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"abstract": "The diagnosis and management of parotitis can be challenging. Patients often present with pain and edema in the neck, jaw, head, and ear due to congestion of the gland. Parotitis is typically caused by an infection within the parotid gland and surrounding lymph nodes, and the infection can spread to nearby cervical fascial planes and cause major complications if not managed successfully. Specific guidelines for the outpatient management of parotitis are limited, and outpatient treatment failures are common, requiring inpatient therapy with multiple broad-spectrum antibiotics. In the current case, a comprehensive patient-centered approach was used to treat a woman whose overlapping clinical conditions, lifestyle, and work factors led to an infection of the parotid gland.",
"affiliations": null,
"authors": "Patel|Puja|P|;Scott|Shannon|S|;Cunningham|Sean|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D064704:Levofloxacin",
"country": "United States",
"delete": false,
"doi": "10.7556/jaoa.2017.152",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-6151",
"issue": "117(12)",
"journal": "The Journal of the American Osteopathic Association",
"keywords": null,
"medline_ta": "J Am Osteopath Assoc",
"mesh_terms": "D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D064704:Levofloxacin; D026301:Manipulation, Osteopathic; D008875:Middle Aged; D010309:Parotitis; D014057:Tomography, X-Ray Computed; D014987:Xerostomia",
"nlm_unique_id": "7503065",
"other_id": null,
"pages": "e137-e140",
"pmc": null,
"pmid": "29181524",
"pubdate": "2017-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Challenging Case of Parotitis: A Comprehensive Approach.",
"title_normalized": "challenging case of parotitis a comprehensive approach"
} | [
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"abstract": "In this case report, we highlight a patient with catatonia secondary to schizoaffective disorder, depressive type. This patient developed a bilateral deep venous thrombosis progressing to a saddle pulmonary embolism without any predisposing factors to hypercoagulability other than immobility and obesity. The goal of this case report is to increase monitoring and prophylactic treatment for deep venous thrombosis in patients with catatonia, retarded type.",
"affiliations": "Psychiatry, Kern Medical, Bakersfield, USA.;Psychiatry, University of California Los Angeles-Kern Medical Center, Bakersfield, USA.;Psychiatry, University of California Los Angeles-Kern Medical Center, Bakersfield, USA.;Psychiatry, American University of the Caribbean, Bakersfield, USA.",
"authors": "Maner|Brittany S|BS|;Singh|Jasbir|J|;Camacho|Homero|H|;Jenson|Andrew K|AK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.14000",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.14000\nCardiac/Thoracic/Vascular Surgery\nInternal Medicine\nPsychiatry\nCatatonia-Induced Saddle Pulmonary Embolism\nMuacevic Alexander\nAdler John R\nManer Brittany S 1\nSingh Jasbir 2\nCamacho Homero 2\nJenson Andrew K 3\n1 Psychiatry, Kern Medical, Bakersfield, USA\n2 Psychiatry, University of California Los Angeles-Kern Medical Center, Bakersfield, USA\n3 Psychiatry, American University of the Caribbean, Bakersfield, USA\nBrittany S. Maner bmaner90@gmail.com\n19 3 2021\n3 2021\n13 3 e1400014 7 2020\n25 2 2021\nCopyright © 2021, Maner et al.\n2021\nManer 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/36624-catatonia-induced-saddle-pulmonary-embolism\nIn this case report, we highlight a patient with catatonia secondary to schizoaffective disorder, depressive type. This patient developed a bilateral deep venous thrombosis progressing to a saddle pulmonary embolism without any predisposing factors to hypercoagulability other than immobility and obesity. The goal of this case report is to increase monitoring and prophylactic treatment for deep venous thrombosis in patients with catatonia, retarded type.\n\ncatatonia\npulmonary embolism\ndeep venous thrombosis\nschizoaffective disorder\nlorazepam\nretarded-type\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nPulmonary embolism (PE) is a potentially life-threatening complication of deep venous thromboses (DVTs). Thrombosis of blood can be caused by a state of hypercoagulability, vessel wall injury, and stasis of blood commonly referred to as Virchow’s triad. There are many factors that can lead to hypercoagulability including genetic factors, acquired factors, environmental factors, mixed factors, and others not well established. One of the most important acquired factors that require focus for patients with mental illness is immobility [1]. Pulmonary emboli are commonly caused by dislodged DVTs provoked by the contractile movement of the lower extremity muscles causing veins to pump blood and emboli back to the heart and pulmonary vasculature. Pulmonary emboli have a high rate of mortality, especially in patients with illnesses causing retarded-type catatonia [2].\n\nCatatonia is a behavioral syndrome with the incapacity to move properly, which occurs in various psychiatric and non-psychiatric illnesses. In fact, 10% of acutely ill psychiatric patients in an inpatient psychiatric unit were found to have catatonia, most of who presented with mood disorders [3]. It is described in the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) as having “three or more of 12 psychomotor features in the diagnostic criteria for catatonia associated with another mental disorder and catatonic disorder due to another medical condition.” These symptoms include stupor, catalepsy, waxy flexibility, mutism, negativism, posturing, mannerism, stereotypy, agitation not influenced by external stimuli, grimacing, echolalia, and echopraxia. The severity of catatonia can be measured through the 23-item Bush-Francis Catatonia Rating Scale, which measures the previously mentioned signs and symptoms of catatonia. Each item is scored 0-3 depending on severity. The higher the score, the more unstable the patient will be [4]. There are three subtypes: retarded, excited, and malignant. The retarded type is described as having an inability to move, staring, posturing, negativism, and mutism [5]. For centuries, schizophrenia has been divided into two different groups: catatonia group and non-catatonia group [6]. Catatonia is now described in the DSM-5 as a separate condition most commonly associated with mood disorders such as bipolar I and II; however, it is also associated with schizophrenia spectrum disorders and autism spectrum disorder [3]. There are many complications to catatonia including malnutrition, dehydration, contractures, pressure ulcers, DVTs, and PEs [7]. Of the three subtypes of catatonia, the retarded subtype is the most susceptible to DVTs and pulmonary emboli due to immobility, and hemoconcentration secondary to decreased food and water intake [2]. Catatonia, retarded type is a dangerous and life-threatening presentation of schizoaffective disorder. Due to their stuporous state, these patients have the potential to develop DVTs for a prolonged period of time. The lorazepam challenge is one of the major forms of diagnosing patients with catatonia. A patient is given 1-2 mg of lorazepam intramuscularly, intravenously, or orally and observed for rapid resolution of symptoms after a 20 to 30-minute time period [5]. Yet, without proper anticoagulation, patients with catatonia and DVTs on the lorazepam challenge can quickly develop pulmonary emboli which can lead to their demise. A 2016 study proposes that patients with catatonia have a 25% incidence of developing DVTs [2]. However, there are only two documented cases of patients with retarded-type catatonia developing DVTs and subsequent PEs. These patients may be more susceptible to a delayed diagnosis and thus decreased standard of care, leading to worse health outcomes. Catatonia and its complications, namely DVT and PE, are important clinical scenario to consider in at-risk populations. Our case can bring proper awareness of the risk of DVT and PE in a patient presenting with retarded subtype of catatonia. The Kern Medical Institutional Review Board approved the study protocol 19067 where we will elaborate on the effect of a retarded-type catatonic patient suffering from a massive PE. Consent to publish the case history was obtained from the patient.\n\nCase presentation\n\nA 19-year-old African American female with a previous diagnosis of catatonia secondary to schizoaffective disorder, post-traumatic stress disorder, hypothyroidism, BMI of 44.4, and history of deep venous thrombosis. She previously had over five episodes of retarded-type catatonia with hospitalizations for being gravely disabled due to decreased food and water intake for various but prolonged periods of time. In the state of California, “gravely disabled” is defined as being unable to utilize food, clothing, and shelter, which is grounds for admission into inpatient psychiatric unit. Her first episode of catatonia began prior to April 2018 according to hospital and outpatient records. She was first diagnosed with a left common femoral venous thrombosis by Hematology and Oncology in April 2018. The patient was then investigated for having risk factors for inherited hypercoagulability where her prothrombin gene mutation, protein C activity, protein S activity, antithrombin III activity, factor V Leiden mutation, and lupus anticoagulant, all returned within normal range; no mutations present. Previous inpatient and outpatient records did not report the use of oral contraceptive pills or tobacco use history, symptoms of irritable bowel disease, and other acquired forms of hypercoagulability. In April 2018, she was prescribed rivaroxaban by Hematology and Oncology for DVT treatment and decreasing risk for further DVT formation. However, she was lost to follow up and was reported medication non-adherent.\n\nIn August 2019, the patient was admitted to the inpatient psychiatric unit. Her catatonia was displayed with stupor, mutism, staring, and immobility. She was referred from a group home five days after being medically cleared from another hospital as gravely disabled for a duration of five days. The patient presented in a mute state refusing psychiatric evaluation, interview, or following any instructions. A preliminary diagnosis of catatonia was made with a Bush-Francis Rating Scale of 14/69. A lorazepam challenge was performed. Thirty minutes after administration of 1 mg lorazepam by mouth, she was significantly more verbal, mobile, and appropriately responding to jokes made by her peers. Her subsequent Bush-Francis Rating Scale decreased to 5/69. She stated that she did not recall the events leading up to her hospitalization.\n\nDuring this admission, risperidone and valproic acid were initiated for treatment of schizoaffective disorder, levothyroxine was initiated for hypothyroidism, and bilateral lower extremity Doppler ultrasound was ordered to assess previously diagnosed left common femoral venous thrombosis. The patient was found to have non-occlusive DVTs extending from the femoral and popliteal veins and their branches (Figures 1-4). The internal medicine team was immediately consulted and recommended rivaroxaban for anticoagulation, prevention of further progression of her bilateral venous thromboses, and PE prophylaxis.\n\nFigure 1 Doppler waveforms and partial occlusion within the left great saphenous vein.\n\nFigure 2 Partial occlusion of the left common femoral vein.\n\nFigure 3 Partial occlusion of the left proximal superficial femoral vein.\n\nFigure 4 Partial occlusion within the left great saphenous vein.\n\nWithin six hours, the patient began complaining of dyspnea. Vital signs were taken and showed saturated oxygen levels of 93%, blood pressure of 83/61 mmHg, heart rate of 124 beats per minute, respiratory rate of 40 breaths per minute, and repeat vital signs showed similar results. The internal medicine team initiated the induction of heparin and performed a computed tomography angiography (CTA). The CTA revealed a saddle embolism within the main pulmonary artery. Additionally, there were filling defects within the proximal right and left main pulmonary arteries extending into the lobar and segmental branches; it also displayed enlargement of the right ventricle. These findings suggested the right heart strain (Figures 5, 6). The patient was then transferred to the intensive care unit (ICU). Early the next morning, mechanical thrombectomy was performed to remove the embolism as well as interventional radiology guided inferior vena cava filter placement. While in the ICU, the patient’s psychiatric state deteriorated back to catatonic symptoms. The patient was then stabilized and transferred to the medicine floor for further observation, heparin level, prothrombin time, and partial thromboplastin time monitoring were done prior to transferring back to the inpatient psychiatric unit. She was transferred to the inpatient psychiatric unit five days later, in a stuporous, mute, and immobile catatonic state. In the unit, she was adherent to psychotropic and medical medications and was given 1 dose of lorazepam 1 mg with an observed resolution of catatonic symptoms.\n\nFigure 5 Sagittal view of the CT angiogram displaying a pulmonary embolism. The red arrows indicate the location of the embolis.\n\nFigure 6 Inferior and sagittal view of a pulmonary embolism within the proximal right and left main pulmonary arteries indicated by the red arrows.\n\nDiscussion\n\nRetarded-type catatonia causes stupor, a state of immobility that leads to blood stasis and the ability for clots to form in patients that are affected. Untreated pulmonary emboli are associated with mortality as high as 30% where up to 10% of patients with PEs die suddenly [8]. Many complications, including right heart strain as found in our patient, can be a cause of death or decreased quality of life. However, medicine often neglects to acknowledge the impact of catatonia secondary to psychiatric disease as a major risk factor for blood stasis and hypercoagulability.\n\nFew case reports have discussed the importance of using anticoagulant prophylaxis in patients with catatonia, retarded type especially prior to administration of lorazepam. A case by King et al. involved a 44-year-old female patient with schizoaffective disorder who suffered from bilateral pulmonary emboli and right heart strain due to sedation and previous psychiatric hospitalization. In fact, this case report recommends screening and assessments for sedentary psychiatric patients [9]. Furthermore, the study by Warriach et al., demonstrates that patients with catatonia secondary to schizophrenia can continue electroconvulsive therapy while on anticoagulants depending on the size and the location of their thromboemboli without complications of bleeding [10]. This supports that prior to the administration of lorazepam, catatonic patients may have similar outcomes and be able to tolerate anticoagulant therapy.\n\nIn our case report, the patient showed significant improvement in her catatonic symptoms after administration of lorazepam, but quickly after, developed a large PE. Our limitations included the bilateral lower extremity studies that were performed after administration of lorazepam, which delayed anticoagulant treatment, increasing the risk for DVT migration to the lungs. We were unable to obtain the images of the previously diagnosed DVT Doppler reading and the most recent right Doppler images. We were also limited by the reported lack of medication adherence with previously diagnosed DVT. However, this shows the importance of prophylactic treatment with anticoagulant therapy and early investigative studies with retarded-type catatonic patients especially those who have had many catatonic episodes and/or have been in a stuporous state for a prolonged period of time. Lorazepam is an effective treatment for patients with catatonia, retarded type. Nevertheless, these patients’ increased risk for DVT needs to be assessed for a proper treatment plan outside of medications for the catatonia causing diseases. Patients with catatonia would benefit from anticoagulant medications to prevent complications as well as decrease morbidity and mortality. A 2013 study indicates a significantly increased risk of DVT in patients with retarded subtype catatonia. The catatonic patients were compared to restrained non-catatonic patients. The incidence of DVT was 25.3% in catatonic patients. Moreover, DVT in retarded-type catatonic patients compared to restrained non-catatonic patients was significantly higher with an incidence rate of 35.7% in retarded type catatonic patients in comparison to 10.6% in restrained non-catatonic patients [2]. This information shows the increased risk of DVTs and possible PEs in patients with catatonia, retarded subtype. The literature recommends increasing exercise and giving high dose heparin for psychiatric patients, such as patients with catatonia retarded type that are at risk for DVTs and PEs [11].\n\nConclusions\n\nThis case report can add to the body of knowledge surrounding DVTs and their subsequent complications in patients with catatonia, retarded type. Our patient in particular presented with high clinical suspicion of catatonia secondary to schizoaffective disorder, depressive type, with a past medical history of previous episodes of DVT. She was adequately treated for her PE using anticoagulation, embolectomy, and an IVC filter. However, if patients with multiple episodes of catatonia are treated with anticoagulation therapy for PE prophylaxis, the mortality rate in this patient population may potentially decrease.\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 Risk factors for venous thrombosis - current understanding from an epidemiological point of view Br J Haematol Lijfering WM Rosendaal FR Cannegieter SC 824 833 149 2010 20456358\n2 Incidence of deep vein thrombosis in catatonic patients: a chart review Psychiatry Res Ishida T Sakurai H Watanabe K Iwashita S Mimura M Uchida H 61 65 241 2016 27156025\n3 Catatonia in psychiatric classification: a home of its own Am J Psychiatry Taylor MA Fink M 1233 1241 160 2003 12832234\n4 Diagnostic and Statistical Manual of Mental Disorders. 5 ed. American Psychiatric Association Arlington, VA American Psychiatric Association 2013\n5 Development and validation of the Bush-Francis Catatonia Rating Scale - Brazilian version Arq Neuropsiquiatr Nunes AL Filgueiras A Nicolato R 44 49 75 2017 28099562\n6 Catatonia: clinical aspects and neurobiological correlates J Neuropsychiatry Clin Neurosci Daniels J 371 380 21 2009 19996245\n7 Catatonia from its creation to DSM-V: considerations for ICD Indian J Psychiatry Fink M 214 217 53 2011 22135438\n8 Pulmonary embolism, part I: epidemiology, risk factors and risk stratification, pathophysiology, clinical presentation, diagnosis and nonthrombotic pulmonary embolism Exp Clin Cardiol Bĕlohlávek J Dytrych V Linhart A 129 138 18 2013 23940438\n9 Two pulmonary emboli in a psych pod J Am Coll Emerg Physicians Open King SA Kelly SM Richardson AC Fischer KR Smedley AD 416 418 4 2020\n10 Association of the thrombo-embolic phenomenon with electroconvulsive therapy treatment in schizophrenia with catatonia patient Cureus Warriach ZI Shamim SA Saeed A Kashif S Malik BH 0 14 2019\n11 The impact of antipsychotics as a risk factor for thromboembolism Pharmacol Rep Ogłodek EA Just MJ Grzesińska AD Araszkiewicz A Szromek AR 533 539 70 2018 29674240\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(3)",
"journal": "Cureus",
"keywords": "catatonia; deep venous thrombosis; lorazepam; pulmonary embolism; retarded-type; schizoaffective disorder",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e14000",
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"pmid": "33889457",
"pubdate": "2021-03-19",
"publication_types": "D002363:Case Reports",
"references": "27156025;23940438;12832234;20456358;19996245;33000064;29674240;31700757;22135438;28099562",
"title": "Catatonia-Induced Saddle Pulmonary Embolism.",
"title_normalized": "catatonia induced saddle pulmonary embolism"
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"abstract": "Diphenhydramine (Benadryl) is a first-generation antihistamine that is used primarily to treat allergic reactions including anaphylaxis, urticaria, and allergic rhinitis. Despite its availability as an over-the-counter medication, toxicity may occur with its use especially when administered in large doses or via the intravenous route. We present a 3-month-old infant with Trisomy 21 who suffered a cardiac arrest immediately following administration of a single 1.25 mg/kg dose of intravenous diphenhydramine, prescribed for sedation in the Pediatric ICU setting. The potential cardiovascular and respiratory effects of diphenhydramine are presented, previous reports of life-threatening adverse effects reviewed, and options to limit these effects discussed.",
"affiliations": null,
"authors": "Andersen|Courtney L|CL|;Tobias|Joseph D|JD|",
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"doi": "10.5863/1551-6776-26.3.311",
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"issue": "26(3)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "adverse drug reaction; cardiac arrest; diphenhydramine; pediatrics; toxicity",
"medline_ta": "J Pediatr Pharmacol Ther",
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"nlm_unique_id": "101089851",
"other_id": null,
"pages": "311-314",
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"title": "Cardiac Arrest Following the Administration of Intravenous Diphenhydramine for Sedation to an Infant With Congenital Heart Disease.",
"title_normalized": "cardiac arrest following the administration of intravenous diphenhydramine for sedation to an infant with congenital heart disease"
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"abstract": "The use of ketamine as a drug of abuse has increased and so too has the risk of accidental overdose. Here, the authors report the case of a 10-month-old infant who inadvertently ingested ketamine. The child demonstrated severe cerebellar swelling that required emergency surgical intervention. The authors describe the clinical course of this child and present the radiographic characteristics of the brain. The imaging characteristics were not consistent with purely anoxic injury, thus suggesting a specific effect of this drug. To the authors' knowledge, similar imaging characteristics in this context have not been described.",
"affiliations": "Department of Neurological Surgery, Division of Pediatric Neurosurgery, Goodman Campbell Brain and Spine; and.;Department of Neurological Surgery, Division of Pediatric Neurosurgery, Goodman Campbell Brain and Spine; and.;Department of Neurological Surgery, Division of Pediatric Neurosurgery, Goodman Campbell Brain and Spine; and.;Department of Clinical Emergency Medicine and Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana.;Department of Neurological Surgery, Division of Pediatric Neurosurgery, Goodman Campbell Brain and Spine; and.",
"authors": "Villelli|Nicolas|N|;Hauser|Natalie|N|;Gianaris|Thomas|T|;Froberg|Blake A|BA|;Fulkerson|Daniel H|DH|",
"chemical_list": "D000700:Analgesics; D007649:Ketamine",
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"delete": false,
"doi": "10.3171/2017.5.PEDS16695",
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"issn_linking": "1933-0707",
"issue": "20(4)",
"journal": "Journal of neurosurgery. Pediatrics",
"keywords": "EVD = external ventricular drain; PEG = percutaneous endoscopic gastrostomy; cerebellar; edema; ketamine; pediatric neurosurgery",
"medline_ta": "J Neurosurg Pediatr",
"mesh_terms": "D000700:Analgesics; D001929:Brain Edema; D002531:Cerebellum; D005260:Female; D006801:Humans; D007223:Infant; D007649:Ketamine; D008279:Magnetic Resonance Imaging",
"nlm_unique_id": "101463759",
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"title": "Severe bilateral cerebellar edema from ingestion of ketamine: case report.",
"title_normalized": "severe bilateral cerebellar edema from ingestion of ketamine case report"
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"abstract": "Fingolimod is the first oral disease-modifying drug approved for the treatment of multiple sclerosis. The drug is usually well tolerated, and common adverse effects include bradycardia, headache, influenza, diarrhea, back pain, increased liver enzyme levels, and cough. Fingolimod is thought to provide therapeutic benefit by preventing normal lymphocyte egress from lymphoid tissues, thus reducing the infiltration of autoaggressive lymphocytes into the central nervous system. However, because the drug acts on different sphingosine-1-phosphate receptors, it may induce several biological effects by influencing endothelial cell-cell adhesion, angiogenesis, vascular development, and cardiovascular function. We describe a patient with multiple sclerosis who, after 3 weeks of fingolimod administration, developed purplish blotches over the dorsal surface of the distal phalanges of the second and fifth digits and the middle phalanx of the fourth ray, itching, and edema on his left hand, without other evident clinical manifestations. When fingolimod therapy was discontinued, the clinical picture regressed within a few days but reappeared after a rechallenge test. Physicians should be aware of unexpected peripheral vascular adverse effects due to fingolimod use, and patients with vascular-based acropathies should be carefully screened and monitored when taking this drug.",
"affiliations": "IRCCS Centro Neurolesi \"Bonino-Pulejo,\" Messina, Italy.;Department of Social Territorial Medicine, Section of Dermatology, University of Messina, Messina, Italy.;IRCCS Centro Neurolesi \"Bonino-Pulejo,\" Messina, Italy.;IRCCS Centro Neurolesi \"Bonino-Pulejo,\" Messina, Italy.;IRCCS Centro Neurolesi \"Bonino-Pulejo,\" Messina, Italy.;IRCCS Centro Neurolesi \"Bonino-Pulejo,\" Messina, Italy. Electronic address: salbro77@tiscali.it.",
"authors": "Russo|Margherita|M|;Guarneri|Claudio|C|;Mazzon|Emanuela|E|;Sessa|Edoardo|E|;Bramanti|Placido|P|;Calabrò|Rocco Salvatore|RS|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride",
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"mesh_terms": "D000328:Adult; D016903:Drug Monitoring; D005385:Fingers; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D009103:Multiple Sclerosis; D016491:Peripheral Vascular Diseases; D012212:Rheology; D016896:Treatment Outcome; D028761:Withholding Treatment",
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"title": "Fingolimod-Associated Peripheral Vascular Adverse Effects.",
"title_normalized": "fingolimod associated peripheral vascular adverse effects"
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... |
{
"abstract": "In Germany, an extended-release (ER) combination of the high-potency opioid (HPO) oxycodone and the antagonist naloxone was approved in 2006. In recent years, the cardio- and cerebrovascular safety of opioid antagonists and of opioids themselves has been discussed.\n\n\n\nThe objective of this study was to estimate the risk of major ischemic cardio- and cerebrovascular events in patients receiving ER oxycodone-naloxone compared with those receiving other ER HPOs.\n\n\n\nWe used the German Pharmacoepidemiological Research Database (GePaRD) to conduct a nested case-control study (2006-2011) within a cohort of ER HPO users. Cases were defined as patients hospitalized for acute myocardial infarction (MI) or ischemic stroke (IS). For each case, up to ten controls were selected by risk-set sampling. Using conditional logistic regression, confounder-adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were obtained for the risk of MI/IS associated with (1) current HPO treatment, (2) recent discontinuation, or (3) recent switch of HPO therapy compared with past treatment.\n\n\n\nIn 309,936 ER HPO users, 12,384 MI/IS events were detected, resulting in a crude incidence rate of 19.48 (95% CI 19.14-19.82) per 1000 person years. A small but significantly elevated aOR was found for morphine (1.12; 95% CI 1.04-1.22) but not for oxycodone-naloxone. Recent discontinuation and recent switch of any ER HPO also had a significant impact on the outcome (aOR 1.12; 95% CI 1.04-1.21 and 1.25; 95% CI 1.03-1.52, respectively).\n\n\n\nOur study does not indicate an association between oxycodone-naloxone and ischemic cardio- or cerebrovascular events. However, our findings do suggest that every change in ER HPO therapy should be conducted with caution.",
"affiliations": "Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany. kathrin.jobski@uni-oldenburg.de.;Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany.;Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany.;Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany.",
"authors": "Jobski|Kathrin|K|0000-0002-3957-9721;Kollhorst|Bianca|B|;Garbe|Edeltraut|E|;Schink|Tania|T|",
"chemical_list": "D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D009270:Naloxone; D010098:Oxycodone",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40264-017-0511-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0114-5916",
"issue": "40(6)",
"journal": "Drug safety",
"keywords": null,
"medline_ta": "Drug Saf",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D016022:Case-Control Studies; D002561:Cerebrovascular Disorders; D003692:Delayed-Action Preparations; D005260:Female; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia; D009270:Naloxone; D010098:Oxycodone; D012189:Retrospective Studies; D012306:Risk",
"nlm_unique_id": "9002928",
"other_id": null,
"pages": "505-515",
"pmc": null,
"pmid": "28194654",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "26757467;19187889;1595690;24452879;26119289;20082204;9554420;25714043;23331508;23841682;23696768;24572005;21149752;27299617;25033926;26292280;26719075;25135384;27060723;26977696;21567652;18200610;15862718;24682186;23413387",
"title": "The Risk of Ischemic Cardio- and Cerebrovascular Events Associated with Oxycodone-Naloxone and Other Extended-Release High-Potency Opioids: A Nested Case-Control Study.",
"title_normalized": "the risk of ischemic cardio and cerebrovascular events associated with oxycodone naloxone and other extended release high potency opioids a nested case control study"
} | [
{
"companynumb": "DE-DEPOMED, INC.-DE-2017DEP001281",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAPENTADOL HYDROCHLORIDE"
},
"drugadd... |
{
"abstract": "OBJECTIVE\nTo investigate the clinical efficacy of L-asparginasum, ASP) combined with CHOP for treating patients with extranodal natural killer/T-cell lymphoma.\n\n\nMETHODS\nA total of 68 patients with extranodal natural killer/T-cell lymphoma in our hospital from August 2007 to May 2009 were enrolled in this study, out of them 34 patients received CHOP regimen (CHOP group) and other 34 patients received CHOP regimen combined with L-Asparaginasum (ASP+CHOP group). The clinical efficacy of both groups was analyzed and compared after treatment.\n\n\nRESULTS\nIn CHOP group 16 patients achieved CR+PR, the total remission rate (TRR) was 47.06%; in ASP+CHOP group 24 patients achieved CR+PR, the TRR was 70.58%, and the TRR in ASP+CHOP group was higher than that in CHOP group, there was statistical significance between these 2 groups (X(2) = 3.886, P < 0.05). The time of PFS in CHOP group was 24.7 months, and the time of PFS in ASP+CHOP group was 47.5 months which was significantly longer than that in CHOP group, and there was statistical siguificance between these 2 groups (P < 0.05). The incidence of anemia with grade I-II and III-IV blood cell reduction in ASP+CHOP group was higher than that in CHOP group (P < 0.05). The incidence of fever with grade I-II and albumin decrease in ASP+CHOP group was higher than that in CHOP group (P < 0.05). The abnormality of coagulation function in ASP+CHOP group was higher than that in CHOP group (P < 0.05). The anaphylactic reaction was found in 6 cases. The increase of serum amylase was observed in 1 case of aggressive NK/T cell lymphoma, the acute pancreatitis occured in 1 case who was inproved after treatment, but this patients died due to rapid progression of disease caused by poor general condition and untolerance to chemotherapy. The incomplete intestinal obstruction was found in 3 patients who recovered after conservative treatment. The grade II serum creatinine was elevated in 2 cases of ASP+CHOP group and in 1 case of CHOP group who was inproved after symptomatic therapy.\n\n\nCONCLUSIONS\nL-Asparaginasum combined with CHOP for treating patients with extranodal natural killer/T-cell lymphoma is effective, and may be used in clinic.",
"affiliations": "Department of Oncology, ishui Center Hospital, Linyi 276400, Shandong Province, China.;Radiotherapy Center, Yishui Center Hospital, Linyi 276400, Shandong Province, China.;Department of Oncology, ishui Center Hospital, Linyi 276400, Shandong Province, China. E-mail: mdeliang-83@163.com.",
"authors": "Zhang|Dian-Fu|DF|;Fang|Rui-Yan|RY|;Ma|De-Liang|DL|",
"chemical_list": "D001224:Aspartic Acid; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; D001215:Asparaginase",
"country": "China",
"delete": false,
"doi": "10.7534/j.issn.1009-2137.2015.04.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1009-2137",
"issue": "23(4)",
"journal": "Zhongguo shi yan xue ye xue za zhi",
"keywords": null,
"medline_ta": "Zhongguo Shi Yan Xue Ye Xue Za Zhi",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D001224:Aspartic Acid; D003520:Cyclophosphamide; D004317:Doxorubicin; D006801:Humans; D016399:Lymphoma, T-Cell; D011239:Prednisolone; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101084424",
"other_id": null,
"pages": "1034-8",
"pmc": null,
"pmid": "26314441",
"pubdate": "2015-08",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Clinical Efficacy of L-Asparaginasum Combined with CHOP for Treating Patients with Extranodal Natural Killer/T Cell Lymphoma.",
"title_normalized": "clinical efficacy of l asparaginasum combined with chop for treating patients with extranodal natural killer t cell lymphoma"
} | [
{
"companynumb": "CN-MYLANLABS-2016M1008466",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,... |
{
"abstract": "A man in his sixth decade with Crohn's colitis and who had been taking infliximab for 18 months presented with fever and weight loss. Chest CT showed numerous nodules in both lungs, and sputum culture grew Mycobacterium tuberculosis. Colonoscopy showed circumferential ulcerations from the cecum to the descending colon, and biopsies showed extensive granulomas with central necrosis, positive for acid-fast bacteria. Brain MRI revealed a thalamic ring-enhanced mass with edema, consistent with tuberculoma. Clinicians should be aware of the appropriate screening and close monitoring of tuberculosis before and during anti-tumor necrosis factor (TNF) therapy.",
"affiliations": "Division of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH.;Division of Pathology, Cleveland Clinic, Cleveland, OH.;Division of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH.",
"authors": "Wang|Ming-Hsi|MH|;Liu|Xiuli|X|;Shen|Bo|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.2015.97",
"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2015.9710.14309/crj.2015.97Case ReportInflammatory Bowel DiseaseDisseminated Tuberculosis in a Patient Taking Anti-TNF Therapy for Crohn's Disease Wang Ming-Hsi MD, PhD1Liu Xiuli MD, PhD2Shen Bo MD11 Division of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH2 Division of Pathology, Cleveland Clinic, Cleveland, OHCorrespondence: Ming-Hsi Wang, Department of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224 (wangmh5811@gmail.com).10 2015 09 10 2015 3 1 45 48 15 6 2015 25 8 2015 Copyright © Wang et al.2015This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/A man in his sixth decade with Crohn's colitis and who had been taking infliximab for 18 months presented with fever and weight loss. Chest CT showed numerous nodules in both lungs, and sputum culture grew Mycobacterium tuberculosis. Colonoscopy showed circumferential ulcerations from the cecum to the descending colon, and biopsies showed extensive granulomas with central necrosis, positive for acid-fast bacteria. Brain MRI revealed a thalamic ring-enhanced mass with edema, consistent with tuberculoma. Clinicians should be aware of the appropriate screening and close monitoring of tuberculosis before and during anti-tumor necrosis factor (TNF) therapy.\n==== Body\nIntroduction\nTuberculosis (TB) remains a major health problem in developing countries. An increasing number of cases of TB in North American since the mid-1980s have been attributed to immigration, coinfection with HIV, and the development of multidrug-resistant TB. The use of a anti-tumor necrosis factor (TNF) agents such as infliximab alone and in combination with other immunosuppressants has become more popular in the treatment of Crohn's disease (CD).1 Reports exist in the literature describing patients developing TB after infliximab therapy.2 Highrisk factors for developing TB with anti-TNF therapy include concomitant use of immunosuppressants, history of latent or active TB, and being born in or spending extensive time in endemic areas.\n\nCase Report\nA man in his sixth decade was admitted to our tertiary hospital for worsening diarrhea. He had been diagnosed with CD 3 years prior, and had been treated with intravenous infliximab for the previous 18 months after failure to respond to treatment with oral mesalamine. Before beginning treatment with the anti-TNF agent, he had a positive tuberculin skin test and a negative chest radiograph. Infliximab was started 2 months after he completed a 9-month course of isoniazid for latent tuberculosis. His CD-related symptoms gradually improved after the initiation of infliximab and had been stable for 16 months.\n\nHe had a 2-month history of intermittent fever, fatigue, and weight loss of 18 kg. On this presentation, chest radiograph and chest CT showed numerous, bilateral, scattered, small (<5 mm) nodules, with some clustered in a tree-in-bed distribution (Figures 1 and 2). Three consecutive sets of sputum showed acid-fast bacteria, and liquid culture grew Mycobacterium tuberculosis (MTB; Figure 3). Colonoscopy showed extensive circumferential ulcerations segmentally distributed from the cecum to the descending colon (Figure 4). Colon biopsies showed large epithelioid granulomas with central necrosis that were positive for acid-fast bacteria (Figure 5).\n\nFigure 1 Chest radiograph showed numerous small nodules in both lungs.\n\nFigure 2 Chest CT showed numerous small nodules (black arrows) in both lungs, with some clustered in tree-in-bed distribution.\n\nFigure 3 Mycobacterium tuberculosis can be seen cording in liquid culture (100x magnification).\n\nFigure 4 Large circumferential ulcerations surrounded by inflamed mucosa at right colon.\n\nFigure 5 (A) Extensive large epithelioid granulomas with central necrosis at colon biopsy. (B) Acid-fast bacteria stained by Ziehl-Neelsen in colon biopsies (400x magnification).\n\nStool culture was positive for MTB. A polymerase chain reaction (PCR) test of the colon biopsy specimens confirmed a diagnosis of MTB.\n\nDuring hospitalization, the patient developed intractable nausea and vomiting. The gadolinium-enhanced MRI of brain revealed a right thalamic ring-enhanced 1.2-cm mass with edema, consistent with tuberculoma, and several smaller punctate lesions in left parietal-temporal lobe and both cerebellar hemispheres (Figure 6). Cerebral spinal fluid analysis revealed high protein and low glucose levels, but a negative MTB culture. Infliximab was discontinued. With the concern of potential isoniazid-resistant tuberculosis (TB), the patient received amikacin in combination with the standard anti-TB regimen for the first 4 weeks before the drug-susceptibility result came back negative for isoniazid resistance. An anti-TB regimen of isoniazid, rifampin, ethambutol, and pyrazinamide for the first 2 months was started, followed by isoniazid and rifampin for an additional 8 months. After antiemetics and the continuation of anti-TB therapy, the patient's symptoms gradually improved. Subsequent sputum cultures were negative for TB. Repeated MRI of the brain showed a decrease in the size of the tuberculoma. Unfortunately, the patient suddenly became ill and died 8 months after diagnosis, presumably from complications of disseminated TB.\n\nFigure 6 A 1.2-cm ring-enhanced mass with peripheral edema at right thalamus in the gadolinium-enhanced brain MRI.\n\nDiscussion\nPatients with a positive tuberculin skin test should receive chemoprophylaxis with either isoniazid for 6–9 months, or rifampin for 3–4 months.3 Shorter regimens might avoid poor adherence and hepatotoxicity; however, rifampin-containing regimens should be prescribed with caution to people who are on antiretroviral treatment due to potential drug-to-drug interactions. In general, anti-TNF therapy may be started 2 months after completion of chemoprophylaxis. During the anti-TNF therapy these patients should be closely monitored at least annually with TB screening tests, starting 12 months after completion of chemoprophylaxis, to identify reactivation of latent TB or new TB infection. Up to a 19% risk of TB reactivation has been reported, mostly during the first year of anti-TNF therapy after completion of chemoprophylaxis.4 A case series of 130 patients who developed TB after infliximab between 2001 and 2006 was reported; 45% of cases had extrapulmonary involvement.2 In the subset analysis, only 3 of the 23 patients with documented normal pretreatment chest radiographs developed disseminated TB after infliximab. T-cell interferon-gamma release assays (IGRAs) are more sensitive and specific than the tuberculin skin test for the diagnosis of latent or new TB infections.\n\nEndoscopic features of intestinal TB and CD are similar, and the distinction between the presentations of these disease entities can be challenging.5 Endoscopic findings of transversely placed ulcers surrounded by diffusely inflamed, nodular mucosa, and patulous ileocecal valves favor TB; in contrast, aphthous and longitudinal, deep, fissuring ulcers, cobblestone appearance, normal surrounding mucosa, and stricturing ileocecal valves suggest CD. Endoscopic examination provides the advantage of obtaining multiple biopsies, especially at ulcer margins, to increase the chance of identifying MTB. Pathological features suggest that granulomata in intestinal TB tend to be multiple, large, and confluent, often with caseating or central necrosis. In contrast, granulomata in CD tend to be less numerous, smaller, and lack necrosis. Identification of acid-fast bacilli on intestinal biopsy tissue followed by PCR provides a definitive diagnosis. Other diagnostic methods include MTB cultures of stool or biopsy tissue, though these methods are time consuming.\n\nOur patient had been diagnosed with Crohn's colitis 3 years prior with colonic biopsies reporting no evidence of TB. His primary CD-related symptoms improved after the initiation of an anti-TNF agent and had been stable until 2 months before this admission. Although it is less likely, we can't completely exclude the possibility of primary intestinal TB imitating IBD. For cases of intestinal biopsies showing suppurative or caseating granulomas, pathologists, incorporating the clinician's concern, should bear a high index of suspicion and examine the acid-fast bacilli stains thoroughly with an appropriately reactive positive control. In cases with negative acid-fast bacilli stain on initial intestinal biopsy, close clinical correlation and follow-up should be attempted to avoid an unnecessarily delayed diagnosis of intestinal TB.\n\nDisclosures\nAuthor contributions: M-H Wang wrote and revised the manuscript. X. Liu described the histopathology and edited the manuscript. B. Shen supervised the process and is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was not obtained for this case report, as the patient is deceased. Next of kin contact information was unavailable. All patient identifying information has been removed.\n==== Refs\nReferences\n1 D'Haens GR \nTop-down therapy for IBD: Rationale and requisite evidence . Nat Rev Gastroenterol Hepatol . 2010 ;7 (2 ):86 –92 .20134490 \n2 Raval A , Akhavan-Toyserkani G , Brinker A , Avigan M \nBrief communication: Characteristics of spontaneous cases of tuberculosis associated with infliximab . Ann Intern Med . 2007 ;147 (10 ):699 –702 .18025446 \n3 World Health Organization . Guidelines on the management of latent tuberculosis infection . http://apps.who.int/medicinedocs/documents/s21682en/s21682en.pdf. Published 2015. Accessed June 1, 2015.\n4 Sichletidis L , Settas L , Spyratos D , \nTuberculosis in patients receiving anti-TNF agents despite chemoprophylaxis . Int J Tuberc Lung Dis . 2006 ;10 (10 ):1127 –1132 .17044206 \n5 Almadi MA , Ghosh S , Aljebreen AM \nDifferentiating intestinal tuberculosis from Crohn's disease: A diagnostic challenge . Am J Gastroenterol . 2009 ;104 (4 ):1003 –1012 .19240705\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2326-3253",
"issue": "3(1)",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "45-8",
"pmc": null,
"pmid": "26504878",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports",
"references": "17044206;18025446;19240705;20134490",
"title": "Disseminated Tuberculosis in a Patient Taking Anti-TNF Therapy for Crohn's Disease.",
"title_normalized": "disseminated tuberculosis in a patient taking anti tnf therapy for crohn s disease"
} | [
{
"companynumb": "US-JNJFOC-20160314376",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "While the docetaxel, carboplatin, and trastuzumab (TCH) regimen is one of the standard treatments in Her2-positive breast cancer, however, acute toxicities, especially those related to the high rate of neutropenia are consistently reported. Primary: To compare the toxicity of TCH in current clinical practice vs the toxicity observed in the pivotal study, comparing the toxicity in patients that received primary prophylaxis (PP) with colony-stimulating factors vs those that did not receive PP. Secondary: To describe the demographic and clinical characteristics of the study sample, as well as the adverse effects and survival. The data regarding 95 patients were analyzed. Observed toxicity (hematological and extra-hematological) was greater compared to the pivotal study, with the exception of neuropathy and neutropenia. Toxicities \"PP\" vs \"no PP\": Extra-hematological grade 3-4 toxicities: Significant reduction was observed in the \"PP\" group vs the \"no PP\" group referred to fatigue, stomatitis, nausea, and vomiting. Hematological grade 3-4 toxicities: Lesser neutropenia, leukopenia, and febrile neutropenia were observed in the \"PP\" group. Complications associated to treatment: No grade 3-4 cardiac toxicity, leukemia or deaths were recorded. DFS and OS: After a mean follow-up of 22.9 months, only one bone metastatic relapse was detected (DFS: 98.9%; OS: 100%). The combination TCH is very active and effective as adjuvant and neo-adjuvant therapy in Her2-positive breast cancer, and is currently regarded as standard treatment. However, global toxicity as well as hematological toxicity is elevated. The incorporation of PP to TCH significantly reduces hematological toxicity and some of the global toxicity, thus favoring treatment implementation and lessening the clinical complications. We therefore recommend generalization of PP with colony-stimulating factors in patients receiving TCH.",
"affiliations": "Department of Medical Oncology, Complejo Hospitalario de Huelva, Huelva, Spain.;Department of Medical Oncology, Complejo Hospitalario de Huelva, Huelva, Spain.;Department of Medical Oncology, Complejo Hospitalario de Huelva, Huelva, Spain.;Department of Medical Oncology, Complejo Hospitalario de Huelva, Huelva, Spain.",
"authors": "Bayo|Juan|J|0000-0002-3428-5708;Aviñó|Victoria|V|;Toscano|Fátima|F|;Jiménez|Francisco|F|",
"chemical_list": "D003115:Colony-Stimulating Factors; D000077143:Docetaxel; D016190:Carboplatin; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.1111/tbj.12927",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-122X",
"issue": "24(4)",
"journal": "The breast journal",
"keywords": "\nTCH\n; G-CSF; Her2+; breast cancer; toxicity",
"medline_ta": "Breast J",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D016190:Carboplatin; D017024:Chemotherapy, Adjuvant; D003115:Colony-Stimulating Factors; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009503:Neutropenia; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"nlm_unique_id": "9505539",
"other_id": null,
"pages": "462-467",
"pmc": null,
"pmid": "29205665",
"pubdate": "2018-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Toxicity of docetaxel, carboplatin, and trastuzumab combination as adjuvant or neo-adjuvant treatment for Her2 positive breast cancer patients and impact of colony-stimulating factor prophylaxis.",
"title_normalized": "toxicity of docetaxel carboplatin and trastuzumab combination as adjuvant or neo adjuvant treatment for her2 positive breast cancer patients and impact of colony stimulating factor prophylaxis"
} | [
{
"companynumb": "ES-ROCHE-2165914",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "High bilirubin levels are nephrotoxic. Bilirubin can cause a functional proximal tubulopathy or may precipitate into casts associated with acute tubular injury. This condition is known as bile cast nephropathy. The kidney injury is generally reversible if bilirubin levels are decreased early. We present a case wherein an alcoholic patient presented with high bilirubin levels and anuric acute kidney injury. The initial urine analysis suggested intrinsic renal disease. A kidney biopsy, performed a few days after the initiation of dialysis, demonstrated the presence of bile casts along with acute tubular injury. The patient however continued to be dialysis dependent inspite of initiating prednisolone to treat acute alcoholic hepatitis.",
"affiliations": "Division of Nephrology and Hypertension, Department of Medicine, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.",
"authors": "Sequeira|Adrian|A|;Gu|Xin|X|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.1111/hdi.12169",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1492-7535",
"issue": "19(1)",
"journal": "Hemodialysis international. International Symposium on Home Hemodialysis",
"keywords": "Bilirubin; bile; cast; tubulopathy",
"medline_ta": "Hemodial Int",
"mesh_terms": "D000328:Adult; D001646:Bile; D005260:Female; D006801:Humans; D007565:Jaundice; D007674:Kidney Diseases",
"nlm_unique_id": "101093910",
"other_id": null,
"pages": "132-5",
"pmc": null,
"pmid": "24725377",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bile cast nephropathy: an often forgotten diagnosis.",
"title_normalized": "bile cast nephropathy an often forgotten diagnosis"
} | [
{
"companynumb": "US-JNJFOC-20150120439",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "Tumor lysis syndrome (TLS) is a potentially lethal complication in cancer therapy. It may occur in highly sensitive tumors, especially in childhood cancer and leukemia, whereas, it is rare in the treatment of solid tumors in adults. TLS results from a sudden and rapid release of nuclear and cytoplasmic degradation products of malignant cells. The release of these can lead to severe alterations in the metabolic profile. Here, we present two cases of large hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE) that resulted in TLS. Although TLS rarely happens in the treatment of adult hepatic tumor, only a few cases have been reported. We should keep in mind that all patients with HCC, particularly those with large and rapidly growing tumors, must be closely watched for evidence of TLS after TACE.",
"affiliations": "Department of General Surgery, E-Da Hospital, E-Da Road, Yan-Chau, Kaohsiung 82445, Taiwan, China.",
"authors": "Hsieh|Pei-Min|PM|;Hung|Kao-Chen|KC|;Chen|Yaw-Sen|YS|",
"chemical_list": "D000970:Antineoplastic Agents; D004317:Doxorubicin",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.15.4726",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "15(37)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D004317:Doxorubicin; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "4726-8",
"pmc": null,
"pmid": "19787837",
"pubdate": "2009-10-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "15063817;16401719;12071597;11343271;7369230;9598857;15384972;16247154;9375703;15189271;16377509;14667750;16166968;12108612;17242878;11106126;11343272",
"title": "Tumor lysis syndrome after transarterial chemoembolization of hepatocellular carcinoma: case reports and literature review.",
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"abstract": "Gemcitabine is frequently used for the treatment of a number of different cancer types. Gemcitabine-related thrombotic microangiopathy (TMA) has rarely been described, but it is a life-threatening complication. The incidence of the complication varies between 0.015 and 1.4%. The present study reports the case of a 63-year-old Caucasian male who was treated with 3 cycles of carboplatin plus gemcitabine, followed by 7 cycles of gemcitabine only, and developed clinical symptoms that, together with laboratory findings, were compatible with a diagnosis of hemolytic uremic syndrome TMA. The patient was admitted to Jean Godinot Cancer Center Institute with hemolysis, thrombocytopenia, macroscopic hematuria, renal dysfunction and worsening high blood pressure. Medical treatment for the high blood pressure, plasma infusion and hemodialysis were implemented without any improvement in creatine levels. The patient recovered from hematological disorders, left hospital and was followed-up. He required hemodialysis until he succumbed ~3 months subsequent to diagnosis of TMA. Even if thrombocytopenia, anemia and renal failure are common observations in patients treated by chemotherapy, clinicians should be aware of this potentially lethal complication. We recommend screening for TMA in such cases of anemia, thrombocytopenia and renal failure.",
"affiliations": "Jean Godinot Institute, 51100 Reims, France.;Jean Godinot Institute, 51100 Reims, France.;Department of Pharmacovigilance and Pharmacoepidemiology, Reims University Hospital, 51100 Reims, France.",
"authors": "Lai-Tiong|Florence|F|;Duval|Yann|Y|;Krabansky|Francois|F|",
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"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2017.5576OL-0-0-5576ArticlesGemcitabine-associated thrombotic microangiopathy in a patient with lung cancer: A case report Lai-Tiong Florence 1*Duval Yann 1*Krabansky Francois 21 Jean Godinot Institute, 51100 Reims, France2 Department of Pharmacovigilance and Pharmacoepidemiology, Reims University Hospital, 51100 Reims, FranceCorrespondence to: Miss. Florence Lai-Tiong, Jean Godinot Institute, 1 Rue du Général Kœnig, 51100 Reims, France, florence.lai-tiongfofo@laposte.net* Contributed equally\n\n3 2017 05 1 2017 05 1 2017 13 3 1201 1203 01 4 2015 16 5 2016 Copyright: © Lai-Tiong et al.2017This 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.Gemcitabine is frequently used for the treatment of a number of different cancer types. Gemcitabine-related thrombotic microangiopathy (TMA) has rarely been described, but it is a life-threatening complication. The incidence of the complication varies between 0.015 and 1.4%. The present study reports the case of a 63-year-old Caucasian male who was treated with 3 cycles of carboplatin plus gemcitabine, followed by 7 cycles of gemcitabine only, and developed clinical symptoms that, together with laboratory findings, were compatible with a diagnosis of hemolytic uremic syndrome TMA. The patient was admitted to Jean Godinot Cancer Center Institute with hemolysis, thrombocytopenia, macroscopic hematuria, renal dysfunction and worsening high blood pressure. Medical treatment for the high blood pressure, plasma infusion and hemodialysis were implemented without any improvement in creatine levels. The patient recovered from hematological disorders, left hospital and was followed-up. He required hemodialysis until he succumbed ~3 months subsequent to diagnosis of TMA. Even if thrombocytopenia, anemia and renal failure are common observations in patients treated by chemotherapy, clinicians should be aware of this potentially lethal complication. We recommend screening for TMA in such cases of anemia, thrombocytopenia and renal failure.\n\ngemcitabinethrombotic microangiopathylung cancer\n==== Body\nCase report\nA 63-year-old Caucasian male without a previous medical history was diagnosed with metastatic non small cell lung cancer (NSCLC) in March 2013 at Jean Godinot Cancer Center Institute (Reims, France). The patient received first-line treatment with gemcitabine (1,250 mg/m2) plus carboplatin (700 mg/m2; area under the curve, 5) every 3 weeks for 3 cycles (overall ~2 months), followed by 7 cycles of gemcitabine alone (1,000 mg/m2; day 1 and day 8; overall ~2 months). Following the seventh cycle, the patient developed high blood pressure (180/100 mmHg) and was subsequently intravenously administered with enalapril-hydrochlorothiazide (1,000 mg/m2; 1,075 mg/30 min).\n\nA week later the patient was admitted to Jean Godinot Cancer Center due to acute renal failure. The patient's serum creatinine level had reached 199 µmol/l (normal range, 65–120 µmol/l), the platelet level was decreased to 17×109/l (normal range, 150–400×109/l) and the hemoglobin level was decreased to 8.3 g/dl (normal range, 129–167 g/l). Ultrasound of the urinary tract did not show any signs of obstruction and a urine test did not reveal a functional profile.\n\nFurther investigations revealed a normal coagulation pattern, with a bilirubin level of 47 µmol/l (normal range, 3.4–17 µmol/l), a lactose dehydrogenase (LDH) level of 2,374 IU/l (normal range, 200–450 IU/l), reticulocytes at 7.5% (normal range, 1–2.5%) and an undetectable haptoglobin level (<0.10 g/l; normal range, 0.5–2.5 g/l). Schiztocytes were found on the peripheral blood smear. Albuminemia (35.4 g/l; normal range, 35–50 g/l) and proteinuria (4.21 g per day; 3.51 g/l; normal range, <150 mg per day ot <0.20 g/l) were noted, in association with macroscopic hematuria. Complement factors were within normal ranges. A disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) activity was also normal.\n\nThrombotic microangiopathy (TMA) was suspected and this diagnosis of hemolytic uremic syndrome (HUS) TMA was later confirmed by renal biopsy.\n\nThe patient received two infusions of three units each of freshly frozen plasma. Also, patient stabilization required three units of packed red cells. Blood pressure was controlled using multiple antihypertensive medications (80 mg furosemide, intravenous nicardipine and 5 mg beta blockers twice a day). At day 16 post-presentation, hemodialysis was started.\n\nThe patient recovered quickly from the thrombopenia and anemia. However, renal failure persisted and the patient required hemodialysis until he succumbed ~3 months subsequent to the diagnosis of TMA.\n\nDiscussion\nTMA is a disorder characterized by microvascular occlusion due to platelet aggregation, thrombocytopenia and organ damage, such as renal failure (1). The main subtypes of TMA are HUS and thrombotic thrombocytopenic purpura (TTP). Thrombocytopenia, schistocytosis and elevated levels of LDH are enough to form a diagnosis in clinical practice. The majority of cases are idiopathic, but several etiologies have been recognized, among which are the use of cytotoxic chemotherapies, including mitomycin C, bleomycin, cisplatin and 5-fluorouracil (2). TMA may also be caused by the underlying malignancy itself (3,4). Indeed, TMA associated with metastatic adenocarcinomas, such as those of the stomach, colorectum, breasts, lungs and prostate, have been reported (5–7). It can be difficult to distinguish between HUS caused by the cancer itself and that caused by the chemotherapy. Certain studies have suggested that malignancy-associated HUS typically occurs during widespread metastatic disease, whereas the chemotherapy-associated type occurs more frequently when the patient is in disease remission. In the present study, the patient had minimal tumor burden.\n\nThe physiopathology of this disease remains unclear. Several mechanisms have been suggested, including an immune-mediated response or a direct toxic effect. Endothelial injury is the main event (8). HUS does not appear to be associated with a deficiency in ADAMTS13 activity; indeed, even if ADAMTS13 activity is absent or deficient in familial TTP, this condition it is not sufficient to cause the syndrome. Also, no specific correlation has been found between TMA and gender or age (9).\n\nADAMTS13 has been shown to be of major pathophysiological importance TMA in the setting of TTP when either lacking antibodies against ADAMTS13 (inherited TTP) or if antibodies against ADAMTS13 are present (acquired TTP). A severe deficiency of <5% ADAMTS-1 activity, with clinical symptoms of an acute thrombocytopenia and evidence of a microangiopathic hemolytic anemia, appropriately defines a diagnosis of TTP (10,11).\n\nGemcitabine is an important chemotherapeutic agent and its indications in oncology and hematology are wide. It is used in the therapy of pancreatic, ovarian, breast and bladder cancers, and NSCLC. Gemcitabine is associated with side effects that can lead to patient mortality (9).\n\nFirst-line gemcitabine combined with cisplatin is indicated in patients with inoperable NSCLC (locally advanced or metastatic). In 1994, the first case of gemcitabine-associated TMA occurred during a phase II trial in pancreatic metastatic adenocarcinoma (12). To the best of our knowledge, there have been only 3 cases of gemcitabine-associated microangiopathy in patients treated for NSCLC to date (6).\n\nThe incidence of gemcitabine-attributed TMA is between 0.015 and 1.4% (13). However, the true incidence is difficult establish due to its underreported nature, the poor recognition of the condition or the failure to diagnose mild symptoms (14). A TMA diagnosis is more difficult in patients treated for cancer compared with otherwise healthy individuals, as certain symptoms may be adverse effects of chemotherapy agents. Clinically, TTP presents with hemolytic anemia, thrombocytopenia and renal insufficiency. Neurological symptoms and a fever are often present. However, anemia and thrombocytopenia are also common side-effects associated with chemotherapy due to myelotoxicity. Data on the incidence of TMA associated with gemcitabine use are conflicting. In 2004, in a study by Humphreys et al (15), the incidence of gemcitabine-associated TMA was shown to be 0.31%. This was in contrast with the estimated incidence of only 0.015% described by Fung et al in 1999 (16). In Boston, a review was performed between 1997 and 2002, and among 2,586 patients, 9 were identified with gemcitabine-associated TMA (15). New or exacerbated hypertension preceded the diagnosis of TMA by 0.5–10 weeks. The study concluded that this could represent an early clinical marker for the presence of a TMA syndrome (8). In the present study, the blood pressure of the patient remained high at 200/110 mmHg for several days.\n\nThe risk for gemcitabine-associated TMA appears to increase with a cumulative drug dose of >20,000 mg/m2 or administration for >18 cycles (14). The condition rarely occurs prior to 7 months of therapy. In the present case, the patient received only 10,750 mg/m2 (cumulative dose) of gemcitabine during 8 months. In the majority of reported cases, gemcitabine has been administered as a single-agent treatment, but in other cases, such as the present study, the condition has been reported during combination therapy (16). Screening for TMA has been proposed for after 10 cycles of gemcitabine. However, the development of TTP has been also reported after a single dose of gemcitabine (17).\n\nA number of different treatments types have been previously suggested for patients with HUS (7,18). Glucocorticoids and plasma infusion may be used, but the interruption of chemotherapy and plasma exchange are the mainstays of treatment, and these therapies are quite effective. Management also involves the control of hypertension. Although these treatments are readily available, HUS remains a highly fatal disease.\n\nThe estimated mortality rate for HUS is 10–40% in the majority of case series (19,20), but has been reported to be as high as 60–70% in others (7,21,22).\n\nHumphreys et al (15) recommend that for patients receiving gemcitabine for >3 months, the creatinine, schistocyte and haptoglobin levels should be checked monthly. Desramé et al (23) proposed that systematic screening should be performed for HUS during gemcitabine therapy. In this series, the frequency of HUS was 2.2%.\n\nIn conclusion, even if TMA is a rare adverse effect of cancer therapy, clinicians should be aware of it due to its potentially lethal evolution. Chemotherapy-induced TMA and that caused by the cancer itself are difficult to differentiate between, but the patient's clinical data can aid the clinician in making the right diagnosis. The precise and regular reporting of chemotherapeutic adverse events may assist in evaluating the frequency of TMA. Although no precise recommendation exists for the diagnosis and treatment of TMA, we suggest that chemotherapy should be halted and a glucocorticoid therapy or a plasma infusion should be introduced. Any worsening of anemia, thrombocytopenia or serum creatinine level with high blood pressure should lead to a prompt examination.\n==== Refs\nReferences\n1 Symmers WS Thrombotic microangiopathic haemolytic anaemia (thrombotic microangiopathy) Br Med J 2 897 903 1952 10.1136/bmj.2.4790.897 12978378 \n2 Anai H Okada Y Okubo K Korenaga D Maehara Y Sugimachi K Ohi Y A case report of hemolytic uremic syndrome (HUS) induced by antineoplastic agents Nihon Gan Chiryo Gakkai Shi 25 1487 1491 1990 (In Japanese) 2120375 \n3 Schjølseth SA Hagen T Ottestad L Jakobsen E Chemotherapy-induced hemolytic uremic syndrome. A complication to mitomycin treatment of breast carcinoma Tidsskr Nor Laegeforen 115 3371 3373 1995 (In Norwegian) 7491579 \n4 Seo DW Lee YS Chae JG Lee MG Choe GY Chi HS Min YI Hepatocellular carcinoma associated hemolytic uremic syndrome unrelated to chemotherapy J Korean Med Sci 9 254 258 1994 10.3346/jkms.1994.9.3.254 7993594 \n5 Murgo AJ Cancer- and chemotherapy-associated thrombotic microangiopathy Hemolytic-Uremic Syndrome and Thrombotic Thrombocytopenic Purpura Kaplan BS Trompeter RS Moake JL Marcel Dekker New York, NY 271 285 1992 \n6 Pisoni R Ruggenenti P Remuzzi G Drug-induced thrombotic microangiopathy: Incidence, prevention and management Drug Saf 24 491 501 2001 10.2165/00002018-200124070-00002 11444722 \n7 Lesesne JB Rothschild N Erickson B Korec S Sisk R Keller J Arbus M Woolley PV Chiazze L Schein PS Cancer-associated hemolytic-uremic syndrome: Analysis of 85 cases from a national registry J Clin Oncol 7 781 789 1989 2497229 \n8 Hillyer CD Duncan A Ledford M Barrett TJ Klumpp SA Anderson DC McClure HM Winton EF Chemotherapy-induced hemolytic uremic syndrome: Description of a potential animal model J Med Primatol 24 68 73 1995 10.1111/j.1600-0684.1995.tb00148.x 8613975 \n9 Feys HB Roodt J Vandeputte N Pareyn I Lamprecht S van Rensburg WJ Anderson PJ Budde U Louw VJ Badenhorst PN Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in the baboon (Papio ursinus) Blood 116 2005 2010 2010 10.1182/blood-2010-04-280479 20551375 \n10 Lichtman LA Beutler E Kipps TJ Seligsohn U Kaushansky K Prchal JT Williams Hematology 7th Sydney McGraw-Hill Medical Sydney 2006 \n11 Tsai HM The molecular biology of thrombotic microangiopathy Kidney Int 70 16 2006 10.1038/sj.ki.5001535 16760911 \n12 Casper ES Green MR Kelsen DP Heelan RT Brown TD Flombaum CD Trochanowski B Tarassoff PG Phase II trial of gemcitabine (2,2′-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas Invest New Drugs 12 29 34 1994 10.1007/BF00873232 7960602 \n13 Oberic L Buffet M Schwarzinger M Veyradier A Clabault K Malot S Schleinitz N Valla D Galicier L Bengrine-Lefèvre L Cancer awareness in atypical thrombotic microangiopathies Oncologist 14 769 779 2009 10.1634/theoncologist.2009-0067 19684072 \n14 Walter RB Joerger M Pestalozzi BC Gemcitabine-associated hemolytic-uremic syndrome Am J Kidney Dis 40 E16 2002 10.1053/ajkd.2002.35758 12324937 \n15 Humphreys BD Sharman JP Henderson JM Clark JW Marks PW Rennke HG Zhu AX Magee CC Gemcitabine-associated thrombotic microangiopathy Cancer 100 2664 2670 2004 10.1002/cncr.20290 15197810 \n16 Fung MC Storniolo AM Nguyen B Arning M Brookfield W Vigil J A review of hemolytic uremic syndrome in patients treated with gemcitabine therapy Cancer 85 2023 2032 1999 10.1002/(SICI)1097-0142(19990501)85:9%3C2023::AID-CNCR21%3E3.0.CO;2-2 10223245 \n17 De Smet D Jochmans K Neyns B Development of thrombotic thrombocytopenic purpura after a single dose of gemcitabine Ann Hematol 87 495 496 2008 10.1007/s00277-007-0429-9 18097666 \n18 Sedlacek SM First-line and salvage therapy of metastatic breast cancer with mitomycin/vinblastine Oncology 50 (Suppl 1) S16 S21 1993 10.1159/000227243 \n19 Hollenbeck M Kutkuhn B Aul C Leschke M Willers R Grabensee B Haemolytic-uraemic syndrome and thrombotic-thrombocytopenic purpura in adults: Clinical findings and prognostic factors for death and end-stage renal disease Nephrol Dial Transplant 13 76 81 1998 10.1093/ndt/13.1.76 9481719 \n20 Sens YA Miorin LA Silva HG Malheiros DM Filho DM Jabur P Acute renal failure due to hemolytic uremic syndrome in adult patients Ren Fail 19 279 282 1997 10.3109/08860229709026289 9101604 \n21 Sheldon R Slaughter D A syndrome of microangiopathic hemolytic anemia, renal impairment, and pulmonary edema in chemotherapy-treated patients with adenocarcinoma Cancer 58 1428 1436 1986 10.1002/1097-0142(19861001)58:7<1428::AID-CNCR2820580709>3.0.CO;2-J 3091244 \n22 Mergenthaler HG Binsack T Wilmanns W Carcinoma-associated hemolytic-uremic syndrome in a patient receiving 5-fluorouracil-adriamycin-mitomycin C combination chemotherapy Oncology 45 11 14 1988 10.1159/000226521 3124028 \n23 Desramé J Duvic C Bredin C Béchade D Artru P Brézault C Defuentes G Poirier JM Dourthe LM Coutant G Hemolytic uremic syndrome as a complication of gemcitabine treatment: Report of six cases and review of the literature Rev Med Interne 26 179 188 2005 (In French) 10.1016/j.revmed.2004.11.016 15777580\n\n",
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"title": "Gemcitabine-associated thrombotic microangiopathy in a patient with lung cancer: A case report.",
"title_normalized": "gemcitabine associated thrombotic microangiopathy in a patient with lung cancer a case report"
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"abstract": "Our laboratory received segments of umbilical cord that originated from identical twins for routine toxicology analysis. The specimens were analyzed multiple times by liquid chromatography tandem mass spectrometry. The umbilical cord from newborn #1 was positive for hydromorphone only (1.06 ng/g), and the umbilical cord from newborn #2 was positive for hydromorphone (0.81 ng/g) and benzoylecgonine (5.41 ng/g). The hydromorphone results are consistent with maternal administration of hydromorphone; however, the cause of the discrepant benzoylecgonine results in the umbilical cords from the identical twins is unknown.",
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"abstract": "Methotrexate, administered for treatment of pediatric and adult malignancies, is a direct renal toxin, which can lead to renal dysfunction, decreased methotrexate clearance, elevated methotrexate concentrations, and systemic toxicity. Although plasma methotrexate concentrations have been shown to decline precipitously after a single dose of glucarpidase, this drug is investigational and available only through compassionate use. Therefore, alternative treatments for methotrexate removal may be required. We describe a 13-year-old girl (body surface area 1.2 m(2)) with osteosarcoma who was treated with high-dose methotrexate 12 g/m(2) infused over 4 hours. Forty-eight hours after the infusion, her plasma methotrexate concentrations were elevated at 446 micromol/L. She exhibited severe signs of methotrexate toxicity, including encephalopathy, liver failure, and acute kidney injury, and could not tolerate conventional hemodialysis. Over the next 12 days, the patient was treated with continuous venovenous hemodialysis (CVVHD), single-pass albumin dialysis (SPAD), continuous venovenous hemodiafiltration (CVVHDF), and glucarpidase to enhance methotrexate elimination. Compared with standard CVVHD, SPAD did not significantly increase methotrexate removal as measured by elimination half-life and methotrexate saturation coefficient. The highest clearance rate among extracorporeal therapies was achieved by CVVHDF, with an effluent rate of 4950 ml/hour. The patient's clinical condition steadily improved, and all extracorporeal therapies were stopped 168 hours after methotrexate administration. The patient was discharged home and continued with chemotherapy, including methotrexate, which was dosed based on iothalamate glomerular filtration rates on the day before infusion. Although extracorporeal treatments appeared to enhance methotrexate clearance, the administration of glucarpidase resulted in the most rapid percentage decline (86%) in methotrexate concentration. Until glucarpidase is readily available, intermittent hemodialysis should be used to enhance methotrexate clearance. If the patient is unable to tolerate hemodialysis, use of CVVHDF with maximum effluent rates will enhance methotrexate clearance.",
"affiliations": "Department of Clinical, Social, and Administrative Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.",
"authors": "Vilay|A Mary|AM|;Mueller|Bruce A|BA|;Haines|Hilary|H|;Alten|Jeffery A|JA|;Askenazi|David J|DJ|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D015507:Drugs, Investigational; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate",
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"title": "Treatment of methotrexate intoxication with various modalities of continuous extracorporeal therapy and glucarpidase.",
"title_normalized": "treatment of methotrexate intoxication with various modalities of continuous extracorporeal therapy and glucarpidase"
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"abstract": "We report the case of a 40-year-old veterinary surgeon who was admitted for spiking fevers, arthralgia, and a complete atrioventricular block. Tests revealed an inflammatory syndrome, hepatic cytolysis, neutrophilic leukocytosis, and increased troponin levels. Cardiac magnetic resonance imaging showed a small myocarditis but no tissue abnormality on the conduction pathways. In the absence of evidence-based infection and favorable evolution under broad spectrum antibiotherapy, an adult-onset Still's disease was suspected and corticosteroid therapy administered. Evolution was then impressively favorable, with a persistent sinus heart rhythm 3 days later. Learning objective: Febrile conductive disorders occurring during a systemic disorder with negative infection and auto-immunity work-up should lead to consider an adult-onset Still's disease, which can be treated and cured, especially with steroids. Moreover, fever, polyarthritis, neutrophilic leukocytosis, pericarditis, and myocarditis should lead to consideration of adult-onset Still's disease.",
"affiliations": "Department of Cardiology, Nantes University Hospital, Nantes, France.;Department of Cardiology, Nantes University Hospital, Nantes, France.;Department of Cardiology, Nantes University Hospital, Nantes, France.;Department of Cardiology, Nantes University Hospital, Nantes, France.;Department of Cardiology, Nantes University Hospital, Nantes, France.;Department of Internal Medicine, Nantes University Hospital, Nantes, France.",
"authors": "Piriou|Pierre-Guillaume|PG|;Plessis|Julien|J|;Letocart|Vincent|V|;Piriou|Nicolas|N|;Probst|Vincent|V|;Néel|Antoine|A|",
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"issue": "21(3)",
"journal": "Journal of cardiology cases",
"keywords": "Adult-onset Still’s disease; Atrioventricular block; Myocarditis; Spiking fever; Steroid",
"medline_ta": "J Cardiol Cases",
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"pmid": "32153686",
"pubdate": "2020-03",
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"abstract": "A 19-year-old female presented at 25-weeks gestation with pancreatitis. She was found to have significant hypertriglyceridaemia in context of an unconfirmed history of familial hypertriglyceridaemia. This was initially managed with fasting and insulin infusion and she was commenced on conventional interventions to lower triglycerides, including a fat-restricted diet, heparin, marine oil and gemfibrozil. Despite these measures, the triglyceride levels continued to increase as she progressed through the pregnancy, and it was postulated that she had an underlying lipoprotein lipase defect. Therefore, a multidisciplinary decision was made to commence therapeutic plasma exchange to prevent further episodes of pancreatitis. She underwent a total of 13 sessions of plasma exchange, and labour was induced at 37-weeks gestation in which a healthy female infant was delivered. There was a rapid and significant reduction in triglycerides in the 48 h post-delivery. Subsequent genetic testing of hypertriglyceridaemia genes revealed a missense mutation of the LPL gene. Fenofibrate and rosuvastatin was commenced to manage her hypertriglyceridaemia postpartum and the importance of preconception counselling for future pregnancies was discussed. Hormonal changes in pregnancy lead to an overall increase in plasma lipids to ensure adequate nutrient delivery to the fetus. These physiological changes become problematic, where a genetic abnormality in lipid metabolism exists and severe complications such as pancreatitis can arise. Available therapies for gestational hypertriglyceridaemia rely on augmentation of LPL activity. Where there is an underlying LPL defect, these therapies are ineffective and removal of triglyceride-rich lipoproteins via plasma exchange should be considered.\nHormonal changes in pregnancy, mediated by progesterone,oestrogen and human placental lactogen, lead to a two- to three-fold increase in serum triglyceride levels. Pharmacological intervention for management of gestational hypertriglyceridaemia rely on the augmentation of lipoprotein lipase (LPL) activity to enhance catabolism of triglyceride-rich lipoproteins. Genetic mutations affecting the LPL gene can lead to severe hypertriglyceridaemia. Therapeutic plasma exchange (TPE) is an effective intervention for the management of severe gestational hypertriglyceridaemia and should be considered in cases where there is an underlying LPL defect. Preconception counselling and discussion regarding contraception is of paramount importance in women with familial hypertriglyceridaemia.",
"affiliations": "Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia.;Department of Maternal-Fetal Medicine, Westmead Institute for Maternal-Fetal Medicine, Westmead Hospital, Westmead, New South Wales, Australia.;Department of Maternal-Fetal Medicine, Westmead Institute for Maternal-Fetal Medicine, Westmead Hospital, Westmead, New South Wales, Australia.;School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia.;The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia.;The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia.;Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia.",
"authors": "Kim|Albert S|AS|0000-0001-5832-0224;Hakeem|Rashida|R|;Abdullah|Azaliya|A|;Hooper|Amanda J|AJ|;Tchan|Michel C|MC|;Alahakoon|Thushari I|TI|;Girgis|Christian M|CM|",
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"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case Rep\nEndocrinol Diabetes Metab Case Rep\nEDM\nEndocrinology, Diabetes & Metabolism Case Reports\n2052-0573 Bioscientifica Ltd Bristol \n\n10.1530/EDM-19-0165\nEDM190165\nPregnant Adult\nFemale\nOther\nAustralia\nAdipose Tissue\nDiabetes\nGestational Hypertriglyceridaemia*\nHypertriglyceridaemia*\nPancreatitis\nPancreatitis\nHypertriglyceridaemia*\nAbdominal pain\nNausea\nPyrexia\nLeukocytosis\nWeight loss\nTriglycerides\nMolecular genetic analysis\nBMI\nWeight\nUltrasound scan\nC-reactive protein\nLipid profile\nLipase (serum)\nTotal cholesterol\nAmniotic fluid index*\nCardiotocography*\nUmbilical artery resistance*\nDNA sequencing\nPlasma exchange\nDiet\nContraception\nInsulin\nHeparin\nMarine oil*\nGemfibrozil*\nFenofibrate\nRosuvastatin*\nStatins\nBetamethasone\nAlbumin\nNovel Treatment\nNovel Treatment\nTherapeutic plasma exchange for the management of severe gestational hypertriglyceridaemic pancreatitis due to lipoprotein lipase mutation\nA S Kim and othersTPE for gestational hypertriglyceridaemiahttp://orcid.org/0000-0001-5832-0224Kim Albert S 12 Hakeem Rashida 3 Abdullah Azaliya 3 Hooper Amanda J 45 Tchan Michel C 26 Alahakoon Thushari I 23 Girgis Christian M 127 1 Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia\n2 The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia\n3 Department of Maternal-Fetal Medicine, Westmead Institute for Maternal-Fetal Medicine, Westmead Hospital, Westmead, New South Wales, Australia\n4 School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia\n5 Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, Perth, Western Australia, Australia\n6 Department of Genetic Medicine, Westmead Hospital, Westmead, New South Wales, Australia\n7 Department of Diabetes and Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia\nCorrespondence should be addressed to A S Kim; Email: dralbertskim@gmail.com\n13 3 2020 \n2020 \n2020 19-016501 2 2020 21 2 2020 © 2020 The authors2020The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..Summary\nA 19-year-old female presented at 25-weeks gestation with pancreatitis. She was found to have significant hypertriglyceridaemia in context of an unconfirmed history of familial hypertriglyceridaemia. This was initially managed with fasting and insulin infusion and she was commenced on conventional interventions to lower triglycerides, including a fat-restricted diet, heparin, marine oil and gemfibrozil. Despite these measures, the triglyceride levels continued to increase as she progressed through the pregnancy, and it was postulated that she had an underlying lipoprotein lipase defect. Therefore, a multidisciplinary decision was made to commence therapeutic plasma exchange to prevent further episodes of pancreatitis. She underwent a total of 13 sessions of plasma exchange, and labour was induced at 37-weeks gestation in which a healthy female infant was delivered. There was a rapid and significant reduction in triglycerides in the 48 h post-delivery. Subsequent genetic testing of hypertriglyceridaemia genes revealed a missense mutation of the LPL gene. Fenofibrate and rosuvastatin was commenced to manage her hypertriglyceridaemia postpartum and the importance of preconception counselling for future pregnancies was discussed. Hormonal changes in pregnancy lead to an overall increase in plasma lipids to ensure adequate nutrient delivery to the fetus. These physiological changes become problematic, where a genetic abnormality in lipid metabolism exists and severe complications such as pancreatitis can arise. Available therapies for gestational hypertriglyceridaemia rely on augmentation of LPL activity. Where there is an underlying LPL defect, these therapies are ineffective and removal of triglyceride-rich lipoproteins via plasma exchange should be considered.\n\nLearning points:\nHormonal changes in pregnancy, mediated by progesterone,oestrogen and human placental lactogen, lead to a two- to three-fold increase in serum triglyceride levels.\n\nPharmacological intervention for management of gestational hypertriglyceridaemia rely on the augmentation of lipoprotein lipase (LPL) activity to enhance catabolism of triglyceride-rich lipoproteins.\n\nGenetic mutations affecting the LPL gene can lead to severe hypertriglyceridaemia.\n\nTherapeutic plasma exchange (TPE) is an effective intervention for the management of severe gestational hypertriglyceridaemia and should be considered in cases where there is an underlying LPL defect.\n\nPreconception counselling and discussion regarding contraception is of paramount importance in women with familial hypertriglyceridaemia.\n\nPatient Demographics\nPregnant adultFemaleOtherAustraliaClinical Overview\nAdipose tissueDiabetesGestational hypertriglyceridaemia*Hypertriglyceridaemia*PancreatitisDiagnosis and Treatment\nPancreatitisHypertriglyceridaemia*Abdominal painNauseaPyrexiaLeukocytosisWeight lossTriglyceridesMolecular genetic analysisBMIWeightUltrasound scanC-reactive proteinLipid profileLipase (serum)Total cholesterolAmniotic fluid index*Cardiotocography*Umbilical artery resistance*DNA sequencingMolecular genetic analysisPlasma exchangeDietContraceptionInsulinHeparinMarine oil*Gemfibrozil*FenofibrateRosuvastatin*StatinsBetamethasoneAlbuminPublication Details\nNovel treatmentMarch2020\n==== Body\nBackground\nHormonal changes in pregnancy lead to a two- to three-fold increase in serum triglyceride levels (1, 2). In women with normal baseline triglyceride levels and normal lipid metabolism, this increase is not clinically significant and no specific intervention is required. However, women with rare genetic abnormalities that affect triglyceride metabolism may develop gestational hypertriglyceridaemia which can be severe and associated with acute complications including pancreatitis, pre-eclampsia or fetal demise (3, 4).\n\nLipoprotein lipase (LPL) mediates catabolism of triglyceride-rich lipoprotein: very-low-density lipoprotein (VLDL) and chylomicrons. Familial chylomicronaemia syndrome is usually caused by mutations in the lipoprotein lipase (LPL) gene, that is, LPL deficiency, with rarer causes being due to mutations in genes responsible for maturation, transport and surface expression of LPL (5, 6).\n\nHere, we present a female whose pregnancy has been complicated by severe hypertriglyceridaemic pancreatitis in the context of a homozygous LPL mutation.\n\nCase presentation\nA primiparous 19-year-old Lebanese female presented at 25-weeks gestation with worsening abdominal pain and nausea. She was known to have hypertriglyceridaemia diagnosed in infancy following an episode of pancreatitis at the age of 3 years and was previous prescribed medium chain triglyceride (MCT) supplementation during adolescence.\n\nHer family history was significant for hypertriglyceridaemia, affecting her younger brother and a paternal cousin who developed pancreatitis in childhood. Our patient was a child of consanguineous parents. There was no family history of diabetes or early-onset coronary artery disease or cerebrovascular accidents. She did not display eruptive xanthoma, lipaemia retinalis or hepatosplenomegaly.\n\nInvestigation\nPrior to this pregnancy, her baseline triglycerides fluctuated between 10.0 and 25.0 mmol/L (886.0 to 2214.0 mg/dL). Her preconception weight was 60 kg with a BMI of 22 kg/m2 ,and triglycerides shortly following conception was 25.6 mmol/L (2268.0 mg/dL).\n\nAt 25-weeks gestation, the patient developed fevers and abdominal pain. Bloods revealed leucocytosis 15.4 × 109/L (RR: 3.9–11.1 × 109/L), c-reactive protein 200 mg/L (RR: <3 mg/L) as well as raised lipase 687 U/L (RR: <400 U/L). Her lipid profile showed triglycerides 41.4 mmol/L (3667.0 mg/dL; RR: <2.0 mmol/L) and elevated cholesterol of 9.3 mmol/L (360.0 mg/dL; RR: 3.0–5.5 mmol/L) (Fig. 1). Ultrasonography revealed a bulky pancreas with peripancreatic free fluid, and the liver had normal sonographic appearance. There was no cholelithiasis or evidence of pyelonephritis.Figure 1 Patient’s blood following centrifugation. Note the layer of lipaemic plasma.\n\n\n\n\nTreatment\nA diagnosis of hypertriglyceridaemic pancreatitis was made and insulin infusion was commenced, in addition to s.c. heparin (5000 IU three times daily) and marine oil (9 g daily), and the subject was kept in a fasting state for 72 h, following which she was commenced on a fat-restricted diet (<10 g/day). Betamethasone was administered to promote fetal lung maturation. The triglycerides improved and reached a nadir of 10.0 mmol/L (886.0 mg/dL). Insulin was ceased and gemfibrozil was commenced at 200 mg TDS.\n\nDespite these measures, the triglyceride levels increased to 24.0 mmol/L (2126.0 mg/dL) in the course of a week. This was concerning for a potential LPL defect due to rise in the triglycerides despite pharmacotherapy to enhance LPL activity. Due to risk of recurrent pancreatitis with persistently elevated triglycerides and increasing concerns with weight loss on such an intensive fat-restricted diet, a multidisciplinary decision was made to pursue therapeutic plasma exchange (TPE).\n\nCentral venous access was established and the first TPE was performed at 28-weeks gestation, in which 2500 mL of plasma was exchanged with 4% albumin, achieving a reduction in triglycerides from 25.0 mmol/L (2214.0 mg/dL) to 13.0 mmol/L (1152.0 mg/dL) (Fig. 2). She continued to undertake weekly TPE, which she tolerated well. However, following four sessions of TPE, and as she entered her third trimester, the peaks and trough triglycerides began to rise (Fig. 3). The frequency of TPE was escalated to twice weekly at 32-weeks gestation and the triglycerides peaked at 56.0 mmol/L (4960.0 mg/dL) at 35-weeks gestation, although pancreatitis was avoided at this time. She required a total of 13 TPE sessions throughout her pregnancy.Figure 2 Approximately 2500 mL of lipaemic plasma following a session of therapeutic plasma exchange (TPE).\n\n\nFigure 3 Serum triglycerides throughout pregnancy. Pancreatitis (A) followed by commencing therapeutic plasma exchange (B) and increased frequency of TPE to twice weekly (C) until delivery (D). TPE sessions marked by T.\n\n\n\n\nDuring this period, fetal ultrasound and cardiotocography (CTG) were reassuring in excluding fetal distress or growth problems. The estimated fetal weight remained between 30–56th centile on ultrasonography between 25- and 36-weeks’ gestation. The amniotic fluid index (AFI) and umbilical artery resistance was appropriate for gestation age at each scan.\n\nOutcome and follow-up\nLabour was induced at 37-weeks gestation, resulting in the delivery of a female infant weighing 2940 g with Apgar scores of 9 at 1 and 5 min following birth. A rapid and significant reduction in triglycerides from 30.0 mmol/L (2657.0 mg/dL) to 8.0 mmol/L (709.0 mg/dL) was noted over 48 h postpartum and she did not require any further TPE (Fig. 3).\n\nMassive parallel sequencing with targeted analysis of hypertriglyceridaemia genes (LPL, APOA5, APOC2, APOE, LMF1, GPIHBP1, PPARG, LMNA, APOC3, and GPD1) was performed following delivery. Our patient was found to be homozygous for a missense mutation in exon 5 of LPL (NM_000237.2: c.602A>T, p.Asp201Val), classified as ‘likely pathogenic’.\n\nThe patient was commenced on fenofibrate 145 mg daily and continues on a fat-restricted diet and marine oil supplementation. Rosuvastatin was then added due to ongoing hypertriglyceridaemia to 9.0 mmol/L (797.0 mg/dL). The importance of preconception counselling for future pregnancies was discussed and an intrauterine device (IUD) contraception was implanted.\n\nDiscussion\nHormonal changes in pregnancy, particularly those mediated by progesterone, estrogen and human placental lactogen, lead to an overall increase in plasma lipids (7). The physiological basis of these hormone-induced lipid changes is to ensure adequate energy source in the mother to ensure nutrient delivery to the fetus. These physiological changes in serum triglyceride levels can be problematic when a genetic abnormality in lipid metabolism exists (familial hypertriglyceridaemia), leading to gestational hypertriglyceridaemia (GHT). Complications arising from gestational hypertriglyceridaemia include pancreatitis preterm labour, pre-eclampsia and fetal death in utero.\n\nTwo main mechanisms have been proposed to explain the pathophysiology of hypertriglyceridaemic pancreatitis. First is the development of pancreatitis by acidosis and ischaemia secondary to free fatty acid (FFA) toxicity. Excess triglyceride-rich chylomicrons are hydrolysed within the pancreas which release high levels of free fatty acids. The unbound FFAs can cause damage to the vascular endothelium and acinar cells resulting in pancreatitis (8, 9). Secondly, excess chylomicronaemia leads to increase in plasma viscosity which can lead to capillary plugging and ischaemia which can also eventually trigger pancreatitis (8, 9).\n\nDetails of 17 reported cases of gestational hypertriglyceridaemic pancreatitis (GHTP) managed with plasma exchange are summarised in Table 1, which demonstrate the onset of pancreatitis typically in the second and third trimester (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). The majority of cases (11/17, 65%) required emergency caesarean section due to fetal distress or complications. Our case is significant as successful early-term vaginal delivery was achieved after multiple TPE sessions throughout pregnancy.\nTable 1 Cases of gestational hypertriglyceridaemic pancreatitis managed with therapeutic plasma exchange.\n\nCase\tPatient age (years)\tTime of pancreatitis during gestation\tTreatment regimen\tTotal sessions required\tClinical outcome\t\nOur case\t19\t25 weeks\tTPE (albumin)\t13\tSuccessful vaginal delivery of health infant at 37 weeks\t\nSwoboda et al. (10)\t23\t24 weeks\tCombined TPE (albumin) and LDL apheresis\t10\t2nd episode of pancreatitis at 32 weeks. Emergency caesarean section (CS) at 36 weeks due to impairment of umbilical blood flow.\t\nBildirici et al. (11)\t26\t24 weeks\tTPE (replacement not reported)\t 3\tEmergency CS due to fetal distress with subsequent infant death. Maternal pseudocyst formation.\t\nAchard et al. (12)\t30\t26 weeks\tCombined TPE (albumin) and LDL apheresis\t 2\tVaginal delivery of healthy infant at 34 weeks\t\nSaravanan et al. (13)\t30\t34 weeks\tTPE (albumin)\t 2\tEmergency CS due to fetal distress and pre-eclampsia. Delivery of health infant. Maternal course complicated by septic shock.\t\nYamauchi et al. (14)\t23\t27 weeks\tTPE (replacement not reported)\t 2\tEmergency CS due to fetal distress. Delivery of healthy infant.\t\nExbrayat et al. (15)\t31\t33 weeks\tTPE (replacement not reported)\t 1\tEmergency CS due to fetal distress. Delivery of healthy infant.\t\nAltun et al. (16)\t27\t5 weeks\tTPE (FFP)\t 3\tFetal demise at 6 weeks.\t\n24\t27 weeks\tTPE (FFP)\t14\tCS at 34 weeks with delivery of healthy infant.\t\nSafi et al. (17)\t24\t28 weeks\tTPE (albumin)\t 9\tCS at 35 weeks due to lack of reduction of TG with TPE. Delivery of healthy infant.\t\nLim et al. (18)\t27\t23 weeks \tTPE (albumin)\t 4\tPreterm birth with placental abruption at 33 weeks.\t\nHuang et al. (19)\tMean age 27.6\tUnknown\tTPE (FFP or albumin)\t1-3\tDelivery of 4 healthy infants via CS. Termination of pregnancy at 21 weeks in one case. \t\nChyzhyk et al. (20)\t28\t20 weeks\tTPE (replacement not reported)\tNot reported\tVaginal delivery of healthy infant at 36 weeks.\t\nCS, Caesarean Section; FFP, Fresh Frozen Plasma; LDL, Low-Density Lipoprotein; TPE, Therapeutic Plasma Exchange.\n\n\n\n\nThe treatment strategy in our case involved the use of TPE to prevent recurrent pancreatitis for the remainder of the pregnancy. In comparison to published reports on the occurrence of hypertriglyceridaemic pancreatitis in pregnancy, unique features of our case include the use of TPE to reduce the risk of hypertriglyceridaemic pancreatitis, targeting a more liberal triglyceride target of preconception levels, delivery at near term through normal vaginal delivery and the identification of an LPL mutation implicated in familial hypertriglyceridaemia. It is important to note that, while TPE is generally well tolerated in pregnancy, there are concerns for the need for central venous access and its associated infection risk, transient anticoagulation related to loss of clotting factors, risk of obstetrics haemorrhage and the potential changes to placental perfusion due to changes in fluid volume. We performed continuous fetal monitoring during TPE sessions and were well tolerated by the mother and the fetus.\n\nGenetic studies have identified that patients with severe hypertriglyceridaemia typically present in childhood and adolescence and display classic autosomal recessive pattern of inheritance. These patients are homozygous or compound heterozygous for large-effect, loss-of-function mutations in genes that regulate catabolism of triglyceride-rich lipoproteins. These include genes coding LPL – which mediate catabolism of chylomicrons and very-low-density-lipoproteins (VLDL), apolipoproteins C-II and A-V (APOC2, APOA5) – which activate LPL and genes responsible for maturation, transport and surface expression of LPL (LMF1, GPIHBP1) (5).\n\nIn our case, a homozygous LPL variant p.Asp201Val was identified. Asp201 occurs in a highly conserved region encoded by exon 5, and Asp201Val is predicted to be pathogenic by in silico algorithms (PolyPhen2, SIFT, MutationTaster). Other pathogenic missense variants in LPL exon 5 have been demonstrated to affect protein folding and stability (21) or interfere with access of the lipid substrate into the catalytic pocket of this important enzyme. (22) A recent crystallography study showed that the carboxylic acid side chain of D201 participates in the coordination of LPL’s calcium ion via an ordered water molecule. A valine in the same position cannot participate in calcium coordination, providing data on the mechanism of disease in the case of the Asp201Val mutation (23). Interestingly, Asp201Val has been described in two Lebanese patients (aged 7 and 34 years) with LPL deficiency and a history of acute pancreatitis (24).\n\nThis is particularly significant as our patient and her husband are second cousins, which confers risk of inheritance of homozygous pathogenic LPL mutations in the new-born. Genetic testing for the infant and the husband is underway.\n\nThe available therapies for gestational hypertriglyceridaemia, such as omega-3 fatty acids, gemfibrozil and insulin, predominantly rely on the augmentation of lipoprotein lipase activity to catabolise triglyceride-rich lipoproteins (25). It is important to note that the fetal risk of the use of gemfibrozil during pregnancy is unclear and the lack of response to gemfibrozil and other therapeutic options led us to postulate a LPL mutation. Treatment of LPL deficiency is based on medical nutrition therapy with restriction of dietary fat to less than 20 g per day to reduce plasma triglyceride concentration (5). However, given the episode of pancreatitis and persistent hypertriglyceridaemia, despite strict fat restriction in the context of pregnancy, treatment was escalated to TPE.\n\nNovel therapies for the management of familial lipoprotein lipase deficiency include alipogene tiparvovec, a gene therapy in which a viral vector is utilised to deliver intact LPL genes into muscle cells (26). While there was significant reduction in serum triglyceride levels following its use, it was prohibitively expensive and is no longer available.\n\nSequencing studies of exomes – which are protein coding regions of the human genome – have identified the association between apolipoprotein C3 (APOC3) mutation and lower triglyceride levels. Carriers of this mutation were found to have a reduced risk of coronary heart disease (27). Volanesorsen is an antisense inhibitor of APOC3 synthesis which lowers plasma APOC3 and triglyceride levels. Use of volanesorsen has been associated with significant reduction in triglyceride levels in patients with familial hyperchylomicronaemia (28), though the efficacy and safety for its use during pregnancy remains to be seen.\n\nOur case highlights the use of TPE as an effective treatment for GHT, which should be considered in cases where usual augmentation of LPL cannot be utilised due to an LPL mutation, and highlights successes in delivering a healthy fetus near term, with a more liberal triglyceride target without acute maternal or fetal complications.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nWritten informed consent has been obtained from the patient for publication of the submitted article.\n\nAuthor contribution statement\nA S K wrote the manuscript. 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(10.4103/0970-9185.94913 )\n17 Safi F Toumeh A Qadan MAA Karaz R AlAkdar B Assaly R \nManagement of familial hypertriglyceridemia-induced pancreatitis during pregnancy with therapeutic plasma exchange: a case report and review of literature\n. American Journal of Therapeutics \n2014 \n21 \ne134 –e136\n. (10.1097/MJT.0b013e31825b9e98 )22926234 \n18 Lim R Rodger SJ Hawkins TL-A \nPresentation and management of acute hypertriglyceridemic pancreatitis in pregnancy: a case report\n. Obstetric Medicine \n2015 \n8 \n200 –203\n. (10.1177/1753495X15605697 )27512482 \n19 Huang C Liu J Lu Y Fan J Wang X Liu J Zhang W Zeng Y \nClinical features and treatment of hypertriglyceridemia-induced acute pancreatitis during pregnancy: a retrospective study\n. Journal of Clinical Apheresis \n2016 \n31 \n571 –578\n. (10.1002/jca.21453 )26946248 \n20 Chyzhyk V Kozmic S Brown AS Hudgins LC Starc TJ Davila AD Blevins TC Diffenderfer MR He L Geller AS , et al\nExtreme hypertriglyceridemia: genetic diversity, pancreatitis, pregnancy, and prevalence\n. Journal of Clinical Lipidology \n2019 \n13 \n89 –99\n. (10.1016/j.jacl.2018.09.007 )30352774 \n21 Hata A Ridinger DN Sutherland SD Emi M Kwong LK Shuhua J Lubbers A Guy-Grand B Basdevant A Iverius PH \nMissense mutations in exon 5 of the human lipoprotein lipase gene. Inactivation correlates with loss of dimerization\n. Journal of Biological Chemistry \n1992 \n267 \n20132 –20139\n.1400331 \n22 Peterson J Ayyobi AF Ma Y Henderson H Reina M Deeb SS Santamarina-Fojo S Hayden MR Brunzell JD \nStructural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene\n. Journal of Lipid Research \n2002 \n43 \n398 –406\n.11893776 \n23 Birrane G Beigneux AP Dwyer B Strack-Logue B Kristensen KK Francone OL Fong LG Mertens HDT Pan CQ Ploug M , et al\nStructure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis\n. PNAS \n2019 \n116 \n1723 –1732\n. (10.1073/pnas.1817984116 )30559189 \n24 Abifadel M Jambart S Allard D Rabès JP Varret M Derré A Chouery E Salem N Junien C Aydénian H , et al\nIdentification of the first Lebanese mutation in the LPL gene and description of a rapid detection method\n. Clinical Genetics \n2004 \n65 \n158 –161\n. (10.1111/j.0009-9163.2004.00205.x )14984478 \n25 Rawla P Sunkara T Thandra KC Gaduputi V \nHypertriglyceridemia-induced pancreatitis: updated review of current treatment and preventive strategies\n. Clinical Journal of Gastroenterology \n2018 \n11 \n441 –448\n. (10.1007/s12328-018-0881-1 )29923163 \n26 Scott LJ \nAlipogene tiparvovec: a review of its use in adults with familial lipoprotein lipase deficiency\n. Drugs \n2015 \n75 \n175 –182\n. (10.1007/s40265-014-0339-9 )25559420 \n27 TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute , Crosby J Peloso GM Auer PL Crosslin DR Stitziel NO Lange LA Lu Y Tang ZZ Zhang H , et al\nLoss-of-function mutations in APOC3, triglycerides, and coronary disease\n. New England Journal of Medicine \n2014 \n371 \n22 –31\n. (10.1056/NEJMoa1307095 )24941081 \n28 Witztum JL Gaudet D Freedman SD Alexander VJ Digenio A Williams KR Yang Q Hughes SG Geary RS Arca M , et al\nVolanesorsen and triglyceride levels in familial chylomicronemia syndrome\n. New England Journal of Medicine \n2019 \n381 \n531 –542\n. (10.1056/NEJMoa1715944 )31390500\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2052-0573",
"issue": "2020()",
"journal": "Endocrinology, diabetes & metabolism case reports",
"keywords": "2020; Abdominal pain; Adipose tissue; Albumin; Amniotic fluid index*; Australia; BMI; Betamethasone; C-reactive protein; Cardiotocography*; Contraception; DNA sequencing; Diabetes; Diet; Female; Fenofibrate; Gemfibrozil*; Gestational hypertriglyceridaemia*; Heparin; Hypertriglyceridaemia*; Insulin; Leukocytosis; Lipase (serum); Lipid profile; March; Marine oil*; Molecular genetic analysis; Nausea; Novel treatment; Other; Pancreatitis; Plasma exchange; Pregnant adult; Pyrexia; Rosuvastatin*; Statins; Total cholesterol; Triglycerides; Ultrasound scan; Umbilical artery resistance*; Weight; Weight loss",
"medline_ta": "Endocrinol Diabetes Metab Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101618943",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32168469",
"pubdate": "2020-03-13",
"publication_types": "D016428:Journal Article",
"references": "26946248;16553649;27512482;25559420;17590306;30559189;8771426;8482465;22557756;12027823;30352774;1400331;25732519;1744310;19747985;11893776;3515632;25269432;24941081;29923163;22926234;19770656;27512474;31390500;22639290;14984478;19935037",
"title": "Therapeutic plasma exchange for the management of severe gestational hypertriglyceridaemic pancreatitis due to lipoprotein lipase mutation.",
"title_normalized": "therapeutic plasma exchange for the management of severe gestational hypertriglyceridaemic pancreatitis due to lipoprotein lipase mutation"
} | [
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"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-251100",
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"activesubstancename": "INSULIN NOS"
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"abstract": "BACKGROUND\nInvasive fungal infection (IFI) is a common and fatal complication in neutropenic patients with hematological malignancy. Empirical antifungal therapy is widely used in practice due to the difficulty of pathogens determination and illness of the hosts. The aim of this study was to evaluate the efficacy and safety of itraconazole as empirical antifungal therapy for persistent fever in neutropenic patients with hematologic malignancies.\n\n\nMETHODS\nTwo hundred and seventy-four patients with hematologic malignancies who had suspected fungal infections were enrolled in 18 centers across China between April 2008 and April 2009. Empirical antifungal therapy with intravenous itraconazole 200 mg twice daily was given for the first two days, followed by 200 mg once daily for the next 12 days. Oral itraconazole solution was sequential for follow-up therapy if necessary. Five composite end points were evaluated for the response, which was more restrictive and adopted for the first time in such study in China.\n\n\nRESULTS\nThe intent-to-treat analysis included data from 274 patients (full analysis set, FAS), of whom 248 were included as the per-protocol population (PPS). As the composite end point of five indices was concerned, the overall response rate was 43.4%. Seperately, defervescence was achieved in 90% of patients in which 55.5% occured during neutropenia. The mean time to defervescence was 2.71 days. Absence of breakthrough IFI during drug administration or within the first 7 days after study completion was observed in 71.5% of patients. Fifty-five point five percent patients with IFI at baseline was successfully treated. Ninety point five percent patients survived for at least 7 days after completing the study. PPS analysis revealed that the duration of neutropenia ≥ 10 days was a statistically significant negative predictor for the response. The withdrawal rate due to drug-related toxicity or lack of efficacy was 11.0%. The incidence of adverse events was 22.6%, in which 11.6% was study drug related. The most frequent adverse events were mild to moderate liver toxicity.\n\n\nCONCLUSIONS\nItraconazole shows desirable efficacy and safety as empirical antifungal therapy for febrile neutropenic patients with hematologic malignancies.",
"affiliations": "Department of Hematology, Shanghai Ruijin Hospital, Medical School of Shanghai Jiao Tong University, Shanghai 200025, China.",
"authors": "Cheng|Shu|S|;Zhou|Jian-Feng|JF|;Zou|Ping|P|;Huang|Xiao-Jun|XJ|;Jin|Jie|J|;Shen|Zhi-Xiang|ZX|",
"chemical_list": "D000935:Antifungal Agents; D017964:Itraconazole",
"country": "China",
"delete": false,
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"issn_linking": "0366-6999",
"issue": "124(22)",
"journal": "Chinese medical journal",
"keywords": null,
"medline_ta": "Chin Med J (Engl)",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D005260:Female; D019337:Hematologic Neoplasms; D006801:Humans; D017964:Itraconazole; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7513795",
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"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of itraconazole as empirical antifungal therapy in febrile neutropenic patients with hematologic malignancies: an open-lable, multicenter, observational trial in a Chinese cohort.",
"title_normalized": "efficacy and safety of itraconazole as empirical antifungal therapy in febrile neutropenic patients with hematologic malignancies an open lable multicenter observational trial in a chinese cohort"
} | [
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"activesubstancename": "ITRACONAZOLE"
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"abstract": "Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A) is a recently defined autoimmune inflammatory disease of the central nervous system in which GFAP IgG is present in the cerebrospinal fluid (CSF). Its primary clinical manifestation is meningoencephalitis, and it usually responds well to corticosteroids. Herein, we report a case of a patient with GFAP-A with initial symptoms of psychological and cognitive impairment, which did not respond to high-dose methylprednisolone therapy but was successfully treated with protein A immunoadsorption (PAIA) therapy.\n\n\n\nGFAP IgG was detected by indirect immunofluorescence assay. The patient's data were analyzed retrospectively.\n\n\n\nA 48-year-old man presented with anxiety, depression, cognitive decline, tremor, gait disturbance, and fecal and urine incontinence. Autoimmune GFAP-A was diagnosed based on the following: (1) T2-weighted and fluid-attenuated inversion recovery MRI findings of hypersensitive lesions in the subcortical and deep white matter of the brain, with multiple longitudinally extensive lesions in the cervical and chest regions of the spinal cord, and (2) high levels of GFAP IgG in the CSF. Clinical symptoms and abnormalities detected on neuroimaging worsened after administration of high-dose intravenous methylprednisolone (IVMP) and intravenous immunoglobulin (IVIG) but improved significantly after PAIA therapy.\n\n\n\nPsychological impairment can be the first sign of autoimmune GFAP-A. PAIA might be an effective treatment for patients with GFAP-A who respond poorly to conventional IVMP and IVIG therapy.",
"affiliations": "Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Immunology, Xiangya School of Medicine, Central South University, Changsha, China.;Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.",
"authors": "Qin|Bing|B|;Wu|Ruizhen|R|;Shu|Yaqing|Y|;Wang|Yuge|Y|;Yu|Boguang|B|;Sun|Xiaobo|X|;Qiu|Wei|W|",
"chemical_list": "D001323:Autoantibodies; D005904:Glial Fibrillary Acidic Protein; D013205:Staphylococcal Protein A; D008775:Methylprednisolone",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000514547",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1021-7401",
"issue": "28(3)",
"journal": "Neuroimmunomodulation",
"keywords": "Astrocytopathy; Glial fibrillary acidic protein; Protein A immunoadsorption",
"medline_ta": "Neuroimmunomodulation",
"mesh_terms": "D001253:Astrocytes; D001323:Autoantibodies; D005904:Glial Fibrillary Acidic Protein; D006801:Humans; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D012189:Retrospective Studies; D013205:Staphylococcal Protein A",
"nlm_unique_id": "9422763",
"other_id": null,
"pages": "187-192",
"pmc": null,
"pmid": "34237754",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Protein A Immunoadsorption Relieves Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy after Unsuccessful Methylprednisolone Treatment.",
"title_normalized": "protein a immunoadsorption relieves autoimmune glial fibrillary acidic protein astrocytopathy after unsuccessful methylprednisolone treatment"
} | [
{
"companynumb": "CN-AMNEAL PHARMACEUTICALS-2021-AMRX-03286",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},... |
{
"abstract": "Arterial dissections are uncommon in neonates. Complications include thrombosis, bleeding, dissection, aneurysm and pseudoaneurysm. We report an unusual case of multisite pathology (dissection and pseudoaneurysm) following common vascular interventions. A term neonate with antenatal diagnosis of congenital heart block secondary to maternal lupus deteriorated clinically at 5 days of life. He was found to have an abdominal aortic thrombus secondary to abdominal aortic dissection, following umbilical arterial catheter placement. Attempted percutaneous treatment was complicated by dissection of the left common carotid artery and formation of a large pseudoaneurysm. Neonatal lupus is associated with weakened vessel wall which may be vulnerable to injury from line placement and endovascular interventions. Various options are available to manage arterial dissection, thrombus, and pseudoaneurysm, but consequences of these options need to be carefully weighed to minimize further complications.",
"affiliations": "Department of Pediatric Intensive Care, Royal Brompton Hospital, London, United Kingdom.;Department of Radiology, Royal Brompton Hospital, London, United Kingdom.;Department of Pediatric Interventional Cardiology, Royal Brompton Hospital, London, United Kingdom.;Department of Congenital Heart Disease Surgery, Royal Brompton Hospital, London, United Kingdom.;Department of Aortic and Vascular Surgery, Royal Brompton Hospital, London, United Kingdom.;Department of Pediatric Intensive Care, Royal Brompton Hospital, London, United Kingdom.",
"authors": "Wang|Justin|J|;Semple|Thomas|T|;Bautista-Rodriguez|Carles|C|;Hoschtitzky|Andreas|A|;Cheshire|Nick|N|;Chan-Dominy|Amy|A|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/apc.APC_67_19",
"fulltext": "\n==== Front\nAnn Pediatr CardiolAnn Pediatr CardiolAPCAnnals of Pediatric Cardiology0974-20690974-5149Wolters Kluwer - Medknow India APC-13-8710.4103/apc.APC_67_19Case ReportUmbilical artery catheter, aortic dissection, carotid cannulation, and pseudoaneurysm in a neonate: A tale of propagating pathology Wang Justin 1Semple Thomas 2Bautista-Rodriguez Carles 3Hoschtitzky Andreas 4Cheshire Nick 5Chan-Dominy Amy 161 Department of Pediatric Intensive Care, Royal Brompton Hospital, London, United Kingdom2 Department of Radiology, Royal Brompton Hospital, London, United Kingdom3 Department of Pediatric Interventional Cardiology, Royal Brompton Hospital, London, United Kingdom4 Department of Congenital Heart Disease Surgery, Royal Brompton Hospital, London, United Kingdom5 Department of Aortic and Vascular Surgery, Royal Brompton Hospital, London, United Kingdom6 Department of Anesthesia and Critical Care, Royal Brompton Hospital, London, United KingdomAddress for correspondence: Dr. Justin Wang, Paediatric Intensive Care Unit, Royal Brompton Hospital, London, United Kingdom. E-mail: qwang@nhs.netJan-Mar 2020 19 7 2019 13 1 87 90 10 5 2019 01 6 2019 Copyright: © 2019 Annals of Pediatric Cardiology2019This 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.Arterial dissections are uncommon in neonates. Complications include thrombosis, bleeding, dissection, aneurysm and pseudoaneurysm. We report an unusual case of multisite pathology (dissection and pseudoaneurysm) following common vascular interventions. A term neonate with antenatal diagnosis of congenital heart block secondary to maternal lupus deteriorated clinically at 5 days of life. He was found to have an abdominal aortic thrombus secondary to abdominal aortic dissection, following umbilical arterial catheter placement. Attempted percutaneous treatment was complicated by dissection of the left common carotid artery and formation of a large pseudoaneurysm. Neonatal lupus is associated with weakened vessel wall which may be vulnerable to injury from line placement and endovascular interventions. Various options are available to manage arterial dissection, thrombus, and pseudoaneurysm, but consequences of these options need to be carefully weighed to minimize further complications.\n\nAortic dissectioncarotid artery pseudoaneurysmneonatal lupusumbilical arterial catheterization\n==== Body\nINTRODUCTION\nArterial dissections are rare in the neonatal period. We describe a case of carotid artery pseudoaneurysm in a newborn with neonatal lupus following percutaneous attempt at revascularization of the superior mesenteric artery (SMA), consequent of abdominal aortic dissection with false lumen thrombosis after removal of umbilical arterial catheter.\n\nCASE REPORT\nA male baby weighing 2.6 kg was delivered by elective cesarean section at term for known congenital heart block and breech presentation. Maternal anti-Ro antibody was positive. He was intubated for increased work of breathing. Electrocardiography showed complete heart block. 5Fr umbilical arterial and venous catheters were inserted before transfer to our pediatric cardiac intensive care unit.\n\nHe was hemodynamically stable. Echocardiography revealed a structurally normal heart with good function. Chest radiograph and cranial ultrasound were unremarkable. He was extubated on day 5 of life, and umbilical lines were removed.\n\nSix hours later, he became pale, mottled, and tachypneic and had temperature instability. Blood gas revealed severe metabolic acidosis (pH 6.78 and lactate 15 mmol/L). He was reintubated and resuscitated. Echocardiography demonstrated impaired systolic function. Blood tests showed disseminated intravascular coagulopathy.\n\nAbdominal distension and frank hematuria were noted. Ultrasound demonstrated a significant aortic thrombus [Figure 1], suspected to be secondary to aortic dissection. The thrombus extended into the SMA [Figure 2] leading to necrotizing enterocolitis (NEC) and right renal artery resulting in renal ischemia [Figure 3]. Repeat cranial ultrasound showed bilateral Grade I germinal matrix hemorrhage.\n\nFigure 1 Large aortic thrombus occluding coeliac axis (white arrow)\n\nFigure 2 Aortic thrombus compromising blood flow to superior mesenteric artery (white arrow)\n\nFigure 3 Aortic thrombus causing reduced right renal blood flow and infarction (white arrow)\n\nSMA revascularization was attempted in view of NEC and critical ischemia (lactate 17 mmol/L). Aortic dissection precluded femoral arterial access. The left common carotid artery (CCA) was punctured, and a 5Fr introducer was placed. The procedure was aborted due to CCA dissection noted in the first angiogram after introducer placement. Doppler ultrasound did not show flow compromise [Figure 4].\n\nFigure 4 Normal bilateral carotid blood flow Doppler\n\nHeparin infusion was commenced with no improvement in SMA blood flow. Thrombolytic therapy (recombinant tissue plasminogen activator) was administered but was discontinued 4 hours later due to a new right thalamic hematoma [Figure 5]. On heparin, the aortic thrombus reduced in size with return of renal arterial flow, but a large left CCA pseudoaneurysm (17 mm × 22 mm × 22 mm) was demonstrated 9 days after CCA dissection [Videos 1, 2 and Figures 6, 7]. This was repaired a few days later by direct suture closure of the pseudoaneurysm neck [Figure 8]. Neonatal lupus was confirmed in the presence of anti-RNP/Sm and anti-Ro antibodies. A permanent dual-chamber pacemaker was inserted, and he was asymptomatic with normal renal profile at the time of discharge to home at 34 days of life.\n\nFigure 5 Thalamic bleed (white arrow) in coronal view (a), sagittal view (b) and computed tomography of brain (c)\n\nFigure 6 Left common carotid artery pseudoaneurysm, “yin-yang sign” (a), blood flow pattern (b), neck (c)\n\nFigure 7 Abnormal Doppler waveform in the left carotid artery\n\nFigure 8 Normalized left carotid artery Doppler waveform after suture closure of the pseudoaneurysm neck\n\nDISCUSSION\nThis case of neonatal lupus with arterial dissections that threatened multiorgan injury serves as caution for vigilance on vascular procedures. Our decision-making on management of the dissections and complications evolved on anticoagulation threshold, technical access for primary and rescue percutaneous and surgical interventions toward multiorgan flow preservation. We believe that this is the youngest and smallest patient reported in literature with both arterial dissection and pseudoaneurysm.\n\nNeonatal lupus and arteriopathy\nNeonatal lupus has been associated with blood vessel wall compromise, possibly due to maternal autoantibodies causing wall inflammation, predisposing to aneurysm formation and dissection.[1] Interventions such as catheterization and use of guidewires are challenging as minor contact can cause dissection.\n\nAortic dissection with occlusive thrombus\nUmbilical arterial catheterization (UAC) is performed for continuous hemodynamic monitoring. Complications include thrombosis, infection, bleeding, dissection, aneurysm, and pseudoaneurysm.[23] Aortic thrombus can occur as a consequence of aortic dissection, like in our case.[3] Once an aortic thrombus forms, the aim is not only to prevent thrombus progression but also to remove the thrombus, if flow to vital organs is compromised. Unfractionated heparin infusion is commonly used for the former, targeting anti-Xa level between 0.3 and 0.7 IU/ml.[4] Available options to improve blood flow include systemic or localized thrombolysis, thrombectomy, and angioplasty/stenting.\n\nIn a case series involving nine premature infants with aorto-iliac thrombosis related to UAC, the outcome of three treatment options was analyzed: unfractionated heparin only infusion, unfractionated heparin infusion followed by intravenous streptokinase, and low-dose intravenous streptokinase only infused through the UAC directly into the thrombus. The third option was most favorable.[5] Thrombectomy has been shown to be technically challenging with poor outcome in infants.[5] As with unfractionated heparin infusion, we considered systemic thrombolysis very carefully in light of the intracranial bleeds. Although evidence in the neonatal population is scarce, localized thrombolysis and/or angioplasty/stenting may be possible if appropriate access was amenable.\n\nPseudoaneurysm management\nIn contrast to a true aneurysm which consists of focal dilatation involving all three layers of the arterial wall, pseudoaneurysm occurs when there is an interruption in the continuity of the arterial wall due to trauma or inflammation causing partial tear or localized disruption of the vessel wall.[6] The sustained arterial pressure leads to blood leaking into the surrounding tissues, forming a sac. If left untreated, the pseudoaneurysm can rupture, become infected, or compress the upper airway and adjacent neurovascular bundles.[7] Various radiological modalities can be used to look for thrombus; however, ultrasonography provided sufficient information to guide management in our case. For detection of postcatheterization pseudoaneurysms of superficial blood vessels, ultrasound has a sensitivity of 94% and a specificity of 97%.[6]\n\nTo treat pseudoaneurysms, confounding factors such as morphology, areas involved, existence of intracranial collateral circulation, and age of the patient will determine the choice for management to be conservative, endovascular, or surgical. The former is suitable for very small pseudoaneurysms and requires surveillance and anticoagulation. The endovascular approach (stenting/coiling) is considered when there is intact circle of Willis. The technique was safe and effective (technical success rate of 98.2%) in 23 children (2–15 years old), with lower mortality rate compared to surgical repair. Internal carotid artery ligation for pseudoaneurysm has been associated with 5%–25% risk of stroke even in patients with sufficient collateral circulation.[7]\n\nCONCLUSIONS\nVascular procedures need to be carried out with considerable vigilance, especially in neonates with antenatal pointers toward the diagnosis of neonatal lupus. Localized aortic thrombolysis seems to be favorable provided access is possible. The management of pseudoaneurysms is controversial when comparing endovascular and surgical options, particularly in newborns.\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\nVideos Available on: www.annalspc.com\n==== Refs\nREFERENCES\n1 Davey DL Bratton SL Bradley DJ Yetman AT Relation of maternal anti-ro/La antibodies to aortic dilation in patients with congenital complete heart block Am J Cardiol 2011 108 561 4 21624539 \n2 Mendeloff J Stallion A Hutton M Goldstone J Aortic aneurysm resulting from umbilical artery catheterization: Case report, literature review, and management algorithm J Vasc Surg 2001 33 419 24 11174798 \n3 Mehanna MJ Haddad MC Malaeb SN Yunis KA Aortic dissection in a neonate: Case report and review of the literature Am J Perinatol 2005 22 397 9 16215929 \n4 Nagel K Tuckuviene R Paes B Chan AK Neonatal aortic thrombosis: A comprehensive review Klin Padiatr 2010 222 134 9 20514615 \n5 Richardson R Applebaum H Touran T Franceschini RE Robbie PA Wirtschafter DD Effective thrombolytic therapy of aortic thrombosis in the small premature infant J Pediatr Surg 1988 23 1198 200 3236188 \n6 Saad NE Saad WE Davies MG Waldman DL Fultz PJ Rubens DJ Pseudoaneurysms and the role of minimally invasive techniques in their management Radiographics 2005 25 Suppl 1 S173 89 16227490 \n7 Pinzón M Lobelo NO Rodríguez MC Villamor P Otoya AM Endovascular management of iatrogenic cervical internal carotid artery pseudoaneurysm in a 9-year-old child: Case report and literature review Int J Pediatr Otorhinolaryngol 2017 95 29 33 28576528\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0974-5149",
"issue": "13(1)",
"journal": "Annals of pediatric cardiology",
"keywords": "Aortic dissection; carotid artery pseudoaneurysm; neonatal lupus; umbilical arterial catheterization",
"medline_ta": "Ann Pediatr Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101495459",
"other_id": null,
"pages": "87-90",
"pmc": null,
"pmid": "32030043",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "21624539;11174798;3236188;28576528;16215929;16227490;20514615",
"title": "Umbilical artery catheter, aortic dissection, carotid cannulation, and pseudoaneurysm in a neonate: A tale of propagating pathology.",
"title_normalized": "umbilical artery catheter aortic dissection carotid cannulation and pseudoaneurysm in a neonate a tale of propagating pathology"
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"companynumb": "GB-ROCHE-2482757",
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{
"actiondrug": "1",
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"activesubstancename": "ALTEPLASE"
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"drugadditional": "1",
