMPG grade 3 after PCI were significantly less prevalent in group B than in groups A and C (p\n<\n0.05,\nTable 2\n).\n\n\nTable 2 – Comparison of the characteristics of coronary artery lesions among the three groups (number of cases, %)\nLesion characteristics\tMale (aspirin + ticagrelor + tirofiban) (Group A, 97 cases)\tFemale (aspirin + ticagrelor) (Group B, 69 cases)\tFemale (aspirin + ticagrelor + tirofiban) (Group C, 93 cases)\tp\t\nSingle branch lesion\t9(9.28)\t6(8.70)\t8(8.60)\t0.992\t\nDouble branch lesion\t11(11.34)\t7(10.14)\t9(9.68)\t0.946\t\nThree branch lesion\t77(79.38)\t56(81.16)\t75(80.65)\t0.956\t\nComplicated with left main lesion\t6(6.19)\t3(4.35)\t6(6.45)\t0.867\t\nSYNTAX score\t22.21±6.18\t21.75±8.57\t22.31±7.27\t0.863\t\nPCI Target vessel Left anterior descending branch\t51(52.58)\t36(52.17)\t49(52.69)\t0.998\t\nRight circumflex branch\t14(14.43)\t11(15.94)\t8(8.60)\t0.314\t\nRight coronary artery\t32(32.99)\t22(31.88)\t36(38.71)\t0.564\t\nDiameter of stents (mm, x±s)\t3.01±0.33\t2.69±0.27a\t2.70±0.39a\t0.046\t\nLength of stents (mm, x±s)\t28.29±3.74\t27.36±5.13\t28.12±5.07\t0.783\t\nPreoperative TIMI classification\t \t \t \t \t\nGrade 0\t95(97.94)\t68(98.55)\t92(98.92)\t0.857\t\nGrade 1 or 2\t2(2.06)\t1(1.45)\t1(1.08)\t0.957\t\nGrade 3\t0\t0\t0\t \t\nPostoperative TIMI grading\t \t \t \t \t\nGrade 0 to 2\t2(2.06)c\t10(14.49)ac\t4(4.30)bc\t0.003\t\nGrade 3\t95(97.94)c\t59(85.51)ac\t89(95.70)bc\t0.003\t\nPreoperative TMPG classification\t \t \t \t \t\nGrade 0 to 2\t97(100)\t69(100)\t93(100)\t \t\nGrade 3\t0\t0\t0\t \t\nPostoperative TMPG grading\t \t \t \t \t\nGrade 0 to 2\t6(6.19)\t20(28.99)ad\t14(15.05 )abd\t0.0003\t\nGrade 3\t91(93.81)d\t49(71.01)ad\t79(84.95)abd\t0.0001\t\n\nPCI: percutaneous coronary intervention. Note:a: p < 0.05 compared with group A;b: p < 0.05 compared with group B;c: comparisons with intra-group preoperative TIMI of the same grade, p < 0.05;d: comparisons with intra-group preoperative TMPG of the same grade, p < 0.05.\n\n\n\n\n\nLength of Hospital Stay, Characteristics of PCI, and Incidence of Complications\nThe average length of hospital stay was significantly higher in group B than in group A and C (p\n<\n0.05). In addition, group B had 14 cases of post-infarction angina pectoris, whereas the other two groups had 5 cases each Nine cases of severe arrhythmia occurred in group B, which was higher than that in other two groups (2 cases in group A and 3 cases in group C). There were 14 cases of heart failure, cardiogenic shock, and 30-day mortality in group B, which was higher than in groups A and C (5 cases and 4 cases, respectively). Furthermore, the incidence of selective PCI, re-infarction, and stent thrombosis during hospitalization was significantly higher in group B, when compared to group A (p\n<\n0.05). In group B, there were 14 cases of post-infarction angina pectoris, 7 cases of re-infarction and 3 cases of stent thrombosis. Moreover, the total incidence of hemorrhage and the incidence of moderate hemorrhage were significantly higher in group C, when compared to groups A and B (p\n<\n0.05,\nTable 3\n). There were 8 cases of moderate hemorrhage in group C, whereas groups A and group B had 1 case each.\n\n\nTable 3 – Comparison of length of hospital stay, characteristics of PCI, and incidence of complications in the three groups\nItem\tMale (aspirin + ticagrelor + tirofiban) (Group A, 97 cases)\tFemale (aspirin + ticagrelor) (Group B, 69 cases)\tFemale (aspirin + ticagrelor + tirofiban) (Group C,93 cases)\tp\t\nAverage length of hospital stay (days)\t7.8±1.5\t11.2±3.3a\t8.3±1.9ab\t0.042\t\nSelective secondary surgery [n(%)]\t12(12.37)\t19(27.54)a\t9(20.93)\t0.047\t\nPost-infarction angina pectoris [n(%)]\t5(5.05)\t14(19.72)a\t5(5.38)b\t0.001\t\nRe-infarction [n(%)]\t0(0)\t7(10.14)a\t6(6.45)\t0.009\t\nStent thrombosis [n(%)]\t0(0)\t3(4.35)a\t1(1.08)\t0.073\t\nSevere arrhythmia [n(%)]\t2(2.06)\t9(13.04)a\t3(3.23)b\t0.004\t\nCardiac function above Killip grade III [n(%)]\t2(2.60)\t14(20.29)a\t8(8.60)ab\t0.0001\t\nPostoperative cardiogenic shock [n(%)]\t0(0)\t5(7.25)a\t1(1.08)b\t0.006\t\n30-day mortality [n(%)]\t0(0)\t4(5.80)a\t1(1.08)\t0.004\t\nTotal hemorrhage [n(%)]\t7(7.22)\t6(8.70)\t20(21.98)ab\t0.005\t\nSevere hemorrhage\t0(0)\t0(0)\t1(1.08)\t0.408\t\nModerate hemorrhage\t1(1.03)\t1(1.45)\t8(8.60)ab\t0.012\t\nMild hemorrhage\t6(6.19)\t5(7.25)\t11(11.83)\t0.344\t\n\na: p < 0.05 compared with group A; b: p < 0.05 compared with group B.\n\n\n\n\n\nDiscussion\nMore than 50% of cardiovascular deaths occur in females. Regardless of the positive results of the pathophysiology, complaints, symptoms, signs and results of auxiliary examinations, or the short-term and long-term therapeutic effects, female patients have their own particularities.16\n,\n17Timely PCI in female patients with acute coronary syndrome can effectively reduce the incidence of MACE.9\n,\n15\n,\n17\n,\n18However, women, especially elderly women, often have no typical chest pain during ischemic attack, which may delay diagnosis and treatment. In the present study, the incidence of angina pectoris before infarction was significantly lower in women, when compared to men. Furthermore, non-specific symptoms, such as post-sternal discomfort, chest tightness, shortness of breath, nausea, vomiting, and fatigue, were more common in females with AMI. In addition, the sensitivity and specificity of electrocardiogram and exercise electrocardiogram in the diagnosis of coronary heart disease are lower in women. The lack of specific symptoms and the corresponding electrocardiogram changes in the pathophysiological condition of ischemia and the lack of timely and necessary medicines and lifestyle intervention, even in critical conditions, such as complete or subtotal vascular occlusion, often lead to late consultation, missing the most treatable stage and resulting in a lack of early intervention, such as emergency PCI, which is one of the main causes of the higher incidence of complications and mortality in female patients with AMI.17\n,\n18\n\nDiabetes mellitus is an isocritical condition of coronary heart disease. The therapeutic effects of antiplatelet drugs in patients with diabetes are worse than in patients without diabetes. Furthermore, the incidence of slow blood flow and no reflow after emergency PCI and MACE are significantly higher than in patients without diabetes.7\n-\n9\n,\n15This suggests that enhanced antiplatelet therapy is needed for patients with diabetes. Diabetes mellitus is one of the most important risk factors for patients with acute coronary syndrome, regardless of whether the GRACE score is used for evaluating ischemic events or the CRUSADE score is used for predicting the risk of bleeding. DAPT is the cornerstone for preventing ischemia and thrombosis after PCI.19After receiving DAPT, some patients still have serious complications of thrombosis, especially in female patients with diabetes and elderly patients with diabetes. IIb/IIIa receptor inhibitors in addition to DAPT can effectively reduce the occurrence of slow blood flow and no reflow, the incidence of acute and subacute thrombosis, and the occurrence of MACE.7\n-\n9\n-\n15However, there were no significant differences in general characteristics, coronary lesion characteristics and GRACE scores among the three groups in the present study. These results revealed that TAPT was significantly superior to DAPT in reducing related ischemia-driven events, such as the incidence of post-infarction angina pectoris, severe arrhythmia, heart failure, cardiogenic shock, and 30-day mortality, in both elderly male and female patients with diabetes and STEMI, when compared to women with diabetes and STEMI who received DAPT. Furthermore, compared to patients receiving DAPT, the average hospital stay was shorter in those receiving TAPT. Moreover, the incidence of selective PCI, re-infarction, and stent thrombosis in elderly male patients with diabetes and STEMI who received TAPT was significantly lower, when compared to elderly female patients with diabetes and STEMI who received DAPT. This suggested that TAPT could effectively reduce the onset of ischemic events in elderly patients with diabetes and STEMI. Furthermore, male patients benefit more than female patients.\n\nThe CRUSADE score is an important index for evaluating the risk of hemorrhage.10Older age, the existence of diabetes mellitus, and female sex are all important risk factors for hemorrhage. Due to the strong antiplatelet effect of tirofiban and the combined application of ticagrelor, hemorrhagic complications have always been a matter of concern for cardiovascular physicians.3\n,\n7\n-\n9\n,\n15Close attention should be given to the application of DAPT and TAPT in order to minimize the occurrence of hemorrhagic complications. DAPT has been applied only for elderly female patients with STEMI, whose CRUSADE score was above middle-risk, while TAPT has been applied for patients with low-risk CRUSADE scores. These results revealed that the total incidence of hemorrhage and the incidence of moderate hemorrhage in elderly female patients with diabetes after TAPT was significantly higher, when compared to that of female patients with relatively high risk of hemorrhage and elderly male patients with diabetes receiving TAPT. However, there was no significant difference in the risk of hemorrhage between male and female patients receiving TAPT. This indicated that the risk of hemorrhage is higher for elderly female patients with diabetes and STEMI. It is noteworthy that there are special pathophysiological conditions in antiplatelet therapy for elderly female patients with diabetes and STEMI, which are different from those of males. While preventing ischemia-driven events, close attention must be given to the increased risk of hemorrhage.\n\nStudy Limitations\nThe study only compared elderly female patients with diabetes who received TAPT and DAPT, and it did not include male patients receiving DAPT as a control. Furthermore, the sample size was small, and there was a lack of long-term follow-up. The team of authors is conducting further research to address these limitations.\n\nConclusion\nThe present study showed that the incidence of complications in elderly female patients with diabetes and STEMI receiving TAPT after PCI was significantly lower than in patients receiving DAPT. However, the incidence of hemorrhage in female patients receiving TAPT was significantly higher, when compared to male patients receiving TAPT and female patients receiving DAPT.