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"abstract": "Transdiaphragmatic extension of pyogenic liver abscess is the rarest cause of pericarditis and pleural empyema. It is a rapidly progressive and highly lethal infection with mortality rates reaching 100% if left untreated. However, the transmission route, treatment methods and prognosis have not been well studied.\n\n\n\nA 65-year-old male patient presented with a fever, dyspnea, and right upper quadrant abdominal pain. Computed tomography of the chest and abdomen showed huge liver abscess without full liquefaction in the left lobe, large amount of left pleural effusion, and mild pericardial effusion, and the patient was treated with parenteral antibiotics and pigtail insertion at the left pleura. However, four days later, cardiac tamponade was developed and surgical drainage of the abscess and pericardium was performed. Klebsiella pneumonia was isolated from pleural empyema. Twenty-five days after surgery, the patient was discharged without any complications.\n\n\n\nHerein, we report a rare case of pleural empyema and pericarditis in that resulted from the extension of huge pyogenic liver abscess. Early surgical treatment may have prevented progression of the pericarditis to the more dismal purulent pericarditis. We also review pertinent English literature on pericarditis as a complication of PLA.",
"affiliations": "Department of Internal Medicine, Chonnam National University Hospital, Gwangju, South Korea.;Department of Internal Medicine, Chonnam National University Hospital, Gwangju, South Korea.;Department of Internal Medicine, Chonnam National University Hospital, Gwangju, South Korea. estevanj@naver.com.;Department of Radiology, Chonnam National University Hospital, Gwangju, South Korea.;Department of Surgery, Chonnam National University Medical School, Gwangju, South Korea.;Department of Thoracic and Cardiovascular Surgery, Chonnam National University Hospital, Gwangju, South Korea.;Department of Internal Medicine, Chonnam National University Hospital, Gwangju, South Korea.;Department of Internal Medicine, Chonnam National University Hospital, Gwangju, South Korea.;Department of Internal Medicine, Chonnam National University Hospital, Gwangju, South Korea.;Department of Internal Medicine, Chonnam National University Hospital, Gwangju, South Korea.;Department of Internal Medicine, Chonnam National University Hospital, Gwangju, South Korea.",
"authors": "Cho|Eunae|E|;Park|Sang Woo|SW|;Jun|Chung Hwan|CH|http://orcid.org/0000-0002-7136-8350;Shin|Sang Soo|SS|;Park|Eun Kyu|EK|;Lee|Kyo Seon|KS|;Park|Seon Young|SY|;Park|Chang Hwan|CH|;Kim|Hyun Soo|HS|;Choi|Sung Kyu|SK|;Rew|Jong Sun|JS|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-018-2953-8",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 295310.1186/s12879-018-2953-8Case ReportA rare case of pericarditis and pleural empyema secondary to transdiaphragmatic extension of pyogenic liver abscess Cho Eunae cea202@hanmail.net 1Park Sang Woo withpsw@naver.com 1http://orcid.org/0000-0002-7136-8350Jun Chung Hwan +82-62-220-6215estevanj@naver.com 1Shin Sang Soo kjradsss@jnu.ac.kr 2Park Eun Kyu iameunkyu@gmail.com 3Lee Kyo Seon waytogosun@naver.com 4Park Seon Young drpsy@naver.com 1Park Chang Hwan p1052ccy@hanmail.net 1Kim Hyun Soo dshskim@jnu.ac.kr 1Choi Sung Kyu choisk@jnu.ac.kr 1Rew Jong Sun jsrew@jnu.ac.kr 11 0000 0004 0647 2471grid.411597.fDepartment of Internal Medicine, Chonnam National University Hospital, Gwangju, South Korea 2 0000 0004 0647 2471grid.411597.fDepartment of Radiology, Chonnam National University Hospital, Gwangju, South Korea 3 0000 0001 0356 9399grid.14005.30Department of Surgery, Chonnam National University Medical School, Gwangju, South Korea 4 0000 0004 0647 2471grid.411597.fDepartment of Thoracic and Cardiovascular Surgery, Chonnam National University Hospital, Gwangju, South Korea 15 1 2018 15 1 2018 2018 18 409 8 2017 8 1 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nTransdiaphragmatic extension of pyogenic liver abscess is the rarest cause of pericarditis and pleural empyema. It is a rapidly progressive and highly lethal infection with mortality rates reaching 100% if left untreated. However, the transmission route, treatment methods and prognosis have not been well studied.\n\nCase presentation\nA 65-year-old male patient presented with a fever, dyspnea, and right upper quadrant abdominal pain. Computed tomography of the chest and abdomen showed huge liver abscess without full liquefaction in the left lobe, large amount of left pleural effusion, and mild pericardial effusion, and the patient was treated with parenteral antibiotics and pigtail insertion at the left pleura. However, four days later, cardiac tamponade was developed and surgical drainage of the abscess and pericardium was performed. Klebsiella pneumonia was isolated from pleural empyema. Twenty-five days after surgery, the patient was discharged without any complications.\n\nConclusions\nHerein, we report a rare case of pleural empyema and pericarditis in that resulted from the extension of huge pyogenic liver abscess. Early surgical treatment may have prevented progression of the pericarditis to the more dismal purulent pericarditis. We also review pertinent English literature on pericarditis as a complication of PLA.\n\nKeywords\nLiver abscessPericarditisEmpyemaKlebsiella pneumoniaeissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nPyogenic liver abscess (PLA) is a life-threatening infectious condition, with an estimated incidence of 2.3 cases per 100,000 persons in the United States [1] and 17.6 cases per 100,000 persons in Taiwan [2]. Despite aggressive treatment, the mortality rate ranges from 6% to 14% [3]. Klebsiella pneumoniae is an important cause of PLA in Asia, and is often associated with invasive liver abscess syndrome, which accompanies metastatic infection at other sites [4, 5]. However, pericarditis by direct PLA invasion has rarely been reported [6]. Herein, we report one case of a transdiaphragmatic extension of a Klebsiella pneumoniae liver abscess, which caused pleural empyema and pericarditis. We also review pertinent English literature on pericarditis as a complication of PLA.\n\nCase presentation\nA 65-year-old man was transferred to our hospital due to dyspnea. Five days prior to his admission, he had presented to another hospital with right upper quadrant abdominal pain accompanied by fever, and a diagnosis of liver abscess was made. He denied any ophthalmological symptoms such as blurred vision or painful eye swelling. The patient was treated with parenteral ceftriaxone and metronidazole, but his condition deteriorated. On admission, his vital signs were as follows: pulse, 122 beats/min; blood pressure, 100/60 mmHg; respiratory rate, 24 breaths/min; and temperature, 38.0 °C. On physical examination, decreased breath sounds in the left lower lung fields and tenderness over the right upper abdomen were noted. Laboratory blood tests revealed leukocytosis, elevated liver enzymes (AST 42 U/L, ALT 74 U/L, ALP 162 U/L, and r-GTP 114 U/L) and a C-reactive protein level of 18.2 mg/dL. A computed tomography (CT) scan of the abdomen revealed one 10x6x8 cm and one 4x4x4 cm liver abscess, without full liquefaction, in the hepatic dome and anterior medial segment, respectively, and a small amount of ascites under the diaphragm. A chest CT revealed a small right pleural effusion, a large left pleural effusion and mild pericardial effusion. A diagnostic thoracentesis was performed. The aspirated pleural fluid was grossly pus (pH, 7.009; LDH, 7974 U/L; and protein, 3.3 g/dL). A pigtail catheter was inserted into the left pleural cavity to drain the empyema. The parenteral ceftriaxone and metronidazole treatment was changed to piperacillin/tazobactam. However, the patient remained febrile and tachypneic and, after four days, he progressed to septic shock. Physical examination revealed jugular venous distension and attenuated heart sounds. The electrocardiogram (ECG) showed multiple premature ventricular complexes. Chest CT revealed an increased volume of the pericardial effusion, with pericardial enhancement (Fig. 1a). Emergent bedside echocardiography showed a moderate amount of pericardial effusion, with some refractile densities in the fluid, suggestive of possible purulent pericarditis. A decision to proceed with surgical drainage of the liver abscess and surgical pericardiostomy was made on post-admission day 5. The abdominal cavity and liver were examined first. The huge abscess in the hepatic dome was adherent to the diaphragm. Moreover, the diaphragm and chest wall were inflamed and necrotic, with loculated pus between the diaphragm and the liver abscess (Fig. 1b). The diaphragm was released from the abscess and, after unroofing of the abscess, a drain was inserted into the liver abscess. Subsequently, after partial resection of the xiphoid process, a pericardial window was created (Fig. 1c), and the pericardial fluid, which was serosanguineous, was aspirated. In addition, inflammation of the pericardium was noted and a drain was inserted into the pericardium. After surgical drainage was performed, the patient’s condition improved and the ECG normalized. The pleural fluid culture was positive for Klebsiella pneumoniae; however, blood, pericardial fluid and liver abscess cultures were negative. Based on antibiotic susceptibility test, piperacillin/tazobactam was changed to ciprofloxacin. Twenty-five days after surgery, the patient was discharged without any complications. Follow-up abdominal ultrasonography performed at 20 days post-discharge showed a decrease in the size of the liver abscess and subphrenic fluid collection, and complete resolution of the pericardial effusion (Fig. 1d).Fig. 1 a. Computed tomography (CT) of chest demonstrated 10 × 6 × 8 cm (segment IV) and 4 × 4 × 4 cm (segment V) sized liver abscesses (black arrows), subphrenic fluid collection (white arrow), and moderate amount of pericaridal effusion (arrowheads). b. Intraoperative findings showed inflamed and necrotic diaphragm (white arrow) abutting liver abscess. c. After pericardial window was created, a pericardial drainage tube was inserted (white arrow). d. Follow-up abdomen CT after 20 days showed decreased size of liver abscess (black arrow) and subphremic fluid collection (white arrow), and complete resolution of pericardial effusion (arrowheads)\n\n\n\nDiscussion and conclusions\nAcute pericarditis is a rare but potentially lethal complication of a liver abscess, with an incidence rate of < 2% in patients with an amebic liver abscess [4]. PLA resulting in pericarditis is a rarer occurrence. In our report, we describe a very rare case of a huge liver abscess in the left lobe of the liver that extended transdiaphragmatically, causing a pleural empyema and pericarditis. Although the pleural empyema was successfully managed with insertion of a percutaneous pigtail catheter, the liver abscess could not be initially drained percutaneously as it was not fully liquefied. Despite adequate antibiotic treatment, which was later confirmed to be appropriate for the causative pathogen Klebsiella pneumoniae, pericarditis developed. Inflammation of the diaphragm and pericardium was confirmed during the surgery. Early surgical treatment may have prevented progression of the pericarditis to the more dismal purulent pericarditis.\n\nA PUBMED search of the English literature identified only a few cases of pericarditis as a complication of PLA [6–17], which we have summarized in Table 1. The median age of these patients was 49 years (range, 20 ~ 73 years), with 8 of the 13 patients (61.5%) being male. The liver abscess was located in the left lobe of the liver in 10 cases (76.9%) [6, 7, 9, 11–17] and in the right lobe (segment V/VIII) in one case (7.7%) [8], with involvement of both right and left lobes in one case (7.7%) [10]. In our case, the abscess was located in the left lobe. The transmission route of the PLA to the pericarditis was transdiaphragmatic in most of the previously reported cases [6, 10–15, 17], including our case.Table 1 Review of thirteen cases of pericarditis complicated by pyogenic liver abscess in English literature\n\nYear\tAge /sex\tComorbidites\tCardiac complications\tLocation of liver abscess\tPathogen\tPositive culture site\tTransmission route\tTreatment other than antibiotics\tClinical outcomes\t\n2015 [6]\t44/M\tHomeless, Cholecystostomy state\tEmpyema, Purulent pericarditis, cardiac tamponade\tLt. lobe\tK. pneumoniae,\n\nC. glabrata\n\tPericardial fluid\tTrans-diaphragmatic\tSurgical pericardial drainage, hepatic abscess resection, cholecystostomy tube removal\tRecovery\t\n2015 [7]\t23/M\tNo\tMyopericarditis\tLt. lobe\t\nF. nucleatum\n\tBlood, hepatic abscess\tReaction to liver abscess\tPercutaneous abscess drainage\tRecovery\t\n2014 [8]\t49/F\tRectal cancer with hepatic metastasis\tPurulent pericarditis, cardiac tamponade\tSegment V/VIII\t\nE .faecalis, E. coli\n\tPericardial fluid, surgical site abscess, laparotomy wound\tN/A\tPericardiocentesis, surgical abscess drainage\tRecovery\t\n2012 [9]\t20/M\tSubtotal esophagectomy\tPurulent pericarditis, cardiac tamponade\tLt. Lobe\tActinomyces spp., Fusobacterium spp., Peptostreptococcus spp.\tPericardial fluid, hepatic abscess\tN/A\tPericardiocentesis, percutaneous abscess drainage\tRecovery\t\n2012 [10]\t60/M\tP/H of Pul. TB & alcoholic pancreatitis\tPurulent pericarditis, cardiac tamponade\tRt. & Lt. Lobes\tActinomyces spp.a, K.oxytoca, C. koseri\tPericardial fluid\tTrans-diaphragmatic\tPericardiocentesis, video-assisted thoracic surgery\tRecovery\t\n2010 [11]\t62/F\tHTN, IHD\tPurulent pericarditis, cardiac tamponade\tLt. Lobe\t\nE. coli\n\tPericardial fluid\tTrans-diaphragmatic\tSubxiphoid pericardial window and drainage\tDeath\t\n2008 [12]\t73/M\tA.fib, OA\tPurulent pericarditis, cardiac tamponade\tLt. Lobe\t\nK. pneumoniae\n\tPericardial fluid, hepatic abscess\tTrans-diaphragmatic\tPericardiocentesis, percutaneous abscess drainage\tDeath\t\n2007 [13]\t73/F\tNo\tPurulent pericarditis, cardiac tamponade\tLt. Lobe\t\nE. coli\n\tBlood, pericardial fluid, hepatic abscess\tTrans-diaphragmatic\tPericardiocentesis, percutaneous abscess drainage\tRecovery\t\n2007 [14]\t73/M\tOA on steroid\tPurulent pericarditis, cardiac tamponade\tLat. segment of Lt. lobe\t\nK. pneumoniae\n\tPericardial fluid, hepatic abscess\tTrans-diaphragmatic\tPericardiocentesis, percutaneous abscess drainage\tDeath\t\n65/M\tDM, CKD\tPurulent pericarditis, cardiac tamponade\tLat. segment of Lt. lobe\t\nK. pneumoniae\n\tPericardial fluid, hepatic abscess\tTrans-diaphragmatic\tPericardiocentesis, percutaneous abscess drainage\tRecovery\t\n2006 [15]\tN/A\tN/A\tPurulent pericarditis, cardiac tamponade\tLt. lobe\tProteus spp., Enterococcus spp.\tPericardial fluid\tTrans-diaphragmatic\tPericardiocentesis, thoracotomy, pericardiectomy\tN/A\t\n2002 [16]\t48/F\tNo\tPurulent pericarditis, cardiac tamponade\tLt. lobe\t\nM. morganii\n\tBlood, pericardial fluid, hepatic abscess\tN/A\tPericardiocentesis, thoracotomy, pericardiectomy\tRecovery\t\n1996 [17]\t32/M\tNo\tPurulent pericarditis, cardiac tamponade\tLt. lobe\t\nE. coli\n\tBlood, pericardial fluid\tTrans-diaphragmatic\tPericardiotomy, hepatic abscess drainage\tRecovery\t\nLt., left; Rt., right; Lat., lateral; N/A, not available; P/H, past history; Pul. TB, pulmonary tuberculosis; HTN, hypertension; IHD, ischemic heart disease; A.fib, atrial fibrillation; OA, osteoarthritis; DM, diabetes mellitus; CKD, chronic kidney disease; K. pneumoniae, Klebsella pneumoniae; C. glabrata, Candida glabrata; F. nucleatum, Fusobacterium nucleatum; E. faecalis, Enterococcus faecalis; E. coli, Escherichia coli; K. oxytoca, Klebsiella oxytoca; C. koseri, Citrobacter koseri; M. morganii, Morganella morganii\n\naHepatic Actinomycosis was diagnosed based on the pathological examination of liver abscess\n\n\n\nIn previously reported cases of PLA with pericarditis, patients complained of various symptoms including a fever, abdominal pain, dyspnea, and chest pain [6–17]. Tachycardia and septic shock were usually present. Distention of the jugular veins or an elevated jugular pressure are the most important finding suggestive of a pericardial involvement, due to the development of septic shock, which usually causes the central venous pressure to fall and the jugular veins to collapse. This finding was positive in twelve patients (92.3%) [6, 8–17], and in our case as well. All of these patients developed a cardiac tamponade that can be fatal if left untreated. Therefore, early identification is crucial. However, ECG findings in these cases can vary, including ST segment elevations [6, 7, 17], low voltage in limb leads [12] and ventricular tachycardia [14], or the ECG can be normal [15]. In our case, the ECG showed multiple premature ventricular complexes. An enlarged cardiac silhouette is frequently observed on chest X-rays [6, 11, 14, 16, 17], with or without pleural effusion. On CT imaging of the abdomen or chest, liver abscesses with pericardial effusion are a frequent finding [6, 8–10, 12–15]. Therefore, if patients with liver abscess complain of dyspnea or chest pain and distended jugular veins are noted, a thorough evaluation, including chest CT or transthoracic echocardiography, for pericardial involvement is needed.\n\nIn terms of causative pathogen for PLA associated with pericarditis, K. pneumoniae was identified in four cases (30.7%) [6, 12, 14], E.coli in four cases (30.7%) [8, 11] and Actinomyces spp. [9, 10] in two cases (15.4%). Other responsible pathogens previously reported include M. morganii [16], K. oxytoca [10], C. koseri [10], Candida [6], Enterococcus [8, 15], Fusobacterium [7, 9], Peptostreptococcus [9], and Proteus [15]. Although various pathogens have been described for the cause of PLA, K. pneumoniae is the most common responsible pathogen in Asia [5]. Jun et al. have reported K. pneumoniae as the most commonly isolated organism in the abscess (49.8%), followed by Streptococcus species (3.8%) and E. coli (3.3%). K. pneumoniae was also the most commonly isolated organism in blood (70.2%), followed by E. coli (10.7%) [18]. However, the most common pathogen associated with bacterial pericarditis is not K. pneumonia. In one study involving 933 acute pericarditis patients, 32 patients had bacterial origin, and staphylococci (21.9%) and streptococci (15.6%) were the most common organisms. K. pneumoniae was responsible for only 3.1% of cases [19]. It is very interesting that K. pneumoniae was the most common pathogen for PLA associated with pericarditis including our case.\n\nIt has been reported that K1 strains of K. pneumoniae are associated with PLA complicated by metastatic endophthalmitis or CNS infections [20], and Yu et al. have reported a case of bacterial pericarditis by genotype K1 [21]. Endophthalmitis is the most common metastatic complication of PLA, and the incidence is reported to be 0.84–1.92%. Symptoms of endophthalmitis are visual impairment leading to blindness, or painful eye swelling. Suggested risk factors of endophthalmitis include diabetes mellitus, K1 strains of K. pneumoniae, abscess in the right superior segment, and other systemic infection. Intravitreal antibiotics and early vitrectomy are the mainstay of the treatment, but the prognosis is poor [4].\n\nThe K1 strain has been reported to be highly virulent because of hypermucoviscosity, which is associated with high serum resistance, high-level resistance to phagocytosis, and resistance to complement deposition [20, 21]. Although the genotypic analysis has not been performed in the reported cases, it is possible that highly virulent strains of K. pneumoniae were associated with PLA complicated by pericarditis. Thus, further studies are needed to identify virulent strains that are responsible for PLA associated with pericarditis.\n\nAmong the 12 cases reporting purulent pericarditis as a complication of PLA, pericardial fluid culture was positive in all patients [6, 8, 9, 11–17]. In contrast, the pericardial fluid in our case did not reveal any microorganism. This is probably because early detection and surgical treatment of pericarditis prevented progression to purulent pericarditis. Although PLA was the primary infection focus, only eight cases (61.5%) reported positive cultures of hepatic abscess [7–9, 12–14, 16]. Rates of positive blood cultures were even lower, with only four (30.8%) reported cases [7, 13, 16, 17]. Both hepatic abscess and blood culture results were negative in our case. The negative culture from hepatic abscess may be due to the delay in obtaining the culture (nine days after initial antibiotic treatment) as the initial percutaneous aspiration was not possible. However, the negative blood culture is noteworthy in light of such an overwhelming infection, with positive blood cultures typically reported in 50% of cases of PLA [22].\n\nThe following treatments for PLA-associated pericarditis have been reported: pericardiocentesis in six cases (46.1%) [8, 9, 12–14]; surgical pericardial drainage or pericardiectomy in six cases (46.1%) [6, 10, 11, 15–17], combined with percutaneous abscess drainage in seven cases (53.8%) [7, 9, 12–14, 17]; and surgical abscess resection in two cases (15.4%) [6, 8]. All patients received antibiotic treatments. Three patients (23%) died among the previously reported cases, indicative of the higher mortality rate for PLA-associated pericarditis than the reported mortality rate of 5–10% for PLA alone [23].\n\nIn conclusion, pericarditis is a rare but fatal complication of left lobe liver abscess. Pericarditis should be highly suspected in patients with cardiac symptoms, jugular vein engorgements and enlarged cardiac silhouette on chest X-ray. Early diagnostic evaluation, using chest CT or transthoracic echocardiography, and immediate treatment, including pericardiocentesis or pericardiotomy and abscess drainage, combined with intravenous antibiotics can lower the risk of patient death.\n\nAbbreviations\nALPAlkaline phosphatase\n\nALTAlanine Aminotransferase\n\nASTAspartate Aminotransferase\n\nC. glabrata\nCandida glabrata\n\n\nC. koseri\nCitrobacter koseri\n\n\nCTComputed tomography\n\nE. coli\nEscherichia coli\n\n\nE. faecalis\nEnterococcus faecalis\n\n\nECGElectrocardiogram\n\nF. nucleatum\nFusobacterium nucleatum\n\n\nK. oxytoca\nKlebsiella oxytoca\n\n\nK. pneumonia\nKlebsella pneumoniae\n\n\nLDHLactate dehydrogenase\n\nM. morganii\nMorganella morganii\n\n\nPLAPyogenic liver abscess\n\nr-GTPGamma Glutamyl Transpeptidase\n\nAcknowledgements\nNone.\n\nFunding\nNone.\n\nAvailability of data and materials\nThe data used in the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nEC, SWP designed the study and wrote the manuscript. CHJ participated in the design of the study and the study’s coordination. SSS contributed to the imaging and interpretation. EKP and KSL performed surgical treatment. SYP managed the patient and helped to draft the manuscript. CHP, HSK acquired and analyzed the laboratory and clinical data. SKC, JSR participated in reviewing the literature and editing the initial manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. 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Chemaly RF Hall GS Keys TF Procop GW Microbiology of liver abscesses and the predictive value of abscess gram stain and associated blood cultures Diagn Microbiol Infect Dis 2003 46 4 245 248 10.1016/S0732-8893(03)00088-9 12944014 \n23. Chen SC Huang CC Tsai SJ Yen CH Lin DB Wang PH Chen CC Lee MC Severity of disease as main predictor for mortality in patients with pyogenic liver abscess Am J Surg 2009 198 2 164 172 10.1016/j.amjsurg.2008.08.022 19268905\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "18(1)",
"journal": "BMC infectious diseases",
"keywords": "Empyema; Klebsiella pneumoniae; Liver abscess; Pericarditis",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D002305:Cardiac Tamponade; D004417:Dyspnea; D016724:Empyema, Pleural; D006801:Humans; D046290:Liver Abscess, Pyogenic; D008297:Male; D010493:Pericarditis; D010996:Pleural Effusion; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "40",
"pmc": null,
"pmid": "29334903",
"pubdate": "2018-01-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25561477;21103806;18826824;9636876;19268905;17083988;17577122;12944014;19216945;15551257;25385432;21611623;25770033;24872819;8909923;18344649;22002733;25530149;12380794;26161011;11425062;22293808;17599305",
"title": "A rare case of pericarditis and pleural empyema secondary to transdiaphragmatic extension of pyogenic liver abscess.",
"title_normalized": "a rare case of pericarditis and pleural empyema secondary to transdiaphragmatic extension of pyogenic liver abscess"
} | [
{
"companynumb": "KR-PFIZER INC-2018059377",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
"dr... |
{
"abstract": "BACKGROUND\nIntravenous immunoglobulin therapy, widely used for various autoimmune and systemic inflammatory diseases including Kawasaki disease (KD), is occasionally associated with thromboembolic adverse effects caused by an abrupt increase in blood viscosity. Scarce information is available, however, regarding the effect of single high-dose immunoglobulin therapy for KD on blood viscosity.\n\n\nRESULTS\nEleven boys and 5 girls (mean age: 2.1 years) with acute-phase KD underwent single high-dose immunoglobulin therapy. Plasma viscosity before the treatment was 1.18 centipoises (SD = 0.06), but it significantly rose to 1.34 centipoises (SD = 0.06) (p < 0.001). Multiple regression analysis revealed that, among various factors including hematocrit, plasma concentrations of total protein, immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM), only plasma IgG concentration was included in the model to explain plasma viscosity (R2 = 0.59, p < 0.001).\n\n\nCONCLUSIONS\nSingle high-dose regimen for acute-phase KD increases blood viscosity and therefore might increase the risk of thromboembolism.",
"affiliations": "Department of Paediatrics, Aichi Medical University School of Medicine, Aichi, Japan. babar@aichi-med-u.ac.jp",
"authors": "Baba|Reizo|R|;Shibata|Atsuko|A|;Tsurusawa|Masahito|M|",
"chemical_list": "D007070:Immunoglobulin A; D007075:Immunoglobulin M; D016756:Immunoglobulins, Intravenous",
"country": "Japan",
"delete": false,
"doi": "10.1253/circj.69.962",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-9843",
"issue": "69(8)",
"journal": "Circulation journal : official journal of the Japanese Circulation Society",
"keywords": null,
"medline_ta": "Circ J",
"mesh_terms": "D001809:Blood Viscosity; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D007070:Immunoglobulin A; D007075:Immunoglobulin M; D016756:Immunoglobulins, Intravenous; D007262:Infusions, Intravenous; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome; D012307:Risk Factors; D013923:Thromboembolism",
"nlm_unique_id": "101137683",
"other_id": null,
"pages": "962-4",
"pmc": null,
"pmid": "16041167",
"pubdate": "2005-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Single high-dose intravenous immunoglobulin therapy for kawasaki disease increases plasma viscosity.",
"title_normalized": "single high dose intravenous immunoglobulin therapy for kawasaki disease increases plasma viscosity"
} | [
{
"companynumb": "JP-BEH-2019105769",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": null,
... |
{
"abstract": "Despite a paucity of data, the role of intravenous lidocaine (IVLI) as adjunctive analgesia in the intensive care unit (ICU) seems promising due to a low potential to contribute to respiratory depression. A retrospective chart review was conducted to evaluate the safety and effectiveness of IVLI for the treatment of pain in ICU patients with varying degrees of organ dysfunction from March 2014 to March 2016. The primary outcomes included the time to a ≥20% reduction in pain scores after the initiation of IVLI and the difference in opioid requirements as well as pain scores prior to and during IVLI therapy. Other variables included the presence of IVLI-related adverse events and the dosage and duration of IVLI. A total of 21 ICU patients were included from 2 different hospitals. The mean time to a ≥20% reduction in pain scores from the start of IVLI was 3.3 hours (SD = 2.2). The median morphine dose equivalents required during 6, 12, and 24 hours pre-IVLI were significantly higher compared to the same time periods after IVLI (18.3 vs 10 mg, P = .002; 41.8 vs 18.3 mg, P = .002; 93.5 vs 30.5 mg, P = .037). Neurological adverse effects of lidocaine were noted in 3 patients, but the effects were reversed on IVLI discontinuation. This report suggests that IVLI as an adjunctive agent in the treatment of acute pain may be a potential option in ICU patients who are refractory to opioids or those in whom opioid-induced respiratory depression is a concern.",
"affiliations": "Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA.;Department of Pharmacy Practice, McWhorter School of Pharmacy, Samford University, Birmingham, AL, USA.;North Florida Regional Medical Center, Gainesville, FL, USA.;University of Florida Health Shands Hospital, Gainesville, FL, USA.;Critical Care Unit, Wound & Hyperbaric Oxygen Therapy Center, and Respiratory Care Services, Mercy Medical Center, Springfield, MA, USA.",
"authors": "Mo|Yoonsun|Y|;Thomas|Michael C|MC|;Antigua|Abigail D|AD|;Ebied|Alex M|AM|;Karras|George E|GE|",
"chemical_list": "D000779:Anesthetics, Local; D008012:Lidocaine",
"country": "England",
"delete": false,
"doi": "10.1002/jcph.874",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-2700",
"issue": "57(7)",
"journal": "Journal of clinical pharmacology",
"keywords": "intensive care unit; intravenous lidocaine; opioids; pain; surgery",
"medline_ta": "J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000698:Analgesia; D000779:Anesthetics, Local; D004333:Drug Administration Routes; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008012:Lidocaine; D008297:Male; D008875:Middle Aged; D010146:Pain; D012189:Retrospective Studies",
"nlm_unique_id": "0366372",
"other_id": null,
"pages": "830-836",
"pmc": null,
"pmid": "28168730",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "26342631;8857633;941829;26913591;22699129;10320260;17197840;7073919;21061107;17592992;12401580;8547556;21343159;17214917;9459225;21149228;18844267;4609637;10969322;17667496;15330376;26184397;19231397",
"title": "Continuous Lidocaine Infusion as Adjunctive Analgesia in Intensive Care Unit Patients.",
"title_normalized": "continuous lidocaine infusion as adjunctive analgesia in intensive care unit patients"
} | [
{
"companynumb": "US-MYLANLABS-2017M1048071",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": "1",
... |
{
"abstract": "Severe Hypertriglyceridemia (HTG) is associated with complications such as acute pancreatitis (AP) with high morbidity and mortality rates. We report a 42 years-old man with refractory HTG diagnosed at 19 years of age, and multiple episodes of AP, admitted with the suspicion of a new AP episode. Serum triglycerides were over 2000 mg/dl. His body mass index was 18 kg/m2, there was no evidence of xanthomas or xanthelasmas, but lipemia retinalis was found. Management included heparin and insulin, added to his usual treatment with fibrates, statins, omega-3 fatty acids, and orlistat. Due to lack of response, apheresis was started. After five sessions, triglycerides decreased to 588 mg/dl (82% reduction) and levels remained below 1000 mg/dl with daily apheresis. The patient continued with weekly sessions as outpatient with a sustained good response.",
"affiliations": "Hospital San Pablo, Coquimbo, Chile.;Hospital San Pablo, Coquimbo, Chile.;Unidad de Tratamiento Intermedio, Hospital San Pablo, Coquimbo, Chile.",
"authors": "Jure B|Camila|C|;Sapiain P|Lucy|L|;González F|Susana|S|",
"chemical_list": "D014280:Triglycerides",
"country": "Chile",
"delete": false,
"doi": "10.4067/S0034-98872020000901362",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0034-9887",
"issue": "148(9)",
"journal": "Revista medica de Chile",
"keywords": null,
"medline_ta": "Rev Med Chil",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D001781:Blood Component Removal; D006801:Humans; D006949:Hyperlipidemias; D015228:Hypertriglyceridemia; D008297:Male; D010195:Pancreatitis; D014280:Triglycerides",
"nlm_unique_id": "0404312",
"other_id": null,
"pages": "1362-1367",
"pmc": null,
"pmid": "33399714",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Refractory severe hypertriglyceridemia treated with apheresis. Report of one case.",
"title_normalized": "refractory severe hypertriglyceridemia treated with apheresis report of one case"
} | [
{
"companynumb": "CL-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-286200",
"fulfillexpeditecriteria": "1",
"occurcountry": "CL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENOFIBRATE"
},
"dru... |
{
"abstract": "The LiverTox database compiles cases of idiosyncratic drug-induced liver injury (iDILI) with the promised aims to help identify hepatotoxicants and provide evidence-based information on iDILI. Weaknesses of this approach include case selection merely based on published case number and not on a strong causality assessment method such as the Roussel Uclaf Causality Assessment Method (RUCAM). The aim of this analysis was to find out whether the promised aims have been achieved by comparison of current iDILI case data with those promised in 2012 in LiverTox. First, the LiverTox criteria of likelihood categories applied to iDILI cases were analyzed regarding robustness. Second, the quality was analyzed in LiverTox cases caused by 46 selected drugs implicated in iDILI. LiverTox included iDILI cases of insufficient quality because most promised details were not fulfilled: (1) Standard liver injury definition; (2) incomplete narratives or inaccurate for alternative causes; and (3) not a single case was assessed for causality with RUCAM, as promised. Instead, causality was arbitrarily judged on the iDILI case number presented in published reports with the same drug. All of these issues characterize the paradox of LiverTox, requiring changes in the method to improve data quality and database reliability. In conclusion, establishing LiverTox is recognized as a valuable effort, but the paradox due to weaknesses between promised data quality and actual data must be settled by substantial improvements, including, for instance, clear definition and identification of iDILI cases after evaluation with RUCAM to establish a robust causality grading.",
"affiliations": "Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany.;Pharmacovigilance Consultancy, F-75020 Paris, France.",
"authors": "Teschke|Rolf|R|0000-0001-8910-1200;Danan|Gaby|G|0000-0001-7580-1505",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/diagnostics11101754",
"fulltext": "\n==== Front\nDiagnostics (Basel)\nDiagnostics (Basel)\ndiagnostics\nDiagnostics\n2075-4418\nMDPI\n\n10.3390/diagnostics11101754\ndiagnostics-11-01754\nArticle\nThe LiverTox Paradox-Gaps between Promised Data and Reality Check\nhttps://orcid.org/0000-0001-8910-1200\nTeschke Rolf 12*\nhttps://orcid.org/0000-0001-7580-1505\nDanan Gaby 3\nTsipouras Markos G. Academic Editor\n1 Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany\n2 Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, D-60590 Frankfurt/Main, Germany\n3 Pharmacovigilance Consultancy, F-75020 Paris, France; gaby.danan@gmail.com\n* Correspondence: rolf.teschke@gmx.de\n24 9 2021\n10 2021\n11 10 175421 5 2021\n16 9 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nThe LiverTox database compiles cases of idiosyncratic drug-induced liver injury (iDILI) with the promised aims to help identify hepatotoxicants and provide evidence-based information on iDILI. Weaknesses of this approach include case selection merely based on published case number and not on a strong causality assessment method such as the Roussel Uclaf Causality Assessment Method (RUCAM). The aim of this analysis was to find out whether the promised aims have been achieved by comparison of current iDILI case data with those promised in 2012 in LiverTox. First, the LiverTox criteria of likelihood categories applied to iDILI cases were analyzed regarding robustness. Second, the quality was analyzed in LiverTox cases caused by 46 selected drugs implicated in iDILI. LiverTox included iDILI cases of insufficient quality because most promised details were not fulfilled: (1) Standard liver injury definition; (2) incomplete narratives or inaccurate for alternative causes; and (3) not a single case was assessed for causality with RUCAM, as promised. Instead, causality was arbitrarily judged on the iDILI case number presented in published reports with the same drug. All of these issues characterize the paradox of LiverTox, requiring changes in the method to improve data quality and database reliability. In conclusion, establishing LiverTox is recognized as a valuable effort, but the paradox due to weaknesses between promised data quality and actual data must be settled by substantial improvements, including, for instance, clear definition and identification of iDILI cases after evaluation with RUCAM to establish a robust causality grading.\n\niDILI\nidiosyncratic drug-induced liver injury\nRoussel Uclaf Causality Assessment Method (RUCAM)\nDILI database case quality\nLiverTox\n==== Body\npmc1. Introduction\n\nThe U.S. LiverTox database and website containing preferentially idiosyncratic drug-induced liver injury (iDILI) cases became available online in April 2012 and was published in March 2013 [1]. This new approach was much appreciated due to the promising intention to provide not only accurate but also complete summary information on the characteristics of clinical liver injury for each drug, along with an exhaustive and annotated reference compilation. Expectations were high because the website was created by the U.S. National Library of Medicine (NLM) and annotated by the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) staff [1]. The initial website version was then replaced by a new version [2]. The data of iDILI cases were said to be collected from various sources, including clinicians submitting case reports [1]. The website of LiverTox consecutively produced a computer-generated history, associated with a table of laboratory data, and a graphic display of clinical details, which included calculations of latency, time to recovery, severity, and causal relationship by applying the scores of RUCAM (Roussel Uclaf Causality Assessment Method), with various steps, thus ensuring data completeness and high-quality data [1]. Additional details were provided and seemed overall promising. As a result, expectations among iDILI experts were high for using the database cases as reference cases for clinical and study purposes. However, expectations were only partially met due to problems such as those related to causality assessment, acknowledged by one of the initiators of the LiverTox database and website [3]. The critical view was in line with views of other groups criticizing shortcomings of the LiverTox initiative [3,4,5,6,7,8,9,10]. It seemed that a gap emerged between the promise to provide valid case data of high quality and the presented case data. Most cases are of insufficient quality, especially in terms of a minimum information and a lack evaluation of a causal relationship by applying a strong method such as the RUCAM, a real paradox with a clinical and research impact requiring additional evaluation.\n\nThe present report analyzed the data quality of selected iDILI cases included in the LiverTox database. It turns out that in a significant number of cases, the presented data are not of sufficient quality to be used in a clinical or research setting. Suggestions of improvement are made, enforcing the application of a strong causality assessment method (CAM) such as the RUCAM in retained cases, whatever the data source.\n\n2. Materials and Methods\n\nA comparison was made between data currently included in the LiverTox database and on its website [2] and the aims or promises provided at LiverTox implementation [1]. First, the LiverTox criteria of likelihood categories applied to iDILI cases were analyzed regarding causality assessment. Second, the data quality was analyzed in iDILI cases selected from LiverTox, which presents on its website all drugs implicated in iDILI as blocks in alphabetic order from A to Z [2]. From each alphabetical block, the first listed single drug was selected for analysis, excluding groups of several drugs or nondrug products such as herbs. This led to 23 drugs from Abacavir to Zafirlukast implicated in iDILI cases. In addition, and to be on the safe side, a second list of 23 drugs from each alphabetical drug block was analyzed. Finally, in order to provide for LiverTox appropriate proposals to improve the data quality of iDILI cases, additional reports were sought to broaden the discussion, starting with a few reports [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25].\n\n3. Results\n\n3.1. LiverTox Criteria of Likelihood Category\n\nIn the LiverTox database, the causality grading is described in seven likelihood categories applied to iDILI cases [3,4]. In other sections of the database, these likelihood categories are termed likelihood “scores,” an inappropriate expression that should no longer be used [2]. Indeed, scores are usually achieved by adding individual scores attributed to specific items in the frame of an algorithm, which is preferentially adherent to Artificial Intelligence (AI) principles [11], conditions that do not apply to LiverTox [1,2,3,4]. Apart from the scoring issue, another problem is the inaccurate definition of the causality categories (Table 1).\n\nContrary to the promised application of RUCAM to assess the causality of iDILI cases in LiverTox as proposed in 2013 [1], this was not carried out for unknown reasons [2]. Early support for RUCAM was provided in 2011 by an expert group of scientists from various countries, including the U.S., stating that the causality of iDILI cases should be assessed with RUCAM [12], considering that approximately half of the cases were misdiagnosed [13,14]. Subsequently, the utility of RUCAM was confirmed in 2020 by an expert review on selected highlights of iDILI, and it was outlined that only iDILI cases assessed with RUCAM should be discussed [9]. In the same year, the RUCAM publications of 1993 by their founding authors [15,16] was one of the topics discussed in a scientometric study focusing on the worldwide knowledge mapping of liver injury caused by drugs, as outlined in a publication by Chinese experts [17].\n\nRather than applying RUCAM as promised in 2013 [1], LiverTox used another approach to assess causality [3,4], not involving RUCAM, as confirmed in 2021 [18], but arbitrarily classifying the iDILI cases of the LiverTox website into seven categories of likelihood, whereby the inclusion criterion was the number of reports retrieved from published studies (Table 1) [2,3,4]. In other words, with an increasing number of published reports, the causality grading of iDILI cases moved to higher causality levels [3,4]. This approach of causality assessment has never been validated and could lead to mistakes and clinical errors. Under these evaluating conditions, among 671 drugs, only 53% were classified as likely causing iDILI, considering the reports in the literature, while 47% were just based on an expert opinion lacking supportive evidence in the literature by previous reports [3,4], as critically discussed [6]. It was also outlined that although in LiverTox a thorough literature search had been approached, it was not attempted to assess the quality of the published reports or to evaluate the causality of liver injury [3]. Other analyses of the iDILI cases of the database found that approximately one half of drugs reviewed met the criteria for causing, or being suspected as causing, iDILI [6,9]. No efforts had been made to improve case data quality [18]. Overall, it seems that quality aspects remain a crucial issue of LiverTox.\n\nCritical situations emerged when studies used iDILI cases retrieved from the LiverTox database, which may call the study results into question. For instance, an association between iDILI and daily dose, liver metabolism, and lipophilicity has been suggested, but proposals were based not on own valid iDILI cases rather than on cases uncritically retrieved from a variety of drug and DILI databases, including LiverTox [19,20,21]. Such an approach was critically discussed [22] in support of the statement that the proposed drug characteristics are not able to predict iDILI with high confidence, associated by a caveat note [23]. It is obvious that this controversy around risk factors of iDILI is fairly limited to FDA scientists [19,20,21,22,23], an interesting constellation calling for internal solutions [8,10,22].\n\nLong before LiverTox was presented to the scientific community [1], national iDILI registries from Spain [24] and Sweden [25] successfully used RUCAM [15,16] for their cases, viewed as pioneering work and early trust in RUCAM [7]. As a sign of appreciation, experts discussed only RUCAM-based iDILI and HILI (herb-induced liver injury) cases, rather than cases of the LiverTox database, which were not assessed with RUCAM [9]. It appears that LiverTox is still far behind mainstream approaches, causing concern about data quality [1,2,8,10,18].\n\n3.2. Quality Assessment of Selected iDILI Cases\n\nSeveral hundred iDILI cases are included on the LiverTox website, but the exact number remains unknown because liver injury cases by nondrugs such as herbs, herbal traditional medicines, common herbal products, and so called dietary supplements are also listed [1,2,3,4,10]. LiverTox data quality was evaluated only in a portion of these iDILI cases [1,2,3,4,5,18]. In the first list, 23 drugs implicated in iDILI cases of LiverTox were available for this analysis (Table 2).\n\nFor each drug, the LiverTox based likelihood categories from A to E were added (Table 2), as retrieved from the website (Table 1) [2]. Where available, additional data were derived from the website for each listed drug and added to the drug, associated with a commentary if applicable (Table 2). No case details were provided for 13/23 (56.5%) drugs implicated in iDILI, and a commentary was, therefore, not possible for these 13 cases (Table 2). In 4/13 cases lacking details, a “probable” likelihood was attributed based on more than 50 published case reports for these drugs (Table 2). Similar insufficient data were obtained for the second list, consisting again of 23 drugs implicated in iDILI (data not shown). Among 10/23 (43.5%) iDILI cases of the first list, incomplete data were presented, not allowing for a case evaluation (Table 2). Overall, in association with insufficient approaches of causality assessment (Table 1), this compilation confirms poor data quality (Table 2).\n\nPublished first in 2005, selected registries reported iDILI cases commonly with a causality grading of “probable” or “highly probable” following assessment with RUCAM that allows for correct case features description [10,24,25]. On the contrary, since 2013 LiverTox has included 60.9% of selected cases with a causality grading of possible or lower, and only 39.1% of the cases can be found in the category of “highly probable,” “highly likely,” or “probable” causality categories (Table 3) [2], calling for a modified approach.\n\nAs compared to LiverTox, iDILI cases of a better quality are available from a large worldwide study on 81,856 published iDILI cases, all assessed with RUCAM [26], either in the original version [15,16] or the updated version published 2016 [27], which should now preferentially be used [28,29]. It is suggested that the scientists involved in LiverTox maintenance are encouraged to search for RUCAM-based iDILI cases to be included in LiverTox.\n\n3.3. LiverTox Paradox Based on Gaps\n\nThere was much hope among members of the iDILI community when LiverTox entered the challenging field of including valid iDILI cases in a new database and on a website [1,2]. Soon, however, it became evident that the applied CAM based on an expert opinion process and the quality of the cases did not meet the expectations (Table 1, Table 2 and Table 3) [2,3,4,5,6,7,8,9,10]. As a result, the gaps created a paradox: The promise of providing valid case data versus presenting cases of insufficient quality. The identified gaps relate to the completeness and accuracy of the case details, evidence-based features, and causality assessment (Table 4).\n\n3.4. Suggestions for Improvement\n\nSince the time of LiverTox implementation, a variety of suggestions have been made to ensure some degree of high quality of the iDILI cases to be included [1]. However, the diagnostic causality approach and data presentation of LiverTox remain outside of mainstream opinion (Table 1 and Table 2). These approaches are not acceptable because they are subjective, not transparent, not structured, not based on strict working procedures leading to variable results, not excluding alternative causes, not validated, and not based on an element scoring allowing for a final causality grading. The results, as presented by LiverTox, are disappointing (Table 1, Table 2, Table 3 and Table 4) and have become a matter of debate [2,3,4,5,6,7,8,9,10]. A new approach is now required to improve the quality of the LiverTox database. To achieve this, some proposals are made (Table 5).\n\n3.5. Use of RUCAM\n\nLiverTox authors should now get started on using RUCAM prospectively for iDILI cases, in line with the promise in 2013 [1] and according to the proposal of extending our knowledge by increasing population analysis with prospective causality evaluation using a scoring approach [30]. RUCAM is appreciated throughout the world [6,7,8,9,12,17,24,25,26,27,31,32] as a structured, transparent, user friendly, objective, and quantitative diagnostic algorithm [27] according to AI recommendations [11]. In addition, RUCAM is conceptualized as a diagnostic method specific for hepatic injury caused by drugs and herbs [27] and rarely needs expert assistance, except perhaps in special populations such as those with hepatitis [33]. As an overview, some specifics of RUCAM are provided in a condensed form (Table 6).\n\nCausality assessment with RUCAM used by an independent team of experts was reproducible within clinical acceptable limits [15,16]. In addition, validation of RUCAM was achieved with cases considering, among other features, a positive test of rechallenge [16]. No validation method was used by authors of any other CAM [34]. The authors of LiverTox should also benefit from the experience of an independent group not involved in any CAM creation, which reported a low variability of intra-observer features without disagreement in the evaluation of iDILI cases when using RUCAM [25].\n\nRUCAM characteristics are at variance with those of other CAMs that are not specifically prepared to evaluate injury of the liver [34], are devoid of element specification, or lack a scoring system [35]. As a result, most of them are not appropriate for application to causality assessment in liver injury cases because they are not liver-specific, are subjective rather than objective as based on variables, are often divergent in terms of the opinions of the assessing scientists of physicians, are not validated with a gold standard such as a positive test of unintentional re-exposure, and finally do not present reproducibility of causality levels derived from scored key elements [27,34]. Known from other well-established methods in medicine, background noise is not unexpected to be provided preferentially by peers, who have never published before a validated diagnostic algorithm of iDILI suitable for worldwide application. In this context, several unsuccessful attempts by authors to add, modify, or delete key elements or to upgrade or downgrade scores were frustrating in the past. Overall, these less-convincing approaches reduced the user-friendly handling of the method, making RUCAM application more complicated without chances of validation. Not unexpected, the data were not published. A discussion is warranted with respect to the diagnostic biomarkers outlined in several critical publications [8,9,36]. They are commonly not based on iDILI cases assessed for causality with RUCAM [36], most of them lost support by the EMA (European Medicines Agency) and the U.S. FDA due to misconducted research as detailed elsewhere [9], and they certainly cannot replace RUCAM [8].\n\n4. Discussion\n\nAround one dozen iDILI databases are publicly available with features and limitations well described, whereby the LiverTox database ranks among the major ones and needs to be further improved [5]. In this context, it has been argued that the interface of LiverTox does not allow for an intuitive approach, impairing for users access to data, and the search request form was found to be limited. Despite these minor shortcomings, there have been many more discussions about the data quality of cases included in the LiverTox database [4,5,6,7,8,9,10]. Currently, there are criteria problems of causality attribution by not using a robust CAM such as RUCAM, as promised (Table 1), and insufficient quality of iDILI cases (Table 2), not allowing for appropriate use of included cases by physicians. Difficult to reconcile is the gap between the initially promised excellence of case data quality and the finally presented quality (Table 4). Despite some shortcomings, case quality is much better in national DILI registries using the prospective RUCAM, with a few exemptions [10]. This suggests their inclusion in the LiverTox database.\n\nThis analysis may have some limitations; for example, only 52 drugs were randomly included. As with any well-working method in medicine, some background noise is expected for various reasons, especially from scientists, who have never established a robust algorithm such as RUCAM. In this context, several unsuccessful attempts by others to add, modify, or delete elements or to upgrade or downgrade scores were frustrating, reducing the user-friendly handling of the method, making the method more complex and not validated. The data were, as expected, not published. In fact, and as in real-life situations, a well running method such as RUCAM should not be changed unless major improvements are expected. If a robust diagnostic biomarker emerges, derived from RUCAM-based DILI and HILI cases, its inclusion in RUCAM is not recommended unless a full and new validation process is carried out. Rather, it should be used in parallel to the updated RUCAM. Finally, causality assessment based on expert opinion is not recommended for various reasons and remains debated due to major shortcomings [27,34,35], a view supported by the above analysis on LiverTox cases.\n\n5. Conclusions\n\nAmong the various iDILI databases or websites, the implementation of the U.S. LiverTox database in 2013 was highly appreciated as a new data source of drugs causing iDILI. However, its use by clinicians can be limited by problems of data quality, including missing detailed narratives and evidence-based case features, a lack of standard definitions such as liver injury, and the failure in all cases to use a strong method for evaluating causality such as RUCAM, although use of this method was initially promised by LiverTox. As it presently stands, there are major gaps between the promised details and the provided facts, as shown in this analysis. These gaps were unexpected and considered as a paradox, calling now for improvements. In essence, LiverTox will gain appreciation if iDILI cases of better quality are included. Courage is now required.\n\nAuthor Contributions\n\nR.T. wrote the first draft, which was edited by G.D., who also contributed substantial improvements to the text and tables. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThere was no funding for this manuscript.\n\nData Availability Statement\n\nData supporting the results of the analysis can be retrived from the following sources: LiverTox. Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. LiverTox Database. Updated: 9 February 2021. Available at: https://www.ncbi.nlm.nih.gov/books/NBK547852/ accessed on 19 May 2021; Hoofnagle JH. Relaunched LiverTox remains important resource to diagnosis DILI. Available at: https://www.aasldnews.org/relaunched-livertox-remains-important-resource-to-diagnosis-dili/ accessed on 19 May 2021.\n\nConflicts of Interest\n\nThe authors declare that they have no conflict of interest regarding this report.\n\nAbbreviations\n\nAI\tArtificial Intelligence\t\nALF\tAcute liver failure\t\nALP\tAlkaline phosphatase\t\nALT\tAlanine aminotransferase\t\nCAM\tCausality assessment method\t\nCMV\tCytomegalovirus\t\nEBV\tEpstein–Barr virus\t\nEMA\tEuropean Medicines Agency\t\nFDA\tFood and Drug Administration\t\nHAV\tHepatitis A virus\t\nHBV\tHepatitis B virus\t\nHCV\tHepatitis C virus\t\nHEV\tHepatitis E virus\t\nHILI\tHerb-induced liver injury\t\nHSV\tHerpes simplex virus\t\niDILI\tIdiosyncratic drug-induced liver injury\t\nNIDDK\tNational Institute of Diabetes and Digestive and Kidney Diseases\t\nNLM\tNational Library of Medicine\t\nRUCAM\tRoussel Uclaf Causality Assessment Method\t\nULN\tUpper limit of normal\t\nVZV\tVaricella zoster virus\t\n\ndiagnostics-11-01754-t001_Table 1 Table 1 Categories of the likelihood of iDILI in LiverTox.\n\nLiverTox Likelihood Categories of iDILI Cases\tCriteria of Likelihood Categories Applied to iDILI Cases Included in the LiverTox Database\t\nCategory A: Highly probable\tThe drug is well known, well described, and well reported to cause either direct or idiosyncratic liver injury, and has a characteristic signature; more than 50 cases, including case series, have been described.\t\nCategory B: Highly likely\tThe drug is reported and known or highly likely to cause idiosyncratic liver injury and has a characteristic signature; between 12 and 50 cases, including small case series, have been described.\t\nCategory C: Probable\tThe drug is probably linked to idiosyncratic liver injury, but has been reported uncommonly and no characteristic signature has been identified; the number of identified cases is less than 12 without significant case series.\t\nCategory D: Possible\tSingle case reports have appeared, implicating the drug, but fewer than three cases have been reported in the literature, no characteristic signature has been identified, and the case reports may not have been very convincing; thus, the agent can only be said to be a possible hepatotoxin and only a rare cause of liver injury.\t\nCategory E: Unlikely\tDespite extensive use, no evidence that the drug has caused liver injury. Single case reports may have been published, but they were largely unconvincing. The agent is not believed or is unlikely to cause liver injury.\t\nCategory E: Unproven\tThe drug is suspected to be capable of causing liver injury or idiosyncratic acute liver injury, but there have been no convincing cases in the medical literature. In some situations, cases of acute liver injury have been reported to regulatory agencies or mentioned in large clinical studies of the drug, but the specifics and details supportive of causality assessment are not available. The agent is unproven but suspected to cause liver injury.\t\nCategory X: Not assessed\tFinally, for medications recently introduced into or rarely used in clinical medicine, there may be inadequate information on the risks of developing liver injury to place it in any of the five categories, and the category is characterized as “unknown.”\t\nListed causality gradings were arbitrary and taken word-by-word from previous publications [2,3,4]. Abbreviations: iDILI, idiosyncratic drug-induced liver injury.\n\ndiagnostics-11-01754-t002_Table 2 Table 2 Selected reports with questionable causality assessed by LiverTox.\n\nDrug\tLiverTox Category\nof Case Likelihood\tLiverTox iDILI Case Details, Confounding Variables,\nAlternative Causes and Comments\t\nAbacavir\tCategory C: Probable\tHEV, HSV, and VZV infections were not excluded.\nComedication with nevirapine, lamivudine, lopinavir.\nCommentary: Consider better as alternative causes:\nHEV, HSV, VZV infection, or comedication.\t\nBaclofen\tCategory D: Possible\tNo details of a specific case provided. No commentary.\t\nCabazitaxel\tCategory E: Unproven\tNo details of a specific case provided. No commentary.\t\nDabigatran\tCategory E: Unproven\tNo details of a specific case provided. No commentary.\t\nEculizumab\tCategory D: Possible\tA specific case presented without details of exclusion of\nalternative causes. Small case series without details\nprovided. No commentary.\t\nFamciclovir\tCategory E: Unlikely\tNo details of a specific case provided. No commentary.\t\nGabapentin\tCategory C: Probable\tNo details of a specific case provided. No commentary.\t\nHaloperidol\tCategory B: Highly likely\tNo details of a specific case provided. No commentary.\t\nIbalizumab\tCategory E: Unlikely\tNo details of a specific case provided. No commentary.\t\nKetamine\tCategory B: Highly likely\tSingle case, no acute DILI because ketamine was inhaled\nfor 9 months. Tests for HAV, HBV, and HCV were\nunremarkable, as were those for autoantibodies and Wilson\ndisease. Liver histology was suggestive of primary\nsclerosing cholangitis (PSC). Commentary: Rather than\nacute iDILI, PSC is the most likely diagnosis.\t\nLabetalol\tCategory C: Probable\tSingle case presented with lethal outcome. Patient was\nnegative for hepatitis A and B. No diagnosis was made, and\nthe patient again received at two different occasions\nof labetalol, leading to lethal ALF. Commentary: Differential\ndiagnosis of ALF poorly assessed.\t\nMacitentan\tCategory E: Unlikely\tNo details of a specific case provided. No commentary.\t\nNabilone\tCategory E: NA\tNo details of a specific case provided. No commentary.\t\nObeticholic acid\tCategory B: Highly likely\tSingle case of a patient with PSC lacking exclusion of\nalternative causes. Commentary: Case is best seen as\nexacerbation of PSC rather than as acute iDILI.\t\nPaclitaxel\tCategory D: Possible\tSingle case of a severely ill patient, with previous pelvic\nradiation and now carboplatin comedication, who experienced a\nsevere hypersensitivity reaction and increased liver tests\nwithout assessing alternative causes. Commentary: Poorly documented case of unclear iDILI.\t\nQuazepam\tCategory E: Unlikely\tNo details of a specific case provided. No commentary.\t\nRabeprazole\tCategory D: Possible\tNo details of a specific case provided. No commentary.\t\nSafinamide\tCategory E: Unlikely\tNo details of a specific case provided. No commentary.\t\nTacrine\tCategory A: Highly probable\tSingle case presented, vague exclusion of alternative\ncauses. Commentary: Poorly documented case.\t\nUrsodiol\tCategory D: Possible\tNo details of a specific case provided. No commentary.\t\nValacyclovir\tCategory D: Possible\tSingle case presented of a patient with shingles; tests for\nhepatitis A, B, and C were negative, as were autoantibodies. Comedication with acetaminophen. Specific note: The\npossibility of varicella zoster-induced hepatitis should also\nbe considered. Commentary: Increased values of ALT and\nALP are best explained by the liver involvement of\nvaricella zoster virus infection and not by iDILI.\t\nWarfarin\tCategory C: Probable\tNo details of a specific case provided. No commentary.\t\nZafirlukast\tCategory C: Probable\tCase 1: Patient was described as having no risk factors for\nviral hepatitis. Test for hepatitis A, B, and C were negative,\nas were autoantibodies, and other parameters to exclude\nalternative causes were not presented. Commentary:\nInsufficiently documented case, not allowing for a valid\ndiagnosis.Case 2: Patient was reported as having no history of\nexposure to viral hepatitis, but details of hepatitis exclusion\nwere not provided. Positive results of unintentional\nreexposure were described without presenting applied\ncriteria. Commentary: Poorly documented case.\t\nListed details were retrieved from an earlier publication [2]. Abbreviations: ALF, acute liver failure; ALP, alkaline phosphatase; ALT, alanine aminotransferase; iDILI, idiosyncratic drug-induced liver injury; NA, not available; PSC, primary sclerosing cholangitis.\n\ndiagnostics-11-01754-t003_Table 3 Table 3 Distribution of causality gradings among the selected iDILI cases of the LiverTox database.\n\nCausality Grading\tiDILI Cases (n)\tiDILI Cases (%)\t\nHighly probable\t1\t4.4\t\nHighly likely\t3\t13.0\t\nProbable\t5\t21.7\t\nPossible\t6\t26.1\t\nUnlikely\t5\t21.7\t\nUnproven\t2\t8.7\t\nNot assessed\t1\t4.4\t\nData were collected from Table 2. Abbreviations: iDILI, idiosyncratic drug-induced liver injury.\n\ndiagnostics-11-01754-t004_Table 4 Table 4 LiverTox paradox: Promised data versus presented data.\n\nPromised Data\tPresented Data and Gaps\t\nCases of iDILI with RUCAM scores [1].\tEvidence is missing that RUCAM was ever used in any iDILI case included in the LiverTox database or presented on the website [2].\t\nA complete and accurate summary of information about the clinical features of liver injury for each drug [1].\tClinical summaries were incomplete due to a lack of a diagnostic algorithm such as RUCAM to assess causality [2]. Instead, causality gradings were arbitrarily published considering the number of published case reports.\t\nA website with comprehensive and evidence-based detailed information on iDILI cases [1].\tInformation was incomplete and not evidence-based, because the causality was not assessed with a robust method such as RUCAM [2] that would have assessed the exclusion of alternative causes.\t\nA separate section on detailed information about formal CAMs such as RUCAM [1].\tThe section is not up to date. References are, for instance, to 2 reports of RUCAM in 1993 [15,16] and not actualized in 2016 [2] with the updated version [27], followed by additional information [28,29].\t\nProviding standardized definitions of terms used [1].\tStandard criteria of liver injury such as ALT higher than 5 × ULN and/or ALP higher than 2 × ULN [12,27] are not presented [2].\t\nDetails were derived from a published report [1], the LiverTox website [2], and Table 2. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; CAMs, causality assessment methods; iDILI, idiosyncratic drug-induced liver injury; RUCAM, Roussel Uclaf Causality Assessment Method.\n\ndiagnostics-11-01754-t005_Table 5 Table 5 Proposals to improve the data quality in LiverTox.\n\nProposals\t\n1. Clinicians, as potential authors of RUCAM-based iDILI case reports, should be encouraged to submit their case reports directly to LiverTox.\n2. Additional RUCAM-based iDILI cases should be retrieved from existing iDILI registries of various countries or regions [10], including, for example, Sweden [25], Iceland [30], Spain [24], and Latin America [31], all of which collect iDILI cases using a prospective approach.\n3. Other RUCAM-based iDILI cases should be selected from the 81,856 cases published from 1993 to mid-2020 [26].\n4. From now on, the prerequisites for iDILI cases to be included in the LiverTox database and website should be:\n● Liver injury must be defined as ALT higher than 5 × ULN (upper limit of normal) and/or ALP higher than 2 × ULN [12,27];\n● An informative case narrative with complete diagnostic and clinical details [27];\n● The R ratio must be calculated based on ALT and ALP values in order to classify the case as hepatocellular injury or cholestatic/mixed liver injury [27];\n● The case should be assessed with the updated RUCAM [27], and the final score should be provided.\t\nAbbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; iDILI, idiosyncratic drug-induced liver injury; RUCAM, Roussel Uclaf Causality Assessment Method; ULN, upper limit of normal.\n\ndiagnostics-11-01754-t006_Table 6 Table 6 Ranges of scores for individual RUCAM elements in iDILI cases of hepatocellular injury or the cholestatic/mixed liver injury.\n\nElements Assessed by RUCAM\tScores of RUCAM for Hepatocellular\nInjury\tScores of RUCAM for the Cholestatic/\nMixed Liver Injury\t\n● Time frame of latency period\tFrom +1 to +2\tFrom +1 to +2\t\n● Time frame of dechallenge\tFrom −2 to +3\tFrom 0 to +2\t\n● Recurrent ALT increase\t−2\t-\t\n● Recurrent ALP increase\t-\t0\t\n● Risk factors\t0 or +1\t0 or +1\t\n● Individual comedication\tFrom −3 to 0\tFrom −3 to 0\t\n● Search for individual alternative causes\tFrom −3 to +2\tFrom −3 to +2\t\n● Verified exclusion of alternative causes\tRequires individual scoring\t\n● Markers of HAV, HBV, HCV, and HEV\t\n● Markers of CMV, EBV, HSV, and VZV\t\n● Evaluation of cardiac hepatopathy\t\n● Liver and biliary tract imaging\t\n● Doppler sonography of liver vessels\t\n● Prior known hepatotoxicity\tFrom 0 to +2\tFrom 0 to +2\t\n● Unintentional reexposure\tFrom −2 to +3\tFrom −2 to +3\t\nPresented in condensed form, the above listed details were retrieved from an earlier publication on the updated RUCAM to be used for causality evaluation [27]. Additional information of each criterion and score is given in the RUCAM worksheet [28]. Total score and resulting causality grading: ≤0, excluded; 1–2, unlikely; 3–5, possible; 6–8, probable; ≥9, highly probable. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; CMV, cytomegalovirus; EBV, Epstein–Barr virus; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HEV, hepatitis E virus; HSV, herpes simplex virus; RUCAM, Roussel Uclaf Causality Assessment Method; VZV, varicella zoster virus.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Hoofnagle J.H. Serrano J. Knoben J.E. Navarro V.J. LiverTox: A website on drug-induced liver injury Hepatology 2012 57 873 874 10.1002/hep.26175\n2. LiverTox Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases, 2012. 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"fulltext_license": "CC BY",
"issn_linking": "2075-4418",
"issue": "11(10)",
"journal": "Diagnostics (Basel, Switzerland)",
"keywords": "DILI database case quality; LiverTox; Roussel Uclaf Causality Assessment Method (RUCAM); iDILI; idiosyncratic drug-induced liver injury",
"medline_ta": "Diagnostics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101658402",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34679453",
"pubdate": "2021-09-24",
"publication_types": "D016428:Journal Article",
"references": "8229110;26861310;33800917;23258593;26517184;32581801;28772086;21544079;33003400;25921378;29502198;25352328;33810530;23419359;26861284;31417407;28717830;30354694;31920666;22710943;16083708;8229111;16025496;10591713;29323538;23456678;26712744;26220713;24464804;10205214;28640208",
"title": "The LiverTox Paradox-Gaps between Promised Data and Reality Check.",
"title_normalized": "the livertox paradox gaps between promised data and reality check"
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"abstract": "Quetiapine is a medication approved for the treatment of psychotic disorders in adults. At this time it is not approved for the treatment of children or adolescents. It is an atypical antipsychotic agent that is efficacious in treating both the positive and negative symptoms of schizophrenia. There is currently little information available concerning the safety of quetiapine in overdose, and there are no previous case reports of quetiapine overdose in the pediatric population. We present the case of a 15-year-old girl who ingested 1250 mg of quetiapine (21.6 mg/kg) in a suicide attempt. She developed multiple symptoms including tachycardia, agitation, hypotension, and unconsciousness. We compare her symptoms to previous adult cases of quetiapine overdose and review overdose treatment recommendations. We also examine clinical situations that may lead to a more severe clinical course.",
"affiliations": "Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida 33613, USA. gcatalan@hsc.usf.edu",
"authors": "Catalano|Glenn|G|;Catalano|Maria C|MC|;Agustines|Rachel E|RE|;Dolan|Erin M|EM|;Paperwalla|Khatija N|KN|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate",
"country": "United States",
"delete": false,
"doi": "10.1089/104454602762599916",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5463",
"issue": "12(4)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": null,
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D017109:Akathisia, Drug-Induced; D014150:Antipsychotic Agents; D001519:Behavior; D003987:Dibenzothiazepines; D005260:Female; D015600:Glasgow Coma Scale; D006439:Hemodynamics; D006801:Humans; D000069348:Quetiapine Fumarate; D012559:Schizophrenia; D013406:Suicide, Attempted",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "355-61",
"pmc": null,
"pmid": "12625997",
"pubdate": "2002",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pediatric quetiapine overdose: a case report and literature review.",
"title_normalized": "pediatric quetiapine overdose a case report and literature review"
} | [
{
"companynumb": "AU-ALKEM LABORATORIES LIMITED-AU-ALKEM-2018-04248",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
... |
{
"abstract": "Hemolytic-uremic syndrome (HUS) is a rare but severe complication of neoplastic disease as well as some of its treatments. The pathophysiology of HUS is poorly understood, but it affects multiple organ systems and carries a high mortality rate. The diagnosis of HUS is based on a clinical triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and renal failure, for which no proven therapies exist. This report describes a case of HUS developing in a patient with stage IVA squamous cell carcinoma of the uterine cervix following treatment with cisplatin/bleomycin/vincristine neoadjuvant chemotherapy prior to radiation therapy.",
"affiliations": "Division of Gynecologic Oncology, University of California, Irvine, Orange 92668.",
"authors": "Angiola|G|G|;Bloss|J D|JD|;DiSaia|P J|PJ|;Warner|A S|AS|;Manetta|A|A|;Berman|M L|ML|",
"chemical_list": "D001761:Bleomycin; D014747:Vinblastine; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1016/0090-8258(90)90435-n",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "39(2)",
"journal": "Gynecologic oncology",
"keywords": null,
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D005260:Female; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D008875:Middle Aged; D002583:Uterine Cervical Neoplasms; D014747:Vinblastine",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "214-7",
"pmc": null,
"pmid": "1699855",
"pubdate": "1990-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hemolytic-uremic syndrome associated with neoadjuvant chemotherapy in the treatment of advanced cervical cancer.",
"title_normalized": "hemolytic uremic syndrome associated with neoadjuvant chemotherapy in the treatment of advanced cervical cancer"
} | [
{
"companynumb": "US-PFIZER INC-2017539181",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": "3",... |
{
"abstract": "The aim was to evaluate the results of diagnosis, follow-up and treatment of the patients who recieved growth hormone (GH) treatment for the last 10 years and to determine the differences in the process and results over the years.\n\n\n\nAnthropometric, clinical, laboratory data, treatment adherence and side effects were evaluated retrospectively in 767 patients who recieved GH treatment between 2009-2018. Patients were grouped as isolated GH deficiency (IGHD), multiple pituitary hormone deficiency (MPHD), small for gestational age (SGA), and Turner syndrome (TS) depending on diagnosis.\n\n\n\nGH treatment was started in 689 cases (89.8%) with IGHD, 24 (3.1%) with MPHD, 26 (3.4%) with SGA and 28 (3.7%) with TS. Median age of GH treatment onset was the earliest in SGA (8.4 years) and the latest in the IGHD group (12.0 years). At the time of treatment cessation, height standard deviation score (SDS) in IGHD and MPHD was significantly higher than treatment initiation time, whereas there was no significant difference in TS and SGA. One hundred eighty-nine cases reached the final height. Final heights for girls/boys were: IGHD 154/164.9 cm; MPHD 156.2/163.5 cm; TS 146.7 cm; and SGA 145.7/-cm, respectively. Target height SDS-final height SDS median values were IGHD: 0.1, MPHD: 0.6, SGA: 0.5, TS: 2.4 respectively. The patients’ treatment compliance was high (92%) and the incidence of side effects was low (2.7%).\n\n\n\nIn our cohort, GH treatment start age was late and no difference in this was observed in the last 10 years. The improvement in the height SDS was most marked in the IGHD and MPHD groups, the least in the TS and SGA groups.",
"affiliations": "University of Health Sciences Turkey, Ankara Dr. Sami Ulus Obstetrics and Gynecology, Children’s Health and Diseases Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey;University of Health Sciences Turkey, Ankara Dr. Sami Ulus Obstetrics and Gynecology, Children’s Health and Diseases Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey;University of Health Sciences Turkey, Ankara Dr. Sami Ulus Obstetrics and Gynecology, Children’s Health and Diseases Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey;University of Health Sciences Turkey, Ankara Dr. Sami Ulus Obstetrics and Gynecology, Children’s Health and Diseases Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey;University of Health Sciences Turkey, Ankara Dr. Sami Ulus Obstetrics and Gynecology, Children’s Health and Diseases Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey",
"authors": "Aycan|Zehra|Z|0000-0003-4584-2976;Araslı Yılmaz|Aslıhan|A|0000-0003-4403-2381;Yel|Servet|S|0000-0001-6889-4504;Savaş-Erdeve|Şenay|Ş|0000-0002-4164-5089;Çetinkaya|Semra|S|0000-0003-3974-2872",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.4274/jcrpe.galenos.2021.2020.0238",
"fulltext": "\n==== Front\nJ Clin Res Pediatr Endocrinol\nJ Clin Res Pediatr Endocrinol\nJCRPE\nJournal of Clinical Research in Pediatric Endocrinology\n1308-5727\n1308-5735\nGalenos Publishing\n\n33749217\n10.4274/jcrpe.galenos.2021.2020.0238\n46957\nOriginal Article\nEvaluation of Growth Hormone Results in Different Diagnosis and Trend Over 10 Year of Follow-up: A Single Center Experience\nAycan Zehra 12https://orcid.org/0000-0003-4584-2976\n\nAraslı Yılmaz Aslıhan 1*https://orcid.org/0000-0003-4403-2381\n\nYel Servet 1https://orcid.org/0000-0001-6889-4504\n\nSavaş Erdeve Şenay 1https://orcid.org/0000-0002-4164-5089\n\nÇetinkaya Semra 1https://orcid.org/0000-0003-3974-2872\n\n1 University of Health Sciences Turkey, Ankara Dr. Sami Ulus Obstetrics and Gynecology, Children’s Health and Diseases Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey\n2 Ankara University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey\n* Address for Correspondence: University of Health Sciences Turkey, Ankara Dr. Sami Ulus Obstetrics and Gynecology, Children’s Health and Diseases Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey Phone: +90 532 648 77 09 E-mail:draslihanarasli@hotmail.com\n9 2021\n23 8 2021\n13 3 332341\n13 10 2020\n25 2 2021\n©Copyright 2021 by Turkish Pediatric Endocrinology and Diabetes Society | The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.\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 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nObjective:\n\nThe aim was to evaluate the results of diagnosis, follow-up and treatment of the patients who recieved growth hormone (GH) treatment for the last 10 years and to determine the differences in the process and results over the years.\n\nMethods:\n\nAnthropometric, clinical, laboratory data, treatment adherence and side effects were evaluated retrospectively in 767 patients who recieved GH treatment between 2009-2018. Patients were grouped as isolated GH deficiency (IGHD), multiple pituitary hormone deficiency (MPHD), small for gestational age (SGA), and Turner syndrome (TS) depending on diagnosis.\n\nResults:\n\nGH treatment was started in 689 cases (89.8%) with IGHD, 24 (3.1%) with MPHD, 26 (3.4%) with SGA and 28 (3.7%) with TS. Median age of GH treatment onset was the earliest in SGA (8.4 years) and the latest in the IGHD group (12.0 years). At the time of treatment cessation, height standard deviation score (SDS) in IGHD and MPHD was significantly higher than treatment initiation time, whereas there was no significant difference in TS and SGA. One hundred eighty-nine cases reached the final height. Final heights for girls/boys were: IGHD 154/164.9 cm; MPHD 156.2/163.5 cm; TS 146.7 cm; and SGA 145.7/-cm, respectively. Target height SDS-final height SDS median values were IGHD: 0.1, MPHD: 0.6, SGA: 0.5, TS: 2.4 respectively. The patients’ treatment compliance was high (92%) and the incidence of side effects was low (2.7%).\n\nConclusion:\n\nIn our cohort, GH treatment start age was late and no difference in this was observed in the last 10 years. The improvement in the height SDS was most marked in the IGHD and MPHD groups, the least in the TS and SGA groups.\n\nRare disease\ngrowth hormone treatment\nfollow-up\n==== Body\nWhat is already known on this topic?\n\nGrowth hormone (GH) treatment has long been used in rare diseases such as isolated GH deficiency (IGHD), multiple pituitary hormone deficiency (MPHD), small for gestational age (SGA), and Turner syndrome (TS). Early diagnosis and early initiation of GH treatment are important to optimize the effects of treatment.\n\nWhat this study adds?\n\nAlthough there are larger series in the literature, our study is one of the largest single-center patient series performed after the The Pfizer International Growth Study database was terminated. GH treatment onset age was late in our cohort and no differences have been observed in the last 10 years. The improvement in the height standard deviation score was seen most in the IGHD and MPHD groups, the least in the TS and SGA groups, the patients’ treatment compliance was high (92%) and the incidence of side effects was low (2.7%).\n\nIntroduction\n\nThe introduction of recombinant human growth hormone (GH) in 1985 ended the phase of pituitary-derived human GH and its associated limitations and risks, opening the possibility of widespread clinical use (1). GH treatment has long been used in rare diseases, such as isolated GH deficiency (IGHD), multiple pitutiary hormone deficiency, (MPHD), small for gestational age (SGA), and Turner syndrome (TS). Today, it is also used in other indications such as chronic renal failure, SHOX deficiency, Prader-Willi syndrome and idiopathic short stature, besides GH deficiency (GHD) (2).\n\nThe foremost aims of GH treatment in children are the normalization of height during childhood, attainment of a timely and normal pubertal growth and the achievement of an adult height that is normal for the population and genetic target, in conjunction with normalization of other aspects, such as body composition, metabolism and quality of life (1). In all pediatric indications, early diagnosis and early initiation of GH treatment are important to optimize the effects of treatment.\n\nThe Pfizer International Growth Study (KIGS) (3), the National Cooperative Growth Study (4)and the NordiNet International Outcome Study (5), are multicenter, international databases created to monitor the efficacy and safety of GH treatment. The advantage of these databases is to create a standardized, common platform for uniform documentation of data on GH treatment in centers participating in the database, potentially reveal differences between clinics, and offer the possibility of reliable observation of potentially rare results due to the large number of participants (6). The KIGS database, in which data entries were made from many centers in our country and where we evaluate the treatment results of patients with GH treatment was terminated approximately 10 years ago. However, there are no new outputs regarding the diagnosis and treatment processes of these diseases in our country in recent years. In this study, we aimed to determine the follow-up, and treatment results and final heights of patients with rare diseases who had been treated with GH treatment in the last 10 years, and to determine the differences in the process and results over the years.\n\nMethods\n\nIn the present study, 767 patients who had received GH treatment in Ankara Dr. Sami Ulus Obstetrics and Gynecology, Children’s Health and Disease Training and Research Hospital between 2009 and 2018 were recruited. The study was conducted in accordance with the principles of the Declaration of Helsinki and approved by a Ankara Keçiören Training and Research Hospital Local Ethics Committee (no: 1686, date: 23.05.2018). Anthropometric, clinical, laboratory findings, treatment adherence and side effects of patients during, admission, GH treatment initiation time, follow-up, and GH treatment cessation time were evaluated retrospectively. Patients were grouped by diagnosis as IGHD, MPHD, TS, and SGA.\n\nAfter systemic disease screening, at least two different GH stimulation tests were performed in patients with pathological short stature whose growth rate <25th percentile and height standard deviation score (SDS) <-2.5. Apart from these, height SDS >-2.5 but with a growth rate below -2 SDS in the last year or below -1.5 SDS in the last two years, cases thought to have GHD, and patients with a regression in growth rate for more than six months clinically and genetically confirmed TS were also evaluated (7,8). Before the last change in the social security institution regulation regarding TS and SGA patients, two different GH tests were required from all patients in order to pay for GH treatment in our country. Since TS and SGA patients included in the study were diagnosed before these changes related to these patients, all patient groups, including TS and SGA cases, were administered a GH stimulation test.\n\nGHD was defined as <10 ng/mL serum peak GH concentration (7). It was required that the bone age should be at least 2 years retarded compared to chronologic age in the prepubertal period, and the epiphyseal plates were open in puberty. In addition, male and female subjects were primed with sex steroids prior to provocative GH testing, particularly in the patients with delayed puberty. For both boys and girls, 2 mg b-oestradiol (1 mg for body weight <20 kg) (not ethinyl oestradiol) was administered orally on each of the two evenings preceding the test, while boys were also given intramuscular testosterone (50-100 mg of a depot formulation administered one week before the test). Puberty was defined as breast development ≥2 Tanner stage in girls and testicular volume ≥4 mL in boys (9).\n\nIGHD was defined as a condition of GHD not associated with other pituitary hormone deficiencies. MPHD was defined as a deficiency of at least two pituitary hormones, with one being GH. SGA was defined as birth weight less than -2 SDS for gestational age. TS was defined as females who have partial or complete absence of the second sex chromosome with a variety of phenotypic features.\n\nAll measurements were calculated with the reference developed for Turkish children and expressed as SDS (10,11). Target (mid-parental) height was calculated by adding 6.5 cm to the mean of the parents’ heights for boys or by subtracting 6.5 cm from the mean of the parents’ heights for girls (12). If those who reached the final height were within range of ±5 cm of the target height, they were considered as having reached target height.\n\nAfter GH tests were evaluated, organic pathology that may accompany cases with GH deficiency was evaluated by performing pituitary magnetic resonance imaging (MRI). GH was administered subcutaneously at a dose range of 0.2-0.4 mg/kg/week, six days per week. According to the rules of the social security institution in our country, the GH treatment is discontinued when height reaches 155 cm in girls and 165 cm in boys. In addition, GH treatment was discontinued if the annual growth rate was <2 cm and/or bone age was ≥16 in boys and ≥14 in girls (7).\n\nGH product, type of injection device, dosage, GH storage conditions, number of missed injections, reasons for missed injections, person administering daily GH injections and problems in follow-up were recorded at each visit and patients’ compliance was evaluated. Adherence categories were established following the criteria of Smith et al (13), and patients were categorized into one of four compliance groups, based on the percent of doses omitted at each evaluation period: excellent if 0%, good if 5%, fair if 5 to 10%, and poor if >10%. Patients in the poor category were considered to be incompatible with treatment.\n\nStatistical Analysis\n\nThe Predictive Analytics Software 18, (2009) program was used for statistical analysis. The conditions where the type-1 error level was below 5% were interpreted statistically. Kolmogorov-Smirnov and Shapiro-Wilk tests were used for assessment of normality of distribution of the data. In descriptive statistics, categorical variables are expressed as number and percentage, and numerical variables are presented as median, and minimum and maximum values. Student’s t-test was used to compare two groups when the parametric test prerequisites were met and Mann-Whitney U test was used otherwise. The Friedman test was used to examine the change in the age, bone age, height SDS, body mass index (BMI) SDS, puberty, and follow-up time, GH treatment initiation time, and GH treatment cessation time separately in all patients and groups. The Wilcoxon signed-ranks test was used in post-hoc analysis. Bonferroni correction was used in post-hoc analysis whenever appropriate. In all patients and in the IGHD group, the Kruskal-Wallis test was used for comparison analysis of numerical values between date groups. To evaluate the relationship between final height-SDS and target height SDS, first year growth velocity, treatment duration, age at GH treatment initiation, bone age, height SDS, puberty, gender, and concentrations of insulin-like growth factor-1 (IGF-1), IGF binding protein 3 (IGFBP3), multiple linear regression analysis was performed with the backward method. A p value <0.05 was considered statistically significant.\n\nResults\n\nThe median age of patients (63% male) who were admitted to the clinic due to short stature was 10.4 years at first visit. GH treatment was started in 689 cases (89.8%) with IGHD, 24 (3.1%) with MPHD, 26 (3.4%) with SGA, and 28 (3.7%) with TS. The median age of GH treatment start was 12.0 years, the earliest was in SGA (8.4 years) and the latest was in IGHD (12.0 years). When the age of first admission to the hospital and the GH treatment onset age were compared by year, it was found that there was no difference between them at the beginning or at the end of the 10 years study period (p>0.05) (Table 1).\n\nThe height SDS at the GH treatment initiation time was below <-2.5 in the entire group and subgroups. The lowest height SDS was in the MPHD group, and the height SDS values of TS, and SGA groups were lower than the IGHD group. The lowest peak response to GH tests was in the MPHD, IGHD, and TS groups, respectively. The lowest serum IGF-1 and IGFBP3 values were in the MPHD group. The serum IGF-1 level was <-2 SDS in 330 (43.9%) patients, between -2 SDS and -1 SDS in 380 (50.5%) patients, and >-1 SDS in 42 (5.6%) patients (Table 2).\n\nThe pituitary MRI was pathological in 27.1% of the patients, and the most common accompanying pathology was pituitary hypoplasia (60%). Various pathologies, including pituitary hypoplasia, ectopic neurohypophysis, microadenoma/suspected microadenoma, empty sella, partial empty sella, Rathke cleft cyst, and arachnoid cyst, were detected in 25.9% of patients with IGHD and 78.3% of patients with MPHD. Patients with suspected microadenoma and microadenoma underwent neurosurgery consultation before GH treatment. In none of the cases, organic pathology that could interfere with GH treatment was found on MRI.\n\nThe median follow-up time without treatment was 11 months and the median follow-up time with treatment was 2.1 years. The longest duration of treatment was in the MPHD group at 3.8 (range, 0.3-9) years, and the shortest duration of treatment was in the IGHD group at 2 (range, 0.3-10.8) years. The median treatment dose was 0.2 (range, 0.2-0.4) mg/kg/week in the entire group and subgroups, while it was 0.3 mg/kg/week in the TS group. During the treatment, the changes in patients’ GH dose were minimal (7.0%) and the doses of GH were adjusted in relation to weight, elevation of IGF-1 concentration or changes in glucose metabolism.\n\nGrowth velocity was highest in the first year of treatment in the entire group and subgroups, and gradually decreased in the following years. The median value of the first-year growth velocity was 8.2 cm/year in entire group, while it was 9.8 cm/year in MPHD, 8.3 cm/year in IGHD, 7.8 cm/year in TS and 7.1 cm/year in SGA.\n\nConsidering GH treatment cessation time, height SDSs in IGHD and MPHD groups were significantly higher than at treatment start (p<0.001), whereas there was no significant difference in TS (p=0.225) and SGA groups (p=0.191). In the same period, no statistically significant difference was found in terms of the BMI SDS in the subgroups, except for the IGHD group (Table 3).\n\nIn total 189 patients reached final height; by diagnosis subgroup this was IGHD n=166, TS n=11, MPHD n=8, SGA n=4. Except for the TS and SGA groups, the percentage of patients reaching final height was higher in boys. In groups outside TS and SGA, final height SDSs were above -2 SDS. Final height for girls/boys were as follows: IGHD: 154/164.9 cm, MPHD: 156.2/163.5 cm, TS:146.7 (range, 133-156.4) cm, and SGA:145.7 (range, 136.7-150.3) cm. Of the 166 IGHD patients who reached final height, 104 (67.5%) were found to reach their target height. Target height SDS-final height SDS was the greatest in the TS group and the proportion reaching final height was the lowest in the TS group (Table 4). The change in height SDS of the patients from the beginning of treatment to the final height is given in Figure 1.\n\nOf our IGHD patients who reached their final height, 93 (56.0%) were prepubertal and 73 (44%) were pubertal at the beginning of GH treatment. At the time of initiation of GH treatment, the age and bone age of pubertal IGHD patients were significantly higher than in prepubertal IGHD patients (p<0.001). The duration of treatment was longer in prepubertal IGHD patients than in pubertal patients (p<0.001) (Table 5). There was no statistically significant difference between prepubertal and pubertal IGHD patients in terms of height SDS, BMI SDS, final height SDS, target height-SDS, first year growth velocity and treatment dose.\n\nIn multiple linear regression analysis, GH treatment start time height SDS, target height SDS, first year growth velocity and puberty status were predictive factors for final height SDS (Table 6).\n\nPatients’ compliance with treatment was high (92%), and treatment was interrupted in 16% of patients due to problems in compliance with treatment during treatment, low growth rate, and high IGF-1. Treatment incompatibility was lowest in the IGHD group and highest in the SGA group. Adverse effects were seen in 2.7% (n=21) of our patients. These side effects were; significant creatinine kinase elevation (n=8), scoliosis (n=5), cardiac causes (n=2 with one each of subaortic segmental hypertrophy and left ventricular hypertrophy), orthopedic causes including slipped capital femoral epiphysis (n=1) and Osgood-Schlatter’s disease (n=1), non-injection site rash (n=2), disorders of glucose metabolism (n=1, impaired fasting glucose) and malignancy (n=1, osteochondroma). Both patients with cardiac side effects were in the IGHD group and neither had syndromic features. Scoliosis, slipped capital femoral epiphysis and impaired fasting glucose were thought to be related to GH treatment. Scoliosis was newly developed in four cases and an increase in existing scoliosis in one case. Our patient with malignancy was followed up because of TS, the total treatment duration was 2.92 years, and the treatment dose was 0.3 mg/kg/week. It was found that the patient, whose treatment was discontinued after malignancy was detected, did not continue with her subsequent follow-ups.\n\nDiscussion\n\nOur study, which is the second largest of pediatric patients receiving GH from Turkey, after the Turkey KIGS Database analysis published in 2004 with 1008 patients, evaluated etiology and treatment outcomes (14). In our study, in keeping with earlier reports, the highest proportion of patients were in the IGHD group and patients were mostly male (14,15).\n\nIt has been shown that the age at initiation of GH treatment is correlated negatively with the response to treatment, which emphasizes the need for early diagnosis and treatment (7). In a recently study by Sävendahl et al (16) data from the American Norditropin Studies: Web-Enabled Research Program (ANSWER-USA) and the NordiNet International Outcome Study (NordiNet IOS-Europe) were compared. Growth hormone initiation age in GHD, TS, and SGA patients were 11.09, 8.92 and 9.0 years in the ANSWER trial, respectively, while it was 9.12, 8.72 and 7.92 years in the NORDINET-IOS trial, respectively. The authors concluded that starting age of GH therapy was higher in all indications in the USA. Pfäffle et al (17) reported that the age of initiation of treatment was similar between the USA and Germany, but higher in the indications in France. Data from these different analyses show that the average age at the start of GH treatment is higher than desired worldwide.\n\nIn the study in which patients were registered in the KIGS database in Turkey and were treated with GH, the age at onset of GH treatment was 11.3 years (14), and 11.2±2.67 years in the study performed by Soyöz and Dündar (18). In our study, the median age at onset of treatment was 12.0 years; the age at onset of treatment was oldest in the IGHD group and youngest in the SGA group, and there was no difference in the ages at first presentation and at initiation of treatment in the last 10 years. Our findings show that despite the increase in health awareness and easier access to health services in recent years, age at onset of GH treatment is still late in our cohort.\n\nIn our study, the highest growth velocity in the first year of treatment was in the MPHD and IGHD groups, besides height SDS was -3.0 and -3.84 in patients in the IGHD and MPHD groups at the GH treatment onset time, while the final height SDS was -1.5 in both of these groups. In previous studies from Turkey final height SDSs in IGHD and MPHD were found to be -1.8 and -1.6 by Kurnaz et al (19) and -1.4 and -1.1 by Darendeliler et al (20). The final height SDSs in the IGHD and MPHD groups in our study, with a similar dose range but shorter median treatment time, were similar to other studies from our country. It was thought that the better response in our patients in the MPHD group was associated with lower IGF-1 and peak GH values in the GH stimulation tests, as well as lower chronological age and bone age at the beginning of treatment compared with patients with IGHD.\n\nThe effect of GH treatment on final height in TS is variable and many factors, such as polymorphisms associated with the GH receptor and/or IGFBP3 gene, age at the beginning of treatment, dose of GH, duration of treatment, bone age retardation, maternal X chromosome origin, first year response to target height, and oxandrolone treatment affect the treatment response (21,22,23). The IGFBP3 gene promoter region contains several single nucleotide polymorphisms (SNPs). The 202 A/C SNP which located 202 bp upstream of the transcription start site consists of an A to C nucleotide change and is correlated with serum IGFBP-3 concentrations in healthy adults. Serum IGFBP-3 levels are highest in patients with the AA genotype, followed by the AC and CC genotypes (24). An association of the A allele in the IGFBP-3 promoter region with increased IGFBP-3 concentration and growth velocity after GH therapy has been observed in prepubertal children with GHD and TS (25,26).\n\nRecently Ahn et al (27), in a study of 73 patients with TS, reported that the height SDS at the beginning was correlated with final height SDS, and that early treatment was very important. Evaluation of the data of 70 TS patients registered from 11 centers in Turkey in the KIGS database who received GH at a dose of 33 µg/kg/d subcutaneously, 6-7 times per week, with onset of therapy at age 12.5 (7.1-15.6) years revealed a non-significant increase in growth velocity 6.3 cm/year in the first year and 5.9 cm/year in the second year (28). In another study in which 842 patients with TS were evaluated with the participation of 35 centers from our country, it was reported that the average age to diagnosis with TS was 10.5±4.8 years and that treatment was initiated at the age of 10.7±3.5 year (29). In our study, the age at onset of treatment, the dose of treatment, and the first year response to treatment in patients with TS were consistent with earlier studies from our country, and although there was no significant difference in terms of height SDS between GH treatment initiation and cessation times, the rate of reaching the target height was the lowest in the TS group. We hypothesize that this was due to the age at onset of treatment being late in our patients and that the height SDS at the beginning of treatment were significantly lower.\n\nGH treatment in infants with SGA is effective in the correction of body composition and improvement of metabolic complications, in addition to its contribution to stature in adulthood (30). The dose recommended by the Pediatric Endocrinology and Growth Hormone Research Society in children with SGA is 35-70 mg/kg/day, and higher doses are recommended for patients with severe growth retardation. Treatment dose, age at initiation, height at initiation of treatment, and mid-parental height are among the factors affecting the response of GH in children with SGA (31). The multidisciplinary follow-up of many of the SGA cases by other departments in our hospital has caused these patients to be referred to our clinic earlier and to start treatment earlier because of earlier diagnosis of growth disorders. However, there was no significant difference between GH treatment initiation and cessation in terms of height SDSs in the SGA group and the final height SDS was the lowest in the SGA group. These findings were thought to be due to the fact that the doses used in the SGA group were at the lower limit of the recommended dose and were associated with a treatment mismatch in this group.\n\nIn this study, although the chronological age and bone age were higher in the pubertal IGHD patients and the duration of GH treatment was longer in the prepubertal IGHD patients, there was no statistically significant difference between the two groups in terms of final height SDS. Similarly, Kurnaz et al’s (19) study did not show a difference in final height SDS of prepubertal and pubertal patients, but it was reported that delta height SDS was higher in pubertal patients (20). These results suggest that even if the GH treatment is initiated at pubertal age, it may be beneficial in achieving a final height compatible with the genetic potential together with the pubertal growth spurt.\n\nFinally, our results justify the incorporation of height SDS at the beginning of treatment, target height SDS, and first-year response to treatment as major parameters in all predictive models of final height in all GH-treated children (21,32,33).\n\nStudy Limitations\n\nThe main limitations of this study are that it was designed retrospectively and the number of patients who could be evaluated in terms of final height was low.\n\nConclusion\n\nThis study has shown that GH treatment was started late in the entire group and there was no improvement in the 10 year study period. It was observed that patients who were admitted with short stature received GH treatment approximately 1.5 years later and this is likely to have negatively affected treatment responses. We suggest that efforts should be made to reduce the period between first presentation at the pediatric endocrinology clinic and initiation of GH therapy, if indicated. As a result of late start of GH treatment, improvement in the height SDSs of SGA and TS groups was minimal. In the IGHD group, it was seen that approximately 68% of those who reached final height also achieved the target height. Treatment compliance of patients receiving GH treatment was high.\n\nAlthough our results cannot be generalized for the whole country, we believe that GH treatment probably does not show significant regional difference, the data obtained from large patient series are important, and in this context, our study may reflect the current situation in GH treatment in our country. Therefore, the results of this study suggest that clinical awareness of causes of short stature should be improved, diagnosis in patients with pathological short stature should be more rapid, the period between first presentation at pediatric endocrinology and initiation of GH therapy should be shortened and that in all children who would benefit from GH therapy, treatment should be started at earlier ages.\n\nTable 1 Age at presentation and growth hormone therapy initiation age by year\n\nTable 2 Anthropometric and laboratory features of patients at start of growth hormone therapy\n\nTable 3 Anthropometric and clinical findings of patients at first presentation, growth hormone therapy start and growth hormone therapy cessation\n\nTable 4 Descriptive analysis of patients reaching final height\n\nTable 5 Comparison of isolated growth hormone deficiency patients reaching final height according to their puberty status at the beginning of treatment\n\nTable 6 Multiple linear regression analysis on final height standard deviation score\n\nFigure 1 Graph of changes in height standard deviation score values of the groups\n\nIGHD: isolated growth hormone deficiency, GH: growth hormone, SGA: small for gestational age, MPHD: multiple pitutiary hormone deficiency, TS: Turner syndrome\n\nEthics\n\nEthics Committee Approval: The study was conducted in accordance with the principles of the Declaration of Helsinki and approved by a Ankara Keçiören Training and Research Hospital Local Ethics Committee (no: 1686, date: 23.05.2018).\n\nInformed Consent: The study was retrospective and no interventions were used. Therefore we did not obtain informed consent from the patients or their parents.\n\nPeer-review: Externally and internally peer-reviewed.\n\nAuthorship Contributions\n\nMedical Practices: Aslıhan Araslı Yılmaz, Servet Yel, Zehra Aycan, Concept: Zehra Aycan, Şenay Savaş-Erdeve, Semra Çetinkaya, Design: Zehra Aycan, Şenay Savaş-Erdeve, Semra Çetinkaya, Data Collection or Processing: Aslıhan Araslı Yılmaz, Servet Yel, Zehra Aycan, Analysis or Interpretation: Aslıhan Araslı Yılmaz, Servet Yel, Zehra Aycan, Şenay Savaş-Erdeve, Semra Çetinkaya, Literature Search: Aslıhan Araslı Yılmaz, Zehra Aycan, Writing: Aslıhan Araslı Yılmaz, Zehra Aycan.\n\nFinancial Disclosure: This study was unrequitedly funded by Pfizer Turkey.\n==== Refs\nReferences\n\n1 Ranke M Wit J Growth hormone-past, present and future Nat Rev Endocrinol 2018 14 285 300 29546874\n2 Collett-Solberg PF Jorge AAL Boguszewski MCS Miller BS Choong CSY Cohen P Hoffman AR Luo X Radovick S Saenger P Growth hormone therapy in children; research and practice –a review Growth Horm IGF Res 2019 44 20 32 30605792\n3 Ranke MB Lindberg A Tanaka T Camacho-Hübner C Dunger DB Geffner ME Baseline characteristics and gender differences in prepubertal children treated with growth hormone in Europe, UAS, and Japan: 25 years’ KIGS experience (1987–2012) and review Horm Res Paediatr 2017 87 30 41 27915352\n4 Kaplowitz PB Shulman DI Frane JW Jacobs J Lippe B Characteristics of children with the best and poorest first- and second-year growth during rhGH therapy: data from 25 years of the Genentech national cooperative growth study (NCGS) Int J Pediatr Endocrinol 2013 9.\n5 Polak M Konrad D Tønnes Pedersen B BT Puras Šnajderová M Still too little, too late? Ten years of growth hormone therapy baseline data from the NordiNet® International Outcome Study J Pediatr Endocrinol Metab 2018 31 521 532 29652668\n6 Schoenfeld A Redberg R The value of using registries to evaluate randomized clinical trial study populations JAMA Intern Med 2017 177 889\n7 Growth Hormone Research Society Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH research society. J Clin Endocrinol Metab 2000;85:3990-3993. [Internet]\n8 Gravholt CH Andersen NH Conway GS Dekkers OM Geffner ME Klein KO Lin AE Mauras N Quigley CA Rubin K Sandberg DE Sas TCJ Silberbach M Söderström- Anttila V Stochholm K van Alfen-van derVelden JA Woelfle J Backeljauw PF International Turner Syndrome Consensus Group Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting Eur J Endocrinol 2017 177 G1 G70 28705803\n9 Rosenfield RL Cooke DW Radovick S Puberty and its disorders in the female. In: Sperling M, ed. Pediatric Endocrinology. 4th ed Philadelphia, PA, Elsevier 2014 569 663\n10 Neyzi O Günoz H Furman A Bundak R Gokcay G Darendeliler F Bas F Weight, height, head circumference and body mass index references for Turkish children Çocuk Sağlığı ve Hastalıkları Dergisi 2008 51 1 14\n11 Kurtoğlu S Hatipoğlu N Mazıcıoğlu MM Akın MA Çoban D Gökoğlu S Baştuğ O Body weight, length and head circumference at birth in a cohort of Turkish newborns J Clin Res Pediatr Endocrinol 2012 4 132 139 22664362\n12 Tanner JM Goldstein H Whitehouse RH Standards for children’s height at ages 2-9 years allowing for heights of parents Arch Dis Child 1970 45 755 762 5491878\n13 Smith SL Hindmarsh PC Brook CG Compliance with growth hormone treatment- are they getting it? Arch Dis Child 1993 68 91 93 8435018\n14 Darendeliler F Berberoğlu M Öcal G Adiyaman P Bundak R Saka N Baş F Darcan Ş Gökşen D İşgüven P Yildiz M Ercan O Ercan G Özerkan E Can Ş Büyükgebiz A Böber E Adal E Sarikaya S Dallar Y Şiklar Z Bircan İ Bideci A Yüksel B Büyüme hormonu eksikliği etiyolojisi, demografik veriler ve tedavi sonuçlarının değerlendirilmesi: Türkiye verileri KIGS analiz sonuçları. Çocuk Dergisi 2004 4 141 148\n15 Kosteria I Aloumanis K Kanaka-Gantenbein C Vlachopapadopoulou E Michalacos S Stamoyannou L Drossinos E Chrousos G Pediatric growth hormone therapy in Greece: analysis of the Hellenic cohort of the GeNeSIS study Hormones (Athens). 2019 18 423 434 31696446\n16 Sävendahl L Polak M Backeljauw P Blair J Miller BS Rohrer TR Pietropoli A Ostrow V Ross J Treatment of children with GH in the United States and Europe: long-term follow-up from NordiNet® IOS and ANSWER program J Clin Endocrinol Metab 2019 104 4730 4742 31305924\n17 Pfäffle R Land C Schönau E Holterhus PM Ross JL Piras de Oliveira C Child CJ Benabbad I Jia N Jung H Blum WF Growth hormone treatment for short stature in the USA, Germany and France: 15 years of surveillance in the Genetics and Neuroendocrinology of Short-Stature International Study (GeNeSIS) Horm Res Paediatr 2018 90 169 180 30199857\n18 Soyöz Ö Dündar B Büyüme hormonu tedavisi alan çocukların klinik özellikleri ve tedaviye yanıtı etkileyen faktörler İzmir Katip Çelebi Üniversitesi Sağlık Bilimleri Fakültesi Dergisi 2016 1 7 13\n19 Kurnaz E Çetinkaya S Aycan Z Near final height in patients with idiopathic growth hormone deficiency: A single-centre experience J Paediatr Child Health 2018 54 1221 1226 29806866\n20 Darendeliler F Lindberg A Wilton P Response to growth hormone treatment in isolated growth hormone deficiency versus multiple pituitary hormone deficiency Horm Res Paediatr 2011 76(Suppl 1) 42 46\n21 Ranke MB Lindberg A Ferrández Longás A Darendeliler F Albertsson- Wikland K Dunger D Cutfield WS Tauber M Wilton P Wollmann HA Reiter EO KIGS International Board Major determinants of height development in Turner syndrome (TS) patients treated with GH: analysis of 987 patients from KIGS Pediatr Res 2007 61 105 110 17211150\n22 Davenport ML Growth hormone therapy in Turner syndrome Pediatr Endocrinol Rev 2012 9(Suppl 2) 723 724 22946284\n23 Özgen İT Adal E Ünüvar T Önal H Sarıkaya AS Akın L Response to growth hormone therapy in patients with Turner syndrome Turk Arch Ped 2013 48 294 298\n24 Deal C Ma J Wilkin F Paquette J Rozen F Ge B Hudson T Stampfer M Pollak M Novel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators J Clin Endocrinol Metab 2001 86 1274 1280 11238520\n25 Costalonga EF Antonini SR Guerra-Junior G Mendonca BB Arnhold IJ Jorge AA The -202 A allele of insulin-like growth factor binding protein-3 (IGFBP3) promoter polymorphism is associated with higher IGFBP-3 serum levels and better growth response to growth hormone treatment in patients with severe growth hormone deficiency J Clin Endocrinol Metab 2009 94 588 595 18984657\n26 Braz AF Costalonga EF Montenegro LR Trarbach EB Antonini SR Malaquias AC Ramos ES Mendonca BB Arnhold IJ Jorge AA The interactive effect of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms on rhGH responsiveness and treatment outcomes in patients with Turner syndrome J Clin Endocrinol Metab 2012 97 E671 E677 22278433\n27 Ahn JM Suh JH Kwon AR Chae HW Kim H-S Final Adult height after growth hormone treatment in patients with turner syndrome Horm Res Paediatr 2019 91 373 379 31480041\n28 Darendeliler F Bas F Berberoglu M Öcal G Günöz H Darcan Ş Bundak R Arslanoğlu İ Yüksel B Bideci A Turner Sendromunda büyüme hormonu tedavi sonuçlarının değerlendirilmesi: Türkiye KIGS verileri (Pfizer Uluslararası büyüme veritabanı) veritabanı analiz sonuçları Çocuk Dergisi 2005 5 21 26\n29 Yeşilkaya E Bereket A Darendeliler F Baş F Poyrazoğlu Ş Küçükemre Aydın B Darcan Ş Dündar B Büyükinan M Kara C Sarı E Adal E Akıncı A Atabek ME Demirel F Çelik N Özkan B Özhan B Orbak Z Ersoy B Doğan M Ataş A Turan S Gökşen D Tarım Ö Yüksel B Ercan O Hatun Ş Şimşek E Ökten A Abacı A Döneray H Özbek MN Keskin M Önal H Akyürek N Bulan K Tepe D Emeksiz HC Demir K Kızılay D Topaloğlu AK Eren E Özen S Abalı S Akın L Selver Eklioğlu B Kaba S Anık A Baş S Ünüvar T Sağlam H Bolu S Özgen T Doğan D Deniz Çakır E Şen Y Andıran N Çizmecioğlu F Evliyaoğlu O Karagüzel G Pirgon Ö Çatlı G Can HD Gürbüz F Binay Ç Baş VN Fidancı K Polat A Gül D Açıkel C Demirbilek H Cinaz P Bondy C Turner syndrome and associated problems in Turkish children: a multicenter study J Clin Res Pediatr Endocrinol 2015 7 27 36 25800473\n30 Zanelli SA Rogol AD Short children born small for gestational age outcomes in the era of growth hormone therapy Growth Horm IGF Res 2018 38 8 13 29291885\n31 Clayton PE Cianfarani S Czernichow P Johannsson G Rappaport R A Management of the child born small for gestational age through to adulthood: a con-sensus statement of the International Societies of Paediatric Endocrinology and the Growth Hormone Research Society J Clin Endocrinol Metab 2007 92 804 810 17200164\n32 Land C Blum WF Shavrikova E Kloeckner K Stabrey A Schoenau E Predicting the growth response to growth hormone (GH) treatment in prepubertal and pubertal children with isolated GH deficiency--model validation in an observational setting (GeNeSIS) J Pediatr Endocrinol Metab 2007 20 685 693 17663293\n33 Ranke MB Lindberg A KIGS International Board Height at start, first-year growth response and cause of shortness at birth are major determinants of adult height outcomes of short children born small for gestational age and Silver-Russell syndrome treated with growth hormone: analysis of data from KIGS Horm Res Paediatr 2010 74 259 266 20431273\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "13(3)",
"journal": "Journal of clinical research in pediatric endocrinology",
"keywords": "Rare disease; growth hormone treatment; follow-up",
"medline_ta": "J Clin Res Pediatr Endocrinol",
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"nlm_unique_id": "101519456",
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"pages": "332-341",
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"pubdate": "2021-08-23",
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"title": "Evaluation of Growth Hormone Results in Different Diagnosis and Trend Over 10 Year of Follow-up: A Single Center Experience",
"title_normalized": "evaluation of growth hormone results in different diagnosis and trend over 10 year of follow up a single center experience"