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"abstract": "Can the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus induce testis damage and dysfunction?\n\n\n\nThis is the description of the case of a young man presenting with heavy testicular pain as the first symptom of COVID-19 infection. A review of the literature is also presented.\n\n\n\nSARS-CoV-2 may enter into the host cell by binding to angiotensin-converting enzyme 2. This receptor seems to be widely expressed in different testicular cell types, making possible the occurrence of orchitis in male patients with COVID-19 infection. From a review of the literature, it seems that there is currently no evidence of sexual transmission of SARS-CoV-2; however, the possibility of virus-induced testis damage and dysfunction cannot be excluded.\n\n\n\nFurther studies are necessary on the pathological effect of SARS-CoV-2 in the male reproductive system and to ensure a proper andrological follow-up for male patients.",
"affiliations": "Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy.;Intensive Care Unit, Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy.;Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy.;Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.;Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy.;Intensive Care Unit, Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy.",
"authors": "La Marca|Antonio|A|;Busani|Stefano|S|;Donno|Valeria|V|;Guaraldi|Giovanni|G|;Ligabue|Guido|G|;Girardis|Massimo|M|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.1016/j.rbmo.2020.07.017",
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"issn_linking": "1472-6483",
"issue": "41(5)",
"journal": "Reproductive biomedicine online",
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"medline_ta": "Reprod Biomed Online",
"mesh_terms": "D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D058873:Pandemics; D017699:Pelvic Pain; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2; D013733:Testicular Diseases; D013737:Testis",
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"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "32329026;11381100;32361911;32297920;32425338;32345362;16237152;32362571;32462316;32283711;32650948;32343996;31754615;15141376",
"title": "Testicular pain as an unusual presentation of COVID-19: a brief review of SARS-CoV-2 and the testis.",
"title_normalized": "testicular pain as an unusual presentation of covid 19 a brief review of sars cov 2 and the testis"
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"abstract": "Permanent junctional reciprocating tachycardia (PJRT) is a rare form of atrioventricular reentrant tachycardia that is commonly resistant to most antiarrhythmic medication therapy and over an extended duration can result in tachycardia-induced cardiomyopathy. The prenatal presentation of PJRT is typically similar to that of other types of fetal supraventricular tachycardia (SVT), making it difficult to distinguish from other forms of SVT in utero by fetal echocardiography. Surface electrocardiography after delivery is typically required to make a definitive diagnosis of PJRT. We report a case of fetal SVT at 19 weeks' gestation refractory to maternal transplacental treatment with digoxin, amiodarone, flecainide, sotalol, metoprolol, intraumbilical amiodarone, and fetal intramuscular digoxin over the course of 12 weeks. Repeat cesarean delivery was performed at 30 2/7 weeks' gestation for tachycardia-induced cardiomyopathy with hydrops fetalis. Postnatal electrocardiogram and continuous rhythm monitoring confirmed the diagnosis of PJRT. Combined neonatal treatment with amiodarone, digoxin, and propranolol was successful in reestablishment of sinus rhythm, with radiofrequency ablation planned if medical therapy eventually fails or once early childhood is reached. To our knowledge, this is the first described case of fetal PJRT refractory to multiple standard in utero antiarrhythmic modalities and highlights the importance of inclusion in the differential diagnosis.",
"affiliations": "Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, MN.;Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, MN.;Division of Cardiovascular Disease, Department of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, MN.;Division of Cardiovascular Disease, Department of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, MN.;Division of Cardiovascular Disease, Department of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, MN.",
"authors": "Narang|Kavita|K|;Rose|Carl H|CH|;Johnson|Jonathan N|JN|;Wackel|Philip L|PL|;Cetta|Frank|F|",
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"doi": "10.1016/j.mayocpiqo.2020.07.002",
"fulltext": "\n==== Front\nMayo Clin Proc Innov Qual Outcomes\nMayo Clin Proc Innov Qual Outcomes\nMayo Clinic Proceedings: Innovations, Quality & Outcomes\n2542-4548\nElsevier\n\nS2542-4548(20)30115-6\n10.1016/j.mayocpiqo.2020.07.002\nCase Report\nRare Case of Fetal Permanent Junctional Reciprocating Tachycardia Refractory to Prenatal Antiarrhythmic Therapy\nNarang Kavita MD narang.kavita@mayo.edu\na∗\nRose Carl H. MD a\nJohnson Jonathan N. MD b\nWackel Philip L. MD b\nCetta Frank MD b\na Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, MN\nb Division of Cardiovascular Disease, Department of Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, MN\n∗ Correspondence: Address to Kavita Narang, MD, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905. narang.kavita@mayo.edu\n05 11 2020\n12 2020\n05 11 2020\n4 6 810814\n© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.\n2020\nMayo Foundation for Medical Education and Research\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nPermanent junctional reciprocating tachycardia (PJRT) is a rare form of atrioventricular reentrant tachycardia that is commonly resistant to most antiarrhythmic medication therapy and over an extended duration can result in tachycardia-induced cardiomyopathy. The prenatal presentation of PJRT is typically similar to that of other types of fetal supraventricular tachycardia (SVT), making it difficult to distinguish from other forms of SVT in utero by fetal echocardiography. Surface electrocardiography after delivery is typically required to make a definitive diagnosis of PJRT. We report a case of fetal SVT at 19 weeks’ gestation refractory to maternal transplacental treatment with digoxin, amiodarone, flecainide, sotalol, metoprolol, intraumbilical amiodarone, and fetal intramuscular digoxin over the course of 12 weeks. Repeat cesarean delivery was performed at 30 2/7 weeks’ gestation for tachycardia-induced cardiomyopathy with hydrops fetalis. Postnatal electrocardiogram and continuous rhythm monitoring confirmed the diagnosis of PJRT. Combined neonatal treatment with amiodarone, digoxin, and propranolol was successful in reestablishment of sinus rhythm, with radiofrequency ablation planned if medical therapy eventually fails or once early childhood is reached. To our knowledge, this is the first described case of fetal PJRT refractory to multiple standard in utero antiarrhythmic modalities and highlights the importance of inclusion in the differential diagnosis.\n\nAbbreviations and Acronyms\n\nAV, atrioventricular\nAVRT, atrioventricular tachycardia\nCS, cesarean section\nFHR, fetal heart rate\nMFM, maternal-fetal medicine\nNICU, neonatal intensive care unit\nPJRT, permanent junctional reciprocating tachycardia\nSVT, supraventricular tachycardia\n==== Body\nSupraventricular tachycardia (SVT) is the most common form of tachyarrhythmia in the fetus and occurs in approximately 0.5% of pregnancies. Atrioventricular tachycardia (AVRT) and atrioventricular nodal reentrant tachycardia represent the 2 most common pathophysiological mechanisms, with AVRT being the predominant (70%-90% of cases).1,2 Permanent junctional reciprocating tachycardia (PJRT), first described by Coumel et al in 1967,3 is a rare form of AVRT that can occur in utero and is often incessant and refractory to pharmacological treatment. PJRT is characterized by an orthrodromic reciprocating tachycardia with anterograde conduction over the atrioventricular (AV) node and retrograde conduction via a slowly conducting accessory pathway that is most commonly located in the posteroseptal region near the coronary sinus. The electrophysiological findings of PJRT are characterized by a long RP interval consistent with slow retrograde conduction and retrograde P waves that are usually negative in leads II, III, and aVF4,5 (see Figure 1).Figure 1 Electrocardiogram showing a long RP interval consistent with slow retrograde conduction and retrograde P waves that are usually negative in leads II, III, and aVF.\n\nM-mode fetal echocardiography is the primary modality for the assessment of fetal tachyarrhythmia. Some authors have reported using the ventriculoatrial to AV ratio to help diagnose PJRT in utero, describing a long ventriculoatrial interval with a short AV interval representing the long RP interval and shorter PR interval seen on the electrocardiogram (ECG).6,7 However, these findings can also be encountered in other types of SVT, such as junctional ectopic tachycardia or atrial ectopic tachycardia; thus, the definite diagnosis of PJRT still requires surface ECG or mapping.8 Fetal magnetocardiography is a noninvasive technology recording magnetic fields generated by the electrical activity of the fetal heart, analogous to ECG, that has revealed promising results for the detection of fetal arrhythmia. However, given the immense cost and requirement for nickel alloy–shielded rooms, it has been primarily confined to selected physics research laboratories and is obsolete in clinical practice.9\n\nBecause of the uniquely delayed conduction in the accessory pathway, PJRT tends to be difficult to control with antiarrhythmic medications; in some cases, only rate control can effectively be achieved, with catheter ablation being the preferred treatment once the patient meets candidacy requirements for an electrophysiological procedure. In utero occurrence of PJRT may result in associated mortality from tachycardia-induced cardiomyopathy and subsequent hydrops fetalis.10 We describe a case of very early onset fetal SVT refractory to treatment, requiring indicated preterm delivery with a confirmed postnatal diagnosis of PJRT.\n\nCase Report\n\nA 33-year-old gravida 3 Para 2-0-0-2 White woman was referred to our institution at 19 3/7 weeks’ gestation for fetal tachycardia. Maternal medical history was pertinent for well-controlled depression and anemia. Both previous pregnancies were uncomplicated, with deliveries at term via cesarean sections (CSs): first for arrest of labor, followed by elective repeat CS. Both children are alive and healthy. The current pregnancy had been uncomplicated to date.\n\nFetal tachyarrhythmia was first observed at 19 3/7 weeks during the screening anatomy ultrasound; there was no pericardial effusion or structural abnormalities, and the remainder of the fetal anatomy was normal. Fetal echocardiography performed the same day revealed a fetal heart rate (FHR) of 233 beats/min, 1:1 AV conduction, and brief transient bradycardia provoked by uterine compression, confirming the diagnosis of fetal SVT. The prenatal course of management is outlined below, and the treatment flow sheet is summarized in the Table.Table Treatment Flow Sheet for the Management of Fetal Supraventricular Tachycardia in Utero\n\nGestational age (wk)\tMedication\tDose\tRoute\t\n19 3/7 to 20 2/7\tDigoxin\tLoad 500 μg ×3 doses\nMaintenance 250 μg every 12 h\tTransplacental (oral)\t\n19 6/7 to delivery\tFlecainide\t150 mg every 12 h\tTransplacental (oral)\t\n20 3/7 to 22 2/7\tSotalol\t160 mg every 12 h\tTransplacental (oral)\t\n22 3/7 once\tAmiodarone\t5 mg\tIntraumbilical\t\n22 3/7 to delivery\tAmiodarone\t600 mg every 8 h ×7 d and then 800 mg daily\tTransplacental (oral)\t\n23 3/7 to delivery\tMetoprolol\t50 mg daily\tTransplacental (oral)\t\n24 0/7 once\tDigoxin\t(88 μg/kg) = 64 μg\tFetal intramuscular\t\n\n19 3/7 Weeks’ Gestation\n\nThe patient was admitted to the hospital for the initiation of antiarrhythmic therapy. Repeat fetal echocardiography revealed persistent fetal SVT after 4 days of treatment with supratherapeutic digoxin, so flecainide was added to her regimen. Fetal SVT was persistent after 1 week of treatment; digoxin was discontinued because of maternal intolerance, and sotalol was added.\n\n20 5/7 Weeks’ Gestation\n\nThe patient was discharged home receiving flecainide 150 mg twice daily and sotalol 200 mg twice daily, with an FHR of 210 beats/min.\n\n21 4/7 Weeks’ Gestation\n\nFollow-up fetal echocardiography continued to reveal fetal tachycardia, with an FHR of 217 beats/min and moderate tricuspid regurgitation and trivial mitral valve regurgitation. There was no evidence of pericardial effusion or hydrops, and decision was made to continue her current medications.\n\n22 3/7 Weeks’ Gestation\n\nFetal SVT persisted. Sotalol was discontinued, and intraumbilical amiodarone (5 mg) was administered, with oral maintenance dosing of 600 mg daily initiated that was increased to 800 mg daily.\n\n23 3/7 Weeks’ Gestation\n\nRepeat fetal echocardiography revealed a slightly decreased FHR in the range of 180 to 200 beats/min, with impaired biventricular systolic function (left ventricular ejection fraction, 25%) and both pericardial and pleural effusions. Oral metoprolol XL 100 mg daily was added, with continuation of flecainide and amiodarone.\n\n24 0/7 Weeks’ Gestation\n\nBecause of the development of hydrops fetalis, fetal intramuscular digoxin (88 μg/kg) was administered.\n\n25 0/7 Weeks’ Gestation\n\nRepeat fetal echocardiography revealed worsening biventricular function (left ventricular ejection fraction, 10%-15%) and worsening multivalvular regurgitation. The fetal heart rate remained between 160 and 175 beats/min, and pericardial and pleural effusions were dimensionally stable.\n\nDuring the treatment course, suspicion for PJRT or a possible diagnosis of an arrhythmia other than SVT were considered because of the refractory nature of SVT. The patient was offered additional testing with fetal magnetocardiography, which was available at another medical center. The family elected not to pursue this.\n\nA multidisciplinary team meeting was held between maternal-fetal medicine (MFM), pediatric cardiology, neonatology, and pediatric electrophysiology to discuss clinical management. Upon weighing the risks and benefits of prematurity against worsening cardiac function and anticipated high likelihood of poor perinatal outcome, the mutual consensus was to not proceed with delivery until at least 28 weeks’ gestation. Weekly fetal cardiac assessment was continued, and FHR remained in the range of 160 to 175 beats/min without progression of hydrops.\n\n27 0/7 Weeks’ Gestation\n\nA course of antenatal corticosteroids was administered for fetal lung maturation with anticipation for possible intervention if delivery occurred at 28 0/7 weeks.\n\n29 5/7 Weeks’ Gestation\n\nOn surveillance sonography, both pleural and pericardial effusions were noted to be markedly increased in size with deterioration in biventricular function (see Figure 2). After combined review by pediatric cardiology and MFM, options of expectant management vs delivery were discussed at length with the patient and repeat CS after a second course of antenatal corticosteroids was elected.Figure 2 Sonographic axial view of fetal thoracic cavity and heart at 29 weeks’ gestation, showing pericardial and pleural effusions. Caliper measurement represents pericardial effusion.\n\n30 2/7 Weeks’ Gestation\n\nA scheduled repeat low transverse CS was performed with neonatology, pediatric cardiology, and pediatric electrophysiology teams present in the operating room. The surgical procedure was uncomplicated, and a live-born female infant weighing 1550 g with Apgar scores 6 and 8 at 1 and 5 minutes, respectively, was delivered. After intubation, the neonatal heart rate was 170 to 180 beats/min with no R-R′ variability reflective of SVT; transthoracic echocardiography revealed a structurally normal heart with severe biventricular dysfunction as well as pericardial and pleural effusions. A temporary conversion to sinus rhythm was achieved after the administration of intravenous adenosine and amiodarone, and concurrent ECG was suggestive of accessory pathway–mediated reentrant SVT. After initial stabilization, amiodarone, dopamine, and milrinone were initiated and the neonate was transferred to the neonatal intensive care unit (NICU). Further ECG evaluation confirmed the diagnosis of PJRT.\n\nPostnatal antiarrhythmic treatment has included various combinations of amiodarone, esmolol, procainamide, flecainide, propranolol, and digoxin, with varying success; normal sinus rhythm has currently been achieved for several weeks using a combination of amiodarone, digoxin, and propranolol. A recent echogram revealed markedly recovered biventricular function, with a left ventricular ejection fraction of 61%. The neonate is presently 3 months of age and was recently discharged from the NICU to home after appropriate management of prematurity and PJRT. Electrophysiology studies and catheter ablation are planned once an appropriate weight and age are reached.\n\nDiscussion\n\nFetal SVT affects approximately 0.5% of pregnancies11 and was first described in 1930 using fetal phonocardiography.12 However, development of M-mode fetal echocardiography in the 1980s allowing simultaneous independent assessment of atrioventricular function permitted the pathophysiology and association with perinatal morbidity and mortality to be more clearly defined.13\n\nTreatment is not always indicated for intermittent fetal tachycardia without evidence of hydrops or ventricular dysfunction; persistent fetal SVT in a preterm fetus mandates treatment regardless of hydrops or ventricular function. Failure to achieve normal rhythm in these cases can result in tachycardia-induced cardiomyopathy and subsequent mortality of up to 50% from nonimmune hydrops fetalis.14 The implication of ongoing cardiac dysfunction in the setting of delayed diagnosis in utero poses a significant threat to the overall outcome of the fetus.11,15\n\nManagement options include transplacental therapy (oral) or transplacental and direct (fetal) therapy, with the latter commonly reserved for cases of fetal hydrops in which transplacental transfer of medication is expected to be decreased. Digoxin is a commonly used initial agent, with a conversion rate of about 50%.16 Second agents include sotalol, flecainide, or amiodarone, recognizing that amiodarone may result in fetal hypothyroidism and growth restriction.10 Addition of a second medication results in an improved response in more than 90% of cases.17\n\nThe present case highlights the significant challenges of in utero diagnosis and treatment of refractory fetal SVT owing to PJRT at an experienced tertiary medical center. Moreover, the early gestational age at diagnosis precluded delivery as a practical option; thus, more aggressive attempts at intrauterine therapy had to be considered as detailed above.\n\nFetal SVT that is refractory to in utero treatment with multiple agents should raise concern for less common forms of fetal tachyarrhythmia, such as PJRT, ventricular tachycardia, or the possibility of more than 1 mechanism of tachycardia.\n\nPermanent junctional reciprocating tachycardia has been described in infants and children, and occasionally diagnosed in adulthood. Surface ECG or invasive electrophysiology testing is required to confirm the diagnosis. Multiple drug regimens have been used to treat PJRT, and amiodarone is commonly used as one of the antiarrhythmic medications of choice, but only 23% of cases show complete resolution with medical therapy. Postnatal radiofrequency catheter ablation procedures are more effective and have a success rate of 90%.18\n\nTo date, there are only a handful of other case reports of in utero PJRT. In most cases, fetal SVT was diagnosed during the third trimester, with some cases showing response to in utero treatment while others had fetal cardiomyopathy with successful postnatal management with amiodarone.5,7,19 To our knowledge, none of the reported cases required 5 prenatal antiarrhythmic medications, suggesting that the earlier development of PJRT may result in a more severe disease process and warrant more aggressive in utero treatment options earlier.\n\nMoreover, the approach of a multidisciplinary team of providers involving MFM, pediatric cardiology, neonatology, and pediatric electrophysiology is vital to the high-complexity critical decision-making process in these cases. Delivery should occur at a specialized tertiary care center with level IV NICU and immediate cardiac resources to optimize outcomes.\n\nConclusion\n\nRefractory fetal SVT should prompt providers to consider PJRT in their differential diagnosis. Because controlling PJRT in utero may prove extremely challenging, the goal of management should focus on a multidisciplinary approach to stabilize fetal status, with determination of the timing of delivery on the basis of prematurity risks and ongoing disease process. This case also argues favorably for continued improvement in prenatal diagnostic tools for fetal arrhythmias. Future improvements in diagnostic modalities could create great potential for fetal therapy before the advent of overt cardiomyopathy.\n\nPotential Competing Interests: The authors report no competing interests.\n==== Refs\nReferences\n\n1 Naheed Z.J. Strasburger J.F. Deal B.J. Benson D.W. Jr. Gidding S.S. Fetal tachycardia: mechanisms and predictors of hydrops fetalis J Am Coll Cardiol 27 7 1996 1736 1740 8636562\n2 Simpson J.M. Sharland G.K. Fetal tachycardias: management and outcome of 127 consecutive cases Heart 79 6 1998 576 581 10078084\n3 Coumel P. Cabrol C. Fabiato A. Gourgon R. Salma R. Tachycardie permanente par rythme reciproque Arch Mal Coeur 60 1967 1830\n4 Gaita F. Giustetto C. Permanent junctional reciprocating tachycardia Card Electrophysiol Rev 1 1997 83 85\n5 Chen R.P. Ignaszewski A.P. Robertson M.A. Successful treatment of supraventricular tachycardia-induced cardiomyopathy with amiodarone: case report and review of literature Can J Cardiol 11 10 1995 918 922 7489531\n6 Ouarda F. Drissa M. Hakim K. Msaad H. Fetal persistent junctional reciprocating tachycardia: a diagnostic and a therapeutic challenge Tunis Med 97 3 2019 500 503 31729726\n7 Oudijk M.A. Stoutenbeek P. Sreeram N. Visser G.H.A. Meijboom E.J. Persistent junctional reciprocating tachycardia in the fetus J Matern Fetal Neonatal Med 13 3 2003 191 196 12820841\n8 Cruz-Martinez R. Martinez-Rodríguez M. Bermúdez-Rojas M. Fetal laser ablation of feeding artery of cystic lung lesions with systemic arterial blood supply Ultrasound Obstet Gynecol 49 6 2017 744 750 27363854\n9 Centers for Disease Control and Prevention (CDC) Racial/ethnic differences in the birth prevalence of spina bifida—United States, 1995-2005 MMWR Morb Mortal Wkly Rep 57 53 2009 1409 1413 19129744\n10 van den Heuvel F. Bink-Boelkens M.T.H.E. du Marchie Sarvaas G.J. Berger R.M.F. Drug management of fetal tachyarrhythmias: are we ready for a systematic and evidence-based approach? Pacing Clin Electrophysiol 31 suppl 1 2008 S54 S57 18226038\n11 Perles Z. Gavri S. AJJT Rein Tachyarrhythmias in the fetus: state of the art diagnosis and treatment Prog Pediatr Cardiol 22 1 2006 95 107\n12 Hyman A.S. Irregularities of the fetal heart: a phonocardiographic study of the fetal heart sounds from the fifth to eighth months of pregnancy Am J Obstet Gynecol 20 3 1930 332 347\n13 Kleinman C.S. Hobbins J.C. Jaffe C.C. Lynch D.C. Talner N.S. Echocardiographic studies of the human fetus: prenatal diagnosis of congenital heart disease and cardiac dysrhythmias Pediatrics 65 6 1980 1059 1067 7375228\n14 Krapp M. Kohl T. Simpson J.M. Sharland G.K. Katalinic A. Gembruch U. Review of diagnosis, treatment, and outcome of fetal atrial flutter compared with supraventricular tachycardia Heart 89 8 2003 913 917 12860871\n15 Sonesson S.E. Winberg P. Lidegran M. Westgren M. Foetal supraventricular tachycardia and cerebral complications Acta Paediatr 85 10 1996 1249 1252 8922095\n16 Oudijk M.A. Ruskamp J.M. Ambachtsheer B.E. Drug treatment of fetal tachycardias Pediatr Drugs 4 1 2002 49 63\n17 Strasburger J.F. Cuneo B.F. Michon M.M. Amiodarone therapy for drug-refractory fetal tachycardia Circulation 109 3 2004 375 379 14732753\n18 Kang K.T. Potts J.E. Radbill A.E. Permanent junctional reciprocating tachycardia in children: A multicenter experience Heart Rhythm 11 8 2014 1426 1432 24769425\n19 Cornette J. ten Harkel A.D.J. Steegers E.A.P. Fetal dilated cardiomyopathy caused by persistent junctional reciprocating tachycardia Ultrasound Obstet Gynecol 33 5 2009 595 598 19402102\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2542-4548",
"issue": "4(6)",
"journal": "Mayo Clinic proceedings. Innovations, quality & outcomes",
"keywords": "AV, atrioventricular; AVRT, atrioventricular tachycardia; CS, cesarean section; FHR, fetal heart rate; MFM, maternal-fetal medicine; NICU, neonatal intensive care unit; PJRT, permanent junctional reciprocating tachycardia; SVT, supraventricular tachycardia",
"medline_ta": "Mayo Clin Proc Innov Qual Outcomes",
"mesh_terms": null,
"nlm_unique_id": "101728275",
"other_id": null,
"pages": "810-814",
"pmc": null,
"pmid": "33367217",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "7375228;19129744;7489531;12820841;10078084;12860871;8922095;27363854;24769425;19402102;31729726;11817986;8636562;18226038;14732753",
"title": "Rare Case of Fetal Permanent Junctional Reciprocating Tachycardia Refractory to Prenatal Antiarrhythmic Therapy.",
"title_normalized": "rare case of fetal permanent junctional reciprocating tachycardia refractory to prenatal antiarrhythmic therapy"
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"abstract": "BACKGROUND\nManagement of severe vasoplegic shock in overdose can be very challenging. We describe a case of severe refractory vasodilatory shock in poisoning where methylene blue (MB) was used with success. However, the patient subsequently developed severe Serotonin Syndrome (SS) as a result of an interaction between serotonergic drugs and MB.\n\n\nMETHODS\nA 15-year-old male developed severe vasoplegic shock 1.5 hours after overdosing on several different medications including quetiapine slow release, quetiapine immediate release, desvenlafaxine slow release, venlafaxine, amlodipine, ramipril, fluoxetine, promethazine and lithium. His vasoplegic shock was resistant to high doses of noradrenaline and vasopressin. MB was administered 6.5 hours post ingestion and within 1 hour there was an improvement in his hemodynamic status and reduction of catecholamine requirements. Twelve hours post ingestion, he developed severe Serotonin Syndrome that lasted 5 days as a result of interaction between MB, a reversible monoamine oxidase inhibitor (MAO-I), and the antidepressants taken in overdose. MB had a calculated half-life of 38 hours.\n\n\nCONCLUSIONS\nMB is a useful additional strategy for severe drug induced vasodilatory shock and may be potentially life-saving. Clinicians should be aware that it can interact with other drugs and cause life-threatening Serotonin Syndrome. Lower doses or shorter durations may be wise in patients at risk of this interaction.",
"affiliations": "Clinical Toxicology Unit & Emergency Medicine, Prince of Wales Hospital, Sydney, New South Wales, Australia. betty.chan1@health.nsw.gov.au.;Clinical Toxicology Unit & Emergency Medicine, Prince of Wales Hospital, Sydney, New South Wales, Australia.;Clinical Toxicology Unit & Emergency Medicine, Prince of Wales Hospital, Sydney, New South Wales, Australia.;School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.;School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.;Therapeutics Research Centre, Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia.;School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.;Department of Clinical Pharmacology, University of Sydney, Sydney, New South Wales, Australia.",
"authors": "Chan|Betty S|BS|;Becker|Therese|T|;Chiew|Angela L|AL|;Abdalla|Ahmed M|AM|;Robertson|Tom A|TA|;Liu|Xin|X|;Roberts|Michael S|MS|;Buckley|Nicholas A|NA|",
"chemical_list": "D000931:Antidotes; D008751:Methylene Blue",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-017-0637-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "14(1)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": "Methylene blue; Overdose; Serotonin syndrome; Vasoplegic shock",
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000293:Adolescent; D000931:Antidotes; D003865:Depressive Disorder, Major; D004347:Drug Interactions; D062787:Drug Overdose; D015600:Glasgow Coma Scale; D006801:Humans; D008297:Male; D008751:Methylene Blue; D020230:Serotonin Syndrome; D013406:Suicide, Attempted; D056987:Vasoplegia",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "100-103",
"pmc": null,
"pmid": "29134498",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22197611;22077248;26132604;24364507;21546119;9494028;21629799;10431961;17874986;28144147;20142303;23432501;12023940;17721552;27196698;18810398;24846936;25613051;24508113",
"title": "Vasoplegic Shock Treated with Methylene Blue Complicated by Severe Serotonin Syndrome.",
"title_normalized": "vasoplegic shock treated with methylene blue complicated by severe serotonin syndrome"
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"activesubstancename": "PROMETHAZINE\\PROMETHAZINE HYDROCHLORIDE"
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{
"abstract": "OBJECTIVE\nTo describe the clinical findings and management of eyes affected by uveal effusion syndrome (UES) presenting with clinical features mimicking inflammatory ocular diseases, treated using individualized surgical approaches.\n\n\nMETHODS\nWe report a consecutive interventional case series of seven eyes of four patients affected by UES. On presentation in our clinic, all patients showed signs of steroid effects as a consequence of a presumptive diagnosis; one eye had undergone vitrectomy for retinal detachment (RD), without benefit. Diagnosis of UES was based on ophthalmic examination, ultrasonography, fluorescein angiography, biometry and magnetic resonance imaging. Five eyes with active disease were treated using scleral thinning surgical procedures based on the extent and characteristics of the disease: sclerectomy sites were ultrasound-guided to the area of maximal choroidal swelling, associated with evacuative puncture in the case of bilateral funnel-shaped RD.\n\n\nRESULTS\nOne patient was diagnosed with type 1 UES, two with type 2, and one with type 3. Mean postoperative follow-up was 26 months. In all eyes, surgery resolved the ciliochoroidal and retinal detachment and improved visual acuity. In two eyes, visual restoration was limited by a prolonged disease course.\n\n\nCONCLUSIONS\nUES may be mistaken for other sources of ciliochoroidal effusion. Early diagnosis and treatment is critical to avoid unnecessary procedures and to prevent severe visual loss as a result of neuroretinal damage. Surgical treatment based on the extent and characteristics of the disease may be effective for the resolution of ciliochoroidal effusion, even in type 3 UES, where conventional surgery has proved unsuccessful.",
"affiliations": "Department of Ophthalmology, Ospedale S. Cuore - Don Calabria, Via Don Sempreboni,5, Negrar, 37024, Verona, Italy. emi_maggio@yahoo.it.;Department of Ophthalmology, Ospedale S. Cuore - Don Calabria, Via Don Sempreboni,5, Negrar, 37024, Verona, Italy.;Department of Ophthalmology, Ospedale S. Cuore - Don Calabria, Via Don Sempreboni,5, Negrar, 37024, Verona, Italy.;Department of Ophthalmology, Ospedale S. Cuore - Don Calabria, Via Don Sempreboni,5, Negrar, 37024, Verona, Italy.",
"authors": "Maggio|Emilia|E|;Polito|Antonio|A|;Prigione|Guido|G|;Pertile|Grazia|G|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00417-015-3176-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0721-832X",
"issue": "254(3)",
"journal": "Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie",
"keywords": "Ciliochoroidal effusion; Multimodal imaging; Scleral thinning surgery; Ultrasound-guided surgery; Uveal effusion syndrome",
"medline_ta": "Graefes Arch Clin Exp Ophthalmol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001699:Biometry; D002908:Chronic Disease; D003937:Diagnosis, Differential; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018918:Phacoemulsification; D012599:Sclerostomy; D041623:Tomography, Optical Coherence; D014603:Uveal Diseases; D015866:Uveitis, Posterior; D014792:Visual Acuity",
"nlm_unique_id": "8205248",
"other_id": null,
"pages": "545-52",
"pmc": null,
"pmid": "26376819",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9186138;10711879;6635350;10606449;3085183;2379646;9101574;7177567;18552396;3549374;7436831;2064556;2969684;23503341;2374682",
"title": "Uveal effusion syndrome mimicking severe chronic posterior uveitis: a case series of seven eyes of four patients.",
"title_normalized": "uveal effusion syndrome mimicking severe chronic posterior uveitis a case series of seven eyes of four patients"
} | [
{
"companynumb": "ALCN2016IT007375",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "1",
"dru... |
{
"abstract": "Myeloid/natural killer cell precursor acute leukemia (MNKL) is an aggressive disease with a high relapse rate even after allogeneic hematopoietic stem cell transplantation (SCT). We report a patient with MNKL who had a donor lymphocyte infusion (DLI) for relapse after T cell-replete human leukocyte antigen (HLA)-haploidentical SCT, but relapsed again 20 months later with loss of mismatched HLA. This case suggests that a strong graft-versus-leukemia effect of haploidentical SCT can be expected in MNKL patients. In the haploidentical setting, DLI should be considered for patients with relapsed leukemia whose leukemic cells have not lost HLA cell surface expression.",
"affiliations": "Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima, Japan.",
"authors": "Kobayashi|Shogo|S|;Kikuta|Atsushi|A|;Ito|Masaki|M|;Sano|Hideki|H|;Mochizuki|Kazuhiro|K|;Akaihata|Mitsuko|M|;Waragai|Tomoko|T|;Ohara|Yoshihiro|Y|;Ogawa|Chitose|C|;Ono|Satoshi|S|;Ohto|Hitoshi|H|;Hosoya|Mitsuaki|M|",
"chemical_list": "D006680:HLA Antigens",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.24962",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "61(10)",
"journal": "Pediatric blood & cancer",
"keywords": "BMT; acute; graft versus host disease; hematology/oncology; leukemias; rare tumors; stem cell transplantation",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D006086:Graft vs Host Disease; D006680:HLA Antigens; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007694:Killer Cells, Natural; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009364:Neoplasm Recurrence, Local",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "1880-2",
"pmc": null,
"pmid": "24464971",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Loss of mismatched HLA in myeloid/NK cell precursor acute leukemia relapse after T cell-replete haploidentical hematopoietic stem cell transplantation.",
"title_normalized": "loss of mismatched hla in myeloid nk cell precursor acute leukemia relapse after t cell replete haploidentical hematopoietic stem cell transplantation"
} | [
{
"companynumb": "JP-ASTELLAS-2013JP000200",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Biologic therapies have revolutionised the treatment of immune-mediated diseases including inflammatory bowel disease [IBD] and rheumatological disorders. However, biologic treatments are associated with an increased risk of reactivation of latent tuberculosis. Data from regular monitoring for latent tuberculosis infection [LTBI] during biologic treatment are lacking.\nConsecutive patients eligible for biologic therapies were screened for LTBI and prospectively followed up for 3 years. Incidence and risk factors of latent tuberculosis tests conversion (interferon gamma release assays [IGRA], tuberculin skin tests [TST], and chest radiography [CXR]) with clinical outcomes were studied.\nA total of 108 patients [83 IBD; 25 rheumatological disorders] were included. At baseline, 18/108 [16.7%] patients [five IBD; 13 rheumatological disorders] were tested positive for LTBI. Of these, 14/18 [77.8%] patients received isoniazid monotherapy for 9 months. Of the remainder, 17/90 [18.9%] patients had LTBI test conversion while on biologic therapies and of these 14/17 [82.4%] received isoniazid monotherapy for 9 months. Age, sex, smoking status, alcohol use, travel history, disease type, and immunosuppressive therapy were not associated with LTBI test conversion. In subjects with IGRA conversion, serial IGRA levels normalised after completion of isoniazid except in one patient whose IGRA remained persistently elevated despite isoniazid and who subsequently developed active TB.\nConversion of LTBI is common and occurred early during biologic therapy in an area with intermediate TB burden. Subjects with latent TB tests conversion and persistently high IGRA levels may have an increased risk of TB reactivation or development of active TB, and they require close observation or intensive workup for active TB.",
"affiliations": "Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China.;Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China.;Department of Medicine and Therapeutics, Division of Infectious Disease, Chinese University of Hong Kong, Hong Kong, China.;Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China.;Department of Medicine and Therapeutics, Division of Rheumatology, Chinese University of Hong Kong, Hong Kong, China.;Department of Microbiology, Chinese University of Hong Kong, Hong Kong, China.;Department of Radiology, Chinese University of Hong Kong, Hong Kong, China.;Department of Gastroenterology and Hepatology, First Affliated Hospital, Sun Yat-Sen University, Guangzhou, China.;Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China.;Department of Medicine and Therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China.",
"authors": "Lee|Choon Kin|CK|;Wong|Sunny H V|SHV|;Lui|Grace|G|;Tang|Whitney|W|;Tam|Lai San|LS|;Ip|Margaret|M|;Hung|Esther|E|;Chen|Minhu|M|;Wu|Justin C|JC|;Ng|Siew C|SC|",
"chemical_list": "D018501:Antirheumatic Agents; D000995:Antitubercular Agents; D005765:Gastrointestinal Agents; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D007538:Isoniazid",
"country": "England",
"delete": false,
"doi": "10.1093/ecco-jcc/jjy057",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1873-9946",
"issue": "12(8)",
"journal": "Journal of Crohn's & colitis",
"keywords": null,
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D000995:Antitubercular Agents; D001691:Biological Therapy; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D059425:Interferon-gamma Release Tests; D007538:Isoniazid; D055985:Latent Tuberculosis; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013902:Radiography, Thoracic; D012216:Rheumatic Diseases; D012307:Risk Factors; D014374:Tuberculin Test; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "101318676",
"other_id": null,
"pages": "954-962",
"pmc": null,
"pmid": "29757355",
"pubdate": "2018-07-30",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Prospective Study to Monitor for Tuberculosis During Anti-tumour Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease and Immune-mediated Inflammatory Diseases.",
"title_normalized": "a prospective study to monitor for tuberculosis during anti tumour necrosis factor therapy in patients with inflammatory bowel disease and immune mediated inflammatory diseases"
} | [
{
"companynumb": "CN-JNJFOC-20181135122",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "Previous research has revealed decreased bone mineral density (BMD) among children and adolescents who receive methylphenidate (MP) treatment for attention deficit hyperactivity disorder (ADHD). These findings have major clinical implications given that the prevalence of medication-treated ADHD is on the rise worldwide. We decided to investigate the clinical effect of MP exposure on the incidence of stress fractures, for which a low BMD is a risk factor.\n\n\n\nExposure to MP is a risk factor for stress fractures.\n\n\n\nCase-control study; Level of evidence, 3.\n\n\n\nThis is a case-control study of combat soldiers who served in the military for 3 years between 2005 and 2015. The case group included 2400 soldiers with at least 1 stress fracture diagnosed by a bone scan. The control group comprised 6187 combat soldiers without a diagnosis of a stress fracture. The use of MP was determined by an automated text search of medical records and manual sorting of the results. Other study variables included age; sex; weight; height; body mass index (BMI); place of birth; and characterization of fractures by location, side, and grade. Odds ratios of stress fractures, the attributable proportion among the exposed, and the population attributable fraction were calculated using standard contingency tables. Logistic regression was fitted after adjusting for covariates.\n\n\n\nThe previous use of MP was associated with a higher risk of stress fractures (odds ratio, 1.15 [95% CI, 1.07-1.24]). The attributable proportion was 13.2%, and the population attributable fraction was 0.3%. Logistic regression demonstrated an increased risk of stress fractures associated with past MP use, preserved after adjusting for BMI, sex, and place of birth ( P = .005). Female sex, BMI ≤20 kg/m2, and 20 < BMI ≤25 kg/m2 were independent positive predictors of a stress fracture, while African origin was a negative predictor. Most participants who used MP had only 1 fracture (77.8%), while the majority of participants who did not use MP in the past had ≥2 coincident fractures (53.5%) ( P = .003).\n\n\n\nThis study supports the hypothesis that an MP-associated reduction in BMD has a clinical effect in the form of an increased incidence of stress fractures. The high percentage of fractures attributed to MP use may serve as a basis for risk stratification, that is, the referral of patients with a history of MP use to BMD measurements.",
"affiliations": "Orthopedic Surgery Division, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.;Orthopedic Surgery Division, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.;Orthopedic Surgery Division, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.;Orthopedic Surgery Division, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.;Orthopedic Surgery Division, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.;Unit of Military Physiology, Heller Institute of Medical Research, Sheba Medical Center at Tel HaShomer, Tel Aviv University, Ramat Gan, Israel.",
"authors": "Schermann|Haggai|H|;Ben-Ami|Ilan Shalom|IS|;Tudor|Adrian|A|;Amar|Eyal|E|;Rath|Ehud|E|;Yanovich|Ran|R|",
"chemical_list": "D008774:Methylphenidate",
"country": "United States",
"delete": false,
"doi": "10.1177/0363546517741705",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-5465",
"issue": "46(3)",
"journal": "The American journal of sports medicine",
"keywords": "attention deficit hyperactivity disorder; bone mineral density; methylphenidate; stress fracture",
"medline_ta": "Am J Sports Med",
"mesh_terms": "D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity; D015992:Body Mass Index; D015519:Bone Density; D016022:Case-Control Studies; D005260:Female; D015775:Fractures, Stress; D006801:Humans; D016015:Logistic Models; D008297:Male; D008774:Methylphenidate; D008889:Military Personnel; D016017:Odds Ratio; D012307:Risk Factors",
"nlm_unique_id": "7609541",
"other_id": null,
"pages": "728-733",
"pmc": null,
"pmid": "29236514",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Past Methylphenidate Exposure and Stress Fractures in Combat Soldiers: A Case-Control Study.",
"title_normalized": "past methylphenidate exposure and stress fractures in combat soldiers a case control study"
} | [
{
"companynumb": "IL-JNJFOC-20171225611",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "To explore the frequent interaction between antiretroviral-boosting agents and corticosteroids causing Cushing's syndrome (CS) in the French Pharmacovigilance Database (FPVD).\n\n\n\nWe conducted a retrospective case-control study describing CS recorded in the FPVD between 1996 and 2018. Case was defined as CS occurring in people living with HIV (PLWH) and control was defined as CS in uninfected individuals. Drug-drug interaction (DDI) was defined as an interaction between corticosteroids and CYP3A4 inhibitors. Data concerning the DDI, corticosteroids involved, route of administration and seriousness of the CS were described.\n\n\n\nAmong the 139 instances of CS identified, 34/35 cases (97%) had DDIs (31 with ritonavir and 3 with cobicistat) and 7/104 controls (7%) had DDIs (6 with itraconazole and 1 with verapamil). The main corticosteroid involved was inhaled fluticasone (28/35, 80%) among the cases and oral prednisone (38/104, 37%) among the controls. More CS cases (30/35, 86%) than CS controls (62/104, 60%) were serious (OR = 4.0, 95% CI = 1.4-14.4; P = 0.007).\n\n\n\nAntiretroviral-boosting agents were responsible for one out of four iatrogenic CS cases in a French national database. Prescribers should be aware of the risk of potentially serious DDIs between antiretroviral-boosting agents and corticosteroids, including single-tablet regimens containing cobicistat.",
"affiliations": "Department of Biostatistics and Clinical Research, University Hospital of Caen Normandy, Caen, France.;Centre Régional de Pharmacovigilance, University Hospital of Caen Normandy, Caen, France.;Centre Régional de Pharmacovigilance, University Hospital of Caen Normandy, Caen, France.;Centre Régional de Pharmacovigilance, University Hospital of Paris Saint-Antoine, Paris, France.;Centre Régional de Pharmacovigilance, University Hospital of Montpellier, Montpellier, France.;Centre Régional de Pharmacovigilance, University Hospital of Toulouse, Toulouse, France.;Centre Régional de Pharmacovigilance, University Hospital of Caen Normandy, Caen, France.;Department of Biostatistics and Clinical Research, University Hospital of Caen Normandy, Caen, France.",
"authors": "Peyro-Saint-Paul|Laure|L|;Besnier|Paul|P|;Demessine|Ludivine|L|;Biour|Michel|M|;Hillaire-Buys|Dominique|D|;de Canecaude|Claire|C|;Fedrizzi|Sophie|S|;Parienti|Jean-Jacques|JJ|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D017320:HIV Protease Inhibitors; D000069547:Cobicistat; D019438:Ritonavir",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkz324",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "74(11)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D000069547:Cobicistat; D003480:Cushing Syndrome; D016208:Databases, Factual; D004347:Drug Interactions; D005260:Female; D005602:France; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D012189:Retrospective Studies; D019438:Ritonavir",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "3291-3294",
"pmc": null,
"pmid": "31369085",
"pubdate": "2019-11-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cushing's syndrome due to interaction between ritonavir or cobicistat and corticosteroids: a case-control study in the French Pharmacovigilance Database.",
"title_normalized": "cushing s syndrome due to interaction between ritonavir or cobicistat and corticosteroids a case control study in the french pharmacovigilance database"
} | [
{
"companynumb": "FR-ALKEM LABORATORIES LIMITED-FR-ALKEM-2019-07595",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
... |
{
"abstract": "A 78-year-old woman with drug-resistant persistent atrial fibrillation was referred for catheter ablation by HotBalloon. All pulmonary veins were successfully ablated by the HotBalloon. During the additional roof ablation by the HotBalloon, sudden hemoptysis developed. It was observed that a guidewire advanced far distal to the left superior pulmonary vein (LSPV) branch. The pulmonary vein angiography demonstrated LSPV branch injury. After activated clotting time control, the hemoptysis disappeared spontaneously. The patient was discharged 6 days after the procedure without any sequela.",
"affiliations": "The Heart Rhythm Center Tokyo Heart Center Osaki Hospital Tokyo Japan.;The Heart Rhythm Center Tokyo Heart Center Osaki Hospital Tokyo Japan.;The Heart Rhythm Center Tokyo Heart Center Osaki Hospital Tokyo Japan.",
"authors": "Nakamura|Yoshinori|Y|0000-0002-9967-6267;Sohara|Hiroshi|H|;Ihara|Minoru|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1002/joa3.12116",
"fulltext": "\n==== Front\nJ ArrhythmJ Arrhythm10.1002/(ISSN)1883-2148JOA3Journal of Arrhythmia1880-42761883-2148John Wiley and Sons Inc. Hoboken 10.1002/joa3.12116JOA312116Case ReportCase ReportsInsights into guidewire related complication during HotBalloon ablation in patients with atrial fibrillation: What should we know? NAKAMURA et al.Nakamura Yoshinori MDhttp://orcid.org/0000-0002-9967-6267nakamurayoshi2004@yahoo.co.jp \n1\nSohara Hiroshi MD\n1\nIhara Minoru MD\n1\n\n1 \nThe Heart Rhythm Center\nTokyo Heart Center\nOsaki Hospital\nTokyo\nJapan\n* Correspondence\n\nYoshinori Nakamura, The Heart Rhythm Center, Tokyo Heart Center, Osaki Hospital, Tokyo, Japan.\n\nEmail: nakamurayoshi2004@yahoo.co.jp\n10 9 2018 12 2018 34 6 10.1002/joa3.2018.34.issue-6650 652 29 6 2018 05 8 2018 © 2018 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.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.Abstract\nA 78‐year‐old woman with drug‐resistant persistent atrial fibrillation was referred for catheter ablation by HotBalloon. All pulmonary veins were successfully ablated by the HotBalloon. During the additional roof ablation by the HotBalloon, sudden hemoptysis developed. It was observed that a guidewire advanced far distal to the left superior pulmonary vein (LSPV) branch. The pulmonary vein angiography demonstrated LSPV branch injury. After activated clotting time control, the hemoptysis disappeared spontaneously. The patient was discharged 6 days after the procedure without any sequela.\n\natrial fibrillationguidewirehemoptysisHotBalloonpulmonary hemorrhage source-schema-version-number2.0component-idjoa312116cover-dateDecember 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.4 mode:remove_FC converted:11.12.2018\n\n\nNakamura \nY \n, \nSohara \nH \n, \nIhara \nM \n. Insights into guidewire related complication during HotBalloon ablation in patients with atrial fibrillation: What should we know? \nJ Arrhythmia . 2018 ;34 :650 –652 . 10.1002/joa3.12116\n==== Body\n1 INTRODUCTION\nHotBalloon ablation is a novel technology for the treatment of atrial fibrillation (AF).1 HotBalloon is considered technically simpler, quicker, and easier than conventional radiofrequency ablation for achieving pulmonary vein (PV) isolation and a further advantage of HotBalloon is its ability to adapt to roof and floor line ablation. Here, we report a case with guidewire injury during roof line ablation and review the available literature about this urgent issue.\n\n2 CASE REPORT\nA 78‐year‐old woman with drug‐resistant persistent AF was referred for HotBalloon ablation. She had histories of coronary stenting and aortic dissection surgery. Apixaban was initiated added to aspirin 3 months before the procedure. Aspirin was continued through and apixaban was discontinued from the procedure day. The patient was anticoagulated with intravenous heparin and the activated clotting time (ACT) was kept at >350 seconds after a transseptal puncture. The right superior pulmonary vein (RSPV), the right PV carina, the right inferior pulmonary vein (RIPV), the RIPV bottom, the left superior pulmonary vein (LSPV), the left PV carina, the left inferior pulmonary vein (LIPV), and the LIPV bottom were targeted using the setting of 70°C. Next, the roof side of the LSPV was targeted using the setting of 70°C to achieve a Box lesion set (the isolation of the posterior left atrium (LA) including all pulmonary PVs). The HotBalloon was stabilized utilizing the action‐reaction law that the balloon gradually shifted from the left to the right at the top of each contralateral PV by pushing the guide wire in LSPV. During the roof line ablation, sudden hemoptysis developed. The patient desaturated to 89% and her blood pressure decreased to 86/50 mm Hg. The guidewire position was checked and it was observed that the guidewire had advanced far distal to the LSPV. The guidewire was removed from the injured PV after the detection of hemoptysis and the PV angiography demonstrated LSPV branch injury (Figure 1). ACT was reversed from 353 seconds to 115 seconds after protamine injection. After ACT control, the hemoptysis disappeared spontaneously, and her saturation and blood pressure gradually improved. A CARTO system was used for the identification of the ablation site. All PV potentials were successfully ablated and the roof line was confirmed using a 3D mapping system (Figure 2), however, the floor line was not created due to hemoptysis. The computed tomography of the chest showed that the consolidation in the left lower lobe was suggestive of pulmonary hemorrhage (Figure 1). Her hemoglobin level decreased from 12.0 g/dL to 8.7 g/dL, however, she needed no blood transfusion. She had no recurrence of hemoptysis and apixaban was restarted the next day after the procedure. The patient was discharged 6 days after the procedure without any sequela. The abnormal shadows of the left lobe on chest X‐ray gradual decreased and disappeared 3 weeks after the procedure.\n\nFigure 1 Left panel: Fluoroscopic image in the anteroposterior view. Upper panel: The guidewire soft tip forms an abrupt bending and the proximal stiff segment spearheaded. The guidewire straightened the LSPV branch (yellow arrow). Lower panel: The LSPV venography demonstrated LSPV branch injury (red arrow). The left superior pulmonary vein (LSPV). Right panel: The computed tomography of the chest. (A) Preablation. (B) Post ablation. The computed tomography confirmed that the consolidation in the left lower lobe was suggestive of a pulmonary hemorrhage after the HotBalloon ablation (black arrow)\n\nFigure 2 Fluoroscopic image in the anteroposterior view. The HotBalloon positioning at each site is shown. Central panel: Electroanatomic bipolar voltage mapping in the posteroanterior view after the HotBalloon ablation. Red color shows low voltage area <0.04 mV, indicating electrically silent area created by the HotBalloon ablation. Note that, all pulmonary veins and the roof line were successfully ablated\n\n3 DISCUSSION\nThe advantage of HotBalloon is its ability to adapt to variable PV and posterior LA anatomy as the balloon membrane material is elastic and compliant. A previous study showed that the Box lesion set was successfully achieved using the HotBalloon system, by wedging the balloon at each PV antrum and dragging the balloon at the roof and at the bottom of the posterior LA.2 In this case, the voltage mapping using CARTO system confirmed that all pulmonary veins were successfully isolated and roof line area showed electrically low voltage like an “Arch” shaped. The other balloon‐based ablation systems using cryogenic energy, laser is applied only for the ablation at the LA‐PV junction, and extensive posterior LA has not been possible with these devices so far. During HotBalloon ablation, a sufficient balloon contact to the target tissue is very important to achieve good ablation. A JPC‐SS 0.032′′ guidewire (produced by Lake Region Manufacturing, Inc) which is commonly used for the HotBalloon ablation has two segments: a 4 cm distal soft segment with J‐tip, a proximal stiff segment which is mainly composed of inner hard coil. A proximal stiff segment helps stabilize the HotBalloon at an optimal position, however, distal advancement of a JPC‐SS guidewire sometimes forms an abrupt bending of the tip and the proximal stiff segment can spearhead. This bending of a guidewire hardly occurs in other balloon‐based ablation. In this case, as her anticoagulation therapy was discontinued on the procedure day, anticoagulation drug seemed to have little influence on hemoptysis. The cause of hemoptysis was to push the bending guidewire into a small PV branch to stabilize the balloon during roof line ablation. There have been two reported cases of guidewire related complication during PV isolation using HotBalloon. Fujii et al. reported a hemoptysis case required positive pressure ventilation due to guidewire injury during the right PV carina ablation.3 The HotBalloon and the guidewire were deeply advanced into RSPV to stabilize the balloon, which is inserted through unusual atrial septal defect. Fluoroscopic image showed spearheaded bending guidewire caused distal PV injury in the same manner of this case. Yamasaki et al. reported a cardiac tamponade case needed pericardiocentesis during the LSPV isolation. In their case, the guidewire inadvertently advanced toward the left appendage and caused roof injury.4\n\n\nIn our consecutive 300 HotBalloon ablation procedures, only one guidewire related complication occurred. While the incidence of this complication is very rare in the HotBalloon ablation, it can occur even with usual PV isolation procedure. When considering the cause of hemoptysis, the guidewire related PV injury might be an important cause and we should confirm the guidewire tip location to avoid injury. It might be useful to check the residual lengths of proximal end of the guidewire outside the balloon during the procedure. In addition, as the excessive difference of the guide wire hardness between the distal soft and proximal stiff segment might cause this problem, it should be necessary to improve the transitional part of the JPC‐SS guidewire into more continuous setting at the earliest opportunity. We believe that the guidewire related complication will become less likely to occur by the improvement of guidewire.\n\nCONFLICT OF INTEREST\nDr. Sohara belongs to the endowed department of Toray Industries. The other authors declare no conflict of interest.\n==== Refs\nREFERENCES\n1 \n\nSohara \nH \n, \nOhe \nT \n, \nOkumura \nK \n, et al. HotBalloon ablation of the pulmonary veins for paroxysmal AF: a multicenter randomized trial in Japan . J Am Coll Cardiol . 2016 ;68 :2747 –57 .28007137 \n2 \n\nSohara \nH \n, \nTakeda \nH \n, \nUeno \nH \n, et al. Feasibility of the radiofrequency hot balloon catheter for isolation of the posterior left atrium and pulmonary veins for the treatment of atrial fibrillation . Circ Arrhythm Electrophysiol . 2009 ;2 :225 –32 .19808472 \n3 \n\nYamasaki \nH \n, \nYamagami \nF \n, \nMachino \nT \n, et al. Perforation of the left atrial appendage caused by inadvertent deployment of a soft J‐tipped guidewire during radiofrequency Hot‐Balloon ablation . Circ J . 2018 ;82 :1476 –77 .28924077 \n4 \n\nFujii \nE \n, \nFujita \nS \n, \nKagawa \nY \n, et al. Acute pulmonary hemorrhage during atrial fibrillation HotBalloon ablation . J Arrhythm . 2018 ;34 :462 –464 . 10.1002/joa3.12080 .30167020\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1880-4276",
"issue": "34(6)",
"journal": "Journal of arrhythmia",
"keywords": "HotBalloon; atrial fibrillation; guidewire; hemoptysis; pulmonary hemorrhage",
"medline_ta": "J Arrhythm",
"mesh_terms": null,
"nlm_unique_id": "101263026",
"other_id": null,
"pages": "650-652",
"pmc": null,
"pmid": "30555611",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": "19808472;28007137;28924077;30167020",
"title": "Insights into guidewire related complication during HotBalloon ablation in patients with atrial fibrillation: What should we know?",
"title_normalized": "insights into guidewire related complication during hotballoon ablation in patients with atrial fibrillation what should we know"
} | [
{
"companynumb": "JP-TEVA-2019-JP-1043594",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe intra-arterial chemotherapy (IAC) is increasingly used as a first-line therapy for retinoblastoma. The IAC has proved to be relatively safe. However, many local side effects of IAC have been described.\n\n\nMETHODS\nThis case report describes a local side effect presenting as proptosis and myositis with vascular access difficulty of the middle meningeal artery, in a 2-year-old male with left eye diffuse multifocal stage Vb retinoblastoma complicated with retinal detachment.\n\n\nCONCLUSIONS\nIAC is assured to provide as efficient results in eliminating the tumor as the systemic chemotherapy, without causing the systemic side effects. It has become an alternative to systemic chemotherapy. A better understanding of the local side effects is required.",
"affiliations": "Murray Ocular Oncology and Retina, Miami, Florida, USA, sophiaelhamichi@gmail.com.;Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.;Murray Ocular Oncology and Retina, Miami, Florida, USA.;Murray Ocular Oncology and Retina, Miami, Florida, USA.;Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.;Murray Ocular Oncology and Retina, Miami, Florida, USA.",
"authors": "El Hamichi|Sophia|S|;Acon|Dhariana|D|;Kon Graversen|Veronica|V|;Gold|Aaron S|AS|;Berrocal|Audina M|AM|;Murray|Timothy G|TG|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000511019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1016-2291",
"issue": "55(5)",
"journal": "Pediatric neurosurgery",
"keywords": "13q deletion syndrome; Intra-arterial chemotherapy; Local complication; Retinoblastoma",
"medline_ta": "Pediatr Neurosurg",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders; D002882:Chromosomes, Human, Pair 13; D005094:Exophthalmos; D006801:Humans; D007269:Injections, Intra-Arterial; D058449:Intravitreal Injections; D008297:Male; D008576:Meningeal Arteries; D009220:Myositis; D009916:Orbital Diseases; D019572:Retinal Neoplasms; D012175:Retinoblastoma",
"nlm_unique_id": "9114967",
"other_id": null,
"pages": "295-298",
"pmc": null,
"pmid": "33176321",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acute Orbital Compromise after Intra-Arterial Chemotherapy in a Complex Retinoblastoma Associated with 13q Deletion Syndrome.",
"title_normalized": "acute orbital compromise after intra arterial chemotherapy in a complex retinoblastoma associated with 13q deletion syndrome"
} | [
{
"companynumb": "US-ACCORD-215570",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "1",
"drug... |
{
"abstract": "Therapy-related myeloid neoplasms are a potentially life-threatening consequence of treatment for autoimmune disease (AID) and an emerging clinical phenomenon.\nTo query the association of cytotoxic, anti-inflammatory, and immunomodulating agents to treat patients with AID with the risk for developing myeloid neoplasm.\nThis retrospective case-control study and medical record review included 40 011 patients with an International Classification of Diseases, Ninth Revision, coded diagnosis of primary AID who were seen at 2 centers from January 1, 2004, to December 31, 2014; of these, 311 patients had a concomitant coded diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Eighty-six cases met strict inclusion criteria. A case-control match was performed at a 2:1 ratio.\nOdds ratio (OR) assessment for AID-directed therapies.\nAmong the 86 patients who met inclusion criteria (49 men [57%]; 37 women [43%]; mean [SD] age, 72.3 [15.6] years), 55 (64.0%) had MDS, 21 (24.4%) had de novo AML, and 10 (11.6%) had AML and a history of MDS. Rheumatoid arthritis (23 [26.7%]), psoriasis (18 [20.9%]), and systemic lupus erythematosus (12 [14.0%]) were the most common autoimmune profiles. Median time from onset of AID to diagnosis of myeloid neoplasm was 8 (interquartile range, 4-15) years. A total of 57 of 86 cases (66.3%) received a cytotoxic or an immunomodulating agent. In the comparison group of 172 controls (98 men [57.0%]; 74 women [43.0%]; mean [SD] age, 72.7 [13.8] years), 105 (61.0%) received either agent (P = .50). Azathioprine sodium use was observed more frequently in cases (odds ratio [OR], 7.05; 95% CI, 2.35- 21.13; P < .001). Notable but insignificant case cohort use among cytotoxic agents was found for exposure to cyclophosphamide (OR, 3.58; 95% CI, 0.91-14.11) followed by mitoxantrone hydrochloride (OR, 2.73; 95% CI, 0.23-33.0). Methotrexate sodium (OR, 0.60; 95% CI, 0.29-1.22), mercaptopurine (OR, 0.62; 95% CI, 0.15-2.53), and mycophenolate mofetil hydrochloride (OR, 0.66; 95% CI, 0.21-2.03) had favorable ORs that were not statistically significant. No significant association between a specific length of time of exposure to an agent and the drug's category was observed.\nIn a large population with primary AID, azathioprine exposure was associated with a 7-fold risk for myeloid neoplasm. The control and case cohorts had similar systemic exposures by agent category. No association was found for anti-tumor necrosis factor agents. Finally, no timeline was found for the association of drug exposure with the incidence in development of myeloid neoplasm.",
"affiliations": "Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona.;Division of Health Sciences Research, Section of Biostatistics, Mayo Clinic, Phoenix, Arizona.;Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, Arizona.;Division of Health Sciences Research, Section of Biostatistics, Mayo Clinic, Phoenix, Arizona.;Department of Information Technology, Mayo Clinic, Phoenix, Arizona.;Division of Planning and Practice Analysis, Mayo Clinic, Phoenix, Arizona.;Division of Planning and Practice Analysis, Mayo Clinic, Phoenix, Arizona.;Department of Hematology and Oncology, Mayo Clinic, Rochester, Minnesota.;Department of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona.;Department of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona.;Department of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona.;Department of Hematology and Oncology, Mayo Clinic, Rochester, Minnesota.;Department of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida.;Department of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona.",
"authors": "Ertz-Archambault|Natalie|N|;Kosiorek|Heidi|H|;Taylor|Gretchen E|GE|;Kelemen|Katalin|K|;Dueck|Amylou|A|;Castro|Janna|J|;Marino|Robert|R|;Gauthier|Susanne|S|;Finn|Laura|L|;Sproat|Lisa Z|LZ|;Palmer|Jeanne|J|;Mesa|Ruben A|RA|;Al-Kali|Aref|A|;Foran|James|J|;Tibes|Raoul|R|",
"chemical_list": "D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D008942:Mitoxantrone; D015122:Mercaptopurine; D009173:Mycophenolic Acid; D001379:Azathioprine; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaoncol.2016.6435",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2374-2437",
"issue": "3(7)",
"journal": "JAMA oncology",
"keywords": null,
"medline_ta": "JAMA Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid; D001327:Autoimmune Diseases; D001379:Azathioprine; D016022:Case-Control Studies; D003520:Cyclophosphamide; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D015470:Leukemia, Myeloid, Acute; D008180:Lupus Erythematosus, Systemic; D008297:Male; D015122:Mercaptopurine; D008727:Methotrexate; D008875:Middle Aged; D008942:Mitoxantrone; D009173:Mycophenolic Acid; D009190:Myelodysplastic Syndromes; D016017:Odds Ratio; D011565:Psoriasis; D012189:Retrospective Studies; D012307:Risk Factors; D014481:United States",
"nlm_unique_id": "101652861",
"other_id": null,
"pages": "936-943",
"pmc": null,
"pmid": "28152123",
"pubdate": "2017-07-01",
"publication_types": "D016428:Journal Article",
"references": "22267604;20064151;26350487;25189344;21039422;20331464;17539774;15695534;24123154;24179152;21941193;9666800;24507810;19828563;16294218;20080917;19259097;26875020;22180424;25487151;18299492;8761185;24582568;24507808;27147709;25120730;15380342;21690473",
"title": "Association of Therapy for Autoimmune Disease With Myelodysplastic Syndromes and Acute Myeloid Leukemia.",
"title_normalized": "association of therapy for autoimmune disease with myelodysplastic syndromes and acute myeloid leukemia"
} | [
{
"companynumb": "US-TEVA-2018-US-853772",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "In patients with hypertrophic cardiomyopathy, clinical symptoms such as exertional dyspnea, angina and collapse are considered to be rather the consequence of diastolic than of systolic dysfunction of the left ventricle. Beta-blocker therapy is aimed at reducing systolic overcontraction while calcium blockers predominantly therapy is aimed at reducing systolic overcontraction while calcium blockers predominantly improve diastolic filling characteristics. Therefore 61 consecutive patients with well defined hypertrophic cardiomyopathy were treated with calcium channel blockers: 60 patients with verapamil at average dose 530 mg (320 to 720 mg/d) and one patient received 30 mg nifedipine. All patients had clinical, noninvasive and cardiac catheterization evaluation at the time of entry into the study. Therapy was continued for an average of 54 months (10 to 96). Follow-up studies were performed at 6-month intervals. Subjective improvement was achieved in 47 of 55 symptomatic patients (85%). Heart size, judged as heart volume from tele-chest X-ray in supine position, showed a reduction in 36/61, no change in 15/61 and increase in 10/61. On average in all 61 patients, a significant reduction from 947 to 833 ml/1.73 m2 was seen. Twenty-six patients who had been followed for an average of 24 months prior to verapamil therapy on beta blockers or no treatment had heart volume increases averaging 12% in the pre-verapamil period. Electrocardiography (ECG) showed a significant reduction in QRS amplitude and a tendency towards normalization of ST/T segments. Serial echocardiography study showed small but significant reduction in left atrial diameter. Repeat catheterization was performed in 19 patients and a significant reduction in intraventricular pressure gradient, left ventricular muscle mass and coronary artery diameter was demonstrated. Three patients died during the study (256 patient-treatment-years) for an annual mortality rate of 1.3%. This mortality is considerably lower than reported for patients receiving no treatment, beta-blockade, or surgery. Of all 61 patients only one had surgery related to the hypertrophic cardiomyopathy. One patient had the dose of verapamil reduced because of the occurrence of heart block. No patient discontinued the drug because of side-effects. Utilizing serial noninvasive and invasive studies, we conclude that verapamil therapy in hypertrophic cardiomyopathy results in objective and subjective improvement, a low death rate and little need for operation as compared to standard therapy.",
"affiliations": null,
"authors": "Kaltenbach|M|M|;Hopf|R|R|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D014700:Verapamil; D009543:Nifedipine",
"country": "England",
"delete": false,
"doi": "10.1016/0022-2828(85)90009-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-2828",
"issue": "17 Suppl 2()",
"journal": "Journal of molecular and cellular cardiology",
"keywords": null,
"medline_ta": "J Mol Cell Cardiol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D006328:Cardiac Catheterization; D002312:Cardiomyopathy, Hypertrophic; D002648:Child; D003131:Combined Modality Therapy; D004452:Echocardiography; D004487:Edema; D005260:Female; D006321:Heart; D006327:Heart Block; D006801:Humans; D008297:Male; D008875:Middle Aged; D009543:Nifedipine; D011859:Radiography; D014700:Verapamil",
"nlm_unique_id": "0262322",
"other_id": null,
"pages": "59-68",
"pmc": null,
"pmid": "4040978",
"pubdate": "1985-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of hypertrophic cardiomyopathy: relation to pathological mechanisms.",
"title_normalized": "treatment of hypertrophic cardiomyopathy relation to pathological mechanisms"
} | [
{
"companynumb": "DE-RECRO GAINESVILLE LLC-REPH-2019-000184",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"... |
{
"abstract": "OBJECTIVE\nTo evaluate the efficacy and tolerance of FOLFIRI plus bevacizumab treatment outcome as second-line treatment for metastatic intrahepatic cholangiocarcinoma.\n\n\nMETHODS\nThirteen consecutive patients with metastatic intrahepatic cholangiocarcinoma who were refractory to first-line therapy consisting of gemcitabine plus oxaliplatin-based first-line chemotherapy given intravenously via intra-arterial infusion were treated with FOLFIRI [irinotecan (180 mg/m² i.v. over 90 min) concurrently with folinic acid (400 mg/m² i.v. over 120 min) followed by fluorouracil (400 mg/m² i.v. bolus) then fluorouracil 2400 mg/m² intravenous infusion over 46 h] and bevacizumab (5 mg/kg) every 2 wk. Tumor response was evaluated by computed tomography scan every 4 cycles.\n\n\nRESULTS\nThe best tumor responses using response evaluation criteria in solid tumor criteria were: complete response for 1 patient, partial response for 4 patients, and stable disease for 6 patients after 6 mo of follow-up. The response rate was 38.4% (95%CI: 12.5-89) and the disease control rate was 84.5% (95%CI: 42-100). Seven deaths occurred at the time of analysis, progression free survival was 8 mo (95%CI: 7-16), and median overall survival was 20 mo (95%CI: 8-48). No grade 4 toxic events were observed. Four grade 3 hematological toxicities and one grade 3 digestive toxicity occurred. An adaptive reduction in chemotherapy dosage was required in 2 patients due to hematological toxicity, and a delay in chemotherapy cycles was required for 3 patients.\n\n\nCONCLUSIONS\nFOLFIRI plus bevacizumab combination treatment showed promising efficacy and safety as second-line treatment for metastatic intrahepatic cholangiocarcinoma after failure of the first-line treatment of gemcitabine plus oxaliplatin chemotherapy.",
"affiliations": "Jean-Florian Guion-Dusserre, Veronique Lorgis, Julie Vincent, Leila Bengrine, Francois Ghiringhelli, Department of Medical Oncology, Centre Georges-François Leclerc, 21000 Dijon, France.;Jean-Florian Guion-Dusserre, Veronique Lorgis, Julie Vincent, Leila Bengrine, Francois Ghiringhelli, Department of Medical Oncology, Centre Georges-François Leclerc, 21000 Dijon, France.;Jean-Florian Guion-Dusserre, Veronique Lorgis, Julie Vincent, Leila Bengrine, Francois Ghiringhelli, Department of Medical Oncology, Centre Georges-François Leclerc, 21000 Dijon, France.;Jean-Florian Guion-Dusserre, Veronique Lorgis, Julie Vincent, Leila Bengrine, Francois Ghiringhelli, Department of Medical Oncology, Centre Georges-François Leclerc, 21000 Dijon, France.;Jean-Florian Guion-Dusserre, Veronique Lorgis, Julie Vincent, Leila Bengrine, Francois Ghiringhelli, Department of Medical Oncology, Centre Georges-François Leclerc, 21000 Dijon, France.",
"authors": "Guion-Dusserre|Jean-Florian|JF|;Lorgis|Veronique|V|;Vincent|Julie|J|;Bengrine|Leila|L|;Ghiringhelli|Francois|F|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v21.i7.2096",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "21(7)",
"journal": "World journal of gastroenterology",
"keywords": "Bevacizumab; Biliary tract cancer; FOLFIRI; Intrahepatic cholangiocarcinoma; Second-line treatment",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D002166:Camptothecin; D018281:Cholangiocarcinoma; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil; D005602:France; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "2096-101",
"pmc": null,
"pmid": "25717243",
"pubdate": "2015-02-21",
"publication_types": "D016428:Journal Article",
"references": "20375404;24827133;15958484;23919111;20628385;24714745;19932054;12365016;22700002;1516000;24423918;24852116;19097774;20530271;17325704;22192731;23265701;22176869;23786845;23744917;8879373;24769639;22433475;22572213;21586659",
"title": "FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma.",
"title_normalized": "folfiri plus bevacizumab as a second line therapy for metastatic intrahepatic cholangiocarcinoma"
} | [
{
"companynumb": "FR-CIPLA LTD.-2015FR01739",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "DNM1L encodes dynamin-related protein 1 (DRP1/DLP1), a key component of the mitochondrial fission machinery that is essential for proper functioning of the mammalian brain. Previously reported probands with de novo missense mutations in DNM1L presented in the first year of life with severe encephalopathy and refractory epilepsy, with several dying within the first several weeks after birth. In contrast, we report identical novel missense mutations in DNM1L in two unrelated probands who experienced normal development for several years before presenting with refractory focal status epilepticus and subsequent rapid neurological decline. We expand the phenotype of DNM1L-related mitochondrial fission defects, reveal common unique clinical characteristics and imaging findings, and compare the cellular impact of this novel mutation to the previously reported A395D lethal variant. We demonstrate that our R403C mutation, which resides in the assembly region of DRP1, acts by a dominant-negative mechanism and reduces oligomerization, mitochondrial fission activity, and mitochondrial recruitment of DRP1, but to a lesser extent compared to the A395D mutation. In contrast to the initial report of neonatal lethality resulting from DNM1L mutation and DRP1 dysfunction, our results show that milder DRP1 impairment is compatible with normal early development and subsequently results in a distinct set of neurological findings. In addition, we identify a common pathogenic mechanism whereby DNM1L mutations impair mitochondrial fission. © 2016 Wiley Periodicals, Inc.",
"affiliations": "Department of Pediatrics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California.;Comprehensive Epilepsy Program, Jane and John Justin Neuroscience Center, Cook Children's Medical Center, Fort Worth, Texas.;Division of Pediatric Neurology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California.",
"authors": "Fahrner|Jill A|JA|;Liu|Raymond|R|;Perry|Michael Scott|MS|;Klein|Jessica|J|;Chan|David C|DC|",
"chemical_list": "D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins",
"country": "United States",
"delete": false,
"doi": "10.1002/ajmg.a.37721",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4825",
"issue": "170(8)",
"journal": "American journal of medical genetics. Part A",
"keywords": "DLP1; DNM1L; DRP1; developmental regression; epileptic encephalopathy; fission; mitochondria; seizures",
"medline_ta": "Am J Med Genet A",
"mesh_terms": "D000367:Age Factors; D000818:Animals; D001921:Brain; D001927:Brain Diseases; D002460:Cell Line; D002675:Child, Preschool; D034281:Dynamins; D004827:Epilepsy; D059472:Exome; D020558:GTP Phosphohydrolases; D015870:Gene Expression; D005799:Genes, Dominant; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins; D008928:Mitochondria; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011485:Protein Binding; D021381:Protein Transport",
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "2002-11",
"pmc": null,
"pmid": "27145208",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": "26302298;21149567;17460227;19752021;21145355;25521375;19578372;26122121;26404827;11514614;21599493;21170049;16186251;17460225;26611353;22934639;12499366;26446846;17932957;26604000;25262651;23092955;17170701;11685207;23283981;15731758;23584531;22233676;21194679",
"title": "A novel de novo dominant negative mutation in DNM1L impairs mitochondrial fission and presents as childhood epileptic encephalopathy.",
"title_normalized": "a novel de novo dominant negative mutation in dnm1l impairs mitochondrial fission and presents as childhood epileptic encephalopathy"
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"abstract": "OBJECTIVE\nA phase II trial was performed to evaluate the safety and efficacy of rituximab, a chimeric anti-CD20 monoclonal antibody, in patients with bulky (> 10-cm lesion) relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (NHL).\n\n\nMETHODS\nThirty-one patients received intravenous infusions of rituximab 375 mg/m(2) weekly for four doses. All patients had at least one prior therapy (median, three; range, one to 13) and had progressive disease at study entry. Patients were a median of 4 years from diagnosis.\n\n\nRESULTS\nNo patient had treatment discontinued because of an adverse event. No patient developed human antichimeric antibody. The overall response rate in 28 assessable patients was 43% with a median time to progression of 8.1 months (range, 4.5 to 18.6+ months) and median duration of response of 5.9 months (range, 2.8 to 12.1+ months). The average decrease in lesion size in patients who achieved a partial response was 76%, and patients with stable disease had a decrease in average lesion size of 26%. Median serum antibody concentration was higher in responders compared with nonresponders, and a negative correlation was shown between antibody concentration and tumor bulk at baseline.\n\n\nCONCLUSIONS\nRituximab single-agent outpatient therapy is safe and shows significant clinical activity in patients with bulky relapsed or refractory low-grade or follicular B-cell NHL.",
"affiliations": "Stanford University Medical Center, Stanford, CA, USA. davist@ctep.nci.nih.gov",
"authors": "Davis|T A|TA|;White|C A|CA|;Grillo-López|A J|AJ|;Velásquez|W S|WS|;Link|B|B|;Maloney|D G|DG|;Dillman|R O|RO|;Williams|M E|ME|;Mohrbacher|A|A|;Weaver|R|R|;Dowden|S|S|;Levy|R|R|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.1999.17.6.1851",
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"issn_linking": "0732-183X",
"issue": "17(6)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D018572:Disease-Free Survival; D005260:Female; D006403:Hematologic Tests; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "1851-7",
"pmc": null,
"pmid": "10561225",
"pubdate": "1999-06",
"publication_types": "D016430:Clinical Trial; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Single-agent monoclonal antibody efficacy in bulky non-Hodgkin's lymphoma: results of a phase II trial of rituximab.",
"title_normalized": "single agent monoclonal antibody efficacy in bulky non hodgkin s lymphoma results of a phase ii trial of rituximab"
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"abstract": "Methylphenidate (MPH) is a stimulant drug and an effective treatment for attention-deficit/hyperactivity disorder (ADHD) in both children and adults. Pre-clinical studies suggest that the response to stimulants is dependent on age, which may reflect the ontogeny of the dopamine (DA) system, which continues to develop throughout childhood and adolescence. Therefore, the aim of this study was to investigate the modulating effect of age on the cerebral blood flow (CBF) response to MPH in stimulant treatment-naive children and adults with ADHD. Ninety-eight stimulant treatment-naive male pediatric (10-12 years) and adult (23-40 years) patients with ADHD were included in this study. The CBF response to an acute challenge with MPH (0.5 mg/kg) was measured using arterial spin labeling (ASL) pharmacological magnetic resonance imaging, as a proxy for DA function. Region-of-interest (ROI) analyses were carried out for the striatum, thalamus and medial prefrontal cortex and in addition voxel-wise analyses were conducted. An acute challenge with MPH decreased CBF in both children and adults in cortical areas, although to a greater extent in adults. In contrast, ROI analyses showed that MPH decreased thalamic CBF only in children, but not adults. Our findings highlight the importance of taking the developmental perspective into account when studying the effects of stimulants in ADHD patients.",
"affiliations": "Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, The Netherlands.;Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.;Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.;Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands.;Department of Child- and Adolescent Psychiatry, Triversum, Alkmaar, The Netherlands.;Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, The Netherlands.",
"authors": "Schrantee|A|A|;Mutsaerts|Hjmm|H|;Bouziane|C|C|;Tamminga|Hgh|H|;Bottelier|M A|MA|;Reneman|L|L|",
"chemical_list": "D000697:Central Nervous System Stimulants; D013113:Spin Labels; D008774:Methylphenidate",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.nicl.2016.11.021",
"fulltext": "\n==== Front\nNeuroimage ClinNeuroimage ClinNeuroImage : Clinical2213-1582Elsevier S2213-1582(16)30229-710.1016/j.nicl.2016.11.021Regular ArticleThe age-dependent effects of a single-dose methylphenidate challenge on cerebral perfusion in patients with attention-deficit/hyperactivity disorder Schrantee A a.g.schrantee@amc.uva.nlab⁎Mutsaerts HJMM acBouziane C aTamminga HGH adBottelier MA eReneman L aba Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlandsb Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, The Netherlandsc Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canadad Department of Psychology, University of Amsterdam, Amsterdam, The Netherlandse Department of Child- and Adolescent Psychiatry, Triversum, Alkmaar, The Netherlands⁎ Corresponding author at: Department of Radiology z0-180, Academic Medical Center, P.O. Box 22660, 1105AZ Amsterdam, The Netherlands.Department of Radiology z0-180Academic Medical CenterP.O. Box 22660Amsterdam1105AZThe Netherlands a.g.schrantee@amc.uva.nl21 11 2016 2017 21 11 2016 13 123 129 21 7 2016 18 11 2016 19 11 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Methylphenidate (MPH) is a stimulant drug and an effective treatment for attention-deficit/hyperactivity disorder (ADHD) in both children and adults. Pre-clinical studies suggest that the response to stimulants is dependent on age, which may reflect the ontogeny of the dopamine (DA) system, which continues to develop throughout childhood and adolescence. Therefore, the aim of this study was to investigate the modulating effect of age on the cerebral blood flow (CBF) response to MPH in stimulant treatment-naive children and adults with ADHD.\n\nNinety-eight stimulant treatment-naive male pediatric (10–12 years) and adult (23–40 years) patients with ADHD were included in this study. The CBF response to an acute challenge with MPH (0.5 mg/kg) was measured using arterial spin labeling (ASL) pharmacological magnetic resonance imaging, as a proxy for DA function. Region-of-interest (ROI) analyses were carried out for the striatum, thalamus and medial prefrontal cortex and in addition voxel-wise analyses were conducted.\n\nAn acute challenge with MPH decreased CBF in both children and adults in cortical areas, although to a greater extent in adults. In contrast, ROI analyses showed that MPH decreased thalamic CBF only in children, but not adults.\n\nOur findings highlight the importance of taking the developmental perspective into account when studying the effects of stimulants in ADHD patients.\n\nHighlights\n• We examined the age-dependent effects of MPH on cerebral blood flow in ADHD patients.\n\n• We included stimulant-treatment naive adolescent and adult male ADHD patients.\n\n• Arterial spin labeling MRI was conducted before and after an acute MPH challenge.\n\n• ROI analyses showed a decrease in thalamic CBF in children but not adults.\n\n• Whole brain analyses showed widespread reduction in cortical CBF following MPH.\n\n\n\nKeywords\nADHDMethylphenidateDopamineAgeCerebral blood flowArterial spin labeling\n==== Body\n1 Introduction\nPharmacological treatment of attention-deficit hyperactivity disorder (ADHD) is increasing in children, but also in the adult population (McCarthy et al., 2012). Stimulants, such as methylphenidate (MPH), are the main pharmacological treatment in both children and adults. MPH is the most frequently prescribed stimulant and is particularly effective in reducing behavioral symptoms (MTA group, 1999), at least on the short term. Its therapeutic efficacy has largely been ascribed to its ability to prevent reuptake of catecholamines, such as dopamine (DA) and noradrenalin (NA), thereby enhancing DAergic and noradrenergic neurotransmission (Arnsten, 2011). Indeed, neuroimaging studies have suggested major DAergic alterations in the pathogenesis of ADHD and thereby lend further support for the efficacy of stimulants (Castellanos et al., 1996, Larisch et al., 2006, Spencer et al., 2013). Thus, assessment of the functioning of the DA system is key for studying the pathophysiology of ADHD across development.\n\nThe DA system develops throughout childhood, but is not fully mature until adulthood (Wahlstrom et al., 2010). Remodeling of pre- and postsynaptic receptors continues during development, resulting in differential functioning and output of the DA system at different developmental stages. For example, preclinical studies have observed a major shift in the ratio of excitatory D1/5 and inhibitory D2/3/4 receptors (Chen et al., 2010). Also, previous studies have demonstrated anatomical developmental abnormalities in patients with ADHD (Shaw et al., 2014, Shaw et al., 2009). In addition, both the structure and function of the DA system may be altered in children and adults with ADHD when compared to healthy controls (Weyandt et al., 2013).\n\nFunctional abnormalities in DAergic areas have originally been assessed using perfusion studies with position emission tomography (PET) and single photon emission computed tomography (SPECT), but more recently also with magnetic resonance imaging (MRI). Using these techniques, not only baseline perfusion in DAergic brain areas can be studied, but also the response to stimulant medication such as MPH. Although early PET studies in children with ADHD suffered from methodological constraints such as small sample size, they consistently reported decreased perfusion in the striatum compared to controls, which was, in some studies, reversed by a single dose of MPH (Kim et al., 2001, Lee et al., 2005, Lou et al., 1989). In contrast, in adult ADHD patients both increases and decreases in CBF have been reported following MPH administration using PET and MRI (O'Gorman et al., 2008, Schweitzer et al., 2003). Thus, the current evidence suggests that the effects of MPH on CBF and DA function may be modified by age, although this has not been properly studied.\n\nTherefore, to further enhance our understanding of the functioning of the DA system in response to MPH, we set up the current study in which we directly investigated the modulating effect of age on the CBF response to MPH in stimulant treatment-naive boys and men with ADHD. We used arterial spin labeling (ASL) based pharmacological MRI (phMRI) with a MPH challenge to assess changes in cerebral perfusion. PhMRI is based on the principle that neurotransmitter-specific drug challenges evoke changes in neurovascular coupling that result in hemodynamic changes (Jenkins, 2012). Non-invasive phMRI measurements have been shown to be well-correlated with PET and SPECT studies of DA function (Chen et al., 1997, Jenkins et al., 2004). Based on previous studies, we hypothesized that a single oral dose of MPH would increase CBF in the striatum, thalamus and prefrontal cortex (PFC) in children, whereas in adults we expected a decrease in perfusion, as a result of the functional ontogeny of the DA receptors (Chen et al., 2010).\n\n2 Methods\n2.1 Participants\nParticipants were stimulant-treatment naive boys and men with ADHD; 50 aged between 10 and 12 years and 49 aged between 23 and 40 years. The children were recruited from clinical programs at the Child and Adolescent Psychiatry Center Triversum (Alkmaar) and from the Department of (Child and Adolescent) Psychiatry of the Bascule/AMC (Amsterdam). The adults were recruited from the clinical programs at the PsyQ Mental Health Facility (The Hague) and from the Department of Psychiatry of the AMC (Amsterdam). Patients were diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV, 4th edition) and the diagnosis was subsequently confirmed with a structured interview: Diagnostic Interview Schedule for Children (National Institute of Mental Health Diagnostic Interview Schedule for Children Version IV (NIMH-DISC-IV, authorized Dutch Translation) in children and Diagnostic Interview for ADHD (DIVA) for adults (Kooij, 2012). Participants were excluded when diagnosed with a co-morbid axis I psychiatric disorder requiring pharmacological treatment at study entry; IQ < 80 (estimated with two subscales of the Wechsler Intelligence Scale for Children-Revised (WISC-R); prenatal use of MPH by the mother; clinical treatment with drugs influencing the DA system (for adults before 23 years of age), such as stimulants, neuroleptics, antipsychotics, and D2/3 agonists; MRI contraindications; or MPH contraindications. ADHD symptoms severity was assessed in children using the DBD-RS (Pelham et al., 1992) and in adults using the ADHD-RS (Kooij et al., 2008).\n\n2.2 Procedure\nThe current study reports data from the baseline MRI assessment of a 16-week double blind, randomized, placebo-controlled trial: the ePOD study (Bottelier et al., 2014). After the screening procedure, but before randomization and onset of treatment, participants underwent two MRI scans, one before and one 90 min after administration of 0.5 mg/kg MPH (with a maximum dose of 20 mg for children and 40 mg for adults), at peak plasma levels (Swanson and Volkow, 2003).\n\n2.3 MRI\n2.3.1 Pharmacological MRI – acquisition\nData were acquired using a 3.0 T Philips Achieva MR Scanner (Philips Medical Systems, Best, The Netherlands). A pseudo continuous arterial spin labeling (pCASL) sequence with a gradient-echo echo-planar imaging readout was used with the following parameters: TR/TE = 4000/14 ms; post-label delay = 1525 ms; label duration = 1650 ms; FOV = 240 × 240 × 119 mm; 75 dynamics; voxel size 3 × 3 × 7 mm, no background suppression, scan time = 10 min. In addition, a high resolution anatomical 3D T1-weighted scan was obtained.\n\n2.3.2 Pharmacological MRI – processing\nASL post-processing was performed with the “ExploreASL” toolbox, an in-house developed toolbox based on SPM (Statistical Parametric Mapping, Wellcome Trust Centre for Neuroimaging, London, UK) (Mutsaerts et al., 2016). First, the T1 images were registered to the MNI template and segmented into gray matter (GM) and white matter (WM) probability maps. Then, for the ASL time series, motion estimation was used to assess large motion artifacts and discard any motion spikes frames, where the spike exclusion threshold was the mean + 3 standard deviations (SD). Participants were removed from the analysis if the mean of the frame-wise displacement vector was > 2 mm. With the cleaned dataset, accurate motion estimation was run. Subsequently, the ASL perfusion-weighted images were registered to the GM tissue probability maps of each subject using 6 parameter rigid body registration. After this, label and control images were pair-wise subtracted (ΔM), corrected for slice gradients and averaged. CBF was calculated according to Alsop et al. (2014) using the mean of the control images as M0 image. Following quantification, voxel-based outlier rejection was applied (mean ± 3 SD) and CBF images were averaged. The GM tissue probability maps were then spatially normalized using the Diffeomorphic Anatomical Registration analysis using Exponentiated Lie algebra (DARTEL) algorithm (Ashburner, 2007), and the transformation fields were applied to the CBF maps as well.\n\n2.4 Statistical analysis\nRegional changes in the striatum, thalamus and medial PFC (mPFC) were assessed with a region of interest (ROI) analysis. These ROIs were selected because the striatum is rich in DAT (the primary target of MPH). The thalamus and ACC were chosen because animal literature has demonstrated the largest age-dependent effects of MPH in these two important projections from the striatum (Andersen et al., 2008). From the CBF maps, the median CBF was extracted for these ROIs within a subject-specific GM mask. Subsequently, the effect of MPH on ROI values was analyzed in SPSS using a mixed model with head motion as a time-variant covariate. Additionally, explorative voxel-wise changes in CBF were determined non-parametrically using the Randomise toolbox in the Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL 4.0, Oxford, UK; http://www.fmrib.ox.ac.uk/fsl) (Winkler et al., 2014). CBF maps were smoothed within the GM mask with a 7 mm FWHM Gaussian kernel for the voxel-based analysis. Permutation inference was used to assess the acute effects of MPH on CBF, thresholded at family-wise error (FWE) corrected p < 0.05 using threshold free cluster enhancement (TFCE) (Smith and Nichols, 2009). An independent t-test was used to assess baseline CBF differences between children and adults. To assess the effect of MPH in each group, and the interaction effect of MPH and age group, we conducted a paired samples t-test and a 2-way mixed effect analysis of variance, respectively. As head motion has been identified as a confounder, particularly in ADHD patient groups, log-transformed head mean motion was added to the model as a nuisance regressor.\n\n3 Results\nTable 1 summarizes the patient characteristics. From the initial sample of 50 children, six children were excluded because of excessive motion. In addition, one child was excluded because we could not obtain the second phMRI scan after MPH administration (due to technical difficulties) and three children were excluded because the ASL scan was obtained with a different protocol. In addition, from the initial sample of 49 adults, one adult was excluded because of undisclosed prior treatment with stimulants. Thus, 40 children and 48 adults were included in the analysis. Mean motion differed between children and adults (t = 5.42, p < 0.01) at baseline. In children, motion was significantly reduced after the MPH challenge (t = 3.93, p < 0.01), whereas in adults this effect was not statistically significant (t = 1.72, p = 0.09). SNR did not change from pre- to post-MPH challenge for children or adults, nor was there an age ∗ challenge interaction for any of the ROIs (striatum F = 0.68 p = 0.42; thalamus F = 0.08 p = 0.78; mPFC F = 1.17 p = 0.28). As expected, baseline CBF was higher in children than in adults (Fig. 1) in both cortical and subcortical areas, and similar to values that have been reported in the literature for the respective age groups (Biagi et al., 2007). Global gray matter perfusion decreased from pre- to post-MPH both in children (− 24%) and adults (− 22%) (Fig. 1). Our ROI analyses demonstrate that in children acute MPH significantly decreased CBF in the thalamus (F = 8.12 p < 0.01) and the mPFC (F = 5.55 p = 0.02), whereas in adults MPH only decreased CBF in the mPFC (F = 11.58 p < 0.01). In addition, we found a significant age ∗ MPH challenge interaction in the thalamus (F = 8.07 p < 0.01) (see Fig. 2), indicating that in this brain region the effects of MPH on CBF differ between children and adults. Our voxel-wise analyses demonstrated a reduction in CBF in cortical areas following MPH administration in children and adults (please see Supplementary Table 1 for more details). In the adults mostly cortical regions showed a response, whereas in children mainly the subcortical areas, such as the thalamus, were affected. Although the global maps (Fig. 3c) indicated that the effect of MPH on CBF differed between children and adults, on the voxel-based analysis we did not identify any clusters that showed a significant interaction between age group and MPH administration.\n\n4 Discussion\nIn this study we investigated the modulating effect of age on CBF response to a DA challenge in stimulant treatment-naive children and adults with ADHD. Whole brain analyses showed more widespread reductions in perfusion in the cortex in adults than children, whereas in ROI analyses we found significant reductions in thalamic CBF in children only. A significant age*MPH challenge interaction in the thalamus on our ROI analyses provided further evidence that the effects of MPH in the human brain differ particularly in this brain region.\n\n4.1 Age-dependent effects of MPH on CBF\nTo our knowledge, this is the first study to directly compare the effect of a single dose of MPH on CBF between stimulant treatment-naive children and adults with ADHD. Interestingly, in this study the only area in which we find significant differences in the CBF response between children and adults was the thalamus (i.e. reduction in children, no change in adults). Activating inhibitory D2 receptors could induce lower CBF, but the thalamus is not rich D2 receptors, but rather contains more vasodilatory DA D5 receptors on the microvasculature (Choi et al., 2006). Activating those receptors would result in increased CBF rather than decreased CBF (Choi et al., 2006). Therefore, it is more likely that the large changes found in the thalamus are due to downstream inhibitory effects from the D2-rich striatum, as the thalamus is the main output structure of the striatal circuitry. Furthermore, the thalamus is also rich in noradrenergic transporters, a secondary target of stimulants, which provides an alternative explanation for the thalamic CBF difference.\n\nAlthough we do not find statistically significant differences between children and adults in the cortex, the extent of activation appeared to be larger in adults. In the cortex, the MPH challenge reduced CBF in frontal and parietal areas in children with ADHD. This is in contrast with previous clinical studies that report increased CBF after MPH administration in subcortical and cortical areas, although this was after prolonged treatment rather than a single dose of MPH (as used here) (Kim et al., 2001, Lee et al., 2005, Lou et al., 1989, Teicher et al., 2000). In adults, the MPH-induced CBF reductions in sensory-motor areas, rostral anterior cingulate cortex, temporal cortex and lateral frontal areas are in line with previous studies in ADHD patients. For example, a study in adults with ADHD demonstrated that 3 weeks of MPH treatment resulted in decreased rCBF, as measured by PET, in the striatum and precentral gyri, but increased CBF in the cerebellum, compared to the off-medication condition (Schweitzer et al., 2003). An ASL study, demonstrated higher CBF in adult ADHD patients in the caudate nucleus as well as frontal and parietal areas when compared to controls, which normalized when on medication (O'Gorman et al., 2008). However, these studies are difficult to compare with this study because of prior stimulant exposure and length of MPH treatment in the study.\n\nIn contrast, studies administering MPH to healthy volunteers report more mixed results. In a small group of adult healthy volunteers, an intravenous challenge with 0.25 mg/kg MPH decreased absolute CBF, but increased relative CBF measured with H2[O15] PET in the anterior cingulate, supplementary motor areas and temporal poles, as well as decreased relative CBF in the superior temporal gyri, right medial frontal gyrus, and right inferior parietal cortex (Udo de Haes et al., 2007). In an ASL-based study, decreased CBF was reported following 30 mg oral MPH in lateral frontal, rostral cingulate and sensorimotor areas, amygdala, parahippocampal gyrus and in multiple regions of the occipital and temporal cortices (Marquand et al., 2012). However, they also report increased CBF, particularly in the striatum and thalamus in adult healthy volunteers. The discrepancy with our study might be explained by the difference in populations, i.e. healthy volunteers vs. ADHD patients. It has been shown previously that DA release to a stimulant challenge is altered in adult ADHD patients compared to healthy controls (Cherkasova et al., 2014, Volkow et al., 2007). Recent studies have suggested that neurobiologically, ADHD is characterized by reduced tonic firing of the DA system and subsequent augmented phasic DA release, which can be normalized by means of stimulant treatment (Badgaiyan et al., 2015). This might seem counterintuitive as MPH blocks the reuptake of DA through the pre-synaptic transporter, thereby increasing extracellular DA levels. Yet, this is specifically thought to increase tonic levels of DA, causing increased stimulation of presynaptic autoreceptors and reduce phasic DA release, which in turn results in lower CBF. Thus, the reductions in CBF we find here are in line with findings on the disturbance of the DA system in ADHD subjects and could therefore explain the discrepancy with studies in healthy volunteers.\n\nSurprisingly, we did not find any changes in striatal CBF in either children or adults, despite the striatum being the area with the highest DAT expression. However, when reviewing the literature, the effects of MPH on the striatum are inconsistent, with both increases in CBF and metabolism, as well as decreases and no change having been reported. This has been attributed to the state of the individual's DA system at baseline resulting in a variable response of the striatum (Ernst et al., 1994, Volkow et al., 1997), or could be a consequence of prior stimulant treatment, which was not taken into account in these previous studies. An additional explanation for the discrepant findings is that particularly the downstream areas, such as the thalamus and frontal cortex, displayed changes in metabolism or perfusion following DA changes in the striatum (Udo de Haes et al., 2007).\n\n4.2 Neurobiological correlates of age-dependent CBF response to MPH\nWe observed age-dependent effects of MPH administration on CBF. Adults showed a more widespread area of decreased perfusion in the cortex than children, whereas subcortically we found significant reductions in thalamic CBF in children only. These findings suggest an age-dependency in the CBF response to MPH, which could reflect different maturational stages of the DA system in children and adults. A preclinical phMRI study has previously demonstrated that MPH reduced subcortical and posterior cingulate rCBV in young rats, whereas it increased rCBV in the striatum and frontal cortex in adult rats (Chen et al., 2010). This was linked to a higher D1/D2 ratio in adult vs young rats, as it has been shown that post-synaptic activation of D1 receptors typically results in increased excitatory neurotransmission, which increases metabolic demand and subsequently increases CBF, whereas post-synaptic activation of the inhibitory D2 receptors generally results in decreased CBF (Choi et al., 2006). The different patterns of activation between children and adults may also be explained in part by the ratio of D1 and D2 receptors and DAT expression in the developing brain. However, as little is known about the development of DA receptors in humans, most evidence comes from preclinical studies. In humans and non-human primates, D1 and D2 receptor expression appears to peak in childhood and to slowly decline thereafter. In contrast, studies in rodents typically show peak receptor expression in peri-adolescence (Wahlstrom et al., 2010). Functionally, adolescent rats express a pattern of D1 hypo-activation in response to a D1 agonist. This suggests a dominant response of the D2 receptor in adolescence with a concomitant decrease in CBF (Chen et al., 2010). These changes in the DA system parallel other changes in structural and functional development during adolescence, with marked differences between subcortical and cortical brain areas (Andersen, 2003). Most studies focus on the prefrontal cortex, as this is the latest brain region to develop, and demonstrate continued development of attention, memory and executive function during adolescence (Casey et al., 2000).\n\n4.3 Clinical relevance\nThis is the first study examining perfusion changes in patients with ADHD in a developmental context. We show that, in accordance with preclinical data from separate studies in children and adults, MPH affects the developing brain differently from the adult brain. Nevertheless, current treatment guidelines are based on weight and the assessment of symptom improvement and side-effects, ignoring age as an important determinant of the neurobiological response to stimulants. The adolescent brain is a rapidly developing system with high levels of plasticity. As such, it may be particularly vulnerable to drugs that interfere with these processes or modify the specific transmitter systems involved. Therefore, future long-term studies will have to show what the consequences of stimulant treatment during development are on the DA system, and how they affect the course and outcome of ADHD. Additionally, these results bear relevance for task-based functional MRI studies, as we show here that is important to take into account developmental differences in CBF response, which is one of the major contributors to the BOLD response. Therefore, we suggest future studies should obtain both task-based BOLD fMRI measurements as well as resting state measurements of CBF.\n\n4.4 Methodological considerations\nAlthough we can explain the subcortical and cortical effects of MPH on CBF partially through the ontogeny of the DA system, other neurotransmitter systems may also contribute to this response. For example, the noradrenalin transporter is more important for clearing DA in (pre)frontal areas relative to DAT and, using phMRI, we cannot distinguish between these neurotransmitter systems. In addition, it is important to realize that both DA and noradrenalin have vasoconstrictive properties and we cannot exclude that our results can partially be explained by direct effects of these neurotransmitters on the microvasculature. In addition, although D1,5 are excitatory post-synaptic receptors and D2,3,4 are inhibitory receptors, it is important to note that those receptors located on GABA-ergic or cholinergic neurons could result in the opposite effect on CBF. Global changes in CBF due to systemic changes can also contribute to the CBF response. It is difficult to correct for these changes, especially if the drug of interest induces widespread neuronal changes, as is the case with MPH. In that case, a large part of the GM CBF is determined by the drug effects and removing this by normalizing the data for GM or adding GM CBF as covariate will also remove a large part of the true variance. Future studies could benefit from combined BOLD/ASL based methods to obtain additional information, such as cerebral metabolic rate of oxygen, in order to better distinguish vascular and neuronal effects (Bulte et al., 2012, Wise et al., 2013). Although there were differences in motion between children and adults, we accounted for this in the data pre-processing and group-level analysis, and together with a similar SNR between both age-groups, it is unlikely that differences in data quality underlie our results.\n\nIt is possible that the effect of MPH on CBF is also influenced by differences in baseline DA release between individuals. Volkow et al. (2001) have shown that there is significant variability among participants in DA release in response to MPH, which could result in different potency of its effects across participants. However, it is still unclear whether baseline DA release changes across the lifespan and this therefore remains to be further investigated.\n\nHere we show lower baseline CBF in children than in adults, comparable to reference values from healthy volunteers in literature (Biagi et al., 2007). However, a well-controlled experimental study has recently demonstrated that small changes in baseline CBF do not alter the absolute response to a neuronal stimulus and there therefore absolute CBF better reflects neuronal activity than relative CBF (Whittaker et al., 2015). This makes us confident that the presently observed changes in CBF after acute MPH administration are not solely due to different baseline CBF levels.\n\nWe included both pediatric and adults patients with ADHD. Although some studies use pediatric templates for analysis, this was not feasible here as we directly compared children and adults. Therefore we chose to use a study specific template which included all T1 scans and was therefore unbiased with regard to age group. This approach is supported by the fact that brain weight does not increase much after the age of 10 (Dekaban and Sadowsky, 1978). Moreover, although we ensured that all participants were stimulant treatment naive, some of the adults patients had a history of recreational drug use. However, when comparing those adult subjects with extensive drug use with those with no or low recreational use we do not find differences between the groups (please see Supplementary Table 2 and Supplementary results for more details). Therefore we conclude that recreational drug use likely did not affect our findings. In addition, as this is a cross-sectional study it is possible that our findings are a result of neuronal differences between pediatric and adult ADHD, because the adult group had persistent ADHD, whereas for the children we do not know this yet. Furthermore, we included only male patients to reduce heterogeneity, but this limits to generalizability to female patients.\n\n4.5 Conclusion\nIn sum, we here provide a direct comparison of the CBF response to MPH between children and adults in a large stimulant treatment-naive ADHD sample using ASL phMRI. The cortical response to MPH appears more widespread in adults than in children, whereas subcortical thalamic CBF was reduced following MPH in children, but not adults with ADHD. These findings confirm the age-dependent effects of MPH on CBF, possibly due to differences in the development of the DA system. Our findings thus highlight the importance of taking a developmental perspective into account for the treatment of ADHD.\n\nThe following are the supplementary data related to this article.Supplementary Table 1\nDifferences between children and adults for the whole brain analyses split per Harvard Oxford area.\n\nSupplementary Table 1 Supplementary data about recreational drug use in the adults with ADHD.\n\nImage 1 \n\nAcknowledgements\nFunding resources: This work was funded by faculty resources of the Academic Medical Center, University of Amsterdam (11.25.017) and 11.32050.26 ERA-NET PRIOMEDCHILD FP 6 (EU) (ZoNMW: 11.32050.26).\n\nDeclaration of interests: None of the authors reported a biomedical financial interest or potential conflict of interest.\n\nFig. 1 Baseline differences in CBF (mL/100 g/min) (left) Brain regions displaying significant higher CBF in children than adults (p < 0.05, FWE corrected). Displayed in radiological convention; coordinates provided in MNI standard space; the color bar represents 1-p-value. (right) Gray matter (GM) CBF (mL/100 g/min) in children and adults before and after MPH.\n\nFig. 1.Fig. 2 ROI analysis. Effect of an acute challenge on the striatum, thalamus and medial PFC. *paired t-test p < 0.05, #age ∗ challenge interaction effect p < 0.05.\n\nFig. 2.Fig. 3 Whole brain analysis. Effect of acute challenge with 0.5 mg/kg MPH on CBF (ml/100 g/min) in (a) children (b) adults (p < 0.05, FWE corrected) (c) differences between reductions in CBF in adults and children (non-significant); red = more reduction in CBF in adults than children, green = more reduction in CBF in children than adults. Displayed in radiological convention; coordinates provided in MNI standard space; the color bar represents 1-p-value.\n\nFig. 3.Table 1 Patient characteristics.\n\nTable 1.\tChildren\tAdults\t\nn = 40\tn = 48\t\nMean (SD)\tMean (SD)\t\nMean age (years)\t11.5 (0.8)\t28.6 (4.6)\t\nEstimated IQa\t104.0 (18.3)\t107.9 (7.6)\t\nADHD symptom severity\t\t\t\n DBD-RS Inattention\t22.3 (3.2)\t\t\n DBD-RS Hyperactivity\t15.9 (5.7)\t\t\n ADHD-SR\t\t31.5 (9.7)\t\nADHD subtype\t\t\t\n Inattentive\t22\t16\t\n Hyperactive/impulsive\t1\t0\t\n Combined\t17\t32\t\nComorbidity\t\t\t\n History of depressive episode(s)b\t\t6\t\n History of anxiety disorderb\t\t1\t\n ODD/CDc\t4\t\t\na For children: WISC, for adults: NART.\n\nb For adults: MINI Plus 5.0.\n\nc For children: NIMH DISC-IV.\n==== Refs\nReferences\nAlsop D.C. Detre J.A. Golay X. Günther M. Hendrikse J. Hernandez-Garcia L. Lu H. MacIntosh B.J. Parkes L.M. Smits M. van Osch M.J.P. Wang D.J.J. Wong E.C. Zaharchuk G. 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Evans A.C. Rapoport J.L. Psychostimulant treatment and the developing cortex in attention deficit hyperactivity disorder Am. J. Psychiatry 166 2009 58 63 18794206 \nSmith S.M. Nichols T.E. Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference NeuroImage 44 2009 83 98 18501637 \nSpencer T.J. Brown A. Seidman L.J. Valera E.M. Makris N. Lomedico A. Faraone S.V. Biederman J. Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies J. Clin. Psychiatry 74 2013 902 917 24107764 \nSwanson J. Volkow N. Serum and brain concentrations of methylphenidate: implications for use and abuse Neurosci. Biobehav. Rev. 27 2003 615 621 14624806 \nTeicher M.H. Anderson C.M. Polcari A. Glod C.A. Maas L.C. Renshaw P.F. Functional deficits in basal ganglia of children with attention- deficit/hyperactivity disorder shown with functional magnetic resonance imaging relaxometry Nat. Med. 6 2000 470 473 10742158 \nUdo de Haes J.I. Maguire R.P. Jager P.L. Paans A.M.J. den Boer J.A. Methylphenidate-induced activation of the anterior cingulate but not the striatum: a [15 O]H2 O PET study in healthy volunteers Hum. Brain Mapp. 28 2007 625 635 17080442 \nVolkow N.D. Wang G.J. Fowler J.S. Logan J. Angrist B. Hitzemann R. Lieberman J. Pappas N. Effects of methylphenidate on regional brain glucose metabolism in humans: relationship to dopamine D2 receptors Am. J. Psychiatry 154 1997 50 55 8988958 \nVolkow N.D. Wang G. Fowler J.S. Logan J. Gerasimov M. Maynard L. Ding Y. Gatley S.J. Gifford A. Franceschi D. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain J. Neurosci. 21 2001 RC121 11160455 \nVolkow N.D. Wang G.-J. Newcorn J. Telang F. Solanto M.V. Fowler J.S. Logan J. Ma Y. Schulz K. Pradhan K. Wong C. Swanson J.M. Depressed dopamine activity in caudate and preliminary evidence of limbic involvement in adults with attention-deficit/hyperactivity disorder Arch. Gen. Psychiatry 64 2007 932 940 17679638 \nWahlstrom D. White T. Luciana M. Neurobehavioral evidence for changes in dopamine system activity during adolescence Neurosci. Biobehav. Rev. 34 2010 631 648 20026110 \nWeyandt L. Swentosky A. Gudmundsdottir B.G. Neuroimaging and ADHD: fMRI, PET, DTI findings, and methodological limitations Dev. Neuropsychol. 38 2013 211 225 23682662 \nWhittaker J.R. Driver I.D. Bright M.G. Murphy K. The absolute CBF response to activation is preserved during elevated perfusion: implications for neurovascular coupling measures NeuroImage 125 2015 198 207 26477657 \nWinkler A.M. Ridgway G.R. Webster M.A. Smith S.M. Nichols T.E. Permutation inference for the general linear model NeuroImage 92 2014 381 397 24530839 \nWise R.G. Harris A.D. Stone A.J. Murphy K. Measurement of OEF and absolute CMRO2: MRI-based methods using interleaved and combined hypercapnia and hyperoxia NeuroImage 83 2013 135 147 23769703\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-1582",
"issue": "13()",
"journal": "NeuroImage. Clinical",
"keywords": "ADHD; Age; Arterial spin labeling; Cerebral blood flow; Dopamine; Methylphenidate",
"medline_ta": "Neuroimage Clin",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D001289:Attention Deficit Disorder with Hyperactivity; D000697:Central Nervous System Stimulants; D002560:Cerebrovascular Circulation; D002648:Child; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008774:Methylphenidate; D017072:Neostriatum; D017397:Prefrontal Cortex; D013113:Spin Labels; D013788:Thalamus; D055815:Young Adult",
"nlm_unique_id": "101597070",
"other_id": null,
"pages": "123-129",
"pmc": null,
"pmid": "27942455",
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"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "The age-dependent effects of a single-dose methylphenidate challenge on cerebral perfusion in patients with attention-deficit/hyperactivity disorder.",
"title_normalized": "the age dependent effects of a single dose methylphenidate challenge on cerebral perfusion in patients with attention deficit hyperactivity disorder"
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"abstract": "Neostigmine is traditionally administered intravenously for treatment of acute colonic pseudo-obstruction (ACPO), though use is associated with administration constraints and adverse effects.\n\n\n\nTo evaluate whether an alternative route of administration for neostigmine via subcutaneous (SQ) delivery is safe and effective in a broad cohort of medical and surgical patients.\n\n\n\nThis multicenter, retrospective observational study included adult patients administered SQ neostigmine for ileus, ACPO, or refractory constipation. Efficacy indicators were time to first bowel movement (BM) following initiation of the medication, total SQ neostigmine dose administered to produce a BM, and administration of a rescue intervention to produce a BM. Safety events evaluated were cardiac arrest, bradycardia, bronchospasm requiring intervention, nausea requiring intervention, or severe salivation, lacrimation, or diarrhea.\n\n\n\nA total of 182 patients were eligible for inclusion. The most commonly utilized dosing strategy of neostigmine was 0.25 mg SQ 4 times daily. The median time to first BM following initiation of SQ neostigmine was 29.19 hours (interquartile range = 12.18-56.84) with a median dose administered before first BM of 1.25 mg. Three patients (1.65%) experienced an adverse drug event leading to drug discontinuation, with 2 developing bradycardia that resolved with drug discontinuation alone.\n\n\n\nSQ neostigmine may be reasonable for management of ileus, ACPO, or refractory constipation, though use should be avoided in patients with new-onset heart block, a history of second-degree heart block, or following bowel resection with primary anastomosis. Despite the low incidence of adverse drug events observed, monitoring for bradycardia with telemetry may be considered.",
"affiliations": "1 Duke University Hospital, Durham, NC, USA.;1 Duke University Hospital, Durham, NC, USA.;2 WakeMed Health & Hospitals, Raleigh, NC, USA.;1 Duke University Hospital, Durham, NC, USA.;3 University of North Carolina Health Care System, Chapel Hill, NC, USA.;1 Duke University Hospital, Durham, NC, USA.",
"authors": "Kram|Bridgette|B|;Greenland|Maegan|M|;Grant|Mollie|M|;Campbell|Michael E|ME|;Wells|Charlotte|C|;Sommer|Courtney|C|",
"chemical_list": "D002800:Cholinesterase Inhibitors; D009388:Neostigmine",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028018754302",
"fulltext": null,
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"issn_linking": "1060-0280",
"issue": "52(6)",
"journal": "The Annals of pharmacotherapy",
"keywords": "drug administration; gastroenterology; laxatives; medication safety; surgery",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D001919:Bradycardia; D002800:Cholinesterase Inhibitors; D003112:Colonic Pseudo-Obstruction; D003248:Constipation; D005260:Female; D006801:Humans; D007077:Ileal Diseases; D007279:Injections, Subcutaneous; D008875:Middle Aged; D009388:Neostigmine; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "505-512",
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"pmid": "29359574",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Efficacy and Safety of Subcutaneous Neostigmine for Ileus, Acute Colonic Pseudo-obstruction, or Refractory Constipation.",
"title_normalized": "efficacy and safety of subcutaneous neostigmine for ileus acute colonic pseudo obstruction or refractory constipation"
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{
"abstract": "Invasive Paget's disease of the vulva (IP) is rare among patients with vulvar cancer. Radiation therapy and chemotherapy are not considered as radical, whereas surgical resection of the tumor with abdominal lymphadenectomy is highly invasive. Thus, more effective and less invasive treatments for IP are required. The present study reports a case of a 64-year-old woman with IP, who was treated with a combination of surgery and concurrent chemoradiotherapy (CCRT). The patient was diagnosed with IP with suspected lymph node metastases to the inguinal and pelvic lymph nodes, after having suffered from pruritus vulvae for 7 years. Following mapping biopsy, wide local excision, bilateral inguinal lymph node resection and laparoscopic pelvic lymphadenectomy were successfully performed. The vulva was reconstructed with a local fat flap. Postoperative pathological examination revealed metastases to the bilateral superficial inguinal and the left obturator and lateral suprainguinal lymph nodes. Adjuvant CCRT (whole pelvic irradiation, 50.4 Gy with weekly cisplatin, 40 mg/m2) was completed without notable complications. Therefore, laparoscopic pelvic lymphadenectomy may be useful in determining the irradiation field for adjuvant CCRT in patients with advanced IP.",
"affiliations": "Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan.;Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan.;Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan.;Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan.;Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Kyoto 612-8555, Japan.;Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan.;Department of Obstetrics and Gynecology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.;Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan.;Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan.",
"authors": "Inayama|Yoshihide|Y|;Abiko|Kaoru|K|;Miyamoto|Taito|T|;Horie|Akihito|A|;Yamaguchi|Ken|K|;Baba|Tsukasa|T|;Matsumura|Noriomi|N|;Minamiguchi|Sachiko|S|;Mandai|Masaki|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2018.1719",
"fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2018.1719MCO-0-0-1719ArticlesInvasive Paget's disease of the vulva treated with a combination of surgery and concurrent chemoradiotherapy: A case report Inayama Yoshihide 12Abiko Kaoru 1Miyamoto Taito 1Horie Akihito 1Yamaguchi Ken 3Baba Tsukasa 1Matsumura Noriomi 4Minamiguchi Sachiko 5Mandai Masaki 11 Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, Japan2 Department of Obstetrics and Gynecology, Toyooka Hospital, Toyooka, Hyogo 668-8501, Japan3 Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Kyoto 612-8555, Japan4 Department of Obstetrics and Gynecology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan5 Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8507, JapanCorrespondence to: Dr Kaoru Abiko, Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan, E-mail: kaoruvc@kuhp.kyoto-u.ac.jp11 2018 17 9 2018 17 9 2018 9 5 489 489 16 7 2018 17 9 2018 Copyright: © Inayama et al.2018This 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.Invasive Paget's disease of the vulva (IP) is rare among patients with vulvar cancer. Radiation therapy and chemotherapy are not considered as radical, whereas surgical resection of the tumor with abdominal lymphadenectomy is highly invasive. Thus, more effective and less invasive treatments for IP are required. The present study reports a case of a 64-year-old woman with IP, who was treated with a combination of surgery and concurrent chemoradiotherapy (CCRT). The patient was diagnosed with IP with suspected lymph node metastases to the inguinal and pelvic lymph nodes, after having suffered from pruritus vulvae for 7 years. Following mapping biopsy, wide local excision, bilateral inguinal lymph node resection and laparoscopic pelvic lymphadenectomy were successfully performed. The vulva was reconstructed with a local fat flap. Postoperative pathological examination revealed metastases to the bilateral superficial inguinal and the left obturator and lateral suprainguinal lymph nodes. Adjuvant CCRT (whole pelvic irradiation, 50.4 Gy with weekly cisplatin, 40 mg/m2) was completed without notable complications. Therefore, laparoscopic pelvic lymphadenectomy may be useful in determining the irradiation field for adjuvant CCRT in patients with advanced IP.\n\nconcurrent chemoradiotherapyinvasive Paget's diseaselaparoscopic pelvic lymphadenectomystaging surgeryvulvar cancer\n==== Body\nIntroduction\nInvasive Paget's disease of the vulva (IP) is a rare entity among patients with vulvar cancer, accounting for <1% of all vulvar malignancies (1). Radiation therapy and chemotherapy are not considered to be radical, whereas surgical resection of the tumor with abdominal lymphadenectomy is highly invasive (2,3). Paget's disease of the vulva is classified into primary and secondary, which may be distinguished using immunohistochemistry (3–5). Primary Paget's disease is subdivided into three categories, namely intraepithelial Paget's disease (IEP), IP, and Paget's disease as a manifestation of an underlying adenocarcinoma of a skin appendage or a vulvar gland (4–6). While IEP is usually treated with surgery and its prognosis is relatively good, IP is associated with a poor prognosis (1,3) and a treatment strategy for advanced IP has not yet been standardized (2,6). Thus, more effective and less invasive treatments for IP are required.\n\nWe encountered a case of IP with metastases to the pelvic lymph nodes, which was effectively treated with a combination of wide local excision, inguinal lymph node resection and laparoscopic pelvic lymphadenectomy, followed by concurrent chemoradiotherapy (CCRT).\n\nCase report\nA 64-year-old woman visited Kyoto University Hospital with a rapidly growing mass in the vulva accompanied by pruritus. The patient had first experienced pruritus in the vulva 7 years prior and visited a local hospital. A topical cream was prescribed, but the pruritus persisted. Finally, the patient found a growing mass in the vulva and visited the hospital again. A wide erythematous rash and a hemorrhagic red mass were observed in the vulva and the patient was diagnosed with vaginal cancer and was referred to our hospital for further evaluation. At presentation, a solid mass measuring 4.3 cm was observed in the right vulva, with bilateral inguinal lymphadenopathy (Fig. 1A). A biopsy of the mass revealed invasive cancer cells. The results of the immunohistochemical examination revealed that the tumor cells were positive for cytokeratin (CK)7 and negative for p63 and CK20. Biopsies from the erythematous rash surrounding the mass revealed Paget's cells in the epithelium, indicating that the invasive tumor cells originated from primary vulvar Paget's cells, and the case was diagnosed as IP. Bilateral superficial inguinal lymphadenopathy and left obturator and lateral suprainguinal lymphadenopathy were observed on computed tomography, magnetic resonance imaging and positron emission tomography examination (Fig. 1B-D). After mapping biopsy, local tumor resection, bilateral inguinal lymph node resection and laparoscopic pelvic lymphadenectomy were performed, followed by adjuvant CCRT. The vulva was reconstructed using a local fat flap (Fig. 2A), and laparoscopic pelvic lymphadenectomy was performed to determine the irradiation field for CCRT (Fig. 2B). The operative time was 8 h and 17 min and the total intraoperative blood loss was 66 g. Postoperative pathological examination revealed invasive adenocarcinoma arising from non-invasive Paget's disease (Fig. 3). Metastases to the bilateral superficial inguinal nodes and left obturator and lateral suprainguinal nodes were identified. CCRT (whole pelvic irradiation, 50.4 Gy/28 fractions with weekly cisplatin 7 cycles, 40 mg/m2) was completed without notable complications. The patient experienced an incomplete fracture of the left femoral head, which was possibly treatment-related, 12 months after the treatment and was treated conservatively with the administration of non-steroidal anti-inflammatory drugs and rest. The patient remained alive without recurrence 15 months after the treatment.\n\nDiscussion\nPaget's disease of the vulva is classified into primary and secondary Paget's disease; the former is of cutaneous origin, whereas the latter originates from other malignancies, such as those from the urogenital or gastrointestinal tracts (3–5). Primary Paget's disease is subdivided into three categories: Intraepithelial Paget's disease (IEP), IP, and Paget's disease as a manifestation of an underlying adenocarcinoma of a skin appendage or vulvar gland (4–6). Immunohistochemistry is useful for the differential diagnosis of primary and secondary Paget's disease; Paget's cells of vulvar origin express CK7 and carcinoembryonic antigen, whereas those secondary to urothelial cancer are positive for CK20, p63, uroplakin-III and GATA-3, and those secondary to anorectal adenocarcinoma are positive for CK20, CDX2 and MUC2, but negative for CK7 (3,7). The tumor cells in the present case were positive for CK7 and negative for p63 and CK20, suggesting a vulvar origin.\n\nWhile IEP is usually treated with surgery and its prognosis is relatively good, the prognosis of IP is poor (1,3) and treatment strategies for advanced IP have not yet been standardized (2,6). IP is usually treated as squamous cell carcinoma (SCC) of the vulva (3). Stage IV SCC of the vulva is usually treated with chemotherapy or CCRT (8–10). When Paget's disease is treated with radiotherapy, a radiation dose of 40–50 Gy is recommended for IEP and 55–65 Gy for IP (3,11,12). A previous case report described the efficacy of CCRT in advanced IP; good disease control was obtained within the irradiation field, although the metastatic lesions outside the irradiation field progressed (2). In the present case, metastases were limited to inguinal and pelvic lymph nodes, both of which were within the field of whole pelvic irradiation. Thus, it was suggested that the disease may be controlled with CCRT.\n\nHistorically, radical vulvectomy was previously performed for vulvar SCC, but this procedure is extremely invasive and severe complications, such as postoperative wound dehiscence, infection, lymphedema and psychosexual impairment, are common (8,13). Moreover, recurrence following radical vulvectomy is not rare in Paget's disease (6). Wide local resection, which is a less invasive approach, is currently becoming the standard treatment modality for early-stage SCC of the vulva and primary IEP (6,14). Our patient did not experience wound dehiscence or infection following wide local resection, and underwent adjuvant CCRT immediately after the surgery. However, it is difficult to obtain clear surgical margins in Paget's disease, as Paget's cells spread through the epidermis (15,16). Intraoperative evaluation of the surgical margins is conducted in some cases, but it is associated with ~10% false negative outcomes, since Paget's cells are difficult to evaluate on frozen sections (3,17). Therefore, in the present case, mapping biopsy was conducted prior to surgery, as it has been reported to be useful for determining the surgical margins in extramammary Paget's disease (16).\n\nAlthough surgery alone does not appear to be sufficient for the treatment of IP (15), surgery as a staging procedure may be useful, as accurate staging is key to determining treatment strategy for IP. It has been reported that over one-third of patients with Paget's disease with metastases to the lymph nodes succumb to the disease (1), which suggests that treating lymph node metastases is crucial. Laparoscopic pelvic lymphadenectomy is widely performed in gynecological malignancies, such as cancers of the uterine corpus and cervix; this procedure is safe and less invasive, with a shorter hospital stay compared with laparotomy (18). Laparoscopic lymphadenectomy is conducted to determine the irradiation field in cervical cancer and in some cases of vulvar SCC (18,19); hence, it may also be useful for IP with suspected lymph node metastases. Bilateral inguinal lymphadenectomy was avoided, as lymphadenectomy combined with radiotherapy may cause severe lymphedema (14). Instead, resection of the enlarged lymph nodes was performed, and the patient did not develop lymphedema after CCRT.\n\nIn conclusion, we herein present a case of invasive Paget's disease treated successfully without severe complications using a combination of local excision and laparoscopic pelvic lymphadenectomy as a staging surgery followed by adjuvant CCRT. Laparoscopic pelvic lymphadenectomy may be useful for determining the irradiation field for adjuvant CCRT in cases with advanced IP. However, further studies are required to establish an optimized treatment strategy for IP.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo specific grant was received.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors' contributions\nYI and KA treated the patient and wrote the paper. TM, AH, KY, TB and NM treated the patient and edited the manuscript. SM made the pathological diagnosis and edited the manuscript. MM approved the final version of the manuscript for publication. All authors agree with the content of the manuscript submitted for publication.\n\nEthics approval and consent to participate\nNot applicable.\n\nPatient consent for publication\nWritten informed consent was obtained from the patient for publication of the case details and associated images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAbbreviations\nCCRTconcurrent chemoradiotherapy\n\nIEPintraepithelial Paget's disease\n\nIPinvasive Paget's disease of the vulva\n\nFigure 1. Preoperative findings of invasive Paget's disease of the vulva. (A) Macroscopic appearance of the vulvar tumor. A red mass measuring 4.3×3.6 cm near the clitoris and a widespread erythematous rash in the vulva were observed. (B) Enlarged bilateral superficial inguinal lymph nodes (arrowheads) were observed on computed tomography scan. (C) Enlarged left obturator and lateral supra-inguinal lymph nodes (arrowheads) were visualized using computed tomography. (D) On positron emission tomography, fluorodeoxyglucose uptake (arrowheads) was observed in the left obturator and lateral supra-inguinal lymph nodes, as well as the vulvar tumor.\n\nFigure 2. Intraoperative findings of the invasive Paget's disease of the vulva. (A) After local resection of the tumor, the vulva was reconstructed with a local fat flap. (B) Laparoscopic pelvic lymphadenectomy; an enlarged left obturator lymph node is indicated.\n\nFigure 3. Hematoxylin and eosin staining of the resected specimen of the invasive Paget's disease of the vulva. Note the protrusion of invasive adenocarcinoma (yellow square) abruptly arising on a background of non-invasive Paget's disease (red square). Left, loupe image; magnification, ~x5. Upper-right; magnification, ×200. Lower-right; magnification, ×200.\n==== Refs\nReferences\n1 Parker LP Parker JR Bodurka-Bevers D Deavers M Bevers MW Shen-Gunther J Gershenson DM Paget's disease of the vulva: Pathology, pattern of involvement, and prognosis Gynecol Oncol 77 183 189 2000 10.1006/gyno.2000.5741 10739709 \n2 Yamamoto R Sakuragi N Shirato H Shimizu M Fujimoto S Radiotherapy with concurrent chemotherapy for vulvar adenocarcinoma associated with extramammary Paget's disease Gynecol Oncol 80 267 271 2001 10.1006/gyno.2000.6054 11161871 \n3 van der Linden M Meeuwis KA Bulten J Bosse T van Poelgeest MI de Hullu JA Paget disease of the vulva Crit Rev Oncol Hematol 101 60 74 2016 10.1016/j.critrevonc.2016.03.008 26971063 \n4 Wilkinson EJ Brown HM Vulvar Paget disease of urothelial origin: A report of three cases and a proposed classification of vulvar Paget disease Hum Pathol 33 549 554 2002 10.1053/hupa.2002.124788 12094382 \n5 Kurman RJ Ellenson LH Ronnett BM Blaustein's Pathology of the Female Genital Tract 6th Springer+Business Media New York 81 86 2011 \n6 Delport ES Extramammary Paget's disease of the vulva: An annotated review of the current literature Australas J Dermatol 54 9 21 2013 10.1111/j.1440-0960.2012.00898.x 22671146 \n7 Kurman RJ Carcangiu ML Herrington CS Young RH World Health Organization Classification of Tumours Int Agency Res Cancer Lyon Cedex 08 236 237 2014 \n8 Deppe G Mert I Winer IS Management of squamous cell vulvar cancer: A review J Obstet Gynaecol Res 40 1217 1225 2014 10.1111/jog.12352 24750413 \n9 Mak RH Halasz LM Tanaka CK Ancukiewicz M Schultz DJ Russell AH Viswanathan AN Outcomes after radiation therapy with concurrent weekly platinum-based chemotherapy or every-3-4-week 5-fluorouracil-containing regimens for squamous cell carcinoma of the vulva Gynecol Oncol 120 101 107 2011 10.1016/j.ygyno.2010.09.004 20950845 \n10 Moore DH Ali S Koh WJ Michael H Barnes MN McCourt CK Homesley HD Walker JL A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: A gynecologic oncology group study Gynecol Oncol 124 529 533 2012 10.1016/j.ygyno.2011.11.003 22079361 \n11 Besa P Rich TA Delclos L Edwards CL Ota DM Wharton JT Extramammary Paget's disease of the perineal skin: Role of radiotherapy Int J Radiat Oncol Biol Phys 24 73 78 1992 10.1016/0360-3016(92)91024-H 1324902 \n12 Hata M Omura M Koike I Wada H Miyagi E Tayama Y Odagiri K Minagawa Y Ogino I Inoue T Role of radiotherapy as curative treatment of extramammary Paget's disease Int J Radiat Oncol Biol Phys 80 47 54 2011 10.1016/j.ijrobp.2010.01.073 20951507 \n13 De Hullu JA Hollema H Lolkema S Boezen M Boonstra H Burger MP Aalders JG Mourits MJ Van Der Zee AG Vulvar carcinoma. The price of less radical surgery Cancer 95 2331 2338 2002 10.1002/cncr.10969 12436439 \n14 Hacker NF Eifel PJ van der Velden J Cancer of the vulva Int J Gynecol Obstet 119 Suppl 2 S90 S96 2012 10.1016/S0020-7292(12)60022-8 \n15 Kodama S Kaneko T Saito M Yoshiya N Honma S Tanaka K A clinicopathologic study of 30 patients with Paget's disease of the vulva Gynecol Oncol 56 63 70 1995 10.1006/gyno.1995.1010 7821849 \n16 Kato T Fujimoto N Fujii N Tanaka T Mapping biopsy with punch biopsies to determine surgical margin in extramammary Paget's disease J Dermatol 40 968 972 2013 10.1111/1346-8138.12347 24304176 \n17 Zhu Y Ye DW Chen ZW Zhang SL Qin XJ Frozen section-guided wide local excision in the treatment of penoscrotal extramammary Paget's disease BJU Int 100 1282 1287 2007 10.1111/j.1464-410X.2007.07188.x 17850363 \n18 Walker JL Piedmonte MR Spirtos NM Eisenkop SM Schlaerth JB Mannel RS Spiegel G Barakat R Pearl ML Sharma SK Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2 J Clin Oncol 27 5331 5336 2009 10.1200/JCO.2009.22.3248 19805679 \n19 Klemm P Marnitz S Köhler C Braig U Schneider A Clinical implication of laparoscopic pelvic lymphadenectomy in patients with vulvar cancer and positive groin nodes Gynecol Oncol 99 101 105 2005 10.1016/j.ygyno.2005.05.027 15982723\n\n",
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"abstract": "Allopurinol is a purine analogue that inhibits xanthine oxidase. It is mainly used for the treatment of hyperuricemia in patients with gout or tumor lysis syndrome. Experience with allopurinol in pregnancy is scarce. In 2011, Kozenko et al. reported on a child with multiple malformations after maternal treatment with allopurinol throughout pregnancy. Possible teratogenicity of allopurinol was proposed due to the similarity of the pattern of malformations in children with mycophenolate embryopathy. A possible common mechanism of both drugs, i.e. disruption of purine synthesis, was discussed. We report on the outcome of 31 prospectively ascertained pregnancies with allopurinol exposure at least during first trimester. Pregnancy outcomes were 2 spontaneous abortions, 2 elective terminations of pregnancy and 27 live born children. The overall rate of major malformations (3.7%) and of spontaneous abortions (cumulative incidence 11%, 95%-CI 3-40) were both within the normal range. However, there was one child with severe malformations including microphthalmia, cleft lip and palate, renal hypoplasia, low-set ears, hearing deficit, bilateral cryptorchidism, and micropenis. The striking similarity of the anomalies in this child and the case described by Kozenko et al. might be considered as a signal for teratogenicity. Thus, we would recommend caution with allopurinol treatment in the first trimester, until further data are available.",
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"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, USA 23840514PONE-D-13-0948710.1371/journal.pone.0066637Research ArticleBiologyDevelopmental BiologyOrganism DevelopmentTeratologyMedicineClinical GeneticsGenetic CounselingDrugs and DevicesDrug Research and DevelopmentObstetrics and GynecologyPregnancyPregnancy ComplicationsPediatricsChild DevelopmentAllopurinol Use during Pregnancy - Outcome of 31 Prospectively Ascertained Cases and a Phenotype Possibly Indicative for Teratogenicity Allopurinol in PregnancyHoeltzenbein Maria \n*\nStieler Katja Panse Mary Wacker Evelin Schaefer Christof \nBerlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité Universitätsmedizin Berlin, Berlin, Germany\nRamchandran Ramani Editor\nMedical College of Wisconsin, United States of America\n* E-mail: Maria.Hoeltzenbein@charite.deCompeting Interests: The authors have declared that no competing interests exist.\n\nAnalyzed the data: MH EW. Wrote the paper: MH CS. Study design: MH CS. Data collection, validation and analysis: MH MP KS EW CS.\n\n2013 19 6 2013 8 6 e666374 3 2013 8 5 2013 © 2013 Hoeltzenbein et al2013Hoeltzenbein 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.Allopurinol is a purine analogue that inhibits xanthine oxidase. It is mainly used for the treatment of hyperuricemia in patients with gout or tumor lysis syndrome. Experience with allopurinol in pregnancy is scarce. In 2011, Kozenko et al. reported on a child with multiple malformations after maternal treatment with allopurinol throughout pregnancy. Possible teratogenicity of allopurinol was proposed due to the similarity of the pattern of malformations in children with mycophenolate embryopathy. A possible common mechanism of both drugs, i.e. disruption of purine synthesis, was discussed. We report on the outcome of 31 prospectively ascertained pregnancies with allopurinol exposure at least during first trimester. Pregnancy outcomes were 2 spontaneous abortions, 2 elective terminations of pregnancy and 27 live born children. The overall rate of major malformations (3.7%) and of spontaneous abortions (cumulative incidence 11%, 95%-CI 3–40) were both within the normal range. However, there was one child with severe malformations including microphthalmia, cleft lip and palate, renal hypoplasia, low-set ears, hearing deficit, bilateral cryptorchidism, and micropenis. The striking similarity of the anomalies in this child and the case described by Kozenko et al. might be considered as a signal for teratogenicity. Thus, we would recommend caution with allopurinol treatment in the first trimester, until further data are available.\n\nThe study has been performed with financial support from the German Federal Institute for Drugs and Medical Devices. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n==== Body\nIntroduction\nAllopurinol is a purin analogue that inhibits xanthine oxidase. It is mainly used for the treatment of hyperuricemia in patients with gout or tumor lysis syndrome. As these conditions are infrequent in women of childbearing age allopurinol use in pregnancy has rarely been observed. The possible antioxidant function of allopurinol has recently led to an increasing discussion on extending treatment indications to cardiovascular disease[1] and pre-eclampsia [2]. In addition, allopurinol is used as adjunct therapy in order to increase efficacy of thiopurines in inflammatory bowel disease, a condition frequently affecting women of childbearing age [3], [4].\n\nA recent publication reported on normal pregnancy outcome after allopurinol treatment throughout pregnancy [5]. On the other hand, possible teratogenicity of allopurinol had been proposed after observation of a child with multiple malformations after maternal treatment throughout pregnancy [6]. So far, there are no prospective data on allopurinol use in pregnancy. Therefore, counseling of allopurinol is difficult. We report the first case series of prospectively followed pregnancies exposed to allopurinol.\n\nMaterials and Methods\nAscertainment of cases and follow-up procedure\nThe Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy offers risk assessment to physicians, other health care providers (HCP) and pregnant women. Patient data are documented through the risk consultation. Usually, data are ascertained prospectively, i.e. neither the outcome of pregnancy nor the results of prenatal diagnostics are primarily known, but are ascertained at a later stage. In retrospectively reported cases, the outcome of pregnancy is already known and has usually prompted the initial contact to our institute. Using structured questionnaires, all relevant data with respect to medications, exposures to other agents and/or diseases and course and outcome of pregnancy are documented with informed consent of the patient. The following information is obtained: obstetric and medical history, family history, patient's profession and education, treatment indications and details of exposures (timing in pregnancy, duration, dose and concomitant medication, vitamins, in particular folic acid), assisted conception, inadvertent use of hormonal contraceptives during pregnancy, social or illicit drugs and smoking. About 8 weeks after the expected date of delivery, information about complications during pregnancy (i.e. infections, gestational diabetes, preeclampsia, etc.), details in case of pregnancy loss, gestational age at birth, sex, birth weight, length, head circumference, pH, and Apgar scores and if applicable details of congenital anomalies and postnatal disorders during neonatal period are obtained. For further details on the methodology see [7].\n\nEthics\nThe study is based on observational data and was approved by the Ethics Committee of the Charité-Universitätsmedizin Berlin, Germany. All patients were informed that their medical information will be stored and used for future scientific research. In case they have contacted us directly they have provided us with a written consent. In case their HCP have contacted us, the HCP confirm that their patients have agreed. All our correspondences to patients and HCP contain information about our data handling and the patient's rights.\n\nStudy design\nProspectively ascertained pregnancies with maternal allopurinol exposure were identified from 1991 until June 2012. Since the vulnerable phase for birth defects induced by teratogens is limited to the 1st trimester, only pregnancies with exposure to allopurinol at least between last menstrual period (LMP) and gestational week 12 were included in the study. Cases were included independent of treatment indication and exposure interval within the 1st trimester. Exposure to allopurinol may have lasted longer than week 12.\n\nThe primary goal of the study was to determine the rate of major birth defects, defined as structural abnormalities of medical, surgical or cosmetic relevance induced during embryogenesis. Special emphasis was to further evaluate the teratogenic potential of allopurinol as proposed by Kozenko et al. [6]. All birth defects were classified according to Merks [8] and Rasmussen [9]. Secondary endpoints of our study were the rates of miscarriage, stillbirth and preterm delivery (<37 weeks). Weeks of pregnancy were defined by LMP. Birth weight was adjusted to gestational age at birth and sex. Percentile categories were calculated according to Voigt et al. [10].\n\nStatistical analysis\nThe birth defect rate was calculated using live births plus pregnancy losses with pathology. For calculating rates of major birth defects, genetic or chromosomal disorders were excluded. Because of the limited number of exposed cases we did not use a control group.\n\nSince crude rates of pregnancy outcome based on observational data are biased we calculated cumulative incidences of spontaneous abortions, elective terminations of pregnancy (ETOP) and live births. For further details of this method see Meister et al. [11].\n\nResults\nMaternal characteristics\nFrom January 1991 until June 2012 a total of 38 pregnancies with maternal allopurinol exposure and complete follow-up were identified (Fig. 1). Thirty-one pregnancies with first trimester exposure fulfilled the criteria of being prospectively ascertained and were included in this study for evaluation of pregnancy outcome. One pregnancy with uneventful outcome after long term allopurinol exposure was reported retrospectively and was therefore not considered for relative risk calculation.\n\n10.1371/journal.pone.0066637.g001Figure 1 Flow chart on cases of allopurinol exposure and pregnancy (FUP = Follow-up).\nTreatment indications were hyperuricemia (n = 18), gout (n = 4), renal diseases (n = 4), rheumatoid arthritis (n = 2), and systemic lupus erythematosus, chronic myeloic leucemia, hyperoxaluria (each n = 1).\n\nMedian dosage of allopurinol was 100 mg (range 50–600 mg/d, interquartile range (IQR) 100–300 mg/d). Treatment with allopurinol was initiated before pregnancy in 27 women. Four patients started allopurinol during 1st trimester. 15/31 patients stopped therapy before week 8 after LMP, only 2 women continued treatment with allopurinol throughout pregnancy (pregnancies #30 and #31) (see Fig. 2).\n\n10.1371/journal.pone.0066637.g002Figure 2 Diagram summarizing pregnancy interval of allopurinol exposure, week at first contact and outcome of 31 prospectively ascertained pregnancies.\nExcept for one mother treated with mycophenolate until week 6+6 after kidney transplantation (pregnancy #12) and one mother with cyclophosphamide (single dose at week 7+3, pregnancy #26) there were no patients with teratogenic co-medication.\n\nOn the other hand only two women were exclusively exposed to allopurinol (pregnancies #3 and #24), indicating the high co-morbidity of our patients. Twelve women were treated for hypertension, nine of whom needed two or more antihypertensives, including methyldopa (n = 5), ACE-Inhibitors or AT II receptor inhibitors (n = 7), ß-blockers (n = 7), diuretics (n = 8), monoxidine (n = 2), dihydralazine (n = 1), and clonidine (n = 1). In addition, three women used diuretics for treatment of edema. There were three women with type 2 diabetes, two women developed gestational diabetes. Interestingly, three women were on tuberculostatic therapy including pyrazinamide, well known to reduce excretion of uric acid. Further details of maternal characteristics are summarized in Table 1. Information on BMI was available from 2005 onwards. In seven of 14 patients the BMI was >35 (see also Table 1).\n\n10.1371/journal.pone.0066637.t001Table 1 Maternal characteristics and obstetrical history of allopurinol exposed women.\n\nAge (yrs)\n\t\t32 (28–37) (22–42)\tn = 30/31\t\n\nBMI\n1\n\t\t33.5 (23–38) (20–50)\tn = 14/31\t\n\nEducational level\n\t9 years exam\t2 (18%)\tn = 11/31\t\n\t10/11 years exam\t6 (55%)\t\t\n\tsecondary school exam\t1 (9%)\t\t\n\tacademic study\t2 (18%)\t\t\n\nSmoking\n\tNo\t26 (90%)\tn = 29/31\t\n\t< = 5 cig/day\t1 (3%)\t\t\n\t>5 cig/day\t2 (7%)\t\t\n\nAlcohol\n\tNo\t30 (100%)\tn = 30/31\t\n\nPrevious pregnancies\n\t0\t13 (43%)\tn = 30/31\t\n\t1\t5 (17%)\t\t\n\t2\t4 (13%)\t\t\n\t3 or more\t8 (27%)\t\t\n\nPrevious parities\n\t0\t13 (43%)\tn = 30/31\t\n\t1\t7 (23%)\t\t\n\t2\t6 (20)\t\t\n\t3 or more\t4 (13%)\t\t\n\nPrevious miscarriages\n\t0\t26 (90%)\tn = 29/31\t\n\t1\t3 (10%)\t\t\n\t2 or more\t0 (0%)\t\t\n\nPrevious children with birth defect\n\t0\t27 (93%)\tn = 29/31\t\n\t1\t2 (7%)\t\t\n\t2 or more\t0 (0%)\t\t\n\nWeek at first TIS contact\n\t\t8.9 (6.9–12.8) (3.1–20)\tn = 31/31\t\nFor age, BMI, and week at first TIS contact, median, interquartile range, and min/max are presented.\n\n1 BMI was only available for cases ascertained after 2004.\n\nFirst contacts to our institute were initiated via gynaecologists (n = 17), clinical geneticists (n = 6), other physicians (n = 4) and patients (n = 4).\n\nPregnancy outcome\nOf the 31 pregnancies exposed to allopurinol, there were 2 spontaneous abortions, 2 elective terminations of pregnancy and 27 live births (see Fig. 2).\n\nOne spontaneous abortion (pregnancy #12) occurred in a patient after renal transplantation receiving several co-medications including mycophenolate, ciclosporine and various antihypertensives. Another spontaneous abortion occurred at week 20 in a patient with hypertension (pregnancy #6) treated with valsartan and hydrochlorothiazide. Chorioamnionitis was diagnosed. No malformations were found in the fetus. Two pregnancies were terminated, both for personal reasons (pregnancy #9 and #28, see Fig. 2).\n\nCumulative incidences were 11% (95%-CI 3–40) for spontaneous abortions and 9% (95%-CI 2–32) for ETOPs (Fig. 3).\n\n10.1371/journal.pone.0066637.g003Figure 3 Estimation of cumulative incidences using survival analysis technique.\nProbability of spontaneous abortion was 11% (95%-confidence interval (CI) 3–40), ETOP 9% (95%-CI 2–32), and live birth 80% (95%-CI 60–85).\n\nThe cumulative incidence for live births was 80% (95%-CI 60–94) (Fig. 3). There were 16 males and 11 females born alive. Five children (19%) were born premature (gestational age at birth <37 weeks). Caesarean section was performed in nearly half of the live births (13/27). Birth weights were within normal range after correction for sex and gestational age (see Table 2 and Fig. 4). Pre-eclampsia had been diagnosed in five pregnancies all exposed during 1st trimester until latest week 14 and a HELLP-syndrome in one exposed throughout pregnancy (#30).\n\n10.1371/journal.pone.0066637.g004Figure 4 Birth weight percentiles.\nBars in colors give the proportions of newborns by percentiles. Grey bars represent the proportion of newborn in the German Perinatal Project general population [10] in each percentile category.\n\n10.1371/journal.pone.0066637.t002Table 2 Child characteristics.\n\nGestational week at birth\n\t\n38.1 (37–40) (28–41.4)\tn = 27/27\t\n\nPreterm birth\n\t\n5 (19%)\tn = 27/27\t\n\nWeight (g)\t\n3340 (2850–3628) (990–4690)\tn = 27/27\t\n\nLength (cm)\t\n50 (48–52) (36–55)\tn = 26/27\t\n\nHead circumference (cm)\t\n35 (33.5–36) (26–38)\tn = 21/27\t\nFor gestational week at birth, weight, length and head circumference, median, interquartile range, and min/max are presented.\n\nThere were 6 infants (5 boys and 1 girl) with congenital anomalies (Table 3). Minor malformations were diagnosed in four (#7, #19, #27, #30). In patient #23 congenital hypoparathyroidism was diagnosed after birth, an autosomal-dominant condition already known in the mother.\n\n10.1371/journal.pone.0066637.t003Table 3 Summary of congenital anomalies after first trimester exposure with allopurinol.\nNr.\tGestational age at call (weeks)\tAllopurinol exposure (weeks after LMP) and dose (mg/d)\tTreatment indication\tComedication\tGestational age at birth\tCongenital anomalies\tClassification of anomalies\t\n\n#7\n\t5+2\t0–5+2 (100)\tHyperuricemia\tRamipril, metoprolol, alpha-methyldopa, hydrochlorothiazide, amlodipine, simvastatin, metformin, venlafaxin, tilidine, naloxone, paracetamol, acetylsalicylic acid, insulin, insulin lispro\t37+2\tPatent foramen ovale, pulmonary artery stenosis (hemodynamically not relevant)\tMinor\t\n\n#19\n\t11+3\t0–8+2 (100)\tGlomerulonephritis\tAmlodipine, valsartan, metoprolol, hydrochlorothiazide, alpha-methyldopa, desloratadin,\t29+2\tSmall patent ductus arteriosus, mild ptosis right eye, umbilical hernia\tMinor\t\n\n#23\n\t9+3\t0–9+3 (50)\tHyperuricemia\tCalcitriol\t36+6\tCongenital hypoparathyroidism (autosomal-dominant)\tGenetic\t\n\n#27\n\t15\t0–14 (300)\tGout\tFurosemide, pravastatin, cerivastatin\t38\tHemangioma\tMinor\t\n\n#30\n\t12+4\t0–28 (100)\tHemolytic uremic syndrome\tAlpha-methyldopa, metoprolol, moxonidine, furosemide clonidine, darbepoetin alfa, danaparoid, enoxaparine, corticosteroids, colecalciferol, alfacalcidol,\t28\tPersistent ductus arteriosus, patent foramen ovale, umbilical hernia\tMinor\t\n\n#31\n\t5\t0–37+3 (100)\tHyperoxaluria type I\tHydrochlorothiazide, sodiumcarbonate, pyridoxine\t37+3\tMultiple malformations (see also Table 4)\tMajor\t\nOne child (#31) with allopurinol exposure throughout pregnancy had multiple malformations (further details are given in Tables 3 and 4). The mother had hyperoxaluria type 1, a rare metabolic disease, and was concomitantly treated with hydrochlorothiazide (12,5 mg/d), pyridoxine (100 mg/d) and sodium carbonate.\n\n10.1371/journal.pone.0066637.t004Table 4 Clinical features of the patient described by Kozenko et al. [6] and our patient # 31.\n\tPatient from Kozenko et al.\tPatient #31 from our case series\t\nGestational age of birth\t41 weeks\t37+3 weeks\t\nAllopurinol exposure throughout pregnancy\t300 mg/d\t100 mg/d\t\nOrofacial anomalies\tCleft lip and palate (right), unilateral microtia, EACA1, Micrognathia\tCleft lip and palate (left), low-set ears, conductive deafness, retrognathia\t\nOphthalmological anomalies\tMicrophthalmia, optic nerve hypoplasia, coloboma upper eyelid\tMicrophthalmia\t\nGastrointestinal anomalies\tDiaphragmatic hernia Pulmonary agenesis (left)\tHepatosplenomegaly/cholestasis\t\nUrogenital anomalies\tUnilateral renal agenesis, bilateral cryptorchidism\tRenal hypoplasia, bilateral cryptorchidism, micropenis\t\nCNS\tHydrocephaly, hypoplasia of corpus callosum\tEnlargement of ventricles\t\nFurther anomalies\t\tOsteopenia\t\nCardiovascular defects\t-\t-\t\nKaryotype\t46,XY\t46,XY\t\n1 External auditory canal atresia.\n\nThe rate of major malformations in our cohort was 3.7% (1/27).\n\nDiscussion\nGout, hyperuricemia and other treatment indications for allopurinol are rare in women of reproductive age. Gout usually improves in pregnancy and attacks recommence after birth, due to the decreased estrogen levels [12]. During 2nd and 3rd trimester allopurinol has been described for tumor lysis syndrome [13]. Gülmezoğlu et al. [14] reported its safe use in a trial including 27 women in the 3rd trimester to evaluate the antioxidant potency of allopurinol for the prevention of pre-eclampsia.\n\nTo our knowledge, first trimester exposure of allopurinol has only been reported in a few case reports including 4 normal outcomes [15], [16] and a recent report [6] on a child with multiple malformations including microphthalmia, cleft lip and palate, microtia and diaphragmatic hernia after maternal allopurinol exposure throughout pregnancy (summary of features in Table 4). The authors proposed a possible teratogenic effect and noted the similarities to the mycophenolate embryopathy based on similar pathways, i.e. the interruption of purine biosynthesis. Data from animal studies indicate teratogenic effects (facial clefts and minor skeletal defects) of allopurinol at high doses in mice [17], but not in rats and other rodents [18].\n\nWe present the first prospective case series covering 31 pregnancies with 1st trimester allopurinol exposure.\n\nThe rate of spontaneous abortions in our case series was in the expected range of 13–21% [19] as was the rate of major malformations (3.7%) based on one infant with multiple malformations. The infant's phenotype resembles the case report of Kozenko et al. [6]. In our infant a Fraser syndrome had been suspected initially but was not confirmed. The karyotype was normal, but further genetic analysis like array-CGH was declined by the parents. Therefore, we cannot exclude a genetic origin of this rare malformation syndrome.\n\nThe mother of our patient had hyperoxaluria, a severe renal disease. In addition to allopurinol, she was treated with hydrochlorothiazide and pyridoxine, both drugs not considered as teratogens based on animal studies and human data [20]. Pyridoxine is widely used for the treatment of hyperemesis in early pregnancy [21].\n\nThe mother of the patient reported by Kozenko et al. [6] received multivitamins and methyldopa, the latter being the first line therapy for hypertension in pregnancy and not suspected as a teratogen. Thus, our patient and the patient reported by Kozenko were not exposed to any teratogenic co-medication in pregnancy that might explain the observed malformations. Furthermore, both co-medications are not directly involved in purine metabolism.\n\nOur case series represents women with either multiple risk factors or severe illness, known to be associated with an increased risk of poor pregnancy outcomes. The high rate of nearly 20% prematurity in our case series may be explained by maternal co-morbidity. To our surprise we did not observe lower birth weights after adjustment for sex and gestational age, which might have been expected in cases of hypertension or autoimmune diseases in pregnancy. The high number of obese women might have compensated this effect, as new-borns of obese mothers tend to be heavier than new-borns of normal weight women [22].\n\nObesity and hypertension were present in the majority of our women. These conditions are risk factors for hyperuricemia or gout in premenopausal women [23]. So far, no substantial malformation risk has been ascribed to the underlying maternal diseases in our cohort such as hypertension, systemic lupus erythematosus or other autoimmune diseases [24]\n[25]. In contrast to other metabolic diseases, such as phenylketonuria, hyperoxaluria has not been suspected to cause teratogenic effects. There are several reports on normal pregnancy outcomes in women with hyperoxaluria [26]. However, a high BMI is associated with an increased malformation risk [27], [28].\n\nAlthough being the largest case series so far, our study is still limited by the small sample size. With only 2 women exposed in the 2nd and 3rd trimester, we are not able to examine any effect on pregnancy outcome of allopurinol exposure after the first trimester. The surprisingly high rate of 6/31 patients with pre-eclampsia or HELLP syndrome in our cohort may be explained by the underlying conditions of the women, A protective effect of allopurinol on pre-eclampsia as postulated by Gülmezoğlu et al. [14] cannot be confirmed by our data.\n\nThe important strength and advantage of our study is the prospective character of data ascertainment, allowing relative risk calculations for adverse pregnancy outcomces.\n\nThe similarity of rare malformations in the infants reported by Kozenko [6] and our study (case #31) requires further exploration by case-control studies to confirm or reject the hypothesis of allopurinol teratogenicity [29]\n[30].\n\nConclusion\nAllopurinol has been used for over 40 years without being suspected for teratogenicity in humans. This is corroborated by the overall malformation rate in our case series lying in the expected range. However, the presence of two infants with a similar rare combination of malformations including microphthalmia, cleft lip and palate, and microtia after first trimester exposure to allopurinol is striking and might be considered as a signal for teratogenicity [29]. Thus, we would recommend caution with allopurinol in the first trimester, unless further data are available. In case of inadvertent exposure during 1st trimester high resolution ultrasound is recommended to confirm normal fetal development.\n\nWe would like to thank all contributing physicians, their patients and families as well as our colleagues in the Berlin TIS.\n==== Refs\nReferences\n1 \nStruthers A , Shearer F (2012 ) Allopurinol: novel indications in cardiovascular disease . Heart \n98 : 1543 –1545 \nheartjnl-2012-302249 [pii];10.1136/heartjnl-2012-302249 [doi] \n22801998 \n2 \nMiller SL , Wallace EM , Walker DW (2012 ) Antioxidant therapies: a potential role in perinatal medicine . Neuroendocrinology \n96 : 13 –23 \n000336378 [pii];10.1159/000336378 [doi] \n22377769 \n3 Hoentjen F, Seinen ML, Hanauer SB, de Boer NK, Rubin DT, et al.. (2012) Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in inflammatory bowel disease. Inflamm Bowel Dis. 10.1002/ibd.23021 [doi].\n4 \nSeinen ML , de Boer NK , Smid K , van Asseldonk DP , Bouma G , et al (2011 ) Allopurinol enhances the activity of hypoxanthine-guanine phosphoribosyltransferase in inflammatory bowel disease patients during low-dose thiopurine therapy: preliminary data of an ongoing series . Nucleosides Nucleotides Nucleic Acids \n30 : 1085 –1090 \n10.1080/15257770.2011.597371 [doi] \n22132961 \n5 Seinen ML, de Boer NK, van Hoorn ME, van Bodegraven AA, Bouma G (2012) Safe use of allopurinol and low-dose mercaptopurine therapy during pregnancy in an ulcerative colitis patient. Inflamm Bowel Dis. 10.1002/ibd.22945 [doi].\n6 \nKozenko M , Grynspan D , Oluyomi-Obi T , Sitar D , Elliott AM , et al (2011 ) Potential teratogenic effects of allopurinol: a case report . Am J Med Genet A \n155A : 2247 –2252 \n10.1002/ajmg.a.34139 [doi] \n21815259 \n7 \nSchaefer C , Ornoy A , Clementi M , Meister R , Weber-Schoendorfer C (2008 ) Using observational cohort data for studying drug effects on pregnancy outcome–methodological considerations . Reprod Toxicol \n26 : 36 –41 .18588969 \n8 \nMerks JH , van Karnebeek CD , Caron HN , Hennekam RC (2003 ) Phenotypic abnormalities: terminology and classification . Am J Med Genet A \n123A : 211 –230 .14608641 \n9 \nRasmussen SA , Olney RS , Holmes LB , Lin AE , Keppler-Noreuil KM , et al (2003 ) Guidelines for case classification for the National Birth Defects Prevention Study . Birth Defects Res A Clin Mol Teratol \n67 : 193 –201 .12797461 \n10 \nVoigt M , Rochow N , Hesse V , Olbertz D , Schneider KT , et al (2010 ) Kurzmitteilung zu den Perzentilenwerten für die Körpermaße der Neugeborenen . Z Geburtshilfe Neonatol \n214 : 24 –29 .20148386 \n11 \nMeister R , Schaefer C (2008 ) Statistical methods for estimating the probability of spontaneous abortion in observational studies–analyzing pregnancies exposed to coumarin derivatives . Reprod Toxicol \n26 : 31 –35 .18620043 \n12 Coddington CC, Albrecht RC, Cefalo RC (1979) Gouty nephropathy and pregnancy. Am J Obstet Gynecol 133: 107–108. 0002-9378(79)90420-4 [pii].\n13 \nBrown ML , Strauss B , Glasser SR (2001 ) Chemotherapy in treatment of non-hodgkin's lymphoma in pregnancy (Abstract) . Obstet Gynecol \n97 : S39 .\n14 \nGulmezoglu AM , Hofmeyr GJ , Oosthuisen MM (1997 ) Antioxidants in the treatment of severe pre-eclampsia: an explanatory randomised controlled trial . Br J Obstet Gynaecol \n104 : 689 –696 .9197872 \n15 \nFarber M , Knuppel RA , Binkiewicz A , Kennison RD (1976 ) Pregnancy and von Gierke's disease . Obstet Gynecol \n47 : 226 –228 .1061911 \n16 \nAli R , Ozkalemkas F , Kimya Y , Koksal N , Ozkocaman V , et al (2009 ) Pregnancy in chronic lymphocytic leukemia: experience with fetal exposure to chlorambucil . Leuk Res \n33 : 567 –569 \nS0145-2126(08)00273-7 [pii];10.1016/j.leukres.2008.05.019 [doi] \n18603296 \n17 \nFujii T , Nishimura H (1972 ) Comparison of teratogenic action of substances related to purine metabolism in mouse embryos . Jpn J Pharmacol \n22 : 201 –206 .4538410 \n18 \nBragonier JR , Roesky N , Carver MJ (1964 ) Teratogenesis: Effects of substituted purines and the influence of the 4 hydroxypyrazolonpyrimidine in the rat . Proc Soc Exp Biol Med \n116 : 685 –688 .14194634 \n19 \nHoeltzenbein M , Elefant E , Vial T , Finkel-Pekarsky V , Stephens S , et al (2012 ) Teratogenicity of mycophenolate confirmed in a prospective study of the European Network of Teratology Information Services . Am J Med Genet A \n158A : 588 –596 \n10.1002/ajmg.a.35223 [doi] \n22319001 \n20 Briggs GG, Freeman RK, and Yaffe SJ (2011) Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Lippincott Williams&Wilkins.\n21 \nAnderka M , Mitchell AA , Louik C , Werler MM , Hernandez-Diaz S , et al (2012 ) Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects . Birth Defects Res A Clin Mol Teratol \n94 : 22 –30 \n10.1002/bdra.22865 [doi] \n22102545 \n22 \nStuebe AM , Landon MB , Lai Y , Spong CY , Carpenter MW , et al (2012 ) Maternal BMI, glucose tolerance, and adverse pregnancy outcomes . Am J Obstet Gynecol \n207 : 62 –67 \nS0002-9378(12)00482-6 [pii];10.1016/j.ajog.2012.04.035 [doi] \n22609018 \n23 \nBhole V , de VM , Rahman MM , Krishnan E , Choi H (2010 ) Epidemiology of gout in women: Fifty-two-year followup of a prospective cohort . Arthritis Rheum \n62 : 1069 –1076 \n10.1002/art.27338 [doi] \n20131266 \n24 \nTendron A , Gouyon JB , Decramer S (2002 ) In utero exposure to immunosuppressive drugs: experimental and clinical studies . Pediatr Nephrol \n17 : 121 –130 .11875675 \n25 \nSmyth A , Oliveira GH , Lahr BD , Bailey KR , Norby SM , et al (2010 ) A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis . Clin J Am Soc Nephrol \n5 : 2060 –2068 .20688887 \n26 Norby SM, Milliner DS (2004) Outcomes and complications of pregnancy in women with primary hyperoxaluria. Am J Kidney Dis 43 : : 277–285. S0272638603014896 [pii].\n27 \nWaller DK , Shaw GM , Rasmussen SA , Hobbs CA , Canfield MA , et al (2007 ) Prepregnancy obesity as a risk factor for structural birth defects . Arch Pediatr Adolesc Med \n161 : 745 –750 \n161/8/745 [pii];10.1001/archpedi.161.8.745 [doi] \n17679655 \n28 \nCarmichael SL , Rasmussen SA , Shaw GM (2010 ) Prepregnancy obesity: a complex risk factor for selected birth defects . Birth Defects Res A Clin Mol Teratol \n88 : 804 –810 \n10.1002/bdra.20679 [doi] \n20973050 \n29 \nCarey JC , Martinez L , Balken E , Leen-Mitchell M , Robertson J (2009 ) Determination of human teratogenicity by the astute clinician method: review of illustrative agents and a proposal of guidelines . Birth Defects Res A Clin Mol Teratol \n85 : 63 –68 \n10.1002/bdra.20533 [doi] \n19107954 \n30 \nJones KL , Carey JC (2011 ) The importance of dysmorphology in the identification of new human teratogens . Am J Med Genet C Semin Med Genet \n157 : 188 –194 \n10.1002/ajmg.c.30311 [doi]\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "8(6)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000032:Abortion, Therapeutic; D000493:Allopurinol; D005260:Female; D006073:Gout; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011446:Prospective Studies; D013723:Teratogens; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e66637",
"pmc": null,
"pmid": "23840514",
"pubdate": "2013",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20148386;19107954;14750093;22801998;4538410;760527;1061911;9197872;20973050;21766438;18620043;22102545;14608641;11875675;18603296;20131266;22132961;14194634;22605661;20688887;12797461;22377769;21815259;22319001;18588969;17679655;22609018;22407929",
"title": "Allopurinol Use during Pregnancy - Outcome of 31 Prospectively Ascertained Cases and a Phenotype Possibly Indicative for Teratogenicity.",
"title_normalized": "allopurinol use during pregnancy outcome of 31 prospectively ascertained cases and a phenotype possibly indicative for teratogenicity"
} | [
{
"companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-97919",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
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"actiondrug": "1",
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"activesubstancename": "ALLOPURINOL"
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"abstract": "The aim of this study was to evaluate tumor control of OSSN with topical IFNα2b alone based on tumor configuration (flat versus (vs.) dome-shaped).\n\n\n\nRetrospective, nonrandomized, interventional cohort study on 64 consecutive tumors in 63 patients with OSSN treated with topical IFNα2b. Topical IFNα2b (1 million international units/cc) was compounded and provided by the Thomas Jefferson University Hospital Pharmacy to be refrigerated and applied 4 times daily until biomicroscopic evidence of tumor resolution was observed.\n\n\n\nThe tumor configuration was flat (n = 15, 23%) or dome-shaped (n = 49, 77%). A comparison (flat vs. dome-shaped) revealed dome-shaped with older mean patient age at presentation (62 vs. 70 years, P = 0.04), greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (7% vs. 82%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean thickness (1.9 vs. 4.3, P = 0.002), and longer mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002). There was no difference in mean follow-up time (22.2 vs 23.1 months) or time to complete response (5.0 vs. 6.1 months). There was no difference in achievement of complete tumor control with IFNα2b alone (93% vs. 96%). There were no cases with metastasis or death.\n\n\n\nTopical IFNα2b alone shows excellent overall tumor control of 95% with no difference in efficacy based on tumor configuration.",
"affiliations": "Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA.;Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA.;Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA.;Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA.;Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA.;Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA.;Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA.",
"authors": "Shields|Carol L|CL|;Constantinescu|Alexandru B|AB|;Paulose|Sefy A|SA|;Yaghy|Antonio|A|;Dalvin|Lauren A|LA|;Shields|Jerry A|JA|;Lally|Sara E|SE|",
"chemical_list": "D000970:Antineoplastic Agents; D016898:Interferon-alpha; D009883:Ophthalmic Solutions",
"country": "India",
"delete": false,
"doi": "10.4103/ijo.IJO_1665_20",
"fulltext": "\n==== Front\nIndian J Ophthalmol\nIndian J Ophthalmol\nIJO\nIndian Journal of Ophthalmology\n0301-4738\n1998-3689\nWolters Kluwer - Medknow India\n\n33595473\nIJO-69-563\n10.4103/ijo.IJO_1665_20\nOriginal Article\nPrimary treatment of ocular surface squamous neoplasia with topical interferon alpha-2b: Comparative analysis of outcomes based on original tumor configuration\nShields Carol L\nConstantinescu Alexandru B\nPaulose Sefy A\nYaghy Antonio\nDalvin Lauren A\nShields Jerry A\nLally Sara E\nOcular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA\nCorrespondence to: Dr. Carol Shields, Ocular Oncology Service, Suite 1440, Wills Eye Hospital, 840 Walnut Street, Philadelphia, PA 19107, USA. E-mail: carolshields@gmail.com\n3 2021\n17 2 2021\n69 3 563567\n25 5 2020\n15 7 2020\n30 8 2020\nCopyright: © 2021 Indian Journal of Ophthalmology\n2021\nThis 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.\nPurpose:\n\nThe aim of this study was to evaluate tumor control of OSSN with topical IFNα2b alone based on tumor configuration (flat versus (vs.) dome-shaped).\n\nMethods:\n\nRetrospective, nonrandomized, interventional cohort study on 64 consecutive tumors in 63 patients with OSSN treated with topical IFNα2b. Topical IFNα2b (1 million international units/cc) was compounded and provided by the Thomas Jefferson University Hospital Pharmacy to be refrigerated and applied 4 times daily until biomicroscopic evidence of tumor resolution was observed.\n\nResults:\n\nThe tumor configuration was flat (n = 15, 23%) or dome-shaped (n = 49, 77%). A comparison (flat vs. dome-shaped) revealed dome-shaped with older mean patient age at presentation (62 vs. 70 years, P = 0.04), greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (7% vs. 82%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean thickness (1.9 vs. 4.3, P = 0.002), and longer mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002). There was no difference in mean follow-up time (22.2 vs 23.1 months) or time to complete response (5.0 vs. 6.1 months). There was no difference in achievement of complete tumor control with IFNα2b alone (93% vs. 96%). There were no cases with metastasis or death.\n\nConclusion:\n\nTopical IFNα2b alone shows excellent overall tumor control of 95% with no difference in efficacy based on tumor configuration.\n\nConfiguration\nconjunctiva\ndome-shaped\nflat\ninterferon alpha-2b\nocular surface squamous neoplasia\nsquamous cell carcinoma\ntreatment\n==== Body\nOcular surface squamous neoplasia (OSSN) is an umbrella term referring to the spectrum of squamous epithelial malignancy that can occur on the ocular surface, from in situ mild dysplasia to invasive epithelial malignant tumors. Based on the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study of 566,401 individuals aged 50-71 years, the incidence of OSSN was 8.4 per million persons, and found to be greater incidence in males (10.3 per million) and age >60 years (10.0 per million).[1] The management of this malignancy involves surgical and non-surgical alternatives, using topical or injection chemotherapy or immunotherapy. Several publications have explored the role of topical interferon alpha 2-B (IFNα2b) for tumor management.[123] A matched comparative analysis (IFNα2b (topical and injections) versus (vs.) surgery) for OSSN therapy revealed no difference in the recurrence rate (3% vs. 5%)[4] and non-significant equivalent cost for the full course of the two alternatives ($2831 vs $3528 US dollars (Medicare allowable charges)).[5] Thus, topical and injection IFNα2b for OSSN remains an important therapeutic alternative to surgery for affected patients.\n\nHerein, we specifically focus on the role of topical IFNα2b monotherapy in the management of OSSN. In this analysis, we explore tumor control with topical IFNα2b based on tumor configuration (flat versus (vs.) dome-shaped). Many clinicians using topical therapies apply the medications based on classic tumor features and without the need for tumor biopsy, to spare the patient surgical intervention. Thus, tumor grouping by the American Joint Committee on Cancer (AJCC) Classification is not possible, as histopathology evaluation of tumor depth (in situ vs. deeper) is not available. However, one might speculate that tumor configuration as flat could serve as a surrogate for Tis and configuration as dome-shaped could represent T1, T2, T3, or T4 based on tumor basal dimension and adjacent tissue involvement as proposed by the AJCC.[6] Herein, we explore outcomes of topical IFNα2b based on practical tumor configuration, whether the tumor is thin (flat) or thick (dome-shaped).\n\nMethods\n\nThe medical records of all patients with clinically-evident OSSN diagnosed and managed on the Ocular Oncology Service at Wills Eye Hospital, Philadelphia USA, between October 4, 2005, and January 28, 2019 were retrospectively reviewed. Patients were included if primary treatment for OSSN consisted only of topical IFNα2b monotherapy. Patients who received treatment prior to referral, or those who received subconjunctival injection of IFNα2b or were treated with prophylactic IFNα2b were excluded. The treatment protocol included use of IFNα2b (Intron-A, Schering-Plough, London UK) in a topical formulation of 1 million international units (IU)/mL compounded by Thomas Jefferson University Hospital Pharmacy, Philadelphia USA, and stored in refrigeration, avoiding disturbance or shaking of the bottle. The eye drops were administered 4 times daily until 1 month beyond clinical evidence of complete tumor resolution or until the time a secondary treatment was deemed necessary due to poor response. The response to treatment was monitored every 3 to 6 months and the duration of treatment was modified on the basis of tumor response. This study was approved by the Institutional Review Board of Wills Eye Hospital, Philadelphia USA and adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all patients.\n\nAll patients were examined by a trained ocular oncologist (CLS, SEL) with slit-lamp biomicroscopy, documentation on detailed, large conjunctival drawings, and with photographic documentation. The demographic data included age, race, sex, and Fitzpatrick skin type. Past medical history included risk factors of smoking status, autoimmune condition, chronic use (>6 months) of topical or systemic corticosteroids or other immunosuppressive medications, organ transplant, corneal graft, human papillomavirus (HPV) infection, human immunodeficiency virus infection, and cutaneous or mucous membrane squamous cell carcinoma. Clinical findings at presentation included best-corrected visual acuity), tumor laterality, tumor multiplicity, tissues involved (bulbar conjunctiva, forniceal conjunctiva, tarsal conjunctiva, plica semilunaris, caruncle, cornea, eyelid, and orbit), quadrant or location involved (superior, temporal, inferior, nasal, diffuse), largest tumor basal diameter, number of clock hours involved, tumor configuraton (flat, dome-shaped), lesion color, feeder and intrinsic vessels, leukoplakia, and internal pigment. The tumor configuration was considered flat if there was a flat surface of ≤1 mm thickness, whereas the tumors were considered dome-shaped if the mass gradually increased in thickness from the margin to a central apex and were >1 mm thickness centrally.\n\nThe number of months of topical IFNα2b therapy were recorded. At each follow-up examination, features were recorded regarding best-corrected visual acuity, tumor basal diameter, tissue involvement, and interferon-induced toxicity. Treatment outcomes included tumor control (complete, partial, or no response), recurrence, treatment for recurrence, metastasis, and death. Complete response was defined as complete tumor regression with total disappearance of tumor. Partial response was defined as tumor regression of less than 100%. No response was defined as no visible change following therapy. Recurrence was defined as reappearance of tumor at the primary tumor location after complete resolution following topical IFNα2b. Additional treatment required for tumor control after primary topical IFNα2b was noted. Spread to regional lymph nodes was assessed by history and palpation of preauricular, submental, submandibular, and cervical lymph nodes at each visit. Distant metastasis and death per the general medical physician were recorded.\n\nDemographics, clinical features, and outcomes were compared by tumor configuration (flat vs. dome-shaped) using Fisher's exact test, Chi-squared test, and Mann Whitney U test. A P value <0.05 was considered significant.\n\nResults\n\nOf the 236 consecutive patients with clinically evident OSSN evaluated and managed on the Ocular Oncology Service, Wills Eye Hospital, during this time period, there were 64 tumors in 63 eyes of 63 patients that met inclusion criteria for this study. Tumors were classified according to surface configuration (flat (thin) (n = 15, 23%) vs. dome-shaped (thick) (n = 49, 77%)).\n\nThe patient demographic features are listed in Table 1. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with older mean patient age (62 vs. 70 years, P = 0.04) and greater frequency of smoking (13% vs. 42%, P = 0.04). There was no difference regarding patient race, sex, or Fitzpatrick Skin Type, autoimmune disease, immunosuppression, medical history of squamous neoplasia elsewhere, and tumor laterality and multiplicity.\n\nTable 1 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases of 63 Patients. Demographic features\n\nDemographic Features\tFlat [Tis] (n=15 patients) [n (%)]\tDome-shaped [T3] (n=48 patients) [n (%)]\tP\tTotal (n=63 patients) [n (%)]\t\nAge (years)\t\t\t\t\t\n Mean (median, range)\t62 (61, 45-85)\t70 (68, 30-97)\t0.04\t68 (64, 30-97)\t\nRace\t\t\t\t\t\n Caucasian\t14 (93)\t45 (94)\t0.67\t59 (94)\t\n African American\t1 (7)\t1 (2)\t\t2 (3)\t\n Hispanic\t0 (0)\t1 (2)\t\t1 (2)\t\n Asian\t0 (0)\t1 (2)\t\t1 (2)\t\nSex\t\t\t\t\t\n Male\t8 (53)\t27 (56)\t0.84\t35 (56)\t\n Female\t7 (47)\t21 (44)\t\t28 (44)\t\nFitzpatrick Skin Type\t\t\t\t\t\n I\t4 (27)\t17 (35)\t0.73\t21 (33)\t\n II\t9 (60)\t23 (48)\t\t32 (51)\t\n III\t1 (7)\t5 (10)\t\t6 (10)\t\n IV\t0 (0)\t2 (4)\t\t2 (3)\t\n V\t0 (0)\t0 (0)\t\t0 (0)\t\n VI\t1 (7)\t1 (2)\t\t2 (3)\t\nSmoking History\t\t\t\t\t\n Yes\t2 (13)\t20 (42)\t0.04\t22 (34)\t\n No\t13 (87)\t28 (58)\t\t42 (66)\t\nMedical History - Autoimmune\t\t\t\t\t\n Celiac\t0 (0)\t1 (2)\t0.77\t1 (2)\t\n Ocular cicatricial pemphigoid\t0 (0)\t1 (2)\t0.77\t1 (2)\t\n Psoriatic arthritis\t1 (7)\t0 (0)\t0.23\t1 (2)\t\n Rheumatoid arthritis*\t0 (0)\t1 (2)\t0.77\t1 (2)\t\n Sjögren’s syndrome*\t0 (0)\t1 (2)\t0.77\t1 (2)\t\n Thyroiditis\t0 (0)\t1 (2)\t0.77\t1 (2)\t\nMedical History - Immunosuppression\t\t\t\t\t\n Chronic systemic corticosteroids\t1 (7)\t2 (4)\t0.56\t3 (5)\t\n Chronic systemic immunosuppressants\t1 (7)\t2 (4)\t0.56\t3 (5)\t\n Chronic topical corticosteroids\t0 (0)\t1 (2)\t0.99\t1 (2)\t\n Organ transplant\t0 (0)\t1 (2)\t0.99\t1 (2)\t\n Corneal graft\t0 (0)\t2 (4)\t0.99\t2 (3)\t\n HPV history\t1 (7)\t1 (2)\t0.42\t2 (3)\t\nMedical History - SCC History\t\t\t\t\t\n Skin SCC\t2 (13)\t6 (13)\t0.93\t8 (13)\t\n Mucosal SCC**\t0 (0)\t2 (4)\t0.99\t2 (3)\t\nLaterality\t\t\t\t\t\n Right\t4 (27)\t25 (52)\t0.40\t29 (46)\t\n Left\t11 (73)\t23 (48)\t\t34 (54)\t\nMultiplicity of tumors\t\t\t\t\t\n Single\t15 (100)\t47 (98)\t0.99\t62 (98)\t\n Multiple\t0 (0)\t1 (2)\t\t1 (2)\t\nHPV=Human papilloma virus, SCC=squamous cell carcinoma. Bold values indicate significant P. * There was one patient diagnosed with both rheumatoid arthritis and Sjögren’s syndrome. **There was one case of oropharyngeal SCC and one case of rectal SCC\n\nThe tumor features are listed in Table 2. At presentation, there was no evidence of lymph node or distant metastatic disease. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with greater corneal involvement (7%% vs. 82%, P < 0.001), greater mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and greater mean clock hour involvement (1.9 vs. 4.1, P = 0.002). There was no difference in tumor quadrant, growth pattern, color, vascularity, or additional features.\n\nTable 2 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Tumor characteristics\n\nTumor Characteristics\tFlat [Tis] (n=15 tumors) [n (%)]\tDome-shaped [T3] (n=49 tumors) [n (%)]\tP\tTotal (n=64 tumors) [n (%)]\t\nTissue involved\t\t\t\t\t\n Bulbar\t13 (87)\t41 (84)\t0.78\t54 (84)\t\n Fornix\t0 (0)\t9 (18)\t0.07\t9 (14)\t\n Tarsus\t2 (13)\t6 (12)\t0.91\t8 (13)\t\n Plica semilunaris\t0 (0)\t1 (2)\t0.99\t1 (2)\t\n Caruncle\t0 (0)\t2 (4)\t0.99\t2 (3)\t\n Cornea\t1 (7%)\t40 (82)\t<0.001\t41 (64)\t\n Eyelid\t0 (0)\t2 (4)\t0.99\t2 (3)\t\n Orbit\t0 (0)\t0 (0)\tNA\t0 (0)\t\nQuadrant involved\t\t\t\t\t\n Superior\t1 (7)\t4 (8)\t0.97\t5 (8)\t\n Temporal\t3 (20)\t10 (20)\t\t13 (20)\t\n Inferior\t2 (13)\t9 (18)\t\t11 (17)\t\n Nasal\t9 (60)\t25 (51)\t\t34 (53)\t\n Diffuse\t0 (0)\t1 (2)\t\t1 (2)\t\n Tumor Size\t\t\t\t\t\nLargest basal diameter (mm) Mean (median, range)\t5.5 (5.0, 1.0-12.0)\t12.4 (10.0, 1.5-60.0)\t0.001\t10.8 (8.2, 1.0-60.0)\t\nNumber of clock hours involved Mean (median, range)\t1.9 (2.0, 1.0-5.0)\t4.1 (3.0, 1.0-12.0)\t0.002\t3.6 (3.0, 1.0-12.0)\t\nTumor Color\t\t\t\t\t\n Pink\t2 (13)\t6 (12)\t0.99\t8 (12)\t\n Yellow\t10 (67)\t34 (69)\t\t44 (69)\t\n White\t3 (20)\t9 (18)\t\t12 (19)\t\nTumor Vascularity\t\t\t\t\t\n Intrinsic vessels\t8 (53)\t28 (57)\t0.80\t36 (56)\t\n Feeder vessels\t6 (40)\t18 (37)\t0.82\t24 (37)\t\nAdditional features\t\t\t\t\t\n Leukoplakia\t5 (33)\t8 (16)\t0.15\t13 (20)\t\n Internal cysts\t1 (7)\t0 (0)\t0.23\t1 (2)\t\n Internal pigment\t0 (0)\t0 (0)\tNA\t0 (0)\t\nBold values indicate significant P\n\nTopical IFNα2b at a dose of 1 million IU/mL administered 4 times daily was used as primary monotherapy for all patients. The tumor response is listed in Table 3. There was no difference in percentage of patients lost to follow-up (7% vs. 2%, P = 0.42) or mean follow-up time (22.2 vs. 23.1 months, P = 0.87). A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with longer mean duration of IFNα2b monotherapy for tumor control (3.7 vs. 6.3 months, P = 0.002). There was no difference in complete tumor response (93% vs. 96%, (P = 0.65), partial response (7% vs. 2%), or no response (0% vs. 2%) (P = 0.54) [Fig. 1]. The single patient with no response had prior corneal graft and received topical IFNα2b with no improvement, and later required subconjunctival IFNα2b injection. There was no difference regarding mean time to complete response (5.0 vs. 6.1 months, P = 0.25). Following initial response, there was no difference in tumor recurrence (7% vs. 2%, P = 0.41). Regarding local treatment side effects, flat tumors had more frequent follicular reaction (20% vs. 2%, P = 0.04). There was no difference in ocular surface irritation or corneal epithelial defect. There were no patients who developed metastatic disease or death.\n\nTable 3 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Outcomes\n\nOutcomes\tFlat [Tis] (n=15 tumors) [n (%)]\tDome-shaped [T3] (n=49 tumors) [n (%)]\tP\tTotal (n=64 tumors) [n (%)]\t\nNo follow-up\t1 (7)\t1 (2)\t0.42\t2 (3)\t\nTumor response\tn=14\tn=48\t\tn=62\t\n Complete\t13 (93)\t46 (96)\t0.54\t59 (95)\t\n Partial\t1 (7)*\t1 (2)**\t\t2 (3)\t\n No response\t0 (0)\t1 (2)***\t\t1 (2)\t\n\tn=14\tn=47\t\tn=61\t\nRecurrence after initial response\t1 (7)\t1 (2)\t0.41\t2 (3)\t\nAdditional treatment needed for complete response\t1 (7)\t6 (13)\t0.68\t7 (11)\t\nTopical mitomycin C\t0 (0)\t1 (2)\t0.99\t1 (2)\t\nSurgical excision\t1 (7)\t5 (9)\t0.99\t6 (10)\t\nLocal treatment side effects\t\t\t\t\t\n Follicular reaction\t3 (20)\t1 (2)\t0.04\t4 (6)\t\n Irritation\t0 (0)\t1 (2)\t0.99\t1 (2)\t\n Corneal epithelial defect\t0 (0)\t1 (2)\t0.99\t2 (3)\t\nSystemic outcomes\t\t\t\t\t\n Metastasis\t0 (0)\t0 (0)\tNA\t0 (0)\t\n Death\t0 (0)\t0 (0)\tNA\t0 (0)\t\nTotal duration of interferon alpha-2b therapy (months)\t\t\t\t\t\n Mean (median, range)\t3.7 (3.0, 0.5-7.0)\t6.3 (6.0, 1.0-13.0)\t0.002\t5.7 (5.0, 0.5-13.0)\t\nTime to complete response (months)\t\t\t\t\t\n Mean (median, range)\t5.0 (3.8, 1.0-11.5)\t6.1 (5.4, 1.3-17.8)\t0.25\t5.8 (5.0, 1.0-17.8)\t\nFollow-up time (months)\tn=14\tn=48\t\tn=62\t\n Mean (median, range)\t22.2 (14.3, 2.9-63.1)\t23.1 (13.9, 1.3-114.6)\t0.87\t23.0 (14.4, 1.3-114.6)\t\nBold values indicate significant P. * Patient lost to follow-up after 7 months of therapy due to liver transplant. ** Patient stopped interferon alpha-2b after 1 month due to ocular surface discomfort and was lost to follow-up. *** Patient elected not to continue treatment after secondary treatment was advised\n\nFigure 1 Treatment of ocular surface squamous neoplasia (OSSN) using topical interferon alpha-2b (IFNa2b) monotherapy. Flat vascular OSSN in a 76-year-old female (a) before and (b) after 4 months of IFNa2b monotherapy. Dome-shaped OSSN in a 57-year-old female (c) before and (d) after 8 months of IFNa2b monotherapy\n\nDiscussion\n\nA recent report of 5002 conjunctival tumors from an ocular oncology center revealed that premalignant/malignant squamous neoplasia (OSSN) represented 729 (15%) of all cases, mostly with diagnoses of conjunctival intraepithelial neoplasia (CIN) (n = 275 tumors) or squamous cell carcinoma (SCC) (n = 440 tumors).[7] In that analysis, CIN or SCC was most often noted at the corneoscleral limbus (575/715, 80%), located nasally (269/715, 38%) or temporally (285/715, 40%), and appearing as a lump/swelling to the patient (434/715, 61%).\n\nIn 2012, Shah et al. reported the results of topical v for OSSN in 23 cases based on the 7th edition AJCC classification and noted that complete control was achieved in 83% of cases, specifically 67% of those labeled as Tis and 85% of the T3 group.[8] In that analysis there were no patients with T1, T2, or T4, as found in our current study. Further investigation of topical or injection IFNα2b for OSSN revealed applications for immunoreduction of giant OSSN, and immunoprevention in immunosuppressed patients, especially those with human immunodeficiency virus (HIV) or organ transplant who are at risk to have numerous and multifocal OSSN.[910] Galor et al. compared the topical dose of 1 million IU/ml to 3 million IU/mL IFNα2b and found no difference in tumor response, treatment duration, recurrence, or adverse effects.[11]\n\nSince the above publications, the AJCC has been updated to the 8th edition. However, classification requires tumor biopsy and histopathologic analysis, but in this current era of topical therapies, clinicians often avoid biopsy when starting topical therapies if the diagnosis is clinical evident. Thus, AJCC classification is not possible for clinicians using purely topical therapies. In this report, we accommodate AJCC 8th edition classification by inferring that flat tumor configuration with no corneal component might serve as a surrogate for Tis and dome-shaped as T1, T2, T3, or T4.\n\nIn this analysis, we were able to provide a comparative analysis of tumor control with topical IFNα2b monotherapy without the need for biopsy. We found important differences in clinical features in that dome-shaped tumors occurred in older mean patient age (62 vs. 70 years, P = 0.04), with greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (0% vs. 84%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean clock hour extent (1.9 vs. 4.3, P = 0.002). To achieve control with topical IFNα2b, dome-shaped tumors tumors required greater mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002) for equivalent complete tumor control (93% vs. 96%, P = 0.65).\n\nThere are limitations to this study that should be considered. The data was a retrospective collection with inherent biases and drawbacks. Additionally, the cohort size was relatively small at 64 cases, resulting in limited statistical power, but due to the rarity of this malignancy and strict inclusion criteria of primary treatment with topical IFNα2b monotherapy only, our data represents pure data with few conflicting events. We recognize that precise AJCC classification could not be performed without histopathologic anaylsis, and microscopic invasion of the basement membrane in the case of flat tumor could have been missed. Nevertheless, with excellent tumor control for both flat and dome-shaped tumor, biopsy would not likely have changed our main study conclusion. Perhaps further studies could evaluate outcomes based on clinical imaging such as anterior segment optical coherence tomography or ultrasound biomicroscopy. Lastly, further follow-up with larger cohort in the future could potentially verify our observations.\n\nMost previous studies on this topic have included pretreatment biopsy for diagnostic and staging confirmation, but that interferes with the ability to promptly employ some topical therapies and adds a confounding factor of the amount of tumor surgically excised versus the remnant of tumor left for treatment with topical therapy. Hence, we chose to avoid biopsy as this is consistent with how most clinicians currently approach clinically-evident OSSN, especially when starting topical therapy. Thus our results reflect the impact of topical IFNα2b monotherapy for the entire OSSN without the need for biopsy.\n\nConclusion\n\nIn conclusion, based on tumor configuration of OSSN, overall tumor control is 95% and does not differ when comparing flat to dome-shaped tumors. In addition, dome-shaped tumors required longer duration of therapy and demonstrated no greater recurrence upon discontinuation of the medication. We conclude that topical IFNα2b monotherapy is highly effective for the treatment of conjunctival OSSN, whether or not the tumor is flat or dome-shaped.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\n1 Emmanuel B Ruder E Lin SW Abnet C Hollenbeck A Mbulaiteye S Incidence of squamous-cell carcinoma of the conjunctiva and other eye cancers in the NIH-AARP Diet and Health Study Ecancermedicalscience 2012 6 254 22654961\n2 Sayed-Ahmed IO Palioura S Galor A Karp CL Diagnosis and medical management of ocular surface squamous neoplasia Expert Rev Ophthalmol 2017 12 11 9 28184236\n3 Cincinelli MV Marchese A Bandello F Modorati G Clinical management of ocular surface squamous neoplasia: A review of the current evidence Ophthalmol Ther 2018 7 247 62 30030703\n4 Nanji AA Moon CS Galor A Sein J Oellers P Karp CL Surgical versus medical treatment of ocular surface squamous neoplasia: A comparison of recurrences and complications Ophthalmology 2014 121 994 1000 24411578\n5 Moon CS Nanji AA Galor A McCollister KE Karp CL Surgical versus medical treatment of ocular surface squamous neoplasia: A cost comparison Ophthalmology 2016 123 497 504 26686965\n6 Conway RM Graue GF Pelayes Amin MB Edge SB Greene FL Conjunctival carcinoma AJCC Cancer Staging Manual 2017 (8th edition) Springer International Publishing 787 93\n7 Shields CL Alset AE Boal NS Casey MG Knapp AN Sugarman JA Conjunctival tumors in 5002 cases. Comparative analysis of benign versus malignant counterparts. The 2016 James D. Allen lecture Am J Ophthalmol 2016 173 106 33 27725148\n8 Shah SU Kaliki S Kim HJ Lally SE Shields JA Shields CL Topical interferon alfa-2b for management of ocular surface squamous neoplasia in 23 cases: Outcomes based on the American Joint Committee on Cancer classification Arch Ophthalmol 2102 130 159 64\n9 Shields CL Kaliki S Kim HJ Al-Dahmash S Shah SU Lally SE Interferon for ocular surface squamous neoplasia in 81 cases: Outcomes based on the American Joint Committee on Cancer classification Cornea 2013 32 248 56 22580436\n10 Kim HJ Shields CL Shah SU Kaliki S Lally SE Shields JA Giant ocular surface squamous neoplasia managed with interferon alpha-2b as immunotherapy or immunoreduction Ophthalmology 2012 119 938 44 22361315\n11 Galor A Karp CL Chhabra S Barnes S Alfonso EC Topical interferon alpha 2b eyedrops for treatment of ocular surface squamous neoplasia: A dose comparison study Br J Ophthalmol 2010 94 551 4 19493859\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0301-4738",
"issue": "69(3)",
"journal": "Indian journal of ophthalmology",
"keywords": "Configuration; conjunctiva; dome-shaped; flat; interferon alpha-2b; ocular surface squamous neoplasia; squamous cell carcinoma; treatment",
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D000287:Administration, Topical; D000970:Antineoplastic Agents; D002294:Carcinoma, Squamous Cell; D015331:Cohort Studies; D003230:Conjunctival Neoplasms; D005134:Eye Neoplasms; D006801:Humans; D016898:Interferon-alpha; D009883:Ophthalmic Solutions; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0405376",
"other_id": null,
"pages": "563-567",
"pmc": null,
"pmid": "33595473",
"pubdate": "2021-03",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "22332208;19493859;27725148;22580436;22361315;26686965;28184236;24411578;30030703;22654961",
"title": "Primary treatment of ocular surface squamous neoplasia with topical interferon alpha-2b: Comparative analysis of outcomes based on original tumor configuration.",
"title_normalized": "primary treatment of ocular surface squamous neoplasia with topical interferon alpha 2b comparative analysis of outcomes based on original tumor configuration"
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"abstract": "BACKGROUND\nReports on malignancies observed in children exposed to TNF-inhibitors have raised questions about a potentially increased risk for lymphoma in particular. To date, the number of children exposed to biologicals is small. In addition, knowledge about the background incidence of malignancies in children with JIA and the influence of co-medication is limited.\n\n\nRESULTS\nBetween 2001 and 2009 five cases of malignancy were documented in the German JIA Etanercept in Children Registry covering 1200 patients, including one case each of non-Hodgkin's lymphoma, Hodgkin's lymphoma, thyroid cancer, yolk sac cancer, and cervical dysplasia. All five patients had been treated with a number of other drugs including cytotoxic drugs (methotrexate, leflunomide, azathioprine, cyclosporine A) before institution of etanercept therapy. All patients were treated with etanercept, while two patients were also treated with adalimumab or infliximab. Malignancy appeared after an etanercept treatment period of between 3 weeks and more than 6 years. At the time of diagnosis, three patients were still on etanercept, five on methotrexate and one on infliximab. In three patients malignancy first occurred in adulthood. All patients recovered.\n\n\nCONCLUSIONS\nThis case series of JIA and malignancy shows that prior to starting treatment with TNF-inhibitors careful consideration needs to be given to the possible benefits and risks. Patients need to be observed long-term and observation should to be continued in adulthood. Although a temporal association has been described to date, a causal role of TNF inhibitors cannot be excluded and parents and/or patients should be appropriately informed about this risk.",
"affiliations": "Asklepios Kinderklinik St Augustin GmbH, Arnold-Janssen-Str 29, 53757 St Augustin. g.horneff@asklepios.com",
"authors": "Horneff|G|G|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001688:Biological Products; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab; D000068800:Etanercept",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00393-010-0655-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-1855",
"issue": "69(6)",
"journal": "Zeitschrift fur Rheumatologie",
"keywords": null,
"medline_ta": "Z Rheumatol",
"mesh_terms": "D000068879:Adalimumab; D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001171:Arthritis, Juvenile; D001688:Biological Products; D002648:Child; D003430:Cross-Sectional Studies; D004359:Drug Therapy, Combination; D000068800:Etanercept; D005858:Germany; D006801:Humans; D007074:Immunoglobulin G; D007938:Leukemia; D008223:Lymphoma; D009369:Neoplasms; D018124:Receptors, Tumor Necrosis Factor; D012042:Registries; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0414162",
"other_id": null,
"pages": "516-26",
"pmc": null,
"pmid": "20532787",
"pubdate": "2010-08",
"publication_types": "D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": "17480018;1549149;10924020;15194580;9734957;17255842;12355487;9489836;15843454;8606720;11054684;16249224;18831464;19954274;18716298;18671329;19439429;18671328;3517321;16732547;15115709;16508929;15979323;18413443;19274799;9623403;19274777;18413440;17763439;10717011;19214541;16372138;10501423;17181934;17729297;15843668;16639486;12688327;19714630",
"title": "Malignancy and tumor necrosis factor inhibitors in juvenile idiopathic arthritis.",
"title_normalized": "malignancy and tumor necrosis factor inhibitors in juvenile idiopathic arthritis"
} | [
{
"companynumb": "PHHY2018DE171867",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "In July 2015, the US Food and Drug Administration (FDA) published a drug safety communication regarding errors in prescribing and dispensing of the antidepressant Brintellix (vortioxetine) and the antiplatelet Brilinta (ticagrelor) that arose due to proprietary drug name confusion. Brintellix is indicated for major depressive disorder; Brilinta is indicated to reduce cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or history of myocardial infarction. Brintellix was renamed to Trintellix in May 2016. Using Brilinta and Brintellix as a proof-of-concept feasibility use case, we assessed whether drug name confusion errors between the pair could be identified in electronic health care data via the combination of a claims-based algorithm and limited manual claims data review.\n\n\n\nUsing data from the Sentinel System, we defined potential errors as Brintellix users without an on- or off-label indication for Brintellix, without a dispensing for a drug with the same indications as Brintellix, and with an on- or off-label indication for Brilinta between -365 and +30 days after index Brintellix dispensing; the reverse was done for Brilinta. We manually reviewed claims profiles of potential cases.\n\n\n\nWe identified 27 (0.1%) potential errors among 21 208 Brintellix users; 16 appeared to be likely errors based on claims profile review. Fifty-one (0.3%) of the 16 779 Brilinta users were identified as potential errors, and four appeared to be likely errors.\n\n\n\nA claims-based algorithm combined with manual review of claims profiles could identify potential drug name confusion errors, and narrow down likely errors that warrant further investigation.",
"affiliations": "Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.;HealthCore, Government and Academic Research, Wilmington, DE, USA.;Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.;Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.;Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.;OptumInsight Life Sciences Inc., Boston, MA, USA.;U.S. Food and Drug Administration, Silver Spring, MD, USA.;U.S. Food and Drug Administration, Silver Spring, MD, USA.;U.S. Food and Drug Administration, Silver Spring, MD, USA.;Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.",
"authors": "Cocoros|Noelle M|NM|0000-0001-7090-2761;Haynes|Kevin|K|0000-0002-2070-2881;Her|Qoua|Q|;Cosgrove|Austin|A|;Dee|Elizabeth|E|;Lin|Nancy D|ND|0000-0003-3927-1871;Tu|Chi-Ming|CM|;Ding|Yulan|Y|;Nguyen|Michael|M|;Toh|Sengwee|S|0000-0002-5160-0810",
"chemical_list": "D000928:Antidepressive Agents; D010975:Platelet Aggregation Inhibitors; D000078784:Vortioxetine; D000077486:Ticagrelor",
"country": "England",
"delete": false,
"doi": "10.1002/pds.4891",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-8569",
"issue": "28(10)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "Sentinel System; claims data; medication errors; pharmacoepidemiology",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000067575:Administrative Claims, Healthcare; D000465:Algorithms; D000928:Antidepressive Agents; D003865:Depressive Disorder, Major; D004348:Drug Labeling; D011307:Drug Prescriptions; D057286:Electronic Health Records; D005240:Feasibility Studies; D006801:Humans; D008508:Medication Errors; D056687:Off-Label Use; D010975:Platelet Aggregation Inhibitors; D011358:Product Surveillance, Postmarketing; D000075082:Proof of Concept Study; D000077486:Ticagrelor; D014481:United States; D014486:United States Food and Drug Administration; D000078784:Vortioxetine",
"nlm_unique_id": "9208369",
"other_id": null,
"pages": "1405-1410",
"pmc": null,
"pmid": "31483085",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Identification of potential drug name confusion errors in the Sentinel System.",
"title_normalized": "identification of potential drug name confusion errors in the sentinel system"
} | [
{
"companynumb": "US-OTSUKA-2019_041903",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe objective of this review is to describe the outcomes of patients treated with ceftaroline in the non-Food and Drug Administration (FDA) approved indication of methicillin-resistant Staphylococcus aureus (MRSA) infections in both pediatric and adult populations.\n\n\nMETHODS\nA systematic overview was conducted by searching PubMed, Medline, and The Cochrane Library up to January 2019.\n\n\nMETHODS\nAll English-language clinical trials and case reports related to the efficacy of ceftaroline in new, not-yet-approved FDA indications in MRSA infections in pediatric or adult populations.\n\n\nRESULTS\nIn the case of MRSA bacteremia (MRSAB) infections, three different randomized studies in pediatric patients showed effectiveness of ceftaroline. When used in the case of adult populations with MRSA bacteremia, a small trial of 16 patients showed 50% clinical success in patients with acute bacterial skin and skin structure infections versus 63% clinical success in patients with community-acquired bacterial pneumonia. Another case series of six refractory case reports showed 50% clinical success of ceftaroline in patients with MRSA.\n\n\nCONCLUSIONS\nAlthough there are few case reports and limited data to date, ceftaroline fosamil should continue to be studied as an alternative therapy in MRSA infections in both pediatric and adult populations. Clinical success rates of ceftaroline were, in most cases, considered high when treating patients with MRSA infection. More clinical trials need to be studied. In the specific case of MRSA bacteremia, the treatment options remain few and ceftaroline should be extensively studied for the salvage treatment of MRSAB.",
"affiliations": "Department of Pharmaceutical Sciences, Larkin University College of Pharmacy, 18301 North Miami Ave, Miami, FL 33169, USA. nlounsbury@ularkin.org.;Department of Pharmaceutical Sciences, Larkin University College of Pharmacy, 18301 North Miami Ave, Miami, FL 33169, USA. mreeber@myularkin.org.;Pharmacy department, Jackson Memorial Hospital, 1611 NW 12th Ave, Miami, FL 33136, USA. bicnu@hotmail.com.;Department of Pharmaceutical Sciences, Larkin University College of Pharmacy, 18301 North Miami Ave, Miami, FL 33169, USA. cchbib@ularkin.org.",
"authors": "Lounsbury|Nicole|N|;Reeber|Mary G|MG|;Mina|Georges|G|;Chbib|Christiane|C|0000-0002-7995-7803",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/antibiotics8010030",
"fulltext": "\n==== Front\nAntibiotics (Basel)Antibiotics (Basel)antibioticsAntibiotics2079-6382MDPI 10.3390/antibiotics8010030antibiotics-08-00030ReviewA Mini-Review on Ceftaroline in Bacteremia Patients with Methicillin-Resistant Staphylococcus aureus (MRSA) Infections Lounsbury Nicole 1Reeber Mary G. 1Mina Georges 2https://orcid.org/0000-0002-7995-7803Chbib Christiane 1*1 Department of Pharmaceutical Sciences, Larkin University College of Pharmacy, 18301 North Miami Ave, Miami, FL 33169, USA; nlounsbury@ularkin.org (N.L.); mreeber@myularkin.org (M.G.R.)2 Pharmacy department, Jackson Memorial Hospital, 1611 NW 12th Ave, Miami, FL 33136, USA; bicnu@hotmail.com* Correspondence: cchbib@ularkin.org; Tel.: +1-305-760-7478; Fax: +1-305-760-745020 3 2019 3 2019 8 1 3012 2 2019 16 3 2019 © 2019 by the authors.2019Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Objective: The objective of this review is to describe the outcomes of patients treated with ceftaroline in the non-Food and Drug Administration (FDA) approved indication of methicillin-resistant Staphylococcus aureus (MRSA) infections in both pediatric and adult populations. Data sources: A systematic overview was conducted by searching PubMed, Medline, and The Cochrane Library up to January 2019. Study selection and data extraction: All English-language clinical trials and case reports related to the efficacy of ceftaroline in new, not-yet-approved FDA indications in MRSA infections in pediatric or adult populations. Data synthesis: In the case of MRSA bacteremia (MRSAB) infections, three different randomized studies in pediatric patients showed effectiveness of ceftaroline. When used in the case of adult populations with MRSA bacteremia, a small trial of 16 patients showed 50% clinical success in patients with acute bacterial skin and skin structure infections versus 63% clinical success in patients with community-acquired bacterial pneumonia. Another case series of six refractory case reports showed 50% clinical success of ceftaroline in patients with MRSA. Conclusions: Although there are few case reports and limited data to date, ceftaroline fosamil should continue to be studied as an alternative therapy in MRSA infections in both pediatric and adult populations. Clinical success rates of ceftaroline were, in most cases, considered high when treating patients with MRSA infection. More clinical trials need to be studied. In the specific case of MRSA bacteremia, the treatment options remain few and ceftaroline should be extensively studied for the salvage treatment of MRSAB.\n\nceftarolinecephalosporinmethicillin resistant Staphylococcus aureus (MRSA)pediatricssafetycommunity-acquired infectionbacteria infectionpneumoniaskin infectionMRSA bacteremia\n==== Body\n1. Introduction\nCeftaroline is a novel cephalosporin, given to patients by intravenous (IV) infusion. It is the active form of ceftaroline fosamil, a bactericidal antibiotic with Gram-positive and -negative coverage. Ceftaroline fosamil, branded as Teflaro® (Forest Laboratories, Inc., New York, NY, USA) in the United States, was approved by the Food and Drug Administration (FDA) in 2010 for adults and in 2016 for children older than two months for two indications: Complicated skin and soft tissue infections (cSSTI) and community-acquired pneumonia (CAP) [1]. Ceftaroline showed superior efficacy to ceftriaxone in adults with CAP in two phase 3 trials: FOCUS 1 and FOCUS 2 [2,3,4]. They were multi-centered, multinational, randomized trials which evaluated the safety and efficacy of 600 mg intravenous (IV) every 12 h ceftaroline fosamil compared to ceftriaxone 1 g IV every 24 h for 5 to 7 days for treatment of hospitalized CAP patients, but did not include patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. In this update, we will discuss new applications of ceftaroline for the treatment of MRSA in both adult and pediatric populations based on new case reports, clinical trials and other observational studies reported in literature. This review will mainly include: (1) the discussion of the mechanism of action of ceftaroline, (2) the antimicrobial activity against S. aureus pathogens isolated from the patients included in this review and (3) the literature updates on ceftaroline use in pediatric and adult population with both MRSA infections in general and MRSA bacteremia.\n\n2. Data Sources\nA systematic overview was conducted by searching PubMed, Medline, The Cochrane Library reports published up to January 2019. The search terms used include ‘’ceftaroline’’, ‘’adult methicillin resistant Staphylococcus aureus’’, ‘’pediatrics’’, ‘’pediatric methicillin resistant Staphylococcus aureus, bacteremia’’ and antimicrobial activity. The studies selected in this review are the ones that provide data for the use of ceftaroline in patients with MRSA infections. Most of the reported studies in literature assess the use of ceftaroline in patients with MRSA bacteremia.\n\n3. Chemistry/Mode of Action/Pharmacology\n3.1. Chemistry and mode of action of ceftaroline\nCeftaroline is described as a “fifth-generation” cephalosporin due to its reported broader activity against Gram-positive bacteria such as MRSA [5]. Its anti-MRSA activity is related to the addition of the 1,3-thiazole ring moiety to its structure. Ceftaroline exerts a bactericidal effect through inhibition of the bacterial cell wall synthesis [6,7]. This is achieved by its binding to the penicillin-binding proteins (PBPs), including PBP2a (which confers resistance to MRSA) and PBP2x (which confers resistance to penicillin-resistant S. pneumoniae) [8]. Ceftaroline causes a conformational change in PBP2a which allows binding to the active site of the protein [9]. The activity of ceftaroline against MRSA is due to its 1,3-thiazole ring on the 3rd position of the cephalosporin and the oxime in the acyl group attached to the 7th position of the cephalosporin [10] (Figure 1). The ability to penetrate Gram-negative bacteria is due to the increase in affinity to the transpeptidase enzyme caused by the 1,2,4-thiadiazole ring of the 7th position of the cephalosporin. To increase water solubility, a phosphono group was added, leading to the prodrug ceftaroline fosamil [10] in the form of acetate. Its active metabolite is ceftaroline which lacks the phosphono group present in the prodrug [11,12] (Figure 1).\n\n3.2. In Vitro Antimicrobial Activity of Ceftaroline against S. aureus\nBased on the breakpoints of ceftaroline against S. aureus followed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), MIC > 1 mg/L is counted as resistant. Whereas, following the breakpoints of the FDA, MIC = 2 mg/L is counted as intermediate and MIC > 2 mg/L is counted as resistant. Two studies reported the isolation of MRSA microorganisms from pediatric patients in literature and their MIC ranges show to be considered susceptible to ceftaroline (Table 1) [13,14]. Based on this evidence, more research needs to be conducted to evaluate ceftaroline susceptibility testing against isolated MRSA strains in pediatrics.\n\n4. Specific Populations\n4.1. Ceftaroline Use in Pediatrics MRSA\nCeftaroline fosamil was approved by the FDA in 2016 for pediatric patients from 2 months to 18 years of age to treat two specific indications: Acute bacterial skin and skin structure infection (ABSSSI) (for methicillin sensitive Staphylococcus aureus MSSA and MRSA pathogens) and community-acquired bacterial pneumonia CABP (for only MSSA). Recent analyses have shown that community-acquired MRSA (CA-MRSA) first occurred in children in the United States instead of adults [15]. A systematic overview was conducted by searching PubMed, Medline, The Cochrane Library and other reliable outlets up to January 2019. Reports of pediatric patients with MRSA infections are documented but no clinical trials exist yet. In this manuscript, we report two studies that evaluated the use of ceftaroline in patients with MRSA infections (MIC = 0.5–1 µg/mL). Even though the number of patients assessed is low, some clinical response and stability was shown after the use of ceftaroline in some patients. Korczowski et al. [13] evaluated the use of ceftaroline in pediatric patients with ABSSSI. Clinical success at day 3 was defined as: ≥20% reduction in total infection area and cessation of spread by length and width and temperature ≤37.6 °C. Clinical cure was defined as total resolution of all signs and symptoms. In a second study conducted by Blumer et al. [16], which evaluated ceftaroline’s safety and effectiveness compared to ceftriaxone plus vancomycin in pediatric patients with complicated CABP [17], clinical response was defined as an improvement in at least two and worsening in none of the following seven symptoms: Cough, dyspnea, chest pain, sputum production, chills, fever and lethargy or exercise intolerance. Clinical stability was defined as being afebrile, normal pulse and respiratory rates, ≥92% oxygen saturation and worsening of none of the seven symptoms stated previously. The percentage of clinical success fluctuated: Korczowski et al. reported it as 50% while Blumer et al. reported it as 89% (Table 2) [13,16]. In 2018, a case report [17] described a pediatric patient with a persistent MRSAB associated with cellulitis, fasciitis, myositis, and a deep vein thrombosis causing septic pulmonary emboli. This condition was unsuccessfully treated with vancomycin monotherapy first, then daptomycin monotherapy afterwards (vancomycin: MIC = 2 mg/L; daptomycin: MIC = 1 mg/L). After nine days of treatment, ceftaroline (MIC = 0.75 mg/L) was added to the latter antibiotic for a period of four weeks. It was reported to have cleared the bacteremia with proven clinical improvement. This fact warrants the instigation of further randomized controlled trials with a larger number of patients.\n\n4.2. Adults MRSAB\nUpon searching the literature, no randomized controlled trials exist for the treatment of MRSAB with ceftaroline. Results from the 2010 AWARE study, which evaluated antimicrobial resistance, showed that ceftaroline has high activity in vitro against MRSA isolates collected from different medical centers in the US [14]. Based on the 2011 Infectious Diseases Society of America (IDSA) MRSA guidelines, vancomycin or daptomycin are still the treatment of choice for both complicated and uncomplicated MRSAB [18,19]. No agent has proven to be superior to vancomycin or daptomycin, but in the case of persistent MRSAB, data of different case reports or small subgroups of clinical trials prove the basis for alternate agents including quinupristin-dalfopristin, trimethoprim-sulfamethoxazole, linezolid, and telavancin [18,19]. In this review, we collected data found in literature that assessed the use of ceftaroline in adult patient population with MRSA infections (MIC = 0.5–1 µg/mL) (Table 3) [20,21,22,23,24,25,26]. The clinical success of ceftaroline in MRSAB patients, reported in Table 3, varied between 50% and 88%. This report indicates the need to initiate further randomized controlled trials with a larger number of patients to increase the evidence for treatment options in the adult population. A systemic review and meta-analysis was conducted by Sotgiu and coworkers [27] for efficacy/effectiveness-related outcomes of ceftaroline in patients with pneumonia. The overall efficacy/effectiveness of ceftaroline was 81.2% in all types of pneumonia. Specifically in MRSA cases, success rates were documented as 71.7%. Additionally, the use of ceftaroline in Gram-positive osteomyelitis was studied by Johnson and co-workers [28]. MRSA pathogens were isolated in 94/150 patients (62.0%) in a phase 4 clinical assessment program. Out of 93 patients with MRSA pathogens receiving ceftaroline therapy, 86 patients showed clinical success (92.5%) defined as discontinuation of ceftaroline following clinical cure with no additional need of antibiotics or switch to another antibiotic. Ceftaroline has also been studied by Destache and coworkers [29] in the treatment of Gram-positive endocarditis. In this study, out of 55 patients, 44 (80%) had isolated blood MRSA pathogens. When given ceftaroline as a monotherapy, clinical success was observed in 19 out of 23 patients (82.6%). When used as first or second line, the clinical success achieved was 75.0% and 70.6% respectively. The patients with MRSA in this study, have exhibited a total of 77.3% (34/44) clinical success rate. This report provides growing evidence of the use of ceftaroline in adult populations with MRSAB infections.\n\nSakoulas et al. [25] described finding in vitro synergy where ceftaroline was shown to induce daptomycin binding in MSSA and MRSA which could be an opportunity to hasten clearance of refractory staphylococcal bacteremia. In an effort to optimize the therapeutic option in MRSA patients, Shafiq et al. [30] studied two clinical isolates from a 68-year-old patient with MRSAB. It was found that the combination of ceftaroline and daptomycin resulted in reduction of time-kill experiments against MRSA isolates. Further research of the in vitro synergy with daptomycin and ceftaroline combination was found to be caused by multiple mechanisms: a decrease in bacterial cell-wall thickness, an increase in daptomycin binding and an increase in daptomycin-induced depolarization [24,31,32]. In 2014, a retrospective, multicenter, study included 23 cases of refractory staphylococcal bacteremia that persisted for a median of 10 days, while the patients were on appropriate therapy regimens. Bacteremia was reported to be cleared in a median of two days after receiving the combination of daptomycin and ceftaroline [25]. It may be a worthwhile addition to daptomycin in refractory cases. In an effort to study further daptomycin-ceftaroline synergism, Cortes-Penfeld and coworkers [33] performed a retrospective chart review of patients with MRSAB after receiving treatment with vancomycin in combination with ceftaroline. Seventeen patients were included in the study: The first group consisted of four patients who received the combination as a second line therapy. The second group of eight patients received the combination as a third line therapy and the third group of five patients received daptomycin alone. This study suggests that 2nd line therapy rather than 3rd line with the combination of daptomycin and ceftaroline resulted in a shorter duration of bacteremia (6.8 vs. 11.5 days; p = 0.08) but there was no difference in the rates of mortality (75% vs. 62%; p = 1.0). It is worthy to note that patients who received daptomycin alone had 20% mortality which is lower than the combination of both groups 1 and 2: 62.5% and 75%, respectively. This scientific fact should trigger further evaluation of ceftaroline in combination with other antibiotics. Many questions arise regarding which combination has led to a faster cure clinically and microbiologically and whether ceftaroline should be given as a combination as well as whether ceftaroline is more efficient in refractory cases, even though there are insufficient data to prove it.\n\n5. Conclusions\nMRSA is known to cause a variety of infectious problems including ABSSSIs, and skin and soft tissue infections in adults and children. Alternative medications must be developed to treat patients who cannot be treated with traditional therapies such as vancomycin and clindamycin. Although there are few case reports and limited data to date, ceftaroline fosamil should continue to be studied as an alternative therapy for patients with MRSA. Ceftaroline fosamil is a broad-spectrum cephalosporin antibiotic that has been used to treat against MRSA in refractory cases. Ceftaroline fosamil has been shown to be safe and well-tolerated among children and adults, including those with MRSA, who are resistant or require an alternative antibiotic to common treatments. Its efficiency still needs to be studied extensively. Since the treatment of bacteremia might extend to over 14 days, hematological complications like neutropenia need to be assessed. The co-administration of ceftaroline and daptomycin in MRSAB has shown to be effective, but more clinical data needs to be evaluated and studied. Ceftaroline’s place in the treatment regimen of pediatric and adult population with MRSA infection needs to be determined.\n\n\nKey points:\nSome evidence in literature suggests that ceftaroline used for the treatment of MRSA has been shown to be successful in some cases in terms of clinical cure.\n\nA combination of ceftaroline and daptomycin has shown to be successful in treating patients with MRSA infections in both adult and pediatric populations.\n\nA synergy mechanism was observed in vitro when ceftaroline was added to daptomycin therapy. Clinical evidence of the benefits of the combination of the two drugs still needs to be thoroughly studied.\n\nThere is still limited data to date regarding the efficacy of ceftaroline alone or when compared to other antibiotics for the treatment of MRSA like quinupristin-dalfopristin, trimethoprim-sulfamethoxazole, linezolid, and telavancin.\n\nEvidence suggests that ceftaroline has been shown to be safe when administered in both adults and pediatrics.\n\n\n\n\nAuthor Contributions\nConceptualization, C.C. and G.M.; methodology, C.C.; software, C.C. and N.L.; validation, C.C., N.L. and M.G.R.; formal analysis, C.C.; investigation, C.C., N.L.; resources, C.C., N.L.; data curation, G.M.; writing—original draft preparation, C.C., M.G.R.; writing—review and editing, C.C.; visualization, C.C., N.L.; supervision, G.M.; project administration, C.C.; funding acquisition, C.C.\n\nFunding\nNo funding or sponsorship was received for this review or for the publication. Chbib is the guarantor for this article and takes full responsibility for the integrity of the work.\n\nConflicts of Interest\nNo conflict of interest exists in this work; No competing interest declared.\n\nFigure 1 Structure–activity relationships for active ceftaroline (R=H); the prodrug ceftaroline fosamil has the phosphono group at R = −P(=O)(OH)2 [11].\n\nantibiotics-08-00030-t001_Table 1Table 1 MIC 50/90 of ceftaroline for MRSA in pediatric patients.\n\nStudy\tMIC 50/90 of Ceftaroline for MRSA\t\nMulticenter, randomized, observer-blinded, active-controlled in pediatrics [13]\tMRSA = 0.5/1 mg/L\t\nAWARE study in pediatrics [14]\tMRSA = 0.5/1 mg/L\t\nantibiotics-08-00030-t002_Table 2Table 2 Reports of trials that used ceftaroline to treat MRSA infection.\n\nCriteria\tKorczowski et al. [13]\tBlumer et al. [16]\t\nTotal number of patients included, n\t159\t5\t\nPatients with MRSA, n (%)\t18 (11%)\t1\t\nPatients who received antibiotics prior to ceftaroline \t9\t1\t\nDuration of treatment with ceftaroline, median (range) \t3 days to 10 days\t-\t\nClinical success of MRSA patients, n (%)\t16/18 (89%) \t1\t\nSafety outcome\t8% diarrhea\n8% rash\n7% vomiting\n1% pruritis\nSerious adverse effects reported: 1 patient experienced hypersensitivity and another clostridium difficile colitis\nNo death reported\tAnemia, pruritus and vomiting \t\nantibiotics-08-00030-t003_Table 3Table 3 Summary of trials for the use of ceftaroline in adult patients with MRSA infection. (ABSSSI = Acute bacterial skin and skin structure infection; CABP = community-acquired bacterial pneumonia; SAB = Staphylococcus aureus bacteremia).\n\nCriteria\tHo et al. [20]\tCasapao et al. [21]\tVazquez et al. [22]\tLin et al. [23]\tPolenakovitch et al. [24]\tSakoulas et al. [25]\tSantos et al. [26]\t\nTotal number of patients who received ceftaroline, n\t6\t630\t48 (27 with ABSSSI and 21 with CABP)\t10 \t31\t26\t647\t\nPatients with MRSA, n (%)\t6 (100%)\t241 (38%)\t16 (59%) with ABSSSI and 16 (76%) with CABP\t10 (100%)\t31 (100%)\t20 (76%)\t191 (29%)\t\nPatients who received antibiotics prior to ceftaroline\t6\t422\t14 with ABSSSI and 13 with SAB \t10\t31\t26\t515 \t\nDuration of treatment with ceftaroline, median (range)\tVaries per case\t6 days\t5.8 days for ABSSSI and 7 days for CABP\tVaries per case\t5 days\t16 days\t6 days \t\nNumber of patients that were treated with ceftaroline as monotherapy \t6 \t447 \t22 in ABSSSI and 10 in CABP\t-\t-\tnone\t114 \t\nClinical success of MRSA patients, n (%)\t5 (83%) \t426/484 (88%)\t8/16 (50%) with ABSSSI\nAnd 10/16 (63%) with CABP\t6 (60%)\t23 (74%)\t23 (88%)\t144/178 (81%)\t\nSafety outcome\tGI bleeding and death reported in one patient\t8% hospital mortality\n0.9% diarrhea\n0.6% vomiting \n1.1% renal failure\t-\tRash, eosinophilia, pruritis and clostridium difficile infection\tEosinophilic pneumonia, rash and diarrhea\t-\t-\n==== Refs\nReferences\n1. Scott L.J. Ceftaroline fosamil: A review in complicated skin and soft tissue infections and community-acquired pneumonia Drugs 2016 76 1659 1674 10.1007/s40265-016-0654-4 27766567 \n2. File T.M. Jr. Low D.E. Eckburg P.B. Talbot G.H. Friedland H.D. Lee J. Llorens L. Critchley I.A. Thye D.A. Focus 1 Investigators FOCUS1: A randomized, double blinded, multicenter, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftaroline in community-acquired pneumonia J. Antimicrob. Chemother. 2011 66 19 32 10.1093/jac/dkr096 21482566 \n3. Low D.E. File T.M. Jr. Eckburg P.B. Talbot G.H. Friedland H.D. Lee J. Llorens L. Crichley I.A. Thye D.A. Focus 2 Investigators FOCUS 2: A randomized, double blinded, multicenter, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia J. Antimicrob. Chemother. 2011 66 33 44 10.1093/jac/dkr097 21482568 \n4. File T.M. Jr. Wilcox M.H. Stein G.E. Summary of ceftaroline fosamil clinical trial studies and clinical safety Clin. Infect. Dis. 2012 55 173 180 10.1093/cid/cis559 \n5. Kollef M.H. New antimicrobial agents for methicillin-resistant Staphylococcus aureus Crit. Care Resusc. 2009 11 282 286 20001879 \n6. Ishikawa T. Matsunaga N. Tawada H. Kuroda N. Nakayama Y. Ishibashi Y. Tomimoto M. Ikeda Y. Tagawa Y. Iizawa Y. Tak-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-01825: Synthesis, physicochemical and pharmacological properties Bioorg. Med. Chem. 2003 11 2427 2437 10.1016/S0968-0896(03)00126-3 12735989 \n7. Zapun A. Contreras-Martel C. Vernet T. Penicillin-binding proteins and beta-lactam resistance FEMS Microbiol. Rev. 2008 32 361 385 10.1111/j.1574-6976.2007.00095.x 18248419 \n8. Kosowska-Shick K. McGhee P.L. Appelbaum P.C. Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae Antimicrob. Agents Chemother. 2010 54 1670 1677 10.1128/AAC.00019-10 20194704 \n9. Llarull L.I. Fisher J.F. Mobashery S. Molecular basis and phenotype of methicillin resistance in Staphylococcus aureus and insights into new beta-lactams that meet the challenge Antimicrob. Agents Chemother. 2009 53 4051 4063 10.1128/AAC.00084-09 19470504 \n10. Zhanel G.G. Sniezek G. Schweizer F. Zelenitsky S. Lagacé-Wiens P.R. Rubinstein E. Gin A.S. Hoban D.J. Karlowsky J.A. Ceftaroline: A novel broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus Drugs 2009 69 809 831 10.2165/00003495-200969070-00003 19441869 \n11. Ge Y. Redman R. Floren L. Liao S. Wikler M. The pharmacokinetics and safety of ceftaroline (PPI-0903) in healthy subjects receiving multiple-dose intravenous infusions Proceedings of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy San Francisco, CA, USA 27–30 September 2006 \n12. Ikeda Y. Ban J. Ishikawa T. Hashiguchi S. Urayama S. Horibe H. Stability and stabilization studies of TAK-599 (ceftaroline fosamil) a novel N-phosphono type prodrug of anti-methicillin resistant Staphylococcus aureus cephalosporin T-91825 Chem. Pharm. Bull. 2008 56 1406 1411 10.1248/cpb.56.1406 18827379 \n13. Korczowski B. Antadze T. Giorgobiani M. Stryjewski M.E. Jandourek A. Smith A. O’Neal T. Bradley J.S. A multicenter, randomized, observer-blinded, active-controlled study to evaluate the safety and efficacy of ceftaroline versus comparator in pediatric patients with acute bacterial skin and skin structure infection Pediatr. Infect. Dis. J. 2016 35 239 247 10.1097/INF.0000000000001191 \n14. Sader H.S. Mendes R.E. Farrell D.J. Flamm R.K. Jones R.N. Ceftaroline activity tested against bacterial isolates from pediatric patients: Results from the assessing worldwide antimicrobial resistance and evaluation program for the United States (2011–2012) Pediatr. Infect. Dis. J. 2014 33 837 842 10.1097/INF.0000000000000307 25222304 \n15. Dukic V.M. Lauderdale D.S. Wilder J. Daum R.S. David M.Z. Epidemics of community associated methicillin-resistant Staphylococcus aureus in the United States; a meta-analysis PLoS ONE 2013 8 e52722 10.1371/journal.pone.0052722 23300988 \n16. Blumer J. Ghonghazde T. Cannavino C. O’Neal T. Jandourek A. Friedland H.D. Bradley J.S. A multicenter, randomized, observer-blinded, active-controlled study evaluating the safety and effectiveness of ceftaroline compared with ceftriaxone plus vancomycin in pediatric patients with complicated community acquired bacterial pneumonia Pediatr. Infect. Dis. J. 2016 35 760 766 10.1097/INF.0000000000001160 27078119 \n17. Hall A.M. McTigue S.M. Ceftaroline Plus Daptomycin for Refractory Methicillin-Resistant Staphylococcus aureus Bacteremia in a Child J. Pediatr. Pharmacol. Ther. 2018 23 490 493 10.5863/1551-6776-23.6.490 30697136 \n18. Fowler V.G. Jr. Boucher H.W. Corey G.R. Abrutyn E. Karchmer A.W. Rupp M.E. Levine D.P. Chambers H.F. Tally F.P. Vigliani G.A. Daptomycin versus standard therapy for bacteremia and endocarditis by Staphylococcus aureus N. Eng. J. Med. 2006 355 653 665 10.1056/NEJMoa053783 \n19. Liu C. Bayer A. Cosgrove S.E. Daum R.S. Fridkin S.K. Gorwitz R.J. Kaplan S.L. Karchmer A.W. Levine D.P. Murray B.E. Clinical practice guidelines by the infectious diseases society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children Clin. Infect. Dis. 2011 52 e18 e55 10.1093/cid/ciq146 21208910 \n20. Ho T.T. Cadena J. Childs L.M. Gonzalez-Velez M. Lewis J.S. 2nd Methicillin resistant Staphylococcus aureus bacteremia and endocarditis treated with ceftaroline salvage therapy J. Antimicrob. Chemother. 2012 67 1267 1270 22311935 \n21. Casapao A.M. Davis S.L. Barr V.O. Klinker K.P. Goff D.A. Barber K.E. Kaye K.S. Mynatt R.P. Molloy L.M. Pogue J.M. Large retrospective evaluation of the effectiveness and safety of ceftaroline fosamil therapy Antimicrob. Agents Chemother. 2014 58 2541 2546 10.1128/AAC.02371-13 24550331 \n22. Vazquez J. Maggiore C.R. Cole P. Smith A. Jandourek A. Friedland H.D. Ceftaroline fosamil for the treatment of Staphylococcus aureus bacteremia secondary to acute bacterial skin and skin structure infections or community acquired bacterial pneumonia Inf. Dis. Clin. Pract. 2015 23 39 43 10.1097/IPC.0000000000000191 25574117 \n23. Lin J.C. Aung G. Thomas A. Jahng M. Johns S. Fierer J. The use of ceftaroline fosamil in methicillin resistant Staphylococcus aureus endocarditis and deep-seated MRSA infections: A restrospective case series of 10 patients J. Infect. Chemother. 2013 19 42 49 10.1007/s10156-012-0449-9 22797874 \n24. Polenakovik H.M. Pleiman C.M. Ceftaroline for methicillin resistant Staphylococcus aureus bacteremia: Case series and review of the literature Int. J. Antimicrob. Agents 2013 42 450 455 10.1016/j.ijantimicag.2013.07.005 23993067 \n25. Sakoulas G. Moise P.A. Casapao A.M. Nonejuie P. Olson J. Okumura C.Y. Rybak M.J. Kullar R. Dhand A. Rose W.E. Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline Clin. Ther. 2014 10 1317 1333 10.1016/j.clinthera.2014.05.061 25017183 \n26. Santos P.D. Davis A. Jandourek A. Smith A. Friedland H.D. Ceftaroline fosamil and treatment of acute bacterial skin and skin structure infections: CAPTURE study experience J. Chemother. 2013 25 341 346 10.1179/1973947813Y.0000000144 24083879 \n27. Sotgiu G. Aliberti S. Gramegna A. Mantero M. Di Pasquale M. Trogu F. Saderi L. Blasi F. Efficacy and effectiveness of ceftaroline fosamil in patients with pneumonia: A systematic review and meta-analysis Respir. Res. 2018 19 205 10.1186/s12931-018-0905-x 30352588 \n28. Johnson L.B. Ramani A. Guervil D. Use of ceftaroline fosamil in osteomyelitis: CAPTURE study experience BMC Infect. Dis. 2019 19 183 10.1186/s12879-019-3791-z 30791894 \n29. Destache C.J. Guervil D.J. Kaye K.S. Ceftaroline fosamil for the treatment of Gram-positive endocarditis: CAPTURE study experience Int. J. Antimicrob. Agents 2019 10.1016/j.ijantimicag.2019.01.014 \n30. Shafiq I. Bulman Z.P. Spitznogle S.L. Osorio J.E. Reilly I.S. Lesse A.J. Parameswaran G.I. Mergenhagen K.A. Tsuji B.T. A combination of ceftaroline and daptomycin has synergistic and bacterial activity in vitro against daptomycin nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA) Infect. Dis. 2017 49 410 416 10.1080/23744235.2016.1277587 \n31. Rose W.E. Schulz L.T. Andes D. Striker R. Berti A.D. Hutson P.R. Shukla S.K. Addition of ceftaroline to daptomycin after emergence of daptomycin-nonsusceptible Staphylococcus aureus during therapy improves antibacterial activity Antimicrob. Agents Chemother. 2012 56 5296 5302 10.1128/AAC.00797-12 22869564 \n32. Werth B.J. Sakoulas G. Rose W.E. Pogliano J. Tewhey R. Rybak M.J. Ceftaroline increases membrane binding and enhances the activity of daptomycin against daptomycin-nonsusceptible vancomycin-intermediate Staphylococcus aureus in a pharmacokinetic/pharmacodynamic model Antimicrob. Agents Chemother. 2013 57 66 73 10.1128/AAC.01586-12 23070161 \n33. Cortes-Penfield N. Oliver N.T. Hunter A. Rodriguez-Barradas M. Daptomycin and combination daptomycin-ceftaroline as salvage therapy for persistent methicillin-resistant Staphylococcus aureus bacteremia Infect. Dis. 2018 50 643 647 10.1080/23744235.2018.1448110 29508663\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2079-6382",
"issue": "8(1)",
"journal": "Antibiotics (Basel, Switzerland)",
"keywords": "MRSA bacteremia; bacteria infection; ceftaroline; cephalosporin; community-acquired infection; methicillin resistant Staphylococcus aureus (MRSA); pediatrics; pneumonia; safety; skin infection",
"medline_ta": "Antibiotics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101637404",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30897759",
"pubdate": "2019-03-20",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "12735989;16914701;18248419;18827379;19441869;19470504;20001879;20194704;21208910;21482566;21482568;22311935;22797874;22869564;22903949;23070161;23300988;23993067;24083879;24550331;25017183;25222304;25574117;27078119;27164462;27766567;28116950;29508663;30352588;30697136;30711613;30791894",
"title": "A Mini-Review on Ceftaroline in Bacteremia Patients with Methicillin-Resistant Staphylococcus aureus (MRSA) Infections.",
"title_normalized": "a mini review on ceftaroline in bacteremia patients with methicillin resistant staphylococcus aureus mrsa infections"
} | [
{
"companynumb": "US-ALLERGAN-1919134US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFTAROLINE FOSAMIL"
},
"drugadditional": null,
... |
{
"abstract": "We assessed the outcomes associated with thiotepa, busulfan and fludarabine (TBF) conditioning regimen in a cohort of 29 consecutive patients allografted for myelofibrosis (MF). The median age was 56 (range 42-70) years. According to the refined Dynamic International Prognostic Scoring System (DIPSS-plus), 15 (52%) patients were classified as high risk. Graft source was peripheral blood stem cells in 27 patients. Donor type was HLA-matched related (n = 5), matched unrelated (n = 16), mismatched unrelated (n = 1), and haploidentical (n = 7). All but 2 patients engrafted. The cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was 21% (95% CI, 10-42) at day 100. The CI of chronic GVHD was 39% (95% CI, 23-65) at 3 years. The median follow-up period was 39 (range 14-60) months. Overall survival was 69% (95% CI, 50-83) at 3 years. No relapse was observed. TBF is a valid conditioning strategy in patients with MF.",
"affiliations": "Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;INSERM, UMRs 938, Paris, France.;INSERM, UMRs 938, Paris, France.;INSERM, UMRs 938, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.;Department of Hematology and Cellular Therapy, Saint Antoine Hospital, AP-HP, Paris, France.",
"authors": "Memoli|Mara|M|0000-0002-1922-6048;Paviglianiti|Annalisa|A|;Malard|Florent|F|;Battipaglia|Giorgia|G|;Brissot|Eolia|E|;Médiavilla|Clémence|C|;Bianchessi|Antonio|A|;Banet|Anne|A|;Van de Wyngaert|Zoé|Z|;Ledraa|Tounes|T|;Belhocine|Ramdane|R|;Sestili|Simona|S|;Lapusan|Simona|S|;Hirsch|Pierre|P|;Favale|Fabrizia|F|;Boussaroque|Agathe|A|;Bonnin|Agnès|A|;Vekhoff|Anne|A|;Legrand|Ollivier|O|;Mohty|Mohamad|M|;Duléry|Rémy|R|",
"chemical_list": "D013852:Thiotepa; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2020.1827246",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "62(2)",
"journal": "Leukemia & lymphoma",
"keywords": "HSCT; TBF; Thiotepa; busulfan; fludarabine; myelofibrosis",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D002066:Busulfan; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008875:Middle Aged; D055728:Primary Myelofibrosis; D013852:Thiotepa; D019172:Transplantation Conditioning; D014740:Vidarabine",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "419-427",
"pmc": null,
"pmid": "33012207",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thiotepa-busulfan-fludarabine as a conditioning regimen for patients with myelofibrosis undergoing allogeneic hematopoietic transplantation: a single center experience.",
"title_normalized": "thiotepa busulfan fludarabine as a conditioning regimen for patients with myelofibrosis undergoing allogeneic hematopoietic transplantation a single center experience"
} | [
{
"companynumb": "FR-OTSUKA-2020_025824",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": "3",
"dr... |
{
"abstract": "There is paucity of data in the literature regarding the safety of combining granulocyte colony stimulating factor (G-CSF) during chemo-radiotherapy (CTRT) in lung cancer patients. The ASCO 2006 recommendations advise against use of CSFs during concomitant mediastinal CTRT. The only randomised study evaluating CSFs in this context showed significant increase in grade 3/4 thrombocytopenia and an excess of pulmonary toxic deaths. In the context of a phase II trial, 38 patients with limited-stage small cell lung cancer were randomised to receive once-daily (66 Gy in 33 fractions) or twice-daily (45 Gy in 30 fractions) radiotherapy. Radiotherapy (RT) was given concurrently with cisplatin and etoposide. G-CSF was given as primary or secondary prophylaxis or as a therapeutic measure during an episode of febrile neutropenia according to local protocols. Common terminology criteria for adverse events (CTCAE) v3.0 was used to record toxicity. Thirteen (34%) of 38 patients received G-CSF concurrently with RT. With a median follow-up of 16.9 months, there were no treatment related deaths reported. Seven (54%) patients experienced grade 3/4 thrombocytopenia and 5 (38%) experienced grade 3/4 anaemia. Thirty-one percent required platelet transfusions. No episodes of bleeding were observed. There were no cases of grade 3/4 acute pneumonitis. These data suggests that with modern three-dimensional (3D) conformal RT, G-CSF administration concurrently with CTRT does not result in the increase risk of pulmonary toxicity, but does increase the risk of thrombocytopenia. Whether the risks of thrombocytopenia are outweighed by the outcome of timely early concurrent CTRT is being evaluated prospectively in the ongoing phase III CONVERT trial (NCT00433563) in which G-CSF is permitted during thoracic irradiation.",
"affiliations": "Dept of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK.",
"authors": "Sheikh|Hamid|H|;Colaco|Rovel|R|;Lorigan|Paul|P|;Blackhall|Fiona|F|;Califano|Raffaele|R|;Ashcroft|Linda|L|;Taylor|Paul|P|;Thatcher|Nicholas|N|;Faivre-Finn|Corinne|C|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D002945:Cisplatin",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2011.01.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "74(1)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": null,
"medline_ta": "Lung Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000740:Anemia; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D002945:Cisplatin; D018450:Disease Progression; D005047:Etoposide; D005260:Female; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017713:Platelet Transfusion; D055752:Small Cell Lung Carcinoma; D016019:Survival Analysis; D013921:Thrombocytopenia",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "75-9",
"pmc": null,
"pmid": "21353720",
"pubdate": "2011-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Use of G-CSF during concurrent chemotherapy and thoracic radiotherapy in patients with limited-stage small-cell lung cancer safety data from a phase II trial.",
"title_normalized": "use of g csf during concurrent chemotherapy and thoracic radiotherapy in patients with limited stage small cell lung cancer safety data from a phase ii trial"
} | [
{
"companynumb": "GB-AMGEN-GBRSP2021034991",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Kaposi sarcoma (KS) is an angioproliferative tumor caused by human herpesvirus 8 (HHV-8). Gastrointestinal (GI) involvement by KS is a rare endoscopic finding, scarcely characterized in the literature.\nTo characterize clinical and endoscopic features of patients with GI KS.\nThis is a single-center retrospective study of GI KS cases confirmed by immunohistochemistry in the last decade (2006-2015). The following variables were analyzed: demographic data; clinical data (extraintestinal involvement, symptoms, presence and stage of HIV infection, immunosuppressive therapy); endoscopic data; stage-stratified therapeutic approach; and mortality (at 3 and 6 months).\nThirteen patients with GI KS were identified: 77% were men, the mean age was 55 years, and 62% of them were Native Africans. In most cases (n = 10, 77%), KS was associated with HIV. A total of 90% of the HIV patients had a CD4+ count of <200/μL (C3, CDC classification), and 80% of them had KS as the initial manifestation of HIV infection. Thirty percent of the cases had other AIDS-defining illnesses, and only 20% received antiretroviral therapy. In the remaining 3 patients (23%), KS was associated with immunosuppressive therapy. Most patients (85%) had cutaneous lesions and 15% lung involvement. In most cases (85%), the lesions were diagnosed in the upper digestive tract in asymptomatic patients (7 stomach; 2 stomach and duodenum; 2 esophagus). Colonic involvement occurred in 2 patients presenting with hematochezia. Nearly half of the patients had more than 3 endoscopic lesions and the most frequent morphologic type was polypoid/nodular (62%). Treatment was based on antiretroviral therapy or reduction of immunosuppression and in 39% of the patients on administration of doxorubicin. Survival at 3 and 6 months was 46 and 39%, respectively.\nGI KS is mostly found in nontreated, stage 3, HIV patients, and particularly in men from areas where HHV-8 is endemic. Involvement of the upper digestive tract is often asymptomatic. The endoscopic appearance is variable and these patients have a poor prognosis.",
"affiliations": "Department of Gastroenterology, Hospital de Egas Moniz - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.;Department of Gastroenterology, Hospital de Egas Moniz - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.;Department of Gastroenterology, Hospital de Egas Moniz - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.;Department of Pathology, Hospital de Egas Moniz - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.;Department of Gastroenterology, Hospital de Egas Moniz - Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal.",
"authors": "Carmo|Joana|J|;Marques|Susana Chaves|SC|;Bispo|Miguel|M|;Pinto|Daniel|D|;Chagas|Cristina|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000461592",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2387-1954",
"issue": "24(5)",
"journal": "GE Portuguese journal of gastroenterology",
"keywords": "Endoscopy; Gastrointestinal tract; Kaposi sarcoma",
"medline_ta": "GE Port J Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101685861",
"other_id": null,
"pages": "219-226",
"pmc": null,
"pmid": "29255756",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
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"title": "Clinical and Endoscopic Features of Gastrointestinal Kaposi Sarcoma: A Single-Center Portuguese Experience over the Last Decade.",
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"abstract": "Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. A boy aged seven years and five months was diagnosed with stage three group III embryonal parameningeal RMS with intracranial extension. He received chemotherapy for 23 weeks in combination with localized radiotherapy during the inductive phase of nine weeks (a total tumor dose of 5040 cGy). Three months later, he was referred to the department of pediatric dentistry for radiation-induced caries, the treatment of which was later terminated because of severe trismus and radiation-induced oropharyngeal mucositis. Three years later, the patient returned for the fitting of a prosthesis because of mastication problems. The dental treatments performed included: extraction, banding, composite resin restorations, root canal fillings, and stainless steel crown fabrication. An interim denture was fitted due to the poor retention of the fixed prosthesis. As the patient grew older, they developed facial asymmetry as a result of the prominent atrophy of their right cheek. By the age of 32, they had lost multiple teeth and exhibited severe facial deformity. Therefore, it is essential not only to involve a multidisciplinary medical team before, during, and after cancer therapy, but also to initiate long-term follow-ups given the potential effects of late sequelae after chemoradiation in multiple developmental areas.",
"affiliations": "Department of Pediatric Dentistry, Taoyuan Chang Gung Memorial Hospital, Taoyuan City 33305, Taiwan.;Department of Pediatric Dentistry, Lin-Kou Chang Gung Memorial Hospital, Taoyuan City 33305, Taiwan.",
"authors": "Chang|Pei-Ching|PC|0000-0002-5398-1071;Lin|Shiao-Yu|SY|0000-0001-9597-0613",
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"doi": "10.3390/ijerph182212158",