\n\nStudy Association\n\nThis study is not associated with any thesis or dissertation work.\n\n\nSources of Funding\n.There were no external funding sources for this study.\n==== Refs\nReferências\n1 . Yoshikawa Y, Shiomi H, Watanabe H, Natsuaki M, Kondo H, Tamura T, et al. Application of DAPT score to predict ischaemic and bleeding events in patients who underwent drug-eluting stent implantation: a landmark analysis of large pooled cohort. EHJ. 2017;38(suppl_1):611-2.Yoshikawa Y Shiomi H Watanabe H Natsuaki M Kondo H Tamura T et al Application of DAPT score to predict ischaemic and bleeding events in patients who underwent drug-eluting stent implantation: a landmark analysis of large pooled cohort \nEHJ\n 2017 38 suppl_1 611 612 \n2 . Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57.Wallentin L Becker RC Budaj A Cannon CP Emanuelsson H Held C et al Ticagrelor versus clopidogrel in patients with acute coronary syndromes \nN Engl J Med\n 2009 9 10 361 11 1045 1057 19717846 \n3 . Brener SJ, Mehran R, Dressler O, Cristea E, Stone GW. Diabetes mellitus, myocardial reperfusion, and outcome in patients with acute ST-elevation myocardial infarction treated with primary angioplasty (from HORIZONS AMI).Am J Cardiol. 2012;109(8):1111-6.Brener SJ Mehran R Dressler O Cristea E Stone GW Diabetes mellitus, myocardial reperfusion, and outcome in patients with acute ST-elevation myocardial infarction treated with primary angioplasty (from HORIZONS AMI) \nAm J Cardiol\n 2012 109 8 1111 1116 22244381 \n4 . Farhan S, Höchtl T, Kautzky-Willer A, Wojta J, Huber K. Antithrombotic therapy in patients with coronary artery disease and with type 2 diabetes mellitus. Wien Med chenschr. 2010;160(1-2):30-8.Farhan S Höchtl T Kautzky-Willer A Wojta J Huber K Antithrombotic therapy in patients with coronary artery disease and with type 2 diabetes mellitus \nWien Med chenschr\n 2010 160 1-2 30 38 \n5 . Liu HL, Liu Y, Hao ZX, Geng GY, Zhang ZF, Jing SB, et al. Comparison of primary coronary percutaneous coronary intervention between Diabetic Men and Women with acute myocardial infarction. Pak J Med Sci. 2015;31(2):420-5.Liu HL Liu Y Hao ZX Geng GY Zhang ZF Jing SB et al Comparison of primary coronary percutaneous coronary intervention between Diabetic Men and Women with acute myocardial infarction \nPak J Med Sci\n 2015 31 2 420 425 26101503 \n6 . Park KH, Jeong MH, Ahn Y, Ahn TH, Seung KB, Oh DJ, et al. Comparison of short-term clinical outcomes between ticagrelor versus.clopidogrel in patients with acute myocardial infarction undergoing successful revascularization; from Korea acute myocardial infarction Registry-Nationgl,Institute of Health. Int J Cardiol.2016;215:193-200.Park KH Jeong MH Ahn Y Ahn TH Seung KB Oh DJ et al Comparison of short-term clinical outcomes between ticagrelor versus.clopidogrel in patients with acute myocardial infarction undergoing successful revascularization; from Korea acute myocardial infarction Registry-Nationgl,Institute of Health \nInt J Cardiol\n 2016 215 193 200 27128530 \n7 . Liu Y, Liu H, Hao Z, Geng G, Chen Q, Han W, et al. Efficacy and safety of different doses of tirofiban combined with ticagrelor on diabetic patients with AMI receiving in emergency percutaneous coronary intervention (PCI). Int J Clin Exp Med. 2015;8(7):11360-9.Liu Y Liu H Hao Z Geng G Chen Q Han W et al Efficacy and safety of different doses of tirofiban combined with ticagrelor on diabetic patients with AMI receiving in emergency percutaneous coronary intervention (PCI) \nInt J Clin Exp Med\n 2015 8 7 11360 11369 26379951 \n8 . Liu Y, Liu HL, Hao Y, Hao Z, Geng G, Han W, et al. Short-term efficacy and safety of three different antiplatelet regimens in diabetic patients treated with primary percutaneous coronary intervention: a randomised study. Kardiol Pol. 2017;75(9):850-8.Liu Y Liu HL Hao Y Hao Z Geng G Han W et al Short-term efficacy and safety of three different antiplatelet regimens in diabetic patients treated with primary percutaneous coronary intervention: a randomised study \nKardiol Pol\n 2017 75 9 850 858 28612911 \n9 . Liu Y, Liu HL, Geng YG, Ba N, Jing SB, Guo W, et al. Effect of intracoronary injection of tirofiban on acute myocardial infarction in elderly patients with diabetes mellitus. Chinese Journal of Geriatric Heart Brain and Vessel Diseases. 2013;15:799-802.Liu Y Liu HL Geng YG Ba N Jing SB Guo W et al Effect of intracoronary injection of tirofiban on acute myocardial infarction in elderly patients with diabetes mellitus \nChinese Journal of Geriatric Heart Brain and Vessel Diseases\n 2013 15 799 802 \n10 . Subherwal S, Bach RG, Chen AY, Gage BF, Rao SV, Newby LK, et al. Baseline risk of major leeding in non·-ST·-segment··elevation myocardial infarction:the CRUSADE (Can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the ACC/AHA Guidelines)Bleeding Score. Circulation. 2009;119(14):1873-82.Subherwal S Bach RG Chen AY Gage BF Rao SV Newby LK et al Baseline risk of major leeding in non·-ST·-segment··elevation myocardial infarction:the CRUSADE (Can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the ACC/AHA Guidelines)Bleeding Score \nCirculation\n 2009 119 14 1873 1882 19332461 \n11 . Wessler JD, Stant J, Duru S, Rabbani L, Kirtane AJ. Updates to the ACCF/AHA and ESC STEMI and NSTEMI Guidelines: Putting Guidelines Into Clinical Practice. Am J Cardiol. 2015;115(5 Suppl):23A-8A.Wessler JD Stant J Duru S Rabbani L Kirtane AJ Updates to the ACCF/AHA and ESC STEMI and NSTEMI Guidelines: Putting Guidelines Into Clinical Practice \nAm J Cardiol\n 2015 115 5 Suppl 23A 28A \n12 . America Disbetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33:204-9.America Disbetes Association Diagnosis and classification of diabetes mellitus \nDiabetes Care\n 2010 33 204 209 \n13 . Bekler A, Altun B, Gazi E, Temiz A, Barutçu A, Güngör Ö, et al. Comparison of the GRACE risk score and the TIMI risk index in predicting the extent and severity of coronary artery disease in patients with acute coronary syndrome. Anatol J Cardiol. 2014;15(10):801-6.Bekler A Altun B Gazi E Temiz A Barutçu A Güngör Ö et al Comparison of the GRACE risk score and the TIMI risk index in predicting the extent and severity of coronary artery disease in patients with acute coronary syndrome \nAnatol J Cardiol\n 2014 15 10 801 806 25592101 \n14 . Schwietz T, Spyridopoulos I, Pfeiffer S, Laskowski R, Palm S, DE Rosa S, et al. Risk stratification following complex PCI: clinical versus anatomical risk stratification including ‘post PCI residual SYNTAX-score’ as quantification of incomplete revascularization. J Interv Cardiol. 2013; 26(1):29-37.Schwietz T Spyridopoulos I Pfeiffer S Laskowski R Palm S DE Rosa S et al Risk stratification following complex PCI: clinical versus anatomical risk stratification including ‘post PCI residual SYNTAX-score’ as quantification of incomplete revascularization \nJ Interv Cardiol\n 2013 26 1 29 37 23419105 \n15 . Chen Q, Liu Y, Liu HL. Effects of intracoronary tirofiban administration on diabetes mellitus complicated by acute myocardial infarction in female patients undergoing emergency percutaneous coronary intervention. Int J Clin Exp Med. 2016;9:11966-73.Chen Q Liu Y Liu HL Effects of intracoronary tirofiban administration on diabetes mellitus complicated by acute myocardial infarction in female patients undergoing emergency percutaneous coronary intervention \nInt J Clin Exp Med\n 2016 9 11966 11973 \n16 . Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2012 update: a report from the American Heart Association. Circulation. 2012;125(1): e2-e220.Roger VL Go AS Lloyd-Jones DM Benjamin EJ Berry JD Borden WB et al American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2012 update: a report from the American Heart Association \nCirculation\n 2012 125 1 e2 e220 22179539 \n17 . D’Ascenzo F, Gonella A, Quadri G, Longo G, Biondi-Zoccai G, Moretti C, et al. Comparison of mortality rates in women versus men presenting with ST-segment elevation myocardial infarction. Am J Cardiol. 2011;107(5):651-4.D’Ascenzo F Gonella A Quadri G Longo G Biondi-Zoccai G Moretti C et al Comparison of mortality rates in women versus men presenting with ST-segment elevation myocardial infarction \nAm J Cardiol\n 2011 107 5 651 654 21195375 \n18 . Fath-Ordoubadi F, Barac Y, Danzi GB, Kerner A, Nikolsky E, Halabi M, et al. Gender impact on prognosis of acute coronary syndrome patients treated with drug-eluting stents. Am J Cardiol. 2012;110(5):636-42.Fath-Ordoubadi F Barac Y Danzi GB Kerner A Nikolsky E Halabi M et al Gender impact on prognosis of acute coronary syndrome patients treated with drug-eluting stents \nAm J Cardiol\n 2012 110 5 636 642 22651877 \n19 . Sathyamurthy I, Jayanthi K. Dual antiplatelet therapy in acute coronary syndromes and coronary artery interventions. J Assoc Physicians India. 2014, 62(7):596-601.Sathyamurthy I Jayanthi K Dual antiplatelet therapy in acute coronary syndromes and coronary artery interventions \nJ Assoc Physicians India\n 2014 62 7 596 601 25672032\n\n",
"fulltext_license": "CC BY",
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"issue": "116(2)",
"journal": "Arquivos brasileiros de cardiologia",
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"medline_ta": "Arq Bras Cardiol",
"mesh_terms": "D000368:Aged; D003920:Diabetes Mellitus; D005260:Female; D006801:Humans; D008297:Male; D009203:Myocardial Infarction; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D000072657:ST Elevation Myocardial Infarction; D016037:Single-Blind Method; D016896:Treatment Outcome",
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"pages": "229-235",
"pmc": null,
"pmid": "33470329",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "25592101;25672032;21195375;25728971;22244381;22651877;26379951;28612911;19717846;23419105;22179539;20229159;27128530;19332461;26101503",
"title": "Therapeutic Effects of Triple Antiplatelet Therapy in Elderly Female Patients with Diabetes and Acute Myocardial Infarction.",
"title_normalized": "therapeutic effects of triple antiplatelet therapy in elderly female patients with diabetes and acute myocardial infarction"
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"abstract": "Many drugs are known to cause systemic lupus erythematosus (SLE), however there are no well defined criteria for drug induced lupus erythematosus (DILE). We present a rare case of lamotrigine induced lupus presenting as acute syndrome of apoptotic pan epidermolysis (ASAP).",