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"abstract": "Severe toxicity is experienced by a substantial minority of patients receiving fluoropyrimidine-based chemotherapy, with approximately 20% of these severe toxicities attributable to polymorphisms in the DPYD gene. The DPYD codes for the enzyme dihydropyrimidine dehydrogenase (DPD) important in the metabolism of fluoropyrimidine-based chemotherapy. We questioned whether prospective DPYD mutation analysis in all patients commencing such therapy would prove more cost-effective than reactive testing of patients experiencing severe toxicity.\nAll patients experiencing severe toxicity from fluoropyrimidine-based chemotherapy for colorectal cancer in an Irish private hospital over a 3-year period were tested for 4 DPYD polymorphisms previously associated with toxicity. The costs associated with an index admission for toxicity in DPD-deficient patients were examined. A cost analysis was undertaken comparing the anticipated cost of implementing screening for DPYD mutations versus current usual care. One-way sensitivity analysis was conducted on known input variables. An alternative scenario analysis from the perspective of the Irish health-care payer (responsible for public hospitals) was also performed.\nOf 134 patients commencing first-line fluoropyrimidine chemotherapy over 3 years, 30 (23%) patients developed grade 3/4 toxicity. Of these, 17% revealed heterozygote DPYD mutations. The cost of hospitalization for the DPYD-mutated patients was €232 061, while prospectively testing all 134 patients would have cost €23 718. Prospective testing would result in cost savings across all scenarios.\nThe cost of hospital admission for severe chemotherapy-related toxicity is significantly higher than the cost of prospective DPYD testing of each patient commencing fluoropyrimidine chemotherapy.",
"affiliations": "Medical Oncology, Bon Secours Cork, University College Cork School of Medicine, Cork, Ireland.;School of Pharmacy, University College Cork National University of Ireland, Cork, Ireland.;Medical Oncology, Bons Secours Cork, Cork, Ireland.;Biochemistry, Bons Secours Cork, Cork, Ireland.;School of Pharmacy, University College Cork National University of Ireland, Cork, Ireland.;University College Cork School of Medicine, Cork, Ireland.;University College Cork School of Medicine, Cork, Ireland.;Medical Oncology, Bon Secours Cork, University College Cork School of Medicine, Cork, Ireland.",
"authors": "Murphy|Con|C|;Byrne|Stephen|S|;Ahmed|Gul|G|;Kenny|Andrew|A|0000-0001-5059-8520;Gallagher|James|J|;Harvey|Harry|H|;O'Farrell|Eoin|E|;Bird|Brian|B|",
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"doi": "10.1177/1559325818803042",
"fulltext": "\n==== Front\nDose ResponseDose ResponseDOSspdosDose-Response1559-3258SAGE Publications Sage CA: Los Angeles, CA 3028815410.1177/155932581880304210.1177_1559325818803042Original ArticleCost Implications of Reactive Versus Prospective Testing for\nDihydropyrimidine Dehydrogenase Deficiency in Patients With Colorectal Cancer: A\nSingle-Institution Experience Murphy Con 1Byrne Stephen 2Ahmed Gul 3http://orcid.org/0000-0001-5059-8520Kenny Andrew 4Gallagher James 2Harvey Harry 5O’Farrell Eoin 5Bird Brian 1\n1 Medical Oncology, Bon Secours Cork, University College Cork School of\nMedicine, Cork, Ireland\n2 School of Pharmacy, University College Cork National University of Ireland,\nCork, Ireland\n3 Medical Oncology, Bons Secours Cork, Cork, Ireland\n4 Biochemistry, Bons Secours Cork, Cork, Ireland\n5 University College Cork School of Medicine, Cork, IrelandEoin O’Farrell, University College Cork, Cork,\nIreland. Email: e.g.ofarrell@umail.ucc.ie1 10 2018 Oct-Dec 2018 16 4 155932581880304206 3 2018 14 8 2018 © The Author(s) 20182018SAGE PublicationsThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits\nnon-commercial use, reproduction and distribution of the work without further permission\nprovided the original work is attributed as specified on the SAGE and Open Access pages\n(https://us.sagepub.com/en-us/nam/open-access-at-sage).Background:\nSevere toxicity is experienced by a substantial minority of patients receiving\nfluoropyrimidine-based chemotherapy, with approximately 20% of these severe toxicities\nattributable to polymorphisms in the DPYD gene. The\nDPYD codes for the enzyme dihydropyrimidine dehydrogenase (DPD)\nimportant in the metabolism of fluoropyrimidine-based chemotherapy. We questioned\nwhether prospective DPYD mutation analysis in all patients commencing\nsuch therapy would prove more cost-effective than reactive testing of patients\nexperiencing severe toxicity.\n\nMethods:\nAll patients experiencing severe toxicity from fluoropyrimidine-based chemotherapy for\ncolorectal cancer in an Irish private hospital over a 3-year period were tested for 4\nDPYD polymorphisms previously associated with toxicity. The costs\nassociated with an index admission for toxicity in DPD-deficient patients were examined.\nA cost analysis was undertaken comparing the anticipated cost of implementing screening\nfor DPYD mutations versus current usual care. One-way sensitivity\nanalysis was conducted on known input variables. An alternative scenario analysis from\nthe perspective of the Irish health-care payer (responsible for public hospitals) was\nalso performed.\n\nResults:\nOf 134 patients commencing first-line fluoropyrimidine chemotherapy over 3 years, 30\n(23%) patients developed grade 3/4 toxicity. Of these, 17% revealed heterozygote\nDPYD mutations. The cost of hospitalization for the\nDPYD-mutated patients was €232 061, while prospectively testing all\n134 patients would have cost €23 718. Prospective testing would result in cost savings\nacross all scenarios.\n\nConclusions:\nThe cost of hospital admission for severe chemotherapy-related toxicity is\nsignificantly higher than the cost of prospective DPYD testing of each\npatient commencing fluoropyrimidine chemotherapy.\n\nDPYDfluoropyrimidinecolorectal cancercost-effectivenesspharmacogenomicscover-dateOctober-December 2018\n==== Body\nIntroduction\nFluoropyrimidine chemotherapy drugs such as 5-fluorouracil (5FU) and the oral 5FU prodrugs\nare widely used as both monotherapies and combination chemotherapy regime in the treatment\nof a wide variety of cancers. Potential toxicities associated with this class of\nchemotherapy include emesis, diarrhea, mucositis, alopecia, myelosuppression, palmar-plantar\nerythrodysesthesia, and cardiac toxicity. These adverse reactions may be severe and rarely\nfatal. They often compromise optimal patient treatment due to delays in drug administration\nor discontinuation of therapy before completion of a planned treatment.\n\nThe DPYD gene encodes for the enzyme dihydropyrimidine dehydrogenase\n(DPD), which functions as the rate-limiting step in the metabolism of fluoropyrimidine chemotherapies1,2; greater than 80% of 5FU is metabolized by DPD, and factors such as age, race,\ncomorbidities, and concomitant therapies also influence metabolism (Figure 1). Over 50 polymorphisms of\nDPYD have been described, with certain alleles associated with reduced\nfunctionality of the enzyme leading to decreased metabolism of 5FU and more treatment-based toxicities.3-8\n\n\nFigure 1. 5-Fluorouracil and capecitabine metabolism in liver and tumor cells. CD indicates\ncytidine deaminase; CE, carboxyl esterase; 5′-DFCR, 5′-deoxy-5-fluorocytidine; 5′-DFUR,\n5′-deoxy-5-fluorouridine; DHFU, dihydro-5-fluorouracil; DPD, dihydropyrimidine\ndehydrogenase; 5FU, fluorouracil; TP, thymidine phosphorylase.\n\nProspective testing for DPYD mutations is not routinely carried out due to\nconcerns over the cost-effectiveness of upfront testing and the absence of clear guidelines\nfor dose reductions in patients found to be DPD deficient on prospective testing.9 In addition, the absence of a mutation does not guarantee freedom from severe\ntoxicity. Nonetheless, the potential advantage of prospectively identifying\nDPYD mutations is that careful monitoring and dose escalation may allow\nDPD-deficient patients to safely receive fluoropyrimidine chemotherapy.6-8\n\n\nWe became concerned by a number of patients treated at our institution (a large Irish\nprivate hospital) suffering prolonged hospitalizations, having to curtail or abandon\nadjuvant chemotherapy due to fluoropyrimidine toxicity.10 In this study, we followed current practice of reactive testing for\nDPYD polymorphisms in patients experiencing severe toxicity. We\nquestioned whether prospective testing of all patients treated during this period would\nreduce the economic and medical toxicity of fluoropyrimidine-based treatment. We examined\nthe costs associated with an index admission for fluoropyrimidine toxicity in DPD-deficient\npatients. A cost analysis was undertaken comparing the anticipated cost and outcomes of\nimplementing screening for DPYD mutations as routine care versus current\npractice.\n\nRoutine prospective screening can potentially benefit our practice through the\nidentification of those patients who are at increased risk of toxicity. Subsequent\nindividualization of affected patients’ chemotherapy management may reduce the risk of\nadverse outcomes.\n\nMethods\nPatient Population\nPatients commencing chemotherapy for colorectal cancer (CRC) at our institution over a\n3-year period between January 1, 2010, and December 31, 2012, who developed severe (grade\n3/4) toxicity were reactively tested for DPYD mutations. The type and\ndurations of toxicity were recorded using the National Cancer Institute Common Toxicity\nCriteria for Adverse Events version 4.0. Following informed consent, EDTA blood samples\nwere procured from each patient and genotyped for 4 DPYD mutations\nassociated with fluoropyrimidine toxicity at St Thomas’ Hospital, London. The specific\ngenotypes tested for were 1905+1G>A (DPYD*2A), 2846A>T, 1601G>A\n(DPYD*4), and 1679T>G (DPYD*13). From June 2011,\nquantitative polymerase chain reaction targeting 4 specific DPYD variants\nassociated with fluoropyrimidine toxicity was adopted as the testing method. Prior to\nthis, testing was performed by sequencing exons 13, 14, and 22 (including 4\nDPYD variants targeted by the later method).\n\nEconomic Analysis\nCost analysis comparing the impact of systematic screening for DPYD\nmutation with routine care was performed, consisting of testing for DPYD\nmutation in the event of severe toxicity following commencement of chemotherapy. All costs\nare in form of Euro (€) at 2012 values.\n\nThe cost of routine DPYD mutation testing if it had been applied\nprospectively in all patients commencing on fluoropyrimidine therapy for CRC in this time\nframe was calculated. Cost per test (€177) was obtained from internal hospital data and\nthen compared with the cost of the index admission with grade 3/4 toxicity for the\npatients identified retrospectively as having DPYD mutations. For\npatients with multiple admissions, the cost of the key admission, which led to\nDPYD mutation testing only, was assessed.\n\nCosts associated with the study are based on microcosting methods unless otherwise\nstated. The study was conducted in a private hospital, enabling analysis of costs of care\nincurred by individual patients. Discounting was not applied as only costs associated with\nthe index admission were evaluated. All costs associated with treatment of severe toxicity\nat the index admission were analyzed. Mean patient costs for an admission for severe\ntoxicity are detailed in Table\n1. Administrative and overhead costs were excluded as they were considered to be\nequivalent in both comparison groups. The primary analysis was conducted from an Irish\nprivate hospital perspective.\n\nTable 1. Mean Patient Costs for Index Admission With Severe Toxicity.\n\nCategory\tMean (€)\tStandard Deviation\t\nAccommodation fees\t25 981\t14 893\t\nConsumables\t114\t242\t\nParamedical\t4063\t4229\t\nPathology\t12 017\t11 570\t\nPathology send outs\t99\t102\t\nPharmacy\t2470\t1759\t\nProcedures\t480\t295\t\nRadiology\t1041\t578\t\nTheater/ward packs\t244\t141\t\nSensitivity Analysis\nOne-way sensitivity analysis was conducted on all known input variables. Variations of\n±50% were applied due to the low numbers involved in the study. An alternative scenario\nanalysis, from the perspective of the Irish health-care payer (responsible for public\nhospitals) based on diagnosis-related group costs, is also presented. Cost was based on an\naverage length of stay of 31.8 days for admission due to sequelae of treatment. Budget\nimpact analysis of potential costs and outcomes associated with implementing DPYD\nscreening at a national level was also conducted. Analysis was informed by national\nincidence, treatment, and mortality data.\n\nResults\nA total of 134 patients were commenced on first-line fluoropyrimidine-based chemotherapy\nfor CRC over the 3-year period, 66 in the adjuvant setting and 68 with metastatic disease.\nIn all, 30 patients (23%) developed grade 3/4 toxicity during chemotherapy and therefore\ntested for DPYD mutations. Of these, 5 (17% of those tested, 4.5% of total\npopulation) revealed heterozygote DPYD mutations. Of the 4 deleterious\nDPYD variants tested for, 2 were identified among our group of patients\nwith severe toxicity (DPYD*2A and *4). The\nDPYD genotype, toxicity type, and duration of hospitalization are\nsummarized in Table 2.\n\nTable 2. Characteristics of Patients Diagnosed With DPYD Mutations.\n\nPt\tGender\tRegimen\tCycle of Toxicity\tType of Toxicity\tMutation\tStatus\tLength of Admission (Days)\t\n1\tFemale\tFLOX\tPost C1D15\tGI\t*4\tHeterozygous\t64\t\n2\tMale\tmFolfox6\tPost C4\tGI and hematologic\t*2A\tHeterozygous\t37\t\n3\tFemale\tXelox\tPost C2*\tGI\tCompound *2A & *4\tHeterozygous\t26\t\n4\tMale\tmFolfox6\tPost C4\tGI\t*4\tHeterozygous\t17\t\n5\tMale\tmFolfox6\tPost C1\tGI and hematologic\t*2A\tHeterozygous\t15\t\nAbbreviations: C, cycle; D, day; GI, gastrointestinal; Pt, patient.\n\n\naPatient 3 had received previous capecitabine therapy with neoadjuvant\nradiation, requiring dose reductions for toxicity.\n\nThe total cost related to hospitalization with toxicity for these 5 patients was €232 061,\nan average of €46 412 per case. At €177 per test, the cost to prospectively test all 134\npatients would have been €23 718. As seen in Table 3, if 60% of patients identified with a\nDPYD mutation were prevented from experiencing a severe toxicity\nresulting in hospitalization, approximately €120 000 in additional cost would have been\navoided over a 3-year period.\n\nTable 3. Costs of Systematic Screening Versus Usual Care of 134 Patients Commenced on First-Line\nFluoropyrimidine-Based Chemotherapy (2010-2012) and 1-Way Sensitivity Analysis.\n\n\tSystematic Screening (€)\tUsual Care (€)\t\nCost of DPYD screening\t23 718\t5310\t\nCost of severe toxicity-related admission to hospital\t92 824a\n\t232 061\t\nTotal cost of care\t116 542\t232 371\t\nIncremental cost of systematic screening versus usual care\t−120 829\t\nEffectiveness of DPYD screening and altered chemotherapy protocols (lower limit\n= 30% success; upper limit = 90% success)\t−51 210\t−190 447\t\nCost of hospital care (±95% confidence interval)\t−37 265\t−204 392\t\nIrish health-care payer scenario\t−54 074\t\n\naBased on the assumption that routine screening for DPYD mutations and\nrevised chemotherapy protocol has a 60% success rate in preventing severe\ntoxicity-related admissions.\n\nSensitivity Analysis\nA wide variation was applied to help address uncertainty surrounding the intervention.\nVariations of ±50% were evaluated during sensitivity analysis (Table 3). If only 30% of the patients identified\nwith DPYD mutations were successfully prevented from experiencing severe\ntoxicity, the proposed update in practice would still result in a cost saving. All\nscenarios evaluated were in favor of routine DPD screening, including an analysis from an\nIrish public hospital scenario.\n\nBudget Impact Analysis\nBased on a 2009 report, the average incidence of early-stage (stage I-III) CRC in the\nRepublic of Ireland is 1484 patients per year11. Of these patients, 40% receive chemotherapy. Based on estimates from the primary\nanalysis presented in this article, the budgetary impact of implementing\nDYPD screening on a routine basis is €105 000 per year; however,\nsavings of approximately €630 000 could be achieved annually through the prevention of\nunexpected hospital admissions for severe toxicity from fluoropyrimidine.\n\nDiscussion\nThe novel finding of our study is that cost of admissions for severe chemotherapy-related\ntoxicity with reactive DPYD testing is higher than the cost of\nprospectively testing each new patient commencing fluoropyrimidine chemotherapy.\n\nUsing a panel of 4 mutations associated with fluoropyrimidine toxicity, we report a\nprevalence of heterozygous DPYD mutation in this Irish population with CRC\nof 4.5%. DPYD mutations were found to be present in a sizeable minority\n(17%) of patients developing grade 3/4 toxicities with fluoropyrimidine therapy. Previous\nstudies have described deleterious mutations in DPYD in up to 12% to 25% of\npatients developing grade 3/4 toxicities with fluoropyrimidine-based chemotherapy,12-15 although curiously one study found the dominant *2A polymorphism in\nas low as 2.2% of patients with severe toxicity.16\n\n\nTo date, there have been some proponents of routine testing for DPD deficiency prior to\nstarting treatment17; however, these remain the minority, the perceived wisdom being that preemptive\nscreening is not cost-effective. This consensus was challenged by a nonrandomized study in\npatients receiving fluoropyrimidine-based chemotherapy for CRC, demonstrating that\nprospective screening for DPD deficiency (genotype ± phenotype) could be a cost-effective strategy.18 Our study supports this finding by showing that routine prospective\nDPYD mutation testing in the Irish population would be associated with\nsignificant cost savings.\n\nPatients reactively diagnosed with DPYD mutations following admissions\nwith severe toxicity were unlikely to resume therapy at reduced doses, potentially\ncompromising curative outcomes.19 Prospective identification of patients with a DPYD mutation, coupled\nwith dose reduction from therapy initiation, may protect patients, improve quality of life,\nand avoid severe and potentially fatal chemotherapy-related toxicity.\n\nAlthough the practice of pharmacogenomic drug dosing is in its infancy, the Clinical\nPharmacogenetics Implementation Consortium (CPIC) has published guidelines containing dosing\nrecommendations for fluoropyrimidines based on DPYD genotype.20 They recommend a minimum of a 50% reduction in the initiation dose in patients\nheterozygous for the nonfunctional alleles *2a, *13, and 2846A>T. Notably, the consortium\ncurrently recommend that the *4 variant be categorized as “normal” activity, in part based\non functional analyses of enzymatic activity in transfected cell lines which suggested\nsupranormal activity.21,22 This is, however, contradictory to our study: the *4 allele was identified as a\nheterozygote variant in 2 of our patients with severe toxicity and a compound heterozygote\nin combination with the *2A variant in another. This variant has been found to be previously\nassociated with decreased enzyme activity in functional analyses of human donor peripheral\nblood mononuclear cells, as well as severe toxicity in patients receiving fluoropyrimidines.6,23-25 We suggest that initial dose reduction for this variant should continue to be\nconsidered, while we recognize that further study is required to produce more definitive\npharmacogenomic-based dosing guidelines.\n\nBy definition, pharmacogenomic dosing will vary between individuals, with initial dose\nreduction needing adjustment on a patient-by-patient basis. Currently, the CPIC guidelines\ndo not report dosing recommendations for all variants of DPYD, due to weak\nor conflicting data on the effect these alleles have on DPD activity.\n\nThere is understandable concern that patients may have dose reductions performed for\nidentified mutations which may not have resulted in increased toxicity, resulting in\npatients receiving reduced doses of potentially curative chemotherapy without achieving a\ngain from toxicity avoidance. Additional information regarding the increased toxicity\nassociated with various polymorphisms is required to optimize pharmacogenomic dosing.\nCurrently, it is reasonable to reduce doses appropriately for the better characterized\npolymorphisms listed above and avoid testing for polymorphisms of as yet undetermined\nsignificance. Similarly, where such polymorphisms are detected, one may recommend increased\neducation and vigilance for toxicity in such patients, without utilizing dose reductions\nfrom the start of therapy.\n\nOne way to clearly establish predictable drug exposure to minimize undue toxicity while\nmaximizing therapeutic exposure is to conduct continuous pharmacokinetic monitoring, as has\nbeen utilized in a French study.26-28 Although this is an interesting concept, it is an excessively labor-intensive and\ntime-consuming approach rendering it impractical in clinical practice.\n\nOur study suggests that while routine testing is economically viable, further research and\nclear guidance on dose reduction are needed. DPYD testing has the potential\nto avoid premature cessation of potentially curative therapy for patients with\ndeficiencies.\n\nWe acknowledge that this was a small single-center-based study and that results may be\nbiased by the fact that 2 of the hospitalized cases required prolonged treatment in an\nintensive care unit. Nonetheless, proposed routine screening of patients remained cost\nbeneficial in all sensitivity analysis conducted, including one encompassing an approximate\n50% reduction in costs. As with the vast majority of clinical-based studies, the diverse\nnature of health-care systems across jurisdictions must be considered when analyzing\nresults; however, it must be noted that the costs of inpatient care for complications due to\nboth medical and surgical therapy were among the fastest rising costs of hospital stays in\nUS health care in 2010.29\n\n\nAcknowledgments\nThe authors would like to thank our patients for participating in this study.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research,\nauthorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nORCID iD: Andrew Kenny \nhttp://orcid.org/0000-0001-5059-8520\n==== Refs\nReferences\n1 \nHeggie GD Sommadossi JP Cross DS \nClinical pharmacokinetics of 5-fluorouracil and its\nmetabolites in plasma, urine, and bile . Cancer Res .\n1987 ;47 (8 ):2203 –2206 .3829006 \n2 \nDeenen MJ Cats A Beijnen JH \nPart 2: pharmacogenetic variability in drug transport and\nphase I anticancer drug metabolism . Oncologist .\n2011 ;16 (6 ):820 –834 .\ndoi:10.1634/theoncologist.2010-0259 .21632461 \n3 \nMaekawa K Saeki M Saito Y \nGenetic variations and haplotype structures of the DPYD\ngene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic\ndifferences . J Hum Genet .\n2007 ;52 (10 ):804 –819 .\ndoi:10.1007/s10038-007-0186-6 .17828463 \n4 \nDeenen MJ Tol J Burylo AM \nRelationship between single nucleotide polymorphisms and\nhaplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal\ncancer . Clin Cancer Res .\n2011 ;17 (10 ):3455 –3468 .\ndoi:10.1158/1078-0432.CCR-10-2209 .21498394 \n5 \nJohnson MR Wang K Diasio RB \nProfound dihydropyrimidine dehydrogenase deficiency\nresulting from a novel compound heterozygote genotype . Clin\nCancer Res .\n2002 ;8 (3 ):768 –774 .11895907 \n6 \nLoganayagam A Arenas Hernandez M Corrigan A \nPharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR\ngenes are clinically significant predictors of fluoropyrimidine\ntoxicity . Br J Cancer .\n2013 ;108 (12 ):2505 –2515 .\ndoi:10.1038/bjc.2013.262 .23736036 \n7 \nRosmarin D Palles C Pagnamenta A \nA candidate gene study of capecitabine-related toxicity in\ncolorectal cancer identifies new toxicity variants at DPYD and a putative role for\nENOSF1 rather than TYMS . Gut .\n2015 ;64 (1 ):111 –120 .\ndoi:10.1136/gutjnl-2013-306571 .24647007 \n8 \nRosmarin D Palles C Church D \nGenetic markers of toxicity from capecitabine and other\nfluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and\nmeta-analysis . J Clin Oncol .\n2014 ;32 (10 ):1031 –1039 .\ndoi:10.1200/JCO.2013.51.1857 .24590654 \n9 \nOpdam FL Swen JJ Wessels JAM \nSNPs and haplotypes in DPYD and outcome of\ncapecitabine—letter . Clin Cancer Res .\n2011 ;17 (17 ):5833 ;\nauthor reply 5835-5836. doi:10.1158/1078-0432.CCR-11-1208. \n21878541 \n10 \nvan Staveren MC Jan Guchelaar H van Kuilenburg ABP \nEvaluation of predictive tests for screening for\ndihydropyrimidine dehydrogenase deficiency . Pharmacogenomics\nJ .\n2013 ;13 (5 ):389 –395 .\ndoi:10.1038/tpj.2013.25 .23856855 \n11 \nNational Cancer Registry of Ireland . http://www.ncri.ie/sites/ncri/files/pubs/ColorectalCancerIncidenceMortalityTreatmentandSurvivalinIreland1994-2010.pdf.\nAccessed September 19, 2018 .\n12 \nSaif MW \nDihydropyrimidine dehydrogenase gene (DPYD) polymorphism\namong Caucasian and non-Caucasian patients with 5-FU- and capecitabine-related toxicity\nusing full sequencing of DPYD . Cancer Genomics\nProteomics .\n2013 ;10 (2 ):89 –92 .23603345 \n13 \nVan Kuilenburg AB Meinsma R Zoetekouw L \nHigh prevalence of the IVS14 + 1G>A mutation in the\ndihydropyrimidine dehydrogenase gene of patients with severe 5-fluorouracil-associated\ntoxicity . Pharmacogenetics .\n2002 ;12 (7 ):555 –558 .12360106 \n14 \nRaida M Schwabe W Häusler P \nPrevalence of a common point mutation in the\ndihydropyrimidine dehydrogenase (DPD) gene within the 5′-splice donor site of intron 14\nin patients with severe 5-fluorouracil (5-FU)-related toxicity compared with\ncontrols . Clin Cancer Res .\n2001 ;7 (9 ):2832 –2839 .11555601 \n15 \nLoganayagam A Arenas-Hernandez M Fairbanks L \nThe contribution of deleterious DPYD gene sequence\nvariants to fluoropyrimidine toxicity in British cancer patients .\nCancer Chemother Pharmacol .\n2010 ;65 (2 ):403 –406 .\ndoi:10.1007/s00280-009-1147-x .19795123 \n16 \nMagné N Etienne-Grimaldi MC Cals L \nDihydropyrimidine dehydrogenase activity and the\nIVS14+1G>A mutation in patients developing 5FU-related toxicity .\nBr J Clin Pharmacol .\n2007 ;64 (2 ):237 –240 .\ndoi:10.1111/j.1365-2125.2007.02869.x .17335544 \n17 \nDel Re M Di Paolo A van Schaik RH \nDihydropyrimidine dehydrogenase polymorphisms and\nfluoropyrimidine toxicity: ready for routine clinical application within personalized\nmedicine? \nEPMA J .\n2010 ;1 (3 ):495 –502 .\ndoi:10.1007/s13167-010-0041-2 .23199091 \n18 \nTraoré S Boisdron-Celle M Hunault G \nDPD deficiency: medicoeconomic evaluation of pretreatment\nscreening of 5-FU toxicity . J Clin Oncol .\n2012 ;30 (suppl\n4 ):410 –410 .\ndoi:10.1200/jco.2012.30.4_suppl.410. \n\n19 \nUnited States Food and Drug Administration label information\non capecitabine . https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020896s037lbl.pdf.\nAccessed September 19, 2018 .\n20 \nCaudle KE Thorn CF Klein TE \nClinical Pharmacogenetics Implementation Consortium\nguidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine\ndosing . Clin Pharmacol Ther .\n2013 ;94 (6 ):640 –645 .\ndoi:10.1038/clpt.2013.172 .23988873 \n21 \nCPIC dosing guideline for fluorouracil and DPYD .\nhttp://www.pharmgkb.org/guideline/PA166122686. Accessed September\n19, 2018. \n\n22 \nOffer SM Fossum CC Wegner NJ \nComparative functional analysis of DPYD variants of\npotential clinical relevance to dihydropyrimidine dehydrogenase\nactivity . Cancer Res .\n2014 ;74 (9 ):2545 –2554 .\ndoi:10.1158/0008-5472.CAN-13-2482 .24648345 \n23 \nLazar A Mau-Holzmann UA Kolb H \nMultiple organ failure due to 5-fluorouracil chemotherapy\nin a patient with a rare dihydropyrimidine dehydrogenase gene variant .\nOnkologie .\n2004 ;27 (6 ):559 –562 .\ndoi:10.1159/000081338 .15591715 \n24 \nCollie-Duguid ESR Etienne MC Milano G \nKnown variant DPYD alleles do not explain DPD deficiency\nin cancer patients . Pharmacogenetics .\n2000 ;10 :217 –223 .10803677 \n25 \nSeck K \nAnalysis of the DPYD gene implicated in 5-fluorouracil\ncatabolism in a cohort of Caucasian individuals . Clin Cancer\nRes .\n2005 ;11 (16 ):5886 –5892 .\ndoi:10.1158/1078-0432.CCR-04-1784 .16115930 \n26 \nGamelin E Delva R Jacob J \nIndividual fluorouracil dose adjustment based on\npharmacokinetic follow-up compared with conventional dosage: results of a multicenter\nrandomized trial of patients with metastatic colorectal cancer .\nJ Clin Oncol .\n2008 ;26 (13 ):2099 –2105 .\ndoi:10.1200/JCO.2007.13.3934 .18445839 \n27 \nBoisdron-Celle M Capitain O Metges JP \nSevere fluoropyrimidines toxicities: a simple and\neffective way to avoid them. Screen effectively for DPD deficiencies .\nAnn Oncol . 2012 ;23 (suppl\n4 ):iv5 –iv18 , abstract\nO-0019 .22774231 \n28 \nBoisdron-Celle M Capitain O Faroux R \nPrevention of 5-FU-induced toxicities using pretherapeutic\nDPD deficiency screening: medical and economic assessment of a multiparametric\napproach . J Clin Oncol .\n2013 ;31 (suppl\n4 ):351 –351 .\ndoi:10.1200/jco.2013.31.4_suppl.351. \n23233706 \n29 \nPfuntner A Wier LM Steiner C \nCosts for hospital stays in the United States,\n2010 . HCUP Statistical Brief #146 . 2013 \nRockville, MD : Agency for Healthcare\nResearch and Quality \nAvailable at : http://www.hcup-us.ahrq.gov/reports/statbriefs/sb146.pdf\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1559-3258",
"issue": "16(4)",
"journal": "Dose-response : a publication of International Hormesis Society",
"keywords": "DPYD; colorectal cancer; cost-effectiveness; fluoropyrimidine; pharmacogenomics",
"medline_ta": "Dose Response",
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"pages": "1559325818803042",
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"pmid": "30288154",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "24648345;18445839;24590654;21498394;23736036;17335544;23856855;21878541;17828463;10803677;19795123;21632461;11895907;3829006;23988873;11555601;24647007;23199091;16115930;15591715;12360106;23603345",
"title": "Cost Implications of Reactive Versus Prospective Testing for Dihydropyrimidine Dehydrogenase Deficiency in Patients With Colorectal Cancer: A Single-Institution Experience.",
"title_normalized": "cost implications of reactive versus prospective testing for dihydropyrimidine dehydrogenase deficiency in patients with colorectal cancer a single institution experience"
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"abstract": "ANCA-associated vasculitis (AAV) is a rare and potentially life threatening complication associated with antithyroid drug use. It is more commonly reported with propylthiouracil, with fewer cases reported with methimazole use. We present the case of a 55-year-old man with toxic multinodular goiter which was treated with methimazole for 6 months. He developed ANCA positive leukocytoclastic vasculitis with hemorrhagic and necrotic bullous lesions of lower extremities. The vasculitis was initially thought to be secondary to recent cephalosporin use; however, the skin lesions progressed despite stopping the cephalosporin and treatment with steroids, and he developed osteomyelitis. His vasculitis resolved after cessation of methimazole use. This case highlights the importance of careful monitoring for variable manifestations of AAV in patients treated with methimazole.",
"affiliations": "Department of Endocrinology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.;Department of Pathology, Maimonides Medical Center, Brooklyn, NY, USA.;Department of Endocrinology, Maimonides Medical Center, Brooklyn, NY, USA.;Department of Endocrinology, Maimonides Medical Center, Brooklyn, NY, USA.",
"authors": "Shikha|Deep|D|;Harris|Jonathan|J|;Resta|Christine|C|;Park|Patricia|P|",
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"doi": "10.1155/2015/530319",
"fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIECase Reports in Endocrinology2090-65012090-651XHindawi Publishing Corporation 10.1155/2015/530319Case ReportAntineutrophilic Cytoplasmic Antibody Positive Vasculitis\nAssociated with Methimazole Use Shikha Deep \n1\n\n*\nHarris Jonathan \n2\nResta Christine \n3\nPark Patricia \n3\n1Department of Endocrinology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA2Department of Pathology, Maimonides Medical Center, Brooklyn, NY, USA3Department of Endocrinology, Maimonides Medical Center, Brooklyn, NY, USA*Deep Shikha: deepshikha.doc@gmail.comAcademic Editor: Najmul Islam\n\n2015 28 4 2015 2015 5303198 12 2014 16 4 2015 Copyright © 2015 Deep Shikha et al.2015This 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.ANCA-associated vasculitis (AAV) is a rare and potentially life threatening complication associated with antithyroid drug use. It is more commonly reported with propylthiouracil, with fewer cases reported with methimazole use. We present the case of a 55-year-old man with toxic multinodular goiter which was treated with methimazole for 6 months. He developed ANCA positive leukocytoclastic vasculitis with hemorrhagic and necrotic bullous lesions of lower extremities. The vasculitis was initially thought to be secondary to recent cephalosporin use; however, the skin lesions progressed despite stopping the cephalosporin and treatment with steroids, and he developed osteomyelitis. His vasculitis resolved after cessation of methimazole use. This case highlights the importance of careful monitoring for variable manifestations of AAV in patients treated with methimazole.\n==== Body\n1. Introduction\nMethimazole (MMI) and propylthiouracil (PTU) are thionamide drugs, which are commonly used as first-line therapy in the treatment of hyperthyroidism due to Grave's disease and toxic nodular goiter in the United States. These medications are not without risk, however, and are associated with potential adverse reactions such as fever, rash, agranulocytosis, and hepatitis. These reactions usually occur within the first few months of initiating treatment [1], although agranulocytosis can occur idiosyncratically at any time during treatment. ANCA positive vasculitis is a serious but lesser known complication of thionamides. Despite being previously described in the literature, there is a lower incidence of reported ANCA positive vasculitis with MMI use as compared to PTU [2, 3]. We report a patient who developed ANCA positive leukocytoclastic vasculitis after six months of MMI treatment.\n\n2. Case\nA 55-year-old male was diagnosed with hyperthyroidism by his primary care physician. Thyroid sonogram showed a multinodular goiter. FNA biopsies of the dominant nodules were benign, and he was started on methimazole 20 mg twice a day for toxic nodular goiter. Six months later, he presented to the emergency department with bilateral lower extremity pain, redness, and swelling. He was diagnosed with cellulitis and discharged home on oral cephalexin; however, his lower extremity lesions progressed over the next month, and he was admitted to the hospital for further management.\n\nDuring that admission, the patient was noted to have hemorrhagic and necrotic bullous lesions on the anterior aspect of the bilateral lower legs and dorsal aspect of the feet. Laboratory data showed elevated C-reactive protein suggestive of an inflammatory reaction, but without leukocytosis or eosinophilia. He had normal levels of rheumatoid factor, ribonucleoprotein antibody, and Sjogren SSA and SSB antibodies. Serum complement C3 and C4 levels were high; C3 was 180 mg/dL (<90 mg/dL) and C4 was 50 mg/dL (6–47 mg/dL). Antinuclear antibody (ANA) was positive in titres of 1 : 80 with a speckled pattern. ANCA screen as measured with indirect immunofluorescence was positive for p-ANCA and detected high MPO antibodies at 5.6 AI (normal < 1 AI). Work-up for HIV, hepatitis B, and hepatitis C was negative. Urinalysis was unremarkable. Skin biopsy of the lesions revealed leukocytoclastic vasculitis with fibrin thrombi. No immune deposits were detected (Figures 1 and 2).\n\nBased on this work-up, the vasculitis was attributed to cephalexin. The patient was treated with high dose prednisone for 2 weeks in the hospital and discharged home with an additional 2 weeks of tapering glucocorticoids. He presented again 2 months later with persistent bilateral lower extremity skin lesions and suppurative discharge from the left foot. MRI and bone biopsy were consistent with acute osteomyelitis.\n\nThe endocrinology team was consulted during this readmission because of high TSH while being on methimazole. On examination, he had no lid lag or exophthalmos. Thyroid was nodular and enlarged about three times the normal size, with left lobe bigger than right. CXR showed an enlarged left thyroid lobe deviating the upper trachea to the right side. Thyroid antibodies were not elevated: thyroid peroxidase antibody was 14 IU/mL (<35 IU/mL), thyroglobulin antibody was <20 IU/mL (<20 IU/mL), and thyroid stimulating immunoglobulin was 125% (<140%).\n\nThe lower extremity lesions did not resolve despite stopping cephalexin and completing month-long course of steroids; therefore, we considered the possibility of methimazole-induced leukocytoclastic vasculitis. Methimazole was discontinued. We then recommended total thyroidectomy for definitive management of a toxic multinodular goiter that was also causing tracheal deviation. Surgical pathology showed nodular hyperplasia with focal Hurthle cell features and calcifications with ossification. He was started on levothyroxine replacement therapy and antibiotics for osteomyelitis and discharged home. On 1-month follow-up in clinic, the patient's skin lesions were largely resolved and he was clinically well.\n\n3. Discussion\nANCA-associated vasculitis (AAV) is a group of small vessel vasculitides that consist of autoantibodies directed against the lysosomal enzymes of neutrophils. These autoantibodies are divided into two main groups: cytoplasmic (c-ANCA) which confers antigen specificity for proteinase 3 and is associated with Wegener's granulomatosis and perinuclear (p-ANCA) which reacts against myeloperoxidase (MPO) and is mainly associated with microscopic polyangiitis (MPA) and Churg-Strauss syndrome. AAV may cause a variety of constitutional symptoms including fever, myalgia, arthralgia, and flu like syndrome. Multisystem involvement can be seen, with the kidneys most commonly affected followed by skin and respiratory tract [3]. Vessels in the joints, eyes, skeletal muscle, gastrointestinal tract, and peripheral nerves may also be involved. The most common cutaneous lesion is leukocytoclastic vasculitis, which preferentially affects the lower extremities [4].\n\nAAV in association with antithyroid drugs is a relatively uncommon entity, and the pathogenesis of vasculitis associated with ATDs is not well understood. There have been reports of cutaneous and systemic AAV, with most of the literature describing p-ANCA vasculitis in the setting of PTU use, particularly in Asian individuals [2–10]. It has been postulated that PTU binds to myeloperoxidase and alters its structure, leading to formation of autoantibodies in susceptible individuals [11]. There are no published data that suggest that methimazole can also alter the configuration of myeloperoxidase. Data from Gao et al. [12] indicate that activated neutrophils produce increased amounts of myeloperoxidase which oxidize the thionamides into reactive intermediates. These intermediates then activate immunocompetent cells such as lymphocytes via covalently binding to self-proteins, leading to production of MPO-ANCA and hence causing vascular injury.\n\nAAV is a rare complication of MMI use, with few cases described in the literature. The first case of MMI-induced AAV was described by Kawachi et al. in 1995 [6]. AAV is also less frequently described in toxic MNG compared to Grave's disease. In 1996, Gunton et al. assembled 27 cases of ATD-induced ANCA positive vasculitis in which only one case was related to MMI and only 1 case had underlying toxic MNG as the etiology of hyperthyroidism [2].\n\nNoh et al. have reported that the incidence for PTU-related AAV is about 39 times that for MMI [3]. Despite being associated with long term antithyroid drug treatment, with median onset time 42 months, it can also occur within a few months of starting the treatment. MPO-AAV can occur even at low doses for both MMI and PTU. It is reported to occur more frequently in women, although this may just reflect the female preponderance of thyroid disease. Interestingly, the appearance of p-ANCA antibodies does not always predict the development of clinical vasculitis [13], and there is also no correlation between the MPO-ANCA titer and the severity of vasculitis [3].\n\nImportantly, p-ANCA-associated vasculitis improves and has a good prognosis if antithyroid drugs are discontinued. Some patients may require steroids and/or immunosuppressive drugs depending upon the severity of the disease. Serious complications (pulmonary hemorrhage, acute kidney failure, and nonhealing ulcers) have been reported when ATDs have been continued due to unawareness of this uncommon adverse reaction.\n\nOur patient had leukocytoclastic vasculitis with cutaneous lesions and no systemic manifestations. His vasculitis was initially thought to be secondary to cephalosporin use, but the skin lesions did not heal despite stopping cephalosporin and completing a course of prednisone. The patient in fact had progression of the lower extremity ulcers and developed osteomyelitis. After MMI was discontinued, the skin lesions resolved. This clinical course along with the presence of high p-ANCA titres suggested that the biopsy-proven leukocytoclastic vasculitis was likely an AAV due to MMI use. We did not recommend PTU therapy after stopping MMI due to the higher reported incidence of vasculitis with PTU use and reports of cross reactivity between PTU and MMI [14] in AAV.\n\nIn conclusion, we suggest that clinicians be aware of this uncommon adverse reaction of MMI treatment. Patients treated with MMI should be carefully monitored for manifestations of AAV such as fever, skin involvement, myalgias, arthralgias, glomerulonephritis, and pulmonary hemorrhage, regardless of the period of administration of MMI. Early recognition of this serious adverse effect is crucial as immediate cessation of MMI is needed, along with possible administration of corticosteroids, in order to prevent progression of the disease and its serious sequelae.\n\nConflict of Interests\nThe authors have no multiplicity of interests to disclose.\n\nFigure 1 Skin biopsy in low power field showing leukocytoclastic vasculitis.\n\nFigure 2 Skin biopsy in high power field showing leukocytoclastic vasculitis.\n==== Refs\n1 Cooper D. S. Antithyroid drugs The New England Journal of Medicine 1984 311 21 1353 1362 10.1056/nejm198411223112106 2-s2.0-0021671462 6387489 \n2 Gunton J. E. Stiel J. Caterson R. J. McElduff A. Anti-thyroid drugs and antincutrophil cytoplasmic antibody positive vasculitis. A case report and review of the literature The Journal of Clinical Endocrinology and Metabolism 1999 84 1 13 16 10.1210/jc.84.1.13 2-s2.0-0032615323 9920055 \n3 Noh J. Y. Yasuda S. Sato S. Clinical characteristics of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis caused by antithyroid drugs Journal of Clinical Endocrinology and Metabolism 2009 94 8 2806 2811 10.1210/jc.2008-2700 2-s2.0-68549117057 19491223 \n4 Martin D. B. Deng A. Gaspari A. Pearson F. Perinuclear antineutrophil cytoplasmic antibody-associated vasculitis in a patient with Graves' disease treated with methimazole Skinmed 2006 5 6 302 305 10.1111/j.1540-9740.2006.05350.x 2-s2.0-39049184533 17086001 \n5 Gammeltoft M. Kjeldstrup Kristensen J. Propylthio-uracil-induced cutaneous vaculitis Acta Dermato-Venereologica 1982 62 2 171 173 2-s2.0-0020060370 6179348 \n6 Kawachi Y. Nukaga H. Hoshino M. Iwata M. Otsuka F. ANCA-associated vasculitis and lupus-like syndrome caused by methimazole Clinical and Experimental Dermatology 1995 20 4 345 347 10.1111/j.1365-2230.1995.tb01340.x 2-s2.0-0028866477 8548997 \n7 Thong H.-Y. Chu C.-Y. Chiu H.-C. Methimazole-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and lupus-like syndrome with a cutaneous feature of vesiculo-bullous systemic lupus erythematosus Acta Dermato-Venereologica 2002 82 3 206 208 10.1080/00015550260132523 2-s2.0-0036022549 12353714 \n8 Tripodi P. F. Ruggeri R. M. Campennì A. Central nervous system vasculitis after starting methimazole in a woman with Graves' disease Thyroid 2008 18 9 1011 1013 2-s2.0-51849137955 10.1089/thy.2008.0121 18788922 \n9 Lau E. Y. F. So S. Y. Chan E. Kwok J. Ma J. Kung A. W. C. Methimazole-induced antineutrophil cytoplasmic antibody-associated diffuse alveolar haemorrhage in a Chinese woman with Graves' disease Hong Kong Medical Journal 2009 15 3 209 212 2-s2.0-67650501030 19494377 \n10 Yasude T. Kishida D. Tazawa K.-I. ANCA-associated vasculitis with central retinal artery occlusion developing during treatment with methimazole Internal Medicine 2012 51 22 3177 3180 2-s2.0-84869811252 23154728 \n11 Lam D. C. C. Lindsay R. H. Accumulation of 2-[14C]propylthiouracil in human polymorphonuclear leukocytes Biochemical Pharmacology 1979 28 15 2289 2296 10.1016/0006-2952(79)90692-0 2-s2.0-0018654464 497011 \n12 Gao Y. Chen M. Ye H. Guo X.-H. Zhao M.-H. Wang H.-Y. The target antigens of antineutrophil cytoplasmic antibodies (ANCA) induced by propylthiouracil International Immunopharmacology 2007 7 1 55 60 10.1016/j.intimp.2006.07.033 2-s2.0-33845196822 17161817 \n13 Gunton J. E. Stiel J. Clifton-Bligh P. Wilmshurst E. McElduff A. Prevalence of positive anti-neutrophil cytoplasmic antibody (ANCA) in patients receiving anti-thyroid medication European Journal of Endocrinology 2000 142 6 p. 587 10.1530/eje.0.1420587 2-s2.0-0034051269 10822221 \n14 Ahmed K. Rao S. Simha V. Antineutrophil cytoplasmic antibody-positive vasculitis in a patient with Graves disease: cross-reaction between propylthiouracil and methimazole Endocrine Practice 2010 16 3 449 451 10.4158/ep09304.cr 2-s2.0-77956645992 20061292\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-651X",
"issue": "2015()",
"journal": "Case reports in endocrinology",
"keywords": null,
"medline_ta": "Case Rep Endocrinol",
"mesh_terms": null,
"nlm_unique_id": "101576457",
"other_id": null,
"pages": "530319",
"pmc": null,
"pmid": "26060588",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "19491223;8548997;19494377;6179348;17161817;6387489;497011;17086001;20061292;23154728;18788922;9920055;12353714;10822221",
"title": "Antineutrophilic Cytoplasmic Antibody Positive Vasculitis Associated with Methimazole Use.",
"title_normalized": "antineutrophilic cytoplasmic antibody positive vasculitis associated with methimazole use"
} | [
{
"companynumb": "US-PFIZER INC-2015182007",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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{
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"activesubstance": {
"activesubstancename": "METHIMAZOLE"
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{
"abstract": "Induction of multiple eruptive dermal and atypical melanocytic naevi has frequently been reported in children with malignant haematological diseases and chemotherapy-induced immunosuppression. This is the first report of an adult patient to develop multiple eruptive melanocytic skin lesions while undergoing chemotherapy with an oral 5-fluorouracil prodrug for metastasizing cancer. Our observation adds further evidence to the link between systemic (iatrogenic or intrinsic) immunosuppression and the induction of melanocyte proliferation and transformation.",
"affiliations": "Department of Dermatology, University of Regensburg Medical Center, Regensburg, Germany.",
"authors": "Bogenrieder|Thomas|T|;Weitzel|Christof|C|;Schölmerich|Jürgen|J|;Landthaler|Michael|M|;Stolz|Wilhelm|W|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000063905",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-8665",
"issue": "205(2)",
"journal": "Dermatology (Basel, Switzerland)",
"keywords": null,
"medline_ta": "Dermatology",
"mesh_terms": "D000284:Administration, Oral; D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D002277:Carcinoma; D015179:Colorectal Neoplasms; D003841:Deoxycytidine; D003875:Drug Eruptions; D005472:Fluorouracil; D006801:Humans; D018327:Hutchinson's Melanotic Freckle; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D016609:Neoplasms, Second Primary; D009508:Nevus, Pigmented; D011355:Prodrugs; D012867:Skin; D012878:Skin Neoplasms",
"nlm_unique_id": "9203244",
"other_id": null,
"pages": "174-5",
"pmc": null,
"pmid": "12218237",
"pubdate": "2002",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Eruptive multiple lentigo-maligna-like lesions in a patient undergoing chemotherapy with an oral 5-fluorouracil prodrug for metastasizing colorectal carcinoma: a lesson for the pathogenesis of malignant melanoma?",
"title_normalized": "eruptive multiple lentigo maligna like lesions in a patient undergoing chemotherapy with an oral 5 fluorouracil prodrug for metastasizing colorectal carcinoma a lesson for the pathogenesis of malignant melanoma"
} | [
{
"companynumb": "DE-MYLANLABS-2020M1042210",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
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{
"abstract": "To identify factors associated with low benzodiazepine (BZD) dosing in patients with refractory status epilepticus (RSE) and to assess the impact of BZD treatment variability on seizure cessation.\n\n\n\nThis was a retrospective study with prospectively collected data of children with convulsive RSE admitted between June 2011 and January 2019. We analyzed the initial and total BZD dose within 10 minutes of treatment initiation. We used logistic regression modeling to evaluate predictors of low BZD dosing and multivariate Cox regression analysis to assess the impact of low BZD dosing on time to seizure cessation.\n\n\n\nWe included 289 patients (55.7% male) with a median age of 4.3 (1.3-9.5) years. BZDs were the initial medication in 278 (96.2%). Of those, 161 patients (57.9%) received a low initial dose. Low initial BZD doses occurred in both out-of-hospital (57 of 106; 53.8%) and in-hospital (104 of 172; 60.5%) settings. One hundred three patients (37.1%) received low total BZD dose. Male sex (odds ratio [OR] 2, 95% confidence interval [CI] 1.18-3.49; p = 0.012), older age (OR 1.1, 95% CI 1.05-1.17; p < 0.001), no prior diagnosis of epilepsy (OR 2.1, 95% CI 1.23-3.69; p = 0.008), and delayed BZD treatment (OR 2.2, 95% CI 1.24-3.94; p = 0.007) were associated with low total BZD dose. Patients who received low total BZD dosing were less likely to achieve seizure cessation (hazard ratio 0.7, 95% CI 0.57-0.95).\n\n\n\nBZD doses were lower than recommended in both out-of-hospital and in-hospital settings. Factors associated with low total BZD dose included male sex, older age, no prior epilepsy diagnosis, and delayed BZD treatment. Low total BZD dosing was associated with decreased likelihood of Seizure cessation.\n\n\n\nThis study provides Class III evidence that patients with RSE who present with male sex, older age, no prior diagnosis of epilepsy, and delayed BZD treatment are more likely to receive low total BZD doses. This study provides Class III evidence that in pediatric RSE low total BZD dose decreases the likelihood of seizure cessation.",
"affiliations": "From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.;From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital. tobias.loddenkemper@childrens.harvard.edu.",
"authors": "Vasquez|Alejandra|A|;Gaínza-Lein|Marina|M|;Abend|Nicholas S|NS|;Amengual-Gual|Marta|M|;Anderson|Anne|A|;Arya|Ravindra|R|0000-0003-0873-9718;Brenton|J Nicholas|JN|0000-0001-9432-1347;Carpenter|Jessica L|JL|;Chapman|Kevin|K|;Clark|Justice|J|;Farias-Moeller|Raquel|R|;Gaillard|William D|WD|;Glauser|Tracy|T|;Goldstein|Joshua L|JL|;Goodkin|Howard P|HP|;Guerriero|Rejean M|RM|0000-0001-7788-6661;Kapur|Kush|K|0000-0001-9022-913X;Lai|Yi-Chen|YC|;McDonough|Tiffani L|TL|;Mikati|Mohamad A|MA|;Morgan|Lindsey A|LA|;Novotny|Edward J|EJ|0000-0001-9726-0447;Ostendorf|Adam P|AP|;Payne|Eric T|ET|0000-0001-6210-3353;Peariso|Katrina|K|;Piantino|Juan|J|;Riviello|James J|JJ|;Sannagowdara|Kumar|K|;Tasker|Robert C|RC|0000-0003-3647-8113;Tchapyjnikov|Dmitry|D|0000-0001-5649-5880;Topjian|Alexis|A|;Wainwright|Mark S|MS|0000-0002-4736-7462;Wilfong|Angus|A|;Williams|Korwyn|K|;Loddenkemper|Tobias|T|;|||",
"chemical_list": "D000927:Anticonvulsants; D001569:Benzodiazepines; D000077287:Levetiracetam; D010672:Phenytoin; C043114:fosphenytoin; D010634:Phenobarbital",
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"issue": "95(19)",
"journal": "Neurology",
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"mesh_terms": "D000293:Adolescent; D000367:Age Factors; D000927:Anticonvulsants; D001569:Benzodiazepines; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D000069279:Drug Resistant Epilepsy; D005260:Female; D019983:Guideline Adherence; D006801:Humans; D007223:Infant; D000077287:Levetiracetam; D008297:Male; D015999:Multivariate Analysis; D010634:Phenobarbital; D010672:Phenytoin; D017410:Practice Guidelines as Topic; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012737:Sex Factors; D013226:Status Epilepticus; D061665:Time-to-Treatment",
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"pubdate": "2020-11-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "26140660;8780085;26293745;6131148;15489391;30661257;21956209;24756515;27080243;15309139;24928286;22335736;29356811;20738380;24183923;9952262;7672465;26900382;17499921;18245435;31161706;11843690;18364657;25948729;16393180;15944904;29055868;11781422;22528274;18602345;24791086;19194344",
"title": "First-line medication dosing in pediatric refractory status epilepticus.",
"title_normalized": "first line medication dosing in pediatric refractory status epilepticus"
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"abstract": "During the recent years, immune checkpoint-based therapy has proven highly effective in microsatellite instable (MSI) solid tumors irrespective of organ site. MSI tumors are associated with a defective mismatch repair (MMR) system and a highly immune-infiltrative tumor microenvironment-both characteristics of Lynch syndrome. Lynch syndrome is a multi-tumor syndrome that not only confers a high risk of colorectal and endometrial cancer but also cancer in, eg the upper urinary tract, ovaries, and small bowel. Since the genetic predisposition for Lynch syndrome are pathogenic variants in one of the four MMR genes, MLH1, MSH2, MSH6 or PMS2, most of the Lynch syndrome cancers show MMR deficiency, MSI, and activation of the immune response system. Hence, Lynch syndrome cancer patients may be optimal candidates for immune checkpoint-based therapies. However, molecular differences have been described between sporadic MSI tumors (developed due to MLH1 promoter hypermethylation) and Lynch syndrome tumors, which may result in different treatment responses. Furthermore, the response profile of the rare Lynch syndrome cases may be masked by the more frequent cases of sporadic MSI tumors in large clinical trials. With this review, we systematically collected response data on Lynch syndrome patients treated with FDA- and EMA-approved immune checkpoint-based drugs (pembrolizumab, atezolizumab, durvalumab, avelumab, ipilimumab, and nivolumab) to elucidate the objective response rate and progression-free survival of cancer in Lynch syndrome patients. Herein, we report Lynch syndrome-related objective response rates between 46 and 71% for colorectal cancer and 14-100% for noncolorectal cancer in unselected cohorts as well as an overview of the Lynch syndrome case reports. To date, no difference in the response rates has been reported between Lynch syndrome and sporadic MSI cancer patients.",
"affiliations": "Department of Surgical Gastroenterology, Copenhagen University Hospital, Copenhagen, Denmark.;Department of Oncology, University Hospital of Southern Denmark, Vejle Hospital, Vejle, Denmark.;The Danish HNPCC Register, Department of Clinical Research, Copenhagen University Hospital, Amager and Hvidovre, Copenhagen, Denmark.;Department of Gastroenterology, Aalborg Hospital, Aalborg, Denmark.",
"authors": "Therkildsen|Christina|C|;Jensen|Lars Henrik|LH|0000-0002-0020-1537;Rasmussen|Maria|M|0000-0003-0902-2540;Bernstein|Inge|I|0000-0003-4095-432X",
"chemical_list": null,
"country": "New Zealand",
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"doi": "10.2147/CEG.S278054",
"fulltext": "\n==== Front\nClin Exp Gastroenterol\nClin Exp Gastroenterol\nceg\nceg\nClinical and Experimental Gastroenterology\n1178-7023\nDove\n\n278054\n10.2147/CEG.S278054\nReview\nAn Update on Immune Checkpoint Therapy for the Treatment of Lynch Syndrome\nTherkildsen et al\nTherkildsen et al\nTherkildsen Christina 12\nhttp://orcid.org/0000-0002-0020-1537\nJensen Lars Henrik 3\nhttp://orcid.org/0000-0003-0902-2540\nRasmussen Maria 2\nhttp://orcid.org/0000-0003-4095-432X\nBernstein Inge 45\n1 Department of Surgical Gastroenterology, Copenhagen University Hospital, Copenhagen, Denmark\n2 The Danish HNPCC Register, Department of Clinical Research, Copenhagen University Hospital, Amager and Hvidovre, Copenhagen, Denmark\n3 Department of Oncology, University Hospital of Southern Denmark, Vejle Hospital, Vejle, Denmark\n4 Department of Gastroenterology, Aalborg Hospital, Aalborg, Denmark\n5 Faculty of Medicine, Aalborg University, Aalborg, Denmark\nCorrespondence: Inge Bernstein Department of Gastroenterology, Aalborg Hospital, Hobrovej 18-22, Aalborg, 9100, DenmarkTel +45 97666805 Email i.bernstein@rn.dk\n24 5 2021\n2021\n14 181197\n14 3 2021\n15 4 2021\n© 2021 Therkildsen et al.\n2021\nTherkildsen et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nAbstract\n\nDuring the recent years, immune checkpoint-based therapy has proven highly effective in microsatellite instable (MSI) solid tumors irrespective of organ site. MSI tumors are associated with a defective mismatch repair (MMR) system and a highly immune-infiltrative tumor microenvironment—both characteristics of Lynch syndrome. Lynch syndrome is a multi-tumor syndrome that not only confers a high risk of colorectal and endometrial cancer but also cancer in, eg the upper urinary tract, ovaries, and small bowel. Since the genetic predisposition for Lynch syndrome are pathogenic variants in one of the four MMR genes, MLH1, MSH2, MSH6 or PMS2, most of the Lynch syndrome cancers show MMR deficiency, MSI, and activation of the immune response system. Hence, Lynch syndrome cancer patients may be optimal candidates for immune checkpoint-based therapies. However, molecular differences have been described between sporadic MSI tumors (developed due to MLH1 promoter hypermethylation) and Lynch syndrome tumors, which may result in different treatment responses. Furthermore, the response profile of the rare Lynch syndrome cases may be masked by the more frequent cases of sporadic MSI tumors in large clinical trials. With this review, we systematically collected response data on Lynch syndrome patients treated with FDA- and EMA-approved immune checkpoint-based drugs (pembrolizumab, atezolizumab, durvalumab, avelumab, ipilimumab, and nivolumab) to elucidate the objective response rate and progression-free survival of cancer in Lynch syndrome patients. Herein, we report Lynch syndrome-related objective response rates between 46 and 71% for colorectal cancer and 14–100% for noncolorectal cancer in unselected cohorts as well as an overview of the Lynch syndrome case reports. To date, no difference in the response rates has been reported between Lynch syndrome and sporadic MSI cancer patients.\n\nKeywords\n\nhereditary colorectal cancer\nHNPCC\nLynch syndrome\nendometrial cancer\ngermline mismatch repair defect\n==== Body\nIntroduction\n\nLynch syndrome, caused by germline pathogenic variants in the mismatch repair (MMR) genes, MLH1, PMS2, MSH2, and MSH6, is the most common type of hereditary colorectal cancer. The syndrome is, however, also associated with a series of other cancer types, including endometrial cancer, ovarian cancer, urothelial tract cancer, small bowel cancer, gastric cancer, brain tumor, and sebaceous skin tumor.1–3 Lynch syndrome-associated tumors develop through inactivation of the second MMR allele leading to biallelic loss of MMR protein expression and hence deficient MMR (dMMR). Tumors with d-MMR have lost the ability to repair DNA errors introduced during replication and these tumors often present with high levels of mutation, reflected as microsatellite instability (MSI).4 The increased number of mutations are often presented as neoantigens that recruit and activate the host immune cells.5 Further tumor progression can be facilitated through immunoediting like T cell exhaustion, eg, by targeting immune checkpoints like the programmed death 1 (PD-1) or cytotoxic T lymphocyte antigen 4 (CTLA-4) receptors.6 Inhibiting these checkpoint blockades may reactivate the anti-tumorigenic T cells.\n\nIn 2017, MSI or dMMR were approved as pan-cancer biomarkers for the anti-PD-1 checkpoint therapy pembrolizumab by the American Food and Drug Administration (FDA).7 The approval was based on multicenter, multicohort, single-arm trials, some of which included Lynch syndrome data.4,8 Shortly after, nivolumab was approved by the FDA in 2017 for MSI colorectal cancer and in 2018 in combination with ipilimumab based on the CheckMate-142 study.7,8 Pembrolizumab has not received a tissue-agnostic indication by the European Medicines Agency (EMA) and despite comparable mechanism of action, the other immune checkpoint inhibitors, like atezolizumab, durvalumab, and avelumab, have neither been approved by the FDA nor the EMA in an MSI/dMMR pan-cancer setting.\n\nBased on the expected tumor-agnostic effects, many Lynch syndrome MSI tumors may have been enrolled in clinical trials using these drugs. However, Lynch syndrome may only be the causative reason for tumor development in a smaller subset of all MSI tumors (3–5%),9–12 hence, their specific response rate may be masked by the responses of sporadic MSI cancers, that may differ molecularly from Lynch syndrome tumors.13–16 Here, we review large clinical trials that have presented data separately for Lynch syndrome and sporadic MSI cancer patients to elucidate the clinical benefit from immune checkpoint-based therapy in Lynch syndrome. Furthermore, we summarize current data on Lynch syndrome case reports, although these may be publication biased.\n\nMaterials and Methods\n\nSystematic Literature Search\n\nA systematic literature search was performed to identify studies with Lynch syndrome specific treatment data to evaluate the clinical benefit of immune checkpoint-based therapies in this cohort. All published studies including patients with Lynch syndrome-associated cancer, who had been treated with one or more of the FDA- and EMA-approved checkpoint-based immunotherapies targeting CTLA-4 (ipilimumab), PD-1 (pembrolizumab and nivolumab), or PD-L1 (atezolizumab, avelumab, and durvalumab) and where data was available on clinical outcomes, were considered eligible for this review.\n\nThe search strategy was developed in collaboration with a research librarian at the Medical Library, Aalborg University Hospital, Denmark. The search string was assembled from MeSH and non-MeSH terms included in the two categories: a cancer subtype specific domain [“Lynch syndrome” OR “hereditary MSI” OR “hereditary MMR-deficiency” OR “colorectal neoplasm, hereditary nonpolyposis”] and a treatment domain [“Ipilimumab” OR “Nivolumab” OR “Atezolizumab” OR “Durvalumab” OR “Pembrolizumab” OR “Avelumab”] combined with a Boolean logical “AND”. In PubMed, all search terms were coined as MESH terms, as SUPPLEMENTARY CONCEPT, or as TEXT WORD (combined with “OR”) securing capture of yet unindexed articles. In Embase, the search terms were used as EMTREE terms and TEXT WORDS. In Web of Science, the search terms were used as TOPIC. In the Cochrane Library, the search terms were used as MeSH terms and as Title, abstract, and keywords terms. No constraints related to language or publication type were applied—except for exclusion of conference abstracts on Embase. Detailed search terms are available from the authors upon request.\n\nThe final search in the four databases was conducted on November 3, 2020. The combined results of the analog searches in PubMed, Embase, Web of Science, and Cochrane Library were imported into the Rayyan QCRI application (Qatar Computing Research Institute, https://libraryguides.mcgill.ca/rayyan, last updated on October 7, 2020).17 Herein, all the items identified from the four databases were imported and the software identified 196 duplicates, which were manually checked before removal (N=195). Studies identified through reference lists from the included studies (N=3)8,18,19 were included if they were scored as relevant (Figure 1).Figure 1 Flowchart showing the systematic literature search and screening procedure following the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Data extraction was performed using modified criteria based on the guidelines given by the Cochrane Collaboration for the 31 studies included.\n\nData Extraction\n\nAll studies identified were independently reviewed by four authors (IB, LHJ, MR, or CT) with at least two reviewers per item analyzing inclusion/exclusion criteria defining the study population. Whenever discrepancy was met, consensus was reached involving a third reviewer.\n\nStudy eligibility was performed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA), while data extraction was performed using modified criteria based on the guidelines given by the Cochrane Collaboration.20 Data were extracted regarding study population (eg, age, sex, race, and MMR germline mutation), tumor type (eg, location, organ, dMMR/MSI status, and stage), treatment regimen (eg, pharmaceutical drug used, line of treatment, combinational treatment, and period), and outcome (eg, objective response rate, overall survival, progression-free survival, and alternative endpoints).\n\nSince this was a scoping review, quality assessment was not conducted. Publication bias was considered, as case reports may only be reported when interesting results are available. Likewise, funding sources were extracted to assess any conflicts of interest. All studies were requested to be on Homo sapiens and written in English and published as original articles unless sufficient data could be extracted from an English abstract (N=1).21 Redundant data, which was published in overlapping studies, motivated exclusion (N=2) or merging of the studies (N=4) (Figure 1).18,22–24 When information on overlapping data was missing, data from the two studies was presented separately according to the outcome in focus.19,25 One study included two cases with two different tumor types and responses and was for clarity depicted as two separate case reports in Table 2.26Table 1 Study Characteristics and Response Data from Included Cohort Studies\n\nStudy\tCountry\tCancer Center\tStudy Design\tLS Cases\tTotal Cohort\tCancer Type\tTreatment\tORR (LS)\tPFS (LS)\tORR (Spor. MSI)\tMMR Germline Mutation\tDetails/Comments\t\nLe et al, 201519\tUSA\tJohns Hopkins University\tProspective, multicenter study (3 centers included)\tN=13\tN=41 (MSS and MSI tumors)\tColorectal cancer and noncolorectal cancer\tPembrolizumab\tCRC: 25% NonCRC: 33% Total: 27%\tPFS: none\tCRC: 100% NonCRC: 100%\tCRC: MLH1 (N=3), MSH2 (N=3), unknown (N=2), non-RC: MSH2 (N=3)\tPhase II trial incl. 13 LS pts. Response evaluable for 11 LS pts and 4 sporadic MSI cases. LS CRC: 2 PR, 5 SD, 1 PD; LS nonCRC: 1 PR, 2 PD; sporadic CRC: 2 PR; sporadic nonCRC: 2 PR\t\nLe et al, 201725\tUSA\tJohns Hopkins University\tProspective, multicenter study (6 centers included)\tN=39\tN=86 (only MSI tumors)\tColorectal cancer and noncolorectal cancer\tPembrolizumab\tCRC: 46% NonCRC: 59%\tNot specified for LS\tNot specified\t3 unknowns, CRC: MLH1 (N=6), PMS2 (N=2), MSH2 (N=9), MSH6 (N=1), VUS (N=2); nonCRC: MLH1 (N=3), MSH2 (N=7), MSH6 (N=3), VUS (N=3)\tPhase II trials incl. 39 LS pts. ORR are calculated for all 39 LS, though germline mutation was only reported for 36 cases including 5 VUS cases. Average time to response for the entire study cohort was 21 weeks. No data available for sporadic MSI alone and no specific PFS or responses for LS alone. ORR for the total cohorts: CRC: 52%; nonCRC: 54%\t\nOverman et al, 20188\tUSA\tMD Andersen Cancer Center\tProspective, multicenter study (28 centers)\tN=35\tN=119 (MSI or dMMR tumors)\tMetastatic colorectal cancer\tNivolumab + ipilimumab\t71%\tNot specified for LS\t48%\t35 LS cases (clinical history, germline testing not mandatory)\tPhase II trial incl. 35 LS pts (25 responders), 31 pts with sporadic MSI tumors (15 responders), and 53 pts with unknown LS status (25 responders).\t\nHu et al, 201833\tUSA\tMemorial Sloan Kettering Cancer Center\tRetrospective cohort study\tN=7\tN=833 (MSS and MSI tumors)\tPancreatic ductal adenocarcinoma\tAnti-PD-1/anti-PD-L1\t60%\tPFS: mean 12,5 months (of 4 pts)\tNA\tMLH1 (N=1), PMS2 (N=1), MSH2 (N=2), MSH6 (N=1)\t833 consecutively collected pancreatic cancers investigated for dMMR/MSI—7 cases with MSI (all LS), of which 5 were treated with evaluable response: 1 CR, 2 PR, 1 SD and 1 PD\t\nRaj et al, 201932\tUSA\tMemorial Sloan Kettering Cancer Center\tProspective, single center study\tN=2\tN=39 (MSS and MSI tumors)\tAdrenocortical carcinoma\tPembrolizumab\t100%\tPFS: mean 27.5 months\t0%\tMSH2 (N=1) MSH6 (N=1)\tPhase II trial with 39 pts not selected for MSI/dMMR. 6 tumors showed MSI/dMMR, incl. 2 LS pts with PR response. 4 pts with sporadic MSI tumors: 2 SD, 2 PD\t\nAbida et al, 201931\tUSA\tMemorial Sloan Kettering Cancer Center\tProspective, single center study\tN=2\tN=1033 (MSS and MSI tumors)\tProstate cancer\tAnti-PD1/PDL1 therapy\t50%\tMean PFS: 5.6 months\t50%\tMSH2 (N=1) MSH6 (N=1)\t1033 consecutively collected prostate cancer patients of which 11 pts were treated, 8 pts completed/evaluated. Sporadic MSI: 3 PR + 1 SD + 2 PD; LS: 1 PR + 1 PD. Only MSI/dMMR tumors were evaluated for response to therapy. One MSS tumor in a patient with an MSH6 germline variant was not treated.\t\nBari et al, 202021\tUSA\tH. Lee Moffitt Cancer Center \tRetrospective, single center study\tN=22\tN=194 (only LS tumors—MSS and MSI)\tDifferent cancer types\tImmune checkpoint inhibitors (80% pembrolizumab)\t14%\tNA\tNA\t262 LS cases (mutated genes not reported)\tRetrospectively collected cohort focused on LS cases identified 22 pts treated, 1 PD after 1 month, 21 pts evaluated: 2 CR, 1 PR, 13 SD and 5 PD\t\nAbbreviations: ORR, objective response rate; PFS, progression-free survival; CRC, colorectal cancer; MSI, microsatellite instable; MSS, microsatellite stable; LS, Lynch syndrome; NA, not available; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; pts, patients.\n\nTable 2 Study Characteristics and Response Data from Included Case Reports\n\nStudy\tCountry\tCancer Center\tStudy Design\tCancer Type\tTreatment\tLine of Therapy\tResponse\tCriteria\tProgression-free survival\tMMR Germline Mutation\tDetails/Comments\t\nChan et al. 202037\tUSA\tSaint Michael’s Medical Center\tCase report (N=1)\tColon cancer\tPembrolizumab\t3. line\tPD (N=1)\tRECIST\tPFS: 1 month\tMSH6 mutation carrier\t1 pt treated with PD after 1 month (1 cycle)\t\n\t\t\t\t\t\t\t\t\t\t\t\t\nSalman et al, 201836\tChile\tArturo Lopez Pérez\tCase report (N=1)\tColorectal cancer\tPembrolizumab\t2. line\tSD (N=1)\tRECIST\tPFS: 7 months\tMSH2/EPCAM mutation carrier\t1 pt treated with SD at 2.8 months (mean of 2 metastases) and PD at 7 months (mean of 2 metastases)\t\n\t\t\t\t\t\t\t\t\t\t\t\t\nKeating et al, 201935\tUSA\tRoger Williams Medical Center\tCase report (N=1)\tMetastatic colorectal cancer\tPembrolizumab\t4. line\tSD (N=1)\tClinical benefit\tPFS: 42 months\tMSH2 mutation carrier\t1 pt treated with SD at 42 months\t\n\t\t\t\t\t\t\t\t\t\t\t\t\nDemisse et al, 202028\tUSA\tUC Davis Comprehensive Cancer Center\tCase report (N=1)\tAdvanced rectal cancer\tPembrolizumab\t1. line\tPR (N=1)\tRECIST\tPFS: 10 months\tUnspecified clinical history, no MMR gene test available\t1 pt treated with pathologic CR after surgery at 10 months\t\n\t\t\t\t\t\t\t\t\t\t\t\t\nZhang et al, 201929\tChina\tThe Sixth Affiliated Hospital, Sun Yat-sen University\tCase report (N=2)\tLocally advanced rectal cancer\tNivolumab\t1. line (pt #1) and 2. line (pts #2)\tCR (N=2)\tPathologic complete response\tPFS: Mean 12 months\tAmsterdam I, no MMR gene test available\t2 pts treated with pathological and clinical CR at 1 year\t\n\t\t\t\t\t\t\t\t\t\t\t\t\nPatel et al, 201826\tUSA\tStanford Cancer University\tCase report (N=1)\tRectal cancer\tPembrolizumab\t2. line\tPD (N=1)\tTumor increase\tPFS: 1.4 months\tCarrier of two MSH6 VUS\t1 pt treated tumor progression after 1.4 month\t\n\t\t\t\t\t\t\t\t\t\t\t\t\nFeng et al, 201938\tChina\tBejing National Cancer Center\tCase report\n(N=1)\tUreter + colorectal cancer\tPembrolizumab\t4. line\tPR (N=1)\nPD (N=1)\tRECIST\tPFS: 7 months\tMSH2 mutation carrier\t1 pt treated: PR in ureter at 7 months and PD in CRC\t\nGhatalia et al, 201718 and\nWiner et al, 201924\tUSA\tBrown University\tCase report (N=1)\tMetastatic colorectal cancer + bilateral ureter cancer + bladder cancer\tPembrolizumab Atezolizumab Pembrolizumab Nivolumab + Ipilimumab Nivolumab\t3. line for CRC and 1 line for urothelial cancers\tSD (CRC) SD (N=3 urothelial cancers)\tTumor decrease\tPFS: 26 months\tMSH2 mutation carrier\t1 pt with 4 cancers (3 urothelial tumors and liver metastases from a previous CRC) treated with different regimens due to progression three times—tumor decrease of urothelial tumors and disease control for CRC metastasis at 26 months\t\nMusher and Rahal, 201934\tUSA\tBaylor College of Medicine\tCase report (N=1)\tColorectal cancer (N=1) and intrahepatic cholangiocarcinoma (N=1)\tPembrolizumab\t1. line\tPR (N=2)\tRECIST\tPFS: 18 months\tMLH1 mutation carrier\t1 pt with 2 primary tumors—both responsive at 16 months\t\nYang et al, 201948\tUSA\tVirginia Commonwealth University\tCase report (N=1)\tGlioblastoma multiforme\tPembrolizumab\t2. line\tSD (N=1)\tRECIST\tPFS: 12 months\tMSH6 mutation carrier\t1 patient treated with SD at 12 months\t\nBouffet et al, 201623 and Larouche et al, 201822\tCanada\tThe hospital for sick children and Montreal Children’s hospital\tCase report (N=2)\tGlioblastoma multiforme\tNivolumab Nivolumab Nivolumab + ipilimumab Nivolumab\t2. line(pt #1) and 1. line (pt #2)\tPR (N=1) (pt #1) CR (N=1) (pt #2)\tRECIST\tPFS: 11 months (pt #1) and 30 months (pt #2)\tHomozygous biallelic PMS2 mutations\tSiblings with biallelic MMR mutations—one had PR at 1,4 months and PD at 11 months and the other had PR at 9 months and CR at 30 months\t\nKawashima et al, 201939\tJapan\tJapanese Foundation for Cancer research\tCase report (N=1)\tLung cancer\tNivolumab\t2. line\tSD (N=1)\tTumor decrease\tPFS: 2 months\tMSH2 mutation carrier\t1 pt treated with tumor decrease at 2 months\t\n\t\t\t\t\t\t\t\t\t\t\t\t\nMasuzawa et al, 202040\tJapan\tKeio University School of Medicine\tCase report (N=1)\tmetastatic non-small-cell lung cancer\tNivolumab\t3. line\tPR (N=1)\tRECIST\tPFS: 27 months\tMLH1 mutation carrier\t1 pt treated with response at 7 months\t\n\t\t\t\t\t\t\t\t\t\t\t\t\nNevgi et al, 202041\tAustralia\tUniversity of Melbourne\tCase report (N=1)\tAdrenocortical carcinoma\tNivolumab + ipilimumab\t2. line\tPR (N=1)\tTumor decrease\tPFS: 23 months\tMSH2 mutation carrier\t1 pt treated with PR of liver metastases at 23 months\t\n\t\t\t\t\t\t\t\t\t\t\t\t\nCasey et al, 201842\tUK\tCambridge University\tCase report (N=1)\tAdrenocortical carcinoma\tPembrolizumab\t2. line\tPD (N=1)\tRECIST\tPFS: 2.8 months\tMSH2 mutation carrier\t1 pt with recurrence and liver metastases treated with progression at 2.8 months\t\nMancuso et al, 202043\tCanada\tCancer Prevention Centre\tCase report (N=1)\tMuscle invasive bladder cancer\tPembrolizumab\t2. line\tCR (N=1)\tRECIST\tPFS: 22 months\tMSH2 mutation carrier\t1 pt treated with CR at 22 months\t\nGraham et al, 202046\tUSA\tUniversity of Washington and University of Michigan\tCase report (N=2)\tMetastatic prostate cancer\tPembrolizumab\t2. line\tSD (N=2)\tPSA decrease\tPFS: Mean 12,5 months\tMSH2 mutation carriers\t2 pts treated with decreasing PSA and clinical response at 10 and 15 months\t\nPatil and Khan, 202047\tUSA\tHenry Ford Health System\tCase report (N=1)\tPancreatic cancer\tPembrolizumab\t3. line\tPR (N=1)\tTumor decrease\tPFS: 11 months\tMLH1 mutation carrier\t1 pt treated with PR in liver metastases at 11 months\t\nHu et al, 201849\tUSA\tMemorial Sloan Kettering Cancer Center\tCase report (N=1)\tPancreatic cancer\tAnti-PD-L1-therapy\t2. line\tPD (N=1)\tClinical benefit\tPFS: 22 months\tMLH1 mutation carrier\t1 pt treated with PD at 22 months. Immunotherapy continued despite gynecological metastases\t\nNgo et al, 202044\tUSA\tUniversity of Louisville School of Medicine\tCase report (N=1)\tPancreatic cancer\tPembrolizumab\t3. line\tPR (N=1)\tTumor decrease\tPFS: 35 months\tMSH2 mutation carrier\t1 pt treated with two liver metastases—1 responded all 35 months and the other progressed after 8 months but remained decreased after radiation\t\nPatel et al, 201826\tUSA\tStanford Cancer Institute\tCase report (N=1)\tPancreatic cancer\tPembrolizumab\t2. line\tSD (N=1)\tTumor decrease\tPFS: 11.9 months\tMLH1 VUS carrier\t1 pt treated with pancreatic cancer and 3 vetebral metastases—tumor decrease after 11.9 months\t\nTlemsani et al, 202045\tFrance\tHôpital Cochin\tCase report (N=1)\tRhabdomyosarcoma\tNivolumab\t2. line\tCR (N=1)\tRECIST\tPFS: 12 months\tMLH1 mutation carrier\t1 pt treated with lung metastases completely removed at 12 months\t\nCarvalho et al, 202027\tBrazil\tUniversity of Sao Paulo\tCase report (N=1)\tEndometrial cancer\tPembrolizumab\t1. line\tPR (N=1)\tRECIST\tPFS: 24 months\tMLH1 VUS carrier\t1 pt treated after hysterectomy with lymph node metastases—PR at 2.1 month and sustained for 24 months\t\nAbbreviations: ORR, objective response rate; PFS, progression-free survival; CRC, colorectal cancer; MSI, microsatellite instable; MSS, microsatellite stable; LS, Lynch syndrome; VUS, variant of unknown significance; NA, not available; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; PSA, prostate specific antigen; pt/pts, patient/patients.\n\nAs this review included all types of MSI or dMMR Lynch syndrome-associated cancers (irrespective of organ or tumor stage) with all lines of therapy, and primarily case reports, meta-analysis was not considered appropriate. Instead, data was grouped by study design with clinical trials in unselected MSI/dMMR cancer cohorts scored as a high level of evidence, while case reports were considered to have a lower level of evidence and a higher level of bias.\n\nDefinitions\n\nLynch syndrome diagnostics were based on individuals with pathogenic or likely pathogenic variants in one of the four MMR genes: MLH1, PMS2, MSH2/EPCAM, and MSH6 found by germline DNA sequencing (18 case studies and three cohort studies). Since some of the cohort studies included few variants of unknown significance (VUS) as causative for Lynch syndrome25 or included Lynch syndrome families based on individuals with dMMR/MSI tumors in families with a cancer history,8,21 we chose to include two case studies with VUS26,27 and two case studies with clinical Lynch syndrome diagnostics, but with unknown germline MMR gene variant.28,29 Lynch syndrome individuals with biallelic MMR variants (also referred to as constitutional MMR deficiency (CMMR-D) syndrome) were also included in this study, since these tumors show the same molecular phenotype as monoallelic Lynch syndrome tumors (N=1). There were no selection criteria regarding tumor type and no restrictions in period.\n\nOutcome Data\n\nThe primary endpoints were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). ORR was measured as the best response during treatment or alternating immune checkpoint-based therapies using the response evaluation criteria in solid tumors (RECIST) guidelines, with partial response (PR) and complete response (CR) categorized as response. In cases where the RECIST criteria were not used, pathological complete response was classified as CR, while nonqualified tumor decrease was categorized as stable disease (SD). Disease control rates were calculated as all CR, PR and SD divided by the total number of treated and evaluable patients. PFS was measured in months from first dose of immune checkpoint-based therapy to tumor progression or end of follow-up. In case of alternating immunotherapeutic regimens, PFS were defined as the time from first dose of immunotherapy to end of the last regimen of immunotherapy caused by disease progression. OS was measured in months from the first dose of immune checkpoint-based therapy to death or end of follow-up. Inclusion of alternative endpoints was motivated when ORR data was not available, as these may translate into a clinically meaningful benefit in PFS and OS. Decreasing prostate specific antigen (PSA) level was categorized as disease control for one case according to the prostate cancer clinical trial working group (PCWG3) guideline.30 Whenever possible, the analyses were based on original raw data and Lynch syndrome cases were sought and extracted from larger studies with separate endpoint data from the sporadic cancers.\n\nResults\n\nLiterature Review\n\nIn total, 492 studies were identified (two from Cochrane Library, 167 from Embase, 130 from PubMed, and 193 from Web of Science) (Figure 1). After removal of 195 duplicates, 297 studies were reviewed on title and abstract level following the PRISMA guidelines. Hereafter, 47 studies were screened on full text level and three additional studies were added to the search based on the references of the reviewed publications.8,18,19 In total, 31 articles were included for this review, six of which included overlapping cases: two cases were described in two case reports18,22–24 and one clinical trial was updated with different data presented in two papers.19,25\n\nCohort Studies\n\nColorectal Cancer\n\nLarge cohort studies of consecutive unselected patients were considered to be less biased by publication and were initially investigated for specific data on Lynch syndrome cases. Seven studies were identified and presented in Table 1. Three studies investigated the response rates in colorectal cancer and found that Lynch syndrome patients had an ORR between 46 and 71% after immune checkpoint-based therapy.8,19 Two of the articles presented data from the MK-3475 study covering three to six centers in the US (NCT01876511), in which Lynch syndrome-associated ORR were calculated in the study from Le et al,25 while individual Lynch syndrome cases could be extracted in the study from Le et al.19,25 In Le et al,19 eight Lynch syndrome patients with colorectal cancer were treated with pembrolizumab, of which two showed PR giving an ORR of 25% and six showed SD reaching disease control in 100% of the patients. In the updated paper from 2017, the Lynch syndrome-associated ORR had increased to 46%.25 The percentage of Lynch syndrome cases presenting with disease control was not specified in here, but 23% of the entire cohort (covering 86 patients) showed SD reaching disease control in 77% of the unselected MSI/dMMR cohort. Furthermore, mean time to response was 21 weeks and mean time for complete response was 42 weeks.25 Corresponding data from the sporadic MSI/dMMR cohort were only specified in the paper from 2015 with two colorectal cancer patients both showing PR (ORR=100%).19 Though similar data was missing in the updated paper from 201725 statistical analyses did not identify significant difference in ORR between Lynch syndrome and sporadic MSI/dMMR colorectal cancers (ORR of the entire study cohort was 52%). The CheckMate-142 study presented by Overman et al, which is a multicenter study covering 28 centers in eight countries, included 35 Lynch syndrome patients of which 25 patients showed objective response (ORR=71%).8 In comparison, sporadic (non-Lynch syndrome) MSI/dMMR colorectal cancers showed an ORR of 48%. No comparison was made between the two groups and lack of individual data restrained further analyses. For both clinical trials, sufficient follow-up to calculate PFS and OS was not reached, and not specified for Lynch syndrome and sporadic MSI cancers individually.\n\nNoncolorectal Cancer\n\nInvestigating noncolorectal cancers, we found four studies with specified Lynch syndrome response data, three of which published from the Memorial Sloan Kettering Cancer Center, New York, USA.21,31–33 Hu et al identified five Lynch syndrome patients in a retrospective cohort of 833 consecutively collected patients with pancreatic ductal carcinomas, of which three responded (ORR=60%) to anti-PD1/anti-PD-L1 drugs—one with a mixed response involving a complete response followed by metastasis eight months later.33 The mean PFS of four cases with available data was 12.5 months, although the responses appeared after 22 and 24 months. No sporadic cases with an MSI phenotype were identified nor treated with immunotherapy. Abida et al, 2019 identified two Lynch syndrome patients among a prospectively collected cohort of 1033 patients with prostate cancer, of which one showed PR and the other had PD after anti-PD-1/anti-PD-L1 therapy.31 Likewise, Raj et al found two Lynch syndrome patients in a prospective phase II study of 39 patients with adrenocortical carcinomas; both showed PR and a mean PFS of 27.5 months when treated with pembrolizumab.32 In 2015, the MK-3475 study from Johns Hopkins University presented three Lynch syndrome-associated noncolorectal cancer patients with an ORR of 33%.19 In the updated cohort from 2017, this increased to 59%.25\n\nAt the American Society of Clinical Oncology (ASCO) in May 2020, Bari et al, presented a large retrospective study design, in which they aimed to describe the response rates in a Lynch syndrome cohort irrespective of tumor type.21 They identified 194 Lynch syndrome patients with different types of solid tumors, of which 22 had received treatment with immune checkpoint-based therapies. Of the 22 patients, two showed CR, one had PR, 13 had SD, and six showed PD giving an ORR of 14% and a disease control rate of 73%. In contrast to the other studies, treatment responses were measured irrespective of MSI status and showed continued response after nine months of treatment in one (out of three) microsatellite stable (MSS) Lynch syndrome tumors.21 Detailed PFS and OS were not calculated but 15 out of 22 patients showed continuous disease control or complete remission at 48 months of follow-up.\n\nIn summary, these studies identified 107 Lynch syndrome cancer patients and individual response data could be collected from 77 cases (excluding Le et al).25 Thirty-six of these cases responded to treatment, giving a summarized ORR of 47% (63% for CRC and 29% for noncolorectal cancer). In comparison, summarized ORR for sporadic MSI colorectal cancer patients were 55% (17 out of 33) and 42% for sporadic MSI noncolorectal cancer patients (five out of 12). PFS was only reported in three studies (all regarding noncolorectal cancers) and summarized to 15.2 months for Lynch syndrome cancer patients.\n\nCase Studies\n\nStudy Eligibility/Data Quality\n\nNext, we reviewed the Lynch syndrome cancer case reports. Twenty-four case reports covering 26 patients (three with multiple cancers) presented treatment response. Two cases were presented in two papers each, but since data was overlapping the studies were merged to two case reports.18,22–24 In contrast, one study presented to cases with two different types of MSI cancers and was for simplicity presented as two separate cases (Table 2).26 Cancer center, country, MMR gene affected, immune checkpoint-based treatment, therapeutic setting, and outcome results for the 26 unique cases are presented in Table 2. Two of the studies did not present data on the MMR gene test analyses nor the MMR variant identified in the patients, and it remains uncertain how Lynch syndrome was diagnosed in these individuals.28,29 The cases were identified in USA (N=13), Canada (N=3), China (N=3), Japan (N=2), France (N=1), Chile (N=1), UK (N=1), Brazil (N=1), and Australia (N=1). The responses were evaluated using the RECIST criteria (N=13), pathologic complete response with no viable tumor cells after surgery (N=2), tumor decrease with unknown percentage of decrease (N=7), clinical response with proceeded treatment due to no or little tumor progression (N=2), and as a decrease in prostate specific antigen (PSA) (N=2).\n\nThe case reports either presented cases with clinical responses/disease control (N=21), or disease progression (N=4), or cases with two primary tumors, of which one progressed and the other responded (N=1). The majority of studies presenting positive treatment responses may indicate publication bias as these cases are more likely to be published.\n\nColorectal Cancer\n\nIn summary, 10 cases were included with a colorectal cancer (three with multiple cancers in other organs as well) and one patient with liver metastases from a previously removed colorectal cancer.18,24,26,28,29,34–38 Two cases obtained CR, two showed PR, three had SD, and three showed PD giving an ORR of 40% and disease control rate of 70%. All the patients, who showed positive response, were given immunotherapy as first (N=3) or second (N=1) line treatment. The mean PFS was 14.9 months with a mean time to response of 13.3 months. As only one patient died one month after treatment end,18,24 PFS was equal to OS in these cases.\n\nNoncolorectal Cancer\n\nInvestigating noncolorectal cancers, 21 MSI/dMMR Lynch syndrome-associated solid tumors developed (three glioblastoma multiforme, four pancreatic cancers, three ureteral cancers, two lung cancers, two prostate cancers, two adrenocortical carcinomas, two bladder cancers, one endometrial cancer, one rhabdomyosarcoma, and one intrahepatic cholangiocarcinoma).18,22–24,26,34,38–49 Although it was not stated, it was considered highly likely that the pancreatic cancer showing PD at 22 months by Hu et al,49 was included in the large pancreatic cancer cohort study.33,49 However, in order to reduce publication bias, this case was included in the following summary. Among the 21 noncolorectal cancers, three showed CR, eight showed PR, eight had SD (two of which had decreased PSA levels as the only response data), and two experienced PD resulting in a summarized ORR of 53% and disease control in 90%. Mean PFS was 14.1 months with a mean time to positive response of 18.3 months. Again, OS was not reported for the majority of the studies as follow-up was ended at tumor progression or with PFS.\n\nMultiple Lines of Immunotherapy\n\nIrrespective of the cancer type, treatment lines of which the immune checkpoint-based therapy was introduced varied across the included studies with seven tumors receiving immunotherapy in first line, 14 in second line, seven in third line, and three in fourth line. Two cases received different regimens of immunotherapy due to local progression or adverse events with the selected treatment. A male 64-year-old Lynch syndrome carrier presenting with three urothelial cancers (bladder and bilateral ureter) and a liver metastasis 10 years after previously removed colorectal cancer was treated with pembrolizumab at the indication of dMMR in one of the urothelial tumors. At nine months, the patient was treated with atezolizumab based on progression of the urothelial cancers. The patient obtained eight months of disease control before progression of the liver metastasis. Pembrolizumab was reintroduced for three months until progression and the patient switched to combination therapy with nivolumab and ipilimumab resulting in tumor decrease after two months. The patient continued therapy with nivolumab alone with disease control for seven months. At this time, his bilirubin levels increased probably attributed to immunotherapy-related adverse events and the patient declined continued therapy and passed away one month later.18,24\n\nThe second case report presented a boy at 3.5 years with homozygous biallelic PMS2 pathogenic variants with a glioblastoma multiforme tumor in the frontal cortex that was surgically removed. Ten months later multinodular recurrence was observed, and he was treated with nivolumab with initial response. Six months later, a new nodal glioblastoma reoccurred at the primary surgical site and ipilimumab was added to the nivolumab treatment for four doses. Significant response was observed after three months (nine months from first immunotherapy dose) and complete response was reached after one year. The patient continued on nivolumab for maintenance and magnetic resonance imaging confirmed CR 30 months from first glioblastoma recurrence and first immunotherapeutic dose.\n\nDiscussion\n\nHerein, we summarized the clinical responses among Lynch syndrome cancer patients treated with FDA- and EMA-approved checkpoint-based immune therapies. We identified 31 studies including 133 unique Lynch syndrome cancer patients. For Lynch syndrome, the large cohort studies showed ORRs between 46–71% for MSI/dMMR colorectal cancers and 14–100% for noncolorectal MSI/dMMR cancers. The corresponding ORRs for sporadic MSI/dMMR cancers were 48–100% and 50–100%, respectively. Summarizing the Lynch syndrome case reports, the ORRs were 40% and 53%, respectively. In addition, the only study investigating a systematic difference between Lynch syndrome and sporadic MSI cancers did not reach any significance. Together the data indicates that Lynch syndrome cancer patients may benefit from immune checkpoint-based therapy to the same extend as sporadic MSI/dMMR tumors, though the sample size is limited and confidence intervals large.\n\nSince the approval of pembrolizumab as a tissue-agnostic drug against MSI/dMMR solid tumors, more than 100 clinical trials have been registered at ClinicalTrial.gov and are still ongoing, testing immunotherapy in a wide range of solid tumors. Many of these studies select tumors based on MSI or dMMR status, but only a few studies choose to investigate hereditary germline MMR variants and even fewer to report the outcome data according to germline MMR status. One of the pioneering studies within this field is Le et al, who showed that Lynch syndrome cancer patients had an ORR of 27% compared to an ORR of 100% for sporadic MSI tumors.19 The reduced response rate observed in these preliminary results is hypothetically supported by molecular differences between the sporadic and hereditary MSI tumors, including different immune evasion mechanism affecting, eg, the antigen processing and presentation pathway.14–16 However, the updated study from Le et al,25 reported no significant difference in response rates between the two subsets though separate ORRs for sporadic or Lynch syndrome MSI/dMMR tumors are not reported. The PFS and OS measures are still not complete and separate data for these groups is awaited.\n\nAlthough many of the immune-checkpoint-based drugs are not approved for MSI/dMMR noncolorectal solid tumors, the case reports and cohort studies presented in here show that Lynch syndrome cancer patients may be potential candidates for such treatments. Complete responses (five out of 26 cases) were reported in advanced rectal cancer, glioblastoma, muscle invasive bladder cancer, and cases with lung metastases, albeit these stories may be more likely to get published than negative findings.22,43,45 It remains very important to publish Lynch syndrome cancer cases with resistance or tumor progression in response to immune checkpoint-based therapy as these tumors may evade the immune system through alternative routes. One such case was presented by Hu et al,49 in which mutation analyses was conducted on the primary pancreatic cancer and the ovarian metastasis. IImmunoediting was suspected to be the cause of acquired resistance, but no mutations were found in the antigen processing and presentation genes, eg the HLA genes, B2M, JAK1, JAK2, PTEN, or TAP1.49 Future molecular studies revealing the genetic makeup of resistant tumors are needed to elucidate why some Lynch syndrome tumors may not respond to immunotherapy.\n\nThe majority of the cases presented here were offered immunotherapy due to an MSI phenotype. It is important to note that while dMMR is largely associated with MSI in Lynch syndrome colorectal (98%)50 and endometrial (94%)51 cancers, the concordance is much lower for other Lynch syndrome cancer types such as urothelial cancer (23%)52 and brain tumors (0%).53 In accordance with this, an MSS phenotype has been found in 36% of Lynch syndrome tumors, with associations to noncolorectal, nonendometrial tumors and MSH6 and PMS2 gene variants.54 Abida et al, presented one case with prostate cancer and an MSH6 germline pathogenic variant, but due to an MSS phenotype this patient was not treated.31 In contrast, Bari et al, reported one MSS Lynch syndrome tumor that had continued response at nine months, but immunohistochemical dMMR was not reported in this abstract.21 Though data is still scarce, it is possible that thorough molecular diagnostics, eg, both dMMR and MSI in addition to deeper analyses such as tumor mutation burden, may help guide treatment decision.21,25,31\n\nTumor mutation burden may add valuable knowledge in the selection of Lynch syndrome patients to immunotherapy, although this has only been investigated and associated with positive responses in some of the included case reports.29,31,32,49 Two cases with locally advanced rectal cancer showed high tumor mutation burden and experienced complete pathological response,29 while two of the cohort studies only associated high tumor mutation burden with MSI status and did not use it as an independent indicator for treatment response.29,31,32 In contrast, a recent case study reported discrepancies between MSI and tumor mutation burden.55 Two Lynch syndrome cancer patients: one with a dMMR and MSI hepatic cholangiocarcinoma and one with a dMMR but MSS neuroendocrine carcinoma were treated with nivolumab in combination with ipilimumab and pembrolizumab, respectively, and both progressed after three cycles of treatment. The authors suspected that the resistance was caused by lack of neoantigen presentation as these tumors showed low tumor mutation burden.55 Yet, the nonresponsive pancreatic cancer reported by Hu et al, presented with a high tumor mutation burden with massive tumor-infiltrating lymphocytes.49 These data emphasize the tumor heterogeneity and lack of solid molecular markers to select responsive cases. To this end, we may add that it is possible that MSS tumors appearing in Lynch syndrome cancer patients may simply not arise from the pathogenic germline MMR variants, and that the specific MMR gene mutated as well as the mutation type may affect cancer risk and survival.56,57 It is possible that the type of mutation may affect the tumor mutation burden and the number of neoantigens presented, hypothetically triggering the immune system differently and affect responses to treatment with immune checkpoint inhibitors.\n\nOwing to scarce Lynch syndrome specific response data, we included case reports in our review. The majority of these cases presented with positive treatment responses indicating publication bias. Hence, these results should be interpreted with caution. However, the summarized ORR from all the cases was 40% for colorectal cancer and 53% for noncolorectal cancers, which is in alignment with the Lynch syndrome-specific ORR presented in the larger cohort studies (ORRs between 46 and 71% for colorectal cancers and between 14 and 100% noncolorectal cancers). Another limitation to this study is the inclusion of eight individuals with VUS alterations. These individuals have previously been categorized as Lynch-like or unexplained MMR deficiency, as they may be caused by biallelic somatic MMR mutations within the tumor.58,59 Though these tumors may mimic Lynch syndrome tumors with an MSI phenotype, the colorectal cancer risk is somewhat lower compared to Lynch syndrome carriers of pathogenic variants.59 Specific response data were not reported according to MMR variants in the unselected cohort described by Le et al,25 but focusing on the case reports with VUS individuals, we observed ORRs of 0% and 50% for colorectal and noncolorectal cancer, respectively. The corresponding numbers were 17% and 53% for verified pathogenic MMR gene variant carriers.\n\nConclusion\n\nDespite the fact that data is still scarce, we have found that Lynch syndrome cancer patients may benefit from immune checkpoint-based therapies and that no difference in the response rates has been reported to date between Lynch syndrome and sporadic MSI cancer patients. It remains unknown, however, why some Lynch syndrome cancer patients do not respond to immune checkpoint-based therapies and thorough molecular profiling including dMMR, MSI, tumor mutation burden, and immunoediting driver mutations may aid in the selection of patients, who are more likely to respond. Until the routes of resistance are clarified, it is encouraged to report Lynch syndrome-specific outcome data from the large clinical trials.\n\nAcknowledgments\n\nThe authors would like to acknowledge the medical librarian Jette Frost, Aalborg University Hospital, for assisting in the different database searches.\n\nDisclosure\n\nDr Lars Henrik Jensen reports he is an investigator for clinical trials run by MSD, BMS and INCYTE. All payments are to institution for the work performed, outside the submitted work. The authors report no other conflicts of interest in this work.\n==== Refs\nReferences\n\n1. Therkildsen C, Ladelund S, Smith-Hansen L, et al. 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Complete clinical response in stage IVB endometrioid endometrial carcinoma after first-line pembrolizumab therapy: report of a case with isolated loss of PMS2 protein. Case Rep Oncol. 2020;13 :1067–1074. doi:10.1159/000510000 33082750\n28. Demisse R, Damle N, Kim E, et al. Neoadjuvant immunotherapy-based systemic treatment in MMR-Deficient or MSI-high rectal cancer: case series. J Natl Compr Cancer Netw JNCCN. 2020;18 :798–804. doi:10.6004/jnccn.2020.7558\n29. Zhang J, Cai J, Deng Y, et al. Complete response in patients with locally advanced rectal cancer after neoadjuvant treatment with nivolumab. Oncoimmunology. 2019;8 (12 ):e1663108. doi:10.1080/2162402X.2019.1663108 31741760\n30. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. 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Prolonged treatment response to pembrolizumab in a patient with pretreated metastatic colon cancer and lynch syndrome. Case Rep Oncol Med. 2019;2019 :3847672. doi:10.1155/2019/3847672 31565451\n36. Salman P, Panay S, Fernández R, et al. Evidence of response to pembrolizumab in a patient with Lynch syndrome-related metastatic colon cancer. OncoTargets Ther. 2018;11 :7295–7300. doi:10.2147/OTT.S167645\n37. Chan KH, Lakkasani S, Ramahi A, et al. Hyperprogressive Disease in an Advanced Stage Colon Cancer Patient on Pembrolizumab: a Case Report. Cureus. 2020;12 :e7764.32455081\n38. Feng Y, Cao Y, Yuan M, et al. Different responses to anti-programmed cell death protein 1 (PD-1) immunotherapy in a patient with Lynch syndrome and metachronous urothelial and colon cancer: a case report. Oncol Lett. 2019;18 :5085–5090. doi:10.3892/ol.2019.10909 31612019\n39. Kawashima Y, Nishikawa S, Ninomiya H, et al. Lung adenocarcinoma with lynch syndrome and the response to nivolumab. 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Lynch syndrome-associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome. Cold Spring Harb Mol Case Stud. 2019;5 (5 ):5. doi:10.1101/mcs.a003863\n49. Hu ZI, Hellmann MD, Wolchok JD, et al. Acquired resistance to immunotherapy in MMR-D pancreatic cancer. J Immunother Cancer. 2018;6 :127. doi:10.1186/s40425-018-0448-1 30458888\n50. Loughrey MB, McGrath J, Coleman HG, et al. Identifying mismatch repair-deficient colon cancer: near-perfect concordance between immunohistochemistry and microsatellite instability testing in a large, population-based series. Histopathology. 2020;3 :401–413.\n51. Stelloo E, Jansen AML, Osse EM, et al. Practical guidance for mismatch repair-deficiency testing in endometrial cancer. Ann Oncol. 2017;28 :96–102. doi:10.1093/annonc/mdw542 27742654\n52. Joost P, Therkildsen C, Dominguez-Valentin M, et al. Urinary Tract Cancer in Lynch Syndrome; Increased Risk in Carriers of MSH2 Mutations. Urology. 2015;86 :1212–1217. doi:10.1016/j.urology.2015.08.018 26385421\n53. Gylling AHS, Nieminen TT, Abdel-Rahman WM, et al. Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors. Carcinogenesis. 2008;29 :1351–1359. doi:10.1093/carcin/bgn133 18550572\n54. Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability is associated with the presence of lynch syndrome pan-cancer. J Clin Oncol. 2019;37 :286–295. doi:10.1200/JCO.18.00283 30376427\n55. Bielska AA, Chatila WK, Walch H, et al. Tumor mutational burden and mismatch repair deficiency discordance as a mechanism of immunotherapy resistance. J Natl Compr Cancer Netw JNCCN. 2021;19 :130–133. doi:10.6004/jnccn.2020.7680\n56. Dominguez-Valentin M, Sampson JR, Seppälä TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med off J Am Coll Med Genet. 2020;22 :15–25.\n57. Maccaroni E, Bracci R, Giampieri R, et al. Prognostic impact of mismatch repair genes germline defects in colorectal cancer patients: are all mutations equal? Oncotarget. 2015;6 :38737–38748. doi:10.18632/oncotarget.5395 26485756\n58. Omark J, Vilar E, You YN, et al. Patients with unexplained mismatch repair deficiency are interested in updated genetic testing. Hered Cancer Clin Pract. 2020;18 :19. doi:10.1186/s13053-020-00150-1 32973963\n59. Rodríguez-Soler M, Pérez-Carbonell L, Guarinos C, et al. Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology. 2013;144 :926–932. doi:10.1053/j.gastro.2013.01.044 23354017\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-7023",
"issue": "14()",
"journal": "Clinical and experimental gastroenterology",
"keywords": "HNPCC; Lynch syndrome; endometrial cancer; germline mismatch repair defect; hereditary colorectal cancer",
"medline_ta": "Clin Exp Gastroenterol",
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"nlm_unique_id": "101532800",
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"pages": "181-197",
"pmc": null,
"pmid": "34079322",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "31092773;32449531;26028255;32658872;32973963;28797715;30264147;27742654;29327160;30458888;28596308;17373663;32453797;31086306;24227356;32634770;32675128;27001570;31337882;17316446;26485756;26385421;16024646;33545685;25673086;30072391;32455081;30425520;23354017;29355075;30352869;31644329;31565451;32241906;32923879;32791559;30376427;29367431;23073952;18550572;28726535;30160041;31604779;26205583;29065108;30589920;18309951;27919275;29764494;31741760;28754778;31612019;31444293;24267189;32512823;33082750;30262398",
"title": "An Update on Immune Checkpoint Therapy for the Treatment of Lynch Syndrome.",
"title_normalized": "an update on immune checkpoint therapy for the treatment of lynch syndrome"
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"abstract": "We report the first case of intraoperatively detected euglycemic diabetic ketoacidosis (DKA) associated with sodium-glucose cotransporter 2 inhibitors during thoracic surgery. A 59-year-old man had a 12-year history of type 2 diabetes mellitus treated with insulin and empagliflozin. The patient developed bacterial empyema and was initiated with antibiotics at a local hospital. Owing to the persistence of his symptoms, he was transferred to our hospital after the medication of empagliflozin the day before surgery. After overnight fasting, the patient underwent thoracoscopic debridement and intrathoracic lavage surgery. During this surgery, he was noted to have euglycemic ketosis and acidosis, and diagnosed as euglycemic DKA. Immediately after the consultation in our department, the patient underwent treatment for DKA. He awoke from anesthesia normally and showed no symptoms of DKA. DKA gradually resolved over the next 24 h. Early identification and management are critical for rapid recovery from perioperative euglycemic DKA associated with sodium-glucose cotransporter 2 inhibitors, especially during thoracic surgery.",
"affiliations": "The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.;The First Department of Medicine, Wakayama Medical University, Wakayama, Japan.",
"authors": "Kitahara|Chie|C|;Morita|Shuhei|S|https://orcid.org/0000-0002-4415-3805;Kishimoto|Shohei|S|;Matsuno|Shohei|S|;Uraki|Shinsuke|S|;Takeshima|Ken|K|;Furukawa|Yasushi|Y|;Inaba|Hidefumi|H|;Iwakura|Hiroshi|H|;Ariyasu|Hiroyuki|H|;Furuta|Hiroto|H|https://orcid.org/0000-0003-1657-3519;Nishi|Masahiro|M|;Akamizu|Takashi|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1111/jdi.13365",
"fulltext": "\n==== Front\nJ Diabetes Investig\nJ Diabetes Investig\n10.1111/(ISSN)2040-1124\nJDI\nJournal of Diabetes Investigation\n2040-1116\n2040-1124\nJohn Wiley and Sons Inc. Hoboken\n\n32686282\n10.1111/jdi.13365\nJDI13365\nCase Report\nArticles\nClinical Science and Care\nEarly detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes: A case report\nIntraoperative DKA and empagliflozin\nKitahara et al.\nKitahara Chie 1\nMorita Shuhei https://orcid.org/0000-0002-4415-3805\n1 smorita@wakayama-med.ac.jp\n\nKishimoto Shohei 1\nMatsuno Shohei 1\nUraki Shinsuke 1\nTakeshima Ken 1\nFurukawa Yasushi 1\nInaba Hidefumi 1\nIwakura Hiroshi 1\nAriyasu Hiroyuki 1\nFuruta Hiroto https://orcid.org/0000-0003-1657-3519\n1\nNishi Masahiro 1\nAkamizu Takashi 1 2\n1 The First Department of Medicine Wakayama Medical University Wakayama Japan\n2 Kuma Hospital Kobe Japan\n* Correspondence\nShuhei Morita\nTel.: +81-73-441-0625\nFax: +81-73-445-9436\nE-mail address: smorita@wakayama-med.ac.jp\n\n26 8 2020\n4 2021\n12 4 10.1111/jdi.v12.4 664667\n10 7 2020\n22 5 2020\n14 7 2020\n© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd\nThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nWe report the first case of intraoperatively detected euglycemic diabetic ketoacidosis (DKA) associated with sodium–glucose cotransporter 2 inhibitors during thoracic surgery. A 59‐year‐old man had a 12‐year history of type 2 diabetes mellitus treated with insulin and empagliflozin. The patient developed bacterial empyema and was initiated with antibiotics at a local hospital. Owing to the persistence of his symptoms, he was transferred to our hospital after the medication of empagliflozin the day before surgery. After overnight fasting, the patient underwent thoracoscopic debridement and intrathoracic lavage surgery. During this surgery, he was noted to have euglycemic ketosis and acidosis, and diagnosed as euglycemic DKA. Immediately after the consultation in our department, the patient underwent treatment for DKA. He awoke from anesthesia normally and showed no symptoms of DKA. DKA gradually resolved over the next 24 h. Early identification and management are critical for rapid recovery from perioperative euglycemic DKA associated with sodium–glucose cotransporter 2 inhibitors, especially during thoracic surgery.\n\nSurgery is a known risk factor of diabetic ketoacidosis (DKA) for patients with an insufficient withdrawal period of sodium–glucose cotransporter 2 (SGLT2) inhibitors. Although there are the cases of DKA associated with sodium–glucose cotransporter 2 inhibitors after surgery, we report the first case of euglycemic DKA associated with empagliflozin detected during thoracic surgery. Awareness of the risk of euglycemic DKA is critical for early identification, management and even prevention when patients are treated with sodium–glucose cotransporter 2 inhibitors.\n\nEmpagliflozin\nIntraoperative euglycemic ketoacidosis\nSodium–glucose cotransporter 2 inhibitor\nSRF source-schema-version-number2.0\ncover-dateApril 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.1 mode:remove_FC converted:01.04.2021\nJ Diabetes Investig 2021\n==== Body\nIntroduction\n\nSodium–glucose cotransporter 2 inhibitors (SGLT2is) are widely used in patients with diabetes mellitus. However, regulatory agencies issued a warning that SGLT2is could cause diabetic ketoacidosis (DKA) 1 . DKA associated with SGLT2is can even occur when glucose levels are lower than expected, known as euglycemic DKA (eDKA), and often occurs during the perioperative period 1 , 2 . Cases of eDKA associated with SGLT2is have been reported after surgery 1 , 2 , but there is no report of occurrence during the surgery. Here, we present a patient with type 2 diabetes and bacterial empyema, who underwent surgery without a sufficient period of empagliflozin withdrawal. He developed intraoperative eDKA, but rapidly recovered after its early identification and management.\n\nCase Report\n\nA 59‐year‐old man had a 12‐year history of type 2 diabetes mellitus initiated with 10 mg of empagliflozin 18 months earlier, and clinically titrated to 25 mg along with intensive insulin therapy. During the period of treatment with empagliflozin, uric ketone had not been detected at every visit. The patient presented with high fever and chest pain for 2 weeks, and was admitted to a neighboring hospital. He was diagnosed as having left bacterial empyema, and treated with antibiotics for 4 days; however, as his symptoms persisted, he was transferred to Wakayama Medica University (Wakayama, Japan) for surgical treatment. He had a fever of 37.2°C, and weak pulmonary sound on the left side. The patient’s bodyweight, height and body mass index were 69 kg, 169 cm and 24.1 kg/m2, respectively. Laboratory data showed a severe infectious state (Table 1). Chest radiography and computed tomography images showed a large pleural effusion (Figure 1). On the day the patient was transferred to our hospital, he was treated with empagliflozin and insulin for diabetes at the former hospital (day 0; Figure 2). Empagliflozin was taken for the last time 28 h before surgery. He had no appetite loss nor digestive symptoms on that day. He was treated with insulin glargine 13 h before surgery.\n\nTable 1 Laboratory data on admission\n\nHematology/biochemistry\t\nWBC\t15,620/μL\tAMY\t39 U/L\t\nRBC\t357 × 104/μL\tNa\t139 mEq/L\t\nHb\t11.2 g/dL\tK\t4.8 mEq/L\t\nPlt\t27.3 × 104/μL\tCl\t103 mEq/L\t\nTP\t5.4 g/dL\tPG\t209 mg/dL\t\nAlb\t2.2 g/dL\tHbA1c\t9.4%\t\nAST\t70 U/L\tC‐peptide\t0.95 ng/mL\t\nALT\t47 U/L\tLactate\t10.6 mg/dL\t\nLDH\t219 U/L\t\t\t\nCPK\t364 U/L\tSerological examination\t\nγ‐GTP\t81 U/L\tC‐reactive protein\t29.8 mg/dL\t\nBUN\t16.6 mg/dL\tAnti‐GAD Ab\t<5.0 U/mL\t\nCr\t1.11 mg/dL\tAnti‐IA‐2 Ab\t<0.6 U/mL\t\nγ‐GTP, gamma‐glutamyl transpeptidase; Ab, antibodies; Alb, albumin; ALT, alanine aminotransferase; AMY, amylase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CPK, creatine kinase; Cr, creatinine; GAD, glutamic acid decarboxylase; Hb, hemoglobin; HbA1c, glycated hemoglobin; IA‐2, islet antigen 2; LDH, lactate dehydrogenase; PG, plasma glucose; Plt, platelets; RBC, red blood cells; TP, total protein; WBC, white blood cells.\n\nJohn Wiley & Sons, Ltd\n\nFigure 1 Chest radiography (a) and computed tomography (b) before thoracoscopic debridement and intrathoracic lavage (day 0).\n\nFigure 2 Patient’s clinical course. Black circles and blank circles represent blood glucose and C‐reactive protein levels, respectively.\n\nAfter overnight fasting for 18 h, the patient underwent thoracoscopic debridement and intrathoracic lavage (day 1; Figure 2). His surgery was initiated with drip infusion of extracellular fluid with 1% glucose without insulin. Based on the information of having diabetes from the former hospital, his arterial blood gas was measured during surgery. Approximately 2 h after the initiation of surgery, he was found to be acidotic on arterial blood gas with 162 mg/dL of blood glucose level (Figure 2). A urine test for ketone showed a positive result. Laboratory tests showed elevated levels of total ketone bodies, acetoacetic acid and 3‐hydroxybutyric acid in serum (Figure 2). Subsequently, the patient was started on an insulin infusion with drip infusion of 5% glucose immediately after the consultation from the anesthesiologist to the first department of medicine. He awoke from anesthesia normally and showed no digestive symptoms. After the continuous insulin infusion, his acidosis and ketosis gradually resolved over the next 24 h. Approximately 2 weeks later, his bacterial empyema had almost resolved. During these 2 weeks, he was treated with insulin alone for diabetes and did not present ketosis or acidosis.\n\nWritten informed consent was obtained from the patient.\n\nDiscussion\n\nSGLT2is are widely used as excellent agents for managing diabetes, while providing metabolic, cardiovascular and renal benefits 1 , 3 , 4 . However, several adverse effects are concerned. DKA is a significant risk for patients taking SGLT2is, especially when there are precipitating factors, such as illness, infection and surgery 1 , 2 . In several countries, it is recommended that SGLT2is be discontinued preoperatively. The half‐life of 25 mg empagliflozin is reported to be 18.0 h according to the package insert. In the present case, empagliflozin was taken for the last time 28 h before surgery. However, in the case of surgery, it might be necessary to consider the potential effects of anesthesia and muscle relaxants on the half‐life. In Australia, for example, cessation at least 3 days preoperatively is recommended based on the half‐life and dose‐dependent offset time of SGLT2is 1 . In the present case, besides the use of SGLT2is with an insufficient withdrawal period, the patient was speculated to have infection with empyema and surgery as risk factors of DKA. In particular, as the present patient initially showed mixed acidemia, possibly as a result of the retention of carbon dioxide under the isolated one‐lung ventilation in addition to accumulation of ketone, it is necessary to pay attention to the management of DKA during thoracic surgery. In addition, the initial drip infusion during surgery was at a low concentration of glucose without insulin. Although insulin glargine was injected the night before, it is also possible that an insufficient dosage of glucose and insulin made the DKA worse in the present case.\n\nEarly detection and intervention are critical for management of DKA associated with SGLT2is. The US Food and Drug Administration highlighted awareness among practitioners, DKA symptoms and the potential for lower than expected blood glucose levels when precipitating factors for DKA associated with SGLT2is are present in patients 5 . However, as the symptoms are atypical and the blood glucose levels could be lower than expected, the diagnosis tends to be delayed in DKA associated with SGLT2is. In the present case, it is possible that eDKA had already developed before the surgery, although the patient had no symptoms of acidemia at that point. Thus, when it is difficult to take a sufficient withdrawal period of SGLT2is preoperatively, it is important to monitor ketone and acidosis, even before surgery, for the early detection and immediate management of DKA.\n\nSeveral situations/diseases are raised as the general differential diagnosis of euglycemic ketoacidosis: pregnancy, restriction on caloric intake, glycogen storage diseases or defective gluconeogenesis as a result of alcohol abuse or chronic liver disease. As for the mechanism of eDKA associated with SGLT2is under stress, situations, such as delivery of a potentially low dose of insulin, increased secretion of counter hormones and dehydration status on the surgical day, could be speculated 1 , 6 , 7 . Under stress, such as surgery or illness, increased secretion of counter hormones, such as glucagon, leads to ketogenesis owing to such reasons as lipolysis providing sufficient free fatty acid substrate for production of ketone bodies or hepatic glucose production. Meanwhile, in patients treated with both SGLT2is and insulin, increased renal excretion of glucose might result in treatment with insufficient insulin to suppress lipolysis and ketogenesis, even if blood glucose levels are not increased. Therefore, sufficient insulin delivery, and careful clinical and biochemical monitoring are required to prevent perioperative eDKA in patients treated with dual SGLT2is and insulin.\n\nIn summary, we presented a patient with type 2 diabetes and bacterial empyema, who developed intraoperative eDKA associated with empagliflozin. This is the first case of eDKA associated with SGLT2is during thoracic surgery, which could be rapidly resolved by emergent intervention. When patients are taking SGLT2is, especially those with precipitating factors, it is clinically important to be aware of the potential risk of eDKA and to increase monitoring for the immediate initiation of treatment.\n\nDISCLOSURE\n\nThe authors declare no conflict of interest.\n\nAcknowledgments\n\nWe acknowledge proofreading and editing by Benjamin Phillis at the Clinical Study Support Center at Wakayama Medical University. This work was supported by SRF (TA).\n==== Refs\nReferences\n\n1 Fleming N , Hamblin PS , Story D , et al. Evolving evidence of diabetic ketoacidosis in patients taking sodium glucose cotransporter 2 inhibitors. J Clin Endocrinol Metab 2020; 105 : dgaa200.32302001\n2 Thiruvenkatarajan V , Meyer EJ , Nanjappa N , et al. Perioperative diabetic ketoacidosis associated with sodium‐glucose co‐transporter‐2 inhibitors: a systematic review. Br J Anaesth 2019; 123 : 27–36.31060732\n3 DeFronzo RA , Norton L , Abdul‐Ghani M . Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol 2017; 13 : 11–26.27941935\n4 Perkovic V , Jardine MJ , Neal B , et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380 : 2295–2306.30990260\n5 Fadini GP , Bonora BM , Avogaro A . SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA adverse event reporting system. Diabetologia 2017; 60 : 1385–1389.28500396\n6 Perry RJ , Rabin‐Court A , Song JD , et al. Dehydration and insulinopenia are necessary and sufficient for euglycemic ketoacidosis in SGLT2 inhibitor‐treated rats. Nat Commun 2019; 10 : 548.30710078\n7 Taylor SI , Blau JE , Rother KI . SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab 2015; 100 : 2849–2852.26086329\n\n",