"fulltext": "\n==== Front\nInt J Environ Res Public Health\nInt J Environ Res Public Health\nijerph\nInternational Journal of Environmental Research and Public Health\n1661-7827\n1660-4601\nMDPI\n\n10.3390/ijerph182212158\nijerph-18-12158\nCase Report\nA Long-Term Follow-Up of Dental and Craniofacial Disturbances after Cancer Therapy in a Pediatric Rhabdomyosarcoma Patient: Case Report\nhttps://orcid.org/0000-0002-5398-1071\nChang Pei-Ching 1*\nhttps://orcid.org/0000-0001-9597-0613\nLin Shiao-Yu 2\nHanisch Marcel Academic Editor\nBohner Lauren Academic Editor\n1 Department of Pediatric Dentistry, Taoyuan Chang Gung Memorial Hospital, Taoyuan City 33305, Taiwan\n2 Department of Pediatric Dentistry, Lin-Kou Chang Gung Memorial Hospital, Taoyuan City 33305, Taiwan; lin321@adm.cgmh.org.tw\n* Correspondence: ma3207@adm.cgmh.org.tw; Tel.: +88-63-319-6200 (ext. 3500)\n19 11 2021\n11 2021\n18 22 1215810 10 2021\n15 11 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nRhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. A boy aged seven years and five months was diagnosed with stage three group III embryonal parameningeal RMS with intracranial extension. He received chemotherapy for 23 weeks in combination with localized radiotherapy during the inductive phase of nine weeks (a total tumor dose of 5040 cGy). Three months later, he was referred to the department of pediatric dentistry for radiation-induced caries, the treatment of which was later terminated because of severe trismus and radiation-induced oropharyngeal mucositis. Three years later, the patient returned for the fitting of a prosthesis because of mastication problems. The dental treatments performed included: extraction, banding, composite resin restorations, root canal fillings, and stainless steel crown fabrication. An interim denture was fitted due to the poor retention of the fixed prosthesis. As the patient grew older, they developed facial asymmetry as a result of the prominent atrophy of their right cheek. By the age of 32, they had lost multiple teeth and exhibited severe facial deformity. Therefore, it is essential not only to involve a multidisciplinary medical team before, during, and after cancer therapy, but also to initiate long-term follow-ups given the potential effects of late sequelae after chemoradiation in multiple developmental areas.\n\ndental disturbance\ncraniofacial disturbance\nchemoradiation therapy\nrhabdomyosarcoma\n==== Body\npmc1. Introduction\n\nRhabdomyosarcoma (RMS), which is composed of neoplastic mesenchymal cells with varying degrees of striated muscle cell differentiation, is an aggressive malignant tumor and the most common soft tissue sarcoma in children and adolescents [1]. The incidence rates of RMS are 3.5% among children younger than 14 and 2% in adolescents aged 15 to 19 [2]. The rate of occurrence between males and females is 1.3–1.5 to 1 [3]. Primary rhabdomyosarcoma in the head and neck accounts for approximately 35% of cases in children, including lesions in parameningeal, orbital, and superficial areas [4]. The majority of pediatric patients suffer from Group-II and Group-III rhabdomyosarcoma with relatively favorable outcomes [5]. The survival rate has improved dramatically over the years [6], thanks to a multimodal regimen consisting of chemotherapy, surgery (for local control), and the selective application of adjuvant radiotherapy (RT) [7]. Chemoradiation, in particular, has been a key treatment strategy in the context of pediatric oncology, as pediatric patients may suffer the loss of oral functions, cosmetic compromise, and psychological distress if they undergo surgeries. However, chemoradiation can also impact the growth of soft and hard tissues in the affected areas, and, in the case of the head and face, cause facial and dental abnormalities. These anomalies become increasingly pronounced as patients grow older and can affect their quality of life. This report details the long-term dental and craniofacial disturbances in a pediatric RMS patient after this cancer therapy based on a follow-up that spanned 25 years.\n\n2. Case Report\n\nA boy aged seven years and five months and suffering from a protruding right eyeball, watering eyes, and sinusitis received a definitive diagnosis of stage three group III embryonal parameningeal RMS with intracranial extension. The large and heterogeneous tumor occupied the entire retrobulbar space and damaged the adjacent bones of the temporal floor, as well as the medial and inferior walls of the right orbital fossa. The lesions in the right parapharyngeal space extended to the maxillary sinus, nasal cavity, paranasal sinuses, ethmoid sinus, nasopharynx, sphenoid sinus, and the right orbital fossa. The intracranial tumor extended to the right para-cavernous sinus and the middle cranial fossa. The patient received chemotherapy (cisplatin, endoxan, adriamycin, oncovin, etoposide, vincristine, and actinomycin-D) for a period of 23 weeks commencing when the patient was seven years and five months old. This was combined with localized RT during the inductive phase of nine weeks. The radiation field included the tumor bed with a safe margin of at least 2 cm, the basal skull meninges, and the upper neck lymph node. These areas were irradiated at the Pediatric-Hematology Oncology Department using six MV X rays via one anterior portal and two lateral opposed portals with a total dose of 5040 cGy. Three months later, the patient was referred to the Department of Pediatric Dentistry for radiation-induced caries. However, the treatment was later terminated because of open-mouth limitation due to trismus and severely painful radiation-induced oropharyngeal mucositis.\n\nThree years later, the patient returned for the fitting of a prosthesis because of mastication problems. The following were found in his primary and developing permanent dentitions: multiple caries and residual roots, crown opacity, hypoplastic teeth with apical lesions, foreshortened and blunted roots, incomplete root development, a prematurely closed root apex, and V-shaped roots (Figure 1a,b).\n\nThe objective of the dental treatment at the time, therefore, was to preserve the existing dentition for masticatory efficiency and to improve the esthetics of the patient’s teeth. Patient. The treatments performed included: extraction, banding, composite resin restorations, root canal fillings, and stainless steel crown fabrication. An interim denture was provided due to the poor retention of the provisional fixed restorations (Figure 2a). Six months later, following root canal fillings, all the new caries were restored, and the provisional prosthesis was fabricated (Figure 2b). Oral hygiene was also encouraged, in particular flossing, brushing, and the application of topical fluoride, during each three-month follow-up.\n\nAs the patient grew older, he developed facial asymmetry, triggered by the prominent atrophy of his right cheek. His chin tilted toward the right side of his face, creating a concave profile (Figure 3). During the six years after the cancer therapy, the maxilla changed little, whereas the mandible rotated counterclockwise (Figure 4). Compared with the age-appropriate norm, the cephalometric tracings taken at the ages of 11 and 17 showed limited craniofacial development (Table 1).\n\nThe orthodontic diagnosis included skeletal Class III malocclusion and dental Class III malocclusion with mandibular prognathism. However, orthodontic treatment coupled with orthognathic surgery was not recommended for this patient because of his susceptibility to pathological mobility and further root resorption due to atypical root morphology at multiple locations. At the age of 32, 25 years after the initial cancer therapy, the patient had lost multiple teeth and suffered severe facial deformity (Figure 5).\n\n3. Discussion\n\nChemotherapy with definitive local RT can successfully treat RMS [8]. Approximately 80% of children diagnosed with RMS will survive after multimodal treatment, improved supportive care, and the refinement of tumor grouping and staging [9]. However, multimodal treatment has also been associated with dental and/or craniofacial complications as well as developmental defects among childhood cancer survivors (CCS) [10]. High-dose radiation and chemotherapy can each provoke dental and craniofacial complications, including mucositis, xerostomia, loss of taste, difficulty in swallowing, loss of appetite, nausea, malaise, weight loss [11], opportunistic infection, trismus, erythema, impaired dental and osseous development [12], and osteoradionecrosis of the mandible due to high bone density and low vascularity [11]. The most common developmental defects associated with chemoradiation therapy are: decreased growth (49%), facial asymmetry (37%), dental abnormalities (30%), visual (20%) and auditory impairment (18%), dysfunction and cognitive problems (17%), endocrine disorder (<10%), and a second malignancy (2%) [5].\n\nChemotherapeutic agents may change the spectrum of bacteria colonizing the oral cavity, favoring caries-related microflora [13]. Chemotherapy-induced xerostomia reduces the salivary flow and promotes a more acidic pH environment conducive to dental caries [14]. Chemotherapeutic agents can also affect mature secretory odontoblasts and ameloblasts and induce qualitative and quantitative changes in dental tissues. The interference with odontoblast microtubules disrupts the formation of collagen fibril and the secretion of dentin matrix, resulting in short and thin tapered roots, and the inhibition of odontogenesis and eruption [15]. Agents such as vincristine, vinblastine, and cyclophosphamide can disrupt the calcium transport mechanism of ameloblast microtubules, leading to hypomineralized enamel defects [16]. Chemotherapy administered during childhood has been associated with high incidences of dental defects, as immature teeth are at greater risk of dental abnormalities than fully developed ones [17]. Given the short half-life of chemotherapeutic agents, dental defects are usually localized as a result of the transient change in the odontoblast function rather than odontoblast cell death. Nevertheless, intensive and repeated chemotherapy during the period when hard tissues are starting to form may still cause tooth agenesis [12].\n\nRadiation interferes with odontogenesis by directly inhibiting the mitotic activity of odontoblasts. The rapidly dividing presecretory odontoblasts in children are particularly vulnerable to the effects of radiation [18]. In contrast, radiation affects amelogenesis indirectly by inducing the formation of osteodentin, which replaces normal dentin [19]. Osteodentin reduces phosphorylated phosphoprotein, which inhibits the nucleation of enamel crystals and leads to deficient enamel mineralization [20]. The following radiation-induced dental disturbances are thus commonly seen: enamel hypoplasia and hypomineralization [17], microdontia and agenesis [21], aplasia, arrested root development with premature apical closure, foreshortening and blunting of roots, and eruption problems [17]. Late dental defects can occur with a radiation dose as low as 4 Gy. Mature ameloblasts can be damaged by 10 Gy. Tooth development can be halted by doses of up to 30 Gy [22]. Doses of over 60 Gy can cause irreversible injuries to bone cells and vascularity, as well as osteoradionecrosis and an unbalanced apposition–resorption pattern during tooth movement [23].\n\nThe patient in the current report regularly consumed unhealthy snacks and had a daily diet high in carbohydrates. The oral medications that he took contained a high amount of sucrose. He also experienced vomiting due to the chemotherapy. Hence, during all of the three-month follow-ups, oral hygiene was encouraged, especially flossing, brushing, and the application of topical fluoride.\n\nPrevious studies have demonstrated that intensive oral care can reduce the risk of moderate/severe mucositis without increasing the likelihood of septicemia and infections in the oral cavity [24,25]. Brushing using a soft toothbrush or an electric brush at least twice daily has been found to be the most efficient method of reducing the risk of significant bleeding and infections in the gingiva. Furthermore, the frequency of oral care should be increased in cases of tissue complications from the cancer treatment. Pain can be reduced by the application of anesthetics, analgesics, or mucosal coating agents, such as Benadryl, Kaopectate, milk of magnesia, Orabase, viscous Xylocaine, Oratect Gel, and systemic analgesics [11].\n\nDue to the fact that used toothbrushes can quickly become oral bacteria colonies and potential sources of infection within two weeks [26], it is highly recommended not only to dry toothbrushes after use, but to soak them in chlorhexidine solution and to replace them regularly [27,28]. Extra soft brushes, sponge toothbrushes, toothettes, or disposable cleaning pads with foam rubber heads are all less effective than toothbrushes with soft nylon bristles when it comes to removing plaque and preventing dental caries [29,30]. These alternatives should only be used during severe mucositis when a patient cannot tolerate a regular toothbrush and flossing, or when their platelet count drops to 20,000 per cubic millimeter [11].\n\nFlossing should be discouraged if the patient is not skilled at it because it can cause trauma and bleeding. Toothpicks and irrigators should also be avoided during neutropenia, as they may disrupt tissue integrity and create entry points for microbial colonization and bleeding [27]. Before the gingiva are healthy again, or mucositis has receded to the initial stage, patients with poor oral hygiene or periodontal disease can use chlorhexidine mouthwash daily to control early periodontal infections [26].\n\nPeriodontal infections are a concern because colonized organisms have been shown to cause bacteremia [24]. To keep the mouth moist and reduce pathogenic flora, an anti-plaque rinse such as isotonic saline or a 5% sodium bicarbonate solution is recommended. To control fungal activity, an antimicrobial agent such as oxytetracycline/amphotericin-B can be used [31]. Other products include artificial saliva, oral rinses, sprays, and fluoride in various forms, concentrations, and delivery methods. Patients who are at risk of caries induced by cancer therapies can continue the daily oral hygiene regimen while also initiating fluoride supplements and 1% neutral fluoride rinses or gels at least one week before the radiation therapy [32]. However, these measures should be performed judiciously if the patient is thrombocytopenic [26,33]. The frequency of professional applications of fluoride—fluoride varnish, fluoride gel, or fluoride foam— should be determined based on the patient’s risk profile [34,35]. High-strength fluoride toothpastes containing 5000 ppm of fluoride should be prescribed only to patients who can reliably spit out the toothpaste [34]. Fluoride trays can be offered to patients who can tolerate wearing them [36]. For those that are unable to excrete properly, products containing casein phosphopeptide and amorphous calcium phosphate (CPP-ACP)—such as MI Paste—can be used to maintain the surface mineralization of enamels [37]. Analgesic rinses, such as 2% viscous lidocaine, are also advisable for oral hygiene during mucositis. If the patient suffers from salivary dysfunction, moistening agents such as cholinergic receptor agonists (e.g., pilocarpine) are recommended [38,39].\n\nChildren who receive radiation therapy in the head and neck region may also develop trismus (painful spasms of the mastication muscles) [40,41]. Therefore, ideally, stretching exercises of the masticatory muscles through physical therapy should be initiated before the start, and continue beyond the completion, of the radiation therapy [42].\n\nChildren with intracranial tumors treated with RT in combination with multi-agent chemotherapy also suffer reduced vertical growth of facial structures [43]. Dahllof et al. reported that the values of all linear variables related to facial height were diminished significantly among bone marrow transplantation (BMT) patients treated with 10 Gy of total body irradiation (TBI). They found shorter anteroposterior facial dimensions and changes in the growth rotation of both the maxilla and mandible [44]. Impaired mandibular development has also been found in young leukemia patients after 24 Gy of cranial RT and chemotherapy [45]. According to Guyuron et al., the harmful dose could be as low as 400 cGy for soft tissue, and 3000 cGy for hard tissue [46]. The patient in the current case received localized RT with a total tumor dose of 5040 cGy, which was large enough to interfere with both the soft and hard tissue growth in his craniofacial structure. Mirroring the findings from previous studies [44], the patient’s limited craniofacial development became even more pronounced as he grew older, evidenced in his cephalometric measurements. Facial deformities and malocclusion also made him very depressed. This resonates with Pruzinsky’s observation that individuals with severe craniofacial deformities are at risk of experiencing social and psychological stress [47].\n\nApproximately 77–100% of survivors who have undertaken head and neck radiation therapy report mild to severe radiation damages to soft tissues and bones [43,48]. The most pronounced complications of radiotherapy include hypovascularity and cytotoxic effects on epiphyseal chondrocytes [49,50]. Chemotherapy and RT also have the most notable effects during puberty [44,45,51]. Such impacts on the thyroid gland and pituitary axis can affect the patient’s overall growth [52].\n\nIn general, orthodontic treatment may start or resume after the completion of all cancer therapies and a disease-free survival of at least two years. By that time, the risk of relapse has decreased and the patient is no longer taking immunosuppressive drugs [53]. However, when treating long-term pediatric cancer survivors, orthodontists need to be mindful of the potential adverse clinical implications and risks of complications that may be triggered by the treatment administered. For example, the orthodontic appliances used may inflict stress to the oral mucosa and impair the membrane’s regenerative capability, leading to ulcerations [54]. To minimize risks, non-irritating orthodontic appliances should also be considered, such as nickel-free brackets (comprised of stainless steel with manganese or with a low nickel content of less than 5%) which reduce free radicals released from the stainless steel [54]. For nickel-sensitive patients, titanium brackets should be the first choice, as these are more resistant to corrosions and do not release nickel into the oral cavity [55].\n\nIn addition, a low force of 20 to 150 g per tooth helps to prevent unpredictable root resorption. [56]. The duration of treatment should be kept short. Research has shown that a pause of two to three months after six months of active treatment could reduce the number of patients experiencing advanced root resorptions [57]. In general, when treating patients at risk, it is recommended that periapical radiographs be taken after 6 months of active treatment. If the film reveals the signs of resorption, orthodontic treatments should be discontinued for three months [57].\n\nDahllof et al. have summarized the following strategies for providing orthodontic care to patients with dental sequelae: using appliances that minimize the risk of root resorption, using lighter forces, terminating treatments earlier than normal, choosing the simplest treatment method, and not treating the lower jaw [58]. However, late dental defects such as hypodontia and root stunting may preclude adequate orthodontic anchorage [59], placing teeth at an additional risk of the damaging effects of gingival and periodontal diseases [60]. This is the reason why orthodontic treatments combined with orthognathic surgeries were not recommended for the patient in the current study, as he had missed his follow-ups from the age of 17 and had only returned for further dental help till the age of 25.\n\nRMS usually occurs in young children, and RT at a young age can lead to abnormal growth and functions of musculoskeletal tissues such as facial disfigurements (incidence rate: 35–77%) [61]. The experience of childhood cancer may also have a long-term impact on survivors’ psychological states and further hinder their post-treatment adjustment and affect their quality of life. As more patients survive cancer for longer periods of time, potentially serious complications of cancer therapies also begin to emerge [62]. Hence, as the prognosis of childhood cancer continues to improve, more attention should be directed towards the long-term side effects of treatment protocols, so as to improve patients’ quality of life and reduce the overall cost of care. General and pediatric dentists should also educate themselves in late complications, aiming for early diagnosis and the delivery of proper dental care for this growing population of patients.\n\n4. Conclusions\n\nIt is essential to involve a multidisciplinary team of medical professionals in patient care before, during, and after cancer therapies. This multidisciplinary team may consist of oncologists, pediatric dentists, and other health care professionals who can collectively determine what combination of therapeutic modalities will deliver the optimal cost–benefit ratio, the best prognosis with minimal morbidity, and the best quality of life for patients. Professional oral and dental supervision are critical components of patient-centered care during pediatric cancer therapies [42]. A comprehensive oral care plan should include pretreatment evaluation and information collection, instructions for oral care, treatment of dental and periodontal diseases, and supportive follow-up care. Patients undergoing either radiation therapy or chemotherapy must understand that good oral hygiene is essential in reducing the chances of oral complications from their cancer treatments. The most important factor in ensuring a healthy oral cavity during cancer therapies is patient compliance. Educating caretakers as well as patients about the importance of oral care is also vital in minimizing discomfort and maximizing the chances of successful outcomes. Furthermore, late sequelae after the chemoradiation therapy may affect a number of developmental areas in pediatric patients: stature growth, cosmetic appearance, dental and maxillofacial abnormalities, and special senses. Long-term follow-ups, which focus on detection, prevention, and remediation of these complications, are thus needed for all patients.\n\nAuthor Contributions\n\nAll authors made substantial contributions to data acquisition or analysis, and the interpretation of data; took part in drafting the manuscript or in revising it critically for important intellectual content; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki of 1975, revised in 2013. Based on the regulations of the Chang Gung Memorial Hospital, an approval by the Institutional Review Board is not required for case reports.\n\nInformed Consent Statement\n\nWritten informed consent was obtained from the patient, permitting the case details and any accompanying images to be published.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 (a) There were multiple caries and residual roots, crown opacity, and hypoplastic teeth in the patient’s primary and developing permanent dentitions. (b) There were many deep caries with apical lesions, foreshortened and blunted roots, incomplete root development, prematurely closed root apex, and V-shaped roots in the developing dentition.\n\nFigure 2 (a) The dental treatments performed included extraction, composite restorations, root canal fillings, stainless steel crown fabrication, banding, provisional restorations, and an interim denture. (b) Following root canal fillings, all new caries were restored, and the provisional prosthesis was fabricated.\n\nFigure 3 Long-term facial asymmetry as a result of pediatric rhabdomyosarcoma (RMS) cancer therapy.\n\nFigure 4 Superimposition of cephalometric tracings taken at the ages of 11 and 17 years.\n\nFigure 5 The patient lost multiple teeth and suffered severe facial deformity 25 years after the pediatric rhabdomyosarcoma (RMS) cancer therapy.\n\nijerph-18-12158-t001_Table 1 Table 1 Cephalometric tracing measurements.\n\n\t\t11 y/o\t\t17 y/o\t\n\tP’t\tMean ± SD\tP’t\tMean ± SD\t\nSN\t58\t67.67 ± 2.82\t58\t73.37 ± 3.64\t\nSN- FH\t5.5\t7.36 ± 2.67\t6.5\t6.04 ± 3.32\t\nSN- MP\t41\t33.10 ± 4.69\t39\t26.38 ± 6.34\t\nSNA\t80\t82.00 ± 3.24\t80\t83.99 ± 4.20\t\nSNB\t82\t77.60 ± 3.21\t81\t81.76 ± 4.03\t\nANB\t−2\t4.40 ± 1.56\t−1\t2.24 ± 2.13\t\nA-Nv\t−5\t−0.81 ± 2.36\t−3.5\t0.02 ± 3.59\t\nB-Nv\t−4\t−8.91 ± 4.07\t−4\t−4.24 ± 5.12\t\nS-Go (PFH)\t64\t75.18 ± 3.99\t72\t94.53 ± 6.89\t\nN- Me (AFH)\t108\t117.41 ± 4.84\t115\t134.09 ± 5.16\t\nN-A (UFH)\t51\t59.27 ± 3.12\t52\t67.66 ± 2.79\t\nA-Me (LFH)\t57\t59.17 ± 3.52\t63\t66.99 ± 4.13\t\nPFH/AFH %\t59.26%\t64.11 ± 3.78\t62.61%\t70.61 ± 5.92\t\nUFH/LFH%\t89.47%\t100.50 ± 7.64\t82.54%\t101.28 ± 6.65\t\nGo-Gn\t67\t71.62 ± 3.09\t67\t85.36 ± 4.65\t\nAr-A (mm)\t69\t83.35 ± 3.41\t69\t94.29 ± 4.82\t\nAr- Gn (mm)\t99\t101.73 ± 3.69\t104\t122.18 ± 6.61\t\nAr-Go (mm)\t39\t42.97 ± 3.00\t46\t58.15 ± 6.15\t\nAr-Go-Gn\t137\t123.35 ± 3.87\t133\t115.96 ± 8.31\t\nU1-SN\t111\t105.13 ± 5.92\t101\t110.46 ± 6.35\t\nL1-MP\t77\t98.31 ± 5.67\t75\t101.56 ± 8.73\t\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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State Dent. J. 2003 69 58\n19. Collett W.K. Thonard J.C. The Effect of Fractional Radiation on Dentinogenesis in the Rat J. Dent. Res. 1965 44 84 90 10.1177/00220345650440013501 14245501\n20. Arsenault A.L. Robinson B.W. The dentino-enamel junction: A structural and microanalytical study of early mineralization Calcif. Tissue Int. 1989 45 111 121 10.1007/BF02561410 2505895\n21. Nawrocki L. Libersa P. Lambilliotte A. Pichon F. Turck D. Lafforgue P. Libersa J.C. Dental anomalies following anticancer chemotherapy Arch Pediatr. 2001 8 754 756 11484461\n22. Näsman M. Forsberg C.M. Dahllöf G. Long-term dental development in children after treatment for malignant disease Eur. J. Orthod. 1997 19 151 159 10.1093/ejo/19.2.151 9183064\n23. Morrish R.B. Jr. Chan E. Silverman S. Jr. Meyer J. Fu K.K. Greenspan D. Osteonecrosis in patients irradiated for head and neck carcinoma Cancer 1981 47 1980 1983 10.1002/1097-0142(19810415)47:8<1980::AID-CNCR2820470813>3.0.CO;2-Y 7226091\n24. Schubert M.M. Epstein J.B. Peterson D.E. Oral complications of cancer therapy Pharmacology and Therapeutics for Dentistry 4th ed. Yagiela J.A. Neidle E.A. Dowd F.J. Mosby-Year Book Inc. St. Louis, MO, USA 1998 644 655\n25. Epstein J.B. Schubert M.M. Oral mucositis in myelosuppressive cancer therapy Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol. 1999 88 273 276 10503852\n26. Kennedy H.F. Morrison D. Tomlinson D. Gibson B.E. Bagg J. Gemmell C.G. Gingivitis and toothbrushes: Potential roles in viridans streptococcal bacteraemia J. Infect. 2003 46 67 70 10.1053/jinf.2002.1084 12504614\n27. Da Fonseca M.A. Dental care of the pediatric cancer patient Pediatric Dent. 2004 26 53 57\n28. American Academy of Pediatric Dentistry Guideline on dental management of pediatric patients receiving chemotherapy, hematopoietic cell transplantation, and/or radiation Pediatric Dent. 2018 40 392 400\n29. Addems A. Epstein J.B. Damji S. Spinelli J. The lack of efficacy of a foam brush in maintaining gingival health: A controlled study Spec. Care Dentist. 1992 12 103 106 10.1111/j.1754-4505.1992.tb00423.x 1440126\n30. Ransier A. Epstein J.B. Lunn R. Spinelli J. A combined analysis of a toothbrush, foam brush, and a chlorhexidine-soaked foam brush in maintaining oral hygiene Cancer Nurs. 1995 18 393 396 10.1097/00002820-199510000-00009 7585494\n31. Daeffler R. Oral hygiene measures for patients with cancer. I Cancer Nurs. 1980 3 347 356 10.1097/00002820-198010000-00001 6996805\n32. Spak C.J. Johnson G. Ekstrand J. Caries incidence, salivary flow rate and efficacy of fluoride gel treatment in irradiated patients Caries Res. 1994 28 388 393 10.1159/000262007 8001064\n33. Barker G.J. Current practices in the oral management of the patient undergoing chemotherapy or bone marrow transplantation Support. Care Cancer 1999 7 17 20 10.1007/s005200050217 9926969\n34. American Academy of Pediatric Dentistry Guideline on Fluoride Therapy Pediatric Dent. 2016 38 181 184\n35. American Academy of Pediatric Dentistry Guideline on Caries-risk Assessment and Management for Infants, Children, and Adolescents Pediatric Dent. 2017 15 197 204\n36. Hong C.H. da Fonseca M. Considerations in the Pediatric Population with Cancer Dent. Clin. N. Am. 2008 52 155 181 10.1016/j.cden.2007.10.001 18154869\n37. Llena C. Forner L. Baca P. Anticariogenicity of casein phosphopeptide-amorphous calcium phosphate: A review of the literature J. Contemp. Dent. Pract. 2009 10 1 9 10.5005/jcdp-10-3-1\n38. Konings A.W. Coppes R.P. Vissink A. On the mechanism of salivary gland radiosensitivity Int. J. Radiat. Oncol. Biol. Phys. 2005 62 1187 1194 10.1016/j.ijrobp.2004.12.051 15990024\n39. Gornitsky M. Shenouda G. Sultanem K. Katz H. Hier M. Black M. Velly A.M. Double-blind randomized, placebo-controlled study of pilocarpine to salvage salivary gland function during radiotherapy of patients with head and neck cancer Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol. 2004 98 45 52 10.1016/j.tripleo.2004.04.009\n40. Rapidis A.D. Dijkstra P.U. Roodenburg J.L. Rodrigo J.P. Rinaldo A. Strojan P. Takes R.P. Ferlito A. Trismus in patients with head and neck cancer: Etiopathogenesis, diagnosis and management Clin. Otolaryngol. 2015 40 516 526 10.1111/coa.12488 26098612\n41. Wang C.J. Huang E.Y. Hsu H.C. Chen H.C. Fang F.M. Hsiung C.Y. The degree and time-course assessment of radiation-induced trismus occurring after radiotherapy for nasopharyngeal cancer Laryngoscope 2005 115 1458 1460 10.1097/01.mlg.0000171019.80351.46 16094124\n42. Dental Management of Pediatric Patients Receiving Immunosuppressive Therapy and/or Radiation Therapy Pediatric Dent. 2018 40 392 400\n43. Karsila-Tenovuo S. Jahnukainen K. Peltomäki T. Minn H. Kulmala J. Salmi T.T. Rönning O. Disturbances in craniofacial morphology in children treated for solid tumors Oral Oncol. 2001 37 586 592 10.1016/S1368-8375(01)00002-1 11564580\n44. Dahllöf G. Forsberg C.M. Ringdén O. Bolme P. Borgström B. Näsman M. Heimdahl A. Modéer T. Facial growth and morphology in long-term survivors after bone marrow transplantation Eur. J. Orthod. 1989 11 332 340 10.1093/oxfordjournals.ejo.a036004 2687011\n45. Sonis A.L. Tarbell N. Valachovic R.W. Gelber R. Schwenn M. Sallan S. Dentofacial development in long-term survivors of acute lymphoblastic leukemia A Comp. Three Treat. Modalities Cancer 1990 66 2645 2652\n46. Guyuron B. Dagys A.P. Munro I.R. Ross R.B. Effect of irradiation on facial growth: A 7- to 25-year follow-up Ann. Plast. Surg. 1983 11 423 427 10.1097/00000637-198311000-00010 6651172\n47. Pruzinsky T. Social and psychological effects of major craniofacial deformity Cleft Palate Craniofacial J. 1992 29 578 584 578–584; discussion 570 10.1597/1545-1569_1992_029_0578_sapeom_2.3.co_2 1450200\n48. Fromm M. Littman P. Raney R.B. Nelson L. Handler S. Diamond G. Stanley C. Late effects after treatment of twenty children with soft tissue sarcomas of the head and neck Cancer 1986 57 2070 2076 10.1002/1097-0142(19860515)57:10<2070::AID-CNCR2820571032>3.0.CO;2-G 3955515\n49. De Smet A.A. Kuhns L.R. Fayos J.V. Holt J.F. Effects of radiation therapy on growing long bones Am. J. Roentgenol. 1976 127 935 939 10.2214/ajr.127.6.935 998830\n50. Samuelsson B.O. Márky I. Rosberg S. Albertsson-Wikland K. Growth and growth hormone secretion after treatment for childhood non-Hodgkin’s lymphoma Med. Pediatric Oncol. 1997 28 27 34 10.1002/(SICI)1096-911X(199701)28:1<27::AID-MPO6>3.0.CO;2-V\n51. Denys D. Kaste S.C. Kun L.E. Chaudhary M.A. Bowman L.C. Robbins K.T. The effects of radiation on craniofacial skeletal growth: A quantitative study Int. J. Pediatric Otorhinolaryngol. 1998 45 7 13 10.1016/S0165-5876(98)00028-7\n52. Mishra S. Orthodontic Therapy for Paediatric Cancer Survivors: A Review J. Clin. Diagn. Res. 2017 11 Ze01 Ze04 10.7860/JCDR/2017/23916.9404 28658925\n53. Sheller B. Williams B. Orthodontic management of patients with hematologic malignancies Am. J. Orthod. Dentofac. Orthop. 1996 109 575 580 10.1016/S0889-5406(96)70068-9\n54. Costa M.T. Lenza M.A. Gosch C.S. Costa I. Ribeiro-Dias F. In vitro evaluation of corrosion and cytotoxicity of orthodontic brackets J. Dent. Res. 2007 86 441 445 10.1177/154405910708600510 17452565\n55. Hamula D.W. Hamula W. Sernetz F. Pure titanium orthodontic brackets J. Clin. Orthod. 1996 30 140 144 8975013\n56. Krishnan V. Davidovitch Z. Cellular, molecular, and tissue-level reactions to orthodontic force Am. J. Orthod. Dentofac. Orthop. 2006 129 469.e1 469.e32 10.1016/j.ajodo.2005.10.007 16627171\n57. Levander E. Malmgren O. Eliasson S. Evaluation of root resorption in relation to two orthodontic treatment regimes. A clinical experimental study Eur. J. Orthod. 1994 16 223 228 10.1093/ejo/16.3.223 8062862\n58. Dahllöf G. Jönsson A. Ulmner M. Huggare J. Orthodontic treatment in long-term survivors after pediatric bone marrow transplantation Am. J. Orthod. Dentofac. Orthop. 2001 120 459 465 10.1067/mod.2001.118102\n59. Rosenberg S.W. Oral complications of cancer therapies. Chronic dental complications NCI Monogr. 1990 9 173 178\n60. Kaste S.C. Hopkins K.P. Micrognathia after radiation therapy for childhood facial tumors: Report of two cases with long-term follow-up Oral Surg. Oral Med. Oral Pathol. 1994 77 95 99 10.1016/S0030-4220(06)80115-5\n61. Lockney N.A. Friedman D.N. Wexler L.H. Sklar C.A. Casey D.L. Wolden S.L. Late Toxicities of Intensity-Modulated Radiation Therapy for Head and Neck Rhabdomyosarcoma Pediatric Blood Cancer 2016 63 1608 1614 10.1002/pbc.26061 27195454\n62. Raney R.B. Anderson J.R. Kollath J. Vassilopoulou-Sellin R. Klein M.J. Heyn R. Glicksman A.S. Wharam M. Crist W.M. Maurer H.M. Late effects of therapy in 94 patients with localized rhabdomyosarcoma of the orbit: Report from the Intergroup Rhabdomyosarcoma Study (IRS)-III, 1984–1991 Med. Pediatric Oncol. 2000 34 413 420 10.1002/(SICI)1096-911X(200006)34:6<413::AID-MPO6>3.0.CO;2-4\n\n",
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"title": "A Long-Term Follow-Up of Dental and Craniofacial Disturbances after Cancer Therapy in a Pediatric Rhabdomyosarcoma Patient: Case Report.",
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"abstract": "Patients with continuous-flow left ventricle assist devices are at risk for gastrointestinal bleeding from angiodysplastic bowel lesions. Neoangiogenesis secondary to von Willebrand factor degradation and increased vascular endothelial growth factor (VEGF) signalling is likely related to their pathophysiology. We speculated that propranolol, known to downregulate VEGF signalling, could be beneficial in patients with recurrent bleeding episodes and anaemia. In this case report, we present a short-term outcome of 2 patients treated with propranolol.",
"affiliations": "Department of Cardiothoracic Surgery, Heart and Lung Center, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland.;Department of Cardiothoracic Surgery, Heart and Lung Center, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland.;Department of Cardiothoracic Surgery, Heart and Lung Center, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland.",
"authors": "Stark|Christoffer|C|;Kiss|Jan|J|;Lemström|Karl|K|",
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"mesh_terms": "D000740:Anemia; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D011433:Propranolol; D014665:Vasodilator Agents",
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"title": "Propranolol for gastrointestinal bleeding in two patients with continuous flow left ventricle assist device.",
"title_normalized": "propranolol for gastrointestinal bleeding in two patients with continuous flow left ventricle assist device"
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"abstract": "Fludarabine and lenalidomide are essential drugs in the front-line treatment of non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), respectively. Data suggests that fludarabine and lenalidomide therapy may have a deleterious effect on stem cell mobilization. In the European compassionate use program, 48 patients (median age 57 years) previously treated with fludarabine (median 5 cycles; range: 1-7 cycles) were given plerixafor plus granulocyte colony-stimulating factor (G-CSF) for remobilization following a primary mobilization attempt. The overall median number of CD34+ cells collected was 2.3 × 10(6)/kg (range: 0.3-13.4). The minimum required number of CD34+ cells (≥2.0 × 10(6)/kg) was collected from 58% of patients in a median of 2 days. Thirty-five patients (median age = 57 years) previously treated with lenalidomide (median 5 cycles; range: 1-10 cycles) were given plerixafor plus G-CSF for remobilization. The overall median number of CD34+ cells collected was 3.4 × 10(6)/kg (range: 1.1-14.8). The minimum required number of CD34+ cells (≥2.0 × 10(6) per kg) was collected from 69% of patients in a median of 2 days. In conclusion, salvage mobilization with plerixafor plus G-CSF is successful in the majority of patients with MM previously treated with lenalidomide. In fludarabine-exposed patients, only 58% of patients will achieve successful salvage mobilization with plerixafor plus G-CSF, suggesting the need for novel mobilization regimens algorithms in this subgroup of patients.",
"affiliations": "Centre Hospitalier et Universitaire de Nantes, Service d'Hématologie Clinique, Nantes, Université de Nantes, Centre d'Investigation Clinique en Cancérologie (CI2C), INSERM CRNCA UMR 892, Nantes, France.",
"authors": "Malard|Florent|F|;Kröger|Nicolaus|N|;Gabriel|Ian H|IH|;Hübel|Kai|K|;Apperley|Jane F|JF|;Basak|Grzegorz W|GW|;Douglas|Kenneth W|KW|;Geraldes|Catarina|C|;Jaksic|Ozren|O|;Koristek|Zdenek|Z|;Lanza|Francesco|F|;Lemoli|Roberto|R|;Mikala|Gabor|G|;Selleslag|Dominik|D|;Worel|Nina|N|;Mohty|Mohamad|M|;Duarte|Rafael F|RF|",
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"mesh_terms": "D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001596:Benzylamines; D057176:Compassionate Use Trials; D000080027:Cyclams; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006571:Heterocyclic Compounds; D006801:Humans; D000077269:Lenalidomide; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D036102:Peripheral Blood Stem Cell Transplantation; D013792:Thalidomide; D013997:Time Factors; D014182:Transplantation, Autologous; D014740:Vidarabine",
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"title": "Plerixafor for autologous peripheral blood stem cell mobilization in patients previously treated with fludarabine or lenalidomide.",
"title_normalized": "plerixafor for autologous peripheral blood stem cell mobilization in patients previously treated with fludarabine or lenalidomide"
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"abstract": "BACKGROUND\nHormone-refractory breast cancer metastatic to bone is a clinically challenging disease associated with high morbidity, poor prognosis, and impaired quality of life owing to pain and skeletal-related events. In a preclinical study using a mouse model of breast cancer and bone metastases, Ra-223 dichloride was incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. Ra-223 dichloride also induced double-strand DNA breaks in cancer cells in vivo.\n\n\nMETHODS\nThe US Food and Drug Administration recently approved radium-223 (Ra-223) dichloride (Ra-223; Xofigo injection) alpha-particle therapy for the treatment of symptomatic bone metastases in patients with castration-resistant prostate cancer. On the basis of a strong preclinical rationale, we used Ra-223 dichloride to treat bone metastases in a patient with breast cancer.\n\n\nRESULTS\nA 44-year-old white woman with metastatic breast cancer who was estrogen receptor-positive, BRCA1-negative, BRCA2-negative, PIK3CA mutation (p.His1047Arg) positive presented with diffuse bony metastases and bone pain. She had hormone refractory and chemotherapy refractory breast cancer. After Ra-223 therapy initiation her bone pain improved, with corresponding decrease in tumor markers and mixed response in (18)F-FDG PET/CT and (18)F-NaF bone PET/CT. The patient derived clinical benefit from therapy.\n\n\nCONCLUSIONS\nWe have shown that Ra-223 dichloride can be safely administered in a patient with hormone-refractory bone metastasis from breast cancer at the US FDA-approved dose for prostate cancer. Furthermore, because the treatment did not cause any drop in hematologic parameters, it has the potential to be combined with other radiosensitizing therapies, which may include chemotherapy or targeted therapies. Given that Ra-223 dichloride is already commercially available, this case report may help future patients and provide a rationale for initiating clinical research in the use of Ra-223 dichloride to treat bone metastasis from breast cancer. A randomized clinical trial is needed to provide evidence of efficacy, safety, and good outcomes.",
"affiliations": "PET Imaging Center, Biomedical Research Foundation of Northwest Louisiana, Shreveport, LA 71103, USA.;PET Imaging Center, Biomedical Research Foundation of Northwest Louisiana, Shreveport, LA 71103, USA.;Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.",
"authors": "Takalkar|Amol|A|;Adams|Scott|S|;Subbiah|Vivek|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/2162-3619-3-23",
"fulltext": "\n==== Front\nExp Hematol OncolExp Hematol OncolExperimental Hematology & Oncology2162-3619BioMed Central 2162-3619-3-2310.1186/2162-3619-3-23Short ReportRadium-223 dichloride bone-targeted alpha particle therapy for hormone-refractory breast cancer metastatic to bone Takalkar Amol 1atakalka@biomed.orgAdams Scott 1sadams@lsuhsc.eduSubbiah Vivek 2vsubbiah@mdanderson.org1 PET Imaging Center, Biomedical Research Foundation of Northwest Louisiana, Shreveport, LA 71103, USA2 Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA2014 8 9 2014 3 23 23 7 7 2014 18 8 2014 Copyright © 2014 Takalkar et al.; licensee BioMed Central Ltd.2014Takalkar et al.; licensee BioMed Central Ltd.This 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 credited. 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\nHormone-refractory breast cancer metastatic to bone is a clinically challenging disease associated with high morbidity, poor prognosis, and impaired quality of life owing to pain and skeletal-related events. In a preclinical study using a mouse model of breast cancer and bone metastases, Ra-223 dichloride was incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. Ra-223 dichloride also induced double-strand DNA breaks in cancer cells in vivo.\n\nMethods\nThe US Food and Drug Administration recently approved radium-223 (Ra-223) dichloride (Ra-223; Xofigo injection) alpha-particle therapy for the treatment of symptomatic bone metastases in patients with castration-resistant prostate cancer. On the basis of a strong preclinical rationale, we used Ra-223 dichloride to treat bone metastases in a patient with breast cancer.\n\nResults\nA 44-year-old white woman with metastatic breast cancer who was estrogen receptor–positive, BRCA1-negative, BRCA2-negative, PIK3CA mutation (p.His1047Arg) positive presented with diffuse bony metastases and bone pain. She had hormone refractory and chemotherapy refractory breast cancer. After Ra-223 therapy initiation her bone pain improved, with corresponding decrease in tumor markers and mixed response in 18F-FDG PET/CT and 18F-NaF bone PET/CT. The patient derived clinical benefit from therapy.\n\nConclusion\nWe have shown that Ra-223 dichloride can be safely administered in a patient with hormone-refractory bone metastasis from breast cancer at the US FDA–approved dose for prostate cancer. Furthermore, because the treatment did not cause any drop in hematologic parameters, it has the potential to be combined with other radiosensitizing therapies, which may include chemotherapy or targeted therapies. Given that Ra-223 dichloride is already commercially available, this case report may help future patients and provide a rationale for initiating clinical research in the use of Ra-223 dichloride to treat bone metastasis from breast cancer. A randomized clinical trial is needed to provide evidence of efficacy, safety, and good outcomes.\n\nRadium 223XofigoBreast cancerBone metastasesAlpha particleUnusual responderOutlier responderExceptional responder\n==== Body\nIntroduction\nHormone-refractory breast cancer metastatic to bone is a clinically challenging disease associated with high morbidity and poor prognosis. Common complications of bone metastasis include skeletal-related events such as pathologic fractures, spinal cord compression, and nerve root compression, as well as hypercalcemia of malignancy. Moreover, bone pain impairs quality of life in patients with bone metastases. Strategies to target bone metastases have included bisphosphonate therapy (zoledronic acid), receptor activator of nuclear factor kappa-B ligand (RANK-L)–directed monoclonal antibody therapy (denosumab), and palliative radiation in addition to systemic therapy [1-4]. A recent major therapeutic advance was the US Food and Drug Administration (FDA) approval of radium-223 (Ra-223) dichloride (Xofigo injection, Bayer HealthCare Pharmaceuticals Inc) alpha particle therapy for the treatment of symptomatic bone metastases in patients with castration-resistant prostate cancer and no known visceral metastatic disease [3,5-8]. Ra-223 is an isotope of radium with an 11.4-day half-life, in contrast with the common isotope Ra-226, discovered by the Curies, which has a 1601-year half-life.\n\nIn a preclinical study using a mouse model of breast cancer and bone metastases, Ra-223 dichloride was incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. Ra-223 dichloride also induced double-strand DNA breaks in cancer cells in vivo[9]. Moreover, Ra-223 dichloride extended survival duration when administered as a single agent or in combination with zoledronic acid or chemotherapy (doxorubicin) compared with control [9]. On the basis of this strong preclinical rationale, we used Ra-223 dichloride to treat bone metastases in a patient with breast cancer, and the patient derived clinical benefit from the therapy. This case report may help future patients and provide a rationale for initiating clinical research in the use of Ra-223 dichloride to treat bone metastases from breast cancer.\n\nClinical case report\nA 44-year-old white woman with a history of hypertension, hypercholesterolemia, hypothyroidism, anxiety, and renal stones presented in September 1992 with metastatic breast cancer. At the time of diagnosis, her breast tumor was estrogen receptor–positive, BRCA1-negative, and BRCA2-negative, and the tumor had spread to 8 of 16 lymph nodes. She received frontline standard chemotherapy with doxorubicin, 5-fluorouracil, methotrexate, and cyclophosphamide for 9 months, followed by oral tamoxifen for 4 years and 6 months.\n\nShe was clinically stable until the summer of 2002, when she started to complain of back pain. Magnetic resonance imaging of the spine revealed osseous metastatic disease in the spine involving the T1 vertebral body. She was treated with directed radiation for 5 weeks and then started taking the oral nonsteroidal aromatase inhibitor letrozole, which she continued for 2 years, along with zoledronic acid.\n\nIn April 2006, her tumor marker CA27-29 levels increased to 76 U/mL. Magnetic resonance imaging and computed tomography (CT) scans showed progressive disease with multifocal osseous metastatic disease involving the spine. She ceased treatment with oral letrozole and started taking fulvestrant, a selective estrogen receptor downregulator, and she continued taking zoledronic acid. Her CA27-29 levels initially decreased but then increased again to 37 U/mL in November 2006. She continued with the anti-hormonal therapy (fulvestrant and zoledronic acid), adding progesterone cream to her regimen in April and May 2007. In November 2007, her CA27-29 levels decreased to 24 U/mL.\n\nShe continued with the same anti-hormonal therapy from 2010 until 2013, when she was once again diagnosed with metastatic disease. In May 2013, she started systemic therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with exemestane. She received only 3 cycles, with a starting dose of 2.5 mg orally every day. The 6-week therapy was complicated by shingles and abnormal liver enzymes, and CA27-29 levels markedly increased to 705 U/mL. A CT scan on August 15, 2013, revealed no evidence of visceral metastatic disease but showed stable osseous metastatic disease in the spine. She reported progressive bone pain affecting her back, shoulder, and pelvic regions.\n\nThe patient was then referred to The University of Texas MD Anderson Cancer Center Clinical Center for Targeted Therapy to receive molecularly targeted therapy. Pathologic review showed that the spinal tumor cells were strongly positive for estrogen receptor (90%) and moderately positive for progesterone receptor (15%). In addition, HER-2/neu protein overexpression was equivocal (score 2+, 80%), and the Ki-67 proliferation index was positive in less than 10% of tumor cells. Consistent with the pathology report, HER-2/neu gene amplification according to fluorescence in situ hybridization was reported as equivocal (score 1.83). This immune profile was consistent with a breast tumor origin. A next generation sequencing–based analysis for the detection of frequently reported (hotspot) mutations in a total of 50 genes was performed on DNA extracted from an archival sample from the patient in the MD Anderson CLIA-certified molecular diagnostics laboratory. PIK3CA mutation was detected in codon 1047, exon 21 (CAT to CGT) of the PIK3CA gene, which would change the encoded amino acid from histidine to arginine (p.His1047Arg). Imaging studies confirmed that the patient had metastatic disease only in her bones, and no visceral disease. Although several trials were available for treatments targeting the PIK3CA pathway, she was unfortunately not a candidate for the trials because she had no RECIST measurable disease.\n\nShe was then referred to Biomedical Research Foundation of Northwest Louisiana for evaluation and treatment with bone-targeted therapy that included Ra-223. Because of the lack of therapy options for hormone-refractory bone metastasis from breast cancer, as well as the strong preclinical data, Ra-223 dichloride therapy was considered. Active osseous metastatic disease without any visceral metastatic disease was confirmed by 18F-FDG positron emission tomography (PET)/CT and 18F-NaF bone PET/CT imaging prior to Ra-223 consideration. The patient was counseled about the risks and potential benefits of the therapy, the off-label nature of the therapy, and expected adverse events, as well as required precautions to be taken after Ra-223 is administered. Laboratory evaluation was then performed (complete blood count and chemistry profile) to ensure that the patient was eligible for Ra-223 dichloride therapy. After the patient provided informed consent for the off-label use of Ra-223, she was treated with Ra-223 dichloride at a dose of 50 KBq/kg (or 1.35 uCi/kg) every 4 weeks. A total of 6 treatments were planned, and at the time this case report was written, she had completed 4 of the 6 planned treatments. Before each treatment, laboratory evaluation was performed to assess for adverse events related to hematologic parameters and to measure markers (CA27-29 and serum alkaline phosphate). After 2 treatments, 18F-FDG PET/CT and 18F-NaF bone PET/CT imaging studies were performed to evaluate disease status.The patient reported significant improvement in her pain soon after the first treatment and has reported incremental and sustained improvement in her pain with subsequent treatments. This was accompanied by laboratory evidence of response: CA27-29 levels were 957.6 U/mL at baseline prior to first treatment and have consistently decreased with each treatment, to 483.9 U/mL after 4 treatments. Serum alkaline phosphate levels were 134 IU/L at baseline prior to first treatment and have also consistently decreased with each treatment, to 99 IU/L after 4 treatments. Figure 1 shows a graphical representation of the decreases in CA27-29 (A) and alkaline phosphate levels (B). At the time of this report (after 4 treatments), she reported being pain-free without any analgesics, with a very good quality of life and without any restrictions in her daily activities.\n\nFigure 1 Graphical representation of tumor marker and alkaline phosphatase over time. A: Tumor marker CA 27–29 levels after each treatment with radium-223 (Ra-223) dichloride, B: Serial alkaline phosphate (ALP) levels after each treatment with Ra-223 dichloride.\n\n18F-FDG PET/CT and 18F-NaF bone PET/CT imaging at baseline prior to the first treatment showed multifocal osseous metastatic disease with intense uptake. Repeat qualitative and quantitative 18F-FDG PET/CT and 18F-NaF bone PET/CT imaging after 2 treatments (but prior to the third treatment) showed an overall mixed change in the lesions, with improvement in some lesions but potential progression in others. The lesions were assessed for their uptake of FDG and NaF (semiquantitatively, using the standardized uptake value [SUV]) as well as for their density on the CT portion of the study (Hounsfield units [HU]).\n\nFor the sake of this report, 2 index lesions were selected for analysis on the 18F-FDG PET/CT (Figure 2) and 18F-NaF bone PET/CT (Figure 3) imaging studies. At baseline, the 18F-FDG PET/CT study showed a lesion in the L-2 vertebral body with a maximum SUV of 9.8 and an average SUV of 6.1, and maximum HU of 573 and average HU of 398.9; as well as a lesion in the right proximal femur with a maximum SUV of 12.3 and an average SUV of 7.6, and maximum HU of 348 and average HU of 130.9. On the 18F-FDG PET/CT study performed after 2 treatments, the lesion in the L-2 vertebral body appeared less intense and more dense or sclerotic, with a maximum SUV of 7.9 and an average SUV of 4.7, and maximum HU of 636 and average HU of 489.8. This indicates interval improvement. However, the lesion in the right proximal femur appeared larger and more intense, with a maximum SUV of 13.2 and an average SUV of 8.2, and maximum HU of 304 and average HU of 95.1. This indicates potential interval worsening or progression.\n\nFigure 2 Imaging study with 18F-FDG PET/CT. A: 18F-FDG PET/CT imaging studies at baseline, before administration of radium-223 (Ra-223) dichloride, B: 8F-FDG PET/CT imaging studies after 2 treatments with Ra-223 dichloride but before the third treatment.\n\nFigure 3 Imaging study with 18Na-F Bone PET/CT. A: 18NA-F bone PET/CT imaging studies at baseline, before administration of radium-223 (Ra-223) dichloride, B: 8NA-F bone PET/CT imaging studies after 2 treatments with Ra-223 dichloride but before the third treatment.\n\nSimilarly, at baseline, the 18F-NaF bone PET/CT study showed a lesion in the left scapula with a maximum SUV of 54.6 and an average SUV of 33.3, and maximum HU of 687 and average HU of 179.6; as well as a lesion in the right proximal femur with a maximum SUV of 31.3 and an average SUV of 17.7, and maximum HU of 431 and average HU of 152.3. On the 18F-NaF bone PET/CT study performed after 2 treatments, the lesion in the left scapula appeared less intense and more dense or sclerotic, with a maximum SUV of 21.4 and an average SUV of 13.4, and maximum HU of 757 and average HU of 234.4. This indicates interval improvement. However, the lesion in the right proximal femur appeared larger and more intense, with a maximum SUV of 52.6 and an average SUV of 31.4, and maximum HU of 265 and average HU of 125.7. This indicates potential interval worsening or progression.\n\nDiscussion\nTo the best of our knowledge, we have reported the first clinical case of hormone-refractory bone metastases from breast cancer responding to alpha-particle Ra-223 therapy outside the context of a clinical trial, soon after US FDA approval of Ra-223 dichloride for the treatment of bone metastases from prostate cancer. After the submission of this case study a phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease was also published [10]. Twenty-three advanced breast cancer patients with relapsed breast cancer in the bone were administered radium-223 (50 kBq/kg IV) every 4 weeks for 4 cycles. It was demonstrated that Radium-223 was safe in breast cancer in addition to clinically target areas of increased bone metabolism [10].\n\nCancer-related mortality is often the result of metastatic disease, especially metastases in the lungs, brain, liver, and bone. For bone metastases, bisphosphonates and RANK-L monoclonal antibody are the mainstay targeted therapies, in addition to the systemic therapy armamentarium [4]. Radiotherapy is palliative, and previous beta particle therapies such as samarium are toxic to bone marrow and have limited effectiveness because they cannot be combined with other systemic therapies.\n\nOngoing clinical trials of treatments involving radium include expanded use of cabazitaxel for the treatment of prostate cancer, Alpharadin for the treatment of bone-dominant metastatic breast cancer no longer considered suitable for hormone therapy (NCT01070485), and a phase I dose escalation trial of monthly intravenous Ra-223 dichloride for the treatment of osteosarcoma (NCT01833520).\n\nFor the patient in the current case report, we observed a positive treatment effect of Radium 223 in hormone-refractory bone metastases from breast cancer. Close follow-up with imaging and monitoring of serial tumor markers is planned. Our initial assessment indicated a very good clinical response, with a significant drop in tumor and alkaline phosphatase marker levels. Imaging results were more mixed, and further investigation is needed to determine the potential for the flare phenomenon and the most optimal imaging modality.\n\nConclusion\nWe have shown that Ra-223 dichloride can be administered without toxicity in a patient with hormone-refractory bone metastasis from breast cancer at the US FDA–approved dose for prostate cancer. Furthermore, because the treatment did not cause any drop in hematologic parameters, it has the potential to be combined with other radiosensitizing therapies, which may include chemotherapy or targeted therapies. Given that Ra-223 dichloride is already available on the market, this case report may help future patients and provide a rationale for initiating clinical research in the use of Ra-223 dichloride to treat bone metastasis from breast cancer. A randomized clinical trial is needed to provide evidence of efficacy, safety, and good outcomes.\n\n• Hormone-refractory bone metastasis from breast cancer is associated with high morbidity, poor prognosis, and impaired quality of life owing to pain and skeletal-related events.\n\n• The US Food and Drug Administration recently approved radium-223 (Ra-223) dichloride (Xofigo injection, Bayer HealthCare Pharmaceuticals Inc) alpha particle therapy for the treatment of symptomatic bone metastases in patients with castration-resistant prostate cancer.\n\n• We used Ra-223 dichloride to successfully treat hormone-refractory bone metastases in a patient with breast cancer.\n\n• Our initial assessment indicated a very good clinical response, with a significant drop in tumor and bone turnover marker levels; however, imaging results were more mixed, and further investigation is needed.\n\n• Ra-223 dichloride can be safely administered in a patient with hormone-refractory bone metastases from breast cancer.\n\n• A randomized clinical trial is needed to provide evidence of efficacy, safety, and good outcomes.\n\nPatient disclosure\nThe authors state that they have obtained informed consent from the patient for the administration of radium off label.\n\nCompeting interests\nAmol Takalkar, MD, is on the Bayer Healthcare Speaker Bureau and has served on the Advisory Committee for Bayer Healthcare Pharmaceuticals. Vivek Subbiah, MD has research support from Bayer and served on medical advisory board. All other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was used in the production of this manuscript.\n\nAuthors’ contributions\nAll authors contributed to writing the manuscript. AT, VS conceived the manuscript. AT, SA, VS analysed the data. VS, and AT wrote the paper. VS provided targeted therapy expertise and AT provided nuclear medicine expertise. All authors read and approved the final manuscript.\n\nAcknowledgments\nWe thank the patient for being motivated to seek treatment with radium-223 dichloride. Xofigo was provided by Bayer through the patient assistance program. The University of Texas MD Anderson Cancer Center is supported by Support grant (P30 CA016672) through the US National Institutes of Health.\n==== Refs\nSze WM Shelley M Held I Mason M Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of the randomised trials Cochrane Database Syst Rev 2004 2 CD004721 15106258 \nAnderson P Salazar-Abshire M Improving outcomes in difficult bone cancers using multimodality therapy, including radiation: physician and nursing perspectives Curr Oncol Rep 2006 8 6 415 422 10.1007/s11912-006-0069-6 17040619 \nKluetz PG Pierce W Maher VE Zhang H Tang S Song P Liu Q Haber MT Leutzinger EE Al-Hakim A Chen W Palmby T Alebachew E Sridhara R Ibrahim A Justice R Pazdur R Radium ra 223 dichloride injection: u.s. Food and drug administration drug approval summary Clin Canc Res 2014 20 1 9 14 10.1158/1078-0432.CCR-13-2665 \nEckhardt BL Francis PA Parker BS Anderson RL Strategies for the discovery and development of therapies for metastatic breast cancer Nat Rev Drug Discov 2012 11 6 479 497 10.1038/nrd2372 22653217 \nBaidoo KE Yong K Brechbiel MW Molecular pathways: targeted alpha-particle radiation therapy Clin Canc Res 2013 19 3 530 537 10.1158/1078-0432.CCR-12-0298 \nBruland OS Jonasdottir TJ Fisher DR Larsen RH Radium-223: From Radiochemical Development to Clinical Applications in Targeted Cancer Therapy Current Radoipharmaceuticals 2008 1 1 203 208 \nBruland OS Nilsson S Fisher DR Larsen RH High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Canc Res 2006 12 20 Pt 2 6250s 6257s \nParker C Nilsson S Heinrich D Helle SI O'Sullivan JM Fossa SD Chodacki A Wiechno P Logue J Seke M Widmark A Johannessen DC Hoskin P Bottomley D James ND Solberg A Syndikus I Kliment J Wedel S Boehmer S Dall'Oglio M Franzén L Coleman R Vogelzang NJ O'Bryan-Tear CG Staudacher K Garcia-Vargas J Shan M Bruland ØS Sartor O Alpha emitter radium-223 and survival in metastatic prostate cancer New Engl J Med 2013 369 3 213 223 10.1056/NEJMoa1213755 23863050 \nSuominen MI Rissanen JP Kakonen R Fagerlund KM Alhoniemi E Mumberg D Ziegelbauer K Halleen JM Kakonen SM Scholz A Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis J Natl Canc Inst 2013 105 12 908 916 10.1093/jnci/djt116 \nColeman R Aksnes AK Naume B Garcia C Jerusalem G Piccart M Vobecky N Thuresson M Flamen P A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease Breast Canc Res Treat 2014 145 2 411 418 10.1007/s10549-014-2939-1\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2162-3619",
"issue": "3()",
"journal": "Experimental hematology & oncology",
"keywords": "Alpha particle; Bone metastases; Breast cancer; Exceptional responder; Outlier responder; Radium 223; Unusual responder; Xofigo",
"medline_ta": "Exp Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "101590676",
"other_id": null,
"pages": "23",
"pmc": null,
"pmid": "25243101",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "23863050;17062709;17040619;23230321;22653217;24728613;24190979;15106258;23682134",
"title": "Radium-223 dichloride bone-targeted alpha particle therapy for hormone-refractory breast cancer metastatic to bone.",
"title_normalized": "radium 223 dichloride bone targeted alpha particle therapy for hormone refractory breast cancer metastatic to bone"
} | [
{
"companynumb": "PHHY2014US146264",
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"activesubstancename": "EVEROLIMUS"
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{
"abstract": "Pipeline Embolization Device (PED; Medtronic) \"twisting\" manifests with the appearance of a \"figure 8\" in perpendicular planes on digital subtraction angiography. This phenomenon has received little attention in the literature, requires technical precision to remediate, and has potential to cause ischemic stroke if not properly remediated.\n\n\n\nTo report incidence, risk factors, and sequelae of PED twisting and to discuss techniques to remediate a PED twist.\n\n\n\nCase images were reviewed for instances of twisting from a prospectively-maintained, Institutional Review Board-approved cohort of patients undergoing flow diversion for cerebral aneurysm.\n\n\n\nFrom August 2011 to December 2017, 999 PED flow diverting stents were attempted in 782 cases for 653 patients. A total of 25 PED twists were observed while treating 20 patients (2.50%, 25/999). Multivariate analysis revealed predictors of twisting to be: Large and giant aneurysms (odds ratio (OR) = 9.66, P = .005; OR = 27.47, P < .001), increased PED length (OR = 1.14, P < .001), and advanced patient age (OR = 1.07, P = .002). Twisted PEDs were able to be remediated 75% of the time, and procedural success was achieved in 90% of cases. PED twisting was not found to be a significant cause of major or minor complications. However, at long-term follow-up, there was a trend towards poor occlusion outcomes for the cases that encountered twisting.\n\n\n\nTwisting is a rare event during PED deployment that was more likely to occur while treating large aneurysms with long devices in older patients. While twisting did not lead to major complications in this study, remediation can be challenging and may be associated with inferior occlusion outcomes.",
"affiliations": "Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York.;Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Neurosurgery, University of California Irvine, Orange, California.;Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.;Department of Neurosurgery, University of California Irvine, Orange, California.;Department of Neurosurgery, University of California Los Angeles, Los Angeles, California.;Department of Neurosurgery, Carondelet Neurological Institute, Tucson, Arizona.",
"authors": "Bender|Matthew T|MT|;Young|Robert W|RW|;Zarrin|David A|DA|;Campos|Jessica K|JK|;Caplan|Justin M|JM|;Huang|Judy|J|;Tamargo|Rafael J|RJ|;Lin|Li-Mei|LM|;Colby|Geoffrey P|GP|;Coon|Alexander L|AL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/neuros/nyaa309",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-396X",
"issue": "88(1)",
"journal": "Neurosurgery",
"keywords": "Cerebral aneurysm; Complication; Flow diversion; Pipeline embolization device; Twisting",
"medline_ta": "Neurosurgery",
"mesh_terms": "D000328:Adult; D000368:Aged; D001807:Blood Vessel Prosthesis; D015331:Cohort Studies; D004621:Embolization, Therapeutic; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D015994:Incidence; D002532:Intracranial Aneurysm; D007431:Intraoperative Complications; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D015607:Stents; D016896:Treatment Outcome",
"nlm_unique_id": "7802914",
"other_id": null,
"pages": "25-35",
"pmc": null,
"pmid": "32658958",
"pubdate": "2020-12-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Twisting: Incidence and Risk Factors of an Intraprocedural Challenge Associated With Pipeline Flow Diversion of Cerebral Aneurysms.",
"title_normalized": "twisting incidence and risk factors of an intraprocedural challenge associated with pipeline flow diversion of cerebral aneurysms"
} | [
{
"companynumb": "US-BAYER-2021-086385",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "The differential diagnoses for preauricular swellings include dermoid cyst, lymph nodes, lipoma, nerve sheath tumours, parotid swelling, mastoiditis, vascular malformations and arterio-venous fistulas aneurysms/pseudoaneurysms. Superficial temporal artery pseudoaneurysm(s) (STAPA) are rare (1% of all aneurysms) vascular complications, which occur following a blunt injury of the head or iatrogenic causes. The use of anticoagulation therapy increases the risk of pseudoaneurysm formation. We present a case of traumatic STAPA while on oral anticoagulation. He was treated with surgical exploration, STAPA excision with ligation of the vessel. He had an uneventful recovery with a good functional and cosmetic outcome at 1 year.",
"affiliations": "Department of Vascular Surgery, Christian Medical College Vellore, Vellore, India.;Department of Vascular Surgery, Christian Medical College Vellore, Vellore, India albertkota@cmcvellore.ac.in.;Department of Vascular Surgery, Christian Medical College Vellore, Vellore, India.",
"authors": "Hazra|Darpanarayan|D|http://orcid.org/0000-0002-5941-0587;Kota|Albert Abhinay|AA|http://orcid.org/0000-0002-4313-803X;Agarwal|Sunil|S|",
"chemical_list": "D000925:Anticoagulants",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-234497",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(7)",
"journal": "BMJ case reports",
"keywords": "drug therapy related to surgery; radiology (diagnostics); valvar diseases; vascular surgery; warfarin therapy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000058:Accidental Falls; D000328:Adult; D017541:Aneurysm, False; D000925:Anticoagulants; D005145:Face; D016489:Head Injuries, Closed; D006801:Humans; D008297:Male; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32646934",
"pubdate": "2020-07-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Post-traumatic preauricular pulsatile swelling in a patient on oral anticoagulation therapy.",
"title_normalized": "post traumatic preauricular pulsatile swelling in a patient on oral anticoagulation therapy"
} | [
{
"companynumb": "IN-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-062079",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"dr... |
{
"abstract": "We report a case of a woman, who initially presented with an non-secreting multiple myeloma, 11 months later, she was diagnosed as an IgD-secreting myeloma. In December, 2010, the patient's serum protein quantification and immunofixation electrophoresis (IFE) revealed polyclonal immunoglobulin with no evidence of monoclonal immunoglobulin. However, her bone marrow smears revealed an abnormal proliferation of atypical plasma cells (46.5%), so she was diagnosed as non-secreting multiple myeloma. After three cycles of administration of Velcade plus Dexamethasone (VD), she achieved a complete remission (CR). Unfortunately, on October 31, 2011, our patient was found to have a separate peak of monoclonal component on the γ-region of cellulose-acetate electrophoresis, and the serum immunofixation electrophoresis revealed the monoclonal component was IgD. Several months later, she presented with a large swelling of the left side of her neck. Microscopic examination of a biopsy specimen from the cervical mass showed a neoplastic plasma cell tumor and she died on January 28, 2013 from acute respiratory failure resulting from neoplastic plasma cells infiltration and infection. Here we report this rare case and review the literature for similar cases.",
"affiliations": "Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430030, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430030, China.;Department of Cytological Room, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430030, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430030, China.;Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430030, China.",
"authors": "Gao|Lili|L|;Li|Qinlu|Q|;Kang|Jinsong|J|;Li|Chunrui|C|;Zhou|Jianfeng|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1940-5901",
"issue": "8(9)",
"journal": "International journal of clinical and experimental medicine",
"keywords": "IgD-λ; Non-secreting multiple myeloma; immunofixation electrophoresis; relapse; serum free light chain",
"medline_ta": "Int J Clin Exp Med",
"mesh_terms": null,
"nlm_unique_id": "101471010",
"other_id": null,
"pages": "16984-90",
"pmc": null,
"pmid": "26629254",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "14253483;14129718;17229655;5064586;16019554;24282995;19838394;15517373;19798094;5276287;3922877;7964956;10626149;1585921;23335087;9231172;12736293;23440663;1182674;9233573;1582977;7871954;9547329;3085748;22381082",
"title": "Non-secreting multiple myeloma switches to IgD of lamda type: a case report and review of literature.",
"title_normalized": "non secreting multiple myeloma switches to igd of lamda type a case report and review of literature"
} | [
{
"companynumb": "CN-CELGENE-CHN-2015120327",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Catheter ablation for atrial fibrillation is associated with a low rate of complications, with few reports of intracranial hemorrhage in the literature. Additionally, subarachnoid hemorrhage with spinal hematoma is also an uncommon pathology with less than 200 total cases to date described. A 78-year-old female with hypertension and atrial fibrillation on warfarin presented for catheter cryoablation and experienced periprocedural hypertension. Subsequently, post-procedure, the patient developed severe back pain, nausea, vomiting, altered consciousness, and paraplegia. Imaging demonstrated subarachnoid hemorrhage with hematoma compressing cord at the T4/5 level and infarction inferior to this level. The rare nature as well as presentation of this pathology, in the setting of a safe procedure, emphasizes the importance to re-evaluate diagnostic plans when patient presentation is inconsistent with expected post procedural course. 〈Learning objective: The rare nature as well as presentation of subarachnoid hemorrhage with spinal hematoma, in the setting of a safe catheter cryoablation for atrial fibrillation, emphasizes the importance to re-evaluate diagnostic plans when patient presentation is inconsistent with expected post procedural course.〉.",
"affiliations": "School of Medicine, University of California, Irvine, Irvine, CA, USA.;School of Medicine, University of California, Irvine, Irvine, CA, USA.",
"authors": "Cooley-Rieders|Keaton|K|;Paredes|Kyle|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2020.04.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "22(1)",
"journal": "Journal of cardiology cases",
"keywords": "Atrial fibrillation; Catheter ablation; Intracranial hemorrhage; Spinal hematoma; Subarachnoid hemorrhage",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "36-39",
"pmc": null,
"pmid": "32636968",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports",
"references": "26705560;15711890;24243785;28314875;8970938;19422987;28356246;31625997;24468720;12520314",
"title": "Rare pathology leading to a diagnostic challenge: A subarachnoid spinal hematoma after catheter cryoablation for atrial fibrillation.",
"title_normalized": "rare pathology leading to a diagnostic challenge a subarachnoid spinal hematoma after catheter cryoablation for atrial fibrillation"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-040640",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"dru... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to examine the impact of excessive caffeine consumption on therapeutic outcomes in bipolar disorder.\n\n\nRESULTS\nWe report on a case of a patient with bipolar disorder whose psychiatric symptoms were ameliorated with the elevation of lithium concentrations after the reduction of excessive daily coffee consumption, and we review the relevant literatures.\n\n\nCONCLUSIONS\nExcessive coffee consumption may exacerbate the therapeutic course of bipolar disorder through its effects on the mechanisms underlying bipolar disorder itself, as well as by affecting the blood concentration of lithium.",
"affiliations": "*Department of Psychiatry, Faculty of Medicine, Saga University; and †Department of Pharmacy, Saga University Hospital, Saga; and ‡Department of Neuropsychiatry, Faculty of Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.",
"authors": "Kunitake|Yutaka|Y|;Mizoguchi|Yoshito|Y|;Sogawa|Rintaro|R|;Matsushima|Jun|J|;Kato|Takahiro A|TA|;Kawashima|Toshiro|T|;Monji|Akira|A|",
"chemical_list": "D003069:Coffee; D002110:Caffeine; D008094:Lithium",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000222",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "40(4)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D001714:Bipolar Disorder; D002110:Caffeine; D003069:Coffee; D018565:Food-Drug Interactions; D006801:Humans; D008094:Lithium; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "160-162",
"pmc": null,
"pmid": "28622205",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Effect of Excessive Coffee Consumption on the Clinical Course of a Patient With Bipolar Disorder: A Case Report and Literature Review.",
"title_normalized": "effect of excessive coffee consumption on the clinical course of a patient with bipolar disorder a case report and literature review"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1059228",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LITHIUM"
},
"drugadditional": "3",
... |
{
"abstract": "In-stent plaque protrusion (ISP) is a predictor for ischemic complications in carotid artery stenting (CAS). Because its mobility would further increase the distal embolization risk, the intraprocedural detection of mobility is important but has not yet been reported. We present an 87-year-old male with symptomatic right carotid artery stenosis who underwent CAS. Intravascular ultrasound (IVUS) after stent deployment revealed a small ISP, and simultaneous extravascular carotid duplex disclosed its mobility. After coverage of the ISP with stent-in-stent implantation, no remaining protrusion was observed with either IVUS or carotid duplex. The patient experienced no periprocedural strokes. Carotid duplex is suited to evaluate targets' movement because of its excellent temporal resolution. Carotid duplex has potential value for intraprocedural risk estimation of ISP.",
"affiliations": "Department of Neurology and Stroke Center, Tenri Hospital, Tenri, Japan. tanaka19830311kanta@gmail.com.;Department of Clinical Pathology, Tenri Hospital, Tenri, Japan. cp-ktgw@tenriyorozu.jp.;Department of Neurosurgery, Tenri Hospital, Tenri, Japan. nyamana829@yahoo.co.jp.;Department of Neurosurgery and Stroke Center, Tenri Hospital, Tenri, Japan. yakiyama@tenriyorozu.jp.",
"authors": "Tanaka|Kanta|K|;Kitagawa|Takamichi|T|;Yamana|Norikazu|N|;Akiyama|Yoshinori|Y|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": "10.11152/mu-1539",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1844-4172",
"issue": "21(1)",
"journal": "Medical ultrasonography",
"keywords": null,
"medline_ta": "Med Ultrason",
"mesh_terms": "D000369:Aged, 80 and over; D002339:Carotid Arteries; D016893:Carotid Stenosis; D006801:Humans; D008297:Male; D058226:Plaque, Atherosclerotic; D015607:Stents; D018616:Ultrasonography, Doppler, Duplex",
"nlm_unique_id": "101522985",
"other_id": null,
"pages": "89-92",
"pmc": null,
"pmid": "30779837",
"pubdate": "2019-02-17",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Mobility of an in-stent plaque protrusion detected with carotid duplex during the carotid artery stenting procedure: a case report.",
"title_normalized": "mobility of an in stent plaque protrusion detected with carotid duplex during the carotid artery stenting procedure a case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-208668",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadd... |
{
"abstract": "Angiotensin-converting enzyme inhibitor induced angioedema commonly involves the head and neck area. We report a case of angiotensin-converting enzyme inhibitor induced intestinal angioedema in a heart transplant recipient on mTOR immunosuppression. A 36-year-old Caucasian woman with history of heart transplantation on sirolimus, tacrolimus and prednisone presented to the Emergency Department with abdominal pain, one day following lisinopril initiation. A computer tomography scan demonstrated diffuse bowel wall thickening consistent with pancolitis and edema. She was subsequently diagnosed with angiotensin-converting enzyme inhibitor induced angioedema. Patients on mTOR immunosuppression are at higher risk for this potentially life-threatening side effect. Knowledge of this interaction is critical for providers prescribing mTOR agents.",
"affiliations": "Department of Internal Medicine, Yale University, New Haven, CT, 06520-9056, USA.;Division of Cardiovascular Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.;Division of Cardiovascular Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.",
"authors": "Srinivasan|Dushyanth|D|;Strohbehn|Garth W|GW|;Cascino|Thomas|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ehf2.12161",
"fulltext": "\n==== Front\nESC Heart FailESC Heart Fail10.1002/(ISSN)2055-5822EHF2ESC Heart Failure2055-5822John Wiley and Sons Inc. Hoboken 2877202910.1002/ehf2.12161EHF212161ESCHF-16-00110Case ReportCase ReportsACE inhibitor‐associated intestinal angioedema in orthotopic heart transplantation Intestinal angioedema in heart transplantationD. Srinivasan et al.Srinivasan Dushyanth dushyanth.srinivasan@yale.edu \n1\nStrohbehn Garth W. \n2\nCascino Thomas \n2\n\n1 \nDepartment of Internal Medicine\nYale University\nNew Haven\nCT\n06520‐9056\nUSA\n\n2 \nDivision of Cardiovascular Diseases, Department of Internal Medicine\nUniversity of Michigan\nAnn Arbor\nMI\n48109\nUSA\n* \nCorrespondence to: Dushyanth Srinivasan, Yale University Department of Internal Medicine, 330 Cedar St. Boardman 110, PO Box 20856, New Haven, CT 06520‐9056, USA.\n\nEmail: dushyanth.srinivasan@yale.edu\n23 3 2017 8 2017 4 3 10.1002/ehf2.v4.3384 386 13 11 2016 01 3 2017 05 3 2017 © 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.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.Abstract\nAngiotensin‐converting enzyme inhibitor induced angioedema commonly involves the head and neck area. We report a case of angiotensin‐converting enzyme inhibitor induced intestinal angioedema in a heart transplant recipient on mTOR immunosuppression. A 36‐year‐old Caucasian woman with history of heart transplantation on sirolimus, tacrolimus and prednisone presented to the Emergency Department with abdominal pain, one day following lisinopril initiation. A computer tomography scan demonstrated diffuse bowel wall thickening consistent with pancolitis and edema. She was subsequently diagnosed with angiotensin‐converting enzyme inhibitor induced angioedema. Patients on mTOR immunosuppression are at higher risk for this potentially life‐threatening side effect. Knowledge of this interaction is critical for providers prescribing mTOR agents.\n\nACE inhibtormTOR inhibitorheart transplantationintestinal angioedema source-schema-version-number2.0component-idehf212161cover-dateAugust 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:29.12.2017\n\n\nSrinivasan , D. \n, \nStrohbehn , G. W. \n, and \nCascino , T. \n (2017 ) ACE inhibitor‐associated intestinal angioedema in orthotopic heart transplantation . ESC Heart Failure , 4 : 384 –386 . doi: 10.1002/ehf2.12161.28772029\n==== Body\nIntroduction\nAngioedema is a swelling of the skin and mucous membranes which typically presents with swelling of the lips, tongue or face; however, it can manifest in any organ system. It is thought to be caused by increases in histamine and bradykinin that cause increased capillary leakage and edema. Angioedema associated with angiotensin‐converting enzyme (ACE) inhibitors is a well‐known phenomenon with incidence rates near 0.4%.1 We report a case of acute intestinal angioedema related to ACE inhibitor administration in an orthotopic heart transplant recipient.\n\nCase report\nA 36‐year‐old Caucasian woman presented with severe diffuse abdominal pain one day following initiation of lisinopril for hypertension. She had a history of a tachycardia‐induced cardiomyopathy requiring orthotopic heart transplantation in 2002 and was maintained on sirolimus, tacrolimus, and prednisone for immunosuppression. She was prescribed an ACE inhibitor the day prior to the admission for elevated blood pressures, a class of medications that she had never taken before. On presentation, she endorsed rapid onset of abdominal pain, dizziness, and sweating. She was without fevers, had a heart rate of 79 beats per minute, a blood pressure of 170/105 mmHg that decreased to 74/52 mmHg 8 h after arrival and normalized with administration of intravenous fluids. She had diffuse tenderness to light palpation below the umbilicus and abdominal guarding on exam with clear lung fields notable for absence of bronchospasm and no urticaria or rash on skin exam. Initial laboratory analyses demonstrated a mild increase in white blood cells and liver tests.\n\nA computer tomography of the abdomen and pelvis (Figure\n1\nA and B) revealed diffuse wall thickening with enhancement affecting both small and large bowels and fat stranding consistent with pancolitis and edema. Given the time of onset and relationship with ACE inhibition, she was diagnosed with intestinal angioedema secondary to ACE inhibitor initiation. Alternative causes for diagnosis were considered; however, there was an absence of risk factors for other causative etiologies, and further lab workup was unremarkable. She was not evaluated for hereditary angioedema. All oral medications were then held. She was monitored with serial abdominal exams and given opiates. All laboratory studies were normalized, and home medications including immunosuppressive agents were restarted the next day except for lisinopril. Over a 72‐h period, her pain resolved, and she was discharged to home with the addition of amlodipine 2.5 mg daily for hypertension.\n\nFigure 1 (A) Computed tomography imaging of intestinal angioedema in the coronal view. Arrow demonstrates profound small and large bowel wall edema and fat stranding. (B) Computed tomography imaging of intestinal angioedema in the transverse view. Arrow demonstrates profound small and large bowel wall edema and fat stranding.\n\nDiscussion\nUse of immunosuppressive medications with ACE inhibitors is a risk factor for angioedema among patients on immunosuppression, including the heart transplant population.2, 3, 4, 5, 6, 7 Isolated involvement of the gastrointestinal tract is a rare presentation of ACE inhibitor induced angioedema. Although not definitively demonstrated in humans, one hypothesis is that immunosuppressive agents increase this risk by decreasing the activity of circulating dipeptidyl peptidase IV (both dipeptidyl peptidase IV and ACE inactivate vasodilatory bradykinin and substance P). This effect is seen with both calcineurin and mTOR inhibitors but is greater with the latter.2, 8 Reports have demonstrated episodes of facial and sublingual angioedema in kidney transplant patients on mTOR inhibitors without concomitant use of an ACE‐inhibitor.4, 9 In September 2015, the Food and Drug Administration (FDA) issued an update on the safety of ACE inhibitors stating that use in combination with mTOR inhibitors may increase the risk for angioedema.10 Despite this, our electronic medical record did not have this as a drug interaction.\n\nIn summary, this case and the relevant medical literature suggest that ACE inhibitor‐induced angioedema of the gastrointestinal tract must be considered in the differential diagnosis of both acute and recurrent abdominal pain in patients receiving concomitant ACE inhibitor and immunosuppression with an mTOR inhibitor. Despite the increasing incidence of ACE inhibitor‐induced angioedema in patients taking calcineurin inhibitors,2, 3, 4, 5, 6, 7, 8, 9 extrapolation of basic science studies suggests that mTOR inhibitors pose a greater risk to interact with ACE inhibitors. Physicians prescribing mTOR inhibitors should have knowledge of the potential interaction.\n\nConflict of interest\nNone declared.\n\nAcknowledgements\nThis research was supported by the University of Michigan, Department of Cardiology. We would like to thank the following colleagues who provided their clinical expertise and insight that greatly assisted in the completion of this project: Dr Keith Aaronson, Dr Brahmajee Nallamothu, Dr Todd Koelling, Dr Nour Al‐Hadidi, and Dr Asad Ghafoor.\n==== Refs\nReferences\n1 \n\nPiller \nLB \n, \nFord \nCE \n, \nDavis \nBR \n, \nNwachuku \nC \n, \nBlack \nHR \n, \nOparil \nS \n, \nRetta \nTM \n, \nProbstfield \nJL \n. Incidence and predictors of angioedema in elderly hypertensive patients at high risk for cardiovascular disease: a report from the antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT) . J Clin Hypertens \n2006 ; 8 : 649 –656 .\n2 \n\nByrd \nJB \n, \nWoodard‐Grice \nA \n, \nStone \nE \n, \nLucisano \nA \n, \nSchaefer \nH \n, \nYu \nC \n, \nEyler \nAE \n, \nSalloum \nNE \n, \nBrown \nNJ \n. Association of angiotensin‐converting enzyme inhibitor‐associated angioedema with transplant and immunosuppressant use . Allergy \n2010 ; 65 : 1381 –1387 .20557296 \n3 \n\nStallone \nG \n, \nInfante \nB \n, \nDi Paolo \nS \n, \nSchena \nA \n, \nGrandaliano \nG \n, \nGesualdo \nL \n, \nSchena \nFP \n. Sirolimus and angiotensin‐converting enzyme inhibitors together induce tongue oedema in renal transplant recipients . Nephrol Dial Transplant \n2004 ; 19 : 2906 –2908 .15496567 \n4 \n\nFuchs \nU \n, \nZittermann \nA \n, \nBerthold \nHK \n, \nTenderich \nG \n, \nDeyerling \nKW \n, \nMinami \nK \n, \nKoerfer \nR \n. Immunosuppressive therapy with everolimus can be associated with potentially life‐threatening lingual angioedema . Transplantation \n2005 ; 79 : 981 –983 .15849555 \n5 \n\nRosenberg \nEI \n, \nMishra \nG \n, \nAbdelmalek \nMF \n. Angiotensin‐converting enzyme inhibitor‐induced isolated visceral angioedema in a liver transplant recipient . Transplantation \n2003 ; 75 : 730 –732 .12640318 \n6 \n\nMahé \nE \n, \nMorelon \nE \n, \nLechaton \nS \n, \nKreis \nH \n, \nde Prost \nY \n, \nBodemer \nC \n. Angioedema in renal transplant recipients on sirolimus . Dermatology \n2007 ; 214 : 205 –209 .17377381 \n7 \n\nJung \nM \n, \nRanpura \nVN \n, \nDunbar \nCE \n, \nTisdale \nJF \n, \nFitzhugh \nCD \n, \nHsieh \nMM \n. Angioedema in patients treated with sirolimus and ACE inhibitor post hematopoietic SCT . Bone Marrow Transplant \n2014 ; 49 : 1448 –1449 .25068425 \n8 \n\nDuerr \nM \n, \nGlander \nP \n, \nDiekmann \nF \n, \nDragun \nD \n, \nNeumayer \nHH \n, \nBudde \nK \n. Increased incidence of angioedema with ACE inhibitors in combination with mTOR inhibitors in kidney transplant recipients . Clin J Am Soc Nephrol \n2010 ; 5 : 703 –708 .20093343 \n9 \n\nWadei \nH \n, \nGruber \nSA \n, \nEl‐Amm \nJM \n, \nGarnick \nJ \n, \nWest \nMS \n, \nGranger \nDK \n, \nSillix \nDH \n, \nMigdal \nSD \n, \nHaririan \nA \n. Sirolimus‐induced angioedema . Am J Transplant \n2004 ; 4 : 1002 –1005 .15147436 \n10 \nFDA \n. ACE Inhibitors and mTOR Inhibitor Coadministration . 2015 \nhttps://www.fda.gov/safety/medwatch/safetyinformation/ucm461227.htm.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2055-5822",
"issue": "4(3)",
"journal": "ESC heart failure",
"keywords": "ACE inhibtor; heart transplantation; intestinal angioedema; mTOR inhibitor",
"medline_ta": "ESC Heart Fail",
"mesh_terms": null,
"nlm_unique_id": "101669191",
"other_id": null,
"pages": "384-386",
"pmc": null,
"pmid": "28772029",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports",
"references": "17377381;25068425;28772029;16957427;20557296;15849555;15147436;12640318;20093343;15496567",
"title": "ACE inhibitor-associated intestinal angioedema in orthotopic heart transplantation.",
"title_normalized": "ace inhibitor associated intestinal angioedema in orthotopic heart transplantation"
} | [
{
"companynumb": "US-ASTELLAS-2017US031574",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "The combination of BRAF inhibitor and MEK inhibitor is one of the first-line treatments for unresectable BRAF-mutant melanoma or as an adjuvant therapy. However, some patients who received the combination of dabrafenib and trametinib (CombiDT) or the combination of encorafenib and binimetinib (CombiEB) had adverse events (AEs) including pyrexia. We herein report a patient with BRAF-mutated melanoma who repeatedly developed elevated levels of D-dimer and pyrexia after CombiDT and CombiEB treatments. Moreover, concomitant edoxaban prevented these AEs, enabling the patient to continue receiving CombiEB.",
"affiliations": "Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.;Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.;Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.;Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.;Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.;Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.;Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.;Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.;Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.;Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.;Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan.",
"authors": "Mukai|Kei|K|;Kamata|Masahiro|M|https://orcid.org/0000-0003-0976-4982;Miyazaki|Mirei|M|;Nagata|Mayumi|M|;Fukaya|Saki|S|;Hayashi|Kotaro|K|;Fukuyasu|Atsuko|A|;Ishikawa|Takeko|T|;Ohnishi|Takamitsu|T|;Tada|Yayoi|Y|https://orcid.org/0000-0003-3743-135X;Tanaka|Takamitsu|T|",
"chemical_list": "D005338:Fibrin Fibrinogen Degradation Products; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011728:Pyridones; D013449:Sulfonamides; D013844:Thiazoles; C036309:fibrin fragment D; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; C552171:edoxaban",
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.15813",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "48(5)",
"journal": "The Journal of dermatology",
"keywords": "BRAF; D-dimer; MEK; anti-coagulant; edoxaban; malignant melanoma",
"medline_ta": "J Dermatol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D005334:Fever; D005338:Fibrin Fibrinogen Degradation Products; D006801:Humans; D008545:Melanoma; D020929:Mitogen-Activated Protein Kinase Kinases; D009154:Mutation; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D011725:Pyridines; D011728:Pyridones; D012878:Skin Neoplasms; D013449:Sulfonamides; D013844:Thiazoles",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "707-709",
"pmc": null,
"pmid": "33600004",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Edoxaban prevented adverse effects including pyrexia and elevation of D-dimer caused by the combination of BRAF and MEK inhibitors in a patient with BRAF-mutant melanoma.",
"title_normalized": "edoxaban prevented adverse effects including pyrexia and elevation of d dimer caused by the combination of braf and mek inhibitors in a patient with braf mutant melanoma"
} | [
{
"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-118263",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRAMETINIB DIMETHYL SULFOXIDE"
},... |
{
"abstract": "A 39-year-old woman with type-2 diabetes mellitus presented with metabolic acidosis due to an attempted suicide with metformin. Despite treatment with activated charcoal and laxation, she experienced cardiac arrest, which required resuscitation. After transfer to another hospital, she was treated with high-volume continuous venovenous haemofiltration. However, she died due to multiple organ failure. Metformin is the most widely used oral antidiabetic agent in the world and the first-choice treatment for patients with type-2 diabetes mellitus. Metformin overdose can cause lactic acidosis, which usually manifests as abdominal pain, vomiting and diarrhoea. Although rare, metformin-associated lactic acidosis carries a high mortality risk. The treatment of choice is immediate haemodialysis and orally administered activated charcoal. If a patient treated with metformin presents with metabolic acidosis, lactic acidosis due to metformin overdose should be suspected and appropriate treatment should be initiated immediately.",
"affiliations": "Academisch Medisch Centrum/Universiteit van Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam. a.c.depont@amc.uva.nl",
"authors": "de Pont|A C J M|AC|;Kerver|E D|ED|;Jansen|M E P|ME|;Bijleveld|Y A|YA|;Franssen|E J F|EJ|;Hoekstra|J B L|JB|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "151(17)",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000138:Acidosis; D000328:Adult; D003924:Diabetes Mellitus, Type 2; D062787:Drug Overdose; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008687:Metformin; D009102:Multiple Organ Failure; D013406:Suicide, Attempted",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": "981-4",
"pmc": null,
"pmid": "17520853",
"pubdate": "2007-04-28",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Fatal autointoxication with metformin.",
"title_normalized": "fatal autointoxication with metformin"
} | [
{
"companynumb": "PHHY2014NL122385",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Most children with exploratory levothyroxine ingestions remain asymptomatic or suffer only minor effects, and most patients can be managed in the home or with supportive care in the hospital. We present a case of a 3-year-old girl who was found after a witnessed massive ingestion of levothyroxine. The patient was initially seen in an emergency department and discharged in stable condition, only to return 4 days after ingestion with thyrotoxicosis, hypertension, tachycardia, 24 hours of persistent vomiting, and clinical and laboratory evidence of dehydration. On the day of hospital admission, her thyroid-stimulating hormone was 0.018 µIU/mL (reference range, 0.6-4.5 µIU/mL); free T4 (tetraiodothyronine) was greater than 6.0 ng/dL (reference range, 0.7-2.1 ng/dL); and T3 (triiodothyronine) total was 494 ng/dL (reference range, 100-200 ng/dL). During a 3-day hospital admission, she was managed with supportive care, including intravenous fluid rehydration and antiemetics, and was ultimately discharged in good condition. The patient was followed up until 2 months after ingestion and remained asymptomatic. Although most exploratory levothyroxine ingestions suffer little to no clinical effects, serious symptoms can occur. Because serious symptoms can occur in a delayed fashion, it is important for clinicians to give proper anticipatory guidance regarding home symptom monitoring, follow-up, and reasons to return to the emergency department when patients present for medical evaluation.",
"affiliations": "From the *Department of Emergency Medicine, The Ohio State University Medical Center; †Department of Pharmacology and Toxicology, Nationwide Children's Hospital; ‡Department of Pediatrics, The Ohio State University College of Medicine; and §Department of Toxicology, The Ohio State University College of Pharmacy, Columbus, OH.",
"authors": "Hays|Hannah L|HL|;Jolliff|Heath A|HA|;Casavant|Marcel J|MJ|",
"chemical_list": "D000932:Antiemetics; D013963:Thyroid Hormones; D017294:Ondansetron; D013972:Thyrotropin; D013974:Thyroxine",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0b013e3182aa4714",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "29(11)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000932:Antiemetics; D002675:Child, Preschool; D003131:Combined Modality Therapy; D003681:Dehydration; D062787:Drug Overdose; D004630:Emergencies; D004636:Emergency Service, Hospital; D005260:Female; D005440:Fluid Therapy; D006801:Humans; D017294:Ondansetron; D010359:Patient Readmission; D062606:Tertiary Care Centers; D013963:Thyroid Hormones; D013971:Thyrotoxicosis; D013972:Thyrotropin; D013974:Thyroxine; D013997:Time Factors; D055986:Vital Signs; D014839:Vomiting",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "1217-9",
"pmc": null,
"pmid": "24196094",
"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Thyrotoxicosis after a massive levothyroxine ingestion in a 3-year-old patient.",
"title_normalized": "thyrotoxicosis after a massive levothyroxine ingestion in a 3 year old patient"
} | [
{
"companynumb": "US-MYLANLABS-2014S1016388",
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"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE SODIUM"
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"drugadditional": n... |
{
"abstract": "Rhabdomyolysis is a rare, but possible, complication of combination antiretroviral therapy (cART). We report a unique case of an HIV-positive patient on cART who came to our attention for suspected ischaemic heart disease. Coronary angiography was carried out and complicated in the following days by rhabdomyolysis. We discuss the possible links between rhabdomyolysis, iodinated contrast media and HAART.",
"affiliations": "Fondazione Toscana Gabriele Monasterio, Pisa, Italy.",
"authors": "Sbrana|Francesco|F|;Coceani|Michele|M|;Iapoce|Riccardo|R|;Petersen|Christina|C|;Rovai|Daniele|D|",
"chemical_list": "D044966:Anti-Retroviral Agents; D003287:Contrast Media; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; C057937:iomeprol; D007479:Iopamidol",
"country": "England",
"delete": false,
"doi": "10.1177/0956462413512809",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "25(6)",
"journal": "International journal of STD & AIDS",
"keywords": "AIDS; HIV; antiretroviral therapy; coronary artery disease; iodinated X-ray contrast medium; rhabdomyolysis; treatment",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D044966:Anti-Retroviral Agents; D003287:Contrast Media; D017023:Coronary Angiography; D001026:Coronary Artery Bypass; D004359:Drug Therapy, Combination; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D006801:Humans; D007479:Iopamidol; D007511:Ischemia; D008297:Male; D008875:Middle Aged; D018894:Reverse Transcriptase Inhibitors; D012206:Rhabdomyolysis; D016896:Treatment Outcome",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "452-4",
"pmc": null,
"pmid": "24256695",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Rhabdomyolysis in an HIV-infected patient following coronary angiography: case report and literature review.",
"title_normalized": "rhabdomyolysis in an hiv infected patient following coronary angiography case report and literature review"
} | [
{
"companynumb": "IT-ROXANE LABORATORIES, INC.-2015-RO-00085RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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"activesubstancename": "SAQUINAVIR"
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"abstract": "A retrospective review of all patients with stage 3 medication-related osteonecrosis of the jaw (MRONJ), treated by surgical resection and immediate vascularized bone reconstruction at a tertiary care medical center, was performed. Eleven patients were included, seven female and four male; their mean age was 65.8 years (range 56-73 years). Mean follow-up was 25 months. Ten patients had received intravenous bisphosphonates. The most common pathology was breast cancer (4/11). Pain (n=8) and pathological fracture (n=7) were the most common presenting symptoms. Microvascular free flaps consisted of seven fibula osteocutaneous flaps and four scapula osteocutaneous free flaps. All patients reported resolution of symptoms, with complete bone union identified radiographically (100%). Complications occurred in three patients (27%). One patient required removal of hardware at 8 months postoperative. Dental implant rehabilitation was completed in two patients. Ten patients are tolerating an oral diet. Ten patients are alive without evidence of MRONJ at any of the surgical sites. One patient died 28 months after surgery from progression of metastatic disease. Advanced MRONJ can be successfully treated in patients using vascularized tissue transfer, including those patients with significant peripheral vascular disease. Dental rehabilitation is a viable option for advanced MRONJ patients treated by vascularized flap reconstruction.",
"affiliations": "Oral-Head and Neck Surgery/Microvascular Surgery, University of Maryland Greenebaum Cancer Center, Baltimore, Maryland, USA.;Oral-Head and Neck Surgery/Microvascular Surgery, University of Maryland Greenebaum Cancer Center, Baltimore, Maryland, USA.;Oral-Head and Neck Surgery/Microvascular Surgery, University of Maryland Greenebaum Cancer Center, Baltimore, Maryland, USA.;Oral-Head and Neck Surgery/Microvascular Surgery, University of Maryland Greenebaum Cancer Center, Baltimore, Maryland, USA. Electronic address: jlubek@umaryland.edu.",
"authors": "Caldroney|S|S|;Ghazali|N|N|;Dyalram|D|D|;Lubek|J E|JE|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1016/j.ijom.2017.01.023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0901-5027",
"issue": "46(7)",
"journal": "International journal of oral and maxillofacial surgery",
"keywords": "MRONJ; mandible; osteonecrosis; vascularized tissue transfer",
"medline_ta": "Int J Oral Maxillofac Surg",
"mesh_terms": "D000368:Aged; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D016025:Bone Transplantation; D018450:Disease Progression; D005260:Female; D058752:Free Tissue Flaps; D006801:Humans; D008297:Male; D008875:Middle Aged; D056948:Orthognathic Surgical Procedures; D010027:Osteotomy; D011183:Postoperative Complications; D019651:Reconstructive Surgical Procedures; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "8605826",
"other_id": null,
"pages": "871-876",
"pmc": null,
"pmid": "28233647",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Surgical resection and vascularized bone reconstruction in advanced stage medication-related osteonecrosis of the jaw.",
"title_normalized": "surgical resection and vascularized bone reconstruction in advanced stage medication related osteonecrosis of the jaw"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-18-03913",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
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... |
{
"abstract": "Prosthetic joint infection (PJI) is a possible complication occurring after prosthesis implantation. We describe the case of a patient with early postoperative multidrug-resistant polymicrobial PJI and mixed infection of the surgical wound. Despite the removal of the prosthesis, the positioning of double-stage exchange, and dehiscence debridement of the surgical wound, the infection continued. Positioning of an external fixator, plastic reconstruction with a skin graft, and continuous (two years) multiple antimicrobial therapy led to the resolution of the knee infection; a knee prosthesis was implanted, but a new infection of the extensus apparatus by multidrug-resistant Klebsiella pnumoniae followed. It was complicated by surgical wound dehiscence, forcing us to remove the prosthesis, put a new external fixator, and continue with the antibiotic treatment, with no results, and, finally, proceed to a leg amputation. Fourteen days after, the patient was discharged in good clinical condition but, fifteen days later, during rehabilitation in another hospital, the patient developed a severe Clostridium difficilis infection with profuse, intense diarrhea, toxic megacolon, and septic shock; despite colectomy and treatment in an intensive care unit, he died four months later. Patients affected by polymicrobial PJI are at high risk of treatment failure and, therefore, should be given a warning, in good time and appropriate form, of the likelihood of leg amputation.",
"affiliations": "Internistic Ultrasound Service, Campus Bio-Medico University, 00128 Rome, Italy.;Department of Plastic, Reconstructive and Aesthetic Surgery, Campus Bio-Medico University, 00128 Rome, Italy.;Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University, 00128 Rome, Italy.;Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University, 00128 Rome, Italy.;Department of Orthopaedic and Trauma Surgery, San Pietro Fatebenefratelli Hospital, 00189 Rome, Italy.",
"authors": "Zardi|Enrico Maria|EM|0000-0002-2476-1213;Persichetti|Paolo|P|;Palumbo|Alessio|A|;Franceschetti|Edoardo|E|;Franceschi|Francesco|F|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/ijerph18179186",
"fulltext": "\n==== Front\nInt J Environ Res Public Health\nInt J Environ Res Public Health\nijerph\nInternational Journal of Environmental Research and Public Health\n1661-7827\n1660-4601\nMDPI\n\n10.3390/ijerph18179186\nijerph-18-09186\nCase Report\nFatal Clostridium Infection in a Leg-Amputated Patient after Unsuccessful Knee Arthroplasty\nhttps://orcid.org/0000-0002-2476-1213\nZardi Enrico Maria 1*\nPersichetti Paolo 2\nPalumbo Alessio 3\nFranceschetti Edoardo 3\nFranceschi Francesco 4\nTchounwou Paul B. Academic Editor\n1 Internistic Ultrasound Service, Campus Bio-Medico University, 00128 Rome, Italy\n2 Department of Plastic, Reconstructive and Aesthetic Surgery, Campus Bio-Medico University, 00128 Rome, Italy; p.persichetti@unicampus.it\n3 Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University, 00128 Rome, Italy; a.palumbo@unicampus.it (A.P.); e.franceschetti@unicampus.it (E.F.)\n4 Department of Orthopaedic and Trauma Surgery, San Pietro Fatebenefratelli Hospital, 00189 Rome, Italy; f.franceschi@unicampus.it\n* Correspondence: e.zardi@unicampus.it\n31 8 2021\n9 2021\n18 17 918622 7 2021\n27 8 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nProsthetic joint infection (PJI) is a possible complication occurring after prosthesis implantation. We describe the case of a patient with early postoperative multidrug-resistant polymicrobial PJI and mixed infection of the surgical wound. Despite the removal of the prosthesis, the positioning of double-stage exchange, and dehiscence debridement of the surgical wound, the infection continued. Positioning of an external fixator, plastic reconstruction with a skin graft, and continuous (two years) multiple antimicrobial therapy led to the resolution of the knee infection; a knee prosthesis was implanted, but a new infection of the extensus apparatus by multidrug-resistant Klebsiella pnumoniae followed. It was complicated by surgical wound dehiscence, forcing us to remove the prosthesis, put a new external fixator, and continue with the antibiotic treatment, with no results, and, finally, proceed to a leg amputation. Fourteen days after, the patient was discharged in good clinical condition but, fifteen days later, during rehabilitation in another hospital, the patient developed a severe Clostridium difficilis infection with profuse, intense diarrhea, toxic megacolon, and septic shock; despite colectomy and treatment in an intensive care unit, he died four months later. Patients affected by polymicrobial PJI are at high risk of treatment failure and, therefore, should be given a warning, in good time and appropriate form, of the likelihood of leg amputation.\n\namputation\nantibiotic\nclostridium infection\nprosthesis\nskin wound\ntherapy\n==== Body\npmc1. Introduction\n\nProsthetic joint infection (PJI) is a complication occurring in 1.4–2.5% of arthroplasties [1]. In most cases, we are dealing with monomicrobial PJIs since polymicrobial PJIs account for 4–19% of cases [2,3], rising to 37% if developed in the early postoperative period [4].\n\nPJI starts when a pathogen, accidentally introduced into the joint, binds to the surface of the prosthesis by means of adhesion molecules; then, thanks to the production of biofilm, the pathogen protects itself from the antibiotic action and strengthens the bond with the implant [5]. The formation of polymicrobial biofilm is an even more serious event that makes any type of treatment more difficult [5].\n\nDebridement, antibiotics, irrigation, and implant retention (DAIR) may be considered effective treatment options for early PJI [6] under some specific conditions: a stable prosthesis, easily treatable pathogen, and absence of a sinus tract [7].\n\nRevision surgery is another important option to treat PJI, but this is burdened by an infection rate over 10% [8], which is not without clinical impact. Indeed, it may raise the risk of prolonged hospitalization and duration of antibiotic therapy at home, increasing costs and causing relevant social and economic problems.\n\nHere, we illustrate a multidrug-resistant polymicrobial PJI of the knee, complicated by a mixed infection of the surgical wound, which broke out within a week of the prosthetic intervention.\n\n2. Case Report\n\nA 76-year-old overweight man (body mass index of 29) with osteoarthrosis, who had already successfully undergone left hip and knee surgeries some years previously, also underwent right knee arthroplasty in another hospital, developing polymicrobial PJI (Enterococcus spp, Klebsiella pneumonia, Staphylococcus aureus), within a few days of surgery. Since the conditions to perform DAIR were not met, he was treated with two-stage exchange and antibiotic therapy (daptomycin and meropenem), suffering side effects (such as anemia and leukopenia) and developing carbapenem resistance. After one year of continued antibiotic treatment with glycopeptides, cephalosporin, and quinolones, a knee prosthesis reimplantation was attempted without success, being complicated by patellar tendon rupture, mixed infection of the wound, and dehiscence. As anemia, leukopenia, and high serum inflammatory markers still persisted and wound dehiscence did not heal with negative pressure wound therapy, the patient was admitted to our hospital. On admission, he was tired, pale, had knee pain that was treated with non-steroid anti-inflammatory drugs, and his inflammatory markers were increased. Laboratory analysis showed: erythrocyte sedimentation rate (ESR) 79 mm/h (normal value <37mm/h), C reactive protein (CRP) 13.6 mg/dL (normal value <0.5mg/dL), white blood cells count 3550 cells/µL, neutrophils count 1750 cells/µL (49%), red blood cells count 3,160,000 cells/µL, hemoglobin 11.1 g/dL, platelets count 286,000/µL, creatinine 0.83 mg/dL. His American Society of Anesthesiologists (ASA) score was 2. The prosthesis was promptly removed, and an antibiotic-impregnated spacer was put. Antibiotic therapy was adjusted according to the microbial cultures collected from (a) the knee surgical wound (Figure 1A) (positive for Staphylococcus hominis) and (b) the knee joint (positive for extended-spectrum β-lactamases (ESBL) Klebsiella pneumoniae, and multidrug-resistant (MDR) Acinetobacter baumannii, only sensitive to colistin). Tigecycline (50 mg every 12 h), daptomycin (500 mg a day), and colistin (4.5 MU every 12 h) were started. Due to the progressive worsening of renal function (creatinine values oscillating between 1.32 and 2.8 mg/dL), the dosage of the latter two antibiotics was gradually reduced within one month to 300 mg a day and to 2 MU every 12 h, respectively, based on estimated creatinine clearance. Rifampin was also orally administered two hours after meals at a dosage of 600 mg a day. Iron deficiency and anemia were corrected with intravenous iron load, intramuscular vitamin B12, erythropoietin administration (10.000 IU twice a week), and, when necessary, red blood cell transfusions (if hemoglobin was less than 7 g/dL). Vitamin D deficiency and low potassium and magnesium were also restored. Reconstructive surgery of the knee wound was attempted, and 40 cycles of hyperbaric treatment were performed with only partial benefit. A number of microbial cultures collected from (a) the knee wound and (b) the knee joint during the change of the first spacer with another one were positive for MDR Pseudomonas aeruginosa (sensitive only to colistin) and Staphylococcus capitis. Inflammatory markers were increased: ESR 52 mm/h, CRP 1.10 mg/dL, D-dimer 1762 ng/mL (normal value <500 ng/mL). Other laboratory analyses showed: white blood cells count 2780 cells/µL, neutrophils count 1290 cells/µL (46%), red blood cell count 2,100,000 cells/µL, hemoglobin 7.2 g/dL, platelets count 216,000/µL, creatinine 1.83 mg/dL. Tygecicline and daptomycin were discontinued, while an antibiotic combination (ceftolozane/tazobactam, 500 mg/250 mg in 100 mL of saline (0.9%) solution intravenously three times a day, according to estimated creatinine clearance) was given in addition to colistin and rifampin; the latter were stopped after two months because of the persistence of high serum inflammatory markers (ESR 60 mm/h, CRP 1.21 mg/dL, D-dimer 1598 ng/mL), while fosfomicin (4 g intravenously, three times a day) was added to ceftolozane/tazobactam, with benefit against Staphylococcus capitis. Due to the persistence of MDR and carbapenem-resistant Pseudomonas aeruginosa in cultures collected from the knee wound, the spacer was removed, an external fixator was put in, and a daily antibiotic treatment was continued in a rehabilitation center. Three months later, healing of the knee wound (Figure 1B) and normalization of all serum inflammatory markers occurred. During this period, Corynebacterium striatum was isolated from a skin purulent fluid collected near the fixator pin of the thigh and treated, with benefit, by administering dalbavancin at a dosage of 1.5 g intravenously (two times, one week apart). After a further three months, thanks to the persistent normal values of serum inflammatory markers, ceftolozane/tazobactam and fosfomicin were stopped; two months later, the patient underwent labeled leucocyte scintigraphy and positron emission tomography, which excluded bone and joint pathogenic processes. Hence, the patient underwent new right knee arthroplasty. Some days after implantation, there was dehiscence of the surgical wound, and MDR Klebsiella pneumoniae was isolated from the surgical wound. The patient had fever and showed a decrease in blood pressure. Blood analysis showed electrolyte disturbances (potassium 1.8 mmol/L (normal value 3.5–5.1 mmol/L), chlorine 85 mmol/L (normal value 98–107 mmol/L), calcium 7.5 mg/dL (normal value 8.4–10.2 mg/dL)), phosphorus 1.7 mg/dL (normal value 2.3–4.7 mg/dL), and high serum inflammatory markers (ESR 51 mm/h, CRP 5.29 mg/dL, D-dimer 1070 ng/mL). A solution for intravenous infusion of 500 mL glucose (5%) combined with potassium 80 mEqs was promptly administered, and calcium and phosphorus were restored orally. Although blood culture and microbial culture collection from the knee joint were negative, antibiotic treatment was started using an antibiotic combination (ceftazidime/avibactam 2/0.5 g in 100 mL of saline (0.9%) solution, administered intravenously three times a day; after a few days, reduced to 1/0.25 g, three times a day) and fosfomicin (4 g in 100 mL water for injection, administered intravenously three times a day). After one week, the clinical conditions of the patient improved; there was normalization of electrolyte balance and reduction of serum inflammatory markers (ESR 34 mm/h, CRP 1.09 mg/dL, D-dimer 830 ng/mL). Unfortunately, the wound showed signs of necrosis; a tomography revealed severe cellulitis of soft tissue near the prosthesis and, during surgical curettage, a severe detachment of the skin, extending over several cm2; the presence of a fistula was noted. The prosthesis was removed, a new external fixator was put in, and, after fifteen days, due to the worsening of the wound, leg amputation was performed (see Figure 2). After two weeks, the wound of the amputation had healed, and he was transferred in good clinical condition to a clinical rehabilitation center. Fifteen days later, the patient developed a severe infection from Clostridium difficile, which quickly caused profuse, intense diarrhea and, after two days, toxic megacolon and septic shock despite treatment with oral vancomycin (125 mg orally, four times daily) and metronidazole (500 mg, three times daily). Therefore, he was urgently transferred to an intensive care unit of a general hospital, where vancomycin and metronidazole were given via rectal Foley and intravenously (500 mg in 100 mL normal saline solution every 6 h and 500 mg every 8 h, respectively) and supplemental oxygen, intravenous fluids (albumin, balanced salt solutions), medications (particularly vasopressors), and blood products were also promptly administered without success, thus making it necessary to perform a colectomy. The postoperative course was complicated by electrolytic disturbances, anemia, acidosis, and malnutrition, which were treated with salt solutions, red blood cells transfusions, bicarbonate, and nutrition support; however, after four months of intensive care, he died.\n\n3. Discussion\n\nWe described an early postoperative multidrug-resistant polymicrobial PJI of the knee, complicated by a surgical wound infection. Despite all attempts to find a long-term surgical and medical cure, our patient’s leg had to be amputated; after discharge to a clinical rehabilitation center, he became infected with a fatal clostridium infection. There was no benefit from long-term antibiotic and surgical treatments that are considered viable options to treat monomicrobial PJI [9] but may fail to treat polymicrobial infections.\n\nIndeed, polymicrobial PJI is an independent risk factor for infection recurrence [10] and has a reduced cure rate when compared with that of monomicrobial PJI [11]. Despite the efficacious use of spacer exchange, in these cases, other therapeutic strategies should become part of the common lexicon, such as leg amputation [5].\n\nPolymicrobial infection, observed in 21–37% of patients with early postoperative PJI [4,12], as is the case of our patient, may be complicated by antibiotic resistance and is considered one of the major problems to be managed now and even more in the future [13].\n\nTo prevent this scenario, a change in treatment management should be planned; old and new antibiotics should be used with thriftiness and in a targeted manner based on microbiologic investigations, avoiding the selection of mechanisms of resistance [14,15].\n\nThe change of the antimicrobial susceptibility pattern in 60% of persistent microorganisms between the first and second stages of the procedure severely complicates the management of the infection [16], contributing to an increase in antibiotic resistance. When the patient came to our attention, having been affected by polymicrobial PJI and after two unsuccessful attempts of prosthesis implantation, we started long-term targeted antibiotic therapy along with surgical treatments, and the patient healed.\n\nThe combination of antibiotic therapy (ceftolozane/tazobactam and fosfomicin) and the use of an external fixator turned out to be a winning strategy to obtain the eradication of the infection.\n\nHowever, after positioning a new knee prosthesis, despite all measures to avoid infections, the patient was infected with PJI again, with no improvement despite clinical and surgical cures, the removal of the prosthesis, and the positioning of another external fixator. In these cases, leg amputation is needed, and this was performed without any complication; the patient was discharged in good clinical condition. How the patient was infected with clostridium infection during hospitalization in a rehabilitation center (with toxic megacolon and septic shock, although he never had diarrheal episodes in the past) is disputed.\n\nC. difficile is a major cause of healthcare-related infection that begins through the production of toxins A and B [17]. Antibiotic selective pressure and resistance can disrupt normal host intestinal microbiota; in addition, C. difficile can be found in meat products, seafood, and salads, and the widespread environmental dispersal of its spores can also play a role [17]. Which one of these causes has favored the insurgence of such violent C. difficile infection is not clear; we cannot rule out a combination of these causes.\n\n4. Conclusions\n\nWe highlight that PJI may be favored by the presence of patient-related risk factors, such as the presence of sociodemographic characteristics, elevated BMI, and history of previous surgery, as occurred in this case. The low resistance of human tissue to tolerate, in elderly age, repeated surgeries in a relatively short period of time may have contributed to the unsuccessful outcome.\n\nMoreover, we reaffirm the difficulties in managing polymicrobial PJIs, especially in patients who have already undergone previous prosthesis implantations. They deserve to be informed promptly about the likelihood of leg amputation since the success rate of multiple revision surgeries, endoprosthetic joint reconstruction, and limb salvage ranges between 43% and 62% only [18], with about half of the cases doomed to failure.\n\nTherefore, it is important to implement the most accurate preventive strategies by adjusting the antibiotic prophylaxis regimen and improving disinfection and postoperative wound care whenever any patient undergoes surgical procedures [19].\n\nThese behaviors, together with all measures to prevent C. difficile infection, including those suitable for identifying healthy carriers [20], should be adopted, especially in the case of patients undergoing long-term antibiotic treatments.\n\nAuthor Contributions\n\nConceptualization, E.M.Z.; methodology, E.M.Z. and F.F.; validation, E.M.Z., E.F. and A.P.; formal analysis, E.M.Z., P.P., E.F. and A.P.; investigation, E.M.Z. and F.F.; resources, E.M.Z., P.P. and F.F.; data curation, E.M.Z., E.F. and A.P.; writing—original draft preparation E.M.Z.; writing—review and editing, E.M.Z., P.P. and F.F.; visualization, E.M.Z., E.F. and A.P.; supervision, E.M.Z., P.P. and F.F.; project administration, E.M.Z. and F.F.; funding acquisition, not applicable. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki. Our Institutional Review Board does not require ethical approval for case reports.\n\nInformed Consent Statement\n\nInformed consent was obtained from the patient.\n\nData Availability Statement\n\nNo new data were created or analyzed in this study. Data sharing is not applicable to this article.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest. The present study was self-funded. Written consent from the patient was obtained.\n\nAbbreviations\n\nCRP\tC reactive protein\t\nDAIR\tDebridement: antibiotics, irrigation, and implant retention\t\nESBL\tExtended spectrum β-lactamases\t\nESR\tErythrocyte sedimentation rate\t\nMDR\tMultidrug resistant\t\nPJI\tProsthetic joint infection\t\n\nFigure 1 A: Photograph demonstrating septic surgical wound of the right knee after removal of the prosthesis (by S. Hominis). B: Photograph demonstrating the wound healing of the right knee after three months from the positioning of the external fixator.\n\nFigure 2 Flow chart summarizing clinical and surgicalinterventions.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Marang-van de Mheen P.J. Bragan Turner E. Liew S. Mutalima N. Tran T. Rasmussen S. Nelissen R.G.H.H. Gordon A. Variation in Prosthetic Joint Infection and treatment strategies during 4.5 years of follow-up after primary joint arthroplasty using administrative data of 41,397 patients across Australian, European and United States hospitals BMC. Musculoskelet. Disord. 2017 18 207 10.1186/s12891-017-1569-2 28532409\n2. Tsukayama D.T. Estrada R. Gustilo R.B. Infection after total hip arthroplasty. A study of the treatment of one hundred and six infections J. Bone Jt. Surg. Am. 1996 78 512 523 10.2106/00004623-199604000-00005 8609130\n3. Marculescu C.E. Cantey J.R. Polymicrobial prosthetic joint infection Clin. Orthop. Relat. Res. 2008 466 1397 1404 10.1007/s11999-008-0230-7 18421538\n4. Moran E. Masters S. Berendt A.R. McLardy-Smith P. Byren I. Atkins B.L. Guiding empirical antibiotic therapy in orthopedics: The microbiology of prosthetic joint infection managed by debridement, irrigation and prosthesis retention J. Infect. 2007 55 1 7 10.1016/j.jinf.2007.01.007 17343916\n5. Zardi E.M. Franceschi F. Prosthetic joint infection. A relevant public health issue J. Infect. Public Health 2020 13 1888 1891 10.1016/j.jiph.2020.09.006 33289642\n6. Tatarelli P. Romani T. Santoro V. Spezia M. Gallo A. Ripamonti G. Carducci M. Trotti C. Parisini A. Nicolini L.A. Debridement, antibiotics and implant retention (DAIR): An effective treatment option for early prosthetic joint infections J. Infect. Chemother. 2021 27 1162 1168 10.1016/j.jiac.2021.03.009 33781690\n7. Achermann Y. Stasch P. Preiss S. Lucke K. Vogt M. Characteristics and treatment outcomes of 69 cases with early prosthetic joint infections of the hip and knee Infection 2014 42 511 519 10.1007/s15010-014-0584-6 24474624\n8. George D.A. Drago L. Scarponi S. Gallazzi E. Haddad F.S. Romano C.L. Predicting lower limb periprosthetic joint infections: A review of risk factors and their classification World J. Orthop. 2017 8 400 411 10.5312/wjo.v8.i5.400 28567344\n9. Sandiford N.A. Hutt J.R. Kendoff D.O. Mitchell P.A. Citak M. Granger L. Prolonged suppressive antibiotic therapy is successful in the management of prosthetic joint infection Eur. J. Orthop. Surg. Traumatol. 2020 30 313 321 10.1007/s00590-019-02559-4 31578679\n10. Chen M.J. Hung J.F. Chang C.H. Lee S.H. Shih H.N. Chang Y.H. Periprosthetic knee infection reconstruction with a hinged prosthesis: Implant survival and risk factors for treatment failure Knee 2020 27 1035 1042 10.1016/j.knee.2020.03.004 32317140\n11. Wimmer M.D. Friedrich M.J. Randau T.M. Ploeger M.M. Schmolders J. Strauss A.A. Hischebeth G.T. Pennekamp P.H. Vavken P. Gravius S. Polymicrobial infections reduce the cure rate in prosthetic joint infections: Outcome analysis with two-stage exchange and follow-up ≥two years Int. Orthop. 2016 40 1367 1373 10.1007/s00264-015-2871-y 26183140\n12. Zeller V. Kerroumi Y. Meyssonnier V. Heym B. Metten M.A. Desplaces N. Marmor S. Analysis of postoperative and hematogenous prosthetic joint-infection microbiological patterns in a large cohort J. Infect. 2018 76 328 334 10.1016/j.jinf.2017.12.016 29395369\n13. Benito N. Franco M. Coll P. Gálvez M.L. Jordán M. López-Contreras J. Pomar V. Monllau J.C. Mirelis B. Gurguí M. Etiology of surgical site infections after primary total joint arthroplasties J. Orthop. Res. 2014 32 633 637 10.1002/jor.22581 24436163\n14. Tornero E. Morata L. Martínez-Pastor J.C. Angulo S. Combalia A. Bori G. García-Ramiro S. Bosch J. Mensa J. Soriano A. Importance of selection and duration of antibiotic regimen in prosthetic joint infections treated with debridement and implant retention J. Antimicrob. Chemother. 2016 71 1395 1401 10.1093/jac/dkv481 26929270\n15. Pasticci M.B. Di Filippo P. Pasqualini L. Mencacci A. Pallotto C. Malincarne L. Baldelli F. Tolerability and efficacy of long-term treatment with daptomycin, ceftazidime and colistin in a patient with a polymicrobial, multidrug-resistant prosthetic joint reinfection: A case report J. Med. Case Rep. 2014 8 186 10.1186/1752-1947-8-186 24923703\n16. Frank B.J.H. Aichmair A. Simon S. Schwarz G.M. Dominkus M. Hofstaetter J.G. Analysis of Culture Positive First and Second Stage Procedures in Periprosthetic Knee and Hip Joint Infections J. Arthroplast. 2021 36 2158 2164 10.1016/j.arth.2021.01.074 33608181\n17. Brown A.W.W. Wilson R.B. Clostridium difficile colitis and zoonotic origins-a narrative review Gastroenterol. Rep. 2018 6 157 166 10.1093/gastro/goy016 30151199\n18. Kheir M.M. Tan T.L. Gomez M.M. Chen A.F. Parvizi J. Patients with failed prior two-stage exchange have poor outcomes after further surgical intervention J. Arthroplast. 2017 32 1262 1265 10.1016/j.arth.2016.10.008 27838014\n19. Löwik C.A.M. Zijlstra W.P. Knobben B.A.S. Ploegmakers J.J.W. Dijkstra B. de Vries A.J. Kampinga G.A. Mithoe G. Al Moujahid A. Jutte P.C. Northern Infection Network Joint Arthroplasty (NINJA). Obese patients have higher rates of polymicrobial and Gram-negative early periprosthetic joint infections of the hip than non-obese patients PLoS ONE 2019 14 e0215035 10.1371/journal.pone.0215035 30958847\n20. Seugendo M. Janssen I. Lang V. Hasibuan I. Bohne W. Cooper P. Daniel R. Gunka K. Kusumawati R.L. Mshana S.E. Prevalence and Strain Characterization of Clostridioides (Clostridium) difficile in Representative Regions of Germany, Ghana, Tanzania and Indonesia—A Comparative Multi-Center Cross-Sectional Study Front. Microbiol. 2018 9 1843 10.3389/fmicb.2018.01843 30131799\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1660-4601",