"affiliations": "Department of Dermatology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India.;Department of Dermatology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India.;Department of Pharmacology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India.;Department of Pathology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India.",
"authors": "Batra|Jaskaran|J|;Kaur|Sukhjot|S|;Kaushal|Sandeep|S|;Singh|Aminder|A|",
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"fulltext": "\n==== Front\nIndian Dermatol Online JIndian Dermatol Online JIDOJIndian Dermatology Online Journal2229-51782249-5673Medknow Publications & Media Pvt Ltd India IDOJ-9-44510.4103/idoj.IDOJ_24_18Case ReportLamotrigine-induced Systemic Lupus Erythematosus: A Diagnostic Dilemma Batra Jaskaran Kaur Sukhjot Kaushal Sandeep 1Singh Aminder 2Department of Dermatology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India1 Department of Pharmacology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India2 Department of Pathology, Dayanand Medical College and Hospital, Ludhiana, Punjab, IndiaAddress for correspondence: Dr. Sukhjot Kaur, Department of Dermatology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India. E-mail: sukhjotgoraya@gmail.comNov-Dec 2018 9 6 445 447 1 2018 2 2018 Copyright: © 2018 Indian Dermatology Online Journal2018This 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.Many drugs are known to cause systemic lupus erythematosus (SLE), however there are no well defined criteria for drug induced lupus erythematosus (DILE). We present a rare case of lamotrigine induced lupus presenting as acute syndrome of apoptotic pan epidermolysis (ASAP).\n\nAcute syndrome of apoptotic pan epidermolysislamotrigineSystemic Lupus erythematosus\n==== Body\nIntroduction\nMany drugs are known to cause systemic lupus erythematosus (SLE).[1] Lamotrigine is a newer anticonvulsant drug that selectively blocks voltage-dependent sodium channels, preventing excitatory neurotransmitter release. It has various neurologic, gastrointestinal, and cutaneous adverse reactions. It has been reported to cause Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and rarely SLE.\n\nCase Report\nA 22-year-old female, known case of generalized tonic-clonic seizures since three—and—a--half years, presented to us with complaint of erythematous rash on face, trunk, and upper limbs since 6 weeks with exacerbation since five days. There was history of photosensitivity since six weeks and oral ulceration on palate since five days. There was no history of fever, joint pains, and dyspnea. Lamotrigine 50 mg once daily was started eight weeks ago for relapse of generalized tonic--clonic seizures and the dose was increased to 50 mg twice daily one week before the presentation. She was previously treated with sodium valproate for three years. On examination, diffuse erythematous maculopapular rash associated with vesiculation, crusting, and erosions was present on face, bilateral upper limbs, and back [Figures 1 and 2]. Periungual erosions and splinter hemorrhages were present [Figure 3]. The buccal, ocular, and genital mucosa were characteristically spared. Systemic examination was unremarkable. Routine blood counts, urine analysis, ECG, and chest X-ray were normal and viral markers for hepatitis B, C, and HIV were nonreactive. Her antinuclear antibodies antinuclear antibodies (ANA) were strongly positive (++++) by immunofluorescence (coarse speckled pattern) and anti--SS-A/Ro60, SS-A/Ro 52, and SS-B/La (++) were also positive, while antihistone and anti--DsDNA antibodies were negative. A skin biopsy was done which showed necrosis of the epidermis with basal layer vacuolar degeneration and presence of interface lymphocytic infiltrate [Figure 4]. In view of sparing of mucosa, photosensitivity and positive ANA, and histopathological findings of interface dermatitis, a diagnosis of SLE presenting as SJS/TEN also known as acute syndrome of apoptotic pan epidermolysis (ASAP) triggered by lamotrigine was made. The patient was started on prednisolone 40 mg and lamotrigine was stopped. Levetiracetam was added to control the seizures. Erythema and edema subsided and the skin started desquamating by the fifth day [Figure 5].\n\nFigure 1 Erythematous maculopapular rash involving the entire face and neck with erosions, crusting, and vesiculation\n\nFigure 2 Diffuse maculopapular erythema on right arm\n\nFigure 3 Periungual erosions and splinter hemorrhage\n\nFigure 4 Basal layer vacuolar degeneration with presence of necrotic keratinocytes and mild superficial perivascular lympho-histiocytic infiltrate [hematoxylin and eosin (H and E 400×)]\n\nFigure 5 Resolution of lesions within 1 week\n\nDiscussion\nCertain drugs have been known to cause SLE.[12] Drugs causing SLE can be divided into different groups based on the level of evidence. The first group of drugs such as isoniazid and quinidine has been demonstrated in well-controlled prospective clinical trials. The second group consists of drugs such as sulfasalazine and several anticonvulsants are probably associated with drug-induced lupus erythematous (DILE), for which evidence is available in the form of case reports, case series, or small studies. For the drugs in the third group (such as lithium and captopril), only anecdotal reports are available. The fourth group contains recently reported drugs. Although there are no universally agreed criteria for DILE, the following proposed criteria[234] are generally used-: presence presence of at least one clinical symptom of SLE plus positive ANA or other lupus serology, administration of the suspect drug over a period of time, roughly from 33 weeks to 2 years before development of any sign or symptom of SLE, prompt improvement in clinical signs after discontinuation of suspected drug, and recurrence of symptoms upon re--challenge.\n\nLamotrigine is a rare cause of drug-induced SLE. Sarzi-Puttini et al.[5] reported a case of 57-year-old woman woman with malar rash, photosensitivity, and positive ANA on lamotrigine since 3 3 years, which resolved on its withdrawal. Ravindran[6] reported an an 18-year-old female taking lamotrigine for 18 months developed facial rash, painless oral ulcers, and small joint arthralgia's arthralgia. She had positive ANA and proteinuria and she improved on stopping lamotrigine. The patient reported by Chang et al. et al.[7] had no skin lesions but recurrent arthralgia and positive ANA. Rarely SLE may present with TEN-like features which has been labeled as ASAP or TEN--like acute cutaneous lupus erythematosus (ACLE). Ting et al.[8] proposed the acronym ASAP for acute syndrome of apoptotic pan epidermolysis to designate a clinical constellation having several causes characterized by acute and massive cleavage of the epidermis resulting from hyperacute epidermal basal cell apoptotic injury. They hypothesized that their patient had an underlying SLE predisposition that remained subclinical until she had oral nonsteroidal antiinflammatory drug intake and tanning bed exposure. ASAP can present from drug hypersensitivity (TEN), following graft versus host disease graft versus host disease, pseudoporphyria, or as TEN-like ACLE. Most cases of ASAP occurring in patients of SLE are drug-induced TEN.[9] Rarely, SLE may present with a presentation similar to TEN but with a subacute onset with lack of systemic involvement and sparing of mucosa. Such patients have an autoimmune serology consistent with SLE that helps reach a diagnosis of SLE. Our patient presented with cutaneous features mimicking SJS/TEN following lamotrigine ingestion and fulfilled four clinical (malar rash, alopecia, photosensitivity, and oral ulcers) and one immunological criteria (positive ANA) according to the Systemic Lupus International Collaborating Clinics criteria for SLE. To the authors’ knowledge, this is the first case in literature of lamotrigine-induced SLE presenting as ASAP. Antihistone antibodies have been reported to be positive in only about 75% of the cases of drug-related lupus.[24] According to Naranjo Probability Scale (score = 5), it is probable that lamotrigine in our case is the triggering drug.[10] Certain features that distinguish this case from SJS/TEN are lack of any characteristic mucosal involvement, presence of periungual lesions and splinter hemorrhages, and biopsy findings of vacuolar interface dermatitis and positive ANA.\n\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 Petri M Orbai AM Alarcon GS Gordon C Merrill JT Fortin PR Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus Arthritis Rheum 2012 64 2677 86 22553077 \n2 Hess E Drug-related lupus N Engl J Med 1988 318 1460 2 3259288 \n3 Pramatarov KD Drug-induced lupus erythematosus Clin Dermatol 1998 16 367 77 9642530 \n4 Antonov D Kazandjieva J Etugov D Gospodinov D Tsankov N Drug-induced lupus erythematosus Clin Dermatol 2004 22 157 66 15234017 \n5 Sarzi-Puttini P Panni B Cazzola M Muzzupappa S Turiel M Lamotrigine-induced lupus Lupus 2000 9 555 7 11035425 \n6 Ravindran V Lamotrigine-induced lupus: A case report Int J Rheum Dis 2011 14 e47 8 21816015 \n7 Chang RS Cole AJ Lamotrigine-induced lupus-like syndrome: A case report and literature review Am J Ther 2014 21 e85 7 23011169 \n8 Ting W Stone MS Racila D Scofield RH Sontheimer RD Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus and the spectrum of the acute syndrome of apoptotic pan-epidermolysis (ASAP): A case report, concept review and proposal for new classification of lupus erythematosus vesiculobullous skin lesions Lupus 2004 13 941 50 15645750 \n9 Paradela S Martínez-Gómez W Fernández-Jorge B Castiñeiras I Yebra-Pimentel T Llinares P Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus Lupus 2007 16 741 5 17728369 \n10 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E A method for estimating the probability of adverse drug reactions Clin Pharacol Ther 1981 30 239 45\n\n",
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"issue": "9(6)",
"journal": "Indian dermatology online journal",
"keywords": "Acute syndrome of apoptotic pan epidermolysis; Systemic Lupus erythematosus; lamotrigine",
"medline_ta": "Indian Dermatol Online J",
"mesh_terms": null,
"nlm_unique_id": "101586880",
"other_id": null,
"pages": "445-447",
"pmc": null,
"pmid": "30505789",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "21816015;15645750;9642530;3259288;7249508;22553077;15234017;11035425;17728369;23011169",