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"issue": "12(4)",
"journal": "Journal of diabetes investigation",
"keywords": "Empagliflozin; Intraoperative euglycemic ketoacidosis; Sodium-glucose cotransporter 2 inhibitor",
"medline_ta": "J Diabetes Investig",
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"title": "Early detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes: A case report.",
"title_normalized": "early detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes a case report"
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"abstract": "Febrile neutropenia(FN)is one of the serious treatment-related toxicities after FEC100(5-fluorouracil 500mg/m2, epiru- bicin 100mg/m2, cyclophosphamide 500 mg/m2)chemotherapy for breast cancer. Granulocyte-colony stimulating factor(GCSF) is used as a support therapy for FN. Thus, we evaluated retrospectively the safety of administering pegfilgrastim the day after FEC100 chemotherapy in Japanese patients with breast cancer as compared with lenograstim. Grade 3 or 4 neutropenia was observed in 91.7% patients after pegfilgrastim administration and in 63.2% after lenograstim. The incidence rate of FN was 7.0%after pegfilgrastim administration and 9.7%after lenograstim, a difference that was not significantly different(p= 0.741). The mean relative dose intensity was good at 0.98 for pegfilgrastim and 0.97 for lenograstim. In conclusion, pegfilgrastim is not inferior to lenograstim in the incidence of FN. However, we do not recommend administering pegfilgrastim on the day after FEC100 therapy because it causes more severe neutropenia and has a high risk of FN. The timing of administration of pegfilgrastim in FEC100 therapy requires further study.",
"affiliations": "Dept. of Pharmacy, Japanese Red Cross Society Wakayama Medical Center.",
"authors": "Fujiwara|Daichiro|D|;Mashimo|Keiji|K|;Kimura|Kayo|K|;Noda|Akihiro|A|;Taki|Kazuo|K|;Yoshibayashi|Hiroshi|H|;Takeda|Tomoya|T|;Tsubaki|Masanobu|M|;Nishida|Shozo|S|;Sakaguchi|Katsuhiko|K|",
"chemical_list": "D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D015251:Epirubicin; D003520:Cyclophosphamide; D000069585:Filgrastim; D005472:Fluorouracil",
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"issue": "44(2)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D015251:Epirubicin; D005260:Female; D000069585:Filgrastim; D005472:Fluorouracil; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007958:Leukocyte Count; D008875:Middle Aged; D009503:Neutropenia; D009504:Neutrophils; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012189:Retrospective Studies",
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"publication_types": "D016428:Journal Article",
"references": null,
"title": "Influence of Next-Day Administration of Pegfilgrastim after FEC100 Chemotherapy in Japanese with Breast Cancer on Neutrophil Count.",
"title_normalized": "influence of next day administration of pegfilgrastim after fec100 chemotherapy in japanese with breast cancer on neutrophil count"
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"abstract": "Paradoxical inflammatory reactions associated with treatment of neurotuberculosis can lead to severe morbidity and mortality and may not be controlled by steroids alone. We report the use of the Janus kinase inhibitor ruxolitinib to treat a steroid-refractory neurotuberculosis paradoxical reaction.",
"affiliations": "Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;New York University Langone, New York, New York, USA.;Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.",
"authors": "Xie|Yingda L|YL|;Ita-Nagy|Fanny|F|;Chen|Ray Y|RY|;Manion|Maura M|MM|;Sereti|Irini|I|;Pei|Luxin|L|;Holland|Steven M|SM|",
"chemical_list": null,
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"doi": "10.1093/ofid/ofz422",
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"issn_linking": "2328-8957",
"issue": "6(10)",
"journal": "Open forum infectious diseases",
"keywords": "JAK inhibitors; neurotuberculosis; paradoxical reaction; ruxolinitib; tuberculosis",
"medline_ta": "Open Forum Infect Dis",
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"other_id": null,
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"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": "20817712;25669480;10318940;22219223;16900926;28705945;26394669;25809754;15983916;18840076;24680563;29104284",
"title": "Neurotuberculosis: Control of Steroid-Refractory Paradoxical Inflammatory Reaction With Ruxolitinib.",
"title_normalized": "neurotuberculosis control of steroid refractory paradoxical inflammatory reaction with ruxolitinib"
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"abstract": "OBJECTIVE\nCharacteristics of drug-related problems and related patient harm has not been evaluated in critically ill patients with decompensated cirrhosis. Our objectives were to identify characteristics and incidence rate of drug-related problems and related preventable harm in critically ill patients with decompensated liver cirrhosis.\n\n\nMETHODS\nA prospective observational study was conducted from February 2018 to January 2019 in 10-bed medical intensive care unit of a tertiary care hospital. Medication charts of 78 patients diagnosed with decompensated cirrhosis were reviewed by the clinical pharmacist. Pharmaceutical care-related standard tools were applied for classification of drug-related problems and their severity of outcomes.\n\n\nRESULTS\nA total of 394 drug-related problems with an incidence rate of 298.48 per 1000 patient medical intensive care unit-day were identified. Most common drug-related problems were drug-drug interaction (48.7%) followed by guideline nonconformity (15.5%), inappropriate drug form (11.9%), and contraindication (9.6%). Approximately 27% of drug-related problems induced preventable harm, which included temporary harm (19.8%), permanent harm (5.8%), and death (0.8%). The incidence rate of preventable harm was found to be 78.78 per 1000 patient medical intensive care unit-day. Nonsteroidal anti-inflammatory drugs were the most common medications involved in drug-drug interaction, guideline nonconformity, and contraindication which led to gastrointestinal bleeding (24%) and worsening of renal function (11.5%).\n\n\nCONCLUSIONS\nDrug-related problems occurred commonly in critically ill patients with decompensated liver cirrhosis and induced preventable harm which jeopardized the safety of these vulnerable patients. Clinical pharmacist's intervention is essential for identification of drug-related problems and related preventable harm among these patients.",
"affiliations": "Department of Pharmacy Practice, Visveswarapura Institute of Pharmaceutical Sciences, Rajiv Gandhi University of Health Sciences.;Department of Pharmacy Practice, Visveswarapura Institute of Pharmaceutical Sciences, Rajiv Gandhi University of Health Sciences.",
"authors": "Aghili|Mina|M|;Neelathahalli Kasturirangan|Meera|M|",
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"journal": "European journal of gastroenterology & hepatology",
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"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D016638:Critical Illness; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies",
"nlm_unique_id": "9000874",
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"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Identifying characteristics of drug-related problems in critically ill patients with decompensated liver cirrhosis.",
"title_normalized": "identifying characteristics of drug related problems in critically ill patients with decompensated liver cirrhosis"
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"abstract": "BACKGROUND\nBurkholderia cepacia complex is a ubiquitous organism with a high virulence potential. It is found most commonly in moist environments. Hospital outbreaks have been reported from diverse sources such as contaminated faucets, nebulizers, disinfectant solutions, multidose antibiotic vials, tap water, bottled water, nasal sprays, and ultrasound gels. In this article, we present our experience in investigating and successfully managing an outbreak of nosocomial transmission of Burkholderia cepacia sepsis in the neonatal intensive care unit at SGT Hospital, Haryana, India.\n\n\nMETHODS\nDuring the month of March, multiple Burkholderia cepacia complex isolates were recovered from blood cultures of Caucasian babies admitted to the neonatal intensive care unit of our hospital. The organisms were multidrug-resistant, with in vitro sensitivity to meropenem alone (minimum inhibitory concentration = 4 μg/ml). An outbreak was suspected, and the neonatal intensive care unit in-charge and hospital infection control teams were alerted. Outbreak investigation was initiated, and surveillance samples were collected. Burkholderia cepacia complex was successfully isolated from suction apparatus. The isolates were phenotypically typed (biotyping and antimicrobial susceptibility testing) and found to be identical.\n\n\nCONCLUSIONS\nIn our study, the index case might have been exposed to infection due to a physiological state of low immunity (preterm, low birth weight, and mechanical ventilation). The rest of the cases might have been exposed to this organism due to inadequate hand hygiene/improper cleaning and disinfection practices. Timely reporting and implementation of infection control measures played a significant role in curtailing this outbreak.",
"affiliations": "Department of Microbiology, SGT University, Gurugram, Haryana, India. tanishabharara.med@gmail.com.;Department of Microbiology, SGT University, Gurugram, Haryana, India.;Department of Microbiology, SGT University, Gurugram, Haryana, India.;Department of Microbiology, SGT University, Gurugram, Haryana, India.",
"authors": "Bharara|Tanisha|T|;Chakravarti|Anita|A|;Sharma|Mukesh|M|;Agarwal|Priti|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-020-02415-8",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2415\n10.1186/s13256-020-02415-8\nCase Report\nInvestigation of Burkholderia cepacia complex bacteremia outbreak in a neonatal intensive care unit: a case series \nBharara Tanisha tanishabharara.med@gmail.com Chakravarti Anita anitachakravarti@gmail.com Sharma Mukesh sharmadrmukesh@gmail.com Agarwal Priti pritidragarwal2@gmail.com grid.449187.70000 0004 4655 4957Department of Microbiology, SGT University, Gurugram, Haryana India \n23 6 2020 \n23 6 2020 \n2020 \n14 7610 7 2019 28 5 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Introduction\nBurkholderia cepacia complex is a ubiquitous organism with a high virulence potential. It is found most commonly in moist environments. Hospital outbreaks have been reported from diverse sources such as contaminated faucets, nebulizers, disinfectant solutions, multidose antibiotic vials, tap water, bottled water, nasal sprays, and ultrasound gels. In this article, we present our experience in investigating and successfully managing an outbreak of nosocomial transmission of Burkholderia cepacia sepsis in the neonatal intensive care unit at SGT Hospital, Haryana, India.\n\nCase presentation\nDuring the month of March, multiple Burkholderia cepacia complex isolates were recovered from blood cultures of Caucasian babies admitted to the neonatal intensive care unit of our hospital. The organisms were multidrug-resistant, with in vitro sensitivity to meropenem alone (minimum inhibitory concentration = 4 μg/ml). An outbreak was suspected, and the neonatal intensive care unit in-charge and hospital infection control teams were alerted. Outbreak investigation was initiated, and surveillance samples were collected. Burkholderia cepacia complex was successfully isolated from suction apparatus. The isolates were phenotypically typed (biotyping and antimicrobial susceptibility testing) and found to be identical.\n\nConclusions\nIn our study, the index case might have been exposed to infection due to a physiological state of low immunity (preterm, low birth weight, and mechanical ventilation). The rest of the cases might have been exposed to this organism due to inadequate hand hygiene/improper cleaning and disinfection practices. Timely reporting and implementation of infection control measures played a significant role in curtailing this outbreak.\n\nKeywords\nBlood cultureSurveillanceHospital infection controlMultidrug resistanceissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nBurkholderia cepacia complex (BCC) consists of a cluster of 18 closely related genomovars. It has been recognized as an opportunistic human pathogen since the early 1980s [1]. BCC has been isolated from numerous water sources and wet surfaces, including disinfectants and intravenous fluids [2]. Hospital outbreaks have been reported due to anesthetics, disinfectants, intravenous solutions, nebulizer solutions, mouthwash, and medical devices, including respiratory therapy equipment (Table 1).\nTable 1 Summary of various outbreaks of Burkholderia cepacia complex in hospital setup in India over the last 5 years [2–8]\n\nSerial number\tAuthor, location (year)\tPlace\tNumber of cases\tDuration of outbreak\tSite of infection\tSource of infection\tMortality rate (%)\t\n1.\tRastogi, New Delhi (2019) [2]\tNeurotrauma intensive care unit\t48\t4 months\tBlood and respiratory samples\tWater\t18.7\t\n2.\tBaul, Kolkata (2014) [3]\tHemato-oncology unit\t29\t6\tBlood\tIntravenous antibiotics\t3.4\t\n3.\tSinghal, Mumbai (2015) [4]\tChemotherapy daycare unit\t13\tNot specified\tBlood\tAntiemetic drug\tNil\t\n4.\tGupta, Rajastha (2018) [5]\tOncology care center\t14\t1 month\tBlood\tCould not be identified\tNil\t\n5.\tMali, Mumbai (2017) [6]\tPICU, pediatric ward\t76\t8 months\tBlood\tAmikacin vial rubber stopper\tNot specified\t\n6.\tAntony, Karnataka (2016) [7]\tPICU\t3\tSporadic episode\tBlood\tWater\tNil\t\n7.\tYamunadevi, Chennai (2018) [8]\tCCU\t24\t3 months\tBlood\tUltrasound gel\tNot specified\t\n8.\tPresent case, Haryana (2019)\tNICU\t4\t1 month\tBlood\tSuction apparatus\t0.53\t\nPICU Pediatric intensive care unit, CCU Cardiac care unit, NICU Neonatal intensive care unit\n\n\n\nIn this article, we present our experience in investigating and managing an outbreak of nosocomial transmission of Burkholderia cepacia sepsis in the neonatal intensive care unit (NICU) at SGT Hospital, Haryana, India.\n\nCase presentation\nDuring the month of March, three blood cultures received in our microbiology laboratory grew organisms, which were morphologically similar. On further investigation, all the samples were traced to neonates admitted to our NICU. An outbreak was suspected, so the NICU in-charge and hospital infection control (HIC) teams were alerted. A fourth sample was received, with similar growth observed. All patient details were anonymized, coded by randomization, and delinked from any identity of the patients (Table 2).\nTable 2 Details of cases of Burkholderia cepacia complex bloodstream infections in our neonatal intensive care unit (March–April 2019)\n\nNeonate\tTerm/preterm (weeks)\tBirth weight (kg)\tPlace and mode of delivery\tRespiratory support\tCRP\tSerum procalcitonin\tOutcome\t\n1\tPreterm (32 + 4)\tLBW (1.78)\tIn-born, NVD\tCPAP\tPositive\tNot done\tDischarged\t\n2\tPreterm (29 + 2)\tELBW (0.9)\tIn-born, NVD\tMechanical ventilation\tNot done\tNot done\tExpired\t\n3\tPreterm (30 + 6)\tLBW (1.64)\tIn-born, NVD\tMechanical ventilation\tPositive\tPositive (2.47)\tDischarged\t\n4\tTerm (36 + 4)\tLBW (1.68)\tIn-born, NVD\tCPAP\tPositive\tNot done\tLAMA\t\nOutbreak investigation was initiated and surveillance samples collected CRP C-reactive protein, LBW Low birth weight, NVD Normal vaginal delivery, CPAP Continuous Positive Airway Pressure, ELBW Extremely low birth weight infant, LAMA Leave against medical advice\n\n\n\nPatient 1 (32 + 4 weeks of gestation)\nA preterm (32 + 4 weeks of gestation), low-birth-weight (1.78 kg) Caucasian male baby was delivered by normal vaginal route at our hospital. The mother had preterm rupture of membrane since 20 days and was receiving antibiotics. The baby cried immediately after birth; however, subsequently, the baby showed signs of respiratory distress (nasal flaring, chest retractions, respiratory rate of 48 breaths/minute). The baby was treated with continuous positive airway pressure (CPAP). Routine investigations showed leukocytosis and metabolic acidosis. The baby’s C-reactive protein (CRP) became positive after 48 hours. A blood culture was sent, and the baby was started on intravenous injections of cefotaxime (90 mg in 10 ml of normal saline twice per day) and amikacin (32 mg every 36 hours). Subsequently, a blood culture grew BCC, and antibiotic treatment was changed to injectable meropenem. The patient improved and was discharged.\n\nPatient 2 (29 + 2 weeks of gestation)\nA preterm (29 + 2 weeks of gestation), extremely low-birth-weight (900 g) Caucasian male baby was delivered by a primigravida by normal vaginal delivery at SGT Hospital. The mother reported a history of oligohydramnios with premature rupture of the membranes since 12 days. The baby was admitted to the NICU of our hospital on day 1 of life. The baby did not cry immediately after birth and was admitted with the complaints of metabolic acidosis, seizures, and shock with sepsis. On day 2 of life, the baby was shifted to mechanical ventilation. A blood culture was sent on day 1 of admission. Empirical treatment with intravenous injections of cefotaxime (90 mg in 10 ml of normal saline twice per day) and amikacin (32 mg every 36 hours) was started. Subsequently, a blood culture grew BCC (day 2), and antibiotic treatment was changed to injectable meropenem. However, the baby did not survive and was declared dead on day 6.\n\nPatient 3 (30 + 6 weeks of gestation)\nA preterm (30 + 6 weeks of gestation), 1.64-kg Caucasian female baby born to a primigravida by normal vaginal delivery was admitted to the NICU of our hospital on day 1 of life. The mother reported a history of preeclampsia during the antenatal period. The baby presented with severe anemia, generalized edema, and pansystolic murmur. She subsequently developed respiratory distress and was put on mechanical ventilation. A blood culture was positive for BCC on day 15.\n\nPatient 4 (32 + 4 weeks of gestation)\nPatient 4 was a term (32 + 4 weeks of gestation), small for gestation age, low-birth-weight (1.68 kg) Caucasian male baby born to a G2 P1 L1 A0 female. The baby was delivered by normal vaginal delivery at SGT Hospital. The baby cried after 1 minute of bag and mask ventilation, a case of perinatal asphyxia. He was admitted to the NICU of our hospital on day 1 of life and subsequently started on CPAP therapy. A blood culture was sent on day 2 of admission. Routine blood tests showed normocytic, normochromic anemia and leukopenia. The patient’s CRP test result was positive. His blood culture result was positive on day 3 of life. He left under medical advice on day 4.\n\nMicrobiological analysis\nBlood culture\nAll the blood culture samples were collected in BacT/ALERT aerobic blood culture bottles (bioMérieux, New Delhi, India) and sent to the hospital’s microbiology laboratory. The samples were incubated and monitored regularly using the BacT/ALERT system (bioMérieux). All bottles with positive signals were removed from the instrument, Gram-stained, and subcultured on blood agar and MacConkey agar plates. On blood agar, the organism grew as opaque, glistening colonies, nonpigmented initially, later developing yellowish pigmentation and non-lactose-fermenting colonies on MacConkey agar. It was catalase-positive and oxidase-positive and produced acid from glucose, mannitol, lactose, and sucrose oxidatively. The isolates decarboxylated lysine and ornithine and were resistant to polymyxin B and colistin. The organism was presumed to be BCC, and the finding was confirmed with the help of VITEK 2 (bioMérieux). Antimicrobial susceptibility was determined by both the Kirby-Bauer disc diffusion method in accordance with the Clinical and Laboratory Standards Institute (2019) recommendations and the VITEK 2 antimicrobial susceptibility testing (AST) card (bioMérieux) [9]. The organism was sensitive only to meropenem (4 μg/ml). It was resistant to piperacillin/tazobactam (> 128 μg/ml), cefoperazone/sulbactam (16 μg/ml), cefepime (4 μg/ml), imipenem (> 16 μg/ml), amikacin (> 64 μg/ml), gentamicin (> 16 μg/ml), ciprofloxacin (2 μg/ml), tigecycline (> 8 μg/ml), colistin (> 16 μg/ml), and trimethoprim/sulbactam (160 μg/ml).\n\nSurveillance cultures\nNICU surveillance samples were collected with the help of sterile swabs and sent immediately to our hospital’s microbiology laboratory. Samples were taken from ventilator tubes, suction apparatus, Ambu bags (Ambu, Ballerup, Denmark), Cheatle forceps, injection preparation areas, amikacin vials, taps, bed rails, and sterile saline for injection preparations. The swabs were plated on blood agar plates and incubated overnight at 36 ± 1 °C under aerobic conditions. The plates were read the next day, and colonies were identified with the help of Gram staining and biochemical tests. The isolates were confirmed using the VITEK 2 system (bioMérieux). Antimicrobial susceptibility of the clinical isolates was determined by both the Kirby-Bauer disc diffusion method and the VITEK 2 AST card. BCC was isolated from a surveillance sample of a suction bottle. All five isolates (clinical = 4 and surveillance = 1) were phenotypically typed (AST) and found to be identical.\n\nCohorting of cases was done. Treatment of babies was changed to injection meropenem. Suction bottles were cleaned with thorough scrubbing followed by decontamination with 2% glutaraldehyde solution. Retraining on hand hygiene, cleaning, and disinfection procedures was provided. The organism was not isolated again. The mortality rate for this outbreak was found to be 0.53%.\n\nDiscussion and conclusions\nHealthcare-associated infections are defined as infections that were neither present nor incubating at the time a patient was admitted to a healthcare facility [10]. According to our infection control policy, an outbreak is suspected when an infection is isolated from two or more patients in a defined time frame. For our study, an outbreak was defined as simultaneous presence of more than two patients with positive culture results for BCC.\n\nOutbreak cases were defined as a neonate with a clinical suspicion of sepsis (fever, tachycardia, tachypnea, leukocytosis, or leukopenia, with or without hypotension) who had one or more BCC-positive blood culture results. The outbreak period was defined as the time between March 2019 and April 2019.\n\nWe have a very vigilant hospital infection control team. Our infection control officer takes regular rounds along with our infection control nurses. The cluster of BCC infections was observed in our nine-bed NICU. The nurse-to-patient ratio and the doctor-to-patient ratio in the NICU are usually 1:4 and 1:3, respectively. The outbreak was suspected in March 2019, and an investigation was triggered when four subsequent cases of bacteremia caused by B. cepacia occurred over a period of 1 month. This prompted a detailed microbiological investigation and hospital infection surveillance activities.\n\nBCC is an opportunistic pathogen of high virulence potential. Various virulence mechanisms associated with this organism are multidrug resistance (bcrA efflux pump), genes determining transmissibility (esmR and cblA genes, and esmR), siderophores (salicylic acid, ornibactin, pyochelin, and cepabactin), and adherence proteins (long flexible type II pili) [11]. They have the potential to survive and multiply in the presence of disinfectants, indwelling invasive medical devices, and antibiotic solutions, thus acting as a potential reservoir for infections in the hospital setting [12, 13].\n\nMinimum inhibitory concentration (MIC) determination of our isolates revealed multidrug resistance. Our isolate showed in vitro resistance to trimethoprim-sulfamethoxazole (TMP-SMZ), with an MIC of 160. Rates of in vitro resistance of BCC to TMP-SMZ range from 5% in Quebec, Canada, and Latin America to 10% in Europe [14, 15]. According to the Clinical and Laboratory Standards Institute guidelines, the antibiotics effective against BCC include levofloxacin, meropenem, cotrimoxazole, ceftazidime, and minocycline [9]. Though BCC organisms are highly resistant, antibiotic combinations have been found to be effective in a few studies [16, 17].\n\nIn our study, all the isolates from patients and the environmental samples belonged to the same biotype and exhibited the same antibiogram where the isolate was sensitive to meropenem alone. The index case might have acquired the infection due to a physiological state of low immunity (preterm, low birth weight, and mechanical ventilation). The rest of the cases might have been exposed to this organism due to inadequate hand hygiene practices/improper cleaning and disinfection practices. In a study by Mali et al. [6], BCC was isolated from the upper surface of the rubber stopper of sealed multidose amikacin injection vials. It was hypothesized that the needle might have become contaminated while amikacin solution was aspirated from the vials [6]. As per our hospital antibiotic policy, all these babies were started on empirical treatment with intravenous injections of cefotaxime and amikacin while blood culture results were awaited. This might have been another risk factor in the spread of BCC sepsis, since the organism was resistant to these antimicrobials.\n\nThe efficacy of control measures was evaluated by continued follow-up of cases after the outbreak, both clinically and microbiologically. Control measures were considered effective because new cases of BCC sepsis ceased to occur. Timely reporting to the clinician, implementation of infection control measures such as hand hygiene, proper cleaning, and disinfection of NICU equipment, and cohorting of infected cases curtailed this outbreak.\n\nAbbreviations\nBCCBurkholderia cepacia complex\n\nCPAPContinuous positive airway pressure\n\nCRPC-reactive protein\n\nHICHospital infection control\n\nLBWLow birth weight\n\nNICUNeonatal intensive care unit\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nTB analyzed and interpreted the results and prepared the manuscript. AC supervised the writing of the manuscript and interpretation of results. MS supervised hospital infection control surveillance activities. PA supervised the microbiological analysis and manuscript writing. All authors read and approved the final manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThe study was approved by our hospital’s ethics committee.\n\nConsent for publication\nWritten informed consent was obtained from the patients' legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Procop GW Procop GW Church DL Hall GS Janda WM Koneman EW The nonfermentative gram-negative bacilli Koneman’s color atlas and textbook of diagnostic microbiology 2017 7 Philadelphia Lippincott Williams & Wilkins 317 431 \n2. Rastogi N Khuranab S Veeraraghavanc B Inbanathanc FY Kumar S Sekarc R Epidemiological investigation and successful management of a Burkholderia cepacia outbreak in a neurotrauma intensive care unit Int J Infect Dis 2019 79 4 11 10.1016/j.ijid.2018.10.008 30342249 \n3. Baul SN De R Mandal PK Roy S Dolai TK Chakrabarti P Outbreak of Burkholderia cepacia infection: a systematic study in a hematolooncology unit of a tertiary care hospital from eastern India Mediterr J Hematol Infect Dis 2018 10 1 e2018051 10.4084/mjhid.2018.051 30210744 \n4. Singhal T Shah S Naik R Outbreak of Burkholderia cepacia complex bacteremia in a chemotherapy day care unit due to intrinsic contamination of an antiemetic drug Indian J Med Microbiol 2015 33 2 117 119 10.4103/0255-0857.148405 25560013 \n5. Gupta P Jain V Hemrajani M Gupta A Sharma U Outbreak of Burkholderia cepacia catheter-related bloodstream infection in cancer patients with long-term central venous devices at a tertiary cancer centre in India Indian Anaesth Forum 2018 19 1 1 5 10.4103/TheIAForum.TheIAForum_46_17 \n6. Mali S Dash L Gautam V Shastri J Kumar S An outbreak of Burkholderia cepacia complex in the paediatric unit of a tertiary care hospital Indian J Med Microbiol 2017 35 2 216 220 28681809 \n7. Antony B Cherian EV Boloor R Shenoy KV A sporadic outbreak of Burkholderia cepacia complex bacteremia in pediatric intensive care unit of a tertiary care hospital in coastal Karnataka, South India Indian J Pathol Microbiol 2016 59 2 197 199 10.4103/0377-4929.182010 27166040 \n8. Yamunadevi VR Ramasubramanian V Nambi PS Samundeewari P Ramakrishnan N Outbreak of Burkholderia cepacia bacteraemia in a tertiary care centre due to contaminated ultrasound probe gel J Hosp Infect 2018 100 4 257 258 10.1016/j.jhin.2018.04.014 30071264 \n9. Clinical and Laboratory Standards Institute (CLSI) document M100-S25 Performance standards for antimicrobial susceptibility testing 29th Inf Suppl 2019 39 1 50 52 \n10. Centers for Disease Control and Prevention (CDC). CDC/NHSN surveillance definitions for specific types of infections. https://www.cdc.gov/nhsn/PDFs/pscManual/17pscNosInfDef_current.pdf. Accessed 8 June 2019.\n11. Maschmeyer G Göbel UB Mandell GL Bennett JE Dolin R Burkholderia cepacia complex, Stenotrophomonas maltophilia Mandell, Douglas, and Bennett’s principles and practice of infectious diseases 2010 7 Philadelphia Churchill Livingstone 2861 2868 \n12. Wigfield SM Rigg GP Kavari M Identification of an immunodominant drug efflux pump in Burkholderia cepacia J Antimicrob Chemother 2002 49 619 624 10.1093/jac/49.4.619 11909835 \n13. Donlan RM Costerton JW Biofilms: survival mechanisms of clinically relevant microorganisms Clin Microbiol Rev 2002 15 2 167 193 10.1128/CMR.15.2.167-193.2002 11932229 \n14. Speert DP Henry D Vandamme P Epidemiology of Burkholderia cepacia complex in patients with cystic fibrosis, Canada Emerg Infect Dis 2002 8 181 187 10.3201/eid0802.010163 11897071 \n15. Coenye T LiPuma JJ Population structure analysis of Burkholderia cepacia genomovar III: varying degrees of genetic recombination characterize major clonal complexes Microbiology 2003 149 77 88 10.1099/mic.0.25850-0 12576582 \n16. Husain S Singh N Burkholderia cepacia infection and lung transplantation Semin Respir Infect 2002 17 284 290 10.1053/srin.2002.36443 12497545 \n17. Blumer JL Saiman L Konstan MW The efficacy and safety of meropenem and tobramycin vs ceftazidime and tobramycin in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis Chest 2005 128 2336 2346 10.1378/chest.128.4.2336 16236892\n\n",
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"title": "Investigation of Burkholderia cepacia complex bacteremia outbreak in a neonatal intensive care unit: a case series.",
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"abstract": "OBJECTIVE\nWe report the response to pre-operative gemcitabine-based chemoradiotherapy for pancreatic adenocarcinoma.\n\n\nMETHODS\nThirty-five consecutive patients with borderline resectable pancreatic adenocarcinoma of UICC Stage II or III with portal vein invasion or tumor abutment of artery received radiotherapy (twice daily fractions of 1.5 Gy, 5 days/week, total dose: 36 Gy; 30 Gy for Phase I Level 1) with weekly intravenous infusions of gemcitabine (400, 600 and 800 mg/m(2)) at Days 1 and 8 for Phase I and 800 mg/m(2) for Phase II. Restaging was repeated after completion of chemoradiotherapy.\n\n\nRESULTS\nTwenty-six of the 35 (74.3%) patients underwent resection. The dose-limiting toxicities were Grade 4 neutropenia and thrombocytopenia. The recommended regimen was total radiation dose of 36 Gy with gemcitabine 800 mg/m(2). Surgical resection was conducted in 11 of the 15 (73.3%) patients in Phase I study and 15 of the 20 (75.0%) in Phase II. After recommended dose chemoradiotherapy and surgical resection, the median disease-free survival was 17.4 months (5-year survival rate = 14.3%). The median overall survival time and 5-year survival rate were 41.2 months and 28.6%, respectively, for the 21 patients who underwent resection and 10.0 months and 0%, respectively, for those 5 who did not (P = 0.004).\n\n\nCONCLUSIONS\nOur pre-operative gemcitabine-based chemoradiotherapy was well tolerated and safe.",
"affiliations": "Department of Surgery, Kansai Rosai Hospital, Hyogo ytakeda@kanrou.net.;Department of Surgery, Osaka National Hospital, Osaka.;Department of Surgery, Graduate School of Medicine, Osaka University, Osaka.;Department of Surgery, Graduate School of Medicine, Osaka University, Osaka.;Department of Surgery, Graduate School of Medicine, Osaka University, Osaka.;Department of Surgery, Graduate School of Medicine, Osaka University, Osaka.;Department of Radiation Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan.;Department of Radiation Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan.;Department of Surgery, Graduate School of Medicine, Osaka University, Osaka.;Department of Surgery, Graduate School of Medicine, Osaka University, Osaka.;Department of Surgery, Graduate School of Medicine, Osaka University, Osaka.;Department of Surgery, Graduate School of Medicine, Osaka University, Osaka.",
"authors": "Takeda|Yutaka|Y|;Nakamori|Shoji|S|;Eguchi|Hidetoshi|H|;Kobayashi|Shogo|S|;Marubashi|Shigeru|S|;Tanemura|Masahiro|M|;Konishi|Koji|K|;Yoshioka|Yasuo|Y|;Umeshita|Koji|K|;Mori|Masaki|M|;Doki|Yuichiro|Y|;Nagano|Hiroaki|H|",
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"title": "Neoadjuvant gemcitabine-based accelerated hyperfractionation chemoradiotherapy for patients with borderline resectable pancreatic adenocarcinoma.",
"title_normalized": "neoadjuvant gemcitabine based accelerated hyperfractionation chemoradiotherapy for patients with borderline resectable pancreatic adenocarcinoma"
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"abstract": "The coronavirus disease (COVID-19), during its course, may involve several organs, including the skin with a petechial skin rash, urticaria and erythematous rash, or varicella-like eruption, representing an additional effect of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as commonly observed in other viral diseases. Considering that symptomatic patients with COVID-19 generally undergo multidrug treatments, the occurrence of a possible adverse drug reaction presenting with cutaneous manifestations should be contemplated. Pleomorphic skin eruptions occurred in a 59-year-old Caucasian woman, affected by a stable form of chronic lymphocytic leukemia, and symptomatic SARS-CoV-2 infection, treated with a combination of hydroxychloroquine sulfate, darunavir, ritonavir, sarilumb, omeprazole, ceftriaxone, high-flow oxygen therapy devices, filgrastim (Zarzio®) as a single injection, and enoxaparin. The patient stopped all treatment but oxygen and enoxaparin were continued and the patient received a high-dose Desametasone with complete remission of dermatological impairment in 10 days. It is very important to differentially diagnose COVID-19 disease-related cutaneous manifestations, where is justified to continue the multidrug antiviral treatment, from those caused by an adverse drug reaction, where it would be necessary to identify the possible culprit drug and to start appropriate antiallergic treatment.",
"affiliations": "Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.;Covid Unit, Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Rome, Italy.",
"authors": "Scala|Enrico|E|0000-0002-9391-9168;Fania|Luca|L|;Bernardini|Filippo|F|;Calarco|Rodolfo|R|;Chiloiro|Sabrina|S|;Di Campli|Cristiana|C|;Erculei|Sabrina|S|;Giani|Mauro|M|;Giordano|Marzia|M|;Panebianco|Annarita|A|;Passarelli|Francesca|F|;Trovè|Andrea|A|;Verkhovskaia|Sofia|S|;Russo|Giandomenico|G|;Sgadari|Antonio|A|;Didona|Biagio|B|;Abeni|Damiano|D|",
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"doi": "10.1002/iid3.382",
"fulltext": "\n==== Front\nImmun Inflamm Dis\nImmun Inflamm Dis\n10.1002/(ISSN)2050-4527\nIID3\nImmunity, Inflammation and Disease\n2050-4527\nJohn Wiley and Sons Inc. Hoboken\n\n33942541\n10.1002/iid3.382\nIID3382\nCommentary\nCommentary\nPleomorphicskin eruptions in a COVID‐19 affected patient: Case report and review of the literature\nSCALA et al.\nScala Enrico http://orcid.org/0000-0002-9391-9168\n1 e.scala@idi.it\n\nFania Luca 1\nBernardini Filippo 1\nCalarco Rodolfo 1\nChiloiro Sabrina 1\nDi Campli Cristiana 1\nErculei Sabrina 1\nGiani Mauro 1\nGiordano Marzia 1\nPanebianco Annarita 1\nPassarelli Francesca 1\nTrovè Andrea 1\nVerkhovskaia Sofia 1\nRusso Giandomenico 1\nSgadari Antonio 1\nDidona Biagio 1\nAbeni Damiano 1\n1 Covid Unit Istituto Dermopatico dellʼImmacolata‐IRCCS, FLMM Rome Italy\n* Correspondence Enrico Scala, Covid Unit, Istituto Dermopatico dellʼImmacolata‐IRCCS, FLMM, via dei Monti di Creta 104, 00167 Roma, Italia.\nEmail: e.scala@idi.it\n\n04 5 2021\n9 2021\n9 3 10.1002/iid3.v9.3 617621\n14 11 2020\n20 10 2020\n17 11 2020\n© 2020 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nThe coronavirus disease (COVID‐19), during its course, may involve several organs, including the skin with a petechial skin rash, urticaria and erythematous rash, or varicella‐like eruption, representing an additional effect of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, as commonly observed in other viral diseases. Considering that symptomatic patients with COVID‐19 generally undergo multidrug treatments, the occurrence of a possible adverse drug reaction presenting with cutaneous manifestations should be contemplated. Pleomorphic skin eruptions occurred in a 59‐year‐old Caucasian woman, affected by a stable form of chronic lymphocytic leukemia, and symptomatic SARS‐CoV‐2 infection, treated with a combination of hydroxychloroquine sulfate, darunavir, ritonavir, sarilumb, omeprazole, ceftriaxone, high‐flow oxygen therapy devices, filgrastim (Zarzio®) as a single injection, and enoxaparin. The patient stopped all treatment but oxygen and enoxaparin were continued and the patient received a high‐dose Desametasone with complete remission of dermatological impairment in 10 days. It is very important to differentially diagnose COVID‐19 disease‐related cutaneous manifestations, where is justified to continue the multidrug antiviral treatment, from those caused by an adverse drug reaction, where it would be necessary to identify the possible culprit drug and to start appropriate antiallergic treatment.\n\nThe coronavirus disease (COVID‐19), during its course, may involve several organs, including the skin with a petechial skin rash, urticaria and erythematous rash, or varicella‐like eruption, representing an additional effect of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, as commonly observed in other viral diseases. Considering that symptomatic patients with COVID‐19 generally undergo multidrug treatments, the occurrence of a possible adverse drug reaction presenting with cutaneous manifestations should be contemplated. Pleomorphic skin eruptions occurred in a 59‐year‐old Caucasian woman, affected by a stable form of chronic lymphocytic leukemia, and symptomatic SARS‐CoV‐2 infection, treated with a combination of hydroxychloroquine sulfate, darunavir, ritonavir, sarilumb, omeprazole, ceftriaxone, high‐flow oxygen therapy devices, filgrastim (Zarzio®) as a single injection, and enoxaparin. The patient stopped all treatment but oxygen and enoxaparin and received a high‐dose Desametasone with complete remission of dermatological impairment in 10 days. It is very important to differentially diagnose COVID‐19 disease‐related cutaneous manifestations, where is justified to continue the multi‐drug antiviral treatment, from those caused by an adverse drug reaction, where it would be necessary to identify the possible culprit drug and to start appropriate antiallergic treatment.\n\nCOVID\ncutaneous reaction\ndermatology\ndrug reaction\nskin\nviral exanthem\nMinistero della Salute: Ricerca Corrente ‐ RC2020‐2‐Scala 10.13039/501100003196 source-schema-version-number2.0\ncover-dateSeptember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:05.08.2021\nScala E , Fania L , Bernardini F , et al. Pleomorphicskin eruptions in a COVID‐19 affected patient: Case report and review of the literature. Immun Inflamm Dis. 2021;9 :617‐621. 10.1002/iid3.382\n==== Body\n1 INTRODUCTION\n\nThe coronavirus disease (COVID‐19), initially appeared in Wuhan (China), 1 is due to an infection by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) 2 often associated with a respiratory failure caused by severe interstitial pneumonia, 3 and has currently reached a pandemic extent.4, 5\n\nThe disease, during its course, may involve several organs, including the skin with a petechial skin rash, 6 urticaria and erythematous rash, or varicella‐like eruption, representing an additional effect of the SARS‐CoV‐2 infection, as commonly observed in other viral diseases. 7\n\nThere is currently no specific treatment recommended for COVID‐19 disease. Several medications are being explored such as dexamethasone, 8 remdesivir, 9 chloroquine, and hydroxychloroquine10, 11 (generally in combination with azithromycin), lopinavir‐ritonavir, 12 Janus kinase inhibitors (baraticinib), 13 monoclonal antibodies against the interleukin‐6 receptor (tocilizumab and sarilumab), 14 SARS patient sera, 15 nonsteroidal anti‐inflammatory drugs, 16 angiotensin‐converting enzyme 2, 16 and anticoagulant therapy with heparin 17 scant, or contrasting data are supporting the efficacy of any of these agents, to date. 18 Considering that symptomatic patients with COVID‐19 generally undergo multidrug treatments, the occurrence of a possible adverse drug reaction (ADR) presenting with cutaneous manifestations should be contemplated.\n\n2 RESULTS\n\nWe present the case of a 59‐year‐old Caucasian woman, affected by a stable form of chronic lymphocytic leukemia, admitted to the emergency room due to fever, cough, rhinorrhea, and dyspnea. A marked respiratory failure, bilateral air‐space opacification on lung radiographs, and bilateral, symmetric areas of ground‐glass attenuation on computed tomographic scans, were recorded. A nasopharyngeal swab specimen was collected and tested for SARS‐CoV‐2 RNA by reverse transcription polymerase chain reaction (RT‐PCR), yielding a positive result. The patient was therefore treated with a combination of hydroxychloroquine sulfate (Plaquenil®), darunavir (Prezista®), ritonavir, monoclonal antibodies against the interleukin‐6 receptor (Sarilumb®), omeprazole, ceftriaxone (Rocephin®), high‐flow oxygen therapy devices (Venturi masks), and filgrastim (Zarzio®) as a single injection for neutropenia arising following antiviral therapy. She continued assuming enoxaparin 4000 IU twice a day.\n\nAbout 20 days later, while respiratory function progressively improved, in the presence of a still positive nasopharyngeal swab, moderately itching widespread and coalescing papular and erythematous lesions with superimposed vesicle or crust, not associated with feverʼs recurrence, appeared on the trunk. In the following days, plaques and papules with erythematous pomphoid appearance emerged symmetrically on the trunk and limbs. Eventually, the same lesions became purple‐colored large patches and maculae symmetrically affecting the trunk and limbs, but sparing the armpits, always with a remarkable symmetry of the lesion (Figure 1A).\n\nFigure 1 (A) Day by day clinical evolution of skin lesions. Day 1: Widespread and coalescing popular and erythematous lesions with superimposed vesicle or crust are present on the trunk. Day 2: Plaques and papules with erythematous pomphoid appearance are arranged symmetrically on the trunk and limbs. Day 3: Flat and erythematous‐violaceous plaques and papules are located symmetrically on the trunk and limbs. Day 4: Purple‐colored large patches and maculae symmetrically affect the trunk and limbs. Day 5: The skin of the trunk and the root of the limbs is edematous and purplish; the skin of the armpits is spared; the symmetry of the lesion is once again remarkable. Day 6: The skin of the trunk and the root of the limbs is moderately erythematous; the skin of the armpits is spared. Day 10: Skin lesions are healing: postlesional peeling and mild erythema are noted. (B) FACS analysis on PBMC showing the four‐color flow cytometry of CD19/CD5/CD3/CD4/CD8 combination. CD45+ live lymphocytes were gated on forward and side light scatter. (B1) Shows the aberrant overexpression of CD5 by the vast majority of circulating neoplastic CD19+ B cells. (B2) Shows the CD3+CD4+ and CD3+CD8+ distribution in the peripheral blood. (C) Hematoxylin and eosin staining. (C1) Ortho‐ and para‐keratosis, modest edema of the papillary dermis with initial dermo‐epidermal detachment and superficial infiltrate mainly peri‐vascular (original magnification ×5). (C2) Vacuolar alteration of the dermo‐epidermal junction with lymphocyte infiltrate. Presence of some intraepidermal necrotic keratinocytes. In the papillary dermis, there are extravasated red cells and infiltrated lymphocytes, eosinophilic, and neutrophilic granulocytes and some lymphoid blasts (original magnification ×20). (C3) Detail of the infiltrate already described in (C2) showing the presence of red blood cells, lymphocytes, neutrophilic, and eosinophilic granulocytes, blasts (original magnification ×40). (C4) Another detail showing mainly eosinophilic granulocytes infiltrate (original magnification ×40). (D) Immunohistochemistry for CD3 (D1), CD5 (D2), and CD30 (D3) showing that most of the infiltrate in the inflamed skin biopsy is represented by CD3+ and CD5+ T lymphocytes, some of them activated and therefore expressing CD30. Original magnification: ×40\n\nA punch biopsy for histological examination was obtained from the patientʼs back on Day 3, and hematoxylin‐eosin stained tissue specimens showed the presence of ortho‐ and para‐keratosis, rare intraepidermal necrotic keratinocytes, edema of the papillary dermis and superficial perivascular, and interstitial infiltrate (Figure 1C), consisting of CD3+CD5+ T lymphocytes, some of them CD30+, having a blastic appearance, very rare CD20+ B cells and exceptional CD79a+ plasma cells, numerous eosinophilic granulocytes, and scant neutrophilic granulocytes. Such histological findings were suggestive of polymorphic erythema, but the presence of numerous eosinophilic granulocytes was indicative of toxidermic reactions (Figure 1D). Flow cytometric immunophenotyping of peripheral blood lymphocytes confirmed the presence of 94.5% (19,781/µl) CD19+ B cells, 87.6% of them beating the T cell marker CD5+, aberrantly and commonly expressed in B cell chronic lymphocytic leukemia (Figure 1B). As a consequence, a clear reduction of all the other subsets (CD3+ = 3.6%, 412/µl; CD3+CD4+ = 2.4%, 272/µl; CD3+CD8+ = 1.1%, 130/µl; and CD3‐CD16+CD56+ = 0.7%, 74/µl) was observed. T cell receptor‐Vβ analysis identified no impairment of the T cell repertoire.19, 20\n\nThe patient received a high‐dose Desametasone (Soldesam®) therapy for 5 days with gradual tapering of dosage for further 2 weeks. The patient resulted negative to the SARS‐CoV‐2 nasopharyngeal swab a week after the rash onset.\n\nTwo months later, after obtaining the patientʼs written consent, an allergy study was carried out for β‐lactam reactivity. Skin tests were done by prick, and since negative results were recorded, the intradermal test were performed. The determinants and maximum concentration used were: benzylpenicilloyl polylysine (Allergopen; 5 × 10−5 mM/L), a minor determinant mixture containing benzylpenicillin and benzylpenicilloate (Allergopen; 2 × 10−2mM/L), penicillin‐G (10.000 UI/ml), and a panel of cephalosporins, including Ceftriaxone (all at 2 mg/ml). The patientʼs serum was tested for the presence of specific IgE to penicilloyl G, penicilloyl V, ampicilloyl, amoxicilloyl, and cefaclor (UniCAP specific IgE; Pharmacia & Upjohn). We also performed patch tests with cephalosporins as previously described. 21 All tests were negative, and the patient refused a challenge test with ceftriaxone as well as a further investigation with the other possible culprit drugs.\n\n3 CONCLUSIONS\n\nSeveral clinical dermatologic presentations could occur during an ADR, including varicella or morbilliform‐like exanthema, urticaria, erythema multiformis, vasculitis reaction with petechial and purpuric lesions, acral ischemia, and livedo reticularis. Since COVID‐19 could present with all these clinical manifestations, a differential diagnosis between the infectious disease and ADR should be reached. Furthermore, it should be taken into account that many of the symptomatic patients with COVID‐19 are elderly individuals who assume several drugs to control various pre‐existing conditions, thus increasing the risk of ADR.\n\nIn Table 1, we differentiate an exanthem triggered by the viral SARS‐CoV‐2 infection from an ADR through the evaluation of clinical, serological, and histological parameters. Marzano et al. 22 reported that the COVID‐19 exanthem appeared 3 days after systemic symptoms and disappeared after 8 days, without facial or mucosal involvement. In the reported cases of COVID‐19 infection, the itch was mild or absent and cutaneous lesions interested mainly the trunk.7, 22 Considering laboratory parameters in COVID‐19 disease, elevated levels of lactate dehydrogenase, ferritin, and aminotransferase have been described. Furthermore, high d‐dimer levels and more severe lymphopenia have been associated with higher mortality, 23 while, on the other hand, atopic status was associated with less severe clinical outcomes. 24 In case of doubts regarding the cause of the rash, a biopsy would be necessary to confirm the diagnosis. Histological examination of the viral exanthema shows a slightly atrophic epidermis with basket‐weave hyperkeratosis and vacuolar degeneration of the basal layer with enlarged and multinucleate keratinocytes, without lymphomonocytic infiltrate. Otherwise, ADRs present histologically with an interface dermatitis characterized by spongiosis and superficial, or superficial and deep, perivascular and interstitial infiltrate of lymphocytes and eosinophils, sometimes with scanty neutrophils; vacuolar changes at the dermo–epidermal junction with necrotic keratinocytes can often be observed. 25 However, the histological examination can also be difficult to interpret, as the appearance of viral lesions and ADR may be quite similar. Besides, it must be remembered that in some cases ADRs occur in conjunction with a viral infection, as it happens for example in the morbilliform exanthema due to taking ampicillin during an EBV infection, or in the DRESS syndrome where there is a reactivation of HHV‐6.\n\nTable 1 Differential diagnosis between viral exanthem of COVID‐19 and adverse drug reaction\n\n\tViral exanthem (Sars‐CoV‐2 infection)\tExanthem in adverse drug reactions\t\nOnset of cutaneous manifestationa\t<10 days\t1‐>10 days\t\nRespiratory, gastro‐intestinal or other symptomsb\t+\t−\t\nMultidrug therapy\t−\t+\t\nSymmetric distribution of cutaneous lesions\t−\t+\t\nFacial or mucosal involvement\t−\t+\t\nItchc\t−\t+\t\nEosinophilia\t−\t+\t\nLymphopenia\t+\t−\t\nIncreased total IgE\t−\t+/−\t\nIncreased LDH, ferritin and d‐dimer\t+\t−\t\nHistology of cutaneous lesionsd\tViral reaction\tDrug reaction\t\nAbbreviations: COVID‐19, coronavirus disease 2019; LDH, lactate dehydrogenase; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2.\n\na Compared with other clinical manifestation or main symptoms of COVID‐19 infection.\n\nb Fever, cough, rhinorrhea, dyspnea, nausea and diarrhea, headaches, myalgia, weakness, coryza, hyposmia, hypogeusia, and pharyngodynia.\n\nc In COVID‐19 infection has been reported no mild itch.\n\nd See description in the text.\n\nJohn Wiley & Sons, Ltd.\n\nWe acknowledge that our findings may not be completely novel, but this “N of 1” case report underlines that It is very important to correctly identify the two different etiological situations since they require diverging treatment approaches. In fact, in case of COVID‐19 disease, it would be justified to continue the multidrug antiviral treatment, while in case of ADR it would be necessary to identify the possible culprit drug, to stop as soon as possible the administration of that drug, and to start appropriate treatment (glucocorticoid and/or antihistamine drug).\n\nCONFLICT OF INTERESTS\n\nThe authors declare that there are no conflict of interests.\n\nAUTHOR CONTRIBUTIONS\n\nSabrina Erculei and Luca Fania conceived the study, and wrote the manuscript. Filippo Bernardini, Rodolfo Calarco, Sabrina Chiloiro, Cristiana Di Campli, Sabrina Erculei, Mauro Giani, Annarita Panebianco, Andrea Trovè, Sofia Verkhovskaia, Giandomenico Russo, and Antonio Sgadari cared for COVID‐19 patient and provided the clinical data. Francesca Passarelli and Biagio Didona performed histological evaluation. Damiano Abeni performed the statistical analysis and wrote the manuscript.\n\nACKNOWLEDGMENT\n\nThis study was supported, in part, by the “Progetto Ricerca Corrente” of the Italian Ministry of Health, Rome, Italy.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n\n1 Ng OT , Marimuthu K , Chia PY , et al. SARS‐CoV‐2 infection among travelers returning from Wuhan, China. N Engl J Med. 2020;382 :1476‐1478.32163698\n2 Zhu N , Zhang D , Wang W , et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382 :727‐733.31978945\n3 Li Q , Guan X , Wu P , et al. Early transmission dynamics in Wuhan, China, of novel coronavirus‐infected pneumonia. N Engl J Med. 2020;382 :1199‐1207.31995857\n4 Knottnerus JA , Tugwell P . Methodological challenges in studying the COVID‐19 pandemic crisis. J Clin Epidemiol. 2020;121 :A5‐A7.32336471\n5 Jewell NP , Lewnard JA , Jewell BL . Predictive mathematical models of the COVID‐19 pandemic: underlying principles and value of projections. JAMA. 2020;323 (19 ):1893‐1894.32297897\n6 Joob B , Wiwanitkit V . COVID‐19 can present with a rash and be mistaken for dengue. J Am Acad Dermatol. 2020;82 :e177.32213305\n7 Recalcati S . Cutaneous manifestations in COVID‐19: a first perspective. J Eur Acad Dermatol Venereol. 2020;34 .\n8 Johnson RM , Vinetz JM . Dexamethasone in the management of COVID‐19. BMJ. 2020;370 :m2648.32620554\n9 Maciorowski D , Idrissi SZE , Gupta Y , et al. A review of the preclinical and clinical efficacy of remdesivir, hydroxychloroquine, and lopinavir‐ritonavir treatments against COVID‐19 [published online ahead of print September 17, 2020]. SLAS Discov. 2020. 10.1177/2472555220958385\n10 Ortolani C , Pastorello EA . Hydroxychloroquine and dexamethasone in COVID‐19: who won and who lost? Clin Mol Allergy. 2020;18 :17.32922210\n11 Vinetz JM . Lack of efficacy of hydroxychloroquine in COVID‐19. BMJ. 2020;369 :m2018.32430461\n12 Liu W , Zhou P , Chen K , et al. Efficacy and safety of antiviral treatment for COVID‐19 from evidence in studies of SARS‐CoV‐2 and other acute viral infections: a systematic review and meta‐analysis. CMAJ. 2020;192 :E734‐E744.32493740\n13 Praveen D , Puvvada RC , VAM . Janus kinase inhibitor baricitinib is not an ideal option for management of COVID‐19. Int J Antimicrob Agents. 2020;55 :105967.32259575\n14 Douedi S , Chaudhri M , Miskoff J . Anti‐interleukin‐6 monoclonal antibody for cytokine storm in COVID‐19. Ann Thorac Med. 2020;15 :171‐173.32831940\n15 Anderson DE , Tan CW , Chia WN , et al. Lack of cross‐neutralization by SARS patient sera towards SARS‐CoV‐2. Emerg Microbes Infect. 2020;9 :900‐902.32380903\n16 Smart L , Fawkes N , Goggin P , et al. A narrative review of the potential pharmacological influence and safety of ibuprofen on coronavirus disease 19 (COVID‐19), ACE2, and the immune system: a dichotomy of expectation and reality. Inflammopharmacology. 2020;28 :1141‐1152.32797326\n17 Gozzo L , Viale P , Longo L , Vitale DC , Drago F . The potential role of heparin in patients with COVID‐19: beyond the anticoagulant effect: a review. Front Pharmacol. 2020;11 :1307.32973526\n18 Paumgartten FJR , Oliveira ACAX . Off label, compassionate and irrational use of medicines in Covid‐19 pandemic, health consequences and ethical issues. Cien Saude Colet. 2020;25 :3413‐3419.32876249\n19 Scala E , Cadoni S , Girardelli CR , et al. Skewed expression of activation, differentiation and homing‐related antigens in circulating cells from patients with cutaneous T cell lymphoma associated with CD7‐ T helper lymphocytes expansion. J Invest Dermatol. 1999;113 :622‐627.10504451\n20 Scala E , Narducci MG , Amerio P , et al. T cell receptor‐Vbeta analysis identifies a dominant CD60+. J Invest Dermatol. 2002;119 :193‐196.12164946\n21 Scala E , Giani M , Pastore S , et al. Distinct delayed T‐cell response to beta‐methasone and penicillin‐G in the same patient. Allergy. 2003;58 :439‐444.12752333\n22 Marzano AV , Genovese G , Fabbrocini G , et al. Varicella‐like exanthem as a specific COVID‐19‐associated skin manifestation: multicenter case series of 22 patients. J Am Acad Dermatol. 2020;83 :280‐285.32305439\n23 Ou M , Zhu J , Ji P , et al. Risk factors of severe cases with COVID‐19: a meta‐analysis. Epidemiol Infect. 2020;148 :e175.32782035\n24 Scala E , Abeni D , Tedeschi A , et al. Atopic status protects from severe complications of COVID‐19 [published online ahead of print August 16, 2020]. Allergy. 2020. 10.1111/all.14551\n25 Weyers W , Metze D . Histopathology of drug eruptions ‐ general criteria, common patterns, and differential diagnosis. Dermatol Pract Concept. 2011;1 :33‐47.24396718\n\n",
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"issn_linking": "2050-4527",
"issue": "9(3)",
"journal": "Immunity, inflammation and disease",
"keywords": "COVID; cutaneous reaction; dermatology; drug reaction; skin; viral exanthem",
"medline_ta": "Immun Inflamm Dis",
"mesh_terms": "D000998:Antiviral Agents; D000086382:COVID-19; D004359:Drug Therapy, Combination; D005076:Exanthema; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008875:Middle Aged",
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"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
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"title": "Pleomorphicskin eruptions in a COVID-19 affected patient: Case report and review of the literature.",
"title_normalized": "pleomorphicskin eruptions in a covid 19 affected patient case report and review of the literature"
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"abstract": "Libman-Sacks endocarditis (LSE) is a rare cardiovascular manifestation of systemic lupus erythematosus/antiphospholipid syndrome that is described as a sterile verrucous nonbacterial vegetative lesion. These lesions can cause progressive damage to the heart valves leading to valve surgery. The most common valves to be affected are the aortic and mitral valves. Libman-Sacks endocarditis is associated with malignancies, other systemic diseases like systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS). The majority of LSE patients are usually asymptomatic. Case Summary. We describe a 39-year-old male patient who presented with increasing shortness of breath and pulmonary congestion. He was found to have severe mitral valve regurgitation and mitral stenosis. Transesophageal echocardiogram confirmed the diagnosis of Libman-Sacks endocarditis with thickened mitral valve leaflets with symmetrical mass-like structure causing a restriction in the valve function during both cardiac phases later diagnosed with systemic lupus erythematosus by immunology. The patient was started on diuretics, anticoagulants, angiotensin inhibitors, beta-blockers, and hydroxychloroquine. He underwent successful mechanical mitral valve replacement with a 27 mm St. Jude valve. The mitral valve was found to be grossly thickened with friable tissue and complete amalgamation of the leaflets with subvalvular apparatus. The patient suffered some warfarin adverse effects a year later but did well otherwise.\nThis case demonstrates that Libman-Sacks endocarditis can be the first manifestation of systemic lupus erythematosus. Early and prompt diagnosis of LSE can prevent and lessen the many side effects associated with thromboembolism. Additionally, addressing the underlying disease is key to successful treatment.",
"affiliations": "King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.;King Abdullah International Medical Research Center, Jeddah, Saudi Arabia.;Department of Internal Medicine, National Guard Hospital, Jeddah, Saudi Arabia.;King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.;King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.;Department of Cardiac Sciences, King Faisal Cardiac Center, National Guard Hospital, Jeddah, Saudi Arabia.",
"authors": "Al-Jehani|Mariann|M|;Al-Husayni|Faisal|F|https://orcid.org/0000-0002-3213-9125;Almaqati|Ahmed|A|;Shahbaz|Jomanah|J|;Albugami|Saad|S|https://orcid.org/0000-0002-4652-3291;Alameen|Wail|W|",
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"doi": "10.1155/2021/5573141",
"fulltext": "\n==== Front\nCase Rep Cardiol\nCase Rep Cardiol\nCRIC\nCase Reports in Cardiology\n2090-6404\n2090-6412\nHindawi\n\n10.1155/2021/5573141\nCase Report\nA Case of Systemic Lupus Erythematosus in a Patient Presenting with Libman-Sacks Endocarditis\nAl-Jehani Mariann 1\nhttps://orcid.org/0000-0002-3213-9125\nAl-Husayni Faisal 2 3\nAlmaqati Ahmed 3\nShahbaz Jomanah 1\nhttps://orcid.org/0000-0002-4652-3291\nAlbugami Saad sbugami@gmail.com\n1 2 4\nAlameen Wail 4\n1King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia\n2King Abdullah International Medical Research Center, Jeddah, Saudi Arabia\n3Department of Internal Medicine, National Guard Hospital, Jeddah, Saudi Arabia\n4Department of Cardiac Sciences, King Faisal Cardiac Center, National Guard Hospital, Jeddah, Saudi Arabia\nAcademic Editor: Christopher S. Snyder\n\n2021\n31 8 2021\n2021 557314117 1 2021\n20 8 2021\nCopyright © 2021 Mariann Al-Jehani 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.\nBackground\n\nLibman-Sacks endocarditis (LSE) is a rare cardiovascular manifestation of systemic lupus erythematosus/antiphospholipid syndrome that is described as a sterile verrucous nonbacterial vegetative lesion. These lesions can cause progressive damage to the heart valves leading to valve surgery. The most common valves to be affected are the aortic and mitral valves. Libman-Sacks endocarditis is associated with malignancies, other systemic diseases like systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS). The majority of LSE patients are usually asymptomatic. Case Summary. We describe a 39-year-old male patient who presented with increasing shortness of breath and pulmonary congestion. He was found to have severe mitral valve regurgitation and mitral stenosis. Transesophageal echocardiogram confirmed the diagnosis of Libman-Sacks endocarditis with thickened mitral valve leaflets with symmetrical mass-like structure causing a restriction in the valve function during both cardiac phases later diagnosed with systemic lupus erythematosus by immunology. The patient was started on diuretics, anticoagulants, angiotensin inhibitors, beta-blockers, and hydroxychloroquine. He underwent successful mechanical mitral valve replacement with a 27 mm St. Jude valve. The mitral valve was found to be grossly thickened with friable tissue and complete amalgamation of the leaflets with subvalvular apparatus. The patient suffered some warfarin adverse effects a year later but did well otherwise.\n\nConclusion\n\nThis case demonstrates that Libman-Sacks endocarditis can be the first manifestation of systemic lupus erythematosus. Early and prompt diagnosis of LSE can prevent and lessen the many side effects associated with thromboembolism. Additionally, addressing the underlying disease is key to successful treatment.\n==== Body\npmc1. Introduction\n\nLibman-Sacks endocarditis (LSE) is noninfectious endocarditis that is sometimes referred to as nonbacterial thrombotic endocarditis (NBTE), marantic endocarditis, or verrucous endocarditis. It is characterized by deposition of thrombi mainly on aortic and mitral valves; involvement of other valves is less common. It was first described by Emanuel Libman and Benjamin Sacks in 1924 [1]. LSE was mostly associated with malignancies, for example, patients with pancreatic adenocarcinoma were found to have a higher risk of developing LSE with systemic embolization being the leading cause of morbidity [2]. Additionally, LSE is linked to other systemic diseases like systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS). LSE is encountered among 10% of patients with SLE; it correlates with the disease activity, duration, anticardiolipin antibodies, and APS manifestations. SLE patients with LSE frequently have evidence of valvular affection and lesion progression as shown by Moyssakis et al. [1].\n\nThe majority of LSE patients are usually asymptomatic, while if the patient was symptomatic it is usually due to embolic infarctions either as cerebrovascular or systemic thromboembolism. SLE and APS patients may present with signs and symptoms of their underlying diseases, such as malar rash and recurrent miscarriages.\n\nThe prognosis of LSE has not been well defined; it is usually considered poor, especially if those patients develop recurrent thromboembolism [3].\n\nWe are describing an adult patient who presented with LSE as the first manifestation of SLE.\n\n2. Case Presentation\n\nA 39-year-old male, who was medically free prior to this, presented complaining of a three-month history of exertional dyspnea classified as New York Heart Association (NYHA) Class III, associated with cough and palpitation. The patient suffered from five ill-defined syncopal attacks during the past year. He reported a three-month history of lethargy, loss of appetite, and weight loss. The patient denied any personal history of fever, joint pain, or drug abuse. Family history was unremarkable for malignancies or cardiac conditions. Upon admission, the patient was vitally stable with normal saturation on ambient air. Chest examination revealed decreased breath sounds in the right lower zone with bilateral basal crackles, soft first heart sound, normal second heart sound, loud pansystolic murmur, and a soft diastolic rumble at the mitral area. His initial blood work is shown in Table 1. ECG revealed T-wave inversion in leads II, III, and AVF (Figure 1).\n\nChest imaging revealed cardiomegaly and right pleural effusion with right lower lobe consolidations (Figure 2). Echocardiogram showed a dilated right ventricle with mild to moderate tricuspid regurgitation and severe rheumatic mitral stenosis with moderate to severe mitral regurgitation (Figure 3). The patient was then commenced on diuretics, anticoagulants, angiotensin inhibitors, and beta-blockers. Transesophageal echocardiogram showed thickened mitral valve leaflets with symmetrical mass-like structure on the ventricular surface involving the tips of both leaflets extending to the body, causing a restriction in the valve function during both cardiac phases (Figure 4). Later, the patient underwent a diagnostic angiography, which showed normal coronary arteries. The immunology test came back confirming the diagnosis of SLE (Table 2). Following cardiac team discussion, the patient underwent mitral valve replacement surgery. During the operation, the mitral valve was found to be grossly thickened with friable tissue and complete amalgamation of the leaflets with subvalvular apparatus (Figure 5). The valve was replaced with a 27 mm St. Jude valve. Postop echocardiogram was performed; thus, the surgery was deemed successful and his hospital stay was uneventful. Tissue biopsy showed degenerative changes, myxoid areas with hemorrhage admixed with acute and chronic inflammatory cell infiltrate. In addition, fibroid necrosis was present without calcification. The diagnosis of LSE was confirmed with SLE as underlying disease. The patient was started on hydroxychloroquine 400 mg daily, warfarin, and aspirin. At one-year follow-up, he had an increased intraocular pressure, hyphema, total vitreous hemorrhage, and choroidal hemorrhage. The patient was admitted and underwent hyphema drainage and trabeculectomy. Otherwise, the patient was doing well.\n\n3. Discussion\n\nCardiac involvement in SLE is common. It is estimated that more than 50% of SLE/APS patients have cardiovascular manifestations in the form of pericarditis, myocarditis, LSE, pulmonary arterial hypertension, conduction disease, and coronary artery disease. Left-sided heart valves are by far the most affected. It has previously been reported to have cardiac involvement as the main reason for presentation; however, this is extremely rare [1–8].\n\nMultivalvular involvement often occurs, but typically, the most frequently affected valve is the mitral valve with the vegetations occurring near the edge of the valve or on both of its surfaces. Involvement of the atrial or ventricular endocardium or the chordae tendineae and papillary muscles is rare.\n\nThe approach to diagnose LSE might not be simple as some SLE or APS patients are asymptomatic. Echocardiography is the best first modality to diagnose LSE, but transesophageal echocardiography is more sensitive and specific than transthoracic echocardiography [9, 10]. Doppler echocardiography detects between 18% and 50% of valve diseases [1–10], while transesophageal echocardiography detects up to 74% [9, 10]. LSE on imaging is described as irregular heterogeneous echo density with the absence of independent motion of the verrucous vegetations on the cardiac valves and endocardium [9, 10]. The mitral and aortic valves are most affected by leaflet thickening and regurgitation. Although the origin of valvular lesions in SLE is closely linked to the presence of antiphospholipid antibodies [10], negative test results have been described in literature in other patients with SLE and LSE [8] or even in nonbacterial thrombotic endocarditis without underlying disease.\n\nThe LSE diagnosis is difficult to be confirmed by laboratory tests; however, patients who are suspected of having LSE must have complete blood count, comprehensive metabolic workup, blood cultures, autoimmune profile, and hypercoagulable workup [1–9].\n\nWhen treating LSE, the underlying disease, either SLE or APS, must be addressed. Hydroxychloroquine (HCQ), an antimalarial drug, has been an effective option for managing SLE, especially in the early stages [1–10]. Its effectiveness has been established in the mild form of SLE, while not as effective in preventing severe SLE manifestations such as glomerulonephritis and central nervous system involvement [11].\n\nCorticosteroids are considered a treatment option to reduce the inflammatory reaction caused by LSE; however, they can lead to tissue scarring and fibrosis, predisposing to further valvular damage [11, 12]. Anticoagulation should be considered in SLE/APS patients as secondary prevention for thromboembolic events, especially those who have had previous thromboembolic events [11–15].\n\nSurgical valve replacement is recommended for symptomatic and severe cases of LSE. Mechanical valve replacement in females of reproductive age is not preferable as they would require to be put on an anticoagulation regime with increased fetal and maternal side effects. Nonetheless, it is still recommended as many authors believe that SLE/APS patients will eventually end up on anticoagulants for the disease-associated thromboembolism [14, 15].\n\n4. Conclusion\n\nLSE is rare as the first manifestation of SLE/APS. We presented a 39-year-old male with LSE as the initial manifestation of SLE. It was successfully diagnosed by echocardiography and treated with mitral valve replacement surgery. The case highlights SLE as a differential diagnosis when encountering a healthy individual with new-onset valve disease. Early and prompt diagnosis of LSE can prevent and lessen the many side effects associated with thromboembolism.\n\nData Availability\n\nThe data used to support the findings of this study are included within the article.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Patient's electrocardiogram showing inverted T-wave in leads II, III, and AVF.\n\nFigure 2 Patient's chest X-ray demonstrating cardiomegaly and right lower lobe consolidations with pleural effusion.\n\nFigure 3 Parasternal long axis view revealing a diffused leaflet thickening of the mitral valve.\n\nFigure 4 Transesophageal echocardiogram showing a symmetrical mass-like structure on the ventricular surface involving the tips of both leaflets extending to the body, causing a restriction in the valve function.\n\nFigure 5 Gross anatomy of the mitral valve leaflets in keeping with Libman-Sacks endocarditis.\n\nTable 1 Initial laboratory data for the patient at presentation.\n\nLabs\tResults\tReference range\t\nWhite blood count\t5.5 × 109/L\t4.0–11.0 × 109/L\t\nHemoglobin\t11.9 g/dL\t11.5–16.5 g/dL\t\nPlatelet\t111 × 109/L\t150–450 × 109/L\t\nNeutrophil count\t3.14 × 109/L\t2–7.5 × 109/L\t\nLymphocyte count\t1.08 × 109/L\t1.5–4 × 109/L\t\nBlood urea nitrogen\t8.1 mmol/L\t2.1–7.1 mmol/L\t\nCreatinine\t150 μmol/L\t62–106 μmol/L\t\nBrain natriuretic peptide\t1585 pg/mL\t<100 pg/mL\t\nHigh-sensitivity troponin\t>0.03 ng/mL\t>0.03 ng/mL\t\n\nTable 2 Autoimmune laboratory tests concerning the diagnosis of systemic lupus erythematosus.\n\nLabs\tResults\tReference range\t\nAntinuclear antibody\tPositive\tNegative\t\nAnti-double-stranded DNA\t355.7\t<68.6 is negative\n68.6–229 is moderately positive\n>229 is strongly positive\t\nRibonucleoprotein antibody\t472.5\t<20 is negative\n20–39 is weakly positive\n40–80 is moderately positive\n>80 is strongly positive\t\nAnti-Smith antibody\t114.71\t<20 is negative\n20–39 is weakly positive\n40–80 is moderately positive\n>80 is strongly positive\t\nC3 complement\t0.8 g/dL\t0.9–1.9 g/dL\t\nC4 complement\t>0.06\t0.1–0.4 g/dL\n==== Refs\n1 Moyssakis I. Tektonidou M. G. Vasilliou V. A. Samarkos M. Votteas V. Moutsopoulos H. M. Libman-Sacks endocarditis in systemic lupus erythematosus: prevalence, associations, and evolution The American Journal of Medicine 2007 120 7 636 642 10.1016/j.amjmed.2007.01.024 2-s2.0-34250902426 17602939\n2 González Quintela A. Candela M. J. Vidal C. Román J. Aramburo P. Non-bacterial thrombotic endocarditis in cancer patients Acta Cardiologica 1991 46 1 1 9 1851590\n3 Roldan C. A. Sibbitt W. L. Qualls C. R. Libman-Sacks endocarditis and embolic cerebrovascular disease JACC: Cardiovascular Imaging 2013 6 9 973 983 10.1016/j.jcmg.2013.04.012 2-s2.0-84883872990 24029368\n4 Doherty N. E. Siegel R. J. Cardiovascular manifestations of systemic lupus erythematosus American Heart Journal 1985 110 6 1257 1265 10.1016/0002-8703(85)90023-7 2-s2.0-0022242685 3907317\n5 Foroughi M. Hekmat M. Ghorbani M. Ghaderi H. Majidi M. Beheshti M. Mitral valve surgery in patients with systemic lupus erythematosus The Scientific World Journal 2014 2014 9 216291 10.1155/2014/216291 2-s2.0-84908310958 25401131\n6 de Godoy M. F. de Oliveira C. M. Fabri V. A. Long-term cardiac changes in patients with systemic lupus erythematosus BMC Research Notes 2013 6 1 10.1186/1756-0500-6-171 2-s2.0-84876789414\n7 Sharma J. Lasic Z. Bornstein A. Cooper R. Chen J. Libman-Sacks endocarditis as the first manifestation of systemic lupus erythematosus in an adolescent, with a review of the literature Cardiology in the Young 2013 23 1 1 6 10.1017/S1047951112001023 2-s2.0-84873362555 22805592\n8 Chen S. Smith B. Ilina M. Bowen C. Martin N. PReS-FINAL-2307: Libman-Sacks endocarditis as a presentation for systemic lupus erythematous in an adolescent with isolated mitrial regurgitation and Noonan syndrome Pediatric Rheumatology 2013 11 Supplement 2 10.1186/1546-0096-11-s2-p297\n9 Gouya H. Cabanes L. Mouthon L. Pavie A. Legmann P. Vignaux O. Severe mitral stenosis as the first manifestation of systemic lupus erythematosus in a 20-year-old woman: the value of magnetic resonance imaging in the diagnosis of Libman-Sacks endocarditis The International Journal of Cardiovascular Imaging 2014 30 5 959 960 10.1007/s10554-014-0418-8 2-s2.0-84905714138 24715438\n10 Roldan C. A. Shively B. K. Lau C. C. Gurule F. T. Smith E. A. Crawford M. H. Systemic lupus erythematosus valve disease by transesophageal echocardiography and the role of antiphospholipid antibodies Journal of the American College of Cardiology 1992 20 5 1127 1134 10.1016/0735-1097(92)90368-W 2-s2.0-0026471774 1341885\n11 Dandekar U. P. Watkin R. Chandra N. Aortic valve replacement for Libman-Sacks endocarditis The Annals of Thoracic Surgery 2009 88 2 669 671 10.1016/j.athoracsur.2008.11.074 2-s2.0-67650760880 19632441\n12 Akhlaq A. Ali T. A. Fatimi S. H. Mitral valve replacement in systemic lupus erythematosus associated Libman- Sacks endocarditis Journal of the Saudi Heart Association 2016 28 2 124 126 10.1016/j.jsha.2015.09.003 2-s2.0-84960964505 27053904\n13 Ibrahim A. M. Siddique M. S. Libman Sacks endocarditis Stat Pearls 2020 Treasure Island FL Stat Pearls Publishing\n14 Doria A. Zen M. Canova M. SLE diagnosis and treatment: when early is early Autoimmunity Reviews 2010 10 1 55 60 10.1016/j.autrev.2010.08.014 2-s2.0-78149359043 20813207\n15 Hojnik M. George J. Ziporen L. Shoenfeld Y. Heart valve involvement (Libman-Sacks endocarditis) in the antiphospholipid syndrome Circulation 1996 93 8 1579 1587 10.1161/01.CIR.93.8.1579 2-s2.0-0029919622 8608627\n\n",
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"title": "A Case of Systemic Lupus Erythematosus in a Patient Presenting with Libman-Sacks Endocarditis.",
"title_normalized": "a case of systemic lupus erythematosus in a patient presenting with libman sacks endocarditis"
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"abstract": "We present the case of a 59-year-old patient admitted with extreme painful erythematous subcutaneous nodules of the lower extremities in association with arthritis and peripheral eosinophilia. Upon skin biopsy, the diagnosis of pancreatic panniculitis was made. On further investigation, an underlying acinar cell type pancreas carcinoma was revealed. This clinical case does illustrate how a seemingly innocuous skin condition may herald an underlying malignant disease. The presence of pancreatic panniculitis should trigger clinicians to undertake further thorough diagnostic investigation of the pancreas.",
"affiliations": "a Department of Dermatology , AZ Sint-Jan , Bruges , Belgium.;b Department of Gastroenterology and Hepatology , AZ Sint-Jan , Bruges , Belgium.;b Department of Gastroenterology and Hepatology , AZ Sint-Jan , Bruges , Belgium.",
"authors": "Naeyaert|Charlotte|C|;de Clerck|Frederik|F|;De Wilde|Vincent|V|",
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"mesh_terms": "D001706:Biopsy; D018267:Carcinoma, Acinar Cell; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D008875:Middle Aged; D010179:Pancreas; D010182:Pancreatic Diseases; D010190:Pancreatic Neoplasms; D015434:Panniculitis; D010257:Paraneoplastic Syndromes; D014057:Tomography, X-Ray Computed",
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"title": "Pancreatic panniculitis as a paraneoplastic phenomenon of a pancreatic acinar cell carcinoma.",
"title_normalized": "pancreatic panniculitis as a paraneoplastic phenomenon of a pancreatic acinar cell carcinoma"
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"abstract": "Differentiated thyroid cancer (DTC) patients with an unresectable primary tumor cannot benefit from curative surgery, and radioiodine treatment for locoregional and distant disease is not possible with the thyroid gland still in place. Due to local invasion, these patients cannot be included in clinical trials, so that treatment options are limited. The aim of this study was to describe the characteristics and the prognosis of patients with these locally unresectable DTC.\n\n\n\nA retrospective and multicentric analysis of consecutive cases of unresectable DTC diagnosed between 2000 and 2015 was performed.\n\n\n\nThe study population consisted in 22 patients, 13 females (59%); median age: 77 years (range: 52-91). Thyroid tumors were papillary in six, follicular in seven, Hürthle cell in one and poorly differentiated in eight patients. Patients were treated with external beam radiation therapy (EBRT) (57%), locoregional therapy of distant metastases (41%), cytotoxic chemotherapy (38%) and tyrosine kinase inhibitors (TKIs) (33%). TKI treatment resulted in median disease control duration of 7 months with a grade 3-4 toxicity rate of 44%. Only one patient had a total thyroidectomy after neo-adjuvant EBRT. The 1, 3 and 5-year cumulative survival rate was 81%, 27.7% and 21.5%, respectively. The cause of death was DTC in 11 cases (local progression in 7), and to other causes in 7 cases; no patient died from treatment toxicity.\n\n\n\nClinical trials and approved treatments are lacking for unresectable DTC. TKI treatment may allow prolonged disease control with acceptable toxicity.",
"affiliations": "Département de Médecine Nucléaire et Cancérologie Endocrinienne, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France. livia.lamartina@gustaveroussy.fr.;Département de Médecine Nucléaire, Institut Bergonié, 33076, Bordeaux, France.;Département de Médecine Nucléaire, Hôpital René Huguenin-Institut Curie, 92210, St Cloud, France.;Département d'Endocrinologie, CHRU de Lille, 5900, Lille, France.;Département de Médecine Nucléaire, Hôpital René Huguenin-Institut Curie, 92210, St Cloud, France.;Département de Biostatistique et épidémiologie, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.;Département de Biologie et pathologie médicales, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.;Département de Chirurgie Cervico-Faciale, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.;Département de Médecine Nucléaire et Cancérologie Endocrinienne, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.;Département d'Imagerie médicale, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.;Département d'Imagerie médicale, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.;Département de Médecine Nucléaire et Cancérologie Endocrinienne, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.;Département de Médecine Nucléaire et Cancérologie Endocrinienne, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.;Département de Médecine Nucléaire et Cancérologie Endocrinienne, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.;Département de Médecine Nucléaire et Cancérologie Endocrinienne, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.;Département de Médecine Nucléaire et Cancérologie Endocrinienne, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.",
"authors": "Lamartina|L|L|0000-0003-3640-1204;Godbert|Y|Y|;Nascimento|C|C|;Do Cao|C|C|;Hescot|S|S|;Borget|I|I|;Al Ghuzlan|A|A|;Hartl|D|D|;Hadoux|J|J|;Pottier|E|E|;Attard|M|M|;Berdelou|A|A|;Terroir|M|M|;Baudin|E|E|;Schlumberger|M|M|;Leboulleux|S|S|;|||",
"chemical_list": "D007457:Iodine Radioisotopes",
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"issue": "69(1)",
"journal": "Endocrine",
"keywords": "Differentiated thyroid cancer; Prognosis; Refractory; Tracheal invasion",
"medline_ta": "Endocrine",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D012189:Retrospective Studies; D013964:Thyroid Neoplasms; D013965:Thyroidectomy; D016896:Treatment Outcome",
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"pubdate": "2020-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Locally unresectable differentiated thyroid cancer: outcomes and perspectives.",
"title_normalized": "locally unresectable differentiated thyroid cancer outcomes and perspectives"
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"abstract": "A female neonate with in utero selective serotonin reuptake inhibitor exposure presented with bradycardia shortly after birth. Electrocardiography showed severe QT prolongation and second-degree atrioventricular block. Over time QT-times spontaneously normalised and genetic testing did not show mutations associated with long QT syndrome making maternal selective serotonin reuptake inhibitor usage the most likely explanation for the observed severe transient neonatal QT prolongation.",
"affiliations": "Department of Paediatric Cardiology, University Medical Centre/Wilhelmina Children's Hospital, Utrecht, the Netherlands.;Department of Paediatric Cardiology, University Medical Centre/Wilhelmina Children's Hospital, Utrecht, the Netherlands.;Department of Paediatric Cardiology, University Medical Centre/Wilhelmina Children's Hospital, Utrecht, the Netherlands.",
"authors": "Leerssen|Eeke C M|ECM|https://orcid.org/0000-0002-9717-9267;Tak|Ramon O|RO|;Breur|Johannes M P J|JMPJ|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D017374:Paroxetine",
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"issue": "29(10)",
"journal": "Cardiology in the young",
"keywords": "Long QT syndrome; in utero exposure; neonate; paroxetine; selective serotonin reuptake inhibitor",
"medline_ta": "Cardiol Young",
"mesh_terms": "D004562:Electrocardiography; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008133:Long QT Syndrome; D018811:Maternal Exposure; D017374:Paroxetine; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017367:Serotonin Uptake Inhibitors; D012720:Severity of Illness Index",
"nlm_unique_id": "9200019",
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"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe transient neonatal long QT syndrome due to maternal paroxetine usage: a case report.",
"title_normalized": "severe transient neonatal long qt syndrome due to maternal paroxetine usage a case report"
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"abstract": "BACKGROUND\nAdult-onset leukoencephalopathies are a group of heterogeneous disorders characterized by white matter abnormalities. Leukoencephalopathy is usually encountered in children, but here we report a case with adult-onset leukoencephalopathy. Also, we explore this concept of uncertainty in medicine by discussing the approach to this case that has multiple possible etiologies.\n\n\nMETHODS\nA 70-year-old Caucasian male presented with a subacute onset of cognitive impairment and mood disturbances associated with behavioral changes. Neuroimaging demonstrated high-intensity lesions involving cerebral white matter. Progressive dementia and cognitive decline followed. Multiple possible etiologies are discussed based on the patient presentation and risk factors.\n\n\nCONCLUSIONS\nAdult-onset leukoencephalopathy can become a diagnostic challenge. Certain approaches need to be developed to explore the uncertainty of such conditions and to improve diagnostic yield.",
"affiliations": "Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA. mtaha@stanford.edu.;Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA.",
"authors": "Taha|Mohamed A|MA|;Diesing|T Scott|TS|",
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"country": "England",
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"doi": "10.1186/s13256-021-03089-6",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n3089\n10.1186/s13256-021-03089-6\nCase Report\nUncertainty of leukoencephalopathies: a case report\nTaha Mohamed A. mtaha@stanford.edu\n\nDiesing T. Scott tdiesing@unmc.edu\n\ngrid.266813.8 0000 0001 0666 4105 Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE USA\n16 11 2021\n16 11 2021\n2021\n15 56118 10 2019\n1 9 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\nAdult-onset leukoencephalopathies are a group of heterogeneous disorders characterized by white matter abnormalities. Leukoencephalopathy is usually encountered in children, but here we report a case with adult-onset leukoencephalopathy. Also, we explore this concept of uncertainty in medicine by discussing the approach to this case that has multiple possible etiologies.\n\nCase presentation\n\nA 70-year-old Caucasian male presented with a subacute onset of cognitive impairment and mood disturbances associated with behavioral changes. Neuroimaging demonstrated high-intensity lesions involving cerebral white matter. Progressive dementia and cognitive decline followed. Multiple possible etiologies are discussed based on the patient presentation and risk factors.\n\nConclusion\n\nAdult-onset leukoencephalopathy can become a diagnostic challenge. Certain approaches need to be developed to explore the uncertainty of such conditions and to improve diagnostic yield.\n\nKeywords\n\nAdult-onset leukoencephalopathies\nWhite matter lesions\nRapidly progressive dementia\nMedical uncertainty\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcIntroduction\n\nLeukoencephalopathies are a group of disorders that affect adults and are characterized by the development of white matter changes seen on imaging. The differential for leukoencephalopathy is broad and can be a diagnostic challenge. In many cases, the diagnosis of leukoencephalopathy requires a brain biopsy to confirm the diagnosis, which is an invasive procedure.\n\nCase presentation\n\nA 70-year-old right-handed Caucasian male was brought by his family for an evaluation of progressive memory loss and change in his behavior over the last month. He had not had any prior neurologic or psychiatric illnesses. He became socially withdrawn, and subsequently became unable to independently perform activities of daily living. His speech output lessened to the point that he would speak only in single words. Up to the time of presentation, there had been no motor or movement concerns, hallucinations, incontinence, or fevers.\n\nHis history was notable for well-controlled hypertension and hyperlipidemia. He had been diagnosed with rheumatoid arthritis 20 years prior and was treated with long-term oral methotrexate (15 mg per week) and occasional use of diclofenac. He was a former smoker (stopped smoking for 30 years) and a social drinker without history of illicit drug use. His family medical history was noncontributory.\n\nPhysical examination\n\nHis affect was flat, and he had impaired attention and concentration. He was unable to follow simple commands. There were no detectable abnormalities on ocular or cranial nerve examinations. Strength was intact throughout, but tone was increased in both lower extremities. Coordination examination was notable for bilateral upper extremity action tremor, and ataxia of gait. Hyperreflexia was noted in both biceps and knee reflexes. Palmomental reflex was present and symmetric. The examination was notably absent of clonus, myoclonus, or excessive movements. His presentation was reminiscent of a partially akinetic-mute state.\n\nInvestigations\n\nTest results are presented below (Tables 1, 2). Cerebrospinal fluid (CSF) analysis showed elevated protein content with normal white blood cell counts. Special CSF testing showed elevated levels of 14-3-3 protein. Real-time quaking-induced conversion (RT-QuIC) was negative. Autoimmune and paraneoplastic studies were negative. Electroencephalography performed over several days on multiple occasions showed diffuse background theta slowing without epileptiform discharges or electrographic seizures. Magnetic resonance imaging (MRI) brain with and without contrast showed extensive patchy subcortical white matter lesions on T2 and fluid-attenuated inversion recovery (FLAIR) sequences (Fig. 1). MRI also showed mild diffuse volume loss without parenchymal or meningeal enhancement. CT angiography of the head and neck was unremarkable. CT of the chest, abdomen, and pelvis showed mild mesenteric and hilar lymphadenopathy. Subsequent mesenteric lymph node biopsy was unremarkable.Table 1 Lists laboratory tests and their results\n\nTest\tResult\tTest\tResult\t\nCSF protein\t94 (15–45)\tAlbumin, CSF\tElevated\t\nCSF glucose\t77 (40–70)\tT-tau protein, CSF\t1973 pg/mL\t\nCSF WBCs\t1\tArylsulfatase A WBC\tWithin normal limits\t\nCSF RBCs\t< 3000\tPhytanic acid\tWithin normal limits\t\nCSF albumin\t43 (14–26)\tHgA1C\t5.3%\t\nCSF IgG\t4 (0–6)\tHilar lymphadenopathy biopsy\tNegative for neoplasm\t\nSerum albumin\t4 (3–4)\tAcetaminophen and salicylate levels\tWithin normal limits\t\nCSF ACE\t2 (0–2)\tCSF T-tau protein\t1900\t\nPET scan\tSmall hilar lymphadenopathy\tCSF 14-3-3 protein\tPositive\t\nCSF, Cerebrospinal fluid; WBCs, White blood cells; RBCs, Red blood cells; ACE, Angiotensin converting enzyme; HgA1C, HemoglobinA1C\n\nTable 2 List of negative laboratory tests\n\nCSF microbiology tests\t\nHIV serology\t\nCSF Lyme antibody\t\nCSF Tropheryma whipplei PCR\t\nCSF RT-QuIC\t\nCSF encephalopathy panel\t\nCSF flow cytometry\t\nCSF JCV DNA (repeated three times)\t\nCSF VDRL\t\nCSF bacterial and fungal cultures\t\nCSF West Nile IgM/IgG\t\nUDS\t\nCBC\t\nUrine heavy metals\t\nSerum ceruloplasmin\t\nRT-QuIC, Real-time quaking-induced conversion; JCV, John Cunningham virus; VDRL, Venereal disease research laboratory; UDS, Urine drug screen; CBC, Complete blood count\n\nFig. 1 FLAIR signal brain MRI showing extensive subcortical white matter hyperintense lesions\n\nThe patient’s cognitive impairment and akinetic mutism continued to deteriorate concurrent with development of urinary incontinence. A 3-day course of high-dose intravenous methylprednisolone (1000 mg each day) was empirically given without any clinical improvement. A selective serotonin reuptake inhibitor was tried without success. Two cycles of electroconvulsive therapy (ECT) were not effective. Unfortunately, the patient died a month after presentation from complications of aspiration pneumonia.\n\nThis clinical presentation is ambiguous. Progressive cognitive impairment was notably involved with memory, behavior, and mood disturbances along with late-onset urinary incontinence. Upper motor neuron signs and spasticity were detected in the lower extremities with mild ataxia. We will discuss the differential diagnoses of this ambiguous presentation.\n\nExploring the uncertainty\n\nProgressive multifocal leukoencephalopathy (PML) is a multifocal, white matter disease that occurs in immunosuppressed patients (Table 3). It is manifested by altered mental status, cortical symptoms (aphasia, motor weakness), and gait ataxia [1]. On neuroimaging, PML can appear as symmetrical or asymmetrical, single or multifocal white matter lesions. Sometimes it can also involve gray cortical matter [2]. The diagnosis is made by demonstrating a positive PCR of John Cunningham (JC) virus DNA with or without brain biopsy. JC virus DNA in CSF has a sensitivity of 92% [3]. PML with negative CSF JC virus PCR can also be seen in patients with human immunodeficiency virus (HIV) [3]. The PML diagnosis is possible in this case as the clinical presentation and MRI findings are suggestive. However, it remains uncertain as CSF was negative for JC virus in two separate samples.Table 3 Summary of the clinical features of a selected leukoencephalopathy group\n\nLeukodystrophy\tClinical and diagnostic features\t\nVanishing white matter disease\tCognitive decline, ataxia, and seizures; MRI showing confluent FLAIR signal abnormalities and global atrophy\t\nMetachromatic leukodystrophy\tProgressive cognitive decline, UMN signs, dystonia and behavioral changes; MRI showing symmetrical periventricular white matter changes; diagnosis by arylsulfatase A enzyme levels\t\nKrabbe disease\tSpastic paraplegia, dystonia sensory symptoms, and ataxia; MRI showing white matter lesions predominately affecting parieto-occipital and cerebellar areas; globoid cells found on biopsy; decrease in galactocerebrosidase levels\t\nAdrenoleukodystrophy\tProgressive spastic paraplegia, urinary and sensory symptoms; MRI showing variable brain white matter changes and spinal myelopathy features; increase in very-long-chain fatty acid levels\t\nAlexander disease\tMotor and ataxia symptoms sometimes associated with bulbar, dementia, and behavioral changes; MRI showing white matter lesions predominantly affecting frontal region\t\nMyelinoclastic diffuse sclerosis (Schilder’s disease)\tAcute inflammatory demyelinating white matter disease associated with increased intracranial pressure and tumor-like presentation\t\nUMN, Upper motor neuron; MRI, Magnetic resonance imaging; FLAIR, Fluid attenuated inversion recovery\n\nCreutzfeldt–Jakob disease (CJD) is a prion disease that is characterized by subacute progressive dementia associated behavioral and motor impairments [4]. Cognitive decline involves areas of high cortical function such as aphasia, apraxia, and frontal lobe function. Behavioral changes include apathy, emotional lability, and anxiety. All these features were found in our patient. Also, myoclonus can be seen in CJD. Spasticity and extensor plantar responses are found in CJD, which were detected in our patient. Akinetic mutism is also one of the features of late-stage CJD. MRI findings commonly seen are diffusion-weighted imaging (DWI) and FLAIR hyperintensity signals in putamen and caudate nucleus. Sometimes white matter changes can be detected [5]. The findings of our case were inconsistent with the commonly seen MRI findings in CJD as MRI showed extensive white matter changes only. Moreover, the progression of MRI findings of cases of CJD was not seen with the repeat MRI in our case. Electroencephalography (EEE) in this case did not show the characteristic periodic spike wave complexes that can be seen in 65% of cases with CJD [6]. Real-time quaking-induced conversion (RT-QuIC) sensitivity ranges from 92% to 95% in cases of CJD [7]. The negative RT-QuIC makes the diagnosis of CJD unlikely. On the other hand, the specificity of 14-3-3 is around 80%, that is, there are high rates of false positives [8]. CSF 14-3-3 can be positive in other cases such as paraneoplastic encephalopathies and metabolic encephalopathy. In conclusion, the clinical features were suggestive of CJD, although neuroimaging and CSF testing made the diagnosis unlikely.\n\nAdult-onset leukoencephalopathies are a heterogeneous group of white matter diseases that affect myelination and are manifested by dementia and psychiatric and movement symptoms. Usually they present early in life, but adult-onset leukodystrophies can be seen [9–11]. Features of leukodystrophies with similar clinical presentation are summarized in Table 3. None of the adult-onset leukoencephalopathies fully explains the clinical picture of this patient. In addition, enzyme levels were not affected.\n\nAutoimmune and paraneoplastic encephalitis have a wide clinical presentation ranging from limbic encephalitis to neuropsychiatric symptoms [12]. FLAIR lesions can affect both white and gray matter, unlike the MRI findings in this case. Antibody panel that screens for autoimmune and paraneoplastic encephalitis was negative. A whole-body scan was unremarkable except for mild hilar and mesenteric lymphadenopathy, which had not shown any neoplastic features on histological assessment. Lastly, the lack of clinical response to a trial dose of intravenous steroids makes this diagnosis unlikely.\n\nPrimary central nervous system (CNS) lymphoma is a rare neoplastic disorder that presents with change in behavior, mood abnormality (depression), and sometimes focal neurological deficits and seizures [13]. Primary CNS lymphoma appears as either hypointense or isointense on T2 MRI sequence and contrast homogeneously [14]. This is different from what was seen in this patient. CSF analysis with two cytology screenings was negative for lymphoma cells. All these findings make this diagnosis unlikely.\n\nFinally, methotrexate (MTX)-induced neurotoxicity has been described in multiple cases. It can be divided into acute, subacute, and chronic [15]. Aseptic meningitis can be seen in the acute setting after receiving MTX. It presents with features of meningitis, including fever, vomiting, and headache, and is generally transient after stopping MTX [15]. Leukoencephalopathy can be detected after long-term use of MRX and is usually mild and symptomatic and can disappear after therapy cessation. On the contrary, disseminated necrotizing leukoencephalopathy (DNL) is a rare, fatal form of methotrexate-induced neurotoxicity [16]. DNL usually occurs with intrathecal and intravenous MTX. However, DNL was also reported in patients on low-dose oral MTX [17]. It can happen months after the initiation of treatment. Clinically, DNL presents with changes in personality, progressive dementia, and sometimes seizures and motor symptoms. It can lead to death in a few months. Brain MRI usually shows extensive subcortical white matter lesions (patchy or confluent) that appear on T2 and FLAIR signals. Sometimes, these lesions can give some contrast enhancement. White matter changes can affect all brain regions, especially the posterior region (occipito-parieto-temporal), and can thus be mistaken for posterior reversible leukoencephalopathy (as initially in this patient), which can also be seen in patients on methotrexate. Finally, DNL is progressive and does not respond to cessation of treatment. The features of DNL do resemble the clinical presentation of this case; however, it is difficult to confirm the diagnosis in the absence of a brain biopsy.\n\nDiscussion\n\nThe case reviewed exemplifies the uncertainty that physicians face in their daily practice. Some cases can be simple and straightforward, while others are more complex and ambiguous. Thus, it is it is important for physicians to be comfortable with the concept of uncertainty, a concept that is rarely discussed in the medical literature.\n\nLeukoencephalopathies are a group of disorders that affect adults and are characterized by the development of white matter changes seen on imaging. The differential for leukoencephalopathy is broad and can be a diagnostic challenge. In many cases, the diagnosis of leukoencephalopathy requires a brain biopsy to confirm the diagnosis, which is an invasive procedure. In this case, the patient’s long-term use of oral methotrexate suppressed his immune system and made him susceptible to opportunistic infections. JC-virus-related leukoencephalopathy is one of the major white matter diseases that can be seen in immunosuppressed patients, and it can be confirmed by demonstrating the presence of JC virus DNA in CSF. However, there are an increasing number of patients who can be diagnosed with JC-negative PML [3]. The clinical presentation of this patient, which can be summarized as progressive dementia with behavioral changes, akinetic mutism, and upper motor neuron signs, can be explained by PML, but the diagnosis is difficult to make given his negative JC virus in CSF. Other etiologies that can present with similar symptoms and signs along with patchy leukoencephalopathy on MRI include adult-onset leukoencephalopathies such as Krabbe, Alexander disease, and metachromatic leukoencephalopathies. However, as mentioned previously, their neuroimaging features differ from this patient, and they are also rare diagnoses. Disseminated necrotizing leukoencephalopathy is the most plausible explanation for this patient’s presentation and is consistent with the MRI findings. However, brain biopsy is needed to confirm the diagnosis and to exclude other causes of leukoencephalopathies. In summary, the approach of white matter disease in adults should involve a multidisciplinary approach that includes a collection of detailed history and risk factors, and the evaluation of subtle clinical signs in addition to gathering laboratory results. Despite that, a brain biopsy will often be needed.\n\nConclusion\n\nThe principle of minimum uncertainty states that, in the case of alternative solutions to a problem, we should accept only the solutions in set solutions that provide the minimal amount of uncertainty [18]. In our medicine practice, we face uncertainty almost on a daily basis. While a diagnosis may not be certain, physicians need to reduce the amount of uncertainty to the smallest solution set, or differential. The diagnostic process of leukoencephalopathy in adults can be complex and requires basic knowledge of processing uncertainty.\n\nAcknowledgements\n\nNo acknowledgements.\n\nAuthors’ contributions\n\nAuthor contributions as in the care document. Both authors read and approved the final manuscript.\n\nFunding\n\nThere is no funding involved in this case report study.\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\nVerbal consent was taken from the patient. The patient information was de-identified. The consent of publication was waived by authors and by the patient.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThere are no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Koralnik IJ Progressive multifocal leukoencephalopathy revisited: has the disease outgrown its name? Ann Neurol 2006 60 2 162 173 10.1002/ana.20933 16862584\n2. Lassmann H Lucchinetti CF Cortical demyelination in CNS inflammatory demyelinating diseases Neurology 2008 10.1212/01.wnl.0000298724.89870.d1\n3. Marzocchetti A Di Giambenedetto S Cingolani A Ammassari A Cauda R De Luca A Reduced rate of diagnostic positive detection of JC virus DNA in cerebrospinal fluid in cases of suspected progressive multifocal leukoencephalopathy in the era of potent antiretroviral therapy J Clin Microbiol 2005 43 8 4175 4177 10.1128/JCM.43.8.4175-4177.2005 16081969\n4. Rabinovici GD Wang PN Levin J Cook L Pravdin M Davis J DeArmond SJ Barbaro NM Martindale J Miller BL Geschwind MD First symptom in sporadic Creutzfeldt-Jakob disease Neurology 2006 66 2 286 287 10.1212/01.wnl.0000196440.00297.67 16434680\n5. Collie DA Sellar RJ Zeidler M Colchester AC Knight R Will RG MRI of Creutzfeldt-Jakob disease: imaging features and recommended MRI protocol Clin Radiol 2001 56 9 726 739 10.1053/crad.2001.0771 11585394\n6. Steinhoff BJ Zerr I Glatting M Schulz-Schaeffer W Poser S Kretzschmar HA Diagnostic value of periodic complexes in Creutzfeldt-Jakob disease Ann Neurol 2004 56 5 702 708 10.1002/ana.20261 15449324\n7. Foutz A Appleby BS Hamlin C Liu X Yang S Cohen Y Chen W Blevins J Fausett C Wang H Gambetti P Diagnostic and prognostic value of human prion detection in cerebrospinal fluid Ann Neurol 2017 81 1 79 92 10.1002/ana.24833 27893164\n8. Muayqil T Gronseth G Camicioli R Evidence-based guideline: diagnostic accuracy of CSF 14-3-3 protein in sporadic Creutzfeldt-Jakob disease: report of the guideline development subcommittee of the American Academy of Neurology Neurology 2012 79 14 1499 1506 10.1212/WNL.0b013e31826d5fc3 22993290\n9. Lynch DS de Rodrigues Brandão Paiva A Zhang WJ Bugiardini E Freua F Tavares Lucato L Macedo-Souza LI Lakshmanan R Kinsella JA Merwick A Rossor AM Clinical and genetic characterization of leukoencephalopathies in adults Brain 2017 140 5 1204 1211 10.1093/brain/awx045 28334938\n10. Baumann N Turpin JC Adult-onset leukodystrophies J Neurol 2000 247 10 751 759 10.1007/s004150070088 11127529\n11. Kotil K Kalayci M Köseoglu T Tugrul A Myelinoclastic diffuse sclerosis (Schilder's disease): report of a case and review of the literature Br J Neurosurg 2002 16 5 516 519 10.1080/026886902320909187 12498501\n12. Kayser MS Titulaer MJ Gresa-Arribas N Dalmau J Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-d-aspartate receptor encephalitis JAMA Neurol 2013 70 9 1133 1139 10.1001/jamaneurol.2013.3216 23877059\n13. Bataille B Delwail V Menet E Vandermarcq P Ingrand P Wager M Guy G Lapierre F Primary intracerebral malignant lymphoma: report of 248 cases J Neurosurg 2000 92 2 261 266 10.3171/jns.2000.92.2.0261 10659013\n14. Bühring U Herrlinger U Krings T Thiex R Weller M Küker W MRI features of primary central nervous system lymphomas at presentation Neurology 2001 57 3 393 396 10.1212/WNL.57.3.393 11515505\n15. Boogerd W vd Sande JJ Moffie D Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate J Neurol Neurosurg Psychiatry 1988 51 10 1277 1283 10.1136/jnnp.51.10.1277 3225584\n16. Kim JY Kim ST Nam DH Lee JI Park K Kong DS Leukoencephalopathy and disseminated necrotizing leukoencephalopathy following intrathecal methotrexate chemotherapy and radiation therapy for central nerve system lymphoma or leukemia J Korean Neurosurg Soc 2011 50 4 304 10.3340/jkns.2011.50.4.304 22200011\n17. Raghavendra S Nair MD Chemmanam T Krishnamoorthy T Radhakrishnan VV Kuruvilla A Disseminated necrotizing leukoencephalopathy following low-dose oral methotrexate Eur J Neurol 2007 14 3 309 314 10.1111/j.1468-1331.2006.01659.x 17355553\n18. Klir GJ Smith RM On measuring uncertainty and uncertainty-based information: recent developments Ann Math Artif Intell 2001 32 1–4 5 33 10.1023/A:1016784627561\n\n",
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"abstract": "A 35-month-old boy was diagnosed with retinoblastoma and underwent combination intra-arterial (IAC) and intravitreal chemotherapy. His course was complicated by anaphylactic reaction to IAC, yet he continued to improve with sustained intravitreal therapy. Eight months into treatment, the affected eye developed exudative retinal detachment, which resolved with sub-Tenon's steroid administration. As the management of retinoblastoma evolves, treaters need to be aware of potential complications of therapy. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:248-252.].",
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"abstract": "Primary Hyperparathyroidism (PHP) in pregnancy constitutes a serious danger to mother and fetus. The diagnosis of PHP in pregnancy presents a challenge, and PHP commonly goes unidentified and untreated in pregnancy. We present four case reports about patients having PHP, which is very rare condition in pregnancy and their treatment modalities. Three patients, not to be controlled biochemically, denied the parathyroidectomy operation although they are informed about the details of their disease. They are followed up with medical therapy. The first one had no maternal or fetal complications, the second one acquired nephrolithiasis crisis in the last trimester and the third one gave birth to a premature baby who succumbed to tetany. The fourth patient who underwent parathyroidectomy operation in the second trimester had no maternal or fetal complications. PHP in pregnancy is a preventable cause of fetal and maternal mortality and morbidity. Thus, suspecting from PHP during the pregnancy and early diagnosis is critically important in terms of maternal and fetal wellness.",