"issue": "18(17)",
"journal": "International journal of environmental research and public health",
"keywords": "amputation; antibiotic; clostridium infection; prosthesis; skin wound; therapy",
"medline_ta": "Int J Environ Res Public Health",
"mesh_terms": "D000900:Anti-Bacterial Agents; D019645:Arthroplasty, Replacement, Knee; D003015:Clostridium Infections; D006801:Humans; D007866:Leg; D008297:Male; D016459:Prosthesis-Related Infections; D012086:Reoperation; D012189:Retrospective Studies",
"nlm_unique_id": "101238455",
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"pages": null,
"pmc": null,
"pmid": "34501775",
"pubdate": "2021-08-31",
"publication_types": "D002363:Case Reports",
"references": "30131799;17343916;30151199;8609130;29395369;26183140;33289642;33608181;28532409;30958847;24436163;26929270;32317140;24923703;24474624;31578679;27838014;18421538;33781690;28567344",
"title": "Fatal Clostridium Infection in a Leg-Amputated Patient after Unsuccessful Knee Arthroplasty.",
"title_normalized": "fatal clostridium infection in a leg amputated patient after unsuccessful knee arthroplasty"
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"abstract": "OBJECTIVE\nThere is ongoing controversy related to the relationship between bisphosphonates and atrial fibrillation (AF). Our aim in this study was to evaluate the potential acute effect of zoledronic acid (ZA) infusion on AF development by using 24-hour Holter recordings.\n\n\nMETHODS\nThe study was designed to be a self-controlled case series study, and 33 consecutive patients with osteoporosis (29 females, age: 62.3±9.0 years) who were scheduled to receive ZA infusion constituted the study population. Patients underwent 24-hour Holter rhythm recordings at two different times; the first one was 48 hours before the planned ZA infusion, and the second one was on the morning of the infusion day. Heart rate, frequency and type of arrhythmias, as well as heart rate variability (HRV) from the two recordings were compared.\n\n\nRESULTS\nThere were no episodes of AF greater than 30 sec in any of the 24-hour Holter recordings obtained before and on the day of drug infusion. Holter recordings before drug infusion showed that only 1 patient had an atrial run of 3 beats long. Holter recordings obtained on the day of drug infusion revealed that 5 patients (15.2%) had atrial runs with lengths ranging between 3 and 12 beats (p=0.046). Regarding HRV variables, SDANN values were found to be significantly depressed on the day of ZA infusion (113.6±26.9 vs. 98.2±29.9, p=0.007).\n\n\nCONCLUSIONS\nNone of the patients developed AF during or early after ZA infusion. However, there was an increase in atrial ectopy in some patients, which might be due to alterations in cardiac autonomic activity.",
"affiliations": "Clinic of Cardiology, Fatih Sultan Mehmet Training and Research Hospital; İstanbul-Turkey. zeynepdemet@gmail.com.",
"authors": "İlgezdi|Zeynep Demet|ZD|;Aktaş|İlknur|İ|;Doğan Metin|Fatma|F|;Kepez|Alper|A|;Ünlü Özkan|Feyza|F|;Şilte|Ayşe Duygu|AD|;Yılmaz Kaysın|Meryem|M|;Kıvrak|Tarık|T|;Çincin|Altuğ|A|;Erdoğan|Okan|O|",
"chemical_list": "D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid",
"country": "Turkey",
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"doi": "10.5152/akd.2014.5333",
"fulltext": "\n==== Front\nAnatol J CardiolAnatol J CardiolAnatolian Journal of Cardiology2149-22632149-2271Kare Publishing Turkey 25413229AJC-15-32010.5152/akd.2014.5333Original InvestigationAcute effect of zoledronic acid infusion on atrial fibrillation development in patients with osteoporosis İlgezdi Zeynep Demet Aktaş İlknur *Metin Fatma Doğan Kepez Alper 1Ünlü Özkan Feyza *Duygu Şilte Ayşe *Yılmaz Kaysın Meryem *Kıvrak Tarık 1Çincin Altuğ 1Erdoğan Okan 1Clinics of Cardiology, Fatih Sultan Mehmet Training and Research Hospital; İstanbul-Turkey1 Clinic of Cardiology, Marmara University Training and Research Hospital; İstanbul-Turkey* Physical Therapy and Rehabilitation, Fatih Sultan Mehmet Training and Research Hospital; İstanbul-TurkeyAddress for Correspondence: Dr. Zeynep Demet İlgezdi, Fatih Sultan Mehmet Eğitim ve Araştırma Hastanesi, Kardiyoloji Kliniği, İstanbul-Türkiye Phone: +90 507 702 76 90 Fax: 216 575 04 06 E-mail: zeynepdemet@gmail.com4 2015 28 4 2014 15 4 320 324 10 4 2014 Copyright © 2016 Turkish Society of Cardiology2015This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International LicenseObjective:\nThere is ongoing controversy related to the relationship between bisphosphonates and atrial fibrillation (AF). Our aim in this study was to evaluate the potential acute effect of zoledronic acid (ZA) infusion on AF development by using 24-hour Holter recordings.\n\nMethods:\nThe study was designed to be a self-controlled case series study, and 33 consecutive patients with osteoporosis (29 females, age: 62.3±9.0 years) who were scheduled to receive ZA infusion constituted the study population. Patients underwent 24-hour Holter rhythm recordings at two different times; the first one was 48 hours before the planned ZA infusion, and the second one was on the morning of the infusion day. Heart rate, frequency and type of arrhythmias, as well as heart rate variability (HRV) from the two recordings were compared.\n\nResults:\nThere were no episodes of AF greater than 30 sec in any of the 24-hour Holter recordings obtained before and on the day of drug infusion. Holter recordings before drug infusion showed that only 1 patient had an atrial run of 3 beats long. Holter recordings obtained on the day of drug infusion revealed that 5 patients (15.2%) had atrial runs with lengths ranging between 3 and 12 beats (p=0.046). Regarding HRV variables, SDANN values were found to be significantly depressed on the day of ZA infusion (113.6±26.9 vs. 98.2±29.9, p=0.007).\n\nConclusion:\nNone of the patients developed AF during or early after ZA infusion. However, there was an increase in atrial ectopy in some patients, which might be due to alterations in cardiac autonomic activity.\n\nosteoporosiszoledronic acidatrial fibrillation24-hour Holter recording\n==== Body\nIntroduction\nOsteoporosis is a common health problem of elderly people, with a number of important consequences, including back pain, disability, and death (1). Bisphosphonates are commonly used in the management of osteoporosis. However, frequent and complex administration of oral bisphosphonates compromises the utility of these agents (2). Zoledronic acid (ZA) is a bisphospho- nate that allows annual treatment in postmenopausal patients affected by osteoporosis or at high risk of fracture. The availability of annual administration and the favorable tolerability has made ZA a comfortable and efficacious treatment option for these patients (3).\n\nThe efficacy of once-yearly, 15-minute infusion of ZA on fractures caused by osteoporosis was investigated in two largescaled multicenter randomized trials. The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly- Pivotal Fracture Trial (HORIZON-PFT) (4) and the Health Outcomes and\n\nReduced Incidence with Zoledronic Acid Once Yearly- Recurrent Fracture Trial (HORIZON-RFT) (5) demonstrated the efficacy of once-yearly infusion of ZA, with significantly reduced rates of vertebral and hip fractures compared to placebo.\n\nAtrial fibrillation (AF) has been reported to be more commonly seen as a serious adverse event compared to placebo in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT). Most of the patients in the ZA group in whom AF was reported as a serious event developed AF-related symptoms more than 30 days after the infusion (4). These observations prompted researchers to investigate the possible link between bisphosphonate therapy and AF; however, subsequent studies have shown conflicting results (6).\n\nThe aim of the present clinical study was to investigate the acute effect of ZA infusion on AF occurrence by using 24-hour rhythm Holter recordings in a population of patients with osteoporosis.\n\nMethods\nStudy design and patients\nThe study was designed as to be a self-controlled case series study. Consecutive patients with osteoporosis who were admitted to our clinic between September 2011 and May 2012 and scheduled to receive ZA infusion constituted our study population (n: 49; 39 females, age: 65.4±8.3 years). A detailed medical history, physical examination, and serum biochemistry were obtained from all patients. Serum calcium, phosphorus, and parathyroid hormone (PTH) levels were also screened for all patients. Parathyroid hormone is a regulatory hormone of calcium homeostasis, and its level increases in the presence of hypocalcemia. Serum PTH level increases as a result of a decrease in serum calcium level in the presence of vitamin D deficiency, which is called secondary hyperparathyroidism. We evaluated all osteoporotic patients for the presence of hypocalcemia and hyperparathyroidism, because treatment with bisphosphonates is known to inhibit bone resorption and increase the tendency for hypocalcemia. All patients underwent a baseline transthoracic echocardiographic examination. Patients with chronic AF, more than mild valvular disease on echocardiography, left ventricular systolic dysfunction (ejection fraction <60%), chronic renal failure, serious electrolyte imbalance, and hyper- or hypothyroidism were excluded from the study. Other exclusion criteria were a history of intravenous bisphosphonate therapy at any time and oral bisphosphonate therapy within 3 months before enrollment into the study. Patients taking any anti-arrhythmic agent, such as a beta-blocker and calcium channel blocker, were also excluded. After exclusion, 33 remaining patients with osteoporosis (29 females, age: 62.3±9.0 years) underwent 24-hour Holter rhythm recordings at two different times: the first recording was started 48 hours before the planned day of ZA infusion and the second was started on the morning of the infusion day. At the time that the Holter ambulatory recordings were commenced, all patients were given intravenous infusion therapy. Heart rate, frequency and type of arrhythmias, as well as heart rate variability from the two recordings were compared. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study.\n\n24-hour Holter recordings\nRecordings were obtained using 3-channel analog recorders (VX3 Holter System) and analyzed by a blinded observer using the Biomedical Systems Century Series C1000 software (version 2.13). Paroxysmal AF was defined as paroxysms of AF lasting for at least for 30 seconds (7). The time domain analysis of heart rate variability (HRV) was performed according to the recommendations of the European Society of Cardiology task force (8). The mean heart rate, standard deviation of all NN intervals (SDNN), standard deviation of the averages of NN intervals in all 5-min segments of the entire recording (SDANN), root mean square of successive differences (RMSSD), and HRV triangular index (TRIA) were measured in the time domain analysis of HRV. SDNN and HRV triangular index have been assumed to reflect overall HRV, SDANN has been assumed to reflect the long-term components of HRV, and RMSSD has been assumed to reflect its short-term components. A reduced SDNN has been considered to reflect diminished autonomic modulation of the sinus node.\n\nStatistical analysis\nStatistical analysis was performed using SPSS for WINDOWS (version 15.0; SPSS Inc., Chicago, Illinois, USA). The distribution of data was assessed using one-sample Kolmogorov-Smirnov test. Ordinal variables displaying normal distribution were expressed as mean±SD, and ordinal variables not displaying normal distribution were expressed as median (interquartile range). Differences regarding the frequency of atrial and ventricular arrhythmias observed on the Holter recordings before and on the day of ZA infusion were evaluated with Wilcoxon signed-rank test. Differences between HRV variables between two Holter recordings were evaluated with paired-samples student t-test. A p value less than 0.05 was considered significant.\n\nResults\nData on 33 patients were used in the analysis. The clinical and biochemical data of these patients are displayed in Table 1. Fifteen patients (45.4%) had intact serum parathyroid hormone (PTH) levels above the normal range (normal range, 12-72 pg/mL), whereas only 2 patients (6%) had serum calcium levels above the normal range (normal range 9-10.5 mg/dL), and 1 patient (3%) had serum phosphate levels below the normal range (normal range: 2.4-4.1 mg/dL). All patients had serum magnesium levels within the normal range. The transthoracic echocardiographic findings of patients are presented in Table 2.\n\nTable 1 Clinical and biochemical data of study population\n\nAge, years\t62.3±9.0\t\nSex, male/female\t4 M, 29 F\t\nSerum PTH level (mean±SD, pg/mL) (normal: 10-55 pg/mL)\t75.9±42.9\t\nSerum TSH level (mean±SD, mIU/L) (normal 0.4-4.2 mIU/L)\t2.1±0.8\t\nSerum calcium level (mean±SD, mg/dL) (normal: 8.5-10.2 mg/dL)\t9.57±0.49\t\nSerum phosphorus level (mean±SD, mg/dL) (normal 2.4-4.1 mg/dL)\t3.41±0.64\t\nSerum magnesium level (mean±SD, mg/dL) (normal: 1.7-2.2 mg/dL)\t1.95±0.15\t\nSerum creatinine level (mean±SD, mg/dL) (normal: 0.6-1.2 mg/dL)\t0.68±0.13\t\nBlood urea nitrogen level (mean±SD, mg/dL) (normal 6-20 mg/dL)\t12.3±4.0\t\nSerum sodium level (mean±SD, mEq/L) (normal 135-145 mEq/L)\t139.5±1.8\t\nSerum potassium level (mean±SD, mEq/L) (normal 3.7-5.2 mEq/L)\t4.4±0.3\t\nHypertension, n (%)\t5 (15%)\t\nDiabetes mellitus, n (%)\t6 (18.7%)\t\nHyperlipidemia, n (%)\t5 (15%)\t\nSmoking, n (%)\t2 (6%)\t\nPTH - parathyroid hormone; SD - standard deviation; TSH - thyroid-stimulating hormone\n\nTable 2 Transthoracic echocardiography variables of the study population\n\nLV end-diastolic diameter (mean±SD, mm)\t37.9±3.9\t\nLV end-systolic diameter (mean±SD, mm)\t22.8±2.8\t\nLV ejection fraction (mean±SD, %)\t65.1±3.9\t\nAortic diameter (mean±SD, mm)\t24.0±2.9\t\nLeft atrial diameter (mean±SD, mm)\t32.6±2.8\t\nTransmitral E velocity (mean±SD, cm/s)\t0.68±0.15\t\nTransmitral A velocity (mean±SD, cm/s)\t0.79±0.15\t\nSeptal end-diastolic thickness (mean±SD, mm)\t0.93±0.1\t\nPosterior wall end-diastolic thickness (mean±SD, mm)\t0.92±0.08\t\nMitral regurgitation (mild), n (%)\t7 (21.2%)\t\nAortic regurgitation (mild), n (%)\t6 (18.2%)\t\nTricuspid regurgitation (mild), n (%)\t7 (21.2%)\t\nLV - left ventricle; SD - standard deviation\n\nA total of 3483 premature ventricular contractions (PVCs) and 44 supraventricular premature contractions (SVPCs) were recorded in the Holter recordings obtained before ZA infusion. On the other hand, 6858 PVCs and 194 SVPCs were recorded in the Holter recordings obtained on the day of drug infusion (p=0.9 for PVCs and p=0.05 for SVPCs). There were no episodes of atrioventricular blocks or pauses in any of the Holter recordings.\n\nThere were no episodes of sustained (lasting more than 30 seconds) or nonsustained ventricular tachycardia in any of Holter recordings obtained before and on the day of drug infusion. Nine (27.2%) patients displayed PVCs on Holter recordings obtained before drug infusion, whereas 10 patients (30.3%) displayed PVCs on Holters obtained on the day of drug infusion (p=0.90). Eight patients displayed PVCs on both Holter recordings; 1 patient displayed PVCs only on the Holter obtained before infusion, and 2 patients displayed PVCs only on the Holter obtained on the day of infusion. The frequency of PVCs was less than 10% of total heart beats for each patient displaying PVCs on the Holter recordings.\n\nThere were no episodes of AF episode, which was defined as more than 30 sec in duration, in any of the 24-hour Holter recordings obtained before and on the day of drug infusion. Pre- infusion Holter recordings showed that only 1 patient had an atrial run of 3 beats long, whereas Holter recordings obtained on the day of drug infusion revealed that 5 patients (15.2%) developed atrial runs between 3 and 10 beats (p=0.046). One patient had 2 atrial runs (3 and 12 beats long) (Fig. 1), and others had only one atrial run on the 24-hour Holter recording obtained on the day of drug infusion (Table 3). None of these 5 patients had hypertension, diabetes mellitus, or smoking habit. Transthoracic echocardiographic examinations of these 5 patients demonstrated normal-sized left atria for each patient, without any valvular regurgitation or stenosis. Regarding HRV variables, only the difference between SDANN values of two Holter recordings was found to be statistically significant (Table 4).\n\nFigure 1 Representation of an atrial run of 12 beats long obtained from a Holter recording on the day of drug infusion\n\nTable 3 Number and durations of atrial runs observed on 24 hour recordings obtained before and on the day of drug infusion\n\nAge\tBefore drug infusion\tOn the day of drug infusion\t\n63\t1 atrial run of 3 beats long\t1 atrial run of 4 beats long\t\n81\t------\t1 atrial run of 6 beats long\t\n60\t------\t1 atrial run of 7 beats long\t\n61\t------\t2 atrial runs; 3 and 12 beats long\t\n58\t------\t1 atrial run of 3 beats long\t\nTable 4 Heart rate variability variables obtained before and on the day of drug infusion\n\n\tBefore drug infusion\tOn the day of drug infusion\tVariation\tP\t\nMaximum heart rate (mean±SD)\t123.9±16.1\t124.6±11.9\t-0.6±21.8\t0.87\t\nMinimum heart rate (mean±SD)\t50.3±5.5\t52.9±5.6\t-2.6±4.7\t0.004\t\nMean heart rate (mean±SD)\t72.8±6.9\t75.0±7.9\t-2.2±8.8\t0.16\t\nSDNN (mean±SD)\t146.8±39.1\t136.9±61.4\t9.9±69.9\t0.42\t\nSDNN5 (mean±SD)\t78.9±45.7\t81.2±64.4\t-2.3±80.2\t0.87\t\nSDANN (mean±SD)\t113.6±26.9\t98.2±29.9\t15.42±30.50\t0.007\t\npNN50 (mean±SD)\t16.5±9.6\t16.9±13.3\t-3.3± 15.9\t0.9\t\nTRIA (mean±SD)\t551.4±169.6\t500.3±143.6\t51.0±196.9\t0.15\t\nRMSSD (mean±SD)\t82.3±55.3\t79.7±63.6\t2.6±85.5\t0.86\t\nSD - standard deviation; TRIA - triangular index\n\nDiscussion\nThe principle finding of the present study is that there is no increase in the frequency of AF and ventricular arrhythmias on the day of ZA infusion. However, there was a statistically significant increase in the frequency of atrial runs only in 5 patients.\n\nThe association between bisphosphonate therapy and AF is mainly derived from serious adverse event (SAE) reports from clinical trials, observational studies, and meta-analyses (6, 9). The observation of an association between ZA therapy and increased risk of AF in HORIZON-PFT raised concerns about arrhythmogenic effects with the use of bisphosphonates, although there was no excess risk of cardiac arrhythmias in patients treated with ZA in HORIZON-RFT (4, 5). A review of the Fracture Intervention Trial (FIT), which was published as a letter to the editor after the publication of the results of HORIZON-PFT, revealed a nominally but not significantly increased risk of AF events with alendronate-treated patients compared to placebo (10). After publication of those reports, meta-analyses of clinical trials have been conducted and retrospective studies have been performed to examine the risk of AF in patients taking bisphosphonates for the treatment of osteoporosis. In most of the metaanalyses and reviews, bisphosphonate use was not associated with an increased risk of AF (6, 9, 11). However, it was difficult to reach a definitive conclusion, since there were no available data gathered from prospective studies directly evaluating effects of bisphosphonates on cardiac arrhythmias. Both osteoporosis and AF usually occur together in elderly people (12). As such, it is difficult to suggest a direct cause-effect relationship between bisphosphonate usage and AF because of the general AF risk in elderly patients. Because of confounding factors, we planned our study by comparing the Holter recordings within the same individuals before and during, as well as after, the infusion period.\n\nZoledronic acid is also used for the treatment of bone metastasis and multiple myeloma. Cumulative ZA dosages of cancer patients with bone metastasis are higher compared with the dosage used in osteoporosis. In a recent study, Yazıcı et al. (13) evaluated the arrhythmogenic effects of ZA infusion in cancer patients with bone metastasis by using 24-h Holter recordings obtained during the first dose ZA infusion day. They reported increased atrial and ventricular premature complexes during and after ZA infusion compared to basal recordings obtained before drug infusion. However, Arslan et al. (14) did not demonstrate an increased risk of AF in a similar study population, using standard 12-lead electrocardiography (ECG) recordings.\n\nThe mechanism of a possible association between bisphosphonates and AF is not well established. Acute changes in myocardial cellular electrolyte homeostasis, particularly involving\n\nCa+2, Mg+2, and Cl-, might have been implicated as contributing factors for atrial ectopy (6). It has been proposed that intracellular electrolyte imbalances may lead to functional abnormalities in the cardiomyocyte and cause reentry or increased auto- maticity (13). This hypothesis raises the question of whether frequent monitoring and prompt correction of electrolyte abnormalities cure ZA-related AF. However, most of the AF events occurred more than 30 days after the infusion in HORIZON-PFT (4), and longer-term proinflammatory, profibrotic, and antiangio- genic effects of bisphosphonates have been accused of contributing to AF (6).\n\nSDANN values are suggested to reflect longer-term components of HRV. SDANN values were found to be depressed on the day of infusion compared to recordings obtained before the infusion, which may imply that alterations in autonomic nervous system activity may also be operative for the increased atrial ectopy in our patients. On the other hand, the depression of SDANN found in our study on the day of drug infusion might be related to increased anxiety of intravenous cannulation and infusion.\n\nStudy limitations\nThe small sample size is the main limitation of this study. We used 24-hour Holter monitoring systems to evaluate the acute effects of ZA infusion on the risk of cardiac arrhythmia. As most of the AF events were reported to occur 30 days after drug infusion in previous studies, it might have been more valuable to use event recorders with longer-term recording capability.\n\nConclusion\nThere were no episodes of AF in any patient on the day of ZA infusion. However, there was an increase in atrial ectopy only in 5 patients, which might be related to alterations in cardiac autonomic activity. Results of prospective studies using systems with longer-term recording capability are required to elucidate the effects of ZA infusion on the risk of AF.\n\nConflict of interest: None declared.\n\nPeer-review: Externally peer-reviewed.\n\nAuthorship contributions: Concept - İ.A., Z.D.İ.; Design - İ.A.; Supervision - İ.A.; Materials - İ.A., F.Ü.Ö., A.D.Ş., M.Y.K., T.K.; Data collection &/or processing - Z.D.İ., F.D.M., T.K.; Analysis &/or interpretation - A.K., A.Ç., O.E.; Literature search - A.K., İ.A.; Writing - A.K., İ.A.; Critical review - İ.A., O.E.\n==== Refs\nReferences\n1 Cummings SR Melton LJ Epidemiology and outcomes of osteoporotic fractures Lancet 2002 359 1761 7 [CrossRef] 12049882 \n2 Boonen S Black DM Colôn-Emeric CS Eastell R Magaziner JS Eriksen EF Efficacy and safety of a once-yearly intravenous zoledronic acid 5 mg for fracture prevention in elderly postmeno- pausal women with osteoporosis aged 75 and older J Am Geriatr Soc 2010 58 292 9 [CrossRef] 20070415 \n3 Dalle Carbonare L Zannatta M Gasparetto A Valenti MT Safety and tolerability of zoledronic acid and other bisphosphonates in osteoporosis management Drug Healthc Patient Saf 2010 2 121 37 [CrossRef] 21701624 \n4 Black DM Delmas PD Eastell R Reid IR Boonen S Cauley JA for the HORIZON Pivotal Fracture Trial Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis N Engl J Med 2007 356 1809 22 [CrossRef] 17476007 \n5 Lyles KW Colon-Emeric CS Magaziner JS Adachi JD Pieper CF Mautalen C for the HORIZON Recurrent Fracture Trial Zoledronic acid and clinical fractures and mortality after hip fracture N Engl J Med 2007 357 1799 809 [CrossRef] 17878149 \n6 Pazianas M Compston J Huang CL Atrial fibrillation and bisphosphonate therapy J Bone Miner Res 2010 25 2 10 [CrossRef] 20091928 \n7 Camm AJ Kirchhof P Lip GY Schotten U Savelieva I Ernst S European Heart Rhythm Association;European Association for Cardio-Thoracic Surgery Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) Eur Heart J 2010 31 2369 429 [CrossRef] 20802247 \n8 Task Force of the European Society of Cardiology and the North American Society of Pacing Electrophysiology Heart rate variability: standards of measurement, physiological interpretation, and clinical use Circulation 1996 93 1043 65 [CrossRef] 8598068 \n9 John Camm A Review of the cardiovascular safety of zoledronic acid and other biphosphonates for the treatment of osteoporosis Clin Ther 2010 32 426 36 [CrossRef] 20399982 \n10 Cummings SR Schwarz AV Black DM Alendronate and atrial fibrillation N Engl J Med 2007 356 1895 6 [CrossRef] 17476024 \n11 Barrett-Connor E Swern AS Hustad CM Bone HG Liberman UA Papapoulos S Alendronate and atrial fibrillation: a meta- analysis of randomized placebo-controlled clinical trials Osteoporos Int 2012 23 233 45 [CrossRef] 21369791 \n12 Melton LJ 3rd Thamer M Ray NF Chan JK Chesnut CH 3rd Einhorn TA Fractures attributable to osteoporosis: report from the National Osteoporosis Foundation J Bone Miner Res 1997 12 16 23 [CrossRef] 9240721 \n13 Yazıcı O Aksoy S Uçar O Özdemir N Demir M Şendur MA Arrhythmias during and after zoledronic acid infusion patients with bone metastasis Med Oncol 2013 30 609 [CrossRef] 23690271 \n14 Arslan C Aksoy S Dizdar O Dede DS Harputluoğlu H Altundağ K Zoledronic acid and atrial fibrillation in cancer patients Support Care Cancer 2011 19 425 30 [CrossRef] 20358384\n\n",
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"mesh_terms": "D001281:Atrial Fibrillation; D004164:Diphosphonates; D004452:Echocardiography; D015716:Electrocardiography, Ambulatory; D005260:Female; D006620:Hip Fractures; D006801:Humans; D007093:Imidazoles; D007262:Infusions, Intravenous; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal; D000077211:Zoledronic Acid",
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"title": "Acute effect of zoledronic acid infusion on atrial fibrillation development in patients with osteoporosis.",
"title_normalized": "acute effect of zoledronic acid infusion on atrial fibrillation development in patients with osteoporosis"
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"abstract": "Growing teratoma syndrome (GTS) is a rare clinical entity first described by Logothetis et al in 1982. Although it is unusual for GTS to be located in the ovary, this report is of a case of an adolescent girl who underwent a complete surgical resection of the mass. Histopathology confirmed only an immature teratoma had originated from the ovary and so she received adjuvant chemotherapy with blemycin, etopside, and cisplatin over 4 cycles. Results from an abdominal enhanced CT (computed tomography) 9 years later revealed a giant mass had compressed adjacent tissues and organs. Laparotomy was performed and a postoperative histopathology showed the presence of a mature teratoma, and so the diagnosis of ovarian GTS was made. One hundred one cases of ovarian GTS from English literature published between 1977 and 2015 were collected and respectively analyzed in large samples for the first time. The median age of diagnosis with primary immature teratoma was 22 years (range 4-48 years, n = 56). GTS originating from the right ovary accounted for 57% (27/47, n = 47) whereas the left contained 43% (20/47, n = 47). Median primary tumor size was 18.7 cm (range 6-45 cm, n = 28) and median subsequent tumor size was 8.6 cm (range 1-25 cm, n = 25). From the primary treatment to the diagnosis of ovarian GTS, median tumor growth speed was 0.94 cm/month (range 0.3-4.3 cm/month, n = 21). Median time interval was 26.6 months (range 1-264 months, n = 41). According to these findings, 5 patients did have a pregnancy during the time interval between primary disease and GTS, making our patient the first case of having a pregnancy following the diagnosis of ovarian GTS. Because of its high recurrence and insensitiveness to chemotherapy, complete surgical resection is the preferred treatment and fertility-sparing surgery should be considered for women of child-bearing age. Anyhow GTS of the ovary has an excellent prognosis. Patients with GTS had no evidence of recurrence or were found to be disease free during a 40.3-month (range 1-216 months, n = 48) median follow-up. Moreover, regular follow-ups with imaging and serum tumor markers are important and must not be neglected.",
"affiliations": "From the Department of General Surgery (SL, ZL, CD, FL, QL, DS, ZG, LW), The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China; and Dalian Medical University (SL, ZL, CD, FL), Dalian, Liaoning Province, China.",
"authors": "Li|Song|S|;Liu|Zhenzhen|Z|;Dong|Chengyong|C|;Long|Fei|F|;Liu|Qinlong|Q|;Sun|Deguang|D|;Gao|Zhenming|Z|;Wang|Liming|L|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2688660410.1097/MD.0000000000002647026475600Research ArticleClinical Case ReportGrowing Teratoma Syndrome Secondary to Ovarian Giant Immature Teratoma in an Adolescent Girl A Case Report and Literature ReviewLi Song Liu Zhenzhen Dong Chengyong Long Fei Liu Qinlong Sun Deguang Gao Zhenming Wang Liming He. Kan From the Department of General Surgery (SL, ZL, CD, FL, QL, DS, ZG, LW), The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China; and Dalian Medical University (SL, ZL, CD, FL), Dalian, Liaoning Province, China.Correspondence: Liming Wang, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China (e-mail: wanglmdoctor@sina.com).2 2016 18 2 2016 95 7 e264724 11 2015 7 1 2016 7 1 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution-NonCommercial License, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be used commercially. http://creativecommons.org/licenses/by-nc/4.0Abstract\nGrowing teratoma syndrome (GTS) is a rare clinical entity first described by Logothetis et al in 1982. Although it is unusual for GTS to be located in the ovary, this report is of a case of an adolescent girl who underwent a complete surgical resection of the mass. Histopathology confirmed only an immature teratoma had originated from the ovary and so she received adjuvant chemotherapy with blemycin, etopside, and cisplatin over 4 cycles. Results from an abdominal enhanced CT (computed tomography) 9 years later revealed a giant mass had compressed adjacent tissues and organs. Laparotomy was performed and a postoperative histopathology showed the presence of a mature teratoma, and so the diagnosis of ovarian GTS was made. One hundred one cases of ovarian GTS from English literature published between 1977 and 2015 were collected and respectively analyzed in large samples for the first time.\n\nThe median age of diagnosis with primary immature teratoma was 22 years (range 4–48 years, n = 56). GTS originating from the right ovary accounted for 57% (27/47, n = 47) whereas the left contained 43% (20/47, n = 47). Median primary tumor size was 18.7 cm (range 6–45 cm, n = 28) and median subsequent tumor size was 8.6 cm (range 1–25 cm, n = 25). From the primary treatment to the diagnosis of ovarian GTS, median tumor growth speed was 0.94 cm/month (range 0.3–4.3 cm/month, n = 21). Median time interval was 26.6 months (range 1–264 months, n = 41). According to these findings, 5 patients did have a pregnancy during the time interval between primary disease and GTS, making our patient the first case of having a pregnancy following the diagnosis of ovarian GTS. Because of its high recurrence and insensitiveness to chemotherapy, complete surgical resection is the preferred treatment and fertility-sparing surgery should be considered for women of child-bearing age.\n\nAnyhow GTS of the ovary has an excellent prognosis. Patients with GTS had no evidence of recurrence or were found to be disease free during a 40.3-month (range 1–216 months, n = 48) median follow-up. Moreover, regular follow-ups with imaging and serum tumor markers are important and must not be neglected.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nThe growing teratoma syndrome (GTS) was originally defined by Logothetis et al in 1982 as the phenomenon of subsequent growth of a benign tumor, following the removal of a primary malignant tumor during or after chemotherapy.1 Growing teratoma syndrome (GTS) is a rare entity related to both testicular and ovarian carcinoma. The incidence of GTS in a nonseminomatous germ cell of the testis is 1.9% to 7.6%, while it has been reported to occur in 12% of ovarian germ cell tumors.2,3 Generally speaking, ovarian GTS typically occurs in young adults and adolescents.4 Some researchers have recommended 3 criteria according to the Logothetis definition. The criteria of GTS includes (1) normalization of serum tumor markers, alpha fetoprotein (AFP), and human chorionic gonadotropin; (2) enlarging or new masses despite appropriate chemotherapy for nonseminomatous germ cell tumors; (3) the exclusive presence of mature teratoma in the resected specimen.5 Herein, we report a rare case of an adolescent girl with ovarian GTS, and 101 cases of ovarian GTS from English literature published between 1977 and 2015 were collected and respectively analyzed in large samples for the first time. This contributed to the understanding of the clinical features of this disease.\n\nCASE REPORT\nA 16-year-old girl was presented in August 2005 with intermittent abdominal pain and distention for half a year. Ultrasonography revealed a right ovarian tumor that occupied the whole right upper abdominal cavity. She received the right oophorectomy and the giant tumor was completely resected, showing about a 40 cm × 25 cm × 15 cm mass with intact capsule. Histopathology revealed skin, cartilage, and a malignant immature teratoma. After surgery, she was treated with 4 cycles of blemycin, etopside, and cisplatin (BEP) chemotherapy but refused any further treatment and missed her follow-up. In the following years, she had not felt any discomfort until August 2014. A mass in the whole right abdomen could be touched about 30 cm × 20 cm, without a clear boundary between surrounding tissues. Abdominal-enhanced CT revealed a giant mass in the retroperitoneum that compressed the postcava, the right hepatic vein, liver, pancreas, and the right kidney. Because of the compression, the portal vein, right renal artery, superior mesenteric artery, and celiac trunk had shifted to the left (Figure 1). Tumor markers, AFP, and human chorionic gonadotropin were normal while the carbohydrate antigen 125 level was 412.30 u/mL (normal, 0–35.00 u/mL), and carbohydrate antigen 199 level was over 7000 u/mL (normal, 0–37.00 u/mL). The rest of the laboratory tests were found to be negative. After a discussion by the departments of general surgery, obstetrics gynecology and urology, the patient underwent a resection of abdominal and pelvic lesions, around the liver and spleen. The giant tumor was completely resected and gross examination revealed a giant mass (29 cm × 24 cm × 12 cm) containing lipid, hair, gelatinous material, and a few nodules (Figure 2). Histopathology revealed only a mature teratoma (Figure 3). Hence, a final diagnosis of “growing teratoma syndrome (GTS)” was made. During the 14-month follow-up, no evidence of recurrence or metastasis was observed and she became pregnant 2 months after her last follow-up.\n\nFIGURE 1 CT showed the mass occupying the right upper abdominal cavity, revealing multiple new masses containing cystic and necrotic elements surrounding the liver (A, D, E). Because of tumor compression, the giant mass had compressed the postcava, liver, pancreas, and the right kidney (B, C). The portal vein, right renal artery, superior mesenteric artery, and celiac trunk shifted to the left and was not invaded by the tumor through the technique of 3-dimensional CT image reconstruction (D, E, F). CT = computed tomography.\n\nFIGURE 2 The whole abdominal lesion reached 29 cm × 24 cm × 12 cm in size (A, the ruler is 20 cm long), 5.015 kg in weight (C). A part of pelvic lesions, lesions in the hepatic envelop, and around the spleen (B).\n\nFIGURE 3 Histopathology of mature teratoma of the abdomen cavity at the age of 24. The carcinoids are distributed in various mature tissues derived from 3 germ cell layers (HE × 100). (A) sebaceous gland (red arrow); (B) muscular tissue (red arrow); (C) bronchus tissue (red arrow). HE = hematoxylin-eosin.\n\nDISCUSSION\nThis is an unusual case in which there were increasing masses 9 years after chemotherapy for an ovarian immature teratoma, but all the masses subsequently resected were shown to contain only mature teratoma. In 1977, DiSaia firstly reported 3 cases of “chemotherapeutic retroconversion” in which benign distant metastasis appeared following adjuvant chemotherapy for immature teratoma of the ovary.6 However, the term GTS was originally defined by Logothetis in 1982, when he described 6 patients with nonseminomatous germ cell tumors who subsequently developed growing metastatic masses despite appropriate systemic chemotherapy and normal range of serum tumor markers.7 The histopathology revealed benign mature teratoma without viable germ cell elements.1\n\nGTS is characterized by an increase in metastatic mass after complete eradication of a primary malignant ovarian germ cell tumor and by normalization of serum tumor markers, either during or after chemotherapy.8,9 Some researchers considered that these 2 characters are in fact the same entity.7,8 There are 2 major inferences of GTS formation. The first hypothesis is that chemotherapy transforms malignant cells into “benign” teratomatous elements. The second hypothesis is that chemotherapy can only destroy malignant cells leaving chemoresistant teratoma behind.3,10 It remains, that there is much uncertainty around GTS due to the limited number of cases, and that either of the inference is in fact possible or that both can play an important roles in the development of GTS.\n\nTo the best of our knowledge, ovarian GTS is only 101 cases in published English literatures (Table 1 ). Most of the patients had abdominal symptoms, such as abdominal pain and distension when they first sought medical advice. In our study, the median age of the diagnosis of primary immature teratoma was 22 years (range 4–48 years, n = 56) (Table 1 ). While Bentivegna et al5 reported the median age at diagnosis was 26 years (range 8–41 years, n = 38). Because of the existence of 10 gliomatosis peritonei cases in 38, this data would not be suitable for pure GTS. GTS originating from the right ovary accounted for 57% (27/47, n = 47) and the left contained 43% (20/47, n = 47) (Table 1 ). Median primary tumor size was 18.7 cm (range 6–45 cm, n = 28) and median subsequent tumor size was 8.6 cm (range 1–25 cm, n = 25) (Table 1 ). Growing teratomas have a rapid expansion rate, with a median linear growth of 0.5 to 0.7 cm/month and volume increase of 9.2 to 12.9 cm3/month.11,12 While from the results of our study, the tumor growth was 0.94 cm/month (range 0.3–4.3 cm/month, n = 21) (Table 1 ). The discrepancy could be explained by different sample sizes.\n\nTABLE 1 Growing teratoma syndrome of ovary\n\nTABLE 1 (Continued) Growing teratoma syndrome of ovary\n\nTABLE 1 (Continued) Growing teratoma syndrome of ovary\n\nThis behavior is unpredictable because of aggressive local spread as well as GTS having the potential for malignant degeneration.11,13,14 The GTS nodules can appear at any stage during or after chemotherapy, and in some cases can be delayed anything up to 8 years, with an average interval of 8 months.5,7,14 In our study, median time interval was 26.6 months (range 1–264 months, n = 41) (Table 1 ) and our patient was delayed up to 9 years. Therefore regular follow-ups contributed to early detection, diagnosis, and treatment. It is reported that the retroperitoneum is the most common site for GTS, followed closely by the lung, cervical lymph nodes, and mediastinum.7,15 To date, there is no reliable indicator for GTS. Close attention should always be paid to an enlarged tumor and/or normalization of serum tumor markers during chemotherapy.16–18\n\nThe preferred treatment is complete surgical resection, because of GTS having a high recurrence rate of 72% to 83% in patients with partial resection, against 0% to 4% in those who undergo complete resections, as teratomas are resistant to chemotherapy and radiation therapy.11 Early detection and reasonable complete resection of the primary lesion and implantation or metastasis are essential. Adjuvant chemotherapy with blemycin, etopside, and cisplatin was recommended for patients when diagnosed with immature teratoma following primary surgery. Palbociclib (PD0332991) is reported that it can stabilize the vascularization of the tumor in pediatric patients with an intracranial teratoma.19 But further investigation of the use of Palbociclib in patients with growing teratoma syndrome should be carried out.19 From these literatures, tumor markers AFP usually returned to within the normal range, with the exception of 2 cases reported by Pendlebury et al and Lorusso et al.18,20\n\nSo far, no standardized management protocol has been established to diagnose and treat GTS.5 However it has shown, GTS has an overall good prognosis with a 5-year overall survival rate of 89% in patients who undergo surgery.3,7 This study has shown, patients with GTS had little or no evidence of recurrence or indeed were disease free for 40.3 months (range 1–216 months, n = 48) median follow-up (Table 1 ). According to our study, 5 patients had a pregnancy during the time interval between primary disease and GTS, with our patient being the first case of having a pregnancy following the diagnosis of ovarian GTS. Therefore fertility-sparing surgery is recommended for women of child-bearing age if conditions allow. Until now, the mechanism of GTS is still unclear and the diagnosis of it has proven difficult. Consequently, the accumulation of additional data from more cases would be necessary to further elucidate this type of tumor and standardize optimal therapy.\n\nPATIENT CONSENT\nPatient consent was obtained for this study.\n\nAbbreviations: AFP = alpha fetoprotein, BEP = blemycin etopside and cisplatin, CA = carbohydrate antigen, CT = computed tomography, GP = gliomatosis peritonei, GTS = growing teratoma syndrome, HCG = human chorionic gonadotropin, HE = hematoxylin-eosin, NSGCT = nonseminomatous germ cell of the testis.\n\nSong Li and Zhenzhen Liu contributed equally to this work.\n\nThe authors have no funding and conflicts of interest to disclose.\n\nThe study was supported by clinical capability construction project for liaoning provincial hospitals(LNCCC-B03-2014) and the National Natural Science Foundation of China (81471755, 81272368). We really appreciate it if you could help us to add our Chinese funding.\n\nFunding: The study was supported by clinical capability construction project for liaoning provincial hospitals(LNCCC-B03-2014) and the National Natural Science Foundation of China (81471755, 81272368).\n==== Refs\nREFERENCES\n1. Logothetis CJ Samuels ML Trindade A \nThe growing teratoma syndrome . Cancer \n1982 ; 50 :1629 –1635 .6288220 \n2. Zagame L Pautier P Duvillard P \nGrowing teratoma syndrome after ovarian germ cell tumors . Obstet Gynecol \n2006 ; 108 :509 –514 .16946208 \n3. Gorbatiy V Spiess PE Pisters LL \nThe growing teratoma syndrome: current review of the literature . Indian J Urol \n2009 ; 25 :186 –189 .19672343 \n4. Lai CH Chang TC Hsueh S \nOutcome and prognostic factors in ovarian germ cell malignancies . Gynecol Oncol \n2005 ; 96 :784 –791 .15721426 \n5. Bentivegna E Azais H Uzan C \nSurgical outcomes after debulking surgery for intraabdominal ovarian growing teratoma syndrome: analysis of 38 cases . Ann Surg Oncol \n2015 ; 22 \nsuppl 3 :964 –970 .\n6. DiSaia PJ Saltz A Kagan AR \nChemotherapeutic retroconversion of immature teratoma of the ovary . Obstet Gynecol \n1977 ; 49 :346 –350 .65751 \n7. Daher P Riachy E Khoury A \nGrowing teratoma syndrome: first case report in a 4-year-old girl . J Pediatr Adolesc Gynecol \n2015 ; 28 :e5 –e7 .25256881 \n8. Amsalem H Nadjari M Prus D \nGrowing teratoma syndrome vs chemotherapeutic retroconversion: case report and review of the literature . Gynecol Oncol \n2004 ; 92 :357 –360 .14751185 \n9. Byrd K Stany MP Herbold NC \nGrowing teratoma syndrome: brief communication and algorithm for management . Aust N Z J Obstet Gynaecol \n2013 ; 53 :318 –321 .23600854 \n10. Panda A Kandasamy D Sh C \nGrowing teratoma syndrome of ovary: avoiding a misdiagnosis of tumour recurrence . 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Shigeta N Kobayashi E Sawada K \nLaparoscopic excisional surgery for growing teratoma syndrome of the ovary: case report and literature review . J Minim Invasive Gynecol \n2015 ; 22 :668 –674 .25620216 \n22. Merard R Ganesan Hirschowitz L \nGrowing teratoma syndrome: a report of 2 cases and review of the literature . Int J Gynecol Pathol \n2015 ; 34 :465 –472 .26262454 \n23. Han NY Sung DJ Park BJ \nImaging features of growing teratoma syndrome following a malignant ovarian germ cell tumor . J Comput Assist Tomogr \n2014 ; 38 :551 –557 .24681864 \n24. De Cuypere M Martinez A Kridelka F \nDisseminated ovarian growing teratoma syndrome: a case-report highlighting surgical safety issues . Facts Views Vis Obgyn \n2014 ; 250 –253 .25593702 \n25. Shibata K Kajiyama H Kikkawa F \nGrowing teratoma syndrome of the ovary showing three patterns of metastasis: a case report . Case Rep Oncol \n2013 ; 6 :544 –549 .24348391 \n26. Kato N Uchigasaki S Fukase M \nHow does secondary neoplasm arise from mature teratomas in growing teratoma syndrome of the ovary? A report of two cases . Pathol Int \n2013 ; 63 :607 –610 .24422957 \n27. Al-Jumaily U Al-Hussaini M Ajlouni F \nOvarian germ cell tumors with rhabdomyosarcomatous components and later development of growing teratoma syndrome: a case report . J Med Case Rep \n2012 ; 6 :13 .22248255 \n28. Mrabti H El Ghissassi I Sbitti Y \nGrowing teratoma syndrome and peritoneal gliomatosis . Case Rep Med \n2011 ; 2011 :123527 .21541214 \n29. Kikawa S Todo Y Minobe S \nGrowing teratoma syndrome of the ovary: a case report with FDG-PET findings . J Obstet Gynaecol Res \n2011 ; 37 :929 –932 .\n30. Sengar AR Kulkarni JN \nGrowing teratoma syndrome in a post laparoscopic excision of ovarian immature teratoma . J Gynecol Oncol \n2010 ; 21 :129 –132 .20613905 \n31. Rashmi Radhakrishnan G Radhika AG \nGrowing teratoma syndrome: a rare complication of germ cell tumors . Indian J Cancer \n2010 ; 47 :486 –487 .21131777 \n32. Matsushita H Arai K Fukase M \nGrowing teratoma syndrome of the ovary after fertility-sparing surgery and successful pregnancy . Gynecol Obstet Invest \n2010 ; 69 :221 –223 .20068327 \n33. Tzortzatos G Sioutas A Schedvins K \nSuccessful pregnancy after treatment for ovarian malignant teratoma with growing teratoma syndrome . Fertil Steril \n2009 ; 91 :936 e1-e3 .19152879 \n34. Hsieh TY Cheng YM Chang FM \nGrowing teratoma syndrome: an Asian woman with immature teratoma of left ovary after chemotherapy . Taiwan J Obstet Gynecol \n2009 ; 48 :186 –189 .19574186 \n35. Hariprasad R Kumar L Janga D \nGrowing teratoma syndrome of ovary . Int J Clin Oncol \n2008 ; 13 :83 –87 .18307026 \n36. Tangjitgamol S Manusirivithaya S Leelahakorn S \nThe growing teratoma syndrome: a case report and a review of the literature . Int J Gynecol Cancer \n2006 ; 16 :384 –390 .16515629 \n37. Dewdney S Sokoloff M Yamada SD \nConservative management of chylous ascites after removal of a symptomatic growing retroperitoneal teratoma . Gynecol Oncol \n2006 ; 100 :608 –611 .16226796 \n38. Umekawa T Tabata T Tanida K \nGrowing teratoma syndrome as an unusual cause of gliomatosis peritonei: a case report . Gynecol Oncol \n2005 ; 99 :761 –763 .16125758 \n39. Rekha W Amita M Sudeep G \nGrowing teratoma syndrome in germ cell tumour of the ovary: a case report . Aust N Z J Obstet Gynaecol \n2005 ; 45 :170 –171 .15760326 \n40. Nimkin K Gupta P McCauley R \nThe growing teratoma syndrome . Pediatr Radiol \n2004 ; 34 :259 –262 .14551755 \n41. Inaoka T Takahashi K Yamada T \nThe growing teratoma syndrome secondary to immature teratoma of the ovary . Eur Radiol \n2003 ; 13 :2115 –2118 .12928961 \n42. Itani Y Kawa M Toyoda S \nGrowing teratoma syndrome after chemotherapy for a mixed germ cell tumor of the ovary . J Obstet Gynaecol Res \n2002 ; 28 :166 –171 .12214834 \n43. David YB Weiss A Shechtman L \nTumor chemoconversion following surgery, chemotherapy, and normalization of serum tumor markers in a woman with a mixed type germ cell ovarian tumor . Gynecol Oncol \n2002 ; 84 :464 –467 .11855890 \n44. Geisler JP Goulet R Foster RS \nGrowing teratoma syndrome after chemotherapy for germ cell tumors of the ovary . Obstet Gynecol \n1994 ; 84 :719 –721 .9205463 \n45. Kattan J Droz JP Culine S \nThe growing teratoma syndrome: a woman with nonseminomatous germ cell tumor of the ovary . Gynecol Oncol \n1993 ; 49 :395 –399 .8314544 \n46. Jumean HG Komorowski R Mahvi D \nImmature teratoma of the ovary—an unusual case . Gynecol Oncol \n1992 ; 46 :111 –114 .1634130 \n47. Moskovic E Jobling T Fisher C \nRetroconversion of immature teratoma of the ovary: CT appearances . Clin Radiol \n1991 ; 43 :402 –408 .2070582 \n48. Aronowitz J Estrada R Lynch R \nRetroconversion of malignant immature teratomas of the ovary after chemotherapy . Gynecol Oncol \n1983 ; 16 :414 –421 .6654184\n\n",
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"mesh_terms": "D000293:Adolescent; D014408:Biomarkers, Tumor; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D011379:Prognosis; D013724:Teratoma",
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"title": "Growing Teratoma Syndrome Secondary to Ovarian Giant Immature Teratoma in an Adolescent Girl: A Case Report and Literature Review.",
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"abstract": "Judicious balance of fluids is needed for optimal management of acute respiratory distress syndrome (ARDS). Achieving optimal fluid balance is difficult in patients with disorders of fluid homeostasis such as diabetes insipidus (DI). There is little data on the use of Furosemide to aid in balancing fluid and electrolytes in patients with DI. Here, we present a critically ill 11-year-old female with developmental delay, septo-optic dysplasia, central DI, and respiratory failure secondary to COVID-19 ARDS. She required careful titration of a Vasopressin infusion in addition to IV Furosemide for successful management of fluid and electrolyte derangements. On admission, she demonstrated high-volume urine output with mild hypernatremia (serum sodium 156 mmol/L). Despite her maximum Vasopressin infusion rate of 8 mU/kg/hr, by day two of admission, she voided a total of 4 L resulting in severe hypernatremia (serum sodium 171 mmol/L). With continually high Vasopressin infusion rates, her overall fluid balance became increasingly net positive, although her hypernatremia persisted. Her ARDS continued to worsen. After 48 hours of the addition of intermittent Furosemide, successful diuresis along with resolution of hypernatremia was achieved. The combination of IV Furosemide with Vasopressin infusion resulted in tailored diuresis and more controlled titration of serum sodium levels than adjustment in Vasopressin and fluids alone. These results are in contradistinction to the published literature, which focuses on the use of thiazide diuretics in managing DI. This experience highlights the potential for loop diuretics to aid in establishing a desired fluid and electrolyte status in managing patients with both DI and ARDS.",
"affiliations": "Stony Brook Children's Hospital, 101 Nicolls Road, Health Sciences Tower Floor 11-040, Stony Brook, New York 11794, USA.;Stony Brook Children's Hospital, 101 Nicolls Road, Health Sciences Tower Floor 11-040, Stony Brook, New York 11794, USA.;Stony Brook Children's Hospital, 101 Nicolls Road, Health Sciences Tower Floor 11-040, Stony Brook, New York 11794, USA.;Stony Brook Children's Hospital, 101 Nicolls Road, Health Sciences Tower Floor 11-040, Stony Brook, New York 11794, USA.",
"authors": "Gungor|Sara D|SD|https://orcid.org/0000-0002-5279-408X;Woroniecki|Robert P|RP|https://orcid.org/0000-0002-5578-4514;Hulfish|Erin|E|https://orcid.org/0000-0002-1572-6969;Biagas|Katherine V|KV|https://orcid.org/0000-0002-4669-703X",
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"fulltext": "\n==== Front\nCase Rep Crit Care\nCase Rep Crit Care\nCRICC\nCase Reports in Critical Care\n2090-6420\n2090-6439\nHindawi\n\n10.1155/2021/5942431\nCase Report\nDiabetes Insipidus Complicating Management in a Child with COVID-19 and Multiorgan System Failure: A Novel Use for Furosemide\nhttps://orcid.org/0000-0002-5279-408X\nGungor Sara D. 1\nhttps://orcid.org/0000-0002-5578-4514\nWoroniecki Robert P. 1 2\nhttps://orcid.org/0000-0002-1572-6969\nHulfish Erin 1 2\nhttps://orcid.org/0000-0002-4669-703X\nBiagas Katherine V. katherine.biagas@stonybrookmedicine.edu\n1 2\n1Stony Brook Children's Hospital, 101 Nicolls Road, Health Sciences Tower Floor 11-040, Stony Brook, New York 11794, USA\n2Renaissance School of Medicine at Stony Brook University, 101 Nicolls Road, Stony Brook, New York 11794, USA\nAcademic Editor: Tuuli Metsvaht\n\n2021\n4 8 2021\n2021 594243128 4 2021\n27 7 2021\nCopyright © 2021 Sara D. Gungor 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.\nJudicious balance of fluids is needed for optimal management of acute respiratory distress syndrome (ARDS). Achieving optimal fluid balance is difficult in patients with disorders of fluid homeostasis such as diabetes insipidus (DI). There is little data on the use of Furosemide to aid in balancing fluid and electrolytes in patients with DI. Here, we present a critically ill 11-year-old female with developmental delay, septo-optic dysplasia, central DI, and respiratory failure secondary to COVID-19 ARDS. She required careful titration of a Vasopressin infusion in addition to IV Furosemide for successful management of fluid and electrolyte derangements. On admission, she demonstrated high-volume urine output with mild hypernatremia (serum sodium 156 mmol/L). Despite her maximum Vasopressin infusion rate of 8 mU/kg/hr, by day two of admission, she voided a total of 4 L resulting in severe hypernatremia (serum sodium 171 mmol/L). With continually high Vasopressin infusion rates, her overall fluid balance became increasingly net positive, although her hypernatremia persisted. Her ARDS continued to worsen. After 48 hours of the addition of intermittent Furosemide, successful diuresis along with resolution of hypernatremia was achieved. The combination of IV Furosemide with Vasopressin infusion resulted in tailored diuresis and more controlled titration of serum sodium levels than adjustment in Vasopressin and fluids alone. These results are in contradistinction to the published literature, which focuses on the use of thiazide diuretics in managing DI. This experience highlights the potential for loop diuretics to aid in establishing a desired fluid and electrolyte status in managing patients with both DI and ARDS.\n==== Body\n1. Introduction\n\nIn the critically ill patient, delicate balance of fluids is needed to achieve optimal outcomes. In critically ill children, several studies demonstrate that those with an overall excess in fluid balance have been shown to have higher levels of both morbidity and mortality [1–3]. In mechanically ventilated children and adults with ARDS, high cumulative fluid balances have been shown to contribute to longer durations of intubation as well as longer intensive care unit (ICU) length of stay (LOS) [4]. When disorders of fluid homeostasis are present, such as diabetes insipidus (DI), achieving optimal fluid balance may be difficult. This is because of the high-volume urine output that can be seen with poorly controlled central and nephrogenic DI. Thiazide diuretics have been shown to be a safe and effective method of achieving fluid homeostasis in children with diabetes insipidus [5]. Their effectiveness is thought to be the result of increased sodium excretion leading to a reflexive uptake of sodium and water within the proximal renal tubule decreasing urine output [5]. There are few data on the use of other classes of diuretics to aid in the management of fluid and electrolyte disorders in patients with DI. Furthermore, no reports exist concerning the successful management of pediatric patients with DI and respiratory failure secondary to acute SARS-CoV-2 infection (COVID-19). We discuss here a unique case of a critically ill pediatric patient with hypoxemic respiratory failure from acute COVID-19 infection and previously diagnosed central DI who had severe fluid and electrolyte abnormalities. Homeostasis was achieved with the use of IV Furosemide in conjunction with a Vasopressin infusion.\n\n2. Case Presentation\n\nWe present an 11-year-old female with complex medical history consisting of developmental delay, septo-optic dysplasia, central DI, panhypopituitarism including central adrenal insufficiency, hypothyroidism, and epilepsy. Her weight at presentation was 49.5 kg. She presented to the emergency department (ED) of a tertiary care academic medical center with impending respiratory failure (approximately two months after the first confirmed case of SARS-CoV-2 within the United States). She became ill eight days before presenting to the ED with fever. At that time, she was taken to a local urgent care facility where she was diagnosed with an acute otitis media. She was started on PO amoxicillin for an anticipated 10-day course of therapy. She was also given stress-dosed hydrocortisone (30 mg PO, twice daily) given her underlying panhypopituitarism. During the subsequent days, there was no reported change in oral intake or urine output (UOP). Her fevers initially improved; however, they never fully resolved. Three days prior to presentation, the patient experienced increased frequency and temperature of fevers. She again presented to a local urgent care facility where a nasopharyngeal swab was positive for the SARS-CoV-2 virus (via the PCR test). Within a few days, she developed a persistent, nonproductive cough, increased work of breathing, and shortness of breath, prompting the evaluation in the ED. Initial vital signs were remarkable for rectal temperature of 40.8°C, heart rate of 163 beats per minute, respiratory rate of 34 breaths per minute, and oxygen saturation of 89%. Physical exam revealed an alert female in a moderate amount of respiratory distress as evidenced by tachypnea and intermittent grunting. Dry oral mucosa was noted indicating a mild amount of dehydration. The remainder of the physical exam was unremarkable. Laboratory results were remarkable for hyperosmolar hypernatremia (serum sodium of 156 mmol/L and serum osmolality of 321 mOsm), mild hyperglycemia (serum glucose of 146 mg/dL), and elevated ESR (21 mm/hr), CRP (2.3 mg/dL), and procalcitonin (6.9 ng/dL). Her respiratory distress acutely worsened within hours of her ED arrival, and she was intubated for acute hypoxic and hypercarbic respiratory failure (immediate postintubation arterial blood gas with pH 7.20, PCO2 78, PO2 132, HCO3 30, and BD 1.7).\n\nThe patient was admitted to the pediatric intensive care unit (PICU). She was transitioned from her home regimen of subcutaneous desmopressin to a 0.5 mU/kg/hr Vasopressin infusion. Review of her baseline condition revealed that her DI was well controlled on her home regimen. She was continued on stress-dosed steroids (methylprednisolone 20 mg q6h IV). The patient had acute lung injury (SaO2/FiO2 = 120). Mechanical ventilator settings were adjusted to minimize ventilator-induced lung injury. Arterial and central venous lines were placed to promote more accurate determination of oxygenation (PaO2/FiO2 ratios) and venous monitoring. She was started on ceftriaxone, azithromycin, and hydroxychloroquine in addition to receiving one dose of tocilizumab. Ceftriaxone was used to treat presumed bacterial superinfection based on the severity of the patient's clinical status. At the time of the patient's presentation, our institutional protocol for the treatment of severe COVID-19 infection was based on current literature suggesting that the combination of azithromycin and hydroxychloroquine may achieve antiviral and anti-inflammatory effects against SARS-CoV-2 [6]. Additionally, at this time, tocilizumab was suggested to have beneficial effects against “cytokine storming” in SARS-CoV-2 patients [7]. The patient had hypotension that was unresponsive to fluid resuscitation. An epinephrine infusion was started to maintain adequate blood pressures. Given the patient's underlying conditions and critical state, chemistry panels were drawn every six hours on day one of admission. These panels quickly revealed a steady worsening of hypernatremia to a maximum value of 171 mmol/L associated with increasingly abundant UOP of more than 4 L on the first day of hospitalization (Figures 1 and 2). These changes occurred despite a maximum Vasopressin infusion rate of 8 mU/kg/hr along with appropriate, simultaneous adjustments in both the sodium concentration and rate of administered IV fluids.\n\nBy the second day of hospitalization, a net positive fluid balance of 2.8 L was noted and severe hypernatremia persisted (serum sodium of 160 mmol/L). Her moderate ARDS continued (PaO2/FiO2 = 132) [8]. When the hypernatremia persisted into the third day of hospitalization, a trial of Furosemide (10 mg IV) in addition to decreasing the Vasopressin dose from 8 mU/kg/hr to 6 mU/kg/hr was attempted. After five doses of IV Furosemide over a 48-hour period along with reduction in the Vasopressin dose, successful diuresis along with resolution of hypernatremia was achieved (net balanced fluid balance of -497 mL and reduction in serum sodium to 138 mmol/L, respectively) (Figures 1 and 2). Her ARDS gradually improved. The patient was extubated on hospital day 10. She remained hospitalized in the PICU for a total of 29 days during which time she was weaned from supplemental oxygen and was gradually weaned from sedative medications. She had normal serum sodium levels and UOP throughout the remainder of her PICU stay. She was discharged to her home with an outpatient subspecialist follow-up.\n\n3. Discussion\n\nThe present case not only demonstrates the importance of adequate fluid balance in achieving optimal outcomes for a critically ill child with moderate ARDS but also highlights a novel use of Furosemide, a loop diuretic, in the management of DI. Fluid management in DI involves both management of fluid removal balanced with the maintenance of normal electrolyte concentrations. Overzealous treatment of central DI with ADH may result in water retention and iatrogenic hyponatremia, while insufficient treatment may result in dehydration and hypernatremia. In this case, the combination of IV Furosemide with a Vasopressin infusion promoted the excretion of sodium with a controlled UOP.\n\nMechanically ventilated patients are not the only population prone to the deleterious effects of fluid overload (FO). Studies have demonstrated that in various subsets of critically ill pediatric patients, including those not experiencing respiratory failure, fluid overload may lead to worse outcomes [2]. The exact degree of FO that yields these outcomes is unknown; however, 10% FO is usually when aggressive intervention is considered. This inconclusiveness has been thought to be a result of the lack of standardization of a method to calculate FO in both pediatric and adult patients [2]. Using the commonly used Goldstein et al.'s FB method [2], our patient had a maximum FO of 8.6% by day one of hospital stay.\n\nThiazide diuretics are a safe and effective method of treating pediatric patients with both central and nephrogenic DI [5]. While there are several proposed mechanisms, thiazide diuretics are thought to paradoxically slow UOP. Thiazides initially inhibit sodium uptake in the distal convoluted tubule yielding increased UOP. This diuresis leads to extracellular volume contraction, a decrease in the glomerular filtration rate, and, as a result, an uptake of sodium in the proximal convoluted tubule slowing further UOP [9]. Another proposed mechanism for their success involves the upregulation of aquaporin channels within collecting ducts. Aquaporin channels are downregulated in cases of both central and nephrogenic DI. Recent studies have shown that administering thiazide diuretics under these conditions results in an upregulation of aquaporin channels that further regulates UOP [10]. As a result of these effects, the UOP and therefore overall fluid balance become normalized.\n\nIt has been well demonstrated that many individuals infected with SARS-CoV-2 have experienced critical illness requiring prolonged ICU LOS and invasive mechanical ventilation [11]. Another complication that has been increasingly appreciated is acute kidney injury (AKI) [12, 13]. This seems to be attributed not only as secondary to hemodynamic and respiratory instability within these patients but also to direct viral insult on the proximal convoluted tubules and glomerulus [12–14]. While most children experience an asymptomatic or mild disease course with SARS-CoV-2 infection, critical illness still occurs and can be significant [15]. The risk of critical illness in pediatric patients may be increased especially in those with comorbidities [16]. Panhypopituitarism, as in this patient, would be expected to alter a patient's immune and homeostatic responses to an overwhelming viral infection making her possibly more susceptible to severe illness.\n\nTo our knowledge, this is the first report of a loop diuretic used in conjunction with a Vasopressin infusion achieving a desirable clinical effect in a child with DI and moderate ARDS [17]. Moreover, this effect was seen in a child with multiple comorbidities and acute COVID-19. The effect of Furosemide in our patient occurred robustly after only five doses. One putative mechanism for the additional action of Furosemide may be that the drug enhanced naturesis in a kidney in which appropriate water regulation had been restored by titration of exogenous Vasopressin. We recognize that a limitation of this report is that the mechanism(s) of the action of Furosemide in this case may remain imprecise.\n\nAcknowledgments\n\nThe authors of this article would like to thank the team of pediatric intensivists and nurses who helped tremendously in the care of this patient. This work was conducted as part of patient care at Stony Brook Children's Hospital and the Renaissance School of Medicine at Stony Brook University.\n\nData Availability\n\nThe data used to support the findings of this study are included within the article.\n\nConsent\n\nNo written consent has been obtained from the patient's parents as there is no patient identifiable data included in this case report.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Overall fluid balance for the first week of PICU hospitalization as demonstrated by bar graphs of daily intake and output totals. The composition of fluids is depicted in color. Daily net fluid balance is depicted by triangles. Note the large net positive fluid balance on day 2 of hospitalization (3/25) with achievement of near net balance after initiation of Furosemide on day 3 (3/26).\n\nFigure 2 Serum sodium levels throughout first few days of admission. Blue arrows represent dates of hospital stay. Note the peak value of 171 mmol/L on day 2 of admission (3/25) with eventual decline after initiation of Furosemide with Vasopressin. Concurrent Vasopressin dosing is evidenced by yellow arrows. Note the initiation at 0.5 mU/kg/hr on 3/24, with a maximum infusion rate of 8 mU/kg/hr on 3/25, and eventual decline in dosing starting 3/26.\n==== Refs\n1 Alobaidi R. Morgan C. Basu R. K. Association between fluid balance and outcomes in critically ill children: a systematic review and meta-analysis JAMA Pediatrics 2018 172 3 257 268 10.1001/jamapediatrics.2017.4540 2-s2.0-85042935248 29356810\n2 Raina R. Sethi S. K. Wadhwani N. Vemuganti M. Krishnappa V. Bansal S. B. Fluid overload in critically ill children Frontiers in Pediatrics 2018 6 p. 306 10.3389/fped.2018.00306 2-s2.0-85057200389\n3 Samaddar S. Sankar J. Kabra S. K. Lodha R. Association of fluid overload with mortality in critically-ill mechanically ventilated children Indian Pediatrics 2018 55 11 957 961 10.1007/s13312-018-1417-y 2-s2.0-85057863808 30587643\n4 Ghosh S. Chawla A. Mishra K. Jhalani R. Salhotra R. Singh A. Cumulative fluid balance and outcome of extubation: a prospective observational study from a general intensive care unit Indian journal of critical care medicine: peer-reviewed, official publication of Indian Society of Critical Care Medicine 2018 22 11 p. 767\n5 Al Nofal A. Lteif A. Thiazide diuretics in the management of young children with central diabetes insipidus The Journal of Pediatrics 2015 167 3 658 661 10.1016/j.jpeds.2015.06.002 2-s2.0-84940452182 26130110\n6 Gautret P. Lagier J. C. Parola P. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial International Journal of Antimicrobial Agents 2020 56 1 p. 105949\n7 Xu X. Han M. Li T. Effective treatment of severe COVID-19 patients with tocilizumab Proceedings of the National Academy of Sciences 2020 117 20 10970 10975 10.1073/pnas.2005615117 32350134\n8 Force A. D. T. Ranieri V. M. Rubenfeld G. D. Acute respiratory distress syndrome JAMA 2012 307 23 2526 2533 22797452\n9 Magaldi A. J. New insights into the paradoxical effect of thiazides in diabetes insipidus therapy Nephrology Dialysis Transplantation 2000 15 12 1903 1905 10.1093/ndt/15.12.1903 2-s2.0-0033661428\n10 Kim G. H. Lee J. W. Oh Y. K. Antidiuretic effect of hydrochlorothiazide in lithium-induced nephrogenic diabetes insipidus is associated with upregulation of aquaporin-2, Na-Cl co-transporter, and epithelial sodium channel Journal of the American Society of Nephrology 2004 15 11 2836 2843 10.1097/01.ASN.0000143476.93376.04 2-s2.0-16644391083 15504936\n11 Serafim R. B. Póvoa P. Souza-Dantas V. Kalil A. C. Salluh J. I. Clinical course and outcomes of critically-ill patients with COVID-19 infection: a systematic review Clinical Microbiology and Infection 2020 27 1\n12 Carriazo S. Kanbay M. Ortiz A. Kidney disease and electrolytes in COVID-19: more than meets the eye 2020\n13 Rudnick M. R. Hilburg R. Acute kidney injury in COVID-19: another challenge for nephrology American Journal of Nephrology 2020 51 10 761 763 10.1159/000511161 33059350\n14 Soleimani M. Acute kidney injury in SARS-CoV-2 infection: direct effect of virus on kidney proximal tubule cells International Journal of Molecular Sciences 2020 21 9 p. 3275 10.3390/ijms21093275 32380787\n15 Yayla B. C. Özsürekçi Y. Aykaç K. Characteristics and management of children with COVID-19 in Turkey Balkan Medical Journal 2020 37 6 p. 341\n16 Oualha M. Bendavid M. Berteloot L. Severe and fatal forms of COVID-19 in children Archives de Pédiatrie 2020 27 5 235 238 10.1016/j.arcped.2020.05.010 32518045\n17 Gungor S. Biagas K. 130: diabetes insipidus complicating management in a child with COVID-19 ARDS: a novel use for furosemide Critical Care Medicine 2021 49 1 p. 50 10.1097/01.ccm.0000726408.16912.eb\n\n",
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"title": "Diabetes Insipidus Complicating Management in a Child with COVID-19 and Multiorgan System Failure: A Novel Use for Furosemide.",
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"abstract": "BACKGROUND\nAntipsychotic medications are increasingly used during pregnancy. Nevertheless, fetal risks are still not fully studied. It is currently unclear whether the antipsychotic treatment might induce a higher risk of fetal death. We aimed to determine if use of antipsychotic medication during pregnancy is associated with an increased risk of spontaneous abortion or stillbirth.\n\n\nMETHODS\nIn a historical cohort study, we identified all clinically recognized pregnancies registered in the nationwide Danish registries from 1997 to 2008 (N = 1,005,319). Exposure was defined as any prescription of antipsychotic medications redeemed by the pregnant women during the exposure window, and recorded in the Danish National Prescription Register. Outcome was defined as any spontaneous abortion or stillbirth recorded in the Danish National Hospital Register and the Danish Medical Birth Register respectively.\n\n\nRESULTS\nWomen exposed to antipsychotic medications during pregnancy had a 34% higher risk of spontaneous abortion (adjusted relative risk = 1.34; 95% confidence interval = 1.22; 1.46) compared to unexposed women, but a similar risk compared to women exposed prior to (but not during) pregnancy (adjusted relative risk = 1.04; 95% confidence interval = 0.93; 1.17). The risk of spontaneous abortion was not increased in exposed pregnancies when compared to unexposed pregnancies in the same women (adjusted hazard ratio = 1.11; 95% CI = 0.94; 1.31). A twofold higher risk of stillbirth was found in women exposed to antipsychotic medications compared with unexposed women (relative risk = 2.27; 95% confidence interval = 1.45; 3.55) and compared with women exposed only prior to pregnancy (relative risk = 2.06; 95% confidence interval = 1.01; 4.19).\n\n\nCONCLUSIONS\nThe increased risk of spontaneous abortion found in women treated with antipsychotic medications during pregnancy is most likely due to confounding factors. The risk of stillbirth was twofold higher in pregnancies exposed to antipsychotic medication during pregnancy. Treatment with antipsychotic medications during pregnancy requires careful consideration.",
"affiliations": "Regional Center for Child and Adolescent Psychiatry, Aarhus University Hospital, Aarhus, Denmark.;Section for Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark.;Research Unit for General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark.;Research Unit for General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark; Section for General Medical Practice, Department of Public Health, Aarhus University, Aarhus, Denmark.;Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark.;Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.;Section for Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark.;Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark; Institute of Clinical Medicine-Obstetrics and Gynaecology, Aarhus University, Aarhus, Denmark.;Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.",
"authors": "Sørensen|Merete Juul|MJ|;Kjaersgaard|Maiken Ina Siegismund|MI|;Pedersen|Henrik Søndergaard|HS|;Vestergaard|Mogens|M|;Christensen|Jacob|J|;Olsen|Jørn|J|;Parner|Erik|E|;Pedersen|Lars Henning|LH|;Bech|Bodil Hammer|BH|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0132280",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2616208710.1371/journal.pone.0132280PONE-D-15-06534Research ArticleRisk of Fetal Death after Treatment with Antipsychotic Medications during Pregnancy Fetal Death and Antipsychotic MedicationsSørensen Merete Juul \n1\n*Kjaersgaard Maiken Ina Siegismund \n2\nPedersen Henrik Søndergaard \n3\nVestergaard Mogens \n3\n\n4\nChristensen Jacob \n5\n\n6\nOlsen Jørn \n7\nParner Erik \n2\nPedersen Lars Henning \n7\n\n8\nBech Bodil Hammer \n7\n\n1 \nRegional Center for Child and Adolescent Psychiatry, Aarhus University Hospital, Aarhus, Denmark\n\n2 \nSection for Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark\n\n3 \nResearch Unit for General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark\n\n4 \nSection for General Medical Practice, Department of Public Health, Aarhus University, Aarhus, Denmark\n\n5 \nDepartment of Neurology, Aarhus University Hospital, Aarhus, Denmark\n\n6 \nDepartment of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark\n\n7 \nSection for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark\n\n8 \nInstitute of Clinical Medicine—Obstetrics and Gynaecology, Aarhus University, Aarhus, Denmark\nAlessi-Severini Silvia Editor\nUniversity of Manitoba, CANADA\nCompeting Interests: Merete Juul Sørensen, Maiken Ina Siegismund Kjaersgaard, Bodil Hammer Bech, Henrik Søndergaard Pedersen, Mogens Vestergaard, Jørn Olsen, Lars Henning Pedersen and Erik Parner have no competing interests. Jakob Christensen reported receiving honoraria for serving on the scientific advisory boards of UCB Nordic and Eisai AB; receiving lecture honoraria from UCB Nordic and Eisai AB; being involved in clinical trials initiated by UCB Nordic, Eisai, Pfizer and Novartis, and receiving travel funding from UCB Nordic. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.\n\nConceived and designed the experiments: MJS MISK MV JO EP JC BHB LHP. Analyzed the data: MISK HSP. Wrote the paper: MJS MISK HSP MV JO EP JC BHB LHP.\n\n* E-mail: meresoer@rm.dk10 7 2015 2015 10 7 e013228016 2 2015 11 6 2015 © 2015 Sørensen et al2015Sørensen 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.Background\nAntipsychotic medications are increasingly used during pregnancy. Nevertheless, fetal risks are still not fully studied. It is currently unclear whether the antipsychotic treatment might induce a higher risk of fetal death. We aimed to determine if use of antipsychotic medication during pregnancy is associated with an increased risk of spontaneous abortion or stillbirth.\n\nMethods\nIn a historical cohort study, we identified all clinically recognized pregnancies registered in the nationwide Danish registries from 1997 to 2008 (N = 1,005,319). Exposure was defined as any prescription of antipsychotic medications redeemed by the pregnant women during the exposure window, and recorded in the Danish National Prescription Register. Outcome was defined as any spontaneous abortion or stillbirth recorded in the Danish National Hospital Register and the Danish Medical Birth Register respectively.\n\nResults\nWomen exposed to antipsychotic medications during pregnancy had a 34% higher risk of spontaneous abortion (adjusted relative risk = 1.34; 95% confidence interval = 1.22; 1.46) compared to unexposed women, but a similar risk compared to women exposed prior to (but not during) pregnancy (adjusted relative risk = 1.04; 95% confidence interval = 0.93; 1.17). The risk of spontaneous abortion was not increased in exposed pregnancies when compared to unexposed pregnancies in the same women (adjusted hazard ratio = 1.11; 95% CI = 0.94; 1.31). A twofold higher risk of stillbirth was found in women exposed to antipsychotic medications compared with unexposed women (relative risk = 2.27; 95% confidence interval = 1.45; 3.55) and compared with women exposed only prior to pregnancy (relative risk = 2.06; 95% confidence interval = 1.01; 4.19).\n\nConclusions\nThe increased risk of spontaneous abortion found in women treated with antipsychotic medications during pregnancy is most likely due to confounding factors. The risk of stillbirth was twofold higher in pregnancies exposed to antipsychotic medication during pregnancy. Treatment with antipsychotic medications during pregnancy requires careful consideration.\n\nThe Regional Center for Child and Adolescent Psychiatry, Aarhus University Hospital, Risskov, Denmark, contributed with funding to the study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityData are available from the Statistics Denmark, Sejrøgade 11, DK-2100 Copenhagen for researchers who meet the criteria for access to confidential data. The research services may be accessed here: http://www.dst.dk/en/OmDS/organisation/TelefonbogOrg.aspx?kontor=13&tlfbogsort=sektion. Further, combination of data from several registries requires permission from The Danish Data Protection Agency, Borgergade 28, 5, 1300 Copenhagen. Conditions regarding handling of confidentiality and security apply. The Danish Data Protection Agency may be accessed here: https://www.datatilsynet.dk/english/the-danish-data-protection-agency/contact/.Data Availability\nData are available from the Statistics Denmark, Sejrøgade 11, DK-2100 Copenhagen for researchers who meet the criteria for access to confidential data. The research services may be accessed here: http://www.dst.dk/en/OmDS/organisation/TelefonbogOrg.aspx?kontor=13&tlfbogsort=sektion. Further, combination of data from several registries requires permission from The Danish Data Protection Agency, Borgergade 28, 5, 1300 Copenhagen. Conditions regarding handling of confidentiality and security apply. The Danish Data Protection Agency may be accessed here: https://www.datatilsynet.dk/english/the-danish-data-protection-agency/contact/.\n==== Body\nIntroduction\nWomen with severe psychiatric disorders, including schizophrenia, are at increased risk of pregnancy-related complications such as premature delivery, low birth weight, stillbirth [1–3] and induced abortion. [4] However, the underlying reasons are poorly understood.\n\nTreatment of pregnant women with antipsychotic medication presents an important clinical challenge. [5–7] As antipsychotic medications may pass the placenta barrier, [8] fetotoxic effects are possible, but the potential impact is not well described. [9] Preterm birth, [10, 11] birth complications, congenital malformations [12–14] and impaired motor functioning in the newborn child [15, 16] have been reported, but information about spontaneous abortion (SA) and stillbirth is sparse. In a large cohort study, Habermann et al found no significantly increased risk of SA in 561 pregnancies exposed to second-generation antipsychotics (SGA) compared with 284 pregnancies exposed to first-generation antipsychotics (FGA) and 1122 pregnancies unexposed to medication with potential teratogenic effects. [14] Only five stillbirths occurred; two in the cohort exposed to FGA and three in the unexposed cohort. Two smaller studies (N = 215 and N = 151) found no increased risk of SA or stillbirth after prenatal exposure to atypical antipsychotic medications. [17, 18] However, both studies were subject to potential bias due to recruitment via self-referral to counselling services. Other papers reporting on risk of SA or stillbirth after prenatal exposure to antipsychotic medications are mainly based on surveillance studies; none of these include comparison groups [19–22] and most are based on only few pregnancies. [19–21]A large Danish cohort study found an increased risk of post-neonatal death and a marginally increased risk of congenital malformations in children born by women diagnosed with schizophrenia, but found no significantly increased risk of stillbirth or neonatal death. [23] However, this study did not include prenatal exposure to antipsychotic medications.\n\nWe conducted a large population-based retrospective cohort study to estimate associations between maternal use of antipsychotic medications during pregnancy and SA or stillbirth while adjusting for potential confounders including prenatal maternal psychiatric disorder. To further disentangle the potential effect of antipsychotic medications and possible confounding factors, we compared the outcome of exposed pregnancies with the outcome of pregnancies in which the mother redeemed a prescription to antipsychotic medications prior to, (but not during) the pregnancy. We further performed a study in women with multiple pregnancies discordant for antipsychotic medications exposure, comparing exposed with non-exposed pregnancies.\n\nMethods\nStudy population\nWe identified all clinically recognized pregnancies in Denmark with an estimated conception date and an observed pregnancy outcome in the period from 1 February 1997 to 31 December 2008. Information was obtained from the nationwide Danish health registries, which include information about all pregnancies, except for very early miscarriages, which may be considered a late menstrual period. Information was linked through the Danish personal identification number, assigned to all citizens. We investigated all inpatient or outpatient contacts involving a diagnosis of spontaneous abortion before 22 weeks of gestation (in Denmark, a child born after 22 weeks of gestation is either stillborn or live born). We also included specific information on pregnancies ending in a molar pregnancy, ectopic pregnancy, induced abortion, stillbirth or live birth.\n\nThe pregnancy period was defined as the time from the estimated date of conception to the date of the outcome (induced or spontaneous abortion, stillbirth or live birth). Date of conception was estimated by subtracting gestational age at pregnancy outcome from date of outcome (induced or spontaneous abortion, stillbirth or live birth). For all abortions (spontaneous or induced), the gestational age was based on records in the Danish National Hospital Register. For live births and stillbirths the gestational age was based on records in the Medical Birth Register. Gestational age of less than 12 weeks was generally based on the last menstrual period, while age above 12 weeks was usually based on ultrasound scans. In case of missing data, gestational age was imputed based on the median of the available values.\n\nWe performed a hierarchical coding of the pregnancies to take repeated contacts into consideration. Any stillbirth or live birth resulted in recoding of former endpoints in the index pregnancy period. Pregnancies with multiple codes for abortion were coded as a SA if indicated by the pattern of codes, even for cases in which the index period also included codes for induced abortion (because a SA might occur in the time period between the initial contact for induced abortion and the planned surgical termination).\n\nThe primary outcome measures were 1) diagnosis of SA before 22 weeks of gestation and 2) diagnosis of stillbirth.\n\nMedication exposure\nAll antipsychotic medications are given by prescription in Denmark. The Danish National Prescription Register [24] holds information on all redeemed prescriptions administered as part of the Danish universal health-care system since 1 January 1996. However, the register does not contain information about medical treatment given only during inpatient hospital admission.\n\nThe medication exposure window was defined as the period from 30 days before the estimated conception date to one day prior to spontaneous abortion/stillbirth/birth. We included the 30 days prior to conception to investigate delayed medication effects and to account for prescriptions in use at the time of conception. We included the day prior to termination of the pregnancy to investigate any possible immediate effects of medication. In the SA analyses, the exposure window ended on the day before the gestational age limit for SA, i.e. 152 days. In sensitivity analyses we extended the exposure window to include the 6 months prior to conception. We defined exposed women as women who redeemed a prescription of antipsychotic medications (Anatomical Therapeutic Chemical (ATC) code: N05A) during the exposure window (3,164 pregnancies, 0.32%). We specifically assessed risks for a number of individual drugs (Chlorprothixene: N05AF03, Flupentixol: N05AF01, Perphenazine: N05AB03, Zuclopenthixol: N05AF05, Levomepromazine: N05AA02, Quetiapine: N05AH04, Olanzapine: N05AH03, Lithium: N05AN01, Risperidone: N05AX08, Aripiprazole: N05AX12, Ziprasidone: N05AE04, Prochlorperazine: N05AB04, Fluphenazine: N05AB02, Chlorpromazine: N05AA01). We defined unexposed women as pregnant women who did not redeem any prescription of antipsychotic medications during the exposure window. We estimated the average daily dose of antipsychotic medications during pregnancy as the total amount of redeemed antipsychotic medications divided by the number of days in the exposure window. The Defined Daily Dose (DDD) was defined as “the assumed average maintenance dose per day for a drug used for its main indication in adults” as also established by the World Health Organization (WHO) (http://www.whocc.no/ddd). Based on the DDD, the estimated daily antipsychotic medication dose was dichotomized into high (>50% of DDD) and low (≤ 50% of DDD).\n\nPregnancy outcome\nAbortions were identified in the Danish National Hospital Register, [25] which contains data on all inpatient and outpatient contacts in Denmark since 1995 coded according to the International Classification of Diseases, 10th revision (ICD-10) [26] Abortions (ICD-10: O02.0-O06.9) were divided into spontaneous abortions (ICD-10: O02.0-O03.9), induced abortions (ICD-10: O04.0-O05.2, O05.5-O06.9) and induced abortions due to fetal disease (ICD-10: O05.3, O05.4). Molar or ectopic pregnancies (ICD-10: O00.0-O01.9) were excluded from the main analyses. Furthermore, failed induced abortions (ICD-10: O07) were disregarded as we assumed that a failed induced abortion would be followed by another abortion, a stillbirth or a live birth, which were all diagnosed separately. Live births and stillbirths were identified in the Danish Medical Birth Register, which holds information on all births in Denmark. [27] The definition of stillbirth changed in Denmark in 2004 from fetal death after 28 weeks of gestation to 22 weeks. Therefore, spontaneous abortions with gestational age (GA) of 22 weeks or more, were recoded as stillbirths in this study.\n\nMaternal psychiatric disorder and covariate information\nThe Danish Psychiatric Central Register [28] was used to identify mothers diagnosed with psychiatric disorder anytime before the end of pregnancy. The Danish Psychiatric Central Register includes information on treatment at psychiatric hospital-based units in Denmark since 1969 and outpatient contacts since 1995. Before 1994, psychiatric disorders were coded according to the ICD-8. From January 1994 and onwards they were coded according to the ICD-10. The register does not include diagnoses made by general practitioners or private psychiatrists.\n\nHistory of severe mental disorder was defined as a diagnosis of bipolar disorder, including mania or schizophrenia (ICD-10: F30-F31 and F20; ICD-8: 296.1–296.8, 298.1 and 295), and history of misuse was defined as a diagnosis of alcohol or drug abuse (ICD-10: F10-F19; ICD-8: 291, 303, 304 and 294.3) at any time before the end of the index pregnancy.\n\nInformation on the following potential confounders was obtained from Statistics Denmark: maternal age at conception, cohabitation at time of conception, income at time of conception and education level at time of conception. From the Danish National Prescription Register, we obtained information on use of other medications.\n\nAnalytic approach\nRisk ratios (RR) for SA and stillbirth were estimated by binomial regression (i.e. we fitted a generalized linear model for our binary outcome and used a log-link) with robust variance estimation to allow for correlation between pregnancy outcomes of each woman. Pregnancies ending in induced abortion were excluded from the analyses (1,164 exposed pregnancies, 176,734 unexposed pregnancies). RRs for SA were adjusted (aRR) for maternal age (corresponding to the three tertiles), history of misuse (yes/no), cohabitation (yes/no), income (dichotomized at the median) and level of education (<10, 10–12, >12 years). To avoid unstable results, RR analysis was performed only when at least 5 exposed events were observed. To ensure anonymity, only cells containing at least 5 observations are displayed. Adjusted analyses for stillbirth included one covariate at a time owing to the low number of exposed stillbirths. We performed a number of sensitivity analyses: 1) extending the medication exposure window to 6 months before conception; 2) excluding women (from the unexposed group) who redeemed a prescription between 6 months and 30 days before conception, 3) including only women (in the exposed group) who redeemed at least two prescriptions of antipsychotic medications during the pregnancy period and 4) because an induced abortion could potentially have ended in a spontaneous abortion, if the pregnancy had not already been terminated, we made a sensitivity analysis using Cox regression including induced abortion and censoring of the pregnancies, when the pregnancy was terminated.\n\nTo assess for potential confounding effects of factors related to the underlying disorders requiring treatment with antipsychotic medications during pregnancy, we estimated the relative risk of SA and stillbirth after exposure to antipsychotic medications during pregnancy, compared with pregnant women who had used antipsychotic medications during the preceding year but not 30 days prior to the estimated conception date and during the pregnancy.\n\nAs a second step to separate potential effects of the medications from a potential effect of the underlying disorder, we assessed the risk of SA after exposure to antipsychotic medication in women with a diagnosis of severe mental disorder and in women without a diagnosis of severe mental disorder, respectively.\n\nAs a third step to adjust for unmeasured shared environmental risk factors and genetic predisposition, we performed a stratified Cox regression analysis with robust variance estimation and included women in the cohort who had at least two pregnancies with discordant exposure status (e.g. exposed in the first pregnancy, but not in the second) and discordant outcome. The stratified Cox regression analysis included a separate stratum for each woman; thus, each woman had her own baseline rate function.\n\nWe performed analyses of pregnancies with high (>50% of DDD) and low (≤ 50% of DDD) exposure to antipsychotic medications, respectively. We performed the main analysis of SA for each individual type of antipsychotic medication. The number of cases was too small to perform these analyses for the risk of stillbirth.\n\nStatistical analyses were performed using Stata 12 (StataCorp, Texas, USA).\n\nResults\nUse of antipsychotic medications in pregnant women\nAmong 1,005,319 pregnancies, 3,164 were exposed to antipsychotic medications. Of these pregnancies, 1,164 ended as an induced abortion, which left 2,000 exposed pregnancies for analysis. These pregnancies resulted in 407 SA, 1,574 live births and 19 stillbirths. Of the 1,002,155 non-exposed pregnancies, 176,734 ended in an induced abortion, which left 825,421 unexposed pregnancies for analysis. These pregnancies resulted in 114,312 spontaneous abortions, 707,594 live births and 3,515 stillbirths. Women taking antipsychotic medications during pregnancy were less educated, more likely to be living alone and more likely to have a history of psychiatric disorder or substance abuse than women unexposed to antipsychotic medications during pregnancy (Table 1).\n\n10.1371/journal.pone.0132280.t001Table 1 Characteristics of study participants (numbers refer to pregnancies studied).\nCharacteristics\tExposed to antipsychotic drugs (APD) (N = 3,164) Number (per cent)\tUnexposed to APD (N = 1,002,155) Number (per cent)\t\nMaternal age at conception\t<21 years\t213 (6.7%)\t56,736 (5.7%)\t\n21–25 years\t527 (16.7%)\t159,487 (15.9%)\t\n26–30 years\t798 (25.2%)\t340,548 (34.0%)\t\n31–35 years\t881 (27.8%)\t297,454 (29.7%)\t\n≥36 years\t745 (23.5%)\t147,883 (14.8%)\t\nCohabitation\tYes\t1693 (53.5%)\t767,510 (76.6%)\t\nNo\t1462 (46.2%)\t219,346 (21.9%)\t\nMissing\t9 (0.3%)\t15,299 (1.5%)\t\nIncome (percentiles)\t0–20 percentile\t892 (28.2%)\t198,906 (19.8%)\t\n>20–40 percentile\t1098 (34.7%)\t198,704 (19.8%)\t\n>40–60 percentile\t657 (20.8%)\t199,144 (19.9%)\t\n>60–80 percentile\t325 (10.3%)\t199,475 (19.9%)\t\n>80–100 percentile\t191 (6.0%)\t199,610 (19.9%)\t\nMissing\tNA (0.0%)\t6316 (0.6%)\t\nMaternal education (years)\t<10 years\t829 (26.2%)\t109,081 (10.9%)\t\n10–12 years\t1325 (41.9%)\t308,456 (30.8%)\t\n>12 years\t906 (28.6%)\t549,147 (54.8%)\t\nMissing\t104 (3.3%)\t35,471 (3.5%)\t\nMaternal psychiatric history*\n\tYes\t2369 (74.9%)\t61,084 (6.1%)\t\nNo\t795 (25.1%)\t941,071 (93.9%)\t\nMissing\t0 (0.0%)\t0 (0.0%)\t\nMaternal history of substance abuse\tYes\t507 (16.0%)\t5097 (0.5%)\t\nNo\t2657 (84.0%)\t997,058 (99.5%)\t\nMissing\t0 (0.0%)\t0 (0.0%)\t\nMaternal history of severe mental disorder**\n\tYes\t794 (25.1%)\t1942 (0.2%)\t\nNo\t2370 (74.9%)\t1,000,213 (99.8%)\t\nMissing\t0 (0.0%)\t0 (0.0%)\t\nCo-medication\tAny medication\t3164 (100.0%)\t627,775 (62.6%)\t\nAntiepileptic drugs\t371 (11.7%)\t4397 (0.4%)\t\nAntidepressant drugs\t1539 (48.6%)\t20,522 (2.0%)\t\nInsulin\t31 (1.0%)\t4628 (0.5%)\t\nPregnancy outcome\tInduced abortion\t1,154\t173,680\t\nInduced abortion due to fetal disease\t10\t3,054\t\nSpontaneous abortion\t407\t114,312\t\nLive birth\t1,574\t707,594\t\nStillbirth\t19\t3,515\t\n*Mother diagnosed with a psychiatric disorder before end of pregnancy (ICD-8: 290–315 and ICD-10: all F codes)\n\n**Mother diagnosed with a severe psychiatric disorder before end of pregnancy (ICD-8: 296.1–296.8, 298.1 and 295; ICD-10: F20 and F30–31)\n\nThe number of redeemed prescriptions for any type of antipsychotic medication during pregnancy increased during the study period from 299.9/100,000 pregnancies in 1997 to 490.8/100,000 pregnancies. An increase was also seen for most individual drugs (S1 Table).\n\nRisk of spontaneous abortion\nPregnancies exposed to any type of antipsychotic medication had an overall 34% increased risk of ending in an SA compared with unexposed pregnancies after adjusting for several confounding factors (aRR = 1.34; 95% confidence interval (CI) = 1.22; 1.46) (Table 2). An analysis restricting exposed women to include only those who redeemed at least two prescriptions during the pregnancy period showed a comparable estimate (aRR = 1.23; 95% CI = 1.08; 1.40).\n\n10.1371/journal.pone.0132280.t002Table 2 Relative risks of spontaneous abortion following APD exposure in pregnancy (numbers refer to pregnancy outcomes studied).\n\tAPD exposure\tNumber\tSpontaneous abortions, number (%)\tRelative risk, crude (95% CI)\tRelative risk, adjusted (95% CI)\t\nOverall\tExposed\t1881\n$\n\n\t407 (21.6%)\t1.59 (1.46; 1.74)\t1.34* (1.22; 1.46)\t\nUnexposed\t841,183\t114,314 (13.6%)\t1.00 (ref)\t1.00 (ref)\t\nExposed to APD\tExposed during pregnancy\t1881\t407 (21.6%)\t1.08 (0.96; 1.21)\t1.04* (0.93; 1.17)\t\nExposed only prior to pregnancy\t2745\t552 (20.1%)\t1.00 (ref)\t1.00 (ref)\t\nDiagnosis of severe mental disorder\tExposed\t461\t109 (23.6%)\t1.20 (0.98; 1.47)\t1.14\n#\n (0.94; 1.39)\t\nUnexposed\t1337\t263 (19.7%)\t1.00 (ref)\t1.00 (ref)\t\nNo diagnosis of severe mental disorder\tExposed\t1420\t298 (21.0%)\t1.55 (1.39; 1.71)\t1.34\n#\n (1.21; 1.49)\t\nUnexposed\t839,846\t114,051 (13.6%)\t1.00 (ref)\t1.00 (ref)\t\n\n$ Number lower than Table 1 due to shorter exposure time\n\n* Adjusted for maternal age divided into three groups, history of drug abuse, cohabitation, income (above or below the median) and education (divided like in Table 1)\n\n\n#Adjusted for maternal age divided into three groups, history of drug abuse, cohabitation and income (above or below the median)\n\nSome women may have redeemed prescriptions before the pregnancy period, but taken the medication during pregnancy. To account for this, we performed additional analyses. In a sensitivity analysis extending the exposure period to 6 months before pregnancy, the risk estimate was similar (aRR = 1.33; 95% CI = 1.24; 1.42). The risk estimate was also similar in a sensitivity analysis excluding women from the unexposed group who redeemed a prescription during the 6 months before conception (aRR = 1.34; 95% CI = 1.22; 1.46). In a Cox regression analysis including induced abortions, the hazard ratio (HR) for spontaneous abortion was almost the same (adjusted HR = 1.25; 95% CI = 1.13; 1.39) as the RR in the main analysis.\n\nIn an attempt to separate the effect of the medication from the effect of the underlying disorder, we compared exposed pregnancies with pregnancies in which the woman was exposed to antipsychotic medications prior to pregnancy, but not during the pregnancy period. In this analysis, the relative risk of SA was close to one (aRR = 1.04; 95% CI = 0.93; 1.17) (Table 2).\n\nIn order to further disentangle the effects of medication from the effects of the underlying disorder, we performed a subanalysis of 323 women who had been pregnant at least twice during the study period, had used antipsychotics in at least one pregnancy and had been unexposed in at least one pregnancy and had experienced at least one SA (N = 994 pregnancies). We found the risk of SA in pregnancies exposed to antipsychotic medications rather similar to the risk in unexposed pregnancies in the same women (aHR = 1.11; 95% CI = 0.94; 1.31) (Table 3).\n\n10.1371/journal.pone.0132280.t003Table 3 Association between the use of APD and SA in pregnancies in 323 women having had at least two pregnancies and at least one abortion.\nAPD exposure\tNumber of pregnancies\tSpontaneous abortion, number\tHazard ratio, crude (95% CI)\tHazard ratio, adjusted* (95% CI)\t\nExposed to APD\t364\t177\t1.04 (0.88; 1.22)\t1.11 (0.94; 1.31)\t\nUnexposed to APD\t630\t282\t1.00 (ref)\t1.00 (ref)\t\n* Adjusted for maternal age divided into three groups, history of drug abuse, cohabitation, income (above or below the median) and education (divided like in Table 1)\n\nWhen the analyses were stratified according to a diagnosis of severe mental disorder, the risk of SA after APD exposure during pregnancy was increased, but not statistically significant (aRR = 1.14; 95% CI = 0.94; 1.39), in women with a diagnosis of severe mental disorder. However, in women without a diagnosis in the psychiatric registry (e.g. potentially treated exclusively by a GP), exposed pregnant women did have an increased risk (aRR = 1.34; 95% CI = 1.21; 1.49) (Table 2).\n\nThe vast majority of women who redeemed antipsychotic medications during pregnancy redeemed prescriptions for mean dose levels of less than 50% of DDD (92.7%). The aRR was increased three-fold in pregnancies exposed to a high dose (aRR = 3.19; 95% CI = 2.65; 3.84) and 36% in pregnancies exposed to a low dose of antipsychotic medications (aRR = 1.36; 95% CI = 1.22; 1.51) (Table 4). When we restricted these analyses to include only women with a diagnosis of severe mental disorder, we found a significantly increased risk only for use of high dose, but not for low (crude RR = 2.22; 95% CI = 1.67; 2.95 and crude RR = 0.96; 95% CI = 0.73; 1.26, respectively).\n\n10.1371/journal.pone.0132280.t004Table 4 Relative risk of SA following high and low dose of APD exposure in pregnancy (numbers refer to pregnancy outcomes).\nAPD dose\tNumber\tSpontaneous abortion, number\tRelative risk, crude (95% CI)\tRelative risk, adjusted* (95% CI)\t\nHigh\t117\t56\t3.52 (2.91; 4.26)\t3.19 (2.65; 3.84)\t\nLow\t1487\t285\t1.41 (1.27; 1.57)\t1.36 (1.22; 1.51)\t\nNo exposure\t841,183\t114,314\t1.00 (ref)\t1.00 (ref)\t\n*Adjusted for maternal age divided into three groups\n\nThe risk estimates for SA were rather similar for several types of antipsychotic medications (Table 5). However, CIs were wide and numbers were too small to perform adjusted analyses for most types of drugs.\n\n10.1371/journal.pone.0132280.t005Table 5 Relative risk of SA following exposure to individual APD (numbers refer to pregnancy outcomes).\nAPD\tExposure\tNumber\tSpontaneous abortions, number\tRelative risk, crude (95% CI)\tRelative risk, adjusted* (95% CI)\t\nChlorprothixene\tTotal\t365\t99\t2.00 (1.69; 2.36)\t1.65 (1.39; 1.95)\t\nNo exposure\t841,183\t114,314\t1 (ref)\t1 (ref)\t\nFlupentixol\tTotal\t233\t56\t1.77 (1.39; 2.24)\t1.55 (1.22; 1.97)\t\nNo exposure\t841,183\t114,314\t1 (ref)\t1 (ref)\t\nPerphenazine\tTotal\t229\t44 (19.2%)\t1.41 81.08; 1.86)\t1.25 (0.95; 1.64)\t\nNo exposure\t841,183\t114,314 (13.6%)\t1 (ref)\t1.(ref)\t\nZuclopenthixol\tTotal\t229\t43 (18.8%)\t1.38 (1.05; 1.82)\t1.26 (0.95; 1.66)\t\nNo exposure\t841,183\t114,314 (13.6%)\t1 (ref)\t1 (ref)\t\nLevomepromazine\tTotal\t200\t42 (21.0%)\t1.55 (1.18; 2.03)\t1.32 (1.01; 1.72)\t\nNo exposure\t841,183\t114,314 (13.6%)\t1 (ref)\t1 (ref)\t\nQuetiapine\tTotal\t174\t42 (24.1%)\t1.78 (1.36; 2.32)\t1.65 (1.28; 2.15)\t\nNo exposure\t841,183\t114,314 (13.6%)\t1 (ref)\t1 (ref)\t\nOlanzapine\tTotal\t223\t39 (17.5%)\t1.29 (0.96; 1.72)\t1.10 (0.83; 1.46)\t\nNo exposure\t841,183\t114,314 (13.6%)\t1 (ref)\t1 (ref)\t\nLithium\tTotal\t104\t26 (25.0%)\t1.84 (1.30; 2.60)\tNA\t\nNo exposure\t841,183\t114,314 (13.6%)\t1 (ref)\tNA\t\nRisperidone\tTotal\t116\t25 (21.6%)\t1.59 (1.12; 2.25)\tNA\t\nNo exposure\t841,183\t114,314 (13.6%)\t1 (ref)\tNA\t\nAripiprazole\tTotal\t45\t15 (33.3%)\t2.45 (1.62; 3.71)\tNA\t\nNo exposure\t841,183\t114,314 (13.6%)\t1 (ref)\tNA\t\nZiprasidone\tTotal\t41\t11 (26.8%)\t1.97 (1.20; 3.25)\tNA\t\nNo exposure\t841,183\t114,314 (13.6%)\t1 (ref)\tNA\t\nHaloperidone\tTotal\t40\t10 (25.0%)\t1.84 (1.04; 3.26)\tNA\t\nNo exposure\t841,183\t114,314 (13.6%)\t1 (ref)\tNA\t\nProchlorperazine\tTotal\t74\t7 (9.3%)\t0.69 (0.34; 1.40)\tNA\t\nNo exposure\t841,183\t114,314 (13.6%)\t1 (ref)\tNA\t\nFluphenazine\tTotal\t14\t5 (35.7%)\t2.63 (1.27; 5.45)\tNA\t\nNo exposure\t841,183\t114,314 (13.6%)\t1 (ref)\tNA\t\nChlorpromazine\tTotal\t38\t5 (13.2%)\t0.97 (0.44; 2.15)\tNA\t\nNo exposure\t841,183\t114,314 (13.6%)\t1 (ref)\tNA\t\n* Adjusted for maternal age divided into three groups and history of drug abuse.\n\nRisk of stillbirth\nPregnancies exposed to any type of investigated antipsychotic medication had a more than twofold increased risk of stillbirth (crude RR = 2.27; 95% CI = 1.45; 3.55) compared with unexposed pregnancies. Due to small sample size, adjustments were performed for one variable at a time. Adjusting for maternal age, cohabitation, income, history of severe mental disorder or history of drug misuse one at a time changed the estimates only slightly. The risk was almost unchanged when comparing with women who redeemed prescriptions for antipsychotic medications before but not during pregnancy (RR = 2.06; 95% CI = 1.01; 4.19) (Table 6).\n\n10.1371/journal.pone.0132280.t006Table 6 Relative risks of stillbirth following APD exposure in pregnancy (numbers refer to pregnancy outcomes studied).\n\tAPD exposure\tNumber\tStillbirth, number (%)\tRelative risk, crude (95% CI)\t\nOverall\tExposed\t1616\t19 (1.2%)\t2.27 (1.45; 3.55)\t\nUnexposed\t726,727\t3771 (0.5%)\t1.00 (ref)\t\nExposed to APD\tExposed during pregnancy\t1474\t18 (1.2%)\t2.06 (1.01; 4.19)\t\nExposed only before pregnancy\t2193\t13 (0.6%)\t1.00 (ref)\t\nDiscussion\nIn this large nationwide cohort study, the risk of SA was not significantly increased in women taking antipsychotic medications during pregnancy compared with women taking antipsychotic medications before, but not during, pregnancy. The findings also indicate, that the risk of SA in women who were pregnant more than once during the study period was similar for women who were exposed and women who were unexposed to antipsychotic medication. Therefore, the overall 34% higher risk of SA in pregnancies exposed to antipsychotic medications compared with unexposed pregnancies may be due to factors related to the underlying disease rather than the treatment.\n\nThe results are in line with previous findings from smaller studies, which found no increased risk of SA after prenatal exposure to atypical antipsychotic medications.[14, 17, 18] Thus the increased risk of SA in women taking antipsychotic medications during pregnancy may be more related to their health problem and social conditions than to the medication. Confounding by indication may arise although it is unclear why a mental disorder in itself could cause an SA. Lifestyle factors and comorbidity may be more likely explanations. Based on the present study, an increased risk cannot be ruled out in women taking high doses of antipsychotic medications through long periods of pregnancy due to a dose response or threshold effect. However, confounding by indication may also explain these findings, because higher doses of antipsychotic medications represent not only a higher dose, but potentially also more severe disorder and more comorbid conditions.\n\nWe found that the risk of stillbirth increased twofold after exposure to antipsychotic medications. A large Danish cohort study has demonstrated an increased risk of stillbirth in pregnant women with previous psychiatric admission, regardless of diagnosis. [3] However, this former study did not include information about medication. Furthermore, in the present study, we were able to compare women who redeemed prescriptions for antipsychotic medications during pregnancy and women who redeemed similar prescriptions earlier in life. Our findings indicate that there may be an increased risk of stillbirth after exposure to antipsychotic medications. Due to small number of cases, we were unable to simultaneously adjust for multiple confounders. However, adjusting for relevant confounders one at a time, did not change the estimates considerably. We did not have the data to perform an analysis of subsequent pregnancies discordant to antipsychotic medication exposure in the same women.\n\nStrengths and weaknesses\nThis population-based cohort included all recorded pregnancies in Denmark between 1997 and 2008. The study had almost complete follow-up owing to the nationwide Danish registries, which makes selection of study participants and loss to follow-up unlikely explanations for our findings.\n\nClassification of outcome is based on registry data that are mandatory for all inpatient treatments. Health care in Denmark is free and universally available. All stillbirths and most clinically recognized SAs are likely to be treated in a hospital setting. Thus misclassification of outcome is likely to be low. However, an SA occurring very early in a pregnancy will generally not be recorded in the hospital registry. These incidences may be interpreted as a late menstrual period or treated outside the hospital system. If SAs are more likely to be missed in women taking antipsychotic medications during pregnancy, or if exposure may interfere with very early survival of the pregnancy, this might lead to an underestimation of the risk associated with use of antipsychotic medication. However, we found no signs of differential timing of these terminations within the exposure groups.\n\nExposure data are based on complete registration of all redeemed prescriptions in Denmark. We assumed that women who redeemed a prescription of antipsychotic medications also took the medicine. A previous study on compliance with prescribed medication in Danish pregnant women showed 80% compliance to antidepressant medications. [29] Compliance to antipsychotic medication may differ from that of antidepressant medication, but a sensitivity analysis which included only women who redeemed at least two prescriptions during pregnancy and an analysis using extended exposure window, did not change the results markedly. The Danish National Prescription Register does not include information on medication administered during inpatient admissions. However, psychiatric disorder severe enough to prompt inpatient treatment would usually lead to continued treatment after discharge. The dosage may thus be underestimated in these cases but exposure is unlikely to have been missed completely.\n\nThe medication exposure window was defined as the period from 30 days before the estimated conception date to one day prior to spontaneous abortion/stillbirth/birth. The 30 days prior to conception were included in order to investigate delayed medication effects and to account for prescriptions in use at the time of conception. We included the day prior to termination of the pregnancy in the exposure window. We did this even though an effect of medication this close to termination of the pregnancy may be unlikely, because we wanted to be sure to investigate any possible immediate effects of medication\n\nThe numbers of women with prescriptions for specific types of antipsychotic drugs were too low to allow for in-depth estimates of the effects of the individual drugs.\n\nWe included lithium in the study, because we wanted to assess all drugs included in the ATC group: “Antipsychotic medication N05A” in spite of different chemical structure and indications. The relative risk of SA after exposure to lithium is quite similar to the risk of other drugs, which suggests that it is acceptable to include it in the general analysis.\n\nThe Danish Psychiatric Central Register contains information on treatment at psychiatric hospital-based units in Denmark. However, data on diagnoses made by general practitioners or private psychiatrists are not included in the register. Only diagnoses recorded in the register can be adjusted for.\n\nInduced abortions occur more frequently in women who take antipsychotic medications during pregnancy than in women who do not take antipsychotic medications. Induced abortion may act as a competing event with regard to SA. This could result in underestimation of the risk of exposure to antipsychotic medications. However, a Cox regression model with induced abortion censored at the time of termination showed almost the same results as our binomial regression analysis.\n\nWe adjusted for several confounding factors in the analyses of SA. Nevertheless, residual and uncontrolled confounding may remain, as we lacked information on some important potential confounders, including smoking, alcohol intake, illegal drugs and poor diet. The results of the analysis restricted to women with severe mental disorder and the discordant pregnancies analysis indicate that such residual confounding is, in fact, present.\n\nStillbirth is a rare outcome. Despite the considerable size of the cohort, the number of fetal deaths was small. Thus, we were unable to adjust for multiple confounders at the same time or to perform sub-analysis of the risk of stillbirth in multiple pregnancies in the same women.\n\nImplications\nThe risk of SA in women taking antipsychotic medications during pregnancy was quite similar to the risk in women taking antipsychotic medications prior to conception but not during the pregnancy, and was almost similar to the risk in unexposed pregnancies in the same women. Thus the increased risk found in women taking antipsychotic medications during pregnancy compared with women not taking antipsychotic medication, may be caused by confounding. In women taking high doses of antipsychotic medications, results indicated a possible increased risk due to the medication itself.\n\nThe risk of stillbirth was twofold higher in pregnancies exposed to antipsychotic medication.\n\nTreatment of pregnant women with antipsychotic medications requires careful consideration of indications and close clinical monitoring. In addition, as low doses as possible should be used. Potentially harmful fetotoxic effects, other than fetal death, should also be studied.\n\nEthics statement\nThe use of registry data, including the combinations of information, was approved by the Danish Data Protection Agency. All data were anonymized before analysis. According to Danish law, approval by a research ethics committee was not needed for the project as the data included only non-personally identifiable information.\n\nSupporting Information\nS1 Table Use of antipsychotic medications in the period from 1997 to 2008.\n(DOC)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \nNilsson E , Lichtenstein P , Cnattingius S , Murray RM , Hultman CM . Women with schizophrenia: pregnancy outcome and infant death among their offspring . Schizophr Res . 2002 ;58 (2–3 ):221 –9 . .12409162 \n2 \nHoward LM , Goss C , Leese M , Thornicroft G . Medical outcome of pregnancy in women with psychotic disorders and their infants in the first year after birth . Br J Psychiatry . 2003 ;182 :63 –7 . .12509320 \n3 \nKing-Hele S , Webb RT , Mortensen PB , Appleby L , Pickles A , Abel KM . Risk of stillbirth and neonatal death linked with maternal mental illness: a national cohort study . Arch Dis Child Fetal Neonatal Ed . 2009 ;94 (2 ):F105 –10 . 10.1136/adc.2007.135459 \n.19000999 \n4 \nGissler M , Artama M , Ritvanen A , Wahlbeck K . Use of psychotropic drugs before pregnancy and the risk for induced abortion: population-based register-data from Finland 1996–2006 . BMC Public Health . 2010 ;10 :383 \n10.1186/1471-2458-10-383 \n20591182 \n5 \nAlexander GC , Gallagher SA , Mascola A , Moloney RM , Stafford RS . Increasing off-label use of antipsychotic medications in the United States, 1995–2008 . Pharmacoepidemiol Drug Saf . 2011 ;20 (2 ):177 –84 . 10.1002/pds.2082 \n21254289 \n6 \nStephenson CP , Karanges E , McGregor IS . Trends in the utilisation of psychotropic medications in Australia from 2000 to 2011 . Aust N Z J Psychiatry . 2013 ;47 (1 ):74 –87 . 10.1177/0004867412466595 \n.23144164 \n7 \nVigod SN , Seeman MV , Ray JG , Anderson GM , Dennis CL , Grigoriadis S , et al\nTemporal trends in general and age-specific fertility rates among women with schizophrenia (1996–2009): a population-based study in Ontario, Canada \n. Schizophr Res . 2012 ;139 (1–3 ):169 –75 . 10.1016/j.schres.2012.05.010 \n.22658526 \n8 \nNewport DJ , Calamaras MR , DeVane CL , Donovan J , Beach AJ , Winn S , et al\nAtypical antipsychotic administration during late pregnancy: placental passage and obstetrical outcomes . Am J Psychiatry . 2007 ;164 (8 ):1214 –20 . 10.1176/appi.ajp.2007.06111886 \n.17671284 \n9 \nGentile S . Antipsychotic therapy during early and late pregnancy. A systematic review . Schizophr Bull . 2010 ;36 (3 ):518 –44 . 10.1093/schbul/sbn107 \n18787227 \n10 \nHironaka M , Kotani T , Sumigama S , Tsuda H , Mano Y , Hayakawa H , et al\nMaternal mental disorders and pregnancy outcomes: a clinical study in a Japanese population . J Obstet Gynaecol Res . 2011 ;37 (10 ):1283 –9 . 10.1111/j.1447-0756.2010.01512.x \n.21535304 \n11 \nLin HC , Chen IJ , Chen YH , Lee HC , Wu FJ . Maternal schizophrenia and pregnancy outcome: does the use of antipsychotics make a difference? \nSchizophr Res . 2010 ;116 (1 ):55 –60 . 10.1016/j.schres.2009.10.011 \n.19896335 \n12 \nSadowski A , Todorow M , Yazdani Brojeni P , Koren G , Nulman I . Pregnancy outcomes following maternal exposure to second-generation antipsychotics given with other psychotropic drugs: a cohort study . BMJ Open . 2013 ;3 (7 ). 10.1136/bmjopen-2013-003062 \n23852139 \n13 \nReis M , Kallen B . Maternal use of antipsychotics in early pregnancy and delivery outcome . J Clin Psychopharmacol . 2008 ;28 (3 ):279 –88 . 10.1097/JCP.0b013e318172b8d5 \n.18480684 \n14 \nHabermann F , Fritzsche J , Fuhlbruck F , Wacker E , Allignol A , Weber-Schoendorfer C , et al\nAtypical antipsychotic drugs and pregnancy outcome: a prospective, cohort study . J Clin Psychopharmacol . 2013 ;33 (4 ):453 –62 . 10.1097/JCP.0b013e318295fe12 \n.23764684 \n15 \nJohnson KC , LaPrairie JL , Brennan PA , Stowe ZN , Newport DJ . Prenatal antipsychotic exposure and neuromotor performance during infancy . Arch Gen Psychiatry . 2012 ;69 (8 ):787 –94 . 10.1001/archgenpsychiatry.2012.160 \n.22474072 \n16 \nPeng M , Gao K , Ding Y , Ou J , Calabrese JR , Wu R , et al\nEffects of prenatal exposure to atypical antipsychotics on postnatal development and growth of infants: a case-controlled, prospective study . Psychopharmacology (Berl) . 2013 ;228 (4 ):577 –84 . 10.1007/s00213-013-3060-6 \n.23559219 \n17 \nMcKenna K , Koren G , Tetelbaum M , Wilton L , Shakir S , Diav-Citrin O , et al\nPregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study . J Clin Psychiatry . 2005 ;66 (4 ):444 –9 ; quiz 546. .15816786 \n18 \nDiav-Citrin O , Shechtman S , Ornoy S , Arnon J , Schaefer C , Garbis H , et al\nSafety of haloperidol and penfluridol in pregnancy: a multicenter, prospective, controlled study . J Clin Psychiatry . 2005 ;66 (3 ):317 –22 . .15766297 \n19 \nTwaites BR , Wilton LV , Shakir SA . The safety of quetiapine: results of a post-marketing surveillance study on 1728 patients in England . J Psychopharmacol . 2007 ;21 (4 ):392 –9 . 10.1177/0269881107073257 \n.17656426 \n20 \nGoldstein DJ , Corbin LA , Fung MC . Olanzapine-exposed pregnancies and lactation: early experience . J Clin Psychopharmacol . 2000 ;20 (4 ):399 –403 . .10917399 \n21 \nBiswasl PN , Wilton LV , Pearcel GL , Freemantle S , Shakir SA . The pharmacovigilance of olanzapine: results of a post-marketing surveillance study on 8858 patients in England . J Psychopharmacol . 2001 ;15 (4 ):265 –71 . .11769820 \n22 \nCoppola D , Russo LJ , Kwarta RF Jr., Varughese R , Schmider J . Evaluating the postmarketing experience of risperidone use during pregnancy: pregnancy and neonatal outcomes . Drug Saf . 2007 ;30 (3 ):247 –64 . .17343431 \n23 \nBennedsen BE , Mortensen PB , Olesen AV , Henriksen TB . Congenital malformations, stillbirths, and infant deaths among children of women with schizophrenia . Arch Gen Psychiatry . 2001 ;58 (7 ):674 –9 . .11448375 \n24 \nKildemoes HW , Sorensen HT , Hallas J . The Danish National Prescription Registry . Scand J Public Health . 2011 ;39 (7 Suppl ):38 –41 . 10.1177/1403494810394717 \n.21775349 \n25 \nAndersen TF , Madsen M , Jorgensen J , Mellemkjoer L , Olsen JH . The Danish National Hospital Register. A valuable source of data for modern health sciences . Dan Med Bull . 1999 ;46 (3 ):263 –8 . .10421985 \n26 \nThe ICD-10 classification of mental and behaviorural disorders: diagnostic criteria for research\n1 ed. ed. World Health Organization : Geneva ; 1993 .\n27 \nKnudsen LB , Olsen J . The Danish Medical Birth Registry . Dan Med Bull . 1998 ;45 (3 ):320 –3 . .9675544 \n28 \nMunk-Jorgensen P , Mortensen PB . The Danish Psychiatric Central Register . Dan Med Bull . 1997 ;44 (1 ):82 –4 . .9062767 \n29 \nOlesen C , Sondergaard C , Thrane N , Nielsen GL , de Jong-van den Berg L , Olsen J , et al\nDo pregnant women report use of dispensed medications? \nEpidemiology . 2001 ;12 (5 ):497 –501 . .11505166\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "10(7)",
"journal": "PloS one",
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"medline_ta": "PLoS One",
"mesh_terms": "D000022:Abortion, Spontaneous; D000328:Adult; D014150:Antipsychotic Agents; D005260:Female; D005313:Fetal Death; D006801:Humans; D011247:Pregnancy; D011256:Pregnancy Outcome; D012307:Risk Factors; D050497:Stillbirth; D055815:Young Adult",
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"pmid": "26162087",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21535304;19000999;12409162;17343431;10421985;19896335;23764684;11505166;23852139;9675544;23144164;10917399;18787227;15766297;15816786;12509320;20591182;22658526;21254289;11448375;17656426;9062767;11769820;18480684;23559219;17671284;21775349;22474072",
"title": "Risk of Fetal Death after Treatment with Antipsychotic Medications during Pregnancy.",
"title_normalized": "risk of fetal death after treatment with antipsychotic medications during pregnancy"
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"abstract": "We herein report a rare case of oral mucormycosis following allogeneic hematopoietic stem cell transplantation. Oral mucormycosis due to Rhizopus microsporus manifested as localized left buccal mucositis with a 1-cm black focus before neutrophil recovery. Combination therapy with liposomal amphotericin B was initiated and surgical debridement was performed; however, the patient died due to progressive generalized mucormycosis. Considerable attention needs to be paid to the diagnosis and management of oral mucormycosis in post-transplant patients, thereby suggesting the importance of fully understanding the risk factors.",