"title": "Lamotrigine-induced Systemic Lupus Erythematosus: A Diagnostic Dilemma.",
"title_normalized": "lamotrigine induced systemic lupus erythematosus a diagnostic dilemma"
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"abstract": "A 28-year-old man with schizophrenia intentionally ingested a lethal dose of acetaminophen and an unknown quantity of ibuprofen. He arrived at the hospital with acute renal and fulminant liver failure complicated by rhabdomyolysis. His creatine kinase level was 20,306 U/L on admission, which increased to 245,595 U/L by hospital day 2, and subsequently decreased to 339 U/L by day 16. The patient underwent liver transplantation on day 3; necrotic bowel was found during surgery. Rhabdomyolysis associated with acetaminophen overdose has been described only in a few case reports, but rarely in association with acetaminophen taken alone. The literature does not provide a clear association between acetaminophen and rhabdomyolysis because of other possible traumatic and nontraumatic causes. In this case, the Naranjo adverse drug reaction probability scale indicated a probable adverse reaction of rhabdomyolysis associated with acetaminophen overdose. In addition, nonsteroidal antiinflammatory agents (NSAIDs) are well known to be ulcerogenic in the upper gastrointestinal tract, but potential effects on the lower tract are less well known. Only a few NSAID-induced cases of ischemic colitis have been reported. Several mechanisms of action have been proposed, such as direct mucosal damage and inhibition of intestinal prostaglandin production. In this patient, the Naranjo scale indicated a probable adverse reaction of ischemic colitis associated with ibuprofen overdose. Patients who have taken an acetaminophen overdose should be assessed for rhabdomyolysis as a possible complication. In addition, an evaluation of ibuprofen-induced bowel necrosis in these patients may be warranted.",
"affiliations": "College of Pharmacy, University of Iowa, Iowa City, Iowa 52242-1056, USA.",
"authors": "Nelson|Holli|H|;Katz|Daniel|D|;Dunn|Ty|T|;Singh|Gajendra|G|;Voigt|Michael|M|;Whitaker|Eric|E|;Thomsen|David|D|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D007052:Ibuprofen",
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"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D018712:Analgesics, Non-Narcotic; D001774:Blood Chemical Analysis; D062787:Drug Overdose; D006801:Humans; D007052:Ibuprofen; D007421:Intestine, Small; D017093:Liver Failure; D016031:Liver Transplantation; D008297:Male; D009336:Necrosis; D006435:Renal Dialysis; D012206:Rhabdomyolysis; D012559:Schizophrenia",
"nlm_unique_id": "8111305",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Rhabdomyolysis and necrotic bowel after acetaminophen and ibuprofen overdose.",
"title_normalized": "rhabdomyolysis and necrotic bowel after acetaminophen and ibuprofen overdose"
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"abstract": "This report highlights an extremely rare genetic condition constitutional mismatch repair deficiency (CMMRD) in an Indian pediatric patient with dual malignancies, who suffered from transient encephalopathy, a rare side effect of the drug Nivolumab and the associated challenge during CSF protein electrophoresis interpretation.",
"affiliations": "Department of Biochemistry All India Institute of Medical Sciences (AIIMS-Kalyani) Kalyani India.;Department of Clinical Biochemistry TATA Medical Center Kolkata India.;Department of Computer Science Engineering Government College of Engineering & Leather Technology Kolkata India.;Department of Biochemistry All India Institute of Medical Sciences (AIIMS-Kalyani) Kalyani India.",
"authors": "Paul|Chandramallika|C|https://orcid.org/0000-0002-1558-1878;Chakraborty|Subhosmito|S|;Chakraborty|Sarit|S|;Goswami|Kalyan|K|",
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"doi": "10.1002/ccr3.3249",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3249\nCCR33249\nCase Report\nCase Reports\nConstitutional Mismatch Repair Deficiency Syndrome in a patient from India\nPAUL et al.Paul Chandramallika https://orcid.org/0000-0002-1558-1878\n1\n\n2\nchandramallikapaul@gmail.com Chakraborty Subhosmito \n2\n Chakraborty Sarit \n3\n Goswami Kalyan \n1\n \n1 \nDepartment of Biochemistry\nAll India Institute of Medical Sciences (AIIMS‐Kalyani)\nKalyani\nIndia\n\n\n2 \nDepartment of Clinical Biochemistry\nTATA Medical Center\nKolkata\nIndia\n\n\n3 \nDepartment of Computer Science Engineering\nGovernment College of Engineering & Leather Technology\nKolkata\nIndia\n\n* Correspondence\n\nChandramallika Paul, NH‐34 Connector, Basantapur, Saguna, Kalyani, District Nadia, West Bengal 741245, India.\n\nEmail: chandramallikapaul@gmail.com\n\n03 9 2020 \n12 2020 \n8 12 10.1002/ccr3.v8.122824 2826\n26 4 2020 04 7 2020 20 7 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons 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.Abstract\nThis report highlights an extremely rare genetic condition constitutional mismatch repair deficiency (CMMRD) in an Indian pediatric patient with dual malignancies, who suffered from transient encephalopathy, a rare side effect of the drug Nivolumab and the associated challenge during CSF protein electrophoresis interpretation.\n\nThis report highlights an extremely rare genetic condition constitutional mismatch repair deficiency (CMMRD) in an Indian pediatric patient with dual malignancies, who suffered from transient encephalopathy, a rare side effect of the drug Nivolumab and the associated challenge during CSF protein electrophoresis interpretation. \n\n\nconstitutional mismatch repair deficiencyelectrophoresismicrosatellite instability source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:21.12.2020\n\n\nPaul \nC \n, \nChakraborty \nS \n, \nChakraborty \nS \n, \nGoswami \nK \n. Constitutional Mismatch Repair Deficiency Syndrome in a patient from India\n. Clin Case Rep . 2020 ;8 :2824 –2826\n. 10.1002/ccr3.3249\n==== Body\n1 INTRODUCTION\nThis is a first case report of a patient with constitutional mismatch repair deficiency (CMMRD) from India who was found to suffer from encephalopathy after treatment with monoclonal antibody, Nivolumab, a check point inhibitor, based on monoclonal band in CSF protein electrophoresis (CSF‐PEP) while no band in serum protein electrophoresis (SPEP) or CSF‐immunofixation (CSF‐IFE).\n\nCMMRD is an autosomal recessive disorder that occurs as a result of homozygous or compound heterozygous biallelic deleterious germline mutations in one of the four well‐characterized mismatch repair (MMR) genes including MLH1, MSH2, MSH6, and PMS2. The patients suffer from a broad spectrum of aggressive and pediatric cancers, like hematological malignancies, brain tumors, and colorectal cancers. In contrast to CMMRD, Lynch Syndrome is an autosomal dominant heterozygous monoallelic germline loss‐of‐function mutations in one of the four MMR genes with an increased risk of colorectal cancer, endometrial carcinoma, and other malignancies in the fourth and fifth decades of life.\n1\n, \n2\n The CMMRD patients usually have very short life span (mostly before adulthood); thus, prompt diagnosis and early intervention are extremely important.\n\nConfirmation of the diagnosis involves the analysis of microsatellite instability panel (MSI) and/or immunohistochemistry (IHC) followed by mutation analysis.\n3\n Current CMMRD treatment is based on immune modulators like checkpoint inhibitors, which counteract the actions of proteins that impede the immune response to cancer. Blocking PD‐1(programmed death) in CMMRD tumors ultimately allows activation of T cells which kills the cancer cells. CMMRD tumors are more responsive to PD‐1 blockers like Nivolumab than MMR proficient tumors as shown in recent literature.\n4\n\n\n\nWe herein report a case with CMMRD with childhood colorectal cancer and brain tumor, GBM (glioblastoma multiforme). He received adjuvant treatment for GBM with Nivolumab, a monoclonal antibody but showed signs of suspected immune encephalopathy post‐Nivolumab, an extremely rare complication of Nivolumab.\n5\n, \n6\n On biochemical evaluation, the CSF PEP showed an unusual and unexplained faint monoclonal M band near beta region without any type of restriction in serum protein electrophoresis (SPEP) or CSF‐IFE.\n\nWe would like to present this case because of its rarity and severity, rare side effect like encephalopathy with new immune modulators like Nivolumab, and its unusual electrophoretic interference.\n\nThe study received approval from the local ethics committee.\n\n2 CASE REPORT\nThe patient is a 11‐year‐old boy from Jharkhand, India, who presented with pain abdomen and intermittent constipation two years back. Colonoscopy revealed polypoid stricturing lesion suggestive of sigmoid colon tumor which was further confirmed by radiological findings on CT (Computed Tomography) scan abdomen. Among nonmalignant features, dermatological feature in the form of hypopigmented macule on left shoulder was present. On reviewing the family history, there was a history of neural tube defect and early death in sibling, and a history of sudden death in paternal cousin at 14 years of age. Few incidences of consanguineous marriage were reported in their extended family. The patient underwent exploratory laparotomy and resection of polypoid segment of sigmoid colon. Histopathological examination (HPE) revealed moderately differentiated adenocarcinoma of the sigmoid colon (pT3N0). The MMR IHC done on colonic tumor block showed intact nuclear staining with MSH2, MSH6, and MLH1 while immunostain for PMS2 was attempted thrice but cannot be reported as the results were noncontributory. In view of the absence of PMS2 in both the tumor tissue and the native normal tissue, a possibility of constitutional MMR deficiency (CMMRD) was considered. The patient was planned for chemotherapy with Capecitabine. After 2 months of chemotherapy, he again presented with episodes of headache, vomiting with left‐sided facial weakness of supranuclear type and difficulty walking. CECT (Contrast‐Enhanced Computed Tomography) scan of the brain revealed right frontoparietal space‐occupying lesion (SOL) with perilesional edema and midline shift suggestive of brain tumor (glioma) for which he underwent craniotomy and surgical removal of the tumor. CNS panel on biopsy diagnosed glioblastoma multiforme (GBM) WHO grade IV. Microscopic examination revealed a proliferating glial tumor with