"affiliations": "a Department of Internal Medicine , Division of Endocrinology and Metabolism, Faculty of Medicine , Central Campus , University of Ataturk , Erzurum , Turkey.;b Department of Internal Medicine , Division of Endocrinology and Metabolism, Faculty of Medicine, University of Ataturk , Erzurum , Turkey , and.;c Department of Internal Medicine , Faculty of Medicine, University of Ataturk , Erzurum , Turkey.;b Department of Internal Medicine , Division of Endocrinology and Metabolism, Faculty of Medicine, University of Ataturk , Erzurum , Turkey , and.;b Department of Internal Medicine , Division of Endocrinology and Metabolism, Faculty of Medicine, University of Ataturk , Erzurum , Turkey , and.;b Department of Internal Medicine , Division of Endocrinology and Metabolism, Faculty of Medicine, University of Ataturk , Erzurum , Turkey , and.",
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"abstract": "OBJECTIVE\nThe purpose of the present study was to determine the complication rate associated with the administration of intravenous (IV) sedation in an oral and maxillofacial surgery (OMS) residency training program.\n\n\nMETHODS\nWe performed a prospective cohort study that enrolled patients who had received IV sedation for various oral surgery procedures in the clinic setting of an oral and maxillofacial surgery residency training program. The composition of the anesthesia team included residents who had completed their anesthesia rotation, ranging from postgraduate year (PGY)-1 to PGY-4. Each trainee chose their own anesthetic technique and completed a form that included demographic data, types and amounts of anesthetic used, and any intraoperative or postoperative complications encountered. All sedations were performed by a single provider with oversight by an attending oral and maxillofacial surgeon. The demographic and medication data were used as predictor variables. The outcome variables included any reported complications. The Fisher exact test was used to compare the complication rate by subgroup.\n\n\nRESULTS\nThe study included 1005 patients treated during an 18-month period. The overall complication rate was 2.29%. The most common complication reported was postoperative nausea (n = 10; 0.99%), with 1 patient experiencing emesis. Other complications included laryngospasm (n = 1), prolonged recovery (n = 3), failed sedation because of agitation (n = 1), intraoperative hypertension (n = 1), postoperative hypertension (n = 1), ST elevation (n = 1), IV infiltration (n = 2), syncope during IV access (n = 1), and respiratory depression (n = 2). No deaths or no adverse events requiring escalation of the level of care occurred. Ketamine use resulted in a greater rate of postoperative nausea (1.21%), and propofol was associated with a lower rate of postoperative nausea (0.68%). Male patients experienced a greater rate of complications compared with female patients overall (2.4 vs 2.2%). However, the female patients had a greater rate of postoperative nausea and vomiting (0.96 vs 1.19%). Of those who had reported a previous history of postoperative nausea and/or vomiting (PONV), 50% experienced symptoms after sedation. The average length of the procedure was longer in the group that had experienced complications compared with those who had not (37.5 vs 31.6 minutes). None of these reported differences were statistically significant.\n\n\nCONCLUSIONS\nThe results of the present study have demonstrated that the modern IV sedation anesthesia technique used in OMS training programs is safe and the complication rate is low. Postoperative nausea was the most common complication. Ketamine can increase the risk of PONV, and propofol can reduce the risk of PONV. However, larger studies are required for conclusive findings. A history of PONV is a good predictor of PONV. The length of the procedure might increase the risk of complications.",
"affiliations": "Attending Surgeon, Department of Oral and Maxillofacial Surgery, Hennepin County Medical Center, Minneapolis, MN. Electronic address: louis.christensen@hcmed.org.;Attending Surgeon, Department of Oral and Maxillofacial Surgery, Hennepin County Medical Center, Minneapolis, MN.;Resident, Department of Oral and Maxillofacial Surgery, University of Minnesota School of Dentistry, Minneapolis, MN.;Resident, Department of Oral and Maxillofacial Surgery, University of Minnesota School of Dentistry, Minneapolis, MN.;Resident, Department of Oral and Maxillofacial Surgery, University of Minnesota School of Dentistry, Minneapolis, MN.;Resident, Department of Oral and Maxillofacial Surgery, University of Minnesota School of Dentistry, Minneapolis, MN.",
"authors": "Christensen|Louis|L|;Svoboda|Lance|L|;Barclay|Joshua|J|;Springer|Brett|B|;Voegele|Brett|B|;Lyu|Diana|D|",
"chemical_list": "D006993:Hypnotics and Sedatives; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": "10.1016/j.joms.2019.07.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "77(12)",
"journal": "Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons",
"keywords": null,
"medline_ta": "J Oral Maxillofac Surg",
"mesh_terms": "D054810:Deep Sedation; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D020250:Postoperative Nausea and Vomiting; D015742:Propofol; D011446:Prospective Studies; D013515:Surgery, Oral",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "2447-2451",
"pmc": null,
"pmid": "31449763",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcomes With Moderate and Deep Sedation in an Oral and Maxillofacial Surgery Training Program.",
"title_normalized": "outcomes with moderate and deep sedation in an oral and maxillofacial surgery training program"
} | [
{
"companynumb": "US-MYLANLABS-2019M1123780",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "KETAMINE"
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"drugadditional": null,
... |
{
"abstract": "We report a case of chronic myeloid leukemia (CML) that developed after postoperative chemotherapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) for breast cancer. A 55-year-old woman was diagnosed with invasive ductal carcinoma which was treated with a modified radical mastectomy followed by six cycles of CAF chemotherapy. Nine years later, she developed CML and locoregional recurrence. Her breast recurrence showed strong estrogen receptor, weak progesterone receptor and strong human epidermal growth factor 2 (score 3+) expression. Her secondary CML in the chronic phase showed a complex variant translocation (CVT) involving chromosomes 9, 22, and 17. Considering that the HER2/neu gene is also located on chromosome 17, this secondary CML in chronic phase with CVT is indeed a rare occurrence. We discuss the associated genetic factors and the possible role of breast cancer chemo/radiotherapy in the development of such CML as well as its treatment and prognosis compared with de novo CML.",
"affiliations": "Department of Oncopathology, Delhi State Cancer Institute, Delhi, India.;Department of Oncopathology, Delhi State Cancer Institute, Delhi, India.;Department of Clinical Oncology, Delhi State Cancer Institute, Delhi, India.",
"authors": "Tikku|Gargi|G|;Jain|Monica|M|;Shukla|Pragya|P|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4048/jbc.2017.20.2.208",
"fulltext": "\n==== Front\nJ Breast CancerJ Breast CancerJBCJournal of Breast Cancer1738-67562092-9900Korean Breast Cancer Society 10.4048/jbc.2017.20.2.208Case ReportChronic Myeloid Leukemia with a Complex Variant ‘Ph’ Translocation That Develops in Breast Carcinoma, Postchemotherapy: A Rare but Treatable Entity Tikku Gargi Jain Monica Shukla Pragya 1Department of Oncopathology, Delhi State Cancer Institute, Delhi, India.1 Department of Clinical Oncology, Delhi State Cancer Institute, Delhi, India.Correspondence to: Gargi Tikku. Department of Oncopathology, Delhi State Cancer Institute, Delhi 110095, India. Tel: +91-9899101454, Fax: +91-11-2211-0505, gargi.tikku@gmail.com6 2017 26 6 2017 20 2 208 211 23 8 2016 14 1 2017 © 2017 Korean Breast Cancer Society2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.We report a case of chronic myeloid leukemia (CML) that developed after postoperative chemotherapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) for breast cancer. A 55-year-old woman was diagnosed with invasive ductal carcinoma which was treated with a modified radical mastectomy followed by six cycles of CAF chemotherapy. Nine years later, she developed CML and locoregional recurrence. Her breast recurrence showed strong estrogen receptor, weak progesterone receptor and strong human epidermal growth factor 2 (score 3+) expression. Her secondary CML in the chronic phase showed a complex variant translocation (CVT) involving chromosomes 9, 22, and 17. Considering that the HER2/neu gene is also located on chromosome 17, this secondary CML in chronic phase with CVT is indeed a rare occurrence. We discuss the associated genetic factors and the possible role of breast cancer chemo/radiotherapy in the development of such CML as well as its treatment and prognosis compared with de novo CML.\n\nBreast neoplasmsChemotherapyChronic-phase myeloid leukemia\n==== Body\nINTRODUCTION\nChronic myeloid leukemia (CML) accounts for a small percentage of secondary leukemias. Secondary leukemias that develop after invasive ductal carcinoma treatment are mostly acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). There is a 1% to 5% lifetime risk of developing therapy-related myeloid neoplasms (t-MN) after breast cancer treatment [1]. We report a rare case in which CML with a complex variant translocation (CVT) developed after postoperative chemotherapy for breast cancer.\n\nCASE REPORT\nA 55-year-old postmenopausal woman presented at our oncology tertiary referral center with a right sternal hard swelling that had increased in size over the past 2 months and measured 2×2 cm. She underwent a right modified radical mastectomy 9 years previously for invasive ductal carcinoma and received six cycles of chemotherapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF). Fine needle aspiration cytology of a chest wall nodule revealed features of ductal carcinoma. The patient's complete blood count at presentation was 9.3 g/dL hemoglobin, the white blood cell (WBC) count was 92.14×103/µL and the platelet count was 675×103/µL. A peripheral blood smear had a differential leucocyte count of 9% myelocytes, 17% metamyelocytes, 72% neutrophils, 1% lymphocytes, and 1% eosinophils. The possibility of a chronic myeloproliferative neoplasm was considered. Contrast-enhanced computed tomography revealed a metastatic lesion involving the sternum with right internal mammary, pretracheal and paratracheal lymphadenopathy.\n\nAnalysis of a trucut biopsy from the chest wall resulted in a diagnosis of infiltrating ductal carcinoma- not otherwise specified, grade 2 (Figure 1A). Hormone receptor studies revealed strong nuclear estrogen receptor positivity in >90% of tumor cells and weak nuclear progesterone receptor positivity in 1% of tumor cells. Human epidermal growth factor 2 (HER2) was strongly positive with a-score of 3+ (Figure 1B).\n\nBone marrow aspiration and biopsy indicated chronic myeloproliferative neoplasm, and more specifically chronic myeloid leukemia in chronic phase (CML-CP) (Figure 1C).\n\nChromosomal analysis using conventional cytogenetics showed complex reciprocal translocation between the long arms of chromosomes 9 and 22 and the short arm of chromosome 17, between regions q34, q11.2, and p12. This was suggestive of “Ph” positive chromosome (variant) complement (karyotype: 46,XX,t[9;22;17][q34;q11.2;p12]) (Figure 1D). The patient's white blood cell count gradually increased from 92.14×103/µL at presentation to 237.78×103/µL- 103 has to be superscripted not subscripted.\n\nThe patient received docetaxel, carboplatin and ifosfamide-based chemotherapy and hormonal therapy in the form of tamoxifen for the chest wall recurrence of ductal carcinoma and imatinib in tablet form for CML. The chest wall nodule responded to three cycles of chemotherapy, as confirmed by contrast-enhanced computed tomography. The patient received 45 Gy in 10 fractions by external beam to the right chest wall followed by 15 Gy in five fractions as a boost to the chest wall nodule. Her CML responded to imatinib as she achieved a hematological response in 3 weeks of treatment and had undetectable minimal residual disease based on real-time polymerase chain reaction (PCR) analysis within 1 year.\n\nDISCUSSION\nBreast cancer treatment has been associated with a 1% to 5% lifetime risk of t-MN [1]. The most common types of t-MN in the World Health Organization classification include AML, MDS, and myelodysplastic/myeloproliferative neoplasms, with the postcytotoxic ther apy incidence of CML being markedly lower [2].\n\nCML is described as a carcinogenic effect of ionizing radiation, especially in atomic bomb survivors [3]. CML that develops after breast cancer treatment is rare. Two patients with CML in a registry cohort analysis of 5,790 breast cancer patients presented with stage I disease and were treated with surgery and radiation without chemotherapy, thus implicating the role of radiotherapy [4]. The risk associated with radiation was significant even for radiotherapy limited to the breast, as seen in a case control study including 182 AML and MDS patients and 534 matched controls [5]. Radiation can be excluded as a risk factor in our case as the patient only received CAF-based chemotherapy postsurgery.\n\nSecondary leukemias that develop after breast cancer treatment are mostly AML and MDS. Amongst chemotherapeutic agents, topoisomerase-II inhibitors (mitoxantrone, anthracyclines, and epipodophyllotoxins) are significantly associated with an increased risk of developing these leukemias, as compared with alkylating agents such as cyclophosphamide. The association between anthracyclines and AML/MDS is of major importance because anthracycline based chemotherapy is currently the gold standard for breast cancer treatment [5]. In contrast radiation and chemotherapy might have a synergistic effect in the development of secondary AML/MDS, as proposed in a previous study [4].\n\nTherapy-related CML cases are increasing, however, only a handful of cases of CML in patients treated for breast cancer have been reported [4678]. In a study of 15 cases of secondary CML at the Memorial Sloan-Kettering Cancer Center, New York, 12 patients received adjuvant radiation, 11 received adjuvant chemotherapy, and 15 received both therapies to the breast. The cumulative dose of anthracycline was 240 mg/m2 while that for alkylator was 4,800 mg/m2 [8]. In another such case report, two patients received cyclophosphamide, epirubicin/doxorubicin (anthracycline) as chemotherapy with axillary radiation applied in one case [7]. Our patient received CAF-based chemotherapy without radiation, thus implicating the role of chemotherapy in the development of secondary CML.\n\nA classical Ph translocation t(9;22)(q34;q11.2) is observed in the majority of CML patients, with only 5% to 10% having variant Ph translocations. These variants are classified as simple variants involving chromosome 22 and a chromosome other than 9, or as complex variants that involve chromosomes 9, 22, and 1 or more other chromosomes [9]. Molecular methods or fluorescence in situ hybridization can be used to detect breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) rearrangement in almost all cases with the variant Ph chromosome. In our case, the patient had CVT involving chromosomes 9, 22, and 17 which was detected using G-banded karyotyping.\n\nRecurrent invasive ductal carcinoma in this case was found to be strongly HER2 positive using immunohistochemistry, which is associated with HER2/neu gene amplification on chromosome 17 [10]. The peculiarity of this case was the simultaneous relapse of invasive ductal carcinoma as bony metastasis and the development of secondary CML with CVT involving chromosome 17, which also harbors the HER2/neu gene. To the best of our knowledge, this is the first such reported case in the literature. Two such cases have been reported where breast cancer recurred as vertebral metastasis: however the concurrent CML had a typical “Ph” chromosome on cytogenetic analysis [7].\n\nImatinib was used as a frontline therapy in the treatment of CML-CP that developed after breast cancer treatment [78]. A large series of 559 early CML-CP patients treated with imatinib as a frontline therapy, which included 30 patients with variant translocations, concluded that the clinical characteristics and outcome of patients with variant Ph translocations are similar to those of patients with classic Ph translocations. The same study showed that patients with variant translocations do not constitute a “warning” category in the imatinib era [11]. We also observed this finding as our patient achieved a hematological response in 3 weeks of treatment and had undetectable minimal residual disease according to real-time-PCR within 1 year.\n\nTo conclude, we therefore infer that breast cancer chemotherapy (CAF) may have an independent role in the development of CML, independently of the well-recognized role of radiation. Hence, complete blood counts should be assessed in the follow-up of all breast cancer patients after treatment. The present case showed that imatinib therapy was as effective for secondary CML with CVT as it is for de novo CML, and that clinical and biological characteristic did not significantly differ between the two diseases. The exact pathogenesis of CML after adjuvant treatment for breast cancer and the reason why patients more commonly develop t-AML require further investigation.\n\nACKNOWLEDGMENTS\nWe acknowledge Dr. M. Sujatha, Cytogeneticist, Vimta Labs Ltd, Cherlapali, Hyderabad for performing chromosomal analysis in this case.\n\nCONFLICT OF INTEREST: The authors declare that they have no competing interests.\n\nFigure 1 Microscopic findings and karyotyping. (A) Trucut biopsy sternal mass: recurrent duct carcinoma, breast (H&E stain, ×200). (B) Immunohistochemistry (IHC) for human epidermal growth factor receptor 2 (HER2), sternal mass shows 3+ positivity (IHC for HER2, ×400). (C) Bone marrow aspirate: chronic myeloid leukemia chronic phase, showing myeloid preponderance (May-Grünwald-Giemsa stain, ×400). (D) G-banded karyotyping: chronic myeloid leukemia with complex variant translocation involving chromosomes 9, 22, and 17.\n==== Refs\n1 Leone G Fianchi L Pagano L Voso MT Incidence and susceptibility to therapy-related myeloid neoplasms Chem Biol Interact 2010 184 39 45 20026017 \n2 Vardiman JW Arber DA Brunning RD Larson RA Matutes E Baumann I Therapy-related myeloid neoplasms Swerdlow SH Campo E Harris NL Jaffe ES Pileri SA Stein H WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th ed Lyon IARC Press 2008 127 129 \n3 Preston DL Kusumi S Tomonaga M Izumi S Ron E Kuramoto A Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and multiple myeloma, 1950-1987 Radiat Res 1994 137 2 Suppl S68 S97 8127953 \n4 Kaplan HG Malmgren JA Atwood MK Increased incidence of myelodysplastic syndrome and acute myeloid leukemia following breast cancer treatment with radiation alone or combined with chemotherapy: a registry cohort analysis 1990-2005 BMC Cancer 2011 11 260 21693006 \n5 Le Deley MC Suzan F Cutuli B Delaloge S Shamsaldin A Linassier C Anthracyclines, mitoxantrone, radiotherapy, and granulocyte colony-stimulating factor: risk factors for leukemia and myelodysplastic syndrome after breast cancer J Clin Oncol 2007 25 292 300 17159192 \n6 Setoodeh R Zhang L Chronic myelogenous leukemia following breast carcinoma: report of two cases and review of the literature Am J Clin Pathol 2012 138 Suppl 1 A170 \n7 Ocakçı S Görümlü G Şahin F Özsan N Zekioğlu O Uslu R Occurrence of chronic myeloid leukemia in two breast cancer survivors after 4 years Ege J Med 2011 50 141 144 \n8 Bowman IA Tallman MS Douer D Berman E Maslak PG Brentjens RJ Chronic myeloid leukemia after adjuvant treatment for breast cancer: is it therapy related? Blood 2013 122 2740 \n9 Huret JL Complex translocations, simple variant translocations and Ph-negative cases in chronic myelogenous leukaemia Hum Genet 1990 85 565 568 2227945 \n10 Slamon DJ Clark GM Wong SG Levin WJ Ullrich A McGuire WL Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene Science 1987 235 177 182 3798106 \n11 Marzocchi G Castagnetti F Luatti S Baldazzi C Stacchini M Gugliotta G Variant Philadelphia translocations: molecular-cytogenetic characterization and prognostic influence on frontline imatinib therapy, a GIMEMA Working Party on CML analysis Blood 2011 117 6793 6800 21447834\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-6756",
"issue": "20(2)",
"journal": "Journal of breast cancer",
"keywords": "Breast neoplasms; Chemotherapy; Chronic-phase myeloid leukemia",
"medline_ta": "J Breast Cancer",
"mesh_terms": null,
"nlm_unique_id": "101314183",
"other_id": null,
"pages": "208-211",
"pmc": null,
"pmid": "28690659",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports",
"references": "21447834;2227945;3798106;20026017;21693006;17159192;8127953",
"title": "Chronic Myeloid Leukemia with a Complex Variant 'Ph' Translocation That Develops in Breast Carcinoma, Postchemotherapy: A Rare but Treatable Entity.",
"title_normalized": "chronic myeloid leukemia with a complex variant ph translocation that develops in breast carcinoma postchemotherapy a rare but treatable entity"
} | [
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"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-147074",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"dr... |
{
"abstract": "BACKGROUND\nPosterior reversible encephalopathy (PRES) is a rare syndrome characterized by headache, confusion, seizures, visual changes and white matter edema at radiological imaging. Its pathophysiology is not clarified and different causes, including uncontrolled hypertension, eclampsia, chemotherapy and hypomagnesemia have been suggested.\n\n\nMETHODS\nA woman affected by stage IV breast cancer with lower extremity deep vein thrombosis treated with low-molecular-weight-heparin, currently in therapy with Palbociclib/Fulvestrant (antiCDK4 and 6/estrogen receptor antagonist) but previously treated with several other chemotherapy lines (including VEGF inhibitor bevacizumab), was admitted to our Internal Medicine department because of ascites and abdominal pain. She was treated with diuretics (and paracentesis). Recently (six-month earlier) a pan-encephalic radiotherapy was done because of brain and skull metastasis. Among blood tests, low serum levels of hypomagnesemia were observed. She developed PRES that rapidly progressed to lethargy, unresponsiveness till coma without changes in blood pressure. Magnetic Resonance Imaging study showed bilateral parieto-occipital edema and a thrombosis of left transverse and sigmoid sinuses. Anti-edema therapy, intravenous supplementation of magnesium and decoagulation were started, with complete and rapid recovery (within 18 hours) of clinical and radiologic changes.\n\n\nCONCLUSIONS\nPRES diagnosis was based on the rapid clinical recovery after antiedema treatment and magnesium supplementation. Low magnesium level related to both diuretic and Fulvestrant/Palbociclib therapies and recent radiotherapy can represent potential mechanisms favouring PRES development. The previous bevacizumab treatment may also be involved as a PRES predisposing factor. The concomitant occurrence of cerebral thrombosis can have precipitated the clinical situation.",
"affiliations": "Università di Parma. federica.zappia@gmail.com.;Università di Parma. ignazio.verzicco@studenti.unipr.it.;Università di Parma. simoniriccardo90@gmail.com.;Università di Parma. massi.ferro76@gmail.com.;Università di Parma. pcoghi@ao.pr.it.;Unità di Neuroradiologia, Azienda Ospedaliera-Universitaria di Parma. bozzetti.francesca@gmail.com.;Università di Parma. valentina.cannone@unipr.it.;Università di Parma. riccardo.volpi@unipr.it.;University of Parma. aderville.cabassi@unipr.it.",
"authors": "Zappia|Federica|F|;Verzicco|Ignazio|I|;Simoni|Riccardo|R|;Ferrari|Massimiliano|M|;Coghi|Pietro|P|;Bozzetti|Francesca|F|;Cannone|Valentina|V|;Volpi|Riccardo|R|;Cabassi|Aderville|A|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Italy",
"delete": false,
"doi": "10.23750/abm.v91i2.8685",
"fulltext": "\n==== Front\nActa Biomed\nActa Biomed\nActa Bio Medica : Atenei Parmensis\n0392-4203 2531-6745 Mattioli 1885 Italy \n\n32420975\nACTA-91-365\n10.23750/abm.v91i2.8685\nCase Report\nPosterior reversible encephalopathy syndrome in an oncological normotensive patient: evidence for a pathogenic role of concomitant low magnesium serum levels and chemotherapy treatment\nZappia Federica 1 Verzicco Ignazio 1 Simoni Riccardo 1 Ferrari Massimiliano 1 Coghi Pietro 1 Bozzetti Francesca 2 Cannone Valentina 1 Volpi Riccardo 1 Cabassi Aderville 1 1 Clinica e Terapia Medica, Dipartimento di Medicina e Chirurgia, Università di Parma\n2 Unità di Neuroradiologia, Azienda Ospedaliera-Universitaria di Parma. Università di Parma, Parma, Italy\nCorrespondence: Prof. Aderville Cabassi Centro per lo Studio dell’Ipertensione Arteriosa e delle malattie Cardiorenali (Affiliate with the Società Italiana dell’Ipertensione Arteriosa), Clinica e Terapia Medica, Department of Medicine and Surgery, DIMEC University of Parma, Via Gramsci 14 - 43126 Parma, Italy Tel. +39 0521 703084 Fax +39 0521 033185 E-mail: aderville.cabassi@unipr.it\n2020 \n11 5 2020 \n91 2 365 372\n21 6 2019 21 7 2019 Copyright: © 2020 ACTA BIO MEDICA SOCIETY OF MEDICINE AND NATURAL SCIENCES OF PARMA2020This work is licensed under a Creative Commons Attribution 4.0 International LicenseBackground:\nPosterior reversible encephalopathy (PRES) is a rare syndrome characterized by headache, confusion, seizures, visual changes and white matter edema at radiological imaging. Its pathophysiology is not clarified and different causes, including uncontrolled hypertension, eclampsia, chemotherapy and hypomagnesemia have been suggested.\n\nCase report:\nA woman affected by stage IV breast cancer with lower extremity deep vein thrombosis treated with low-molecular-weight-heparin, currently in therapy with Palbociclib/Fulvestrant (antiCDK4 and 6/estrogen receptor antagonist) but previously treated with several other chemotherapy lines (including VEGF inhibitor bevacizumab), was admitted to our Internal Medicine department because of ascites and abdominal pain. She was treated with diuretics (and paracentesis). Recently (six-month earlier) a pan-encephalic radiotherapy was done because of brain and skull metastasis. Among blood tests, low serum levels of hypomagnesemia were observed. She developed PRES that rapidly progressed to lethargy, unresponsiveness till coma without changes in blood pressure. Magnetic Resonance Imaging study showed bilateral parieto-occipital edema and a thrombosis of left transverse and sigmoid sinuses. Anti-edema therapy, intravenous supplementation of magnesium and decoagulation were started, with complete and rapid recovery (within 18 hours) of clinical and radiologic changes.\n\nConclusions:\nPRES diagnosis was based on the rapid clinical recovery after antiedema treatment and magnesium supplementation. Low magnesium level related to both diuretic and Fulvestrant/Palbociclib therapies and recent radiotherapy can represent potential mechanisms favouring PRES development. The previous bevacizumab treatment may also be involved as a PRES predisposing factor. The concomitant occurrence of cerebral thrombosis can have precipitated the clinical situation. (www.actabiomedica.it)\n\nposterior reversible encephalopathy syndromehypomagnesemiabreast cancerchemotherapycerebral thrombosis\n==== Body\nIntroduction\nPosterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by headache, confusion or decreased level of consciousness, visual changes and seizures, associated with typical neuroimaging findings of posterior cerebral white matter edema, first described in 1996 (1). Despite its name, the clinical condition is not always reversible, and it represents a medical emergency, leading rapidly to permanent cerebral damage or to death (2, 3). In addition to the clinical features that can include elevated blood pressure levels, it has to be noted that the classic symmetrical white matter changes leading to neurological manifestations of PRES are visible on diffusion-weighted imaging (DWI), but not to standard magnetic Resonance Imaging (MRI) (4). PRES can occur in a variety of clinical conditions, such as in autoimmune disease (5, 6), eclampsia (7), hypertensive emergencies (8, 9), immunosuppressive therapy (10-12), red cell blood transfusions (13) or in clinical situations where electrolyte disorders are present such as hypomagnesemia (14). It is more common in women (3, 15) than in men and its exact incidence is not known. PRES pathogenic mechanisms are still unclear.\n\nWe present a clinical case involving an oncological patient with multiple factors contributing to the development of PRES focusing on a hypomagnesemia as a potential precipitating mechanism that was reversed by magnesium salt supplementation.\n\nCase presentation\nA 60 years old Caucasian woman was admitted to the Emergency Department of our Hospital because of ascites and abdominalgia. Twenty years earlier she was diagnosed with breast cancer, subjected to mastectomy and then treated with several chemotherapy lines, including the inhibitor of vascular endothelial growth factor A Bevacizumab, hormonal therapy and local radiotherapy. About 5 months before the admission, she developed seizures and sudden cognitive impairment, with loss of contact: a MRI revealed cranial and cerebral metastasis. An antiepileptic drug Levetiracetam was started as well panencephalic radiotherapy was given for five days. Chemotherapy was also administered with resolution of symptoms and regression of metastasis. One month before the hospitalization, she developed lower limb deep vein thrombosis, so she started fondaparinux as anticoagulation therapy. The patient continued its oncological follow-up schedule of a stage IV breast cancer, with multiple liver, pleural, pulmonary and bone metastasis, treated with Palbociclib, anti-CDK4 and 6 antagonist and Fulvestrant, an estrogen receptor antagonist. At two follow-up visits during the 4 weeks prior to admission to the Emergency Department because of low circulating serum magnesium levels, magnesium and potassium salts supplementation was reported and then suspended due to the appearance of abdominal pain. She was sent to the Emergency department by the oncologist because of abdominalgia associated to nausea and vomiting. She has been treated with a proton pump inhibitor for at least 6 months because of heartburn, regurgitation, and symptoms related to gastroesophageal reflux disease. An abdominal ultrasound highlighted abundant ascites. She was vigilant and collaborating, without alteration on neurological exam. Her vital parameters were normal, and laboratory tests showed mild anemia (Hemoglobin 10.6 g/dl, hematocrit 32%), no renal (creatinine 0.4 mg/dL) or hepatic (GOT 21 U/L; GPT 13 U/L; total bilirubin 0.4 mg/dL, albumin 3.2 g/dL) impairment and a moderate increase in C reactive protein (63 mg/L; normal values < 5 mg/L). Plasma sodium (135 mEq/L), potassium (3.9 mEq/L), chloride (98 mEq/L), calcium (8.2 mg/dL) and phosphate (4.0 mg/dL) concentration were normal, whereas magnesium levels were at the lower limit (1.8 mg/dL). Within the normal range was also pH and bicarbonate. Coagulation was normal, except for a significant increase of d-dimer. On physical examination, she had ascites and abdominalgia without breathing impairment. She felt nausea and vomit; symptomatic therapy with metoclopramide was given and a parenteral nutrition infusion with Olimel N4 (1500 ml/day, Glucose 112,5 g, Lipids 45 g, Amino-acids 38 g, Nitrogen 6 g; sodium 21 mEq/L, potassium 16 mEq/L, Mg 2.2 mEq/L, osmolarity 760 mOsm/L) was started. She was treated parenterally with loop of Henle diuretic therapy, furosemide associated with potassium sparing diuretic canrenoate, associated to water restriction. An abundant diuretic response and the reduction of ascites was observed in the 48 hours following, with a significant weight loss and an almost complete resolution of the abdominalgia. No changes in blood pressure or heart rate were measured. She suddenly presented confused and disoriented. She was not able to attempt a simple order and she complained headache. Her blood pressure was still normal and the neurological exam did not show any focal or lateral abnormality. Ammonium blood levels were normal (37 uM/L, normal values between 10-50). An urgent cerebral tomography was performed, showing a diffuse cerebral edema (Figure 1,ABC). Patient neurological condition rapidly got worse, till vigil coma, with loss of interaction ability, while her vital parameters (blood pressure, heart rate and peripheral oxygen saturation) remained normal. Treatment with intravenous desametasone (8 mg twice a day) and mannitol (mannitol 18%, 100 ml four times per day followed by 50 ml four times per day), associated with magnesium sulphate (40 mEq in saline solution 250 ml per day in 6-hour infusion period) was immediately started and continued for three days. A cerebral MRI was urgently performed showing diffuse increase in signal alteration of the periventricular, deep and sub-cortical white matter in parieto-occipital region of the two sides, as from leukoencephalopathy, also in relation to post-radiotherapy modifications. venous thrombosis of the distal segment of the transverse sinus and of part of the left sigmoid sinus (Figure 2A1-3).\n\nFigure 1. (A,B,C). Brain CT Scan performed upon the admission and showing a diffuse bilateral cerebral edema, especially in posterior cerebral lobes (parietal and occipital): radiological signs suspected for Posterior reversible encephalopathy syndrome (PRES)\n\nFigure 2. (A1,2,3, B1,2,3, C1,2,3). Brain MRI urgently performed upon admission to the Emergency Department (A1-3), ten days (B1-3) and one month later (C1-3). Axial FSE T2 w-i showed diffuse symmetrical hyperintensities in the periventricular, deep and subcortical white matter, consistent with leukoencephalopathy, both in relation to concomitant PRES and to post-radiotherapy modifications\n\nShe continued subcutaneous Fondaparinux at anticoagulating dose (7,5 mg/die) while Palbociclib and Fulvestrant were discontinued. Anti-edema (desametasone and mannitol) treatment as well magnesium sulphate infusion were continued. Her clinical condition rapidly improved with resolution of the acute episode.\n\nA brain MRI was performed after 10 days, showing less but still persistent bilateral parieto-temporal-occipital vasogenic edema, partial resolution of the cerebral vein thrombosis, but evidencing the presence of few micro-haemorrhages in left temporal and parietal site (Figure 2B1-3).\n\nPatient neurological status completely recovered and after 2 weeks, she was discharged with the diagnosis of PRES.\n\nAt a MRI brain scan, performed the following month, a reduction of the vasogenic edema but a persistent even if reduced left transverse sinus thrombosis (Fig. 2C1-3). After a month, she was admitted to the hospital because of severe respiratory distress due to pneumonia and after three days she passed away.\n\nDiscussion\nPRES is an increasingly recognizable neuro-clinical syndrome where a posterior white matter brain edema represents the classic radiological feature. PRES should be distinguished from other causes of cerebral edema as depicted in Figure 3. Several mechanisms have been suggested to participate to PRES development, including endothelial dysfunction, as a result of cytotoxic therapy (chemotherapy and immunosuppressive therapies) or electrolyte disorders, altered cerebral autoregulation, often occurring during eclampsia or severe arterial hypertension or hypertensive emergencies (16,17). Recently, another fascinating hypothesis regards the increase in arginine vasopressin secretion as a pathogenic mechanism occurring in many clinical scenarios preluding PRES development; if this hypothesis will be validated the Authors suggested arginine vasopressin system as a target for possible treatment (Figure 4) (18).\n\nFigure 3. Posterior reversible encephalopathy syndrome differential diagnosis includes vascular and non vascular causes of cerebral edema\n\nFigure 4. The three main hypotheses explaining the pathophysiology of posterior reversible encephalopathy and associated conditions\n\nIn the present case, a cluster of factors combined contributes to PRES development in a normotensive condition. First, our patient underwent multiple cycle of chemiotherapic drugs, including Bevacizumab, a monoclonal antibody anti-VEGF that has been associated with various cases of PRES in literature (19-24); in some cases, PRES developed months after discontinuing the therapy (21). Bevacizumab is associated to the development of hypertension (25) and proteinuria (26,27). It is hypothesized that it disrupts the blood-brain barrier through endothelial dysregulation resulting in hyperperfusion and vasogenic edema leading to failure of cerebral autoregulation. In addition to bevacizumab-induced hypertension as a mechanism of PRES development, cases of bevacizumab-induced PRES have been also reported in normotensive patients (28), as the case of our patient.\n\nSecond, a confounding element was observed in our patient that could have precipitated her clinical neurological status, and is represented by the coexistence of the thrombosis of left transverse and sigmoid sinuses, which has been associated in several case report to PRES, especially in eclampsia or in postpartum females (29-31).\n\nWhat really surprised us in the clinical management of the patient, was the observation of the concomitant presence of magnesium plasma levels at lower limit of range potentially contributing to PRES development and its rapid resolution followed intravenous magnesium salt supplementation together with anti-edema therapies, desametasone and mannitol. Altered magnesium circulating levels can contribute to endothelial dysfunction and cerebral edema of the posterior circulation territories often observed in patients with PRES (14, 32) and cerebellar syndromes (33, 34). Magnesium owns a role as a regulator of endothelial integrity and function as well as vascular tone and reactivity (35). Decline in intracellular free magnesium concentration reduces ATP synthesis and influence cell membrane permeability, induces an impairment of membrane stability by promoting free radical production, cellular entry of Ca2+ and endothelial activation trough cytokines generation and intercellular leaking (36-41). The blood-brain barrier constituted by capillary endothelial cells is essential for optimal brain function. A crucial role in the pathogenesis of brain edema development is represented by Aquaporin (AQP)-4, a bidirectional transmembrane water channel expressed mainly in astrocytes (42,43); the upregulation of AQP-4 in brain injury leads to an increase in brain water content, resulting in brain edema (43). Magnesium treatment induces a down-regulation of AQP-4 (44) and attenuates brain edema in an experimental model of brain injury (45). In our case, the patient was in treatment with Fulvestrant (an estrogen receptor antagonist) and Palbociclib, (a selective inhibitor of CDK4 and CDK6, which are critical components of the cell-cycle regulatory machinery); the association of these drugs has been reported to reduce magnesium serum levels and induce hypomagnesemia in clinical and preclinical studies in 13-20% of treated patients (46). Our patient was underweight, the chemotherapy was associated to proton pump inhibitor, the latter also a potentially inducer of hypomagnesemia (47). A relation between Fulvestrant/Palbociclib and PRES development has never been described in literature.\n\nFigure 5. Mechanism of Brain Edema and Blood Brain Barrier Disruption linked to Magnesium depletion\n\nRadiotherapy could have also contributed to PRES development. Our patient had radiotherapy almost six months before PRES development Radiotherapy can cause endothelial damage that lead to disruption of the blood-brain barrier and other late vascular effects, such as telangiectasias, microvascular dilatation, thickening and hyalinization of the vessel wall, microbleeds, as observed in our case. These changes as reported in literature can occur months to years after brain radiotherapy (48).\n\nConclusion\nOur case highlights the particular attention that the clinician must have when cancer patients are treated with new molecular-targeted agents because of the potential PRES development especially when multiple factors combined can facilitate the onset of such a neurological status that represents an oncological emergency despite its rarity. Attention should be paid specifically to check electrolytes levels, especially magnesium levels, whose alterations (especially hypomagnesemia) can concurrently with several types of chemotherapies and radiotherapy lead to this severe but reversible\n\nneurological status impairment. In this case, we cannot exclude that the resolution of the patient neurological status could be attributed only to the anti-edema treatment or to the magnesium salt supplementation but their combination proved to be effective in resolving leading to a full recovery of patient neurological condition. The concomitant presence of thrombosis could have potentially precipitated and complicated the clinical setting, but we can exclude that the subsequent anticoagulant therapy could have improved the patient clinical condition so rapidly, with complete neurological status recovery, because at the brain MRI performed after a month, the thrombosis was still present.\n\nThe concomitant presence of several factors inducing PRES should make the clinicians think about all potential multiple causes whose consideration and correction allow the best therapeutic strategy for this very serious neurological complication.\n\nConflict of interest:\nEach author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article\n==== Refs\nReferences\n1 Hinchey J Chaves C Appignani B A Reversible Posterior Leukoencephalopathy syndrome N Engl J Med 1996 494 500 8559202 \n2 Stott V Hurrell M Anderson TJ Reversible posterior leukoencephalopathy syndrome: a misnomer reviewed Intern Med J 2005 35 2 83 90 15705136 \n3 Siebert E Bohner G Liebig T Endres M Liman TG Factors associated with fatal outcome in posterior reversible encephalopathy syndrome: a retrospective analysis of the Berlin PRES study J Neurol 2017 264 2 237 242 27815684 \n4 Ay H Buonanno F Schaefer P Posterior leukoencephalopathy without severe hypertension: utility of diffusion-weighted MRI Neurology 1998 51 5 1369 1376 9818862 \n5 Mar GR Encefalopatía reversible posterior en una niña con lupus eritematoso sistémico. Presentación de un caso Arch Argent Pediatr 2015 113 5 271 274 \n6 Gatla N Annapureddy N Sequeira W Jolly M Posterior reversible encephalopathy syndrome in systemic lupus erythematosus J Clin Rheumatol 2013 19 6 334 340 23965484 \n7 Camara-Lemarroy C Escobedo-Zúñiga N Villarreal-Garza E García-Valadez E Góngora-Rivera F Villarreal-Velázquez HJ Posterior reversible leukoencephalopathy syndrome (PRES) associated with severe eclampsia: Clinical and biochemical features Pregnancy Hypertens 2017 7 44 49 28279447 \n8 Toledano M Fugate JE Posterior reversible encephalopathy in the intensive care unit Handb Clin Neurol 2017 141 467 483 28190431 \n9 Thompson R Sharp B Pothof J Hamedani A Posterior Reversible Encephalopathy Syndrome in the Emergency Department: Case Series and Literature Review West J Emerg Med 2015 16 1 5 10 25671001 \n10 Maur M Tomasello C Frassoldati A Dieci M Barbieri E Conte P Posterior reversible encephalopathy syndrome during ipilimumab therapy for malignant melanoma J Clin Oncol 2012 30 6 76 78 \n11 Malkan UY Gunes G Demiroglu H Goker H Immunosuppression-associated posterior reversible encephalopathy syndrome in an acute leukemia case Hematol Rep 2018 10 4 96 97 \n12 Yafour N Krim A Bouhass R Bekadja MA Cyclosporine-related brainstem atypical posterior reversible leukoencephalopathy syndrome following hematopoietic stem cell transplant Hematol Oncol Stem Cell Ther 2016 9 1 36 38 25979822 \n13 Nakamura Y Sugino M Tsukahara A Nakazawa H Yamamoto N Arawaka S Posterior reversible encephalopathy syndrome with extensive cytotoxic edema after blood transfusion: a case report and literature review BMC Neurol 2018 18 1 190 30419835 \n14 Chardain A Mesnage V Alamowitch S Posterior reversible encephalopathy syndrome (PRES) and hypomagnesemia: A frequent association Rev Neurol (Paris) 2016 172 384 388 27371132 \n15 Schweitzer A Parikh N Askin G Imaging Characteristics Associated with Clinical Outcomes in Posterior Reversible Encephalopathy Syndrome Neuroradiology 2017 59 4 379 386 28289809 \n16 Bartynski WS Posterior reversible encephalopathy syndrome, Part 2: Controversies surrounding pathophysiology of vasogenic edema Am J Neuroradiol 2008 29 6 1043 1049 18403560 \n17 Fugate J Rabinstein AA Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions Lancet Neurol 2015 14 9 914 925 26184985 \n18 Largeau B Le Tilly O Sautenet B Salmon Gandonnière C Barin-Le Guellec C Ehrmann S Arginine Vasopressin and Posterior Reversible Encephalopathy Syndrome Pathophysiology: the Missing Link Mol Neurobiol 2019 \n19 Seet R Rabinstein AA Clinical features and outcomes of posterior reversible encephalopathy syndrome following bevacizumab treatment Qjm 2012 105 1 69 75 21865314 \n20 Katada E Mitsui A Sasaki S Uematsu N Anan C Posterior Reversible Encephalopathy Syndrome after a Variety of Combined Chemotherapies Containing Bevacizumab for Metastatic Colon Cancer Intern Med 2018 57 16 2403 2407 29526944 \n21 Eryllmaz MK Mutlu H Salim DK Musri FY Coşkun HŞ Fatal posterior revesible leukoencephalopathy syndrome associated coma induced by bevacizumab in metastatic colorectal cancer and review of literature J Oncol Pharm Pract 2016 22 6 806 810 26467267 \n22 El Maalouf G Mitry E Lacout A Lièvre A Rougier P Isolated brainstem involvement in posterior reversible leukoencephalopathy induced by bevacizumab J Neurol 2008 255 2 295 296 18283405 \n23 Hamid M Ghani A Micaily I Sarwar U Lashari B Malik F Posterior reversible encephalopathy syndrome (PRES) after bevacizumab therapy for metastatic colorectal cancer J Community Hosp Intern Med Perspect 2018 8 3 130 133 29915651 \n24 Munoz J Kumar V Hamilton J Posterior Reversible Encephalopathy Syndrome: More Than Meets the Eye J Clin Oncol 2013 31 20 360 363 \n25 Ozcan C Wong S Hari P Reversible posterior leukoencephalopathy syndrome and bevacizumab N Engl J Med 2006 354 9 980 982 \n26 Wu S Kim C Baer L Zhu X Bevacizumab increases risk for severe proteinuria in cancer patients J Am Soc Nephrol 2010 21 8 1381 1389 20538785 \n27 Lafayette RA McCall B Li N Incidence and Relevance of Proteinuria in Bevacizumab-Treated Patients: Pooled Analysis from Randomized Controlled Trials Am J Nephrol 2014 40 75 83 25059491 \n28 Lazarus M Amundson S Belani R An Association between Bevacizumab and Recurrent Posterior Reversible Encephalopathy Syndrome in a Patient Presenting with Deep Vein Thrombosis: A Case Report and Review of the Literature Case Rep Oncol Med 2012 2012 1 4 \n29 Lio CF Lee YH Chan HY Yu CC Peng NJ Chan HP Posterior reversible encephalopathy syndrome in a postpartum hemorrhagic woman without hypertension Med (United States) 2017 96 16 \n30 Dabla S Juneja H Garg A Bansal R Kumar S Cerebral Venous Sinus Thrombosis and Posterior Reversible Encephalopathy Syndrome Coexisting in a Woman: A Rare Coincidence J assoc Physicians India 2017 65 4 90 92 \n31 Saran S Bansal P Singhal S Malik A Coexisting cerebral venous sinus thrombosis and posterior reversible encephalopathy syndrome in a preeclamptic female Ann Afr Med 2018 17 2 94 95 29536965 \n32 Almoussa M Goertzen A Brauckmann S Fauser B Zimmermann CW Posterior Reversible Encephalopathy Syndrome due to Hypomagnesemia: A Case Report and Literature Review Case Rep Med 2018 2018 1 6 \n33 Santos AF Sousa F Rodrigues M Ferreira C Soares-Fernandes J Maré R Reversible cerebellar syndrome induced by hypomagnesemia Neurol Clin Neurosci 2015 3 5 190 191 \n34 Blasco LM Cerebellar Syndrome in Chronic Cyclic Magnesium Depletion The Cerebellum 2013 12 4 587 588 23184528 \n35 Laurant P Touyz RM Physiological and pathophysiological role of magnesium in the cardiovascular system: implications in hypertension J Hypertens 2000 18 9 1177 1191 10994748 \n36 Grubbs RD Maguire ME Magnesium as a regulatory cation: criteria and evaluation Magnesium 1987 6 3 113 127 3306178 \n37 Ebel H Günther T Magnesium metabolism: a review J Clin Chem Clin Biochem 1980 18 5 257 270 7000968 \n38 Bara M Guiet-Bara A Potassium, magnesium and membranes. Review of present status and new findings Magnesium 1984 3 4-6 215 225 6399343 \n39 Altura B Gebrewold A Zhang A Altura B Low extracellular magnesium ions induce lipid peroxidation and activation of nuclear factor-kappa B in canine cerebral vascular smooth muscle: possible relation to traumatic brain injury and strokes Neurosci Lett 2003 341 3 189 192 12697280 \n40 Billard JM Ageing, hippocampal synaptic activity and magnesium Magnes Res 2006 19 3 199 215 17172010 \n41 Rayssiguier Y Libako P Nowacki W Rock E Magnesium deficiency and metabolic syndrome: stress and inflammation may reflect calcium activation Magnes Res 2010 23 2 73 80 20513641 \n42 Amiry-Moghaddam M Otsuka T Hurn P An alfa-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain Proc Natl Acad Sci 2003 100 4 2106 2111 12578959 \n43 Zador Z Stiver S Wang V Manley GT Role of aquaporin-4 in cerebral edema and stroke Handb Exp Pharmacol 2009 190 159 170 \n44 Ghabriel M Thomas A Vink R Magnesium restores altered aquaporin-4 immunoreactivity following traumatic brain injury to a pre-injury state Acta Neurochir Suppl 2006 96 402 406 16671494 \n45 Okiyama K Smith D Gennarelli T Simon R Leach M McIntosh TK The sodium channel blocker and glutamate release inhibitor BW1003C87 and magnesium attenuate regional cerebral edema following experimental brain injury in the rat J Neurochem 1995 2 802 809 \n46 Palbociclib (PD-0332991), Investigator’s Brochure February, 2015 \n47 Regolisti G Cabassi A Parenti E Maggiore U Fiaccadori E Severe Hypomagnesemia During Long-term Treatment With a Proton Pump Inhibitor Am J Kidney Dis 2010 56 1 168 174 20493607 \n48 Roongpiboonsopit D Kuijf HJ Charidimou A Evolution of cerebral microbleeds after cranial irradiation in medulloblastoma patients Neurology 2017 88 8 789 796 28122904\n\n",
"fulltext_license": "CC BY-NC-SA",
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"issue": "91(2)",
"journal": "Acta bio-medica : Atenei Parmensis",
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"mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008275:Magnesium Deficiency; D054038:Posterior Leukoencephalopathy Syndrome",
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"pubdate": "2020-05-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Posterior reversible encephalopathy syndrome in an oncological normotensive patient: evidence for a pathogenic role of concomitant low magnesium serum levels and chemotherapy treatment.",
"title_normalized": "posterior reversible encephalopathy syndrome in an oncological normotensive patient evidence for a pathogenic role of concomitant low magnesium serum levels and chemotherapy treatment"
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"abstract": "The Legionellaceae family consists of approximately 50 species, of which the most commonly identified species is L. pneumophila, the causative agent of Legionnaires' disease. Other Legionella ssp. most often cause clinical infections in the immune-compromised patients, in which L. bozemanii has been known to cause both pneumonia and lung abscesses. In the presented case, a soft tissue infection in a patient with ongoing immunosuppression was determined to be due to L. bozemanii. Hence, in immune-deficient patients, L. bozemanii could be considered a possible agent in soft tissue infections when other common pathogens have been ruled out.",
"affiliations": "Section of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.",
"authors": "Neiderud|Carl-Johan|CJ|;Vidh|Angela Lagerqvist|AL|;Salaneck|Erik|E|",
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"doi": "10.3402/iee.v3i0.20739",
"fulltext": "\n==== Front\nInfect Ecol EpidemiolInfect Ecol EpidemiolIEEInfection Ecology & Epidemiology2000-8686Co-Action Publishing 2073910.3402/iee.v3i0.20739Case StudySoft tissue infection caused by Legionella bozemanii in a patient with ongoing immunosuppressive treatment Neiderud Carl-Johan MD1*Vidh Angela Lagerqvist 2Salaneck Erik MD, PhD11 Section of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden2 Department of Clinical Microbiology, Uppsala University Hospital, Uppsala, Sweden* Carl-Johan Neiderud, Section of Infectious Diseases, Department of Medical Sciences, Uppsala University, SE-75185 Uppsala, Sweden. Email: carl-johan.neiderud@akademiska.se06 9 2013 2013 3 10.3402/iee.v3i0.2073901 3 2013 20 6 2013 22 7 2013 © 2013 Carl-Johan Neiderud et al.2013This 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.The Legionellaceae family consists of approximately 50 species, of which the most commonly identified species is L. pneumophila, the causative agent of Legionnaires’ disease. Other Legionella ssp. most often cause clinical infections in the immune-compromised patients, in which L. bozemanii has been known to cause both pneumonia and lung abscesses. In the presented case, a soft tissue infection in a patient with ongoing immunosuppression was determined to be due to L. bozemanii. Hence, in immune-deficient patients, L. bozemanii could be considered a possible agent in soft tissue infections when other common pathogens have been ruled out.\n\nLegionella bozemaniisoft tissue infectionimmunosuppressionopportunistic infection\n==== Body\nThe Legionella bacteria are small Gram-negative rods with specific growth and culture requirements, which lead to certain diagnostic limitations. Approximately 50 species belonging to the Legionellaceae family have been identified, of which about 20 can cause infections in human beings. The most common clinical manifestation of these infections is pneumonia, and the vast majority of these are caused by L. pneumophila, commonly denominated Legionnaires’ disease. Mortality rates for Legionnaires’ disease vary widely, depending on the underlying condition of the patient as well as promptness of diagnosis and treatment. Legionella may also cause extra-pulmonary infections, such as Pontiac fever, which is almost always self-limited. The symptoms include flulike illness, with fever, headache, and myalgia (1). There are reports of skin and soft tissue infections caused by Legionella spp., including both L. pneumophila and other species, but these infections are rare and often appear in immunocompromised patients (2–9). Legionella species are found primarily in aqueous environments and in soil (10, 11), and thrive in artificial water and ventilation systems, which can disperse the bacteria causing outbreaks (12).\n\nAlthough L. pneumophila can cause infection in immune competent subjects, other Legionella species, including L. bozemanii, are most frequently associated with some form of immune suppression, such as hematological malignancies, corticosteroid treatment, or other immune suppressive therapies (13). L. bozemanii has been described to cause pneumonia, both community acquired and nosocomial, whereas only a few case reports of lung abscesses have been published, all of these affecting immunosuppressed patients (14–16). We present here the first report of a soft tissue infection with L. bozemanii, in this case in an immunocompromised patient.\n\nCase\nDuring a 3-year period, a previously healthy 82-year-old male repeatedly consulted a general practitioner as well as a rheumatologist because of joint pains. The patient was eventually diagnosed with seronegative rheumatoid arthritis. During this 3-year period, the patient was treated with increased doses of PO prednisolone to 20 mg daily and, eventually, the addition of methotrexate gradually increased to 15 mg weekly. Two series of intra-articular injections of methylprednisolone were administered to several metacarpophalangeal joints of the right hand as well as the right shoulder.\n\nThe patient was later admitted to the emergency department at the University Hospital, Uppsala, Sweden, 1 week after the last injections, with complaints of fever, chills, myalgia as well as an open wound on the right hand but denied any respiratory symptoms. The wound had appeared approximately at the time of the latest methylprednisolone injections and was open and purulent, with swelling of the dorsal side of the right hand. The left elbow and the dorsal side of the left hand were also swollen. The patient was circulatory stabile and afebrile. Auscultation of the heart and lungs revealed no abnormalities. Plasma CRP-levels (301 mg/l) and total leucocytes (15 × 10(9)/l) were elevated.\n\nBlood and tissue samples were taken for routine cultures before treatment with cefotaxime 1 g IV q8h was started. Surgical exploration and debridement of the wound was performed upon arrival, revealing damage to extensor tendons of the forearm/hand. The swollen left elbow was also punctured and clear fluid was extracted and these particular symptoms were therefore suspected to be due to a non-infectious process, e.g. reactive arthritis. Several surgical revisions were performed during the first 10 days, due to the emergence of novel abscesses on the hands and forearms.\n\nAll cultures acquired prior to antibiotic therapy resulted negative. Due to non-satisfactory effect 11 days after admission, treatment was replaced with a combined therapy of imipenem + cilastatin (500 mg/500 mg IV q8h) and clindamycin (600 mg IV q8h). Supplementary cultures were taken, as well as biopsies subsequently analyzed for non-tuberculous mycobacteria (NTM) (culture, microscopy, and PCR), fungus (microscopy), Nocardia and Actinomyces (cultures). Samples were taken from wound material for bacterial 16S-RNA PCR. TBC-specific IGRA (QuantiFERON, Cellestis) turned out negative.\n\nAll further wound cultures as well as direct microscopy for acid-fast rods (mycobacteria ssp.) resulted negative. The 16S-RNA PCR did though indicated the presence of L. bozemanii in wound material. No reports of L. bozemanii causing soft tissue infections were previously reported and, therefore, NTM was still considered a possible cause and the therapy was now altered to target mycobacteria. A combination of moxifloxacin (400 mg PO q24h), amikacin (500 mg IV q24h), and clarithromycin (500 mg IV q12h) was introduced. Additional tissue samples were taken from the right upper arm and again 16S-RNA PCR was positive for L. bozemanii, and a Legionella-specific PCR was performed which also detected L. bozemanii DNA. Serological analysis was undertaken and compared to blood samples acquired on admission, which revealed a fivefold increase of anti-body titers of L. bozemanii and L. longbeachae serogroup 1 and 2 during a 12-day period. Treatment was now continued with moxifloxacin and clarithromycin.\n\nDue to inadequate improvement of the patient's general condition a chest X-ray was performed on day 16. This revealed widespread perihilar consolidations, interpreted as alveolar edema. During the next 2 weeks, repeated X-rays showed only minor improvement, and a CT scan was therefore performed, revealing bilateral alveolar consolidations as well as consolidations in the left lung. These abnormalities were interpreted by radiologists to be due to a previous infection. During this period, several novel abscesses appeared on both upper limbs, requiring additional surgical evacuation.\n\nHowever, the patient eventually did show clear general improvement as well as reduction of skin lesions and could be discharged from the hospital, after approximately 3 months. Treatment with moxifloxacin and clarithromycin was continued for a further 2 months. Follow-up examination was performed after a further 4 months. No new abscesses had developed and the previous lesions had completely healed.\n\nDiscussion\nThis is the first reported case of L. bozemanii causing soft tissue infection. The patient was, at the time of presentation, undergoing treatment with both corticosteroids, per oral as well as with intra-articular injections, and methotrexate. Previously described manifestations of L. bozemanii, as well as other ‘non-pneumophila’ Legionella species, are primarily associated with ongoing immunosuppression, such as corticosteroid treatment. Extensive analyses, including PCR, cultures, and microscopy, were employed before serological methods could help conclude that the infecting agent was indeed L. bozemanii. Since this particular Legionella species had not previously been found to cause soft tissue infections, repeated analyses were required in order to definitely determine the diagnosis. The increase in antibody titers for L. longbeachae was interpreted as cross reactivity as several separate PCR analyses specifically and repeatedly identified L. bozemanii from wound tissue. In this case, these findings were considered relevant due to a majority of Legionella soft tissue infections being reported in patients with ongoing immune suppression (2–9).\n\nNo further epidemiological investigations were initiated and no plausible source of infection was identified. Other described cases of L. bozemanii infections have been found to have connection to aqueous exposure (15), as is the case with most Legionella species, including L. pneumophila\n(13). The patient's home was connected to the public water system, and no extensive exposure to water from private wells or bathing facilities could be identified. Gardening, one of the patient's recreational activities could also be considered as a mode of infection since soil is a reservoir for many Legionella bacteria (17). The radiological findings interpreted as a previous pulmonary infection could possibly indicate the respiratory tract as path of entry. Intra-articular steroid injections may subsequently have facilitated metastatic wound infections. In order to more clearly determine this scenario, further investigations of the respiratory tract would have be performed, such as bronchoscopy and bronchoalveolar lavage (BAL).\n\nThis case illustrates the need to consider Legionella species as a possible agent in soft tissue infections of immune-deficient patients. In the group of patients receiving immunosuppressive treatment, it may be likely that that this family of bacteria will be found to cause clinical manifestations that have so far not been reported. It is also likely that the difficulties in culturing Legionella bacteria have previously obscured diagnosis. In respect to this, further investigations of the manifestations of Legionella species during immunosuppressive treatment are highly motivated. In particular, L. bozemanii may be considered in immune-deficient patients with soft tissue infections.\n\nAcknowledgment\nWe thank Fredrik Sund, MD, PhD, Section of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden, for his participation in this case.\n\nConflict of interest and funding\nThe authors have not received any funding or benefits from industry or elsewhere to conduct this study.\n==== Refs\nReferences\n1 Fields BS Benson RF Besser RE Legionella and Legionnaires’ disease: 25 years of investigation Clin Microbiol Rev 2002 15 506 26 12097254 \n2 Han JH Nguyen JC Harada S Baddour LM Edelstein PH Relapsing Legionella pneumophila cellulitis: a case report and review of the literature J Infect Chemother 2010 16 439 42 20526646 \n3 Waldor MK Wilson B Swartz M Cellulitis by Legionella pneumophila \n Clin Infect Dis 1993 16 51 3 8448318 \n4 Arnow PM Boyko EJ Friedman EL Perirectal abscess caused by Legionella pneumophila and mixed anaerobic bacteria Ann Intern Med 1983 98 184 5 6824252 \n5 Brabender W Hinthorn DR Asher M Lindsey NJ Liu C \nLegionella pneumophila wound infection JAMA 1983 250 3091 2 6644990 \n6 Gubler JG Schorr M Gaia V Zbinden R Altwegg M Recurrent soft tissue abscesses caused by Legionella cincinnatiensis \n J Clin Microbiol 2001 39 4568 70 11724886 \n7 Loridant S Lagier JC La Scola B Identification of Legionella feeleii cellulitis Emerg Infect Dis 2011 17 145 6 21192884 \n8 Kilborn JA Manz LA O'Brien M Douglass MC Horst HM Kupin W Necrotizing cellulitis caused by Legionella micdadei \n Am J Med 1992 1 104 6 1731498 \n9 Chee CE Baddour LM \nLegionella maceachernii soft tissue infection Am J Med Sci 2007 334 410 13 18004100 \n10 Tison DL Baross JA Seidler RJ \nLegionella in aquatic habitats in the Mount Saint Helens blast zone Curr Microbiol 1983 9 345 8 \n11 Joly JR Boissiot M Duchaine J Duval M Rafrafi J Ramsay D Ecological distribution of Legionellaceae in the Quebec city area Can J Microbiol 1984 30 63 7 6713304 \n12 Knirsch CA Jakob K Schoonmaker D Kiehlbauch JA Wong SJ Della-Latta P An outbreak of Legionella micdadei pneumonia in transplant patients: evaluation, molecular epidemiology, and control Am J Med 2000 108 290 5 11014721 \n13 Muder RR Yu VL Infection due to Legionella species other than L. pneumophila \n Clin Infect Dis 2002 35 990 8 12355387 \n14 Miller M Hayden R Gaur A \nLegionella Bozemanii pulmonary abscess in a pediatric allogeneic stem cell transplant recipient Pediatr Infect Dis J 2007 26 760 2 17848897 \n15 Parry MF Stampleman L Hutchinson J Folta D Steinberg MG Krasnogor LJ Waterborne Legionella bozemanii and nosocomial pneumonia in immunosuppressed patients Ann Intern Med 1985 103 205 10 4014902 \n16 Taylor TH Albrecht MA \nLegionella bozemanii cavitary pneumonia poorly responsive to erythromycin: case report and review Clin Infect Dis 1995 20 329 34 7742438 \n17 Steele TW Moore CY Sangster N Distribution of Legionella longbeachae serogroup 1 and other legionella e in potting soils in Australia Appl Environ Microbiol 1990 56 2984 8 2285311\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2000-8686",
"issue": "3()",
"journal": "Infection ecology & epidemiology",
"keywords": "Legionella bozemanii; immunosuppression; opportunistic infection; soft tissue infection",
"medline_ta": "Infect Ecol Epidemiol",
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"title": "Soft tissue infection caused by Legionella bozemanii in a patient with ongoing immunosuppressive treatment.",
"title_normalized": "soft tissue infection caused by legionella bozemanii in a patient with ongoing immunosuppressive treatment"
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"abstract": "BACKGROUND\nThis study aimed to evaluate the efficacy of combined vancomycin and steroid therapy for the treatment of culture-proven bacterial meningitis in pediatric patients.\n\n\nMETHODS\nWe identified a total of 86 pediatric patients with culture-positive cerebrospinal fluid who were treated at our facility between 2005 and 2015. Ten of these patients (5 boys and 5 girls) received first-line treatment with vancomycin as the initial form of therapy. All cultured bacteria were sensitive to vancomycin. We retrospectively analyzed these cases to examine the relationship between concomitant steroid dosage and antibiotic treatment effectiveness.\n\n\nRESULTS\nNine of the 10 patients included in our analysis received steroid treatment. Of these, 3 received high-dose steroid therapy and 6 received low-dose steroid therapy. Five patients did not respond to vancomycin, including all 3 patients in the high-dose steroid group and 2 patients in the low-dose steroid group. Our analysis confirmed that the response rate to vancomycin treatment was significantly reduced in accordance with steroid dosage (P = 0.035). Patients who did not to respond to vancomycin with concomitant high-dose steroid administration improved clinically after the substitution of vancomycin with teicoplanin.\n\n\nCONCLUSIONS\nThe use of steroids, especially in high doses, may impair the effectiveness of vancomycin for treating bacterial meningitis in pediatric patients. Physicians should be cautious when administering concomitant steroid therapy and should carefully monitor the steroid dosage.",
"affiliations": "Department of Pediatrics, Chonbuk National University Medical School, Jeonju, Korea.;Department of Pediatrics, Chonbuk National University Medical School, Jeonju, Korea.;Department of Pediatrics, Chonbuk National University Medical School, Jeonju, Korea.;Department of Pediatrics, Chonbuk National University Medical School, Jeonju, Korea.",
"authors": "Lee|Shin Ae|SA|https://orcid.org/0000-0002-2463-5508;Kim|Jin Kyu|JK|https://orcid.org/0000-0002-3502-7604;Jo|Dae Sun|DS|https://orcid.org/0000-0002-3141-9539;Kim|Sun Jun|SJ|https://orcid.org/0000-0002-7673-8728",
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"doi": "10.3947/ic.2017.49.4.262",
"fulltext": "\n==== Front\nInfect ChemotherInfect ChemotherICInfection & Chemotherapy2093-23402092-6448The Korean Society of Infectious Diseases and Korean Society for Chemotherapy 2929989310.3947/ic.2017.49.4.262Original ArticleResponse of Vancomycin according to Steroid Dosage in Pediatric Patients with Culture-Proven Bacterial Meningitis https://orcid.org/0000-0002-2463-5508Lee Shin-Ae 1https://orcid.org/0000-0002-3502-7604Kim Jin Kyu 1https://orcid.org/0000-0002-3141-9539Jo Dae Sun 1https://orcid.org/0000-0002-7673-8728Kim Sun Jun 121 Department of Pediatrics, Chonbuk National University Medical School, Jeonju, Korea.2 Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, Korea.Corresponding Author: Sun Jun Kim, MD, PhD. Department of Pediatrics, Chonbuk National University Children's Hospital, Geonji-ro 20, Jeonju 54907, Korea. Tel: +82-63-250-1460, Fax: +82-63-250-1464, sunjun@jbnu.ac.kr12 2017 01 12 2017 49 4 262 267 28 3 2017 29 8 2017 Copyright © 2017 by The Korean Society of Infectious Diseases and Korean Society for Chemotherapy2017The Korean Society of Infectious Diseases and Korean Society for ChemotherapyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nThis study aimed to evaluate the efficacy of combined vancomycin and steroid therapy for the treatment of culture-proven bacterial meningitis in pediatric patients.\n\nMaterials and Methods\nWe identified a total of 86 pediatric patients with culture-positive cerebrospinal fluid who were treated at our facility between 2005 and 2015. Ten of these patients (5 boys and 5 girls) received first-line treatment with vancomycin as the initial form of therapy. All cultured bacteria were sensitive to vancomycin. We retrospectively analyzed these cases to examine the relationship between concomitant steroid dosage and antibiotic treatment effectiveness.\n\nResults\nNine of the 10 patients included in our analysis received steroid treatment. Of these, 3 received high-dose steroid therapy and 6 received low-dose steroid therapy. Five patients did not respond to vancomycin, including all 3 patients in the high-dose steroid group and 2 patients in the low-dose steroid group. Our analysis confirmed that the response rate to vancomycin treatment was significantly reduced in accordance with steroid dosage (P = 0.035). Patients who did not to respond to vancomycin with concomitant high-dose steroid administration improved clinically after the substitution of vancomycin with teicoplanin.\n\nConclusion\nThe use of steroids, especially in high doses, may impair the effectiveness of vancomycin for treating bacterial meningitis in pediatric patients. Physicians should be cautious when administering concomitant steroid therapy and should carefully monitor the steroid dosage.\n\nBacterial meningitisPediatricsSteroidVancomycin\n==== Body\nIntroduction\nBacterial meningitis persists as one of the most serious diseases in pediatric patients despite vaccine development and recent advancements in critical care techniques [1]. Failure to sufficiently treat bacterial meningitis can result in serious neurological sequelae such as hearing loss, seizures, cognitive impairment, sensory motor impairment, cerebrovascular abnormalities, subdural effusion, and other life-threatening complications [2]. Therefore, first-line therapy for bacterial meningitis in pediatric patients involves aggressive treatment with vancomycin and third-generation cephalosporins.\n\nStudies indicate that adjunct steroid administration can reduce the likelihood of hearing loss and neurological complications, especially in cases of meningitis caused by Haemophilus influenzae type B [3, 4]. Other reports suggest that the use of steroids can inhibit the penetration of vancomycin into brain parenchyma by stabilizing the blood-brain barrier [5, 6]. Hence, adjunct steroid therapy remains controversial and is not widely used for the treatment of bacterial meningitis [7, 8]. Moreover, the utility of this treatment approach in pediatric patients is unknown, and there are no representative clinical reports describing the effects of steroid therapy on vancomycin efficacy. The purpose of this study was to verify the efficacy of combined vancomycin and steroid therapy for the treatment of culture-proven bacterial meningitis in pediatric patients.\n\nMaterials and Methods\n1. Patients and treatment groups\nWe performed a retrospective analysis of pediatric patients with culture-proven bacterial meningitis who were admitted to Chonbuk National University Hospital between January 2005 and December 2015. This study adhered to the Declaration of Helsinki and Ethics Regulations, and was approved by the Life Science Research Ethic Council Committee at Chonbuk National University Hospital (CUH 2015-06-031-001). Included patients had confirmation of a pathogen in cerebrospinal fluid (CSF) and/or blood culture and were initially treated with vancomycin and third-generation cephalosporins. Of 86 eligible cases (Table 1), 69 were excluded because vancomycin was not used as an initial treatment, and 7 cases were excluded because the patients were neonates (age <1 month). Ultimately, 10 pediatric patients (5 boys and 5 girls) were enrolled. All patients were treated with intravenous vancomycin (60 mg/kg/day) and cefotaxime (200 mg/kg/day) as an initial empirical treatment. Additionally, all patients were positive for vancomycin-sensitive bacteria on CSF culture.\n\nTable 1 Causative organisms of bacterial meningitis\nOrganism\tNumber (%) (n=86)\t\nStreptococcus agalactiae\t10 (11.6%)\t\nStreptococcus pneumoniae\t8 (9.3%)\t\nEscherichia coli\t7 (8.1%)\t\nHaemophilus influenza type b\t1 (1.2%)\t\nKlebsiella pneumoniae\t1 (1.2%)\t\nUnspecified\t\t\n\tStaphylococcus spp.\t27 (31.4%)\t\n\tStreptococcus spp.\t25 (29.1%)\t\n\tEnterococcus spp.\t5 (5.8%)\t\n\tPseudomonas spp.\t2 (2.3%)\t\nThe 10 patients were divided into 3 groups based on methylprednisolone treatment and dosage; a no steroid group, a low-dose steroid group (median dosage: 2 mg/kg/day, <5 mg/kg/day), and a high-dose steroid group (25 mg/kg/day, maximum dosage: 1 g/day for 3 days and 1 mg/kg/day thereafter). All patients had normal kidney and liver function and underwent similar adjunctive treatments for the control of fever, seizures, and intracranial pressure. The following patients were classified into the therapeutic failure group: patients with reappearance of fever [9]; those with an increased white blood cell count on follow-up CSF tap (performed in patients who showed exacerbation of clinical manifestations); those who showed positive results in follow-up CSF culture tests repeatedly. For these patients, teicoplanin was substituted with vancomycin.\n\n2. Statistical analysis\nStatistical analyses were performed using SPSS version 18.0 (SPSS, Chicago, IL, USA) and R version 3.2.1 (R Development Core Team, R Foundation, Vienna, Austria). The efficacy of antibiotics for culture-proven bacterial meningitis in pediatric patients, the vancomycin response rate according to steroid usage and neurological complications according to steroid dosage were analyzed using Fisher's exact tests. The correlation between steroid dosage and vancomycin response was analyzed using the Cochran-Armitage test. P <0.05 was the threshold for statistical significance.\n\nResults\n1. Clinical characteristics\nFor the 10 patients included in this study (5 boys and 5 girls), the median age was 6.5 months (range, 1–156 months) and all patients were diagnosed with bacterial meningitis by bacterial culture. Six patients were positive for Streptococcus pneumoniae and 4 patients were positive for Streptococcus agalactiae. All pathogens were vancomycin-sensitive. Six of the pathogens showed intermediate sensitivity to third-generation cephalosporins and 4 showed complete sensitivity to third-generation cephalosporins.\n\nThe mean white blood cell count was 2,241 ± 2,831 cells/mm3 on initial examination and 718 ± 752 cells/mm3 on follow-up examination performed within 48 h after the start of initial treatment. Almost all CSF samples had high neutrophil content (mean, 74 ± 25%). Brain magnetic resonance imaging performed on patients within 24 h of visiting the hospital identified infarction in 4 patients, meningeal enhancement in 3 patients, hydrocephalus in 2 patients, and diffuse cystic degeneration in 1 patient (Table 2). Electroencephalography performed on 8 of the 10 patients within 24 h of visiting the hospital, with the following results. Two patients showed brain dysfunction, one patient exhibited diffuse brain dysfunction, and the other presented focal brain dysfunction (Table 3). One patient showed spikes in the occipital area and the other was observed to have electrographic seizure activity in the right temporal area.\n\nTable 2 Abnormal brain MRI findings in meningitis patient\nClssification\tNumber (%) (n=10)\t\nInfarction\t4 (40.0%)\t\nMeningeal enhancement\t3(30.0%)\t\nHydrocephalus\t2 (20.0%)\t\nDiffuse cystic degeneration\t1(10.0%)\t\nTable 3 Initial electroencephalography in meningitis patients\nClassification\tNumber (n=8)\t\nBrain dysfunction\t\t\n\tDiffuse\t1\t\n\tFocal\t1\t\nSpike\t\t\n\tOccipital\t1\t\n\tIctal seizure activity – Right temporal area\t1\t\n\tNonspecific\t4\t\n2. Antibiotics response rate\nFive of the 10 patients (50.0%) responded well to vancomycin treatment (Fig. 1). The vancomycin cure rate did not differ in accordance with bacterial strain (P = 1.000, Fig. 2). The degree to which the pathogen was sensitive to third-generation cephalosporin did not affect the treatment outcome (P = 1.000).\n\nFigure 1 Vancomycin response in bacterial meningitis patients\n\nFigure 2 Degree of response to vancomycin according to bacterial strain\n\n3. The influence of concomitant steroid treatment on vancomycin efficacy\nWe analyzed vancomycin response rates based on the dosage of concomitant steroid treatment in order to examine effects on vancomycin efficacy. In 9 of 10 patients, methylprednisolone was used as an adjunctive therapy and was initiated concurrently with antibiotic treatment. Of the 9 patients who received steroid therapy, 4 (44.5%) responded fairly well to vancomycin while the remaining 5 (55.5%) did not respond to vancomycin at all, including all 3 patients who received high-dose steroid treatment (mean dose, 25 mg/kg/day) and 2 of 6 patients who received low-dose steroid treatment (< 5 mg/kg/day). In the 5 patients who did not respond to vancomycin, antibiotic therapy was changed to teicoplanin and steroid therapy was continued. All 5 of these patients showed good responses to combination teicoplanin and steroid therapy. Further analysis revealed that vancomycin responsiveness was significantly associated with steroid dosage (P = 0.035, Fig. 3); that is, patients receiving higher steroid dosages showed decreased responsiveness to vancomycin.\n\nFigure 3 Vancomycin response according to steroid dosage\n\nThree out of the ten patients received high steroid doses (mean dose: 25 mg/kg/day) with vancomycin and 3rd cephalosporin; however, none of them responded to antibiotics. Owing to their non-responsiveness, the patients were administered teicoplanin instead of vancomycin and steroid administration was continued. After the antibiotic was changed, all three patients responded both clinically and in follow-up CSF tap results.\n\nFour of the six patients (66.6%) who received less than 5 mg/kg/day of steroid responded to vancomycin; however, two (33.3%) did not respond to vancomycin and were administered teicoplanin. One patient showed reappearance of spiking fever, which subsided after having received teicoplanin instead. For the other patient, CSF cultures continued to be positive in follow-up assessments, and the patient also responded on being administered teicoplanin instead. The S. pneumoniae patient group was more responsive to vancomycin with low-dose steroid treatment compared to the S. agalactiae group (Fig. 4). However, there was no significant difference in vancomycin response rate according to bacterial strain in the low-dose steroid group (P = 1.000).\n\nFigure 4 Low-dose steroid group vancomycin response according to bacterial strain\n\n4. Neurological findings\nIn our cohort, 9 patients experienced seizures and changes in mental status as initial symptoms; these patients were given antiepileptic treatment in combination with initial meningitis treatment. At two months after discharge, 4 of them were taking the antiepileptic drugs prescribed to them, 1 had spastic cerebral palsy and showed language impairment, and 1 had hemiplegia and showed mental retardation. One patient required surgical shunt treatment for hydrocephalus. When the data were analyzed in terms of steroid dose and neurological complications, the low-dose steroid group had a 33.3% complication rate and the high-dose steroid group had a 100% complication rate (P = 0.167).\n\nDiscussion\nBacterial meningitis is associated with high morbidity and mortality rates and warrants prompt initial treatment with antibiotics. Currently, combination therapy is widely used, comprising vancomycin and third-generation cephalosporin. When antibiotic therapy is initiated in a timely manner, follow-up CSF cultures can be negative within the first few hours after treatment initiation [8].\n\nBacterial meningitis can cause serious neurological complications such as impaired mental status, cerebral edema, seizure, hearing loss, ataxia, cerebrovascular abnormality, and subdural effusion [2]. The pathophysiological mechanism of these complications involves inflammation in the CSF and subarachnoid space [10-12], which ultimately leads to cellular energy failure and death [13, 14].\n\nSteroids can suppress inflammation in brain parenchyma and blood-brain barrier and can modulate the enhanced meningeal inflammatory response [15]. However, steroid use remains controversial because of the high incidence of recently reported complications [16] and interference with vancomycin, which can reduce the therapeutic efficacy [17-19].\n\nHigh doses of steroids can stabilize the blood brain barrier (BBB), which in turn reduces its permeability and lowers the efficacy of large molecular-sized antibiotics, such as vancomycin [17]. The use of steroids dose-dependently influences the levels of key permeability regulating factors, such as angiopoietin-1 and vascular endothelial growth factor, in the cells that comprise the BBB [20-23]. Steroids can affect transcriptional regulation and have been found to increase the levels of angiopoietin-1 mRNA and protein, a strong BBB stabilizing factor, and decrease the levels of vascular endothelial growth factor mRNA and protein, which is a strong permeabilizing factor, in brain astrocytes and pericytes [24]. Thus, steroids can stabilize the BBB, thereby preventing vancomycin from penetrating the CSF, and significantly decrease the antibiotic response, especially at high doses.\n\nConsistent with this idea, we identified dose-dependent steroid effects on vancomycin treatment efficacy in our pediatric cohort. Whereas the low-dose steroid group had a 66.6% response rate to vancomycin, the high-dose steroid group was non-responsive. Importantly, patients who were non-responsive to vancomycin therapy responded to teicoplanin co-administered with an identical steroid regimen. Similarly, Fernandez et al. [25], using a rabbit model of bacterial meningitis, reported that administration of vancomycin with a steroid was associated with therapeutic failure, whereas the use of teicoplanin with a steroid was not, despite penetration of both glycopeptides into the CSF being significantly reduced. Although the authors did not provide a complete explanation or identify possible mechanisms underlying this phenomenon, our study corroborates the observation of clinical improvement after changing the antibiotic regimen from vancomycin to teicoplanin.\n\nThe present study had some limitations. First, we included a small number of patients, such that a larger-scale study is needed to verify our results. Second, our study is limited by a retrospective design; we were not able to ensure the consistency of patient status prior to the start of treatment. Third, we did not measure levels of vancomycin in serum or CSF in our study. Despite these limitations, this study demonstrated that steroids, especially in high doses, may impair the effectiveness of vancomycin for the treating bacterial meningitis in pediatric patients. Therefore, physicians need to be more cautious with maintaining steroid therapy and the use of steroids should be decided depending on the patient's condition.\n\nConflict of Interest: No conflicts of interest.\n==== Refs\n1 Chávez-Bueno S McCracken GH Jr Bacterial meningitis in children [vii.] Pediatr Clin North Am 2005 5 795 810 \n2 van de Beek D de Gans J Spanjaard L Weisfelt M Reitsma JB Vermeulen M Clinical features and prognostic factors in adults with bacterial meningitis N Engl J Med 2004 351 1849 1859 15509818 \n3 Brouwer MC McIntyre P Prasad K van de Beek D Corticosteroids for acute bacterial meningitis Cochrane Database Syst Rev 2015 12 CD004405 \n4 Wubbel L McCracken GH Jr Management of bacterial meninigitis: 1998 Pediatr Rev 1998 19 78 84 9509854 \n5 Brady MT Kaplan SL Taber LH Association between persistence of pneumococcal meningitis and dexamethasone administration J Pediatr 1981 99 924 926 7310585 \n6 Scheld WM Brodeur JP Effect of methylprednisolone on entry of ampicillin and gentamicin into cerebrospinal fluid in experimental pneumococcal and Escherichia coli meningitis Antimicrob Agents Chemother 1983 23 108 112 6338816 \n7 Pfausler B Schmutzhard E Controversies in neurology, Vienna, 2012: steroids in bacterial meningitis J Neural Transm (Vienna) 2013 120 343 346 23263539 \n8 Spapen H Van Berlaer G Moens M Hubloue I Adjunctive steroid treatment in acute bacterial meningitis, “To do or not to do: that is the question Acta Clin Belg 2011 66 42 45 21485762 \n9 Viladrich PF Management of meningitis caused by resistant Streptococcus pneumoniae Gillespie SH Management of multiple drug-resistance infections Totowa, NJ Humana Press 2004 31 48 \n10 Täuber MG Moser B Cytokines and chemokines in meningeal inflammation: biology and clinical implications Clin Infect Dis 1999 28 1 11 10028061 \n11 Täuber MG Khayam-Bashi H Sande MA Effects of ampicillin and corticosteroids on brain water content, cerebrospinal fluid pressure, and cerebrospinal fluid lactate levels in experimental pneumococcal meninigits J Infect Dis 1985 151 528 534 3973406 \n12 Mai NT Tuan TV Wolbers M Hoang DM Nga TV Chau TT Chuong LV Sinh DX Nghia HD Phong ND Phu NH Diep TS Hang HT Chau Nv Farrar J Schultsz C Hien TT Simmons CP Immunological and biochemical correlates of adjunctive dexamethasone in Vietnamese adults with bacterial meningitis Clin Infect Dis 2009 49 1387 1392 19814625 \n13 Gerber J Nau R Mechanisms of injury in bacterial meningitis Curr Opin Neurol 2010 23 312 318 20442574 \n14 Esposito S Semino M Picciolli I Principi N Should corticosteroids be used in bacterial meningitis in children? Eur J Paediatr Neurol 2013 17 24 28 22789668 \n15 Gerber J Tauber SC Armbrecht I Scchmidt H Brück W Nau R Increased neuronal proliferation in human bacterial meningitis Neurology 2009 73 1026 1032 19786694 \n16 Leib SL Heimgartner C Bifrare YD Loeffler JM Täauber MG Dexamethasone aggravates hippocampal apoptosis and learning deficiency in pneumococcal meningitis in infant rates Pediatr Res 2003 54 353 357 12788989 \n17 Viladrich PF Gudiol F Liñares J Pallarés R Sabaté I Rufí G Ariza J Evaluation of vancomycin for therapy of adult pneumococcal meningitis Antimicrob Agents Chemother 1991 35 2467 2472 1810180 \n18 París MM Hickey SM Uscher MI Shelton S Olsen KD McCracken GH Jr Effect of dexamethasone on therapy of experimental penicillin and cephalosporin resistant pneumococcal meningitis Antimicrob Agents Chemother 1994 38 1320 1324 8092832 \n19 Cabellos C Martinez-Lacasa J Martos A Tubau F Fernández A Viladrich PF Gudiol F Influence of dexamethasone on efficacy of ceftriaxone and vancomycin therapy in experimental pneumococcal meningitis Antimicrob Agents Chemother 1995 39 2158 2160 8540738 \n20 Kaal EC Vecht CJ The management of brain edema in brain tumors Curr Opin Oncol 2004 16 593 600 15627023 \n21 Lee SW Kim WJ Choi YK Song HS Son MJ Gelman IH Kim YJ Kim KW SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier Nat Med 2003 9 900 906 12808449 \n22 Hori S Ohtsuki S Hosoya K Nakashima E Terasaki T A pericyte-derived angiopoietin-1 multimeric complex induces occluding gene expression in brain capillary endothelial cells through Tie-2 activation in vitro J Neurochem 2004 89 503 513 15056293 \n23 Nag S Papneja T Venuqopalan R Stewart DJ Increased angiopoietin2 expression is associated with endothelial apoptosis and blood brain barrier breakdown Lab Invest 2005 85 1189 1198 16056241 \n24 Kim H Lee JM Park JS Jo SA Kim YO Kim CW Jo I Dexamethasone coordinately regulates angiopoietin-1 and VEGF: a mechanism of glucocorticoid-induced stabilization of blood-brain barrier Biochem Biophys Res Commun 2008 372 243 248 18485896 \n25 Fernández A Cabellos C Tubau F Maiques JM Doménech A Ribes S Liñares J Viladrich PF Gudiol F Experimental study of teicoplanin, alone and in combination, in the therapy of cephalosporin-resistant pneumococcal meningitis J Antimicrob Chemother 2005 55 78 83 15546968\n\n",
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"issue": "49(4)",
"journal": "Infection & chemotherapy",
"keywords": "Bacterial meningitis; Pediatrics; Steroid; Vancomycin",
"medline_ta": "Infect Chemother",
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"title": "Response of Vancomycin according to Steroid Dosage in Pediatric Patients with Culture-Proven Bacterial Meningitis.",
"title_normalized": "response of vancomycin according to steroid dosage in pediatric patients with culture proven bacterial meningitis"
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"abstract": "In patients with ischemic stroke who receive systemic recombinant tissue plasminogen activator (rt-PA), the risk of secondary hemorrhage is 1-7%. Fibrinogen supplementation with cryoprecipitate is recommended in patients with rt-PA-associated symptomatic hemorrhage. We examined whether fibrinogen concentrate can be used safely in this setting. A single-center retrospective case series was performed in patients who received fibrinogen concentrate for post-rt-PA hemorrhage between January-2012 and December-2017. The primary outcome was the incidence of in-hospital thromboembolic events and infusion reactions. Secondary outcomes included incidence of clinically significant ICH expansion within 24-hours and patient serum fibrinogen response to fibrinogen concentrate therapy. Thromboembolic events occurred in 3 (12.5%) of 24 patients included in the analysis. No patients experienced infusion-related reactions. Five of 22 patients with ICH experienced clinically significant hemorrhage expansion. Hypofibrinogenemia was corrected in 87.5%(7/8) of patients with baseline hypofibrinogenemia, with a median increase in serum fibrinogen 166 mg/dL. Median fibrinogen increase in patients without baseline hypofibrinogenemia was 18 mg/dL. Fibrinogen concentrate is a safe potential therapeutic option to restore fibrinogen levels in acute ischemic stroke patients with thrombolysis-associated hemorrhage.",
"affiliations": "Department of Pharmacy, 2348Massachusetts General Hospital, Boston, MA, USA.;Department of Neurology, 1861Brigham and Women's Hospital, Boston, MA, USA.;Department of Pharmacy, 1861Brigham and Women's Hospital, Boston, MA, USA.;Department of Neurology, 1836Boston University School of Medicine, Boston Medical Center, Boston, MA, USA.;Department of Pharmacy, 1861Brigham and Women's Hospital, Boston, MA, USA.;Department of Pharmacy, 1861Brigham and Women's Hospital, Boston, MA, USA.;Department of Neurology, 1861Brigham and Women's Hospital, Boston, MA, USA.;Department of Pharmacy, 1861Brigham and Women's Hospital, Boston, MA, USA.",
"authors": "Barra|Megan E|ME|https://orcid.org/0000-0002-7696-1540;Feske|Steven K|SK|;Sylvester|Katelyn W|KW|;Ong|Charlene|C|;Culbreth|Sarah E|SE|;Krause|Patricia|P|;Henderson|Galen V|GV|;Rybak|Eva|E|",
"chemical_list": "D005340:Fibrinogen",
"country": "United States",
"delete": false,
"doi": "10.1177/1076029620951867",
"fulltext": "\n==== Front\nClin Appl Thromb Hemost\nClin. Appl. Thromb. Hemost\nCAT\nspcat\nClinical and Applied Thrombosis/Hemostasis\n1076-0296 1938-2723 SAGE Publications Sage CA: Los Angeles, CA \n\n32946279\n10.1177/1076029620951867\n10.1177_1076029620951867\nTherapeutic Approaches for the Treatment of Cerebral-Neurovascular Diseases\nOriginal Article\nFibrinogen Concentrate for the Treatment of Thrombolysis-Associated Hemorrhage in Adult Ischemic Stroke Patients\nhttps://orcid.org/0000-0002-7696-1540Barra Megan E. PharmD, BCPS, BCCCP1 Feske Steven K. MD2 Sylvester Katelyn W. PharmD, BCPS3 Ong Charlene MD, MPHS4 Culbreth Sarah E. PharmD, BCPS3 Krause Patricia PharmD, BCPS3 Henderson Galen V. MD2 Rybak Eva PharmD, BCPS3 \n1 Department of Pharmacy, 2348Massachusetts General Hospital, Boston, MA, USA\n\n2 Department of Neurology, 1861Brigham and Women’s Hospital, Boston, MA, USA\n\n3 Department of Pharmacy, 1861Brigham and Women’s Hospital, Boston, MA, USA\n\n4 Department of Neurology, 1836Boston University School of Medicine, Boston Medical Center, Boston, MA, USA\nMegan E. Barra, Department of Pharmacy, Massachusetts General Hospital, Boston, MA, USA. Email: mbarra@mgh.harvard.edu\n18 9 2020 \nJan-Dec 2020 \n26 1076029620951867© The Author(s) 20202020SAGE Publications Inc. unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).In patients with ischemic stroke who receive systemic recombinant tissue plasminogen activator (rt-PA), the risk of secondary hemorrhage is 1-7%. Fibrinogen supplementation with cryoprecipitate is recommended in patients with rt-PA-associated symptomatic hemorrhage. We examined whether fibrinogen concentrate can be used safely in this setting. A single-center retrospective case series was performed in patients who received fibrinogen concentrate for post-rt-PA hemorrhage between January-2012 and December-2017. The primary outcome was the incidence of in-hospital thromboembolic events and infusion reactions. Secondary outcomes included incidence of clinically significant ICH expansion within 24-hours and patient serum fibrinogen response to fibrinogen concentrate therapy. Thromboembolic events occurred in 3 (12.5%) of 24 patients included in the analysis. No patients experienced infusion-related reactions. Five of 22 patients with ICH experienced clinically significant hemorrhage expansion. Hypofibrinogenemia was corrected in 87.5%(7/8) of patients with baseline hypofibrinogenemia, with a median increase in serum fibrinogen 166 mg/dL. Median fibrinogen increase in patients without baseline hypofibrinogenemia was 18 mg/dL. Fibrinogen concentrate is a safe potential therapeutic option to restore fibrinogen levels in acute ischemic stroke patients with thrombolysis-associated hemorrhage.\n\nintracerebral hemorrhagethrombolysisfibrinogencerebral infarctionstrokehemostasiscover-dateJanuary-December 2020typesetterts3\n==== Body\nIntroduction\nIntravenous recombinant tissue plasminogen activator (rt-PA) has become the mainstay of treatment in patients presenting within 4.5 hours of the onset of acute ischemic stroke.1,2 Early thrombolysis has been associated with improved functional outcomes but is not without significant bleeding risks. In patients who receive systemic rt-PA for the treatment of ischemic stroke, the risk of secondary hemorrhage is 3-7% for intracerebral hemorrhage (ICH) and 1-7% for extracranial hemorrhage.2–4 Acquired coagulopathies due to decreased fibrinogen levels, increased international normalized ratio (INR), prolonged prothrombin (PT) and activated partial thromboplastin (aPTT) times have all been observed.5 Despite the short plasma half-life of rt-PA (5 minutes) and rapid clearance of the drug after cessation of the infusion, coagulopathy may occur within 2 hours of thrombolysis, and hemorrhage risk can persist for over 24 hours.4 This may be in part due to a longer biologic half-life (15-20 minutes) of rt-PA compared to its plasma half-life. The longer antifibrinolytic effect of rt-PA after plasma clearance is attributable to persistent presence of rt-PA in the thrombus after administration and a slower beta clearance from the peripheral compartment.5 Hypofibrinogenemia occurs in approximately 5% of rt-PA treated patients and has been identified as an important risk factor for bleeding in rt-PA treated patients.4,6\n\n\nLimited evidence guides the management of patients who experience hemorrhagic complications from rt-PA administration after acute ischemic stroke. Treatment strategies include empiric replacement of platelets or coagulation factors with fresh frozen plasma (FFP), cryoprecipitate, prothrombin complex concentrates (PCC), aminocaproic acid, tranexamic acid, and vitamin K.7 The 2018 American Heart Association/American Stroke Association (AHA/ASA) guideline for early management of patients with acute ischemic stroke and Neurocritical Care Society’s guideline for the reversal of anti-thrombotic agents in ICH suggests cryoprecipitate for fibrinogen supplementation in patients with thrombolysis-associated symptomatic ICH. If cryoprecipitate is not readily available or contraindicated, alternative antifibrinolytic agents are recommended.8,9\n\n\nPurified human fibrinogen concentrate, RiaSTAP™, may be a reasonable alternative to cryoprecipitate for the repletion of serum fibrinogen in post-thrombolysis hemorrhage management. Compared to cryoprecipitate, there is negligible risk for immunological reactions or pathogen transmission with fibrinogen concentrate. The product is available as a lyophilized powder that can be stored at room temperature and rapidly reconstituted at the patient bedside, which may expedite administration times.10 Fibrinogen concentrate also has standardized contents, while cryoprecipitate and fresh frozen plasma do not. Per the American Association of Blood Banks (AABB), one unit of cryoprecipitate must contain a minimum of 150 mg fibrinogen and 80 IU Factor VIII per unit. Cryoprecipitate also contains von Willebrand factor and Factor XIII in appreciable amounts, though not standardized. FFP contains approximately 280 mg/dL fibrinogen, 81 IU/dL Factor VIII, along with appreciable amounts of Factor II, Factor V, Factor VII, Factor IX, Factor X, von Willebrand factor, antithrombin, Protein C, and Protein S.11\n\n\nDespite limited use in the neurocritical care patient population, fibrinogen concentrate has been used in the treatment of congenital and acquired fibrinogen deficiency due to hemorrhage secondary to surgery, trauma, in obstetrics.12 The objective of this study was to evaluate the safety and effectiveness of fibrinogen concentration for the treatment of thrombolysis-associated hemorrhage at our institution.\n\nMethods\nWe performed a single-center retrospective case series of patients who received fibrinogen concentrate for the treatment of major hemorrhage after systemic thrombolysis between January 2012 and December 2017 at Brigham and Women’s Hospital in Boston, Massachusetts. We included adult ischemic stroke patients treated with intravenous rt-PA who received at least one dose of fibrinogen concentrate for the management of secondary rt-PA related hemorrhage. We excluded patients who were less than 18 years old or who received fibrinogen concentrate for other indications. Our local institutional review board approved the study.\n\nThe primary safety outcomes assessed were the incidence of in-hospital thromboembolic events and infusion or anaphylactic reactions. Secondary outcomes evaluated included ICH expansion in the first 24 hours after fibrinogen concentrate administration and adequate patient response to fibrinogen concentrate administration in patients with post rt-PA serum fibrinogen levels collected. Response to fibrinogen concentrate was defined as serum fibrinogen normalization to > 200 mg/dL in patients with hypofibrinogenemia. Target serum fibrinogen of > 200 mg/dL, is consistent with the 2018 AHA/ASA Guidelines for the early management of patients with acute ischemic stroke.9 Hypofibrinogenemia was defined as a serum fibrinogen level ≤200 mg/dL. Other outcomes included change in fibrinogen levels from post rt-PA baseline levels, in-hospital mortality, intensive care unit (ICU) length of stay, and hospital length of stay.\n\nSince 2013, our institutional guideline recommends a STAT fibrinogen level immediately after a CT scan confirmed thrombolysis-related symptomatic ICH, followed by administration of 2 vials of fibrinogen concentrate (approximately 900-1300 mg of fibrinogen per vial) without waiting for results of the baseline fibrinogen level. A repeat fibrinogen level is checked 1 hour after fibrinogen concentrate administration and every 2 hours thereafter until serum fibrinogen is > 200 mg/dL. Additional fibrinogen concentrate is administered until the serum fibrinogen level is greater than 200 mg/dL. Supplemental FFP, platelets, aminocaproic acid, vitamin K, or PCC may be administered based on individual patient need per treating provider’s clinical judgment. (Supplemental Figure E-1).\n\nHemorrhagic events were classified based on clinical and radiographic criteria. ICH were classified as either hemorrhagic infarction 1 (HI1), hemorrhagic infarction 2 (HI2), parenchymal hemorrhage 1 (PH1), or parenchymal hemorrhage 2 (PH2) in accordance with the ECASS II trial hemorrhage grading scale.13 ICH expansion was determined to be clinically significant if classification changed or new intraventricular extension was found on follow up imaging. Extracranial hemorrhages were identified based on clinical exam. Descriptive statistics were performed for this analysis.\n\nResults\nWe identified 24 patients who received fibrinogen concentrate for the management of thrombolysis-associated hemorrhage post-acute ischemic stroke (Table 1). The median patient age was 74.1 years and 66.7% of patients were female. Median NIHSS score prior to rt-PA administration was 12 [interquartile range (IQR) 5-19]. The median time to administration of IV rt-PA was 2.2 hours [IQR 1.6-2.7] after ischemic stroke symptom onset. Most rt-PA associated bleeds were ICH (91.7%) with a median time from rt-PA administration to confirmation of hemorrhage of 4.6 hours [IQR 3.3-6.0]. The median time of administration of fibrinogen concentrate was 1.2 hours after hemorrhage confirmation. In addition to fibrinogen concentrate, 25% (6/20) of patients received concurrent cryoprecipitate. Other hemostatic products administered included FFP, platelets, tranexamic acid, aminocaproic acid, intravenous vitamin K, and additional clotting factors (Table 2). Three patients underwent urgent neurosurgical procedures including an external ventricular drain placement (n = 1), hemicraniectomy (n = 1), and dural arteriovenous fistula embolization (n = 1).\n\nTable 1. Patient Characteristics.\n\nBaseline characteristics—no. (%)\tN = 24\t\nAge, yearsa\n\t74.1 [61.8-87.9]\t\nFemale gender\t16 (66.7)\t\nAnti-thrombotic therapy\t\t\n Aspirin\t12 (50)\t\n Clopidogrel\t2 (8.3)\t\n Warfarin\t2 (8.3)\t\n\nIschemic Stroke Presentation and Management—no. (%)\n\t\n NIHSS Scorea\n\t12 [5\n\n\n\n\n\n\n\n\n\n\n\n\n–19]\t\n Stroke onset to rt-PA treatment time, hoursa\n\t2.2 [1.6–2.7]\t\n Intravenous rt-PA—no. (%)\t24 (100)\t\n rt-PA initiated at OSH—no. (%)\t20 (83.3)\t\n Mechanical recanalization—no. (%)\t4 (16.7)\t\n Intra-arterial rt-PA—no. (%)\t1 (4.2)\t\n\nLaboratory Parameters Pre rt-PAa\n\t\n Platelets, k/mm3\n\t203 [161–303]\t\n INR\t1 [1–1.1]\t\n PT, seconds\t12.6 [11.2–13.4]\t\n aPTT, seconds\t28.4 [26.3–29.6]\t\n Glucose\t159 [110–199]\t\n\nHemorrhage Presentation—no. (%)\n\t\n Symptom onset at OSH\t8 (33.3)\t\n Time from rt-PA to hemorrhage confirmation, hoursa,b\n\t4.6 [3.3–6.0]\t\n Hemorrhage type\t\t\n ICH\t22 (91.7)\t\n GIc\n\t2 (8.3)\t\n Groin puncture site\t1 (4.2)\t\nTime from hemorrhage confirmationb to fibrinogen concentrate administration, hoursa\n\t1.2 [0.5–2.3]\t\n\nLaboratory Parameters Post rt-PA Prior to Fibrinogen Concentratea\n\t\n Fibrinogen, mg/dL\t256 [130–347]\t\n Platelets, k/mm3\n\t197 [150–287]\t\n INR\t1.2 [1.1–1.6]\t\n PT, seconds\t15.1 [14.4–18.9]\t\n aPTT, seconds\t33.4 [27.8–39.6]\t\n Hematocrit, %\t37.4 [34.1–41.4]\t\n Hemoglobin, mg/dL\t12.6 [11–13.9]\t\nOSH: Outside hospital; ICH: Intracerebral Hemorrhage; GI: Gastrointestinal.\n\n\na Data presented as median [interquartile range.\n\n\nb On radiographic imaging (ICH) or clinical presentation (gastrointestinal, groin puncture hemorrhage).\n\n\nc One patient had concurrent ICH and GI bleed.\n\nTable 2. Pharmacologic Management of Hemorrhage.\n\n\tNo. (%)\tDosea\n\t\nFibrinogen concentrate, mg\t24 (100)\t2215 [2188–4371]\t\nCryoprecipitate, units\t6 (25)\t20 [10–20]\t\nFresh frozen plasma, units\t7 (29.2)\t2 [1–4]\t\nPlatelets, units\t6 (25)\t1 [1–1]\t\nIntravenous Vitamin K, mg\t4 (16.7)\t10 [10–10]\t\nAminocaproic acid, grams\t3 (12.5)\t5.5 [5.3–6.3]\t\nTranexamic acid, grams\t2 (8.3)\t1 [1–1]\t\nProthrombin Complex Concentrate, units\t2 (8.3)\t2417 [2060–2773]\t\n\na Data presented as median [interquartile range].\n\nSafety Outcomes\nDocumented thromboembolic events occurred in 3 patients (12.5%) who received fibrinogen concentrate. Two patients with thromboembolic complications had post rt-PA hypofibrinogenemia. Patient 11 was found to have a left lower extremity deep vein thrombosis (DVT) 10 days after fibrinogen concentrate administration. Pertinent coagulation products the patient received were 6,846 mg of fibrinogen concentrate along with 10 units of cryoprecipitate, 2 units of FFP, and 1 gram of tranexamic acid. Venous thromboembolism (VTE) prophylaxis with heparin 5,000 units subcutaneously 3 times daily was started on day 3 of hospital admission. Patient 14 was found to have an upper extremity superficial and deep vein thrombosis 9 days after presentation and treatment with 2,198 mg fibrinogen concentrate (no additional coagulation products). VTE prophylaxis was started on day 2 of hospital admission. Patient 20 was found to have a superficial upper extremity vein thrombosis on hospital day 3. Patient’s initial treatment course included 4,356 mg of fibrinogen concentrate and was not receiving VTE prophylaxis at the time of VTE diagnosis. Both upper extremity thromboembolic events (Patient 14 and Patient 20) were associated with access lines. No patients who received fibrinogen concentrate had a documented infusion or anaphylactic reaction.\n\nSerum Fibrinogen Response to Fibrinogen Concentrate Administration\nOf 20 patients with post rt-PA fibrinogen levels collected prior to fibrinogen concentrate administration, 8 (40%) patients had serum fibrinogen ≤200 mg/dL and 12 (60%) patients had serum fibrinogen > 200 mg/dL (Table 3).\n\nTable 3. Plasma Fibrinogen Response to Fibrinogen Concentrate Administration.\n\n\tAll patients N = 24\tPatients with baseline hypofibrinogenemia N = 8\tPatients without hypofibrinogenemia at baseline N = 12\t\nBaseline fibrinogen, mg/dL\t256 [130–347]\t119 [68–159]\t306 [263–388]\t\nInitial fibrinogen concentrate dose administered, mg\t2188 [2181–2198]\t2198 [2188–2282]\t2193 [2178–2198]\t\nIncrease in fibrinogen after initial dose, mg/dL\t35 [16–65]\t40 [31–130]\t25 [-6–54]\t\nTotal fibrinogen concentrate dose administered, mg\t2215 [2188–4371]\t4376 [2232–5495]\t2193 [2116–2198]\t\nIncrease in fibrinogen levels after completion of therapy, mg/dL\t72 [13–117]\t133 [108–153]\t27 [-7–57]\t\nFinal fibrinogen level by the end of the 24 hour follow-up period, mg/dL\t316 [246–391]\t287 [238–331]\t344 [316–401]\t\nIncrease in fibrinogen levels by the end of the 24 hour follow-up period, mg/dL\t73 [2–131]\t166 [121–201]\t18 [-10–56]\t\nData presented as median [interquartile range].\n\nNote: Four patients did not have baseline fibrinogen levels prior to fibrinogen concentrate administration.\n\nIn the 8 patients with post rt-PA hypofibrinogenemia prior to fibrinogen concentrate administration, median fibrinogen level was 119 mg/dL. Six patients with post rt-PA hypofibrinogenemia presented with ICH post thrombolysis. Fibrinogen levels normalized to > 200 mg/dL in 7 (87.5%) hypofibrinogenemic patients. The median time required to increase plasma fibrinogen above 200 mg/dL in hypofibrinogenemic patients was 4.1 hours (range 1.5–14.8 hours). The median dose administered was 4366 mg (range 2174–6846 mg). Three of 8 patients with post rt-PA hypofibrinogenemia had fibrinogen levels > 200 mg/dL after receiving a median fibrinogen concentrate dose of 2,205 mg. One patient’s fibrinogen increased from 166 mg/dL to 200 mg/dL after 2178 mg fibrinogen concentrate, and subsequently received an additional 2178 mg dose to target fibrinogen > 200 mg/dL. Finally, one patient’s fibrinogen level increased from 60 to 188 mg/dL after administration of 4,396 mg but repeat labs were not available to confirm that serum fibrinogen returned to more than 200 mg/dL.\n\nTwelve patients had normal fibrinogen levels post rt-PA, with a median baseline fibrinogen of 306 mg/dL. After a median total dose of 2,193 mg, fibrinogen levels increased by a median of 18 mg/dL. Further information on coagulation results pre- and post- fibrinogen concentrate administration is reported in Figure 1 and Supplemental Table E-1.\n\nFigure 1. Patient-specific fibrinogen response to fibrinogen concentrate administration. ***Patient received concurrent cryoprecipitate. Note: Four patients did not have baseline fibrinogen and were excluded from evaluation of serum fibrinogen response to fibrinogen concentrate administration.\n\nIntracranial Hemorrhagic Expansion After Fibrinogen Concentrate Administration\nTwenty-two patients with ICH were included in this analysis. Twenty patients were noted to have symptomatic ICH and 2 patients were found to have an ICH on routine imaging post-thrombectomy procedure or repeat imaging upon transfer to our institution’s emergency department. On neuroimaging of the 22 patients with ICH prior to fibrinogen concentrate administration, 45.5% (10/22) were originally classified as PH2 classified hemorrhage, followed by 31.8% (7/22) PH1, 13.6% (3/22) HI2, 4.5% (1/22) HI1, and 4.5% (1/22) isolated subarachnoid hemorrhage (Table 4). Additionally, 36% (8/22) had intraventricular extension, 40.9% (9/22) exhibited SAH, and 13.6% (3/22) subdural hematoma (SDH). Five patients suffered clinically significant hemorrhage expansion despite fibrinogen concentrate administration (Patient 7,10, 12, 21, 24). All 5 patients were treated within 3.5 hours of stroke onset with intravenous rt-PA and 3 patients were over 80 years of age. One patient had post rt-PA hypofibrinogenemia with concurrent coagulation laboratory elevations prior to fibrinogen concentrate therapy and 2 patients without baseline fibrinogen levels were noted to have hypofibrinogenemia on follow up laboratory testing post-treatment. While the other 2 patients did not exhibit coagulation abnormalities, they were on antiplatelet therapy at baseline (clopidogrel and aspirin). Four of the 5 patients received fibrinogen concentrate as the only source of fibrinogen replacement, 1 patient received concurrent aminocaproic acid and vitamin K, 1 patient received additional platelets, and 1 patient received additional cryoprecipitate and fresh frozen plasma (Table 2).\n\nTable 4. Intracerebral Progression After Fibrinogen Concentrate Administration.\n\nPatient number\tICH classification pre fibrinogen concentrate\tIntraventricular extension pre-fibrinogen concentrate\tICH classification post fibrinogen concentrate 24 hour head-CT\tIntraventricular extension post fibrinogen concentrate\tBaseline fibrinogen level (mg/dL)\tFinal fibrinogen level after fibrinogen concentrate treatment (mg/dL)\t\n1\tPH1\tNo\tPH1\tNo\t116\t307\t\n2\tPH1/IVH\tYes\tPH1/HI1\tYes\t160\t389\t\n3\tPH1/IVH\tYes\tPH1\tYes\t465\t457\t\n4\tPH1/IVH\tYes\tPH1multiple\tYes\t445\t417\t\n6\tPH1/SAH\tNo\tPH1multiple\tNo\t288\t320\t\n\n7a\n\t\nSAH\n\t\nNo\n\t\nPH2/SAH\n\t\nYes\n\t\n93\n\t\n236\n\t\n8\tPH2/SAH/SDH\tYes\tPH2/SAH/SDH\tYes\t258\t241\t\n9\tPH2/SAH\tYes\tPH2/SAH\tYes\t221\t322\t\n\n10a\n\t\nHI2\n\t\nNo\n\t\nP\nH2\n\t\nNo\n\t\n291\n\t\n363\n\t\n11\tHI2\tNo\tHI2\tNo\t60\t415\t\n\n12a\n\t\nPH2\n\t\nNo\n\t\nPH2\n\t\nYes\n\t\n254\n\t\n305\n\t\n\n13a\n\t\nPH1\n\t\nNo\n\t\nPH1/SDH\n\t\nYes\n\t\nNot available\n\t\n226\n\t\n14\tPH1\tNo\tPH1\tNo\t122\t311\t\n15\tPH2\tNo\tPH2/SAH\tNo\t359\t432\t\n16\tHI2\tNo\tHI2\tNo\t276\t248\t\n18\tPH2/SAH\tNo\tPH2/SAH\tNo\t321\t325\t\n19\tPH2/SAH/SDH\tNo\tPH2/SAH/SDH\tNo\t397\t393\t\n20\tPH2/SAH\tYes\tPH2/SAH\tYes\tNot available\tNot available\t\n21\tHI1\tYes\tHI1\tYes\t356\t397\t\n22\tPH2/SAH\tYes\tPH2/SAH\tYes\tNot available\t309\t\n\n23a\n\t\nPH2/SDH\n\t\nNo\n\t\nPH2/SDH\n\t\nYes\n\t\nNot available\n\t\n354\n\t\n24\tPH2/SAH\tNo\tPH2/SAH\tNo\t166\t267\t\n\naPatient 7, 10, 12, 13, 23 were considered to have clinically significant progression after fibrinogen concentrate administration.\n\nNote: Patient 5 and 17 was excluded due to extracerebral hemorrhage origin.\n\nExtracranial Hemorrhage Management\nThree patients included in our analysis developed extracranial hemorrhage post rt-Pa and were treated with fibrinogen concentrate. Two patients had a gastrointestinal hemorrhage (1 with concurrent ICH) while 1 patient had a groin puncture hemorrhage. Two of these patients were hypofibrinogenemic post rt-PA prior to fibrinogen concentrate administration. All patients who developed extracranial hemorrhages had elevated coagulation laboratory results (INR, PT, PTT) compared to baseline.\n\nClinical Outcomes\nThe median ICU length of stay was 4 days (range 1–17) and the median hospital length of stay was 5.5 days (range 1–22). In-hospital mortality occurred in 50% (12/24) of patients. All 12 patients with in-hospital mortality were transitioned to comfort measures only. Four of these 12 patients had documented post rt-PA hypofibrinogenemia.\n\nSubgroup Analysis of Thrombolysis-Associated Hemorrhage Management With Fibrinogen Concentrate Monotherapy\nOf the 15 patients who received fibrinogen concentrate as the sole source of fibrinogen supplementation, 5 had post rt-PA hypofibrinogenemia. Two patients experienced significant radiographic hematoma expansion (Patient 7 and 21). Patient 7 had a post rt-PA fibrinogen level of 93 mg/dL. The patient’s fibrinogen level rose to 115 mg/dL within 1 hour of treatment initiation, 192 mg/dL 4.9 hours after initiation and to a final level of 236 mg/dL after 11.6 hours and a total of 5,495 mg fibrinogen concentrate in conjunction with 5 grams of aminocaproic acid and 10 mg intravenous vitamin K administered. Patient 21 did not have post rt-PA baseline fibrinogen, but after receiving an initial dose of 2,174 mg fibrinogen concentration fibrinogen level was 136 mg/dL which rose to 225 mg/dL after an additional 2,175 mg were administered. No other hemostatic agents were administered.\n\nIn hospital mortality was 46.7% (7/15) for patients managed with fibrinogen concentrate monotherapy. No patients who received fibrinogen concentrate therapy as the sole fibrinogen repletion treatment modality experienced VTE events.