"affiliations": "Department of Hematology, Nagasaki University Hospital, Japan.;Department of Hematology, Nagasaki University Hospital, Japan.;Department of Hematology, Nagasaki University Hospital, Japan.;Department of Hematology, Japanese Red Cross Nagasaki Genbaku Hospital, Japan.;Department of Respiratory Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Japan.;Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Japan.;Department of Pathology, Nagasaki University Hospital, Japan.;Department of Pathology, Nagasaki University Hospital, Japan.;Department of Plastic and Reconstructive Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Japan.;Department of Plastic and Reconstructive Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Japan.;Department of Laboratory Medicine, Nagasaki University Hospital, Japan.;Department of Dermatology, Nagasaki Ekisaikai Hospital, Japan.;Department of Plastic and Reconstructive Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Japan.;Department of Laboratory Medicine, Nagasaki University Hospital, Japan.;Department of Respiratory Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Japan.;Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Japan.;Department of Hematology, Nagasaki University Hospital, Japan.",
"authors": "Sakamoto|Hikaru|H|;Itonaga|Hidehiro|H|;Sawayama|Yasushi|Y|;Taguchi|Jun|J|;Saijo|Tomomi|T|;Kuwatsuka|Sayaka|S|;Hashisako|Mikiko|M|;Kinoshita|Naoe|N|;Oishi|Masao|M|;Doi|Hanako|H|;Kosai|Kosuke|K|;Nishimoto|Katsutaro|K|;Tanaka|Katsumi|K|;Yanagihara|Katsunori|K|;Mukae|Hiroshi|H|;Izumikawa|Koichi|K|;Miyazaki|Yasushi|Y|",
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"doi": "10.2169/internalmedicine.0474-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3017572810.2169/internalmedicine.0474-17Case ReportPrimary Oral Mucormycosis Due to Rhizopus microsporus after Allogeneic Stem Cell Transplantation Sakamoto Hikaru 1Itonaga Hidehiro 1Sawayama Yasushi 1Taguchi Jun 2Saijo Tomomi 3Kuwatsuka Sayaka 4Hashisako Mikiko 5Kinoshita Naoe 5Oishi Masao 6Doi Hanako 6Kosai Kosuke 7Nishimoto Katsutaro 8Tanaka Katsumi 6Yanagihara Katsunori 7Mukae Hiroshi 3Izumikawa Koichi 910Miyazaki Yasushi 111\n1 Department of Hematology, Nagasaki University Hospital, Japan\n2 Department of Hematology, Japanese Red Cross Nagasaki Genbaku Hospital, Japan\n3 Department of Respiratory Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Japan\n4 Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Japan\n5 Department of Pathology, Nagasaki University Hospital, Japan\n6 Department of Plastic and Reconstructive Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Japan\n7 Department of Laboratory Medicine, Nagasaki University Hospital, Japan\n8 Department of Dermatology, Nagasaki Ekisaikai Hospital, Japan\n9 Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Japan\n10 Infection Control and Education Center, Nagasaki University Hospital, Japan\n11 Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, JapanCorrespondence to Dr. Hidehiro Itonaga, itonaga-ngs@umin.ac.jp\n\n1 9 2018 57 17 2567 2571 9 11 2017 14 1 2018 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).We herein report a rare case of oral mucormycosis following allogeneic hematopoietic stem cell transplantation. Oral mucormycosis due to Rhizopus microsporus manifested as localized left buccal mucositis with a 1-cm black focus before neutrophil recovery. Combination therapy with liposomal amphotericin B was initiated and surgical debridement was performed; however, the patient died due to progressive generalized mucormycosis. Considerable attention needs to be paid to the diagnosis and management of oral mucormycosis in post-transplant patients, thereby suggesting the importance of fully understanding the risk factors. \n\noral mucormycosisallogeneic hematopoietic stem cell transplantationacute myeloid leukemia\n==== Body\nIntroduction\nMucormycosis is a rare infectious complication with an incidence of 0.6% among patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) (1). Mucormycosis as a breakthrough infection appears to have increased among patients with hematological diseases because of the use of anti-aspergillus azoles or echinocandins as routine prophylaxis (2). Mucormycosis typically presents as an acute, aggressive, and frequently angio-invasive mold infection, and it is often a life-threating opportunistic infection after allo-HSCT (1). The risk factors for mucormycosis include poorly controlled diabetes mellitus, iron overload, a previous history of iron-chelating therapy, the development of graft-versus-host disease, prolonged neutropenia, and systemic corticosteroid administration (3-5). However, no risk-stratified therapeutic modality has yet been established. Therefore, mucormycosis needs to be diagnosed at an early stage. Based on previous findings showing the successful outcomes of complete surgical debridement together with liposomal amphotericin B (L-AMB) (4,6,7), an early diagnosis of oral mucormycosis appears to be advantageous for minimizing the amount of tissue that needs to be removed.\n\nMucormycosis manifests in 6 predominant clinical forms: rhino-cerebral, pulmonary, cutaneous, gastrointestinal, disseminated, and miscellaneous, including oral (3). Pulmonary lesions are a common manifestation in patients with hematological diseases including post-transplant patients (4); however, manifestations other than the pulmonary form are very rare. Oral mucormycosis has been reported to also develop in immunocompromized patients, such as those with poorly controlled diabetes mellitus, and Rhizopus oryzae is the most frequent pathogen. (4,8). But it is unclear whether the clinical manifestation of oral mucormycosis differs according to the type of the pathogen. In this article, we describe a rare case of oral mucormycosis caused by Rhizopus microsporus in post-transplant patients.\n\nCase Report\nA 56-year-old male was diagnosed with secondary acute myeloid leukemia (AML) which had transformed from polycythemia vera in September, 2009. The laboratory findings were as follows: white blood cell count, 54.8×109/L with 37% myeloblasts and 49% neutrophils; hemoglobin level, 15.0 g/dL; platelet count, 502×109/L. The patient had no apparent underlying complications, potential infectious diseases or any specific opportunity of environment, including his occupation, exposure to Mucor species (e.g., decaying vegetation and soil, barns, compost piles, plants, and smoking), and had not been administered voriconazole or iron chelators. Standard chemotherapy with cytarabine and daunorubicin did not result in hematological remission. The patient was isolated in a laminar air flow room from the initiation of induction therapy. Treatment with low-dose cytarabine was subsequently administered to debulk AML blasts before allo-HSCT. The patient's general condition was maintained without any infectious diseases or oral mucositis despite prolonged severe neutropenia. The patient did not have any donor candidates among his siblings or in the Japan Marrow Donor Program. After receiving one course of low-dose cytarabine, unrelated cord blood transplantation (total nucleated cell dose, 4.28×107 cells/kg; CD34-positive cell dose, 0.62×105 cells/kg; HLA 4/6 loci mismatched, from a male donor) was performed using myeloablative conditioning (fludarabine 120 mg/m2, intravenous busulfan 12.8 mg/m2, and total body irradiation 4 Gy / 2 fr.) in October 2010. Tacrolimus and oral mycophenolate mofetil were used as agents for graft-versus-host disease (GVHD) prophylaxis. Micafungin at 50 mg daily and levofloxacin at 500 mg daily were administered for anti-fungal and -bacterial prophylaxis, respectively.\n\nOn day +6 of transplantation, the patient developed fever with grade 3 oral mucositis during persistent severe neutropenia. According to the c-D-index, the scoring system to predict invasive mold infection, such as aspergillosis, based on the severity and duration of neutropenia (9), his condition was classified as high-risk (c-D-index 6,940). However, routine microbiological tests were negative: neither bacteria nor fungi were detected in the blood cultures. Furthermore, β-D glucan and galactomannan antigens were not elevated and computed tomography did not reveal any infectious lesions. Antibiotic agents were initiated for the oral infection and improved his fever and oral mucositis. On day +15, the patient re-presented with fever and localized left buccal mucositis with a 1-cm black focus in swollen cheek skin. Dermatitis progressed rapidly despite treatments with 5 different antibiotics, and his general condition deteriorated (Fig. 1A and B). Computed tomography revealed edematous changes in the larynx and pharynx, and subcutaneous swelling from the left cheek to the neck (Fig. 1C and D). Oral mucormycosis was clinically diagnosed based on the clear boundary of necrotic tissue with an obstructed airway. A skin biopsy on day +24 showed that the necrotic surface layer was covered with non-septate hyphae with branching at wide angles (Fig. 2A-C). Fungal cultures revealed broad hyphae with very few septa that produced long sporangiospores terminating with a dark and round sporangium (Fig. 2D). A molecular analysis using a polymerase chain reaction method identified Rhizopus microsporus as follows; DNA was extracted from fungi cultured in Sabouraud agar using a nucleic acid extraction kit (Kyokuto Pharmaceutical Industrial, Tokyo, Japan). Next, using the extracted DNA as a template, PCR was carried out with the fungal D1/D2 region as a target using a kit [Fungal rDNA (D1/D2) PCR kit fast, Takara, Kusatsu, Japan] (http://www.clontech.com/JP/Products/PCR/Pathogen_Detection_and_Screening_Kits/Bacterial_Pathogen_Detection/rDNA_PCR_Kits?sitex=10025:22372:US), as previously described (10). The PCR amplification product of approximately 650 bps was purified and labeled, and the nucleotide sequence was determined by direct sequencing (Genetic Analyzer 3130, Applied Biosystems, Tokyo, Japan). Based on the obtained nucleotide sequence, the homology of the nucleotide sequence was analyzed using a database (BLAST), and the one having the highest homology was used to identify the fungal species.\n\nFigure 1. Skin appearance and computed tomography findings of oral mucormycosis. A black necrotic area progressively enlarged on day+15 (A) and day+24 (B) after transplantation. Computed tomography showed swelling of the oral mucosa and lower jaw skin that rapidly progressed on day+18 (C) and day+20 (D).\n\nFigure 2. Pathological findings and a tissue culture of oral mucormycosis. A skin biopsy specimen was completely necrotic, with a surface that was covered by non-septate hyphae with branching at wide angles [Hematoxylin and Eosin (H&E) staining, 100×] (A). Hyphae infiltrated the vessels and surrounding subcutaneous tissue (H&E staining, 200×) (B). Grocott’s methenamine silver stain revealed the presence of fungal hyphae (400×) (C). A skin culture grew Mucor spp. (D).\n\nThe administration of 5 mg/kg/day L-AMB was initiated and surgical debridement was performed on day +24, as described previously (4,6,7). However, debridement could not be completed due to the presence of a large necrotic lesion involving the floor of the mouth, tongue, and mandibula. The patient was treated with L-AMB for 7 days, but died on day +31 after allo-HSCT (Fig. 3).\n\nFigure 3. The clinical course from the initiation of low-dose Ara-C to post-transplantation. The intensity and duration of neutropenia persisted before and after allo-HSCT, and the c-D-index exceeded 5,800 (i.e., the cut-off point of the c-D-index to estimate the risk of mold infection, mainly aspergillosis) on day+4 after allo-HSCT. Fever with oral mucositis developed on day+6, and a black necrotic area due to mucormycosis was identified on day+15. L-AMB: liposomal amphotericin B, CPFG: caspofungin, MCFG: micafungin, TBI: total body irradiation, Ara-C: cytosine arabinose, uCBT: unrelated cord blood transplantation, WBC: white blood cell, allo-HSCT: allogeneic stem cell transplantation, c-D-index: cumulative D-index\n\nDiscussion\nOral mucormycosis in this patient occurred before neutrophil engraftment after transplantation, rapidly progressed despite combination therapy with the administration of L-AMB and surgical debridement, and resulted in a fatal outcome. Mucormycosis mostly involves pulmonary or rhino-cerebral lesions at the late phase after allo-HSCT (3-5), while oral mucormycosis is more likely to occur before neutrophil recovery (11-14). The clinical course of this case indicated the important risk factors for oral mucormycosis after allo-HSCT.\n\nThis case had sustained neutropenia, even before undergoing allo-HSCT, which may have been related to refractory AML itself and chemotherapy until shortly before HSCT. The prolonged neutropenic period before and after HSCT (high c-D-index on day +6 of allo-HSCT) may have had an unfavorable influence on mucormycosis. Although the D-index and c-D-index were originally established to estimate the risk of mold infection, mainly aspergillosis, these indexes might be also useful for predicting the risk of mucormycosis, which was calculated including the neutropenic period before and after transplantation. Considering the serious clinical course of mucormycosis, it is necessary to establish either a scoring system for its prediction or a risk assessment system using a large cohort of patients under severe immune suppression, such as those with prolonged neutropenia, and those after transplantation.\n\nOral mucositis in the present case may have been closely related to the development of oral mucormycosis. Mucosal toxicity appeared to have been enhanced by cytotoxic chemotherapy before the conditioning regimen, and conditioning with radiation severely aggravated it, thus increasing the risk of invasive oral infection.\n\nFurthermore, the prolonged use of Micafungin from before transplantation also promoted the development of oral mucormycosis through selective pressure on molds (15,16). Based on the efficacy of L-AMB for patients with febrile neutropenia (17), its administration represents an important therapeutic option as an initial empirical therapy when patients have a condition similar to that observed in the present case. Because there is a report demonstrating that Rhizopus microporus was less sensitive to posaconazole than other Mucor speices in vitro (18), the use of L-AMB as an initial empirical therapy should thus be considered for patients suspected of having oral mucormycosis.\n\nThe early application of combination therapy with complete surgical debridement and L-AMB administration has been reported to be successful in some cases with oral mucormycosis (12,13). Surgical debridement was performed and the administration of L-AMB was also initiated for the present case, but these treatments failed to successfully treat the disease. Due to the limitations associated with the diagnostic modality used to detect mucormycosis at an early phase, the development of novel methods is required for severely neutropenic patients. Recent studies reported that a quantitative polymerase chain reaction (PCR) for the detection of circulating DNA using serum samples is effective for diagnosing mucormycosis at an early stage (19,20), and a novel antigen specific to Rhizopus species was identified using an animal model (21). A preemptive strategy for mucormycosis using L-AMB guided by a PCR method and antigen detection to identify invasive aspergillosis using the galactomannan test may thus be warranted in the future (22,23).\n\nIn conclusion, considerable attention needs to be paid to the diagnosis and management of oral mucormycosis in post-transplant patients with the following risk factors: (i) persistent neutropenia before and after transplantation, (ii) the potential risk of oral mucositis by cytotoxic treatments before the initiation of a conditioning regimen, and (iii) the use of azole or echinocandin as prophylaxis. In the present practice, performing combination therapy with complete surgical debridement and the administration of L-AMB should be applied as early as possible when mucositis with a small necrotic area develops in patients with such risk factors.\n\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nKosuke Kosai: Honoraria, Sumitomo Dainippon Pharma and MSD; Research funding, MSD. Katsunori Yanagihara: Honoraria, Sumitomo Dainippon Pharma, Astellas Pharma and MSD; Research funding, Sumitomo Dainippon Pharma, Astellas Pharma and MSD. Hiroshi Mukae: Honoraria, Sumitomo Dainippon Pharma, Astellas Pharma and MSD; Fees for promotional materials, Sumitomo Dainippon Pharma, Astellas Pharma and MSD. Koichi Izumikawa: Honoraria, Sumitomo Dainippon Pharma, Astellas Pharma and MSD; Research funding, Sumitomo Dainippon Pharma, Astellas Pharma and MSD.\n==== Refs\n1. Riches ML , Trifilio S , Chen M , et al \nRisk factors and impact of non-Aspergillus mold infections following allogeneic HCT: a CIBMTR infection and immune reconstitution analysis . Bone Marrow Transplant \n51 : 277 -282 , 2016 .26524262 \n2. Kume H , Yamazaki T , Togano T , et al \nEpidemiology of visceral mycoses in autopsy cases in Japan: comparison of the data from 1989, 1993, 1997, 2001, 2005 and 2007 in annual of pathological autopsy cases in Japan . Med Mycol J \n52 : 117 -127 , 2011 .21788723 \n3. Petrikkos G , Skiada A , Lortholary O , Roilides E , Walsh TJ , Kontoyiannis DP \nEpidemiology and clinical manifestations of mucormycosis . Clin Infect Dis \n54 (Suppl 1 ): S23 -34 , 2012 .22247442 \n4. Roden MM , Zaoutis TE , Buchanan WL , et al \nEpidemiology and outcome of zygomycosis: a review of 929 reported cases . Clin Infect Dis \n41 : 634 -653 , 2005 .16080086 \n5. Leithauser M , Kahl C , Aepinus C , Prall F , Maruschke M , Junghanss C \nInvasive zygomycosis in patients with graft-versus-host disease after allogeneic stem cell transplantation . Transpl Infect Dis \n12 : 251 -257 , 2010 .20002357 \n6. Tissot F , Agrawal S , Pagano L , Petrikkos G , Groll AH , Herbrecht R \nECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients . Haematologica \n102 : 433 -444 , 2017 .28011902 \n7. Kontoyiannis DP , Lewis RE \nHow I treat mucormycosis . Blood \n118 : 1216 -1224 , 2011 .21622653 \n8. Deepa A , Nair BJ , Sivakumar T , Joseph AP \nUncommon opportunistic fungal infections of oral cavity: A review . J Oral Maxillofac Pathol \n18 : 235 -243 , 2014 .25328305 \n9. Portugal RD , Garnica M , Nucci M \nIndex to predict invasive mold infection in high-risk neutropenic patients based on the area over the neutrophil curve . J Clin Oncol \n27 : 3849 -3454 , 2009 .19597026 \n10. Yamada A , Hashikura Y , Takeda N , et al \nA case of Kerion Celsi caused by Trichophyton tonsurans identified using nucleotide sequence analysis . Jpn J Med Technol \n63 : 216 -220 , 2014 (in Japanese, Abstract in English).\n11. Metzen D , Böhm H , Zimmermann M , Reuther T , Kübler AC , Müller-Richter UD \nMucormycosis of the head and neck . J Craniomaxillofac Surg \n40 : 321 -327 , 2012 .21664828 \n12. McDermott NE , Barrett J , Hipp J , et al \nSuccessful treatment of periodontal mucormycosis: report of a case and literature review . Oral Surg Oral Med Oral Pathol Oral Radiol Endod \n109 : e64 -e69 , 2010 .20219588 \n13. Epstein JB , Kupferman SB , Zabner R , Rejali A , Hopp ML , Tzachanis D \nEarly diagnosis and successful management of oral mucormycosis in a hematopoietic stem cell transplant recipient: case report and literature review . Early Support Care Cancer \n24 : 3343 -3346 , 2016 .26971955 \n14. Al Akhrass F , Debiane L , Abdallah L , et al \nPalatal mucormycosis in patients with hematologic malignancy and stem cell transplantation . Med Mycol \n49 : 400 -405 , 2011 .21077735 \n15. Trifilio S , Singhal S , Williams S , Frankfurt O , Gordon L , Mehta J \nBreakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole . Bone Marrow Transplant \n40 : 451 -456 , 2007 .17589527 \n16. Marty FM , Cosimi LA , Baden LR \nBreakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants . N Engl J Med \n350 : 950 -952 , 2004 .14985500 \n17. Walsh TJ , Finberg RW , Arndt C , Hiemenz J , Schwartz C , Holcenberg JS \nLiposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group . N Engl J Med \n340 : 764 -771 , 1999 .10072411 \n18. Dannaoui E , Meis JF , Loebenberg D , Verweij PE \nActivity of posaconazole in treatment of experimental disseminated zygomycosis . Antimicrob Agents Chemother \n47 : 3647 -3650 , 2003 .14576138 \n19. Millon L , Larosa F , Lepiller Q , Legrand F , Rocchi S , Grenouillet F \nQuantitative polymerase chain reaction detection of circulating DNA in serum for early diagnosis of mucormycosis in immunocompromised patients . Clin Infect Dis \n56 : e95 -e101 , 2013 .23420816 \n20. Millon L , Herbrecht R , Grenouillet F , et al; French Mycosis Study Group . \nEarly diagnosis and monitoring of mucormycosis by detection of circulating DNA in serum: retrospective analysis of 44 cases collected through the French Surveillance Network of Invasive Fungal Infections (RESSIF) . Clin Microbiol Infect \n22 : 810.e1 -810.e8 , 2016 .26706615 \n21. Sato K , Oinuma KI , Niki M , Yamagoe S , Kakeya H \nIdentification of a novel rhizopus-specific antigen by screening with a signal sequence trap and evaluation as a possible diagnostic marker of mucormycosis . Med Mycol \n55 : 713 -719 , 2017 .28199672 \n22. Cordonnier C , Pautas C , Maury S , Vekhoff A , Farhat H , Schwarzinger M \nEmpirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial . Clin Infect Dis \n48 : 1042 -1051 , 2009 .19281327 \n23. Herbrecht R , Patterson TF , Slavin MA , Marchetti O , Maertens J , Pappas PG \nApplication of the 2008 definitions for invasive fungal diseases to the trial comparing voriconazole versus amphotericin B for therapy of invasive aspergillosis: a collaborative study of the Mycoses Study Group (MSG 05) and the European Organization for Research and Treatment of Cancer Infectious Diseases Group . Clin Infect Dis \n60 : 713 -720 , 2015 .25414266\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(17)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "acute myeloid leukemia; allogeneic hematopoietic stem cell transplantation; oral mucormycosis",
"medline_ta": "Intern Med",
"mesh_terms": "D000666:Amphotericin B; D000935:Antifungal Agents; D003131:Combined Modality Therapy; D003646:Debridement; D017809:Fatal Outcome; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009091:Mucormycosis; D012233:Rhizopus; D012307:Risk Factors; D013280:Stomatitis",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2567-2571",
"pmc": null,
"pmid": "30175728",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19281327;14985500;10072411;21077735;25328305;21788723;26706615;25414266;22425500;20219588;26524262;26971955;23420816;28011902;17589527;22247442;20002357;16080086;19597026;28199672;14576138;21622653",
"title": "Primary Oral Mucormycosis Due to Rhizopus microsporus after Allogeneic Stem Cell Transplantation.",
"title_normalized": "primary oral mucormycosis due to rhizopus microsporus after allogeneic stem cell transplantation"
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"abstract": "We present a patient with chronic postmenopausal estrogen intake with presence of Kayser-Fleischer ring in the cornea and Alzheimer's disease and discuss the pathophysiological mechanisms of estrogen intake and copper accumulation in various tissues, including the central nervous system. Sonography was compatible with copper accumulation in the basal ganglia, but the patient showed no clinical signs of Wilson's disease. Magnetic resonance imaging and positron emission tomography revealed a typical pattern for Alzheimer's disease. We propose increased copper levels as a direct effect of estrogen intake due to an augmented ATP7A-mRNA in the intestine. Moreover, we discuss the impact of elevated free serum copper on accompanying Alzheimer's disease, knowing that copper plays a crucial role in the formation of amyloid plaques and tau aggregation. This might offer a partial explanation for the observation that postmenopausal estrogen therapy is associated with a higher risk of mild cognitive impairment and Alzheimer's disease.",
"affiliations": "Department of Neurology, University Medical Center Freiburg, Germany.;Department of University Eye Hospital Freiburg, Freiburg, Germany.;Department of University Eye Hospital Freiburg, Freiburg, Germany.;Department of Neurology, University Medical Center Freiburg, Germany.;Department of Neurology, University Medical Center Freiburg, Germany.;Department of Neuroradiology, University Medical Center Freiburg, Germany.;Department of Nuclear Medicine, University Medical Center Freiburg, Germany.;Department of Neurology, University Medical Center Freiburg, Germany.",
"authors": "Amtage|Florian|F|;Birnbaum|Dzelila|D|;Reinhard|Thomas|T|;Niesen|Wolf-Dirk|WD|;Weiller|Cornelius|C|;Mader|Irina|I|;Meyer|Philipp T|PT|;Rijntjes|Michel|M|",
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"doi": "10.1159/000363688",
"fulltext": "\n==== Front\nCase Rep NeurolCase Rep NeurolCRNCase Reports in Neurology1662-680XS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000363688crn-0006-0181Published online: June, 2014Estrogen Intake and Copper Depositions: Implications for Alzheimer's Disease? Amtage Florian a*Birnbaum Dzelila dReinhard Thomas dNiesen Wolf-Dirk aWeiller Cornelius aMader Irina bMeyer Philipp T. cRijntjes Michel aaDepartment of Neurology, University Medical Center Freiburg, GermanybDepartment of Neuroradiology, University Medical Center Freiburg, GermanycDepartment of Nuclear Medicine, University Medical Center Freiburg, GermanydDepartment of University Eye Hospital Freiburg, Freiburg, Germany*Florian Amtage, MD, Department of Neurology, University Medical Center Freiburg, Breisacherstrasse 64, DE-79106 Freiburg (Germany), E-Mail florian.amtage@uniklinik-freiburg.deMay-Aug 2014 19 6 2014 19 6 2014 6 2 181 187 Copyright © 2014 by S. Karger AG, Basel2014This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.We present a patient with chronic postmenopausal estrogen intake with presence of Kayser-Fleischer ring in the cornea and Alzheimer's disease and discuss the pathophysiological mechanisms of estrogen intake and copper accumulation in various tissues, including the central nervous system. Sonography was compatible with copper accumulation in the basal ganglia, but the patient showed no clinical signs of Wilson's disease. Magnetic resonance imaging and positron emission tomography revealed a typical pattern for Alzheimer's disease. We propose increased copper levels as a direct effect of estrogen intake due to an augmented ATP7A-mRNA in the intestine. Moreover, we discuss the impact of elevated free serum copper on accompanying Alzheimer's disease, knowing that copper plays a crucial role in the formation of amyloid plaques and tau aggregation. This might offer a partial explanation for the observation that postmenopausal estrogen therapy is associated with a higher risk of mild cognitive impairment and Alzheimer's disease.\n\nKey words\n[11C]PIB PETAlzheimer's diseaseCeruloplasminCopperEstrogen\n==== Body\nIntroduction\nCopper deposition in the Descemet membrane of the cornea, known as Kayser-Fleischer ring, is a rare finding in daily practice. If present, it is usually assumed to be pathognomonic for Wilson's disease (WD; a hepatolenticular degeneration and autosomal recessive movement disorder), but a Kayser-Fleischer ring is also rarely seen in other diseases, mainly of hepatic or hematological origin, indicating an imbalance of copper homeostasis [1, 2]. Copper is virtually totally incorporated into ceruloplasmin while small amounts are bound to serum albumin. In WD, ceruloplasmin deficiency leads to copper depositions in the cornea and brain via a consecutive rise of free serum copper. Frequently, a Kayser-Fleischer ring can be detected prior to the appearance of neurological symptoms [3] and an efficient diagnosis and treatment of copper accumulation may prevent the development of the movement disorder.\n\nContraceptives with estrogenic effects are known to elevate serum copper and ceruloplasmin levels [4, 5]. The underlying pathomechanism is not fully understood, but several authors propose an increase of ceruloplasmin as a direct effect of estrogen and, consequently, a rise of total copper content in the serum [4, 5]. Whatever the mechanism, the alteration of copper homeostasis is not listed in the drug information of oral contraceptives. However, in the last years, 3 cases with corneal deposition due to chronic intake of contraceptives have been reported, showing that changes in serum copper can be of clinical importance [6, 7].\n\nCase Report\nA 68-year-old woman with a 4-year history of Alzheimer's disease (AD) was admitted to the University Eye Hospital in Freiburg, Germany, for surgery of a bilateral pterygium and cataract. Preinterventional slit-lamp examination revealed a yellow-greenish deposition in the posterior corneal stroma and the Descemet membrane at the limbus of both corneas (fig. 1a, b). Urine copper (58.5 µg/24 h), serum copper (106 µg/dl) and ceruloplasmin (38 mg/dl) levels as well as transaminases and bilirubin were within the normal ranges. Neurological examination showed a slight postural tremor of both upper limbs and the head. The tremor syndrome had been present since the patient's adolescence and, in the light of a positive family history, it was judged to be an essential tremor. Neither dystonic, atactic or bulbar symptoms nor extrapyramidal signs including rigidity were present. Thus, the diagnosis of WD could not be made. Due to progressive AD (‘probable AD’ according to NINCDS-ADRDA criteria), anomia and apraxia were present. The cognitive state of the patient was evaluated by Mini-Mental State Examination, where she reached 10 of 30 points, with 4 points for orientation (time, town, country, district), all 3 points for the registration of 3 words, 1 point for language (name a pencil) and 2 points for the 3-stage command; all speaking for a moderate to severe impairment. The patient reported a daily 2-mg postmenopausal hormone estradiol intake over the past 22 years until one year before.\n\nMagnetic resonance imaging (MRI) revealed brain atrophy of the temporal and parietal lobes (fig. 1c). Susceptibility-weighted MRI showed no copper accumulation in the basal ganglia. Neurosonography of the midbrain and basal ganglia displayed a right accentuated hyperechogenicity of both lentiform nuclei (fig. 1d). In line with the clinical diagnosis, positron emission tomography (PET) studies revealed typical features of AD (fig. 2): [18F]fluorodeoxyglucose (18FDG) PET demonstrated a pronounced bilateral temporoparietal hypometabolism, while 11C-labeled Pittsburgh Compound-B ([11C]PIB) PET showed strong binding to cortical fibrillar amyloid-β depositions in an AD-typical distribution.\n\nDiscussion\nThe enzyme ATP7B facilitates the transfer of copper into the Golgi apparatus of hepatocytes, where copper is incorporated into ceruloplasmin. In WD, a mutation of the copper-transporting gene ATP7B leads to secondary ceruloplasmin deficiency with a reduced half-life. Free serum copper accumulates in tissues like the eye (Kayser-Fleischer ring, sunflower cataract), brain (mainly basal ganglia), kidney and liver. A Kayser-Fleischer ring can be detected in approximately 60% of presymptomatic patients with WD, whereas virtually every patient with WD and neurological symptoms presents corneal copper deposition [3, 8]. Furthermore, a Kayser-Fleischer ring has been reported in other hepatic and hematological diseases [1, 2]. In the latter cases, elevated serum copper level was detected, whereas ceruloplasmin remained normal. Therefore, a relative surplus of free serum copper seems to be the common factor for tissue accumulation, rather than the absolute amount of copper or ceruloplasmin.\n\nAn increase of ceruloplasmin and serum copper due to chronic estrogen administration has been known since 1966 [4, 5]. Moreover, both serum copper and ceruloplasmin are elevated during pregnancy [9], a physiologic state of raised estrogen levels. Several authors suggest an estrogen-induced increase of ceruloplasmin and, secondary to that, a rise of the amount of total copper [4, 5]. An explanation for a missing clinical manifestation of these increased serum copper levels might be that copper is incorporated into ceruloplasmin, preventing the accumulation of free serum copper. However, the occurrence of copper depositions in the cornea due to long-lasting estrogen intake argues for a direct impact of estrogens on copper uptake, since ceruloplasmin remains normal in these cases [6, 7].\n\nHardman et al. [10] found evidence that estrogen has a direct impact on the ATP7A transporter of human placental cells, leading to a stimulation of the copper transport via an increase of ATP7A-mRNA expression. Transferring these data to enterocytes, where ATP7A plays a crucial role for the regulation of copper uptake [11], estrogen could upregulate ATP7A-mRNA, inducing an increased copper uptake via the intestine. This seems plausible, since an adequate copper supply to the embryo under physiologic conditions must be on the basis of an elevated intestinal copper uptake of the expectant mother. Therefore, we propose that the increase of ceruloplasmin after estrogen treatment is secondary to an enhanced copper uptake. However, in patients with a Kayser-Fleischer ring under estrogen therapy, this hepatic compensatory mechanism seems to be disturbed, possibly due to having a defect on the ceruloplasmin gene or being heterocygotes for WD. New findings suggest an association of an ATP7B polymorphism and sporadic AD which might be of interest in this context, since this polymorphism results in a disturbed function of the copper transporter, leading to an increased level of free serum copper [12]. Since in our case estradiol therapy was discontinued one year ago, ceruloplasmin and serum copper were at normal levels. We did not restart estradiol therapy to prove the pathomechanism because of ethical considerations mentioned below. However, in the 3 cases previously described, the causality between estrogen intake and enhanced serum copper has been described [6, 7].\n\nIn WD, copper accumulation can be diagnosed by basal ganglia sonography, showing hyperechogenicity of the lentiform nucleus [13]. In our patient, neurosonography of the basal ganglia revealed a right accentuated hyperechogenicity of both lentiform nuclei, supporting copper deposition in the basal ganglia, without presenting neurological symptoms compatible with WD. Walter et al. [13] also found this hyperechogenicity in 2 of 3 presymptomatic patients with WD. This could be explained by the time lag ranging from 7 to 37 years between copper accumulation (with secondary neurodegeneration due to oxidative stress) and overt neurological symptoms [8]. Susceptibility-weighted MRI showed no incidence of copper accumulation in the brain, but abnormal MRI findings in presymptomatic WD seem to be rare [3].\n\nThe role of copper in the pathogenesis of AD is still controversial, but there is increasing evidence that besides iron and zinc, free serum copper is involved in the aggregation of amyloid-β-forming amyloid plaques [14]. Moreover, a meta-analysis confirmed increased serum copper levels in patients with AD [15]. Copper is a redox-active metal and plays an important role as a catalyst in the production of reactive oxygen species. Furthermore, copper is assumed to build complexes with tau protein [16], the second pathologic hallmark of AD. It seems noteworthy that the copper transporter ATP7A is present in the brain. A co-release of amyloid-β and copper into the synaptic cleft increases the probability of building a redox-active amyloid-β-copper complex leading to oxidative stress, which enhances the forming of amyloid plaques. Estrogen therapy could have an impact on the expression of the ATP7A transporter in the brain as well, but this has not been demonstrated yet.\n\nAlthough a case report like ours does not necessarily provide evidence for causal relationships, it allows, nevertheless, formulating hypotheses for further investigations and research. Certainly, it cannot be proven that the occurrence of AD in the present case is due to estrogen therapy. However, it is very tempting to assume a causal role after more than 20 years of estradiol intake leading to a Kayser-Fleischer ring and presumed copper depositions in the basal ganglia and given the crucial role of copper in the pathogenesis of AD pathology. Furthermore, this hypothesis might offer a partial explanation for the observation that postmenopausal estrogen therapy is associated with a higher risk of mild cognitive impairment, which is commonly the first stage of AD [17].\n\nIn conclusion, we suggest that augmented ATP7A-mRNA in the intestine as a direct effect of estrogen therapy facilitates the absorption of copper, leading to increased serum copper levels. In some patients, hepatic function might be unable to cope with an increased copper load, resulting in corneal copper depositions and cerebral copper accumulation in the basal ganglia. Furthermore, similar to findings in WD patients, we demonstrate hyperechogenicity of both lentiform nuclei, indicating cerebral copper accumulation in the basal ganglia in our patient. Increased levels of free serum copper might have an impact on AD, since the same ATP7A transporter for copper homeostasis is present in the brain and copper plays a crucial role in oxidative stress, the formation of amyloid plaques and tau aggregation. Although we cannot provide evidence for causality in the present case, we want to stimulate further investigations on the impact of estrogen on copper homeostasis and the link between serum copper and the pathophysiology of AD, since this might have consequences for monitoring hepatic regulatory mechanisms in patients receiving estrogens.\n\nDisclosure Statement\nThe authors have no relevant financial disclosures or conflict of interests to declare.\n\nFig. 1 Ophthalmological findings: macroscopic view (a) and slit-lamp examination (b) revealed copper depositions within the Descemet membrane. c Coronary T1-weighted MRI showed temporoparietal-accentuated brain atrophy. d Sonography of the basal ganglia revealed hyperechogenicity of both lentiform nuclei, demonstrated here for the right lentiform nucleus (yellow) neighboring the right lateral ventricle (red).\n\nFig. 2 Results of 18FDG (a) and [11C]PIB (b) PET examinations. a The upper- and lower-row images show transaxial 18FDG PET images and three-dimensional surface projections (left and right lateral views, top view, right and left mesial views) of regions with decreased 18FDG uptake (color-coded as Z score), respectively. Note the marked bilateral hypometabolism of the temporoparietal region and of the posterior cingulate gyrus/precuneus. A less marked hypometabolism was also found in the bilateral frontal and mesiotemporal lobe. b Depiction of the corresponding transaxial [11C]PIB PET images that show the typical regional pattern of fibrillar amyloid-β binding in AD (strongest in the frontal cortex and posterior cingulate gyrus/precuneus, less so in the temporoparietal cortex).\n==== Refs\nReferences\n1 Aldave AJ King JA Kim BT Hopp L Corneal copper deposition associated with chronic lymphocytic leukemia Am J Ophthalmol 2006 142 174 176 16815276 \n2 Tauber J Steinert RF Pseudo-Kayser-Fleischer ring of the cornea associated with non-Wilsonian liver disease. A case report and literature review Cornea 1993 12 74 77 8458236 \n3 Taly AB Meenakshi-Sundaram S Sinha S Swamy HS Arunodaya GR Wilson disease: description of 282 patients evaluated over 3 decades Medicine (Baltimore) 2007 86 112 121 17435591 \n4 Carruthers ME Hobbs CB Warren RL Raised serum copper and caeruloplasmin levels in subjects taking oral contraceptives J Clin Pathol 1966 19 498 500 5919365 \n5 O'Leary JA Spellacy WN Serum copper alteration after ingestion of an oral contraceptive Science 1968 162 682 4879933 \n6 Garmizo G Frauens BJ Corneal copper deposition secondary to oral contraceptives Optom Vis Sci 2008 85 E802 E807 18772711 \n7 Orlin A Orlin SE Makar GA Bunya VY Presumed corneal copper deposition and oral contraceptive use Cornea 2010 29 476 478 20168218 \n8 Machado A Chien HF Deguti MM Cancado E Azevedo RS Scaff M Barbosa ER Neurological manifestations in Wilson's disease: report of 119 cases Mov Disord 2006 21 2192 2196 17078070 \n9 Louro MO Cocho JA Tutor JC Assessment of copper status in pregnancy by means of determining the specific oxidase activity of ceruloplasmin Clin Chim Acta 2001 312 123 127 11580917 \n10 Hardman B Michalczyk A Greenough M Camakaris J Mercer JF Ackland ML Hormonal regulation of the Menkes and Wilson copper-transporting ATPases in human placental Jeg-3 cells Biochem J 2007 402 241 250 17109627 \n11 van den Berghe PV Klomp LW New developments in the regulation of intestinal copper absorption Nutr Rev 2009 67 658 672 19906252 \n12 Bucossi S Mariani S Ventriglia M Polimanti R Gennarelli M Bonvicini C Pasqualetti P Scrascia F Migliore S Vernieri F Rossini PM Squitti R Association between the c. 2495 A>G ATP7B polymorphism and sporadic Alzheimer's disease Int J Alzheimers Dis 2011 2011 973692 21760992 \n13 Walter U Krolikowski K Tarnacka B Benecke R Czlonkowska A Dressler D Sonographic detection of basal ganglia lesions in asymptomatic and symptomatic Wilson disease Neurology 2005 64 1726 1732 15911799 \n14 Bucossi S Ventriglia M Panetta V Salustri C Pasqualetti P Mariani S Siotto M Rossini PM Squitti R Copper in Alzheimer's disease: a meta-analysis of serum, plasma, and cerebrospinal fluid studies J Alzheimers Dis 2011 24 175 185 21187586 \n15 Squitti R Salustri C Agents complexing copper as a therapeutic strategy for the treatment of Alzheimer's disease Curr Alzheimer Res 2009 6 476 487 19747159 \n16 Ma QF Li YM Du JT Kanazawa K Nemoto T Nakanishi H Zhao YF Binding of copper (II) ion to an Alzheimer's tau peptide as revealed by MALDI-TOF MS, CD, and NMR Biopolymers 2005 79 74 85 15986501 \n17 Shumaker SA Legault C Kuller L Rapp SR Thal L Lane DS Fillit H Stefanick ML Hendrix SL Lewis CE Masaki K Coker LH Women's Health Initiative Memory Study: Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study JAMA 2004 291 2947 2958 15213206\n\n",
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"medline_ta": "Case Rep Neurol",
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"title": "Estrogen intake and copper depositions: implications for Alzheimer's disease?",
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"abstract": "Rituximab, a chimeric anti-CD20 monoclonal antibody, is an effective treatment in steroid-dependent nephrotic syndrome (SDNS). However, some patients develop adverse reactions.\n\n\n\nPatient 1, a 14-year-old boy with SDNS since the age of 2, was treated with oral prednisone, cyclosporine A (CsA) and mycophenolate mofetil. A first infusion of rituximab at age 12 years was well tolerated, but this was followed by a prolonged relapse unresponsive to oral prednisone, mycophenolate mofetil and CsA. A second rituximab infusion was attempted, but treatment was interrupted due to severe dyspnea. Treatment with a humanized anti-CD20 monoclonal antibody, ofatumumab, was then attempted. The patient experienced a mild allergic reaction and maintained remission despite interruption of all treatment at >12 months of follow-up. Patient 2, a 3-year-old boy who presented at 18 months with nephrotic syndrome initially resistant to treatment with oral prednisone, was given with three intravenous boluses of methylprednisolone followed by CsA and achieved remission. Upon steroid discontinuation, the NS relapsed. Prednisone was restarted and treatment with a single dose of rituximab was never completed due to a severe allergic reaction. Ofatumumab infusion was uneventful, and he maintained remission during the follow-up period (>12 months) despite interruption of prednisone therapy. B cells reappeared at 7 months in both patients.\n\n\n\nOfatumumab may be a therapeutic option in severe forms of NS with allergy to rituximab.",
"affiliations": "Division of Nephrology and Dialysis, IRCCS-Bambino Gesù Children's Hospital, Rome, Italy. marina.vivarelli@opbg.net.;Division of Nephrology and Dialysis, IRCCS-Bambino Gesù Children's Hospital, Rome, Italy.;Division of Nephrology, Dialysis, and Transplantation, IRCCS-Istituto Giannina Gaslini, Genoa, Italy.;Division of Nephrology and Dialysis, IRCCS-Bambino Gesù Children's Hospital, Rome, Italy.;Division of Nephrology and Dialysis, IRCCS-Bambino Gesù Children's Hospital, Rome, Italy.;Division of Nephrology and Dialysis, IRCCS-Bambino Gesù Children's Hospital, Rome, Italy.;Division of Nephrology, Dialysis, and Transplantation, IRCCS-Istituto Giannina Gaslini, Genoa, Italy.",
"authors": "Vivarelli|Marina|M|;Colucci|Manuela|M|;Bonanni|Alice|A|;Verzani|Martina|M|;Serafinelli|Jessica|J|;Emma|Francesco|F|;Ghiggeri|Gianmarco|G|",
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"keywords": "Adverse reaction; Children; Ofatumumab; Rituximab; Steroid-dependent nephrotic syndrome; Steroid-resistant nephrotic syndrome",
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"mesh_terms": "D000293:Adolescent; D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001402:B-Lymphocytes; D002675:Child, Preschool; D016572:Cyclosporine; D004342:Drug Hypersensitivity; D004351:Drug Resistance; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008775:Methylprednisolone; D009173:Mycophenolic Acid; D009404:Nephrotic Syndrome; D011241:Prednisone; D000069283:Rituximab; D016896:Treatment Outcome",
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"title": "Ofatumumab in two pediatric nephrotic syndrome patients allergic to rituximab.",
"title_normalized": "ofatumumab in two pediatric nephrotic syndrome patients allergic to rituximab"
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"abstract": "BACKGROUND\nPrimary hypoparathyroidism is a rare condition caused by parathyroid hormone deficiency and characterized by hypocalcemia. The clinical manifestations of primary hypoparathyroidism include tetany, seizures, paresthesias, dementia, and parkinsonism. Psychiatric manifestations such as mood disorders are unusual and may constitute a major diagnostic challenge, especially if the typical manifestations caused by hypocalcemia are absent.\n\n\nMETHODS\nThe patient was a 22-year-old Caucasian man with a history of chronic omeprazole use and periodic seizures, who presented to the emergency department of a secondary hospital in Southern Brazil with symptoms of major depression (sadness, anhedonia, loss of appetite, insomnia, and fatigue) associated with paresthesias affecting his toes. The initial electrocardiogram revealed a prolonged QTc interval. A computed tomography scan of his brain revealed bilateral, nonenhancing hyperdense calcifications involving the putamen and caudate nucleus. An electroencephalogram showed generalized bursts of slow spikes. Blood laboratory study results indicated serum hypocalcemia, hypomagnesemia, and hyperphosphatemia associated with a low parathyroid hormone level. His serum levels of albumin, 25-hydroxyvitamin D, thyroid-stimulating hormone, T3 and T4 thyroid hormones, as well as the results of kidney function tests, were normal. The definitive diagnosis was primary hypoparathyroidism with psychiatric manifestations due to chronic hypomagnesemia induced by proton pump inhibitor use.\n\n\nCONCLUSIONS\nIn some cases, to differentiate between a primary psychiatric disorder and primary hypoparathyroidism with neuropsychiatric symptoms may represent a challenge given that the classical manifestations of hypocalcemia, especially tetany, may be absent in the setting of chronic hypoparathyroidism. Clinicians and psychiatrists should consider primary hypoparathyroidism part of the differential diagnosis during the evaluation of patients with mood symptoms, especially in the context of atypical presentations associated with hypocalcemia.",
"affiliations": "Internal Medicine Division, Hospital Municipal Getúlio Vargas, Pinheiro Machado 331, Sapucaia do Sul, RS 93210-180, Brazil. regisgoulartrosa@gmail.com.",
"authors": "Rosa|Regis G|RG|;Barros|Alcina J S|AJ|;de Lima|Antonio R B|AR|;Lorenzi|William|W|;Da Rosa|Rafael R|RR|;Zambonato|Karine D|KD|;Alves|Gustavo V|GV|",
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"doi": "10.1186/1752-1947-8-326",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-3262528046810.1186/1752-1947-8-326Case ReportMood disorder as a manifestation of primary hypoparathyroidism: a case report Rosa Regis G 1regisgoulartrosa@gmail.comBarros Alcina JS 1alcina.forense@gmail.comde Lima Antonio RB 1antonioramireslima@yahoo.com.brLorenzi William 1williamlorenzi@gmail.comDa Rosa Rafael R 1rafa.ramon1@gmail.comZambonato Karine D 1karinezambonato@gmail.comAlves Gustavo V 1gustavovalves@gmail.com1 Internal Medicine Division, Hospital Municipal Getúlio Vargas, Pinheiro Machado 331, Sapucaia do Sul, RS 93210-180, Brazil2014 3 10 2014 8 326 326 28 2 2014 28 7 2014 Copyright © 2014 Rosa et al.; licensee BioMed Central Ltd.2014Rosa et al.; licensee BioMed Central Ltd.This 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 credited. 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.Introduction\nPrimary hypoparathyroidism is a rare condition caused by parathyroid hormone deficiency and characterized by hypocalcemia. The clinical manifestations of primary hypoparathyroidism include tetany, seizures, paresthesias, dementia, and parkinsonism. Psychiatric manifestations such as mood disorders are unusual and may constitute a major diagnostic challenge, especially if the typical manifestations caused by hypocalcemia are absent.\n\nCase presentation\nThe patient was a 22-year-old Caucasian man with a history of chronic omeprazole use and periodic seizures, who presented to the emergency department of a secondary hospital in Southern Brazil with symptoms of major depression (sadness, anhedonia, loss of appetite, insomnia, and fatigue) associated with paresthesias affecting his toes. The initial electrocardiogram revealed a prolonged QTc interval. A computed tomography scan of his brain revealed bilateral, nonenhancing hyperdense calcifications involving the putamen and caudate nucleus. An electroencephalogram showed generalized bursts of slow spikes. Blood laboratory study results indicated serum hypocalcemia, hypomagnesemia, and hyperphosphatemia associated with a low parathyroid hormone level. His serum levels of albumin, 25-hydroxyvitamin D, thyroid-stimulating hormone, T3 and T4 thyroid hormones, as well as the results of kidney function tests, were normal. The definitive diagnosis was primary hypoparathyroidism with psychiatric manifestations due to chronic hypomagnesemia induced by proton pump inhibitor use.\n\nConclusions\nIn some cases, to differentiate between a primary psychiatric disorder and primary hypoparathyroidism with neuropsychiatric symptoms may represent a challenge given that the classical manifestations of hypocalcemia, especially tetany, may be absent in the setting of chronic hypoparathyroidism. Clinicians and psychiatrists should consider primary hypoparathyroidism part of the differential diagnosis during the evaluation of patients with mood symptoms, especially in the context of atypical presentations associated with hypocalcemia.\n\nCalcium homeostasisDepressionHypoparathyroidismMental disordersMood disorder\n==== Body\nIntroduction\nParathyroid hormone (PTH) plays an important role in the metabolism of calcium and phosphate. In response to a decrease in the serum calcium level, parathyroid cells increase PTH secretion physiologically. Through direct action on the kidney and bone cells, and indirect effects on the bowels, PTH increases serum calcium levels and decreases serum phosphate levels. In addition, PTH promotes bone resorption, decreases urinary calcium excretion, enhances the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, and increases intestinal calcium absorption, and renal phosphate excretion [1-3].\n\nPrimary hypoparathyroidism is characterized by the absence or decreased secretion of PTH. As a consequence, patients with primary hypoparathyroidism often present clinical manifestations related to hypocalcemia such as tetany, seizures, muscle cramps, paresthesias (affecting the fingertips, toes, and perioral area), and carpopedal spasms. In cases of chronic hypocalcemia, symptoms become less specific, ranging from asymptomatic states to atypical clinical presentations, such as neuropsychiatric manifestations. In this sense, mood disorders, such as depression have been reported rarely as the main manifestation of hypoparathyroidism. The typical laboratory findings of primary hypoparathyroidism include hypocalcemia and hyperphosphatemia in the presence of undetectable or abnormally low levels of PTH. Skull radiographs or computed tomography scans of the brain may reveal symmetrical bilateral basal ganglia calcification. The typical electroencephalogram pattern includes bursts of high-voltage paroxysmal slow waves. Electrocardiography may reveal a prolonged QTc interval and T wave abnormalities owing to hypocalcemia [4-6].\n\nThe etiology of primary hypoparathyroidism includes surgical destruction of parathyroid glands (the most common cause), neck irradiation, autoimmune hypoparathyroidism (isolated or combined with other endocrine deficiencies, for example, polyglandular autoimmunity), idiopathic hypoparathyroidism, hypomagnesemia, Wilson’s disease, hemochromatosis, and congenital syndromes (for example, DiGeorge syndrome) [7,8].\n\nHere we describe an unusual case of primary hypoparathyroidism with an atypical predominant manifestation of major depression secondary to hypomagnesemia induced by chronic proton pump inhibitor use. Following the case presentation, we provide a brief discussion and review of previously published data regarding psychiatric manifestations of primary hypoparathyroidism.\n\nCase presentation\nA 22-year-old Caucasian man with a history of periodic generalized tonic–clonic seizures was admitted to a secondary hospital because of symptoms of major depression. He experienced depressed mood, decreased interest in most activities, loss of appetite (with 10% weight change), insomnia, fatigue, loss of concentration, and thoughts of death (without suicidal ideation) in the previous 3 months. In addition, he complained of paresthesias involving his toes. He had no history of substance abuse and presented no symptoms of mania. He had been undergoing treatment with valproic acid 600mg/day orally for the last 2 years (for seizures treatment) and omeprazole 40mg/day orally during the last 5 years (for dyspepsia treatment). His physical examination was normal. No sensory or motor deficit was found objectively, and Chvostek and Trousseau signs were absent. The psychiatric evaluation was compatible with major depressive symptoms according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) [9]. A routine computed tomography scan of his brain revealed bilateral nonenhancing hyperdense calcifications involving the putamen and caudate nucleus in a symmetrical pattern (Figure 1). The electroencephalogram showed bursts of high-voltage paroxysmal slow waves. The electrocardiography demonstrated a prolonged QTc interval without other abnormalities (Figure 2). He had a low total calcium level (5.4mg/dL; normal range 8.8mg/dL to 11.0mg/dL), low ionic calcium level (0.73mg/dL; normal range 1.0mg/dL to 1.3mg/dL), elevated serum phosphate level (6.3mg/dL; normal range 2.5mg/dL to 4.8mg/dL), low intact PTH level (8.3pg/mL; normal range 12.0pg/mL to 88.0pg/mL), and low magnesium level (0.7mg/dL; normal range 1.9mg/dL to 2.5mg/dL). His serum levels of albumin, 25-hydroxyvitamin D, thyroid-stimulating hormone, T3 and T4 thyroid hormones, creatinine, and blood urea nitrogen were normal. His 24-hour urine excretion of magnesium was low (62mg; normal range 75mg to 150mg). His fractional magnesium clearance was 0.8%, suggesting that his renal retention of magnesium was appropriate. A definitive diagnosis was made of primary hypoparathyroidism due to hypomagnesemia with major depressive symptoms as the predominant clinical manifestation. The probable etiology of the hypomagnesemia was the chronic pump proton inhibitor use, given that other causes of chronic hypomagnesemia were absent (that is, malabsorption, alcoholism, diuretic therapy, and tubulointerstitial kidney diseases). Omeprazole was discontinued promptly given that the upper gastrointestinal endoscopy was normal. He received oral treatment with calcium carbonate 3g/day, calcitriol 0.50mcg/day, magnesium pidolate 366mg/day, and sertraline 50mg/day. Of interest, during his hospitalization period of 41 days, his symptoms of major depression began to improve only after correction of total serum calcium levels. He was discharged with normal total calcium (9.5mg/dL) and magnesium levels (2.0mg/dL). His clinical and laboratory improvement was sustained as verified by a routine out-patient medical visit 2 months after hospital discharge.\n\nFigure 1 Computed tomography scan of the brain.\n\nFigure 2 Electrocardiogram. Note: Normal QTc interval in men is <430ms.\n\nDiscussion\nThe present report describes a case of primary hypoparathyroidism as the unusual etiology of major depressive symptoms. The chronic course of the disease probably contributed to its atypical presentation, which consisted of depressive mood symptoms predominantly. Because of the high prevalence of depressive syndromes, this case alerts us to the need of investigating clinical causes intensively before diagnosing a patient with a primary mental disorder. Furthermore, a delay in the identification of the underlying cause could represent serious consequences for the patient, culminating in behavioral manifestations and increased risk of death.\n\nThe DSM-IV-TR [9] criteria state that a mood disorder can be a result of a medical condition, exemplified by Parkinson’s disease and hypothyroidism. The DSM-IV-TR also states that “the criteria for the diagnosis are similar to those for major depressive episode or a manic episode; however, the full criteria for these diagnoses need not be met. It is important to establish if the depressive symptoms are a direct physiological result of the medical condition, instead of a psychological response to a medical problem”.\n\nThe relationship between hypoparathyroidism and psychiatric syndromes is supported by previous studies. A study by Aggarwal et al. [10] demonstrated an association between idiopathic hypoparathyroidism and neuropsychological dysfunction, which was correlated with the duration of illness, female sex, serum calcium, and calcium-phosphorus product during follow-up but not with intracranial calcifications. These results alert us to the fact that patients with hypoparathyroidism may have psychiatric manifestations even in the absence of brain calcifications. Moreover, distinct psychiatric manifestations, such as depression, psychosis, and anxiety in the context of hypoparathyroidism, have also been reported [11-16] (Table 1). Among all of these reported cases, psychiatric manifestations seemed predominant in settings of long-term hypoparathyroidism. Of interest, a clinical history of seizures was common among most reported cases, which may represent an important clue to the suspicion of hypocalcemia and hypoparathyroidism. In addition, psychiatric symptoms were characteristically resistant to conventional psychopharmacological treatment (for example, antidepressants and antipsychotics) until the serum calcium levels were corrected. These findings underscore the importance of establishing the primary cause of major depressive symptoms, given that the proper treatment of the baseline medical condition may be essential for the control of the psychiatric symptoms.\n\nTable 1 Published cases of primary hypoparathyroidism with predominant psychiatric manifestations\n\nAuthor [reference], year\tPatient age, years\tSex\tPsychiatric manifestation\tEtiology of hypoparathyroidism\t\nAng et al. [11], 1995\t15\tFemale\tPsychosis\tIdiopathic\t\nIlievski et al. [12], 2002\t26\tFemale\tParanoid schizophrenia\tIdiopathic\t\nBohrer and Krannich [13], 2007\t68\tMale\tMajor depression\tSurgical destruction of parathyroids\t\nPatil et al. [14], 2010\t30\tFemale\tPsychosis\tIdiopathic\t\nBertola et al. [15], 2013\t51\tFemale\tChronic psychosis\tDiGeorge syndrome\t\nMirhosseini et al. [16], 2013\t28\tFemale\tPanic attacks\tSurgical destruction of parathyroids\t\nPresent study\t22\tMale\tMajor depression\tHypomagnesemia\t\nConclusions\nPatients with chronic hypocalcemia secondary to primary hypoparathyroidism may present clinically with predominant psychiatric symptoms. Primary hypoparathyroidism should be considered part of the differential diagnosis of patients with psychiatric syndromes such as depression, anxiety, or psychosis, especially when the clinical presentation is atypical and associated with abnormalities of calcium metabolism. Routine serum calcium measurement may represent an important tool for the identification of such cases.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nDSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision; PTH: Parathyroid hormone.\n\nCompeting interests\nThe authors have no financial disclosures or conflicts of interest to declare.\n\nAuthors’ contributions\nRGR, AJSB, ARBL, WL, RRR, KDZ and GVA arrived at the diagnosis of the patient and management, literature review, and writing of the final manuscript. All authors read and approved the final manuscript.\n\nAuthors’ information\nRGR and GVA are internal medicine physicians; AJSB is a psychiatrist; ARBL and WL are surgeons; RRR and KDZ are emergency physicians.\n\nAcknowledgements\nThe authors did not receive any funding for this work.\n==== Refs\nPeacock M Calcium metabolism in health and disease Clin J Am Soc Nephrol 2010 5 S23 S30 Doi: 10.2215/CJN.05910809 10.2215/CJN.05910809 20089499 \nAhn JE Jeon S Lee J Han S Yim DS Modeling of the parathyroid hormone response after calcium intake in healthy subjects Korean J Physiol Pharmacol 2014 18 217 223 doi:10.4196/kjpp.2014.18.3.217 10.4196/kjpp.2014.18.3.217 24976761 \nTejwani V Qian Q Calcium regulation and bone mineral metabolism in elderly patients with chronic kidney disease Nutrients 2013 5 6 1913 1936 doi:10.3390/nu5061913 10.3390/nu5061913 23760058 \nDe Sanctis V Soliman A Fiscina B Hypoparathyroidism: from diagnosis to treatment Curr Opin Endocrinol Diabetes Obes 2012 19 6 435 442 doi:10.1097/MED.0b013e3283591502 10.1097/MED.0b013e3283591502 23128574 \nAl-Azem H Khan AA Hypoparathyroidism Best Pract Res Endocrinol Metab 2012 26 4 517 522 doi:10.1016/j.beem.2012.01.004 10.1016/j.beem.2012.01.004 \nShoback D Clinical practice. Hypoparathyroidism N Engl J Med 2008 359 4 391 403 doi:10.1056/NEJMcp0803050 10.1056/NEJMcp0803050 18650515 \nMaeda SS Fortes EM Oliveira UM Borba VC Lazaretti-Castro M Hypoparathyroidism and pseudohypoparathyroidism Arq Bras Endocrinol Metabol 2006 50 4 664 673 10.1590/S0004-27302006000400012 17117292 \nAl-Azem H Khan A Hypoparathyroidism Best Pract Res Clin Endocrinol Metab 2012 26 4 517 522 doi:10.1016/j.beem.2012.01.004 10.1016/j.beem.2012.01.004 22863393 \nAmerican Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev) doi:10.1176/appi.books.9780890423349 \nAggarwal S Kailash S Sagar R Tripathi M Sreenivas V Sharma R Gupta N Goswami R Neuropsychological dysfunction in idiopathic hypoparathyroidism and its relationship with intracranial calcification and serum total calcium Eur J Endocrinol 2013 168 6 895 903 doi:10.1530/EJE-12-0946 10.1530/EJE-12-0946 23482593 \nAng AW Ko SM Tan CH Calcium, magnesium, and psychotic symptoms in a girl with idiopathic hypoparathyroidism Psychosom Med 1995 57 3 299 302 10.1097/00006842-199505000-00013 7652132 \nIlievski B Rodzevski K Gibbon M Dwork A Fahr’s disease and schizophrenia in a patient with secondary hypoparathyroidism J Neuropsychiatry Clin Neurosci 2002 14 3 357 358 10.1176/appi.neuropsych.14.3.357 12154165 \nBohrer T Krannich JH Depression as a manifestation of latent chronic hypoparathyroidism World J Biol Psychiatry 2007 8 1 56 59 10.1080/15622970600995146 17366354 \nPatil NJ Yadav SS Gokhale YA Padwa N Primary hypoparathyroidism: psychosis in postpartum period J Assoc Physicians India 2010 58 506 508 21189701 \nBertola G Giambona S Bianchi R Girola A Berra SA Di George syndrome: not always a pediatric diagnosis Recenti Prog Med 2013 104 2 69 doi:10.1701/1241.13707 23535960 \nMirhosseini SMM Bidaki R Ostadebrahimi H Eslamian Z Panic attacks due to total thyroidectomy: a case report World J MedMed Sci 2013 1 6 108 111\n\n",
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"mesh_terms": "D002908:Chronic Disease; D003865:Depressive Disorder, Major; D006801:Humans; D007011:Hypoparathyroidism; D008297:Male; D055815:Young Adult",
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"title": "Mood disorder as a manifestation of primary hypoparathyroidism: a case report.",
"title_normalized": "mood disorder as a manifestation of primary hypoparathyroidism a case report"
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"abstract": "A 54-year-old woman was seen by her primary care internist for a general health maintenance visit. Her major chronic illness was immune thrombocytopenic purpura (ITP) for which she had been treated with prednisone therapy for the past 15 years. Recent review of possible aetiologies of her chronic thrombocytopenia revealed infection with Helicobacter pylori. Successful eradication resulted in complete resolution of her thrombocytopenia within 2 months. She was weaned from steroid therapy and at 1-year follow-up, her platelet counts remained in the normal range. This case report summarises what is known about the association of H. pylori infection and ITP.",
"affiliations": "Mayo Medical School, Rochester, Minnesota, USA.;The Division of Primary Care Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.",
"authors": "Hill|Larisa J N|LJ|;Tung|Ericka E|EE|",
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"title": "From prednisone to pylori: a case of Helicobacter pylori-induced chronic immune thrombocytopenia.",
"title_normalized": "from prednisone to pylori a case of helicobacter pylori induced chronic immune thrombocytopenia"
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"abstract": "A 66-year-old man was referred to our hospital for an incidentally detected 40-mm mass located at the inter-aortocaval area around the renal hilum. Positron emission tomography CT revealed high accumulation (SUVmax 12.382) without distant metastasis. Bilateral testes were normal by ultrasonography and physical examination, but the serum AFP level was increased to 1161 ng/mL. The pathology based on trans-duodenal needle biopsy demonstrated a yolk sac tumor; therefore, we diagnosed him with retroperitoneal primary germ cell tumor. Due to old age, the potential toxicity of systemic chemotherapy, and no significant signs of invasion to adjacent organs, we performed surgical resection. Although the AFP level decreased to 13.2 ng/mL postoperatively, it increased to 553 ng/mL 2 months after surgery without clinical recurrence on imaging studies. Four cycles of a VIP regimen (VP-16, ifosfamide, and CDDP) were performed, and the AFP level normalized to 2.4 ng/mL. The patient is now disease-free 1 year and 6 months after surgery.",
"affiliations": "1Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.;1Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.;1Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.;1Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.;1Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.;2Department of Surgical Pathology, Hokkaido University Hospital, Hokkaido, Japan.;1Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.",
"authors": "Furumido|Jun|J|;Osawa|Takahiro|T|;Kikuchi|Hiroshi|H|;Matsumoto|Ryuji|R|;Abe|Takashige|T|;Takakuwa|Emi|E|;Shinohara|Nobuo|N|",
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"issue": "9(1)",
"journal": "International cancer conference journal",
"keywords": "Mortality; Radical cystectomy",
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"title": "Retroperitoneal extragonadal germ cell tumor without distant metastasis: a case report.",
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"abstract": "Immunotherapy of cancer with checkpoint inhibitors has been associated with a spectrum of autoimmune and systemic inflammatory reactions known as immune-related adverse events (irAEs). Rheumatic irAEs are infrequently reported and extensively described. Here, we report our experience over an 18-month period with 15 patients evaluated in the rheumatology department for rheumatic irAEs. We identified 13 patients without pre-existing autoimmune disease (AID) who subsequently developed rheumatic irAEs, and two with established AID referred pre-emptively. irAEs encountered included: inflammatory arthritis, sicca syndrome, polymyalgia rheumatica-like symptoms and myositis. All cases required glucocorticoids, and three required a biological agent. Rheumatic irAEs led to temporary or permanent cessation of immunotherapy in all but five patients. One patient with pre-existing AID experienced a flare after starting immunotherapy. Our findings underscore that rheumatic irAEs are complex, at times require additional immunosuppressive therapy, and may influence ongoing immunotherapy regimens for the primary disease. Similar irAEs will be increasingly seen as checkpoint inhibitors adopted as standard of care in the community.",
"affiliations": "Cleveland Clinic Foundation, Cleveland, Ohio, USA; Departmentof Rheumatology and Immunology, Cleveland Clinic, Cleveland, Ohio, USA.;Cleveland Clinic Foundation, Cleveland, Ohio, USA; Departmentof Rheumatology and Immunology, Cleveland Clinic, Cleveland, Ohio, USA.;Cleveland Clinic Foundation, Cleveland, Ohio, USA; Departmentof Rheumatology and Immunology, Cleveland Clinic, Cleveland, Ohio, USA.;Cleveland Clinic Foundation, Cleveland, Ohio, USA; Department of Hematology and Oncology, Cleveland Clinic, Cleveland, Ohio, USA.;Cleveland Clinic Foundation, Cleveland, Ohio, USA; Departmentof Rheumatology and Immunology, Cleveland Clinic, Cleveland, Ohio, USA.",
"authors": "Calabrese|C|C|;Kirchner|E|E|;Kontzias|A|A|;Velcheti|V|V|;Calabrese|L H|LH|",
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"fulltext": "\n==== Front\nRMD OpenRMD OpenrmdopenrmdopenRMD Open2056-5933BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR 28405474rmdopen-2016-00041210.1136/rmdopen-2016-000412Autoimmunity1506Clinical caseRheumatic immune-related adverse events of checkpoint therapy for cancer: case series of a new nosological entity Calabrese C 12Kirchner E 12Kontzias K 12Velcheti V 13Calabrese L H 12\n1 Cleveland Clinic Foundation, Cleveland, Ohio, USA\n2 Department\nof Rheumatology and Immunology, Cleveland Clinic, Cleveland, Ohio, USA\n3 Department of Hematology and Oncology, Cleveland Clinic, Cleveland, Ohio, USACorrespondence to Dr Leonard H Calabrese; calabrl@ccf.org2017 20 3 2017 3 1 e00041221 11 2016 19 1 2017 5 2 2017 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/2017This 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/Immunotherapy of cancer with checkpoint inhibitors has been associated with a spectrum of autoimmune and systemic inflammatory reactions known as immune-related adverse events (irAEs). Rheumatic irAEs are infrequently reported and extensively described. Here, we report our experience over an 18-month period with 15 patients evaluated in the rheumatology department for rheumatic irAEs. We identified 13 patients without pre-existing autoimmune disease (AID) who subsequently developed rheumatic irAEs, and two with established AID referred pre-emptively. irAEs encountered included: inflammatory arthritis, sicca syndrome, polymyalgia rheumatica-like symptoms and myositis. All cases required glucocorticoids, and three required a biological agent. Rheumatic irAEs led to temporary or permanent cessation of immunotherapy in all but five patients. One patient with pre-existing AID experienced a flare after starting immunotherapy. Our findings underscore that rheumatic irAEs are complex, at times require additional immunosuppressive therapy, and may influence ongoing immunotherapy regimens for the primary disease. Similar irAEs will be increasingly seen as checkpoint inhibitors adopted as standard of care in the community.\n\nAutoimmune DiseasesInflammationMultidisciplinary team-care\n==== Body\nIntroduction\nThe introduction of biological agents targeting immunological checkpoints represents a major advance in the field of oncology. At the present time, there are four Food and Drug Administration (FDA)-approved drugs: ipilimumab, targeting cytotoxic T-lymphocyte-associated protein (CTLA-4), nivolumab and pembrolizumab, targeting programmed cell death protein 1 (PD-1), and atezolizumab which targets programmed cell death ligand 1 (PD-L1). These medications have produced significant survival benefits in patients with metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma and urothelial carcinoma and are in investigation for many others. Many other targets for checkpoint therapy are now in clinical trials.1\n\nCheckpoint inhibitors exploit suppressor and regulatory pathways, thereby boosting integrated immunity against tumours. Unfortunately, these new therapies are attended by a unique spectrum of immune-related adverse events (irAEs) related to overactivation of the immune system with resultant autoimmune disease (AID). The most commonly affected systems are the dermatological, gastrointestinal and endocrine. Reports of rheumatic irAEs have been sparse, not systematically reported, and have only been described in case reports or small series. These adverse events have recently been described in what was the largest case series to date.2 Most clinical trials for immunotherapy agents do not report on the rheumatic manifestations and have excluded patients with pre-existing AID.3\n\nAt our institution, we created a multidisciplinary referral process to evaluate and manage irAEs. In this article, we report a series of patients evaluated at the Cleveland Clinic Foundation from 2015 to 2016 with rheumatic irAEs as a result of immunotherapy, as well as patients with pre-existing rheumatic AID who were evaluated pre-emptively.\n\nMethods\nIn February 2016, an interdisciplinary group was created at the Cleveland Clinic Foundation to manage irAEs occurring in patients on approved and experimental immune-based therapies for cancer. Patients were identified by the treating oncologist and then triaged by a designated advanced practitioner and seen in a facilitated fashion. Two designated rheumatologists saw all patients referred to the rheumatology arm of the multidisciplinary clinic. Two types of referrals were made: (1) patients without pre-existing AID who developed a rheumatic irAE after start of immunotherapy and (2) patients with pre-existing AID referred for pre-emptive evaluation. Patients were determined to have no pre-existing AID based on no prior diagnosis in their medical record, as well as through history taking during clinic visits with the treating rheumatologist. All patients were over the age of 18 and receiving or scheduled to receive ipilimumab, nivolumab, tremelimumab (anti-CTLA-4), durvalumab (anti-PD-L1) or atezolizumab either as monotherapy or in combinations. Patients were classified as having sicca syndrome, polymyalgia rheumatica (PMR)-like symptoms, inflammatory arthritis or myositis based on history, examination, imaging and laboratory findings as determined by the treating rheumatologist.\n\nAll patients were included in a database of information culled from the electronic medical record including: gender, date of birth, age at diagnosis of malignancy, type and stage of malignancy, prior treatment (chemotherapy, radiation, surgery), checkpoint inhibitor (drug(s), date started, date of last dose), pre-existing autoimmune history, nosology of irAE (type, date of onset, diagnostic testing), irAE treatment and global response to treatment, and prior autoimmune serology. Response was clinically defined as significant on near-complete resolution of rheumatic irAE symptoms, moderate on improvement to the point that symptoms were tolerable but still present and minimal if symptoms remained severe despite treatment.\n\nResults\nDemographics\nRheumatic irAEs were evaluated in 15 patients between February 2015 and September 2016. Thirteen patients without pre-existing rheumatic AID were referred to our rheumatology department for evaluation after onset of irAE. Two patients with established AID (one rheumatoid arthritis, one psoriatic arthritis) were evaluated pre-emptively prior to starting immunotherapy. In the entire group, the median age was 63 years and 67% were male. The most common malignancy was melanoma (seven), followed by non-small cell lung cancer (four) and renal cell carcinoma (four) (table 1). All had been previously treated with surgery, chemotherapy, radiation or a combination of two or all three treatments. Seven patients received combination therapy with ipilimumab and nivolumab, one patient received tremelimumab followed by durvalumab, one received ipilimumab followed by pembrolizumab, and the remaining six received monotherapy with either nivolumab (five) or atezolizumab (one). Patients were receiving immunotherapy as standard of care and as participants in clinical trials.\n\nTable 1 Demographic features, cancer types, immunotherapy and rheumatic immune-related adverse events (irAEs)\n\nPatient\tAge\tSex\tMalignancy\tImmunotherapy\tirAE\tSerology\tTime to onset (weeks)\tTreatment\tImprovement\tImmunotherapy held for irAE\t\n1\t74\tF\tNSCL\tNivolumab\tArthritis\tANA 1:160\nAnti-dsDNA 77\t7.3\tPrednisone 40 mg\tSignificant\tY\t\n2\t49\tF\tMelanoma\tIpilimumab\nPembrolizumab\tArthritis\t\t52.7\tPrednisone 20 mg\nHCQ\tModerate\tY\t\n3\t42\tF\tRCC\tIpilimumab/nivolumab\tArthritis\t\t3\tPrednisone\nInfliximab, MTX\nEtanercept\tModerate\tN\t\n4\t57\tM\tRCC\tIpilimumab/nivolumab\tArthritis\tRF 214\t48.4\tPrednisone\nMTX\nEtanercept\nAdalimumab\tSignificant\tN\t\n5\t59\tF\tMelanoma\tIpilimumab/nivolumab\tArthritis\t\t21.7\tPrednisone 60 mg\tMinimal\tN\t\n6\t81\tM\tMelanoma\tIpilimumab/nivolumab\tArthritis\tANA 1.5\t13.1\tPrednisone 15 mg\tModerate\tY\t\n7\t57\tF\tMelanoma\tIpilimumab/nivolumab\tArthritis\nSicca\tANA 1:320\t6.7\tPrednisone 30 mg\tSignificant\tY\t\n8\t61\tM\tMelanoma\tIpilimumab/nivolumab\tSicca\t\t5.3\tPrednisone 60 mg*\tSignificant\tY†\t\n9\t63\tM\tRCC\tAtezolizumab\tSicca\t\t21.9\tPrednisone 60 mg*\tSignificant\tY†\t\n10\t68\tM\tMelanoma\tIpilimumab/nivolumab\tSicca\nPMR\tANA 1:1280\nSSA\t8.1\tPrednisone 30 mg\tSignificant\tY\t\n11\t79\tM\tMelanoma\tNivolumab\tPMR\nSicca\t\t2\tPrednisone 20 mg\tModerate\tY\t\n12\t63\tM\tRCC\tNivolumab\tPMR\t\t213\tPrednisone 40 mg\nInfliximab\tMinimal\tY\t\n13\t68\tM\tNSCL\tTremelimumab\nDurvalumab\tMyositis\t\t4.6\tIV methylpred\nPrednisone 60 mg\tModerate\tY\t\n*Prednisone given for hypophysitis.\n\n†Immunotherapy held for hypophysitis.\n\nAtezolizumab, anti-PD-L1; durvalumab, anti-PD-L1; HCQ, hydroxychloroquine; MTX, methotrexate; NSCL, non-small cell lung cancer; PMR, polymyalgia rheumatica; RCC, renal cell carcinoma; RF, rheumatoid factor; tremelimumab, anti-CTLA-4.\n\nNo pre-existing autoimmune disease\nIn the group without AID (n=13) the median age was 63 years with median age at diagnosis of malignancy of 58 years. Rheumatic irAEs included seven patients with inflammatory arthritis, three with PMR-like syndrome, five with sicca syndrome and one with myositis. The majority of patients had more than one irAE (table 2) with patient 10 experiencing irAEs involving five different systems. Patients with arthritis exhibited different clinical phenotypes with the majority having a combination of small and large joint involvement (table 3). Regarding the patients with a PMR-like phenotype, all three had clinical features consistent with PMR including pain and stiffness involving the shoulders, hips/lower extremities and neck with associated severe morning stiffness. Two of the three had elevated inflammatory markers, and the third had normal inflammatory markers but levels had not been checked prior to initiation of prednisone to treat these symptoms. None had symptoms concerning for giant cell arteritis. Four of the five patients with sicca syndrome were xerostomic without keratoconjunctivitis. ANA was positive in two of the five, and SSA was positive in one (table 1). One sicca patient had a Schirmer's test performed, which was negative, and none underwent minor salivary gland biopsy. The myositis patient presented with proximal muscle weakness with diaphragmatic dysfunction, diplopia and dysphagia all attributable to myositis. Testing confirmed respiratory neuromuscular dysfunction and absence of primary oesophageal peristalsis. Electromyogram was consistent with severe inflammatory/necrotising myopathy. Imaging evaluation in our cohort was limited, but patient 11 did have a shoulder MRI to evaluate PMR symptoms which revealed extensive rotator cuff tendinosis and bursitis.\n\nTable 2 Non-rheumatic immune-related adverse events (irAEs)\n\nPatient\tNon-rheumatic irAE\t\n2\tHypothyroid\t\n4\tColitis\t\n5\tRash\nHypothyroid\nColitis\t\n8\tHypophysitis\nThyroiditis\t\n9\tHypophysitis\t\n10\tHypophysitis\nPneumonitis\nNeuropathy\t\n11\tHypophysitis\t\n12\tColitis\t\nTable 3 Clinical phenotypes of inflammatory arthritis\n\nPatient\tJoint pattern\tSymmetrical\tTenosynovitis\t\n1\tPIPs, MCPs, wrists, elbows, knees\tYes\t\t\n2\tGeneralised involvement of small hand joints\tYes\tYes\t\n3\tPIPs, MCPs, PIPs, elbows, knees, ankles, feet, toes\tYes\t\t\n4\tPIPs, MCPs, ankles, knees\tYes\t\t\n5\tPIPs, MCPs, wrists, knees\tYes\t\t\n6\tGeneralised involvement of small hand joints, wrists\tYes\t\t\n7\tGeneralised involvement of small hand joints, left knee\tNo\tYes\t\nMCP, metacarpal phalangeal joints; PIP, proximal interphalangeal joint.\n\nWith the exception of two patients who experienced irAEs over 1 year after starting immunotherapy, the median time to onset of irAE was 7.3 weeks (range 2–48.4). The longest time between start of immunotherapy and development of irAE was 213 weeks in a patient who developed a PMR-like syndrome after over 4 years on nivolumab for renal cell carcinoma. Rheumatic irAEs led to holding of immunotherapy in eight patients and immune-related hypophysitis led to cessation of therapy in two of the remaining patients. Autoimmune testing was performed in the majority of patients (table 1). Four patients had a positive ANA with one also having anti-double stranded DNA antibodies and another anti-SSA antibodies. One patient with inflammatory arthritis was positive for rheumatoid factor (RF) but negative for anti-cyclic citrullinated protein antibodies. Eleven patients were treated with glucocorticoids for their rheumatic irAE; five required additional therapy with either anti-tumour necrosis factor (TNF) α medications, intravenous immunoglobulin or hydroxychloroquine. Treatment of irAEs led to significant improvement in six patients, moderate improvement in five patients and only minimal improvement in two. Non-rheumatic irAEs (table 2) were addressed per guidelines on an individualised basis.\n\nPatients with pre-existing autoimmune disease\nOf the two patients with pre-established AID, one experienced a disease flare after starting immunotherapy: a patient with psoriatic arthritis previously treated with apremilast had experienced remission of his psoriatic arthritis (PsA) while on chemotherapy. He experienced a psoriasis flare 2.8 weeks after starting nivolumab and apremilast was resumed. He experienced mild psoriasis flares on his face during therapy but inflammatory arthritis remained quiet. The patient with rheumatoid arthritis had seropositive, non-erosive disease; he remained without disease activity on hydroxychloroquine throughout his course of immunotherapy.\n\nDiscussion\nirAEs of any type are common in patients receiving immunotherapy, occurring in up to 90% of patients receiving anti-CTLA-4 agents4 and 70% of those receiving anti-PD-1/PD-L1 agents.5\n6 Somewhat lower rates of irAEs have been seen with anti-PD-1 agents, but incidence increases when they are used in combination with inhibitors of CTLA-4.7 The most common irAEs are gastrointestinal, hepatic, endocrine and dermatological events.7\n8 Rheumatic irAEs, however, have been infrequently reported in clinical trials9 and generally have been the subject of isolated case reports.9 One single-centre case series of rheumatic irAEs was recently published, in which Cappelli et al2 described inflammatory arthritis and sicca syndrome in 13 patients receiving nivolumab and/or ipilimumab.2 In this report, they described nine patients who developed inflammatory arthritis; synovitis was confirmed by imaging in four. Overall, a variety of rheumatic manifestations have been described in these reports including arthralgia, inflammatory arthritis, sicca complex as well as rare reports of vasculitis, myositis and lupus. Our series of 15 patients now expands the description of rheumatic irAEs and describes a wider variety of rheumatic irAEs than seen in previous reports, including inflammatory arthritis, sicca syndrome, a PMR-like syndrome and myositis in patients receiving monotherapy and combination therapy with checkpoint inhibitors.\n\nIn our study, in 13 of 15 subjects the median time to onset of rheumatic irAE was 7.3 weeks after initiation of immunotherapy, which is consistent with previous reports. In clinical trials for ipilimumab, the majority of all irAEs have been reported to occur within 12 weeks of initial dosing, and this seems to be consistent across numerous studies.4\n7 Interestingly there were two outliers in our cohort with one patient developing a PMR-like syndrome after over 4 years of being stable on nivolumab. Reasons for the delay in irAE presentation are unknown. Several patients were noted to have persistent symptoms for months after immunotherapy was stopped. The longest persistence of symptoms in one patient was over 2 years after the last dose of immunotherapy. This persistence of rheumatic symptoms long after discontinuation of immunotherapy has also been previously described.2\n\nThe pathophysiology of each respective irAE remains to be fully elucidated albeit it seems that they are at least partially T cell-mediated as expected by the mechanism of action of these medications.10 To date, there have been no detailed pathophysiological studies investigating the mechanism of any rheumatic irAE.\n\nManagement of rheumatic irAEs remains an area of uncertainty. In general, irAEs have been reported to be steroid sensitive and in most cases resolve within 6–12 weeks.8 While some patients in our series were responsive to glucocorticoids, three out of 13 required more aggressive immunosuppression with TNF inhibitors. We also observed that these patients required higher doses of glucocorticoids and largely more intense therapy than our traditional experience with inflammatory arthritis seen in rheumatoid arthritis or associated with connective tissue disease.\n\nAn important clinical question is whether patients with pre-existing rheumatic diseases undergoing cancer immunotherapy with checkpoint inhibitors are at increased risk for flares of their underlying diseases. The largest series to date describes 30 patients with pre-existing AIDs of a variety of sorts; eight experienced flares 3 days to 7 months after starting ipilimumab.11 In our study, one of two patients experienced a flare of underlying AID. The patient had psoriatic arthritis and the flare was managed with apremilast without interruption of immunotherapy. In our entire cohort, treatment discontinuation rate owing to irAEs was significantly higher (10 of 13 patients) compared with the literature. Immunotherapy was discontinued for rheumatic irAEs in eight of the 10, and for endocrine irAE in two patients. This needs to be validated in larger prospective cohort trials.\n\nA comprehensive grading system for rheumatic irAEs is lacking as opposed to other more common irAEs. Additionally, despite a standardised grading system, toxicity evaluation and treatment for all irAEs is highly subjective based on the treating oncologist.9 Incorporating rheumatic irAEs in the grading system of adverse effects of immunotherapy would facilitate early recognition, referral and expeditious management which may translate to decreased need for immunosuppressive medications and/or cessation of immunotherapy. It would also allow a more accurate assessment of the incidence and prevalence of these complications. New-onset inflammatory symptoms pertaining to the broad spectrum of rheumatological conditions postadministration of immune checkpoint inhibitors should be further investigated.\n\nThere are several limitations of our study. While our series is the largest to date, it is a single-centre experience and retrospective in nature. Accordingly diagnostic testing, including laboratory tests, imaging and organ-specific testing, was not standardised and thus subject to diagnostic bias. For those patients who did have positive tests (ie, ANA, RF, etc), there was no testing prior to immunotherapy for comparison. There was limited use of imaging and no synovial fluid analysis to confirm inflammatory arthritis. All rheumatic irAE diagnoses were based on expert opinion of the rheumatologist. We also were unable to determine the true incidence of rheumatic irAEs given the observational basis of this cohort.\n\nAt present, it is clear that we are in the early stages of diagnosing and treating rheumatic irAEs secondary to immunotherapy of cancers with checkpoint inhibitors. Numerous questions are unanswered regarding these complications. These questions include: what is the true incidence of these disorders with individual and combined therapies? What are the risk factors and what is the underlying pathophysiology of these disorders? What are the risks of disease flare with these types of immunotherapy in patients with pre-existing autoimmune conditions? In terms of therapy, what is the optimal treatment of these types of complications and finally what are the ramifications of concomitant immunosuppressive therapy for irAEs on antitumorous responses? Given the proliferation of checkpoint inhibitor therapy into the general oncology armamentarium and the rise of new therapeutics with similar mechanisms of action, it is assured that rheumatic adverse events will be seen by general rheumatologists in academic and community settings. Rheumatologists must be alerted to these complications and acquire knowledge to accurately diagnose and manage these disorders in collaboration with treating oncologists.\n\nTwitter: Follow cassandra calabrese @CCalabreseDO\n\nContributors: All authors contributed to data acquisition, analysis and manuscript preparation.\n\nCompeting interests: LHC reports personal fees from Bristol-Myers Squibb, outside the submitted work. VV reports grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Genentech, grants and personal fees from Merck, grants and personal fees from Astra Zeneca, personal fees from Celgene, grants and personal fees from Genoptix, personal fees from Foundation medicine, outside the submitted work. CC, KK and EK have nothing to disclose.\n\nEthics approval: Cleveland Clinic Foundation IRB.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData sharing statement: No additional data are available.\n==== Refs\nReferences\n1 Topalian SL , Drake CG , Pardoll DM \nImmune checkpoint blockade: a common denominator approach to cancer therapy . Cancer Cell \n2015 ;27 :450 –61 . 10.1016/j.ccell.2015.03.001 25858804 \n2 Cappelli LC , Gutierrez AK , Baer AN \nInflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab . Ann Rheum Dis \n2017 ;76 :43 –50 . 10.1136/annrheumdis-2016-209595 27307501 \n3 Donia M , Pedersen M , Svane IM \nCancer immunotherapy in patients with preexisting autoimmune disorders . Semin Immunopathol \n2016 \nPublished Online First 11 October 2016 . 10.1007/s00281-016-0595-8 \n4 Hodi FS , O'Day SJ , McDermott DF \nImproved survival with ipilimumab in patients with metastatic melanoma . N Engl J Med \n2010 ;363 :711 –23 . 10.1056/NEJMoa1003466 20525992 \n5 Topalian SL , Hodi FS , Brahmer JR \nSafety, activity, and immune correlates of anti-PD-1 antibody in cancer . N Engl J Med \n2012 ;366 :2443 –54 . 10.1056/NEJMoa1200690 22658127 \n6 Brahmer JR , Tykodi SS , Chow LQM \nSafety and activity of anti-PD-L1 antibody in patients with advanced cancer . N Engl J Med \n2012 ;366 :2455 –65 . 10.1056/NEJMoa1200694 22658128 \n7 Boutros C , Tarhini A , Routier E \nSafety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination . Nat Rev Clin Oncol \n2016 ;13 :473 –86 . 10.1038/nrclinonc.2016.58 27141885 \n8 Michot JM , Bigenwald C , Champiat S \nImmune-related adverse e vents with immune checkpoint blockade: a comprehensive review . Eur J Cancer \n2016 ;54 :139 –48 . 10.1016/j.ejca.2015.11.016 26765102 \n9 Horvat TZ , Adel NG , Dang TO \nImmune-related adverse events, needs for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center . J Clin Onc \n2015 ;33 :3193 –8 .\n10 Johnson DB , Balko JM , Compton ML \nFulminant myocarditis with combination immune checkpoint blockade . N Engl J Med \n2016 ;375 :1749 –55 . 10.1056/NEJMoa1609214 27806233 \n11 Johnson DB , Sullivan RJ , Ott PA \nIpilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders . JAMA Oncol \n2016 ;2 :234 –40 . 10.1001/jamaoncol.2015.4368 26633184\n\n",
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"issn_linking": "2056-5933",
"issue": "3(1)",
"journal": "RMD open",
"keywords": "Autoimmune Diseases; Inflammation; Multidisciplinary team-care",
"medline_ta": "RMD Open",
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"title": "Rheumatic immune-related adverse events of checkpoint therapy for cancer: case series of a new nosological entity.",
"title_normalized": "rheumatic immune related adverse events of checkpoint therapy for cancer case series of a new nosological entity"
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"abstract": "There remains variability in both practice and evidence related to optimal initial empiric dosing strategies for vancomycin.\nOur primary objective was to describe the percentage of obese patients receiving vancomycin doses consistent with nomogram recommendations achieving targeted initial steady-state serum vancomycin concentrations. Secondary objectives were to describe the primary endpoint in subgroups based on patient weight and estimated creatinine clearance, to describe the rate of supratherapeutic vancomycin accumulation following an initial therapeutic trough concentration, and to describe the rate of vancomycin-related adverse events.\nThis single-center, IRB-approved, retrospective cohort included adult patients ≥ 100 kilograms total body weight with a body mass index (BMI) >30 kilograms/m2 who received a stable nomogram-based vancomycin regimen and had at least one steady-state vancomycin trough concentration. Data collected included vancomycin regimens and concentrations, vancomycin indication, serum creatinine, and vancomycin-related adverse events. Patients were divided into two cohorts by goal trough concentration: 10-15 mcg/mL and 15-20 mcg/mL.\nOf 325 patients screened, 85 were included. Goal steady-state concentrations were reached in 42/85 (49.4%) of total patients.\nAchievement of initial steady-state vancomycin serum concentrations in the present study (approximately 50%) was consistent with the use of published vancomycin dosing nomograms.",
"affiliations": "Department of Pharmacy Practice, College of Pharmacy & Health Sciences, Campbell University. Buies Creek, NC; & Cape Fear Valley Medical Center. Fayetteville, NC (United States). bowers@campbell.edu.;Department of Pharmacy Practice, College of Pharmacy & Health Sciences, Campbell University. Buies Creek, NC; & Duke Regional Hospital. Durham, NC (United States). april.cooper@duke.edu.;Department of Pharmacy Practice, College of Pharmacy & Health Sciences, Campbell University. Buies Creek, NC; & Duke Regional Hospital. Durham, NC (United States). Catherine.d.lewis@duke.edu.;Department of Pharmacy Practice, College of Pharmacy & Health Sciences, Campbell University. Buies Creek, NC; & Duke University Hospital. Durham, NC (United States). wilsond@campbell.edu.;Department of Pharmacy Practice, College of Pharmacy & Health Sciences, Campbell University. Buies Creek, NC; & Novant Health - Forsyth Medical Center. Winston-Salem, NC (United States). johnsonsw@campbell.edu.;Department of Pharmacy Practice, College of Pharmacy & Health Sciences, Campbell University. Buies Creek, NC; & Duke University School of Medicine. Durham, NC (United States). Richard.drew@duke.edu.",
"authors": "Bowers|Riley D|RD|0000-0002-6889-0156;Cooper|April A|AA|0000-0002-1141-3666;Wente|Catherine L|CL|0000-0001-8501-3772;Wilson|Dustin T|DT|0000-0001-8053-8473;Johnson|Steven W|SW|0000-0002-2150-5812;Drew|Richard H|RH|0000-0003-0406-0804",
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"doi": "10.18549/PharmPract.2018.03.1204",
"fulltext": "\n==== Front\nPharm Pract (Granada)Pharm Pract (Granada)Pharmacy Practice1885-642X1886-3655Centro de Investigaciones y Publicaciones Farmaceuticas pharmpract-16-120410.18549/PharmPract.2018.03.1204Original ResearchEvaluation of a vancomycin dosing nomogram in obese patients weighing at least 100 kilograms http://orcid.org/0000-0002-6889-0156Bowers Riley D. Department of Pharmacy Practice, College of Pharmacy & Health Sciences, Campbell University. Buies Creek, NC; & Cape Fear Valley Medical Center. Fayetteville, NC (United States). bowers@campbell.eduhttp://orcid.org/0000-0002-1141-3666Cooper April A. Department of Pharmacy Practice, College of Pharmacy & Health Sciences, Campbell University. Buies Creek, NC; & Duke Regional Hospital. Durham, NC (United States). april.cooper@duke.eduhttp://orcid.org/0000-0001-8501-3772Wente Catherine L. Department of Pharmacy Practice, College of Pharmacy & Health Sciences, Campbell University. Buies Creek, NC; & Duke Regional Hospital. Durham, NC (United States). Catherine.d.lewis@duke.eduhttp://orcid.org/0000-0001-8053-8473Wilson Dustin T. Department of Pharmacy Practice, College of Pharmacy & Health Sciences, Campbell University. Buies Creek, NC; & Duke University Hospital. Durham, NC (United States). wilsond@campbell.eduhttp://orcid.org/0000-0002-2150-5812Johnson Steven W. Department of Pharmacy Practice, College of Pharmacy & Health Sciences, Campbell University. Buies Creek, NC; & Novant Health - Forsyth Medical Center. Winston-Salem, NC (United States). johnsonsw@campbell.eduhttp://orcid.org/0000-0003-0406-0804Drew Richard H. Department of Pharmacy Practice, College of Pharmacy & Health Sciences, Campbell University. Buies Creek, NC; & Duke University School of Medicine. Durham, NC (United States). Richard.drew@duke.eduJul-Sep 2018 13 8 2018 16 3 120401 2 2018 04 7 2018 Copyright: © Pharmacy Practice2018This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY-NC-ND 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nThere remains variability in both practice and evidence related to optimal initial empiric dosing strategies for vancomycin.\n\nObjective:\nOur primary objective was to describe the percentage of obese patients receiving vancomycin doses consistent with nomogram recommendations achieving targeted initial steady-state serum vancomycin concentrations. Secondary objectives were to describe the primary endpoint in subgroups based on patient weight and estimated creatinine clearance, to describe the rate of supratherapeutic vancomycin accumulation following an initial therapeutic trough concentration, and to describe the rate of vancomycin-related adverse events.\n\nMethods:\nThis single-center, IRB-approved, retrospective cohort included adult patients ≥ 100 kilograms total body weight with a body mass index (BMI) >30 kilograms/m2 who received a stable nomogram-based vancomycin regimen and had at least one steady-state vancomycin trough concentration. Data collected included vancomycin regimens and concentrations, vancomycin indication, serum creatinine, and vancomycin-related adverse events. Patients were divided into two cohorts by goal trough concentration: 10-15 mcg/mL and 15-20 mcg/mL.\n\nResults:\nOf 325 patients screened, 85 were included. Goal steady-state concentrations were reached in 42/85 (49.4%) of total patients.\n\nConclusions:\nAchievement of initial steady-state vancomycin serum concentrations in the present study (approximately 50%) was consistent with the use of published vancomycin dosing nomograms.\n\nDrug MonitoringVancomycinNomogramsDrug Dosage CalculationsObesityRetrospective Studies\n==== Body\nINTRODUCTION\nMore than one-third of adults in the United States are obese and consequently at a significantly increased risk for heart disease, stroke, and type 2 diabetes.1 In addition to these health implications, the physiologic changes from obesity also impact pharmacokinetic and pharmacodynamic properties of drugs. These changes can impact both efficacy and toxicity, especially in antimicrobials such as vancomcyin.2\n\nVancomycin is a tricyclic glycopeptide antibiotic commonly used as therapy for infections caused by Gram-positive organisms, most notably methicillin-resistant Staphylococcus aureus (MRSA).3 Published adult dosing recommendations for vancomycin in the general population are 15 to 20 mg/kg per dose every 8 to 24 hours (based upon total body weight [TBW] and estimated renal function).4 However, such recommendations may be inadequate in obese patients due to increases in vancomycin clearance and volume of distribution.5 In addition, when applied to obese patients, the large single doses resulting from such weight-based recommendations increase the risk of dose-related toxicities.5\n\nVariability in both practice and lack of evidence related to optimal initial dosing strategies\nfor vancomycin exist.5 For example, dosing\nbased on TBW achieves target steady-state trough concentrations more frequently then\nwhen based on ideal body weight (IBW).2 In\ncontrast, one study5 demonstrated that use of adjusted body weight (ABW) provided\nthe best predictor to serum concentrations, and another6 recommended using 45 to 65 mg/kg/day based on IBW.5,6 In\naddition to weight-based dosing, published dosing nomograms have also been\nextensively evaluated.7-9 Their efficacy in achieving initial goal trough concentrations\n(10-20 mcg/mL) has been shown to range from 40-60% on the initial regimen,\nbut the majority excluded patients weighing more than 120 kg or limited the maximum\nsingle dose to 2 gms.7-9 Studies analyzing appropriate vancomycin dosing and monitoring\nin obese patients have reported variable success rates. In one, approximately\n60% of initial vancomycin steady-state concentrations were subtherapeutic\n(<10 mcg/mL), leading to increased risk of resistance and treatment\nfailure.8 Another concluded that obese\npatients most often reached target trough concentrations when given 20-30 mg/kg/day\nbased on TBW.9\n\nThere has yet to be a consensus or guideline recommendations for dosing and monitoring in obese\npatients. At Duke University Hospital, a validated empiric dosing nomogram for\npatients weighing 50-100 kg has been in place since 2010. In order to fulfill an\nincreasing and unmet need, an empiric vancomycin dosing nomogram was developed at\nDuke Regional Hospital (DRH) in 2016 targeting patients weighing 100 to 160 kg (see\nAppendix Click here for additional data file.\n\n ). While we hypothesized this nomogram would provide\nappropriate initial vancomycin dosing guidelines in this population, it had not been\npreviously evaluated. The purpose of our study was to evaluate this\nnewly-implemented vancomycin dosing nomogram in achieving goal steady-state trough\nconcentrations for obese adult patients.\n\nMETHODS\nThe primary objective of this single-center, retrospective cohort study was to describe the percentage of obese patients receiving initial vancomycin doses consistent with nomogram recommendations achieving targeted initial steady-state serum vancomycin concentrations. The secondary objectives were to describe the primary endpoint in subgroups based on patient weight and estimated creatinine clearance (CrCl). We also sought to describe the percentage of patients maintaining a target steady-state trough concentration, on a consistent regimen, for one subsequent level following an initial target steady-state trough concentration to assess the rate of accumulation. Lastly, patients were evaluated for vancomycin-related adverse effects, including new-onset kidney injury and Red Man syndrome.\n\nThis single-center, retrospective cohort study was approved by the Duke University Health System Institutional Review Board and conducted at DRH, a 369-bed community hospital in Durham, NC. Patients >18 years-old, admitted to a general medicine or surgery unit from December 1, 2015 to February 1, 2017 were included. Subjects who weighed >100 kg and had a BMI of >30 kg/m2 who received at least 2 scheduled vancomycin doses following the appropriate loading dose (per nomogram recommendations) were included if at least one steady-state trough vancomycin concentration (defined as following at least the third dose of the regimen and drawn within 2 hours of the next sequential dose) was measured. Patients were excluded for any of the following: renal dysfunction (defined as an estimated CrCl <10 mL/min), unstable renal function (defined as a change in serum creatinine (SCr) of 0.5 mg/dL or 50% reduction in estimated CrCl between initial dose and time of subsequent trough measurement), moderate to severe liver dysfunction at baseline (defined as aspartate aminotransferase or alanine aminotransferase levels >two times the upper limit of normal (ULN), or a total bilirubin level >two times the ULN), ascites, burns (>20% total body surface area), within 30 days of solid organ or hematopoietic stem cell transplantation, had cystic fibrosis, were patients in the critical care unit, or were pregnant.\n\nPatients were identified utilizing the Duke Enterprise Data Unified Content Explorer (DEDUCE). Separate admissions for the same patient were counted as individual cases. Data were collected using a Microsoft Access database and entry form. Patient demographics collected included gender, age, weight, height, BMI, and the presence of chronic kidney disease (CKD). Other data collected included vancomycin indication, vancomycin dosing regimens, and vancomycin serum trough concentrations, dates, and collection times. SCr and estimated CrCl at time of vancomycin initiation and trough concentration of maintenance regimen utilizing a modified Cockroft-Gault equation (removing weight and 72 from numerator and denominator, respectively).10 Of note, in patients >70 years old, a SCr below 1 mg/dL was rounded to 1 mg/dL to calculate CrCl. For initial loading doses, patients received 25 mg/kg TBW unless they had impaired renal function indicated by new-onset kidney injury or CKD Stage IV or worse. In this case, patients were loaded with 20 mg/kg TBW. However, we incorporated our institution’s policy of vancomycin dose capping at 2500 mg. For patients with therapeutic serum trough concentrations that were continued on the same regimen, SCr was collected again at the time of the next trough concentration. Lastly, presence of Red Man syndrome and new-onset kidney injury at the time of concentration collection (defined as an increase in SCr by 0.3 mg/dL or more within 48 hours, or an increase in SCr to 1.5 times baseline or more within the last 7 days, or urine output less than 0.5 mL/kg/h for 6 hours) was collected.11 The institutional nomogram was developed with the above in mind, utilizing traditional vancomycin pharmacokinetic calculations including the Matzke equation for the elimination rate constant. For patients receiving multiple courses of vancomycin during a single admission, only the first course was included in the study.12\n\nData Analysis\nThe primary endpoint (initial steady-state serum vancomycin concentration within the indication-specific target range) and patient demographics were characterized using descriptive statistics. For the secondary objectives, the endpoints utilized were percentage of therapeutic trough concentrations in the pre-specified cohorts, percentage of patients experiencing vancomycin accumulation to a supratherapeutic level following an initial therapeutic concentration, and percentage of patients experiencing a vancomycin-related adverse event such as new-onset kidney injury. Patients were cohorted by CrCl (10-39 mL/min, 40-69 mL/min, 70-99 mL/min, and 100+ mL/min) and weight (100-119 kg, 120-139 kg, 140-159 kg, and 160+ kg).\n\nRESULTS\nOf 325 patients weighing over 100 kg and on vancomycin identified and screened, 85 (26.2%) met inclusion criteria. Patients were excluded for the following: doses were not consistent with nomogram recommendations (n=168), no trough concentration level (n=36), critical care unit status (n=28), BMI <30 kg/m2 (5), and weight <100 kg at time of vancomycin initiation (3). The study population was predominantly male with an average age of 60 years. Remaining subject demographics are summarized in Table 1. All subjects had an estimated CrCl > 30 mL/min and the mean CrCl was 81.3 mL/min. The majority of patients were in the 15-20 mcg/mL goal trough cohort and were receiving therapy for complicated skin and skin structure infections (SSTI).\n\nTable 1 Baseline demographic characteristics of included subjects (by cohort)\n\nCohort\t\nParameter\t10-15 mcg/mL (n=28)\t15-20 mcg/mL (n=57)\tAll patients (n=85)\t\nAge, yr\t56.1 (11.8)\t57.5 (15.2)\t56.9 (13.0)\t\nGender, n (Male:Female)\t15:13\t37:20\t52:33\t\nWeight, kg\t133.2 (35.6)\t122.0 (17.6)\t125.1 (25.3)\t\nBMI, kg/m2a\t44.8 (12.7)\t39.5 (7.3)\t40.9 (9.5)\t\nCrClb, mL/min\t98.8 (22.1)\t72.7 (24.6)\t81.3 (26.7)\t\nIndications, n(%)\t\t\t\t\nSSTIc\t26 (92.9)\t17 (29.8)\t43 (50.1)\t\nOsteomyelitis\t0\t16 (28.1)\t16 (18.8)\t\nSepsis\t0\t11 (19.3)\t11 (12.9)\t\nPneumonia\t0\t6 (10.5)\t6 (7.1)\t\nBacteremia\t1 (3.6)\t4 (7.0)\t5 (5.9)\t\nIntra-abdominal\t0\t3 (5.3)\t3 (3.5)\t\nOther\t1 (3.6)\t0\t1 (1.2)\t\nVancomcyin regimen\t\t\t\t\n1.5g Q12H\t11\t11\t22 (25.9)\t\n1.75g Q12H\t5\t10\t15 (17.6)\t\n2g Q12H\t4\t8\t12 (14.1)\t\n1.75g Q18H\t0\t8\t8 (9.4)\t\n1.25g Q8H\t0\t6\t6 (7.1)\t\nOther\t8\t14\t22 (25.9)\t\nBaseline renal disease\t\t\t\t\nCKDd Stage III-V\t1 (3.6)\t9 (15.8)\t10 (11.8)\t\na. Body Mass Index\n\nb. Creatinine clearance in normalized Cockroft-Gault\n\nc. skin and soft tissue infections\n\nd. Chronic Kidney Disease\n\nGoal steady-state trough concentrations were reached in 42 patients (49.4%) with 27 (47.4%) in the 15-20 mcg/mL cohort and 15 (53.6%) in the 10-15 mcg/mL cohort. In the total population, 24.7% had subtherapeutic levels at steady state and 25.9% had supratherapeutic levels. There was also a similar distribution of subtherapeutic levels and supratherapeutic levels in each goal trough subgroup (Figure 1). Trough levels ranged from 6.1-30.9 mcg/mL. When this data was combined, 58 patients (68.2%) had levels that fell in the 10-20 mcg/mL range.\n\nFigure 1 Number achieving trough concentrations based on target trough concentration goal.\n\nWhen divided into pre-specified subgroups based on goal trough concentrations, weight, and estimated CrCl (Table 2), the majority of patients fell into the 100-119 kg groups (n= 47, 55%). There were a limited number of patients >140 kg (n=13, 15%), and only 28 patients had an estimated CrCl <70 mL/min. 69% of the pre-specified subgroups containing at least one patient in the 15-20 mcg/mL goal cohort and 67% of the subgroups in the 10-15 mcg/mL cohort had mean trough concentrations at goal, respectively (Table 2). Notably, 16/21 (76%) of total patients with subtherapeutic trough concentrations had an estimated CrCl >70 mL/min. However, there were more patients in these subgroups and the majority still achieved goal trough concentrations (n=30, 52.6%). There was a noticeably higher rate of patients reaching initial supratherapeutic trough concentrations in the CrCl <70 mL/min subgroups compared to those with a CrCl >70 mL/min (35.7% vs. 19.3%).\n\nTable 2 Subgroup analysis – average trough concentration (SD), mcg/mL\n\n10-15 mcg/mL goal\t100-119 kg\t120-139 kg\t140-159 kg\t> 160 kg\t\n10-39 mL/min\tN/A\tN/A\tN/A\tN/A\t\n40-69 mL/min\t17.0 (3.6)\t22.8 (0)*\tN/A\tN/A\t\n70-99 mL/min\t14.4 (5.7)\t11.5 (0)*\tN/A\t13.8 (1.6)\t\n> 100 mL/min\t10.7 (2.9)\t9.8 (3.6)\t14.5 (0)*\t14.8 (3.8)\t\n15-20 mcg/mL goal\t100-119 kg\t120-139 kg\t140-159 kg\t> 160 kg\t\n10-39 mL/min\t18.6 (2.4)\t16.1 (0)*\tN/A\tN/A\t\n40-69 mL/min\t17.2 (4.8)\t18.8 (4.3)\t19.9 (0)*\t14.2 + 6.1*\t\n70-99 mL/min\t16.9 (5.6)\t18.7 (4.0)\t11.5 (0)*\tN/A\t\n> 100 mL/min\t12.6 (3.0)\t23.2 (2.1)*\t17.8 (0)*\t15.4 (0)*\t\n* <2 patients represented in the subgroup\n\nVery few patients were continued on the same vancomycin regimen following the achievement of a target trough concentration long enough to check a second concentration (n=11, 26.2%). Of these 11 patients, 5 experienced accumulation to a supratherapeutic trough concentration on the subsequent level, with a mean (SD) time to next level of 2.9 (SD=1.2) days. However, 3 (60%) of these patients developed new-onset kidney injury between the first and second concentration drawn.\n\nNo patients had to have vancomycin discontinued due to adverse events. Five patients experienced new-onset kidney injury during treatment and one patient was reported to have Red Man syndrome which was noted to improve when the infusion was administered at a slower rate. No other drug-related adverse effects were reported.\n\nDISCUSSION\nThe results of our study found that our nomogram achieved target trough concentrations nearly 50% of the time. Prior attempts to utilize nomograms to provide initial dosing recommendations for vancomycin in obese patients have been met with variable success. One protocol employed a 20 mg/kg loading dose followed by 10 mg/kg/dose (based on TBW) every 12-24 hours in morbidly obese adults (BMI >40).8 This dose was chosen based on previous findings that demonstrated a high rate of supratherapeutic concentrations with higher doses.8 With this decreased dose, initial goal trough concentrations were achieved in 35.4% of patients, while subtherapeutic troughs occurred in 56.3% and supratherapeutic troughs in only 8.3% of patients.8 Another recent retrospective study concluded that obese (BMI 30-40) and morbidly obese (BMI >40) patients most often reached target trough concentrations when given 20-30 mg/kg/day based on TBW.9 However, this study had limitations which included a high rate of subtherapeutic trough concentrations (48%) and no loading doses were given.9\n\nCompared to the aformentioned studies and another by Morrill et al, which utilized a similar dosing strategy and yielded 48% subtherapeutic initial trough levels, our study had a more even distribution of non-therapeutic trough concentrations.7-9 Approximately 25% of patients had subtherapeutic trough levels with no level being lower than 6 mcg/mL, while another 25% of patients had supratherapeutic levels with only one level being greater than 30 mcg/mL (30.9). While we had a slightly higher rate of new-onset kidney injury during therapy compared to the previous trials, all patients experiencing kidney injury were on concomitant nephrotoxic medications including piperacillin-tazobactam, thiazide diuretics, and intravenous acyclovir.8,9,13\n\nThe results of this study fall within the range of results in previous studies evaluating vancomycin dosing nomograms, achieving goal steady-state trough concentrations nearly 50% of the time.7,14-16 Unlike the majority of previous studies analyzing vancomycin nomograms, this study only included obese patients weighing at least 100 kg with no maximum weight.4-7,14-16 When looking at the limited previous literature on vancomycin dosing in obese patients, our nomogram appears to be safe and similarly effective. Notable studies analyzing vancomycin dosing in obese patients have utilized protocols or nomograms that have based dosing on simplified mg/kg calculations paired with estimated renal function for determining frequency.8,9,13 Our nomogram was developed utilizing traditional pharmacokinetic calculations for each subgroup using TBW for volume of distribution calculations and normalized CrCl which ultimately leads to a lower estimation of drug clearance in these patients. Utilizing this method of dosing, we predicted that our patients would receive large enough doses without experiencing toxic levels as a result of too frequent dosing.\n\nThis was also the first study to our knowledge to collect data on vancomycin accumulation in the real-world obese patient population. While our data is limited to 11 patients who were continued on their original therapeutic regimen long enough to receive a second trough level, it does reveal a concern for drug accumulation in this population. Nearly half (45%) of these patients experienced a subsequent supratherapeutic level following an initial therapeutic trough concentration and no change in dosing regimen. It is important to note that 3 of these patients had significant increases in SCr levels near the time of the follow-up level. Further studies are needed in this area to assess vancomycin adjustments in these patients to avoid potentially toxic accumulation.\n\nOur study was not without limitations. Though our nomogram was designed using common calculations utilized in clinical practice, there are potential limitations with the pharmacokinetics of using the standard Vd, Matzke equation, and SCr rounding in the obese population.12 However, there is no current consensus on the best method. AUC-based monitoring has also shown promising data, but until more implementable evidence exists, many institutions will continue traditional vancomycin dosing.17 With no active or historical comparator, we were only able to report descriptive statistics limiting ability to show any association with patient specific factors and vancomycin concentrations. We were also limited to a small sample size. Although over 300 patients were screened for inclusion, pharmacists were not required to utilize the nomogram during the evaluation period which led to many exclusions. We also excluded patients in the critical care unit per the institution’s pharmacokinetic policy which limits extrapolation to these patients. This limited sample size and utilization also inhibited our ability to truly evaluate the effectiveness of our nomogram in patients with poor CrCl and those weighing over 140 kg. Lastly, we did not evaluate clinical outcomes of the patients.\n\nCONCLUSIONS\nOverall achievement of initial steady-state vancomycin serum concentrations in our study of obese patients (approximately 50%) was consistent with the use of published vancomycin dosing nomograms. Notably, our study had an even distribution of non-therapeutic trough concentrations (25% subtherapeutic and 25% supratherapeutic). Our study also added evidence for the risk vancomycin accumulation in continued dosing in this patient population. Future plans should include identifying patient-specific factors associated with non-therapeutic trough levels in the obese patient population and developing accurate pharmacokinetic models for this population. \n\nACKNOWLEDGEMENTS\nThis study was granted exempted status by the Duke University Health System Institutional Review Board\n\nCONFLICT OF INTEREST\n\nThe authors of this manuscript have nothing to disclose concerning possible\nfinancial or personal relationships with commercial entities that may affect\nthis presentation.\n\nFUNDING\nNone.\n==== Refs\nREFERENCES\n1 Centers for disease control and prevention Adult obesity facts. September 21, 2015 https://www.cdc.gov/obesity/data/adult.html (accessed July 17, 2016) \n2 Polso AK Lassiter JL Nagel JL Impact of hospital guideline for weight-based antimicrobial dosing in morbidly obese adults and comprehensive literature review J Clin Pharm Ther 2014 12 39 6 584 608 10.1111/jcpt.12200 25203631 \n3 Vancomycin [prescribing information] Lake Forest, IL: Hospira; November 2014 \n4 Rybak MJ Lomaestro BM Rotschafer JC Moellering RC Craig WA Billeter M Dalovisio JR Levine DP Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists Clin Infect Dis 2009 49 3 325 327 10.1086/600877 19569969 \n5 Leong JV Boro MS Winter M Determining vancomycin clearance in an overweight and obese population Am J Health Syst Pharm 2011 68 7 599 603 10.2146/ajhp100410 21411801 \n6 Kubiak DW Alquwaizani M Sansonetti D Barra ME Calderwood MS An Evaluation of systemic vancomycin dosing in obese\npatients Open Forum Infect Dis 2015 2 4 ofv176 10.1093/ofid/ofv176 26716105 \n7 Elyasi S Khalili H Vancomycin dosing nomograms targeting high serum trough levels in different populations: pros and cons Eur J Clin Pharmacol 2016 72 7 777 788 10.1007/s00228-016-2063-8 27117446 \n8 Kosmisky DE Griffiths CL Templin MA Norton J Martin KE Evaluation of a new vancomycin dosing protocol in morbidly obese patients Hosp Pharm 2015 10 50 9 789 797 10.1310/hpj5009-789 26912920 \n9 Morrill HJ Caffrey AR Noh E Laplante KL Vancomycin dosing considerations in a real-world cohort of obese and extremely obese patients Pharmacotherapy 2015 35 9 869 875 10.1002/phar.1625 26343549 \n10 Wilhelm SM Kale-Pradhan PB Estimating creatinine clearance: a meta-analysis Pharmacotherapy 2011 31 7 658 664 10.1592/phco.31.7.658 21923452 \n11 Acute Kidney Injury Work Group KDIGO Clinical Practice Guideline for Acute Kidney Injury Kidney Inter 2012 2 1 1 138 \n12 Matzke GR Zhanel GG Guay DR Clinical pharmacokinetics of vancomycin Clin Pharmacokinet 1986 11 4 257 282 10.2165/00003088-198611040-00001 3530582 \n13 Reynolds DC Waite LH Alexander DP DeRyke CA Performance of a vancomycin dosage regimen developed for obese patients Am J Health Syst Pharm 2012 69 11 944 950 10.2146/ajhp110324 22610026 \n14 Kullar R Leonard SN Davis SL Delgado G Jr Pogue JM Wahby KA Falcione B Rybak MJ Validation of the effectiveness of a vancomycin nomogram in achieving target trough concentrations of 15-20 mg/L suggested by the vancomycin consensus guidelines Pharmacotherapy 2011 31 5 441 448 10.1592/phco.31.5.441 21923425 \n15 O'brien KA Mok S Evaluation of the safety of a vancomycin nomogram used to achieve target trough concentrations Hosp Pharm 2015 50 10 900 910 10.1310/hpj5010-900 27729678 \n16 Leu WJ Liu YC Wang HW Chien HY Liu HP Lin YM Evaluation of a vancomycin dosing nomogram in achieving high target trough concentrations in Taiwanese patients Int J Infect Dis 2012 16 11 e804 e810 10.1016/j.ijid.2012.07.005 22917921 \n17 Finch NA Zasowski EJ Murray KP Mynatt RP Zhao JJ Yost R Pogue JM Rybak MJ The impact of vancomycin area under the concentration-time curve-guided dosing on vancomycin-associated nephrotoxicity: a quasi-experiment Antimicrob Agents Chemother 2017 61 12 e01293 e01217 10.1128/AAC.01293-17\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1885-642X",
"issue": "16(3)",
"journal": "Pharmacy practice",
"keywords": "Drug Dosage Calculations; Drug Monitoring; Nomograms; Obesity; Retrospective Studies; Vancomycin",
"medline_ta": "Pharm Pract (Granada)",
"mesh_terms": null,
"nlm_unique_id": "101530029",
"other_id": null,
"pages": "1204",
"pmc": null,
"pmid": "30416622",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "22917921;22610026;28923869;26716105;19569969;26912920;27117446;27729678;25203631;21411801;26343549;21923425;3530582;21923452",
"title": "Evaluation of a vancomycin dosing nomogram in obese patients weighing at least 100 kilograms.",
"title_normalized": "evaluation of a vancomycin dosing nomogram in obese patients weighing at least 100 kilograms"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2018SP008838",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional"... |
{
"abstract": "The myelopathy and neuropathy associated with chronic misuse of nitrous oxide are potentially reversible if the habit is discontinued. This occurred in each of the reported cases, including our case, when it was transiently discontinued. Although a causal relationship between nitrous oxide and this myelopathy-neuropathy has not been proved, the circumstantial evidence is convincing. Both physicians and dentists should be aware of this potentially serious complication of chronic self-administration of nitrous oxide, especially in persons inclined to misuse drugs. Dentists, with their access to nitrous oxide, may be particularly at risk.",
"affiliations": null,
"authors": "Gutmann|L|L|;Farrell|B|B|;Crosby|T W|TW|;Johnsen|D|D|",
"chemical_list": "D009609:Nitrous Oxide",
"country": "England",
"delete": false,
"doi": "10.14219/jada.archive.1979.0009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-8177",
"issue": "98(1)",
"journal": "Journal of the American Dental Association (1939)",
"keywords": null,
"medline_ta": "J Am Dent Assoc",
"mesh_terms": "D000328:Adult; D003815:Dentists; D006801:Humans; D008297:Male; D009609:Nitrous Oxide; D010292:Paresthesia; D012651:Self Medication; D019966:Substance-Related Disorders",
"nlm_unique_id": "7503060",
"other_id": null,
"pages": "58-9",
"pmc": null,
"pmid": "282345",
"pubdate": "1979-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nitrous oxide-induced myelopathy-neuropathy: potential for chronic misuse by dentists.",
"title_normalized": "nitrous oxide induced myelopathy neuropathy potential for chronic misuse by dentists"
} | [
{
"companynumb": "US-ALSI-201400248",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NITROUS OXIDE"
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"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTuberculosis is an important concern following organ transplantation. Unfortunately, several antituberculosis drugs interact with immunosuppressants. This report describes our experience with rifabutin (RBT) in the treatment of acute tuberculosis in a cardiac transplant recipient.\n\n\nMETHODS\nA 61-year-old cardiac transplant recipient developed tuberculosis meningitis during treatment of miliary tuberculosis. RBT was given for 27 days concomitantly with cyclosporine (CsA). CsA concentrations at 0 hour (C<sub>0</sub>) decreased within 3 days of starting RBT. The serum concentration-curve from 0 to 12 hours (AUC<sub>0-12h</sub>)/dose 7 days after starting RBT therapy decreased by 28%, compared to the values before RBT therapy. The apparent clearance at both 7 and 21 days after starting RBT therapy was 1.4 times higher than before RBT therapy.\n\n\nCONCLUSIONS\nRBT has fewer drug-drug interactions than rifampin and should be preferentially used for the treatment of tuberculosis in transplant patients treated with CsA. Close monitoring of CsA blood concentration during RBT therapy minimized the risk of under- or over-immunosuppression in a cardiac transplant patient.