marked nuclear pleomorphism, mitosis, necrosis, and microvascular proliferation. IHC showed tumor cells to be positive for GFAP (focal, strong), IDH1(R‐132H) was negative signifying a poorer outcome, ATRX was retained, high Ki67 index of around 70% signifying higher tumor recurrence and progression. IHC done for mismatch repair (MMR) proteins on the block of GBM showed intact nuclear staining for MLH1 and loss of nuclear expression for PMS2 in both the tumor cells and the normal brain tissue. Because of the absence of PMS2 in the tumor tissue, native normal tissue of both GBM block and prior colonic block, the diagnosis of constitutional MMR deficiency (cMMRD) was established. Mutation analysis subsequently confirmed the diagnosis. The patient had a disease‐free survival for next 3 months after which he again showed signs of progressive disease He was then further managed by salvage immunotherapy with Nivolumab, a monoclonal antibody. After 2 courses of Nivolumab given 1 month apart, the patient had episodes of vomiting, but not associated with headache or other clinical signs of raised intracranial pressure. As a part of management, Ommaya shunt was done with drainage of approximately 7.5 mL clear CSF (cerebrospinal fluid). CSF routine examination showed cell counts within normal limits and absence of any malignant cell while on biochemical evaluation CSF glucose was within normal limit but protein concentration was highly elevated to 563 mg/dL, the reference range being 12‐60 mg/dL. No metabolic abnormalities or acute infections or disease progression was evident from pathological, or microbiological work up. Contrast‐enhanced MRI (Magnetic resonance imaging) brain revealed right frontal lobe enhancing lesion and significant cerebral edema. CSF electrophoresis was done to rule out any inflammatory or noninflammatory neurological disease. In CSF electrophoresis (CSF‐PEP), an unusual faint M band near the beta region was seen, while in SPEP and CSF‐IFE, no heavy or light chain restriction pattern was noted corresponding to the M band as shown in Figure S1, S2, and S3, respectively. The patient was therefore diagnosed with immune encephalopathy post‐Nivolumab therapy. He was further treated with intravenous dexamethasone. The patient became stable and was discharged after 2 days on a dexamethasone taper. Considering the benefits of significant tumor reduction in contrast to the rare side effect malignant cerebral edema as reported by \n5\n, the patient was further managed by 6 courses of salvage Nivolumab therapy for next 6 months. Significant reduction of tumor lesions was evident from subsequent brain MRI without any repeat episode of nivolumab induced cerebral edema. However, despite 6 months of salvage immunotherapy, the patient suffered from progressive disease owing to the severity of glioblastoma and CMMRD disease spectrum. The patient was managed henceforth by only palliative therapy. Age at last follow‐up of the patient was 11 years.\n\n3 DISCUSSION\nThe patient was diagnosed and treated for CMMRD at Tata Medical Center, Kolkata, India. The characteristics are evaluated and presented in supporting information Table S1. Age at diagnosis is consistent with the available literature on CMMRD.\n2\n The diagnosis was established by immunohistochemical stain (IHC) with lack of PMS2 staining suggestive of microsatellite instability and subsequently confirmed by molecular genetic testing. The patient suffered from the classical CMMRD tumor spectrum involving colorectal cancer and glioblastoma. The patient underwent surgical and medical management with radiotherapy. Check point inhibitor Nivolumab was used as salvage therapy for GBM. Nivolumab is a monoclonal antibody that acts as an immune checkpoint by blocking programmed cell death protein 1 and activating the immune system against cancer cells. It is noteworthy that the patient experienced signs of transient immune encephalopathy, an extremely rare side effect of Nivolumab therapy.\n5\n, \n6\n During the biochemical evaluation, CSF and serum protein electrophoresis results showed an unusual correlation in the form of a faint M band near the beta region in CSF‐PEP while in SPEP/CSF‐IFE, no corresponding heavy or light chain restriction pattern was noted. Usually, the detection of multiple bands or oligoclonality in CSF study is a sign of intrathecal immunoglobulin synthesis indicating a variety of immunological disorders mostly multiple sclerosis. Very few studies\n7\n, \n8\n have addressed the issue of this type of unusual solitary bands in CSF protein electrophoresis especially in cases of drug‐induced immune encephalopathy.\n\nIn a study done by\n7\n six classic electrophoretic patterns were observed from a wide patient group mostly involving multiple sclerosis (Table S2). Types 2 and 3 indicated intrathecal synthesis, and types 1, 4, 5, and 6 were considered as negative results. Since cerebrospinal fluid (CSF) is an ultrafiltrate of plasma, it has much lower concentrations of the highest molecular weight proteins such as IgG, IgA, and IgM.\n\nIn conclusion, this case report justifies the need for CMMRD reports in a developing country like India and a better understanding of the associated challenges in electrophoresis with emerging therapeutics like Nivolumab.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nAll authors: involved in the conception, design, write‐up, and revision of this article. CP1 and SC2: planned the study. CP1: collected the data and wrote the report. SC3 and KG1: analyzed, edited, and revised the manuscript.\n\n4 ETHICS APPROVAL\nThis study was approved by the institutional ethical committee of the TATA MEDICAL CENTER, KOLKATA, INDIA. All personal identifiers (name, employer, and contact) were removed from the data set, and analyses were carried out at the institution level.\n\nSupporting information\nFigures S1‐S3\n\nClick here for additional data file.\n\n Tables S1‐S2\n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nThe authors have no conflict of interest relevant to this manuscript. Published with written consent of the patient.\n==== Refs\nREFERENCES\n1 \n\nWimmer \nK \n, \nKratz \nCP \n.Constitutional mismatch repair‐deficiency syndrome\n. Haematologica . 2010 ;95 (5 ):699 ‐701\n.20442441 \n2 \n\nLavoine \nN \n, \nColas \nC \n, \nMuleris \nM \n, et al. Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort\n. J Med Genet . 2015 ;52 (11 ):770 ‐778\n.26318770 \n3 \n\nWimmer \nK \n, et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘Care for CMMRD’ (C4CMMRD)/\n. J Med Genet . 2014 ;51 (6 ):355 ‐365\n.24737826 \n4 \n\nAbedalthagafi \nM \n. Constitutional mismatch repair‐deficiency: current problems and emerging therapeutic strategies\n. Oncotarget . 2018 ;9 (83 ):35458 ‐35469\n.30459937 \n5 \n\nZhu \nX \n, \nMcDowell \nMM \n, \nNewman \nWC \n, \nMason \nGE \n, \nGreene \nS \n, \nTamber \nMS \n. Severe cerebral edema following nivolumab treatment for pediatric glioblastoma: case report\n. J Neurosurg Pediatr . 2017 ;19 (2 ):249 ‐253\n.27858578 \n6 \n\nLeitinger \nM \n, \nVarosanec \nMV \n, \nPikija \nS \n, et al. Fatal Necrotizing Encephalopathy after Treatment with Nivolumab for Squamous Non‐Small Cell Lung Cancer: Case Report and Review of the Literature\n. Front Immunol . 2018 ;9 :108 .29441072 \n7 \n\nPinar \nA \n, \nKurne \nAT \n, \nLay \nI \n, et al. Cerebrospinal fluid oligoclonal banding patterns and intrathecal immunoglobulin synthesis: Data comparison from a wide patient group\n. Neurol Sci Neurophysiol . 2018 ;35 (1 ):21 ‐28\n.\n8 \n\nHegen \nH \n, \nZinganell \nA \n, \nAuer \nM \n, \nDeisenhammer \nF \n. The clinical significance of single or double bands in cerebrospinal fluid isoelectric focusing. A retrospective study and systematic review\n. PLoS ONE . 2019 ;14 (4 ):e0215410.30986255\n\n",
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"medline_ta": "Clin Case Rep",
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"other_id": null,
"pages": "2824-2826",
"pmc": null,
"pmid": "33363830",
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"publication_types": "D002363:Case Reports",
"references": "24737826;30459937;29441072;20442441;30986255;27858578;26318770",
"title": "Constitutional Mismatch Repair Deficiency Syndrome in a patient from India.",
"title_normalized": "constitutional mismatch repair deficiency syndrome in a patient from india"
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"abstract": "BACKGROUND\nA recent randomized control trial in children with steroid-resistant nephrotic syndrome revealed that two doses of rituximab did not reduce proteinuria.\nA 14-month-old boy developed refractory steroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis.\n\n\nMETHODS\nThe patient achieved complete remission 11 months after disease onset following eight doses of rituximab combined with steroids and cyclosporine.\nLong-lasting B cell depletion with repeated rituximab administrations may be required to achieve complete remission in patients with steroid-resistant nephrotic syndrome and massive proteinuria.",
"affiliations": "Division of Nephrology, Saitama Childrens Medical Center and *Department of Pediatrics, Juntendo University School of Medicine; Japan. Correspondence to: Dr Shuichiro Fujinaga, Division of Nephrology, Saitama Childrens Medical Center, 2100 Magome, Iwatsuki-ku, Saitama-city Saitama 339 8551, Japan. f_shuich@d2.dion.ne.jp.",
"authors": "Fujinaga|Shuichiro|S|;Sakuraya|Koji|K|",
"chemical_list": "D007166:Immunosuppressive Agents; D013256:Steroids; D000069283:Rituximab",
"country": "India",
"delete": false,
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"issue": "54(1)",
"journal": "Indian pediatrics",
"keywords": null,
"medline_ta": "Indian Pediatr",
"mesh_terms": "D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D008297:Male; D009404:Nephrotic Syndrome; D000069283:Rituximab; D013256:Steroids",
"nlm_unique_id": "2985062R",
"other_id": null,
"pages": "49-50",
"pmc": null,
"pmid": "28141565",
"pubdate": "2017-01-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Repeated Administrations of Rituximab along with Steroids and Immunosuppressive Agents in Refractory Steroid-resistant Nephrotic Syndrome.",
"title_normalized": "repeated administrations of rituximab along with steroids and immunosuppressive agents in refractory steroid resistant nephrotic syndrome"
} | [
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"companynumb": "JP-BAUSCH-BL-2017-002735",