\n\nDiscussion\nIn this descriptive report, we identified 24 patients who were treated with fibrinogen concentrate for the management of thrombolysis-associated hemorrhage after acute ischemic stroke. We found fibrinogen concentrate administration to be associated with a low rate of complications in our patient population. No patients experienced infusion reactions, secondary ischemic stroke, or myocardial infarction.\n\nApproximately 12.5% of patients in our cohort experienced thromboembolic events. One patient in our study was diagnosed with a lower extremity DVT 10 days after fibrinogen concentrate administration while on VTE prophylaxis. This patient received higher than average doses of fibrinogen concentrate along with concurrent cryoprecipitate and tranexamic acid to manage their ICH and thus the VTE complication could not be attributed to the fibrinogen concentrate alone. Two patients experienced upper extremity thromboembolic events associated with access lines. The thromboembolic rate described in our case-series is higher than reported when fibrinogen concentrate was used in the non-ischemic stroke patient population, however patients with acute ischemic stroke are at a 20-fold increased risk of VTE events within the first month of diagnosis.14–16 This increased risk is attributed to prolonged hospitalization, prolonged immobilization in the setting of neurologic deficits, increased risk of secondary acute infection (e.g. aspiration pneumonia, urinary tract infection), high rate of co-morbid inflammatory conditions, and prolonged access line placement.15\n\n\nAdditionally, we found that fibrinogen concentrate corrected hypofibrinogenemia in all but one patient and maintained fibrinogen levels close to baseline in non-hypofibrinogenemic patients. There is a paucity of data to guide clinicians in the management of thrombolysis associated bleeding secondary to acquired coagulopathy. Administration of rt-PA has been associated with prolongation of the PT, reduction in fibrinogen and plasminogen levels, and increased fibrinogen degradation products in the immediate 24-hours post administration. A study by Huang et al. found that within 3–12 hours after rt-PA administration, the mean decrease in fibrinogen was 29% in patients treated with rt-PA and 3% in those treated with tenecteplase.17 In a cohort of 128 patients with thrombolysis-associated hemorrhage, a fibrinogen level of ≤150 mg/dL was the only risk factor on univariate analysis associated with an increased risk of hematoma expansion.18 A decrease in fibrinogen levels more than 200 mg/dL from baseline within 6 hours of thrombolysis has also been identified as a significant predictor for bleeding risk, with a 39.9% risk for major bleeding events.19 Baseline fibrinogen levels prior to rt-PA administration were not available in our patient population, and therefore we cannot determine if patients with normal fibrinogen levels had a decrease of ≥200 mg/dL from their baseline, thus increasing the risk of major hemorrhage. Hypofibrinogenemic patients who had a major hemorrhage as a complication from systemic thrombolysis for acute ischemic stroke were more likely to have a prolonged PT/INR prior to fibrinogen concentrate administration than non-hypofibrinogenemic patients; the PT/INR normalized after administration of fibrinogen concentrate.\n\nSystemic fibrinogen decrease in response to rt-PA administration has been correlated with an increase in fibrinogen degradation products, signifying excessive fibrinogenolysis—an important predictor for parenchymal hematomas.3 The majority (70.8%) of patients with ICH included in our retrospective case series exhibited parenchymal hematomas with approximately 40% experiencing an intraventricular extension. While symptomatic ICH after rt-PA administration is infrequent, it is associated with significant morbidity and mortality.20 Early identification and empiric treatment of rt-PA induced fibrinogen deficiency may mitigate clinical hematoma progression. In our retrospective analysis, after administration of fibrinogen concentrate (and limited cryoprecipitate), 22.7% (5/22) of patients had clinically relevant hemorrhagic expansion on neuroimaging. Of those with clinically relevant hemorrhagic expansion, only 1 patient had baseline hypofibrinogenemia with elevated INR, PT, and PTT. Two patients with clinically relevant hemorrhagic expansion who did not have post rt-PA serum fibrinogen available were hypofibrinogenemic on follow up laboratory monitoring despite initial fibrinogen concentration administration. This suggests that fibrinogen deficiency may not be the only risk factor for hematoma progression. Whether antiplatelet therapy at baseline played a significant role in hematoma expansion in the 2 patients without hypofibrinogenemia is unknown.\n\nCryoprecipitate is often used to restore fibrinogen levels in the management of symptomatic intracranial hemorrhage after rt-PA administration, despite limited published evidence.21 Cryoprecipitate has several limitations, including the need for ABO matching, delay in administration due to product thawing, and concerns regarding potential transmission of viral pathogens.\n\nGiven the limited data in treating thrombolysis-associated hemorrhages, a task force at our institution was developed to create institutional guidelines for the management of symptomatic ICH after thrombolysis for acute ischemic stroke. In non-ischemic stroke patients, a median 4,000 mg dose has been associated with a 109 mg/dL increase in plasma fibrinogen.22 Fibrinogen concentrate was approved for use by our Pharmacy and Therapeutics Committee in patients for thrombolysis associated bleeding in place of the previous institutional standard—cryoprecipitate—in October 2013, prior to the release of the Neurocritical Care Society’s guideline for reversal of anti-thrombotic agents in intracranial hemorrhage in December 2015, AHA/ASA 2017 Consensus statement on the treatment of hemorrhagic transformation after intravenous alteplase in acute ischemic stroke, or publication of the updated 2018 AHA/ASA Guidelines for the early management of patients with acute ischemic stroke.8,9,23 In our patient population, the median increase in fibrinogen at 24 hours was 73 mg/dL after a median dose of fibrinogen concentrate of 2,198 mg. However, upon post hoc subgroup analysis, increases in fibrinogen levels were more pronounced in the hypofibrinogenemic group compared to the non-hypofibrinogenemic group (median increase of 166 mg/dL versus 18 mg/dL, respectively). Fibrinogen concentrate did not result in a hyperfibrinogenemic state in patients with normal fibrinogen when used in the management of hemorrhages secondary to rt-PA administration, possibly due to an ongoing consumptive process in those patients with normal post rt-PA fibrinogen levels. Vandelli and colleagues evaluated 39 ischemic stroke patients with severe hypofibrinogenemia after rt-PA, 25.6% of which had symptomatic ICH, who received fibrinogen concentrate therapy to normalize serum fibrinogen.24 Similar to our findings, serum fibrinogen increased from a median of 133 mg/dL (range 18-231) pre-fibrinogen concentrate administration to a median of 160.5 mg/dL (range 56-337) post-fibrinogen concentrate administration. Two patients experienced thromboembolic events after administration, with unclear onset.\n\nAdditional agents have been explored in case reports for the management of rt-PA related hemorrhage, such as tranexamic acid and aminocaproic acid. These agents competitively inhibit activation of plasminogen to plasmin compared to direct fibrinogen replenishment. Tranexamic acid has been associated with decreased hematoma expansion in ICH not associated with rt-PA administration and may be a useful adjunct agent.7,25 Four patients in our study received adjunct tranexamic acid or aminocaproic acid, 2 of whom had hemorrhage expansion on repeat imaging. While the use of antifibrinolytic agents is recommended when cryoprecipitate cannot be administered within a reasonable timeframe, the role of concurrent antifibrinolytic agents or platelet transfusions with fibrinogen products remains unclear.8\n\n\nIn addition to rt-PA induced coagulopathy, reperfusion of ischemic vasculature and damage to the blood brain barrier secondary to activation of matrix metalloproteinases in the setting of ischemia may also play a role in the risk for ICH after rt-PA administration.26 While there is much to be discovered in the pathophysiology of hemorrhagic complications following rt-PA administration, utilization of products containing fibrinogen has become standard practice. Further investigations are warranted to determine optimal agents and the role of adjunct treatments. Fibrinogen concentrate appears to be a promising alternative to cryoprecipitate in this patient population.\n\nThis descriptive report has several limitations. This was a single-center retrospective analysis with a small sample size. Many patients received thrombolysis at an outside facility, and records were based on transfer documents, limiting our baseline demographic knowledge. In addition, baseline fibrinogen prior to rt-PA administration was often not collected at outside institutions. Because most patients received rt-PA at an outside institution and transferred, we were unable to determine the true incidence of post rt-PA hemorrhage or capture the quantity of patients who received rt-PA within the study period through medication dispense reports. Additionally, our institution established a standardized protocol for the management of symptomatic ICH after rt-PA administration utilizing fibrinogen concentrate as the primary treatment modality in 2013, not all patients were treated uniformly over the study period. Some patients received both cryoprecipitate and fibrinogen concentrate, limiting our ability to assess the effect of fibrinogen concentrate alone. Lastly, our population consists mostly of patients with thrombolysis-associated ICH with only 2 isolated extra-cranial hemorrhages, and therefore our interpretations are limited to this patient group. Due to the heterogeneous patient population and small sample size, the effectiveness of fibrinogen concentrate therapy could not be inferred. Furthermore, the institutional guideline (Supplemental Figure 1) was developed through expert opinion based on limited data available in this patient population. Despite these limitations, we believe our study provides further insight into the management of rt-PA induced hemorrhage, a rare but serious complication of thrombolytic treatment. There are limited data to guide clinicians in the optimal agents to manage these patients and this study highlights our experience using fibrinogen concentrate with or without adjunctive agents as empiric therapy.\n\nConclusion\nOur study found fibrinogen concentrate to be a safe alternative therapeutic option for restoring fibrinogen levels in ischemic stroke patients with post rt-PA hypofibrinogenemia complicated by hemorrhage. Fibrinogen concentrate administration did not induce a hyperfibrinogenemic state in patients without initial hypofibrinogenemia. Most patients who were treated with fibrinogen concentrate had stable hemorrhages at 24 hours. Further research is required to determine the efficacy of fibrinogen concentrate in comparison to alternative therapies in the treatment of patients with post rt-PA hemorrhage.\n\nSupplemental Material\nSupplemental Material, MBarra_CATH_Fibrinogen_Concentrate_STROBE_checklist_ - Fibrinogen Concentrate for the Treatment of Thrombolysis-Associated Hemorrhage in Adult Ischemic Stroke Patients\nClick here for additional data file.\n\nSupplemental Material, MBarra_CATH_Fibrinogen_Concentrate_STROBE_checklist_ for Fibrinogen Concentrate for the Treatment of Thrombolysis-Associated Hemorrhage in Adult Ischemic Stroke Patients by Megan E. Barra, Steven K. Feske, Katelyn W. Sylvester, Charlene Ong, Sarah E. Culbreth, Patricia Krause, Galen V. Henderson and Eva Rybak in Clinical and Applied Thrombosis/Hemostasis\n\n Supplemental Material, MBarra_CATH_Fibrinogen_Concentrate_Supplemental_Figure_1 - Fibrinogen Concentrate for the Treatment of Thrombolysis-Associated Hemorrhage in Adult Ischemic Stroke Patients\nClick here for additional data file.\n\nSupplemental Material, MBarra_CATH_Fibrinogen_Concentrate_Supplemental_Figure_1 for Fibrinogen Concentrate for the Treatment of Thrombolysis-Associated Hemorrhage in Adult Ischemic Stroke Patients by Megan E. Barra, Steven K. Feske, Katelyn W. Sylvester, Charlene Ong, Sarah E. Culbreth, Patricia Krause, Galen V. Henderson and Eva Rybak in Clinical and Applied Thrombosis/Hemostasis\n\n Supplemental Material, MBarra_CATH_Fibrinogen_Concentrate_Supplemental_Table_E1 - Fibrinogen Concentrate for the Treatment of Thrombolysis-Associated Hemorrhage in Adult Ischemic Stroke Patients\nClick here for additional data file.\n\nSupplemental Material, MBarra_CATH_Fibrinogen_Concentrate_Supplemental_Table_E1 for Fibrinogen Concentrate for the Treatment of Thrombolysis-Associated Hemorrhage in Adult Ischemic Stroke Patients by Megan E. Barra, Steven K. Feske, Katelyn W. Sylvester, Charlene Ong, Sarah E. Culbreth, Patricia Krause, Galen V. Henderson and Eva Rybak in Clinical and Applied Thrombosis/Hemostasis\n\n Authors’ Note: Ethical approval to report this case series was obtained from Brigham and Women’s Hospital (Protocol Number 2016P002079). Informed consent for patient information to be published in this article was not obtained because a wavier of consent was approved by the Brigham and Women’s Hospital Institutional Review Board.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nORCID iD: Megan E. Barra \nhttps://orcid.org/0000-0002-7696-1540\n\n\nSupplemental Material: Supplemental material for this article is available online.\n==== Refs\nReferences\n1 \nGross H Guilliams KP Sung G \nEmergency neurological life support: acute ischemic stroke\n. Neurocritical Care . 2015 ;23 (suppl 2 ):S94 –102\n.26438453 \n2 \nAlbers GW Olivot JM \nIntravenous alteplase for ischaemic stroke\n. Lancet . 2007 ;369 (9558 ):249 –250\n.17258646 \n3 \nTrouillas P Derex L Philippeau F , et al.\nEarly fibrinogen degradation coagulopathy is predictive of parenchymal hematomas in cerebral rt-PA thrombolysis: a study of 157 cases\n. Stroke . 2004 ;35 (6 ):1323 –1328\n.15105521 \n4 \nMatrat A De Mazancourt P Derex L , et al.\nCharacterization of a severe hypofibrinogenemia induced by alteplase in two patients thrombolysed for stroke\n. Thromb Res . 2013 ;131 (1 ):e45 –48\n.23199548 \n5 \nSane DC Califf RM Topol EJ Stump DC Mark DB Greenberg CS \nBleeding during thrombolytic therapy for acute myocardial infarction: mechanisms and management\n. Ann Intern Med . 1989 ;111 (12 ):1010 –1022\n.2688504 \n6 \nAlonso A Dempfle CE Szabo K Zohsel K Hennerici MG \nDrop of PT Quick percent value is associated with both symptomatic and asymptomatic intracranial hemorrhage in patients treated with rt-PA for acute ischemic stroke\n. Thromb Res . 2011 ;127 (1 ):65 –66\n.20537372 \n7 \nYaghi S Eisenberger A Willey JZ \nSymptomatic intracerebral hemorrhage in acute ischemic stroke after thrombolysis with intravenous recombinant tissue plasminogen activator: a review of natural history and treatment\n. JAMA Neurol . 2014 ;71 (9 ):1181 –1185\n.25069522 \n8 \nFrontera J \nGuideline for reversal of antithrombotics in intracranial hemorrhage\n. Neurocritical care . 2016 ;24 :6 –46\n.26714677 \n9 \nPowers WJ Rabinstein AA Ackerson T , et al.\n2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professions from the American Heart Association/American Stroke Association\n. Stroke . 2018 ;49 (3 ):e46 –e110\n.29367334 \n10 \nSorensen B Bevan D \nA critical evaluation of cryoprecipitate for replacement of fibrinogen\n. Br J Haematol . 2010 ;149 (6 ):834 –843\n.20456356 \n11 \nAABB ARC, America’s Blood Centers, Armed Services Blood Program . Circular of information for the use of human blood and blood components\n. AABB , 2017 .\n12 \nSoloman C Groner A Ye J Pendrak I \nSafety of fibrinogen concentrate: analysis of more than 27 years of pharmacovigilance data\n. Thromb Haemost . 2015 ;113 (4 ):759 –771\n.25502954 \n13 \nHacke W Kaste M Fieschi C , et al.\nRandomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators\n. Lancet. \n1998 ;352 (9136 ):1245 –1251\n.9788453 \n14 \nBilecen S de Groot JA Kalkman CJ , et al.\nEffect of fibrinogen concentrate on intraoperative blood loss among patients with intraoperative bleeding during high-risk cardiac surgery: a randomized clinical trial\n. JAMA . 2017 ;317 (7 ):738 –747\n.28241354 \n15 \nRinde LB Småbrekke B Mathiesen EB , et al.\nIschemic stroke and risk of venous thromboembolism in the general population: the Tromsø Study\n. J Am Heart Assoc . 2016 ;5 (11 ):e004311 .27821402 \n16 \nWikkelsø AJ Edwards HM Afshari A , et al.\nPre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial\n. Br J Anaesth . 2015 ;114 (4 ):623 –633\n.25586727 \n17 \nHuang X Moreton FC Kalladka D , et al.\nCoagulation and fibrinolytic activity of tenecteplase and alteplase in acute ischemic stroke\n. Stroke . 2015 ;46 (12 ):3543 –3546\n.26514192 \n18 \nYaghi S Boehme AK Dibu J , et al.\nTreatment and outcome of thrombolysis-related hemorrhage: a multicenter retrospective study\n. JAMA Neurol . 2015 ;72 (12 ):1451 –1457\n.26501741 \n19 \nMatosevic B Knoflach M Werner P , et al.\nFibrinogen degradation coagulopathy and bleeding complications after stroke thrombolysis\n. Neurology . 2013 ;80 (13 ):1216 –1224\n.23486872 \n20 \nSaver JL \nHemorrhage after thrombolytic therapy for stroke: the clinically relevant number needed to harm\n. Stroke . 2007 ;38 (8 ):2279 –2283\n.17641238 \n21 \nFranchini M Lippi G \nFibrinogen replacement therapy: a critical review of the literature\n. Blood Transfu . 2012 ;10 (1 ):23 –27\n.\n22 \nDanes AF Cuenca LG Bueno SR Mendarte Barrenechea L Ronsano JB \nEfficacy and tolerability of human fibrinogen concentrate administration to patients with acquired fibrinogen deficiency and active or in high-risk severe bleeding\n. Vox Sang . 2008 ;94 (3 ):221 –226\n.18179679 \n23 \nYaghi S Willey JZ Cucchiara B , et al.\nTreatment and outcome of hemorrhagic transformation after intravenous alteplase in acute ischemic stroke\n. Stroke . 2017 ;48 (12 ):343 –361\n.\n24 \nVandelli L Marietta M Trenti T , et al.\nFibrinogen concentrate replacement in ischemic stroke patients after recombinant tissue plasminogen activator treatment\n. Adv Clin Exp Med . 2019 ;28 (2 ):219 –222\n.30507073 \n25 \nFrench KF White J Hoesch RE \nTreatment of intracerebral hemorrhage with tranexamic acid after thrombolysis with tissue plasminogen activator\n. Neurocrit Care . 2012 ;17 (1 ):107 –111\n.22311234 \n26 \nLeigh R Jen SS Hillis AE Krakauer JW Barker PB \nPretreatment blood-brain barrier damage and post-treatment intracranial hemorrhage in patients receiving intravenous tissue-type plasminogen activator\n. Stroke . 2014 ;45 (7 ):2030 –2035\n.24876245\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1076-0296",
"issue": "26()",
"journal": "Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis",
"keywords": "cerebral infarction; fibrinogen; hemostasis; intracerebral hemorrhage; stroke; thrombolysis",
"medline_ta": "Clin Appl Thromb Hemost",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia; D005260:Female; D005340:Fibrinogen; D006801:Humans; D000083242:Ischemic Stroke; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "9508125",
"other_id": null,
"pages": "1076029620951867",
"pmc": null,
"pmid": "32946279",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "25586727;25502954;27821402;26514192;17258646;28241354;23486872;26438453;29367334;9788453;22153684;18179679;22311234;26501741;26714677;29097489;20537372;23199548;2688504;30507073;25069522;15105521;17641238;20456356;24876245",
"title": "Fibrinogen Concentrate for the Treatment of Thrombolysis-Associated Hemorrhage in Adult Ischemic Stroke Patients.",
"title_normalized": "fibrinogen concentrate for the treatment of thrombolysis associated hemorrhage in adult ischemic stroke patients"
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"abstract": "Chlorpheniramine is a widely prescribed H1-antihistamine for relieving urticaria or histamine-mediated allergic reactions. However, although rare, it may cause immediate hypersensitivity reactions. The diagnosis is usually made by provocation test, but its application is often limited due to comorbidities or potential risk of severe reactions. In those cases, skin tests and basophil activation tests can be considered as additional diagnostic tests for the drug allergy. Here, we report a 33-year-old female with underlying chronic urticaria, who recurrently developed anaphylaxis after chlorpheniramine administration. Intradermal test showed positive responses in the patient at 0.02 mg/mL of chlorpheniramine, but not in healthy controls. Basophil activation test showed significant up-regulation of CD63 and CD203c by chlorpheniramine. The present case reminds the rare but potential allergic risk of chlorpheniramine, and also suggests the potential utility of basophil activation test in making the diagnosis.",
"affiliations": "Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea. ; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 110-799, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea. ; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 110-799, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea. ; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 110-799, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea. ; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 110-799, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea. ; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 110-799, Korea.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea. ; Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 110-799, Korea.;Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang 410-773, Korea.",
"authors": "Lee|Hyun-Seung|HS|;Song|Woo-Jung|WJ|;Lee|Ji-Won|JW|;Cho|Young-Yoon|YY|;Park|Han-Ki|HK|;Kang|Min-Gyu|MG|;Cho|Sang-Heon|SH|;Sohn|Seong-Wook|SW|",
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"country": "Korea (South)",
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"doi": "10.5415/apallergy.2015.5.3.177",
"fulltext": "\n==== Front\nAsia Pac AllergyAsia Pac AllergyAPAAsia Pacific Allergy2233-82762233-8268Asia Pacific Association of Allergy, Asthma and Clinical Immunology 10.5415/apallergy.2015.5.3.177Hypothesis & ExperienceChlorpheniramine-induced anaphylaxis diagnosed by basophil activation test Lee Hyun-Seung 12†Song Woo-Jung 12†Lee Ji-Won 12Cho Young-Yoon 1Park Han-Ki 12Kang Min-Gyu 12Cho Sang-Heon 12Sohn Seong-Wook 31 Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.2 Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 110-799, Korea.3 Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang 410-773, Korea.\nCorrespondence: Seong-Wook Sohn. Department of Internal Medicine, Dongguk University Ilsan Hospital, 27, Donggung-ro, Ilsandong-gu, Goyang 410-773, Korea. Tel: +82-31-961-7148, Fax: +82-31-961-8449, seongwook@dumc.or.kr†Hyun-Seung Lee and Woo-Jung Song contributed equally to this article.\n\n7 2015 29 7 2015 5 3 177 180 22 6 2015 08 7 2015 Copyright © 2015. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Chlorpheniramine is a widely prescribed H1-antihistamine for relieving urticaria or histamine-mediated allergic reactions. However, although rare, it may cause immediate hypersensitivity reactions. The diagnosis is usually made by provocation test, but its application is often limited due to comorbidities or potential risk of severe reactions. In those cases, skin tests and basophil activation tests can be considered as additional diagnostic tests for the drug allergy. Here, we report a 33-year-old female with underlying chronic urticaria, who recurrently developed anaphylaxis after chlorpheniramine administration. Intradermal test showed positive responses in the patient at 0.02 mg/mL of chlorpheniramine, but not in healthy controls. Basophil activation test showed significant up-regulation of CD63 and CD203c by chlorpheniramine. The present case reminds the rare but potential allergic risk of chlorpheniramine, and also suggests the potential utility of basophil activation test in making the diagnosis.\n\nDrug HypersensitivityAnaphylaxisBasophilsMinistry of Health and WelfareA092076\n==== Body\nINTRODUCTION\nChlorpheniramine is one of the most classical H1-antihistamines, primarily prescribed for histamine-mediated hypersensitivity reactions such as urticaria. In the literature, cases have been rarely reported for chlorpheniramine-induced immediate hypersensitivity reactions [12], even when including pheniramine [3] or dexchlorpheniramine [456]. The mechanisms are still unclear, but IgE-mediated mechanisms have been suggested. The diagnosis is made by a drug provocation test (DPT), but may be supported by skin tests or basophil activation test (BAT) in cases needed. BAT is a safe and useful in vitro test [7], and the clinical application is expanding in diagnosing drug hypersensitivity [8]. Here we report a case of chlorpheniramine-induced anaphylaxis, of which diagnosis has been supported by skin tests and BAT.\n\nCASE REPORT\nA 33-year-old female with underlying chronic urticaria developed anaphylaxis after intravenous chlorpheniramine injection. She had visited the Emergency Department for acute flare-up of urticaria, and had been given intravenous chlorpheniramine. However, about 10 minutes later, she suddenly developed abdominal discomfort, urticarial aggravation, dizziness and hypotension (blood pressure, 72/44 mm Hg). The reactions resolved after treatments with epinephrine, corticosteroids and saline hydration. Any previous history was denied regarding prior food allergy, syncope or hypotensive episodes. At discharge, she was prescribed oral medications including prednisolone, levocetirizine and chlorpheniramine. However, she redeveloped dizziness and urticarial aggravation immediately after taking the medications, and thus attended the allergy clinic for further investigations.\n\nIn allergen skin prick tests (SPTs) and multiple allergosorbent test system analyses, only house dust mites and dog allergens showed positive responses. None of tested food allergens were positive. Serum total IgE level was 113 kU/L. Autologous serum skin test was negative. Electrocardiogram and chest x-ray were normal.\n\nOral provocation test was considered to determine the causal relationship with chlorpheniramine, but it could not be carried out due to the patient's personal reasons. Therefore, skin tests were performed for H1-antihistamines that she had recently taken. No skin reactions developed with levocetirizine or fexofenadine (prick and intradermal concentrations: 1 mg/mL for levocetirizine and 2.5 mg/mL for fexofenadine). No skin responses developed in SPT for 2 mg/mL chlorpheniramine maleate; however, positive intradermal test (IDT) responses were elicited at 1:100 dilution (increased wheal by 3 mm × 3.5 mm). In healthy volunteers (n = 4), only slight flare (2 mm × 2 mm) but no wheal reactions developed at the 1:100 dilution (0.02 mg/mL). The original concentration of chlorpheniramine increased wheal sizes by ≥3 mm in both of patient and healthy controls.\n\nThe relationship with chlorpheniramine was further assessed by BAT, using a commercially available Flow-CAST highsens kit according to the manufacturer's instructions (Bühlmann Laboratories AG, Schönenbuch, Switzerland). Briefly, the Flow-CAST highsens determines the basophil activation by measuring the relative amount of CD63 and CD203c positive basophils among the total population of CCR3 positive basophils in whole blood [9]. We performed the BAT using two forms of chlorpheniramine (0.1 mg/mL); a raw form and a conjugated form with albumin. The conjugation process was carried out overnight before the BAT day, using Imject PharmaLink Immunogen Kit, according to the manufacturer's instructions (Pierce, Rockford, IL, USA). Briefly, the kit facilitates the coupling process between the drug and bovine serum albumin, via the Mannich reaction using formaldehyde. In the molecular structure of chlorpheniramine, a single hydrogen associated with the aryl carbon atom is likely to react in the Mannich reaction. The expression of activation markers was 38.5% by negative control, and 92.5% by positive control (anti-FcεRI monoclonal antibody). Interestingly, we found that the expression of basophil activation markers (CD63 or CD203c) was increased by the conjugated-chlorpheniramine (59.9%), but not by chlorpheniramine (38.1%) or albumin (42.2%) alone (Fig. 1). On the basis of her recurrent history and the investigation results, we diagnosed the patient to have chlorpheniramine-induced anaphylaxis.\n\nDISCUSSION\nThe present report describes a case with chlorpheniramine-induced anaphylaxis. The diagnosis was made on the basis of recurrent history, and supplemented by skin tests and BAT.\n\nIn general, DPT is necessary to identify a culprit drug. However, the test is potentially harmful, and thus the risk-benefit needs to be carefully assessed [10]. Recently, the diagnostic roles of skin tests or in vitro tests have been focused for drug allergy [7811]. They may not assess the causal relationships but only the sensitization, but have potentially wider clinical applications for their better safety. In the literature, several tests have been utilized for chlorpheniramine allergy [123456]. Oral or intramuscular provocation tests were performed in four cases [125], whereas skin tests were used in three cases [346].\n\nDespite that the precise mechanisms of chlorpheniramine allergy are unknown, skin tests and BAT could have potential diagnostic utility for the immediate hypersensitivity reactions. The first discussion point is the utility of skin tests in chlorpheniramine hypersensitivity. SPT and IDT are used for evaluating immediate allergic reactions; however, it is necessary to determine maximum nonirritating test concentration for excluding false positivity, particularly in IDT [11]. We found that chlorpheniramine has a potential irritating property at the concentration of 2 mg/mL, which is the usual concentration for intravenous administration. Therefore, we determined the skin test positivity at the 100-fold diluted concentration (0.02 mg/mL), which did not increase wheals in four healthy controls but only in the patient. The findings indicate that a skin irritating potential of chlorpheniramine should be considered in skin testing. In the literature, dexchlorpheniramine was reported as nonirritating at 1/100 dilution [6], but chlorpheniramine has not been reported in controls.\n\nAnother point is the performance of BAT. Until now, the clinical application of BAT in drug hypersensitivity has been limited to a few drugs such as beta-lactams, neuromuscular blocking agents, nonsteroidal anti-inflammatory drugs, or radiocontrast media [8]. One case has been reported for dexchlorpheniramine [4], but not for chlorpheniramine yet. We suppose that BAT has a potential utility for particular drugs which have skin irritating potency like fluoroquinolones [12]. Interestingly, we found that chlorpheniramine increased in vitro basophil activation particularly when conjugated with albumin. The findings should be further evaluated, and the immunogenic or haptenic structure should be clarified. However, there are recent reports which assessed the basophil activation by protein bound drugs [1314]. In this regard, we suggest that the conjugation with albumin might be a possible option when considering BAT for chlorpheniramine.\n\nDrug allergens usually induce lower activation% than inhalant or food allergens [15]. Therefore, the cutoff for drug BAT has been empirically recommended as the stimulation index (SI = allergen stimulation per negative control) ≥ 2. In this respect, it may be argued that the present case did not show positive results to chlorpheniramine (SI, 1.56). However, the patient showed enhanced baseline basophil activation (38.5% by negative control), which is more than 10 folds higher than the expected levels of 2-2.5%. We presume that the enhanced basophil activation was attributed to her underlying disorder-chronic urticaria, as the smaller findings were previously reported in those patients [16]. Collectively, we interpreted the basophil activation results (59.9% and SI 1.56 by the conjugated chlorpheniramine) to be positive.\n\nChlorpheniramine has been prescribed for more than several decades, and is still widely used for relieving urticaria or histamine-related reactions. Physicians should be aware that chlorpheniramine could occasionally be a cause for allergic reactions or fatal anaphylaxis. In addition, we suggest that BAT could be considered as a supplementary test for diagnosing chlorpheniramine allergy.\n\nACKNOWLEDGEMENTS\nThe study was supported by the grant A092076 from the Korea Healthcare Technology R & D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea.\n\nFig. 1 Basophil activation tests with chlorpheniramine. The bar results indicate the percentage of basophil activation markers CD63/CD203c after stimulation with positive control (anti-FcεRI monoclonal antibody), negative control (buffer), chlorpheniramine, carrier protein, or chlorpheniramine conjugated with carrier protein.\n==== Refs\n1 Kim MH Lee SM Lee SH Kwon HS Kim SH Cho SH Min KU Kim YY Chang YS A case of chlorpheniramine maleate-induced hypersensitivity with aspirin intolerance Allergy Asthma Immunol Res 2011 3 62 64 21217928 \n2 Lee SH Jung HS Yoon TY Chang EJ Kim MK Kim KS Allergic reaction to chlorpheniramine in a patient with aspirin-intolerant asthma Korean J Asthma Allergy Clin Immunol 2010 30 55 58 \n3 Kim YJ Choi JH Bang JS Suh MK Lee JW Kim TH A case of pheniramine maleate - aggravated chronic urticaria Korean J Dermatol 2000 38 1414 1415 \n4 Caceres Calle O Fernandez-Benitez M Allergy to dexchlorpheniramine: study of a case Allergol Immunopathol (Madr) 2004 32 306 309 15456628 \n5 Rodríguez del Río P Gonzalez-Gutierrez ML Sanchez-Lopez J Nunez-Acevedo B Bartolome Alvarez JM Martinez-Cocera C Urticaria caused by antihistamines: report of 5 cases J Investig Allergol Clin Immunol 2009 19 317 320 \n6 Thurot-Guillou C Bourrain JL Jacquier JP Beani JC Anaphylactic reaction to ranitidine and dexchlorpheniramine Eur J Dermatol 2007 17 170 171 17337410 \n7 Romano A Torres MJ Castells M Sanz ML Blanca M Diagnosis and management of drug hypersensitivity reactions J Allergy Clin Immunol 2011 127 3 Suppl S67 S73 21354502 \n8 Song WJ Chang YS Recent applications of basophil activation tests in the diagnosis of drug hypersensitivity Asia Pac Allergy 2013 3 266 280 24260732 \n9 McGowan EC Saini S Update on the performance and application of basophil activation tests Curr Allergy Asthma Rep 2013 13 101 109 23188565 \n10 Aberer W Bircher A Romano A Blanca M Campi P Fernandez J Brockow K Pichler WJ Demoly P European Network for Drug Allergy (ENDA) EAACI interest group on drug hypersensitivity Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations Allergy 2003 58 854 863 12911412 \n11 Brockow K Garvey LH Aberer W Atanaskovic-Markovic M Barbaud A Bilo MB Bircher A Blanca M Bonadonna B Campi P Castro E Cernadas JR Chiriac AM Demoly P Grosber M Gooi J Lombardo C Mertes PM Mosbech H Nasser S Pagani M Ring J Romano A Scherer K Schnyder B Testi S Torres M Trautmann A Terreehorst I ENDA/EAACI Drug Allergy Interest Group Skin test concentrations for systemically administered drugs: an ENDA/EAACI Drug Allergy Interest Group position paper Allergy 2013 68 702 712 23617635 \n12 Empedrad R Darter AL Earl HS Gruchalla RS Nonirritating intradermal skin test concentrations for commonly prescribed antibiotics J Allergy Clin Immunol 2003 112 629 630 13679828 \n13 Steiner M Harrer A Lang R Schneider M Ferreira T Hawranek T Himly M Basophil activation test for investigation of IgE-mediated mechanisms in drug hypersensitivity J Vis Exp 2011 55 pii: 3263 \n14 Mayorga C Andreu I Aranda A Dona I Montanez MI Blanca-Lopez N Ariza A Nuin E Blanca M Miranda MA Torres MJ Fluoroquinolone photodegradation influences specific basophil activation Int Arch Allergy Immunol 2013 160 377 382 23183272 \n15 De Week AL Sanz ML Gamboa PM Aberer W Bienvenu J Blanca M Demoly P Ebo DG Mayorga L Monneret G Sainte Laudy J Diagnostic tests based on human basophils: more potentials and perspectives than pitfalls II Technical issues J Investig Allergol Clin Immunol 2008 18 143 155 \n16 Vasagar K Vonakis BM Gober LM Viksman A Gibbons SP Jr Saini SS Evidence of in vivo basophil activation in chronic idiopathic urticaria Clin Exp Allergy 2006 36 770 776 16776678\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2233-8276",
"issue": "5(3)",
"journal": "Asia Pacific allergy",
"keywords": "Anaphylaxis; Basophils; Drug Hypersensitivity",
"medline_ta": "Asia Pac Allergy",
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"title": "Chlorpheniramine-induced anaphylaxis diagnosed by basophil activation test.",
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"abstract": "For sebaceous carcinoma (SC), a rare malignant tumor, no standard chemotherapy regimen for patients with distant metastasis has been studied. We experienced a case of eyelid SC with multiple lung metastases that responded to combination chemotherapy with carboplatin and paclitaxel with 11-month progression-free survival (PFS). This patient also responded to second-line treatment with docetaxel, another taxane, with 7-month PFS, resulting in at least 18 months of survival at the time of reporting. This report shows that taxane-based chemotherapy may be effective for advanced SC, for which no standard therapy has been established.",
"affiliations": "Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.;Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.;Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.;Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.;Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.;Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.;Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.;Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.;Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.;Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.;Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.;Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.;Department of Pathology, Teikyo University School of Medicine, Tokyo, Japan.;Department of Ophthalmology, Teikyo University School of Medicine, Tokyo, Japan.;Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.",
"authors": "Ota|Shuji|S|;Sakamoto|Takahiko|T|;Ochiai|Ryosuke|R|;Haruyama|Terunobu|T|;Ishihara|Masashi|M|;Natsume|Maika|M|;Fukasawa|Yoko|Y|;Tanzawa|Shigeru|S|;Usui|Ryo|R|;Honda|Takeshi|T|;Ichikawa|Yasuko|Y|;Watanabe|Kiyotaka|K|;Sasajima|Yuko|Y|;Mizota|Atsushi|A|;Seki|Nobuhiko|N|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. 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 10.1159/000493850cro-0012-0047Case ReportSuccessful Treatment with Taxane-Based Chemotherapy in Advanced Sebaceous Carcinoma: A Case Report and Literature Review Ota Shuji aSakamoto Takahiko aOchiai Ryosuke aHaruyama Terunobu aIshihara Masashi aNatsume Maika aFukasawa Yoko aTanzawa Shigeru aUsui Ryo aHonda Takeshi aIchikawa Yasuko aWatanabe Kiyotaka aSasajima Yuko bMizota Atsushi cSeki Nobuhiko a*aDivision of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, JapanbDepartment of Pathology, Teikyo University School of Medicine, Tokyo, JapancDepartment of Ophthalmology, Teikyo University School of Medicine, Tokyo, Japan*Nobuhiko Seki, MD, PhD, Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8606 (Japan), E-Mail nseki@med.teikyo-u.ac.jpJan-Apr 2019 11 1 2019 11 1 2019 12 1 47 52 13 9 2018 13 9 2018 2019 Copyright © 2019 by S. Karger AG, Basel2019This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.For sebaceous carcinoma (SC), a rare malignant tumor, no standard chemotherapy regimen for patients with distant metastasis has been studied. We experienced a case of eyelid SC with multiple lung metastases that responded to combination chemotherapy with carboplatin and paclitaxel with 11-month progression-free survival (PFS). This patient also responded to second-line treatment with docetaxel, another taxane, with 7-month PFS, resulting in at least 18 months of survival at the time of reporting. This report shows that taxane-based chemotherapy may be effective for advanced SC, for which no standard therapy has been established.\n\nKey Words\nSebaceous carcinomaTaxaneCarboplatinPaclitaxelDocetaxel\n==== Body\nIntroduction\nSebaceous carcinoma (SC) is a rare malignant tumor characterized by sebaceous differentiation [1]. SC is broadly classified into ocular SC, which is eyelid SC of meibomian gland or Zeis gland origin, and extraocular SC, which is SC of sebaceous gland origin [1]. Ocular SC most often originates from the meibomian gland, an independent sebaceous gland of the eyelid. By primary lesion, ocular SC accounts for approximately 75% of all cases, and extraocular SC accounts for approximately 25% [1]. While first-line therapy is surgical treatment, SC has been reported to be likely to recur or metastasize. Ginsberg et al. reported a metastasis rate of 17% and a local recurrence rate of 32% in 142 patients with ocular SC [2], and Bailet et al. reported a metastasis rate of 21% and a local recurrence rate of 29% in 91 patients with SC of the head and neck [3]. To date, no chemotherapy regimen has been established for SC with distant metastasis. According to the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute, there is no report of outcomes of chemotherapy for ocular SC with distant metastasis.\n\nHere, we report a case of eyelid SC with lung and subcutaneous metastases that responded to both first-line and second-line treatments with taxane-based chemotherapy, resulting in at least 18 months of long-term survival at the time of reporting.\n\nCase Report\nThis case was a 69-year-old female. Right eyelid tumor appeared and grew rapidly. A biopsy strongly indicated a pathological diagnosis of SC, leading to surgical resection (orbital exenteration). Given postoperative pathological findings of nests of polygonal tumor cells with highly heteromorphic nuclei and foamy lipid droplets, a final diagnosis of SC was made (Fig. 1).\n\nFour months after surgery, multiple lung metastases (Fig. 2a) and abdominal subcutaneous metastases occurred. Chemotherapy with carboplatin (AUC5) and paclitaxel (200 mg/m2) was started as combination therapy with platinum and taxane, which have been shown to be effective for adenocarcinomas of various origins. At the start of chemotherapy, performance status (PS) was 2. After the second cycle of chemotherapy, computed tomography (CT) for response assessment revealed a partial response (PR) with an at least 50% reduction in total maximum diameter of lung (Fig. 2b) and subcutaneous metastatic nodules. A total of 7 cycles of chemotherapy was given, at 3-weeks per cycle. Hematotoxicity was Grade 3 neutropenia, but febrile neutropenia did not occur, and non-hematological toxicity was Grade 1 peripheral nerve disorder. Nonetheless, treatment was well tolerated. Combination therapy with carboplatin and paclitaxel resulted in 11-month progression-free survival (PFS).\n\nLater, however, multiple lung metastatic nodules increased in number and grew, and multiple brain metastases occurred. Whole-brain irradiation was performed for the treatment of multiple brain metastases, resulting in disappearance of brain metastatic nodules. After whole-brain irradiation, second-line treatment with docetaxel (60 mg/m2) alone was administered. At the start of monotherapy, PS was 2. A total of 6 cycles was given, at 3-weeks per cycle. A PR was achieved with a 45% regression of multiple lung metastatic nodules. Hematotoxicity was Grade 4 neutropenia and Grade 3 febrile neutropenia; nonetheless, treatment was well tolerated.\n\nChemotherapy is currently suspended at the request of the patient. However, she has survived for 18 months with 7-month PFS after the start of docetaxel.\n\nDiscussion\nSebaceous carcinoma (SC) is classified into ocular SC and extraocular SC according to the primary lesion, and Russel et al. reported that ocular SC was more malignant [4]. In addition, Rao et al. reported that, among 104 patients with eyelid SC, all of 23 (22%) who died had distant metastasis, emphasizing the importance of distant metastasis control [5]. Our patient has successfully survived for a long period of time after combination therapy with carboplatin and paclitaxel and subsequent monotherapy with docetaxel, despite more malignant ocular SC with distant metastasis and active tumor as indicated by relapse at 4 months after surgery.\n\nTable 1 lists case reports of chemotherapy for SC with distant metastasis [6, 7, 8, 9, 10, 11, 12]. There were three reports, including one by Jung et al., of antitumor efficacy of platinum used in combination with 5-FU [10, 11, 12]. In addition, there were two reports, including one by Husain et al., of antitumor efficacy of platinum used in combination with taxane such as docetaxel or paclitaxel [8, 9]. Platinum and taxane have been shown to be effective for adenocarcinomas of various origins, including adenocarcinoma of unknown primary origin. In a comparative study of monotherapy with paclitaxel versus combination therapy with paclitaxel and carboplatin in lung adenocarcinoma, subgroup analysis in patients with PS 2 showed that combination therapy significantly prolonged overall survival (OS), with no significant difference in the incidence of febrile neutropenia or treatment-related mortality [13]. Therefore, our patient with PS 2, which appeared to indicate poor tolerability of combination therapy with CDDP and 5-FU, received combination therapy with carboplatin and paclitaxel. Combination therapy with carboplatin and paclitaxel resulted in PR, 11-month PFS, and at least 18 months of survival at the time of reporting. In addition, this patient had a PR to second-line treatment with docetaxel, another taxane, with 7-month PFS, suggesting that SC may be sensitive to taxanes.\n\nDue to rarity of SC, no standard chemotherapy regimen for patients with distant metastasis has been established. In clinical settings, therefore, these patients are treated based on reference to only a few case reports. Our current report shows that taxanes may be effective for SC. Availability of a wider range of effective chemotherapeutic options is beneficial for patients. Hence, this report may provide valuable information to clinicians in chemotherapy for SC with distant metastasis.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors have no conflicts of interest to disclose.\n\nFig. 1 In the surgical specimen, there were irregular nests of polygonal cells with heteromorphic nuclei. Some tumor cells had foamy cytoplasm, and sebaceous differentiation was observed (hematoxylin-eosin ×20).\n\nFig. 2 a: Chest computed tomography images show multiple lung metastases. b: After two cycles of chemotherapy with carboplatin and paclitaxel, all lung metastatic nodules regressed.\n\nTable 1 Case reports of systemic chemotherapy for sebaceous carcinoma\n\nAuthor (year)\tSex\tAge\tPrimary lesion\tChemotherapy\tRR\tPFS, months\tOS, months\t\nKoyama et al. [6] (1994)\tM\t47\tO\tDoxorubicin 50 mg/m2 and Cisplatin 75 mg/m2*1\tPR\t7\t7.8\t\n\t\nDe Leo et al. [7] (2006)\tF\t42\tEO\tCisplatin 80 mg/m2 and Gemcitabine 1250 mg/m2 (every 3 weeks)*2\tPD\tNA\t7.6\t\n\t\nHusain et al. [8] (2008)\tF\t50\tO\tCarboplatin and Docetaxel and Bevacizumab (dose was not clarified)\tPR\tNA*3\tNA\t\n\t\nJoshi et al. [9] (2012)\tM\t21\tEO\tCarboplatin (AUC5) and Paclitaxel 175 mg/m2 (every 3 weeks)\tCR\t6*4\tNA\t\n\t\nJung et al. [10] (2013)\tM\t66\tO\tCisplatin 75 mg/m2 and 5-FU 750 mg/m2 (daily for 5 days)*5\tresponse\tNA\tNA*6\t\n\t\n\tF\t59\tO\t\tresponse\tNA*7\tNA\t\n\t\nOrcurto et al. [11] (2014)\tM\t69\tEO\t5-FU 750 mg/m2 (daily for 4 days) and Cisplatin 100 mg/m2 and Docetaxel 75 mg/m2 (every 3 weeks)*8, *9\tCR\t20*10\tNA\t\n\t\nKumar et al. [12] (2015)\tF\t81\tO\tFOLFOX [oxaliplatin, 5-FU, and leucovorin]*11\tSD\t5\t17\t\n\t\nPresent report\tF\t80\tO\tCarboplatin (AUC5) and Paclitaxel 200 mg/m2 (every 3 weeks)\tPR\t11\t18\t\nO, ocular lesion; EO, extraocular lesion; RR, response rate; PFS, progression-free survival; OS, overall survival; M, male; F, female; PR, partial response; PD, progressive disease; SD, stable disease; NA, not available; AUC, area under the curve; 5-FU, 5-Fluorouracil.\n\n*1 Treatment schedule was not clarified.\n\n*2 In this case, docetaxel (25 mg/m2) weekly and 5-FU 200 mg/m2 daily were administered as the second-line treatment.\n\n*3 The patient underwent subtotal resection and radiotherapy for target lesion following chemotherapy.\n\n*4 At the time of reporting, the remission had been stable for 6 months.\n\n*5 Chemotherapy interval was not clarified.\n\n*6 At the time of reporting, the patient was under supportive care at 15 months after initial chemotherapy.\n\n*7 At the time of reporting, 3 months after initial chemotherapy, the patient was due for the fourth cycle of chemotherapy.\n\n*8 Due to myelosuppression, the decision was made to remove docetaxel from the regimen after the first cycle.\n\n*9 Treatment was subsequently maintained with single-agent capecitabine (1,000 mg/m2/day) on days 1–10 every 3 weeks.\n\n*10 At the time of reporting, the remission had been stable for over 20 months.\n\n*11 At the time of reporting, the patient was undergoing chemotherapy with paclitaxel at the second-line and gemcitabine at the third-line chemotherapy.\n==== Refs\nReferences\n1 Nelson BR Hamlet KR Gillard M Railan D Johnson TM Sebaceous carcinoma J Am Acad Dermatol 1995 7 33 (1) 1 15 7601925 \n2 Ginsberg J Present status of meibomian gland carcinoma Arch Ophthalmol 1965 2 73 (2) 271 7 14237799 \n3 Bailet JW Zimmerman MC Arnstein DP Wollman JS Mickel RA Sebaceous carcinoma of the head and neck. Case report and literature review Arch Otolaryngol Head Neck Surg 1992 11 118 (11) 1245 9 1418905 \n4 Russell WG Page DL Hough AJ Rogers LW Sebaceous carcinoma of meibomian gland origin. The diagnostic importance of pagetoid spread of neoplastic cells Am J Clin Pathol 1980 4 73 (4) 504 11 7369174 \n5 Rao NA Hidayat AA McLean IW Zimmerman LE Sebaceous carcinomas of the ocular adnexa: A clinicopathologic study of 104 cases, with five-year follow-up data Hum Pathol 1982 2 13 (2) 113 22 7076199 \n6 Koyama S Honda T Hayano T Shinozaki S Kubo K Kobayashi T [A case of lung metastasis from Meibomian gland carcinoma of eyelid with effective chemotherapy] Gan To Kagaku Ryoho 1994 12 21 (16) 2809 12 7993118 \n7 De Leo A Innocenzi D Onesti MG Potenza C Toscani M Scuderi N Extraocular sebaceous carcinoma in Muirr Torre Syndrome with unfavorable prognosis Cancer Chemother Pharmacol 2006 12 58 (6) 842 4 16699794 \n8 Husain A Blumenschein G Esmaeli B Treatment and outcomes for metastatic sebaceous cell carcinoma of the eyelid Int J Dermatol 2008 3 47 (3) 276 9 18289332 \n9 Joshi P Joshi A Norohna V Prabhash K Kane S D'cruz AK Sebaceous carcinoma and systemic chemotherapy Indian J Med Paediatr Oncol 2012 10 33 (4) 239 41 23580828 \n10 Jung YH Woo IS Kim MY Han CW Rha EY Palliative 5-fluorouracil and cisplatin chemotherapy in recurrent metastatic sebaceous carcinoma: case report and literature review Asia Pac J Clin Oncol 2016 3 12 (1) e189 93 23981285 \n11 Orcurto A Gay BE Sozzi WJ Gilliet M Leyvraz S Long-term remission of an aggressive sebaceous carcinoma following chemotherapy Case Rep Dermatol 2014 3 6 (1) 80 4 24748864 \n12 Kumar V Xu Y Unusual presentation of metastatic sebaceous carcinoma and its response to chemotherapy: is genotyping a right answer for guiding chemotherapy in rare tumours? Curr Oncol 2015 8 22 (4) e316 9 26300682 \n13 Lilenbaum RC Herndon JE 2nd List MA Desch C Watson DM Miller AA Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730) J Clin Oncol 2005 1 23 (1) 190 6 15625373\n\n",
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"title": "Successful Treatment with Taxane-Based Chemotherapy in Advanced Sebaceous Carcinoma: A Case Report and Literature Review.",
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"abstract": "Loperamide is an over-the-counter anti-diarrhoeal agent. In supratherapeutic doses, loperamide penetrates the blood-brain barrier, exceeds the efflux capacity of P-glycoprotein and binds to central opioid receptors. We report a case of a 33-year-old woman with a history of opioid abuse, who had a long-term excessive daily intake of loperamide in order to achieve a euphoric effect. Cardiac arrhythmias, respiratory depression and death have been reported in relation to excessive loperamide use.",
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"abstract": "Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a hypersensitivity reaction associated with a variety of drugs, mainly anticonvulsants, which is characterized by systemic symptoms and erythematous lesions, common to other toxicodermas. It is an uncommon clinical entity that requires a high suspicion by clinical staff given its varied initial presentation, and the fact that symptoms can overlap with those of other adverse cutaneous reactions to drugs. Without early diagnosis and appropriate treatment, mortality increases.We report the case of a 22-year-old patient with impaired neurodevelopment who received treatment with carbamazepine. Two months later he presented with general symptoms and skin erythematous lesions that began on his trunk. The patient received outpatient care with antihistamines and antipyretics without an appropriate response. His case progressed with increased skin lesions and systemic symptoms that met the diagnostic criteria for DRESS syndrome. He was hospitalized and received medical treatment according to recommended guidelines. The patient's condition improved as his symptoms and associated complications resolved. He was discharged with gradual clearing of the steroid therapy.",
"affiliations": "Hospital Marco Fidel Suárez, Bello, Colombia; Facultad de Medicina, Universidad Cooperativa de Colombia, Medellín, Colombia; Facultad de Medicina, Universidad Pontificia Bolivariana, Medellín, Colombia; Asociación de Toxicología Clínica Colombiana, Medellín, Colombia Grupo de Investigaciones Biomédicas UniRemington, Facultad de Ciencias de la Salud, Corporación Universitaria Remington, Medellín, Colombia. jorgeamarinc@gmail.com.",
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"abstract": "Resistance to EGFR tyrosin kinase inhibitors (TKI) inevitably occurs. Here it is reported the case of a young patient affected by lung adenocarcinoma harboring the L858R EGFR sensitive mutation. The patient developed multiple TKI resistance mechanisms: T790M EGFR resistance mutation, detected only on tumor cell-free DNA, squamous cell transformation and MET amplification, both detected on a tumor re-biopsy. The co-occurrence of squamous cell transformation and de novo MET amplification is an extremely rare event, and this case confirms how dynamic and heterogeneous can be the temporal and spatial tumor evolution under treatment pressure.",
"affiliations": "Unit of Pathological Anatomy, University Hospital of Pisa, Pisa, Italy.;Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy.;Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy.;General Pathology, University of Pisa, Pisa, Italy.;Unit of Pathological Anatomy, University Hospital of Pisa, Pisa, Italy.;Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy.;Unit of Pathological Anatomy, University Hospital of Pisa, Pisa, Italy.;Unit of Pneumology, University Hospital of Pisa, Pisa, Italy.;Unit of Pneumology, University Hospital of Pisa, Pisa, Italy.;Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy.;Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.",
"authors": "Bruno|Rossella|R|;Del Re|Marzia|M|;Cucchiara|Federico|F|;Petrini|Iacopo|I|;Alì|Greta|G|;Crucitta|Stefania|S|;Proietti|Agnese|A|;Valleggi|Simona|S|;Chella|Antonio|A|;Danesi|Romano|R|;Fontanini|Gabriella|G|",
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"doi": "10.3389/fonc.2021.674604",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.674604\nOncology\nCase Report\nMultiple Resistance Mechanisms to Tyrosine Kinase Inhibitors in EGFR Mutated Lung Adenocarcinoma: A Case Report Harboring EGFR Mutations, MET Amplification, and Squamous Cell Transformation\nBruno Rossella 1 †\n\nDel Re Marzia 2 †\n\nCucchiara Federico 2\n\nPetrini Iacopo 3\n\nAlì Greta 1\nCrucitta Stefania 2\n\nProietti Agnese 1\nValleggi Simona 4\n\nChella Antonio 4\nDanesi Romano 2\nFontanini Gabriella 5 *\n\n1 Unit of Pathological Anatomy, University Hospital of Pisa, Pisa, Italy\n2 Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy\n3 General Pathology, University of Pisa, Pisa, Italy\n4 Unit of Pneumology, University Hospital of Pisa, Pisa, Italy\n5 Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy\nEdited by: Giovanni Gaudino, University of Hawaii Cancer Center, United States\n\nReviewed by: Paola Francica, University of Bern, Switzerland; Luca Tamagnone, Institute for Cancer Research and Treatment (IRCC), Italy\n\n*Correspondence: Gabriella Fontanini, gabriella.fontanini@med.unipi.it\n†These authors have contributed equally to this work\n\nThis article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology\n\n11 6 2021\n2021\n11 67460401 3 2021\n27 5 2021\nCopyright © 2021 Bruno, Del Re, Cucchiara, Petrini, Alì, Crucitta, Proietti, Valleggi, Chella, Danesi and Fontanini\n2021\nBruno, Del Re, Cucchiara, Petrini, Alì, Crucitta, Proietti, Valleggi, Chella, Danesi and Fontanini\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nResistance to EGFR tyrosin kinase inhibitors (TKI) inevitably occurs. Here it is reported the case of a young patient affected by lung adenocarcinoma harboring the L858R EGFR sensitive mutation. The patient developed multiple TKI resistance mechanisms: T790M EGFR resistance mutation, detected only on tumor cell-free DNA, squamous cell transformation and MET amplification, both detected on a tumor re-biopsy. The co-occurrence of squamous cell transformation and de novo MET amplification is an extremely rare event, and this case confirms how dynamic and heterogeneous can be the temporal and spatial tumor evolution under treatment pressure.\n\nEGFR\nlung adenocarcinoma\ncase report\nmultiple resistance mechanisms\nMET amplification\nsquamous cell transformation\n==== Body\nIntroduction\n\nPatients with metastatic lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations benefit from tyrosine kinase inhibitors (TKI) treatment, but acquired resistance is inevitable (1, 2). Half of patients treated with first or second generation TKIs develops the EGFR secondary mutation T790M, being eligible for osimertinib second-line treatment (3). Besides T790M, pathways bypassing EGFR signaling and lineage transformation have been reported as resistance mechanisms, impacting on therapeutic assessment (4).\n\nHere, it is presented a case with a rare coexistence of different resistance mechanisms: squamous cell transformation and MET amplification.\n\nCase Presentation\n\nIn August 2017, a 38-year-old man, former smoker, with cervical pain irradiated to the thorax left side underwent a computerized tomography (CT) scan evaluation, showing bone metastases in multiple vertebras and left pleural effusion. Thorax and abdomen CT scan, brain Magnetic Resonance Imaging (MRI), and 18-fluorodeoxyglucose positron emission tomography (PET) demonstrated a 3 cm tumor of the left lung inferior lobe with metastatic lymph nodes of the pulmonary hilum and homolateral mediastinum. Metastases were present in liver (3 lesions), right adrenal gland, multiple bone locations and brain (multiple sites). A diagnosis of cT1cN2M1c, stage IVc lung adenocarcinoma was made.\n\nThe tumor was characterized by immunohistochemical (IHC) stain on cell-block from pleural effusion with anti-thyroid transcription factor (TTF-1) antibody (mouse monoclonal antibody; clone 8G7G3/1; Ventana Medical System - Roche, Monza, Italy), which showed a strong positive nuclear staining ( Figure 1 ). The evaluation of the mutational status of EGFR, KRAS proto-oncogene, GTPase (KRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and erb-b2 receptor tyrosine kinase 2 (HER2) genes was performed on the Sequenom MassArray platform using the Myriapod Lung Status kit (Diatech Pharmacogenetics, Jesi, Italy). Before DNA extraction and purification by the QIAamp DNA Mini Kit (Qiagen, Hilden, Germany), tissue enrichment for cancer cells was performed by manual macrodissection. The expression of CD274 molecule (PD-L1) and ALK receptor tyrosine kinase (ALK) was determined by IHC on the Ventana Medical System (Roche). The monoclonal primary antibody SP263 clone and the monoclonal primary antibody D5F3 clone were used for PD-L1 and ALK, respectively. The presence of gene fusions involving ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) (Break Probe ROS1 (6q22) Kreatech - Leica Biosystems, Amsterdam, Netherlands) and ret proto-oncogene (RET) (Break Probe RET (10q11) Kreatech - Leica Biosystems) was evaluated by fluorescence in situ hybridization (FISH). FISH tests were executed also to analyze the amplification of MET proto-oncogene, receptor tyrosine kinase (MET) (Probes: LSI MET spectrum red and CEP7 spectrum green – Vysis - Abbott, Illinois, USA) and HER2 (Probes: LSI HER2/neu spectrum orange and CEP17 spectrum green – Vysis, Abbott).\n\nFigure 1 Timeline and histological transformation. H&E: Hematossil and Eosin staining (magnification 20X). Immunohistochemistry analyses were performed using mouse monoclonal antibodies anti TTF-1 and p40, clone 8G7G3/1 and clone BC28 respectively, on the Ventana Medical System (Roche). Immonuhistochemistry images have been reported with a 20X magnification. Gene mutational analysis was performed by Sequenom MassArray at baseline, EGFR mutational status was determined by digital droplet PCR at progression times. ALK and PD-L1 were evaluated by immunohistochemistry and gene fusions and amplifications by fluorescent in situ hybridization. LUAD, lung adenocarcinoma; LUSC, lung squamous-cell carcinoma.\n\nThe sensitive EGFR mutation L858R, within exon 21, was detected and 10% of cancer cells expressed PD-L1 ( Figure 2 ). No other gene alterations were identified.\n\nFigure 2 Clinical Timeline. The immunohistochemistry evaluation of PD-L1 was performed using a monoclonal primary antibody SP263 clone on the Ventana Medical System (Roche). MET amplification was evaluated by fluorescence in situ hybridization using the probes: LSI MET spectrum red and CEP7 spectrum green (Vysis – Abbott). PR, partial response; SD, stable disease; PD, progression disease; NGS, Next Generation Sequencing; LUAD, lung adenocarcinoma; LUSC, lung squamous-cell carcinoma.\n\nIn September 2017, erlotinib treatment was started (150 mg/die) with zoledronate (4 mg every 28 days). In October, the patient completed the palliative radiotherapy on vertebral metastases of D9-11 (20 Gy in 10 fractions). After 2 months of treatment a partial response (PR) was observed with reduction of all disease localizations. EGFR mutational status in circulating tumor DNA (ctDNA) was evaluated every 3 months ( Figure 1 ). ctDNA was purified from 3 ml of plasma by the QIAamp Circulating kit (Qiagen) and EGFR was analyzed by the digital droplet PCR (Bio-Rad, Hercules, California, USA) with the PrimePCR™ ddPCR™ Mutation Assay for human EGFR. In January 2018, erlotinib dosage was reduced to 100 mg because of a grade 3 skin rush of the face, truncus and extremities (National Cancer Institute – Common Terminology Criteria for Adverse Events). The CT scan confirmed the PR and the ctDNA analysis highlighted a decrease of L858R amount ( Figures 1 and 2 ).\n\nIn May 2018, the patient presented with dyspnea and left hemithorax pain. A chest X-ray showed massive pleural effusion, an ultrasound-guided thoracentesis was performed. Tumor cells were not detected in the effusion, but ctDNA analysis revealed an increased L858R amount ( Figure 1 ). The radiological response was maintained until August 2018, when a CT scan documented a pleural metastasis enlargement with pleural effusion. MRI of liver metastasis and brain demonstrated an enlargement of the left prerolandic metastasis and disease meningeal diffusion. An ultrasound-guided thoracentesis was performed with a diagnosis of adenocarcinoma metastasis, TTF1 positive ( Figure 1 ). Cell-block from pleural effusion had a low percentage of tumor cells (<5%) and EGFR mutational status was evaluated by the same highly sensitive droplet PCR assay used for ctDNA analysis. On the pleural effusion only the L858R mutation was detected, whereas L858R sensitive and T790M resistance EGFR mutations were both detected on ctDNA. Therefore, in August 2018, the treatment was switched to osimertinib. However, the patient experienced thoracic pain and in October 2018 a CT scan demonstrated an oligoprogression of a sternal bone metastasis. A biopsy of the lesion showed a histological switch towards squamous cell carcinoma positive for tumor protein p63 (p40) (IHC was performed using a mouse monoclonal antibody, clone BC28, on the Ventana Medical System - Roche) and negative for TTF1, with PD-L1 expression observed in 60% of cancer cells ( Figure 2 ). MET amplification (MET/CEP7: 5,8 - cut-off<2; MET copy number: 16,6 – cut-off<5) and EGFR L858R mutation were detected on the squamous lesion ( Figure 2 ). The MRI showed the disappearance of brain metastases, and T790M mutation was no longer detectable in ctDNA, but the L858R amount increased. At the same time the ctDNA was analyzed also by Next Generation Sequencing (NGS) using the 56G Oncopanel (Diatech Pharmacogenetics) on a MiSeq platform (Illumina, San Diego, California, USA): the L858R mutation was confirmed (4.14 allele frequency) and a missense mutation, the S215R (4.73 allele frequency), within exon 6 of tumor protein p53 (TP53) gene was detected. The TP53 mutation was confirmed both on the first pleural effusion and on the squamous lesion specimens. The patient underwent radiotherapy for the sternal metastasis, he experienced a pulmonary embolism with type I respiratory failure, and he received low molecular weight heparin with progressive recovery of the respiratory failure. Osimertinib was continued with a stable disease until December 2018. The ctDNA analysis found an increased L858R amount, in January 2019 the patient expedited a severe headache with retro-orbital pain and a skull CT scan showed a large secondary cranio-facial lesion, treated with radiotherapy (30Gy, 5 fractions). In March 2019, the patient showed neurologic and clinical deterioration without radiologic evidence of encephalic disease progression. A CT scan demonstrated an increase of the sternal metastasis infiltrating the surrounding soft tissues and an enlargement of liver metastases. The patient discontinued osimertinib, and, being not eligible for a systemic chemotherapy, died in April 2019.\n\nDiscussion\n\nTKIs significantly improved survival of EGFR mutated lung adenocarcinoma patients, but acquired resistance inevitably occurs. While on-target resistance mutations are more common with first/second generation TKIs (i.e. EGFR T790M), by-pass signaling pathways are prevalent with osimertinib (4). During treatment, multiple resistance mechanisms can arise simultaneously, and their detection can be challenging because of tumor heterogeneity, thus having important implications for treatment strategies. Herein, we presented an interesting case with the unusual coexistence of three specific resistance mechanisms, underlining the complementary role of both liquid and solid biopsy to monitor tumor dynamics. In the described case resistance to erlotinib was observed after 12 months of treatment and was associated with T790M mutation detected only on ctDNA, which disappeared under osimertinib treatment, according to previous published data (4). However, the tumor progressed, and a fine-needle aspiration of the sternal metastasis revealed the squamous cell transformation and MET amplification. The squamous lesion retained the sensitive EGFR mutation L858R and the TP53 mutation S215R, suggesting the same clonal origin, without the T790M. The absence of T790M in the squamous lesion was confirmed also by digital droplet PCR. Considering that sternal lesion started progressing during the first line treatment, it is likely that both the squamous cell transformation and the MET amplification were already present, but not detectable, before osimertinib treatment. An important limitation of this case report is that it was not possible to determine MET status also on pleural effusion at erlotinib progression, because of the scarce available biological material.\n\nOverall, the identification of alterations driving acquired resistance can provide patients with new therapeutic perspectives. For instance, MET inhibitors, such as savolitinib and tepotinib have been synthetized for patients with EGFR mutations that acquire resistance to TKI through MET alterations (5, 6). Unfortunately, the combined use of EGFR and MET TKIs was not considered because patient’s clinical conditions did not leave room for further lines of treatment after osimertinib failure.\n\nAnother interesting aspect is the increased PD-L1 expression, which was 10% at baseline and raised to 60% in the sternal metastasis during osimertinib treatment, confirming that some EGFR-TKIs resistant lung tumors can express high levels of PD-L1. It has been proven that this can be favored by some resistance mechanisms, such as MET amplification (7). Peng and collaborators demonstrated that MET amplification can cause an upregulation of PD-L1 expression and favors immune escape ability of EGFR mutant cancer cells (7). However, few studies have deeply examined the connection between EGFR TKI resistance and PD-L1 expression, and, consequently, the role of immunotherapy in this setting of patients is still unclear. The temporal and spatial tumor evolution is highly dynamic, making the management of EGFR-TKI resistant tumors challenging. Here it is described a case of EGFR-TKI resistance driven by T790M mutation with the rare co-occurrence of squamous cell transformation, MET amplification, and increased PD-L1 expression, mirroring the high degree of tumor heterogeneity induced by treatment pressure. In addition, a TP53 mutation was detected: TP53 alterations often co-occur with EGFR mutations and have a negative impact on TKI response and patient’s prognosis (8).\n\nDespite the rare coexistence of multiple resistance mechanisms, response to first and second line EGFR TKIs was in good agreement with literature data (2, 3). Of course, squamous cell transformation is in itself associated with a poor prognosis and it is likely that MET amplification has greatly contributed to tumor progression.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nAuthor Contributions\n\nAll authors were involved in the clinical management of the presented case and participated in manuscript preparation. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n\n1 Passiglia F Pilotto S Facchinetti F Bertolaccini L Del Re M Ferrara R . Treatment of Advanced non-Small-Cell Lung Cancer: The 2019 AIOM (Italian Association of Medical Oncology) Clinical Practice Guidelines. Crit Rev Oncol Hematol (2019) 146 :102858. 10.1016/j.critrevonc.2019.102858 31918343\n2 Westover D Zugazagoitia J Cho BC Lovly CM Paz-Ares L . Mechanisms of Acquired Resistance to First- and Second-Generation EGFR Tyrosine Kinase Inhibitors. Ann Oncol (2018) 29 :i10–9. 10.1093/annonc/mdx703\n3 Andrews Wright NM Goss GD . Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for the Treatment of non-Small Cell Lung Cancer. Transl Lung Cancer Res (2019) 8 :S247–64. 10.21037/tlcr.2019.06.01.4\n4 Lee J Kim HS Lee B Kim HK Sun JM Ahn JS . Genomic Landscape of Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors in EGFR T790M-Mutant non-Small Cell Lung Cancer. Cancer (2020) 126 :2704–12. 10.1002/cncr.32809\n5 Shi P Oh YT Zhang G Yao W Yue P Li Y . Met Gene Amplification and Protein Hyperactivation is a Mechanism of Resistance to Both First and Third Generation EGFR Inhibitors in Lung Cancer Treatment. Cancer Lett (2016) 380 :494–504. 10.1016/j.canlet.2016.07.021 27450722\n6 Zhang Z Yang S Wang Q . Impact of MET Alterations on Targeted Therapy With EGFR-tyrosine Kinase Inhibitors for EGFR-mutant Lung Cancer. Biomark Res (2019) 7 :27. 10.1186/s40364-019-0179-6 31832192\n7 Peng S Wang R Zhang X Ma Y Zhong L Li K . Egfr-TKI Resistance Promotes Immune Escape in Lung Cancer Via Increased PD-L1 Expression. Mol Cancer (2019) 18 :165. 10.1186/s12943-019-1073-4 31747941\n8 Canale M Petracci E Delmonte A Chiadini E Dazzi C Papi M . Impact of TP53 Mutations on Outcome in EGFR -Mutated Patients Treated With First-Line Tyrosine Kinase Inhibitors. Clin Cancer Res (2017) 23 :2195–202. 10.1158/1078-0432.CCR-16-0966\n\n",
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"keywords": "EGFR; MET amplification; case report; lung adenocarcinoma; multiple resistance mechanisms; squamous cell transformation",
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"title": "Multiple Resistance Mechanisms to Tyrosine Kinase Inhibitors in EGFR Mutated Lung Adenocarcinoma: A Case Report Harboring EGFR Mutations, MET Amplification, and Squamous Cell Transformation.",
"title_normalized": "multiple resistance mechanisms to tyrosine kinase inhibitors in egfr mutated lung adenocarcinoma a case report harboring egfr mutations met amplification and squamous cell transformation"
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"abstract": "The purpose of this study was to describe the local experience in terms of drug efficacy and safety using a new xanthine oxidase inhibitor, febuxostat, as a second-line urate-lowering therapy (ULT) in gout patients with normal renal function and chronic kidney disease.\nThis cross-sectional study included all gout patients who attended the rheumatology clinic from January 2013 to June 2018 and had received febuxostat as a second-line ULT. Analysis focused on the proportion of gout patients who achieved target serum urate (sUA) of <360 μmol/L, duration taken to achieve target sUA, and febuxostat dosage at achievement of target sUA. Safety assessments included comparison of serum creatinine, estimated glomerular filtration rate (eGFR), and serum alanine aminotransferase (ALT) at baseline, at achievement of target sUA, and at 12-monthly intervals.\nMajority (90.9%) of patients achieved target sUA. Median duration required to achieve target sUA was 5.5 months with IQR (interquartile range) of 8.5. Five (22.7%) patients achieved target sUA within one month of therapy with febuxostat 40 mg per day. Eleven (55%) patients achieved target sUA within six months and 16 (80%) by 12 months. Equal proportion of patients achieved target sUA with febuxostat 40 mg per day and 80 mg per day, respectively. There was no significant difference in the changes in serum creatinine level, eGFR and ALT from baseline and at achievement of target sUA, nor at 12-monthly intervals throughout the duration of febuxostat therapy. Apart from three patients who developed hypersensitivity reactions to febuxostat, no other adverse events were reported.\nA significant proportion of gout patients with CKD managed to achieve target sUA with a lower dose of febuxostat at 40 mg per day and it is reasonable to maintain this dose for up to six months before considering dose escalation.",
"affiliations": "MD, MRCP, Rheumatology Unit, Department of Medicine, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia Email: ongsweeg@gmail.com.;MBChB, MRCP, Rheumatology Unit, Department of Medicine, Kuala Lumpur Hospital, Jalan Pahang, Kuala Lumpur, Malaysia.",
"authors": "Ong|Swee Gaik|SG|;Ding|Hui Jen|HJ|",
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"keywords": "febuxostat; gout; second-line; urate-lowering therapy",
"medline_ta": "Malays Fam Physician",
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"title": "A single-centre experience of febuxostat as a second-line urate-lowering therapy.",
"title_normalized": "a single centre experience of febuxostat as a second line urate lowering therapy"
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"abstract": "Beta-blockers are widely prescribed in elderly patients and may induce severe adverse drug reactions. We report a case of bisoprolol-induced bradycardia in an elderly patient with impaired renal function and use of cytochrome P450 inhibitors. A literature review has been performed in order to analyze pharmacokinetic risk factors of beta-blockers overdosing in geriatrics. Various mechanisms can result in decreased elimination of beta-blockers. These mechanisms vary according to the beta-blocker agent and may be combined in some individuals, especially elderly patients. This can lead to unexpected overexposure. Knowledge about drug interactions and pharmacokinetic elimination pathways is important for preventing overexposure and adverse drug reactions when using beta-blockers.",
"affiliations": "Service pharmaceutique, centre hospitalier Pierre-Garraud, groupement hospitalier Nord, hospices civils de Lyon, 136, rue Commandant-Charcot, 69005 Lyon, France. Electronic address: l.lafarge@sfr.fr.;Service pharmaceutique, centre hospitalier Pierre-Garraud, groupement hospitalier Nord, hospices civils de Lyon, 136, rue Commandant-Charcot, 69005 Lyon, France; ISPB, faculté de pharmacie de Lyon, université de Lyon-1, 69008 Lyon, France; UMR CNRS 5558, laboratoire de biométrie et biologie évolutive, université Lyon-1, 69100 Villeurbanne, France.;Centre régional de pharmacovigilance, hospices civils de Lyon, 162, avenue Lacassagne, 69003 Lyon, France.;Centre régional de pharmacovigilance, hospices civils de Lyon, 162, avenue Lacassagne, 69003 Lyon, France.;Gériatrie, centre hospitalier Pierre-Garraud, groupement hospitalier Nord, hospices civils de Lyon, 136, rue Commandant-Charcot, 69005 Lyon, France.;Gériatrie, centre hospitalier Pierre-Garraud, groupement hospitalier Nord, hospices civils de Lyon, 136, rue Commandant-Charcot, 69005 Lyon, France.;Service pharmaceutique, centre hospitalier Pierre-Garraud, groupement hospitalier Nord, hospices civils de Lyon, 136, rue Commandant-Charcot, 69005 Lyon, France; ISPB, faculté de pharmacie de Lyon, université de Lyon-1, 69008 Lyon, France; UMR CNRS 5558, laboratoire de biométrie et biologie évolutive, université Lyon-1, 69100 Villeurbanne, France.",
"authors": "Lafarge|L|L|;Bourguignon|L|L|;Bernard|N|N|;Vial|T|T|;Dehan-Moya|M-J|MJ|;De La Gastine|B|B|;Goutelle|S|S|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D017298:Bisoprolol",
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"title": "Pharmacokinetic risk factors of beta-blockers overdose in the elderly: Case report and pharmacology approach.",
"title_normalized": "pharmacokinetic risk factors of beta blockers overdose in the elderly case report and pharmacology approach"
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"abstract": "Autism comprises a growing segment of the population and can be a management challenge in the intensive care unit (ICU). We present the case of a 22-year-old male with severe autism and intellectual disorder who developed respiratory failure and required a prolonged ICU course. This patient exhibited severe distress, aggression, and self-injurious behavior. Management challenges included sedation, weaning from sedation, and liberation from mechanical ventilation. Success was achieved with a multispecialty team and by tailoring the environment and interactions to the patient's known preferences. The use of dexmedetomidine to wean high-dose benzodiazepines and opiates also permitted successful liberation from mechanical ventilation.",
"affiliations": "Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.",
"authors": "Hsieh|Emily|E|;Oh|Scott S|SS|;Chellappa|Parkavi|P|;Szeftel|Roxy|R|;Jones|Heather D|HD|",
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"keywords": "acute respiratory distress syndrome (ARDS); autism; dexmedetomidine; intensive care unit",
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"pmc": null,
"pmid": "23753225",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of autism in the adult intensive care unit.",
"title_normalized": "management of autism in the adult intensive care unit"
} | [
{
"companynumb": "US-TEVA-517240USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": null,
"druga... |
{
"abstract": "DRESS syndrome is an idiosyncratic reaction to drugs, which can occur in both adults and children. To date there is no agreed upon criteria for its diagnosis; there is even less consensus on its management. We report the case of a 14- year-old boy with carbamazepine induced DRESS syndrome, predominantly involving the liver. He responded rapidly to high dose pulsed intravenous corticosteroids.",
"affiliations": "Queensland Institute of Dermatology Greenslopes.",
"authors": "Teng|Paul|P|;Tan|Boon|B|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000927:Anticonvulsants; D004643:Emollients; D005446:Fluocinolone Acetonide; D002220:Carbamazepine; D014580:Ursodeoxycholic Acid; D008899:Mineral Oil; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "19(5)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000293:Adolescent; D000893:Anti-Inflammatory Agents; D000927:Anticonvulsants; D001930:Brain Injuries; D002220:Carbamazepine; D063926:Drug Hypersensitivity Syndrome; D004359:Drug Therapy, Combination; D004643:Emollients; D005446:Fluocinolone Acetonide; D006529:Hepatomegaly; D006801:Humans; D008297:Male; D008775:Methylprednisolone; D008899:Mineral Oil; D020551:Pulse Therapy, Drug; D012640:Seizures; D012867:Skin; D014580:Ursodeoxycholic Acid",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": "18170",
"pmc": null,
"pmid": "24011271",
"pubdate": "2013-05-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Carbamazepine-induced DRESS syndrome in a child: rapid response to pulsed corticosteroids.",
"title_normalized": "carbamazepine induced dress syndrome in a child rapid response to pulsed corticosteroids"
} | [
{
"companynumb": "AU-ACTAVIS-2014-24546",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report cases of acute serous macular detachment and edema after uncomplicated phacoemulsification.\n\n\nMETHODS\nRetrospective case series.\n\n\nMETHODS\nWe reviewed the clinical data of 5 patients who developed an acute serous macular detachment and edema after uncomplicated phacoemulsification with intraocular lens implantation by the same expert surgeon and without any complication during surgery.\n\n\nMETHODS\nBest corrected visual acuity (BCVA), biomicroscopy, fundus examination, and optical coherence tomography were performed at 1, 3, 7, and 30 postoperative days.\n\n\nRESULTS\nOn the first postoperative day, all eyes had low visual acuity (median 1.0 logMAR) despite normal postoperative appearance of the anterior segment. Optical coherence tomography showed serous macular detachment with intraretinal fluid accumulation. After treatment with oral indomethacin and acetazolamide, at 7 days, intraretinal and subretinal fluid were fully reabsorbed and BCVA improved (at least 0.1 logMAR). In the following 6 months, no eye had recurrence of macular edema.\n\n\nCONCLUSIONS\nAcute serous macular detachment and edema can occur after uncomplicated phacoemulsification. It should be considered in cases of low visual acuity during the early postoperative period.",
"affiliations": "Eye Clinic, University of Catania, Catania, Italy.;Eye Clinic, University of Catania, Catania, Italy. Electronic address: mreibaldi@libero.it.;Eye Clinic, University of Catania, Catania, Italy.;Eye Clinic, University of Catania, Catania, Italy.;Eye Clinic, University of Catania, Catania, Italy.;Eye Clinic, University of Catania, Catania, Italy.;Eye Clinic, University of Catania, Catania, Italy.;Eye Clinic, University of Catania, Catania, Italy.;Eye Clinic, University of Catania, Catania, Italy.",
"authors": "Longo|Antonio|A|;Reibaldi|Michele|M|;Uva|Maurizio G|MG|;Bonfiglio|Vincenza|V|;Strano|Maria Cordelia|MC|;Russo|Andrea|A|;Toro|Mario Damiano|MD|;Bellino|Michele|M|;Avitabile|Teresio|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-4182",
"issue": "50(6)",
"journal": "Canadian journal of ophthalmology. Journal canadien d'ophtalmologie",
"keywords": null,
"medline_ta": "Can J Ophthalmol",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D005260:Female; D006801:Humans; D019654:Lens Implantation, Intraocular; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D018918:Phacoemulsification; D011183:Postoperative Complications; D012163:Retinal Detachment; D012189:Retrospective Studies; D058471:Subretinal Fluid; D041623:Tomography, Optical Coherence; D014792:Visual Acuity",
"nlm_unique_id": "0045312",
"other_id": null,
"pages": "476-9",
"pmc": null,
"pmid": "26651309",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute serous macular detachment and edema after uncomplicated phacoemulsification: A case series.",
"title_normalized": "acute serous macular detachment and edema after uncomplicated phacoemulsification a case series"
} | [
{
"companynumb": "IT-ALKEM LABORATORIES LIMITED-IT-ALKEM-2022-01924",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFUROXIME AXETIL"
},
... |
{
"abstract": "Diphenhydramine, a common ingredient in over-the-counter medications, is often taken in overdose. Toxicity is usually limited to anticholinergic symptoms. However, because diphenhydramine also exhibits type IA sodium channel blockade, cardiac toxicity is also possible. Although it would be expected that, like other type IA toxicities, diphenhydramine-induced cardiotoxicity could be responsive to hypertonic sodium bicarbonate, this finding is largely unappreciated. We describe 3 cases of diphenhydramine-induced cardiac toxicity that were responsive to bicarbonate.",
"affiliations": "New York City Poison Control Center, New York, NY, USA. ansharma@pol.net",
"authors": "Sharma|Adhi N|AN|;Hexdall|Aaron H|AH|;Chang|Elbert K|EK|;Nelson|Lewis S|LS|;Hoffman|Robert S|RS|",
"chemical_list": "D004338:Drug Combinations; D006982:Hypertonic Solutions; D006993:Hypnotics and Sedatives; D004366:Nonprescription Drugs; D012457:Salicylamides; D000082:Acetaminophen; D004155:Diphenhydramine; D017693:Sodium Bicarbonate; D008701:Methapyrilene; D001241:Aspirin",
"country": "United States",
"delete": false,
"doi": "10.1016/s0735-6757(02)42248-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "21(3)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D001145:Arrhythmias, Cardiac; D001241:Aspirin; D004155:Diphenhydramine; D004338:Drug Combinations; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006982:Hypertonic Solutions; D006993:Hypnotics and Sedatives; D007262:Infusions, Intravenous; D008297:Male; D008701:Methapyrilene; D004366:Nonprescription Drugs; D012457:Salicylamides; D017693:Sodium Bicarbonate; D013406:Suicide, Attempted; D016896:Treatment Outcome",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "212-5",
"pmc": null,
"pmid": "12811715",
"pubdate": "2003-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diphenhydramine-induced wide complex dysrhythmia responds to treatment with sodium bicarbonate.",
"title_normalized": "diphenhydramine induced wide complex dysrhythmia responds to treatment with sodium bicarbonate"
} | [
{
"companynumb": "US-PFIZER INC-202200814020",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN\\DIPHENHYDRAMINE\\DIPHENHYDRAMINE CITRATE"
... |
{
"abstract": "Allergic contact dermatitis (ACD) is a common occupational disease. Hairdressers and beauticians are at increased risk of occupational chronic hand eczema. We present a case of mixed occupational, non-occupational and iatrogenic ACD in a hairdresser which illustrates that delayed diagnosis can result in high morbidity, and unnecessary treatment and cost. A hairdresser with chronic hand and facial eczema failed medical management with topical steroids and dupilumab. Patch testing revealed contact allergy to multiple occupational exposures, home exposures and topical medicaments.",
"affiliations": "University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA.;Contact Dermatitis Institute, Phoenix, AZ, USA.",
"authors": "Koblinski|J E|JE|;Hamann|D|D|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D006203:Hair Preparations",
"country": "England",
"delete": false,
"doi": "10.1093/occmed/kqaa152",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0962-7480",
"issue": "70(7)",
"journal": "Occupational medicine (Oxford, England)",
"keywords": "Hairdressers; iatrogenic illness; occupational contact dermatitis",
"medline_ta": "Occup Med (Lond)",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D001461:Barbering; D017449:Dermatitis, Allergic Contact; D009783:Dermatitis, Occupational; D004342:Drug Hypersensitivity; D005260:Female; D017575:Gloves, Protective; D006203:Hair Preparations; D006229:Hand Dermatoses; D006801:Humans; D007049:Iatrogenic Disease; D016273:Occupational Exposure",
"nlm_unique_id": "9205857",
"other_id": null,
"pages": "523-526",
"pmc": null,
"pmid": "32851406",
"pubdate": "2020-10-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mixed occupational and iatrogenic allergic contact dermatitis in a hairdresser.",
"title_normalized": "mixed occupational and iatrogenic allergic contact dermatitis in a hairdresser"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP006744",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
"dr... |
{
"abstract": "Skin graft versus host disease (GVHD) can affect quality of life in hematopoietic stem cell transplant recipients. Therapeutic options for steroid-refractory GVHD are limited. We report the first prospective pilot study evaluating the topical vitamin D3 analog Calcipotriene (DOVONEX 0.005% cream) for acute skin GVHD in children, with associated analyses of target organ chemokine CXCL10 changes in response to therapy. We observed that Calcipotriene applications were safe and well tolerated. There were no symptom progression nor new symptoms requiring GVHD therapy escalation during study period. The most consistent response observed by study subjects was resolution of pruritus in eight patients and significant improvement in pruritus in two study subjects. Nine of ten patients had improvement or resolution of skin rash. In addition, we documented reduction of CXCL10 levels in the skin of seven subjects with GVHD after Calcipotriene course using non-invasive D-Squame® disc application to the skin for chemokine analysis. Our pilot study shows promising observation that topical Calcipotriene could be a novel therapeutic option for acute skin GVHD, especially in patients presenting with pruritus and should be studied in larger prospective studies.",
"affiliations": "Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH and Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA. Gregory.Wallace@cchmc.org.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH and Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH and Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH and Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH and Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.;Department of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH and Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH and Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH and Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.",
"authors": "Wallace|Gregory|G|http://orcid.org/0000-0002-8435-9648;Khandelwal|Pooja|P|http://orcid.org/0000-0002-8627-6408;Myers|Kasiani C|KC|http://orcid.org/0000-0002-5528-4405;Perentesis|Emma M R|EMR|;Lane|Adam|A|;Teusink-Cross|Ashley|A|;Smiley|Kristi|K|;Davies|Stella M|SM|;Jodele|Sonata|S|",
"chemical_list": "C055085:calcipotriene; D002117:Calcitriol",
"country": "England",
"delete": false,
"doi": "10.1038/s41409-020-01189-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "56(6)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000208:Acute Disease; D002117:Calcitriol; D002648:Child; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D010865:Pilot Projects; D011446:Prospective Studies; D011788:Quality of Life",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "1441-1444",
"pmc": null,
"pmid": "33420390",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "24914140;20655952;30605776;23690671;21131424",
"title": "Prospective pilot trial of calcipotriene as a novel topical treatment for acute skin graft versus host disease.",
"title_normalized": "prospective pilot trial of calcipotriene as a novel topical treatment for acute skin graft versus host disease"
} | [
{
"companynumb": "US-OTSUKA-2021_033924",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Phase 3 trials have shown the efficacy of vedolizumab, which binds to integrin α4β7, in patients with Crohn's disease (CD) or ulcerative colitis (UC). We investigated the effectiveness and safety of vedolizumab in patients who failed anti-tumor necrosis factor therapy.\n\n\n\nFrom June through December 2014, there were 173 patients with CD and 121 patients with UC who were included in a multicenter nominative compassionate early access program granted by French regulatory agencies. This program provided patients with access to vedolizumab before it was authorized for marketing. Vedolizumab (300 mg) was administered intravenously at weeks 0, 2, and 6, and then every 8 weeks. Disease activity was assessed using the Harvey-Bradshaw Index for CD and the partial Mayo Clinic score for UC. We report results obtained after the 14-week induction phase.\n\n\n\nAmong the 294 patients treated with vedolizumab (mean age, 39.5 ± 14.0 y; mean disease duration, 10.8 ± 7.6 y; concomitant steroids, 44% of cases), 276 completed the induction period, however, 18 discontinued vedolizumab because of a lack of response (n = 14), infusion-related reaction (n = 2), or infections (n = 2). At week 14, 31% of patients with CD were in steroid-free clinical remission and 51% had a response; among patients with UC, 36% were in steroid-free clinical remission and 50% had a response. No deaths were reported. Severe adverse events occurred in 24 patients (8.2%), including 15 (5.1%) that led to vedolizumab discontinuation (1 case of pulmonary tuberculosis and 1 rectal adenocarcinoma).\n\n\n\nIn a cohort of patients with CD or UC who failed previous anti-tumor necrosis factor therapy, approximately one third of patients achieved steroid-free clinical remission after 14 weeks of induction therapy with vedolizumab. This agent had an acceptable safety profile in these patients.",
"affiliations": "Department of Gastroenterology, Henri Mondor Hospital, Assistance Publique - Hôpitaux de Paris, EC2M3-Equipe Universitaire, Paris Est-Créteil Val de Marne University, Creteil, France. Electronic address: aurelien.amiot@hmn.aphp.fr.;Hôpital Nord, Centre d'Investigation Clinique Marseille Nord, Université Méditerranée, Marseille, France.;Inserm U954 and Department of Gastroenterology, Université de Lorraine, Nancy, France.;Department of Gastroenterology and Clinical Nutrition, Nice University Hospital, University of Nice Sophia-Antipolis, Nice, France.;Department of Gastroenterology, Huriez Hospital, Université Lille Nord de France, Lille, France.;Department of Gastroenterology, Saint-Etienne University Hospital, Saint-Etienne, France.;Department of Hepato-Gastroenterology, University Hospital Estaing of Clermont-Ferrand, Université d'Auvergne, Clermont-Ferrand, France.;Department of Gastroenterology, IBD and Nutrition Support, Beaujon Hospital, University Paris 7 Denis Diderot, Clichy, France.;Department of Gastroenterology, Institut des Maladies de l'Appareil Digestif, University Hospital of Nantes, Nantes University, Nantes, France.;Department of Gastroenterology, Hôpital Saint-Eloi, University Hospital of Montpellier, Montpellier, France.;Medicosurgical Department of Digestive Diseases, Hôpital Lariboisière, AP-HP, University Denis Diderot, Paris, France.;Department of Gastroenterology, Bicetre University Hospital, APHP, Université Paris Sud, le Kremlin Bicêtre, Paris, France.;Department of Gastroenterology, AP-HP, Hôpital Saint-Antoine, Inserm/UMRS 7203, UPMC Université Paris, Paris, France.;Department of Gastroenterology, Hospices Civils de Lyon and University Claude Bernard Lyon 1, Pierre-Benite, France.;Department of Hepato-Gastroenterology, University Hospital of Bordeaux, Hôpital Haut-Lévêque, Bordeaux, France.;Department of Gastroenterology, Hôpital Saint Louis APHP, Paris, France.;Department of Gastroenterology, Rouen University and Hospital, Rouen, France.;Department of Gastroenterology, Hôpital Rangueil, University of Toulouse, Toulouse, France.;Department of Gastroenterology, Henri Mondor Hospital, Assistance Publique - Hôpitaux de Paris, EC2M3-Equipe Universitaire, Paris Est-Créteil Val de Marne University, Creteil, France.;Department of Gastroenterology, Besançon University Hospital, Besançon, France.;Department of Gastroenterology, Caen University Hospital, Caen, France.;Department of Gastroenterology, Trousseau University Hospital, Tours, France.;Department of HepatoGastroenterology, Bichat Hospital, Paris 7 Denis Diderot, Paris, France.;Department of Gastroenterology, Pontchaillou Hospital and Rennes University, Rennes, France.;Department of Gastroenterology, Cochin Hospital, University Paris 5 Descartes, Paris, France.;Department of Gastroenterology, IBD and Nutrition Support, Beaujon Hospital, University Paris 7 Denis Diderot, Clichy, France.",
"authors": "Amiot|Aurelien|A|;Grimaud|Jean-Charles|JC|;Peyrin-Biroulet|Laurent|L|;Filippi|Jerome|J|;Pariente|Benjamin|B|;Roblin|Xavier|X|;Buisson|Anthony|A|;Stefanescu|Carmen|C|;Trang-Poisson|Caroline|C|;Altwegg|Romain|R|;Marteau|Philippe|P|;Vaysse|Thibaud|T|;Bourrier|Anne|A|;Nancey|Stephane|S|;Laharie|David|D|;Allez|Matthieu|M|;Savoye|Guillaume|G|;Moreau|Jacques|J|;Gagniere|Charlotte|C|;Vuitton|Lucine|L|;Viennot|Stephanie|S|;Aubourg|Alexandre|A|;Pelletier|Anne-Laure|AL|;Bouguen|Guillaume|G|;Abitbol|Vered|V|;Bouhnik|Yoram|Y|;|||;|||",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; C543529:vedolizumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cgh.2016.02.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-3565",
"issue": "14(11)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "Cell Adhesion; Drug; IBD; Inhibitor",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D015212:Inflammatory Bowel Diseases; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "1593-1601.e2",
"pmc": null,
"pmid": "26917043",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Effectiveness and Safety of Vedolizumab Induction Therapy for Patients With Inflammatory Bowel Disease.",
"title_normalized": "effectiveness and safety of vedolizumab induction therapy for patients with inflammatory bowel disease"
} | [
{
"companynumb": "FR-TAKEDA-2016TUS004668",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VEDOLIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "The prognosis of out-of-hospital cardiac arrest (OHCA) due to intoxication is dismal. Tricyclic antidepressants (TCAs) are widely used in the treatment of depression, but possess significant cardiotoxicity, and are one of the most common medications used in suicide attempts worldwide. TCA poisoning can cause hypotension, seizures, and cardiac conduction disturbances, which can lead to life-threatening arrhythmia. Current guidelines recommend mild therapeutic hypothermia (TH) for unconscious survivors of OHCA, but hypothermia treatment itself can cause disturbances in cardiac conduction, which could aggravate the effect of TCAs on cardiac conduction. We report the successful use of TH in a 19-year-old woman who was resuscitated from ventricular tachycardia after intentional ingestion of amitriptyline and venlafaxine, a serotonin-norepinephrine reuptake inhibitor. The cardiac arrest was witnessed, but no bystander cardiopulmonary resuscitation (CPR) was performed. The initial rhythm was ventricular tachycardia with no detectable pulse. Three defibrillations, magnesium sulfate, and sodium bicarbonate were given and her trachea was intubated, after which return of spontaneous circulation (ROSC) was achieved in 26 minutes. After ROSC, she had seizures and was sedated with propofol. Out-of-hospital TH was initiated with 1500 mL of cold Ringer's acetate. An infusion of norepinephrine was initiated for low blood pressure. On arrival at the university hospital, she was unconscious and had dilated pupils. She was tachycardic with a body temperature of 33.5°C. She was transferred to the intensive care unit and TH was maintained with invasive cooling. During the TH treatment, she did not experience any serious cardiac arrhythmia, transthoracic echocardiogram was normal, and the electrocardiogram (ECG) returned to normal. The patient was extubated 45 hours after the cardiac arrest. After the extubation, she was alert and cooperative, but slightly delusional. She was transferred to a ward on the third day and discharged from hospital on the sixth day of admission. Ambulatory psychiatric follow-up was organized. Neuropsychological examinations were later performed and she was estimated to be able to work at her previous job. This case report suggests that mild TH is safe even in case of intoxication with a drug known to cause serious cardiac conduction disturbances and arrhythmia.",
"affiliations": "1 Division of Intensive Care Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital , Helsinki, Finland .;2 Emergency Medical Services, Department of Emergency Medicine, University of Helsinki and Helsinki University Hospital , Helsinki, Finland .;1 Division of Intensive Care Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital , Helsinki, Finland .;3 Department of Cardiology, Helsinki University Hospital , Helsinki, Finland .;1 Division of Intensive Care Medicine, Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital , Helsinki, Finland .",
"authors": "Kontio|Terhi|T|;Salo|Ari|A|;Kantola|Teemu|T|;Toivonen|Lauri|L|;Skrifvars|Markus B|MB|",
"chemical_list": "D018759:Adrenergic Uptake Inhibitors; D007552:Isotonic Solutions; C028570:Ringer's acetate; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D000639:Amitriptyline; D000069470:Venlafaxine Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1089/ther.2014.0030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2153-7658",
"issue": "5(2)",
"journal": "Therapeutic hypothermia and temperature management",
"keywords": null,
"medline_ta": "Ther Hypothermia Temp Manag",
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"title": "Successful use of therapeutic hypothermia after cardiac arrest due to amitriptyline and venlafaxine intoxication.",
"title_normalized": "successful use of therapeutic hypothermia after cardiac arrest due to amitriptyline and venlafaxine intoxication"
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"abstract": "A 57-year-old man with a 10-year history of proton pump inhibitor (PPI) use presented with multiple fundic gland polyps (FGPs) including one >20 mm, whitish, semi-pedunculated polyp. Black spots and cobblestone-like mucosa were also observed in the stomach upon endoscopy; therefore, the lesion was considered to result from long-term PPI administration. Endoscopically, we diagnosed this polyp as a neoplastic lesion with gastric phenotype rather than a non-neoplastic lesion. Biopsy revealed an atypical glandular lesion that was indeterminate for neoplasia; therefore, we performed en bloc resection via endoscopic submucosal dissection (ESD) of the 22 × 22 × 10 mm-sized polyp. Histologically, the polyp was composed of hyperplastic foveolar epithelia in the upper half of the mucosa and hyperplastic fundic glands in the lower half of the mucosa, with luminal dilatation and parietal cell protrusion. The pathological diagnosis for this ESD specimen was FGP associated with PPI administration. We herein describe this rare case of a large FGP in Helicobacter pylori-uninfected gastric mucosa associated with long-term PPI administration, which was mimicking gastric-type neoplasm and resected by endoscopy.",
"affiliations": "Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan.;Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan.;Department of Pathology, Toranomon Hospital, Tokyo, Japan.;Department of Pathology, Toranomon Hospital, Tokyo, Japan.;Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan.",
"authors": "Ochiai|Yorinari|Y|;Kikuchi|Daisuke|D|;Ito|Shinji|S|;Takazawa|Yutaka|Y|;Hoteya|Shu|S|",
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"fulltext": "\n==== Front\nCase Rep Gastroenterol\nCase Rep Gastroenterol\nCRG\nCase Reports in Gastroenterology\n1662-0631 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000512399\ncrg-0015-0123\nSingle Case\nLarge Fundic Gland Polyp Associated with Long-Term Proton Pump Inhibitor Administration Mimicking Gastric-Type Neoplasm\nOchiai Yorinari a* Kikuchi Daisuke a Ito Shinji b Takazawa Yutaka b Hoteya Shu a aDepartment of Gastroenterology, Toranomon Hospital, Tokyo, Japan\nbDepartment of Pathology, Toranomon Hospital, Tokyo, Japan\n*Yorinari Ochiai, Department of Gastroenterology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470 (Japan), y.ochiai.1987@gmail.com\nJan-Apr 2021 \n3 2 2021 \n3 2 2021 \n15 1 123 130\n10 10 2020 16 10 2020 2021 Copyright © 2021 by S. Karger AG, Basel2021This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.A 57-year-old man with a 10-year history of proton pump inhibitor (PPI) use presented with multiple fundic gland polyps (FGPs) including one >20 mm, whitish, semi-pedunculated polyp. Black spots and cobblestone-like mucosa were also observed in the stomach upon endoscopy; therefore, the lesion was considered to result from long-term PPI administration. Endoscopically, we diagnosed this polyp as a neoplastic lesion with gastric phenotype rather than a non-neoplastic lesion. Biopsy revealed an atypical glandular lesion that was indeterminate for neoplasia; therefore, we performed en bloc resection via endoscopic submucosal dissection (ESD) of the 22 × 22 × 10 mm-sized polyp. Histologically, the polyp was composed of hyperplastic foveolar epithelia in the upper half of the mucosa and hyperplastic fundic glands in the lower half of the mucosa, with luminal dilatation and parietal cell protrusion. The pathological diagnosis for this ESD specimen was FGP associated with PPI administration. We herein describe this rare case of a large FGP in Helicobacter pylori-uninfected gastric mucosa associated with long-term PPI administration, which was mimicking gastric-type neoplasm and resected by endoscopy.\n\nKeywords\nProton pump inhibitorEndoscopic submucosal dissectionFundic gland polypEndoscopyNarrow-band imagingGastric-type neoplasm\n==== Body\nIntroduction\nProton pump inhibitors (PPIs) are considered relatively safe drugs and are widely used. However, after long-term PPI administration, the gastric mucosa may develop fundic gland polyps (FGPs), black spots, and cobblestone-like mucosa [1, 2]. Pathologically, hyperplasia of parietal cells and parietal cell protrusion into the lumen are typical findings [3]. Although hypoacidity and hypergastrinemia increase the risk of gastric cancer in the corpus and fundus [4, 5], the relationship between long-term PPI administration and tumor development remains unclear. Herein, we report the rare case of a 22 × 22 × 10 mm FGP in Helicobacter pylori (H. pylori)-uninfected gastric mucosa associated with long-term PPI administration that was mimicking gastric-type neoplasm and resected via endoscopy.\n\nCase Report\nA 57-year-old Japanese man had been taking lansoprazole for at least 10 years for gastroesophageal reflux. He had no new symptoms and no major medical history. Upper gastrointestinal endoscopy conducted for routine screening revealed multiple hydrops-like FGPs in the background mucosa without atrophy. A semi-pedunculated polyp >20 mm in size with black spots on the surface was found on the posterior wall of the greater curvature of the stomach (Fig. 1). In narrow-band imaging magnifying endoscopy (NBI-ME), the microsurface pattern showed circular gland duct openings in some areas, though the pattern was obscure in parts of the lesion. The microvascular pattern showed an enlarged blood vessel that ran laterally on the surface in most of the lesion. In addition, microvessels presenting tortuosity and slight dilatation were recognized in the parts where the microsurface pattern was obscure, although no caliber change or shape variations were noted (Fig. 2). Based on these endoscopic findings, we diagnosed this polyp as a neoplastic lesion with gastric phenotype rather than a non-neoplastic lesion. Biopsy results confirmed an atypical glandular lesion that was indeterminate for neoplasia. Therefore, we performed en bloc resection by endoscopic submucosal dissection (ESD) using a dual knife (Olympus Co., Ltd., Tokyo, Japan). Macroscopically, the lesion was a semi-pedunculated polyp that was 22 × 22 × 10 mm in size (Fig. 3). Histologically, the polyp was composed of hyperplastic foveolar epithelia in the upper half of the mucosa and hyperplastic fundic glands in the lower half of the mucosa, with luminal dilatation and parietal cell protrusion, which is typical of PPI-related FGPs (Fig. 4). No structural or cytological atypia was observed in the lesion and it was pathologically diagnosed as an FGP associated with PPI administration.\n\nThe patient had no history of H. pylori eradication, and H. pylori antibody and stool H. pylori antigen were both negative, which suggests no prior H. pylori infection of the gastric mucosa. As such, this large FGP associated with PPI administration was considered to have developed in H. pylori-uninfected gastric mucosa.\n\nDiscussion\nIn this case, the patient presented with a large FGP which was determined to result from extended PPI use. FGPs may occur sporadically or in association with syndromes such as familial adenomatous polyposis (FAP). Sporadic FGPs have been reported in 0.8–1.9% of patients undergoing esophagogastroduodenoscopy, and their occurrence has been associated with prolonged use of PPIs [6]. In our case, there was no clinical or colonoscopic evidence of FAP. Therefore, the lesion in our case was sporadic. In addition, the ESD specimen in this case demonstrated fundic gland hyperplasia and parietal cell protrusion, which have been widely observed in patients with long-term PPI administration. Therefore, our case was considered a PPI-related lesion. A report from Japan [7] indicated that 13.6% of patients developed new FGPs after rabeprazole administration for 104 weeks. These developed mainly in the corpus and were <5 mm. In this case, the 22 × 22 × 10 mm lesion was much larger than a common FGP. Although the mechanism of such large, sporadic FGP growth over long-term observation is unknown, our case suggests that FGPs could enlarge with long-term administration of PPI.\n\nEndoscopic changes after long-term PPI administration include FGPs, black spots, and cobblestone-like mucosa; however, there are few detailed reports about PPI-related polyps, and characteristic findings in NBI-ME have not been well investigated. In our case, we found two patterns via NBI-ME: one pattern that was consistent with an FGP and one pattern that demonstrated microsurface and microvascular irregularities. We were unsure whether this lesion was neoplastic because the microsurface pattern did not present irregularities typical of neoplasia and the microvascular pattern did not meet all four signs of neoplasia (dilatation, tortuosity, caliber change, and various shapes). These findings might have been caused by inflammation due to polyp size or location in the stomach. As mentioned above, it is sometimes difficult to endoscopically determine whether a large lesion is neoplastic or non-neoplastic.\n\nIn the present case, we selected ESD as the treatment strategy because this large semi-pedunculated polyp was suspected to be neoplastic based on endoscopic findings and the preoperative biopsy could not rule out neoplasm either. There are few reports of treatment for PPI-related gastric polyps; however, we found one report of endoscopic mucosal resection for a 10-mm FGP with low-grade dysplasia [8].\n\nIt is also sometimes difficult to pathologically differentiate large FGPs from gastric-type neoplasia by biopsy specimen because FGPs associated with PPI use might show slight atypia or dysplastic changes. Previous literature reported that FGPs were detected in 88% of FAP patients and were dysplastic in 41% of patients [9]. In contrast, low-grade epithelial dysplasia has been reported in sporadic FGPs; however, its prevalence is said to be extremely low (approximately 1%) [10]. One paper reported that an FGP with dysplasia did not transform into invasive cancer although the patient underwent 14 years of PPI therapy [11]. Follow-up data from 26 cases of sporadic FGP with low-grade dysplasia also suggested that these lesions might be indolent in nature [10]. The malignant potential of PPI-related FGPs remains to be elucidated.\n\nIn conclusion, we herein report a rare case of a large FGP in H. pylori-uninfected gastric mucosa associated with long-term PPI administration, which was mimicking gastric-type neoplasm and resected by endoscopy.\n\nStatements of Ethics\nThe patient provided written informed consent for publication of data and images.\n\nConflict of Interest Statement\nThe authors declare that they have no conflicts of interest to disclose.\n\nFunding Sources\nNone declared.\n\nAuthor Contributions\nY. Ochiai wrote the draft of the research study. Y. Ochiai, D. Kikuchi, and S. Hoteya conducted the data acquisition and revised the draft. S. Ito and Y. Takazawa analyzed the pathological findings. S. Hoteya supervised this case report.\n\nFig. 1 White-light images of the lesion and background of the stomach. a, b A whitish elevated polyp with black spots on the surface. Hydrops-like whitish polyps (c) and cobblestone-like mucosa (d) are seen in the background.\n\nFig. 2 Images of the lesion by NBI-ME. a The entire lesion by unmagnified NBI-ME. b The anal side of the lesion in retroflex observation by unmagnified NBI-ME. c Magnified NBI-ME view of the area framed by the white solid box in b. d Magnified NBI-ME view of the area framed by the white dashed box in b. NBI-ME, narrow-band imaging magnifying endoscopy.\n\nFig. 3 Specimen resected by endoscopic submucosal dissection. a The resected lesion. b Green lines show the area of the lesion. c Side view of the resected lesion.\n\nFig. 4 Histological images of the lesion (hematoxylin and eosin staining). a The section of the lesion showing polypoid proliferation with cystic glands and mild foveolar hyperplasia. b Higher magnification of the area framed by the black solid box in a showing hyperplastic changes and parietal cell protrusion.\n==== Refs\nReferences\n1 Jalving M Koornstra JJ Wesseling J Boezen HM DE Jong S Kleibeuker JH Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy Aliment Pharmacol Ther 2006 11 24 (9) 1341 8 17059515 \n2 Hatano Y Haruma K Ayaki M Kamada T Ohtani H Murao T Black Spot, a Novel Gastric Finding Potentially Induced by Proton Pump Inhibitors Intern Med 2016 55 (21) 3079 84 27803398 \n3 Parfitt JR Driman DK Pathological effects of drugs on the gastrointestinal tract: a review Hum Pathol 2007 4 38 (4) 527 36 17367604 \n4 Fossmark R Martinsen TC Waldum HL Adverse Effects of Proton Pump Inhibitors-Evidence and Plausibility Int J Mol Sci 2019 10 20 (20) E5203 31640115 \n5 Fukuda M Ishigaki H Sugimoto M Mukaisho KI Matsubara A Ishida H Histological analysis of fundic gland polyps secondary to PPI therapy Histopathology 2019 10 75 (4) 537 45 31087669 \n6 Kinoshita Y Tojo M Yano T Kitajima N Itoh T Nishiyama K Incidence of fundic gland polyps in patients without familial adenomatous polyposis Gastrointest Endosc 1993 Mar-Apr 39 (2) 161 3 8388344 \n7 Hongo M Fujimoto K Gastric Polyps Study Group Incidence and risk factor of fundic gland polyp and hyperplastic polyp in long-term proton pump inhibitor therapy: a prospective study in Japan J Gastroenterol 2010 6 45 (6) 618 24 20177714 \n8 Shibukawa N Wakahara Y Ouchi S Wakamatsu S Kaneko A Synchronous Three Gastric Fundic Gland Polyps with Low-grade Dysplasia Treated with Endoscopic Mucosal Resection after Being Diagnosed to Be Tubular Adenocarcinoma Based on a Biopsy Specimen Intern Med 2019 7 58 (13) 1871 5 30918177 \n9 Bianchi LK Burke CA Bennett AE Lopez R Hasson H Church JM Fundic gland polyp dysplasia is common in familial adenomatous polyposis Clin Gastroenterol Hepatol 2008 2 6 (2) 180 5 18237868 \n10 Levy MD Bhattacharya B Sporadic Fundic Gland Polyps With Low-Grade Dysplasia: A Large Case Series Evaluating Pathologic and Immunohistochemical Findings and Clinical Behavior Am J Clin Pathol 2015 10 144 (4) 592 600 26386080 \n11 Fukuda M Ishigaki H Ban H Sugimoto M Tanaka E Yonemaru J No transformation of a fundic gland polyp with dysplasia into invasive carcinoma after 14 years of follow-up in a proton pump inhibitor-treated patient: A case report Pathol Int 2018 12 68 (12) 706 11 30511782\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "15(1)",