.",
"affiliations": null,
"authors": "Takayoshi|Maya|M|;Wada|Kyoichi|K|;Terada|Yuka|Y|;Matsuda|Sachi|S|;Nakagita|Kazuki|K|;Oita|Akira|A|;Takada|Mitsutaka|M|;Shionoiri|Aki|A|;Sunami|Haruki|H|;Nakajima|Seiko|S|;Kuroda|Kensuke|K|;Sato|Takuma|T|;Seguchi|Osamu|O|;Yanase|Masanobu|M|;Fukushima|Norihide|N|",
"chemical_list": "D000904:Antibiotics, Antitubercular; D017828:Rifabutin; D016572:Cyclosporine",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP203137",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "56(4)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000904:Antibiotics, Antitubercular; D016572:Cyclosporine; D004347:Drug Interactions; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D017828:Rifabutin; D014376:Tuberculosis",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "184-188",
"pmc": null,
"pmid": "29350178",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of rifabutin to treat tuberculosis in a cardiac transplant recipient: A case report
.",
"title_normalized": "use of rifabutin to treat tuberculosis in a cardiac transplant recipient a case report"
} | [
{
"companynumb": "JP-CONCORDIA PHARMACEUTICALS INC.-E2B_00011461",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
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"drugaddi... |
{
"abstract": "Finasteride is an important drug for the management of androgenetic alopecia. However, there are concerns about the possible side effects of the drug such as impotence. Recently stray reports have appeared about the occurrence of male breast carcinoma in patients who received the drug. These have been looked in to by Medicines and Health care products Regulatory Agency (MHRA). This article summarizes the MHRA report.",
"affiliations": "#301-B, Ranka Colony, Bilekahalli, Bannerghatta Road, Bangalore - 560 076, India.",
"authors": "Shenoy|Niraj K|NK|;Prabhakar|Sangolli M|SM|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0974-2077.69022",
"fulltext": "\n==== Front\nJ Cutan Aesthet SurgJCASJournal of Cutaneous and Aesthetic Surgery0974-20770974-5157Medknow Publications India 21031070JCAS-3-10210.4103/0974-2077.69022CommentaryFinasteride and Male Breast Cancer: Does the MHRA Report Show a Link? Shenoy Niraj K Prabhakar Sangolli M 1#301-B, Ranka Colony, Bilekahalli, Bannerghatta Road, Bangalore - 560 076, India1 11th Cross, Gayathrinagar HBCS Layout, Basaveshwaranagar, Bangalore - 560 079, IndiaAddress for correspondence:Dr. Niraj Shenoy, #301-B, Ranka Colony, Bilekahalli, Bannerghatta Road, Bangalore - 560 076, India. E-mail: knirajshenoy@gmail.comMay-Aug 2010 3 2 102 105 © Journal of Cutaneous and Aesthetic Surgery2010This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Finasteride is an important drug for the management of androgenetic alopecia. However, there are concerns about the possible side effects of the drug such as impotence. Recently stray reports have appeared about the occurrence of male breast carcinoma in patients who received the drug. These have been looked in to by Medicines and Health care products Regulatory Agency (MHRA). This article summarizes the MHRA report.\n\nFinasteridebreast cancermale\n==== Body\nINTRODUCTION\nFinasteride is a competitive and specific inhibitor of type II 5α-reductase, an enzyme involved in the conversion of testosterone to dihydrotestosterone (DHT), which is the main androgen involved in the pathogenesis of benign prostatic hyperplasia (BPH) and androgenetic alopecia. Five milligrams finasteride daily is used as a treatment for BPH and 1 mg Finasteride daily is used in the treatment of androgenetic alopecia. Inhibition of type II 5a-reductase with finasteride results in significant and rapid decrease in serum and tissue DHT concentrations, with significant suppression of DHT reached within 24 hours of dosing. Finasteride inhibits DHT-mediated effects on target tissues without lowering serum testosterone levels or affecting testosterone-mediated effects in tissues.[1]\n\nThere have been several questions raised about the safety profile of finasteride. Possible side effects such as decreased libido and other sexual side effects, like gynecomastia, and possible link to prostatic cancer have been the topics of debate.[2–5] Since finasteride is an important drug in the management of androgenetic alopecia and BPH, this issue has received a lot of publicity, particularly over the Internet. While several studies have established its safety, there is generally a great hesitation to accept the drug among patients, particularly because the drug is not completely curative, and hence, needs to be taken for several years.\n\nIn addition to these previously reported side effects, recently a possible and rather disturbing effect is also observed. There has been an increase in the number of case reports of male breast cancer associated with the use of finasteride as pointed out in a recent report[6] of Medicines and Health care products Regulatory Agency (MHRA). MHRA is the government agency responsible for the regulation medicines and medical devices in the United Kingdom (UK). They regularly review safety of all medicines in UK and inform health care personnel and public of the latest updates. In public assessment reports, they discuss evidence-based concerns associated with a particular drug or its class. Present report presents a summary of the MHRA report on the possible risk of carcinoma of breast in males with long term usage of finasteride.\n\nBACKGROUND INFORMATION ABOUT CARCINOMA BREAST IN MEN\nMale breast cancer is a rare disease with an incidence in general population of 1/100000 man- years which is 100 times less in comparison to the incidence observed in finasteride-treated population.[7] The consequence of this rarity is that male breast cancer has been understudied in comparison to female breast cancer, and the existing small sample size limits the epidemiological methodology available to study the disease. In men, its behaviour is similar to breast carcinoma in postmenopausal women. Age of onset is between 52–71 years in females and 71 years in males.[8] The clinical manifestations of male breast cancer include breast mass (seen in 75% of patients), nipple retraction (9%), nipple discharge (6%), skin/nipple ulceration (6%) and Paget’s disease of the nipple (1%).[9] The survival rate for men with breast cancer is lower than the rate of survival for women with the same disease because of their increased age at diagnosis and more advanced stage of the disease at presentation. Carcinoma of breast is more often than not an oestrogen receptor sensitive tumour. The source of oestrogen in males is conversion of testosterone to oestrogen and androstenedione to oestrone in fat cells.[10] Survival rate is less in male patients due to the advanced age of patients, advanced stage of disease at the time of detection and lack of awareness in men.[11] However, there is no significant difference in survival rates in men in comparison with female patients if age-matched and stage-matched incidence is compared.[12] Nearly 20% of male patients have a family history of carcinoma of breast among female relatives.[13] Risk factors for male breast carcinoma include BRCA1 and BRCA2 mutations, Klinefelter’s syndrome, altered testosterone and oestrogen balance, testicular disorders, obesity, carcinoma of prostate and its treatment. Contradictory evidence has been reported in literature about gynecomastia as a risk factor for breast cancer in males with evidence both for[14] and against it.[15]\n\nREVIEW OF DATA ABOUT MALE BREAST CARCINOMA OCCURRING IN PATIENTS RECEIVING FINASTERIDE\nAs of November 2009, there have been 50 worldwide case reports of male breast cancer in BPH patients aged between 54 and 88 years (mean age of 71 years), who received 5 mg finasteride. The time to onset could be estimated in 35 of the reports; a mean time to onset being approximately 44.4 months from the commencement of treatment. The median time to onset was 36 months (range: 5 weeks–11 years). Twenty-seven cases occurred after finasteride treatment for a minimum of 1 year. Three cases have been reported with the use of Propecia® 1 mg for androgenetic alopecia. Of the 3 cases of male breast cancer reported with Propecia® 1 mg, inadequate information and the relatively short times to onset in these cases makes the causal association between male breast cancer and finasteride unlikely.[6]\n\nPre-clinical data\nIn rats, high dose of finasteride for a long period did not result in malignancy.[16] However, clinical data have emerged on this subject, which are reviewed below.\n\nClinical data\nData from UK\nFive cases of carcinoma of breast were retrieved from the Adverse Drug Reaction (ADR) profile involving finasteride for treatment of BPH.[17] Gynecomastia was the most common ADR in reproductive and breast disorders system organ class (SOC). A total of 75 cases of carcinoma of breast were recorded (69 with 5 mg/d, 4 cases with 1 mg/d, 2 cases the dosage was unknown).\n\nData from world literature\nWorldwide search yielded 50 cases in BPH patients including 44 cases with medically proven reports. Time to onset could be estimated in 35 cases, with the mean being 44.4 months from the commencement of treatment (range: 5 weeks–11 years). Out of the 35 cases, 27 developed malignancy more than one year after treatment initiation and 8 developed carcinoma within 1 year after initiation of therapy. In 7 patients, finasteride was discontinued (7–24 months) before the onset of cancer. Eight patients continued finasteride even after the detection of malignancy. In 3 cases, finasteride was administered for only a few months before the appearance of malignancy, and hence, the drug could not be regarded to have been causative. Under reporting is the major problem in ADR scheme.[18]\n\nAlso, 4 cases of carcinoma of breast have been reported in female patients within 1 year of finasteride administration. It is possible that short duration of finasteride therapy may be sufficient to induce carcinoma of breast in women because of the presence of endogenous oestrogen.\n\nProscar long term efficacy and safety study\nProscar long term efficacy and safety study (PLESS), 3040 patients were followed up for a period of 4 years.[19] The patients were randomised in approximately equal proportions to receive either 5 mg finasteride or placebo for up to 4 years In this study, there were no cases of male breast cancer reported in finasteride-treated subjects, and 2 cases were reported in placebo-treated subjects.\n\nMedical therapy of prostatic symptoms\nIn this study,[20] 3047 patients were randomised to a double-blind, multi-centre, placebo-controlled clinical trial for 4-6 years. The 4 different patient groups were administered different drugs: placebo; 8 mg doxazosin; 5 mg finasteride and a combination of 8 mg doxazosin and 5 mg finasteride. Three cases of breast cancer occurred in the finasteride-treated group and 1 case of breast cancer occurred in the combination group. No predisposing factors were identified. Duration of treatment ranged from 1.8 years to 5 years. The occurrence of 4 cases of breast cancer in 3047 patients was considered high considering the incidence in the general population of 1 case in 100,000 man-years. There was temporal relationship in all the 4 cases and it cannot be stated to have occurred by chance, as suggested by some authors. Treatment with finasteride appeared to confer 200-fold risk for breast cancer in comparison to patients not receiving the drug.\n\nProstate cancer prevention trial (PCPT)\nIn the PCPT study,[3] 18882 men aged 55 years or older with a normal digital rectal examination and a prostate-specific antigen (PSA) level of 3 ng/mL or lower were randomized to treatment with 5 mg/day finasteride (n = 9423) or placebo (n = 9459) for 7 years. Prostate biopsy was recommended if the annual PSA level, adjusted for the effect of finasteride, exceeded 4 ng/mL or if the result of a digital rectal examination was abnormal. The primary endpoint was the prevalence of prostate cancer during the 7 years of the study. One case of breast cancer was reported as an adverse experience in each treatment group during the study. The temporal relationship of 7 years makes a causal association in the finasteride case possible. However, a similar time to onset of 6 years was observed in the placebo case. In this very large long-term study, an increased incidence of breast cancer in the finasteride group compared to placebo was not observed.\n\nPrescription event monitoring\nWas conducted by Drug Safety Research Unit (DSRU).[4] In a non-intervention observation cohort study, a total of 14772 patients were under observation of General Practitioners from 1992–1994. Of the patients, all but 5 were male (2 were female and the gender was unknown for 3 patients), and the average age was (mean [standard deviation]) 69 (9·2) years. The indication for use in 83% of the cases was prostatism and related conditions, and was unspecified in 15%, although 1 female was treated with finasteride for hirsutism. During this period, 95 events with finasteride use were reported as ADRs in 75 patients. The most frequent ADR reported was impotence, with impotence or ejaculatory failure occurring in 2.1% of the cohort. Gynecomastia and related conditions occurred in 0·4% of the cohort; 17 patients experienced other unspecified breast disorders and mastalgia occurred in 4 patients. A total of 33 events concerning malignancies were reported in patients, of these, 2 were reported as breast carcinoma. For one of the events, the time to onset from commencement of finasteride treatment was recorded as 5 months, the other was unknown. Four events of non-malignant breast tumour were also recorded but no further information is known about these cases.\n\nThe PEM study concludes overall that that finasteride is acceptably safe when used in accordance with the current prescribing information. However, it is not possible from this study to evaluate the cases of breast cancer and their causal relationship with finasteride, as enough data is not available regarding the 2 events of breast carcinoma and 4 events of non-malignant breast tumour. Furthermore, the short period of observation limits the possible number of cases which could be identified within this period.\n\nOther reports\nOther reports have revealed confusing data. Food and Drug Administration (FDA) reported 13 cases who had received finasteride for BPH between 1992 and 2003.[21] Average age of the patients was 66 years. Duration of the treatment was 21 months. Among the 13, 4 patients had gynecomastia. Carter[22] reported 2 cases, 1 on finasteride for 35 days (age-59 years), and the other on finasteride (age-63 years) for 21 months.\n\nSurprisingly, 3 cases of cancer of breast have been reported in patients on selective serotonin reuptake inhibitors (SSRI).[23] Ekman did not find any patient with breast cancer in his study of patients on finasteride for BPH.[5] Gynecomastia was not considered a risk factor for malignancy in finasteride treated patients as its incidence is only 9%[24] as compared to 50% incidence in general population.\n\nPOTENTIAL BIOLOGICAL MECHANISMS\nRisk factors for breast carcinomas stated earlier include age, Klinefelter’s syndrome, genetic mutations, family history of breast cancer, radiation exposure, alcohol cirrhosis, chronic liver disease leading on to hyperoestrogenism, testicular diseases like cryptorchidism, orchitis, orchiectomy, testicular injury, obesity, working in hot environments, exposure to gasoline fumes, benign breast conditions like nipple discharge, breast cyst and Jewish ancestory.[25]\n\nThe mechanism by which finasteride could cause male breast cancer is thought to be via altering hormone levels. As stated earlier, finasteride leads to altered oestrogen/testosterone balance. Role of oestrogen in breast carcinoma is considered important. Testosterone is converted to oestradiol and androstenedione is converted to oestrone in fat cells. Increased oestrogen/testosterone ratio in a patient may lead to malignant transformation.[26] Oestrogen-blocking drug like tamoxifen and aromatase inhibitor anastrozole prove this point.[27] Either the slight increase in oestrogen or the reduction in the ratio of potency of androgens to that of oestrogens (due to reduced DHT levels) or both could be the responsible mechanism/s in finasteride-associated male breast cancer.\n\nOestrogen is genotoxic, mutagenic and has transforming and carcinogenic potential.[28] It increases telomerase activity which causes cell division, hence may cause neoplasia. Increased concentration of testosterone leads to its conversion to oestradiol resulting in increased levels of oestrogen as has been established in finasteride (1 mg/d) study by Vaughen et al.[29]\n\nCONCLUSION\nThe exhaustive and meticulous analysis of data presented in MHRA report need to be considered seriously and the matter needs to be investigated further. Whether the reported link needs to be informed during the patient’s counselling is a matter under consideration of the drug authorities. Any symptom suggestive of breast pathology (nipple discharge, pain or swelling in the breast) in a patient on finasteride needs to be seriously examined and investigated thoroughly. MHRA report is available on the internet, which may be read by prospective patients and hence treating physicians need to be aware of the report so that proper counseling can be provided. Topical finasteride, in better pharmulations, to ensure proper absorption, is a possible alternative for management androgenetic alopecia. This also underscores the need for greater research in to the pharmacological treatment of androgenetic alopecia.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Stoner E The Clinical Development of 5α-reductase inhibitor, finasteride J Steroid Biochem Mol Biol 1990 37 375 8 1701660 \n2 Nickel JC Fradet Y Boake RC Pommerville PJ Perreault JP Afridi SK Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2 year randomized controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two Year Study CMAJ 1996 155 1251 9 8911291 \n3 Thompson IM Goodman PJ Tangen CM Lucia MS Miller GJ Ford LG The Influence of finasteride on the development of prostate cancer N Engl J Med 2003 349 215 24 12824459 \n4 Wilton L Pearce G Edet E Freemantle S Stephens sMD Mann RD The safety of finasteride used in benign prostatic hypertrophy: a non-interventional observational cohort study in 14,772 patients Br J Urol 1996 78 379 84 8881946 \n5 Ekman P A risk- benefit assessment of treatment with finasteride in benign prostatic hyperplasia Drug Saf 1998 18 161 70 9530536 \n6 Post-marketing reports of male breast cancer, UK MHRA Assessment, April 2010 \n7 Lee SC Ellis RJ Male breast cancer during finasteride therapy J Natl Cancer Inst 2004 96 338 9 14970289 \n8 Anderson WF Althuis MD Brinton LA Is male breast cancer similar or different from female breast cancer? Br Cancer Res Treat 2004 83 77 86 \n9 Jepson AS Fentiman IS Male breast cancer Int J Clin Pract 1998 52 571 6 10622057 \n10 Siiteri PK MacDonald PC Greep RO Astwood EB Role of extra glandular estrogen in human endocrinology Handbook of Physiology 1973 Vol 2 Washington, DC American Physiological Society \n11 Erhan Y Zekloglu O Erhan Y Invasive lobular carcinoma of the male breast Can J Surg 2006 49 365 6 17152578 \n12 Ioka A Tsukuma H Ajiki W Oshima A Survival of male breast cancer patients: a population-based study in Osaka, Japan Jpn J Clin Oncol 2006 36 699 703 17012302 \n13 Ewertz M Holmberg L Tretli S Pedersen BV Kristensen A Risk factors for male breast cancer-a case control study from Scandinavia Acta Oncol 2001 1 467 71 11504305 \n14 Weiss JR Moysich KB Swede H Epidemiology of male breast cancer Cancer Epidemiol Biomarkers Prev 2005 14 20 6 15668471 \n15 Fentiman IS Fourquet A Hortobagyi G Male breast cancer Lancet 2006 367 595 604 16488803 \n16 Available from: http://www.medsafe.govt.nz/Profs/Datasheet/f/Fintraltab.pdf [last cited on 2010 Jun 2] \n17 UK cases of male breast cancer with finasteride reported to the MHRA;3.1.1; The risk of male breast cancer with finasteride; MHRA Public Assessment Report, December 2009 \n18 Rawlins MD EURO-ADR: pharmacovigilance and research: a european perspective Pharmacoepidemiol Drug Saf 1992 1 262 8 \n19 McConnell JD Bruskewitz R Walsh P Andriole G Lieber M Holtgrewe HL The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia N Engl J Med 1998 338 557 63 9475762 \n20 McConnell JD Roehrborn CG Bautista OM Andriole GL Jr Dixon CM Kusek JW The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia N Eng J Med 2003 349 2387 98 \n21 Wysowski DK Farinas E Finasteride in benign prostatic hyperplasia N Engl J Med 2004 350 1359 61 15044649 \n22 Carter HB Pearson JD Metter J Finasteride-an update and review Cutis 1999 64 167 72 10500917 \n23 Wallace WA Balsitis M Harrison BJ Male breast neoplasia in association with selective serotonin reuptake inhibitor therapy: a report of three cases Eur J Surg Oncol 2001 27 429 31 11417992 \n24 Fentiman IS Detection and treatment of early breast cancer 1990 London Martin Dunitz 207 17 \n25 Giordano SH Buzdar AU Hortobagyi GN Breast cancer in men Ann Intern Med 2002 137 678 87 12379069 \n26 Thomas DB Jimenez LM McTiernan A Rosenblatt K Stalsberg H Stemhagen A Breast cancer in men: Risk factors and hormonal implications Am J Epidemiol 1992 135 734 8 1350708 \n27 Suzuki T Miki Y Ohuchi N Sasano H Intratumoral estrogen in breast carcinoma: significance of aromatase Breast Cancer 2008 15 270 7 18622573 \n28 Yager JD Davidson N Estrogen carcinogenesis in male breast cancer N Engl J Med 2006 354 270 82 16421368 \n29 Vaughan C Felicia C Goldstein J Lisa Tenover. Exogenous testosterone alone or with finasteride does not improve measurements of cognition in healthy older men with low serum testosterone J Androl 2007 28 875 82 17609296\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0974-2077",
"issue": "3(2)",
"journal": "Journal of cutaneous and aesthetic surgery",
"keywords": "Finasteride; breast cancer; male",
"medline_ta": "J Cutan Aesthet Surg",
"mesh_terms": null,
"nlm_unique_id": "101525405",
"other_id": null,
"pages": "102-5",
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"pmid": "21031070",
"pubdate": "2010-05",
"publication_types": "D016428:Journal Article",
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"title": "Finasteride and Male Breast Cancer: Does the MHRA Report Show a Link?",
"title_normalized": "finasteride and male breast cancer does the mhra report show a link"
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"abstract": "To describe and evaluate the effectivity of a novel precision intravitreal injection technique for select cases of localized vitreous seeding in retinoblastoma.\nPatients with localized vitreous seeds from retinoblastoma received intravitreal chemotherapy via a precision injection technique (P-IVitC) intended to optimize local delivery of melphalan to target seeds. The needle was inserted trans-pars plana and chemotherapy deposited within 3 mm of the target seed(s) under indirect ophthalmoscopic guidance. Without subsequent globe manipulation, the head was then positioned to promote gravity-dependent settling of chemotherapy.\nThere were 8 eyes of 8 patients treated with P-IVitC for active vitreous seeds following adequate solid tumor control with intravenous chemotherapy (n = 3, 38%) or intra-arterial chemotherapy (n = 5, 63%). Viable vitreous seeds were primarily solitary spheres (n = 6, 75%) and measured an average of 2.7 mm in diameter. Vitreous seed resolution (n = 8, 100%) was noted after a mean of 2.6 injections (median 2; range 1-3) of 20 μg melphalan. There was no recurrence at a mean follow-up of 10.0 months. Only 1 eye had an associated complication (focal retinal pigment epithelial mottling, n = 1, 13%).\nWith direct delivery of chemotherapy to within 3-4 mm of vitreous seed activity, P-IVitC provided complete control of localized vitreous seeds with minimal toxicity.",
"affiliations": "Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.;Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.;Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.;Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.",
"authors": "Yu|Michael D|MD|;Dalvin|Lauren A|LA|;Welch|R Joel|RJ|;Shields|Carol L|CL|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000491432",
"fulltext": null,
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"issn_linking": "2296-4657",
"issue": "5(4)",
"journal": "Ocular oncology and pathology",
"keywords": "Intravitreal chemotherapy; Melphalan; Precision injection; Retina; Retinal toxicity; Retinoblastoma",
"medline_ta": "Ocul Oncol Pathol",
"mesh_terms": null,
"nlm_unique_id": "101656139",
"other_id": null,
"pages": "284-289",
"pmc": null,
"pmid": "31367592",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "17934752;22581303;23044940;23459465;24227979;24407202;24819859;24949111;25014750;25667683;25795478;26378747;26630319;26785130;27486728;28264098;29098285;8533651",
"title": "Precision Intravitreal Chemotherapy for Localized Vitreous Seeding of Retinoblastoma.",
"title_normalized": "precision intravitreal chemotherapy for localized vitreous seeding of retinoblastoma"
} | [
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"companynumb": "US-APOPHARMA USA, INC.-2018AP022840",
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"abstract": "We describe a woman with no previous liver disease who developed drug-induced autoimmune hepatitis from hydralazine prescribed to her for hypertension. Despite the discontinuation of the medication, she developed acute liver failure and subsequently underwent successful liver transplantation. She survived and had a good clinical outcome.",
"affiliations": "Department of Medicine, University of California at Los Angeles, Los Angeles, CA.;Department of Medicine, University of California at Los Angeles, Los Angeles, CA.;Department of Medicine, University of Nevada Las Vegas, Las Vegas, NV.;Department of Surgery, University of California at Los Angeles, Los Angeles, CA.;Department of Pathology, University of California at Los Angeles, Los Angeles, CA.;Department of Medicine, University of California at Los Angeles, Los Angeles, CA.;Department of Medicine, University of California at Los Angeles, Los Angeles, CA.;Department of Medicine, University of California at Los Angeles, Los Angeles, CA.",
"authors": "Grewal|Jasleen|J|;Doan|Angela|A|;Hong|Annie S|AS|;Amin|Arpit|A|;Scapa|Jason V|JV|;Hanna|Ramy|R|;Durazo|Francisco|F|;Yanny|Beshoy|B|",
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"doi": "10.14309/crj.0000000000000252",
"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JACGCRJACGCRJAC9ACG Case Reports Journal2326-3253Wolters Kluwer Maryland, MD ACGCR-19-042110.14309/crj.000000000000025200025Case ReportLiverDrug-Induced Autoimmune Hepatitis From Hydralazine Leading to Acute Liver Failure and Liver Transplantation Grewal Jasleen MD1Doan Angela NP1Hong Annie S. MD2Amin Arpit MD3Scapa Jason V. MD4Hanna Ramy MD1Durazo Francisco MD13Yanny Beshoy MD11 Department of Medicine, University of California at Los Angeles, Los Angeles, CA2 Department of Medicine, University of Nevada Las Vegas, Las Vegas, NV3 Department of Surgery, University of California at Los Angeles, Los Angeles, CA4 Department of Pathology, University of California at Los Angeles, Los Angeles, CACorrespondence: Beshoy Yanny, MD, UCLA Health Santa Monica, 1223 16th St Suite: 3100, Santa Monica, CA 90404 (byanny@mednet.ucla.edu).10 2019 23 10 2019 6 10 e0025229 5 2019 11 9 2019 © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.2019This 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.ABSTRACT\nWe describe a woman with no previous liver disease who developed drug-induced autoimmune hepatitis from hydralazine prescribed to her for hypertension. Despite the discontinuation of the medication, she developed acute liver failure and subsequently underwent successful liver transplantation. She survived and had a good clinical outcome.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nDrug-induced liver injury (DILI) is a significant cause of morbidity and mortality, accounting for at least 13% of acute liver failure cases in the United States.1 It is the leading cause of acute liver failure among patients referred for liver transplantation and the most common reason that drugs in development do not obtain the Food and Drug Administration approval. The incidence of DILI has been reported to be 1:10,000 to 1:100,000 patients; however, the actual incidence is probably higher in part because of the difficulty in diagnosis.2 Liver damage can range from benign elevations in the liver enzymes that resolve after the discontinuation of the offending agent, all the way to liver failure and even death. This case highlights a rare but important cause of drug-induced autoimmune liver injury, ultimately leading to acute liver failure and requiring liver transplantation.\n\nCASE REPORT\nA 51-year-old woman with a history of hypertension, diabetes, coronary artery disease requiring stent placement, and cerebrovascular accident with left-sided residual weakness presented to the hospital for 2 months of generalized fatigue, malaise, poor appetite, nausea, and worsening altered mental status. In the last 2 weeks, her symptoms had progressively worsened and were subsequently brought into the hospital by her family.\n\nThe patient had no known drug allergies. Three months before admission, the patient was started on hydralazine 10 mg per oral (PO), 3 times per day because of difficulty in controlling high blood pressure. She had no other new medications but was also taking the following at home: amlodipine 10 mg PO daily, carvedilol 6.25 mg PO 2 times per day, lisinopril 5 mg PO daily, and aspirin 325 mg PO daily. Owing to the patient's altered mental status, a thorough social history was obtained from the family. They reported that the patient did not engage in any high-risk behaviors that would put her at risk for viral hepatitis, alcoholic hepatitis, or nonprescription DILI.\n\nVitals signs were within the normal range, and physical examination findings were consistent with scleral icterus, dry mucous membranes, and no rashes on the skin including the face. Her chest was without spider angiomas, abdomen with no hepatosplenomegaly, no shifting dullness, no surgical scar, normoactive bowel sounds, extremities without palmar erythema, and no pitting edema. The neurological examination noted that the patient opens her eyes to noxious stimuli (sternal rub) but otherwise does not respond to verbal commands. Asterixis were present; Table 1 lists all pertinent laboratory findings.\n\nTable 1. Laboratory studies\n\nWith no previous history of chronic liver disease, international normalized ratio above 1.5, and worsening altered mental status, the patient was deemed to be in acute liver failure meeting King's College criteria for nonacetaminophen-induced acute liver failure.3 After extensive negative workup, the etiology was determined to be secondary to DILI in an autoimmune fashion, likely because of hydralazine. The remainder of the patient's medications were reviewed on the National Institute of Health LiverTox website showing no association with drug-induced autoimmune hepatitis (DI-AIH), in particular, carvedilol and lisinopril.4 The patient required a liver transplantation and explant pathology confirmed the diagnosis (Figure 1). A liver biopsy was not obtained before transplantation because of the patient's continued coagulopathy and high risk of bleeding. Furthermore, the patient had no contraindications to liver transplantation. Therefore, a liver biopsy would not have changed the management. Post-transplant, the patient recovered well and was discharged home after 10 days of postoperative hospitalization. The patient presented to the liver transplant clinic at a follow-up and was back to functional baseline having normal graft function without evidence of graft rejection in the first-year post-transplant.\n\nFigure 1. Histologic hematoxylin and eosin stained sections of explant pathology at (A) magnification 4×, (B) magnification 10×, and (C) magnification 20×, showing diffuse panlobular hepatocyte necrosis and focal areas of centrilobular zone III necrosis and small areas of intact tissue. There was extensive hepatocellular dropout with stromal collapse and replacement by mixed inflammatory cell infiltrates composed predominantly of lymphocytes and ductular reaction. Minimal hepatocellular cholestasis was seen. The native bile ducts appeared unremarkable. (D) Trichrome and (E) reticulin stain showing similar findings with no fibrosis (magnification 10×). An iron stain shows (F) focal hemosiderin deposition within viable hepatocytes (magnification 10×).\n\nThe gross examination of the 833 g total hepatectomy specimen, and the attached gallbladder showed a smooth pink liver capsule with cut sections, demonstrating a tan-brown homogeneous surface with focal hemorrhage. No masses, lesions, or dominant nodules were identified within the liver parenchyma, grossly. The hepatic and portal veins were patent without evidence of thrombi. The gallbladder was unremarkable. Histologic sections of the liver demonstrated diffuse hepatocyte necrosis and interface hepatitis, consistent with fulminant autoimmune hepatitis.\n\nDISCUSSION\nHydralazine is a commonly used antihypertensive drug which acts by direct relaxation of arteriolar smooth muscle, probably by alteration in intracellular calcium signaling.1 The mechanism for liver injury is thought to be because of its metabolism to an immunologic adduct that can result in immunoallergic hepatitis or delayed lupus-like and/or autoimmune hepatitis-like syndrome.1 Hydralazine, similar to isoniazid, is metabolized by N-acetyltransferase, and hepatic injury may be more frequent with specific genetic variants in N-acetyltransferase activity.1 Liver injury secondary to hydralazine can range from a mild immunologic reaction that self-resolves after discontinuation of the drug to liver failure requiring liver transplantation.\n\nThis case highlights the findings in DI-AIH and persistence of liver failure requiring transplantation despite discontinuation of the offending agent. We noted antinuclear antibodies and anti-smooth muscle positivity on serology suggestive of AIH, which were negative in the past in our patient. Workup, including urine and blood drug screens, resulted negative. Liver biopsy described scarce plasma cells and interphase hepatitis further supporting the diagnosis of AIH. The temporal relationship of hydralazine use, the absence of a previous history of liver disease, and compatible histology are highly suggestive of hydralazine as the culprit cause. Furthermore, the liver biopsy did not show any evidence of steatosis or steatohepatitis. Our patient met several diagnostic criteria for AIH as established in the AASLD guidelines for AIH, with previously described compatible liver histology, positive AIH serum biomarkers, immunochemistries, and autoantibodies, along with negative viral markers and other potential etiological factors for her fulminant hepatitis. Her pretreatment aggregate score for AIH was > 15, which correlated with a “definitive diagnosis.”5 Physical examination findings included the absence of spider angiomas, palmar erythema, and ascites; therefore, there was no suggestion of chronic liver disease on history and physical examination to indicate previous non-alcoholic steatohepatitis of episodes or multiple episodes of AIH flares. A computed tomography scan of the abdomen also did not show any findings suggestive of sequela of portal hypertension such as splenomegaly or formation of collaterals. This was a new insult to the liver causing acute liver failure with very low likelihood of acute on chronic liver injury.\n\nAutoimmune hepatitis and DI-AIH can mimic each other serologically, and on liver biopsy, a high clinical suspicion must be present.6 On pathology, both idiopathic AIH and DI-AIH cases will have interface hepatitis, focal necrosis, and portal inflammation, but these findings tend to be more severe in idiopathic AIH rather than DI-AIH. Our patient had some hepatocellular cholestasis which can help distinguish idiopathic AIH from DI-AIH. However, we did not see portal neutrophils which tend to be more prevalent in DI-AIH.7 In our case, the temporal relationship with hydralazine administration, lack of evidence for chronic liver disease, and negative AIH serologies in the past were key in diagnosing DI-AIH. Our patient was instructed not to receive hydralazine in the future as the liver damage can recur. Hydralazine has been implicated in DI-AIH in the past with a similar pattern of DI-AIH liver injury.8–10 The previously reported case studies suggest that a lupus-like syndrome can be present at times.10 Our patient did not have any rashes to suggest a lupus-like syndrome.\n\nIn conclusion, DI-AIH is a rare but serious event that can often be difficult to diagnose.1,2,11 A high degree of clinical suspicion is required for the diagnosis of DI-AIH. This diagnosis should be suspected in patients who develop liver injury and an immunoallergic reaction while taking a drug implicated in this type of liver injury. Complete recovery of liver injury is most often seen with DI-AIH; however, cases of prolonged injury may occur, requiring treatment with immunosuppressive therapy, and cases such as ours requiring liver transplantation have been described. This type of liver injury should be documented in the medical record to avoid rechallenge with the drug in the future.\n\nDISCLOSURES\nAuthor contributions: J. Grewal analyzed and interpreted the data and drafted and revised the manuscript. A. Doan and AS Hong wrote and revised the manuscript. A. Amin acquired the data and wrote and revised the manuscript. JV Scapa acquired the data. R. Hanna wrote the manuscript. F. Durazo analyzed the data and revised the manuscript. B. Yanny acquired the data, wrote and revised the manuscript, and is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n1. Ostapowicz G Fontana RJ Schiødt FV \nResults of a prospective study of acute liver failure at 17 tertiary care centers in the United States . Ann Intern Med. \n2002 ;137 :947 –54 .12484709 \n2. Larry D \nEpidemiology and individual susceptibility to adverse drug reaction affecting the liver . Semin Liver Dis. \n2002 ;22 :145 –55 .12016546 \n3. O'Grady JG Alexander GJM Hayllar KM \nEarly indicators of prognosis in fulminant hepatic failure . Gastroenterology. \n1989 ;97 :439 –45 .2490426 \n4. National Institutes of Health . Clinical and research information on drug-induced liver injury . https://livertox.nlm.nih.gov/Hydralazine.htm. Accessed July 1, 2019.\n5. Manna M Czaja A Gorham J \nDiagnosis and management of autoimmune hepatitis. AASLD practice guidelines . Hepatology. \n2010 ;51 (6 ):2193 –213 .20513004 \n6. Sebode M Schulz L Lohse AW \n“Autoimmune(-Like)” drug and herb induced liver injury: New insights into molecular pathogenesis . Int J Mol Sci. \n2017 ;18 (9 ):E1954 .28895915 \n7. Suzuki A Brunt E Kleiner D \nThe use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug‐induced liver injury . Hepatology. \n2011 ;54 (3 ):931 –9 .21674554 \n8. Myers JL Augur NA \nHydralazine-induced cholangitis . Gastroenterology. \n1984 ;87 :1185 –8 .6479540 \n9. Hassan A Hammad R Cucco R Niranjan S \nHydralazine-induced cholestatic hepatitis . Am J Ther. \n2009 ;16 :371 –3 .19092641 \n10. Tameda Y Hamada M Takes K Nakano T Kosaka Y \nFulminant hepatic failure caused by ecarazine hydrochloride (a hydralazine derivative) . Hepatology. \n1996 ;23 :465 –70 .8617425 \n11. Russmann S Kullak-Ublick GA Grattagliano I \nCurrent concepts of mechanisms in drug-induced hepatotoxicity . Curr Med Chem. \n2009 ;16 :3041 –53 .19689281\n\n",
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"title": "Drug-Induced Autoimmune Hepatitis From Hydralazine Leading to Acute Liver Failure and Liver Transplantation.",
"title_normalized": "drug induced autoimmune hepatitis from hydralazine leading to acute liver failure and liver transplantation"
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{
"abstract": "It has remained elusive whether standard chemotherapy regimens are safe for patients with ovarian cancer and poor general condition. The purpose of the present study was to assess the response to and toxicity of weekly paclitaxel and carboplatin (W-PC) in patients with ovarian cancer and poor general condition. The subjects were patients with ovarian cancer who received W-PC at Jichi Medical University Hospital (Shimotsuke, Japan) between January 2008 and December 2016. Patients who were ≥80 years old and/or had a performance status ≥3 and/or severe complications/underlying diseases were selected. Patients received paclitaxel (60 mg/m2) and carboplatin (area under the curve 2 mg/ml/min) on days 1, 8, and 15 of a 28-day cycle. Their medical records were retrospectively reviewed. A total of 31 patients were included in the study. Grade 3/4 neutropenia, anemia and thrombocytopenia developed in 18 (58%), 5 (16%) and 1 (3%) patients, respectively. Furthermore, three (10%) patients had a complete response (CR), 12 (39%) had a partial response (PR), 5 (16%) had stable disease and 11 (35%) had progressive disease. The overall response rate was 48% (15/31) and the disease control rate was 65% (20/31). The 5-year progression-free survival was 15% and the 5-year overall survival was 15%. A total of 9 patients survived for >40 months, one of whom survived without recurrence for 122 months. Performance status <3, a tumor response of CR or PR and >5 chemotherapy cycles were indicators of favorable prognosis. Only >5 chemotherapy cycles (vs. ≤5; P=0.002) was an independent good prognostic factor according to multivariate analysis. In conclusion, W-PC was tolerable and slightly effective in patients with ovarian cancer and poor general condition. W-PC may be one option for patients who are unable to receive standard chemotherapy regimens.",
"affiliations": "Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.;Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.;Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.;Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.;Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.;Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.;Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.;Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.;Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.;Department of Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.",
"authors": "Takahashi|Suzuyo|S|;Takei|Yuji|Y|;Tamura|Kohei|K|;Taneichi|Akiyo|A|;Takahashi|Yoshifumi|Y|;Yoshiba|Takahiro|T|;Koyanagi|Takahiro|T|;Narumi|Risa|R|;Saga|Yasushi|Y|;Fujiwara|Hiroyuki|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2021.2449",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "16(1)",
"journal": "Molecular and clinical oncology",
"keywords": "ovarian cancer; poor general condition; response; toxicity; weekly paclitaxel and carboplatin",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "14",
"pmc": null,
"pmid": "34881034",
"pubdate": "2022-01",
"publication_types": "D016428:Journal Article",
"references": "19097774;12792751;12953086;31791688;19767092;15661216;29572761;24219974;24582486;20129130;31851799;22204724;22204725;23208313;30345884;12860964;31562799;25296594",
"title": "Response to and toxicity of weekly paclitaxel and carboplatin in patients with stage IIIC-IV ovarian cancer and poor general condition.",
"title_normalized": "response to and toxicity of weekly paclitaxel and carboplatin in patients with stage iiic iv ovarian cancer and poor general condition"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-339031",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"dru... |
{
"abstract": "During autologous stem cell transplant, granulocyte colony-stimulating factors (G-CSF) serve the integral role of mobilizing hematopoietic cells into the peripheral blood for subsequent collection by leukapheresis. Filgrastim (Neupogen®) is a G-CSF and affects hematopoietic cells by stimulating growth and differentiation of neutrophils. Filgrastim-sndz (Zarxio®), a biosimilar of filgrastim, received landmark approval as the first biosimilar product approved by the FDA in the United States. As a result of the recent FDA approval, our medical center made the conversion in August 2016 from using filgrastim to filgrastim-sndz to provide patients the same benefits of the filgrastim injection at a reduced cost. This retrospective, observational cohort study evaluated the comparative efficacy of the filgrastim-sndz biosimilar in 147 patients who underwent mobilization prior to stem cell transplant with filgrastim between 1 August 2015 and 31 July 2016 or filgrastim-sndz between 1 September 2016 and 30 November 2017. The mean number of CD34 cells collected during apheresis was 7.38 × 106 in the filgrastim group and 8.86 × 106 in the filgrastim-sndz group. Filgrastim-sndz was significantly non-inferior, as the difference between filgrastim and filgrastim-sndz was -1.48 × 106 with an upper 95% confidence bound equal to -0.24 × 106 that did not include the non-inferiority margin of 1 × 106 (p = 0.0006). The median number of days of apheresis was 2 in both groups (p= 0.3273). In conclusion, the biosimilar product was non-inferior for mobilization and the conversion from filgrastim to filgrastim-sndz afforded patients similar efficacy for mobilization in stem cell transplant at a reduced cost.",
"affiliations": "Department of Pharmacy, Wake Forest Baptist Health, Winston-Salem, NC, USA.;Department of Pharmacy, Wake Forest Baptist Health, Winston-Salem, NC, USA.;Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.;Department of Pharmacy, Wake Forest Baptist Health, Winston-Salem, NC, USA.",
"authors": "Curry|Lauren D|LD|https://orcid.org/0000-0002-0410-5358;Anders|Brandi|B|;Dressler|Emily V|EV|;Kennedy|LeAnne|L|",
"chemical_list": "D018952:Antigens, CD34; D059451:Biosimilar Pharmaceuticals; D000069585:Filgrastim",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220941582",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "27(4)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Mobilization; biosimilar; filgrastim; filgrastim-sndz",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34; D059451:Biosimilar Pharmaceuticals; D001781:Blood Component Removal; D018795:Device Approval; D005260:Female; D000069585:Filgrastim; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "871-876",
"pmc": null,
"pmid": "32686616",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy of a conversion from filgrastim to filgrastim-sndz in stem cell transplant patients undergoing mobilization.",
"title_normalized": "efficacy of a conversion from filgrastim to filgrastim sndz in stem cell transplant patients undergoing mobilization"
} | [
{
"companynumb": "US-AMGEN-USASP2021096283",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "Immune checkpoint inhibitor (ICI) therapy has been described to markedly improve patient survival. However, reports describing the antitumor therapeutic efficacy and safety of ICIs in patients with autoantibodies are scarce.\nThis study examined the efficacy and feasibility of ICIs in antinuclear antibody (ANA)-positive patients with non-small cell lung cancer (NSCLC). An ANA titer greater than 1:40 and 1:80 was defined as positive and high, respectively. Patients who were treated with ICIs at Saitama Medical University, International Medical Center between January 2016 and December 2018 were retrospectively reviewed.\nOne hundred and nineteen of the 266 patients (44.7%) who received nivolumab, pembrolizumab, and atezolizumab had positive ANA titers. Their median age was 69 (range, 39-84) years. The overall response rate of the ANA-positive patients was 35.9% (37/103), which was not less than that of the ANA-negative group. The median progression-free survival in the ANA-positive group was 6.3 months versus 4.3 months in the ANA-negative group (p = 0.08). Twenty-seven ANA-positive patients (10.2%) had high ANA titers. However, ICI efficacy was not decreased in these patients. Regardless of the cutoff of ANA titers (1:40 or 1:80), the rate of patients who experienced adverse events were not significantly different between the two groups.\nThe administration of ICIs to ANA-positive patients has clinical benefits. The prevalence of adverse events in the ANA-positive group was not higher than that in the ANA-negative group.",
"affiliations": "Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan.;Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan.;Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan.;Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan.;Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan.;Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan.;Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan.;Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan.;Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan.;Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan.;Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan.",
"authors": "Mouri|Atsuto|A|;Kaira|Kyoichi|K|;Yamaguchi|Ou|O|;Hashimoto|Kosuke|K|;Miura|Yu|Y|;Shiono|Ayako|A|;Shinomiya|Shun|S|;Akagami|Tomoe|T|;Imai|Hisao|H|;Kobayashi|Kunihiko|K|;Kagamu|Hiroshi|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.610952",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.610952\nOncology\nOriginal Research\nEfficacy and Feasibility of Programmed Death-1/Programmed Death Ligand-1 Blockade Therapy in Non-Small Cell Lung Cancer Patients With High Antinuclear Antibody Titers\nMouri Atsuto *\n\nKaira Kyoichi\n\nYamaguchi Ou\nHashimoto Kosuke\nMiura Yu\nShiono Ayako\nShinomiya Shun\nAkagami Tomoe\nImai Hisao\nKobayashi Kunihiko\n\nKagamu Hiroshi\nDepartment of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Saitama, Japan\nEdited by: Antonio Calles, Gregorio Marañón Hospital, Spain\n\nReviewed by: Miguel García Pardo De Santayana, University Health Network, Canada; Jordi Remon, Hospital HM Delfos, Spain\n\n*Correspondence: Atsuto Mouri, mouria@saitama-med.ac.jp\nThis article was submitted to Thoracic Oncology, a section of the journal Frontiers in Oncology\n\n15 3 2021\n2021\n11 61095228 9 2020\n28 1 2021\nCopyright © 2021 Mouri, Kaira, Yamaguchi, Hashimoto, Miura, Shiono, Shinomiya, Akagami, Imai, Kobayashi and Kagamu\n2021\nMouri, Kaira, Yamaguchi, Hashimoto, Miura, Shiono, Shinomiya, Akagami, Imai, Kobayashi and Kagamu\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.\nBackground\n\nImmune checkpoint inhibitor (ICI) therapy has been described to markedly improve patient survival. However, reports describing the antitumor therapeutic efficacy and safety of ICIs in patients with autoantibodies are scarce.\n\nMethods\n\nThis study examined the efficacy and feasibility of ICIs in antinuclear antibody (ANA)-positive patients with non-small cell lung cancer (NSCLC). An ANA titer greater than 1:40 and 1:80 was defined as positive and high, respectively. Patients who were treated with ICIs at Saitama Medical University, International Medical Center between January 2016 and December 2018 were retrospectively reviewed.\n\nResults\n\nOne hundred and nineteen of the 266 patients (44.7%) who received nivolumab, pembrolizumab, and atezolizumab had positive ANA titers. Their median age was 69 (range, 39–84) years. The overall response rate of the ANA-positive patients was 35.9% (37/103), which was not less than that of the ANA-negative group. The median progression-free survival in the ANA-positive group was 6.3 months versus 4.3 months in the ANA-negative group (p = 0.08). Twenty-seven ANA-positive patients (10.2%) had high ANA titers. However, ICI efficacy was not decreased in these patients. Regardless of the cutoff of ANA titers (1:40 or 1:80), the rate of patients who experienced adverse events were not significantly different between the two groups.\n\nConclusion\n\nThe administration of ICIs to ANA-positive patients has clinical benefits. The prevalence of adverse events in the ANA-positive group was not higher than that in the ANA-negative group.\n\nantinuclear antibodies\nimmune-check point inhibitor\nnon-small cell lung cancer\nimmune-related adverse events\nfeasibility\n==== Body\nIntroduction\n\nImmune checkpoint inhibitors (ICIs) improve the survival of patients with advanced lung cancer (1–4). ICIs such as anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) antibodies and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are widely administered to patients with different kinds of neoplasms such as lung cancer, melanoma, renal cancer, urothelial cancer, and Hodgkin’s lymphoma (5–7). However, the management of adverse events is a critical issue, and this needs to be done carefully for the maximum efficacy of ICIs to be obtained. To avoid severe ICI toxicity, physicians should accurately judge the patient’s eligibility for ICI therapy. To prevent unnecessary immune-related adverse events (irAEs), the patient’s autoantibodies are often examined prior to treatment. Antinuclear antibody (ANA) is a key biomarker for evaluating autoimmune disorders (AIDs). Pre-existing AIDs can exacerbate irAEs. Thus, patients with AIDs are excluded from clinical trials. Khan et al. reported that 13.5% of 210,509 patients with lung cancer had AIDs, and majority of the patients were females, elderly, and had early stage disease (8). According to their study, rheumatoid arthritis (5.9%), psoriasis (2.8%), and polymyalgia rheumatica (1.8%) were the most common AIDs (8). It is common to find lung cancer patients with AIDs.\n\nCheckpoint pathways such as PD-1, PD-L1, and CTLA-4 are mechanisms that regulate the immune response. Therefore, it is possible to encounter patients with AIDs during the administration of ICIs, requiring systemic steroid therapy. If there are any patients with active AIDs, ICIs should be avoided to prevent severe irAEs. Regarding patients with increased ANA titers and without active AIDs, it is still unclear whether the initiation of ICIs is clinically possible. Recently, several researchers have reported that it may be possible to administer ICIs without exacerbation of irAEs in patients with advanced non-small cell lung cancer (NSCLC) (9–12). However, the potential of ANA titer as a predictive marker for the efficacy and toxicity of ICIs is still controversial (9–12). As previous research has several limitations, such as limited sample sizes and varying ANA titer cutoffs, we cannot administer ICIs in NSCLC patients without AIDs based on increased ANA titers.\n\nBased on this background, we retrospectively investigated the efficacy and tolerability of anti-PD-1 antibody monotherapy in advanced ANA-positive NSCLC patients without any AIDs.\n\nMaterials and Methods\n\nStudy Design and Patients\n\nBetween February 2016 and December 2018, the data of 271 patients with advanced NSCLC who received anti-PD-1/PD-L1 antibody monotherapy (single-agent nivolumab, pembrolizumab, and atezolizumab) at Saitama Medical University, International Medicine Center were obtained from the hospital’s medical records. Of these 271 patients, 2 patients whose pre-treatment ANA titers were not available were excluded. Three patients with active rheumatoid arthritis were excluded. Finally, 266 patients were eligible for the study. Figure 1 shows the patient selection consort diagram.\n\nFigure 1 Study schema, antinuclear antibody (ANA) titers in 271 patients with advanced NSCLC were assessed before anti-PD-1/PD-L1 antibodies monotherapy administration at Saitama Medical University, International Medicine Center. Patients treated previously with other ICIs (Pembrolizumab and nivolumab including 1st-line therapy) or who did not have pre-treatment ANA titers before ICI or who had active major AIDs were excluded. Nivolumab, pembrolizumab, and atezolizumab were administered to 192, 72 (55 as 1st setting), and 2 patients. PFS, progression-free survival; OS, overall survival; ICI, immune checkpoint inhibitors; PD-1, programmed death-1; PD-L1, programmed death ligand 1; ANA, antinuclear antibody.\n\nAll procedures performed were in accordance with the ethical standards of the Institutional Ethics Committee of Saitama Medical University, International Medical Center and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.\n\nAssessment of Antinuclear Antibody and Rheumatoid Factor\n\nSerum ANA titers were assessed before ICI initiation in all the patients. The ANA titer was measured by immunofluorescence at our institution. The ANA cutoff titer was set at 1:40 or 1:80. Because rheumatoid factor (RF) had been measured in 264 of the 266 enrolled before ICI treatment, we analyzed the survival efficacy according to high-grade RF using a cutoff of 15 IU/ml as an additional examination. The cut-off value of ANA and RF was defined according to previous studies. It is controversial which cut-off values of ANA are suitable for the survival analysis, 1:40 or 1:80. Thus, we analyzed using both cut-off points.\n\nTreatment and Evaluation\n\nNivolumab, pembrolizumab, and atezolizumab were administered intravenously at 3 mg/kg or 240 mg/day every 2 weeks, 200 mg/day every 3 weeks, and 1,200 mg/day every 3 weeks, respectively. Complete blood cell count, differential count, routine chemistry measurements, physical examination, and toxicity levels were evaluated. Acute toxicity was graded according to the Common Terminology Criteria for Adverse Events version 5.0. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria ver. 1.1 (13).\n\nAssessment of Clinical Data\n\nA baseline tumor assessment and response evaluation was carried out before ICI administration based on computed tomography (CT), magnetic resonance imaging, or proton emission tomography-CT findings according to the local standard of practice.\n\nThe overall response rate (ORR), defined as the proportion of patients who achieved a complete response (CR) or partial response (PR); and the disease control rate (DCR), defined as the proportion of patients who achieved CR, PR, or stable disease (SD) were evaluated in this study. Progression-free survival (PFS) was defined as the time from the initiation of ICI therapy to confirmed disease progression or death by any cause. PFS was censored at the date of the last follow-up visit for progression-free patients. OS was defined as the time from the initiation of ICI therapy to death due to any cause (event) or last contact (censored). The minimum follow-up period to ascertain the PFS and OS was 5 days after ICI therapy administration. At each follow-up, a routine physical examination, and laboratory and imaging investigations were done to assess safety. We obtained clinical information from the medical records without any protocol restriction.\n\nStatistical Analysis\n\nP values < 0.05 were considered statistically significant. Fisher’s exact test, chi-squared, and Mann-Whitney U tests were used to examine the association between two categorical variables. The Kaplan–Meier method was used to estimate survival as a function of time, and survival differences were analyzed by log-rank tests. Patients with ANA titers above 1:40 were considered ANA-positive, and those with ANA titers > 1:80 were considered as having high ANA titers. Statistical analyses were performed using JMP 10 software, SASS. Corresponding confidence intervals were calculated using the Cox proportional hazards model.\n\nResults\n\nPatients’ Characteristics\n\nThere were 95 males (79.8%) and 24 females (20.2%). The median patient age was 69 (range, 39–84) years. A total of 119 (44.7%) patients were ANA-positive, while 27 (10.2%) had high ANA titers. Ninety-six patients (80.7%) had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Seventeen patients (14.3%) were never smokers. Of all patients, nivolumab, pembrolizumab, and atezolizumab were administered to 192, 72 (55 as 1st setting), and 2 patients, respectively ( Figure 1 ). Table 1 shows the patient characteristics according to the ANA cutoff titer. Squamous cell carcinoma was observed in 26 cases (21.8%), adenocarcinoma in 71 (59.7%), and other histology types in 22 patients (18.5%). Epidermal growth factor receptor mutations were observed in 13 patients (10.9%) and rearrangement of anaplastic lymphoma kinase-echinoderm microtubule-associated protein-like 4 in 1 patient (0.8%). Nineteen patients (16.0%) experienced recurrence after operation or radiation therapy, and 23 (19.3%) and 77 (64.7%) patients had stage III and IV tumors, respectively. The tumor proportion score using PD-L1 immunohistochemistry (clone 22C3) was not significantly different between the ANA-positive and ANA-negative groups. As shown in Table 1 , no significant differences in age, sex, PS, smoking history, tumor type, staging, mutation, PD-L1 status, and treatment lines were observed according to the ANA titer (1:40 or 1:80).\n\nTable 1 Patient characteristics according to ANA titer.\n\nVariables\tAll patients n = 266 (%)\tANA<40 n = 147 (%)\tANA≧40 n = 119 (%)\tp-value\tANA<80 n = 239 (%)\tANA≧80 n = 27 (%)\tp-value\t\nAge [Median]\t69 (31–86)\t69 (31–86)\t69 (39–84)\t\t69 (31–86)\t69 (43–79)\t\t\nGender\nMale/Female\t204/62\n(76.7/23.3)\t109/38\n(74.1/25.9)\t95/24\n(79.8/20.2)\t0.31\t183/56\n(76.6/23.4)\t21/6\n(77.8/22.2)\t0.99\t\nPS\n0–1/Above 2\t217/49\n(81.6/18.4)\t121/26\n(82.3/17.7)\t96/23\n(80.7/19.3)\t0.75\t194/45\n(81.2/18.8)\t23/4\n(85.2/14.8)\t0.80\t\nSmoking history\nFormer/Never\t217/49\n(81.6/18.4)\t115/32\n(78.2/21.8)\t102/17\n(85.7/14.3)\t0.15\t192/47\n(80.3/19.7)\t25/2\n(92.6/7.4)\t0.19\t\nHistology\nAdeno/Squamous/Others\t150/67/49\n(56.4/25.2/18.4)\t79/41/27\n(53.7/27.9/18.4)\t71/26/22\n(59.7/21.8/18.5)\t0.51\t132/61/46\n(55.2/25.5/19.2)\t18/6/3\n(66.7/22.2/11.1)\t0.47\t\nDisease stage\nIII/IV/Recurrence\t45/172/49\n(16.9/64.7/18.4)\t22/95/30\n(15.0/64.6/20.4)\t23/77/19\n(19.3/64.7/16.0)\t0.50\t38/156/45\n(15.9/65.3/18.8)\t7/16/4\n(25.9/59.3/14.8)\t0.42\t\nRadiotherapy\nRadical/Palliative/None\t40/65/161\n(15.0/24.4/60.5)\t25/37/85\n(17.0/25.2/57.8)\t15/28/76\n(12.6/23.5/63.9)\t0.53\t35/61/143\n(14.6/25.5/59.8)\t5/4/18\n(18.5/14.8/66.7)\t0.42\t\nDriver mutation\nWild type/EGFR or ALK\t225/41\n(84.6/15.4)\t120/27\n(81.6/18.4)\t105/14\n(88.2/11.8)\t0.17\t200/39\n(83.7/16.3)\t25/2\n(92.6/7.4)\t0.40\t\nPD-L1 (TPS)\n<1%/1–49%/≥50%/Unknown\t10/15/63/178\n(3.8/5.6/23.7/66.9)\t5/9/30/103\n(3.4/6.1/20.4/70.1)\t5/6/33/75\n(4.2/5.0/27.7/63.0)\t0.53\t10/14/56/159\n(4.2/5.9/23.4/66.5)\t0/1/7/19\n(0.0/3.7/25.9/70.4)\t0.91\t\nTreatment lines\n1st/2nd/Above 3rd\t55/138/73\n(20.7/51.9/27.4)\t25/83/39\n(17.0/56.5/26.5)\t30/55/34\n(25.2/46.2/28.6)\t0.17\t50/124/65\n(20.9/51.9/27.2)\t5/14/8\n(18.5/51.9/29.6)\t0.94\t\nPS, performance status; ANA, antinuclear antibody; RT, radiotherapy; EGFR, epidermal growth factor receptor; ALK, Anaplastic lymphoma kinase; TPS, Tumor Proportion Score; adeno, adenocarcinoma; squamous, squamous cell carcinoma; PD-L1, programmed death ligand-1; Recurrence, recurrence after surgical resection.\n\nThe proportion of RF-positive patients at RF cutoff values of 5 IU/ml and 15 IU/ml were observed in 28.7% (77/268) and 12.3% (33/268), respectively.\n\nEfficacy and Survival Analysis According to the Antinuclear Antibody Titer\n\nPR was observed in 37 patients (35.9%), SD in 32 patients (26.9%), and PD in 34 patients (28.6%). The ORR and DCR were 35.9% and 67.0%, respectively. Table 2 shows the response rate of PD-1/PD-L1 blockade according to the ANA titer. The patients with positive and high ANA titers yielded an ORR of 35.9% and 43.5%, respectively, without any significant difference.\n\nTable 2 Response rate of the ICI treatment according to ANA titer.\n\nResponse\tAll patients\nn = 266\tANA< 40\nn = 147\tANA≧40\nn = 119\tp-value\tANA< 80\nn = 239\tANA≧80\nn = 27\tp-value\t\nCR\t1\t1\t0\t\t1\t0\t\t\nPR\t71\t34\t37\t61\t10\t\nSD\t73\t41\t32\t66\t7\t\nPD\t93\t59\t34\t87\t6\t\nNE\t28\t12\t16\t24\t4\t\nORR\t30.2%\t25.9%\t35.9%\t0.21\t28.8%\t43.5%\t0.25\t\nDCR\t60.9%\t56.2%\t67.0%\t0.32\t59.5%\t73.9%\t0.42\t\nICI, immune checkpoint inhibitor; ANA, antinuclear antibody; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable; ORR, overall response rate; DCR, disease control rate.\n\nNext, we performed a survival analysis according to the ANA titer. Of 266 patients, 117 experienced recurrence after ICI initiation, and 76 died. Figure 2 shows the Kaplan-Meier survival curve according to the different ANA cutoff values (1:40 and 1:80). The median PFS in the patients with positive and negative ANA were 6.3 and 4.3 months (p = 0.08), respectively, and the median OS was 19.4 and 16.5 months (p = 0.14), respectively ( Figures 2A, B ). The median PFS was 6.5 and 4.7 months (p = 0.42) in patients with high and low ANA titers, respectively, while the median OS was 18.3 and 17.6 months (p = 0.41), respectively ( Figures 2C, D ). In the survival analysis according to histology, PFS was longer in the ANA-positive patients with adenocarcinoma (p = 0.03) than in the ANA-negative patients, though no significant difference was observed in OS (p = 0.18) ( Supplementary Figure A1 , online only). No significant differences were observed in the PFS (p = 0.76) and OS (p = 0.63) between the ANA-positive and ANA-negative patients with non-adenocarcinoma tumors ( Supplementary Figure A1 , online only). However, no significant differences between the patients with high and low ANA titers in the PFS and OS were observed, regardless of the histological types ( Supplementary Figure A2 , online only).\n\nFigure 2 Kaplan–Meier survival curves of PFS and OS according to ANA positivity in the low and high cohorts. PFS (A) and OS (B) when a positive ANA cutoff of 1:40 was used, PFS (C) and OS (D) when a positive ANA cutoff of 1:80 was used. Survival analysis with ICI treatment: no significant difference in the PFS and OS was observed between the ANA-positive and ANA-negative patients or high and low ANA titer cohorts. PFS, progression-free survival; OS, overall survival; ANA, anti-nuclear antibody.\n\nUsing an RF cutoff value of 15, the median PFS in RF-positive and RF-negative patients was 6.3 months and 4.7 months (p = 0.45), respectively, while the median OS was 11.5 months and 18.5 months (p = 0.66), respectively ( Supplementary Figure A3 , online only).\n\nClinical Outcome Feasibility\n\nTable 3 shows the comparison of irAEs according to the ANA cutoff value. There were no significant differences in the frequency of irAEs between ANA-positive and ANA-negative patients ( Table 3 and Figure 3A ) and between those with high and low ANA titers ( Table 3 and Figure 3B ). The frequency of steroid therapy in irAEs was 26.0% (31/119) in ANA-positive patients and 24.8% (35/148) in ANA-negative patients (p = 0.78) ( Supplementary Table A8 , online only). Likewise, a similar trend was observed between the patients with high and low ANA titers ( Supplementary Table A8 , online only). One ANA-positive patient experienced Sjögren syndrome (SjS) related to ICI use.\n\nTable 3 Immune-related adverse events.\n\n\tAll grade (ANA 1:40)\t>≧Grade3 (ANA 1:40)\t>All grade (ANA 1:80)\t>≧Grade3 (ANA 1:80)\t\nVariables\tAll patients\tANA<40\tANA≧40\t \tAll patients\tANA<40\tANA≧40\t \tAll patients\tANA<80\tANA≧80\t \tAll patients\tANA<80\tANA≧80\t \t\n \tn = 266 (%)\tn = 147 (%)\tn = 119 (%)\tp-value\tn = 266 (%)\tn = 147 (%)\tn = 119 (%)\tp-value\tn = 266 (%)\tn = 239 (%)\tn = 17 (%)\tp-value\tn = 266 (%)\tn = 239 (%)\tn = 17 (%)\tp-value\t\nILD\t58 (21.8)\t31 (21.1)\t27(22.7)\t0.77\t16 (6.0)\t9 (6.1)\t7 (5.9)\t0.99\t58 (21.8)\t49 (20.5)\t9 (33.3)\t0.14\t16 (6.0)\t13 (5.4)\t3 (11.1)\t0.21\t\nHypothyroidism\t28 (10.5)\t18 (12.2)\t10(8.4)\t0.32\t0 (0)\t0 (0)\t0 (0)\t0.99\t28 (10.5)\t27 (11.3)\t1 (3.7)\t0.33\t0 (0)\t0 (0)\t0 (0)\t0.99\t\nAdrenal insufficiency\t10 (3.8)\t4 (2.7)\t6(5.0)\t0.35\t7 (2.6)\t3 (2.0)\t4 (3.4)\t0.7\t10 (3.8)\t9 (3.8)\t1 (3.7)\t0.99\t7 (2.6)\t6 (2.5)\t1 (3.7)\t0.53\t\nLiver dysfunction\t41 (15.4)\t20 (13.6)\t21(17.6)\t0.4\t8 (3.0)\t3 (2.0)\t5 (4.2)\t0.47\t41 (15.4)\t37 (15.5)\t4 (14.8)\t0.78\t8 (3.0)\t8 (3.3)\t0 (0)\t0.99\t\nRenal dysfunction\t28 (10.5)\t18 (12.2)\t10(8.4)\t0.32\t1 (0.4)\t1 (0.7)\t0 (0)\t0.99\t28 (10.5)\t25 (10.5)\t3(11.1)\t0.92\t1 (0.4)\t1 (0.4)\t0 (0)\t0.99\t\nSkin disorder\t42 (15.8)\t21 (14.3)\t21(17.6)\t0.5\t3 (1.1)\t2 (1.4)\t1 (0.8)\t0.99\t42 (15.8)\t35 (14.6)\t7 (25.9)\t0.17\t3 (1.1)\t2 (0.8)\t1 (3.7)\t0.28\t\nFever\t18 (6.8)\t6 (4.1)\t12(10.1)\t0.08\t2 (0.8)\t2 (1.4)\t0 (0)\t0.5\t18 (6.8)\t15 (6.3)\t3 (11.1)\t0.41\t2 (0.8)\t2 (0.8)\t0 (0)\t0.99\t\nColitis\t26 (9.8)\t17 (11.6)\t9(7.6)\t0.31\t7 (2.6)\t3 (2.0)\t4 (3.4)\t0.7\t26 (9.8)\t23 (9.6)\t3 (11.1)\t0.74\t7 (2.6)\t5 (2.1)\t2 (7.4)\t0.15\t\nNervous system disorder\t5 (1.9)\t2 (1.4)\t3(2.5)\t0.66\t0 (0)\t0 (0)\t0 (0)\t0.99\t5 (1.9)\t5 (2.1)\t0 (0)\t0.99\t0 (0)\t0 (0)\t0 (0)\t0.99\t\nArthralgia\t6 (2.3)\t3 (2.0)\t3(2.5)\t0.99\t1 (0.4)\t0 (0)\t1 (0.8)\t0.45\t6 (2.3)\t5 (2.1)\t1 (3.7)\t0.48\t1 (0.4)\t1 (0.4)\t0 (0)\t0.99\t\nAMY\t18 (6.8)\t7 (4.8)\t11(9.2)\t0.22\t0 (0)\t0 (0)\t0 (0)\t0.99\t18 (6.8)\t15 (6.3)\t3 (11.1)\t0.41\t0 (0)\t0 (0)\t0 (0)\t0.99\t\nCK\t15 (5.6)\t11 (7.5)\t4(3.4)\t0.19\t1 (0.4)\t1 (0.7)\t0 (0)\t0.99\t15 (5.6)\t14 (5.9)\t1 (3.7)\t0.99\t1 (0.4)\t1 (0.4)\t0 (0)\t0.99\t\nγ-GTP\t7 (2.6)\t4 (2.7)\t3(2.5)\t0.99\t0 (0)\t0 (0)\t0 (0)\t0.99\t7 (2.6)\t6 (2.5)\t1 (3.7)\t0.53\t0 (0)\t0 (0)\t0 (0)\t0.99\t\nEosinophil\t36 (13.5)\t24 (16.3)\t12(10.1)\t0.15\t0(0)\t0 (0)\t0 (0)\t0.99\t36 (13.5)\t32 (13.4)\t4 (14.8)\t0.77\t0 (0)\t0 (0)\t0 (0)\t0.99\t\nThe irAE was listed at frequency 2% or more in either group.\n\nANA, antinuclear antibody; ILD, interstitial lung injury; AMY, amylase; CK, creatine kinase; γGTP, γ- Glutamyl transpeptidase.\n\nFigure 3 Immune-related adverse events between ANA-positive and ANA-negative patients (cutoff of 1:40) or high and low ANA (cutoff of 1:80). The irAEs were listed at frequency 2% or more in either group. (A) When a positive ANA cutoff of 1:40 was used, (B) when a positive ANA cutoff of 1:80 was used. irAEs, immune-related adverse events; AMY, amylase; CK, creatine kinase; γGTP, γ- Glutamyltranspeptidase.\n\nDiscussion\n\nThis study is the largest study to verify the efficacy and toxicity of anti-PD-1/PD-L1 therapies in ANA-positive NSCLC patients. We found that the effectiveness and prevalence of irAEs were consistent regardless of the ANA titer. Even with high ANA titers, the usefulness of ICI was unrelated to the occurrence of AIDs, and the presence of ANA did not affect the efficacy and outcome after the PD-1/PD-L1 blockade treatment. According to our results, the proportion of ANA-positive NSCLC patients was similar to that in the healthy population (14). In this study, the frequency of ANA positivity was 44.7% (119/266) with the cutoff value at 1:40 and 10.2% (27/266) with the cutoff value at 80. Previous research shows that the presumptive rate of ANA positivity in a healthy population is 31.7% in individuals at 1:40 serum dilution, 13.3% at 1:80, 5.0% at 1:160, and 3.3% at 1:320 (14). Our study results indicated that the ANA positivity rate in patients with NSCLC was similar to that in a healthy population. Thus, serum ANA levels may not correlate with an increased risk of cancer (15).\n\nIn our study, the positive rates of RF at cutoff values of 5 IU/ml and 15 IU/ml before ICI treatment were recognized in 28.7% (77/268) and 12.3% (33/268), respectively. It has been already reported that RF yielded positive findings of 5%–25% in patients with malignant disease (16). Compared with previous investigations, the positive rates of ANA and RF in patients with NSCLC were similar to that of the healthy population. Aside from ANA, we investigated the efficacy according to the level of RF. However, there was no relationship between the expression of RF and ICI therapeutic efficacy in lung cancer.\n\nRecently, five reports including our study described ICI efficacy and toxicity, and patient survival according to the ANA titer (9–12). Yoneshima et al. reported that the incidence of irAEs did not differ between patients with positive and negative ANA, and PFS and OS were significantly shorter in patients with positive ANA than in those with negative ANA (9). In their study, the ANA cutoff titer was defined as 1:40, and 21.7% (18/83) of all patients with advanced NSCLC were positive for ANA (9). They discussed why there was no difference in the ORR of PD-1 blockade between the positive and negative ANA groups, despite the worse survival of the positive ANA group. The frequency of the ANA-positive patients with a cutoff value of 1:40 in our study was 45%, which substantially differed from 21.7% in their study. Our study indicated no significant difference in the ORR for PD-1 blockade according to the ANA cutoff titer of 1:40 or 1:80. Generally, the ORR of PD-1 inhibitor is considered to reflect survival. Therefore, a small sample size of 83 patients in their study may have biased their results. Sakakida et al. investigated 191 patients treated with PD-1 blockade monotherapy, and the patients were divided into positive and negative ANA groups according to the cutoff value of 1:160 (10). Although a positive ANA titer was observed in 4.7% (9/191) in their study, the incidence of irAEs except for colitis, the ORR and survival did not differ between the groups (10). Toi et al. assessed the efficacy and safety of PD-1 blockade in 137 patients with advanced NSCLC based on the existence of preexisting autoimmune markers such as rheumatoid factor, ANA, antithyroglobulin, and anti-thyroid peroxidase (11). The results of their study indicated that PFS was significantly longer in patients with RF than in those without, but not significantly different between ANA-positive and ANA-negative patients. The ANA cutoff titer in their study was 1:40. Moreover, the development of irAEs and the ORR did not differ between the patients with positive and negative ANA titers (11). Giannicola et al. reported that patients with ANA, antibodies to extractable nuclear antigens, and anti-smooth muscle antibodies exhibited significantly better PFS and OS than those without those antibodies (12). However, it remains unclear whether ANA alone could predict the outcome and the exacerbation of irAEs after PD-1/PD-L1 blockade. Meanwhile, we investigated the efficacy and toxicity of ICI treatment according to histological type (adenocarcinoma or non-adenocarcinoma). Although the PFS of patients receiving ICI was not different between the high and low groups at the ANA cutoff titer of 1:80, it was significantly better in the positive group than in the negative group when using a cutoff of 1:40. This finding is in contrast to the results of previous studies wherein the ICI efficacy at an ANA cutoff titer of 1:40 was controversial. Although little is known about ICI treatment between positive and negative ANA titers according to histological type, the ANA cutoff titer of 1:40 may not be suitable for the analysis based on the ANA titer. Considering the results of these previous studies and ours, we can consider that the presence of ANA was not a significant predictor of the efficacy, patient survival, and irAEs after PD-1/PD-L1 blockade monotherapy. In the absence of AIDs, the administration of PD-1/PD-L1 blockade is feasible regardless of the ANA titers.\n\nHowever, autoantibodies are not necessarily specific to the diagnosis of AIDs, and some additional laboratory investigations are needed for its diagnosis. Soyoung et al. discussed the intervention of regulatory T cells characterized by the expression of CD4+, CD25+, and Foxp3+ in patients with rheumatoid arthritis (17). It has been reported that the number or function of regulatory T cells decreases according to the severity of active SLE (18, 19). Leonardi et al. carried out a retrospective study in which 23% of 56 NSCLC patients with a history of AIDs experienced AID exacerbation after ICI treatment (20). A recent review described that the frequency of adverse events related to ICI therapy was not different between patients with and without AIDs (21). In the patients with AIDs who received ICI, AID exacerbation was observed in a few patients, and the incidence of irAEs and ICI efficacy was almost similar to those of previous clinical trials.\n\nOur study has the largest sample size compared to previous studies. However, there are several limitations to our study. First, our study was a retrospective investigation; thus, it may have biased the results of our study. Second, we could not obtain adequate information on PD-L1 expression; therefore, little is known about the relationship between PD-L1 and ANA. Toi et al. described no close correlation between PD-L1 and ANA (11). Finally, our study did not include patients with AIDs who received ICI treatment. In our institute, we experienced 3 cases of AIDs who were treated with ICI (data not shown). All three patients contracted rheumatoid arthritis before ICI treatment, and one patient had SjS in addition to pre-existing rheumatoid arthritis without requiring administration of systemic steroids after obtaining polymyalgia rheumatica by ICI treatment. The other patients with rheumatoid arthritis did not experience exacerbation of their connective tissue disease. None of the patients who had existing AIDs before ICI treatment experienced serious irAEs (≥ grade 3). According to previous studies, ICIs may be used with adequate caution in patients with AIDs. Further studies should focus on the efficacy and safety of ICI treatment in patients with AIDs.\n\nIn conclusion, the efficacy of ICIs and incidence of irAEs after ICI initiation were not absolutely affected by high ANA titers. ICIs can be administered even in patients with high ANA titers and without AIDs. The potential of ANA as a predictive marker for NSCLC patients treated with ICI remains unclear. Physicians should consider the therapeutic possibility of ICI regardless of the ANA titer.\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\nAll procedures performed were in accordance with the ethical standards of the Institutional Ethics Committee of Saitama Medical University, International Medical Center and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.\n\nAuthor Contributions\n\nAM, KyK, and OY conceptualized the study and prepared the manuscript. KH, YM, AS, SS, TA, and HI were in charge of patient management. OY and KuK performed the statistical analysis and collected the patient data. AM, OY, KyK, KH, and HK revised the manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nAM, KyK, OY, and HK received research grants and received honorarium as speakers from the Ono Pharmaceutical Company, Bristol-Myers Company, and Chugai Pharmaceutical Company.\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\nAcknowledgments\n\nWe thank Drs. Yoshitake Murayama, Fuyumi Nishihara, Takahiro Uchida, and KyK for their assistance in preparing this manuscript. We would also like to thank Editage (www.editage.jp) for English language editing.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.610952/full#supplementary-material\n\nSupplementary Figure 1 Kaplan-Meier survival curves of PFS and OS in the positive and negative ANA cohorts when a positive ANA cutoff of 1:40 was used. (A) PFS in patients with non-adenocarcinoma tumors, (B) OS in patients with non-adenocarcinoma tumors, (C) PFS in patients with adenocarcinoma, (D) OS in patients with adenocarcinoma PFS, progression-free survival; OS, overall survival; ANA, anti-nuclear antibody.\n\nClick here for additional data file.\n\nSupplementary Figure 2 Kaplan-Meier survival curves of PFS and OS in the positive and negative ANA cohorts with a positive ANA cutoff of 1:80. (A) PFS in patients with non-adenocarcinoma tumors, (B) OS in patients with non-adenocarcinoma tumors, (C) PFS in patients with adenocarcinoma, (D) OS in patients with adenocarcinoma PFS, progression-free survival; OS, overall survival; ANA, anti-nuclear antibody.\n\nClick here for additional data file.\n\nSupplementary Figure 3 Kaplan-Meier survival curves of PFS and OS in the positive and negative RF cohorts when a positive RF cutoff of 15 was used. Survival analysis with ICI treatment: no significant difference in the PFS and OS was observed between the RF-positive and RF-negative patients. PFS, progression-free survival; OS, overall survival; RF, rheumatoid factor.\n\nClick here for additional data file.\n\nSupplementary Figure 4 Kaplan-Meier survival curves of PFS and OS in both positive ANA (≧1:40) and RF (≧15) or not. Survival analysis with ICI treatment: no significant difference in the PFS and OS was observed between both ANA and RF-positive and negative patients. PFS, progression-free survival; OS, overall survival; ANA, anti-nuclear antibody; RF, rheumatoid factor.\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Brahmer J Reckamp KL Baas P Crinò L Eberhardt WEE Poddubskaya E . Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med (2015) 373 :123–35. 10.1056/NEJMoa1504627\n2 Borghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE . Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med (2015) 373 :1627–39. 10.1056/NEJMoa1507643\n3 Reck M Rodríguez-Abreu D Robinson AG Hui R Csőszi T Fülöp A . Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med (2016) 375 :1823–33. 10.1056/NEJMoa1606774\n4 Rittmeyer A Barlesi F Waterkamp D Park E Ciardiello F Pawel JV . 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JAMA Oncol (2016) 2 :1507–8. 10.1001/jamaoncol.2016.2238\n9 Yoneshima Y Tanaka K Shiraishi Y Hata K Watanabe H Harada T . Safety and efficacy of PD-1 inhibitors in non-small cell lung cancer patients positive for antinuclear antibodies. Lung Cancer (2019) 130 :5–9. 10.1016/j.lungcan.2019.01.014 30885351\n10 Sakakida T Ishikawa T Chihara Y Harita S Uchino J Tabuchi Y . Safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies. Clin Transl Oncol (2020) 22 :919–27. 10.1007/s12094-019-02214-8\n11 Toi Y Sugawara S Sugisaka J Ono H Kawashima Y Aiba T . Profiling Preexisting Antibodies in Patients Treated with Anti–PD-1 Therapy for Advanced Non–Small Cell Lung Cancer. JAMA Oncol (2019) 5 :376–83. 10.1001/jamaoncol.2018.5860\n12 Giannicola R D’Arrigo G Botta C Agostino R Medico PD Falzea AC . Early blood rise in auto−antibodies to nuclear and smooth muscle antigens is predictive of prolonged survival and autoimmunity in metastatic−non−small cell lung cancer patients treated with PD−1 immune−check point blockade by nivolumab. Mol Clin Oncol (2019) 11 :81–90. 10.3892/mco.2019.1859 31289683\n13 Eisenhauer E Therasse P Bogaerts J Schwartz LH Sargent D Ford R . New response evaluation criteria in solid tumour: revised RECIST guideline (version 1.1). Eur J Cancer (2009) 45 :228–47. 10.1016/j.ejca.2008\n14 Tan EM Feltkamp TE Smolen JS Butcher B Dawkins R Fritzler MJ . Range of antinuclear antibodies in “healthy” individuals. Arthritis Rheum (1997) 40 :1601–11. 10.1002/art.1780400909\n15 Selmi C Ceribelli A Generali E Scirè CA Alborghetti F Colloredo G . Serum Antinuclear and Extractable Nuclear Antigen Antibody Prevalence and Associated Morbidity and Mortality in the General Population Over 15 Years. Autoimmun Rev (2016) 15 :162–6. 10.1016/j.autrev.2015.10.007\n16 Ingegnoli F Castelli R Gualtierotti R . Rheumatoid factors: clinical applications. Dis Markers (2013) 35 :727–34. 10.1155/2013/726598\n17 Oh S Rankin AL Caton AJ . CD4+CD25+ Regulatory T Cells in Autoimmune Arthritis. Immunol Rev (2010) 233 :97–111. 10.1111/j.0105-2896.2009.00848.x 20192995\n18 Miyara M Amoura Z Parizot C Badoual C Dorgham K Trad S . Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol (2005) 175 :8392–400. 10.4049/jimmunol.175.12.8392\n19 Valencia X Yarboro C Illei G Lipsky PE . Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol (2007) 178 :2579–88. 10.4049/jimmunol.178.4.2579\n20 Leonardi GC Gainor JF Altan M Kravets S Dahlberg SE Gedmintas L . Safety of Programmed Death 1 Pathway Inhibitors Among Patients with Non-Small Cell Lung Cancer and Preexisting Autoimmune Disorders. J Clin Oncol (2018) 36 :1905–12. 10.1200/JCO.2017.77.0305\n21 Abdel-Wahab N Shah M Lopez OMA Suarez-Almazor ME . Use of Immune Checkpoint Inhibitors in the Treatment of Patients with Cancer and Preexisting Autoimmune Disease: A Systematic Review. Ann Intern Med (2018) 168 :121–30. 10.7326/M17-2073\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "antinuclear antibodies; feasibility; immune-check point inhibitor; immune-related adverse events; non-small cell lung cancer",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "610952",
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"pmid": "33791204",
"pubdate": "2021",
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"title": "Efficacy and Feasibility of Programmed Death-1/Programmed Death Ligand-1 Blockade Therapy in Non-Small Cell Lung Cancer Patients With High Antinuclear Antibody Titers.",
"title_normalized": "efficacy and feasibility of programmed death 1 programmed death ligand 1 blockade therapy in non small cell lung cancer patients with high antinuclear antibody titers"
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"abstract": "Serratia marcescens is a well-known cause of nosocomial infectious outbreaks in the neonatal intensive care unit, with a high mortality rate in the vulnerable preterm population. However, it is not typically associated with neonatal sepsis secondary to intrapartum vertical transmission. We present the case of a preterm male born at 25 weeks and 4 days of gestation in Okinawa, Japan with culture-proven S. marcescens chorioamnionitis and sepsis, as well as a review of the previously published literature.\n\n\n\nWe conducted a literature search utilizing MeSH indexing with the headings [chorioamnionitis], [Serratia], and [infant, newborn] limited to \"humans\" with a publication date range between 1950 and 2020.\n\n\n\nAll reported cases of preterm S. marcescens chorioamnionitis occurred in coastal locations. The majority of cases resulted in spontaneous abortion, and we found no published reports of confirmed S. marcescens chorioamnionitis in conjunction with viable preterm delivery and positive neonatal cultures. In the case presented herein, S. marcescens chorioamnionitis with associated neonatal sepsis was confirmed by positive placental and blood cultures. Bacterial clearance was achieved following an antibiotic course consisting of 5 days of gentamicin and 14 days of meropenem therapy.\n\n\n\nS. marcescens is an uncommon cause of chorioamnionitis that can have devastating neonatal consequences, especially in the at-risk preterm population.",
"affiliations": "From the Department of Neonatology, 18th Medical Operations Squadron, Kadena AB, Okinawa, Okinawa, Japan.;From the Department of Neonatology, 18th Medical Operations Squadron, Kadena AB, Okinawa, Okinawa, Japan.;Department of Pediatrics, Division of Neonatology, Uniformed Services University, Bethesda, Maryland.;From the Department of Neonatology, 18th Medical Operations Squadron, Kadena AB, Okinawa, Okinawa, Japan.",
"authors": "Ottolini|Katherine M|KM|;Litke-Wager|Carrie A|CA|;Johnson|Rebecca L|RL|;Schulz|Elizabeth V|EV|",
"chemical_list": "D000900:Anti-Bacterial Agents",
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"doi": "10.1097/INF.0000000000002962",
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"issn_linking": "0891-3668",
"issue": "40(2)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D002821:Chorioamnionitis; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D011247:Pregnancy; D018805:Sepsis; D012705:Serratia; D016868:Serratia Infections",
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"references": null,
"title": "Serratia Chorioamnionitis and Culture Proven Sepsis in a Preterm Neonate: A Case Report and Review of the Literature.",
"title_normalized": "serratia chorioamnionitis and culture proven sepsis in a preterm neonate a case report and review of the literature"
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"abstract": "Metronidazole is a nitroimidazole antibacterial agent that is highly effective for the treatment of protozoal and anaerobic infections. Metronidazole is known to cause hematologic adverse effects, including a reversible mild neutropenia; in rare circumstances, thrombocytopenia has been associated with metronidazole treatment. We present a case of aplastic anemia related to the extended use of metronidazole.",
"affiliations": "Department of Pharmacy, UC San Diego Health, San Diego, CA, USA.;UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA, USA.;Division Infectious Diseases, Department of Medicine, UC San Diego Health, La Jolla, CA, USA.;Division of Blood and Marrow Transplantation, Department of Medicine, UC San Diego Health, La Jolla, CA, USA.",
"authors": "Sam|Andrew M|AM|;Saunders|Ila M|IM|https://orcid.org/0000-0002-8805-3734;Taplitz|Randy|R|;Koura|Divya|D|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008795:Metronidazole",
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"issue": "33(4)",
"journal": "Journal of pharmacy practice",
"keywords": "aplastic anemia; hematologic dyscrasia; metronidazole; neutropenia",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000741:Anemia, Aplastic; D000900:Anti-Bacterial Agents; D006801:Humans; D008795:Metronidazole; D013921:Thrombocytopenia",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "540-542",
"pmc": null,
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"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Aplastic Anemia Associated With Long-Term Metronidazole Use.",
"title_normalized": "a case of aplastic anemia associated with long term metronidazole use"
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"activesubstancename": "AZITHROMYCIN ANHYDROUS"
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"abstract": "Infliximab is a monoclonal antibody that binds to tumour necrosis factor-alpha and blocks its biological activity. It is approved for use in patients with rheumatoid arthritis, Crohn's disease and ankylosing spondylitis.black triangle In well designed, placebo-controlled trials of 12 or 24 weeks' duration in patients with active ankylosing spondylitis, more infliximab 5 mg/kg recipients achieved a response than placebo recipients according to Ankylosing Spondylitis Assessment Study 20% (61.2% vs 19.2%) or Bath Ankylosing Spondylitis Disease Activity Index 50% (53% vs 9%) criteria (primary endpoints). black triangle Infliximab was also superior to placebo in terms of various secondary clinical endpoints and in reducing spinal inflammation (as assessed by magnetic resonance imaging).black triangle Prolonged efficacy has been demonstrated in patients with ankylosing spondylitis who received infliximab for up to 3 years.black triangle Infliximab is generally well tolerated in patients with ankylosing spondylitis, with most adverse events being of mild-to-moderate severity.",
"affiliations": "Adis International Limited, Auckland, New Zealand. demail@adis.co.nz",
"authors": "Robinson|Dean M|DM|;Keating|Gillian M|GM|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000069285:Infliximab",
"country": "New Zealand",
"delete": false,
"doi": "10.2165/00003495-200565090-00006",
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"issn_linking": "0012-6667",
"issue": "65(9)",
"journal": "Drugs",
"keywords": null,
"medline_ta": "Drugs",
"mesh_terms": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D002986:Clinical Trials as Topic; D006801:Humans; D000069285:Infliximab; D013167:Spondylitis, Ankylosing",
"nlm_unique_id": "7600076",
"other_id": null,
"pages": "1283-91; discussion 1292-4",
"pmc": null,
"pmid": "15916451",
"pubdate": "2005",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "7699629;12422001;14672897;15187239;11508441;15535831;15457463;9751087;12463444;15757965;15061685;15692973;12632433;15478146;15989547;15899030;11985485;11955536;12922952;11469469;15022354;15388511;14644863;11053096;7921752;12905476;15226514;12687557;7799351;7699630",
"title": "Infliximab: in ankylosing spondylitis.",
"title_normalized": "infliximab in ankylosing spondylitis"
} | [
{
"companynumb": "IN-JNJFOC-20171125619",
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"abstract": "Anaplastic large cell lymphoma (ALCL) is a common subtype of the heterogeneous group of peripheral T-cell lymphomas, which is characterized by large pleomorphic cells with strong expression of CD30. Translocations involving ALK, the anaplastic lymphoma kinase gene, are associated with a favorable clinical outcome. Such ALK-positive ALCLs are usually responsive to a multidrug chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). However, there is no general consensus on the optimal therapy for relapsed or refractory ALCL. We report the case of a 24-year-old male suffering from ALK-positive ALCL with an uncommon manifestation of only extranodal disease in the gastric cardia region that showed primary refractoriness to standard CHOP chemotherapy. A combination therapy consisting of the anti-CD30 drug conjugate, brentuximab vedotin, and classical lymphoma salvage regimen DHAP (cisplatin, high-dose cytarabine and dexamethasone) was administered. Following two treatment cycles in 21-day intervals, the lymphoma showed considerable regression based on imaging diagnostics and no evidence of vital lymphoma in a subsequent biopsy. We did not observe any increase in toxicity; in particular, polyneuropathy and febrile neutropenia were not observed. In summary, we report that the antibody-drug conjugate brentuximab vedotin and a classical regimen used for aggressive lymphoma, DHAP, could be combined as salvage therapy in a case of refractory ALK-positive ALCL. Phase I/II studies will be required for safety and efficacy analysis.",
"affiliations": "III Medical Department, Technische Universität München, Munich, Germany.;Nuclear Medicine Department, Technische Universität München, Munich, Germany.;Institute of Pathology, University of Würzburg, Würzburg, Germany.;Institute of Pathology, University of Würzburg, Würzburg, Germany.;III Medical Department, Technische Universität München, Munich, Germany.;III Medical Department, Technische Universität München, Munich, Germany.;III Medical Department, Technische Universität München, Munich, Germany.",
"authors": "Heidegger|Simon|S|;Beer|Ambros J|AJ|;Geissinger|Eva|E|;Rosenwald|Andreas|A|;Peschel|Christian|C|;Ringshausen|Ingo|I|;Keller|Ulrich|U|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S59795",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S59795ott-7-1123Case ReportCombination therapy with brentuximab vedotin and cisplatin/cytarabine in a patient with primarily refractory anaplastic lymphoma kinase positive anaplastic large cell lymphoma Heidegger Simon 1Beer Ambros J 2Geissinger Eva 3Rosenwald Andreas 3Peschel Christian 1Ringshausen Ingo 1Keller Ulrich 11 III Medical Department, Technische Universität München, Munich, Germany2 Nuclear Medicine Department, Technische Universität München, Munich, Germany3 Institute of Pathology, University of Würzburg, Würzburg, GermanyCorrespondence: Simon Heidegger; Ulrich Keller, III Medical Department, Technische Universität München, Ismaninger Str 22, 81675 Munich, Germany, Tel +49 89 4140 4111, Fax +49 89 4140 4879, Email simon.heidegger@lrz.tum.de; ulrich.keller@lrz.tum.de2014 20 6 2014 7 1123 1127 © 2014 Heidegger et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Anaplastic large cell lymphoma (ALCL) is a common subtype of the heterogeneous group of peripheral T-cell lymphomas, which is characterized by large pleomorphic cells with strong expression of CD30. Translocations involving ALK, the anaplastic lymphoma kinase gene, are associated with a favorable clinical outcome. Such ALK-positive ALCLs are usually responsive to a multidrug chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). However, there is no general consensus on the optimal therapy for relapsed or refractory ALCL. We report the case of a 24-year-old male suffering from ALK-positive ALCL with an uncommon manifestation of only extranodal disease in the gastric cardia region that showed primary refractoriness to standard CHOP chemotherapy. A combination therapy consisting of the anti-CD30 drug conjugate, brentuximab vedotin, and classical lymphoma salvage regimen DHAP (cisplatin, high-dose cytarabine and dexamethasone) was administered. Following two treatment cycles in 21-day intervals, the lymphoma showed considerable regression based on imaging diagnostics and no evidence of vital lymphoma in a subsequent biopsy. We did not observe any increase in toxicity; in particular, polyneuropathy and febrile neutropenia were not observed. In summary, we report that the antibody-drug conjugate brentuximab vedotin and a classical regimen used for aggressive lymphoma, DHAP, could be combined as salvage therapy in a case of refractory ALK-positive ALCL. Phase I/II studies will be required for safety and efficacy analysis.\n\nKeywords\nanaplastic large cell lymphoma (ALCL)refractory relapsed lymphomaanti-CD30 drug conjugateDHAPcombined therapy\n==== Body\nIntroduction\nThe primary systemic type of anaplastic large cell lymphoma (ALCL) is a common subtype of the heterogeneous group of peripheral T-cell lymphomas (PTCL). PTCL together account for less than 15% of all non-Hodgkin lymphomas in adults.1 The ALK-positive subtype of ALCLs is defined by different translocations involving the anaplastic lymphoma kinase (ALK) gene on chromosome 2 that result in an overexpression of a constitutively active kinase. Such ALK-positive ALCLs proved to have a more favorable outcome compared to ALK-negative lymphomas.2 ALCLs show bimodal age distribution, peaking in early and late adulthood, with the median age at the time of diagnosis being much lower in patients with ALK-positive ALCL (34 years versus 58 years in ALK-negative ALCL).3 Patients typically present with painless lymphadenopathy with concomitant B-symptoms. Extranodal disease manifestations are most common in skin, bone, lung, and liver. The neoplastic cells characteristically show strong expression of CD30 and cytotoxicity-associated antigens, while the expression of pan-T-cell antigens is often lost.4 Clinically, ALK-positive ALCLs typically show an aggressive course but are usually responsive to standard CHOP or CHOP-like therapy, with the most important prognostic factor being the International Prognostic Index (IPI) at the time of diagnosis.2 However, there is no general consensus on the optimal therapy for relapsed or refractory ALCL.5 Here, we report on a combination therapy with cisplatin, high-dose cytarabine, and dexamethasone (DHAP) and brentuximab vedotin, a CD30-directed antibody linked to the antitubulin agent monomethyl auristatin E,6,7 in a young patient with primarily refractory ALK-positive ALCL.\n\nCase presentation\nA 24-year-old male was admitted to a primary care hospital because of persistent dyspepsia, epigastric pain, and weight loss. A gastroscopy revealed an exophytic, ulcerating tumor in the cardia region and proximal corpus of the stomach with extension into the distal esophagus. Mucosal biopsies showed infiltration by an ALK-positive, CD20-negative large cell lymphoma accompanied by chronic Helicobacter pylori-negative antrum gastritis. A subsequent computed tomography (CT) scan and bone marrow biopsy showed exclusive involvement of the stomach. The IPI score was 0. Standard chemotherapy with CHOP was initiated. Under such anthracycline-based chemotherapy, patients with ALK-positive ALCL generally show a favorable outcome with a 5-year overall survival ranging from 70% to 93%.8,9 In this particular case, following three cycles of the CHOP regimen, a CT scan demonstrated partial remission. However, following cycle five, a CT scan of the chest and upper abdomen was performed because of productive coughing, which showed local tumor progression. The CHOP regimen was discontinued and the patient was subsequently transferred to our hospital.\n\nOn admission the patient presented in good general condition but was suffering from worsening dyspepsia, shoulder pain, and night sweats. Physical examination was unremarkable; blood count and laboratory values were – apart from mild anemia (hemoglobin 13.7 g/dL) – within normal limits. [18F]Fluorodeoxyglucose positron emission tomography (PET)-CT revealed intensive tracer uptake by the known lymphoma manifestation in the cardia region, with a tumor size of 60 × 60 × 65 mm. Two additional nodules cranial to the primary tumor with enhanced glucose uptake were considered as affected lymph nodes (Figure 1A). Other manifestations were not identified. A second endoscopic mucosal biopsy showed infiltration by highly-proliferating lymphoid cells, staining positive for CD30 and CD3 with nuclear and cytoplasmic expression of ALK and negativity for CD19, CD79a, and CD38 (Figure 2), again showing ALK-positive large cell lymphoma, Ann Arbor stage IIE, age-adjusted IPI low risk. Based on the immunohistochemical features and the refractoriness to CHOP, ALK-positive large B-cell lymphoma (LBCL), which is usually characterized by CD20 negativity and sometimes stains positive for CD30,10 was also considered, and the biopsy was sent to a national reference center for hematopathology.\n\nConsidering the primary refractoriness towards standard CHOP treatment and the possibility of ALK-positive LBCL, which is associated with a poor prognosis,10 we discussed with the patient an individual treatment plan, consisting of the anti-CD30 drug conjugate, brentuximab vedotin and the classical lymphoma salvage regimen DHAP11 (brentuximab vedotin 1.2 mg/kg [day 0], cisplatin 70 mg/m2 [day 1] over a period of 22 hours, cytarabine [2 × 2,000 mg/m2 on day 2] and dexamethasone [40 mg on days 2–5]) (Figure 3). Standard supportive care was administered. For primary prophylaxis of prolonged neutropenia, pegfilgrastim 6 mg was administered on day 4. Because of the experimental chemotherapeutic design, dosing of the first cycle was reduced to 75%. The treatment was very well tolerated by the patient. Erosion bleedings related to tumor lysis were not observed. The shoulder pain and night sweats rapidly improved under therapy. Leukapheresis for autologous peripheral blood stem cells was performed following cycle one. A short-term interim staging by CT scan showed partial tumor regression. Reference pathology finally confirmed the diagnosis of ALCL against ALK-positive LBCL (Figure 2). The second cycle brentuximab vedotin/DHAP was administered without complications with 100% dose levels as stated above. The patient denied sensory or motor polyneuropathy; focal neurological deficiencies were not observed. Serum analysis showed normal liver and renal function tests. On the scale for Common Terminology Criteria for Adverse Events (CTCAE), hematological toxicity was limited to the expected grade 2–3 neutropenia and thrombocytopenia. No infections occurred during the course of chemotherapy. A second PET-CT scan after cycle two showed further tumor regression, both morphologically and with regards to glucose uptake (Figure 1B). A discrete swelling of the gastric wall with enhanced glucose metabolism remained. Biopsy and immunohistological analysis revealed inflammation without evidence of lymphoma. The presumably affected lymph nodes cranial to the primary tumor were no longer detectable. There was no evidence of any new lesions. The treatment response was considered as complete remission. Three weeks later, the treatment was continued with consolidation high-dose chemotherapy using the BEAM protocol (bis-chloroethylnitrosourea [BCNU], etoposide, AraC, melphalan)12 and autologous peripheral blood hematopoietic stem cell transplantation (HSCT). Considering the primary refractoriness to CHOP and stage II disease, consolidating involved-field radiotherapy was applied. At the time of submission of this manuscript, the patient had just finished radiotherapy and was doing very well without any clinical signs of relapse.\n\nDiscussion\nThere is no general consensus regarding the optimal treatment regimen in patients with refractory or relapsed PTCL. Such patients are generally treated with combination chemotherapy regimens in an attempt to achieve a remission, followed by consolidating high dose chemotherapy and autologous HSCT, or allogeneic HSCT in medically fit individuals. Consolidation therapy with autologous HSCT is a highly promising option only in patients with ALK-positive ALCL,13,14 with a complete remission at the time of transplantation and lack of extranodal disease being important predictors for a favorable outcome.15 Recently, novel agents for the treatment of refractory or relapsed PTCL have emerged, such as brentuximab vedotin, an anti-CD30 antibody-drug conjugate. In a Phase I clinical trial involving 45 patients with relapsed or refractory CD30+ hematopoietic neoplasms that were treated with brentuximab vedotin, 17 patients showed an objective response, and stable disease was reported in 19 patients.16 In a Phase II multicenter study, 58 patients with relapsed or refractory ALCL were treated with brentuximab vedotin (1.8 mg/kg every 3 weeks for up to 16 cycles). The overall response rate was 86% with an updated median progression-free survival of 14.6 months.17,18 As reported previously, most common adverse events were peripheral sensory neuropathy, nausea, fatigue, pyrexia, diarrhea, rash, constipation, and neutropenia. On the basis of these data, brentuximab vedotin was approved by the US Food and Drug Administration and the European Medicines Agency for monotherapy of ALCL after failure of at least one prior multiagent chemotherapy regimen. For a more detailed discussion of the most recent clinical studies on brentuximab vedotin in the treatment of ALCL and Hodgkin lymphoma, we refer to a recent review by Chen et al.5 Preliminary studies also showed effectiveness of brentuximab vedotin in CD30+ non-ALCL PTCL.5,19,20 Numerous clinical trials are now ongoing to evaluate the clinical benefit of combination of brentuximab vedotin with classical chemotherapy agents. Table 1 gives an overview on already active trials that investigate the combination of brentuximab vedotin and chemotherapy in adult patients with CD30+ ALCL or Hodgkin lymphoma. First studies have proven the feasibility of such an approach in patients with Hodgkin lymphoma.21–23 Preliminary data from an ongoing Phase I clinical study showed substantial antitumor activity and manageable toxicity with the combination of brentuximab vedotin and CHP (CHOP without vincristine) in patients with newly-diagnosed ALCL or other CD30+ mature T-cell/natural killer-cell lymphomas.24\n\nHere, we report that the antibody-drug conjugate brentuximab vedotin and a multidrug chemotherapy regimen used for the treatment of aggressive lymphoma, DHAP, can be efficiently and safely combined as salvage treatment prior to autologous stem cell transplantation in a case of refractory ALK-positive ALCL. We did not observe an overt increase in toxicity; in particular, polyneuropathy and febrile neutropenia were not observed. Because of the experimental character of this treatment, brentuximab vedotin has been limited to 1.2 mg/kg. Such combination therapy might improve the outcome in patients with ALK-positive ALCL that do not meet favorable prerequisites for consolidating autologous HSCT. Furthermore, in some cases, the differentiation of ALCL from the anaplastic type diffuse LBCL or other lymphoid neoplasms of T or null cell origin can be challenging. In patients with arguable histological findings and thus uncertain prognosis, a monotherapy with brentuximab vedotin seems not sufficient, and such patients might benefit from the combination of a multiagent chemotherapy. In consideration of the encouraging data from preliminary studies of combination therapies, an individual treatment plan in such patients could be considered. In general, combined therapy with the anti-CD30 drug conjugate brentuximab vedotin with a classical chemotherapy backbone may be a promising approach in the future treatment of CD30-expressing lymphomas. Phase I/II trials for safety and efficacy assessment will be required.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 FDG-PET/CT images before and after chemotherapy with BV-DHAP.\n\nNotes: (A) FDG-PET/CT performed as restaging prior to salvage chemotherapy shows massively enhanced glucose uptake by the known lymphoma in the cardia region of the stomach (black arrows). Two additional nodules cranial to the primary tumor with enhanced glucose utilization were considered as affected lymph nodes (grey arrow). (B) FDG-PET/CT images obtained after two cycles of the BV-DHAP regimen showed tumor regress, while a discrete lesion with enhanced glucose metabolism remained detectable (white arrow).\n\nAbbreviations: BV-DHAP, brentuximab vedotin and cisplatin/cytarabine; CT, computed tomography; FDG, fludeoxyglucose; PET, positron emission tomography.\n\nFigure 2 Histopathology of the biopsied gastric mucosa.\n\nNotes: Hematoxylin and eosin (HE) staining and immunohistochemistry using the indicated antibodies. The large tumor cells stain positive for CD30, the cytotoxic marker perforin, ALK, and CD3 while CD5 remains negative.\n\nAbbreviation: ALK, anaplastic lymphoma kinase.\n\nFigure 3 Schematic overview of the timing and dosing of the BV-DHAP regimen.\n\nNotes: Dosage in cycle 1 was reduced to 75%. Cycle 2 was administered at 100% as indicated.\n\nAbbreviations: BV-DHAP, brentuximab vedotin and cisplatin/cytarabine; d, day; iv, intravenous; po, per os; sc, subcutaneous.\n\nTable 1 Overview of active clinical trials that investigate brentuximab vedotin in combination with chemotherapy in adult patients with ALCL or Hodgkin lymphoma\n\nClinical trial ID\tEntity\tStatus\tCombination therapy\tPhase\t\nNCT01771107\tStage III–IV HIV-associated HL\tUntreated\tAVD\tPhase I/II\t\nNCT01534078\tLimited-stage HL\tUntreated\tAVD\tPhase II\t\nNCT01657331\tHL or ALCL\tRelapsed or refractory\tBendamustine\tPhase I/II\t\nNCT01950364\tHL or ALCL\tRelapsed or refractory\tRifampicin\tPhase I\t\nNCT01780662\tHL\tRelapsed or refractory\tGemcitabine\tPhase I/II\t\nNCT01979536\tStage III–IV ALCL\tUntreated\tDXM, IFF, MTX, AraC, VP-16, CTX, ADR\tPhase II\t\nNCT01902160\tHL\tRelapsed or refractory\tTemsirolimus\tPhase I\t\nNCT01874054\tHL\tRelapsed or refractory\tBendamustine\tPhase I/II\t\nNCT01578967\tStage I–II HL\tUntreated\tABVD\tPhase II\t\nNCT01868451\tStage I–II HL\tUntreated\tABVD + 30 Gy ISRT\tPhase II\t\nNCT01476410\tStage II–IV HL\tUntreated\tAVD\tPhase II\t\nNCT01712490\tHL\tUntreated\tAVD\tPhase III\t\nNCT01777152\tALCL\tUntreated\tCHP\tPhase III\t\nNCT01569204\tHL\tUntreated\tECAPP/ECADD\tPhase II\t\nAbbreviations: ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; ADR, doxorubicin; ALCL, anaplastic large cell lymphoma; AraC, cytarabine; AVD, doxorubicin, vinblastine, dacarbazine; CHP, cyclophosphamide, doxorubicin, and prednisone; CTX, cyclophosphamide; DXM, dexamethasone; ECADD, etoposide, cyclophosphamide, doxorubicin, dexamethasone, dacarbazine; ECAPP, etoposide, cyclophosphamide, doxorubicin, prednisone, procarbazine; HIV, human immunodeficiency virus; HL, Hodgkin lymphoma; IFF, ifosfamide; ISRT, involved-site radiation therapy; MTX, methotrexate; VP-16, etoposide.\n==== Refs\nReferences\n1 Morton LM Wang SS Devesa SS Hartge P Weisenburger DD Linet MS Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001 Blood 2006 107 1 265 276 16150940 \n2 Savage KJ Harris NL Vose JM International Peripheral T-Cell Lymphoma Project ALK-anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project Blood 2008 111 12 5496 5504 18385450 \n3 Vose J Armitage J Weisenburger D International T-Cell Lymphoma Project International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes J Clin Oncol 2008 26 25 4124 4130 18626005 \n4 Sabattini E Bacci F Sagramoso C Pileri SA WHO classification of tumours of haematopoietic and lymphoid tissues in 2008: an overview Pathologica 2010 102 3 83 87 21171509 \n5 Chen X Soma LA Fromm JR Targeted therapy for Hodgkin lymphoma and systemic anaplastic large cell lymphoma: focus on brentuximab vedotin Onco Targets Ther 2013 7 45 56 24379682 \n6 Senter PD Sievers EL The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma Nat Biotechnol 2012 30 7 631 637 22781692 \n7 Okeley NM Miyamoto JB Zhang X Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate Clin Cancer Res 2010 16 3 888 897 20086002 \n8 Falini B Pileri S Zinzani PL ALK+ lymphoma: clinico- pathological findings and outcome Blood 1999 93 8 2697 2706 10194450 \n9 Gascoyne RD Aoun P Wu D Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma Blood 1999 93 11 3913 3921 10339500 \n10 Reichard KK McKenna RW Kroft SH ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature Mod Pathol 2007 20 3 310 319 17277765 \n11 Velasquez WS Cabanillas F Salvador P Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP) Blood 1988 71 1 117 122 3334893 \n12 Gaspard MH Maraninchi D Stoppa AM Intensive chemotherapy with high doses of BCNU, etoposide, cytosine arabinoside, and melphalan (BEAM) followed by autologous bone marrow transplantation: toxicity and antitumor activity in 26 patients with poor-risk malignancies Cancer Chemother Pharmacol 1988 22 3 256 262 3044633 \n13 Rodriguez J Caballero MD Gutiérrez A High-dose chemotherapy and autologous stem cell transplantation in peripheral T-cell lymphoma: the GEL-TAMO experience Ann Oncol 2003 14 12 1768 1775 14630683 \n14 Jagasia M Morgan D Goodman S Histology impacts the outcome of peripheral T-cell lymphomas after high dose chemotherapy and stem cell transplant Leuk Lymphoma 2004 45 11 2261 2267 15512815 \n15 Fanin R Ruiz de Elvira MC Sperotto A Baccarani M Goldstone A Autologous stem cell transplantation for T and null cell CD30-positive anaplastic large cell lymphoma: analysis of 64 adult and paediatric cases reported to the European Group for Blood and Marrow Transplantation (EBMT) Bone Marrow Transplant 1999 23 5 437 442 10100556 \n16 Younes A Bartlett NL Leonard JP Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas N Engl J Med 2010 363 19 1812 1821 21047225 \n17 Pro B Advani RH Brice P Three-year survival results from an ongoing phase 2 study of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma Blood 2013 122 21 1809 \n18 Pro B Advani R Brice P Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study J Clin Oncol 2012 30 18 2190 2196 22614995 \n19 Duvic M Tetzlaff M Clos AL Gangar P Talpur R Results of a phase II trial of brentuximab vedotin (SGN-35) for CD30+ cutaneous T-cell lymphomas and lymphoproliferative disorders. Abstract presented at: 54th ASH Annual Meeting and Exposition; December 8–11, 2012; Atlanta, GA Blood 2012 120 21 Abstract 3688 \n20 Jacobsen ED Advani RH Oki Y A phase 2 Study of brentuximab vedotin in patients with relapsed or refractory CD30-positive non-Hodgkin lymphomas: interim results. Abstract presented at: 54th ASH Annual Meeting and Exposition; December 8–11, 2012; Atlanta, GA Blood 2012 120 21 Abstract 2746 \n21 Eichenauer DA Plütschow A Kreissl S Targeted Beacopp variants In patients with newly diagnosed advanced stage classical Hodgkin lymphoma: interim results of a randomized phase II study. Abstract presented at: 55th ASH Annual Meeting and Exposition; December 7–10, 2012; New Orleans, LA Blood 2013 122 21 Abstract 4344 \n22 Moskowitz A Schoder H Gerecitano JF FDG-PET adapted sequential therapy with brentuximab vedotin and augmented ICE followed by autologous stem cell transplant for relapsed and refractory Hodgkin lymphoma. Abstract presented at: 55th ASH Annual Meeting and Exposition; December 7–10, 2012; New Orleans, LA Blood 2013 122 21 Abstract 2099 \n23 Younes A Connors JM Park SI Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study Lancet Oncol 2013 14 13 1348 1356 24239220 \n24 Fanale MA Horwitz SM Forero-Torres A Brentuximab vedotin administered before, during, and after multi-agent chemotherapy in patients (pts) with newly-diagnosed CD30+ mature T- and NK-cell lymphomas. Abstract presented at: 55th ASH Annual Meeting and Exposition; December 7–10, 2012; New Orleans, LA Blood 2013 122 21 Abstract 4386\n\n",
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"journal": "OncoTargets and therapy",
"keywords": "DHAP; anaplastic large cell lymphoma (ALCL); anti-CD30 drug conjugate; combined therapy; refractory relapsed lymphoma",
"medline_ta": "Onco Targets Ther",
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"title": "Combination therapy with brentuximab vedotin and cisplatin/cytarabine in a patient with primarily refractory anaplastic lymphoma kinase positive anaplastic large cell lymphoma.",
"title_normalized": "combination therapy with brentuximab vedotin and cisplatin cytarabine in a patient with primarily refractory anaplastic lymphoma kinase positive anaplastic large cell lymphoma"
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"abstract": "Acute-on-chronic liver failure (ACLF) represents a reversible syndrome associated with high short-term mortality, characterized by acute decompensation in patients with chronic liver disease and extrahepatic organ failure. Diagnosis and prognosis assessment is based on a newly developed diagnostic score, the Chronic Liver Failure Consortium Organ Failure score. Susceptibility to infections and systemic inflammation are typical triggers. The authors report a case in which a patient with alcohol-related cirrhosis was admitted to the hospital with acute decompensation and developed ACLF during hospitalization. This case led to an evaluation of the underlying process causing ACLF: infection versus acute alcoholic hepatitis.",
"affiliations": "Inter-Centre Unit of Digestive Diseases and CIBERehd, Virgen Macarena - Virgen del Rocío University Hospitals, University of Sevilla, Sevilla, Spain.;Inter-Centre Unit of Digestive Diseases and CIBERehd, Virgen Macarena - Virgen del Rocío University Hospitals, University of Sevilla, Sevilla, Spain.;Inter-Centre Unit of Digestive Diseases and CIBERehd, Virgen Macarena - Virgen del Rocío University Hospitals, University of Sevilla, Sevilla, Spain.;Inter-Centre Unit of Digestive Diseases and CIBERehd, Virgen Macarena - Virgen del Rocío University Hospitals, University of Sevilla, Sevilla, Spain.;Pathology Unit, Virgen del Rocio University Hospital, Sevilla, Spain.;Inter-Centre Unit of Digestive Diseases and CIBERehd, Virgen Macarena - Virgen del Rocío University Hospitals, University of Sevilla, Sevilla, Spain.",
"authors": "Sendra|Carmen|C|;Ampuero|Javier|J|;Gallego|Álvaro Giráldez|ÁG|;Sousa|José Manuel|JM|;Jiménez|María Serrano|MS|;Romero-Gómez|Manuel|M|",
"chemical_list": "D000900:Anti-Bacterial Agents",
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"issue": "36(2)",
"journal": "Seminars in liver disease",
"keywords": null,
"medline_ta": "Semin Liver Dis",
"mesh_terms": "D058186:Acute Kidney Injury; D065290:Acute-On-Chronic Liver Failure; D061605:Administration, Intravenous; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D003937:Diagnosis, Differential; D006519:Hepatitis, Alcoholic; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic; D008297:Male; D008875:Middle Aged; D063305:Organ Dysfunction Scores; D011859:Radiography; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed",
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"title": "Case Report: Acute-on-Chronic Liver Failure: Making the Diagnosis between Infection and Acute Alcoholic Hepatitis.",
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"abstract": "Cases of concurrent immunoglobulin A nephropathy (IgAN) and IgG4-related tubulointerstitial nephritis (IgG4-TIN) are rare and previous case reports have lacked important data. KDIGO suggests a treatment with systemic glucocorticoids in IgAN patients. Glucocorticoids are recommended as the first-line therapy for IgG4-TIN. The use of tacrolimus as a long-term maintenance treatment has not been described. We report the case of a man who developed IgAN and IgG4-TIN without abnormalities in extra-renal tissue, without renal function abnormalities or impairment as well, and was treated by tacrolimus as a long-term maintenance during 45 months follow-up.\n\n\n\nA 56-year-old Chinese man first presented to our hospital with the chief complaint of foamy urine for 1 year and hematuria for 3 months, with a medical history of hypertension. Testing revealed a notable increase in serum IgG4 level without abnormalities in renal function or imaging, or in dysfunction other organs. Renal biopsy showed mesangial extracellular matrix proliferation, increased mesangial cell numbers and infiltration of plasma cells. Immunofluorescence showed mesangial positivity for IgA and C3. Immunohistochemistry staining showed widespread IgG4 and increased CD38 and CD138 expression. Electron microscopy showed immune complexes located on the tubular basement membrane. He was diagnosed with IgAN and IgG4-TIN. He received glucocorticoids, leflunomide and tacrolimus to induce remission. He was given tacrolimus as long-term maintenance treatment. When tacrolimus was temporarily withdrawn, proteinuria recurred. After resuming tacrolimus therapy, he again entered complete remission. After 45 months of therapy, he remains in complete remission and the serum IgG4 level is normal.\n\n\n\nThe finding of concurrent IgAN and IgG4-TIN without abnormalities in renal function, imaging or extra-renal tissue is rare and their coexistence may be coincidental. Long-term treatment with tacrolimus proved effective and he has remained in remission during 45 months follow-up.",
"affiliations": "Department of Nephrology, Shengjing Hospital of China Medical University, 36 Sanhao St, Shenyang, 110004, Liaoning, China.;Department of Nephrology, Shengjing Hospital of China Medical University, 36 Sanhao St, Shenyang, 110004, Liaoning, China.;Department of Nephrology, Shengjing Hospital of China Medical University, 36 Sanhao St, Shenyang, 110004, Liaoning, China.;Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.;Renal Diagnostics and Therapeutics Unit, NIDDK/NIH, Bethesda, MD, USA.;Department of Nephrology, Shengjing Hospital of China Medical University, 36 Sanhao St, Shenyang, 110004, Liaoning, China. huazhou_cmu@163.com.",
"authors": "Tian|Mi|M|;Luan|Junjun|J|;Jiao|Congcong|C|;Chang|Qing|Q|;Kopp|Jeffrey B|JB|;Zhou|Hua|H|0000-0003-0429-116X",
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"doi": "10.1186/s12882-021-02477-w",