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"activesubstancename": "PREDNISOLONE"
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"abstract": "Gastrointestinal bleeding complicated with protein-losing enteropathy after the Fontan procedure has been often reported in recent years, but there is no established therapy for it.We report the case of an 18-year-old boy who suffered from abdominal pain, melena, and anaemia due to intractable haemorrhagic protein-losing enteropathy after the Fontan procedure. He was successfully treated with octreotide therapy.",
"affiliations": "Department of Paediatrics, The Jikei University School of Medicine, Tokyo, Japan.;Department of Paediatrics, The Jikei University School of Medicine, Tokyo, Japan.;Department of Paediatrics, The Jikei University School of Medicine, Tokyo, Japan.",
"authors": "Kogawa|Kentaro|K|https://orcid.org/0000-0002-4091-9068;Ando|Tatsuya|T|;Fujiwara|Masako|M|",
"chemical_list": "D015282:Octreotide",
"country": "England",
"delete": false,
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"issue": "31(8)",
"journal": "Cardiology in the young",
"keywords": "The Fontan procedure; gastrointestinal bleeding; intramuscular injection; octreotide; protein-losing enteropathy",
"medline_ta": "Cardiol Young",
"mesh_terms": "D000293:Adolescent; D018729:Fontan Procedure; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008297:Male; D015282:Octreotide; D011183:Postoperative Complications; D011504:Protein-Losing Enteropathies",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "1333-1335",
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"pmid": "33588957",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful use of long-acting octreotide for protracted gastrointestinal bleeding related to protein-losing enteropathy after the Fontan procedure: a case report.",
"title_normalized": "successful use of long acting octreotide for protracted gastrointestinal bleeding related to protein losing enteropathy after the fontan procedure a case report"
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"abstract": "BACKGROUND\nAcquired C1-esterase inhibitor (C1-INH) deficiency angioedema (C1-INH-AAE) is a form of bradykinin-mediated angioedema. This rare disorder is due to acquired consumption of C1-INH, hyperactivation of the classic pathway of human complement, and potentially fatal recurrent angioedema symptoms. Clinical symptoms of C1-INH-AAE are very similar to those of hereditary angioedema (HAE) but usually appear after the fourth decade of life and induce abdominal pain less frequently. Laboratory tests are essential in establishing the diagnosis with low levels or abnormal structure and function of C1-INH. Most patients present C1-INH autoantibodies. Furthermore, C1q is reduced in AAE, contrary to HAE. The long-term prognosis is determined by associated hematologic malignancies.\n\n\nMETHODS\nWe report 4 cases of C1-INH-AAE associated with lymphoproliferative disorders referred to the Reference Centre for Angioedema of Besançon, France. The patients were aged between 60 and 77 years. C1 INH antibodies were found in three patients. Symptoms were triggered by angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in 3 patients. Hematologic malignancy was present at diagnosis (one case of chronic lymphoid leukemia) or was diagnosed during follow-up (one case of indolent marginal zone non-Hodgkin lymphoma and two cases of monoclonal gammopathy).\n\n\nCONCLUSIONS\nC1-INH-AAE induced by ACE inhibitors or ARBs may be associated with hematologic malignancies. This form of revelation does not necessarily indicate a diagnosis of ACE or ARBs angioedema, and screening should therefore be performed for C1 Inh and C1q. An underlying hematologic malignancy should be routinely sought and the long-term prognosis determined.",
"affiliations": "Dermatologie, CHRU Minjoz, 3, boulevard Alexandre-Fleming, 25030 Besançon, France. Electronic address: cljacquin@gmail.com.;Dermatologie, CHRU Minjoz, 3, boulevard Alexandre-Fleming, 25030 Besançon, France.;Hématologie, CHRU Minjoz, 3, boulevard Alexandre-Fleming, 25030 Besançon, France.;Hématologie, CHRU Minjoz, 3, boulevard Alexandre-Fleming, 25030 Besançon, France.;Dermatologie, CHRU Minjoz, 3, boulevard Alexandre-Fleming, 25030 Besançon, France.;Dermatologie, CHRU Minjoz, 3, boulevard Alexandre-Fleming, 25030 Besançon, France.;Dermatologie, CHRU Minjoz, 3, boulevard Alexandre-Fleming, 25030 Besançon, France.",
"authors": "Jacquin-Porretaz|C|C|;Castelain|F|F|;Daguindau|E|E|;Seilles|E|E|;Nardin|C|C|;Aubin|F|F|;Pelletier|F|F|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001323:Autoantibodies; D050718:Complement C1 Inhibitor Protein; D001920:Bradykinin",
"country": "France",
"delete": false,
"doi": "10.1016/j.annder.2018.02.012",
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"fulltext_license": null,
"issn_linking": "0151-9638",
"issue": "145(10)",
"journal": "Annales de dermatologie et de venereologie",
"keywords": "Acquired bradykinin-mediated angioedema; Angiœdème bradykinique acquis; Anticorps anti-C1 inhibiteur; C1-inhibitor antibodies; C1-inhibitor deficiency; Déficit en C1 inhibiteur; Hémopathie maligne; Malignant hemopathy",
"medline_ta": "Ann Dermatol Venereol",
"mesh_terms": "D015746:Abdominal Pain; D000368:Aged; D000799:Angioedema; D054179:Angioedemas, Hereditary; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001323:Autoantibodies; D001327:Autoimmune Diseases; D001920:Bradykinin; D050718:Complement C1 Inhibitor Protein; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D018442:Lymphoma, B-Cell, Marginal Zone; D008297:Male; D008875:Middle Aged; D010265:Paraproteinemias",
"nlm_unique_id": "7702013",
"other_id": null,
"pages": "598-602",
"pmc": null,
"pmid": "29673745",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acquired C1 esterase inhibitor deficiency via bradykinin-mediated angioedema: Four cases.",
"title_normalized": "acquired c1 esterase inhibitor deficiency via bradykinin mediated angioedema four cases"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1082296",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BENDAMUSTINE"
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"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRespiratory syncytial virus (RSV) is a single-stranded negative-sense RNA virus that belongs to the family of paramyxoviruses. RSV is the most common pathogen that causes acute lower respiratory tract infection in infants and young children. However, its incidence in immunocompromised adults remains unclear. In the present study, we report an adult patient with chronic nephropathy, who received long-term immunosuppressants and died of rapid respiratory failure due to RSV infection.\nA 54-year-old male patient with chronic nephropathy, who received long-term immunosuppressants, was admitted to the Department of Respiratory Medicine due to the symptoms of fever, cough, expectoration, and dyspnea.\nPulmonary radiology revealed multiple bilateral ground-glass opacity. Laboratory tests revealed elevated inflammation indicators, implying infection with bacteria, viruses, and/or fungi. Furthermore, the patient was positive for RSV antibodies, without positive results for other pathogens. Moreover, the patient was immunocompromised due to the long-term use of corticosteroids and immunosuppressants, as evidenced by decreased total IgG levels and reduced CD4 and CD8 T-lymphocyte counts.\n\n\nRESULTS\nDespite the intensive anti-infection treatment and respiratory support, the patient developed rapid progression, and subsequently died of respiratory failure.\n\n\nCONCLUSIONS\nRSV infection should be fully considered in adults who are immunocompromised or have underlying diseases, such as nephropathy patients receiving long-term immunosuppressants, especially in the presence of respiratory symptoms and computed tomography (CT) chest findings of diffuse ground-glass opacities.",
"affiliations": "Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Jilin University, Changchun, Jilin, China.",
"authors": "Wang|Qi|Q|;Li|Wei|W|;Qu|Danhua|D|;Xin|Tong|T|;Gao|Peng|P|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30024538MD-D-18-0110910.1097/MD.0000000000011528115284900Research ArticleClinical Case ReportFatal pulmonary infection with respiratory syncytial virus in an immunocompromised adult patient A case reportWang Qi PhDLi Wei PhDQu Danhua MDXin Tong MDGao Peng PhD∗NA. Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Jilin University, Changchun, Jilin, China.∗ Correspondence: Peng Gao, Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Jilin University, Changchun, Jilin 130041, China (e-mail: gaopeng1234@sina.com).7 2018 20 7 2018 97 29 e115282 3 2018 21 6 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nRespiratory syncytial virus (RSV) is a single-stranded negative-sense RNA virus that belongs to the family of paramyxoviruses. RSV is the most common pathogen that causes acute lower respiratory tract infection in infants and young children. However, its incidence in immunocompromised adults remains unclear. In the present study, we report an adult patient with chronic nephropathy, who received long-term immunosuppressants and died of rapid respiratory failure due to RSV infection.\n\nPatient concerns:\nA 54-year-old male patient with chronic nephropathy, who received long-term immunosuppressants, was admitted to the Department of Respiratory Medicine due to the symptoms of fever, cough, expectoration, and dyspnea.\n\nDiagnoses:\nPulmonary radiology revealed multiple bilateral ground-glass opacity. Laboratory tests revealed elevated inflammation indicators, implying infection with bacteria, viruses, and/or fungi. Furthermore, the patient was positive for RSV antibodies, without positive results for other pathogens. Moreover, the patient was immunocompromised due to the long-term use of corticosteroids and immunosuppressants, as evidenced by decreased total IgG levels and reduced CD4 and CD8 T-lymphocyte counts.\n\nInterventions and outcome:\nDespite the intensive anti-infection treatment and respiratory support, the patient developed rapid progression, and subsequently died of respiratory failure.\n\nLessons:\nRSV infection should be fully considered in adults who are immunocompromised or have underlying diseases, such as nephropathy patients receiving long-term immunosuppressants, especially in the presence of respiratory symptoms and computed tomography (CT) chest findings of diffuse ground-glass opacities.