"journal": "Case reports in gastroenterology",
"keywords": "Endoscopic submucosal dissection; Endoscopy; Fundic gland polyp; Gastric-type neoplasm; Narrow-band imaging; Proton pump inhibitor",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "123-130",
"pmc": null,
"pmid": "33708059",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "30511782;31640115;31087669;20177714;26386080;18237868;17367604;27803398;8388344;30918177;17059515",
"title": "Large Fundic Gland Polyp Associated with Long-Term Proton Pump Inhibitor Administration Mimicking Gastric-Type Neoplasm.",
"title_normalized": "large fundic gland polyp associated with long term proton pump inhibitor administration mimicking gastric type neoplasm"
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"abstract": "BACKGROUND\nCefazolin is a first-generation cephalosporin commonly used for skin and soft tissue infections, abdominal and orthopedic surgery prophylaxis, and methicillin-sensitive staph aureus. Cephalosporins as a whole are known potential inducers of hemolytic anemia; however, mechanism of action is primarily autoimmune, and compared to other drugs, cefazolin is the least common.\n\n\nMETHODS\nA rare case report of cefazolin-induced hemolytic anemia \"CIHA\" and a systematic review of CIHA articles in English literature. Two authors performed review of publications and articles were selected based on inclusion and exclusion criteria. A systematic search of the literature yielded 768 entries with five case reports on cefazolin-induced hemolytic anemia.\nAn 80-year-old female with methicillin-sensitive Staphylococcus aureus \"MSSA\" endocarditis. The patient was started on intravenous \"IV\" cefazolin that that resulted in hemolytic anemia and eosinophilia. Switching to vancomycin improved hemoglobin level and resolved eosinophilia. Four cefazolin-induced hemolytic anemia case reports and one population-based article with a case reported were analyzed with respect to direct antiglobulin test \"DAT\" (also known as the direct Coombs test) results, prior penicillin sensitivity, and acute anemia causes exclusion.\n\n\nCONCLUSIONS\nCIHA is a rare cause of clinically significant anemia. The diagnosis of drug-induced anemia is one of exclusion. It is important to consider DAT results and prior penicillin sensitivity when evaluating a patient for cefazolin-induced hemolytic anemia. However, the frequency of cefazolin use and resultant anemia necessitates early recognition of hemolytic anemia and prompt discontinuation of cefazolin, especially with long-term use.",
"affiliations": "Creighton University School of Medicine, Omaha, NE, USA. eam19739@creighton.edu.;Department of Internal Medicine, Creighton University, Omaha, NE, USA.;Department of Infectious Disease, Creighton University, Omaha, NE, USA.",
"authors": "Mause|Elizabeth|E|http://orcid.org/0000-0002-4405-9210;Selim|Mohammad|M|;Velagapudi|Manasa|M|",
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"fulltext": "\n==== Front\nEur J Med Res\nEur J Med Res\nEuropean Journal of Medical Research\n0949-2321\n2047-783X\nBioMed Central London\n\n604\n10.1186/s40001-021-00604-9\nCase Report\nCefazolin-induced hemolytic anemia: a case report and systematic review of literature\nhttp://orcid.org/0000-0002-4405-9210\nMause Elizabeth eam19739@creighton.edu\n\n1\nSelim Mohammad MohammadSelim@creighton.edu\n\n2\nVelagapudi Manasa ManasaVelagapudi@creighton.edu\n\n3\n1 grid.254748.8 0000 0004 1936 8876 Creighton University School of Medicine, Omaha, NE USA\n2 grid.254748.8 0000 0004 1936 8876 Department of Internal Medicine, Creighton University, Omaha, NE USA\n3 grid.254748.8 0000 0004 1936 8876 Department of Infectious Disease, Creighton University, Omaha, NE USA\n24 11 2021\n24 11 2021\n2021\n26 13325 8 2021\n7 11 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\nCefazolin is a first-generation cephalosporin commonly used for skin and soft tissue infections, abdominal and orthopedic surgery prophylaxis, and methicillin-sensitive staph aureus. Cephalosporins as a whole are known potential inducers of hemolytic anemia; however, mechanism of action is primarily autoimmune, and compared to other drugs, cefazolin is the least common.\n\nMethods\n\nA rare case report of cefazolin-induced hemolytic anemia “CIHA” and a systematic review of CIHA articles in English literature. Two authors performed review of publications and articles were selected based on inclusion and exclusion criteria. A systematic search of the literature yielded 768 entries with five case reports on cefazolin-induced hemolytic anemia.\n\nCase presentation/results\n\nAn 80-year-old female with methicillin-sensitive Staphylococcus aureus “MSSA” endocarditis. The patient was started on intravenous “IV” cefazolin that that resulted in hemolytic anemia and eosinophilia. Switching to vancomycin improved hemoglobin level and resolved eosinophilia. Four cefazolin-induced hemolytic anemia case reports and one population-based article with a case reported were analyzed with respect to direct antiglobulin test “DAT” (also known as the direct Coombs test) results, prior penicillin sensitivity, and acute anemia causes exclusion.\n\nConclusions\n\nCIHA is a rare cause of clinically significant anemia. The diagnosis of drug-induced anemia is one of exclusion. It is important to consider DAT results and prior penicillin sensitivity when evaluating a patient for cefazolin-induced hemolytic anemia. However, the frequency of cefazolin use and resultant anemia necessitates early recognition of hemolytic anemia and prompt discontinuation of cefazolin, especially with long-term use.\n\nKeywords\n\nCefazolin\nHemolytic anemia\nAdverse drug reaction\nCefazolin allergy\nHemolysis\nEosinophilia\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nHemolytic anemia has an extensive differential diagnosis. Common causes include autoimmune, drug-induced, or infections. The most common drug families include antibiotics, nonsteroidal anti-inflammatory drugs “NSAIDs”, and anti-cancer drugs. A 2007 article review identified 125 drugs evidenced to cause drug-induced hemolytic anemia “DIHA”. Cephalosporins were frequent culprits, especially cefotetan and ceftriaxone; however, a review article published in 2008 identified only two cases of cefazolin induced hemolytic anemia between 1971 and 2008 [1]. The present review focuses on case reports of cefazolin-induced hemolytic anemia with particular attention to the exclusion of other causes of anemia, direct antiglobulin test “DAT” results, and prior penicillin sensitivity. A review of articles from 1970 to 2021 revealed only a few case reports, and no other studies on CIHA were found. We also present an 80-year-old patient with cefazolin-induced hemolytic anemia diagnosed with CIHA and improved after cessation of the drug.\n\nCase presentation\n\nAn 80-year-old woman presented complaining of back pain and shortness of breath for 4 days. She had a past medical history of minor penicillin allergy, hypertension, hypothyroidism, gout, diastolic dysfunction, hyperlipidemia, transient ischemic attack, and non-ST-elevation myocardial infarction “NSTEMI.” Initial workup revealed elevated troponin and leukocytes/bacteria on urinalysis. Computed tomography angiogram “CTA” chest revealed bibasilar atelectasis/consolidation suspicious for pneumonia. The patient was diagnosed with severe sepsis secondary to bacterial pneumonia and urinary tract infection. She was started at an outside hospital on piperacillin–tazobactam, vancomycin, and azithromycin. The patient then developed acute anemia, and gastrointestinal bleeding was suspected. Esophagogastroduodenoscopy “EGD” was done and revealed a gastric ulcer with visible vessels that were treated. Hemoglobin had stabilized for days post-therapy. Then the patient was transferred to our tertiary center.\n\nThe first set of blood cultures came back positive for MSSA; antibiotics were downgraded to cefazolin. Magnetic resonance imaging “MRI” of the back was done given the patient’s bacteremia and back pain. Results demonstrated discitis and osteomyelitis at the level of T1–T2 vertebrae. Repeat blood cultures were positive again for MSSA. At this point, a transesophageal echocardiogram revealed mitral valve endocarditis. However, after visiting with the cardiothoracic surgeon, she decided to continue on medical treatment without surgical intervention.\n\nSeven days after switching to cefazolin, the patient’s hemoglobin started to downtrend again and required multiple blood transfusions. Suspicion of recurrent gastric ulcer bleeding was high, but a repeated EGD revealed a healing gastric ulcer with no evidence of active bleeding. The patient’s workup for hemolytic anemia showed elevated lactate dehydrogenase “LDH,” indirect bilirubin levels, and low haptoglobin. DAT and complement testing yielded negative results. Peripheral blood smear showed schistocytes. Differential included side effects of one of the medications, shearing force from the endocarditis, or autoimmune hemolytic anemia “AIHA.” However, other bloodwork showed an up-trending of eosinophil count from the 5th-day post-switching to cefazolin. Presumptively, the patient was diagnosed with a possible allergic reaction to cefazolin resulting in CIHA. The diagnosis was in light of her prior known allergy to penicillin, declining hemoglobin, workup picture consistent with hemolytic anemia, the elevation of eosinophils after starting cefazolin, and the exclusion of other plausible causes of acute anemia. After switching to vancomycin, hemoglobin level gradually up-trended, and eosinophil count down-trended. The patient was discharged on a regimen of vancomycin for 6 weeks.\n\nMethods\n\nA literature review was conducted on March 7, 2021, using the following databases: Academic Search Premier, JAMA Network, MEDLINE Complete, PubMed, Sage Journals, Science Direct, Wiley Online Library, and Springer Link. The language was restricted to English. There was no time restriction. The following search terms were used: cefazolin hemolytic anemia, cefazolin-induced hemolytic anemia, cefazolin drug-induced immune hemolytic anemia. Two authors reviewed publications. Articles were selected based on inclusion and exclusion criteria. The inclusion criteria were as follows: medical science journal articles, review articles, or research articles on:Cefazolin-induced hemolytic anemia case reports\n\nLiterature reviews that mention cefazolin hemolytic anemia\n\nMechanism articles of cefazolin-induced hemolytic anemia.\n\nExclusion criteria included journal articles that only mention cephalosporins in general or other cephalosporins/beta-lactams antibiotic reactions (vs. cefazolin) or thrombocytopenic or neutropenic reactions to cefazolin (vs. anemia).\n\nDisagreement between the two reviewers concerning the inclusion of particular studies was resolved. Selected studies were included for detailed analysis and data extraction. The parameters for data extraction were the following: exclusion of other causes of anemia, direct antiglobulin test “DAT” results, and prior penicillin sensitivity (Fig. 1).Fig. 1 Systematic review of the literature for cefazolin induced hemolytic anemia\n\nA systematic review of the literature was conducted with progressive exclusion of entries. Exclusion was initially based on entry type (i.e., book chapters were excluded) and only full text, English language entries were included. Results were further stratified based on relevance and specificity for CIHA.\n\nResults\n\nThe systematic search yielded 768 entries after the removal of book chapters. After reviewing the titles and abstracts, 13 articles were included in the full-text review. Four case reports and one population-based article with a case reported were identified based on the inclusion criteria. The detailed selection process is shown in Fig. 1. We identified five reports of cefazolin-induced hemolytic anemia (Table 1).Table 1 Cefazolin-induced anemia\n\nAuthor (Year)\tStudy design\tPresentation\tHemo-globin nadir\tPenicillin sensitivity\n(Y/N)\tDAT result ( ±)\tOther anemia causes excluded (Y/N)\tOutcome\t\nMoake et al. [2]\tCase report\t39 yo F with right renal artery stenosis underwent a renal artery bypass with pre-operative and 4-day postoperative use of cefazolin\t6.3\tY\t + \tY\tComplete resolution\t\nImam et al. [3]\tCase report\t70 yo M with acute anemia and elevated LDH post cefazolin administration; underwent mitral and tricuspid valve repair and Maze procedure\tΔ3.0 g\tNS\t–\tN\n\nceftriaxone induced hemolytic anemia was also implicated\n\n\tComplete resolution\t\nCerynik et al. [4]\tCase report\t50 yo M right total knee arthroplasty given pre-operative cefazolin developed anemia, then recovered; administration cefazolin 10 week postop due to knee swelling induced anemia again\t14.9 6.9\n\nΔ8\n\n\tN\t + \tY\tComplete resolution\t\nMacy, E. and Contreras, R. [5]\tRetrospective population based analysis\t37 yo F cardiac catheterization given pre-operative cefazolin with elevated lactate dehydrogenase post cefazolin administration\t7.6\tNS\tNS\tNS\tComplete resolution\t\nMoghaddam et al. [6]\tCase report\t24 yo F hysteroscopy for resection of the uterine septum\t12.5 7.0\n\nΔ5.5\n\n\tN\t + \tN\tThe patient died of multiple organ failure\t\n*NS not specified, Δ delta change\n\nTable describing each study with reported cefazolin-induced hemolytic anemia. Characteristics of study design, patient presentation, hemoglobin lowest reported value, penicillin sensitivity, DAT result, and exclusion of other causes of anemia is specified for each case\n\nLowest hemoglobin value recorded and delta hemoglobin value was reported if available\n\nIn the 1978 study by Moake et al., a 39-year-old woman with a history of penicillin allergy received cefazolin prophylactically for renal artery bypass surgery [2]. Hemoglobin dropped on the 4th day, which prompted discontinuation of cefazolin with an improvement in the hemoglobin. A urinary tract infection “UTI” developed on the 6th day after the surgery. This prompted cephalothin administration, which resulted in the recurrence of the hemoglobin drop. Again, the patient had normalization of hemoglobin after discontinuation of cephalothin. Hemolytic anemia workup was positive, and she had positive IgG and complement components. Furthermore, the authors reported appropriate exclusion of other potential causes of anemia. The suspected mechanism was an interaction of cefazolin-coated red blood cells with preexisting anti-penicillin antibodies.\n\nAnother case was reported by Imam et al. published in 2007, of a 70-year-old man who had open-heart surgery for mitral and tricuspid valve repair and MAZE procedure for atrial fibrillation [3]. The patient’s recovery was complicated with Serratia pericarditis with bacteremia and pericardial effusion. The patient was discharged on daily ceftriaxone for 6 weeks, but he developed ceftriaxone-induced immune-mediated hemolytic anemia. We include this case report in our review, because the patient was on cefazolin for 2 day postoperative with a significant drop in hemoglobin count and a highly elevated lactate dehydrogenase level “LDH”. Acute blood loss anemia due to intra-operative or postoperative bleed was excluded, because the estimated blood loss during the surgery was 800 cc, and anemia developed 2 days after the surgery. Moreover, there were no apparent sources of blood loss in the few days post-surgery. The authors drew a direct connection between the later onset of ceftriaxone-induced hemolytic anemia and early exposure to cefazolin and considered it a CIHA.\n\nCerynik et al. reported a case of a 50-year-old man with hemolytic anemia secondary to cefazolin administration for right total knee arthroplasty [4]. Prophylactic cephalosporin was administered and postoperatively, IV cefazolin was continued, with anemia developing postoperative day 1. The patient received two units of packed red blood cells “PRBC” and was discharged home. He returned 10 weeks later with a knee swelling and was started empirically on IV cefazolin, after joint aspiration, with resultant hemolytic anemia. This prompted the discontinuation of cefazolin, which led to complete resolution of anemia. The underlying hemolytic anemia mechanism was suspected to be immune-mediated due to a rapid decrease in hemoglobin on the second exposure to cefazolin. Positive DAT, the presence of spherocytosis, and exclusion of other possible causes confirmed the diagnosis.\n\nMacy, E. and Contreras, R. investigated the incidence of reported cephalosporin allergies among members of the Kaiser Permanente Southern California health plan between 2010 and 2012 via the electronic health record “EHR” [5]. In that analysis, the authors identified three possible cases of cephalosporin-induced hemolytic anemia. One of which involved cefazolin: a 37-year-old woman who underwent cardiac catheterization received cefazolin and was reported to have idiopathic hemolytic anemia that the authors suspected was likely cefazolin-induced. The patient recovered uneventfully over the next month. The authors of this review did not report workup for hemolytic anemia or exclusion of other possible causes.\n\nIn 2016, Moghaddam et al. reported a 24-year-old woman who developed hemolytic anemia after receiving pre-operative and postoperative cefazolin for a hysteroscopy [6]. Post-surgery anemia and hemoglobinuria were identified, and shortly after, disseminated intravascular coagulation “DIC” developed. She received several units of PRBCs and developed acute respiratory distress syndrome followed by complete anuria. The patient passed away from multi-organ failure. The authors hypothesized that preexisting antibodies were responsible for the hemolytic response due to rapid hemoglobin drop only a few hours after drug administration. The patient had no reported drug allergies; however, antibiotic use in livestock transmitted to meat products was cited as a potential exposure.\n\nConclusions and discussion\n\nWe report a rare case of cefazolin-induced hemolytic anemia that developed 7 days after starting the medication. Markers of the hemolytic picture were positive. However, indicators of immune-mediated mechanisms such as DAT and complement were negative. The underlying mechanism of this hemolytic process was unclear. This prompted a revision of the English medical literature from 1970 till March 2021, in which we found only a handful of reported cases and articles on this topic.\n\nDIHA is suspected in patients who present with anemia and hemolysis findings within days or weeks of exposure to a drug. Common mechanisms of DIHA include immune hemolysis or non-immune-mediated (oxidant injury). Naturally, with drug-induced immune hemolytic anemia “DIIHA”, DAT tends to be positive, with IgG or complement attached to the surface of red blood cells.\n\nHowever, to our knowledge, a negative DAT does not definitively rule out DIIHA, because there are several drug-induced immune hemolytic anemia mechanisms [7]. First, the drug can act as a hapten—where antibodies are only detected in the presence of the drug [1, 4, 8]. Second, the drug can elicit an immune response mediated by autoantibodies—antibodies are drug-independent. Many penicillin and cephalosporin antibiotics such as cefazolin have been reported to cause hemolysis via the hapten reaction, where the drug is required for antibody binding [9].\n\nWe are suggesting that in our case, prior penicillin allergy might have played a role. The cross-reactivity between penicillins and cephalosporins can be attributed to similarities in their side chains [10]. Aminopenicillins (ampicillin) and aminocephalosporins (first generation—cefaclor, cefalexin, and cefadroxil) share an NH2 group at the R1 position and are susceptible to cross-reactivity [10]. Cefazolin (also a first-generation cephalosporin) does not have an NH2 group, making it less likely, but not impossible, for it to have cross-reactivity [11, 12]. Notably, cefazolin-induced hemolytic anemia is not always associated with a prior penicillin allergy. Besides our case, it was only reported in one out of the five case reports we reviewed.\n\nIn an attempt to understand the underlying mechanism of cefazolin-induced hemolysis, we have reviewed the better-studied mechanism of penicillin-induced hemolysis. The most accepted penicillin-induced hemolytic anemia mechanism involves penicillin-binding to RBC membrane proteins that antibodies (IgG usually) subsequently bind to, resulting in clearance via macrophages [1]. However, this exact mechanism is controversial for other antibiotics.10 In addition, the logistics of the second mechanism of drug-induced immune hemolytic anemia—autoantibody production—is still unknown [13]. There was no clear consensus among the five case reports about the mechanism of cefazolin-induced hemolytic anemia.\n\nThe first case has a clear link between the development of anemia and starting cefazolin with workup positive for immune-mediated hemolytic anemia. The perceived mechanism was an interaction of cefazolin-coated red blood cells with preexisting anti-penicillin antibodies.\n\nThe link is unclear in the second case, especially considering that the anemia started days after the surgery. At that time, no workup for hemolytic anemia was done nor exclusion of other possible causes. The diagnosis of CIHA was more theoretical based on the later ceftriaxone-induced immune-mediated hemolytic anemia.\n\nThe third case represents a strong link between anemia development and cefazolin exposure. The patient was diagnosed with immune-mediated hemolytic anemia.\n\nThe fourth case is a retrograde data collection with no clear evidence that the anemia was secondary to hemolysis nor immune-mediated. The authors of the article suspected a link to cefazolin but did not establish clear causation or speculate on the mechanism.\n\nIn the fifth case, although DAT was strongly positive, the diagnosis of cefazolin-induced immune hemolytic anemia is not convincing. The author’s conducted several lab experiments to exclude other possible causes of hemolysis, but the patient developed DIC post major surgery. Many studies indicate that hemolytic anemia might be an early sign of DIC; however, there is a lack of evidence that this development was linked to cefazolin.\n\nCIHA is a rare cause of clinically significant anemia. Five case reports of CIHA exist in the literature with varying degrees of DAT reactivity. Mechanism of action in three of five is most consistent with an immune-mediated process. Although the prevalence and molecular mechanism of CIHA are not well understood, the frequency of cefazolin use and resultant potentially severe anemia necessitates a high degree of clinical suspicion for early recognition of hemolytic anemia and prompt discontinuation of cefazolin.\n\nAbbreviations\n\nCIHA Cefazolin-induced hemolytic anemia\n\nMSSA Methicillin-sensitive Staphylococcus aureus\n\nIV Intravenous\n\nDAT Direct antiglobulin test\n\nNSAIDs Nonsteroidal anti-inflammatory drugs\n\nDIHA Drug-induced hemolytic anemia\n\nNSTEMI Non-ST-elevation myocardial infarction\n\nCTA Computed tomography angiogram\n\nEGD Esophagogastroduodenoscopy\n\nMRI Magnetic resonance imaging\n\nLDH Lactate dehydrogenase\n\nAIHA Autoimmune hemolytic anemia\n\nUTI Urinary tract infection\n\nPRBC Packed red blood cells\n\nEHR Electronic health record\n\nDIC Disseminated intravascular coagulation\n\nDIIHA Drug-induced immune hemolytic anemia\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nEM performed literature review, wrote and reviewed the manuscript MS identified unique patient case and need for literature review; performed literature review, wrote and reviewed the manuscript. MV reviewed article. All authors read and approved the final manuscript.\n\nFunding\n\nThere was no funding obtained in this study.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nThe patient has consented to the submission of the case report to the journal. Informed consent was obtained from the patient for publication. A copy of the written consent is available for review by the Editors-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Garratty G Drug-induced immune hemolytic anemia Hematology 2009 2009 1 73 79 10.1182/asheducation-2009.1.73\n2. Moake JL Hemolysis induced by cefazolin and cephalothin in a patient with penicillin sensitivity Transfusion 1978 18 3 369 10.1046/j.1537-2995.1978.18378205151.x 96555\n3. Imam SN Wright K Bhoopalam N Choudhury A Hemolytic anemia from ceftriaxone in an elderly patient: a case report J Am Med Dir Assoc 2008 9 8 610 611 10.1016/j.jamda.2008.05.001 19083297\n4. Cerynik DL Lee G Fayssoux R Amin NH Case report: cefazolin-induced hemolytic anemia Clin Orthop Relat Res 2007 459 260 262 10.1097/BLO.0b013e31803d3aad 17308481\n5. Macy E Contreras R Adverse reactions associated with oral and parenteral use of cephalosporins: a retrospective population-based analysis J Allergy Clin Immunol 2014 135 3 745 752 10.1016/j.jaci.2014.07.062 25262461\n6. Moghaddam M Razzaghi F Sheibani H Pourfathollah AA A fatal case of cefazolin-induced immune hemolytic anemia in Iran J Clin Exp Pathol 2016 10.4172/2161-0681.1000296\n7. Johnson ST Fueger JT Gottschall JL One center’s experience: the serology and drugs associated with drug-induced immune hemolytic anemia—a new paradigm Transfusion 2007 47 4 697 702 10.1111/j.1537-2995.2007.01173.x 17381629\n8. Johnson ST Drug-induced immune hemolytic anemia Transfus Apheres Sci 2009 40 3 205 207 10.1016/j.transci.2009.03.017\n9. Mine Y Nishida M Goto S Kuwahara S Studies on direct coombs reaction by cefazolin in vitro J Antibiot 1970 23 12 575 580 10.7164/antibiotics.23.575\n10. Wurpts G Aberer W Dickel H Guideline on diagnostic procedures for suspected hypersensitivity to beta-lactam antibiotics Allergo J Int 2019 28 121 151 10.1007/s40629-019-0100-8\n11. Shenoy ES Macy E Rowe T Blumenthal KG Evaluation and management of penicillin allergy: a review JAMA 2019 321 2 188 199 10.1001/jama.2018.19283 30644987\n12. Pipet A Veyrac G Wessel F A statement on cefazolin immediate hypersensitivity: data from a large database, and focus on the cross-reactivities Clin Exp Allergy 2011 41 11 1602 1608 10.1111/j.1365-2222.2011.03846.x 22093010\n13. Garraty G Immune hemolytic anemia associated with drug therapy Blood Rev 2010 24 4–5 143 150 10.1016/j.blre.2010.06.004 20650555\n\n",
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"title": "Cefazolin-induced hemolytic anemia: a case report and systematic review of literature.",
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"abstract": "Botulism is a rare and potentially fatal disease caused by toxins produced by Clostridum botulinum. This is a case report of severe and fatal food-borne botulism in a 59-year-old woman. She developed cardiac arrest shortly after admission, most likely due to paralysis of the respiratory muscles. Food botulism was suggested, and she was treated with antiserum pending confirmation of the diagnosis by detection of botulinum toxin in a serum sample. The source of botulism was never confirmed, but was likely to be home-canned fish.",
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"abstract": "Two children with developmental delay and seizure disorders had Fanconi syndrome associated with valproate therapy. Both recovered normal proximal tubular function within 4 months of discontinuing valproate therapy.",
"affiliations": "Division of Nephrology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.",
"authors": "Lande|M B|MB|;Kim|M S|MS|;Bartlett|C|C|;Guay-Woodford|L M|LM|",
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"abstract": "Mycophenolate mofetil (MMF) is a commonly used immunosuppressive drug in the management of transplant recipients. Gastrointestinal (GI) toxicity (diarrhea) is the most frequently reported adverse event in MMF-treated transplant patients. MMF-induced Graft versus Host Disease has rarely been reported in literature. We report a case of MMF-induced colitis with Graft versus Host Disease-like features, to highlight the importance of high clinical suspicion for its diagnosis, and that appropriate management in such a setting can reduce morbidity and mortality. We also review the relevant literature.",
"affiliations": "Department of Pathology, Global Hospitals and Health City, Chennai, Tamilnadu, India.",
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"title": "Mycophenolate mofetil-induced colitis with graft versus host disease-like features in a liver transplant recipient.",
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"abstract": "Continuous-flow left ventricular assist devices (LVAD) have become an increasingly utilized treatment strategy for patients with end-stage heart failure. Despite the improved outcomes evident with current generation pumps, proper patient selection remains crucial to minimize the risk of potential adverse events. The evolving use of these devices as destination therapy (DT) has led to growing numbers of patients with higher risk comorbid conditions being evaluated as potential LVAD candidates. Understanding which patient and disease-specific characteristics increase postoperative morbidity and mortality is paramount as this technology continues to expand and the experience with select populations remains limited. Presented here is a case of a patient with systemic lupus erythematosus receiving a HeartWare LVAD as DT complicated by recurrent, diffuse spontaneous bleeding. The case presented here highlights a potential unique bleeding complication in a high-risk patient cohort and underscores the need to enhance our understanding of factors influencing outcomes in high-risk populations after LVAD therapy.",
"affiliations": "From the Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio.;Department of Internal Medicine, University of Miami/Jackson Memorial Hospital, Miami, Florida.;Section of Heart Failure, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio.",
"authors": "Gage|Ann|A|;Blumer|Vanessa|V|;Joyce|Emer|E|",
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"title": "Lupus and Left Ventricular Assist Devices: High-Risk for Bleeding?",
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"abstract": "We report on a 32-year-old male patient presenting with anti-MDA-5 and anti-Ro52 antibody positive hypomyopathic dermatomyositis (CADM) with clinically leading interstitial pulmonary involvement. Under several immunosuppressive treatment regimens including high-dose steroids, cyclophosphamide, rituximab, immunoglobulins, plasmapheresis, ciclosporin and mycophenolate mofetil, pulmonary involvement was refractory to progressive. Based on the detection of a clear-cut interferon signature by flow cytometric determination of SIGLEC-1 as an interferon-dependent marker, treatment with the Janus kinase inhibitor tofacitinib was initiated. This resulted in a response to treatment with a significant increase in physical performance, an ameliorated skin condition and computed tomographic (CT) morphologically improved interstitial lung disease with overall good tolerability.",
"affiliations": "Medizinische Klinik D, Sektion Rheumatologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Deutschland. johannes.hornig@web.de.;Klinik für Pädiatrische Rheumatologie und Immunologie, Universitätsklinikum Münster, Münster, Deutschland.;Medizinische Klinik A, Sektion Pneumologie, Universitätsklinikum Münster, Münster, Deutschland.;Institut für klinische Radiologie, Universitätsklinikum Münster, Münster, Deutschland.;Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin Berlin, Berlin, Deutschland.;Medizinische Klinik D, Sektion Rheumatologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Deutschland.;Medizinische Klinik D, Sektion Rheumatologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Deutschland.;Medizinische Klinik D, Sektion Rheumatologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Deutschland.",
"authors": "Hornig|J|J|;Weinhage|T|T|;Schmidt|L H|LH|;Buerke|B|B|;Schneider|U|U|;Pavenstädt|H|H|;Becker|H|H|;Gabriëls|G|G|",
"chemical_list": "D001323:Autoantibodies; D007166:Immunosuppressive Agents; D000075242:Janus Kinase Inhibitors; D009173:Mycophenolic Acid",
"country": "Germany",
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"medline_ta": "Z Rheumatol",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D003882:Dermatomyositis; D006801:Humans; D007166:Immunosuppressive Agents; D000075242:Janus Kinase Inhibitors; D017563:Lung Diseases, Interstitial; D008297:Male; D009173:Mycophenolic Acid",
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"title": "Response of dermatomyositis with lung involvement to Janus kinase inhibitor treatment.",
"title_normalized": "response of dermatomyositis with lung involvement to janus kinase inhibitor treatment"
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"abstract": "BACKGROUND\nMaternal sartan intake during pregnancy has been associated with several fetal/neonatal complications related to disturbed renal development. Description of cases: We present two cases of neonatal acute kidney injury (AKI) following valsartan administration during pregnancy and provide evidence for the use of novel AKI biomarkers in these neonates. The first case was a female neonate, delivered at 32+4 weeks of gestation after maternal valsartan intake from 24 to 32 gestational weeks. In the second case, ultrasound examination revealed a growth-restricted fetus with severe oligohydramnios following maternal valsartan intake during the first 29 gestational weeks. In the absence of any improvement in amniotic fluid, the neonate was born at 31+5 weeks. In both cases, AKI was documented after birth, but renal function progressively recovered. Urine cystatin-C and neutrophil gelatinase-associated lipocalin were found abnormally increased during the first week of life.\n\n\nCONCLUSIONS\nSartan use during pregnancy is associated with the development of neonatal AKI. Novel urine biomarkers may be used to document renal injury. Hippokratia 2016, 20(1): 73-75.",
"affiliations": "1st Department of Neonatology and Intensive Care Unit, Aristotle University of Thessaloniki, Hippokratio General Hospital, Thessaloniki, Greece.;1st Department of Neonatology and Intensive Care Unit, Aristotle University of Thessaloniki, Hippokratio General Hospital, Thessaloniki, Greece.;2nd Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Hippokratio General Hospital, Thessaloniki, Greece.;2nd Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Hippokratio General Hospital, Thessaloniki, Greece.;1st Department of Neonatology and Intensive Care Unit, Aristotle University of Thessaloniki, Hippokratio General Hospital, Thessaloniki, Greece.",
"authors": "Tsepkentzi|E|E|;Sarafidis|K|K|;Sotiriadis|A|A|;Chatzistamatiou|K|K|;Drossou-Agakidou|V|V|",
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"issn_linking": "1108-4189",
"issue": "20(1)",
"journal": "Hippokratia",
"keywords": "Valsartan; cystatin-C; neonate; neutrophil gelatinase-associated lipocalin; pregnancy",
"medline_ta": "Hippokratia",
"mesh_terms": null,
"nlm_unique_id": "101296613",
"other_id": null,
"pages": "73-75",
"pmc": null,
"pmid": "27895448",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "23771844;15329835;15590878;21271514;14632309;22424940;24022367;22816796;8518103;16427219;21823839;22532328;18412789",
"title": "Neonatal acute kidney injury following Valsartan exposure in utero: report of two cases.",
"title_normalized": "neonatal acute kidney injury following valsartan exposure in utero report of two cases"
} | [
{
"companynumb": "GR-ALEMBIC PHARMACUETICALS LIMITED-2016SCAL000818",
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"abstract": "The use of high-dose intravenous immunoglobulin (IVIG) is an accepted therapy for patients with refractory dermatomyositis. Cases of eczematous reactions to IVIG have been reported in the literature, but to our knowledge, none in patients being treated for dermatomyositis. We report on the cases of two female patients with refractory dermatomyositis who developed pruritic, scaly pink plaques after receiving high-dose IVIG. This diffuse eczematous skin reaction to high-dose IVIG is a rare adverse event that most often occurs days after administration of therapy. Practitioners should be aware of this entity because the eczematous eruption may be extensive and can commonly worsen with subsequent re-exposure to IVIG.",
"affiliations": "The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York.;Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, New York.;The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York.;The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York.",
"authors": "Berk-Krauss|J|J|;Lee|K|K|;Lo Sicco|K I|KI|;Liebman|T N|TN|",
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"doi": "10.1016/j.ijwd.2018.03.004",
"fulltext": "\n==== Front\nInt J Womens DermatolInt J Womens DermatolInternational Journal of Women's Dermatology2352-6475Elsevier S2352-6475(18)30015-710.1016/j.ijwd.2018.03.004ArticleEczematous reaction to IVIG for the treatment of dermatomyositis☆☆☆ Berk-Krauss J. abLee K. cLo Sicco K.I. aLiebman T.N. Tracey.Liebman@nyumc.orga⁎a The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New Yorkb Yale School of Medicine, New Haven, Connecticutc Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, New York⁎ Corresponding Author. Tracey.Liebman@nyumc.org23 6 2018 9 2018 23 6 2018 4 3 170 173 17 11 2017 10 3 2018 11 3 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).The use of high-dose intravenous immunoglobulin (IVIG) is an accepted therapy for patients with refractory dermatomyositis. Cases of eczematous reactions to IVIG have been reported in the literature, but to our knowledge, none in patients being treated for dermatomyositis. We report on the cases of two female patients with refractory dermatomyositis who developed pruritic, scaly pink plaques after receiving high-dose IVIG. This diffuse eczematous skin reaction to high-dose IVIG is a rare adverse event that most often occurs days after administration of therapy. Practitioners should be aware of this entity because the eczematous eruption may be extensive and can commonly worsen with subsequent re-exposure to IVIG.\n\nKeywords\nintravenous immunoglobulindermatomyositisdrug reactioneczematous skin eruptionimmunomodulatorssystemic steroid medications\n==== Body\nIntroduction\nIntravenous immunoglobulin (IVIG) is an accepted off-label immunomodulatory therapy for patients with refractory dermatomyositis (Dalakas et al., 1993). The most common adverse reactions to IVIG are mild and transient, present in approximately one-third of patients, and include fatigue, chills, headache, myalgias, and nausea (Brannagan III et al., 1996, Gerstenblith et al., 2012, Kazatchkine and Kaveri, 2001, Orbach et al., 2005). Rare side effects include aseptic meningitis, hemolytic anemia, thrombosis, anaphylactic shock, and acute renal failure (Brannagan III et al., 1996, Gerstenblith et al., 2012, Misbah and Chapel, 1993, Orbach et al., 2005, Tan et al., 1993). Cutaneous adverse events can occur in up to 6% of patients, with reports of morbilliform eruptions, pruritus, urticaria, alopecia, and erythema multiforme (Brannagan III et al., 1996, Chan-Lam et al., 1987, Gerstenblith et al., 2012, Misbah and Chapel, 1993, Orbach et al., 2005, Rodeghiero et al., 1988, Vecchietti et al., 2006).\n\nAlthough rare, eczematous eruptions have been described in patients treated with IVIG. The most extensive literature review of eczematous skin reactions to IVIG was conducted in 2011. Of the 64 identified cases, 86% were treated for neurologic diseases (none for dermatomyositis) and the vast majority of eczematous eruptions (77%) occurred within 8 days of treatment (Gerstenblith et al., 2012). We present the cases of two female patients with dermatomyositis who developed eczematous eruptions that appeared after receiving IVIG.\n\nCase 1\nA 42-year old woman with a history of dermatomyositis presented to her rheumatologist for a flare up of arthritis, fatigue, and Gottron’s papules while on methotrexate 20 mg and long-standing systemic steroids. Methotrexate was discontinued due to pulmonary basilar fibrosis that was evident on a computed tomography (CT) scan, and she was started on IVIG 2 g/kg divided over 2 consecutive days.\n\nSeven weeks after the IVIG infusion, while tapering off of prednisone, the patient developed a pruritic, scaly eruption on the face, trunk, palms, arms, and legs. Her cutaneous symptoms initially improved with topical hydrocortisone. However, 1 week later, this eruption recurred 2 days after receiving the second IVIG course while off of systemic steroids.\n\nOn physical examination after the second eruption, the patient had diffuse erythematous scaly plaques on the trunk and the bilateral upper and lower extremities (Fig. 1) as well as mild desquamation on the lips and scaling at the lateral edge of the right palm. Baseline dermatomyositis findings of Gottron’s papules over the dorsal surface of the metacarpophalangeal joints were also noted.Fig. 1 Eczematous eruption of patient 1: Representative clinical image of right ventral forearm\n\nFig. 1\n\nThe patient reported no further cutaneous reactions after her third and fourth IVIG treatments, which were administered over 4 days and when she was no longer taking systemic steroids. She did experience an improvement in her skin and articular disease.\n\nCase 2\nA 27-year old woman presented to her dermatologist with refractory dermatomyositis. Previous therapies included hydroxychloroquine, which caused a cutaneous reaction, and methotrexate, which resulted in no clinical improvement. She was started on IVIG 2 g/kg divided over 3 days.\n\nOne week after the first IVIG dose, the patient developed a pruritic eruption on the neck and small, clear vesicles on the hands. There was no involvement of the feet. After topical triamcinolone treatment, the patient reported some improvement of the eruption.\n\nOn physical examination, erythematous scaly thin plaques on the neck and bilateral axillae were noted (Fig. 2). Small 1 mm to 2 mm vesicles were seen on the bilateral palms and lateral digits (Fig. 3). There were pink to violaceous patches on the bilateral lateral arms, chest, and back that were stable from her prior examination. Baseline dermatomyositis findings of Gottron’s papules over the dorsal surface of the metacarpophalangeal joints and faint erythematous patches on the cheeks and nose were reduced in size from the prior examination. There was no visible swelling or tenderness to palpation of the joints.Fig. 2 Eczematous eruption or patient 2: Representative clinical image of left axilla\n\nFig. 2Fig. 3 Eczematous eruption of patient 2: Representative clinical image of left second digit\n\nFig. 3\n\nThe patient reported a subtler reaction to her subsequent IVIG dose, which was administered over 4 days. She experienced only mild pruritus and a few vesicles on bilateral palms.\n\nDiscussion\nIVIG is an accepted therapy for patients with a variety of autoimmune, inflammatory, dermatologic, hematologic, and neurologic disorders (Kazatchkine and Kaveri, 2001). One such example is dermatomyositis. Dermatologists should be aware that IVIG can cause rare dermatologic side effects, including this entity of diffuse eczematous skin eruption. This reaction most often occurs within days after administration of therapy, typically beginning as dyshidrotic lesions on the palms or soles with subsequent progression into a more diffuse eczematous eruption (Vecchietti et al., 2006). Systemic glucocorticoids may be used as complementary therapy in patients with dermatomyositis and thus could mask or delay rare but significant immune-mediated adverse reactions to IVIG. Patient 1 experienced a delayed reaction to high-dose IVIG that occurred several weeks after dose administration and at the end of her prednisone taper.\n\nThe exact mechanism of this cutaneous reaction has not been established. However, the eruption typically wanes over a period of a few weeks in response to topical steroids (Gerstenblith et al., 2012, Vecchietti et al., 2006). Since the eczematous reaction is often manageable, IVIG is commonly recommended to be continued for patients who demonstrate clinical improvement (Gerstenblith et al., 2012). Switching the type of IVIG preparation has resulted in variable responses in the literature (Gerstenblith et al., 2012). Both of our patients experienced either no or less of a reaction when the same IVIG preparation was administered over a longer time course. Dermatologists should be aware of this entity as the eczematous eruption may be extensive and can worsen with subsequent re-exposure to high-dose IVIG.\n\n☆ Funding sources: None.\n\n☆☆ Conflicts of interest: None declared.\n==== Refs\nReferences\nBrannagan T.H. III Nagle K.J. Lange D.J. Rowland L.P. Complications of intravenous immune globulin treatment in neurologic disease Neurology 47 3 1996 674 677 8797463 \nChan-Lam D. Fitzsimons E.J. Douglas W.S. Alopecia after immunoglobulin infusion Lancet 1 8547 1987 1436 \nDalakas M.C. Illa I. Dambrosia J.M. Soueidan S.A. Stein D.P. Otero C. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis N Engl J Med 329 27 1993 1993 2000 8247075 \nGerstenblith M.R. Antony A.K. Junkins-Hopkins J.M. Abuav R. Pompholyx and eczematous reactions associated with intravenous immunoglobulin therapy J Am Acad Dermatol 66 2 2012 312 316 21601310 \nKazatchkine M.D. Kaveri S.V. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin N Engl J Med 345 10 2001 747 755 11547745 \nMisbah S.A. Chapel H.M. Adverse effects of intravenous immunoglobulin Drug Saf 9 4 1993 254 262 8260119 \nOrbach H. Katz U. Sherer Y. Shoenfeld Y. Intravenous immunoglobulin: Adverse effects and safe administration Clin Rev Allergy Immunol 29 3 2005 173 184 16391392 \nRodeghiero F. Castaman G. Vespignani M. Dini E. Bertazzoni M. Erythema multiforme after intravenous immunoglobulin Blut 56 3 1988 145 3128353 \nTan E. Hajinazarian M. Bay W. Neff J. Mendell J.R. Acute renal failure resulting from intravenous immunoglobulin therapy Arch Neurol 50 2 1993 137 139 8431131 \nVecchietti G. Kerl K. Prins C. Kaya G. Saurat J.H. French L.E. Severe eczematous skin reaction after high-dose intravenous immunoglobulin infusion: Report of 4 cases and review of the literature Arch Dermatol 142 2 2006 213 217 16490849\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-6475",
"issue": "4(3)",
"journal": "International journal of women's dermatology",
"keywords": "dermatomyositis; drug reaction; eczematous skin eruption; immunomodulators; intravenous immunoglobulin; systemic steroid medications",
"medline_ta": "Int J Womens Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101654170",
"other_id": null,
"pages": "170-173",
"pmc": null,
"pmid": "30175220",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports",
"references": "3128353;11547745;8247075;21601310;16391392;2884527;8260119;8797463;16490849;8431131",
"title": "Eczematous reaction to IVIG for the treatment of dermatomyositis.",
"title_normalized": "eczematous reaction to ivig for the treatment of dermatomyositis"
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{
"companynumb": "US-ORION CORPORATION ORION PHARMA-18_00004508",
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"abstract": "BACKGROUND\nThe current study was performed to determine the efficacy and safety of first-line combination therapy with bevacizumab, paclitaxel, and capecitabine for triple-negative, locally advanced/metastatic breast cancer (LA/MBC).\n\n\nMETHODS\nPatients with measurable triple-negative LA/MBC who had received no prior chemotherapy for their disease received 4-weekly cycles of paclitaxel (80 mg/m2 on days 1, 8, and 15 for up to 6 cycles) combined with capecitabine (800 mg/m2 twice daily on days 1-5, 8-12, and 15-19) and bevacizumab (10 mg/kg on days 1 and 14) repeated every 4 weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was the objective response rate; secondary endpoints were progression-free survival, duration of response, overall survival, and safety.\n\n\nRESULTS\nBetween April 2010 and March 2012, 62 eligible patients were enrolled. The median age of the patients was 57 years, 74% had received adjuvant chemotherapy, and 65% had visceral metastases. Patients received a median of 6 cycles (range, 1-45 cycles). The objective response rate was 77% (95% confidence interval [95% CI] 66%-88%), including complete response in 19% of patients. The median duration of response was 5.6 months (range, 1.3-27.6 months). The median progression-free survival was 7.6 months (95% CI, 6.3-9.0 months) and the median overall survival was 19.2 months (95% CI, 17.4-20.9 months). The most common grade ≥3 adverse events were hypertension (35% of patients) and neutropenia (23% of patients); 5% of patients experienced febrile neutropenia. Grade ≥2 hand-foot syndrome, alopecia, and nail toxicity each occurred in 40% of patients (adverse events were recorded before every cycle and graded according to Common Terminology Criteria for Adverse Events [version 4.0]). Treatment was interrupted because of toxicity in 22% of patients.\n\n\nCONCLUSIONS\nA triplet regimen of paclitaxel, capecitabine, and bevacizumab followed by maintenance therapy with capecitabine and bevacizumab demonstrated high activity and manageable safety in this difficult-to-treat population. Cancer 2016;122:3119-26. © 2016 American Cancer Society.",
"affiliations": "Department of Medical Oncology, Antoine-Lacassagne Centre, Nice, France. jean-marc.ferrero@nice.unicancer.fr.;Armorican Radiology Clinic, Saint-Brieuc, France.;Department of Medical Oncology, Paul Papin Western Oncology Institute, Angers, France.;Catherine of Sienne Centre, Nantes, France.;Department of Medical Oncology, William Morey Hospital, Chalon-sur-Saone, France.;Department of Medical Oncology, Antoine-Lacassagne Centre, Nice, France.;Clairval Private Hospital, Marseille, France.;Department of Medical Oncology, Lorraine Cancer Institute, Vandoeuvre-les-Nancy, France.;Department of Medical Oncology, Mont de Marsan Hospital, Mont de Marsan, France.;Department of Medical Oncology, Le Mans Hospital, Le Mans, France.;Azure Cancer Centre, Mougins, France.",
"authors": "Ferrero|Jean-Marc|JM|;Hardy-Bessard|Anne-Claire|AC|;Capitain|Olivier|O|;Lortholary|Alain|A|;Salles|Bruno|B|;Follana|Philippe|P|;Herve|Robert|R|;Deblock|Mathilde|M|;Dauba|Jérôme|J|;Atlassi|Mustapha|M|;Largillier|Rémy|R|",
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"issue": "122(20)",
"journal": "Cancer",
"keywords": "bevacizumab; capecitabine; combination chemotherapy; maintenance therapy; metastatic breast cancer; triple negative",
"medline_ta": "Cancer",
"mesh_terms": "D002288:Adenocarcinoma, Mucinous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D000069287:Capecitabine; D018270:Carcinoma, Ductal, Breast; D018275:Carcinoma, Lobular; D017024:Chemotherapy, Adjuvant; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D017239:Paclitaxel; D011379:Prognosis; D012074:Remission Induction; D015996:Survival Rate; D064726:Triple Negative Breast Neoplasms",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "3119-3126",
"pmc": null,
"pmid": "27412268",
"pubdate": "2016-10-15",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Weekly paclitaxel, capecitabine, and bevacizumab with maintenance capecitabine and bevacizumab as first-line therapy for triple-negative, metastatic, or locally advanced breast cancer: Results from the GINECO A-TaXel phase 2 study.",
"title_normalized": "weekly paclitaxel capecitabine and bevacizumab with maintenance capecitabine and bevacizumab as first line therapy for triple negative metastatic or locally advanced breast cancer results from the gineco a taxel phase 2 study"
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"abstract": "Although the use of treosulfan (TREO) in conventional donor hematopoietic cell transplantation (HCT) has been extensively evaluated, its use in cord blood transplantation (CBT) for hematologic malignancies has not been reported. Between March 2009 and October 2019, 130 CBT recipients were enrolled in this prospective multicenter phase 2 study. The conditioning regimen consisted of TREO, fludarabine, and a single fraction of 2 Gy total-body irradiation. Cyclosporine and mycophenolate mofetil were used for graft-versus-host disease prophylaxis. The primary end point was incidence of graft failure (GF), and based on risk of GF, patients were classified as low risk (arm 1, n = 66) and high risk (arm 2, n = 64). The median age was 45 years (range, 0.6-65 years). Disease status included acute leukemias in first complete remission (CR; n = 56), in ≥2 CRs (n = 46), and myelodysplastic (n = 25) and myeloproliferative syndromes (n = 3). Thirty-five patients (27%) had received a prior HCT. One hundred twenty-three patients (95%) engrafted, with neutrophil recovery occurring at a median of 19 days for patients on arm 1 and 20 days for patients on arm 2. The 3-year overall survival, relapse-free survival (RFS), transplant-related mortality, and relapse for the combined groups were 66%, 57%, 18%, and 24%, respectively. Among patients who had a prior HCT, RFS at 3 years was 48%. No significant differences in clinical outcomes were seen between the 2 arms. Our results demonstrate that TREO-based conditioning for CBT recipients is safe and effective in promoting CB engraftment with favorable clinical outcomes. This trial was registered at www.clinicaltrials.gov as #NCT00796068.",
"affiliations": "Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.;Division of Hematology, University of Colorado, Denver, CO.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.;Division of Hematology Oncology, Oregon Health & Science University, Portland, OR.;Medac GmbH, Wedel, Germany; and.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.",
"authors": "Milano|Filippo|F|;Gutman|Jonathan A|JA|;Deeg|H Joachim|HJ|;Nemecek|Eneida R|ER|;Baumgart|Joachim|J|;Thur|Laurel|L|;Dahlberg|Ann|A|;Salit|Rachel B|RB|;Summers|Corinne|C|;Appelbaum|Frederick R|FR|;Delaney|Colleen|C|",
"chemical_list": "C018404:treosulfan; D002066:Busulfan",
"country": "United States",
"delete": false,
"doi": "10.1182/bloodadvances.2020002222",
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"fulltext_license": null,
"issn_linking": "2473-9529",
"issue": "4(14)",
"journal": "Blood advances",
"keywords": null,
"medline_ta": "Blood Adv",
"mesh_terms": "D002066:Busulfan; D005312:Fetal Blood; D006086:Graft vs Host Disease; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies",
"nlm_unique_id": "101698425",
"other_id": null,
"pages": "3302-3310",
"pmc": null,
"pmid": "32706891",
"pubdate": "2020-07-28",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "17222756;18246351;29247780;12064362;12947008;7581076;26409924;20081862;19660726;20686119;23241738;29274396;16338616;18492101;17569820;30668198;9828244;21659356;19104080;21527516;20697368;26367221;18986389;8657213;19041062;21988645;17310135;18410902;23416850;12176879;26238810;29155317;29753157;27602666;21937692;9241126;31606445",
"title": "Treosulfan-based conditioning is feasible and effective for cord blood recipients: a phase 2 multicenter study.",
"title_normalized": "treosulfan based conditioning is feasible and effective for cord blood recipients a phase 2 multicenter study"
} | [
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"companynumb": "NVSC2020US221285",
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"activesubstancename": "CYCLOSPORINE"
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"drugadditional": "3",
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"abstract": "Bipolar disorder is a mental illness with a lifetime prevalence of 2% and has a dramatic impact on quality of life. Mania is a distinct period of abnormal and sustained elevated, expansive, or irritable mood and increase in goal-directed activity or energy that lasts at least 1 week and is present for most of each day. Quetiapine is an atypical antipsychotic approved for the treatment of bipolar depression and mania. For the treatment of acute mania, a dose of 600 to 800 mg/day is recommended. There has been concern of potential induction or worsening of hypomanic or manic symptoms at low doses via the ratio of 5HT2A/D2 receptor antagonism, which at lower doses favors greater 5HT2A receptor blockade and thus increases dopamine concentrations. This article describes a case report of hypomania worsening to mania with psychotic features in a drug-naïve patient who was started on low-dose quetiapine. This case adds to the existing literature of case reports indicating that low-dose quetiapine may be associated with induction or worsening of hypomanic/manic symptoms, while acknowledging the difficulty of suggesting a causal relationship.",
"affiliations": "From the Department of Psychiatry, Geisel School of Medicine, Dartmouth University, Dartmouth-Hitchcock Medical Center, Lebanon, NH. hun.millard@yale.edu.;From the Department of Psychiatry, Geisel School of Medicine, Dartmouth University, Dartmouth-Hitchcock Medical Center, Lebanon, NH.;From the Department of Psychiatry, Geisel School of Medicine, Dartmouth University, Dartmouth-Hitchcock Medical Center, Lebanon, NH.",
"authors": "Millard|Hun Y|HY|;Wilson|Barbara A|BA|;Noordsy|Douglas L|DL|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate",
"country": "United States",
"delete": false,
"doi": "10.3122/jabfm.2015.01.140105",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1557-2625",
"issue": "28(1)",
"journal": "Journal of the American Board of Family Medicine : JABFM",
"keywords": "Bipolar Disorder; Mental Health; Pharmacotherapy; Psychiatry; Quetiapine",
"medline_ta": "J Am Board Fam Med",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D003987:Dibenzothiazepines; D006708:Homicide; D006801:Humans; D008297:Male; D000069348:Quetiapine Fumarate",
"nlm_unique_id": "101256526",
"other_id": null,
"pages": "154-8",
"pmc": null,
"pmid": "25567837",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Low-dose quetiapine induced or worsened mania in the context of possible undertreatment.",
"title_normalized": "low dose quetiapine induced or worsened mania in the context of possible undertreatment"
} | [
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"companynumb": "US-ROXANE LABORATORIES, INC.-2015-RO-02105RO",
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
"d... |
{
"abstract": "Direct oral anticoagulants, such as apixaban, are increasingly used in everyday practice in order to treat or prevent thromboembolic diseases. To date, there is no available data about apixaban pharmacokinetics in children, and no intoxication has previously been described.\n\n\n\nA 23-month-old boy, with no medical history, was admitted to the emergency department 2 h after accidentally ingesting 40 mg apixaban and 0.75 mg digoxin. No adverse event was observed. Digoxin trough level was within therapeutic values. Apixaban blood concentration increased up to 1712 μg/L at H + 6 (1000-2750 μg/L using 2-5 mg/kg of apixaban in adults). The terminal half-life was 8.2 h (6-15 h in adults). The rapid elimination may explain the absence of bleeding despite high concentrations.\n\n\n\nDespite an important intake of apixaban and a real disturbance in routine coagulation assays, no clinical sign of bleeding was observed, perhaps due to wide therapeutic range of apixaban. It may also be explained by its rapid elimination. Considering the high Cmax and a possible enteroenteric recycling, the use of activated charcoal should be considered in such situations in order to prevent eventual bleeding.",
"affiliations": "Laboratoire de Pharmacologie-Toxicologie-Gaz du Sang, CHU Saint-Etienne, Albert Raimond avenue, Saint-Etienne, France. manon.launay@chu-st-etienne.fr.;Laboratoire de Pharmacologie-Toxicologie-Gaz du Sang, CHU Saint-Etienne, Albert Raimond avenue, Saint-Etienne, France.;Laboratoire d'analyses médicales, CH Emile Roux, le Puy-en-Velay, France.;Service de Médecine Intensive et Réanimation Pédiatrique, CHU Saint-Etienne, Saint-Etienne, France.;Laboratoire de Pharmacologie-Toxicologie-Gaz du Sang, CHU Saint-Etienne, Albert Raimond avenue, Saint-Etienne, France.",
"authors": "Launay|Manon|M|0000-0003-3113-7301;Nasser|Yara|Y|;Maubert|Isabelle|I|;Chaux|Anne-Cécile|AC|;Delavenne|Xavier|X|",
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"fulltext": "\n==== Front\nBMC Pediatr\nBMC Pediatr\nBMC Pediatrics\n1471-2431 BioMed Central London \n\n2448\n10.1186/s12887-020-02448-4\nCase Report\nAccidental apixaban intoxication in a 23-month-old child: a case report\nhttp://orcid.org/0000-0003-3113-7301Launay Manon manon.launay@chu-st-etienne.fr 1 Nasser Yara 1 Maubert Isabelle 2 Chaux Anne-Cécile 3 Delavenne Xavier 14 1 grid.412954.f0000 0004 1765 1491Laboratoire de Pharmacologie-Toxicologie-Gaz du Sang, CHU Saint-Etienne, Albert Raimond avenue, Saint-Etienne, France \n2 Laboratoire d’analyses médicales, CH Emile Roux, le Puy-en-Velay, France \n3 grid.412954.f0000 0004 1765 1491Service de Médecine Intensive et Réanimation Pédiatrique, CHU Saint-Etienne, Saint-Etienne, France \n4 grid.7849.20000 0001 2150 7757INSERM U1059, Dysfonctions Vasculaires et de l’Hémostase, Université de Lyon, Saint-Etienne, France \n5 12 2020 \n5 12 2020 \n2020 \n20 54630 9 2020 30 11 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nDirect oral anticoagulants, such as apixaban, are increasingly used in everyday practice in order to treat or prevent thromboembolic diseases. To date, there is no available data about apixaban pharmacokinetics in children, and no intoxication has previously been described.\n\nCase presentation\nA 23-month-old boy, with no medical history, was admitted to the emergency department 2 h after accidentally ingesting 40 mg apixaban and 0.75 mg digoxin. No adverse event was observed. Digoxin trough level was within therapeutic values. Apixaban blood concentration increased up to 1712 μg/L at H + 6 (1000–2750 μg/L using 2–5 mg/kg of apixaban in adults). The terminal half-life was 8.2 h (6–15 h in adults). The rapid elimination may explain the absence of bleeding despite high concentrations.\n\nConclusions\nDespite an important intake of apixaban and a real disturbance in routine coagulation assays, no clinical sign of bleeding was observed, perhaps due to wide therapeutic range of apixaban. It may also be explained by its rapid elimination. Considering the high Cmax and a possible enteroenteric recycling, the use of activated charcoal should be considered in such situations in order to prevent eventual bleeding.\n\nKeywords\nApixabanDOACPediatricsIntoxicationPharmacokineticsChildOverdoseDigoxinCase reportissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nDirect oral anticoagulants, such as apixaban, are increasingly used in everyday practice in order to treat or prevent thromboembolic diseases [1, 2]. Apixaban is a reversible and selective FXa inhibitor (activated factor X) and inhibits free, clot-bound FXa, and prothrombinase activity [3]. Apixaban has linear pharmacokinetics, and concentration-related pharmacodynamic effects have been described in adults [4]. Many clinical cases reported severe self-poisoning with apixaban among adult patients [5–9]. To date, there is no available data about apixaban pharmacokinetics in children, and no intoxication has previously been described. Digoxin, on the other hand, is better known in pediatrics as it is commonly used for arrhythmias and heart failure treatment.\n\nCase presentation\nA 23-month-old boy (12.9 Kg), with no medical history, was admitted to the emergency department 2 h after accidentally ingesting 8 pills of apixaban 5 mg (40 mg) and 3 pills of digoxin 0.25 mg (0.75 mg). His clinical exam was normal. No hemorrhagic sign was identified. His heart rate (105 pulsations/minute) and the ECG were normal. The child remained under medical supervision for 48 h. Four blood tests were withdrawn during hospitalization at 2, 6, 21.5 and 48 h after the ingestion (H + 2, H + 6, H + 21.5, H + 48), for digoxin concentrations monitoring and routine coagulation assays. After H + 6, the child was transferred to the University Hospital of Saint Etienne, where apixaban monitoring was available using a published Liquid Chromatography-Mass Spectrometry method [10]. Apixaban monitoring was initiated at H + 21.5. Apixaban concentrations were also retrospectively analyzed at H + 2 and H + 6. The renal function was normal and remained stable (Creatinine between 17 and 24 μmol/L (normal range: 15–35 μmol/L [11])). No clinical sign of bleeding was observed. Apixaban concentration increased up to 1712 μg/L at H + 6, then decreased to 7 μg/L at H + 48 (Fig. 1). Apixaban was eliminated with a terminal half-life of 8.2 h and its distribution volume indexed to bioavailability was 23 L or 1.8 L/Kg. As expected, aPTT ratio (activated partial thromboplastin time ratio: Patient aPTT (sec) /Normal plasma aPTT (sec)) and PT were prolonged [4] (Fig. 1).\nFig. 1 Variation of apixaban (μg/L), PT (%) (blue line) and aPTT ratio (red line) of a 23-month-old child at different times after accidentally ingesting 40 mg of apixaban and 0.75 mg of digoxin\n\n\n\nRegarding digoxin, the concentration at H + 2 was 5.9 μg/L and decreased to 0.4 μg/L at H + 48. Digoxin was eliminated with a half-life of approximatively 15.6 h.\n\nThe patient left the hospital after 48 h without any complication or sequelae.\n\nDiscussion/conclusion\nTo our knowledge, this is the first case reporting apixaban intoxication in children. Apixaban blood concentration increased up to a high level of 1712 μg/L at H + 6 after ingesting 40 mg of apixaban (3.1 mg/Kg). Cmax was consistent with data in adults overdose (between 1000 and 2750 μg/L after ingesting 2 to 5 mg/kg of apixaban) [5, 6].\n\nDespite multiple ongoing studies on apixaban in the pediatric population [12–15], there is currently no available data on apixaban pharmacokinetics and pharmacodynamics properties among children. As previously reported, the apixaban plasma concentration vs. time profile exhibited a multiphasic elimination profile, with an initial rapid decline followed by a more gradual terminal phase [4]. Apixaban was eliminated with a terminal half-life of 8.2 h. The half-life described in adults overdose was between 6 h and 15 h depending on the patient and other co-administered drugs [6–9]. The rapid elimination may explain the absence of bleeding despite high concentrations. The results observed during the clinical development of new oral anticoagulants have shown that the inexplicable variability of drug response is quite low in highly selected populations, so there is no sense in recommending drug monitoring for such patients. However, sources of inter- and intra-individual variability (such as renal and/or hepatic function, advanced age, relevant drug-drug interaction, …) have been identified, concerning a restricted population at very high risk of clinical events [16]. Drug overdose could also be at high risk of clinical event and the monitoring of apixaban concentrations should be assessed for these patients, if available. As no apixaban dosage was performed within the first 20 h after the ingestion, the patient was followed-up with PT and aPTT ratio monitoring. As expected, because apixaban is a reversible anti-Xa with concentration-related pharmacodynamic effects, aPTT ratio and PT were prolonged with an interesting overlap as shown in Fig. 1. Thus, routine coagulation assays could be monitored when apixaban monitoring is not available. The distribution volume indexed to bioavailability was markedly different than the one reported in adults, 23 L vs 73 L in adults, or 1.8 L/Kg vs 0.9 L/Kg [4].\n\nFurthermore, a peak concentration was probably reached between H + 2 and H + 6 and apixaban was still detectable at H + 48 (Fig. 1), with a possible enteroenteric recycling (i.e., reabsorption of drug excreted from the systemic circulation directly into the intestine) [17]. The use of activated charcoal in similar cases would be interesting in order to prevent eventual bleeding. A 28% decrease in apixaban exposure was indeed observed following administration of activated charcoal at 6 h post-dose [17]. Apixaban monitoring was done retrospectively in this case, and no antidote was administered but no side effect was reported.\n\nThe patient has also ingested 0.75 mg (0.06 mg/kg) of digoxin when the mean therapeutic dose is around 0.01 mg/kg/day for children [18–20]. The half-life was 15.6 h, a figure markedly shorter than the described half-life in the pediatric population (36 h) [18, 19]. Digoxin pharmacokinetic parameters have indeed already shown extensive variation in children, with clearance ranging from 6.0 to 3331.8 mL/kg/h [21]. Digoxin level at 24 h was 1.3 μg/L, which is an usual therapeutic value [18–20, 22], and no adverse event was observed. Toxicity (such as nausea, vomiting and ECG abnormalities, etc.) is indeed frequently reported for trough level greater than 2 μg/L [20, 22].\n\nDespite an important intake of apixaban and a real disturbance in routine coagulation assays, no clinical sign of bleeding was observed, perhaps due to wide therapeutic range of apixaban. It may also be explained by its rapid elimination. Considering the high Cmax and a possible enteroenteric recycling, the use of activated charcoal should be considered in such situations in order to prevent eventual bleeding.\n\nAbbreviations\naPTTactivated partial thromboplastin time\n\nFXaactivated factor X\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nA-C.C collected clinical data, Y. N, ML and IM collected biological data, M. L, Y. N, X. D contributed to data interpretation and writing of manuscript; all authors contributed to reviewed and approved the final version of the manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nA written and signed consent to publish the information was obtained from the guardians prior to submission.\n\nCompeting interests\nNone.\n==== Refs\nReferences\n1. Gross PL Weitz JI New anticoagulants for treatment of venous thromboembolism Arterioscler Thromb Vasc Biol 2008 28 380 386 10.1161/ATVBAHA.108.162677 18296593 \n2. Metha RS Novel oral anticoagulants for prophylaxis and treatment of venous thromboembolism: part I (factor Xa inhibitors) expert Rev Hematol 2019 3 227 241 \n3. Wieland E Shipkova M Pharmacokinetic and Pharmacodynamic drug monitoring of direct-acting Oral anticoagulants: where do we stand? Ther Drug Monit 2019 41 2 180 191 10.1097/FTD.0000000000000594 30883512 \n4. Frost C Wang J Nepal S Schuster A Barett YC Mosqueda-Garcia R Reeves RA LaCreta F Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects Br J Clin Pharmacol 2013 75 2 476 487 10.1111/j.1365-2125.2012.04369.x 22759198 \n5. Ilicki J Höjer J Djärv T Massive apixaban overdose - a comparison of three cases Am J Emerg Med 2018 36 5 891 893 10.1016/j.ajem.2017.09.035 28964584 \n6. Franck B Dulaurent S El Balkhi S Monchaud C Picard N Couderc S Marquet P Saint-Marcoux F Woillard JB Self-poisoning with 60 tablets of Apixaban, a pharmacokinetics case report Br J Clin Pharmacol 2019 85 1 270 272 10.1111/bcp.13790 30421528 \n7. Barton J Wong A Graudins A Anti-Xa activity overdose: a case report Clin Toxicol 2016 20 9 1 6 \n8. Mast L Rj V Reijnen R van Rossen RCJM Overdiek JWPM Wilms EB Apixaban auto-intoxication: Toxicokinetics and coagulation tests Thromb Haemost 2017 117 2209 2211 10.1160/th17-07-0474 28981556 \n9. Leikin SM Patel H Welker KL Leikin JB The X factor: lack of bleeding after an acute apixaban overdose Am J Emerg Med 2017 35 05 801.e5 801.e6 10.1016/j.ajem.2016.11.035 \n10. Delavenne X Mismetti P Basset T Rapid determination of apixaban concentration in human plasma by liquid chromatography /tandem mass spectrometry: application to pharmacokinetic study J Pharm Biomed Anal 2013 78-79 150 153 10.1016/j.jpba.2013.02.007 23499913 \n11. Pottel H Vrydags N Mahieu B Vandewynckele E Croes K Martens F Establishing age/sex related serum creatinine reference intervals from hospital laboratory data based on different statistical methods Clin Chim Acta 2008 396 1–2 49 55 10.1016/j.cca.2008.06.017 18621041 \n12. Von Vajna E Alam R So TY Current clinical trials on the use of direct Oral anticoagulants in the pediatric population Cardiol Ther 2016 5 19 41 10.1007/s40119-015-0054-y 26739579 \n13. Radulescu VC Anticoagulation therapy in children Semin Thromb Hemost 2017 43 877 885 10.1055/s-0036-1598004 28346967 \n14. Payne M Burns K Glatz A Li D Li X Monagle P Newburger J Swan E Wheaton O Male C A multi-national trial of a direct oral anticoagulant in children with cardiac disease: design and rationale of the safety of ApiXaban on pediatric heart disease on the preventioN of embolism (SAXOPHONE) study Am Heart J 2019 217 52 63 10.1016/j.ahj.2019.08.002 31493728 \n15. O'Brien SH Li D Mitchell LG Hess T Zee P Yee DL Newburger JW Sung L Rodriguez V PREVAPIX-ALL: Apixaban compared to standard of Care for Prevention of venous thrombosis in Paediatric acute lymphoblastic Leukaemia (ALL)-rationale and design Thromb Haemost 2019 119 5 844 853 10.1055/s-0039-1679938 30861550 \n16. Mismetti P Laporte S New oral antithrombotics: a need for laboratory monitoring For J Thromb Haemost 2010 8 4 621 626 10.1111/j.1538-7836.2010.03764.x 20102486 \n17. Wang X Mondal S Wang J Tirucherai G Zhang D Boyd RA Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects Am J Cardiovasc Drugs 2014 14 147 154 10.1007/s40256-013-0055-y 24277644 \n18. Hastreiter AR van der Horst RL Voda C Chow-Tung E Maintenance digoxin dosage and steady-state plasma concentration in infants and children J Pediatr 1985 107 1 140 146 10.1016/s0022-3476(85)80636-3 4009331 \n19. EL Desoky ES Nagaraja NV Derendorf H Population pharmacokinetics of digoxin in Egyptian pediatric patients: impact of one data point utilization Am J Ther 2002 9 6 492 498 10.1097/00045391-200211000-00006 12424506 \n20. Zalzstein E Zucker N Lifshitz M Digoxin concentration in saliva and plasma in infants, children, and adolescents with heart disease Curr Ther Res Clin Exp 2003 64 9 743 749 10.1016/j.curtheres.2003.09.015 24944422 \n21. Lares-Asseff I Juárez-Olguín H Flores-Pérez J Bobadilla-Chávez J Pharmacokinetics of digoxin in children with congestive heart failure aggravated by other diseases Rev Investig Clin 2004 56 1 32 37 15144040 \n22. Moffett BS Garner A Zapata T Orcutt J Niu M Lopez KN Serum digoxin concentrations and clinical signs and symptoms of digoxin toxicity in the paediatric population Cardiol Young 2016 26 03 493 498 10.1017/s1047951115000505 25912244\n\n",
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"mesh_terms": "D000284:Administration, Oral; D000925:Anticoagulants; D006470:Hemorrhage; D006801:Humans; D007223:Infant; D008297:Male; D011720:Pyrazoles; D011728:Pyridones",
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"title": "Accidental apixaban intoxication in a 23-month-old child: a case report.",
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"abstract": "OBJECTIVE\nResults of a study of medication-related problems (MRPs) associated with lithium use on nonpsychiatric inpatient medical units are reported.\n\n\nMETHODS\nIn a single-center, retrospective study, the records of all patients hospitalized over a 21-month period who received lithium or had a documented serum lithium concentration during hospitalization were evaluated. The primary objective was to identify patient-specific factors associated with lithium MRPs on nonpsychiatric inpatient medical units. Secondary objectives included characterization of lithium MRPs. Identified MRP occurrences were further evaluated to determine if an intervention was necessary to resolve the MRP and whether or not an intervention was made.\n\n\nRESULTS\nA total of 150 patients were included in the study sample. One or more lithium MRPs were identified in 85% of the patients, with a total of 255 lithium MRPs identified. None of the patient-specific factors analyzed were significantly associated with MRP occurrence. Of the 128 patients in whom a lithium MRP occurred, 92.2% (n = 118) were judged to be appropriate candidates for interventions as defined per the study definitions; among those 118 patients, such interventions were documented for only 40.7% (n = 48).\n\n\nCONCLUSIONS\nLithium MRPs were found to have occurred frequently on nonpsychiatric inpatient medical units at 1 hospital. Laboratory test- related MRPs and drug-drug interactions were the most commonly identified types of MRPs. Interventions to address MRPs were not made in the majority of patients; however, interventions were more frequently made when psychiatry consultation was involved.",
"affiliations": "St. Joseph's Behavioral Health Center, BayCare Health System, Tampa, FL.;Virginia Commonwealth University Health System, Richmond, VA.;Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University School of Pharmacy, Richmond, VA.",
"authors": "Alastanos|Jennifer N|JN|;Potter|Teresa G|TG|;Crouse|Ericka L|EL|",
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"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": "drug interactions; lithium; medication-related problem",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000339:Affect; D015897:Comorbidity; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D057286:Electronic Health Records; D005260:Female; D006333:Heart Failure; D006760:Hospitalization; D006801:Humans; D018020:Lithium Compounds; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors",
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"title": "Lithium-related medication problems on nonpsychiatric inpatient medical units.",
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"abstract": "TPF (docetaxel, cisplatin, fluorouracil) is the standard chemotherapy used for induction in locally advanced head and neck squamous cell carcinoma (LAHNSCC). Its toxicity limits it to younger patients with good functional status and without significant comorbidity. Since modified TPF (mTPF) demonstrated higher tolerability with similar efficacy in gastric cancer, we tested this scheme on frail patients.From July 2010 to July 2014, the files of the 48 patients treated for LAHNSCC with mTPF in three French institutions were retrospectively collected.mTPF was chosen because of age>70 years, or severe denutrition, or PS>1, or severe comorbidities or after severe toxicity of standard TPF. During the first 4 cycles, 2 patients died, 14 secondary hospitalizations were required and 10 patients stopped treatment due to no lethal toxicity. Two patients died during radiotherapy.The response rate was 83% (19% complete response). With a median follow-up of 15.2 months, 4 patients died during treatment, 8 died of non-head and neck cancer related disorders, 18 progressed (17 deaths) and 18 were free of disease. The median overall survival was 18.5 months (95% IC: 16.9-30.0).mTPF is effective in terms of response rate compared with the standard TPF and could become a new option in induction for frail patients with LAHNSCC.",
"affiliations": "Department of Medicine, Léon Bérard Center, University of Lyon, Lyon, France.;Department of Medicine, Léon Bérard Center, University of Lyon, Lyon, France.;Department of Surgery, Croix-Rousse Hospital, University of Lyon, Lyon, France.;Department of Surgery, Edouard Herriot Hospital, University of Lyon, Lyon, France.;Department of Surgery, Croix-Rousse Hospital, University of Lyon, Lyon, France.;Department of Surgery, Edouard Herriot Hospital, University of Lyon, Lyon, France.;Department of Surgery, Léon Bérard Center, University of Lyon, Lyon, France.;Department of Medicine, Léon Bérard Center, University of Lyon, Lyon, France.;Department of Medical Oncology, Institut du Cancer des Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, University of Lyon, Pierre-Bénite, France.;Department of Surgery, Lyon Sud Hospital Center, University of Lyon, Pierre-Bénite, France.;Department of Surgery, Edouard Herriot Hospital, University of Lyon, Lyon, France.",
"authors": "Fayette|Jérôme|J|;Fontaine-Delaruelle|Clara|C|;Ambrun|Alexis|A|;Daveau|Clémentine|C|;Poupart|Marc|M|;Ramade|Antoine|A|;Zrounba|Philippe|P|;Neidhardt|Eve-Marie|EM|;Péron|Julien|J|;Diallo|Alpha|A|;Céruse|Philippe|P|",
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"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 27119503893410.18632/oncotarget.8934Clinical Research PaperNeoadjuvant modified TPF (docetaxel, cisplatin, fluorouracil) for patients unfit to standard TPF in locally advanced head and neck squamous cell carcinoma: a study of 48 patients Fayette Jérôme 1Fontaine-Delaruelle Clara 1Ambrun Alexis 2Daveau Clémentine 3Poupart Marc 2Ramade Antoine 3Zrounba Philippe 4Neidhardt Eve-Marie 1Péron Julien 56Diallo Alpha 7Céruse Philippe 371 Department of Medicine, Léon Bérard Center, University of Lyon, Lyon, France2 Department of Surgery, Croix-Rousse Hospital, University of Lyon, Lyon, France3 Department of Surgery, Edouard Herriot Hospital, University of Lyon, Lyon, France4 Department of Surgery, Léon Bérard Center, University of Lyon, Lyon, France5 Department of Medical Oncology, Institut du Cancer des Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, University of Lyon, Pierre-Bénite, France6 CNRS-UMR 5558, Biometry and Evolutive Biology Laboratory, Health and Biostatistics Team, Villeurbanne, France7 Department of Surgery, Lyon Sud Hospital Center, University of Lyon, Pierre-Bénite, FranceCorrespondence to:Jérôme Fayette,jerome.fayette@lyon.unicancer.fr14 6 2016 22 4 2016 7 24 37297 37304 26 1 2016 16 4 2016 Copyright: © 2016 Fayette et al.2016This 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.TPF (docetaxel, cisplatin, fluorouracil) is the standard chemotherapy used for induction in locally advanced head and neck squamous cell carcinoma (LAHNSCC). Its toxicity limits it to younger patients with good functional status and without significant comorbidity. Since modified TPF (mTPF) demonstrated higher tolerability with similar efficacy in gastric cancer, we tested this scheme on frail patients.\n\nFrom July 2010 to July 2014, the files of the 48 patients treated for LAHNSCC with mTPF in three French institutions were retrospectively collected.\n\nmTPF was chosen because of age>70 years, or severe denutrition, or PS>1, or severe comorbidities or after severe toxicity of standard TPF. During the first 4 cycles, 2 patients died, 14 secondary hospitalizations were required and 10 patients stopped treatment due to no lethal toxicity. Two patients died during radiotherapy.\n\nThe response rate was 83% (19% complete response). With a median follow-up of 15.2 months, 4 patients died during treatment, 8 died of non-head and neck cancer related disorders, 18 progressed (17 deaths) and 18 were free of disease. The median overall survival was 18.5 months (95% IC: 16.9-30.0).\n\nmTPF is effective in terms of response rate compared with the standard TPF and could become a new option in induction for frail patients with LAHNSCC.\n\nTPFhead and neck cancerinductioncisplatinfrail patients\n==== Body\nINTRODUCTION\nFor locally advanced head and neck squamous cell carcinoma (LAHNSCC), radiotherapy potentiated by cisplatin remains a standard attested by a large meta-analysis [1]. Induction chemotherapy by PF (cisplatin and fluorouracil (5FU)) increases overall survival, but at a lower level than chemoradiotherapy. TPF (docetaxel, cisplatin and 5FU) as induction chemotherapy is superior to PF [2, 3]. Then, TPF followed by radiotherapy or chemoradiotherapy is a valid therapeutic option but still largely debated. All guidelines are ancient (ESMO guidelines were published in 2010) and do not take into account recent data. None of the four direct comparisons between TPF followed by radiotherapy and exclusive chemoradiotherapy could demonstrate any significantly superior strategy [4–7]. TPF is the gold standard for larynx preservation [8].\n\nTPF is toxic and should be saved for patients in good general condition: performance status 0 or 1, no loss of weight > 10%, no severe comorbidities, age < 70 years.\n\nSeveral of our patients met one of these criteria and could not receive TPF. Due to their fragility or to avoid mutilation, they were not operated on in first intent. Also due to their fragility, definitive chemoradiotherapy (even with cetuximab) was objected to by the radiotherapist. Radiotherapy alone is inferior to induction chemotherapy followed by radiotherapy. So we needed a specific induction chemotherapy.\n\nIn metastatic gastric cancer, TPF is a standard. Due to its toxicities, a randomized phase II study compared standard TPF (T and P 75 mg/m2 d1, F 750 mg/m2/d d1 to d5, every 3 weeks) and modified TPF (mTPF, T and P 40 mg/m2 d1, leucovorin 400 mg/m2 followed by a bolus of F 400 mg/m2 then 1000 mg/m2/d, d1-2, every 2 weeks). The tolerability was better with mTPF: with 6% vs 17% of febrile neutropenia, and 3% vs 20% of grade 3-4 nausea/vomiting. Furthermore, overall survival was in favor of mTPF with 18.8 months vs 12.6 months (p = 0.007) [9].\n\nSo after these promising results we decided to give mTPF to patients who had received standard TPF and experienced a great toxicity. We observed a good tolerability with apparently similar efficacy. We thus drafted a prospective phase II study and submitted it for public financing. However we were not selected and since all the drugs were generics, we could not obtain industrial financing. So we used this protocol for patients for whom a multidisciplinary team had chosen induction chemotherapy and who were unfit to standard TPF because we thought it better than palliative chemotherapy. Seeing these good results, we decided to collect the data of all our patients treated by mTPF in induction chemotherapy over a period of 4 years to show its tolerability and efficacy in fragile patients.\n\nPATIENTS AND METHODS\nData collection\nWe retrospectively reviewed the files of all patients with histologically confirmed LAHNSCC for whom a decision of neoadjuvant chemotherapy was made by a multidisciplinary board but who were unfit for TPF. After the mTPF for gastric cancer was presented, they received mTPF in three institutions (Léon Bérard Center, Edouard Herriot Hospital, Croix-Rousse Hospital) between July 2010 and July 2014. Most patients had refused radical surgery at first, and were unfit for exclusive chemoradiotherapy. Tumors were classified using the UICC staging system [16].\n\nPatient data were collected in accordance with the CNIL rules (the French authority for the protection of patient data) and kept anonymous.\n\nTreatment\nmTPF consisted of docetaxel and cisplatin at 40 mg/m2 each on day 1, leucovorin 400 mg/m2 followed by a bolus of Fluorouracil (5FU) at 400 mg/m2 then 1000 mg/m2/d, d1-2, every 2 weeks. All patients received adequate antiemetic prophylaxis and prednisolone (50 mg, orally, twice a day for three days, starting on the morning before chemotherapy) to prevent hypersensitivity reactions and reduce docetaxel-related skin toxicity and fluid retention. Granulocyte colony-stimulating factor (G-CSF) was administered for primary prophylaxis, from day 4 for three days. No antibiotic was administered prophylactically. The number of planned cycles varied from 3 to 12.\n\nAfter mTPF, and according to multidisciplinary decisions, patients underwent surgery (neck dissection and/or tumor surgery) followed by radiotherapy within three to seven weeks of completion of chemotherapy or surgery. Radiation was delivered over a seven-week period using conventional fractionation (total dose of 66 to 70 Gy). Radiotherapy was administered alone if the patient was judged unsuitable for potentiation or was potentiated with weekly cisplatin (40 mg/m2) or cetuximab (400 mg/m2 one week before radiotherapy, then 250 mg/m2 weekly).\n\nAssessment\nTumor responses were evaluated according to RECIST 1.1 criteria. Patients had cervical and thoracic CTs before treatment and after one or two months of chemotherapy. Patients with hypopharyngeal or laryngeal cancer underwent another panendoscopy.\n\nStatistical analysis\nThe response rate was estimated as being the proportion of patients who achieved complete or partial response out of the total number of patients who received at least one cycle of mTPF. Overall survival (OS) was defined as the time from the date of diagnosis to the date of death or to the date of the last follow-up visit for surviving patients (censored cases). Time to relapse (TTR) was defined as the time from the date of diagnosis to the date of recurrence. Survival estimates were calculated using the Kaplan-Meier method. The analysis was performed with SAS (version 9.2).\n\nRESULTS\nPatient characteristics\nBetween July 2010 and July 2014, 48 patients with histologically confirmed locally advanced or metastatic HNSCC were treated with mTPF in the three French institutions taking part in the study. Patient characteristics are summarized in Table 1. They were predominantly men (n = 41; 85%) with a median age of 59 years (range: 48-85) at onset of mTPF. For all these patients the multidisciplinary team recommended neoadjuvant chemotherapy. But they were unfit for standard TPF, due to age > 70 years (n = 10; 21%), PS > 1 (n = 19; 40%), loss of weight > 10% (n = 7; 15%) or severe comorbidities (n = 7; 15%: chronic obstructive pneumopathy, history of acute renal failure, concomitant rectal cancer, liver transplantation, adrenal insufficiency, severe arteriopathy, psychiatric disorders). Four patients had a sever toxicity after the first standard TPF (one febrile neutropenia, two colitis and one severe asthenia) and we decided to pursue with mTPF (n = 4; 8%). One patient received mTPF for unknown reason.\n\nTable 1 Patient characteristics at onset of mTPF (n = 48)\n\tN\t%\t\nMedian age, years [range]\t59 [48-85]\t\nSex\t\t\t\n Female\t7\t15\t\n Male\t41\t85\t\nTumor site at initial diagnosis\t\t\t\n Oral cavity\t8\t17\t\n Oropharynx\t18\t38\t\n Hypopharynx\t15\t31\t\n Larynx\t6\t12\t\nNeck node without primary\t1\t2\t\nTumor stage at initial diagnosis\t\t\t\n II\t1\t2\t\n III\t6\t13\t\nIVa\t29\t60\t\nIVb\t12\t25\t\nIntent of treatment\t\t\t\nOperable patient, organ preservation\t28\t58\t\nInoperable patient, palliation\t20\t42\t\nPS at the onset of mTPF\t\t\t\n0\t12\t25\t\n1\t17\t35\t\n2\t16\t33\t\n3\t3\t6\t\nReason for choice of mTPF instead of standard TPF\t\t\t\n Age > 70 years\t10\t21\t\nPS > 1\t19\t40\t\nLoss of weight > 10%\t7\t15\t\nSevere Comorbidities\t7\t15\t\nToxicity after a first cycle of standard TPF\t4\t8\t\nUnknown\t1\t2\t\nThe two most common primary tumor sites were the oropharynx (n = 18; 38%) and the hypopharynx (n = 15; 31%). Twenty patients (42%) were judged inoperable. Overall, tumors were advanced at the time of diagnosis, with 29 (60%) and 12 (25%) patients with stage IVa or IVb tumors respectively.\n\nmTPF delivery and safety\nData on mTPF delivery and toxicities are summarized in Table 2. The vast majority of patients were scheduled to receive 4 cycles of chemotherapy and the median number of cycles administered was 4 (range 1-12). In total 214 cycles were administered.\n\nTable 2 Delivery and toxicity of mTPF (median number of cycles: 4; total number of cycles: 214)\nToxicities\tFirst cycle (n = 48)\tSecond cycle (n = 44)\tThird cycle (n = 38)\tFourth cycle (n = 27)\t\nFebrile neutropenia\t2 (4%)\t0\t1 (3%)\t1 (4%)\t\nDiarrhea (gr 3-4)\t3 (6%)\t1 (2%)\t1 (3%)\t0\t\nSecondary hospitalization\t5 (10%)\t4 (9%)\t2 (5%)\t3 (8%)\t\nTransient creatinine elevation\t4 (8%)\t5 (11%)\t2 (5%)\t2 (5%)\t\nCause of discontinuation\t4 interruptions for toxicity (8%)\t1 death (2%) 4 interruptions for toxicity (8%)\t1 death (3%) 2 interruptions for toxicity (5%)\tPlanned. No toxicity\t\nTwo patients (4%) died during chemotherapy and 10 patients (21%) stopped treatment due to toxicity. The levels of febrile neutropenia or grade 3-4 diarrhea were very low: for example 2 (4%) and 3 (6%) respectively for the first cycle. The numbers of secondary hospitalizations were 5 (10% of patients treated for this cycle), 4 (9%), 2 (5%) and 3 (8%) for the 4 first cycles respectively. For patients who pursued chemotherapy for more than 4 cycles, we did not observe particular toxicity.\n\nEfficacy of mTPF\nThe overall response rate according to RECIST intent-to-treat criteria was 83%, of which 19% were complete responses and 65% partial responses (Table 3); 10% of patients had stable disease, and 2% progressed on treatment.\n\nTable 3 Best response to mTPF and type of treatment after induction\nBest response to TPF\tN\t%\t\n\tOverall response rate\t40\t83\t\n\t\tComplete response\t9\t19\t\n\t\tPartial response\t31\t65\t\n\tStable disease\t5\t10\t\n\tProgressive disease\t1\t2\t\n\tNot evaluable\t2\t4\t\n\t\t\t\nSurgery of the tumor\t8\t17\t\n\tMutilating\t4\t8\t\n\tNon-mutilating\t4\t8\t\n\t\t\t\t\nNode dissection (of whom 14 had only node dissection)\t20\t42\t\n\t\t\t\nRadiotherapy\t39\t81\t\n\tExclusive\t22\t46\t\n\tPotentiated\t17\t35\t\n\t\tWeekly cisplatin\t8\t17\t\n\t\tWeekly cetuximab\t6\t12\t\n\t\tUnknown\t3\t6\t\nTreatments after mTPF\nAfter mTPF, 8 (17%) patients had surgery, of whom 4 (7%) had non-mutilating surgery and 4 (8%) had mutilating surgery (due to insufficient response in operable patients). Neck dissection was performed on 20 (42%) patients because of persistent nodal disease (of whom 14 had only neck dissection). Indeed in France we prefer to perform node dissection if large involvement before radiotherapy. After mTPF, 39 (81%) patients were irradiated, 22 (46%) without potentiation, and 17 (35%) with potentiation. The type of potentiation was weekly cisplatin (40 mg/m2) for 8 patients and cetuximab for 6 patients (3 unknown). Four patients had temporary arrest of radiation (2 deaths, both potentiated −1 weekly cisplatin, 1 unknown- 2 others without potentiation) and all but the two dead received the planned cumulative dose of radiotherapy. In case of toxicity the potentation was stopped in order to favour the total dose of radiotherapy: 4/6 patients with cetuximab, 2/8 with weekly cisplatin and 1/3 with unknown potentation had to stop potentiation.\n\nSurvival data\nAfter a median follow-up of 15.2 months (range between 0.3 and 42 months), 18 (37.5%) patients relapsed and 17 died, and 18 patients were alive with no evidence of disease. Four died during treatment, and 8 died of non-head and neck cancer related disorders (2 cardiac failures, 2 secondary cancers - oesophagus, colorectal-, 3 unknown -probably cardiac failures, 1 anaphylaxis shock), due to the high fragility of these patients.\n\nAs shown in Figure 1, the median overall survival was 18.5 months (95% IC: 16.9-30.0).\n\nFigure 1 Overall survival\nDue to the frailty of these patients it seems more interesting to evaluate the median time to relapse instead of the progression-free survival. As shown in Figure 2, the median time to relapse was 22.2 months (95% IC: 13.2-NR).\n\nFigure 2 Time to relapse\nDISCUSSION\nThis retrospective study met its objectives and demonstrated tolerability and efficacy of mTPF in fragile patients with a LAHNSCC. Even if of course no direct comparison can be made between different studies, we should discuss our results in the light of the three pivotal phase III trials of standard TPF [2, 3, 10], and of our previously reported retrospective study of TPF by the same institutions in routine practice [11]. The patients were all PS 0-1 and had a median age of 53-57 years compared to 40% of patients who were at least PS 2 and had a median age of 59 years (and 21% of patients older than 70 years) in our study.\n\nIn terms of efficacy, at 83% the response rate of mTPF is similar to the 68-84% reported [2, 3, 10]. In terms of tolerability, with mTPF we observed only 2 toxic deaths (4%) and 4 febrile neutropenia (8%) despite 3 days of G-CSF. We did not use prophylactic ciprofloxacin because monotherapy with fluoroquinols induces a high level of bacterial mutations that lead to resistance and the expected duration of neutropenia is less than 7 days. On account of age and comorbidities, the use of G-CSF prophylaxis is recommended by ASCO guidelines but we probably chose too short a duration and for future treatments we will recommend at least 5 days of G-CSF. Because of our prudence with fragile patients treated by mTPF, we interrupted treatment for 10 (21%) of them (vs 6% with standard TPF). The rate of secondary hospitalization (29% vs 27%) was similar to that in our previous study with TPF for fit patients [11]. 3 out of 4 patients who experienced severe acute toxicity to TPF could receive mTPF safely. The continuation of treatment is not compromised by mTPF since 39 patients (82%) were irradiated, similar to other studies [2, 3, 10].\n\nWhat is the optimal number of mTPFcycles? In the pivotal studies patients received 3 to 4 cycles of TPF with a cumulative dose of cisplatin and docetaxel of 225-300 mg/m2 for a duration of 2 to 3 months. So we propose 4 to 6 cycles of mTPF for the same length of time and doses ranging from 140 to 240 mg/m2. In our study, 5 and 3 patients received 8 and 12 cycles respectively on account of its good tolerability and efficacy in a context of severe comorbidities. So we decided to favour the quality of life and decided not to irradiate 5 patients and to delay the decision of radiotherapy for 3 others (radiation was finally performed after their health had generally improved).\n\nThe place of induction chemotherapy is still debated. Induction by TPF has demonstrated superiority to PF in terms of overall survival and laryngeal preservation and has become the standard treatment when induction is chosen [2, 3, 10, 12]. TPF is largely accepted for larynx preservation with an impressive level of larynx dysfunction-free survival at 10 years of 63,7% [8].\n\nFor other localizations or for inoperable tumors, chemoradiation with cisplatin remains the standard. But guidelines are ancient (ESMO guidelines were published in 2010) and do not take into account the most recent data. Clearly our population could not receive radiotherapy potentiated by cisplatin every three weeks at the dose of 100 mg/m2. Similarly our radiotherapists objected to potentiation by cetuximab (that was not directly compared to cisplatin) due to its toxicity in frail patients with gross tumors in our experience. Since induction chemotherapy is superior to radiation alone [13] we then preferred induction chemotherapy before radiation.\n\nNo study has yet demonstrated superiority of chemoradiation versus induction followed by radiotherapy (eventually with potentiation). Four phase III studies failed to draw a conclusion mainly because of methodological problems. In the first trial the per-protocol analysis showed superiority of induction followed by chemoradiation but did not reach a statistical significance as intent to treat, due to high levels of toxicity [7]. In two others, only 50% of the planned patients were included and finally no statistical difference could be shown [4, 6]. The last study compared four arms to take into account the role of cetuximab in combination with radiotherapy. Patients received TPF followed by chemoradiation or chemoradiation alone. For chemoradiation, patients received a potentiation by weekly cetuximab or by 2 cycles of cisplatin and 5FU. The data of patients irradiated with cisplatin or cetuximab were pooled to compare induction versus no induction: the median overall survival was significantly better with induction by TPF (53.3 months vs 30.3 months, HR = 0.72, 95% IC 0.55-0.96, p = 0.025) [5]. But since i) there is no direct demonstration of similar efficacy of potentiation by cisplatin or cetuximab, ii) the subgroup analysis of patients irradiated with cisplatin did not achieve significance, no definitive conclusion could be drawn.\n\nIn conclusion, our study demonstrated the safety of mTPF and its efficacy on response rate for patients unfit to TPF. mTPF could increase tolerability of induction chemotherapy for fit patients with similar efficacy and could increase compliance and efficacy of the entire sequence of treatment. Indeed induction proved superior to chemoradiation if the entire sequence could be administered [7]. These encouraging results lead us to a randomized study for fit patients comparing mTPF and TPF.\n\nCONFLICTS OF INTEREST\n\nDr. Philippe Ceruse is a member of the board of Merck-Serono.\n\nOther authors have no conflict of interest.\n\nAuthors' contributions\n\nJF contributed to the study design, patient selection, data collection, data analysis, and manuscript drafting and approval.\n\nCFD, AA, CD, AD contributed to data collection.\n\nJP contributed to data analysis.\n\nMP, AR, PZ, EMN, PC contributed to patient selection.\n\nAll authors read and approved the final manuscript.\n==== Refs\nREFERENCES\n1 Pignon JP le Maitre A Maillard E Bourhis J Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients Radiother Oncol 2009 92 4 14 19446902 \n2 Posner MR Hershock DM Blajman CR Mickiewicz E Winquist E Gorbounova V Tjulandin S Shin DM Cullen K Ervin TJ Murphy BA Raez LE Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer N Engl J Med 2007 357 1705 15 17960013 \n3 Vermorken JB Remenar E van Herpen C Gorlia T Mesia R Degardin M Stewart JS Jelic S Betka J Preiss JH van den Weyngaert D Awada A Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer N Engl J Med 2007 357 1695 704 17960012 \n4 Cohen EE Karrison TG Kocherginsky M Mueller J Egan R Huang CH Brockstein BE Agulnik MB Mittal BB Yunus F Samant S Raez LE Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer J Clin Oncol 2014 32 2735 43 25049329 \n5 Ghi MG Paccagnella A Ferrari D Foa P Rocca MC Verri E Morelli F Azzarello G D'Ambrosio C Cruciani G Guaraldi M Massa E Concomitant chemoradiation (CRT) or cetuximab/RT (CET/RT) versus induction Docetaxel/Cisplatin/5-Fluorouracil (TPF) followed by CRT or CET/RT in patients with Locally Advanced Squamous Cell Carcinoma of Head and Neck (LASCCHN) A randomized phase III factorial study (NCT01086826) 32 2014 Abstr 6004 \n6 Haddad R O'Neill A Rabinowits G Tishler R Khuri F Adkins D Clark J Sarlis N Lorch J Beitler JJ Limaye S Riley S Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial Lancet Oncol 2013 14 257 64 23414589 \n7 Hitt R Grau JJ Lopez-Pousa A Berrocal A Garcia-Giron C Irigoyen A Sastre J Martinez-Trufero J Brandariz Castelo JA Verger E Cruz-Hernandez JJ A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer Ann Oncol 2014 25 216 25 24256848 \n8 Janoray G Pointreau Y Garaud P Chapet S Alfonsi M Sire C Tuchais C Calais G Long-term results of GORTEC 2000-01: A multicentric randomized phase III trial of induction chemotherapy with cisplatin plus 5-fluorouracil, with or without docetaxel, for larynx preservation 33 2015 Abstr 6002 \n9 Shah MA Janjigian YY Stoller R Shibata S Kemeny M Krishnamurthi S Su YB Ocean A Capanu M Mehrotra B Ritch P Henderson C Randomized Multicenter Phase II Study of Modified Docetaxel, Cisplatin, and Fluorouracil (DCF) Versus DCF Plus Growth Factor Support in Patients With Metastatic Gastric Adenocarcinoma: A Study of the US Gastric Cancer Consortium J Clin Oncol 2015 20 3874 9 \n10 Pointreau Y Garaud P Chapet S Sire C Tuchais C Tortochaux J Faivre S Guerrif S Alfonsi M Calais G Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation J Natl Cancer Inst 2009 101 498 506 19318632 \n11 Fayette J Bonnin N Ferlay C Lallemant B Ramade A Favrel V Zrounba P Chabaud S Pommier P Poupart M Ceruse P Neoadjuvant TPF in locally advanced head and neck cancer can be followed by radiotherapy combined with cisplatin or cetuximab: a study of 157 patients Anticancer Drugs 2013 24 623 9 23542750 \n12 Blanchard P Bourhis J Lacas B Posner MR Vermorken JB Hernandez JJ Bourredjem A Calais G Paccagnella A Hitt R Pignon JP Taxane-cisplatin-fluorouracil as induction chemotherapy in locally advanced head and neck cancers: an individual patient data meta-analysis of the meta-analysis of chemotherapy in head and neck cancer group J Clin Oncol 2013 31 2854 60 23835714 \n13 Forastiere AA Goepfert H Maor M Pajak TF Weber R Morrison W Glisson B Trotti A Ridge JA Chao C Peters G Lee DJ Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer N Engl J Med 2003 349 2091 8 14645636\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "7(24)",
"journal": "Oncotarget",
"keywords": "TPF; cisplatin; frail patients; head and neck cancer; induction",
"medline_ta": "Oncotarget",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D016330:Frail Elderly; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D012189:Retrospective Studies; D043823:Taxoids",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "37297-37304",
"pmc": null,
"pmid": "27119503",
"pubdate": "2016-06-14",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "23414589;25049329;23542750;19446902;19318632;17960012;17960013;24256848;14645636;23835714;26438119",
"title": "Neoadjuvant modified TPF (docetaxel, cisplatin, fluorouracil) for patients unfit to standard TPF in locally advanced head and neck squamous cell carcinoma: a study of 48 patients.",
"title_normalized": "neoadjuvant modified tpf docetaxel cisplatin fluorouracil for patients unfit to standard tpf in locally advanced head and neck squamous cell carcinoma a study of 48 patients"
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"abstract": "BACKGROUND Crohn's disease (CD) is an inflammatory bowel disease affecting approximately 1 in 3000 people in the United States. Since the inflammation of CD is transmural, patients are at risk for fistula and abscess formation. Retroperitoneal abscesses are one type of which physicians must be aware. CASE REPORT We present the case of a 29-year-old woman with CD who complained of right hip and flank pain that began when she was 6-months pregnant. After delivery, she continued to complain of severe right flank pain and was admitted to the hospital 1 month later. CT scan imaging revealed a complicated retroperitoneal and right flank abscess, possibly due to a colonic intramural fistula. She developed severe acute necrotizing soft-tissue infection requiring 13 days of intensive care. She required debridement of the necrotizing infection of the right flank, drainage of the abscess, and washout for intraperitoneal sepsis. The patient tolerated the procedures well and was discharged 1 month later. CONCLUSIONS Given that the clinical manifestation of retroperitoneal fistula with abscess is insidious and its formation is less common than intraperitoneal abscesses, we hope healthcare providers learn from this case to avoid morbidity and mortality. When presented with a pregnant CD patient complaining of nonspecific abdominal symptoms, providers should consider fistulization and/or abscess formation. The option to evaluate pregnant patients using noninvasive methods, such as ultrasound or low-dose CT scan, can decrease radiation exposure to the fetus and prevent delays in diagnosis and treatment.",
"affiliations": "Campbell University School of Osteopathic Medicine, Lillington, NC, USA.;Department of Internal Medicine, Cape Fear Valley Hospital, Fayetteville, NC, USA.;Campbell University School of Osteopathic Medicine, Lillington, NC, USA.;Department of Internal Medicine, Cape Fear Valley Hospital, Fayetteville, NC, USA.;Department of General Surgery, Cape Fear Valley Hospital, Fayetteville, NC, USA.",
"authors": "Elshazzly|Mohamed|M|;Bashjawish|Fuad|F|;Shahid|Muhammad A|MA|;Marrero|Dana A|DA|;Horowitz|Joel|J|",