"fulltext": "\n==== Front\nBMC Nephrol\nBMC Nephrol\nBMC Nephrology\n1471-2369\nBioMed Central London\n\n2477\n10.1186/s12882-021-02477-w\nCase Report\nCo-occurrence of IgA nephropathy and IgG4-Tubulointersitial nephritis effectively treated with tacrolimus: a case report\nTian Mi 1\nLuan Junjun 1\nJiao Congcong 1\nChang Qing 2\nKopp Jeffrey B. 3\nhttp://orcid.org/0000-0003-0429-116X\nZhou Hua huazhou_cmu@163.com\n\n1\n1 grid.412467.2 0000 0004 1806 3501 Department of Nephrology, Shengjing Hospital of China Medical University, 36 Sanhao St, Shenyang, 110004 Liaoning China\n2 grid.412467.2 0000 0004 1806 3501 Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China\n3 grid.419635.c 0000 0001 2203 7304 Renal Diagnostics and Therapeutics Unit, NIDDK/NIH, Bethesda, MD USA\n12 8 2021\n12 8 2021\n2021\n22 27924 5 2021\n19 7 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nCases of concurrent immunoglobulin A nephropathy (IgAN) and IgG4-related tubulointerstitial nephritis (IgG4-TIN) are rare and previous case reports have lacked important data. KDIGO suggests a treatment with systemic glucocorticoids in IgAN patients. Glucocorticoids are recommended as the first-line therapy for IgG4-TIN. The use of tacrolimus as a long-term maintenance treatment has not been described. We report the case of a man who developed IgAN and IgG4-TIN without abnormalities in extra-renal tissue, without renal function abnormalities or impairment as well, and was treated by tacrolimus as a long-term maintenance during 45 months follow-up.\n\nCase presentation\n\nA 56-year-old Chinese man first presented to our hospital with the chief complaint of foamy urine for 1 year and hematuria for 3 months, with a medical history of hypertension. Testing revealed a notable increase in serum IgG4 level without abnormalities in renal function or imaging, or in dysfunction other organs. Renal biopsy showed mesangial extracellular matrix proliferation, increased mesangial cell numbers and infiltration of plasma cells. Immunofluorescence showed mesangial positivity for IgA and C3. Immunohistochemistry staining showed widespread IgG4 and increased CD38 and CD138 expression. Electron microscopy showed immune complexes located on the tubular basement membrane. He was diagnosed with IgAN and IgG4-TIN. He received glucocorticoids, leflunomide and tacrolimus to induce remission. He was given tacrolimus as long-term maintenance treatment. When tacrolimus was temporarily withdrawn, proteinuria recurred. After resuming tacrolimus therapy, he again entered complete remission. After 45 months of therapy, he remains in complete remission and the serum IgG4 level is normal.\n\nConclusions\n\nThe finding of concurrent IgAN and IgG4-TIN without abnormalities in renal function, imaging or extra-renal tissue is rare and their coexistence may be coincidental. Long-term treatment with tacrolimus proved effective and he has remained in remission during 45 months follow-up.\n\nKeywords\n\nIgA nephropathy\nIgG4-related tubulointerstitial nephritis\nTacrolimus\nSerum IgG4\nNational Science Foundation of China81770698 Zhou Hua liao ning revitalization talents programXLYC2002081 Zhou Hua National Key R&D Program of China2017YFC0907400 Chang Qing Key R & D guidance plan of Liaoning Province 2019JH8/10300009 Zhou Hua Pandeng Scholar of Education Department of Liaoning Province 2013222 Zhou Hua issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nIgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis worldwide [1], and is particularly common among Asians [2]. Predominant IgA deposition in the glomerular mesangium by biopsy has been used as the defining characteristics for the diagnosis of IgAN [3]. IgAN was the most common glomerulopathy, with a frequency of 28.1% [4].\n\nIgG4-related disease (IgG4-RD) is an fibroinflammatory condition involved multiple organs characterized by IgG4 positive plasma cells infiltration in the involved tissues and elevated serum IgG4 level [5], with a prevalence of IgG4-RD in Japan estimated as 0.28–1.08/100,000 people in 2012 [6]. IgG4-related tubulointerstitial nephritis (IgG4-TIN), is the common manifestation of IgG4-related kidney disease (IgG4-RKD), accounting for about 15–25% of all IgG4-RD [5, 7].\n\nGlomerular disease in patients with IgG4-RD has been reported in the setting of IgG4-TIN, but most such patients had extrarenal involvement and multiorgan involvement [8–10]. Only one case co-existing IgAN and IgG4-TIN has been reported, with dacryoadenitis and sialadenitis, but treatment was not discussed [5]. The co-occurrence of IgAN and IgG4-TIN without extrarenal involvement has not been previously reported. While glucocorticoids are recommended as the first-line therapy for IgG4-TIN, the role of tacrolimus as a long-term maintenance treatment has no report. Tacrolimus effectively reduces proteinuria in IgAN [11]. Here we report the case of a man who developed IgAN and IgG4-TIN without extra-renal manifestations and was treated with tacrolimus as maintenance therapy during 45 months of follow-up.\n\nCase presentation\n\nClinical history and initial laboratory data\n\nA 56-year-old Chinese man was admitted with the chief complaint of foamy urine for 1 year and hematuria for 3 months. Medical history was notable for hypertension for 5 years; the highest blood pressure was 180/110 mmHg. His blood pressure was poorly controlled, 140–150/90–100 mmHg, while he took candesartan irregularly.\n\nHe denied diabetes, hepatitis, tuberculosis, and coronary heart diseases. His medical family history was unremarkable. He denied use of illicit drugs and exposure to pesticides and other toxins. Medications included an angiotensin-converting enzyme inhibitor. His weight was 79 kg, blood pressure was 170/90 mmHg, and physical examination was otherwise unremarkable.\n\nOn admission, laboratory data showed urinary total proteinuria (URTP) 3.4 g/d, serum total protein 75.3 g/l, serum albumin (Alb)33.5 g/l, serum creatinine (Cr) 86 umol/l, (suggesting an eGFR of 87 ml/min/1.73m2 by the CKD-EPI equation) (Fig. 1), and C-response protein (CRP) increased at 21.90 mg/l. Urinalysis showed hematuria with 482 red blood cells (RBC) per high-power field, with 80% dysmorphic RBC. Fig. 1 Clinical course of kidney disease activity after admission. Urinary total proteinuria (URTP) (a); creatinine (Cr) (b); serum albumin (Alb) (c); eGFR-EPI (d) based on the administration or stopping of glucosteroid and immunosuppressants\n\nClinical immunology tests revealed the following: anti-nuclear antibody (+), anti-neutrophil cytoplasmic antibodies (−), IgG4 3.68 g/l, IgG 25.70 g/l, IgA 5.96 g/l, IgM 1.41 g/l, IgE 1586 IU/ml (Fig. 2), complement 3 (C3) 0.99 g/l, C4 0.20 g/l, CRP 46 mg/l, and erythrocyte sedimentation rate 58 mm/h. Serum immune electrophoresis, glucose, thyroid function, and tumor markers were all normal. Fig. 2 The serum levels of serum IgG4-RD related immunoglobulins after therapy. IgG4 (a); IgG (b); IgE (c). serum IgA (d). Both tacrolimus and leflunomide reduced serum IgG4 levels\n\nEvaluation for infectious disease was negative, including serologies for hepatitis, HIV, and syphilis. Chest computerized tomogram (CT) scan and enhanced abdominal CT scan were normal. Renal ultrasound showed left kidney dimensions was 12.61 cm in height 5.58 cm in width and 5.43 cm in depth, while the right kidney dimensions were 11.22 by 5.62 by 7.86 cm. Both kidneys were slightly enlarged and hyperechoic (Fig. 3). Fig. 3 Ultrasound images of extrarenal and renal manifestations. No enlargement of lacrimal gland (a), parotid gland (b), submandibular glands (c), pancreas and retroperitoneal fibrosis (d). Normal size kidney and renal cortex thickness and ureteral inflammatory pseudotumor (e) at initial admission\n\nKidney biopsy\n\nOn periodic acid Schiff (PAS) staining under light microscopy, one out of fourteen glomeruli showed global sclerosis. The mild to moderate mesangial proliferation was present. The two glomeruli showed ischemic shrinkage (Fig. 4a). There was no endocapillary hypercellularity, fibrosis of Bowman’s capsule wall, or glomerular crescents. A few glomeruli manifest adhesion of the capillary tuft to Bowman capsule. Fig. 4 Typical pathological features of IgA nephropathy in renal biopsy. Total 14 glomeruli were present in the renal biopsy specimen. Glomeruli exhibited proliferation of mesangial cells and increased mesangial matrix with no apparent intraductal hyperplasia or crescentic lesions on periodic acid-Schiff (PAS) staining (a). Immunofluorescence staining demonstrated strongly positive punctate staining within the mesangium for IgA (b) and C3 (c). Original magnification 400 ×\n\nRenal tubules exhibited multifocal atrophy and proteinaceous casts. Renal tubular epithelial cells showed granular and vacuolar degeneration. Focal interstitial fibrosis and interstitial edema with significant inflammatory cell infiltration, including lymphocytes and plasma cells were present, (Fig. 5a, b). Occasional hyaline degeneration in arteriolar walls was observed. Fig. 5 Typical pathological features of IgG4-Tubulointersitial nephritis and immunohistochemistry staining of surface biomarkers of plasma cells in renal biopsy. The renal interstitium is infiltrated by plasma cells and lymphocytes predominantly with fibrosis on periodic acid-Schiff (PAS) staining. Original magnification 100x (a) and 400× (b). TBM electron-dense deposits were seen under electron microscope. Original magnification 8000x (c). Marked increase in IgG4-positive plasma cells was seen in the infiltrated cells on immunohistochemistry staining. Original magnification 400× (d). CD38-positive plasma cells (e), CD138-positive plasma cells (f), CD56-positive plasma cells (g), and MUM1-positive plasma cells (h) were seen in the interstitium on immunohistochemistry staining. Original magnification 400 ×\n\nOn immunofluorescence staining, a pattern of lumpy-like deposition was seen in the mesangium (for the following: IgA was 3+, C3 was 3+, while immunostaining for C1q, fibrinogen, IgG, IgM was negative (Fig. 4b and c).\n\nThe elevated serum IgG4 level led us to further examine the infiltrated monocytes in renal biopsy. The absolute number of positive IgG4+ cells per high power field> 10 (Fig. 5d). As surface biomarkers of plasma cells, positive staining of CD38, CD138, CD56, and MUM1 were seen in the interstitium (Fig. 5e-h).\n\nElectron micrographs also revealed immune complexes deposited on tubular basement membranes (Fig. 5c).\n\nDiagnosis of IgAN and IgG4-TIN\n\nThis patient manifested typical features of IgAN, including hematuria, proteinuria, mesangial cell proliferation, mesangial matrix expansion, and positive immunofluorescence staining of mesangial IgA and C3 deposits [3]. Plasma cells were identified on PAS-stained sections and EM demonstrated immune complexes on basement membranes. CD38+/CD138+ plasma cells in kidney expressed IgG4. The absolute number of IgG4+ cells per high power field was > 10. Serum IgG4 level was elevated, with values of 3.7 g/l. The size of kidney was enlarged.\n\nIn summary, the combination of clinical, serologic, radiologic, and pathologic data, in this patient fulfilled the 2019 American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) criteria for the diagnosis of IgG4-renal disease [12].\n\nTreatment course and clinical follow up\n\nAfter the diagnosis of IgAN and IgG4-TIN was made, prednisolone (45 mg/d) therapy was initiated, based on the KDIGO guideline for IgAN [13] therapies included the Chinese herb Tripterygium wilfordii, angiotensin converting enzyme-inhibitor was replaced by an angiotensin receptor blocker, together with amlodipine to maintain his blood pressure below 130/80 mmHg. After 12 weeks, the prednisolone reduced gradually and proteinuria level reached complete remission (< 0.3 g/d), and Tripterygium wilfordii was administered for 18 months maintenance (Fig. 1).\n\nFrom the 15th month on, serum IgG4 and IgA re-elevated as well as serum albumin dropped. Tacrolimus was put on the patient as immunosuppresent based on a Cochane systematic review [14]. Before tacrolimus was chosen, other traditional immunosuppressants were also considered. The patient declined intravenous cyclophosphamide due to the inconvenience of hospitalization and concern for tumor occurrence. Mycophenolate mofetil was excluded because the increased local risk for Pneumocystis carinii infection which requires sulfamethoxazole, which can also cause interstitial nephrititis. Rituximab therapy was not available for this patient because of his financial reasons.\n\nAfter 3 months of tacrolimus treatment, kidney disease activity and immune indices were remitted again for 8 months (Fig. 1). When the COVID-19 pandemic emerged and the patient was no longer able to travel to our hospital. His local physician stopped tacrolimus from the 30th month and replaced it with leflunomide for 2 months. Both renal diseases relapsed. When he was able to return to our clinic at 32th month, tacrolimus was administered again. After 3 months treatment with tacrolimus, he again entered complete remission and the remission remains over 45 months of follow up (Figs. 1 and 2) as of this writing.\n\nAt the most recent visit in June 2021, URTP remained < 0.3 g/d, IgG4 plasma was negative (Figs. 1 and 2). In addition, the IgG4-RD Responder Index (RI) was calculated and revealed the suppression of IgG4 production (Fig. 6). Although abnormalities in renal function was present with normal size and cortical thickness of the kidney, but no extrarenal lesions appeared, such as gland swelling, lymphadenopathy and retroperitoneal fibrosis compared to those images at the initial presentation of the kidney disease was diagnosed. Fig. 6 The dynamic changes of IgG4-RD Responder Index (RI) from the intitially presentation to 45 mouths of follow-up. Tacrolimus reduced the scores of IgG4-RD RI\n\nDiscussion and conclusions\n\nThis study reported a man patient with concurrence of IgAN and IgG4-TIN without renal function abnormalities or impairment at the initial hospitalization. At admission, the patient presented marked proteinuria, the decreased serum albumin level, and normal renal function. The renal biopsy showed typical mild-moderate mesangial proliferation, predominant IgA, and C3 deposition. However, abundant monocytes infiltrated in the tubule-interstitium of the kidney biopsy and serum IgG4 level increased near two-fold. On immunohistochemistry of renal biopsy, absolute number of positive IgG4 cells was more than 10/high power field and plasma surface biomarkers were positive. Concurrence of IgAN and IgG4-TIN was diagnosed. Oral prednisone and tacrolimus showed effective for both IgAN and IgG4-TIN with over than 45 months follow up (Figs. 1 and 2).\n\nTakako Saeki et al. firstly reported a patient biopsy proven as IgG4-TIN without prominent proteinuria and microscopic hematuria. However dominant mesangial IgA deposition is also seen in one case [5]. This case is IgG4-TIN predominant with an additional IgA deposition. The abnormality is mild in urine analysis. Our patient presented typical clinical nephritis syndrome with predominant proteinuria, microscopic hematuria, and decreased serum albumin level. Renal biopsy revealed a typical IgAN. However, large amount of the infiltrated lymphocytes led us to think about a possible co-existing tubule-interstitial disease. With blood examination, serum IgG4 level was elevated. Further immunohistochemistry staining showed plenty positive IgG4 cells and positive cells stained with multiple plasma surface biomarkers such as CD38, CD138, CD56, and MUM1 (Fig. 5). Even though both case presented similar co-concurrence of IgAN and IgG4-TIN. The clinical kidney disease activity was quite different. Saeki et al. reported the rare pathological co-existing phenomenon of both diseases. We followed up over 45 months to explore the effective treatment when kidney disease showed significant active.\n\nIgAN is the most common glomerulonephritis in the world [4] and it is easy to be diagnosed if biopsy is available. IgAN is diagnosed by the presence of mesangial dominant IgA staining on immunofluorescence and mesangial hyper-cellularity by light microscopy [15]. Our patient presented as a feature of a typical IgAN. On the other hand, IgG4-RD is a multi-organ immune-mediated condition associated with fibroinflammatory lesions [16, 17]. In 2019, ACR/ EULAR made new diagnostic criteria for IgG4-RD, providing a more specific and sensitive scoring system [12]. IgG4-related kidney disease (IgG4-RKD) is a comprehensive term for the renal lesions associated with IgG4-RD [18]. IgG4-related tubulointerstitial nephritis (IgG4-TIN) is the most common renal manifestation of IgG4-RKD [19, 20]. The diagnosis of IgG4-TIN is based on the presence of four criteria: (1) plasma cell-rich TIN, with renal IgG4-positive plasma cells > 10 / high power field; (2) an increased IgG4+/IgG+ plasma cell ratio (> 40%) in the most concentrated field; (3) TBM immune complex deposits in the tubular basement membrane, identified by immunohistochemistry, immunofluorescence, and/or electron microscopy; and (4) at least one imaging feature (multiple cortical low-density nodules, round wedge-shaped lesions on enhanced CT, or diffuse kidney enlargement), OR characteristic serologic abnormality (most commonly elevated total IgG or IgG4 level), OR other organ involvement [6, 8]. Our case met the above criteria and was diagnosed as IgG4-TIN. We firstly reported this case with co-concurrence of dominant IgAN and IgG4-TIN without extra-renal organ impairment.\n\nIn terms of the treatment, KDIGO suggested a treatment course of systemic glucocorticoids in IgAN patients with proteinuria above 1 g/day and eGFR higher than 50 ml/min/1.73 m2 despite supportive care. The benefit of immunosuppressive agents remains controversy [21]. No randomized clinical trials have been evaluated and compared the efficacy of different treatment regimens for IgG4-RD [19]. Glucocorticoids are recommended as the first-line therapy for IgG4-RKD [19, 22]. However, to avoid steroid resistance or relapse at discontinuation and long-term undesirable side effects, other steroid sparing agents, such as B cell depleting agents with example of rituximab, azathioprine, MMF and cyclophosphamide [23], are reasonable choices for second-line agents. Tripterygium wilfordii, a traditional Chinese medicine, was beneficial for numerous Chinese IgAN patients [24]. Considering the side effects of long-term steroid, we used Tripterygium wilfordii as the treatment for IgAN in first 18 months. When we followed up this patient on 15th month, tacrolimus was administered due to the elevated serum IgG4, IgA and total IgG levels, and the decreased albumin level indicating the activity of the disease. Recent meta-analysis and RCTs showed that tacrolimus was beneficial for the remission of proteinuria in patients with IgAN, showing that tacrolimus may be a promising agent for IgAN [11, 25–29]. IgAN mainly contributed to prominent proteinuria for this patient. Our patient showed a good response to tacrolimus indicating as proteinuria reduction and serum albumin recovery (Fig. 1). With the diagnosis of IgAN, co-existing IgG4-TIN was diagnosed. A recent retrospective study reported the effectiveness of tacrolimus in five relapsed IgG4-RD patients without increasing glucocorticoids [30]. T follicular helper cell is involved in the pathogenesis of IgG4-RD [31–33]. Tacrolimus can prevent calcineurin activation and block dephosphorylation of nuclear factor of activated T cells, and specifically suppresses both lymph nodes and circulating T follicular helper cells. Thus, tacrolimus can be a reasonable choice for IgG4-RD. Tacrolimus treatment can be used for either reducing IgAN proteinuria [11, 25–29] or serum IgG4 level [30–33]. These data provided us evidence to use tacrolimus to treat co-existing IgAN and IgG4-TIN condition. Our patient showed good response to tacrolimus with a comprehensive evaluation using the reduction of IgG4-RD RI values (Fig. 6), which was demonstrated to be a practical, reliable, and responsive tool for assessing the progression of IgG4-RD [34–36]. During the treatment, the local physician stopped tacrolimus and put leflunomide on him, when the patient reach completed remission. Leflunomide was reported to reduce kidney damage of IgAN patients [37] and to be effective in tapering glucocorticoids and maintaining glucocorticoid-induced remission in IgG4-RD [38], However, our patient showed failure of maintaining remission by leflunomide. We reused tacrolimus to replace leflunomide. The patient again entered complete remission 3 months after resuming tacrolimus. Fortunately, the patient remained the remission over 45 months follow-up. It is important to watch out the possible IgAN and IgG4-TIN and to take a continuous and reliable close follow-up when tacrolimus is used for a treatment regimen for this condition.\n\nIn summary, we presented a case of a 56-year-old male without renal function abnormalities or impairment who was diagnosed as concurrence of IgAN and IgG4-TIN without extrarenal involvement and follow up 45 months. Tacrolimus was effective for the both diseases. In the early stage of IgG4-TIN without extrarenal involvement, tacrolimus was beneficial for development of the extrarenal tissue impairment by controlling serum IgG4 level and was also effective for IgAN.\n\nAbbreviations\n\nACR American College of Rheumatology\n\nAlb Albumin\n\nC3 Third complement component\n\nCr Creatinine\n\nCR Complete remission\n\nCRP C-response protein\n\nEULAR European League Against Rheumatism\n\nIgAN Immunoglobulin A nephropathy\n\nIgG4-RD IgG4-related disease\n\nIgG4-RKD IgG4-related kidney disease\n\nIgG4-TIN IgG4-related tubulointerstitial nephritis\n\nMN Membranous nephropathy\n\nPAS Periodic acid Schiff\n\nRBC Red blood cells\n\nRI Responder index\n\nURTP Urinary total proteinuria\n\nAcknowledgements\n\nThe authors thanks Christine Wang for illustration assistance.\n\nAuthors’ contributions\n\nM.T. contributed to data collection and manuscript writing. H.Z. supervised the data and finalized the manuscript. J.L. and C.J. contributed to data collection. Q.C. participated in data collection and analysis. J.B.K. provided advice on data presentation and edited the manuscript. The author(s) read and approved the final manuscript.\n\nFunding\n\nThis research was supported by the National Science Foundation of China (81770698, H.Z.), Liao Ning Revitalization Talents Program (XLYC2002081, H.Z), National Key R&D Program of China (2017YFC0907400, Q.C.), Key R & D guidance plan of Liaoning Province (2019JH8/10300009, H.Z.), and the Pandeng Scholar of Education Department of Liaoning Province (2013222, H.Z.). The funders had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, provided critical review comments and also submission for the manuscript.\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\nDeclarations\n\nEthics approval and consent to participate\n\nA human subject research protocol was approved in advance by the Institutional Review Boards of Affiliated Hospital of China Medical University. The patient provided written informed consent prior to research participation.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\n\nThe authors declare no conflict of interest.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Schena F Nistor I Epidemiology of IgA nephropathy: a global perspective Semin Nephrol 2018 38 5 435 442 10.1016/j.semnephrol.2018.05.013 30177015\n2. Kiryluk K Li Y Scolari F Sanna-Cherchi S Choi M Verbitsky M Fasel D Lata S Prakash S Shapiro S Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens Nat Genet 2014 46 11 1187 1196 10.1038/ng.3118 25305756\n3. Roberts I Cook H Troyanov S Alpers C Amore A Barratt J Berthoux F Bonsib S Bruijn J Cattran D The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility Kidney Int 2009 76 5 546 556 10.1038/ki.2009.168 19571790\n4. Xu X Wang G Chen N Lu T Nie S Xu G Zhang P Luo Y Wang Y Wang X Long-term exposure to air pollution and increased risk of membranous nephropathy in China J Am Soc Nephrol 2016 27 12 3739 3746 10.1681/ASN.2016010093 27365535\n5. Saeki T Nishi S Imai N Ito T Yamazaki H Kawano M Yamamoto M Takahashi H Matsui S Nakada S Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis Kidney Int 2010 78 10 1016 1023 10.1038/ki.2010.271 20720530\n6. Raissian Y Nasr S Larsen C Colvin R Smyrk T Takahashi N Bhalodia A Sohani A Zhang L Chari S Diagnosis of IgG4-related tubulointerstitial nephritis J Am Soc Nephrol 2011 22 7 1343 1352 10.1681/ASN.2011010062 21719792\n7. Lin W Lu S Chen H Wu Q Fei Y Li M Zhang X Tian X Zheng W Leng X Clinical characteristics of immunoglobulin G4-related disease: a prospective study of 118 Chinese patients Rheumatology (Oxford) 2015 54 11 1982 1990 10.1093/rheumatology/kev203 26106212\n8. Cornell L IgG4-related kidney disease Semin Diagn Pathol 2012 29 4 245 250 10.1053/j.semdp.2012.07.004 23068304\n9. Wang G Chen Y Cheng H Xu X Sun L Dong H Antineutrophil cytoplasmic antibody and/or antiglomerular basement membrane antibody associated crescentic glomerulonephritis in combination with IgG4-related tubulointerstitial nephritis Clin Exp Rheumatol 2019 37 2 279 285 30183608\n10. Kawano M Saeki T IgG4-related kidney disease--an update Curr Opin Nephrol Hypertens 2015 24 2 193 201 10.1097/MNH.0000000000000102 25594543\n11. Yu M Kim Y Koo H Chin H Short-term anti-proteinuric effect of tacrolimus is not related to preservation of the glomerular filtration rate in IgA nephropathy: a 5-year follow-up study PLoS One 2017 12 11 e0188375 10.1371/journal.pone.0188375 29155873\n12. Wallace Z Naden R Chari S Choi H Della-Torre E Dicaire J Hart P Inoue D Kawano M Khosroshahi A The 2019 American College of Rheumatology/European league against rheumatism classification criteria for IgG4-related disease Ann Rheum Dis 2020 79 1 77 87 10.1136/annrheumdis-2019-216561 31796497\n13. Floege J, Barbour SJ, Cattran DC, Hogan JJ, Nachman PH, Tang SCW, et al. Management and treatment of glomerular diseases (part 1): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2019;95(2):268-280.\n14. Tan J, Dong L, Ye D, Tang Y, Hu T, Zhong Z, et al. The efficacy and safety of immunosuppressive therapies in the treatment of IgA nephropathy: A network meta-analysis. Sci Rep. 2020;10(1):6062.\n15. Hassler J IgA nephropathy: a brief review Semin Diagn Pathol 2020 37 3 143 147 10.1053/j.semdp.2020.03.001 32241578\n16. Stone J Zen Y Deshpande V IgG4-related disease N Engl J Med 2012 366 6 539 551 10.1056/NEJMra1104650 22316447\n17. Kamisawa T Zen Y Pillai S Stone J IgG4-related disease Lancet. 2015 385 9976 1460 1471 10.1016/S0140-6736(14)60720-0 25481618\n18. Kawano M Saeki T Nakashima H Nishi S Yamaguchi Y Hisano S Yamanaka N Inoue D Yamamoto M Takahashi H Proposal for diagnostic criteria for IgG4-related kidney disease Clin Exp Nephrol 2011 15 5 615 626 10.1007/s10157-011-0521-2 21898030\n19. Cortazar F Stone J IgG4-related disease and the kidney Nat Rev Nephrol 2015 11 10 599 609 10.1038/nrneph.2015.95 26122730\n20. Zhang P Cornell L IgG4-related Tubulointerstitial nephritis Adv Chronic Kidney Dis 2017 24 2 94 100 10.1053/j.ackd.2016.12.001 28284385\n21. Wyatt R Julian B IgA nephropathy N Engl J Med 2013 368 25 2402 2414 10.1056/NEJMra1206793 23782179\n22. Saeki T Kawano M IgG4-related kidney disease Kidney Int 2014 85 2 251 257 10.1038/ki.2013.393 24107849\n23. Yunyun F Yu C Panpan Z Hua C Di W Lidan Z Linyi P Li W Qingjun W Xuan Z Efficacy of cyclophosphamide treatment for immunoglobulin G4-related disease with addition of glucocorticoids Sci Rep 2017 7 1 6195 10.1038/s41598-017-06520-5 28733656\n24. Wang Z Yu C Zhou L Chen X Effects of Tripterygium wilfordii induction therapy to IgA nephropathy patients with heavy proteinuria Biol Pharm Bull 2017 40 11 1833 1838 10.1248/bpb.b17-00134 28867717\n25. Zheng J Gong X Wu Z Immunosuppressive agents in the treatment of IgA nephropathy: a meta-analysis of clinical randomized controlled literature Niger J Clin Pract 2020 23 4 437 449 32246648\n26. Zhang Y Luo J Hu B Ma T Efficacy and safety of tacrolimus combined with glucocorticoid treatment for IgA nephropathy: a meta-analysis J Int Med Res 2018 46 8 3236 3250 10.1177/0300060518776566 29882450\n27. Peng W Tang Y Jiang Z Li Z Mi X Qin W The effect of calcineurin inhibitors in the treatment of IgA nephropathy: a systematic review and meta-analysis (PRISMA) Medicine. 2016 95 35 e4731 10.1097/MD.0000000000004731 27583915\n28. Song Y Cai G Xiao Y Wang Y Yuan B Xia Y Wang S Chen P Liu S Chen X Efficacy and safety of calcineurin inhibitor treatment for IgA nephropathy: a meta-analysis BMC Nephrol 2017 18 1 61 10.1186/s12882-017-0467-z 28193247\n29. Fan L Liu Q Liao Y Li Z Ji Y Yang Z Chen J Fu J Zhang J Kong Y Tacrolimus is an alternative therapy option for the treatment of adult steroid-resistant nephrotic syndrome: a prospective, multicenter clinical trial Int Urol Nephrol 2013 45 2 459 468 10.1007/s11255-012-0205-1 22684795\n30. Takanashi S Kaneko Y Takeuchi T Effectiveness of tacrolimus on IgG4-related disease Mod Rheumatol 2019 29 5 892 894 10.1080/14397595.2018.1532560 30285576\n31. Akiyama M Suzuki K Yasuoka H Kaneko Y Yamaoka K Takeuchi T Follicular helper T cells in the pathogenesis of IgG4-related disease Rheumatology (Oxford) 2018 57 2 236 245 10.1093/rheumatology/kex171 28460058\n32. Akiyama M Suzuki K Yamaoka K Yasuoka H Takeshita M Kaneko Y Kondo H Kassai Y Miyazaki T Morita R Number of circulating follicular helper 2 T cells correlates with IgG4 and Interleukin-4 levels and Plasmablast numbers in IgG4-related disease Arthritis Rheumatol 2015 67 9 2476 2481 10.1002/art.39209 25989153\n33. Akiyama M Yasuoka H Yamaoka K Suzuki K Kaneko Y Kondo H Kassai Y Koga K Miyazaki T Morita R Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease Arthritis Res Ther 2016 18 167 10.1186/s13075-016-1064-4 27411315\n34. Fernández-Codina A Pinilla B Pinal-Fernández I López C Fraile-Rodríguez G Fonseca-Aizpuru E Carballo I Brito-Zerón P Feijóo-Massó C López-Dupla M Treatment and outcomes in patients with IgG4-related disease using the IgG4 responder index Joint Bone Spine 2018 85 6 721 726 10.1016/j.jbspin.2018.01.014 29452298\n35. Carruthers M Stone J Deshpande V Khosroshahi A Development of an IgG4-RD responder index Int J Rheumatol 2012 2012 259408 10.1155/2012/259408 22611406\n36. Wallace Z Khosroshahi A Carruthers M Perugino C Choi H Campochiaro C Culver E Cortazar F Della-Torre E Ebbo M An international multispecialty validation study of the IgG4-related disease responder index Arthritis Care Res (Hoboken) 2018 70 11 1671 1678 10.1002/acr.23543 29457382\n37. Yi J, He Z, Xu S, Feng S. Efficacy and safety of leflunomide in IgA nephropathy: a systematic review and meta-analysis. Int Urol Nephrol. 2019;51(11):1987-1998.\n38. Wang Y Li K Gao D Luo G Zhao Y Wang X Zhang J Jin J Zhao Z Yang C Combination therapy of leflunomide and glucocorticoids for the maintenance of remission in patients with IgG4-related disease: a retrospective study and literature review Intern Med J 2017 47 6 680 689 10.1111/imj.13430 28321964\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "22(1)",
"journal": "BMC nephrology",
"keywords": "IgA nephropathy; IgG4-related tubulointerstitial nephritis; Serum IgG4; Tacrolimus",
"medline_ta": "BMC Nephrol",
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"nlm_unique_id": "100967793",
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"pages": "279",
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"pmid": "34384379",
"pubdate": "2021-08-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Co-occurrence of IgA nephropathy and IgG4-Tubulointersitial nephritis effectively treated with tacrolimus: a case report.",
"title_normalized": "co occurrence of iga nephropathy and igg4 tubulointersitial nephritis effectively treated with tacrolimus a case report"
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"companynumb": "CN-ALKEM LABORATORIES LIMITED-CN-ALKEM-2021-05362",
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"abstract": "OBJECTIVE\nTo investigate the clinical results and prognostic factors of multiple dose methotrexate (Mtx) treatment of ectopic pregnancy patients with high initial serum (human chorionic gonadotropin [hCG]).\n\n\nMETHODS\nRetrospective cohort study.\n\n\nMETHODS\nTwenty-six ectopic pregnancy patients with serum (βhCG) > 5,000 mIU/mL who received multiple doses of Mtx (1 mg/kg) with folinic acid rescue on the alternating days.\n\n\nRESULTS\nSuccess rate was 88.5%. All failures were tubal ruptures in those who underwent surgery. Median initial hCG values of the success and the failure patients were 8,582 (5,058-31,114) and 5,280 (5,042-13,563) mIU/mL respectively (p > 0.05). Side effects were seen in 18 patients (69.2%, one bone marrow suppression and 17 minor side effects). The number of Mtx injections (7.04 ± 1.71), Mtx dose (71.35 ± 13.16 mg) and follow-up period (42.04 ± 23.77 days) did not differ between groups. Body mass index (BMI), Mtx dose, number of Mtx and change in βhCG levels between the initials and the levels measured 2 days after the 3rd, 4th, and 5th Mtx injections were found to be highly predictive for tubal rupture.\n\n\nCONCLUSIONS\nMultiple-dose Mtx treatment of ectopic pregnancies with high initial hCG is safe and effective. BMI, Mtx dose, number of Mtx injections and the decrement of βhCG levels were found as highly predictive for the success of the treatment.",
"affiliations": "Fatih Sultan Mehmet Research Hospital, Clinic of Obstetrics and Gynecology, Istanbul, Turkeyniyazitug@hotmail.com.;Fatih Sultan Mehmet Research Hospital, Clinic of Obstetrics and Gynecology, Istanbul, Turkey.;Fatih Sultan Mehmet Research Hospital, Clinic of Obstetrics and Gynecology, Istanbul, Turkey.",
"authors": "Tug|Niyazi|N|;Sargin|Mehmet Akif|MA|;Yassa|Murat|M|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D018997:Chorionic Gonadotropin, beta Subunit, Human; D008727:Methotrexate",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000491083",
"fulltext": null,
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"issn_linking": "0378-7346",
"issue": "84(1)",
"journal": "Gynecologic and obstetric investigation",
"keywords": "Body mass index; Ectopic pregnancy; Human Chorionic Gonadotropin; Methotrexate; β-Human Chorionic Gonadotropin",
"medline_ta": "Gynecol Obstet Invest",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000328:Adult; D018997:Chorionic Gonadotropin, beta Subunit, Human; D005184:Fallopian Tube Diseases; D005260:Female; D006801:Humans; D008727:Methotrexate; D008875:Middle Aged; D011247:Pregnancy; D011274:Pregnancy, Tubal; D012189:Retrospective Studies; D012422:Rupture, Spontaneous; D017211:Treatment Failure; D055815:Young Adult",
"nlm_unique_id": "7900587",
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"pages": "56-63",
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"pmid": "30099453",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Multidose Methotrexate Treatment of Ectopic Pregnancies with High initial β-Human Chorionic Gonadotropin: Can Success Be Predicted?",
"title_normalized": "multidose methotrexate treatment of ectopic pregnancies with high initial human chorionic gonadotropin can success be predicted"
} | [
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"companynumb": "PHHY2019TR053361",
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"abstract": "Psychotropic drug exposure during pregnancy is a common problem. Among the 601 cases exposed to drugs during pregnancy, who were followed by our Toxicology Information and Follow-up Service, 124 cases had used psychotropic drugs for depression, anxiety, or psychotic disorders. As the control group, 248 women, who did not use any drugs were selected. Of the 124 cases, 80 (64.5%) had healthy babies, and 17 (13.7%) decided to terminate the pregnancy. Spontaneous abortions, intrauterine death (in the 38th week) and premature deliveries were observed in the 9 (7.3%), 1 (0.8%) and 3 (2.4%) cases, respectively, in the drug exposure group. Pregnancies of the 14 (11.3%) cases were continuing during the preparation of this manuscript. Of the 248 controls, 151 (60.9%) had healthy babies, 9 (3.6%) experienced spontaneous abortion and 3 (1.2%) decided to terminate their pregnancies, 3 (1.2%) had premature deliveries, and we observed one (0.4%) congenital abnormality, 81 (32.7%) cases were still pregnant. Odds Ratio (95% confidence interval) for spontaneous abortion was found to be 1.35 (1.27-11.82) in the cases exposed to psychotropic drugs (P=0.02). No developmental problems were observed in the babies followed for 12 months. These data may give information about the early- but not the late-term effects of psychotropic drugs used in pregnant women.",
"affiliations": "Department of Family Medicine, Karadeniz Technical University, School of Medicine, TR-61187, Trabzon, Turkey. fyaris@meds.ktu.edu.tr",
"authors": "Yaris|Fusun|F|;Ulku|Cunay|C|;Kesim|Murat|M|;Kadioglu|Mine|M|;Unsal|Mesut|M|;Dikici|Mustafa Fevzi|MF|;Kalyoncu|Nuri Ihsan|NI|;Yaris|Ersin|E|",
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"issue": "29(2)",
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"mesh_terms": "D000022:Abortion, Spontaneous; D000328:Adult; D016022:Case-Control Studies; D003863:Depression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007752:Obstetric Labor, Premature; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D037841:Pregnant Women; D011618:Psychotic Disorders; D011619:Psychotropic Drugs; D012307:Risk Factors",
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"title": "Psychotropic drugs in pregnancy: a case-control study.",
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"abstract": "Dysgerminomas are aggressive germ cell tumors that typically have a favorable prognosis, especially in patients diagnosed with early stage disease. We recount the history of a 23-year-old woman who was treated for a stage IA ovarian dysgerminoma in November 2017. Postoperatively, the patient was noncompliant insofar as obtaining routine lab evaluations; ten months later, she was diagnosed with a cranial metastasis that extended into the meninges. The patient subsequently underwent a posterior fossa craniotomy and adjuvant etoposide, bleomycin and cisplatin chemotherapy to which she initially responded; however, during cycle 4, she developed pancytopenia whereupon the chemotherapy was summarily discontinued. Thereafter, the patient was surveilled and currently, she remains in clinical remission. Early stage ovarian dysgerminoma, albeit rarely, has the capacity to metastasize to the cranium or brain, further underscoring the significance of employing active follow-up with these patients.",
"affiliations": "Gynecologic Oncology Associates, Newport Beach, CA, United States of America.;St. Joseph Health, Department of Pathology, Mission Viejo, CA, United States of America.;St. Joseph Health, Department of Radiology, Mission Viejo, CA, United States of America.;St. Joseph Health, Department of Neurosurgery, Mission Viejo, CA, United States of America.;Oso Home Care, 17175 Gillette Avenue, Irvine, CA 92614, United States of America.;Oso Home Care, 17175 Gillette Avenue, Irvine, CA 92614, United States of America.",
"authors": "Beck|Tiffany L|TL|;Momose|Hitomi|H|;Dym|Jeffrey M|JM|;Rao|Vikas Y|VY|;Bohart|Randy|R|;Goldstein|Bram H|BH|",
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"doi": "10.1016/j.gore.2019.06.006",
"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(19)30061-X10.1016/j.gore.2019.06.006Case ReportCranial and intra-axial metastasis originating from a primary ovarian Dysgerminoma☆ Beck Tiffany L. aMomose Hitomi bDym Jeffrey M. cRao Vikas Y. dBohart Randy eGoldstein Bram H. bram@gynoncology.come⁎1a Gynecologic Oncology Associates, Newport Beach, CA, United States of Americab St. Joseph Health, Department of Pathology, Mission Viejo, CA, United States of Americac St. Joseph Health, Department of Radiology, Mission Viejo, CA, United States of Americad St. Joseph Health, Department of Neurosurgery, Mission Viejo, CA, United States of Americae Oso Home Care, 17175 Gillette Avenue, Irvine, CA 92614, United States of America⁎ Corresponding author at: Women's Cancer Research Foundation, 351 Hospital Road, Suite #506, Newport Beach, CA 92663, United States of America. bram@gynoncology.com1 Request for reprints: Bram Goldstein, Ph.D., Women's Cancer Research Foundation, 351 Hospital Road, Suite #506, Newport Beach, CA 92663.\n\n22 6 2019 8 2019 22 6 2019 29 55 57 8 5 2019 15 6 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Dysgerminomas are aggressive germ cell tumors that typically have a favorable prognosis, especially in patients diagnosed with early stage disease. We recount the history of a 23-year-old woman who was treated for a stage IA ovarian dysgerminoma in November 2017. Postoperatively, the patient was noncompliant insofar as obtaining routine lab evaluations; ten months later, she was diagnosed with a cranial metastasis that extended into the meninges. The patient subsequently underwent a craniotomy and adjuvant etoposide, bleomycin and cisplatin chemotherapy to which she initially responded; however, during cycle 4, she developed pancytopenia whereupon the chemotherapy was summarily discontinued. Thereafter, the patient was surveilled and currently, she remains in clinical remission. Early stage ovarian dysgerminoma, albeit rarely, has the capacity to metastasize to the cranium or brain, further underscoring the significance of employing active follow-up with these patients.\n\nHighlights\n• Dysgerminomas often afflict young adults and can exhibit a rapid growth pattern.\n\n• We describe a dysgerminoma patient who developed an cranial and intra-axial metastasis.\n\n• The patient initially responded to adjuvant therapy and is currently being surveilled.\n\n\n\nKeywords\nOvarian dysgerminomaCranial metastasisTreatment\n==== Body\n1 Introduction\nDysgerminomas comprise approximately 2% of all ovarian malignancies and nearly 33% of malignant ovarian germ cell neoplasms (Zogbi et al., 2018). They frequently manifest themselves in young adults or adolescents and have a proclivity for rapid growth (Mangili et al., 2011). When they manifest themselves, ovarian dysgerminomas routinely coincide with abdominal distention, pain and menstrual abnormalities (Zogbi et al., 2018).\n\nDysgerminoma, the ovarian counterpart of testicular seminoma, is composed of undifferentiated germ and large vesicular cells with interspersed, scant fibrous stroma (Zaloudek et al., 1981). They are characteristically unilateral and grossly, resemble a tan-colored, lobulated, firm mass (Gordon et al., 1981). On ultrasound, dysgerminomas are depicted as a highly vascularized, large, solid, lobulated adnexal mass with irregular, internal echogenicity (Guerriero et al., 2011).\n\nDespite their malignant propensity, stage I dysgerminoma patient 5-year survival rates are approximately 90% (Gallion et al., 1988). Conversely, relapse rates for stage IA disease are nearly 20%, (Patterson et al., 2008) wherein the disease is often identified within the contralateral ovary, pelvis and abdomen (Mangili et al., 2011; A L Husaini et al., 2012).\n\nWhen dysgerminomas metastasize, the disease is typically encountered in the para-aortic or supraclavicular lymph nodes (Mangili et al., 2011; A L Husaini et al., 2012), whereas the breast is very uncommon (Kattan et al., 1992) and neurologic involvement is exceedingly rare (Afridi et al., 1976; Jolles et al., 1989). In the current study, we recount the extraordinary occurrence of an ovarian dysgerminoma patient who developed metastatic disease that infiltrated her cranium and dura mater.\n\n2 Case report\nA 23-year-old, nulligravid woman with a history of polycystic ovary syndrome, migraines and bipolar disorder originally presented to an outside medical facility in November 2017 with pelvic pain and a 11 cm pelvic mass depicted on ultrasound. She had a CA-125 of 55.7 U/mL, a negative beta human chorionic gonadotropin (HCG) test, a carcinoembryonic antigen (CEA) of 0.8 ng/mL and alpha-fetoprotein (AFP) <0.7 ng/mL; her lactate dehydrogenase (LDH) was not measured.\n\nThe patient underwent a diagnostic laparoscopy, exploratory laparotomy and right salpingo-oophorectomy for a presumed stage IA dysgerminoma. Postoperatively, a CT scan of the chest, abdomen and pelvis in November 2017 precluded tumor deposits, ascites or adenopathy; notably, the resected right ovary contained a 5 cm cyst. Final pathology revealed a stage IA ovarian dysgerminoma. The patient was subsequently referred to our gynecologic oncology service for surveillance.\n\nIn January 2018, the patient's LDH was 361 U/L, her CA-125 was 9 U/mL and a CT scan of the abdomen and pelvis was negative for recurrent disease. She was prescribed bi-monthly evaluations although the patient was non-compliant and only returned in May 2018; nevertheless, she was asymptomatic and her LDH and CA-125 levels were 147 U/L and 3 U/mL, respectively.\n\nIn July 2018, the patient complained of neck swelling, malaise, anorexia, abdominal bloating, diarrhea and migratory pain; her CA-125 was 133 U/mL but she neglected to have her LDH levels measured. Additionally, the patient developed a persistent cough and scalp cellulitis for which she was prescribed Bactrim at an urgent care facility.\n\nIn September 2018, the patient was admitted to the emergency room for a painful, enlarging right parietal scalp mass; her LDH was >4000 U/L. Preoperative cranial CT imaging revealed a 6.4 cm × 5.2 cm right posterior lesion infiltrating the right parietal bone with superficial extension into the skull and intra-axial involvement (Fig. 1). The patient subsequently underwent a right parietal craniotomy with resection of the skull mass and attendant dura mater (Fig. 2); a postoperative PET scan was negative for residual disease. The frozen section was consistent with her primary ovarian dysgerminoma (Fig. 3a & b).Fig. 1 Axial post contrast MRI demonstrates the aggressive enhancing mass (arrow) involving the right parietal bone with both extra- and intracranial involvement.\n\nFig. 1Fig. 2 Gross photograph of the skull through which the metastatic dysgerminoma has invaded.\n\nFig. 2Fig. 3 a. Dysgerminoma in the right ovary. b. Dysgerminoma involving the skull bone, with the morphology identical to that of the right ovarian tumor.\n\nFig. 3\n\nIn October 2018, the patient's LDH was 271 U/L and her CA-125 was 19 U/mL. She commenced with four cycles of intravenous bleomycin (15 units/wk. on days 1, 8, and 15), intravenous etoposide 120 (mg/m2), and intravenous cisplatin (40 mg/m2 on days 1–5); her November 2018 lab values remained stable. Inauspiciously, at cycle 3, the patient's LDH was elevated at 380 U/L but during cycle four, her LDH (254 U/L) and CA-125 (15 U/mL) levels decreased; unfortunately, the patient thereupon developed pancytopenia whereupon the chemotherapy was discontinued. Currently, she is doing well and undergoing routine surveillance by her gynecologic oncologist.\n\n3 Conclusions\nDysgerminomas are aggressive lesions that predominantly infiltrate via direct extension, the lymphatic system or in advanced cases, hematogenously (Mangili et al., 2011; Patterson et al., 2008). Characteristically, they respond favorably to treatment and are associated with an overall 5-year survival rate approximating 90% (Mangili et al., 2011; Gallion et al., 1988). Similarly, relapse rates for dysgerminoma patients with early stage disease are approximately 20% and often attributed to postoperative residual disease (Patterson et al., 2008). In one dysgerminoma study, the 5-year survival rate was 61% for the optimally cytoreduced group (≤1 cm), compared with 14% in the sub-optimal surgery cohort (Li and Xiaohua, 2016).\n\nWe describe herein, a patient who underwent surgical treatment for a stage IA ovarian dysgerminoma. Postoperatively, she was relatively noncompliant and did not adhere to her prescribed surveillance; within ten months of the patient's initial diagnosis, she developed an ovarian dysgerminoma that was metastatic to the cranium and meninges.\n\nThere have been reported studies documenting ovarian dysgerminomas that metastasize to the lymph nodes (A L Husaini et al., 2012) and albeit rarely, the breast (Kattan et al., 1992). However, the identification of an ovarian dysgerminoma metastatic to the brain (Afridi et al., 1976; Jolles et al., 1989), let alone the cranium, is exceptionally uncommon. Jolles et al. reported on an advanced ovarian dysgerminoma patient who developed carcinomatous meningitis while undergoing vinblastine, cisplatin and bleomycin chemotherapy (Jolles et al., 1989). In another study, a 21-year-old woman was treated with a total abdominal hysterectomy, bilateral salpingo-oophorectomy and pelvic radiotherapy (30 Gy) for a stage IB, 25 cm ovarian dysgerminoma (Afridi et al., 1976). However, she recurred in the pelvic lymph nodes within 6 months and afterward developed pulmonary metastases; in both instances, she was treated with radiotherapy. Five months later, the patient complained of a headache and weakness, which was ascribed to a right parietal lobe metastasis originating from her primary disease.\n\nDespite the similarities, our patient had a stage IA dysgerminoma, whereas the aforesaid subjects were afflicted with advanced stage disease. However, we recognize that our patient was initially not surgically staged, which might have eventuated upstaging; accordingly, the potential inclusion of adjuvant chemotherapy may have attenuated the patient's risk for recurrence. Moreover, the two case studies reported on disease involving either the brain parenchyma or extra-parenchymal tissue (Afridi et al., 1976; Jolles et al., 1989); in contradistinction, our patient was afflicted with metastatic cancer that infiltrated the cranium and meninges. While there have been reports depicting cranial metastases originating from a testicular germ cell tumor (Uygun et al., 2006), we were only able to identify one gynecologic case study involving a mature ovarian teratoma patient whose disease metastasized to the cranial vault (Tokuda et al., 1993).\n\nWhen managing a dysgerminoma, surgery is not only beneficial but the sine qua non for diagnosis and staging (Mangili et al., 2011). Young patients diagnosed with a dysgerminoma who desire fertility and are at risk for recurrence should be counseled regarding the potential for oocyte/embryo cryopreservation before and/or after the completion of chemotherapy. Bleomycin, etoposide, and cisplatin is an established regimen for advanced disease and an independent prognostic indicator for improved patient outcomes (Mangili et al., 2011). Regrettably, persistent disease may be ultimately discerned in the brain due to the blood-brain barrier's ability to preclude chemotherapy delivery (Weidle et al., 2015); in select cases with CNS disease involvement, radiation therapy may also confer a limited benefit (Fosså et al., 1999). Vigilant surveillance of patients, comprising frequent clinic evaluations, serial tumor marker (e.g., LDH, beta-hCG, CA-125) and routine imaging (Zogbi et al., 2018; Gordon et al., 1981), is strongly recommended.\n\nDeclaration of Competing Interests\nAll authors deny any conflict of interest associated with this manuscript.\n\nAuthor contributions\nTB contributed significantly to the study's initiation, development and manuscript revision.\n\nBG substantially contributed to the study's development and manuscript revision.\n\nHM conducted the review of the patient's pathologic diagnosis and treatment history and also substantially contributed to the study's development and manuscript revision.\n\nJD was instrumental in reviewing the patient's charge and conducting the radiologic evaluation.\n\nRB reviewed the patient's chart, analyzed the chemotherapy treatment lines and corresponding outcomes, and significantly assisted with the manuscript development and revision.\n\nVR commented on the surgical evaluation, reviewed the patient's postop data and significantly assisted with the manuscript development and revision.\n\n☆ This study was supported by the Women's Cancer Research Foundation.\n==== Refs\nReferences\nA L Husaini H. Soudy H. El Din Darwish A. Ahmed M. Eltigani A. A L Mubarak M. Pure dysgerminoma of the ovary: a single institutional experience of 65 patients Med. Oncol. 29 2012 2944 2948 22407668 \nAfridi M.A. Vongtama V. Tsukada Y. Piver M.S. Dysgerminoma of the ovary: radiation therapy for recurrence and metastases Am. J. Obstet. Gynecol. 126 1976 190 194 822717 \nFosså S.D. Bokemeyer C. Gerl A. Culine S. Jones W.G. Mead G.M. Treatment outcome of patients with brain metastases from malignant germ cell tumors Cancer 85 1999 988 997 10091779 \nGallion H.H. van Nagell J.R. Jr. Donaldson E.S. Powell D.E. Ovarian dysgerminoma: report of seven cases and review of the literature Am. J. Obstet. Gynecol. 158 1988 591 595 3279788 \nGordon A. Lipton D. Woodruff J.D. Dysgerminoma: a review of 158 cases from the Emil Novak Ovarian Tumor Registry Obstet. Gynecol. 58 1981 497 504 7279343 \nGuerriero S. Testa A.C. Timmerman D. Van Holsbeke C. Ajossa S. Fischerova D. Imaging of gynecological disease (6): clinical and ultrasound characteristics of ovarian dysgerminoma Ultrasound Obstet. Gynecol. 37 2011 596 602 21305635 \nJolles C.J. Karayianis S. Smotkin D. DeLia J.E. Advanced ovarian dysgerminoma with cure of tumor persistent in meninges Gynecol. Oncol. 33 1989 389 391 2722068 \nKattan J. Droz J.P. Charpentier P. Michel G. Lhommé C. Boutan-Laroze A. Prade M. Ovarian dysgerminoma metastatic to the breast Gynecol. Oncol. 46 1992 104 106 1634128 \nLi J. Xiaohua W. Current strategy for the treatment of ovarian germ cell tumors: role of extensive surgery Curr. Treat. Options in Oncol. 17 2016 44 \nMangili G. Sigismondi C. Lorusso D. Cormio G. Scollo P. Viganò R. Is surgical restaging indicated in apparent stage IA pure ovarian dysgerminoma? The MITO group retrospective experience Gynecol. Oncol. 121 2011 280 284 21277010 \nPatterson D.M. Murugaesu N. Holden L. Seckl M.J. Rustin G.J. A review of the close surveillance policy for stage I female germ cell tumors of the ovary and other sites Int. J. Gynecol. Cancer 18 2008 43 50 17466047 \nTokuda Y. Hatayama T. Sakoda K. Metastasis of malignant struma ovarii to the cranial vault during pregnancy Neurosurgery 33 1993 515 518 8413886 \nUygun K. Karagol H. Kocak Z. Cicin I. Yalcin O. Caloglu M. Isolated bone metastasis in testicular germ cell tumors: a case report and review of the literature Onkologie 29 2006 93 95 16514270 \nWeidle U.H. Niewöhner J. Tiefenthaler G. The blood-brain barrier challenge for the treatment of brain cancer, secondary brain metastases, and neurological diseases Cancer Genomics Proteomics 12 2015 167 177 26136217 \nZaloudek C.J. Tavassoli F.A. Norris H.J. Dysgerminoma with syncytiotrophoblastic giant cells. A histologically and clinically distinctive subtype of dysgerminoma Am. J. Surg. Pathol. 5 1981 361 367 7270783 \nZogbi L. Gonçalves C.V. Tejada V.F. Martins D. Karam F. Machado Dos Santos S. Treatment of bilateral ovarian dysgerminoma with 11-year follow-up: A case report Ann. Med. Surg. 33 2018 50 52\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "29()",
"journal": "Gynecologic oncology reports",
"keywords": "Cranial metastasis; Ovarian dysgerminoma; Treatment",
"medline_ta": "Gynecol Oncol Rep",
"mesh_terms": null,
"nlm_unique_id": "101652231",
"other_id": null,
"pages": "55-57",
"pmc": null,
"pmid": "31317066",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
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"title": "Cranial and intra-axial metastasis originating from a primary ovarian Dysgerminoma.",
"title_normalized": "cranial and intra axial metastasis originating from a primary ovarian dysgerminoma"
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"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-19-04261",
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"abstract": "BACKGROUND\nRenal denervation (RDN) with radiofrequency ablation substantially reduces blood pressure in patients with treatment-resistant hypertension. We assessed the long-term antihypertensive effects and safety.\n\n\nMETHODS\nSymplicity HTN-1 is an open-label study that enrolled 153 patients, of whom 111 consented to follow-up for 36 months. Eligible patients had a systolic blood pressure of at least 160 mm Hg and were taking at least three antihypertensive drugs, including a diuretic, at the optimum doses. Changes in office systolic blood pressure and safety were assessed every 6 months and reported every 12 months. This study is registered with ClinicalTrials.gov, numbers NCT00483808, NCT00664638, and NCT00753285.\n\n\nRESULTS\n88 patients had complete data at 36 months. At baseline the mean age was 57 (SD 11) years, 37 (42%) patients were women, 25 (28%) had type 2 diabetes mellitus, the mean estimated glomerular filtration rate was 85 (SD 19) mL/min per 1·73 m(2), and mean blood pressure was 175/98 (SD 16/14) mm Hg. At 36 months significant changes were seen in systolic (-32·0 mm Hg, 95% CI -35·7 to -28·2) and diastolic blood pressure (-14·4 mm Hg, -16·9 to -11·9). Drops of 10 mm Hg or more in systolic blood pressure were seen in 69% of patients at 1 month, 81% at 6 months, 85% at 12 months, 83% at 24 months, and 93% at 36 months. One new renal artery stenosis requiring stenting and three deaths unrelated to RDN occurred during follow-up.\n\n\nCONCLUSIONS\nChanges in blood pressure after RDN persist long term in patients with treatment-resistant hypertension, with good safety.\n\n\nBACKGROUND\nArdian LLC/Medtronic Inc.",
"affiliations": "Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, VIC, Australia. Electronic address: henry.krum@monash.edu.;Neurovascular Hypertension and Kidney Disease Laboratory, Baker IDI Heart and Diabetes Institute and Heart Centre, Alfred Hospital, Melbourne, VIC, Australia.;Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH, USA.;Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinium des Saarlandes, Homburg, Germany.;Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinium des Saarlandes, Homburg, Germany.;Prairie Heart Institute at St John's Hospital, Springfield, IL, USA.;Prairie Heart Institute at St John's Hospital, Springfield, IL, USA.;Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.",
"authors": "Krum|Henry|H|;Schlaich|Markus P|MP|;Sobotka|Paul A|PA|;Böhm|Michael|M|;Mahfoud|Felix|F|;Rocha-Singh|Krishna|K|;Katholi|Richard|R|;Esler|Murray D|MD|",
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"mesh_terms": "D000959:Antihypertensive Agents; D001794:Blood Pressure; D017115:Catheter Ablation; D002908:Chronic Disease; D003925:Diabetic Angiopathies; D004351:Drug Resistance; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D006973:Hypertension; D008297:Male; D008875:Middle Aged; D013562:Sympathectomy; D016896:Treatment Outcome",
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"title": "Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study.",
"title_normalized": "percutaneous renal denervation in patients with treatment resistant hypertension final 3 year report of the symplicity htn 1 study"
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"abstract": "Delirium may present with hyperactive, hypoactive or mixed clinical pictures. The signs of hypoactive delirium are lethargy, confusion, apathy, hypersomnia, muttering, difficulty in maintaining attention, and difficulty in understanding and performing commands. Valproate is commonly used for the treatment of epilepsy and bipolar disorders. It is also used for the management of alcohol withdrawal delirium and agitative-aggressive deliriums. However, few reports are available about the valproate-induced delirium. In this report, we present a 46 years-old woman with bipolar disorder for 14 years. During her last two hospital admissions, she had been diagnosed with manic episode with psychotic features and she had received valproate. She experienced three hypoactive delirium episodes lasting 2-3 days throughout the treatment period of first week. The patient predominantly had the following signs; vomiting, hypersalivation, confusion, drowsiness, dysphasia, and hypoactivity. At the first day of delirium episode, serum valproate level was found to be within the therapeutic range (98.4, 117.1, and 65.6 mug/ml; respectively). In addition, she had normal results of cranial MRI, complete blood count, urine analysis, electrocardiogram, ALT, AST, albumin, bilirubin, BUN, creatinine and electrolytes. The serum ammonia level of the patient could not been measured due to limitations of laboratory facilities. The patient's consciousness improved dramatically 2-3 days after cessation of valproate. In conclusion, valproate can induce delirium at therapeutic blood levels in some patients via various mechanisms and this side effect has to be considered during valproate use.",
"affiliations": "ozensakir@gmail.com",
"authors": "Ozen|Sakir|S|;Bülbül|Israfil|I|;Soyuçok|Etem|E|",
"chemical_list": "D018692:Antimanic Agents; D014635:Valproic Acid",
"country": "Turkey",
"delete": false,
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"issue": "21(1)",
"journal": "Turk psikiyatri dergisi = Turkish journal of psychiatry",
"keywords": null,
"medline_ta": "Turk Psikiyatri Derg",
"mesh_terms": "D018692:Antimanic Agents; D001714:Bipolar Disorder; D001774:Blood Chemical Analysis; D003693:Delirium; D005260:Female; D006801:Humans; D008875:Middle Aged; D014635:Valproic Acid",
"nlm_unique_id": "9425936",
"other_id": null,
"pages": "79-84",
"pmc": null,
"pmid": "20204907",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Valproate induced hypoactive delirium in a bipolar disorder patient with psychotic features.",
"title_normalized": "valproate induced hypoactive delirium in a bipolar disorder patient with psychotic features"
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"companynumb": "TR-TEVA-2010R0302058",
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"occurcountry": "TR",
"patient": {
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"actiondrug": "1",
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"activesubstancename": "LORAZEPAM"
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"abstract": "BACKGROUND\nSurgical resection of a lesion that correlates with seizure onset in patients with epilepsy can dramatically improve seizure burden and quality of life. For bilateral hippocampal lesions, bilateral resection comes with a risk of severe cognitive deficits. Responsive neurostimulation (RNS) devices offer a new modality to treat multifocal lesions in a reversible manner including bilateral hippocampal stimulation. We describe technical aspects of Nexframe-assisted placement of bilateral NeuroPace mesial temporal electrodes and case examples.\n\n\nMETHODS\nRetrospective chart review was performed for 4 patients who underwent bilateral mesial temporal RNS placement for medically intractable epilepsy. Operative techniques were assessed and modified. Ambulatory electrocorticographic recordings and a subanalysis of available data are summarized.\n\n\nRESULTS\nEight electrodes were placed in 4 patients, who were followed for up to 6 months. One out of 8 electrodes was revised due to vector error >3 mm; after surgical technique modification, all subsequent electrodes were reliably placed in a single pass with <2-mm vector error. Using patients' seizure diaries, seizure semiologies were correlated with ambulatory ECoG recording patterns and subanalyzed; 51.4% were left sided, 15% were right sided, and 33.6% were indeterminate.\n\n\nCONCLUSIONS\nWe report herein the technical nuances of adapting Nexframe to hippocampal-based depth electrode RNS system placement. Our group has extensive experience with Nexframe for accurate and safe deep brain stimulation electrode placement. Our preliminary data with bitemporal RNS placement suggest similar accuracy and safety.",
"affiliations": "Department of Neurological Surgery, Oregon Health & Science University, Portland, Oregon, USA.;Department of Neurological Surgery, Oregon Health & Science University, Portland, Oregon, USA.;Department of Neurological Surgery, Oregon Health & Science University, Portland, Oregon, USA. Electronic address: raslana@ohsu.edu.",
"authors": "Gupta|Kunal|K|;Raskin|Jeffrey S|JS|;Raslan|Ahmed M|AM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2017.01.109",
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"issue": "101()",
"journal": "World neurosurgery",
"keywords": "Epilepsy; Frameless stereotaxy; Mesial temporal sclerosis; Nexframe; Responsive neurostimulator/neurostimulation",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D046690:Deep Brain Stimulation; D000069279:Drug Resistant Epilepsy; D004567:Electrodes, Implanted; D005260:Female; D006624:Hippocampus; D006801:Humans; D064795:Intraoperative Neurophysiological Monitoring; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D038361:Neuronavigation; D056888:Patient Positioning; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "161-169",
"pmc": null,
"pmid": "28185967",
"pubdate": "2017-05",
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"abstract": "Immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4 antibodies) are a standard of care for advanced melanoma. Novel toxicities comprise immune-related adverse events (irAE). With increasing use, irAE require recognition, practical management strategies, and multidisciplinary care. We retrospectively evaluated the incidence, kinetics, and management of irAE in 41 patients receiving anti-PD-1 antibody therapy (pembrolizumab) for advanced melanoma. 63% received prior anti-CTLA-4 antibody therapy (ipilimumab). IrAE occurred in 54%, most commonly dermatological (24%), rheumatological (22%), and thyroid dysfunction (12%). Thyroiditis was characterised by a brief asymptomatic hyperthyroid phase followed by a symptomatic hypothyroid phase requiring thyroxine replacement. Transplant rejection doses of methylprednisolone were necessary to manage refractory hepatotoxicity. A bullous pemphigoid-like skin reaction with refractory pruritus responded to corticosteroids and neuropathic analgesia. Disabling grade 3-4 oligoarthritis required sulfasalazine therapy in combination with steroids. The median interval between the last dose of anti-CTLA-4 antibody and the first dose of anti-PD-1 therapy was 2.0 months (range: 0.4 to 22.4). Toxicities may occur late; this requires vigilance and multidisciplinary management which may allow effective anticancer therapy to continue. Management algorithms for thyroiditis, hypophysitis, arthralgia/arthritis, colitis, steroid-refractory hepatitis, and skin toxicity are discussed.",
"affiliations": "Chris O'Brien Lifehouse, Camperdown, NSW, Australia.;Chris O'Brien Lifehouse, Camperdown, NSW, Australia.;Concord Repatriation General Hospital, Sydney, NSW, Australia.;Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.;Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.;Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.;Centenary Institute, Sydney, NSW, Australia.;Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.;Chris O'Brien Lifehouse, Camperdown, NSW, Australia.",
"authors": "Lomax|Anna J|AJ|0000-0002-6087-2826;Lim|Jennifer|J|;Cheng|Robert|R|;Sweeting|Arianne|A|;Lowe|Patricia|P|;McGill|Neil|N|;Shackel|Nicholas|N|;Chua|Elizabeth L|EL|0000-0002-7670-4579;McNeil|Catriona|C|",
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"doi": "10.1155/2018/9602540",
"fulltext": "\n==== Front\nJ Skin CancerJ Skin CancerJSCJournal of Skin Cancer2090-29052090-2913Hindawi 10.1155/2018/9602540Research ArticleImmune Toxicity with Checkpoint Inhibition for Metastatic Melanoma: Case Series and Clinical Management http://orcid.org/0000-0002-6087-2826Lomax Anna J. anna.lomax@lh.org.au\n1\nLim Jennifer \n1\nCheng Robert \n2\n\n3\nSweeting Arianne \n4\n\n5\nLowe Patricia \n4\n\n5\nMcGill Neil \n4\n\n5\nShackel Nicholas \n3\n\n4\n\n5\nhttp://orcid.org/0000-0002-7670-4579Chua Elizabeth L. \n4\n\n5\nMcNeil Catriona \n1\n\n4\n\n5\n\n1Chris O'Brien Lifehouse, Camperdown, NSW, Australia\n2Concord Repatriation General Hospital, Sydney, NSW, Australia\n3Centenary Institute, Sydney, NSW, Australia\n4Sydney Medical School, University of Sydney, Camperdown, NSW, Australia\n5Royal Prince Alfred Hospital, Camperdown, NSW, AustraliaAcademic Editor: Arash Kimyai-Asadi\n\n2018 21 1 2018 2018 960254015 8 2017 31 10 2017 6 11 2017 Copyright © 2018 Anna J. Lomax et al.2018This 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.Immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4 antibodies) are a standard of care for advanced melanoma. Novel toxicities comprise immune-related adverse events (irAE). With increasing use, irAE require recognition, practical management strategies, and multidisciplinary care. We retrospectively evaluated the incidence, kinetics, and management of irAE in 41 patients receiving anti-PD-1 antibody therapy (pembrolizumab) for advanced melanoma. 63% received prior anti-CTLA-4 antibody therapy (ipilimumab). IrAE occurred in 54%, most commonly dermatological (24%), rheumatological (22%), and thyroid dysfunction (12%). Thyroiditis was characterised by a brief asymptomatic hyperthyroid phase followed by a symptomatic hypothyroid phase requiring thyroxine replacement. Transplant rejection doses of methylprednisolone were necessary to manage refractory hepatotoxicity. A bullous pemphigoid-like skin reaction with refractory pruritus responded to corticosteroids and neuropathic analgesia. Disabling grade 3-4 oligoarthritis required sulfasalazine therapy in combination with steroids. The median interval between the last dose of anti-CTLA-4 antibody and the first dose of anti-PD-1 therapy was 2.0 months (range: 0.4 to 22.4). Toxicities may occur late; this requires vigilance and multidisciplinary management which may allow effective anticancer therapy to continue. Management algorithms for thyroiditis, hypophysitis, arthralgia/arthritis, colitis, steroid-refractory hepatitis, and skin toxicity are discussed.\n==== Body\n1. Introduction\nImmune checkpoint inhibition is the established immunotherapy treatment for advanced melanoma. Induction of a tumour-directed immune response due to T-cell activation halts tumour evasion from immune surveillance [1, 2]. Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4) with ipilimumab showed the first evidence of improved survival in advanced melanoma [3] and long-term survival can be achieved [3, 4]. Novel side-effects include autoimmune toxicities referred to as immune-related adverse events (irAE). With the increasing use of these agents (as monotherapy or in combination) irAE require recognition and practical management strategies.\n\nPembrolizumab and nivolumab are anti-programmed cell death 1 (PD-1) antibodies targeting the effector arm of the immune checkpoint pathway. Benefit has been demonstrated in ipilimumab pretreated and naïve patients [5]. Anti-PD-1 antibodies have superseded ipilimumab as a first-line immunotherapy treatment for advanced melanoma. Both anti-PD-1 agents have superior response rates (36–44%) [6, 7] compared to ipilimumab (13–19%) [6, 7] and improved 3-year survival (40–52%) [7, 8] versus 20–34% [3, 7]. Estimates of anti-PD-1 efficacy outside of clinical trials have been reported with response rates of 14–39% [9–11]. Anti-PD-1 agents have activity in other solid cancers including non-small cell lung cancer, genitourinary cancers, and Hodgkin's lymphoma [12–15].\n\nCombining anti-PD-1 and anti-CTLA-4 checkpoint inhibitors improves response rate (58–61%) but at the cost of increased toxicity [7, 16]. Grade 3-4 or 3–5 treatment-related adverse events for combination therapy and anti-PD-1 or anti-CTLA-4 monotherapies have been reported in randomised trials: 45–59%, 17–21%, and 20–28%, respectively [6, 7, 16]. 3-year overall survival with dual checkpoint inhibition (nivolumab plus ipilimumab) is also superior to ipilimumab alone (58% vs 20–34%) [7] but what is critical is whether this adds a survival benefit over anti-PD-1 therapy alone given the added toxicity with this regimen. IrAE due to CTLA-4 blockade have an earlier onset and are more commonly associated with diarrhoea, colitis, and hypophysitis. Fatigue, arthralgia, and thyroid irAE are more frequently seen with PD-1 blockade [17]. IrAE with combination checkpoint inhibition can have a rapid onset and be associated with a protracted duration [18].\n\nIn clinical practice, patients are older with poorer Eastern Cooperative Oncology Group (ECOG) performance status than those enrolled in clinical trials. An early study of pembrolizumab after prior ipilimumab therapy required patients to have received the final dose of ipilimumab ≥ 6 weeks before commencing pembrolizumab [5], a period not necessarily pragmatic in clinical practice. Reduced dosing intervals between therapeutic agents impact severity and pattern of toxicities as observed in patients receiving these checkpoint inhibitors, albeit in different sequence [19].\n\nThis is a retrospective review of patients with advanced melanoma that received pembrolizumab at Chris O'Brien Lifehouse through compassionate access. We evaluated patients who were ipilimumab naïve and pretreated with respect to irAE and describe the management of these irAE in real clinical practice.\n\n2. Methods\nPatients with advanced melanoma were included. In patients who had received prior ipilimumab, disease had to be documented as progressive, recurrent, or persistent. Patients were excluded if they were receiving or were eligible for treatment with a BRAF or MEK inhibitor. Patients were also excluded if they had significant autoimmune disease requiring chronic immunosuppression.\n\nPembrolizumab was administered intravenously at 2 mg/kg of body weight every three weeks. Drug supply was via a compassionate access program. At the time of patient enrolment into the program, pembrolizumab therapy was not yet approved for use in Australia on the Pharmaceutical Benefits Scheme. Therapy was continued until disease progression or unacceptable toxicity. Response to pembrolizumab was assessed at week 12 after commencement and 12 weekly thereafter or as clinically appropriate. Where available, imaging was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. IrAE were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE). Ethics committee approval was obtained (X15-0193 LNR/15/RPAH/256).\n\n3. Results\nFrom November 2013 to August 2015, 41 patients were identified. Patient and disease characteristics are described (Table 1). Median age was 65, 81% had an ECOG performance status of 0 or 1 and 71% had an elevated LDH. BRAF V600 mutations were identified in 24% of patients and 76% had M1c disease. Twenty-six patients (63%) had received prior ipilimumab. The median interval between the last ipilimumab dose and the first pembrolizumab dose was 2.0 months (range: 0.4 to 22.4). The median duration of follow-up was 4.1 months (range: 0 to 14.9). The median and mean number of pembrolizumab cycles received were 4 and 6, respectively (range: 1 to 20). In 15 patients, treatment was ongoing.\n\nIn patients whose tumour harboured a BRAF V600 mutation, one patient received one dose of pembrolizumab on the compassionate program while awaiting results of BRAF molecular testing. Once it was known that his tumour harboured an actionable V600K mutation, he was transitioned to dabrafenib plus trametinib and achieved a partial response. A second patient received 2 doses of pembrolizumab before also confirming the presence of a V600K mutation. This patient was commenced on dabrafenib and trametinib but developed progressive disease. Initial testing had demonstrated a negative immunostain for BRAF VE1 for these 2 patients but due to symptomatic disease needing swift commencement of treatment, pembrolizumab was started while formal molecular testing was performed.\n\nThe remaining 8 patients with a BRAF V600 mutation had received prior BRAF/MEK inhibitor therapy. These numbers are small and make it difficult to draw conclusions regarding response in this subgroup.\n\nObjective response rates (ORR) were 26% and disease control rates (DCR) were 49% (n = 39, excluding the n = 2 BRAF V600K patients that received pembrolizumab before formal molecular results were reported). This was determined by RECIST 1.1 assessment for n = 20; imaging assessment but not per RECIST 1.1 n = 12 (imaging modality was not uniform between serial scans or performed offsite, precluding formal RECIST 1.1 assessment); clinical progression in n = 3 and unknown n = 4 patients. The median time to response was 2.7 months (range: 0.9 to 4.9). Three (7%) patients achieved a complete response.\n\nIrAE were documented in 22 (54%) patients while receiving anti-PD-1 therapy. Common irAE were dermatological (24%), rheumatological (22%), and thyroid dysfunction (12%) (Table 1). Grade 3-4 irAE were uncommon (15%) with individual event rates of 2–5%. Of the 26 patients that received prior ipilimumab, 13 patients (50%) developed irAE secondary to ipilimumab. Of these 13 patients, 10 (38%) experienced subsequent irAE while receiving pembrolizumab. Of these 10 patients, 8 had an event of grade 1-2 severity during treatment with pembrolizumab and 2 developed grade 3-4 hepatotoxicity in the context of a short interval between ceasing ipilimumab and commencing pembrolizumab. Of the 13 patients who did not have irAE on ipilimumab, 6 (23%) patients had subsequent irAE while receiving pembrolizumab.\n\nPatients with M1c disease or an elevated LDH appeared to have worse survival outcomes (Figures 1(a) and 1(b)).\n\n4. Organ Specific Toxicities and Treatment Algorithms\nOwing to the mechanism of action of immunotherapy agents, manifestations of autoimmune toxicity can involve any organ. General principles of management revolve around managing mild (grade 1) toxicity with supportive measures and considering steroids in moderate (grade 2) toxicity. For severe (grades 3-4) toxicity, intervening with high-dose steroids or additional immunosuppressive therapy may be necessary. We outline management algorithms for the toxicities observed in our cohort of patients which overlap with established algorithms such as “eviQ Cancer Treatments Online” [20] but also include recommendations from our institutional experience. Specifically, we have documented general skincare supportive measures and the possible use of neuropathic analgesia for refractory pruritus. For endocrine toxicities, we have highlighted the expected clinical course of thyroiditis and have suggested a management algorithm for rheumatological irAE. Other guidelines, such as the ESMO Clinical Practice Guidelines [18], differ from the eviQ and our guidelines with respect to the grading of liver toxicity for autoimmune hepatitis. The ESMO statement refers to grade 3 ALT/AST elevation as 5–20x the upper limit of normal (ULN) and grade 4 elevation as >20x the ULN [18], whereas our algorithm and eviQ specify grade 3-4 AST/ALT elevation as >5x the ULN [20].\n\n4.1. Dermatological Toxicity\nCutaneous toxicity of any grade occurred in 10 (24%) patients (Table 1). Common presentations included pruritus, cutaneous eruptions, for example, maculopapular, eczematous, flare of Grover's disease (transient acantholytic dermatosis), and less commonly vitiligo. Nine patients had rash/pruritus (one case involved a bullous pemphigoid-like reaction described below) and 1 patient was documented to have developed vitiligo. No presentations had mucosal involvement.\n\nAn elderly female developed grade 3 skin toxicity on pembrolizumab [21] having displayed grade 1 toxicity (pruritic maculopapular eruption) during prior ipilimumab therapy. The latter improved with supportive therapy. Due to progressive metastatic disease, pembrolizumab was commenced 6 weeks after ipilimumab cessation. A bullous pemphigoid-like drug reaction developed after 8 months of pembrolizumab. Skin biopsies demonstrated a subepidermal blister with inflammatory cells, predominantly eosinophils. A perivascular and interstitial inflammatory cell infiltrate of lymphocytes, eosinophils, and neutrophils was within the dermis with adjacent spongiotic epidermis (Figure 2). Direct immunofluorescence was negative. Pembrolizumab was ceased. Although the rash was steroid responsive, the pruritus proved refractory until pregabalin was commenced (25 mg daily and titrated to 25 mg twice daily). Neuropathic analgesia [22, 23] has shown efficacy in the management of uraemic pruritus; however, oversedation was observed in 12–30% [23]. The patient had a complete disease response to pembrolizumab.\n\n4.2. Dermatological irAE Management Algorithm\nRash due to anti-PD-1 antibodies may occur in 13–26% and 15–33% for anti-CTLA-4 therapy. Pruritus can occur in 14–19% and 25–35%, respectively [17, 24]. Skin toxicity due to anti-PD-1 therapy is potentially mediated by a shared antigen coexpressed by the dermoepidermal junction and tumour cells [25]. Most presentations are mild, usually a nonspecific maculopapular pruritic eruption, occasionally eczematous. As would be expected in immunotherapy of melanoma, hypopigmentation and depigmentation (vitiligo) have been reported [26, 27] with sites of predilection, including trunk and limbs, but can be limited to photoexposed sites. Rarely, life-threatening conditions such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) occur [28–30].\n\nUpon development of a nonspecific rash, flare of preexisting dermatosis and secondary cutaneous infections needs to be excluded. Perform skin swabs (bacterial MCS, viral PCR) and scrapings (fungal KOH) if indicated. Skin biopsy (with direct immunofluorescence if blisters present) and FBC may reveal eosinophilic infiltrate and eosinophilia, respectively, supporting the diagnosis of drug exanthem. Tissue reactions are most commonly spongiotic or lichenoid in nature.\n\nThe majority of skin irAE are managed supportively. Avoidance of common irritants (soap and excess water) should be reinforced. Liberal amounts of emollients and ointment-based preparations, if xerotic or pruritic, are advised. Specific therapies include moderate to very potent topical corticosteroid ointments (under wet dressing occlusion) and low to high doses of oral antihistamines. Severe skin toxicity requires hospital admission and high doses of corticosteroid administration [28–30] orally or intravenously. Consider commencement of IVIG and/or cyclosporine if SJS/TEN is suspected or confirmed on urgent skin biopsy. Transfer to a burns unit is essential if skin loss is >10%. The management of skin toxicity is outlined in Table 2.\n\n4.3. Gastrointestinal and Hepatic Toxicity\nGastrointestinal irAE were infrequent, occurring in 3 (7%) patients, with none experiencing grade 3 or 4 toxicity (Table 1). One patient developed grade 2 colitis with proctitis and had never received prior ipilimumab. Two ipilimumab pretreated patients developed diarrhoea of grade 1-2 severity.\n\nTwo patients (5%) experienced grade 3-4 hepatotoxicity (Table 1). A 58-year-old male received 4 cycles of ipilimumab with the final dose administered 22 days before starting pembrolizumab. Liver function test derangement (LFT) of grade 4 severity with transaminases 15–30 times the ULN and elevated bilirubin occurred one month later. Biopsy confirmed lobular and portal hepatitis consistent with drug-induced injury. Methylprednisolone 0.5 mg/kg for 3 days was initiated and escalated to 1 g for 3 days with concurrent mycophenolate mofetil 500 mg twice daily due to lack of improvement. Prednisolone was weaned and mycophenolate mofetil continued with resolution of biochemical abnormalities. Due to significant immunosuppression he developed presumed pneumocystis jiroveci pneumonia and died of respiratory failure and sepsis.\n\nThe second patient was a 67-year-old male who had a single dose of ipilimumab 27 days prior to commencing pembrolizumab. Following the second cycle of pembrolizumab he presented with fever and grade 3 ALT elevation at >5 times the ULN. Liver biopsy showed nonspecific mild portal and interface hepatitis. Methylprednisolone 1 mg/kg was commenced followed by weaning prednisolone and mycophenolate mofetil 1 g twice daily. The LFT derangement resolved. Due to this irAE and progressive disease, he did not receive subsequent therapy and died 6 months later.\n\n4.4. Management of Refractory Hepatitis and Gastrointestinal Toxicity\nGastrointestinal toxicity is more commonly described with ipilimumab. Any grade of diarrhoea may occur in 23–33% with 3–6% of patients experiencing severe diarrhoea. Rates for significant colitis are 7–9% [17, 24]. Lower rates are documented with anti-PD-1 therapy with grade 3-4 or 3–5 diarrhoea described in 1–3% and similarly for severe colitis [17, 24]. Rates of severe diarrhoea or colitis for combined therapy are 9% and 8%, respectively [17, 24]. Management of colitis due to ipilimumab is well documented [31]. The management of single agent and combination checkpoint inhibitor induced colitis are outlined in Table 3.\n\nIn clinical trials, the rate of significant hepatitis or deranged liver function is identified at <1-2% for anti-CTLA-4 agents and 1-2% with anti-PD-1 therapies but increased to 6–8% with combined therapy [17, 24]. Grade 3-4 hepatotoxicity in our cohort was 5% and may reflect a short dosing interval between checkpoint inhibitors. The 2 patients in our cohort who developed hepatic toxicity required treatment with mycophenolic acid. Mycophenolate mofetil exerts its immunosuppressive effects through a cytostatic effect on lymphocytes [32]. Its use is outlined in clinical trial and ipilimumab irAE guidelines [31]. Doses of methylprednisolone required to treat transplant rejection have been used for ipilimumab-induced hepatotoxicity at our institution [33] and were necessary in 1 patient from our study cohort. From our experience, methylprednisolone 15 mg/kg (maximum 1 gm/day) is suggested for steroid-refractory hepatitis and is considered part of our management algorithm at our institution (Table 3).\n\n4.5. Endocrine Toxicity, Thyroiditis-Kinetics, and Management\nThyroid dysfunction of grade 2 severity occurred in 5 (12%) patients (Table 1). Four patients had received prior ipilimumab. The onset of biochemical hyperthyroidism signalled the development of clinical thyroiditis in all patients. Thyroiditis was characterised by a brief asymptomatic hyperthyroid phase followed by a symptomatic hypothyroid phase (Figure 3(a)) requiring thyroxine replacement. This pattern is consistent with other case series [34, 35]. Hyperthyroidism occurred within 3–6 weeks of pembrolizumab initiation. The hypothyroid phase was generally evident within 3 weeks of the onset of thyroiditis. In most cases, the hypothyroid phase was evident by week 9 of pembrolizumab therapy and was characterised by markedly elevated TSH levels (Figure 3(b)). Despite age and comorbidities of the patients, initiation of high-dose thyroxine (i.e., 100 mcg daily) at the onset of hypothyroidism was required. Thyroxine should be uptitrated to achieve normalisation of TSH. No evidence of thyroid function recovery occurred in our series, demonstrating the need for serial TSH monitoring.\n\nFrom clinical trial data, hypophysitis is more commonly associated with ipilimumab and thyroid toxicity with anti-PD-1 agents [17]. In our cohort of 26 patients that had been pretreated with ipilimumab, 2 patients developed hypophysitis prior to receiving pembrolizumab and in 2 patients this occurred during anti-PD-1 therapy. Thyroiditis and hypophysitis management is described in Table 4.\n\n4.6. Rheumatological Toxicity\nRheumatological toxicity occurred in 9 (22%) of patients (Table 1) and most events were managed with low-dose prednisolone. One patient developed a grade 3-4 irAE. He received prior ipilimumab without complication. A disabling inflammatory arthropathy occurred 8 months after starting pembrolizumab. Synovial fluid aspirate showed an inflammatory infiltrate (white cell count 16.4 × 109/L) and no crystals were seen on microscopy, with CRP 60 and ESR 103 reflecting systemic inflammation. Rheumatoid factor, cyclic citrullinated peptide, and antinuclear antibodies and human leukocyte antigen B27 were negative. Anti-PD-1 therapy was ceased. The arthropathy was refractory to prednisolone doses up to 75 mg daily and required the addition of sulfasalazine, and the dose increased from 500 mg daily to 1 g twice daily over 10 days and continued with a good clinical response. Eight months after pembrolizumab cessation, prednisolone was weaned to 5 mg daily and sulfasalazine continued at 1 g twice daily. This patient achieved a complete disease response to pembrolizumab.\n\nA 64-year-old male with a history of childhood glomerulonephritis developed significant sicca symptoms (xerophthalmia, xerostomia, and significant parotid swelling) after 3 cycles of pembrolizumab. Antinuclear antibody was elevated with high titres of 1 : 640 consistent with new onset immune-mediated Sjogren syndrome. He was treated with prednisolone 25 mg daily and the symptoms resolved, allowing steroids to be weaned. A postulated mechanism is an aberrant T-cell activation that is not dissimilar to that induced by graft versus host disease [36].\n\n4.7. Arthralgia and Arthritis Management Algorithm\nRheumatological toxicity in clinical trials is higher for anti-PD-1 (8–12%) than anti-CTLA-4 therapy (5-6%) [17, 24]. Severe toxicity is rare but has also been reported in 2 patients that received prolonged pembrolizumab therapy [37]. Sulfasalazine was used with benefit and may be of use in conditions refractory to corticosteroids or to expedite steroid tapering. A suggested algorithm for the management of arthralgia and arthritis is outlined (Table 5).\n\n4.8. Pneumonitis\nPneumonitis was observed in 2 (5%) patients of grade 2 severity. One patient had a short interval (47 days) between anti-CTLA-4 and anti-PD-1 dosing. Pneumonitis rates due to checkpoint inhibitors are low in the published literature (<1–4%) across several cancer types [12, 13, 17]. Pneumonitis is important to consider in the differential diagnosis of new cough or dyspnoea; however, other causes such as infection, exacerbation of airways disease, cancer progression, or sarcoidosis should be considered. Assessment requires imaging with CT, respiratory review, and in some circumstances, bronchoscopy. Grade 2 and Grade 3-4 pneumonitis require high-dose steroids with slow taper and prophylaxis against opportunistic infections [38].\n\nNo patients in our cohort experienced neurological toxicities. Fulminant myocarditis has been documented in patients receiving dual checkpoint inhibitor therapy [39] and in a patient that received prior combination therapy and later received single agent anti-PD-1 therapy [7]. \n\n5. Conclusion\nOur cohort of patients receiving anti-PD-1 therapy for advanced melanoma included patients with poorer prognostic features with higher rates of elevated LDH, M1c disease, and poorer ECOG [5, 17], in comparison with patients enrolled on clinical trials. In the subset of patients that had a prior ipilimumab irAE, 62% and 23% developed mild irAE or no irAE on pembrolizumab, respectively, demonstrating that the development of irAE to anti-CTLA-4 therapy did not preclude subsequent treatment with another checkpoint inhibitor.\n\nRecommencing anti-PD-1 therapy may be considered for selected significant irAE, dependent upon perceived benefits and risks of immunotherapy rechallenge. Toxicities may occur late and require vigilance and multidisciplinary management. This may allow effective anticancer therapy to continue. Limitations of the cohort are small patient numbers and retrospective nature of the data. Furthermore, a significant number of patients received first-line anti-CTLA-4 therapy. The current evidence is for anti-PD-1 agents to be delivered first-line. However, the cases highlight a range of autoimmune toxicities and management in patients treated outside of a clinical trial. The use of overlapping anti-CTLA-4 and anti-PD-1 therapies demonstrates potentially added toxicity, having relevance in view of treatment approaches heading towards dual combinations of these and newer agents.\n\nAcknowledgments\nA. J. Lomax holds a position supported in 2015 and 2016 by the Simon Kerr Fellowship. The authors thank S. Anand at the Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW.\n\nConflicts of Interest\nCatriona McNeil received honoraria from MSD, BMS, Roche, and Novartis; she has a consulting or advisory role at MSD, BMS, and Roche; she is a speaker's bureau member at MSD and BMS; her institution received a research funding from MSD.\n\nFigure 1 OS by M stage and LDH. Logrank statistic M stage (p = 0.28) and LDH level (p = 0.06).\n\nFigure 2 Pemphigoid-like reaction. Skin biopsies demonstrated a subepidermal blister (arrow) with inflammatory cells, predominantly eosinophils.\n\nFigure 3 (a) Thyroiditis: hyperthyroid phase followed by hypothyroid phase in a patient treated with pembrolizumab. (b) Hyperthyroidism generally occurred within 3–6 weeks of initiation of pembrolizumab therapy (time = 0). Hypothyroid phase was evident by week 9 of pembrolizumab therapy and was characterised by markedly elevated TSH levels.\n\nTable 1 Patient characteristics and immune-related adverse events.\n\nCharacteristics\tCompassionate pembrolizumab (n = 41)\t\nMedian age (range), yr\t65 (37–90)\t\nMale sex, number (%)\t32 (78%)\t\nPrimary type\t \t\n Cutaneous\t31 (76%)\t\n Mucosal\t2 (5%)\t\n Occult\t7 (17%)\t\n Unknown\t1 (2%)\t\nECOG performance status, number (%)\t \t\n 0-1\t33 (81%)\t\n >1\t7 (17%)\t\n Unknown\t1 (2%)\t\nLactate dehydrogenase, number (%)\t \t\n ≤ULN (≤250 U/L)\t7 (17%)\t\n >ULN (>250 U/L)\t29 (71%)\t\n Unknown\t5 (12%)\t\nMetastasis stage, number (%)\t \t\n In-transit disease\t1 (2%)\t\n M1a\t5 (12%)\t\n M1b\t4 (10%)\t\n M1c\t31 (76%)\t\nNumber of organ sites of disease\t \t\n ≤3\t24 (58%)\t\n >3\t15 (37%)\t\n Unknown\t2 (5%)\t\nBRAF V600 mutation, number (%)\t10 (24%)\t\nPrior lines of treatment, number (%)\t \t\n 0\t10 (24%)\t\n 1\t20 (49%)\t\n 2-3\t10 (24%)\t\n Unknown\t1 (2%)\t\nPreexisting autoimmune condition\t2 (5%)\t\nIpilimumab pretreated, number (%)\t26 (63%)\t\nIpilimumab-related irAE, number (%)\t13 (50%)\t\n\n\n\t\nRates of irAE during anti-PD-1 therapy\tAny grade\tGrade 3 or 4\t\n\n\n\t\nAny\t22 (54%)\t4 (15%)\t\nSkin\t10 (24%)\t1 (2%)\t\nArthralgia/arthritis\t9 (22%)\t1 (2%)\t\nThyroid dysfunction\t5 (12%)\t0\t\nGastrointestinal∗\t3 (7%)\t0\t\nHypophysitis\t2 (5%)\t2 (5%)\t\nHepatitis\t2 (5%)\t2 (5%)\t\nPneumonitis\t2 (5%)\t0\t\nUveitis\t1 (2%)\t0\t\nParotitis\t1 (2%)\t0\t\n\n∗Colitis and proctitis n = 1 and diarrhoea n = 2.\n\nTable 2 Skin irAE: management algorithm.\n\nDermatology irAE\tInvestigations\tManagement\t\n\nGrade 1/mild\n\t\nRash < 10% body surface area (BSA), pruritus\t \tContinue checkpoint inhibitor therapy\nGeneral skin care measures:\nAvoid irritants: soap and excess water\nEmollients: creams and ointments\nOral antihistamines: \nNonsedating (daytime); sedating (nocte)\nTopical corticosteroids (moderate potency, ointment > cream vehicle)\nPhototherapy for pruritus: short course narrow band UVB, for example, 3x week for 4 weeks (relatively contraindicated with history of melanoma)\t\n\n\n\t\n\nGrade 2/moderate\n\t\nRash (10–30% BSA), pruritus\tSkin swabs MCS, viral PCR, scrapings (fungal KOH)\nProlonged symptoms (1-2 weeks): consider skin biopsy\tContinue checkpoint inhibitor therapy\nConsider dermatology review\nGeneral skin care measures and emollients as above\nOral antihistamines (increased dosing may be required: 2–4x standard dose), depending on renal and liver function\nTopical corticosteroid (moderate to very potent, ointment > cream vehicle)\nWet dressings (educate at outpatient dermatology treatment centre)\nProlonged symptoms:\nDelay immunotherapy until resolving to ≤ Grade 1\nPrednisolone 0.5–1 mg/kg/day with slow taper\nConsider hospital admission for wet dressings\nRefractory pruritus: \nConsider neuropathic analgesia, for example, pregabalin 25 mg daily and titrate to response\t\n\n\n\t\n\nGrade 3-4/severe/life-threatening\n\t\nRash (≥30% BSA), pruritus, blisters, ulceration\tSkin biopsy (with direct immunofluorescence if blisters present)\tDelay immunotherapy if Grade 3 until resolving to Grade ≤ 1\nCease immunotherapy if SJS/TEN (Grade 4)\nUrgent dermatology review and biopsy\nPrednisolone 1 mg/kg/day or pulse with methylprednisolone 1-2 mg/kg/day for 3 days∗Consideration of IVIG and/or cyclosporin\nTransfer to burns unit if skin loss > 10%\t\n\n∗Switch to oral prednisolone 1 mg/kg/day with slow taper over 1 month or longer. PJP (e.g., bactrim DS 1/2 tablet daily) and GIT ulcer prophylaxis therapy when patients are on prolonged steroid taper. Monitor blood glucose.\n\nTable 3 Gastrointestinal and hepatic irAE: management algorithm.\n\n(a) Gastrointestinal irAE\tInvestigations\tManagement\t\n\nGrade 1/mild\n\t\nDiarrhoea (<4 stools/day over baseline)\tStool MCS\tContinue checkpoint inhibitor monotherapy\n(If on dual checkpoint inhibitor therapy, patient will need careful consideration and monitoring closely)\nAntimotility agents, for example, loperamide\nFluid replacement\nIf prolonged symptoms, treat as Grade 2\t\n\n\n\t\n\nGrade 2/moderate\n\t\nDiarrhoea (4–6 stools/day over baseline)\nColitis (pain, mucus, or blood)\tStool MCS\nConsider colonoscopy\tDelay immunotherapy until resolving to Grade ≤ 1\n(If on dual checkpoint inhibitor therapy, consider ceasing anti-CTLA-4)\nConsider hospital admission\nGastroenterology referral\nOral prednisolone 1 mg/kg/day for colitis or persistent diarrhoea\t\n\n\n\t\n\nGrade 3-4/severe/life-threatening\n\t\nDiarrhoea (≥7 stools/day over baseline, incontinence, life-threatening)\nColitis (severe pain, blood, mucus, and peritonism)\tStools MCS\nColonoscopy, if colitis suspected or persistent diarrhoea despite steroids\nAXR/CT if suspected perforation\tGrade 3 toxicity:\nDelay anti-PD-1 until resolving to Grade ≤ 1 with careful consideration as to retreatment\nCease anti-CTLA-4 \nGrade 4 toxicity (life-threatening, perforation):\nDiscontinue immunotherapy permanently\nHospital admission\nGastroenterology referral\nPulse with methylprednisolone 1-2 mg/kg/day∗ \n If no response to steroid therapy (3–5 days), consider infliximab 5 mg/kg (if no perforation/sepsis) \t\n(b) Hepatic irAE\tInvestigations\tManagement\t\n\nGrade 1/mild\n\t\nHepatic (AST/ALT < 3x ULN and/or total bilirubin < 1.5x ULN)\tLFTs and viral serology\nMonitor LFTs weekly\nExclude disease progression or medication-related causes\tContinue checkpoint inhibitor therapy\t\n\n\n\t\n\nGrade 2/moderate\n\t\nHepatic (AST/ALT >3–≤5x ULN and/or total bilirubin >1.5–≤3x ULN)\tLFTs and viral serology\nExclude disease progression or medication-related causes\nLFTs every 3 days\tDelay checkpoint inhibitor therapy until improving to baseline \nConsider gastroenterology referral\nConsider oral prednisolone 1 mg/kg/day with slow taper\t\n\n\n\t\n\nGrade 3-4/severe/life-threatening\n\t\nHepatic (AST/ALT >5x ULN and/or total bilirubin >3x ULN)\tLFTs and viral serology\nExclude disease progression or medication-related causes\nLFTs daily\tDiscontinue checkpoint inhibitor therapy \nHospital admission\nGastroenterology referral\nPulse with methylprednisolone 1-2 mg/kg/day for 3 days∗\nSteroid refractory hepatitis:\nIf no improvement after 3–5 days consider the following: \nMycophenolate mofetil 500 mg–1 g bd and escalation of methylprednisolone to 15 mg/kg daily (maximum 1 gm/day) for 3 days\t\n\n∗Switch to oral prednisolone 1 mg/kg/day with slow taper over 1 month or longer. PJP (e.g., bactrim DS 1/2 tablet daily) and GIT ulcer prophylaxis therapy when patients are on prolonged steroid taper. Monitor blood glucose.\n\nTable 4 Endocrine irAE management algorithm.\n\nEndocrine irAE\tInvestigations\tManagement\t\n\nGrade 1/mild\n\t\nThyroid dysfunction (asymptomatic)\tTFTs (TSH, FT4, FT3)\tContinue checkpoint inhibitor therapy\nMild biochemical abnormality: monitor TFTs prior to each infusion\nConsider endocrine referral\t\n\n\n\t\n\nGrade 2/moderate\n\t\nThyroiditis\n(initial hyperthyroid phase\n preceding prolonged hypothyroid phase)\tTFTs prior to each infusion\tContinue checkpoint inhibitor therapy\nEndocrine referral\nHyperthyroidism may require medical management, if symptoms exist, but with close monitoring as this phase is usually short-lived\nOnset of hypothyroid phase (generally by week 9 of treatment):\n Commence thyroxine 50–100 mcg/daily\nIncrease by 50 mcg in 3 weeks if TSH is still high until TSH is within normal range\nContinue thyroxine maintenance dose\n\t\nHypophysitis \n(symptomatic but clinically stable)\t(AM) ACTH, cortisol, TFTs, LH, FSH, testosterone, oestrogen, prolactin, GH, IGF-1, blood glucose\nMRI pituitary\tConsider delay of checkpoint inhibitor therapy\nPrednisolone 1 mg/kg/day \nTaper glucocorticoid to maintenance oral hydrocortisone (e.g., 10 mg hysone 0600/1500)\nIt will generally require lifelong physiological \nreplacement of steroid\nAdrenal sick day education\nCommence thyroxine/gonadal hormone replacement if required†\t\n\n\n\t\n\nGrade 3-4/severe/life-threatening\n\t\nHypophysitis\n(adrenal crisis: fatigue, headache, dizziness, hypotension, and hypoglycaemia shock)\t(AM) ACTH, cortisol, TFTs, LH, FSH, testosterone, oestrogen, prolactin, GH, IGF-1, blood glucose\nMRI pituitary\tDelay checkpoint inhibitor therapy\nUrgent endocrine review\nPulse with methylprednisolone 1-2 mg/kg/day if indicated (e.g., headache); or high dose intravenous glucocorticoids (i.e., hydrocortisone 50 mg QID)\nManage/exclude sepsis\nFluid replacement\nTaper glucocorticoid to maintenance oral hydrocortisone (e.g., 10 mg hysone 0600/1500)\nIt will generally require lifelong physiological replacement of steroid\nAdrenal sick day education\nCommence thyroxine/gonadal hormone replacement if required†\t\n\n†Ensure steroid repletion prior to initiation of thyroxine to avoid precipitating adrenal crisis. Gonadal hormone replacement therapy can be initiated nonurgently when hypogonadotropic hypogonadism (secondary to hypophysitis) is confirmed to be persistent.\n\nTable 5 Suggested algorithm arthralgia and arthritis.\n\nRheumatological irAE\tInvestigations\tManagement\t\n\nGrade 1/mild\n\t\nArthralgia and arthritis (minimal symptoms or signs)\t \tContinue checkpoint inhibitor therapy\nSimple analgesia as required\t\n\n\n\t\n\nGrade 2/moderate\n\t\nArthralgia and arthritis (moderate pain, inflammation, and impacting on daily function)\t\nExclude:\n\nSepsis, crystal-induced arthritis, and coincidental inflammatory arthritis\nPerform:\nSynovial fluid cell count, polarised microscopy for crystals, gram stain and culture, blood culture\nRF, CCP, ANA, HLA-B27 (if positive, consider coincidental disease)\tConsider delay of checkpoint inhibitor therapy\nConsider rheumatology referral\nMonoarthritis or oligoarthritis:\nConsider intra-articular corticosteroid\nModerate inflammatory arthritis:\nConsider low dose prednisolone 5–10 mg daily \nFor more significant symptoms, higher doses may be required, for example, prednisolone 25 mg daily\nIf response is not rapid, consider addition of sulphasalazine (immunomodulator without immunosuppressive effect)\t\n\n\n\t\n\nGrade 3-4/severe/life-threatening\n\t\nArthralgia and arthritis (severe pain or inflammation, disabling, and impacting on self-care)\t\nExclude:\n\nSepsis, crystal-induced arthritis, and coincidental inflammatory arthritis\nPerform:\nSynovial fluid cell count, polarised microscopy for crystals, gram stain and culture, blood culture\nRF, CCP, ANA, HLA-B27 (if positive, consider coincidental disease)\tDiscontinue immunotherapy\nRheumatology referral\nModerate-severe inflammatory arthritis:\nPrednisolone 25 mg–40 mg daily\nIf response is not rapid, consider addition of sulphasalazine \nSevere:\nPulse with methylprednisolone 1-2 mg/kg/day for 3 days∗\t\n\n∗Switch to oral prednisolone 1 mg/kg/day with slow taper over 1 month or longer. PJP (e.g., bactrim DS 1/2 tablet daily) and GIT ulcer prophylaxis therapy when patients are on prolonged steroid taper. Monitor blood glucose.\n==== Refs\n1 Ribas A. Tumor immunotherapy directed at PD-1 The New England Journal of Medicine 2012 366 26 2517 2519 10.1056/nejme1205943 2-s2.0-84862882003 22658126 \n2 O'Day S. J. Hamid O. Urba W. J. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies Cancer 2007 110 12 2614 2627 10.1002/cncr.23086 2-s2.0-36849035139 18000991 \n3 Hodi F. S. O'Day S. J. McDermott D. F. Improved survival with ipilimumab in patients with metastatic melanoma The New England Journal of Medicine 2010 363 8 711 723 10.1056/NEJMoa1003466 2-s2.0-77954801079 20525992 \n4 Schadendorf D. Hodi F. S. Robert C. 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Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: A single-institution cohort Journal of the American Academy of Dermatology 2016 74 3 455 461 2-s2.0-84958150171 10.1016/j.jaad.2015.10.029 26793994 \n28 Weber J. S. Kähler K. C. Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab Journal of Clinical Oncology 2012 30 21 2691 2697 2-s2.0-84864052441 10.1200/JCO.2012.41.6750 22614989 \n29 Postow M. A. Managing immune checkpoint-blocking antibody side effects American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting 2015 76 83 2-s2.0-84969710115 10.14694/EdBook_AM.2015.35.76 \n30 Fecher L. A. Agarwala S. S. Stephen Hodi F. Weber J. S. Ipilimumab and its toxicities: a multidisciplinary approach The Oncologist 2013 18 6 733 743 10.1634/theoncologist.2012-0483 2-s2.0-84879477789 23774827 \n31 Yervoy (ipilimumab) immune-related adverse reaction (irAR) management guide 2013 \n32 Allison A. C. Eugui E. M. Mycophenolate mofetil and its mechanisms of action International Journal of immunopharmacology 2000 47 2-3 85 118 10.1016/S0162-3109(00)00188-0 2-s2.0-0034045586 \n33 Cheng R. Cooper A. Kench J. Ipilimumab-induced toxicities and the gastroenterologist Journal of Gastroenterology and Hepatology 2015 30 4 657 666 2-s2.0-84924797761 10.1111/jgh.12888 25641691 \n34 Tanaka R. Fujisawa Y. Maruyama H. Nakamura Y. Yoshino K. Ohtsuka M. Case series of thyroid dysfunction induced by nivolumab (anti-PD-1; ONO-4538) Annals of Oncology 2015 26 supplement 2 ii34 ii35 \n35 Mace C. Diem S. Gore M. Larkin J. Morganstein D. 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"journal": "Journal of skin cancer",
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"medline_ta": "J Skin Cancer",
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"pages": "9602540",
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"pubdate": "2018",
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"references": "26412456;25415286;18000991;27124339;10878285;28729151;23548570;22614989;26793994;25216852;20969735;22658126;25667295;25482239;26406148;28889792;20525992;26501224;23724846;25641691;25891173;23774827;28881921;25993145;27858975;28822576;26027431;27806233;27072927",
"title": "Immune Toxicity with Checkpoint Inhibition for Metastatic Melanoma: Case Series and Clinical Management.",
"title_normalized": "immune toxicity with checkpoint inhibition for metastatic melanoma case series and clinical management"
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"abstract": "Histoplasmosis is a systemic mycosis caused by the dimorphic fungus Histoplasma capsulatum. We report a case of disseminated cutaneous histoplasmosis with mucocutaneous involvement in an AIDS patient paradigmatic of the multifaceted nature of the disease, which is an expression of the immune reconstitution inflammatory syndrome (IRIS).\nA 39-year-old man presented with a three month history of asymptomatic papules and nodules with necrotic centres involving the centrofacial region. The patient was diagnosed as being HIV-positive a month earlier and was commenced on antiretroviral treatment. Two weeks after the development of skin lesions, the patient complained of a sore throat and hoarseness of his voice. A fibre-optic laryngoscopy and biopsies of the skin, larynx and liver were performed.\nThe CD4 counts increased from 2 cells/µL to 124 cells/µL, whereas the viral load decreased from one million to less than 20 copies/mL. A fibre-optic laryngoscopy revealed a supraglottitis with ulceration on the epiglottis. Histology of the liver, larynx and sections of the skin demonstrated pandermal necrotising granulomatous inflammation. Grocott-Gomori methenamine silver and Periodic acid-Schiff (PAS) stains revealed a relative paucity of intracellular, narrow-neck budding fungal organisms. Culture findings confirmed the diagnosis of histoplasmosis. The patient was treated with intravenous amphotericin B for two weeks followed by oral itraconazole 100 mg twice a day, with an excellent response to treatment.\nWe present this case to remind clinicians that disseminated histoplasmosis in AIDS patients may occur as an expression of IRIS. A sudden onset of hoarseness with cutaneous lesions in a patient with disseminated disease should alert one to possible laryngeal histoplasmosis. Prompt recognition and treatment will avert the potential fatal complications of this disease.",
"affiliations": "Department of Dermatology, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, South Africa.",
"authors": "Sacoor|Mohamed F|MF|0000-0003-3273-6656",
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"country": "South Africa",
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"doi": "10.4102/sajhivmed.v18i1.693",
"fulltext": "\n==== Front\nSouth Afr J HIV MedSouth Afr J HIV MedHIVMEDSouthern African Journal of HIV Medicine1608-96932078-6751AOSIS HIVMED-18-69310.4102/sajhivmed.v18i1.693Case ReportsDisseminated cutaneous histoplasmosis with laryngeal involvement in a setting of immune reconstitution inflammatory syndrome http://orcid.org/0000-0003-3273-6656Sacoor Mohamed F. 11 Department of Dermatology, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, South AfricaCorresponding author: Mohamed Sacoor, drmfsacoor@gmail.com28 4 2017 2017 18 1 69319 9 2016 02 3 2017 © 2017. The Authors2017Licensee: AOSIS. This work is licensed under the Creative Commons Attribution License.Introduction\nHistoplasmosis is a systemic mycosis caused by the dimorphic fungus Histoplasma capsulatum. We report a case of disseminated cutaneous histoplasmosis with mucocutaneous involvement in an AIDS patient paradigmatic of the multifaceted nature of the disease, which is an expression of the immune reconstitution inflammatory syndrome (IRIS).\n\nPatient presentation\nA 39-year-old man presented with a three month history of asymptomatic papules and nodules with necrotic centres involving the centrofacial region. The patient was diagnosed as being HIV-positive a month earlier and was commenced on antiretroviral treatment. Two weeks after the development of skin lesions, the patient complained of a sore throat and hoarseness of his voice. A fibre-optic laryngoscopy and biopsies of the skin, larynx and liver were performed.\n\nManagement and outcome\nThe CD4 counts increased from 2 cells/µL to 124 cells/µL, whereas the viral load decreased from one million to less than 20 copies/mL. A fibre-optic laryngoscopy revealed a supraglottitis with ulceration on the epiglottis. Histology of the liver, larynx and sections of the skin demonstrated pandermal necrotising granulomatous inflammation. Grocott-Gomori methenamine silver and Periodic acid–Schiff (PAS) stains revealed a relative paucity of intracellular, narrow-neck budding fungal organisms. Culture findings confirmed the diagnosis of histoplasmosis. The patient was treated with intravenous amphotericin B for two weeks followed by oral itraconazole 100 mg twice a day, with an excellent response to treatment.\n\nConclusion\nWe present this case to remind clinicians that disseminated histoplasmosis in AIDS patients may occur as an expression of IRIS. A sudden onset of hoarseness with cutaneous lesions in a patient with disseminated disease should alert one to possible laryngeal histoplasmosis. Prompt recognition and treatment will avert the potential fatal complications of this disease.\n==== Body\nIntroduction\nHistoplasmosis is a systemic mycosis caused by the dimorphic fungus Histoplasma capsulatum. We report a case of disseminated histoplasmosis (DH) with mucocutaneous involvement in an AIDS patient paradigmatic of the multifaceted nature of the disease, which is an expression of the immune reconstitution inflammatory syndrome (IRIS).\n\nEthical considerations\nThe sub-committee of the Biomedical Research Ethics Committee at the University of Kwazulu-Natal has given their full ethical approval for this study with BREC reference number: BE068/17.\n\nCase report\nA 39-year-old man presented with a 3-month history of skin lesions involving the face, neck and extremities. The patient was diagnosed as being HIV-positive a month earlier and was commenced on antiretroviral treatment abacavir 300 mg bd, lamivudine 300 mg bd and efavirenz 600 mg once daily, because of impaired renal function or pre-renal failure. The patient was hydrated with an improvement in the renal function. Two weeks after the development of the skin lesions, the patient complained of a sore throat and hoarseness of his voice.\n\nOn clinical examination, the patient had multiple translucent, clustered, umbilicated papules and nodules in the centrofacial region and neck with necrotic centres. In addition, there were verrucous plaques and nodules on the ears and upper limbs (Figure 1a and b). Chest X-ray was normal with no lung, hilar or mediastinal lymph nodes. A fibre-optic laryngoscopy revealed a supraglottitis with ulceration on the lingual surface of the epiglottis (Figure 1c).\n\nFIGURE 1 (a) Multiple pearly papules and nodules with necrotic centres on the face and neck, (b) well-circumscribed verrucous papules and plaques on the ear and (c) a supraglottitis with ulceration on the lingual surface of the epiglottis.\n\nRoutine blood investigations demonstrated elevation of the liver enzymes with an infiltrative pattern (AST-63/ALT 70/ALP -219/Gamma GT-291). Abdominal ultrasound revealed an enlarged liver with abnormal parenchyma. The kidneys and the rest of the abdomen were normal. The initial CD4 count performed prior to the commencement of antiretrovirals was 2 cells/µL with a viral load greater than one million copies/mL. A repeat test (eight weeks later) showed a CD4 count of 124 cells/µL with a viral load of less than 20 copies/mL. Urinalysis and urine histoplasma antigen test were negative. Histology of the liver, larynx and sections of the skin demonstrated pandermal necrotising granulomatous inflammation. Grocott-Gomori methenamine silver and PAS stains revealed a relative paucity of intracellular oval, narrow-neck budding fungal organisms morphologically in keeping with Histoplasma capsulatum var. capsulatum (Figure 2a and b). Fungal culture of liver, epiglottis ulcer and skin confirmed the diagnosis of histoplasmosis.\n\nFIGURE 2 (a) Haematoxylin–eosin 40x – shows features of a pandermal granulomatous inflammatory reaction comprising aggregates of epithelioid histiocytes and Langerhans giant cells; (b) PAS stain 40x reveals the presence of intracellular uninucleate oval yeast-like, narrow-neck budding fungal organisms; and (c) Grocott-Gomori methenamine silver stain 40x – shows a narrow-neck budding fungal organism.\n\nOn the basis of the clinical presentation, initial worsening of the disease and rapid elevation of the CD4+ T-cell count with lowering of the HIV viral load, the patient most likely has histoplasmosis associated IRIS. The patient was commenced on intravenous amphotericin B (0.8 mg/kg/day) for two weeks and continued with his antiretroviral treatment. He had an excellent response to this treatment and was discharged on itraconazole 100 mg twice a day.\n\nDiscussion\nDisseminated histoplasmosis is most frequently described among patients with CD4+ T-cell counts below 50 cells/mm3.1 It occurs in 5% – 75% of AIDS patients, with mucocutaneous manifestations seen among 11% – 25% of cases.2 Cutaneous lesions can take a number of forms from inflammatory folliculitis, molluscum-like papules, verrucous plaques, erythema multiforme-like lesions, vasculitic lesions, exfoliative dermatitis, ulcers and nodular lesions.2,3\n\nImmune reconstitution inflammatory syndrome is an inflammatory disease and is the consequence of an exaggerated dysregulated immune antigen interaction following highly active antiretroviral therapy (HAART) induced immune restoration.4 The disseminated clinical presentation may probably be due to a low CD4 count as well as a high antigen burden prior to HAART initiation.4 Nacher et al.5 reported that patients taking HAART were more likely to develop DH than untreated patients. The exacerbation of skin and laryngeal symptoms in our patient after starting HAART may be due to an exaggerated cell-mediated inflammatory response. IRIS is a diagnosis of exclusion. Although it is the most likely diagnosis in our patient, the natural progression of a pre-existing opportunistic infection cannot be excluded.5\n\nLaryngeal histoplasmosis is a rare phenomenon.6 Since 1952, when laryngeal histoplasmosis was initially described in the literature, less than 100 cases have been reported to date.7 Common initial manifestations are pain when swallowing, hoarseness, gingival ulceration and dysphagia.7,8 Firm, painful ulcers, with elevated borders, involving the oral mucosa and larynx are characteristic.7,8\n\nAmphotericin B and itraconazole are the antifungal agents that were noted to be effective in the treatment of histoplasmosis.9 Treatment should be continued until clinical and laboratory findings are normal.9,10 However, 9% of patients will experience a relapse.10\n\nAccording to the evidence-based guidelines for the management of DH presented by the Infectious Diseases Society of America (IDSA), it is recommended that patients with moderate to severe disease be treated with liposomal amphotericin B (3.0 mg/kg daily for 12 weeks), followed by oral itraconazole (200 mg three times daily for three days and then 200 mg twice daily for a total of at least 12 months).11 The deoxycholate formulation of amphotericin B (0.7 mg/kg – 1.0 mg/kg daily) is an alternative to a lipid formulation in patients who are at low risk for nephrotoxicity. For mild to moderate disease, itraconazole (200 mg three times daily for three days and then 200 mg twice daily for at least 12 months) is recommended.11\n\nLifelong suppressive therapy with itraconazole (200 mg daily) may be required in immunosuppressed patients if immunosuppression cannot be reversed and in patients who relapse despite receipt of appropriate therapy.11\n\nConclusion\nWe are presenting this case to remind clinicians that DH in AIDS patients may occur as an expression of IRIS. A sudden onset of hoarseness with cutaneous lesions in a patient with disseminated disease should alert one to possible laryngeal histoplasmosis. Prompt recognition and treatment will avert the potential fatal complications of this disease.\n\nAcknowledgements\nCompeting interests\nThe author declares that he has no financial or personal relationships which may have inappropriately influenced him in writing this article.\n\nHow to cite this article: Sacoor MF. Disseminated cutaneous histoplasmosis with laryngeal involvement in a setting of immune reconstitution inflammatory syndrome. S Afr J HIV Med. 2017;18(1), a693. https://doi.org/10.4102/sajhivmed.v18i1.693\n==== Refs\nReferences\n1. Angius AG , Viviani MA , Muratori S , Cusini M , Brignolo L , Alessi E \nDisseminated histoplasmosis presenting with cutaneous lesions in a patient with acquired immunodeficiency syndrome . J Eur Acad Dermatol Venereol . 1998 ;10 :182 –185 . https://doi.org/10.1111/j.1468-3083.1998.tb00724.x 9553921 \n2. Ramdial P , Mosam A , Dlova N , Satar N , Aboobaker J , Singh SM \nDisseminated cutaneous histoplasmosis in patients infected with human immunodeficiency virus . J Cutan Pathol . 2002 ;29 :215 –225 . https://doi.org/10.1034/j.1600-0560.2002.290404.x 12028154 \n3. Radhakrishnan S , Adulkar NG , Kim U \nPrimary cutaneous histoplasmosis mimicking basal cell carcinoma of the eyelid: A case report and review of literature . Indian J Pathol Microbiol . 2016 ;59 (2 ):227 –228 . https://doi.org/10.4103/0377-4929.182017 27166049 \n4. Ogoina D , Adekunle V , Obiako R , Umar A , Akolawole M , Ovosi J \nDisseminated infections due to immune reconstitution inflammatory syndrome after highly active antiretroviral therapy-report of 3 cases from Nigeria . Pan Afr Med J . 2011 ;9 :38 \nhttps://doi.org/10.4314/pamj.v9i1.71216 22355437 \n5. Sarazin E , Nacher M , Toure Y , et al \nDermatologic manifestations associated with immune reconstitution syndrome in HIV+ patients starting HAART . Bull Soc Pathol Exot . 2005 ;98 (3 ):187 –192 .16267958 \n6. Solari R , Corti M , Cangelosi D , et al \nDisseminated histoplasmosis with lesions restricted to the larynx in a patient with AIDS. Report of a case and review of the literature . Rev Iberoam Micol . 2007 ;24 (2 ):164 –166 . https://doi.org/10.1016/S1130-1406(07)70036-0 17604440 \n7. Pochini Sobrinho F , Della Negra M , Queiroz W , Ribeiro UJ , Bittencourt S , Klautau G \nHistoplasmosis of the larynx . Braz J Otorhinolaryngol . 2007 ;73 (6 ):857 –861 . https://doi.org/10.1016/S1808-8694(15)31187-3 18278237 \n8. Sanmani L , Randall CJ , Palfrey J , Rowen D \nHoarseness of voice in an AIDS patient: A rare presenting feature of disseminated histoplasmosis . Int J STD AIDS . 2011 ;22 (2 ):115 –116 . https://doi.org/10.1258/ijsa.2010.010356 21427437 \n9. Marques SA , Silvares MR , Camargo RM , Marques ME \nCutaneous histoplasmosis disclosing an HIV-infection . An Bras Dermatol . 2013 ;88 (3 ):420 –423 . https://doi.org/10.1590/abd1806-4841.20131812 23793220 \n10. Assi MA , Sandid MS , Baddour LM , Roberts GD , Walker RC \nSystemic histoplasmosis: A 15-year retrospective institutional review of 111 patients . Medicine (Baltimore) . 2007 ;86 (3 ):162 –169 .17505255 \n11. Wheat LJ , Freifeld AG , Kleiman MB , et al \nClinical practical guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America . Clin Infect Dis . 2007 ;45 :807 –808 . https://doi.org/10.1086/521259 17806045\n\n",
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"title": "Disseminated cutaneous histoplasmosis with laryngeal involvement in a setting of immune reconstitution inflammatory syndrome.",
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"abstract": "We report the first case of disseminated infection by Gymnascella hyalinospora in a solid organ transplant recipient. This case highlights the role of low-virulence environmental molds as an emerging cause of breakthrough invasive fungal infection in immunocompromised hosts. Nosocomial strategies of infection control including antimicrobial stewardship and advances on fast diagnostic methods are strongly encouraged to improve patient prognosis.",
"affiliations": "Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.;Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.;Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain.",
"authors": "Agnelli|Caroline|C|https://orcid.org/0000-0003-3784-3266;Valerio|Maricela|M|https://orcid.org/0000-0001-6394-2861;Olmedo|María|M|;Guinea|Jesús|J|;Zatarain-Nicolás|Eduardo|E|;Del Carmen Martínez-Jiménez|María|M|;Alcalá|Luis|L|;Escribano|Pilar|P|;Cebollero Presmanes|María|M|;Bouza|Emilio|E|;Muñoz|Patricia|P|https://orcid.org/0000-0001-5706-5583;Martín-Rabadán|Pablo|P|",
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"keywords": "antimicrobial stewardship; heart transplantation; immunocompromised host; invasive fungal infections",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D001203:Ascomycota; D017809:Fatal Outcome; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D016867:Immunocompromised Host; D000072742:Invasive Fungal Infections; D009181:Mycoses; D009894:Opportunistic Infections; D014057:Tomography, X-Ray Computed; D066027:Transplant Recipients",
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"title": "Fatal disseminated infection by Gymnascella hyalinospora in a heart transplant recipient.",
"title_normalized": "fatal disseminated infection by gymnascella hyalinospora in a heart transplant recipient"
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"abstract": "A 65-year-old man with chronic hepatitis C virus and hepatocellular carcinoma, after surgical resection and chemotherapy, was started on a regimen of glecaprevir and pibrentasavir for treatment of his hepatitis C virus. Ten days later, he developed hepatotoxicity with subsequent progression to hepatorenal syndrome (HRS). On discontinuation of glecaprevir/pibrentasavir and initiation of HRS treatment, he had improvement in his renal and hepatic function. Although there have been recent safety concerns surrounding hepatocellular injury secondary to glecaprevir/pibrentasavir, this is the first case report of HRS secondary to severe hepatotoxicity induced by glecaprevir/pibrentasavir.",
"affiliations": "New York University Grossman School of Medicine, New York, NY.;New York University Grossman School of Medicine, New York, NY.;New York University Grossman School of Medicine, New York, NY.",
"authors": "Fansiwala|Kush|K|;Saltiel|Jason|J|;Poles|Michael|M|",
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"fulltext": "\n==== Front\nACG Case Rep J\nACG Case Rep J\nACGCRJ\nACGCRJ\nAC9\nACG Case Reports Journal\n2326-3253\nWolters Kluwer Maryland, MD\n\nACGCR-20-0719\n10.14309/crj.0000000000000587\n00008\nCase Report\nLiver\nAcute Kidney Injury Presenting as Hepatorenal Syndrome in the Setting of Glecaprevir/Pibrentasvir Treatment for Hepatitis C\nFansiwala Kush BA 1*\nSaltiel Jason MD 1*Jason.Saltiel@nyulangone.org\n\nPoles Michael MD, PhD 1Michael.Poles@nyulangone.org\n\n1 New York University Grossman School of Medicine, New York, NY\nCorrespondence: Kush Fansiwala, BA (kush.fansiwala@nyulangone.org).\n5 2021\n12 5 2021\n8 5 e0058714 6 2020\n04 12 2020\n© 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This 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.\n\nABSTRACT\n\nA 65-year-old man with chronic hepatitis C virus and hepatocellular carcinoma, after surgical resection and chemotherapy, was started on a regimen of glecaprevir and pibrentasavir for treatment of his hepatitis C virus. Ten days later, he developed hepatotoxicity with subsequent progression to hepatorenal syndrome (HRS). On discontinuation of glecaprevir/pibrentasavir and initiation of HRS treatment, he had improvement in his renal and hepatic function. Although there have been recent safety concerns surrounding hepatocellular injury secondary to glecaprevir/pibrentasavir, this is the first case report of HRS secondary to severe hepatotoxicity induced by glecaprevir/pibrentasavir.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\n\nThe combined regimen of glecaprevir and pibrentasvir is a highly effective treatment for hepatitis C virus (HCV), with sustained virologic responses (SVR) of over 95%, regardless of HCV genotype.1 Despite its effectiveness, data from the Food and Drug Administration (FDA) suggest that there can be significant hepatotoxicity with the regimen.2 We discuss the first published description of hepatorenal syndrome (HRS) secondary to hepatotoxicity from glecaprevir/pibrentasvir.\n\nCASE REPORT\n\nA 65-year-old man with chronic HCV (genotype 1a), remote alcohol use disorder, hepatocellular carcinoma (HCC), and chronic inactive hepatitis B presented with abdominal distention and jaundice for 1 month. In 2014, he was found to have a 3.9 × 3.3 × 3.4 cm liver mass. On biopsy, HCC was confirmed, and he was treated with surgical wedge resection of segment 4, percutaneous ablation of segment 2, and adjuvant sorafenib. The sorafenib was discontinued 9 months before this admission because of side effects, including diarrhea and bloating. He had been clinically stable without evidence of recurrence on multiphase computed tomography 6 months earlier, and his α-fetoprotein was 6.8 ng/mL 3 weeks before admission. At the initiation of glecaprevir/pibrentasvir, he had no evidence of chronic kidney disease or chronic kidney disease risk factors such as hypertension or diabetes. His hepatic function was notable for low albumin, elevated transaminases, and elevated alkaline phosphatase (Table 1). He had no previous history of hepatic encephalopathy or ascites suggestive of decompensated cirrhosis and was categorized as Child-Pugh class A.\n\nTable 1. Significant laboratory values during clinical course\n\n\tMost recent value before treatment initiation\tValue on admission\tValue 4 months after discharge\t\nCreatinine (mg/dL)\t1.0\t1.6\t1.1\t\nTotal bilirubin (mg/dL)\t0.9\t25.5\t3.7\t\nDirect bilirubin (mg/dL)\t0.6\t16.1\t2.1\t\nInternational normalized ratio\t0.95\t1.64\t1.71\t\nAlbumin (g/dL)\t3.2\t2.6\t2.9\t\nAspartate aminotransferase (U/L)\t113\t127\t30\t\nAlanine aminotransferase (U/L)\t42\t55\t11\t\nAlkaline phosphatase (U/L)\t196\t105\t109\t\nPlatelet count (109/mL)\t112\t213\t130\t\nSodium (mEq/L)\t138\t132\t135\t\nMELDNa\t11\t31\t20\t\nHCV viral load (IU/mL)\t2,443,203\tn/a\t<12\t\nHCV, hepatitis C virus; MELDNa, Model for End-Stage Liver Disease Sodium.\n\nTen days after starting glecaprevir/pibrentasvir, he presented to the emergency department with jaundice and abdominal pain. Laboratories were notable for an elevated total (7.7 mg/dL) and direct (5.2 mg/dL) bilirubin with an alkaline phosphatase of 105 U/L and creatinine of 1.1 mg/dL (Table 1). Ultrasound demonstrated moderate ascites, and paracentesis demonstrated a serum ascites albumin gradient of 1.8 and no evidence of spontaneous bacterial peritonitis. He was advised to follow-up as an outpatient.\n\nTwo weeks later, he returned to the emergency department with fevers, chills, fatigue, and darkening urine. On examination, he had diffuse jaundice, increased abdominal distension, and right upper quadrant tenderness. His laborateries now showed total bilirubin of 25.5 mg/dL, direct bilirubin of 16.1 mg/dL, the international normalized ratio of 1.64, and creatinine of 1.6 mg/dL. Abdominal computed tomography and ultrasound showed no evidence of biliary obstruction or portal vein thrombosis. Hepatitis B DNA levels were undetectable, and core IgM was negative. Given his impaired synthetic function, acute decompensated cirrhosis, and rapidly declining renal function, there was a concern for type 1 HRS. He received a 3-day albumin challenge, after which his fractional urinary excretion of sodium decreased from 15% to less than 10%, and his creatinine increased to 2.0 mg/dL. He was subsequently started on octreotide, midodrine, and albumin. Glecaprevir/pibrentasvir was discontinued after 29 days of treatment because of his acute liver decompensation.\n\nOver the following 8 days, the patient's creatinine decreased to 1.3 mg/dL and his total bilirubin decreased from 25.6 to 16.4 mg/dL. Four months after discharge, he has remained clinically stable, with improvement in his renal function and hyperbilirubinemia, but not in his synthetic function (Table 1). Despite discontinuing glecaprevir/pibrentasvir after 29 days, his HCV viral load remained undetectable 4 months later.\n\nDISCUSSION\n\nIn August 2019, the FDA distributed a safety communication outlining serious liver injury in 46 individuals on glecaprevir/pibrentasvir. These patients presented with varying symptoms including hyperbilirubinemia, jaundice, ascites, and hepatic encephalopathy.3 The communication suggested avoidance of this medication in patients with Child-Pugh class B and C. Although further research is needed on the safety of glecaprevir/pibrentasvir in Child-Pugh class A, this case highlights the importance of regular monitoring of liver and renal function in patients on this regimen. In this case, a more cautious approach and earlier discontinuation at the initial emergency department visit may have helped avoid further complications.\n\nGiven this patient's HCC, a regimen without a protease inhibitor may have carried less risk of hepatotoxicity. There are some data to suggest that direct-acting antiviral regimens for HCV genotype 1 that include a protease inhibitor have high SVRs in patients with a previous history of HCC. However, data for regimens including glecaprevir/pibrentasavir are lacking.4 In part, this is due to HCC being part of the exclusion criteria for many HCV clinical trials. We believe that future clinical trials should seek to assess safety and SVR in this patient population.\n\nNotably, sorafenib was discontinued after 9 months because of gastrointestinal intolerance. There are minimal data on whether to continue sorafenib after achieving a complete response, but the prevailing approach is to continue indefinitely.5 However, given the side effects in this patient and lack of clinical recurrence, his care team elected to discontinue the medication. It should also be noted that glecaprevir/pibrentasvir may not be the sole precipitant of this patient's decompensation. Although he took no medications with known interactions with glecaprevir/pibrentasvir, the patient had a remote history of alcohol use and reported mild continued drinking up to this admission (3 beers per week).\n\nAccording to the FDA Adverse Event Reporting System database, 171 adverse hepatocellular reactions have been reported after glecaprevir/pibrentasvir administration since 2017. Of those, 12 patients (7%) developed renal pathology. Six of those required hospitalizations, and 3 led to death.2 Only 1 previous case report has explored glecaprevir/pibrentasvir-associated liver injury, but that patient had no pre-existing cirrhosis, had elevated transaminases with a milder hyperbilirubinemia, and no kidney injury.6 To our knowledge, this is the first case report identifying glecaprevir/pibrentasvir-induced HRS secondary to hepatotoxicity. Current glecaprevir/pibrentasvir regimens range from 8 to 12 weeks, yet a 4-week regimen was still effective in virus eradication for this patient. Recent literature has suggested that a large percentage of patients on glecaprevir/pibrentasvir may be cured with less than 7 weeks of treatment, and a personalized treatment regimen based on viral load may be effective.7 This could reduce potential side effects and the cost of antiviral therapy.\n\nDISCLOSURES\n\nAuthor contributions: All authors contributed equally to this article. M. Poles is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n\n* Kush Fansiwala, BA and Jason Saltiel, MD are cofirst authors.\n==== Refs\nREFERENCES\n\n1. Zeuzem S Foster GR Wang S Glecaprevir–pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection. N Engl J Med. 2018;378 (4 ):354–69.29365309\n2. Center for Drug Evaluation and Research. FDA Adverse Event Reporting System (FAERS) Public Dashboard. U.S. Food and Drug Administration: Silver Spring, MD, 2019 (https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard). Published December 24, 2019.Accessed May 7, 2020.\n3. Center for Drug Evaluation and Research. Risk of liver injury with certain HCV drugs in advanced liver disease. U.S. Food and Drug Administration (https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrence-serious-liver-injury-use-hepatitis-c-medicines-mavyret-zepatier-and). Published August 28, 2019. Accessed May 7, 2020.\n4. Beste LA Green PK Berry K Effectiveness of hepatitis C antiviral treatment in a USA cohort of veteran patients with hepatocellular carcinoma. J Hepatol. 2017;67 (1 ):32–9.28267622\n5. Poullenot F Bioulac-Sage P Laumonier H Hepatocellular carcinoma treated by sorafenib with complete radiological response according to mRECIST criteria: Could we stop the treatment? About four cases. Acta Oncologica. 2013;53 (3 ):420–3.23713857\n6. Hammami MB Aboushaar R Alsabbagh E . Glecaprevir/pibrentasvir-associated acute liver injury in non-cirrhotic, chronic HCV infection without HBV co-infection. BMJ Case Rep. 2019;12 (5 ):e226622.\n7. Dasgupta S Imamura M Gorstein E Modeling-based response-guided therapy for chronic hepatitis C under glecaprevir/pibrentasvir may identify patients for ultra-short treatment duration. J Infect Dis 2020;222 (7 ):1165–9.32363394\n\n",
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"activesubstance": {
"activesubstancename": "GLECAPREVIR\\PIBRENTASVIR"
},
"drugadditio... |
{
"abstract": "Mercaptopurine (6-mercaptopurine, 6MP) is a mainstay of curative therapy in childhood acute lymphoblastic leukemia (ALL), and contributes to its 90% overall survival rate. We present two patients with ALL who suffered with severe pancreatitis secondary to 6MP. Through the use of allopurinol in conjunction with reduced dose 6MP, we were able to continue 6MP without further pancreatitis. This report contributes to the small body of literature on 6MP associated pancreatitis in childhood ALL and describes a novel approach to continued use of 6MP during therapy.",
"affiliations": "Emory University/Children's Healthcare of Atlanta, Aflac Cancer Center and Blood Disorders Service, Atlanta, Georgia.;Emory University/Children's Healthcare of Atlanta, Aflac Cancer Center and Blood Disorders Service, Atlanta, Georgia.;Emory University/Children's Healthcare of Atlanta, Aflac Cancer Center and Blood Disorders Service, Atlanta, Georgia.;Emory University/Children's Healthcare of Atlanta, Aflac Cancer Center and Blood Disorders Service, Atlanta, Georgia.;Emory University/Children's Healthcare of Atlanta, Aflac Cancer Center and Blood Disorders Service, Atlanta, Georgia.",
"authors": "Zerra|Patricia|P|;Bergsagel|John|J|;Keller|Frank G|FG|;Lew|Glen|G|;Pauly|Melinda|M|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000493:Allopurinol; D015122:Mercaptopurine",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25841",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "63(4)",
"journal": "Pediatric blood & cancer",
"keywords": "acute lymphoblastic leukemia; allopurinol; mercaptopurine; pancreatitis",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000493:Allopurinol; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D006801:Humans; D008297:Male; D015122:Mercaptopurine; D010195:Pancreatitis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "712-5",
"pmc": null,
"pmid": "26878433",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Maintenance Treatment With Low-Dose Mercaptopurine in Combination With Allopurinol in Children With Acute Lymphoblastic Leukemia and Mercaptopurine-Induced Pancreatitis.",
"title_normalized": "maintenance treatment with low dose mercaptopurine in combination with allopurinol in children with acute lymphoblastic leukemia and mercaptopurine induced pancreatitis"
} | [
{
"companynumb": "US-MYLANLABS-2016M1018842",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
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