\n\nKeywords\nadultground-glass opacityimmunosuppressionrespiratory syncytial virusOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nRespiratory syncytial virus (RSV) is the most common pathogen that induces acute lower respiratory tract infection in infants, and has caused approximately 66,000 to 199,000 child deaths worldwide in 2005.[1] It is a single-stranded negative-sense RNA virus that belongs to the family of paramyxoviruses. These viruses transmit through respiratory droplets and intimate contact. The seasonal trends for RSV suggest that infection occurs throughout the year, with the peak in winter, followed by spring and autumn. The typical histological finding of RSV pneumonia is the interstitial infiltration of mononuclear cells, which mainly manifests as the widening of the alveolar space and interstitial monocyte-predominant exudates. Specific diagnosis depends on the isolation of the virus and the demonstration of a serological response, such as serum complement fixation assay and neutralization assay.\n\nRSV is not only a major cause of severe lower respiratory tract infection in young children, but also in the elderly and in severely immunocompromised individuals, which incurs serious complications, respiratory failure, prolonged hospital stay, and even high mortality.[2] The immunity generated after RSV infection is transient, and does not provide long-lasting protection, allowing re-infection even with the same strain of RSV.[3] During RSV infection, humoral immunity to viral exposure plays an important role in the identification of viral surface proteins, and cellular immunity helps the body recognize the virus and infected cells. As an impairment of cellular and humoral immunity in immunocompromised patients, those patients are more susceptible to RSV.[4]\n\nHowever, rare cases of RSV infection that cause adult lower respiratory tract infection, or even mortality, have been reported. In the present study, we present a 54-year-old patient, who was receiving immunosuppressants and admitted to a hospital with symptoms of fever, cough, expectoration, and dyspnea, and was subsequently diagnosed with RSV infection. This patient eventually died, emphasizing the precaution of RSV infection in immunocompromised adults, especially in presence of respiratory symptoms and chest computed tomography (CT) findings of diffuse ground-glass opacities of the lung.\n\n2 Case presentation\nA 54-year-old male who had a medical history of membranous nephropathy II with nephrotic syndrome (Fig. 1A and B) was administered with long-term oral glucocorticoids and immunosuppressants. The patient had a 20 pack-year history of smoking, and denied a family history of hereditary diseases. Chest x-ray demonstrated normal findings at one month before admission (Fig. 1C–E). On August 8, 2016, the patient was hospitalized for fever accompanied by progressive dyspnea, cough, and expectoration for 5 days. On admission, the BMI of the patient was 24.5 kg/m2, and his body temperature was 39.0°C. Furthermore, the patient had symptoms of tachypnea (35 bpm) and severe hypoxemia (SaO2 86%). On auscultation, the patient had good air entrance bilaterally with scattered diffuse crackles and rhonchi. Furthermore, the chest CT scan revealed multiple ground-glass opacities (Fig. 1F–H), and laboratory tests (Table 1) revealed normal white blood cell (WBC) count, but with elevated neutrophil count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and (1→3)-β-D-glucan (Table 2). The patient was diagnosed as RSV infection on the fourth day of hospitalization when positive RSV-Ab was detected.\n\nFigure 1 (A) Histological analysis for renal biopsy (H&E staining) revealed focal segmental glomerulosclerosis with mild mesangial cell hyperplasia, endothelial cell proliferation and thickening of the glomerular capillary walls, but with open glomerular tuft. Focal tubular epithelial cell atrophy was observed. (B) Periodic acid methenamine–Masson staining revealed diffuse, segmental lesions as visible mesangial deposition, without “tram-track\" appearance. (C–E) Chest CT scan at one month before admission revealed normal findings. (F–H) Chest CT scan on admission revealed bilaterally diffuse ground-glass opacities in the lungs. (I–K) Chest CT scan at the 10th day after admission indicated disease progression. (L) Chest x-ray at 15th days after admission revealed extensive diffuse ground-glass opacification, which worsened compared to that of before. (M) Bronchoscopy pathology revealed pulmonary interstitial fibrosis, hyperplasia of the alveolar epithelium and necrosis in the alveolar cavity.\n\nTable 1 Results of the laboratory tests.\n\nTable 2 Etiological tests.\n\nOn admission, the patient was immediately given respiratory monitoring and supplemental oxygen to improve the low oxygen saturation, as well as antibiotics (moxifloxacin for 4 days, followed by cefminoxine for 8 days), and antifungal therapy (voriconazole for 10 days). The dose of the glucocorticoids and immunosuppressants remained largely unchanged (Table 3). After 10 days of treatment, the patient's condition became worse. Chest CT revealed the progression of the disease (Fig. 1I–K), and oxygen partial pressure was further decreased (Table 4). The patient was transferred to the Emergency Intensive Care Unit, where the patient was intensively treated, including noninvasive mechanical ventilation, broad-spectrum antibiotics (i.v. meropenem, oral moxifloxacin, and cotrimoxazole), antifungal therapy (micafungin), corticosteroids (methylprednisolone 40 mg bid iv) to relieve the inflammation, and other supportive treatment. Ganciclovir was also prescribed due to a possibility of viral infection, such as cytomegalovirus. Five days later, the patient's condition was further aggravated based on the chest x-ray evaluation (Fig. 1L). Despite receiving another round of treatments, including invasive ventilator-assisted ventilation therapy, methylprednisolone (80 mg bid), antibacterial agents (cefoperazone sulbactam, tigecycline, and cotrimoxazole) and antifungal (micafungin) therapy, the patient eventually died after 2 days.\n\nTable 3 Medical history and medications.\n\nTable 4 Arterial blood gas analysis.\n\n3 Discussion\nGround-glass opacification refers to an area of increased attenuation in the lungs on CT, which result from the partial filling of air spaces in the lungs by exudates, and is probably accompanied by interstitial thickening or partial collapse of the lung alveoli. This specific image indicates some non-infectious diseases, such as pulmonary vasculitis, eosinophilic pneumonia and radiation-induced lung injury (listed in detail in Fig. 2), and infectious diseases. Pathogens that cause ground-glass opacities on CT images include bacteria (Pseudomonas aeruginosa, Staphylococcus aureus, etc.), fungi (Aspergillus, Mucormycosis, and Candida), viruses (cytomegalovirus, varicella zoster virus, herpes simplex virus, parainfluenza, influenza, etc.), mycobacterium (tuberculosis and nontuberculous mycobacteria) and others (e.g., pneumocystis carinii pneumonia). A previous study revealed that hydrostatic pulmonary edema was the most common cause (56%) for ground-glass opacities on CT images, followed by interstitial lung diseases, and infection accounted for 5%.[5] In particular, diffuse infection (24%) was the second most common cause in immunocompromised patients. In another study, it was shown that the diagnosis of infectious pneumonia mostly caused by pneumocystis, cytomegalovirus, and RSV is common in non-HIV immunosuppressed patients, representing 44% of cases.[6]\n\nFigure 2 The clinical process for the diagnosis of widespread ground-glass opacity. BAL = bronchoalceolar lavage, COP = cryptogenic organizing pneumonia, DAH = diffuse alveolar haemorrhage, ELISA = enzyme linked immunosorbent assay, ILD = interstitial lung disease, PCP = pneumocystis carinii pneumonia, PCR = polymerase chain reaction.\n\nIn the present case, the patient was receiving immunosuppressants and admitted to our hospital with symptoms of fever, cough, expectoration, and dyspnea. Laboratory tests revealed elevated inflammation indicators and positive RSV-Ab, implying possible infection with bacteria, viruses, and/or fungi. The long-term use of immunosuppressive agents led to the abnormal condition of the immune system, in which cellular or humoral immunity was inadequate, and the resistance to infection decreased, allowing opportunistic infections caused by pathogenic bacteria, fungi and viruses. In response to invading microbes, an acute inflammatory response was mounted with the release of pro-inflammatory mediators and the recruitment of inflammatory cells into the lungs, which resulted to increased vascular permeability and pulmonary edema.[7] Immunocompromised patients are at risk for infection with severe acute respiratory manifestation from a variety of opportunistic viral pathogens.[8–10] RSV infection in adults is often asymptomatic, but causes severe lower respiratory tract infection in adults who are immunocompromised, older, and/or have underlying cardiopulmonary diseases.[11] In the present study, the diagnosis of RSV infection was made on the following basis: the patient might have been immunocompromised due to the long-term use of corticosteroid immunosuppressive therapy, as evidenced by the decrease in total IgG level and reduced CD4+ and CD8+ T-lymphocyte count; the illness developed in the epidemic season of RSV; the patient had radiologic imaging changes, in which the initial performance of diffuse ground-glass opacities was accompanied by interstitial fibrosis, and this subsequently gradually developed into pulmonary fibrosis and traction bronchiectasis with a small amount of inflammatory exudates; the patient presented with positive RSV-Ab without positive results for other pathogens. Considering the impairment of immunity in the patient, empiric broad-spectrum antibiotics were used to ensure coverage of both typical and atypical organisms. The determination of serum (1→3)-β-D-glucan level is a noninvasive assay for circulating fungal cell wall components, which allows for the rapid identification of fungal infections.[12] Fungal pneumonia is increasingly common, particularly in highly immunosuppressed patients, and the measurement of serum (1→3)-β-D-glucan level has emerged as an adjunct method for the diagnosis of invasive fungal infections.