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"doi": "10.12659/AJCR.909545",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2996175010.12659/AJCR.909545909545ArticlesA Challenging Case of Retroperitoneal Abscess in a Post-Partum Crohn’s Disease Patient Elshazzly Mohamed ABCDEFG1Bashjawish Fuad ACDEF2Shahid Muhammad A. ABCDE1Marrero Dana A. DE2Horowitz Joel AD3\n1 Campbell University School of Osteopathic Medicine, Lillington, NC, U.S.A.\n2 Department of Internal Medicine, Cape Fear Valley Hospital, Fayetteville, NC, U.S.A.\n3 Department of General Surgery, Cape Fear Valley Hospital, Fayetteville, NC, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Mohamed Elshazzly, e-mail: Meelshazzly0201@email.campbell.edu2018 02 7 2018 19 773 777 18 2 2018 26 4 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 29\n\nFinal Diagnosis: Retroperitoneal abscess\n\nSymptoms: Flank bruising • flank pain\n\nMedication: —\n\nClinical Procedure: Incision • drainage • debridement of the necrotizing soft-tissue infection\n\nSpecialty: Infectious Diseases\n\nObjective:\nUnusual clinical course\n\nBackground:\nCrohn’s disease (CD) is an inflammatory bowel disease affecting approximately 1 in 3000 people in the United States. Since the inflammation of CD is transmural, patients are at risk for fistula and abscess formation. Retroperitoneal abscesses are one type of which physicians must be aware.\n\nCase Report:\nWe present the case of a 29-year-old woman with CD who complained of right hip and flank pain that began when she was 6-months pregnant. After delivery, she continued to complain of severe right flank pain and was admitted to the hospital 1 month later. CT scan imaging revealed a complicated retroperitoneal and right flank abscess, possibly due to a colonic intramural fistula. She developed severe acute necrotizing soft-tissue infection requiring 13 days of intensive care. She required debridement of the necrotizing infection of the right flank, drainage of the abscess, and washout for intraperitoneal sepsis. The patient tolerated the procedures well and was discharged 1 month later.\n\nConclusions:\nGiven that the clinical manifestation of retroperitoneal fistula with abscess is insidious and its formation is less common than intraperitoneal abscesses, we hope healthcare providers learn from this case to avoid morbidity and mortality. When presented with a pregnant CD patient complaining of nonspecific abdominal symptoms, providers should consider fistulization and/or abscess formation. The option to evaluate pregnant patients using noninvasive methods, such as ultrasound or low-dose CT scan, can decrease radiation exposure to the fetus and prevent delays in diagnosis and treatment.\n\nMeSH Keywords:\nAbdominal AbscessCrohn DiseaseFistulaObstetricsPregnancyRetroperitoneal Space\n==== Body\nBackground\nPatients with Crohn’s disease (CD) may report nonspecific symptoms such as fatigue, bloody or non-bloody diarrhea, abdominal pain, and/or weight loss [1]. In certain CD patients, transmural bowel inflammation triggers the development of sinus tracts that can connect to other epithelial-lined organs, leading to the formation of fistulas. According to population-based studies, 14% to 38% of CD patients have a lifetime risk of developing a fistula [2,3]. These fistulas can connect to bowel (enteroenteric), to skin (enterocutaneous), to bladder (enterovesical), to the vagina (enterovaginal), or to the retroperitoneum. However, fistulas that extend posteriorly through the retroperitoneum and iliopsoas space are rare and we will discuss that type here [4].\n\nThe diagnosis of retroperitoneal abscess, in the peri- and post-partum period, raises significant challenges due to frequent overlap of nonspecific symptoms and concerns regarding the safety of imaging studies. There still remains much to learn regarding the impact of pregnancy on CD and the impact of usual treatment on the developing fetus. We report the case of a post-partum patient who was found to have a large retroperitoneal abscess that required 14 days of intensive medical and surgical care.\n\nCase Report\nOur patient was a gravida I para I, 29-year-old woman who presented to us 3 weeks post-partum with right hip and flank pain and right flank bruising. The pain initially started 4 months prior when she was 6-months pregnant. She had an uncomplicated spontaneous vaginal delivery of a healthy son. After the delivery, she continued to complain of severe right flank pain. Our patient’s past medical history was significant for a 5-year opioid addiction for which she was on Methadone, and Crohn’s disease diagnosed at the age of 17. Since her diagnosis, she was on Azathioprine 100 mg twice a day for immunosuppression of her CD. Two years prior to this admission to the hospital, she started to experience acute flares that included severe abdominal pain, vomiting, and bloody diarrhea. She started receiving Infliximab infusions monthly, which successfully suppressed the acute flares. Six months prior to her hospital admission, she stopped getting the Infliximab infusions due to financial concerns, although she continued to have mild acute flares. She was also discharged from 2 separate GI practices due to noncompliance with recommended therapy. She treated the flares before and during the pregnancy with oral prednisone 80 mg. Our patient’s contraception of choice prior to her pregnancy was a copper intrauterine device, and she reported no history of sexually transmitted diseases.\n\nVital signs upon admission showed fever of 100.9°F (38.3°C), pulse 177 bpm, and blood pressure 106/62 mmHg. Admission lab results revealed a white blood cell count of 50 000 cells/mm3, elevated platelet count of 717 mcL, and hemoglobin of 6.0 g/dL (Table 1). Serum chemistries were within normal limits, except for a lactic acid level of 5.2 mmol/L. Liver function tests revealed an elevated alkaline phosphatase of 207 unit/L. Chest X-ray upon admission revealed no acute abnormalities. Non-contrast computerized tomography (CT) scans of the abdomen and pelvis revealed a large complex air-fluid collection within the right flank, right retroperitoneum, and right lateral abdominal wall just superior to the right iliac crest (Figure 1).\n\nThe patient was diagnosed with severe sepsis due to retroperitoneal abscess based on her clinical presentation, lab results, and CT scan findings, and she was quickly taken to the operating room (OR). In the OR, our patient was found to have a complicated pelvic inguinal and right flank abscess secondary to a colonic intramural retroperitoneal fistula that emanated from the cecum. Incision, drainage, and debridement of the necrotizing soft-tissue infection in the area of the right flank were performed. Additionally, the patient had an ileal perforation for which an ileal resection was performed. She was transferred to the intensive care unit (ICU) intubated in stable condition for close postoperative monitoring. OR cultures grew Escherichia coli and Beta Hemolytic Group C Streptococcus (GCS). The patient was started on IV Meropenem 500 mg daily for treatment of E. coli, IV Vancomycin 1000 mg daily for coverage of GCS, and IV Clindamycin 900 mg TID for its anti-toxin effect.\n\nOn post-op day 1, the patient was taken back to the OR for additional debridement and irrigation of the necrotizing soft-tissue infection. The area was washed out with 3000 mL of saline fluid and a wound vacuum-assisted closure (VAC) device was placed in the area of the right flank. Her sepsis improved as evidenced by her laboratory results (Table 1) and she was transferred to the medical floor on hospital day 4.\n\nOn hospital day 7, the patient was transferred back to the ICU for worsening sepsis with tachycardia, tachypnea, fever, and leukocytosis of 62 000 cells/mm3. Additionally, the patient developed acute respiratory failure requiring 4 liters oxygen via nasal cannula. On hospital day 9, she was taken back to the OR and underwent an exploratory laparotomy, which revealed formation of an intraperitoneal abscess and transverse colon staple line leak with purulence. Drainage of the abscess and repair of the leak with an omental patch were performed. The pathology findings supported CD as the final diagnosis due to the presence of transmural chronic inflammation, serosal fibrous adhesions with granulation, and peri-colonic abscesses.\n\nCultures from her second operation grew Enterococcus faecalis susceptible to Vancomycin, and light growth of Candida albicans. Vancomycin was continued along with Micafungin 100 mg daily. Blood cultures revealed no growth throughout the patient’s course. On hospital day 11, she was transferred to the medical floor, where she continued to improve. On hospital day 14, she was discharged to long-term acute care for continued IV antibiotic therapy and aggressive wound management. She left the long-term care facility 4 weeks later.\n\nDiscussion\nCrohn’s disease predisposes patients to spontaneous abscess formation and potential subsequent fistulization. In our literature review, we found that CD patients are known to form enterovesical [5] and ileovesical fistulas [6], and more rarely, enterouterine fistulas [7]. A study examining worldwide variations in etiology of pyogenic psoas abscesses, a type of retroperitoneal abscess, found that CD is the most frequent cause of secondary pyogenic abscess formation worldwide. This finding highlights the importance of keeping such a complication high in the differential for CD patients presenting with insidious onset of abdominal pain, especially in pregnancy, where there are many confounding factors for such symptoms. Previous case reports have reported CD patients presenting with unique clinical manifestations of retroperitoneal abscesses. One CD patient presented with sudden onset of leg claudication due to a psoas abscess and fistula [8]. Another presented with back pain and was found to have a retroperitoneal abscess with formation of a fistula between the abscess and colon [9].\n\nOur patient experienced a 4-month delay in diagnosis from the onset of symptoms. One reason may have been her physician’s anchoring bias: the physician attributed the patient’s complaints to drug-seeking behavior due to her history of opioid addiction. The second reason could be attributed to the insidious onset of CD symptoms and their waxing and waning course. It is likely that, particularly during her final months of pregnancy, the pain was attributed to pre-natal symptoms. The third reason may be related to the lack of awareness of rare complications of CD, such as retroperitoneal abscess and hesitation to expose the pregnant patient to radiation for the sake of diagnostic testing. Studies show that it takes 12.7 days on average to establish the diagnosis of retroperitoneal abscess [10,11], so although our patient eventually did well, her delay in care was well outside the expected range. In the above-mentioned study examining worldwide variation in retroperitoneal abscess formation, all 7 patients who died from their infections received delayed care [8].\n\nIt is important to know at the beginning of pregnancy if a CD patient has active bowel disease, as she will likely have a milder course during pregnancy if her disease is quiescent at conception [10]. It is recommended that pregnant CD patients have sigmoidoscopy, rectal mucosal biopsy, and stool examination to document nonspecific inflammatory bowel disease as opposed to a specific treatable infection capable of causing bowel inflammation [12]. Should these patients have flares of abdominal pain during gestation, they may receive appropriate doses of prednisone or sulfasalazine to suppress any inflammation and to prevent complications. The decision to use tumor necrosis factor-alpha inhibitor therapy (e.g., Infliximab) in pregnant patients with CD is complex: it seems to be safe if used short-term but may have detrimental effects on the fetus’s immune system if used during the 2nd and 3rd trimester, where transfer of the drug from mother to fetus is maximized [13,14]. Therefore, the decision should be made on an individual basis and should favor minimizing fetal exposure to the drug.\n\nIt is difficult to make a definitive association between our patient’s pre-partum back pain and the post-partum retroperitoneal abscess. CD is known for its waxing and waning course and we suspect that our patient suffered from active bowel disease early in her pregnancy course, with active inflammation playing a role in the fistulization and abscess formation. The chronic transmural inflammation, as evidenced by the pathology report, coupled with the cessation of her Infliximab infusions, might have contributed to the fistulization process and subsequent penetration of the psoas muscle into the retroperitoneum. Unfortunately, in our patient’s case, none of the appropriate imaging studies were performed early enough during pregnancy to detect active inflammation.\n\nThe current recommendation is that non-urgent radiologic testing should be avoided in pregnant patients [15]. However, radiologic testing is permitted in pregnant patients who require acute medical care, as it will likely affect the management of the disease in a substantial way [15]. Given our patient’s history of CD and the known complications of CD as discussed above, the use of noninvasive ultrasound should be considered. If the results are inconclusive, then 3-way films of the abdomen or low-dose CT scan [<0.05 Gy] are recommended [16]. Moreover, after approximately 20 to 25 weeks of gestation, the fetus is relatively resistant to teratogenic effects of ionizing radiation [16]. Given that our patient presented at 28 weeks of gestational age, a low-dose CT scan would have been justified given her overall clinical presentation.\n\nRegarding the treatment for retroperitoneal abscess, the standard of care involves surgical drainage followed by diversion, and, ultimately, definitive resection [4]. The most successful approach for any perinephric, musculoskeletal, or upper-retroperitoneal infection is a retroperitoneal flank incision with dependent drainage [11]. Medical management of these infections is aimed at treating mixed aerobic and anaerobic bacterial infections with common enteric organisms [14,17]. The combination of an aminoglycoside, penicillin, and clindamycin are recommended in the medical literature, although we note our patient had a penicillin allergy and treatment was adjusted accordingly [14,17]. In addition to drainage of the retroperitoneal abscess, she underwent an ileal resection for her ileal perforation. According to studies done by Regueiro et al. and Yoshida et al., there is strong evidence that starting TNF-α inhibitor therapy within 6 months after an ileocecal resection prevents postoperative recurrence of CD [18,19]. However, the duration of TNF-α inhibitor maintenance post-operatively still remains a subject for future study. Furthermore, it is recommended that all patients should have endoscopic monitoring within the first year after surgery [20].\n\nConclusions\nOur case report provides important medical, surgical, and obstetric considerations in the management of a pregnant Crohn’s disease patient. It is important to note that further long-term research is needed to exclude fetal injury from prednisone or sulfasalazine use. Additionally, further research on the effects of exposure of TNF-α inhibitor therapy on the fetus is warranted. Whenever active bowel disease is suspected in pregnant patients, evaluation with ultrasound, X-rays, and/or low-dose CT scan is indicated. If any intra-abdominal complication occurs during pregnancy and warrants intervention, surgery should not be delayed, as the benefits greatly outweigh the possible risks of operating while gravid. Our patient’s critical illness on presentation, prolonged ICU stay, and need for multiple operations highlight the importance of early diagnosis of retroperitoneal abscesses. Our hope is that healthcare providers learn from this case to avoid serious complications from inadequate pre- and peri-natal medical management of CD and diagnostic delay of its surgical sequelae.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Preoperative CT scan of the abdomen and pelvis without IV and PO contrast reveals large complex air-fluid collection within the right flank, right retroperitoneum, and right lateral abdominal wall just superior to the right iliac crest (see arrows). Air extends through the right retroperitoneum infiltrating the iliopsoas space.\n\nTable 1. Blood monitoring during the first 11 days of hospitalization.\n\n\tDay 1\tDay 2\tDay 3\tDay 4\tDay 5\tDay 6\tDay 7\tDay 8\tDay 9\tDay 10\tDay 11\t\nWhite blood cell count\t49.8\t32\t40.4\t30\t24\t25\t62.8\t48\t43\t32\t–\t\nRed blood cell count\t2.4\t2.2\t3.4\t3.4\t3.5\t4\t4.6\t4.5\t3.5\t3.2\t–\t\nHemoglobin\t6\t5.7\t8.7\t9\t9.3\t10.4\t12.2\t12\t9.5\t8.3\t–\t\nPlatelet count\t717\t388\t436\t499\t436\t510\t650\t631\t411\t461\t–\t\nLactic acid\t5.2\t–\t–\t–\t–\t–\t4.3\t2.2\t–\t–\t1.9\t\nSodium\t134\t143\t140\t–\t141\t137\t140\t137\t140\t139\t137\t\nPotassium\t3.3\t3.3\t4.8\t–\t3.7\t3.2\t3.3\t3.4\t3.1\t2.5\t3.3\t\nCalcium\t8.7\t7.1\t8.3\t–\t7.4\t7.8\t7.3\t7.9\t7.7\t8\t7.6\t\nAlbumin\t1.4\t0.9\t1\t–\t–\t–\t1.2\t–\t1\t1\t1\t\nAlkaline phosphatase\t207\t148\t128\t–\t––\t–\t77\t–\t85\t105\t120\n==== Refs\nReferences:\n1. Mekhjian HS Switz DM Melnyk CS Clinical features and natural history of Crohn’s disease Gastroenterology 1979 4 pt 2 898 906 \n2. Schwartz DA Loftus EV Jr Tremaine WJ The natural history of fistulizing Crohn’s disease in Olmsted County, Minnesota Gastroenterology 2002 122 4 875 80 11910338 \n3. Hellers G Bergstrand O Ewerth S Holmström B Occurrence and outcome after primary treatment of anal fistulae in Crohn’s disease Gut 1980 21 6 525 27 7429313 \n4. Greenstein AJ Dreiling DA Aufses AH Jr Crohn’s disease of the colon. V. Retroperitoneal lumbocrural abscess in Crohn’s disease involving the colon Am J Gastroenterol 1975 64 4 306 18 1200016 \n5. Kawakami S Yamada T Watanabe T Negishi T Enterovesical fistula complicating Crohn’s disease: Report of two cases Hinokika Kiyo 1992 38 1 71 75 \n6. Mizungaga M Uchida A Park YC Ileovesical fistula complicating Crohn’s disease: A case report Hinyokika Kiyo 1989 35 7 1223 27 2678984 \n7. Wulfeck D Williams T Amin A Huang TY Crohn’s disease with unusual enterouterine fistula in pregnancy J Ky Med Med Asoc 1994 92 7 267 69 \n8. Moon SB Successful conservative management of a retroperitoneal abscess with a sinus to the colon: a case report Int Surg 2016 101 3 133 36 \n9. Christodoulou D Tzambouras N Katsanos K Psoas fistula and abscess in a patient with Crohn’s Disease presenting as claudication and hip arthritis Annals of Gastroenterology 2001 14 4 314 18 \n10. Donaldson R Jr Management of medical problems in pregnancy – inflammatory bowel disease N Engl J Med 1985 312 1616 19 2860564 \n11. Richards RJ Management of abdominal and pelvic abscess in Crohn’s disease World J Gastrointest Endosc 2011 3 11 209 12 22110836 \n12. Ricci MA Rose FB Meyer KK Pyogenic psoas abscess: Worldwide variations in etiology World J Surg 1986 10 5 834 43 3776220 \n13. Gisbert JP Chaparro M Safety of anti-TNF agents during pregnancy and breastfeeding in women with inflammatory bowel disease Am J Gastroenterol 2013 108 9 1426 38 23752881 \n14. Skomsvoll JF Wallenius M Koksvik HS Drug insight: anti-tumor necrosis factor therapy for inflammatory arthropathies during reproduction, pregnancy and lactation Nat Clin Pract Rheumatol 2007 3 3 156 64 17334338 \n15. Toppenberg KS Hill DA Miller DP Safety of radiographic imaging during pregnancy Am Fam Physician 1999 59 7 1813 18 1820 10208701 \n16. De Santis M Di Gianantonio E Straface G Ionizing radiations in pregnancy and teratogenesis: A review of literature Reprod Toxicol 2005 20 3 323 29 15925481 \n17. Feagins LA Holubar SD Kane SV Current strategies in the management of intra-abdominal abscesses in Crohn’s disease Clin Gastroenterol Hepatol 2011 9 10 842 50 21679776 \n18. Regueiro MG Wolfgang SC Leonard BO Infliximab prevents Crohn’s disease recurrence after ileal resection Gastroenterology 2009 136 2 441 50 19109962 \n19. Yoshida K Fukunaga K Ikeuchi H Scheduled infliximab monotherapy to prevent recurrence of Crohn’s disease following ileocolic or ileal re-section: A 3-year prospective randomized open trial Inflamm Bowel Dis 2011 18 9 1617 23 22081474 \n20. Domènech E Mañosa M Lobatón T Optimizing post-operative Crohn’s disease treatment Ann Gastroenterol 2014 27 4 313 19 25331779\n\n",
"fulltext_license": "CC BY-NC-ND",
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"journal": "The American journal of case reports",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D018784:Abdominal Abscess; D000328:Adult; D003108:Colonic Diseases; D003424:Crohn Disease; D003646:Debridement; D057210:Delayed Diagnosis; D004322:Drainage; D005260:Female; D006801:Humans; D007412:Intestinal Fistula; D049590:Postpartum Period; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011645:Puerperal Infection; D012187:Retroperitoneal Space",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "773-777",
"pmc": null,
"pmid": "29961750",
"pubdate": "2018-07-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15925481;1546574;3776220;22081474;23752881;11910338;2860564;1200016;19109962;25331779;21679776;10208701;27042756;8064202;2678984;17334338;381094;22110836;7429313",
"title": "A Challenging Case of Retroperitoneal Abscess in a Post-Partum Crohn's Disease Patient.",
"title_normalized": "a challenging case of retroperitoneal abscess in a post partum crohn s disease patient"
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"abstract": "Mycobacterium marinum is an atypical mycobacterium usually found in non-chlorinated water. It rarely disseminates, except in the setting of a severely immunosuppressed patient, and usually follows a sporotrichotic type of distribution. We report the case of a 45-year-old man who had ankylosing spondylitis and was receiving infliximab and isoniazid for latent tuberculosis. The patient presented with a 5-month history of painful erythematous and suppurative nodules and abscesses on the right upper extremity. M. marinum was not isolated in cultures and histologic findings together with clinical examination provided evidence of sporotrichoid-like fish tank granuloma. The patient was treated with rifampin (rifampicin) and ethambutol for 8 months and responded satisfactorily while continuing to receive infliximab. In accordance with data in the published literature, isoniazid proved ineffective in preventing M. marinum infection in this patient. While mycobacterial complications of tumor necrosis factor-alpha (TNFalpha) inhibitor therapy are well established, our case appears to be the first reported instance of M. marinum infection in a patient taking infliximab. As anti-TNFalpha agents become increasingly used for a variety of conditions, awareness of the potential infectious complications associated with use of these agents will be vital for clinicians.",
"affiliations": "Department of Dermatology, Army General Hospital, Athens, Greece.efrall@otenet.gr",
"authors": "Rallis|Efstathios|E|;Koumantaki-Mathioudaki|Elma|E|;Frangoulis|Effie|E|;Chatziolou|Eftihia|E|;Katsambas|Andreas|A|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D000995:Antitubercular Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D007538:Isoniazid",
"country": "New Zealand",
"delete": false,
"doi": "10.2165/00128071-200708060-00009",
"fulltext": null,
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"issn_linking": "1175-0561",
"issue": "8(6)",
"journal": "American journal of clinical dermatology",
"keywords": null,
"medline_ta": "Am J Clin Dermatol",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D000995:Antitubercular Agents; D004781:Environmental Exposure; D006099:Granuloma; D006801:Humans; D016867:Immunocompromised Host; D000069285:Infliximab; D007538:Isoniazid; D008297:Male; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D019910:Mycobacterium marinum; D017192:Skin Diseases, Bacterial; D013167:Spondylitis, Ankylosing; D014376:Tuberculosis; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "100895290",
"other_id": null,
"pages": "385-8",
"pmc": null,
"pmid": "18039022",
"pubdate": "2007",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe sporotrichoid fish tank granuloma following infliximab therapy.",
"title_normalized": "severe sporotrichoid fish tank granuloma following infliximab therapy"
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"companynumb": "GR-JNJFOC-20070405736",
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"activesubstancename": "INFLIXIMAB"
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"abstract": "BACKGROUND\nDexmedetomidine has been widely used in critical care settings because of its property of maintaining stable hemodynamics and inducing conscious sedation. The use of dexmedetomidine is in increasing trend particularly in patients with neurological disorders. Very few studies have focused on the cerebral hemodynamic effects of dexmedetomidine. This study is aimed to address this issue.\n\n\nMETHODS\nThirty patients without any intracranial pathology were included in this study. Middle cerebral artery flow velocity obtained from transcranial color Doppler was used to assess the cerebral hemodynamic indices. Mean flow velocity (mFV), pulsatility index (PI), cerebral vascular resistant index (CVRi), estimated cerebral perfusion pressure (eCPP), and zero flow pressure (ZFP) were calculated bilaterally at baseline and after infusion of injection Dexmedetomidine 1 mcg/Kg over 10 min.\n\n\nRESULTS\nTwenty-six patients completed the study protocol. After administration of loading dose of dexmedetomidine, mFV and eCPP values were significantly decreased in both hemispheres (P < 0.05); PI, CVRi, and ZFP values showed significant increase (P < 0.05) after dexmedetomidine infusion.\n\n\nCONCLUSIONS\nIncrease in PI, CVRi, and ZFP suggests that there is a possibility of an increase in distal cerebral vascular resistance (CVR) with loading dose of dexmedetomidine. Decrease in mFV and eCPP along with an increase in CVR may lead to a decrease in cerebral perfusion. This effect can be exaggerated in patients with preexisting neurological illness. Further studies are needed to evaluate the effect of dexmedetomidine on various other pathological conditions involving brain like traumatic brain injury and vascular malformations.",
"affiliations": "Department of Anesthesiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Ulloor, Trivandrum, Kerala, India.;Department of Anesthesiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Ulloor, Trivandrum, Kerala, India.;Department of Anesthesiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Ulloor, Trivandrum, Kerala, India.;Department of Anesthesiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Ulloor, Trivandrum, Kerala, India.",
"authors": "Arulvelan|Appavoo|A|;Manikandan|Sethuraman|S|;Easwer|Hari Venkat|HV|;Krishnakumar|Kesavapisharady|K|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0972-5229.173680",
"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-20-910.4103/0972-5229.173680Research ArticleCerebral vascular effects of loading dose of dexmedetomidine: A Transcranial Color Doppler study Arulvelan Appavoo Manikandan Sethuraman Easwer Hari Venkat Krishnakumar Kesavapisharady From: Department of Anesthesiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Ulloor, Trivandrum, Kerala, IndiaCorrespondence: Dr. Appavoo Arulvelan, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Ulloor, Trivandrum - 695 011, Kerala, India. E-mail: drarulvelan@gmail.com1 2016 20 1 9 13 Copyright: © 2016 Indian Journal of Critical Care Medicine2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background:\nDexmedetomidine has been widely used in critical care settings because of its property of maintaining stable hemodynamics and inducing conscious sedation. The use of dexmedetomidine is in increasing trend particularly in patients with neurological disorders. Very few studies have focused on the cerebral hemodynamic effects of dexmedetomidine. This study is aimed to address this issue.\n\nMethods:\nThirty patients without any intracranial pathology were included in this study. Middle cerebral artery flow velocity obtained from transcranial color Doppler was used to assess the cerebral hemodynamic indices. Mean flow velocity (mFV), pulsatility index (PI), cerebral vascular resistant index (CVRi), estimated cerebral perfusion pressure (eCPP), and zero flow pressure (ZFP) were calculated bilaterally at baseline and after infusion of injection Dexmedetomidine 1 mcg/Kg over 10 min.\n\nResults:\nTwenty-six patients completed the study protocol. After administration of loading dose of dexmedetomidine, mFV and eCPP values were significantly decreased in both hemispheres (P < 0.05); PI, CVRi, and ZFP values showed significant increase (P < 0.05) after dexmedetomidine infusion.\n\nConclusion:\nIncrease in PI, CVRi, and ZFP suggests that there is a possibility of an increase in distal cerebral vascular resistance (CVR) with loading dose of dexmedetomidine. Decrease in mFV and eCPP along with an increase in CVR may lead to a decrease in cerebral perfusion. This effect can be exaggerated in patients with preexisting neurological illness. Further studies are needed to evaluate the effect of dexmedetomidine on various other pathological conditions involving brain like traumatic brain injury and vascular malformations.\n\nCerebral vascular resistancedexmedetomidinetranscranial color Doppler\n==== Body\nIntroduction\nDexmedetomidine belongs to imidazole subclass of α2 adrenoceptor agonists, now widely used in anesthesia and critical care arena. It has been approved for use as sedative and analgesic in the Intensive Care Unit (ICU) setting. It activates presynaptic α2 adrenoceptor in the locus coeruleus of pons and inhibits the release of norepinephrine thus leading to sedation and hypnosis.[1] The action of dexmedetomidine is unique as it mimics natural sleep, thus resulting in cooperative form of sedation, in which the patients easily transform from sleep to wakefulness when aroused. This characteristic allows for wake up test where the patients are assessed daily for improvement in neurological status, even without stopping sedation thus preventing sympathetic surges during the test. Dexmedetomidine is shown to maintain cognitive and immunologic function in the sleep-deprived states as in the ICU. Clinical side effects of dexmedetomidine described in literature mainly focus on hemodynamic effects such as hypotension and bradycardia. Very few studies have focused on the cerebral hemodynamic effects of dexmedetomidine.[2] Most of the studies on dexmedetomidine and cerebral hemodynamics were conducted upon either animals or in healthy human volunteers with varying doses.\n\nThe use of dexmedetomidine is in increasing trend particularly in patients with neurological disorders because of its property of maintaining stable hemodynamics and inducing conscious sedation. In the present study, we tested the cerebral hemodynamic effects of initial loading dose of dexmedetomidine (1 mcg/kg over 10 min) with the help of transcranial color Doppler (TCCD) imaging.\n\nMethods\nA pilot study was designed after getting necessary approval from the Institutional Ethical Committee. Thirty American Society of Anesthesiology (ASA) class one patients planned for lumbar discectomy procedure aged between 18 and 40 years were included after obtaining informed consent. Exclusion criteria were: ASA class 2 and above; comorbidities including systemic hypertension and diabetes mellitus, preoperative heart rate <50/min, the presence of heart block of any degree, and known allergy to dexmedetomidine or other α2 agonists.\n\nNo premedication was given to the patients. On arrival in the operating room, patients were monitored with electrocardiography (ECG) and pulse oximetry (SpO2 ). Under local anesthesia, intravenous and intra-arterial cannulations were performed. Lactated ringer was given at rate of 4 ml/kg/hr. After application of nose clip, end tidal CO2 estimation (EtCO2 ) was obtained from mouthpiece and analyzed inside stream monitor (S/5 monitor, GE healthcare, UK). ECG, SpO2, EtCO2, respiratory rate (RR), and invasive blood pressure were monitored and recorded continuously.\n\nTCCD imaging using 2 MHz probe (Vivid-i, GE healthcare, UK) was used to record cerebral blood flow velocities (FV). Through temporal window M1 segment (horizontal segment) of middle cerebral artery (MCA) was identified according to anatomical location, depth of insonation, and direction of flow. After a steady state of FV recording, angle correction was applied so that the angle between linear segment of M1 and angle of insonation was less than 15°. Bilateral probes were fixed with custom made headband. FV waveforms were recorded from right and left MCA for consecutive ten cardiac cycles [Figure 1].\n\nFigure 1 Middle cerebral artery flow velocity obtained from transcranial color Doppler imaging\n\nLoading dose of dexmedetomidine was given in the dose of 1 mcg/kg over 10 min as infusion. During infusion, blood pressure and heart rate were maintained with infusion of lactated ringer solution, injection Ephedrine in 3 mg increments and injection Glycopyrrolate 0.2 mg. FV waveforms were recorded from both MCA after 10 min. Once the study protocol was completed, infusion of dexmedetomidine was stopped and routine anesthesia was used for induction and maintenance.\n\nPatients were further excluded if EtCO2 change of more than 2 mmHg from baseline and difficulty in locating MCA with TCCD.\n\nThe data collected included demographic data, heart rate, invasive blood pressure, RR, SpO2, EtCO2, and bilateral MCA FV at baseline and at the end of the dexmedetomidine infusion.\n\nMean values of simultaneously measured invasive blood pressure recordings and the outer envelope of time averaged MCA FV recordings during ten consecutive cardiac cycles were used to calculate the following cerebral hemodynamic parameters.[34]\n\n\nMean flow velocity (mFV)\n\nPulsatility index ([PI] = (systolic FV − diastolic FV)/mean FV)\n\nCerebral vascular resistant index ([CVRi] = mean BP/mean FV)\n\nEstimated cerebral perfusion pressure ([eCPP] = mean FV × [mean BP − diastolic BP/mean FV − diastolic FV]) and\n\nZero flow pressure ([ZFP] = mean BP − eCPP).\n\n\n\n\n\nStatistics\nSPSS version 16 (SPSS, Inc., Chicago, IL, USA, 2007) was used for statistical analysis. Results obtained from the study were expressed in mean ± SD. Changes in vital parameters during dexmedetomidine administration were assessed using one-way ANOVA. Paired t-test was used to assess the statistical difference of cerebral hemodynamic parameters (mFV, PI, CVRi, eCPP, and ZFP) between baseline and after infusion of loading dose of dexmedetomidine. A P < 0.05 was considered as statistically significant.\n\nResults\nAs hemodynamic indices were assessed from both hemispheres, the study groups were subdivided and tabulated as “RIGHT” and “LEFT” representing data from MCA that supplies right and left hemisphere respectively.\n\nTwo patients were excluded due to difficulty in localizing MCA, and two patients were excluded because of change in EtCO2 >2 mmHg. Twenty-six patients completed the study protocol. Mean age was 32 ± 2.7 years, mean weight was 67 ± 7.2 kg; 12 were male and 14 were female. Vital parameters that can affect cerebral arterial FV were maintained comparable to baseline values [Table 1].\n\nTable 1 Vital parameters\n\nmFV was significantly decreased in both hemispheres after administration of loading dose of dexmedetomidine (P < 0.001). PI and CVRi showed significant increase (P < 0.05) after dexmedetomidine loading dose [Table 2]. In both hemispheres, significant decrease in eCPP (P - 0.005; P < 0.001) and significant increase in ZFP (P < 0.001; P = 0.004) were observed [Table 2].\n\nTable 2 Cerebral hemodynamic indices\n\nDiscussion\nThe results of our study showed that the loading dose of dexmedetomidine (1 mcg/kg over 10 min) resulted in significant decrease in mFV and eCPP. We also observed an increase in PI, CVRi, and ZFP after loading dose.\n\nCerebral vasculature and thus cerebral blood flow is affected by various physiological factors including paCO2, PaO2, temperature, cerebral metabolic rate, and blood viscosity.[5] These factors are often deranged by disease process or manipulated for therapeutic purposes in anesthesia and critical care environments. Apart from these physiological factors, anesthetic drugs and other vasoactive drugs used in critical care environments can also directly or indirectly affect cerebral blood flow.[6789] As the use of dexmedetomidine is in increasing trend, knowledge about the cerebral vascular effects will help in the optimal use of this drug with minimal alteration in cerebral hemodynamics.\n\nTranscranial Doppler (TCD) is a simple noninvasive bedside tool to assess the cerebral blood flow pattern. The new development of transcranial color Doppler with angle correction option helps to improve the sensitivity of test results.\n\n\nMean flow velocity\nThe relationship between TCD-derived FV and actual cerebral blood flow is confounded by various factors such as metabolic state, cerebral vascular resistance (CVR), and cerebral perfusion pressure (CPP).[1011] In a study by Zornow et al., six healthy volunteers were infused with four different doses of dexmedetomidine.[12] This study showed that hypnotic dose of dexmedetomidine results in a modest decrease in FV corresponding to the increase in dexmedetomidine dosage. Similar results were obtained in our study where the loading dose of dexmedetomidine resulted in a decrease in blood FV. Although mFV derived from TCD is not synonymous with actual cerebral blood flow, studies have shown that the changes in mFV correlate well with trends of blood flow alteration.[13] As an experimental condition, the blood pressure and PaCO2 were maintained comparable to baseline during the administration of dexmedetomidine, and we have observed decrease in blood FV. However, in patients admitted in critical care units, the baseline blood pressure may be low because of the primary disease or as a side-effect of dexmedetomidine itself. Administration of dexmedetomidine in this scenario can exaggerate the decrease in mFV and thus compromise on cerebral blood flow.\n\nPulsatility index and cerebral vascular resistant index\nThe normal value for PI is quoted between 0.6 and 0.9.[3] Studies have shown that Gosling PI can be the reliable monitor of cerebral hemodynamic asymmetry and CPP.[14]\n\nStimulation with α2 agents such as clonidine and dexmedetomidine has shown to cause vasoconstriction in isolated cerebral vessels and in various animal models.[151617] Vasoconstrictive property and increase in CVR were also demonstrated in studies where the administration of dexmedetomidine prevented inhalational anesthetics and CO2 induced vasodilatation.[1819] In a study by Schregel et al., cerebral vascular effects of halothane, alfentanil, and propofol were compared.[20] The PI showed a shortterm increase after alfentanil, decrease after halothane, and strong increase after infusion of propofol. The changes in PI values were consistent with vasodilatory effect of halothane and vasoconstrictory effect of propofol and alfentanil. Increase in PI values obtained from our study suggests the vasoconstrictory effect of dexmedetomidine and possibility of decreased cerebral perfusion. This fact is also supported by the significant decrease in mFV and increase in CVRi observed in our study.\n\nCerebral perfusion pressure and zero flow pressure\nCPP is the net pressure gradient causing blood flow to the brain, and it is calculated as the difference between effective upstream pressure and downstream pressure.[21] It must be maintained within narrow limits because decrease in CPP could cause brain tissue to become ischemic and an increase in CPP can lead to an increase in intracranial pressure (ICP), both detrimental for the survival of neurons. The upstream pressure is usually the mean arterial pressure. As the cranium is a closed cavity, the effective downstream pressure can be central venous pressure (CVP) or ICP or CVR. Thus, a more general concept of ZFP has been introduced, where ZFP is defined as the pressure at which flow in a vessel would cease. Thus, the CPP can be estimated from the difference between MAP and ZFP [CPP = MAP – ZFP].\n\nIn our study, significant decrease in eCPP and increase in ZFP were observed. It is shown that, in conditions of normal ICP and CVP, vascular tone may be the dominant component of ZFP.[22] Dexmedetomidine is shown to act as vasoconstrictor in cerebral circulation in various studies. Increase in CVRi values in our study also supports the fact that dexmedetomidine increases cerebral arteriolar tone. Dexmedetomidine is also shown to increase the cerebral venous tone.[23] Thus, it can be explained that the decrease in eCPP and increase in ZFP observed in our study can be due to dexmedetomidine-induced cerebral vasoconstriction and increase in CVR.\n\n“Hypotension” is proven cardiovascular side effect of dexmedetomidine and in our study the “increase in ZFP” is also demonstrated. As the CPP = MAP – ZFP, there is possibility that administration of loading dose of dexmedetomidine can lead to reduction in cerebral blood flow. Apart from CVR, intracranial pathological conditions like cerebral edema, space occupying lesions, blood clots, and elevated venous pressure have shown to increase distal resistance to blood flow.[421] When dexmedetomidine is used in these conditions because of vasoconstrictory action, there is a possibility of exaggerated reduction in cerebral blood flow and can be detrimental to neurological outcome.\n\nInadequate supply of oxygen and glucose to brain leads to cerebral ischemia and excitotoxicity. Adequate supply of substrates depends on adequate perfusion pressure and normal CVR. Results from our study show that after loading dose of dexmedetomidine, there is a possibility of decreased CPP and increased CVR. Our study was done in patients without any systemic comorbid illness and in controlled condition such as maintained blood pressure, maintained EtCO2, and without any other sedative drugs. In ICU setting, these factors may not be under ideal conditions and presence of primary brain pathology may complicate the scenario, further compromising cerebral blood supply.\n\nThere are few limitations in our study that are needed to be discussed. In this study, the initial bolus dose of dexmedetomidine (1 mcg/Kg over 10 min) was used. Many studies have suggested that the systemic hemodynamic effects such as hypotension and bradycardia can be minimized by omitting the bolus dose and initiating the maintenance dose as an infusion. Like the systemic effects, the cerebral vascular effects of the maintenance dose of dexmedetomidine may be different. Thus, further studies are warranted to assess the effect of dexmedetomidine on cerebral hemodynamics with varying maintenance doses. The phenomenon of flow-metabolism coupling with dexmedetomidine is not well defined.[2] Decrease in FV due to metabolic suppression could not be ruled out in our study. We have included patients without intracranial pathology and without any comorbid illness. Studies have shown altered cerebral blood flow and abnormal vascular reactivity in patients with intracranial pathological conditions like infection, trauma, tumor, and vascular malformations. Further adequately powered studies are warranted to address the effect of cerebral hemodynamic effect of dexmedetomidine in pathological conditions involving the brain. TCD-derived parameters correlate well with gross cerebral blood flow. However, the use of monitors such as laser Doppler flowmetry and microdialysis can further help to understand the action of dexmedetomidine at the tissue level.\n\nConclusion\nIn summary, we observed that loading dose of dexmedetomidine (1 mcg/kg over 10 min) resulted in decrease in FV and estimated CPP even after maintaining blood pressure comparable to baseline values. Increase in PI, CVRi, and ZFP suggests an increase in distal CVR. All these findings collectively suggest the possibility of a decrease in cerebral blood flow after loading dose of dexmedetomidine (1 mcg/Kg over 10 min). This effect can be exaggerated in patients with preexisting neurological illness and hemodynamic instability. Further studies are needed to evaluate the effect of dexmedetomidine on various other pathological conditions involving brain like traumatic brain injury and vascular malformations.\n\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Gerlach AT Dasta JF Dexmedetomidine: An updated review Ann Pharmacother 2007 41 245 52 17299013 \n2 Bekker A Sturaitis MK Dexmedetomidine for neurological surgery Neurosurgery 2005 57 1 Suppl 1 10 15987564 \n3 van Beek AH Claassen JA Rikkert MG Jansen RW Cerebral autoregulation: An overview of current concepts and methodology with special focus on the elderly J Cereb Blood Flow Metab 2008 28 1071 85 18349877 \n4 Hancock SM Mahajan RP Athanassiou L Noninvasive estimation of cerebral perfusion pressure and zero flow pressure in healthy volunteers: The effects of changes in end-tidal carbon dioxide Anesth Analg 2003 96 847 51 12598272 \n5 Wahl M Schilling L Regulation of cerebral blood flow - A brief review Acta Neurochir Suppl (Wien) 1993 59 3 10 7508677 \n6 Dagal A Lam AM Cerebral autoregulation and anesthesia Curr Opin Anaesthesiol 2009 22 547 52 19620861 \n7 Schlünzen L Vafaee MS Cold GE Rasmussen M Nielsen JF Gjedde A Effects of subanaesthetic and anaesthetic doses of sevoflurane on regional cerebral blood flow in healthy volunteers. A positron emission tomographic study Acta Anaesthesiol Scand 2004 48 1268 76 15504187 \n8 Endoh H Honda T Ohashi S Hida S Shibue C Komura N The influence of nicardipine-, nitroglycerin-, and prostaglandin E(1)-induced hypotension on cerebral pressure autoregulation in adult patients during propofol-fentanyl anesthesia Anesth Analg 2002 94 169 73 11772822 \n9 Moppett IK Sherman RW Wild MJ Latter JA Mahajan RP Effects of norepinephrine and glyceryl trinitrate on cerebral haemodynamics: Transcranial Doppler study in healthy volunteers Br J Anaesth 2008 100 240 4 18211997 \n10 Ulrich PT Becker T Kempski OS Correlation of cerebral blood flow and MCA flow velocity measured in healthy volunteers during acetazolamide and CO2 stimulation J Neurol Sci 1995 129 120 30 7608725 \n11 van der Linden J Wesslén O Ekroth R Tydén H von Ahn H Transcranial Doppler-estimated versus thermodilution-estimated cerebral blood flow during cardiac operations. Influence of temperature and arterial carbon dioxide tension J Thorac Cardiovasc Surg 1991 102 95 102 1906562 \n12 Zornow MH Maze M Dyck JB Shafer SL Dexmedetomidine decreases cerebral blood flow velocity in humans J Cereb Blood Flow Metab 1993 13 350 3 8094720 \n13 Kontos HA Validity of cerebral arterial blood flow calculations from velocity measurements Stroke 1989 20 1 3 2911822 \n14 Czosnyka M Richards HK Whitehouse HE Pickard JD Relationship between transcranial Doppler-determined pulsatility index and cerebrovascular resistance: An experimental study J Neurosurg 1996 84 79 84 8613840 \n15 Ishiyama T Dohi S Iida H The vascular effects of topical and intravenous alpha2-adrenoceptor agonist clonidine on canine pial microcirculation Anesth Analg 1998 86 766 72 9539599 \n16 Ganjoo P Farber NE Hudetz A Smith JJ Samso E Kampine JP In vivo effects of dexmedetomidine on laser-Doppler flow and pial arteriolar diameter Anesthesiology 1998 88 429 39 9477064 \n17 Asano Y Koehler RC Kawaguchi T McPherson RW Pial arteriolar constriction to alpha 2-adrenergic agonist dexmedetomidine in the rat Am J Physiol 1997 272 6 Pt 2 H2547 56 9227530 \n18 Zornow MH Fleischer JE Scheller MS Nakakimura K Drummond JC Dexmedetomidine, an alpha 2-adrenergic agonist, decreases cerebral blood flow in the isoflurane-anesthetized dog Anesth Analg 1990 70 624 30 1971500 \n19 Fale A Kirsch JR McPherson RW Alpha 2-adrenergic agonist effects on normocapnic and hypercapnic cerebral blood flow in the dog are anesthetic dependent Anesth Analg 1994 79 892 8 7978406 \n20 Schregel W Bredenkötter U Sihle-Wissel M Cunitz G Transcranial Doppler ultrasound: Effects of intravenous anesthetics in neurosurgical patients Ultraschall Med 1995 16 60 4 7624757 \n21 White H Venkatesh B Cerebral perfusion pressure in neurotrauma: A review Anesth Analg 2008 107 979 88 18713917 \n22 Weyland A Buhre W Grund S Ludwig H Kazmaier S Weyland W Cerebrovascular tone rather than intracranial pressure determines the effective downstream pressure of the cerebral circulation in the absence of intracranial hypertension J Neurosurg Anesthesiol 2000 12 210 6 10905568 \n23 Ulrich K Kuschinsky W In vivo effects of alpha-adrenoceptor agonists and antagonists on pial veins of cats Stroke 1985 16 880 4 2864755\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0972-5229",
"issue": "20(1)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Cerebral vascular resistance; dexmedetomidine; transcranial color Doppler",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "9-13",
"pmc": null,
"pmid": "26955211",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article",
"references": "19620861;9227530;12598272;11772822;9539599;1906562;9477064;7608725;7624757;7978406;18211997;7508677;18713917;8613840;10905568;1971500;15987564;15504187;8094720;2911822;18349877;17299013;2864755",
"title": "Cerebral vascular effects of loading dose of dexmedetomidine: A Transcranial Color Doppler study.",
"title_normalized": "cerebral vascular effects of loading dose of dexmedetomidine a transcranial color doppler study"
} | [
{
"companynumb": "IN-PAR PHARMACEUTICAL COMPANIES-2016SCPR015153",
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"activesubstancename": "EPHEDRINE"
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"abstract": "Soluble fms-like tyrosine kinase-1 (sFlt1), a circulating vascular endothelial growth factor receptor 1 antagonist, is associated with the pathogenesis of pre-eclampsia. Extracorporeal removal of sFlt1 (sFlt1 apheresis) is emerging as a treatment for pre-eclampsia. We performed sFlt1 apheresis for a patient with very early onset pre-eclampsia, beginning at 15 weeks' gestation. She underwent sFlt1 apheresis 13 times from 19 to 23 weeks' gestation. The series of treatments lowered circulating sFlt1, stabilized blood pressure, reduced urinary protein, and preserved renal function, which contributed to a successful prolongation of pregnancy for 4 weeks and a live birth at 23(+3) weeks' gestation. Further studies are necessary for clinical application of sFlt1 apheresis as sFlt1 might have a protective function for the placenta and fetus in pre-eclampsia.",
"affiliations": "Department Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.",
"authors": "Nakakita|Baku|B|;Mogami|Haruta|H|;Kondoh|Eiji|E|;Tsukamoto|Tatsuo|T|;Yanagita|Motoko|M|;Konishi|Ikuo|I|",
"chemical_list": "C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1",
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.12760",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "41(10)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "apheresis; dextran sulfate cellulose columns; pre-eclampsia; pregnancy; soluble fms-like tyrosine kinase 1",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D001781:Blood Component Removal; D005260:Female; D006801:Humans; D011225:Pre-Eclampsia; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D040281:Vascular Endothelial Growth Factor Receptor-1",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "1661-3",
"pmc": null,
"pmid": "26094569",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Case of soluble fms-like tyrosine kinase 1 apheresis in severe pre-eclampsia developed at 15 weeks' gestation.",
"title_normalized": "case of soluble fms like tyrosine kinase 1 apheresis in severe pre eclampsia developed at 15 weeks gestation"
} | [
{
"companynumb": "JP-BAYER-2015-450988",
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"patient": {
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"activesubstancename": "NIFEDIPINE"
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... |
{
"abstract": "Dronedarone is a promising, relatively new antiarrhythmic agent characterized by structural similarities to amiodarone but without amiodarone's severe organ toxicity. The proarrhythmic potential of dronedarone, however, is of increasing concern. We describe a 76-year-old woman who had been receiving dronedarone 400 mg twice/day to prevent recurrent atrial tachycardia with rapid ventricular response. Several months later, she came to the emergency department with decompensated congestive heart failure and episodes of atrial tachycardia; digoxin 0.5 mg and furosemide 40 mg were administered intravenously. Thereafter nonsustained torsade de pointes (TdP) tachycardia occurred. She was transferred to the intensive care unit where a dose of amiodarone 150 mg was administered intravenously by mistake. Thereafter, the patient showed sustained TdP necessitating cardiac resuscitation. Dronedarone was discontinued, and digoxin and amiodarone were not administered again. Under dronedarone a relevant QT prolongation was documented that was additionally augmented after concomitant treatment with digoxin and amiodarone. Use of the Naranjo adverse drug reaction probability scale indicated a probable adverse drug reaction to dronedarone (score of 7). To our knowledge, this is the first case report of a patient who experienced TdP tachycardias while receiving dronedarone therapy in connection with a worsening of heart failure and possible drug interactions with digoxin and amiodarone. Clinicians should be aware of this potential adverse drug reaction and perform repeated heart rate-corrected QT (QTc) interval measurements as well as screening for congestive heart failure in patients receiving dronedarone therapy.",
"affiliations": "Department of Cardiology, Division for Rhythmology and Electrophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Clinical Pharmacology and Toxicology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Clinical Pharmacology and Toxicology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Clinical Pharmacology and Toxicology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology, Bremen, Germany.;Department of Cardiology, Division for Rhythmology and Electrophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany.",
"authors": "Huemer|Martin|M|;Sarganas|Giselle|G|;Bronder|Elisabeth|E|;Klimpel|Andreas|A|;Garbe|Edeltraut|E|;Haverkamp|Wilhelm|W|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000077764:Dronedarone; D000638:Amiodarone",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.1573",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "35(5)",
"journal": "Pharmacotherapy",
"keywords": "cardiac arrest; dronedarone; long QT syndrome; torsade de pointes; ventricular fibrillation; ventricular tachycardia",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000368:Aged; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D000077764:Dronedarone; D005260:Female; D006801:Humans; D016171:Torsades de Pointes",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "e61-5",
"pmc": null,
"pmid": "25823967",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Torsade de pointes tachycardia in a patient on dronedarone therapy.",
"title_normalized": "torsade de pointes tachycardia in a patient on dronedarone therapy"
} | [
{
"companynumb": "DE-IMPAX LABORATORIES, INC-2015-IPXL-00623",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DRONEDARONE"
},
"drugadditio... |
{
"abstract": "A 60-year-old man underwent surveillance colonoscopy that demonstrated five subcentimetre polyps, all of which were biopsied. One of the five polyps had histopathology consistent with small cell lung carcinoma (SCLC) metastasis from primary lung cancer. Subsequent imaging demonstrated a spiculated mass in the right upper lung lobe with metastasis to the brain, liver and spleen. He was immediately treated with palliative whole-brain irradiation followed by eight cycles of carboplatin and etoposide. Despite aggressive management, he had disease progression characterised by worsening performance status and development of transfusion-dependent anaemia, new blastic bone lesions and epidural disease. Given his liver failure, he was not considered a candidate for second-line topotecan. After discussion with the patient, family and palliative services, he was discharged with home hospice. This report describes a rare case of advanced SCLC presenting as a metastatic caecal polyp on surveillance colonoscopy.",
"affiliations": "Department of Internal Medicine, Rutgers-NJMS, Newark, New Jersey, USA.",
"authors": "Khan|Abdullah Mohammad|AM|;Khan|Sunniya|S|;Dave|Vinnidhy|V|;Bhurgri|Hadi|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003106:Colon; D003110:Colonic Neoplasms; D003111:Colonic Polyps; D003113:Colonoscopy; D003937:Diagnosis, Differential; D006801:Humans; D008175:Lung Neoplasms; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D055752:Small Cell Lung Carcinoma; D014057:Tomography, X-Ray Computed; D051598:Whole Body Imaging",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24667947",
"pubdate": "2014-03-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21714641;21623258;16022008;21577115;17410025;23649448;17008692;21390139;19696259;23335087;21043816;23307984;23497006;6274500",
"title": "Small cell lung carcinoma presenting as a caecal polyp on surveillance colonoscopy.",
"title_normalized": "small cell lung carcinoma presenting as a caecal polyp on surveillance colonoscopy"
} | [
{
"companynumb": "US-CIPLA LTD.-2014US00340",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nOver a period of 1 year in our hospital, 3 patients were diagnosed with 'ileitis following capecitabine use'. The case of 1 of these patients is presented in this article.\n\n\nMETHODS\nA 73-year-old man known to be suffering from liver metastases from rectal cancer was treated with oxaliplatin, bevacizumab and capecitabine. He was admitted to our hospital with abdominal pain, diarrhoea, nausea and a subfebrile temperature. A CT scan of the abdomen showed marked bowel wall thickening, particularly of the ileum, consistent with terminal ileitis. The diagnosis was 'ileitis following capecitabine use' since other disorders were excluded or seemed less likely, and the Naranjo score was compatible with 'possible adverse reaction'. Capecitabine treatment was discontinued. Following recovery, treatment was resumed without complications.\n\n\nCONCLUSIONS\nSmall intestine toxicity during capecitabine use has, to our knowledge, not been described previously. It is important to recognise this side-effect in order to avoid obstruction and perforation. Conservative treatment including an adapted diet and intravenous hydration is the therapy of choice. Surgery does not seem to be indicated.",
"affiliations": "Deventer Ziekenhuis, afd. Interne Geneeskunde, Deventer, the Netherlands. g.bouma@dz.nl",
"authors": "Bouma|Grietje|G|;Imholz|Alex L T|AL|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "155()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D006801:Humans; D007079:Ileitis; D008297:Male; D012004:Rectal Neoplasms",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": "A3064",
"pmc": null,
"pmid": "21486509",
"pubdate": "2011",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Ileitis following capecitabine use.",
"title_normalized": "ileitis following capecitabine use"
} | [
{
"companynumb": "NL-PFIZER INC-2018486966",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "1",
... |
{
"abstract": "Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.",
"affiliations": "Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, China.;Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, China.;Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, China.;Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, China.;Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, China.;Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, China.;Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, China.;Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, China.;Nanfang-Chunfu Children's Institute of Hematology and Oncology, Taixin Hospital, Dongguan, China.;Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, China.",
"authors": "Wang|Xiaodong|X|;Zhang|Xiaoling|X|0000-0002-1940-0202;Yu|Uet|U|0000-0003-4391-3398;Wang|Chunjing|C|;Yang|Chunlan|C|;Li|Yue|Y|;Li|Changgang|C|;Wen|Feiqiu|F|;Li|Chunfu|C|;Liu|Sixi|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0963689721994808",
"fulltext": "\n==== Front\nCell Transplant\nCell Transplant\nCLL\nspcll\nCell Transplantation\n0963-6897 1555-3892 SAGE Publications Sage CA: Los Angeles, CA \n\n33593080\n10.1177/0963689721994808\n10.1177_0963689721994808\nOriginal Article\nCo-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major\nWang Xiaodong 1* https://orcid.org/0000-0002-1940-0202Zhang Xiaoling 1* https://orcid.org/0000-0003-4391-3398Yu Uet 1* Wang Chunjing 1 Yang Chunlan 1 Li Yue 1 Li Changgang 1 Wen Feiqiu 1 Li Chunfu 23 Liu Sixi 1 \n1 Department of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, China\n\n2 Nanfang-Chunfu Children’s Institute of Hematology and Oncology, Taixin Hospital, Dongguan, China\n\n3 Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China\nSixi Liu, Department of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen, China. Email: tiger647@126.comChunfu Li, Nanfang-Chunfu Children’s Institute of Hematology and Oncology, Taixin Hospital, Dongguan, China. Email: chunfugzcn@126.com*These authors contributed equally to this article\n\n\n17 2 2021 \nJan-Dec 2021 \n30 096368972199480811 11 2020 13 1 2021 26 1 2021 © The Author(s) 20212021SAGE Publications Inc, unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.\n\nhaploidentical stem cell transplantationcord blood transplantthalassemiaSanming Project of Medicine in ShenzhenSZSM 201512033cover-dateJanuary-December 2021typesetterts3\n==== Body\nIntroduction\nAllogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.\n\nHowever, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.\n\nThe current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.\n\nSubjects and Methods\nPatient Characteristics\nWe retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.\n\nTM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.\n\nHaploidentical Donor Selection\nWe performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.\n\nCord Blood\nCord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.\n\nPreparative Regimen\nPre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.\n\nPost-Transplantation Immunosuppression\nGVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.\n\nSupportive Care\nPatients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.\n\nPatients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.\n\nPatient Evaluations\nAll patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.\n\nDefinition of Engraftment\nMyeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.\n\nStatistical Methods\nOS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.\n\nResults\nPatient Characteristics\nPatient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.\n\nTable 1. Patient Characteristics.\n\nPatient characteristics\t\t\n\nTotal number\n\t73\t\n\nMedian age at transplantation age (years, range)\n\t7 (3 to 14)\t\n\nRisk assessment\n\t\t\n Low\n\t2 (3%)\t\n Intermediate\n\t42 (57%)\t\n High\n\t29 (40%)\t\n\nSex\n\t\t\n Female\n\t27 (37%)\t\n Male\n\t46 (63%)\t\n\nHLA matching\n\t\t\n 5/10\n\t45 (62%)\t\n 6/10\n\t15 (21%)\t\n 7/10\n\t9 (12%)\t\n 8/10\n\t4 (5%)\t\n\nDonor\n\t\t\n Brother\n\t14 (19%)\t\n Sister\n\t10 (15%)\t\n Father\n\t39 (54%)\t\n Mother\n\t8 (11%)\t\n Other relative\n\t1 (1%)\t\n\nABO blood type\n\t\t\n Matched\n\t23 (32%)\t\n Mismatched\n\t50 (68%)\t\n\nStem cell source\n\t\t\n PBSC alone\n\t57 (78%)\t\n PBSC + BM\n\t16 (22%)\t\n\nStem cell engraftment\n\t\t\n Haplo\n\t43 (59%)\t\n Cord blood\n\t30 (41%)\t\n\nMNC dose (108/kg) (median, range)\n\t20 (10.60 to 32.20)\t\n\nCD34+ dose (106/kg) (median, range)\n\t15.45 (2.60 to 62.00)\t\n\nCell engraftment (median, range)\n\t\t\n Days to neutrophil engraftment\n\t22 (15 to 48)\t\n Days to platelet engraftment\n\t20 (8 to 99)\t\n\nPrimary or secondary graft failure\n\t0\t\nBM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.\n\nNo primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.\n\nGVHD and Other Complications\nAs shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).\n\nTable 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.\n\nComplications\tNumber of patients\t\n\nAcute GVHD\n\t38 (52%)\t\n I to II\n\t20 (27%)\t\n III to IV\n\t18 (25%)\t\n Use of steroids\n\t18\t\n\nChronic GVHD\n\t27 (37%)\t\n Mild\n\t26 (36%)\t\n Severe\n\t1 (1%)\t\n\nInfections\n\t\t\n CMV-DNAemia\n\t35 (48%)\t\n CMV diseases\n\t5 (7%)\t\n EBV-DNAemia\n\t19 (26%)\t\n PTLD\n\t5 (7%)\t\n Herpetic zoster reactivation\n\t6 (10%)\t\n HHV6\n\t1 (1%)\t\n BKV related hemorrhagic cystitis\n\t7 (9%)\t\n Sepsis\n\t3 (5%)\t\n Tuberculosis\n\t1 (1%)\t\n Streptococcus meningitis\n\t1 (1%)\t\n Invasive fungal infection\n\t7 (10%)\t\n\nOther complications\n\t\t\n Poor graft function (PGF)\n\t6 (8%)\t\n Primary PGF\n\t4 (5%)\t\n Secondary PGF\n\t2 (3%)\t\n SOS/VOD\n\t6 (8%)\t\n Mucositis\n\t18 (25%)\t\n Refractory autoimmune haemolytic anemia\n\t1 (1%)\t\n\nCause of death\n\t\t\n Chronic GVHD\n\t1\t\n Secondary PGF\n\t1\t\n Refractory autoimmune hemolytic anaemia\n\t1\t\n\nFollow up time (median, range)\n\t811 (370 to 1433)\t\nGVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.\n\nCytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.\n\nOverall Survival and Transfusion-Free Survival\nThe estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).\n\nFig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).\n\nCord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity\nPatient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).\n\nFig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.\n\nFig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).\n\nDiscussion\nThis is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.\n\nMost TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.\n\nAs a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.\n\nA relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.\n\nThe percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.\n\nCompared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.\n\nOf the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.\n\nAnother limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.\n\nIn conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.\n\nSupplemental Material\nSupplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major\nClick here for additional data file.\n\nSupplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation\n\n Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major\nClick here for additional data file.\n\nSupplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation\n\n Acknowledgments\nWe thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.\n\nEthical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.\n\nStatement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.\n\nStatement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).\n\nORCID iDs: Xiaoling Zhang \nhttps://orcid.org/0000-0002-1940-0202\n\n\nUet Yu \nhttps://orcid.org/0000-0003-4391-3398\n\n\nSupplemental Material: Supplemental material for this article is available online.\n==== Refs\nReferences\n1 \nJohn MJ Jyani G Jindal A Mashon RS Mathew A Kakkar S Bahuguna P Prinja S \nCost effectiveness of hematopoietic stem cell transplantation compared with transfusion chelation for treatment of thalassemia major\n. 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Blood Adv . 2018 ;2 (3 ):263 –270\n.29431621 \n53 \nTorres Canizales J Ferreras C Pascual A Alonso L Regueiro A Plaza M Pérez Hurtado JM Benito A Couselo JM Fuster JL Díaz-Almirón M , et al.\nHaploidentical transplantation in pediatric non-malignant diseases: a retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation (GETH)\n. Eur J Haematol . 2020 ;106 (2 ):196 –204\n. Epub 2020 Nov 17. \n33084101 \n54 \nTao T Li Z Chu XL Zhu WJ Xu Y Wu DP Ma X Xue SL \nClinical features of chronic graft-versus-host disease following haploidentical transplantation combined with infusion of a cord blood\n. 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"fulltext_license": "CC BY-NC",
"issn_linking": "0963-6897",
"issue": "30()",
"journal": "Cell transplantation",
"keywords": "cord blood transplant; haploidentical stem cell transplantation; thalassemia",
"medline_ta": "Cell Transplant",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D036101:Cord Blood Stem Cell Transplantation; D005260:Female; D006801:Humans; D008297:Male; D019172:Transplantation Conditioning; D000075442:Transplantation, Haploidentical; D017086:beta-Thalassemia",
"nlm_unique_id": "9208854",
"other_id": null,
"pages": "963689721994808",
"pmc": null,
"pmid": "33593080",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22645178;24790059;28651066;29673692;30878605;28436973;18489989;27081180;33084101;31777304;30446741;28482908;26577457;26348869;27788764;26152553;20492708;31488878;25649994;26752139;30180460;27909435;27537474;29288821;24370862;15050742;31265729;31070946;24296492;21976674;26878659;31431703;26088837;31913152;30977441;22968457;21933603;23160007;25612623;8634461;16339666;25882700;24869942;29962035;28456009;28263918;31471325;23879970;29431621;10808201;31410846;31931116;29128555;31202429;31495699",
"title": "Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.",
"title_normalized": "co transplantation of haploidentical stem cells and a dose of unrelated cord blood in pediatric patients with thalassemia major"
} | [
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"companynumb": "CN-ROCHE-2997846",
"fulfillexpeditecriteria": "1",
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"patient": {
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"actiondrug": "5",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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{
"abstract": "After approval of anti-programmed cell death (PD)-1 antibodies, treatment for non-small cell lung cancer (NSCLC) has drastically changed. However, even in patients with favorable effects, therapeutic efficacy does not last long. Recently, retreatment with anti-PD-1 antibody has received attention. The aim of this study was to evaluate the efficacy and safety of retreatment with pembrolizumab in NSCLC patients previously treated with nivolumab.\n\n\n\nWe retrospectively reviewed NSCLC patients retreated with pembrolizumab who were previously treated with nivolumab. We collected the following data: patient characteristics, number of cycles of nivolumab and pembrolizumab, treatment interval between nivolumab and pembrolizumab, best response, and immune-related adverse events.\n\n\n\nTwelve patients were reviewed. The median number of cycles of nivolumab was 12.5 (range 2-32 cycles). Seven patients (58.3%) achieved a partial response (PR) and two patients (16.7%) achieved stable disease (SD). Eight patients (66.7%) received cytotoxic chemotherapy between nivolumab and pembrolizumab. The median number of cycles of chemotherapy treatment was 4 (range 1-9 cycles). The median number of cycles of pembrolizumab was 3.5 (range 1-17 cycles). One patient (8.3%) achieved PR and four patients (33.3%) achieved SD as their best response to pembrolizumab. All patients showing response to pembrolizumab had very high (≥ 80%) tumor PD-Ligand 1 expression.\n\n\n\nThis study suggested that retreatment with anti-PD-1 antibody is a reasonable option for selected NSCLC patients.",
"affiliations": "Division of Respiratory Medicine, National Hospital Organization Kyoto Medical Center, 1-1, Fukakusa-Mukaihata-Cho, Fushimi-Ku, Kyoto, Japan. kfujita-oka@umin.ac.jp.;Division of Respiratory Medicine, National Hospital Organization Kyoto Medical Center, 1-1, Fukakusa-Mukaihata-Cho, Fushimi-Ku, Kyoto, Japan.;Division of Respiratory Medicine, National Hospital Organization Kyoto Medical Center, 1-1, Fukakusa-Mukaihata-Cho, Fushimi-Ku, Kyoto, Japan.;Division of Respiratory Medicine, National Hospital Organization Kyoto Medical Center, 1-1, Fukakusa-Mukaihata-Cho, Fushimi-Ku, Kyoto, Japan.;Division of Respiratory Medicine, National Hospital Organization Kyoto Medical Center, 1-1, Fukakusa-Mukaihata-Cho, Fushimi-Ku, Kyoto, Japan.;Division of Respiratory Medicine, National Hospital Organization Kyoto Medical Center, 1-1, Fukakusa-Mukaihata-Cho, Fushimi-Ku, Kyoto, Japan.",
"authors": "Fujita|Kohei|K|0000-0002-6902-9085;Uchida|Naohiro|N|;Kanai|Osamu|O|;Okamura|Misato|M|;Nakatani|Koichi|K|;Mio|Tadashi|T|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C582435:pembrolizumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-018-3585-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "81(6)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Immune checkpoint inhibitors; NSCLC; Nivolumab; Pembrolizumab; Relapse; Retreatment",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor; D019233:Retreatment; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "1105-1109",
"pmc": null,
"pmid": "29675747",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Retreatment with pembrolizumab in advanced non-small cell lung cancer patients previously treated with nivolumab: emerging reports of 12 cases.",
"title_normalized": "retreatment with pembrolizumab in advanced non small cell lung cancer patients previously treated with nivolumab emerging reports of 12 cases"
} | [
{
"companynumb": "JP-009507513-1805JPN004718",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMultiple xanthogranulomas (XGs) in adults are rare, although an increasing number of case reports are being published. The most frequent association is hematologic malignancies, but the majority of cases remain idiopathic, with occasional spontaneous resolution.\n\n\nOBJECTIVE\nThe aims of this report are to describe a case of eruptive XG in a woman with a solid neoplasia who was receiving imatinib and to review the literature.\n\n\nRESULTS\nThis 33-year-old woman had a gastrointestinal stromal tumor. After undergoing surgical removal and being on imatinib for 1 year, the patient developed multiple slightly erythematous papules with an orange hue on the axillary region, trunk, abdomen, and thighs. A biopsy confirmed the diagnosis of XG.\n\n\nCONCLUSIONS\nThis is to the investigators' knowledge the first case of eruptive XG in the setting of a solid neoplasia. The possibility of drug-induced XG lesions due to imatinib cannot be excluded. This presentation could be added to the list of associations of adult XG.",
"affiliations": "Division of Dermatology, Université de Montréal, Montreal, QC, Canada sophie.vadeboncoeur@umontreal.ca.;Division of Dermatology, Université de Montréal, Montreal, QC, Canada.",
"authors": "Vadeboncoeur|Sophie|S|;Provost|Nathalie|N|",
"chemical_list": "D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate",
"country": "United States",
"delete": false,
"doi": "10.1177/1203475416640795",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1203-4754",
"issue": "20(5)",
"journal": "Journal of cutaneous medicine and surgery",
"keywords": "GIST; adult xanthogranuloma; dermatology",
"medline_ta": "J Cutan Med Surg",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D017024:Chemotherapy, Adjuvant; D003875:Drug Eruptions; D005260:Female; D046152:Gastrointestinal Stromal Tumors; D006099:Granuloma; D015616:Histiocytosis, Non-Langerhans-Cell; D006801:Humans; D000068877:Imatinib Mesylate; D013274:Stomach Neoplasms; D014973:Xanthomatosis",
"nlm_unique_id": "9614685",
"other_id": null,
"pages": "474-7",
"pmc": null,
"pmid": "27006313",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple Xanthogranulomas in an Adult: Known Entity, New Association.",
"title_normalized": "multiple xanthogranulomas in an adult known entity new association"
} | [
{
"companynumb": "PHHY2016CA161765",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": "3",
"drugadm... |
{
"abstract": "BACKGROUND\nPatients with metastatic castration-resistant prostate cancer have few treatment options. We investigated the safety and efficacy of lenalidomide, an immunomodulatory agent with anti-angiogenic properties, in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer.\n\n\nMETHODS\nIn this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned chemotherapy-naive patients with progressive metastatic castration-resistant prostate cancer in a 1:1 ratio to receive docetaxel (75 mg/m(2)) on day 1 and prednisone (5 mg twice daily) on days 1-21 and either lenalidomide (25 mg) or placebo once daily on days 1-14 of each 21 day treatment cycle. Permuted block randomisation was done with an interactive voice response system and stratified by Eastern Cooperative Oncology Group performance status, geographic region, and type of disease progression. Clinicians, patients, and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy analysis was by intention to treat. Patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00988208.\n\n\nRESULTS\n1059 patients were enrolled and randomly assigned between Nov 11, 2009, and Nov 23, 2011 (533 to the lenalidomide group and 526 to the control group), and 1046 patients received study treatment (525 in the lenalidomide group and 521 in the placebo group). At data cutoff (Jan 13, 2012) after a median follow-up of 8 months (IQR 5-12), 221 patients had died: 129 in the lenalidomide group and 92 in the placebo group. Median overall survival was 17·7 months (95% CI 14·8-18·8) in the lenalidomide group and not reached in the placebo group (hazard ratio [HR] 1·53, 95% CI 1·17-2·00, p=0·0017). The trial was subsequently closed early due to futility. The number of deaths that occurred during treatment or less than 28 days since the last dose were similar in both groups (18 [3%] of 525 patients in the lenalidomide group vs 13 [2%] of 521 patients). 109 (21%) patients in the lenalidomide group and 78 (15%) in the placebo group died more than 28 days from last dose, mainly due to disease progression. At least one grade 3 or higher adverse event was reported in 381 (73%) of 525 patients receiving lenalidomide and 303 (58%) of 521 patients receiving placebo. Grade 3-4 neutropenia (114 [22%] for lenalidomide vs 85 [16%] for placebo), febrile neutropenia (62 [12%] vs 23 [4%]), diarrhoea (37 [7%] vs 12 [2%]), pneumonia (24 [5%] vs five [1%]), dyspnoea (22 [4%] vs nine [2%]), asthenia (27 [5%] vs 17 [3%]), and pulmonary embolism (32 [6%] vs seven [1%]) occurred more frequently in the lenalidomide group than in the placebo group.\n\n\nCONCLUSIONS\nOverall survival with the combination of lenalidomide, docetaxel, and prednisone was significantly worse than with docetaxel and prednisone for chemotherapy-naive men with metastatic, castration-resistant prostate cancer. Further research with this treatment combination is not warranted.\n\n\nBACKGROUND\nCelgene Corporation.",
"affiliations": "Yale Cancer Center, Department of Medicine Division of Oncology, New Haven, CT, USA. Electronic address: daniel.petrylak@yale.edu.;US Oncology Research, Houston, TX, USA; Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA.;NSHI Dorozhnaya Clinical Hospital of OAO Russian Railways, Rostov-on-Don, Russia.;Department of Uro-Oncology, Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie, Warsaw, Poland.;San Camillo and Forlanini Hospitals, Department of Medical Oncology, Rome, Italy.;Texas Oncology, Austin, TX, USA.;University Hospital del Mar-IMIM, Barcelona, Spain; Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;US Oncology Research, Houston, TX, USA; Rocky Mountain Cancer Centers, Aurora, CO, USA.;Catalan Institute of Oncology, Department of Medical Oncology, Barcelona, Spain.;Department of Clinical Oncology, The Christie NHS Foundation Trust and Institute of Cancer Sciences, University of Manchester, Manchester, UK.;Department of Urology, Rechts der Isar Medical Center, Technische Universität München, München, Germany.;State Institution of Healthcare \"Regional Clinical Oncology Dispensary\", Omsk, Russia.;Centre Léon Bérard, Department of Medical Oncology, Lyon, France.;Department of Clinical Oncology, Royal Marsden Hospital, London, UK.;Medical Oncology Department, Groupe Hospitalier Universitaire Caremeau Place du Professeur Robert Debré, Nîmes, France.;Celgene Corporation, Summit, NJ, USA.;Celgene Corporation, Summit, NJ, USA.;Celgene Corporation, Summit, NJ, USA.;Celgene Corporation, Summit, NJ, USA.;ErasmusMC Cancer Institute, Rotterdam, Netherlands.;Institut Gustave Roussy, Department of Cancer Medicine, University of Paris Sud, Villejuif, France.",
"authors": "Petrylak|Daniel P|DP|;Vogelzang|Nicholas J|NJ|;Budnik|Nikolay|N|;Wiechno|Pawel Jan|PJ|;Sternberg|Cora N|CN|;Doner|Kevin|K|;Bellmunt|Joaquim|J|;Burke|John M|JM|;de Olza|Maria Ochoa|MO|;Choudhury|Ananya|A|;Gschwend|Juergen E|JE|;Kopyltsov|Evgeny|E|;Flechon|Aude|A|;Van As|Nicolas|N|;Houede|Nadine|N|;Barton|Debora|D|;Fandi|Abderrahim|A|;Jungnelius|Ulf|U|;Li|Shaoyi|S|;de Wit|Ronald|R|;Fizazi|Karim|K|",
"chemical_list": "D010919:Placebos; D043823:Taxoids; D000077143:Docetaxel; D013792:Thalidomide; D000077269:Lenalidomide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "16(4)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077143:Docetaxel; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011241:Prednisone; D064129:Prostatic Neoplasms, Castration-Resistant; D043823:Taxoids; D013792:Thalidomide",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "417-25",
"pmc": null,
"pmid": "25743937",
"pubdate": "2015-04",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial.",
"title_normalized": "docetaxel and prednisone with or without lenalidomide in chemotherapy naive patients with metastatic castration resistant prostate cancer mainsail a randomised double blind placebo controlled phase 3 trial"
} | [
{
"companynumb": "US-PFIZER INC-2018253557",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAcute Compartment syndrome (ACS) with subsequent need for fasciotomy is a serious and insidious complication after revascularization for acute lower limb ischemia (ALI). The development of ACS during endovascular catheter directed thrombolysis is particularly difficult to identify. The aim was to identify the incidence, predisposing factors, wound treatment, and outcome in terms of amputation and survival for patients presenting with ALI that develop ACS during catheter directed thrombolysis. Patients who did not develop ACS after thrombolysis were analyzed as controls.\n\n\nMETHODS\nDescriptive retrospective analysis of prospective databases from two large tertiary-referral vascular centers. Patients with ACS after thrombolysis for ALI between 2001-2017 were analyzed.\n\n\nRESULTS\nSeventy-eight cases and 621 controls were identified. Mean age was 72 years and 30 (38.5%) were women in the ACS group. Patients that developed ACS presented with significantly more severe preoperative ischemia. With 38.5% having Rutherford 2b classification as compared to 22.7 % in the control group (P = 0.002). Occluded popliteal artery aneurysms were also associated with a higher incidence of ACS (P = 0.041). Treatment of the fasciotomy wound was most commonly treated with regular wound dressing in 45 (58%) of cases, while wound dressing and foot pump and vacuum assisted closure were used in 14 (18%) and 19 (24%) respectively. These differing approaches did not affect the number of wound infections and amputations, which was similar regardless of treatment type. Vacuum assisted closure was associated with a higher degree of skin graft closure (P = 0.001). The median time to complete wound closure was 10 days. One year after thrombolysis, the major amputation rate in the ACS group was 31% as opposed to 17% in control group, P = 0.003. Mortality measured at 16.7% and 15.3%, respectively, P = 0.872. Amputation-free survival in the ACS group was 62% vs. 73% in the control group, P = 0.035. These differences level out, however, when applying long-term analysis of amputation-free survival in Kaplan-Meier analysis (log-rank 0.103).\n\n\nCONCLUSIONS\nPatients that developed ACS during endovascular CDT presented with a more severe pre-operative ischemia, more occluded popliteal artery aneurysms and had a higher amputation rate during the first year, compared to controls. The development of ACS during endovascular treatment of ALI with thrombolysis is not uncommon and warrants both clinical awareness and rapid treatment.",
"affiliations": "Uppsala University, Department of Surgical Sciences, Section of Vascular Surgery, Uppsala, Sweden.;Lund University, Department of Clinical Sciences, Faculty of Medicine, Lund, Sweden.;Linköping University, Department Biomedical and Clinical Sciences, Linköping, Sweden. Electronic address: hakan.parsson@liu.se.",
"authors": "Olivia|Grip|G|;Petter|Lindahl|L|;Håkan|Pärsson|P|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.avsg.2021.07.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-5096",
"issue": null,
"journal": "Annals of vascular surgery",
"keywords": null,
"medline_ta": "Ann Vasc Surg",
"mesh_terms": null,
"nlm_unique_id": "8703941",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34644632",
"pubdate": "2021-10-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Acute Compartment Syndrome Following Thrombolysis For Acute Lower Limb Ischemia.",
"title_normalized": "acute compartment syndrome following thrombolysis for acute lower limb ischemia"
} | [
{
"companynumb": "SE-BoehringerIngelheim-2022-BI-156359",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "... |
{
"abstract": "Seventeen patients with refractory (7 cases) or relapsed (10 cases) lymphoma were treated with a continuous infusion of etoposide, vincristine, and doxorubicin, in addition to cyclophosphamide (bolus) and prednisone (regimen EPOCH). Six patients (4 with Hodgkin's disease) achieved a complete response (CR) (35%; 95% CI: 14-62%). However, 5 of 6 patients had achieved a CR with their initial therapy. Myelosuppression was the most serious effect (29% of patients with grade IV leukopenia after the first course). There were two treatment-related deaths. Doses were lower than originally reported (median: 68%). Infusional therapy with EPOCH is an active regimen in these heavily pretreated patients, particularly in relapsed Hodgkin's disease. It seems a useful protocol to prove chemosensitivity before bone marrow transplantation. However, the true role of infusional treatment has to be determined in clinical trials.",
"affiliations": "Service of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.",
"authors": "Carrión|J R|JR|;García Arroyo|F R|FR|;Salinas|P|P|",
"chemical_list": "D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1097/00000421-199502000-00009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "18(1)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D004351:Drug Resistance; D005047:Etoposide; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D007262:Infusions, Intravenous; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011241:Prednisone; D012008:Recurrence; D016019:Survival Analysis; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "44-6",
"pmc": null,
"pmid": "7847258",
"pubdate": "1995-02",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Infusional chemotherapy (EPOCH) in patients with refractory or relapsed lymphoma.",
"title_normalized": "infusional chemotherapy epoch in patients with refractory or relapsed lymphoma"
} | [
{
"companynumb": "ES-BAXTER-2021BAX006855",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "We describe a case of a 61-year-old man with chronic hepatitis B, hepatitis B e antibody (HBeAb) positive, treated with tenofovir disoproxil fumarate (TDF), who developed virological and biochemical viremic reactivation with an increase in transaminase plasma levels. The patient's history revealed that he had discontinued TDF about 5 days before admission and, from December 2013, had been taking venlafaxine, paroxetine and zolpidem for some episodes of depression. Clinical evaluation and laboratory findings excluded the presence of systemic diseases that might have been able to explain the drug inefficacy, while pharmacological evaluation suggested a possible drug-drug interaction. In order to assess the possible occurrence of resistance, mutational analysis of hepatitis B virus (HBV) was performed and excluded the presence of resistance for TDF. TDF was prescribed, and venlafaxine, paroxetine and zolpidem were discontinued. The follow-up at 3, 6 and 12 months documented a good response to TDF with a time-related decrease of HBV-DNA and alanine aminotransferase.",
"affiliations": "University of Catanzaro, Catanzaro, Italy.;University of Catanzaro, Catanzaro, Italy.;University of Catanzaro, Catanzaro, Italy.;University of Catanzaro, Catanzaro, Italy.",
"authors": "Caroleo|Benedetto|B|;Staltari|Orietta|O|;Gallelli|Luca|L|;Perticone|Francesco|F|",
"chemical_list": "D000998:Antiviral Agents; D002491:Central Nervous System Agents; D005650:Fumarates; D000068698:Tenofovir; D000637:Transaminases; D000410:Alanine Transaminase",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000410:Alanine Transaminase; D000998:Antiviral Agents; D002491:Central Nervous System Agents; D003863:Depression; D004347:Drug Interactions; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005650:Fumarates; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D000068698:Tenofovir; D000637:Transaminases; D019562:Viral Load; D014775:Virus Activation",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26123461",
"pubdate": "2015-06-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24929235;22293326;18171292;14709940;22123153;22400085;24516494;23897419;23234725;17372702;7811041;10462545;15217303;18537180;23716900;23437966;19075267;16352363;23939953;24701043;21716719;11563082;22436845;21743991;20955704;23983956;20888661;25453573;18331765;21994680;17005808",
"title": "Reactivation of chronic hepatitis B during treatment with tenofovir disoproxil fumarate: drug interactions or low adherence?",
"title_normalized": "reactivation of chronic hepatitis b during treatment with tenofovir disoproxil fumarate drug interactions or low adherence"
} | [
{
"companynumb": "IT-MEDA-2016050055",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAROXETINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Minocycline, a derivative of tetracycline, is a broad-spectrum antibiotic used in the treatment of various infections. Black discolouration of the skin, teeth, bones and the thyroid gland are sequelae of long-term minocycline therapy. We report an unusual case of minocycline-induced pigmentation of the aortic valve and sinuses of Valsalva.",
"affiliations": "Division of Cardiovascular and Thoracic Surgery, Intermountain Medical Center, Murray, UT, USA ttsune0707@hotmail.co.jp.;Division of Cardiovascular and Thoracic Surgery, Intermountain Medical Center, Murray, UT, USA.;Division of Cardiovascular and Thoracic Surgery, Intermountain Medical Center, Murray, UT, USA.",
"authors": "Tsunekawa|Tomohiro|T|;Jones|Kent W|KW|;Doty|John R|JR|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008911:Minocycline",
"country": "England",
"delete": false,
"doi": "10.1093/icvts/ivu142",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1569-9285",
"issue": "19(2)",
"journal": "Interactive cardiovascular and thoracic surgery",
"keywords": "Aortic valve; Heart valve disease; Surgery",
"medline_ta": "Interact Cardiovasc Thorac Surg",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001018:Aortic Diseases; D001021:Aortic Valve; D001024:Aortic Valve Stenosis; D001706:Biopsy; D004334:Drug Administration Schedule; D005260:Female; D006349:Heart Valve Diseases; D019918:Heart Valve Prosthesis Implantation; D016575:Hidradenitis; D006801:Humans; D008911:Minocycline; D010858:Pigmentation; D010859:Pigmentation Disorders; D012850:Sinus of Valsalva",
"nlm_unique_id": "101158399",
"other_id": null,
"pages": "339-40",
"pmc": null,
"pmid": "24824497",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Black pigmented aortic valve and sinus of Valsalva caused by life-long minocycline therapy.",
"title_normalized": "black pigmented aortic valve and sinus of valsalva caused by life long minocycline therapy"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/14/0042848",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MINOCYCLINE HYDROCHLORIDE"
},
"drugaddit... |
{
"abstract": "We report the case of a 52-year-old man with type 2 diabetes, who developed severe mucosal erosions of the tongue, glans penis and perianal area, induced by glimepiride. A tissue biopsy was performed and revealed the characteristics of lichen planus (LP). The improvement of the patient's condition after withdrawal of glimepiride added to recurrence of the lesions when medication was reintroduced confirmed that the second generation anti-diabetic was the causative agent. To the best of our knowledge, this has not been reported previously.",
"affiliations": "Department of Pharmacology, Faculty of Medicine of Sfax, Sfax, Tunisia. hammamj_serria@yahoo.fr.",
"authors": "Hammami|S|S|;Ksouda|K|K|;Affes|H|H|;Sahnoun|Z|Z|;Zeghal|K|K|",
"chemical_list": "D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C057619:glimepiride",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1128-3602",
"issue": "19(12)",
"journal": "European review for medical and pharmacological sciences",
"keywords": null,
"medline_ta": "Eur Rev Med Pharmacol Sci",
"mesh_terms": "D003924:Diabetes Mellitus, Type 2; D003875:Drug Eruptions; D006801:Humans; D007004:Hypoglycemic Agents; D017512:Lichenoid Eruptions; D008297:Male; D008875:Middle Aged; D013453:Sulfonylurea Compounds; D014059:Tongue",
"nlm_unique_id": "9717360",
"other_id": null,
"pages": "2301-2",
"pmc": null,
"pmid": "26166659",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mucosal lichenoid drug reaction associated with glimepiride: a case report.",
"title_normalized": "mucosal lichenoid drug reaction associated with glimepiride a case report"
} | [
{
"companynumb": "TN-GLAXOSMITHKLINE-TN2015GSK142875",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GLIMEPIRIDE"
},
"drugadditional": nu... |
{
"abstract": "We present a case of 36-year-old woman with twin pregnancy, Chagas cardiomyopathy and history of multiple episodes of dizziness and syncope. The patient's Holter study revealed sinus pauses of up to 5.3 seconds, frequent premature ventricular contractions (PVC) and some episodes of non-sustained ventricular tachycardia at 110 bpm. To avoid teratogenic radiation, dual chamber pacemaker implantation was performed guided by transthoracic echocardiography. The patient was treated with metoprolol succinate 100 mg once a day to reduce PVC and nonsustained ventricular tachycardia. During follow up, the patient reported complete resolution of syncope and dizziness. She went on to have a normal delivery without complications. PCRs for Chagas in both twins were negative.",
"affiliations": "Hospital Nacional Arzobispo Loayza, Av. Alfonso Ugarte 848, Lima, PC 15082, Peru. Electronic address: paul.preza.c@upch.pe.;Hospital Nacional Arzobispo Loayza, Av. Alfonso Ugarte 848, Lima, PC 15082, Peru. Electronic address: mauricio.guerra.r@upch.pe.;Hospital Nacional Arzobispo Loayza, Av. Alfonso Ugarte 848, Lima, PC 15082, Peru. Electronic address: ladyscarlev@yahoo.es.;Hospital Nacional Arzobispo Loayza, Av. Alfonso Ugarte 848, Lima, PC 15082, Peru. Electronic address: vikyarmas@gmail.com.",
"authors": "Preza|Paul M|PM|;Guerra|Mauricio|M|;Cárdenas|Ladys R|LR|;Armas|Victoria C|VC|",
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"doi": "10.1016/j.ipej.2021.10.001",
"fulltext": "\n==== Front\nIndian Pacing Electrophysiol J\nIndian Pacing Electrophysiol J\nIndian Pacing and Electrophysiology Journal\n0972-6292\nElsevier\n\nS0972-6292(21)00146-7\n10.1016/j.ipej.2021.10.001\nImage\nDual chamber pacemaker implantation in woman with twin pregnancy and Chagas cardiomyopathy guided by 2D transthoracic echocardiography\nPreza Paul M. paul.preza.c@upch.pe\n∗\nGuerra Mauricio mauricio.guerra.r@upch.pe\n\nCárdenas Ladys R. ladyscarlev@yahoo.es\n\nArmas Victoria C. vikyarmas@gmail.com\n\nHospital Nacional Arzobispo Loayza, Av. Alfonso Ugarte 848, Lima, PC 15082, Peru\n∗ Corresponding author. Jirón Real 205, Dpto 301 Santiago de Surco, Lima, PC 15039, Peru. paul.preza.c@upch.pe\n08 10 2021\nJan-Feb 2022\n08 10 2021\n22 1 4446\n20 3 2021\n22 9 2021\n6 10 2021\n© 2022 Indian Heart Rhythm Society. Published by Elsevier B.V.\n2021\nIndian Heart Rhythm Society\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nWe present a case of 36-year-old woman with twin pregnancy, Chagas cardiomyopathy and history of multiple episodes of dizziness and syncope. The patient's Holter study revealed sinus pauses of up to 5.3 seconds, frequent premature ventricular contractions (PVC) and some episodes of non-sustained ventricular tachycardia at 110 bpm. To avoid teratogenic radiation, dual chamber pacemaker implantation was performed guided by transthoracic echocardiography. The patient was treated with metoprolol succinate 100 mg once a day to reduce PVC and nonsustained ventricular tachycardia. During follow up, the patient reported complete resolution of syncope and dizziness. She went on to have a normal delivery without complications. PCRs for Chagas in both twins were negative.\n\nKeywords\n\nChagas cardiomyopathy\nTwin pregnancy\nTransthoracic echocardiography\nSick sinus syndrome\nArtificial pacemaker\n==== Body\npmcA 36-year-old woman originally from the indigenous community of Andoas in the jungle of Perú was referred to our hospital in Lima. She arrived with a 2-years history of fatigue, dizziness and one year of recurrent syncope. At the time of admission, she was 16 weeks pregnant with a viable twin pregnancy.\n\nThe Holter study revealed sinus pauses of up to 5.3 seconds, frequent premature ventricular contractions (PVC) and some episodes of non-sustained ventricular tachycardia at 110 bpm (Fig. 1A) Serological tests for Chagas disease were positive.Fig. 1 Figure A shows the pre implantation Holter with frequent PVC and several pauses including one of 5.29s. Figure B shows the post implantation Holter showing pacemaker rhythm with atrial pacing and ventricular sensing.\n\nFig. 1\n\nDecision was made to proceed with implantation of a dual chamber permanent pacemaker guided by transthoracic echocardiography. The implantation technique is described below.\n\nTwo-dimensional transthoracic echocardiography was performed with a Phillips i33 machine. Right ventricle lead (Biotronik Safio S60) was implanted using the technique previously described by Güldal [1]. Thereafter, the atrial lead (Biotronik Safio S53), with a J stylet inside, was introduced through the left subclavian vein with the distal curve and the point of its tip towards the anterior region of the chest (Fig. 2C). After applying clockwise and counter-clockwise torque alternatively on the lead, the tip of the atrial lead was placed in the right atrial appendage. Lead positioning and stability were also confirmed by echocardiography through a subxiphoid window under the following approaches: in the bicaval view, it was possible to visualize the entire route of the atrial lead within the right atrium (Fig. 2A, B, C and online video 1) and in the four-chamber view, it was possible to confirm the so-called windshield wiper appearance of the atrial lead motion (online video 2). After that, the retractable screw was deployed for active fixation, and the capture thresholds were verified at 0.7mV/0.4s both in the atrium and in the ventricle. The procedure was completed according to the usual technique without any complication.Fig. 2 The figure A shows a subxiphoid window of the 2D transthoracic echocardiography taken intraprocedural. Figure B is for enhance the recognition of the leads in this view. Figure C shows a graphical representation of the position of the echocardiography probe and beam. Notice how the curve and tip of the atrial lead point toward the front of the patient. RV right ventricle, IVC inferior vena cava, RA right atrium, RAA right atrial appendage, SVC superior vena cava.\n\nFig. 2\n\nThe patient was treated with metoprolol succinate 100 mg once a day to reduce ventricular arrhythmias. Dual chamber pacemaker (Biotronik Etrinsa 6 DR-T) was programed in DDDR mode with a lower rate limit of 70 ppm to improve the cardiac output and to avoid R on T episodes related to the frequent premature ventricular contractions. The post implantation Holter study showed reduction of ventricular tachycardia episodes compared to the previous study. The patient remained paced in the atrium nearly 100% (Fig. 1B).\n\nDuring follow up, the patient reported complete resolution of syncope and dizziness stopped. She went on to have a normal delivery without complications. PCRs for Chagas in both twins were negative.\n\nAs far as we're concerned, this is the first description of dual chamber permanent pacemaker implantation guided by transthoracic echocardiography.\n\nCredit author statement\n\nPaul M Preza: Clinical management and follow up, original draft preparation.\n\nMauricio Guerra: Clinical management, Writing, Reviewing and Editing.\n\nLadys R. Cárdenas: Echocardiography Images.\n\nVictoria C Armas: Supervision.\n\nFunding support\n\nNone.\n\n“All authors have read and approved the manuscript.”\n\nDeclaration of competing interest\n\nThe authors have no conflicts to disclose.\n\nAcknowledgements\n\nTo Erin Cooney and Mevan Wijetunga for helping with the English translation.\n\nPeer review under responsibility of Indian Heart Rhythm Society.\n\nAppendix A Supplementary video related to this article can be found at https://doi.org/10.1016/j.ipej.2021.10.001\n\nThe following are the supplementary data related to this article:s video 3\n\nThis is a video that shows a subxiphoid window of the 2D transthoracic echocardiography taken intraprocedural. This is a bicaval view.\n\ns video 3\n\nSupplementary video 1\n\nThis is a video that shows a subxiphoid window of the 2D transthoracic echocardiography taken intraprocedural. This is a bicaval view.\n\nSupplementary video 1\n\nSupplementary video 2\n\nThis is a video that shows a subxiphoid window of the 2D transthoracic echocardiography taken intraprocedural. This is a four chamber view with the windshield wiper movement of the atrial lead.\n\nSupplementary video 2\n==== Refs\nReference\n\n1 Güldal M. Kervancioglu C. Oral D. Gurel T. Erol C. Sonel A. Permanent pacemaker implantation in a pregnant woman with the guidance of ECG and two-dimensional echocardiography Pacing Clin Electrophysiol 10 1987 543 545 2440004\n\n",
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"journal": "Indian pacing and electrophysiology journal",
"keywords": "Artificial pacemaker; Chagas cardiomyopathy; Sick sinus syndrome; Transthoracic echocardiography; Twin pregnancy",
"medline_ta": "Indian Pacing Electrophysiol J",
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"pmid": "34628037",
"pubdate": "2021-10-08",
"publication_types": "D016428:Journal Article",
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"title": "Dual chamber pacemaker implantation in woman with twin pregnancy and Chagas cardiomyopathy guided by 2D transthoracic echocardiography.",
"title_normalized": "dual chamber pacemaker implantation in woman with twin pregnancy and chagas cardiomyopathy guided by 2d transthoracic echocardiography"
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"abstract": "Although considered a saprophyte, Actinomyces naeslundii can cause invasive infection leading to significant morbidity and mortality. Rarely encountered, bacteremia with this agent occurs in the setting of disrupted mucosal barriers. Previous studies suggest that actinomycosis may be a surrogate marker for poor prognosis in immunocompromised hosts. We report herein a case of a patient with metastatic pancreatic cancer who not only had a prompt resolution of Actinomyces bacteremia and a complete response to chemotherapy, but also remained disease free at 12 months after diagnosis. Our case may suggest that concomitant actinomycosis may not necessarily portend a poor prognosis in all immunocompromised patients.",
"affiliations": null,
"authors": "De Keyser|Roberta|R|;Ram|Arleen|A|;Dasanu|Constantin A|CA|",
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"issn_linking": "0010-6178",
"issue": "80(7)",
"journal": "Connecticut medicine",
"keywords": null,
"medline_ta": "Conn Med",
"mesh_terms": "D000190:Actinomyces; D000196:Actinomycosis; D000230:Adenocarcinoma; D000667:Ampicillin; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D016470:Bacteremia; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms; D011379:Prognosis; D016896:Treatment Outcome",
"nlm_unique_id": "0372745",
"other_id": null,
"pages": "417-418",
"pmc": null,
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"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Curious Case of Actinomyces Naeslundii Bacteremia in a Patient with Metastatic Pancreatic Cancer.",
"title_normalized": "a curious case of actinomyces naeslundii bacteremia in a patient with metastatic pancreatic cancer"
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"abstract": "Calcineurin inhibitors (CNI) are the base of immunosuppressive regimens in liver transplantation but they are associated with significant side effects, namely nephrotoxicity, which leads to increased morbidity and mortality. Through time, mycophenolate mofetil (MMF) as monotherapy has been suggested as an alternative in patients with CNI-related toxicity, but still no consensus has been reached as to its efficacy. We have evaluated the safety, efficacy, and tolerability of MMF monotherapy in selected patients, developing CNI-associated events, focusing primarily on kidney dysfunction. Thirty patients were selected (60% men) with a mean age of 48.5 years. Four patients (13%) were initially on a multidrug regimen that included MMF ad initio due to increased risk of kidney dysfunction. CNI tapering was initiated 5.1 years after liver transplantation (5 months to 13.9 years). The mean time of follow-up after conversion to monotherapy with MMF was 5.6 years (14 months to 12 years). Kidney function analysis accessed by creatinine values and glomerular filtration rate measurement showed a gradual improvement (P < .01). Graft dysfunction after conversion to monotherapy was observed in three patients who required reintroduction of the previous immunosuppressive regimen. Four patients referred minor side effects that were managed with dose reduction. None required MMF withdrawal. Ten patients died during follow up, mainly due to disease progression, 6.8 years after MMF conversion. In conclusion, MMF monotherapy seems to be safe, effective, and well tolerated in selected patients.",
"affiliations": "Unidade de Transplante Hepático e Pancreático, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal. Electronic address: celiamaiacruz@gmail.com.;Unidade de Transplante Hepático e Pancreático, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal.;Unidade de Transplante Hepático e Pancreático, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.;Unidade de Transplante Hepático e Pancreático, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.;Unidade de Transplante Hepático e Pancreático, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.;Unidade de Transplante Hepático e Pancreático, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.;Unidade de Transplante Hepático e Pancreático, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal; Instituto de Saúde Pública do Porto, Universidade do Porto, Porto, Portugal.",
"authors": "Cruz|C M|CM|;Pereira|S|S|;Gandara|J|J|;Ferreira|S|S|;Lopes|V|V|;Daniel|J|J|;Miranda|H P|HP|",
"chemical_list": "D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
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"issue": "48(7)",
"journal": "Transplantation proceedings",
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"mesh_terms": "D000328:Adult; D000368:Aged; D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007674:Kidney Diseases; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D012189:Retrospective Studies",
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"title": "Efficacy and Safety of Monotherapy With Mycophenolate Mofetil in Liver Transplantation Patients With Nephrotoxicity.",
"title_normalized": "efficacy and safety of monotherapy with mycophenolate mofetil in liver transplantation patients with nephrotoxicity"
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"abstract": "Although colonic injury is a well-known complication of mycophenolic acid (MPA), the involvement of the upper gastrointestinal tract is less extensively documented. We present the occurrence of celiac-like duodenopathy manifested as a severe diarrhea syndrome in 2 renal transplant recipients on enteric-coated mycophenolate sodium.\nThe patients belong to a setting of 16 renal transplant recipients under MPA suffering from chronic diarrhea in the absence of MPA-related colitis.\nBoth patients had a history of persistent diarrhea with significant weight loss. Colonic mucosa was unremarkable, whereas duodenal biopsies revealed celiac-like changes with increased epithelial cell apoptosis. Clinical symptoms completely resolved, and follow-up biopsies demonstrated normalization of histology after enteric-coated mycophenolate sodium withdrawal and switching to azathioprine.\nCeliac-like enteropathy seems to represent a rare side effect of MPA-associated immunosuppressive therapy and should be taken into account in the differential diagnosis of diarrhea in transplant recipients treated with MPA particularly in the absence of MPA-related colitis. As macroscopic lesions are usually missing, blind duodenal biopsies are necessary to establish the diagnosis.",
"affiliations": "Department of Nephrology and Renal Transplantation Unit, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.;1st Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;Department of Gastroenterology, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.;Department of Nephrology and Renal Transplantation Unit, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.;Department of Nephrology and Renal Transplantation Unit, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.;Department of Nephrology and Renal Transplantation Unit, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.;1st Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.",
"authors": "Filiopoulos|Vassilis|V|;Sakellariou|Stratigoula|S|;Papaxoinis|Konstantinos|K|;Melexopoulou|Christina|C|;Marinaki|Smaragdi|S|;Boletis|John N|JN|;Delladetsima|Ioanna|I|",