[13,14] In the present case report, the patient presented with elevated (1→3)-β-D-glucan levels, and was treated with adequate anti-fungal therapy. Despite the intensive anti-infection treatment, the patient developed rapid progression of respiratory failure.\n\nGiven RSV infection rarely caused diffuse ground-glass opacities of the lung on chest CT images, highly pathogenic viruses such as cytomegalovirus and adenovirus, rather than RSV, were initially considered, until positive RSV-Ab was detected. This led to a failure to early diagnose and treat RSV infection. The patient experienced rapid deterioration and mortality even under efficient treatment. Lessons should be learned from this case that RSV infection should be fully considered in adults who are immunocompromised or have underlying diseases, such as nephropathy patients on long-term immunosuppressants, especially in the presence of respiratory symptoms and CT chest findings of diffuse ground-glass opacities of the lungs.\n\nAuthor contributions\nQW and WL carried out the data collection, literature review and drafting of the manuscript. DQ contributed to the drafting of the manuscript and literature review. TX participated in the data collection and drafting of the manuscript. PG helped to draft the manuscript and revised the final version of the manuscript. All authors read and approved the final manuscript.\n\nData curation: Tong Xin.\n\nInvestigation: Danhua Qu.\n\nResources: Tong Xin.\n\nSupervision: Peng Gao.\n\nWriting – original draft: Wei Li.\n\nAbbreviations: BMI = body mass index, CRP = C-reactive protein, CT = computed tomography, ESR = erythrocyte sedimentation rate, RSV = respiratory syncytial virus, WBC = white blood cell.\n\nQW and WL contributed equally to this work.\n\nEthics approval and consent to participate: Not applicable.\n\nConsent to publish: A written informed consent was obtained from the patient for the publication of this case report with accompanying images.\n\nAvailability of data and materials: All data generated or analyzed during this study are included in this published article.\n\nCompeting interests: All authors have read and approved the content, and declare no conflicts of interest.\n\nThere are no ethical/legal conflicts involved in the article.\n==== Refs\nReferences\n[1] Nair H Nokes DJ Gessner BD \nGlobal burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis . Lancet \n2010 ;375 :1545–55 .20399493 \n[2] Falsey AR Hennessey PA Formica MA \nRespiratory syncytial virus infection in elderly and high-risk adults . N Engl J Med \n2005 ;352 :1749–59 .15858184 \n[3] Lambert L Sagfors AM Openshaw PJ \nImmunity to RSV in early-life . Front Immunol \n2014 ;5 :466.25324843 \n[4] Collins PL Graham BS \nViral and host factors in human respiratory syncytial virus pathogenesis . J Virol \n2008 ;82 :2040–55 .17928346 \n[5] Hewitt MG Miller WT JrReilly TJ \nThe relative frequencies of causes of widespread ground-glass opacity: a retrospective cohort . Eur J Radiol \n2014 ;83 :1970–6 .25082478 \n[6] Shah RM Miller W Jr \nWidespread ground-glass opacity of the lung in consecutive patients undergoing CT: does lobular distribution assist diagnosis? \nAJR Am J Roentgenol \n2003 ;180 :965–8 .12646436 \n[7] Brazee PL Soni PN Tokhtaeva E \nFXYD5 is an essential mediator of the inflammatory response during lung injury . Front Immunol \n2017 ;8 :623.28620381 \n[8] Kim YJ Boeckh M Englund JA \nCommunity respiratory virus infections in immunocompromised patients: hematopoietic stem cell and solid organ transplant recipients, and individuals with human immunodeficiency virus infection . Semin Respir Crit Care Med \n2007 ;28 :222–42 .17458776 \n[9] Cunha BA Pherez F Walls N \nSevere cytomegalovirus (CMV) community-acquired pneumonia (CAP) in a nonimmunocompromised host . Heart Lung \n2009 ;38 :243–8 .19486794 \n[10] Englund J Feuchtinger T Ljungman P \nViral infections in immunocompromised patients . Biol Blood Marrow Transplant \n2011 ;17 (1 suppl) :S2–5 .21195305 \n[11] Falsey AR Walsh EE \nRespiratory syncytial virus infection in adults . Clin Microbiol Rev \n2000 ;13 :371–84 .10885982 \n[12] Son HJ Sung H Park SY \nDiagnostic performance of the (1-3)-beta-D-glucan assay in patients with Pneumocystis jirovecii compared with those with candidiasis, aspergillosis, mucormycosis, and tuberculosis, and healthy volunteers . PLoS One \n2017 ;12 :e0188860.29190812 \n[13] Ostrosky-Zeichner L Alexander BD Kett DH \nMulticenter clinical evaluation of the (1-->3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans . Clin Infect Dis \n2005 ;41 :654–9 .16080087 \n[14] Lease ED Alexander BD \nFungal diagnostics in pneumonia . Semin Respir Crit Care Med \n2011 ;32 :663–72 .22167394\n\n",
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"title": "Fatal pulmonary infection with respiratory syncytial virus in an immunocompromised adult patient: A case report.",
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"abstract": "Haemophagocytic lymphohistiocytosis (HLH) is a rare diagnosis that carries a high degree of mortality. We present this case of a previously healthy 22-year-old woman, who was admitted acutely ill to the hospital. One week prior, she had been seen by her primary care physician for fatigue and malaise. At that time, she was noted to have anterior and posterior cervical lymphadenopathy. She was referred to the emergency room and was diagnosed with acute Epstein-Barr virus (EBV) mononucleosis based on her clinical symptoms and positive heterophile antibody test. She was discharged after an uneventful 48-hour stay on the wards. She represented 7 days after discharge with cough, fatigue, nausea, vomiting, epigastric abdominal pain, diarrhoea, weight loss and subjective fevers. She had also reported haematemesis, epistaxis and melaena. Vital signs included temperature 36.9°C, blood pressure 90/50 mm Hg, heart rate 130 beats per minute and respiratory rate 32 breaths per minute. Physical examination was notable for an acutely ill appearing woman with scleral icterus, hepatosplenomegaly and palpable cervical and axillary lymphadenopathy. Complete blood count showed pancytopaenia with haemoglobin 59 g/L (normal 120-160 g/L), white blood cell count 2.7×109/L (normal 4-10.5×109/L) and platelet count 50×109/L (normal 150-450×109/L). The white blood cell count differential included 58% neutrophils (normal 38%-77%) with immature neutrophils in band form elevated at 45% (normal <14%), 16% lymphocytes (normal 20%-48%), 7% monocytes (normal <12%) and no eosinophils (normal <6%). Blood smear revealed anisocytosis, poikilocytosis and hypochromia. Coagulation panel showed elevated levels of d-dimer level at 1.39 µg/mL (normal <0.45 µg/mL), prolonged prothrombin time at 34.4 s (normal 11-15 s), prolonged activated partial thromboplastin time of 55.6 s (normal 25-34 s), prolonged international normalised ratio at 3.31 (normal <1.1) and low fibrinogen 60 mg/dL (normal >200 mg/dL). Lipid panel showed cholesterol at 114 mg/dL (normal 125-200 mg/dL), triglycerides 207 mg/dL (normal 30-150 mg/dL), high-density lipoprotein cholesterol 10 mg/dL (normal 40-60 mg/dL) and low-density lipoprotein cholesterol 63 mg/dL (normal <100 mg/dL). Other lab abnormalities included elevated ferritin of 6513 ng/mL (normal 10-150 ng/mL) and elevated lactate dehydrogenase of 1071 unit/L (normal 95-240 unit/L). Soluble interleukin-2 receptor alpha level was elevated at 60 727 units/mL (normal 223-710 units/mL). Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed abnormal tracer localisation within the paratracheal, hilar, pelvic, abdominal and subcarinal lymph nodes, along with FDG-PET positive hepatosplenomegaly. A bone marrow biopsy showed hypercellular marrow (95% cellularity) with trilineage haematopoiesis, haemophagocytic cells, polytypic plasmacytosis and T-cell lymphocytosis, along with positive latent membrane protein-1 immunohistochemical staining for EBV. EBV quantitative DNA PCR showed >1 million copies. These findings were consistent with a diagnosis of HLH secondary to EBV infection. Despite intense therapy with the HLH-94 protocol, the patient expired from her illness after a prolonged hospital course.",
"affiliations": "Pulmonary, Critical Care and Sleep Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA valerikr@buffalo.edu.;Internal Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA.;Pulmonary, Critical Care and Sleep Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA.",
"authors": "Kraskovsky|Valeri|V|http://orcid.org/0000-0002-8427-6922;Harhay|Jason|J|http://orcid.org/0000-0001-7055-6037;Mador|Martin Jeffery|MJ|",
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"title": "Case of haemophagocytic lymphohistiocytosis following Epstein-Barr virus infection.",
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"abstract": "Amiodarone is a class III antiarrhythmic drug widely used for the treatment of both supraventricular and ventricular arrhythmias in intensive care unit. Hepatotoxicity of amiodarone is usually mild and delayed onset. Acute hepatotoxicity is a rare side effect and usually correlated to intravenous form use. In this case, acute hepatocellular injury occurred within 24 hours after the administration of intravenous amiodarone. Liver enzyme significantly improved after holding intravenous amiodarone use. Because ventricular arrhythmia persisted and side effects occurred to alternative therapy, low dose of oral amiodarone was resumed and hepatotoxicity did not occur afterward. Acute hepatotoxicity of intravenous amiodarone is possibly related to polysorbate 80, the solubilizer of amiodarone infusion or higher dose. As a result, when intravenous amiodarone is prescribed, closely monitoring liver enzyme is highly suggested. If acute hepatitis takes place secondary to intravenous amiodarone, oral therapy should not be resumed afterward. If there is no alternative treatment, lower dose of oral amiodarone (≤200 mg/d) could be tried and should monitor liver function regularly.",
"affiliations": "1Department of Pharmacy, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan; and 2Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.",
"authors": "Chen|Chia-Chi|CC|;Wu|Chien-Chih|CC|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000638:Amiodarone",
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"title": "Acute Hepatotoxicity of Intravenous Amiodarone: Case Report and Review of the Literature.",
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