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"fulltext": "\n==== Front\nTransplant DirectTransplant DirectTXDTransplantation Direct2373-8731Lippincott Williams & Wilkins TXD5029210.1097/TXD.000000000000081200003016Kidney TransplantationCeliac-like Enteropathy Associated With Mycophenolate Sodium in Renal Transplant Recipients Filiopoulos Vassilis MD1Sakellariou Stratigoula MD, PhD2Papaxoinis Konstantinos MD3Melexopoulou Christina MD1Marinaki Smaragdi MD1Boletis John N. PhD1Delladetsima Ioanna PhD21 Department of Nephrology and Renal Transplantation Unit, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.2 1st Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.3 Department of Gastroenterology, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.Correspondence: Vassilis Filiopoulos, MD, Department of Nephrology and Renal Transplantation Unit, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 17 Agiou Thoma Street, 11527, Athens, Greece. (vassilis.filiopoulos@hotmail.com).8 2018 20 7 2018 4 8 e37521 5 2018 24 5 2018 30 5 2018 Copyright © 2018 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.2018The Authors. Transplantation Direct. Published by Wolters Kluwer Health, Inc.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.Background\nAlthough colonic injury is a well-known complication of mycophenolic acid (MPA), the involvement of the upper gastrointestinal tract is less extensively documented. We present the occurrence of celiac-like duodenopathy manifested as a severe diarrhea syndrome in 2 renal transplant recipients on enteric-coated mycophenolate sodium.\n\nMethods\nThe patients belong to a setting of 16 renal transplant recipients under MPA suffering from chronic diarrhea in the absence of MPA-related colitis.\n\nResults\nBoth patients had a history of persistent diarrhea with significant weight loss. Colonic mucosa was unremarkable, whereas duodenal biopsies revealed celiac-like changes with increased epithelial cell apoptosis. Clinical symptoms completely resolved, and follow-up biopsies demonstrated normalization of histology after enteric-coated mycophenolate sodium withdrawal and switching to azathioprine.\n\nConclusions\nCeliac-like enteropathy seems to represent a rare side effect of MPA-associated immunosuppressive therapy and should be taken into account in the differential diagnosis of diarrhea in transplant recipients treated with MPA particularly in the absence of MPA-related colitis. As macroscopic lesions are usually missing, blind duodenal biopsies are necessary to establish the diagnosis.\n\n OPEN-ACCESSTRUE\n==== Body\nMycophenolic acid (MPA) in its 2 available formulations, mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), is commonly used in solid organ transplantation as part of the maintenance immunosuppressive regimen. Gastrointestinal (GI) toxicity is the most common side effect occurring in up to 45% of renal transplant recipients.1,2 The pattern of colonic injury has been well described as MMF-associated colitis characterized by crypt distortion and prominent crypt cell apoptosis mimicking inflammatory bowel disease and, less often, graft-versus-host disease (GVHD).2,3 The upper GI tract is less frequently involved, whereas only few reports refer to isolated involvement of the small intestine causing chronic diarrhea and severe weight loss with no sufficient information available regarding pattern of injury.4 In the present short communication, we report the development of celiac-like enteropathy in 2 renal transplant patients under EC-MPS treatment with a clinical history of chronic diarrhea and substantial weight loss.\n\nMATERIALS AND METHODS\nThe cases to be presented belong to a series of 70 renal transplant recipients under MMF or EC-MPS and persistent diarrhea who underwent colonoscopy between 2003 and 2016 at Laiko General Hospital (Athens, Greece). Patients with infectious colitis have been excluded, whereas no patient had a clinical history of inflammatory bowel disease. In 54 (77.15%) patients, MPA-related colitis was diagnosed histologically, whereas in 16 (22.85%) patients colonic biopsies did not display any significant changes. These 16 patients underwent upper GI endoscopy, and duodenal biopsies were obtained from different parts of the duodenum, including bulbus. Histological evaluation showed no significant findings in 3 cases, nonspecific duodenitis in 9 cases (1 with mild villous atrophy), peptic duodenitis in 2, and in the remaining 2 cases, celiac-like changes were identified. Immunohistochemical staining was performed for intraepithelial T lymphocytes assessment using anti-CD3 and anti-CD8 antibodies (DAKO A/S, Denmark). The number of CD3+ intraepithelial lymphocytes (IEL)/100 villous epithelial cells (IEL count) was evaluated. Epithelial cell apoptosis was separately estimated in a total of 100 villi and 100 crypts on hematoxylin and eosin (H&E). Apoptotic index was defined as the mean number of apoptotic bodies per villous and crypt.\n\nThe study was performed in accordance with the Declaration of Helsinki and with the approval of the local ethics committee. Informed consent was obtained from both renal transplant patients whose cases were presented in this manuscript.\n\nRESULTS\nCase 1\nA 76-year-old man presented 16 months after kidney transplantation from deceased donor with intermittent watery, nonbloody diarrhea, and substantial weight loss. Before transplantation, he was 8 years on hemodialysis due to end-stage renal disease attributed to presumed glomerulonephritis. His daily maintenance immunosuppressive regimen comprised 1080-mg EC-MPS, 4-mg tacrolimus, and 4-mg methylprednisolone. He denied use of nonsteroidal anti-inflammatory drugs and antibiotics, alcohol abuse, recent travel, or similar symptoms among family members.\n\nSymptoms manifested 13 months posttransplantation with sudden onset of semiwatery stools, approximately 5 per day. At presentation, almost 3 months after diarrhea onset, the patient complained of severe and almost daily episodes of watery diarrhea associated with abdominal cramps and low-grade fever as well as of weigh loss of approximately 10 kilos. Blind colonic biopsies did not display any significant changes. Considering that the absence of histological evidence does not rule out the possibility of MPA-induced colitis, the dose of EC-MPS was reduced to 720 mg daily, whereas the rest of the immunosuppressive regimen remained unchanged. After 3 months of clinical improvement, intermittent episodes of large-volume watery diarrhea reappeared. In addition, the patient reported nausea, decreased appetite, fatigue, and further weight loss of at least 10 kilos after his last visit. Of note, he was already following a gluten-free diet for at least 4 months with no beneficial effect. On admission, he had a body mass index of 19 kg/m2 with significant muscle wasting and blood pressure of 100/70 mm Hg. Laboratory investigation showed normocytic, normochromic anemia with hemoglobin of 9.6 g/dL, leukocyte count of 4.9 × 105/L, serum creatinine level of 4.17 mg/dL (367 μmol/L), and serum albumin 2.7 g/dL (27 g/L). Fecal leukocyte count, stool cultures, stool Clostridium difficile toxin, and examination for parasites were repeatedly negative. Cytomegalovirus was excluded by quantitative polymerase chain reaction in plasma and immunohistochemically in all biopsy specimens.\n\nEsophagogastroduodenoscopy and colonoscopy did not show any macroscopic abnormalities. However, blind duodenal biopsies revealed mild villous atrophy and increased number of intraepithelial T lymphocytes expressing CD3 and CD8 immunohistochemically (Figures 1A and B). These findings were compatible with celiac-like duodenopathy analogous to type 3A of the modified Marsh classification.5 In addition, apoptotic index was found increased, especially in the epithelium of the villi (Figure 1C). Histological findings are shown in detail in Table 1. Colonic biopsies from different parts of the colon exhibited mild nonspecific changes.\n\nFIGURE 1 Case 1. A, Duodenal mucosa with mild villous atrophy (H&E ×100). B, Intraepithelial lymphocytosis (CD3 immunostain ×200). C, Apoptotic bodies outlined in squares (H&E ×400). D, Normal duodenal mucosa (H&E ×100).\n\nTABLE 1 Histological findings\n\nSmall bowel capsule examination was normal. Celiac serologies (IgA and IgG gliadin antibodies, endomysium antibody, tissue transglutaminase antibody) were negative while consuming gluten. HLA genotyping was inconsistent with celiac disease.\n\nEnteric-coated mycophenolate sodium was discontinued, and the patient was switched to azathioprine 2 mg/kg once daily. After cessation, GI symptoms resolved completely within 1 week. The patient also underwent gluten challenge without symptom recurrence. Follow-up laboratory tests showed recovery of renal function and correction of anemia. One month later, the patient reported significant improvement of his appetite with subsequent weight gain. A follow-up biopsy, 9 months after EC-MPS withdrawal while consuming gluten-containing diet, revealed normalization of villous atrophy and of IEL count with no evidence of abnormal apoptotic rate (Figure 1D). At his last visit, 20 months after EC-MPS withdrawal, the patient had regained nearly 20 kilos and had no GI complaints.\n\nCase 2\nA 70-year-old male patient, who had received a renal graft from a deceased donor, developed a posttransplant progressively aggravating diarrhea syndrome. Before transplantation, the patient was on hemodialysis for 4 years due to end-stage renal disease on a background of unknown nephropathy. Patient's daily maintenance immunosuppressive regimen comprised 1080-mg EC-MPS, 1-mg tacrolimus, and 5-mg prednisolone. There was no history of nonsteroidal anti-inflammatory drugs and antibiotics use, alcohol abuse, recent travel, or similar symptoms in his household.\n\nPatient's symptoms began 6 months after kidney transplantation when he reported loose stools and rare episodes of nonbloody watery diarrhea with no other GI or systemic complaints. The dose of EC-MPS was reduced to 720 mg daily. Afterward, GI symptoms resolved completely for 2 and half years. Subsequently, diarrhea recurred and manifested with up to 6 episodes of severe watery, nonbloody stools per day. The patient also complained of abdominal colicky pain, anorexia, bloating, and intermittent nausea and stated weight loss of approximately 5 kilos. Physical examination revealed a body mass index of 24 kg/m2. Laboratory investigation showed hemoglobin of 13 g/dL, leukocyte count and CRP within the normal range, a serum creatinine level of 2.3 mg/dL (202 μmol/L), and serum albumin of 3.5 g/dL (35 g/L). Fecal leukocyte count, stool cultures, stool Clostridium difficile toxin, and examination for parasites were repeatedly negative. Cytomegalovirus was excluded by quantitative polymerase chain reaction in plasma and immunohistochemically in all biopsy specimens.\n\nColonic biopsies exhibited mild nonspecific colitis, whereas esophagogastroduodenoscopy was unremarkable. However, blind duodenal biopsies revealed moderate villous atrophy and increased number of intraepithelial CD3, CD8-positive T lymphocytes (Figures 2A, B). These findings were compatible with celiac-like duodenopathy corresponding to type 3B according to the modified Marsh classification.5 A high apoptotic index predominantly in the villous epithelium constituted an additional finding (Figure 2C). All histological findings are included in Table 1.\n\nFIGURE 2 Case 2. A, Duodenal mucosa with moderate villous atrophy (H&E ×100). B, Intraepithelial lymphocytosis (CD3 immunostain ×200). C, Apoptotic bodies outlined in squares (H&E ×400). D, Normal duodenal mucosa (H&E ×100).\n\nSmall bowel capsule did not reveal any changes. Celiac serology and HLA genotyping for DQ2/DQ8 were negative. Nevertheless, gluten-free diet was instituted for at least 3 months with no significant clinical response. Subsequently, EC-MPS was discontinued, and the patient was switched to azathioprine 2 mg/kg once daily. After the switch, GI symptoms resolved completely within 1 week and did not recur after gluten challenge. Follow-up laboratory studies showed return of renal function to baseline values. One month later, the patient reported significant improvement of his appetite with subsequent weight gain of approximately 6 kilos. Repeat endoscopy was performed 8 months after EC-MPS withdrawal while consuming gluten-containing diet and demonstrated restitution of all pathological lesions (Figure 2D). At the most recent follow-up, 20 months later, he was in excellent clinical condition with no GI manifestations.\n\nDISCUSSION\nThese 2 cases provide sufficient evidence of celiac-like duodenopathy as a highly potential, although rare, complication of EC-MPS in kidney transplant recipients. The clinical manifestations in both cases included severe chronic diarrhea and substantial weight loss. Serology and HLA genotyping for celiac disease were negative. Gastrointestinal endoscopy was unremarkable, and only blind duodenal biopsies made the final diagnosis. Histology exhibited a combination pattern of villous atrophy and intraepithelial lymphocytosis differing from genuine celiac disease by the coexistence of epithelial cell apoptosis and absence of prominent lymphoplasmacytic mucosa infiltrates.5 Lack of crypt damage and the presence of increased number of IEL constituted differential diagnostic criteria from GVHD.6 Besides apoptosis, there were no other similarities with the histological features encountered in our cohort of MMF-associated colitis.3 Complete clinical response and normalization of histology were achieved after EC-MPS withdrawal.\n\nMycophenolic acid has the potential to affect both the upper and lower GI tracts, although large bowel involvement clearly predominates presenting a rather common side effect in renal transplant patients.1-4 Mycophenolic acid–associated colitis is widely recognized as a distinct drug-induced colitis, whereas the spectrum of endoscopic and histological features has been well documented.2,3,7 Limited data are available regarding upper GI tract involvement, including duodenum, in symptomatic solid organ mainly kidney transplant patients on MPA. The first histological description of MPA-associated damage of the duodenal mucosa was reported by Ducloux et al8 in 1998 who described villous blunting and crypt hyperplasia in the duodenum of a kidney transplant patient receiving MMF. Subsequently, a similar observation derived from a large series of patients with chronic diarrhea and significant weight loss.9 Duodenal villous atrophy was encountered in 16% of patients and was attributed to MMF and EC-MPS therapy in 86% of these cases. Mycophenolic acid withdrawal or dose reduction resulted in diarrhea cessation and normal histology in all patients but one. It should be mentioned that in a small number of cases, azathioprine has been implicated for chronic diarrhea and duodenal villous atrophy which resolved after drug discontinuation.9,10\n\nAnother specific finding identified as MPA-associated lesion not only in the lower but also in the upper GI tract is prominent apoptosis.3,4,11 In a small series of 12 duodenal biopsies, 4 cases presented GVHD-like features associated with villous blunting.11 In another study of 17 duodenal biopsies, 82% exhibited increased apoptotic counts (>2 apoptotic bodies/100 crypts) with or without mucosa abnormalities.4 In 2 cases, mucosa changes were determined as celiac-like due to additional intraepithelial lymphocytosis.4\n\nOur presented cases as well as the 2 aforementioned are the only reported cases diagnosed as celiac-like duodenopathy in the setting of symptomatic renal transplant patients receiving EC-MPS and MMF.4 It should be stressed that the referred study was designed to evaluate mucosa injury and apoptotic counts in upper GI compared with normal controls. The fact that clinicopathological data both at baseline and during follow-up are largely missing renders our cases of prime importance in the presentation of an emerging drug-related entity.\n\nCeliac-like duodenal pathology potentially associated with MPA therapy has been described in orthotopic liver transplant patients as well.12 Four of 16 patients showing abnormal histology were on MPA and displayed celiac-like changes combining villous atrophy and intraepithelial lymphocytosis in addition to increased apoptotic and endocrine cell counts and lamina propria eosinophils. Similar to our presented cases, MPA discontinuation or dose reduction resulted in improvement of symptoms within 1 to 3 weeks. However, follow-up biopsies were not available.12\n\nCeliac-like enteropathy represents an increasingly recognized broad clinical and pathological spectrum of possibly unrelated disorders that share celiac-like changes in small intestinal biopsies and respond to withdrawal of the offending agent with clinical and histopathological improvement and not to a gluten-free diet.13,14 Among the most frequently recognized celiac-like enteropathies are “medication-related.” The list of implicated drugs is expanding and includes angiotensin receptor blockers, antimicrobials, chemotherapeutic, and immunosuppressive agents.14 In a study evaluating adult patients with villous atrophy and negative celiac serology over a 10-year period, the 2 most common diagnoses were seronegative celiac disease (28%) and medication-related villous blunting (26%), the latter attributed to olmesartan in 16 of 19 cases, and MMF and methotrexate in the remaining 3 cases.15\n\nCeliac-like duodenopathy seems to present a rare complication of immunosuppressive therapy with MPA manifesting few months to several years after medication initiation with persistent diarrhea and weight loss. A celiac-like histological pattern combined with apoptosis is encountered reminiscent of autoimmune enteropathy. One should be aware that this condition may be underdiagnosed because duodenal mucosa may appear endoscopically normal. In addition, a precedent diagnosis of MMF-induced colitis usually renders upper GI endoscopy superfluous.\n\nOur cases were both treated with EC-MPS, whereas most cases of villous atrophy including those with celiac-like enteropathy described so far in the literature received MMF.4,9 Although the beneficial effect of switching from MMF to EC-MPS presents a common observation in graft recipients, there are findings demonstrating no significant clinical differences between these 2 MPA formulations.16-18\n\nComplete resolution of histological lesions in our 2 cases few months after MPA withdrawal is in agreement with the experience on olmesartan-associated enteropathy.19 The common course provides evidence of underlying drug-induced mechanisms different from those of celiac disease per se, which resides months and even years after initiation of a gluten-free diet.14,20 Although the association between MPA and celiac enteropathy has not yet been clarified, robust literature data support a causative link.9,21 The multiple properties of MPA imply a complex pathogenetic process and incriminate possible immunologic, toxic, and inflammatory mechanisms. The direct action of MPA is determined by its antiproliferative impact, whereas its metabolites display proinflammatory effects.1 Acyl-MPA glucuronide, a toxic metabolite produced by GI cells, may be pathogenetically involved, although local metabolite concentrations have not been reported.22 Mycophenolic acid–induced alteration in cytokine production, which potentially affects gut homeostasis, may also play a contributory role.17,23 However, the long latency period between drug initiation and development of symptoms and in particular the presence of histological features indicative of T lymphocytes induced epithelial cell apoptosis support, an immune-mediated process. An underlying MPA-related immune dysregulation in association with an immune response to putative autoantigens, such as adducts formed by Acyl-MPA glucuronide metabolites or altered cellular proteins should be considered.24 The latter hypothesis is strengthened by the recognition of immunological disorders of the small intestine, such as autoimmune enteropathy and common variable immunodeficiency, which share a common histological pattern on the background of immunodeficiency.3,25\n\nIn summary, celiac-like enteropathy seems to represent a rare side effect of MPA-associated immunosuppressive therapy and should be taken into account in the differential diagnosis of diarrhea in transplant recipients treated with MPA in particular in the absence of MPA-related colitis. As macroscopic lesions are usually missing, blind duodenal biopsies are necessary to establish the diagnosis. Clinical response appears to occur immediately after MPA withdrawal with complete reversal of mucosa lesions.\n\nPublished online 20 July, 2018.\n\nThe authors declare no funding or conflicts of interest.\n\nV.F. had substantial contribution to the conception of the article, literature search, and the writing of the article. Furthermore, he was taking care, as a nephrologist, of the 2 patients presented in this article. S.S. did the histopathological examination of the biopsy specimens and participated in the writing of the article. K.P. performed the upper and lower gastrointestinal tract endoscopies and participated in the writing of the article. C.M. participated to the conception of the article, literature review, and the writing of the article. S.M. participated to the conception of the article, literature review, and the writing of the article. J.N.B. had substantial contribution to the conception of the article, literature review, and the revision of the article. He also approved the final version of the article. I.D. had substantial contribution to the conception of the article, literature review, and the revision of the article. She also approved the final version of the article.\n==== Refs\nREFERENCES\n1 Davies NM Grinyo J Heading R \nGastrointestinal side effects of mycophenolic acid in renal transplant patients: a reappraisal . Nephrol Dial Transplant . 2007 ;22 :2440–2448 .17557774 \n2 Calmet FH Yarur AJ Pukazhendhi G \nEndoscopic and histological features of mycophenolate mofetil colitis in patients after solid organ transplantation . Ann Gastroenterol . 2015 ;28 :366–373 .26126799 \n3 Liapis G Boletis J Skalioti C \nHistological spectrum of mycophenolate mofetil-related colitis: association with apoptosis . Histopathology . 2013 ;63 :649–658 .24025088 \n4 Nguyen T Park JY Scudiere JR \nMycophenolic acid (cellcept and myofortic) induced injury of the upper GI tract . Am J Surg Pathol . 2009 ;33 :1355–1363 .19542873 \n5 Oberhuber G Granditsch G Vogelsang H \nThe histopathology of coeliac disease: time for a standardized report scheme for pathologists . Eur J Gastroenterol Hepatol . 1999 ;11 :1185–1194 .10524652 \n6 Shulman HM Kleiner D Lee SJ \nHistopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report . Biol Blood Marrow Transplant . 2006 ;12 :31–47 .\n7 Dalle IJ Maes BD Geboes KP \nCrohn's like changes in the colon due to mycophenolate? \nColorectal Dis . 2005 ;7 :27–34 .15606581 \n8 Ducloux D Ottignon Y Semhoun-Ducloux S \nMycophenolate mofetil-induced villous atrophy . Transplantation . 1998 ;66 :1115–1116 .9808503 \n9 Weclawiak H Ould-Mohamed A Bournet B \nDuodenal villous atrophy: a cause of chronic diarrhea after solid-organ transplantation . Am J Transplant . 2011 ;11 :575–582 .21299830 \n10 Ziegler TR Fernández-Estívariz C Gu LH \nSevere villus atrophy and chronic malabsorption induced by azathioprine . Gastroenterology . 2003 ;124 :1950–1957 .12806628 \n11 Parfitt JR Jayakumar S Driman DK \nMycophenolate mofetil-related gastrointestinal mucosal injury: variable injury patterns, including graft-versus-host disease-like changes . Am J Surg Pathol . 2008 ;32 :1367–1372 .18763324 \n12 Cotter MB AbuShanab A Merriman R \nCoeliac-like duodenal pathology in orthotopic liver transplant patients on mycophenolic acid therapy . Histopathology . 2015 ;66 :500–507 .25195696 \n13 Panarelli NC \nDrug-induced injury in the gastrointestinal tract . Semin Diagn Pathol . 2014 ;31 :165–175 .24815941 \n14 Freeman HJ \nCeliac disease: a disorder emerging from antiquity, its evolving classification and risk, and potential new treatment paradigms . Gut Liver . 2015 ;9 :28–37 .25547088 \n15 DeGaetani M Tennyson CA Lebwohl B \nVillous atrophy and negative celiac serology: a diagnostic and therapeutic dilemma . Am J Gastroenterol . 2013 ;108 :647–653 .23644957 \n16 Burg M Säemann MD Wieser C \nEnteric-coated mycophenolate sodium reduces gastrointestinal symptoms in renal transplant patients . Transplant Proc . 2009 ;41 :4159–4164 .20005359 \n17 Filler G Buffo I \nSafety considerations with mycophenolate sodium . Expert Opin Drug Saf . 2007 ;6 :445–449 .17688388 \n18 Langone AJ Chan L Bolin P \nEnteric-coated mycophenolate sodium versus mycophenolate mofetil in renal transplant recipients experiencing gastrointestinal intolerance: a multicenter, double-blind, randomized study . Transplantation . 2011 ;91 :470–478 .21245794 \n19 Choi EY McKenna BJ \nOlmesartan-associated enteropathy: a review of clinical and histologic findings . Arch Pathol Lab Med . 2015 ;139 :1242–1247 .26414468 \n20 Tursi A Brandimarte G Giorgetti GM \nEndoscopic and histologic findings in the duodenum of adults with celiac disease before and after changing to a gluten-free diet: a 2-year prospective study . Endoscopy . 2006 ;38 :702–707 .16810593 \n21 Kamar N Faure P Dupuis E \nVillous atrophy induced by mycophenolate mofetil in renal-transplant patients . Transpl Int . 2004 ;17 :463–467 .15322747 \n22 Arns W \nNoninfectious gastrointestinal (GI) complications of mycophenolic acid therapy: a consequence of local GI toxicity? \nTransplant Proc . 2007 ;39 :88–93 .17275481 \n23 Ianiro G Bibbo S Montalto M \nSystematic review: sprue-like enteropathy associated with olmesartan . Aliment Pharmacol Ther . 2014 ;40 :16–23 .24805127 \n24 Maes BD Dalle I Geboes K \nErosive enterocolitis in mycophenolate mofetil treated renal-transplant recipients with persistent afebrile diarrhea . Transplantation . 2003 ;75 :665–672 .12640307 \n25 Daniels JA Lederman HM Maitra A \nGastrointestinal tract pathology in patients with common variable immunodeficiency (CVID): a clinicopathologic study and review . Am J Surg Pathol . 2007 ;31 :1800–1812 .18043034\n\n",
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"title": "Celiac-like Enteropathy Associated With Mycophenolate Sodium in Renal Transplant Recipients.",
"title_normalized": "celiac like enteropathy associated with mycophenolate sodium in renal transplant recipients"
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"abstract": "Solitary fibrous tumor of the pleura is a rare and usually benign primary neoplasm arising from mesenchymal cells of the submesothelial tissue. We present here the case of a patient diagnosed with CD34-positive advanced malignant solitary fibrous tumor of the pleura whose disease failed to respond to combination cytotoxic chemotherapy agents, but demonstrated a prompt near-complete response to checkpoint blockade treatment using the anti-programmed death (PD)-1 monoclonal antibody pembrolizumab, based on tumor molecular profiling revealing tumoral expression positivity for both programmed death-ligand 1 (PD-L1) and PD-1. The patient experienced minimal adverse effects from the treatment with durable favorable response lasting up to cycle 26.",
"affiliations": "WVU Cancer Institute, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, USA.;Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA.;WVU Cancer Institute, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, USA.;WVU Cancer Institute, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, USA.",
"authors": "Boothe|James T|JT|;Budd|G Thomas|GT|;Smolkin|Matthew B|MB|;Ma|Patrick C|PC|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. 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 10.1159/000484041cro-0010-0998Case ReportDurable Near-Complete Response to Anti-PD-1 Checkpoint Immunotherapy in a Refractory Malignant Solitary Fibrous Tumor of the Pleura Boothe James T. abBudd G. Thomas cSmolkin Matthew B. adMa Patrick C. abe*aWVU Cancer Institute, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, USAbWVU School of Medicine, West Virginia University, Morgantown, West Virginia, USAcCleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USAdDepartment of Pathology, WVU Medicine Ruby Memorial Hospital, West Virginia University, Morgantown, West Virginia, USAeWest Virginia Clinical and Translational Science Institute, Morgantown, West Virginia, USA*Patrick C. Ma, MD, MSc, WVU Cancer Institute, West Virginia University, 1 Medical Center Drive, Rm. 1814 HSS, PO Box 9300, Morgantown, WV 26506-9300 (USA), E-Mail pcma@hsc.wvu.eduSep-Dec 2017 13 11 2017 13 11 2017 10 3 998 1005 2 10 2017 5 10 2017 Copyright © 2017 by S. Karger AG, Basel2017This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Solitary fibrous tumor of the pleura is a rare and usually benign primary neoplasm arising from mesenchymal cells of the submesothelial tissue. We present here the case of a patient diagnosed with CD34-positive advanced malignant solitary fibrous tumor of the pleura whose disease failed to respond to combination cytotoxic chemotherapy agents, but demonstrated a prompt near-complete response to checkpoint blockade treatment using the anti-programmed death (PD)-1 monoclonal antibody pembrolizumab, based on tumor molecular profiling revealing tumoral expression positivity for both programmed death-ligand 1 (PD-L1) and PD-1. The patient experienced minimal adverse effects from the treatment with durable favorable response lasting up to cycle 26.\n\nKeywords\nCancer immunotherapyCheckpoint blockadeSolitary fibrous tumor of the pleuraPD-L1PD-1\n==== Body\nIntroduction\nSolitary fibrous tumor of the pleura (SFTP) is a rare primary neoplasm that arises from mesenchymal cells of the areolar tissue in the submesothelial layer of the pleura. It accounts for less than 5% of primary pleural neoplasms [1]. The neoplasm is usually benign, with reported malignancy accounting for up to 20% of cases. Surgical resection of SFTP usually yields a favorable outcome with a 5-year disease-free survival rate of 81% [2]. However, malignant SFTP has a 63% recurrence rate even following curative-intent complete surgical resection [3]. Due to the rarity of malignant SFTP, there is a striking lack of published literature on the efficacy of specific therapeutic regimens. Much focus has recently been directed by the clinical oncology community towards immune system-modulating therapies, including immune checkpoint blockade therapy [4]. One such approach involves administration of monoclonal antibodies with binding specificity to the programmed cell death protein 1 (PD-1) expressed on the surface of T cells or the programmed death-ligand 1 (PD-L1) expressed on the surface of tumor cells [5, 6].\n\nPD-L1 on healthy human cells binds to T-cell PD-1, initiating an inhibitory signaling cascade that has the effect of preventing development of a cytotoxic T-cell attack against the cells. We present the case of a patient with malignant SFTP whose disease failed to respond to several combination chemotherapy regimens but eventually demonstrated a durable near-complete response to checkpoint immunotherapy in the form of the anti-PD-1 monoclonal antibody pembrolizumab.\n\nCase Report\nA 50-year-old Caucasian male with a 30 pack-year smoking history, who was healthy with the only known medical issue being controlled hypertension, presented to the clinic with a sore lump over the right lower chest wall between the 6th and 7th ribs. Initial workup with CT chest imaging in December 2014 revealed a soft tissue mass arising within the right chest wall underlying the palpable lump. A follow-up CT of the chest, abdomen, and pelvis in January 2015 confirmed an enlarging underlying soft tissue mass arising within the chest wall soft tissue/pleural tissue space, centered over the intercostal space, measuring 3.0 × 5.9 × 5.0 cm. An enlarged right mid-hilar lymph node superior to the right pulmonary artery measuring 2.7 × 3.1 × 2.7 cm was seen as well. Ultrasound-guided needle biopsy was performed on the chest wall mass, and subsequent pathological analysis, including a pathology review at the Mayo Clinic, revealed an extensively necrotic, poorly differentiated malignant neoplasm possibly representing a malignant SFTP (Fig. 1a). Immunohistochemistry analysis revealed that the neoplastic cells were diffusely positive for CD34 (Fig. 1b) and focally wide-spectrum cytokeratin-positive. INI-1 expression was retained. WT-1, calretinin, ER, CD31, ERG protein, FLI-1, and high MW cytokeratin were negative. PET/CT imaging in February 2015 showed no evidence of metastatic lesions in the abdomen, pelvis, or bones, and a bone scan was also negative for any distant metastases. The right lower chest wall mass was found intensely hypermetabolic with SUVmax 23, with the right hilar mass having SUVmax 20 (Fig. 2a, b, c, d).\n\nThe patient received front-line definitive concurrent chemoradiation treatment at a local cancer center using low-dose weekly carboplatin and paclitaxel and daily radiotherapy to a total dose of 64 Gy. Restaging by PET/CT showed shrinkage of the primary chest wall mass to 2.8 × 1.4 cm and persistence of the right hilar nodal mass. However, new soft tissue foci with FDG hypermetabolism were seen in the deep subcutaneous tissue of the left posterior abdominal wall at the level of the transverse process of the third vertebra, as well as two nodular foci at the pleural thickening of the right lung apex. Further consideration of surgical resection was canceled. Punch biopsy of the new subcutaneous mass revealed pathological characteristics similar to the previous biopsy, confirming metastatic dissemination. Based on this finding, a second-line palliative chemotherapy regimen of gemcitabine and docetaxel was initiated. However, after the first cycle of treatment, the patient suffered severe life-threatening treatment-related toxicities, including neutropenic fever, pneumonia, severe fatigue, mouth sores, oral candidiasis, nausea/vomiting, decreased oral intake, and prerenal acute renal failure secondary to dehydration, requiring hospitalization. The chemotherapy regimen was aborted after successful treatment with antimicrobials and rehydration therapy in the hospital. The patient sought second opinion from a tertiary cancer institute, and was started on the MD Anderson regimen, which has reported efficacy for malignant SFTP in the literature, using temozolomide and bevacizumab (temozolomide 150 mg/m2 orally on days 1–7 and days 15–21, plus bevacizumab 5 mg/kg i.v. on days 8 and 22, repeated every 28-day cycle) [7]. However, after three cycles of this combination regimen, PET imaging in October 2015 showed further progression of the disease (Fig. 2e).\n\nGenomic profiling analysis of the primary tumor using the FoundationHeme® assay revealed possible amplification of EGFR (equivocal), CDKN2A p16INK4a-R112P, TP53-V157F, CPS1-L878fs*8, and SMARCA4-E1364*. Since no definitive actionable genomic alterations were evident, we sought comprehensive multi-platform molecular and genomic profiling with the Caris Molecular Intelligence® (CMI-X) test (Table 1) while the patient was undergoing temozolomide plus bevacizumab therapy. CMI-X tumor profiling confirmed positive results for PD-1 and PD-L1 (2+, 5%; Fig. 1c) in immunohistochemistry assays. Temozolomide/bevacizumab treatment was eventually found ineffective soon thereafter.\n\nNotably, the CMI-X molecular profiling also suggested potential lack of benefit to temozolomide therapy based on being MGMT-positive via IHC (1+, 45%; Table 1). The key genomic alterations found in the next-generation sequencing (NGS) test include: TP53-V157F (56%), CDKN2A-R112P (62%), and MLH1-E234Q (52%). Altogether, these above findings prompted us to switch treatment strategy and ultimately we initiated treatment with an anti-PD-1 immune checkpoint monoclonal antibody in October 2015; pembrolizumab was selected for off-label use, using the FDA-approved dose regimen of 2 mg/kg intravenously every 3 weeks. When the patient returned for tumor response assessment in December 2015 after 2 cycles of treatment, he reported excellent tolerance and notable diminution of the left abdominal wall mass, which was confirmed as a prompt partial response by CT scan imaging (Fig. 2e). Restaging scan via CT imaging after the 5th cycle of pembrolizumab confirmed a near-complete response in February 2016. Prior to the planned 13th course of therapy, the patient reported no palpable masses, and restaging via CT scan imaging in July 2016 confirmed an ongoing persistent near-complete response with no new disease recurrence (Fig. 2e). To date, the patient has durable near-complete response after up to a total of 26 cycles of pembrolizumab infusions, and he remains well with excellent tolerance without significant adverse effects except for mild dry skin. The patient reported progressively improved energy throughout therapy, and his family reported that he regained his appetite and his ability to complete all tasks of daily living. He was found to have a new solitary left apical PET-avid pleural based mass biopsy-proven to be of similar histologic diagnosis as PD-1 therapy-acquired resistant disease after cycle 26. He received local radiotherapy to the isolated pembrolizumab-resistant tumor mass and continuation PD-1 immunotherapy with resultant ongoing response after cycle 31.\n\nDiscussion\nOur case report highlights the substantial potential of PD-1/PD-L1 checkpoint pathway blockade in cancer immunotherapy. To date, the anti-PD-1 checkpoint antibodies nivolumab and pembrolizumab have been FDA-approved for the treatment of previously treated advanced melanoma and non-small cell lung cancer (NSCLC) [8, 9, 10]. Expansion of its use is evident in the growing list of tumor types that show treatment response with such treatment strategy, including classic Hodgkin lymphoma [11] and head and neck cancer [12]. While the role of PD-L1 tumoral expression as a predictive biomarker for anti-PD-1 immunotherapy remains to be better refined, it has been approved as a companion diagnostic in the pembrolizumab approval by the FDA. Pembrolizumab has also recently been approved as first-line therapy in advanced NSCLC patients whose tumor has strong PD-L1 expression as defined by tumor proportion score (TPS) ≥50%, based on the positive survival data from the phase III KEYNOTE-024 study of single-agent pembrolizumab versus standard-of-care platinum-based doublet chemotherapy [13]. In May 2017, pembrolizumab received additional FDA approval as a first-line checkpoint inhibitor in combination with carboplatin and pemetrexed in advanced non-squamous NSCLC regardless of PD-L1 status [14]. A cancer type such as malignant SFTP is so rare that it is unrealistic to expect completion of phase III clinical studies to validate the treatment efficacy of immune checkpoint therapies. Thus, it is of practical value to observe and report remarkable responders in N = 1 study or case reports. Our case study also illustrates that even with a low level of detected PD-L1 expression status of TPS 5%, a prompt and ultimately durable remarkable near-complete response in chemotherapy- and radiation-refractory disease is possible. To our knowledge, this is the first report of a treatment response of a malignant SFTP to cancer checkpoint immunotherapy. Our PD-1 blockade strategy success serves as a reminder that the new paradigm of cancer immunotherapy can unleash significant anti-tumor effects even in heavily pretreated or chemotherapy- and radiation-refractory tumors. Moreover, other immune checkpoint inhibitors such as PD-L1 antibodies (e.g., atezolizumab, durvalumab/MEDI4736) or immune-modulating agents such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTL4) antibodies (e.g., tremelimumab, ipilimumab) would also merit further studies to determine their potential efficacy in orphan diseases like SFTP. Further research in cancer immunotherapy predictive biomarkers is urgently necessary for optimizing patient selection for treatment. Undoubtedly, cancer immunotherapy has revolutionized modern cancer treatment and will continue to make further strides in improving cancer patients' treatment outcomes in future years.\n\nStatement of Ethics\nThe subject described in this case report has given his written informed consent for the publication of the report. The case study protocol has been approved by the Institution Review Board on human research.\n\nDisclosure Statement\nSpeaker's bureau of Merck, Takeda-ARIAD (P.C.M.).\n\nAcknowledgements\nThis work was supported by IDeA CTR support – National Institute of Health (NIH)/National Institute of General Medical Sciences (NIGMS), U54GM104942 (P.C.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. P.C.M. is supported by WVU Cancer Institute, and the West Virginia Clinical and Translational Science Institute (WVCTSI).\n\nFig. 1 Histopathologic features of the malignant solitary fibrous tumor of the pleura (SFTP). a A low-powered view of hematoxylin and eosin staining, demonstrating the hypercellularity of the tumor (mag. 100×) with the high-powered view demonstrating numerous mitoses shown in the inset (mag. 400×). b A high-powered view demonstrating positive immunohistochemical staining for CD34 expression of the SFTP (mag. 400×). c A low-powered view demonstrating positive immunohistochemical staining for PD-L1 expression of the SFTP (left, mag. 200×), with a corresponding high-powered view also shown (right, mag. 400×).\n\nFig. 2 Positron-emission tomography (PET)/computed tomography (CT) scan imaging of the patient with malignant solitary fibrous tumor of the pleura (SFTP) at the time of initial diagnosis and during PD-1 checkpoint inhibition response. Shown here are the selected sites of disease (yellow arrows) in the right hilar mass (a, b) and in the right lower chest wall mass (c, d) at the time of initial diagnosis. e Tumor response of the refractory malignant SFTP in the left posterior abdominal wall mass to PD-1-targeting checkpoint immunotherapy using pembrolizumab. Serial imaging in the pulmonary hilar region (top panels) and in the lower abdominal region (lower panels) during the course of treatment with pembrolizumab are shown here for illustration. Yellow arrows, pretreatment tumor burden; red arrow, early tumor response; white arrow, near-complete tumor response after pembrolizumab anti-PD-1 checkpoint immunotherapy.\n\nTable 1 Comprehensive molecular tumor profiling with Caris Molecular Intelligence (CMI)-X assay\n\nMolecular-genomic alterations\tTherapy options with potential benefits\tTherapy options with potential lack of benefits\t\nTP53 exon 5 | V157F (56%)\tn/a\tn/a\t\n\t\nCDKN2A exon 2 | R112P (62%)\tn/a\tn/a\t\n\t\nMLH1 exon 9 | E234Q (52%)\tn/a\tn/a\t\n\t\nPTEN IHC – positive\tn/a\tn/a\t\n\t\nTS IHC – positive (1+ 75%)\tn/a\tCapecitabine, fluorouracil, pemetrexed\t\n\t\nTOPO1 IHC – positive (2+ 35%)\tIrinotecan, topotecan\tn/a\t\n\t\nTOP2A IHC – positive (2+ 30%)\tDoxorubicin, epirubicin, liposomal doxorubicin\tn/a\t\n\t\nTUBB3 IHC – positive (2+ 85%)\tn/a\tn/a\t\n\t\nTLE3 IHC – positive (2+ 30%)\tDocetaxel, nab-paclitaxel, paclitaxel\tn/a\t\n\t\nPGP IHC – negative\tDocetaxel, nab-paclitaxel, paclitaxel, doxorubicin, epirubicin, liposomal doxorubicin\tn/a\t\n\t\nERCC1 IHC – negative\tCarboplatin, cisplatin, oxaliplatin\tn/a\t\n\t\nMGMT IHC – positive (1+ 45%)\t\tDacabazine, temozolomide\t\n\t\nPD-L1 IHC positive (2+ 5%)\tNivolumab, pembrolizumab\tn/a\t\n\t\nPD-1 IHC – positive (1/HPF)\tNivolumab, pembrolizumab\tn/a\n==== Refs\nReferences\n1 Lu C Ji Y Shan F Guo W Ding J Ge D Solitary fibrous tumor of the pleura: an analysis of 13 cases World J Surg 2008 32 1663 1668 18427887 \n2 Lococo F Cesario A Cardillo G Malignant solitary fibrous tumors of the pleura: retrospective review of a multicenter series J Thorac Oncol 2012 7 1698 1706 23070244 \n3 Robinson LA Solitary fibrous tumor of the pleura Cancer Control 2006 4 264 269 \n4 Pardoll DM The blockade of immune checkpoints in cancer immunotherapy Nat Rev Cancer 2012 12 252 264 22437870 \n5 Medina PJ Adams VR PD-1 pathway inhibitors: immuno-oncology agents for restoring antitumor immune responses Pharmacotherapy 2016 36 317 334 26822752 \n6 Ma W Gilligan BM Yuan J Li T Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy J Hematol Oncol 2016 9 47 27234522 \n7 Park MS Patel SR Ludwig JA Activity of temozolomide and bevacizumab in the treatment of locally advanced, recurrent, and metastatic hemangiopericytoma and malignant solitary fibrous tumor Cancer 2011 117 4939 4947 21480200 \n8 Herbst RS Baas P Kim DW Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial Lancet 2016 387 1540 1550 26712084 \n9 Brahmer J Reckamp KL Baas P Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer N Engl J Med 2015 373 123 135 26028407 \n10 Borghaei H Paz-Ares L Horn L Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer N Engl J Med 2015 373 1627 1639 26412456 \n11 Ansell SM Lesokhin AM Borrello I PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma N Engl J Med 2015 372 311 319 25482239 \n12 Ferris RL Blumenschein G Fayette J Nivolumab for recurrent squamous-cell carcinoma of the head and neck N Engl J Med 2016 375 1856 1867 27718784 \n13 Reck M Rodríguez-Abreu D Robinson AG Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer N Engl J Med 2016 375 1823 1833 27718847 \n14 Langer CJ Gadgeel SM Borghaei H Carboplatin and pemetrexed with or without pembrolizumab for advanced non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study Lancet Oncol 2016 17 1497 1508 27745820\n\n",
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"issue": "10(3)",
"journal": "Case reports in oncology",
"keywords": "Cancer immunotherapy; Checkpoint blockade; PD-1; PD-L1; Solitary fibrous tumor of the pleura",
"medline_ta": "Case Rep Oncol",
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"title": "Durable Near-Complete Response to Anti-PD-1 Checkpoint Immunotherapy in a Refractory Malignant Solitary Fibrous Tumor of the Pleura.",
"title_normalized": "durable near complete response to anti pd 1 checkpoint immunotherapy in a refractory malignant solitary fibrous tumor of the pleura"
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"abstract": "Posthypoxic myoclonus is a rare and devastating complication of near-fatal cardiopulmonary arrest. Despite treatment with available anti-myoclonic agents, some patients may recover cognitively but remain completely disabled by severe myoclonus. We report a 16-year-old patient with severe treatment-refractory posthypoxic myoclonus, which improved markedly with administration of the drug sodium oxybate.",
"affiliations": "Department of Intensive Care and Emergency Unit, Ospedale Civile, Voghera, Italy.",
"authors": "Arpesella|R|R|;Dallocchio|C|C|;Arbasino|C|C|;Imberti|R|R|;Martinotti|R|R|;Frucht|S J|SJ|",
"chemical_list": "D012978:Sodium Oxybate",
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"mesh_terms": "D000293:Adolescent; D004569:Electroencephalography; D006323:Heart Arrest; D006801:Humans; D002534:Hypoxia, Brain; D008297:Male; D009207:Myoclonus; D012978:Sodium Oxybate; D013577:Syndrome",
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"title": "A patient with intractable posthypoxic myoclonus (Lance-Adams syndrome) treated with sodium oxybate.",
"title_normalized": "a patient with intractable posthypoxic myoclonus lance adams syndrome treated with sodium oxybate"
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"abstract": "The rate of invasive fungal infection (IFI) in patients with myelodysplasia (MDS) and acute myeloid leukemia (AML) receiving 5-azacytidine is incompletely defined and published recommendations for mold-active fungal prophylaxis in such patients vary according to source. We performed a retrospective cohort study in order to identify contemporary IFI rates and infection-related mortality in relation to known risk factors and the use of antifungal prophylaxis. One hundred and seventeen patients receiving 5-azacytidine for MDS and low blast count AML were identified, of whom 71 (61%) received antifungal prophylaxis. The IFI rate was 7.7% across the entire cohort: 5.6% in those receiving prophylaxis vs 10.9% in the subgroup who did not (P = .30). The presence of neutropenia at three months of treatment was associated with increased IFI risk (hazard ratio [HR] 8.29; (95% confidence interval [CI)] 1.61-42.6; P = .01), and on multivariate analysis, IFI was independently associated with increased all-cause mortality risk (HR 8.37; 95% CI 3.67 - 19.11; P < .0001). These data further highlight the risk of IFI in this population and support the use of mold-active prophylaxis in neutropenic patients receiving 5-azacytidine for MDS and AML.",
"affiliations": "Pharmacy Department, Monash Health, Clayton, Vic., Australia.;Monash Haematology, Monash Health, Clayton, Vic., Australia.;Monash Infectious Diseases, Monash Health, Clayton, Vic., Australia.;Pharmacy Department, Monash Health, Clayton, Vic., Australia.;School of Public Health and Preventive Medicine, Monash Centre for Health Research and Implementation, Monash University, Clayton, Vic., Australia.;Monash Infectious Diseases, Monash Health, Clayton, Vic., Australia.;Monash Haematology, Monash Health, Clayton, Vic., Australia.",
"authors": "Tey|Amanda|A|https://orcid.org/0000-0002-7992-2838;Shaw|Briony|B|;Cardamone|Luke|L|;Shepherd|Sam|S|;Paul|Eldho|E|;Rogers|Ben|B|;Shortt|Jake|J|https://orcid.org/0000-0003-3185-6488",
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"title": "Risk factors for invasive fungal infection in 5-azacytidine treated patients with acute myeloid leukemia and myelodysplastic syndrome.",
"title_normalized": "risk factors for invasive fungal infection in 5 azacytidine treated patients with acute myeloid leukemia and myelodysplastic syndrome"
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"abstract": "BACKGROUND\nYoung-onset colorectal cancer is clinicopathologically different from older-onset colorectal cancer and tends to occur in patients with hereditary germline conditions such as Lynch syndrome and familial adenomatous polyposis.\n\n\nMETHODS\nWe describe the case of a 44-year-old man with a paternal history of colon polyps, a personal 2-year history of hematochezia, and a diagnosis of rectal cancer. Further clinical evaluation of the patient at our institution determined the cancer to be stage IIIA. The patient underwent genetic counseling and testing, which indicated he was negative for the most common familial cancer syndromes. After treatment with neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy, the patient has done well. We review the hereditary cancer syndromes and genetic tests to consider for patients with early-onset colorectal cancer.\n\n\nCONCLUSIONS\nThis case underscores the importance of following cancer-screening guidelines.",
"affiliations": "Mayo Medical School, College of Medicine, Mayo Clinic, Rochester, Minnesota.",
"authors": "Zhou|Yaolin|Y|;Boardman|Lisa A|LA|;Miller|Robert C|RC|",
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"fulltext": "\n==== Front\nRadiol OncolRadiol OncolRADORadiology and Oncology1318-20991581-3207Versita, Warsaw 10.2478/v10019-010-0005-0rado-44-01-57Case ReportGenetic testing for young-onset colorectal cancer: case report and evidence-based clinical guidelines Zhou Yaolin 1Boardman Lisa A. 2Miller Robert C. 31 Mayo Medical School, College of Medicine, Mayo Clinic, Rochester, Minnesota2 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota3 Department of Radiation Oncology, Mayo Clinic, Rochester, MinnesotaCorrespondence to: Robert C. Miller, MD, MS, Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail: miller.robert@mayo.eduDisclosure: No potential conflicts of interest were disclosed.\n\n3 2010 18 3 2010 3 2010 44 1 57 61 29 12 2009 10 1 2010 Copyright © by Association of Radiology & Oncology2010This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).Background\nYoung-onset colorectal cancer is clinicopathologically different from older-onset colorectal cancer and tends to occur in patients with hereditary germline conditions such as Lynch syndrome and familial adenomatous polyposis.\n\nCase report.\nWe describe the case of a 44-year-old man with a paternal history of colon polyps, a personal 2-year history of hematochezia, and a diagnosis of rectal cancer. Further clinical evaluation of the patient at our institution determined the cancer to be stage IIIA. The patient underwent genetic counseling and testing, which indicated he was negative for the most common familial cancer syndromes. After treatment with neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy, the patient has done well. We review the hereditary cancer syndromes and genetic tests to consider for patients with early-onset colorectal cancer.\n\nConclusions\nThis case underscores the importance of following cancer-screening guidelines.\n\nadenomatous polyposis coliattenuated familial adenomatous polyposiscolorectal cancerfamilial adenomatous polyposismicrosatellite instabilityMYH-associated polyposis\n==== Body\nIntroduction\nColorectal cancer (CRC) is a common malignancy in North America and Europe; most patients have sporadic disease without a known genetic predisposition to the illness. With the exception of the hereditary germline conditions Lynch syndrome, familial adenomatous polyposis (FAP), and attenuated FAP, which are marked by an early age of onset and familial CRC clustering, most cases of CRC do not develop until age 65 years or older. Still, up to 20% of all cases of CRC arise in persons aged 50 years or younger who do not have Lynch syndrome or FAP.1–3\n\nLynch syndrome, formerly known as hereditary nonpolyposis colorectal cancer, is caused by a germline mutation in 1 of several DNA mismatch repair (MMR) genes and is the most common single-gene–related cause of hereditary colon cancer in North American and European populations.4,5 CRC in Lynch syndrome has unique histopathologic and clinical findings. These cancers tend to be more responsive to treatment despite being poorly differentiated.2\n\nOne report based on the experience from 2 cancer registries in the United States, the National Program of Cancer Registries and the Surveillance, Epidemiology and End Results studies, emphasized that CRC is of concern for young adults: it is among the top 10 cancers in persons aged 20 to 49 years of all races.6 Young-onset and older-onset CRC are clinicopathologically different in that young-onset CRC usually presents at a later stage and is more poorly differentiated.6 Here, we present the case of a young middle-aged man with rectal cancer.\n\nCase report\nA 44-year-old man sought medical care in 2001 for a 2-year history of hematochezia. Colonoscopy performed at an outside institution in September 2001 showed a lesion within the rectum. Biopsy performed at that time confirmed a poorly differentiated, grade 3 adenocarcinoma, which measured 2×1.3×1 cm, with invasion through the muscularis mucosa. He came to our institution in October 2001 for further evaluation.\n\nThe patient’s family history of cancer was primarily limited to a brother who received a diagnosis of chronic myelogenous leukemia at age 47 years. His father had colon polyps removed in his mid 50s, and a maternal aunt had colon polyps at age 35 years. Distant paternal relatives may have had CRC in old age.\n\nThe patient had been a smoker for the previous 16 years and had a history of gastroesophageal reflux disease. He had a history of sebaceous cysts on the left scapula and the back of the thighs and a lipoma on the inferior border of the right scapula. He did not have supernumerary teeth.\n\nEvaluation of the patient included genetics counseling and testing because of his young age at diagnosis (Figure 1). Immunohistochemical testing (IHC) for MLH1, MSH2, and MSH6 showed intact MMR. The patient was not tested for the APC gene mutation because he was not suspected to have FAP (Figure 2). He was also not tested for MYH, which was not discovered until later.7\n\nEndorectal ultrasonography with guided fine-needle aspiration biopsy of suspicious lymph nodes confirmed an ulcerated lesion extending from the anal verge to 3.5 cm proximally along the anterior wall of the rectum. Fine-needle aspirates from 2 enlarged perirectal lymph nodes were positive for adenocarcinoma. In the ascending colon, a 5-mm hyperplastic polyp was removed with cold snare.\n\nAbdominal and pelvic computed tomography detected a 0.6-cm sclerotic lesion within the left iliac bone, which was considered benign after a bone scan demonstrated no bony metastases. Results of upper endoscopy were normal. On the basis of the clinical evaluations, the patient’s cancer was determined to be stage IIIA (T2N1M0) by the American Joint Committee on Cancer 6th edition criteria.\n\nNeoadjuvant chemoradiotherapy was recommended on the basis of the tumor stage and the proximity of the tumor to the prostate. From November through December 2001, the patient was given a continuous infusion of radiosensitizing 5-fluorouracil (5-FU) (225 mg/m2). He was treated with 180 cGy in 28 fractions, for a total of 5040 cGy. He tolerated the therapy well, with some mild diarrhea, weight loss, decreased energy, and perianal irritation. The cancer in the rectum showed complete response to therapy.\n\nIn January 2002, the patient underwent surgery to have an abdominoperineal resection and permanent colostomy. He tolerated the procedure well, and no residual tumor was identified. Two of 31 regional lymph nodes were positive for grade 3 mucinous adenocarcinoma. In the following month, the patient had several perineal drain site infections and was treated for depression.\n\nIn April 2002 the patient began his first of 4 cycles of adjuvant 5-FU and leucovorin systemic chemotherapy. Prolonged neutropenia and gastrointestinal tract bleeding occurred in the middle of the first cycle of chemotherapy; therefore, the dosage of 5-FU (425 mg/m2) was decreased by 10% (to 380 mg/m2). He completed chemotherapy in August 2002.\n\nSurveillance colonoscopies in the following years have been negative. The patient was last seen at our institution in January 2007. He has had no new gastrointestinal tract or genitourinary symptoms or problems. His appetite has returned to normal, and he feels strong. He has returned to work as a carpenter and is now being monitored with colonoscopy every 3 years.\n\nDiscussion\nAccording to the Fearon and Vogelstein model of carcinogenesis, the accumulation of multiple mutations is required for the transformation of normal colonic mucosa into dysplastic adenomas and then into invasive carcinomas.4 CRC can be classified broadly as exhibiting either chromosomal instability through gain-of-function mutations (APC/β-catenin pathway) or microsatellite instability (MSI) (defects in DNA MMR). In sporadic CRC, mutations are acquired in a stepwise fashion. In the case of single-gene hereditary colorectal cancer syndromes, all DNA-containing cells have a germline mutation in one allele of the involved gene and thus are a step closer to the accumulation of additional acquired mutations necessary to lead to CRC.\n\nIn human CRC, 80% of the tumors are micro-satellite stable, which means they have intact DNA MMR and can correct single-base and small-loop base-pair mismatches present throughout the non-coding and coding regions of the genome. The remaining 20% of CRC tumors exhibit MSI due to defects in this DNA MMR pathway that corrects small base-pair mistakes in mononucleotide, dinucleotide, and trinucleotide repeat regions throughout the genome and are classified as having high or low MSI (MSI-H or MSI-L, respectively).5 A small fraction of MSI-H tumors result from germline mutations in 1 of 4 DNA MMR genes—MLH1, MSH2, MSH6, and PMS2—and result in the hereditary CRC condition called Lynch syndrome. However, the greater proportion of MSI-H tumors arises via impairment of DNA MMR through hypermethylation of the MLH1 gene.\n\nAlthough only 15% to 20% of sporadic cancers are MSI-H, 90% of patients who meet the Amsterdam criteria for Lynch syndrome have MSI-H CRC.8 Tumor DNA can be evaluated for MSI using polymerase chain reaction to amplify a panel of DNA sequences with nucleotide repeats.\n\nLynch syndrome, an autosomal dominant disorder, is the most common hereditary colon cancer syndrome. Mutations in 1 of the MMR genes usually result in truncated or lost protein product. Thus, tumors can be screened for defective DNA MMR by using polymerase chain reaction to test for MSI or IHC to test for loss of MMR protein expression. The results of IHC may then be used to direct germline sequencing toward a specific DNA MMR gene in young-onset cases or in persons with clinical or family history criteria suggestive of Lynch syndrome. Hypermethylation assays and BRAF V600E mutation testing of tumor DNA can be used to distinguish an MSI-H tumor with absent MLH1 expression caused by hypermethylation of the MLH1 promoter from a tumor caused by a germ-line MLH1 mutation. Tumors with hypermethylation of MLH1 and with the BRAF V600E mutation nearly always represent sporadic CRC not caused by a germline MLH1 mutation and not associated with Lynch syndrome.\n\nIn the case presented here, the patient was tested for a familial syndrome because of his relatively young age at presentation (44 years); however, he lacked many of the features of either FAP or Lynch syndrome. The genetic diagnosis of Lynch syndrome requires a germline mutation in 1 of the MMR genes. The patient’s tumor showed normal expression of the MMR genes MLH1, MSH2, and MSH6 by IHC. MSI testing was not performed. A previous study from our institution showed that a normal IHC test for MLH1 and MSH2 has a 96.7% positive predictive value for a microsatellite stable/MSI-L phenotype.9 On the basis of the IHC data alone, it is highly unlikely that the patient has a germline mutation in an MMR gene, which would lead to Lynch syndrome with MSI.9\n\nAnother hereditary CRC syndrome that can be considered is MYH-associated polyposis (MAP). MAP has a phenotypic overlap with FAP, attenuated FAP, and Lynch syndrome; biallelic carriers have an 80% cumulative lifetime risk of CRC by age 70 years.10 In several studies, among patients with early-onset CRC (diagnosed before age 50 years) who tested negative for Lynch syndrome, 1% to 2% were biallelic carriers of the MYH mutation.11–13\n\nCRC screening and testing recommendations\nAlthough CRC does not usually develop until age 65 years or older, up to 20% of CRC cases will arise in persons 50 years or younger who do not have either of the known hereditary CRC conditions.1–3,6,14 The American Gastroenterological Association has published guidelines for CRC screening for average-risk and higher-risk patients.15,16 Persons with a family history of CRC or adenomatous polyps (a first-degree relative with CRC or adenomatous polyps diagnosed before age 60 years, or 2 first-degree relatives with CRC diagnosed at any age) should have screening colonoscopy starting at age 40 years, or 10 years younger than the earliest diagnosis, whichever comes first, with repeat colonoscopy every 5 years.\n\nIf testing for MMR is negative, patients with early-onset CRC may be tested for MYH mutations, regardless of their family history or the number of colon polyps. IHC can be used in clinical practice to test for MAP regardless of the specific MYH mutations.17\n\nConclusions\nThe case presented here highlights that CRC can occur at an age younger than the cancer-screening guidelines suggest for average-risk patients and also shows the importance of using family history to determine the timing of the first CRC screening. Had our patient undergone his first screening colonoscopy at age 40 years as recommended by the American Gastroenterological Association—given that the patient’s father had colon polyps removed before age 60 years—his CRC might have been diagnosed at an earlier stage. Similarly, the patient’s 2-year history of hematochezia warranted a colon examination. We stress the importance of acknowledging and pursuing these symptoms, even in younger patients.\n\nFIGURE 1 Scheme describing the recommended initial evaluation of a patient aged 50 years or younger with a diagnosis of colorectal cancer (CRC). AFAP indicates attenuated familial adenomatous polyposis; FAP, familial adenomatous polyposis; IHC, immunohistochemistry; JPS, juvenile polyposis syndrome; MAP, MYH-associated adenomatous polyposis; MSI, microsatellite instability; PJS, Peutz-Jeghers syndrome.\n\nFIGURE 2 Scheme describing the recommended genetic testing for a patient with a diagnosis of colorectal cancer. AFAP indicates attenuated familial adenomatous polyposis; APC, adenomatous polyposis coli; BRAF, v-raf murine sarcoma viral oncogene homolog B1; FAP, familial adenomatous polyposis; IHC, immunohistochemistry; MAP, MYH-associated adenomatous polyposis; MLH1, MutL homolog 1; MMR, mismatch repair; MSI, microsatellite instability; MYH, MutY homolog.\n==== Refs\nReferences\n1 Adloff M Arnaud JP Schloegel M Thibaud D Bergamaschi R Colorectal cancer in patients under 40 years of age Dis Colon Rectum 1986 29 322 5 3009108 \n2 Gryfe R Kim H Hsieh ET Aronson MD Holowaty EJ Bull SB Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer N Engl J Med 2000 342 69 77 10631274 \n3 Moore PA Dilawari RA Fidler WJ Adenocarcinoma of the colon and rectum in patients less than 40 years of age Am Surg 1984 50 10 4 6691626 \n4 Lynch HT Smyrk TC Watson P Lanspa SJ Lynch JF Lynch PM Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review Gastroenterology 1993 104 1535 49 8482467 \n5 Peltomaki P Vasen HF the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study Gastroenterology 1997 113 1146 58 9322509 \n6 Fairley TL Cardinez CJ Martin J Alley L Friedman C Edwards B Colorectal cancer in U.S. adults younger than 50 years of age, 1998–2001 Cancer 2006 107 5 Suppl 1153 61 16862554 \n7 Al-Tassan N Chmiel NH Maynard J Fleming N Livingston AL Williams GT Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors Nat Genet 2002 30 227 32 11818965 \n8 Jenkins MA Hayashi S O’Shea AM Burgart LJ Smyrk TC Shimizu D Colon Cancer Family Registry Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study Gastroenterology 2007 133 48 56 17631130 \n9 Lindor NM Burgart LJ Leontovich O Goldberg RM Cunningham JM Sargent DJ Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors J Clin Oncol 2002 20 1043 8 11844828 \n10 Jenkins MA Croitoru ME Monga N Cleary SP Cotterchio M Hopper JL Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study Cancer Epidemiol Biomarkers Prev 2006 15 312 4 16492921 \n11 Eliason K Hendrickson BC Judkins T Norton M Leclair B Lyon E The potential for increased clinical sensitivity in genetic testing for polyposis colorectal cancer through the analysis of MYH mutations in North American patients J Med Genet 2005 42 95 6 15635083 \n12 Riegert-Johnson DL Johnson RA Rabe KG Wang L Thomas B Baudhuin LM The value of MUTYH testing in patients with early onset microsatellite stable colorectal cancer referred for hereditary nonpolyposis colon cancer syndrome testing Genet Test 2007 11 361 5 18294051 \n13 Wang L Baudhuin LM Boardman LA Steenblock KJ Petersen GM Halling KC MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps Gastroenterology 2004 127 9 16 Erratum in: Gastroenterology 2004; 127 : 1651 15236166 \n14 O’Connell JB Maggard MA Liu JH Etzioni DA Livingston EH Ko CY Rates of colon and rectal cancers are increasing in young adults Am Surg 2003 69 866 72 14570365 \n15 American Gastroenterological Association American Gastroenterological Association medical position statement: hereditary colorectal cancer and genetic testing Gastroenterology 2001 121 195 7 11438508 \n16 Winawer S Fletcher R Rex D Bond J Burt R Ferrucci J Gastrointestinal Consortium Panel Colorectal cancer screening and surveillance: clinical guidelines and rationale: update based on new evidence Gastroenterology 2003 124 544 60 12557158 \n17 Di Gregorio C Frattini M Maffei S Ponti G Losi L Pedroni M Immunohistochemical expression of MYH protein can be used to identify patients with MYH-associated polyposis Gastroenterology 2006 131 439 44 16890597\n\n",
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"issue": "44(1)",
"journal": "Radiology and oncology",
"keywords": "MYH-associated polyposis; adenomatous polyposis coli; attenuated familial adenomatous polyposis; colorectal cancer; familial adenomatous polyposis; microsatellite instability",
"medline_ta": "Radiol Oncol",
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"nlm_unique_id": "9317213",
"other_id": null,
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"abstract": "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with many potentially fatal complications. Renal involvement in various forms is common in addition to serum electrolyte disturbances. Early reports suggest that hypokalaemia may frequent those with SARS-CoV-2 infection and various aetiological factors may cause this electrolyte disturbance. A Chinese retrospective study has demonstrated renal potassium wasting in patients infected with SARS-CoV-2, however, it is not known if these patients were receiving diuretic therapy which may be a contributing factor. This case report illustrates an example of renal potassium wasting in SARS-CoV-2 infection in the absence of diuretics and extra-renal mechanisms with important lessons learned.",
"affiliations": "Renal Services, The Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, Tyne and Wear, NE77DN, UK.;Department of Respiratory Medicine, The Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, Tyne and Wear, NE14LP, UK.;Department of Gastroenterology, The Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, Tyne and Wear, NE14LP, UK.;Department of Infection and Tropical Medicine, The Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, Tyne and Wear, NE14LP, UK.;Department of Infection and Tropical Medicine, The Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, Tyne and Wear, NE14LP, UK.;Renal Services, The Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, Tyne and Wear, NE77DN, UK.",
"authors": "Mabillard|Holly|H|;Tedd|Hilary|H|;Speight|Ally|A|0000-0003-3184-9181;Duncan|Christopher|C|;Price|David A|DA|;Sayer|John A|JA|0000-0003-1881-3782",
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"doi": "10.12688/f1000research.24621.2",
"fulltext": "\n==== Front\nF1000Res\nF1000Res\nF1000Research\nF1000Research\n2046-1402 F1000 Research Limited London, UK \n\n10.12688/f1000research.24621.2\nCase Report\nArticles\nCase Report: Renal potassium wasting in SARS-CoV-2 infection\n[version 2; peer review: 2 approved]\n\nMabillard Holly Writing – Original Draft Preparation1 Tedd Hilary InvestigationMethodology2 Speight Ally InvestigationMethodologyhttps://orcid.org/0000-0003-3184-91813 Duncan Christopher InvestigationWriting – Review & Editing45 Price David A. ConceptualizationSupervisionWriting – Review & Editing45 Sayer John A. ConceptualizationSupervisionWriting – Original Draft PreparationWriting – Review & Editinghttps://orcid.org/0000-0003-1881-3782a156 \n1 Renal Services, The Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, Tyne and Wear, NE77DN, UK\n\n2 Department of Respiratory Medicine, The Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, Tyne and Wear, NE14LP, UK\n\n3 Department of Gastroenterology, The Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, Tyne and Wear, NE14LP, UK\n\n4 Department of Infection and Tropical Medicine, The Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, Tyne and Wear, NE14LP, UK\n\n5 Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, Tyne and Wear, NE13BZ, UK\n\n6 NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, Tyne and Wear, NE45PL, UK\na john.sayer@ncl.ac.ukNo competing interests were disclosed.\n\n\n13 11 2020 \n2020 \n13 11 2020 \n9 65910 11 2020 Copyright: © 2020 Mabillard H et al.2020This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with many potentially fatal complications. Renal involvement in various forms is common in addition to serum electrolyte disturbances. Early reports suggest that hypokalaemia may frequent those with SARS-CoV-2 infection and various aetiological factors may cause this electrolyte disturbance. A Chinese retrospective study has demonstrated renal potassium wasting in patients infected with SARS-CoV-2, however, it is not known if these patients were receiving diuretic therapy which may be a contributing factor. This case report illustrates an example of renal potassium wasting in SARS-CoV-2 infection in the absence of diuretics and extra-renal mechanisms with important lessons learned.\n\nCOVID-19hypokalaemiapotassiumtubulopathyNorthern Counties Kidney Research FundKidney Research UKJAS is supported by Kidney Research UK and Northern Counties Kidney Research Fund.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Revised Amendments from Version 1\nWe have refined the clinical tables to make the time course of the patient's condition more well defined. We have expanded the discussion to improve the flow and narrative of the case report, highlighting the reasons for electrolyte disturbance.\n==== Body\nIntroduction\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with many potentially fatal complications\n1. Renal involvement in various forms is common in addition to serum electrolyte disturbances\n2. Renal pathologies identified so far include acute tubular injury, proteinuria, rhabdomyolysis, secondary focal segmental glomerulosclerosis and possible renin-angiotensin-aldosterone system (RAS) activation\n2.\n\nEarly reports suggest that hypokalaemia may frequent those with SARS-CoV-2 infection\n3 and various aetiological factors may cause this electrolyte disturbance such as gastrointestinal potassium loss, diuretic-induced potassium wasting, renal tubulopathy and RAS activation. An early Chinese retrospective study has demonstrated renal potassium wasting in patients infected with SARS-CoV-2, however it is not known if these patients were receiving diuretic therapy which may have been a contributing factor\n3. This case report illustrates an example of renal potassium wasting in SARS-CoV-2 infection in the absence of diuretics and extra-renal mechanisms in addition to lessons learned from an important and potentially dangerous complication of the disease. \n\nCase report\nOur patient, an 82 year old Caucasian female, was admitted to the medical admissions unit with confusion and drowsiness in April 2020. She was noted to be pyrexial (38.6 degrees Celsius) and hypoxic (oxygen saturations 86% on room air) on admission and had a Glasgow coma score of 14/15. She had a chronic cough with intermittent clear sputum. Bilateral inspiratory crackles were reported on chest auscultation and she looked hypovolaemic. Blood pressure was 90/60 mmHg and heart rate was 100 bpm. Her comorbidities include chronic obstructive pulmonary disease, previous dynamic hip screw following a right fractured neck of femur, osteoarthritis, hypertension, thoracoabdominal aortic aneurysm and osteoporosis. Usual medications included oral cholecalciferol 1600 units daily, diazepam 2mg nocte as required, lercanidipine 10mg daily, omeprazole 20mg daily, sertraline 50mg daily, tolterodine 1mg twice daily and a salbutamol inhaler. Her chest x-ray did not show evidence of infection. Her diazepam and antihypertensives were suspended and she was commenced on oxygen therapy aiming for saturations between 88 and 92%. Her coronavirus disease 2019 (COVID-19) RT-PCR test from a deep throat swab was positive. The patient developed systemic symptoms the next day and a rise in C-reactive protein (CRP) was seen (\nTable 1) so she was commenced on doxycycline 100mg once daily for five days to cover a lower respiratory tract infection. Both urine and blood cultures were negative. 3 Days after admission she developed hypokalaemia which was treated with 72 mmol oral SandoK (potassium bicarbonate and potassium chloride therapy) daily (in divided doses) and she was given 1L intravenous Hartman’s solution (containing 5 mmol/L potassium) daily for three days (\nFigure 1). Six days after admission the patient’s oxygen requirements had returned to baseline but hypokalaemia (serum potassium 3.4 mmol/L) persisted despite treatment. A trans-tubular potassium gradient was found to be significantly elevated at 10.7. Her serum potassium level normalised to 3.9 mmol/L eight days later. Clinical improvement was noted at this point and the patient received physiotherapy until her mobility was safe enough to be discharged after a total of 20 days in hospital. Given her COVID-19 positive status she received four weeks of rivaroxaban therapy post discharge to reduce the chance of venous thromboembolism. At no point did our patient have diarrhoea or receive any medications that would interfere with her serum or urine potassium such as RAS inhibitors or loop or thiazide diuretics. Her renal function remained at baseline throughout her admission (serum Creatinine 60–77 µmol/L and eGFR 70–82 mL/min/1.73m\n2).\n\nTable 1. Biochemical tests.\nTest\tBaseline Results\n\n(start of admission)\tPatient\n\nResults\tNormal Values\t\nBlood pH\t7.38\t7.48\t7.35-7.42\t\npCO2 (kPa)\t6.0\t6.2\t4.5-6.0\t\nBaseline serum potassium (mmol/L)\t5.4\t4.1\t3.5-5.3\t\nNadir serum potassium (mmol/L)\t-\t3.4\t3.5-5.3\t\nSerum bicarbonate (mmol/L)\t25.6\t32\t21-28\t\nPeak CRP (mg/L)\t23\t152\t<5\t\nPeak Ferritin (µ/L)\t237\t555\t<200 in pre-menopausal women and <300\n\nin men and post-menopausal women\t\nPeak Lactate Dehydrogenase (unit/L)\t-\t216\t135-225\t\nPeak Procalcitonin (ng/mL)\t-\t0.85\t<0.05\t\nTTKG\t-\t10.7\t>4.0 indicates renal potassium loss\t\nPlasma renin (mIU/L)\t-\t6.7\t<59.7\t\nPlasma Aldosterone (pmol/L)\t-\t<103\t103-859\t\nAldosterone/Renin Ratio (pmol/mIU)\t-\t<16\t<30\t\nUrine creatinine (mmol/l)\t-\t7.9\t-\t\nUrine sodium (mmol/l)\t-\t7.9\t-\t\nUrine potassium (mmol/l)\t-\t75\t-\t\nUrine osmolality (mOsm/Kg)\t-\t565\t-\t\nFigure 1. Serum potassium changes during Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.\nDiscussion\nThe renal complications that are known from this devastating disease so far include proteinuria, acute tubular injury, rhabdomyolysis, secondary focal segmental glomerulosclerosis and possible RAS activation (both directly and indirectly)\n2. This case demonstrates evidence of renal potassium wasting as an example of a further renal complication of SARS-CoV-2 infection which has, so far, only been reported in China yet without the knowledge of contribution from diuretics. Although, the patient’s chronic obstructive pulmonary disease would naturally lead us to speculate this as a cause for her metabolic alkalosis; her serum bicarbonate has always been normal, her COPD was mild, she had an elevated blood pH despite high pCO2 levels and renal potassium wasting is not a known sequela of COPD. Renal potassium wasting was transient and the patient had never before suffered with hypokalaemia, been treated with diuretics, laxatives, mineralocorticoid agonists or had diarrhoea. This would exclude chronic causes of renal potassium wasting such as Glucocorticoid Remedial Aldosteronism, adrenal adenoma/carcinoma, Bartter’s syndrome, Gitelman Syndrome and other disorders of steroid metabolism. She did not have a history of liquorice ingestion or exogenous steroid use. She was not Cushingoid or hypertensive and, when measured, she did not have hyperreninaemia or hyperaldosteronism. It is therefore likely that she had direct tubular loss of potassium probably secondary to direct tubular injury. This could have been a result of her documented hypotension causing acute tubular necrosis but she did not have acute kidney injury or any significant eGFR drop during admission which you would expect to justify her hypokalaemia. Our hypothesis of direct viral injury of the tubular epithelium however, could explain this tubular loss of potassium in the absence of an eGFR decline although this cannot be proven in this patient.\n\nA retrospective pre-print Chinese study highlighted hypokalaemia as a complication early on in the pandemic which contributed to the momentum in speculation of RAS involvement\n3. This was due to chronic kidney disease, hypertension, cardiovascular disease and diabetes mellitus being more commonly observed in those with severe SARS-CoV-2 infection along with the knowledge that SARS-CoV-2 enters host cells through the angiotensin-converting enzyme 2 (ACE2) receptor on the surface of pulmonary type 2 alveolar cells. The Chinese data (n = 175) reported the presence of hypokalaemia in 62% of patients with SARS-CoV-2 infection and 22% of all patients had severe hypokalaemia (serum potassium <3.0 mmol/L). Many (28%) had concomitant metabolic alkalosis and of the 20 patients who had a spot urine potassium/creatinine ratio, their degree of urine potassium wasting was significantly higher than those with normokalaemia and that this correlated with the degree of infection severity. It was also noted in two patients that their renal potassium wasting persisted until complete clinical recovery from the virus which was the case with our patient. Hypokalaemia was also documented in 41.3% of a cohort of SARS-CoV infection during the 2003 epidemic but it should be noted that the largest SARS-CoV-2 case series to date (n = 1099) did not find a major difference in serum potassium between those with mild and severe disease. \n\nResearch into the renin-angiotensin-aldosterone system has shown that genetic polymorphisms in the ACE2 gene are associated with a difference in blood pressure response to sodium and potassium intake\n4. One study reported that ACE2 SNPs are associated with a blood pressure reduction in response to potassium intake during a period of high salt intake where blood pressure would typically be expected to rise and that ‘potassium sensitivity’ of blood pressure may exist\n5. Further research using the 100 000 genomes project has suggested that ACE2 polymorphisms could explain the higher risk of severe disease and death amongst males and those of African and East Asian origin in SARS-CoV-2 infection. The Chinese SARS-CoV-2 study could reflect the literature which suggests subjects with ‘severe disease’ may represent a sub-group with ACE2 polymorphisms\n6. It is already known that rs182366225 and rs2097723 polymorphisms are more frequent in the East Asian population and increase the expression of ACE2. It may therefore be that certain ACE2 polymorphisms are a risk factor for hypokalaemia. It should also be noted that, if this is the case, then there may be a greater prevalence of hypokalaemia amongst certain ethnic populations and that the study by Chen, D.\net al. demonstrates a higher prevalence of hypokalaemia than in other studies because of this.\n\nComplications from hypokalaemia can be life-threatening\n7. Hypokalaemia can result in muscle weakness and cramps, thirst and paraesthesia but when serum potassium drops below 3.0 mmol/L arrhythmias such as QTc prolongation, torsades de pointes, ventricular fibrillation and sudden cardiac death can occur\n8. The incidence of ventricular fibrillation is five-fold higher in those with hypokalaemia in comparison to hyperkalaemia\n9. Inadequate management of hypokalaemia in hospitalised patients has been reported in as much as 24% in one study demonstrating an at-risk group of patients and a need for therapeutic vigilance here\n10. \n\nThe SARS-CoV-2 pandemic gives us many reasons to be vigilant with the detection and management of hypokalaemia. First, many of the SARS-CoV-2 clinical trial drugs prolong the QTc interval which adds to the arrhythmogenic effect of hypokalaemia. Some of the trial drugs can induce hypokalaemia themselves risking severe electrolyte disturbances. Second, arrhythmia induction has more than one risk factor in this patient population, for example, hypoxia-mediated, cytokine-storm-syndrome and direct viral cardiac myocyte damage which all make these patients vulnerable to cardiac complications\n11. Third, the use of diuretics to improve oxygenation in those with acute respiratory distress syndrome also risks hypokalaemic complications. Finally, the data for return of spontaneous circulation (ROSC) during cardiac arrest in a retrospective study (n = 136) is unfortunately very poor (13.2% achieved ROSC and less than 3% were alive at 30 days post-cardiac arrest) which reiterates the importance of vigilance for electrolyte disturbance in this patient population\n12.\n\nThe popular mechanism for hypokalaemia remains RAS system activation and it should be noted that not all patients with RAS activation are hypokalaemic, due to the renal potassium switch mechanism\n13,\n14. Early reports demonstrate good histopathological evidence of tubular injury which seem to have a multifactorial aetiology in SARS-CoV-2 patients\n15,\n16. These include acute tubular necrosis from cytokine-storm syndrome, direct virion invasion of tubular cells, peritubular congestion, drug toxicity and pigment-cast nephropathy from rhabdomyolysis. Based on these mechanisms it seems likely that tubular injury is difficult to avoid in these patients.\n\nCurrent evidence for mechanisms of renal injury in SARS-CoV-2 infection is early and much of which is based on speculation, case reports and case series. It is clear that we need more studies that measure all components of the RAS pathway in SARS-CoV-2 patients to truly determine RAS involvement and more data on serum and urine electrolytes in infected patients including the trans-tubular potassium gradient (TTKG). It is easy to measure the TTKG and measurement only requires serum and urine osmolality and potassium (urine potassium/serum potassium)/(urine osmolality/ serum osmolality). Estimation is accurate providing urine is not dilute and that urine sodium concentration is >25mmol/l so that distal sodium delivery is not a limiting factor\n17. A urine potassium: creatinine ratio can also be used and is preferred over a spot urine potassium or 24-hour urinary potassium collection as, because creatinine is theoretically secreted in a constant state (in the absence of an GFR drop), a urine potassium: creatinine ratio corrects for urine volume variations. The TTKG is beneficial as it does not overestimate the gradient for collecting duct potassium secretion, however it is not without flaws which are discussed elsewhere\n18.\n\nConclusion\nHere we summarise a case of severe SARS-CoV-2 infection with evidence of significant renal potassium wasting resulting in hypokalaemia. Complications from hypokalaemia can be life-threatening, especially during critical illness, thus we advocate checking the trans-tubular potassium gradient in patients with moderate-severe infection. This should help identify those at risk of hypokalaemia so appropriate monitoring and electrolyte replacement can be promptly instituted to prevent this potentially fatal complication.\n\nConsent\nWritten informed consent for publication of their clinical details was obtained from the patient.\n\nData availability\nUnderlying data\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nAcknowledgements\nJAS is supported by Kidney Research UK and Northern Counties Kidney Research Fund.\n\n10.5256/f1000research.30666.r74801\nReviewer response for version 2\nTsai Ming-Hsien 1Refereehttps://orcid.org/0000-0003-3561-4689 \n1 Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Fu-Jen Catholic University School of Medicine, Taipei, Taiwan\n\nCompeting interests: No competing interests were disclosed.\n\n\n26 11 2020 \nCopyright: © 2020 Tsai MH2020This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 2recommendationapproveI am satisfied with this revision.\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nPartly\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nPartly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nPartly\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nnephrology\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.27159.r71137\nReviewer response for version 1\nTsai Ming-Hsien 1Refereehttps://orcid.org/0000-0003-3561-4689 \n1 Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Fu-Jen Catholic University School of Medicine, Taipei, Taiwan\n\nCompeting interests: No competing interests were disclosed.\n\n\n7 10 2020 \nCopyright: © 2020 Tsai MH2020This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 1recommendationapprove-with-reservationsThe authors reported a case with hypokalemia may relate to SARS-Cov-2 infection. This case is well written but still, some concerns need to be clarified.\n\n\n \n\n\n\n Major:\nThe timeline in this case is important for a comprehensive understanding. I suggest that the authors can modify Table 1 to show the baseline data and consequent laboratory change.\n\nDid the authors have the result of urine nitrogen, creatinine, sodium, potassium, calcium, Mg, phosphate, and osmolarity levels? If yes, please provide.\n\n\nMinor:\nThe dosed of medications that she used in OPD should be provided in the part of the case report.\n\nThe author should focus on this case and clearly tell us that what is the most possible etiology of renal wasting in this case. \n\nThe urine K/Cr ratio can offer a more quick and reliable interpretation of the hypokalemia. I suggest the author can discuss this.\n\n\n\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nPartly\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nPartly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nPartly\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nnephrology\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.\n\n10.5256/f1000research.27159.r68472\nReviewer response for version 1\nMoochhala Shabbir 1Referee \n1 UCL Centre for Nephrology, Royal Free Campus and Hospital, University College London Medical School, London, UK\n\nCompeting interests: No competing interests were disclosed.\n\n\n17 8 2020 \nCopyright: © 2020 Moochhala S2020This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Version 1recommendationapproveThe authors present a well-observed, useful and much needed case and comment on an important renal complication of SARS-CoV-2 infection in a co-morbid patient.\n\n My main concern is that the possibility of this being a primary metabolic alkalosis (with secondary hypokalaemia) has not been adequately refuted. The blood gas data show a metabolic alkalosis with respiratory compensation, and simultaneously a relatively modest hypokalaemia for this degree of alkalosis. Contraction alkalosis (due to pyrexia causing volume depletion/hypotension) or hypercapnoeic metabolic alkalosis (hypoxic on admission with COPD) might be explanations for this\n1. Results for chloride and CK, if available, may be helpful. \n\n I agree that the results do not support aldosterone-mediated hypokalaemia. \n\n In fig 1, Hartmann's and sando K on day 3 should be mentioned together for clarity. \n\n I am not clear about when TTKG was measured. Presumably this was before potassium replacement on day 3 to avoid confounding, but this should be mentioned.\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?\n\nYes\n\nIs the case presented with sufficient detail to be useful for other practitioners?\n\nYes\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?\n\nYes\n\nIs the background of the case’s history and progression described in sufficient detail?\n\nYes\n\nReviewer Expertise:\n\nClinical renal disease, renal tubular disease\n\nI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n==== Refs\n1 \nHuang C Wang Y Li X :\nClinical features of patients infected with 2019 novel coronavirus in Wuhan, China.\n\nLancet. \n2020 ;395 (10223 ):497 –506\n.\n10.1016/S0140-6736(20)30183-5 \n\n31986264 \n2 \nBatlle D Soler MJ Sparks MA :\nAcute kidney injury in COVID-19: Emerging evidence of a distinct pathophysiology.\n\nJ Am Soc Nephrol. \n2020 ;31 (7 ):1380 –1383\n.\n10.1681/ASN.2020040419 \n32366514 \n3 \nChen D JrLi X Song Q Sr :\nHypokalaemia and Clinical Implications in Patients with Coronavirus Disease 2019 (COVID-19).\n\nmedRxiv. \n2020 \n10.1101/2020.02.27.20028530 \n\n4 \nPatel SK Velkoska E Freeman M :\nFrom gene to protein—experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension.\n\nFront Physiol. \n2014 ;5 :227 .\n10.3389/fphys.2014.00227 \n\n25009501 \n5 \nZhao Q Gu D Kelly TN :\nAssociation of genetic variants in the apelin-APJ system and ACE2 with blood pressure responses to potassium supplementation: the GenSalt study.\n\nAm J Hypertens. \n2010 ;23 (6 ):606 –613\n.\n10.1038/ajh.2010.36 \n\n20224560 \n6 \nKhayat AS de Assumpcao PP Khayat BMC :\nACE2 polymorphisms as potential players in COVID-19 outcome.\n\nMedRxiv. \n2020 \n10.1101/2020.05.27.20114843 \n\n7 \nCrop MJ Hoorn EJ Lindemas J :\nHypokalemia and subsequent hyperkalemia in hospitalized patients.\n\nNephrol Dial Transplant. \n2007 ;22 (12 ):3471 –3477\n.\n10.1093/ndt/gfm471 \n17848395 \n8 \nWidimsky P :\nHypokalaemia and the heart.\n\nE-journal of Cardiology Practice. \n2008 ;7 (9 ).\nReference Source\n\n9 \nClausen TG Brocks K Ibsen H :\nHypokalemia and ventricular arrhythmias in acute myocardial infarction.\n\nActa Med Scand. \n1988 ;224 (6 ):531 –537\n.\n10.1111/j.0954-6820.1988.tb19623.x \n3207065 \n10 \nKjeldsen K :\nHypokalemia and sudden cardiac death.\n\nExp Clin Cardiol. \n2010 ;15 (4 ):e96 –9\n.\n\n21264075 \n11 \nZheng YY Ma YT Zhang JY :\nCOVID-19 and the cardiovascular system.\n\nNat Rev Cardiol. \n2020 ;17 (5 ):259 –260\n.\n10.1038/s41569-020-0360-5 \n\n32139904 \n12 \nShao F Xu S Ma X :\nIn-hospital cardiac arrest outcomes among patients with COVID-19 pneumonia in Wuhan, China.\n\nResuscitation. \n2020 ;151 :18 –23\n.\n10.1016/j.resuscitation.2020.04.005 \n\n32283117 \n13 \nKamel KS Schreiber M Halperin ML :\nRenal potassium physiology: integration of the renal response to dietary potassium depletion.\n\nKidney Int. \n2018 ;93 (1 ):41 –53\n.\n10.1016/j.kint.2017.08.018 \n29102372 \n14 \nMabillard H Sayer JA :\nThe Molecular Genetics of Gordon Syndrome.\n\nGenes (Basel). \n2019 ;10 (12 ):986 .\n10.3390/genes10120986 \n\n31795491 \n15 \nSu H Yang M Wan C :\nRenal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.\n\nKidney Int. \n2020 ;98 (1 ):219 –227\n.\n10.1016/j.kint.2020.04.003 \n\n32327202 \n16 \nDiao B Wang C Wang R :\nHuman Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.\n\nMedRxiv. \n10.1101/2020.03.04.20031120 \n\n17 \nElisaf M Rizos E Siamopoulos K :\nPotassium excretion indices in the diagnostic approach to hypokalaemia.\n\nQJM. \n2000 ;93 (5 ):318 –9\n.\n10.1093/qjmed/93.5.318 \n10825410 \n18 \nMabillard H Sayer JA :\nElectrolyte Disturbances in SARS-CoV-2 Infection [version 2; peer review: 2 approved].\n\nF1000Res. \n2000 ;9 :587 .\n10.12688/f1000research.24441.2 \n\n33093945\n\n",
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"keywords": "COVID-19; hypokalaemia; potassium; tubulopathy",
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"mesh_terms": "D000086382:COVID-19; D006801:Humans; D007668:Kidney; D007674:Kidney Diseases; D011188:Potassium; D011191:Potassium Deficiency; D012189:Retrospective Studies; D000086402:SARS-CoV-2",
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"title": "Case Report: Renal potassium wasting in SARS-CoV-2 infection.",
"title_normalized": "case report renal potassium wasting in sars cov 2 infection"
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"abstract": "Angiotensin-converting enzyme (ACE) inhibitors are known to cause angioedema. Most ACE inhibitor-induced angioedema cases describe swelling in the periorbital region, tongue, and pharynx. We describe a case of a 62-year-old female with presumed angioedema of the small bowel after more than a 2-year history of lisinopril use (with no recent changes in her dose of 40 mg orally twice daily). The patient presented with nausea and intermittent left middle and upper quadrant abdominal pain and denied history of angioedema or swelling with any medications or any history of abdominal pain. On physical examination, bowel sounds, liver, and spleen were normal. Laboratory tests revealed leukocytosis (15 400 per mm3) and normal complement 1 esterase inhibitor levels. Abdominal computed tomography (CT) showed segmental small bowel thickening and edema with ascites and surrounding inflammatory changes. There was no lymphadenopathy, obstruction, or ileus. Two days after discontinuation of the lisinopril, the patient reported improvement in symptoms. The Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 7) between the development of angioedema of the small bowel and the lisinopril therapy. This case highlights the unique manner in which ACE inhibitor-induced angioedema may present. A review of published cases of ACE inhibitor-induced angioedema of the small bowel is provided.",
"affiliations": "1 PGY2 Critical Care Pharmacy Resident, Department of Pharmacy, University of Tennessee Medical Center, Knoxville, TN, USA.;2 PGY1 Clinical Pharmacy Resident, Department of Pharmacy, Cleveland Clinic Fairview Hospital, Cleveland, OH, USA.;3 The Kroger Co, Westerville, OH, USA.;4 Department of Internal Medicine, PGY-3 Internal Medicine Resident, University of Toledo Medical Center, Toledo, OH, USA.;5 Department of Pharmacy Practice, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH, USA.",
"authors": "Wilin|Kent L|KL|;Czupryn|Michael J|MJ|;Mui|Richard|R|;Renno|Anas|A|;Murphy|Julie A|JA|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190017690641",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "31(1)",
"journal": "Journal of pharmacy practice",
"keywords": "ACE inhibitor; adverse drug reaction; angioedema; small bowel; small intestine",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D015746:Abdominal Pain; D000799:Angioedema; D000806:Angiotensin-Converting Enzyme Inhibitors; D005260:Female; D006801:Humans; D007421:Intestine, Small; D008875:Middle Aged",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "99-103",
"pmc": null,
"pmid": "28125922",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "ACE Inhibitor-Induced Angioedema of the Small Bowel: A Case Report and Review of the Literature.",
"title_normalized": "ace inhibitor induced angioedema of the small bowel a case report and review of the literature"
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"abstract": "BACKGROUND Plasma cell myeloma is a neoplastic plasma cell disorder that usually presents after the fifth decade of life; it is rarely described in younger population especially under 30 years of age. However, there are conflicting reports in the literature about the clinical behavior and overall survival in younger age groups. In approximately 2% of plasma cell myeloma, the morphology of the neoplastic cells is highly pleomorphic, quite anaplastic, and may resemble metastatic tumor cells. While this poses a challenge for morphological interpretation during diagnosis, it has been demonstrated that bone marrow morphologic features (including diffuse sheet growth pattern, immature cell morphology and high mitotic index) significantly correlates with high risk disease. Moreover, there is limited description available about the morphology of the neoplastic cells when correlating the age at presentation with the clinical outcome/biological behavior; hence, the need to report and collect such cases. CASE REPORT We report a case of plasma cell myeloma in a 22-year-old male who presented with non-specific clinical features and posed a diagnostic challenge during clinical, radiological, and laboratory examination. The pathology specimens showed anaplastic morphology. Unfortunately, after diagnosis, despite treatment with brotezomib, his disease had an aggressive clinical course and he passed away 4 months after diagnosis. CONCLUSIONS Although plasma cell myeloma is rare in patients younger than 30 years, it must be considered in the differential diagnosis and investigated properly especially in patients with clinical suspicion of a metastatic non-hematological tumor. The anaplastic variant in a young patient is a diagnostic challenge and is associated with bizarre morphology, aggressive presentation, adverse cytogenetics, resistance to chemotherapy, and poor, short-term, survival.",
"affiliations": "Department of Medical Oncology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar.;Department of Laboratory Medicine and Pathology, National Centre for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar.;Department of Laboratory Medicine and Pathology, National Centre for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar.;Department of Laboratory Medicine and Pathology, National Centre for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar.;Department of Medical Oncology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar.;Department of Radiology (Clinical Imaging), National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar.;Cancer Clinical Trials Unit, Department of Medical Oncology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar.;Department of Laboratory Medicine and Pathology, National Centre for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar.;Department of Medical Oncology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar.",
"authors": "Elsabah|Hesham|H|;Soliman|Dina S|DS|;Ibrahim|Feryal|F|;Al-Sabbagh|Ahmad|A|;Yassin|Mohamed|M|;Moustafa|Abbas|A|;Nashwan|Abdulqadir M|AM|;Nawaz|Zafar|Z|;ElOmri|Halima M|HM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.920489",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32152261\n10.12659/AJCR.920489\n920489\nArticles\nPlasma Cell Myeloma with an Aggressive Clinical Course and Anaplastic Morphology in a 22-Year-Old Patient: A Case Report and Review of Literature\nElsabah Hesham *EF1 Soliman Dina S. *EFG234 Ibrahim Feryal EF2 Al-Sabbagh Ahmad DE2 Yassin Mohamed AB1 Moustafa Abbas D5 Nashwan Abdulqadir M. E6 Nawaz Zafar D2 ElOmri Halima M. B1 \n1 Department of Medical Oncology, National Center for Cancer Care and Research(NCCCR), Hamad Medical Corporation, Doha, Qatar\n\n2 Department of Laboratory Medicine and Pathology, National Centre for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar\n\n3 Department of Laboratory Medicine and Pathology, Weill Cornell Medical College, Doha, Qatar\n\n4 Department of Clinical Pathology, National Cancer Institute, Cairo, Egypt\n\n5 Department of Radiology (Clinical Imaging), National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar\n\n6 Cancer Clinical Trials Unit, Department of Medical Oncology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar\nCorresponding Author: Dina S. Soliman, e-mail: dsoliman@hamad.qaAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\n* Hesham Elsabah and Dina S. Soliman had equal contribution\n\nConflict of interest: None declared\n\n\n2020 \n10 3 2020 \n21 e920489-1 e920489-8\n05 10 2019 26 11 2019 28 1 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 22-year-old\n\nFinal Diagnosis: Anaplastic plasma cell myeloma\n\nSymptoms: Bone pain\n\nMedication:—\n\nClinical Procedure: BM examination\n\nSpecialty: Hematology\n\nObjective:\nUnusual clinical course\n\nBackground:\nPlasma cell myeloma is a neoplastic plasma cell disorder that usually presents after the fifth decade of life; it is rarely described in younger population especially under 30 years of age. However, there are conflicting reports in the literature about the clinical behavior and overall survival in younger age groups. In approximately 2% of plasma cell myeloma, the morphology of the neoplastic cells is highly pleomorphic, quite anaplastic, and may resemble metastatic tumor cells. While this poses a challenge for morphological interpretation during diagnosis, it has been demonstrated that bone marrow morphologic features (including diffuse sheet growth pattern, immature cell morphology and high mitotic index) significantly correlates with high risk disease. Moreover, there is limited description available about the morphology of the neoplastic cells when correlating the age at presentation with the clinical outcome/biological behavior; hence, the need to report and collect such cases.\n\nCase Report:\nWe report a case of plasma cell myeloma in a 22-year-old male who presented with non-specific clinical features and posed a diagnostic challenge during clinical, radiological, and laboratory examination. The pathology specimens showed anaplastic morphology. Unfortunately, after diagnosis, despite treatment with brotezomib, his disease had an aggressive clinical course and he passed away 4 months after diagnosis.\n\nConclusions:\nAlthough plasma cell myeloma is rare in patients younger than 30 years, it must be considered in the differential diagnosis and investigated properly especially in patients with clinical suspicion of a metastatic non-hematological tumor. The anaplastic variant in a young patient is a diagnostic challenge and is associated with bizarre morphology, aggressive presentation, adverse cytogenetics, resistance to chemotherapy, and poor, short-term, survival.\n\nMeSH Keywords:\nBone Marrow NeoplasmsMultiple MyelomaNeoplasms, Plasma Cell\n==== Body\nBackground\nPlasma cell myeloma (PCM), a malignant, clonal plasma cell disorder that accounts for 1.6% of all malignancies and 10% of all hematologic neoplasms [1] is most commonly seen after the fifth decade of life [2] and is more common in males. The most common presenting clinical features are bone pain, anemia, impaired renal function, and hypercalcemia. The frequency of PCM in younger patients (less than 30 years of age) is extremely rare and account for 0.26% [3] of cases. In the majority of published series/case reports presentation at an earlier age is not associated with adverse clinical outcomes when compared to patients falling within the ‘usual’ age range of presentation. Rare case reports have mentioned an aggressive clinical course.\n\nCase Report\nClinical presentation was of a 22-year-old male with low back pain and significant weight loss of 12 kg for 2 months with no fever, trauma, or neurological symptoms. Physical examination revealed localized tenderness in the anterior chest wall and lumbosacral spine but was otherwise unremarkable.\n\nLaboratory workup revealed an increase in creatinine level 179 µmol/L (normal range 62–124 µmol/L) and hypercalcemia with a calcium level of 3.39 mmol/L (normal range 2.1–2.6 mmol/L) and high lactate dehydrogenase (LDH) 308 U/L (normal range 135–225). The complete blood count was normal with a hemoglobin of 13.6 g/dL (normal range 13–17 g/DL). Albumin was 44 g/L (normal range 35–50 g/L).\n\nComputed tomography (CT) scan was done to rule out malignancy and it revealed the presence of a soft tissue mass at the anterior end of the 7th rib (6.5×4×7 cm) (Figure 1A), and extensive lytic lesions involving the skull base (Figure 1B), sternum, and clavicle.\n\nRadiologically, the features were suspicious of metastatic infiltration. Magnetic resonance imaging (MRI) spine showed disseminated bony lesions involving the whole spine and iliac bone (Figure 2A, 2B).\n\nThe clinical and radiological findings somewhat favored a metastatic tumor over PCM, though myeloma remained in the working differential diagnoses given the laboratory results.\n\nFurther workup, including a peripheral blood smear which showed increased rouleaux formation with few circulating neoplastic cells with “blastoid” morphology (6%) (Figure 3A).\n\nThe bone marrow aspirate smear was heavily infiltrated with cohesive clusters/sheets of highly pleomorphic neoplastic cells, many of which showed anaplastic morphology and mimicked the morphological changes seen in metastatic tumors (Figure 3B). The cells with anaplastic morphology were very large with abundant cytoplasm and markedly irregular contours. The nuclei were multi-lobated/abnormally lobated or multi-nucleated, and hyperchromatic and had very prominent nucleoli (Figure 3C–3F). Few cells show blast-like morphology. There were very few scattered plasma cells. Some cells with hyperchromatic nuclei and mitotic figures were also noted (Figure 3G).\n\nFlow cytometry analysis on bone marrow aspirate revealed an abnormal population of CD45-negative cells (11%), showing moderate side scatter and high heterogeneous forward light scatter. The population were positive for CD38 and CD138, indicative of plasma cells and showing cytoplasmic kappa light chain restriction (monotypic) with aberrant surface kappa light chain expression and negative for CD56 and CD117 (Figure 4).\n\nThe bone marrow biopsy showed effacement of normal architecture due to a prominent interstitial infiltrate of neoplastic plasma cells that are arranged in large aggregates and a diffuse sheet-like distribution (Figure 5A) with focal areas of necrosis. The infiltrating cells exhibited anaplastic morphology with marked nuclear irregularities, prominent nucleoli, and multi-nucleation. The infiltrating plasma cells were positive for CD138 with kappa light chain restriction and high proliferation fraction (over 90% nuclear expression of Ki67 in plasma cells, Figure 5B–5E). The infiltrate was negative for CD20, CD56, IgG, IgM, IgD, and IgE.\n\nSerum protein electrophoresis showed no monoclonal band. However, light chain analysis revealed free kappa light chain 329.2 mg/L (range 3.3–19.4) and free light chain lambda 1.24 mg/L (range 0.26–1.65), with kappa/lambda ratio at 265.\n\nBence-Jones protein was detected at 0.1 g/L and beta-2 microglobulin was 2.8 mg/L (range 0.8–2.2).\n\nCytogenetic studies performed on G-banded metaphase cells isolated from unstimulated short-term culture and Interleukin 4 stimulated long-term culture revealed a complex karyotype with 2 abnormal clones containing multiple numeric and structural abnormalities. A normal clone was also present, 4 cells.\n\nThe main clone represented by 20 cells contained derivative chromosomes 16, 19, 20, and iso-chromosome 9q10, additional material on chromosome 14, and monosomy chromosome 13. A subclone represented by 6 cells contained derivative chromosome 16, insertional duplication in chromosome 1 at cyto-genetic bands 1q21q32, additional material on chromosome 14, monosomy of chromosomes 13 and 19. Furthermore, FISH analysis after cytogenetics studies confirmed a translocation between long arms of chromosomes 14 and 16 at cytogenetics bands 14q32.3 and 16q23, which results in fusion of IGHMAF genes (Figure 6).\n\nIn view of these findings, the final diagnosis was (light chain) plasma cell myeloma, anaplastic morphological variant.\n\nConcurrent with the bone marrow diagnosis; a CT guided biopsy (of the lower rib) confirmed infiltration by CD138-positive atypical cell infiltrate; compatible with plasma cell neoplasm.\n\nManagement and outcome\nThe patient was started on bortezomib-based triple therapy (bortezomib (1.3 mg/m2), cyclophosphamide (300 mg/m2), dexamethasone (40 mg), (D1, D4, D8, D11 every 21 days). Being a very young patient who presented with an advanced disease that demonstrated an aggressive clinical behavior, we planned an autologous stem cell transplantation for the patient. However, the patient travelled abroad and passed away in less than 4 months after his initial diagnosis.\n\nDiscussion\nPCM is primarily and predominantly a disease of the bone marrow characterized by neoplastic plasma cell proliferation associated with a monoclonal immunoglobulin (M protein) in serum or urine. The diagnosis is based on clinical, radiological, laboratory, and cyto-histological findings.\n\nBone marrow examination is essential for the diagnosis of PCM, even in the presence of clinical, radiological and laboratory evidence of the disease. The bone marrow is used for both qualitative and quantitative assessment using immunophenotyping. Further cytogenetic studies, a key component of the diagnostic workup, provide prognostic information.\n\nBased on the cytomorphology, myeloma cells are classified into 4 types: mature, immature, pleomorphic, and plasmablastic [4]\n\nThe well-differentiated or “mature” plasma cell (so called Marshalko-type) shows the characteristic round eccentric nuclei with “clock face” chromatin without nucleoli and abundant dense basophilic cytoplasm with clear perinuclear hof corresponding to the Golgi zone. In contrast, plasmablasts have vesicular nuclei with dispersed chromatin, a prominent nucleolus or nucleoli with loss of the perinuclear hof and some of the dense cytoplasmic texture and a high nucleocytoplasmic ratio [5]. Patients with plasmablastic myeloma have a median survival significantly shorter than for the other cytologic categories. It has been recently demonstrated by Hao et al. that bone marrow morphologic features, including diffuse sheet growth pattern, immature cell morphology, and high mitotic index, significantly correlates with high risk disease [6].\n\nIn approximately 2% of PCM cases, the morphology of the neo-plastic cells is highly pleomorphic, and may resemble that of metastatic epithelial tumor cells.\n\nAnaplastic cells, by definition, show a marked degree of cytological atypia and pleomorphism with loss of features that can identify any relationship with a normal counterpart/cell of origin. Anaplastic pleomorphic plasma cells mimicking dysplastic megakaryocytes and osteoclast giant cells (similar to our case) have been recently reported in the literature [7]. The plasmablastic and anaplastic morphological variants that do not bear any resemblance to plasma cells can be very difficult to recognize on morphology alone, which may complicate the diagnosis without the aid of immunophenotyping by flow cytometry or immunohistochemistry [8].\n\nAnaplastic myeloma variant has been reported to be more common in younger patients with a predisposition for the extramedullary site and poor prognosis. It may present initially at diagnosis [9,10] or as a feature of disease progression [11,12]. It is commonly associated with 1q21 amplification [13], 17p (p53) deletion, t(4;14), and/or chromosome 13 anomalies [14].\n\nMost cases of PCM typically have low proliferation rate with Ki67 reported to be less than 10% [15]. In contrast, morphologically aggressive PCM with extramedullary involvement has been found to show very high Ki67 proliferative index.\n\nThere has been much interest in proliferation fraction-based prediction of clinical behavior in myeloma since the work done by Drach et al. [16].\n\nIn 2015, Juskevicius et al. [17] reported a Ki67 index up to 55% to 96% in 5 patients with morphologically aggressive myeloma and/or extramedullary involvement. All showed 13q deletion and +1q and 80% of patients were relatively young (in their 50s) and had kappa light chain restriction with serum M band of less than 3 g/dL. There was one report of a rising Ki67 in serial samples that correlated with adverse clinical outcome [18] and a proposal that the plasma cell proliferation index in light chain myeloma should be treated by stem cell transplantation [19].\n\nPCM is a disease of the elderly and the incidence in patients younger than 30 years old is a very rare event. In 1976, Hewell et al. [20] described the first 3 well-documented cases of young patients with PCM, their ages ranged from 17 to 22 years with frequency of 1%.\n\nBlade et al. [21] reviewed the record of 3278 patient treated with PCM at the Mayo Clinic between 1956 and 1992; the incidence of PCM in patients less than 30 years of age accounted for 0.3%. An analysis of a large case series including 10 549 patients by Ludwig et al. [3] found that only 27 patients were reported to be less than 30 years old, with a frequency of 0.26% [3]. Sophia et al. recently described the clinicopathologic features of PCM in children and young adolescent [22].\n\nMost publications suggest that patients at a younger age present with more desirable features such as low International Staging System (ISS) and Durie-Salmon stage, good performance status, and absence of poor prognostic features as high C-reactive protein (CRP), anemia, and severe renal impairment and they have a better chance of survival [3,21,23] with rare exceptions reporting poor outcomes [24]. Hypercalcemia, thrombocytopenia, bone marrow plasmacytosis, and elevated serum LDH were associated with impaired survival among younger patients with myeloma.\n\nAs in the older age group, it appears that PCM in patients aged 30 years or less is a heterogeneous disease with some patients progressing rapidly despite therapy, and others remaining stable for years without treatment.\n\nThe median duration of survival for myeloma patients with standard cytogenetic risk is 8 to 10 years and 2 to 3 years for high-risk patients [25]. The survival of young patients with PCM was reported to be considerably longer than that of patients of all ages with PCM [21].\n\nIn contrast, young patients with anaplastic myeloma, as reported in this case, usually run an aggressive course with poor outcome even with novel therapy [26].\n\nThe poor outcome in our case could be attributed to several poor clinical and pathologic features including renal impairment at diagnosis, extensive bony lesions with extramedullary involvement, poor cytogenetics, and anaplastic morphology with very high proliferative index (Ki67 >90%).\n\nConclusions\nIn conclusion, our case demonstrates that although PCM is rare in patients younger than 30 years old, it must be considered in the differential diagnosis and investigated properly especially in patients with clinical suspicion of a metastatic non-hematological tumor. The anaplastic variant in a young patient is associated with the aggressive presentation, atypical morphology, adverse cytogenetics, resistance to chemo-therapy, and poor short-term survival. This case emphasizes the crucial role of the multidisciplinary approach in diagnosing hematological neoplasms. Prompt radiological and histo-pathological evaluation may help guide effective therapeutic interventions for aggressive cases.\n\nDr. Hasan Rivsi at University of Cambridge is acknowledged for his significant contribution to manuscript review.\n\nConflict of interests\n\nNone.\n\nAbbreviations\nPCMplasma cell myeloma;\n\nCTcomputed tomography;\n\nMRImagnetic resonance imaging\n\nFigure 1. Computed tomography (CT) scan. (A) Selective axial CT image showing expanding soft tissue density mass lesion with underlying right rib osseous destruction. (B) A small lytic lesion is noted within the diploic space of the left posterior bony calvarium.\n\nFigure 2. Magnetic resonance imaging (MRI). (A) Coronal SITR of the sacrum and sacroiliac joints showing multiple bright foci of infiltration are noted bilaterally involving the sacrum and iliac side of both sacroiliac joints. (B) Sagittal reconstruction of the dorso-lumbosacral spine (bone window setting) showing multiple hypodense lytic lesions notably at L5, D11, D10, D9 as well as the proximal sacral pieces.\n\nFigure 3. (A) Peripheral blood smear (50×) showing few circulating neoplastic cells of blastoid morphology. (B) Bone marrow aspirate smear showing cohesive clusters/sheets of neoplastic cells mimicking metastatic tumors. (C–F) The malignant cells are large to giant in size with irregular cytoplasmic boundaries, bizarre shaped nuclei with markedly irregular contours (multilobated/abnormally lobated or multinucleated) with hyperchromatic nuclei and very prominent nucleoli (100×).(G) Some scattered plasma cells with hyperchromatic nuclei (red arrows) with frequent mitotic figures noted (black arrows).\n\nFigure 4. Flow cytometry analysis revealed a population comprising approximately 11% of the total showing moderate side light scatter and high heterogeneous forward light scatter and negative for CD45. The population was positive for CD38 and CD138 indicative of plasma cell showing cytoplasmic kappa light chain restriction (monotypic) with aberrant surface kappa light chain expression and negative for CD56 and CD117.\n\nFigure 5. (A) Bone marrow biopsy specimen with hematoxylin and eosin stain (20×) shows core biopsy is diffusely infiltrated by sheets of neoplastic plasma cells. The cells are markedly pleomorphic, with marked nuclear irregularities, prominent nucleoli and some mitotic figures (black arrow). (B–E) Immunohistochemistry on core biopsy specimen (10×) shows (B) CD138 positive, (C) kappa: positive, (D) lambda: negative, and (E) Ki-67 (>90%).\n\nFigure 6. Representative karyotype of a metaphase cell with multiple numeric and structural abnormalities. ISCN nomenclature: 44,XY,i(9)(q10),-13,add(14)(q32),der(16)add(16)(p13q24),der(19)add(19)(p13.3),der(20)t(20;?)(p11;?)[20]/44,XY,dup(1) (q21q32),-13,add(14)(q32), der(16)add(16)(p13,q24),-19[6]/46,XY[4].\n==== Refs\nReferences:\n1. Michels TC Petersen KE Multiple myeloma: Diagnosis and treatment Am Fam Physician 2017 95 6 373 83 28318212 \n2. Kyle RA Gertz MA Witzig TE Review of 1027 patients with newly diagnosed multiple myeloma Mayo Clin Proc 2003 78 1 21 33 12528874 \n3. Ludwig H Durie BG Bolejack V Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: An analysis of 10 549 patients from the International Myeloma Working Group Blood 2008 111 8 4039 47 18268097 \n4. Masahiko F The histopathology of myeloma in the bone marrow J Clin Exp Hematop 2018 58 2 61 67 29998977 \n5. Rajkumar SV Dimopoulos MA Palumbo A International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol 2014 15 12 e538 48 25439696 \n6. Hao Y Khaykin D Machado L Bone marrow morphologic features, MyPRS, and gene mutation correlations in plasma cell myeloma Mod Pathol 2019 [Epub ahead of print] \n7. Xie W Tang G Li S Anaplastic multiple myeloma resembling dysplastic megakaryocytes Clin Case Rep 2019 00 1 2 \n8. Aasen G McKenna R Plasma cell neoplasms: Morphology and Immunohistochemistry Linden M McKenna R Plasma cell neoplasms Springer Cham, Switzerland 2016 43 64 \n9. Rao S Kar S Pati H Anaplastic myeloma: A morphologic diagnostic dilemma Indian J Hematol Blood Transfus 2008 24 4 188 89 23100962 \n10. Subitha K Renu T Lillykutty P Letha V Anaplastic myeloma presenting as mandibular swelling: Diagnosis by cytology J Cytol 2014 31 2 114 16 25210245 \n11. Foucar K Raber M Foucar E Anaplastic myeloma with massive extramedullar involvement: report of two cases Cancer 1983 51 1 166 74 6336972 \n12. Akihito F Yasuhiro N Naofumi Y Yuji K Morphological transformation of myeloma cells into multilobated plasma cell nuclei within 7 Days in a case of secondary plasma cell leukemia that finally transformed as anaplastic myeloma Case Rep Hematol 2017 2017 5758368 29430310 \n13. Bahmanyar M Qi X Chang H Genomic aberrations in anaplastic multiple myeloma: High frequency of 1q21 (CKS1B) amplifications Leuk Res 2013 37 12 1726 28 24169086 \n14. Sethi S Miller I Plasma cell myeloma with anaplastic transformation Blood 2016 128 16 2106 28157681 \n15. Marković O Marisavljević D Cemerikić V Proliferative activity of myeloma cells determined by Ki-67 antibody: Biological and clinical significance Vojnosanit Pregl 2005 62 1 33 38 15715347 \n16. Drach J Gattringer C Glassl H The biological and clinical significance of the Ki-67 growth fraction in multiple myeloma Hematol Oncol 1992 10 2 125 34 1592363 \n17. Juskevicius R Murthy H Dangott B Plasma cell myeloma with very high Ki67 proliferation rate: comparison of visual estimation and computational image analysis with description of clinical and pathologic features Am J Clin Pathol 2015 144 2 A132 \n18. Forsberg PA Mark TM Yadlapati S Rising plasma cell proliferation by Ki67/CD138 ratio at relapse is a marker of high-risk disease in multiple myeloma Blood 2015 126 23 2991 \n19. Sidiqi H Aljama MA Jevremovic D Plasma cell proliferative index predicts outcome in immunoglobulin light chain amyloidosis treated with stem cell transplantation Haematologica 2018 103 1229 34 29674497 \n20. Hewell G Alexanian R Multiple myeloma in young persons Ann Intern Med 1976 84 4 441 43 1259287 \n21. Bladé J Kyle R Greipp P Presenting features and prognosis in 72 patients with multiple myeloma who were younger than 40 years Br J Haematol 1996 93 2 345 51 8639427 \n22. Sophia Y Mark L Troy L Plasma cell myeloma in children and young adults: A report of 4 cases from a single institution and a review of the literature J Pediatr Hematol Oncol 2017 39 452 57 28719511 \n23. Corso A Klersy C Lazzarino M Bernasconi C Multiple myeloma in younger patients: The role of age as prognostic factor Ann Hematol 1998 76 2 67 72 9540760 \n24. Costello CL Multiple myeloma in patients under 40 years old is associated with high-risk features and worse outcomes Blood 2013 122 5359 \n25. Chng WJ Dispenzieri A Chim CS IMWG consensus on risk stratification in multiple myeloma Leukemia 2014 28 2 269 77 23974982 \n26. Ammannagari N Celotto K Neppalli V Anaplastic multiple myeloma: An aggressive variant with a poor response to novel therapies Clin Lymphoma Myeloma Leuk 2016 16 9 e129 31 27375159\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "21()",
"journal": "The American journal of case reports",
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"mesh_terms": "D017668:Age of Onset; D001854:Bone Marrow Cells; D019046:Bone Marrow Neoplasms; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D006801:Humans; D059785:Karyotype; D008297:Male; D009101:Multiple Myeloma; D010950:Plasma Cells; D055815:Young Adult",
"nlm_unique_id": "101489566",
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"pages": "e920489",
"pmc": null,
"pmid": "32152261",
"pubdate": "2020-03-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "28318212;28157681;18268097;24169086;23974982;29998977;28719511;23100962;1592363;6336972;12528874;9540760;25210245;15715347;25439696;1259287;8639427;29430310;31375765;29674497;27375159",
"title": "Plasma Cell Myeloma with an Aggressive Clinical Course and Anaplastic Morphology in a 22-Year-Old Patient: A Case Report and Review of Literature.",
"title_normalized": "plasma cell myeloma with an aggressive clinical course and anaplastic morphology in a 22 year old patient a case report and review of literature"
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{
"abstract": "BACKGROUND\nThe possibility of nicotine toxicity, although rare, should be considered in cases of acute edematous pancreatitis.\n\n\nMETHODS\nA 30-year-old woman was hospitalized to identify the cause of an initial episode of acute edematous pancreatitis. The observation of native anti-DNA and antiphospholipid antibodies suggested lupus pancreatitis and/or an antiphospholipid syndrome, both subsequently ruled out. The final diagnosis was nicotine poisoning induced by the combination of a nicotine patch and tobacco smoking.\n\n\nCONCLUSIONS\nAlthough a nicotine patch has never been reported in connection with an episode of acute pancreatitis before, this case suggests that such an event might be a rare complication of an overdose of nicotine.",
"affiliations": "Service de médecine interne et immunologie clinique, Hôpital Le Bocage, Bd de Lattre de Tassigny, 21000 Dijon. sabine.berthier@chu-dijon.fr",
"authors": "Berthier|S|S|;Michiels|C|C|;Sgro|C|C|;Bonnotte|B|B|;Lorcerie|B|B|",
"chemical_list": "D018722:Nicotinic Agonists; D009538:Nicotine",
"country": "France",
"delete": false,
"doi": "10.1016/s0755-4982(05)84044-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0755-4982",
"issue": "34(11)",
"journal": "Presse medicale (Paris, France : 1983)",
"keywords": null,
"medline_ta": "Presse Med",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D005260:Female; D006801:Humans; D009538:Nicotine; D018722:Nicotinic Agonists; D010195:Pancreatitis",
"nlm_unique_id": "8302490",
"other_id": null,
"pages": "795-6",
"pmc": null,
"pmid": "16097380",
"pubdate": "2005-06-18",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Acute nonalcoholic nonbiliary pancreatitis. Difficulties in diagnosis and possibility of nicotine toxicity.",
"title_normalized": "acute nonalcoholic nonbiliary pancreatitis difficulties in diagnosis and possibility of nicotine toxicity"
} | [
{
"companynumb": "FR-GLAXOSMITHKLINE-FR2018GSK093513",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NICOTINE"
},
"drugadditional": "1",
... |
{
"abstract": "Low-frequency epidermal growth factor receptor (EGFR) T790M mutation could be detected by ultrasensitive methods in EGFR tyrosine kinase inhibitor (TKI)-naïve non-small cell lung cancer (NSCLC). However, the impact of pretreatment T790M (preT790M) on the efficacy of EGFR-TKIs and on resistance remains unclear.\n\n\n\nTwo independent cohorts consisting of advanced EGFR-mutated NSCLC patients treated with first-line EGFR-TKIs, a derivation cohort that started treatment between August 2013 and July 2016 (cohort A, n = 44) and a validation cohort between August 2016 and December 2017 (cohort B, n = 22), were examined in this study. Among these, 28 patients underwent re-biopsy at disease progression. DNAs from pretreatment tumor biopsy samples and re-biopsy samples were assessed to detect T790M by the Cobas EGFR Mutation Test v2 (Cobas) and for quantitating T790M by droplet digital polymerase chain reaction (ddPCR).\n\n\n\nDetection rates of preT790M were 40.9% (18/44) in cohort A and 45.5% (10/22) in cohort B by ddPCR, and none by Cobas. A cutoff value of 0.3% for dividing into high- vs. low-preT790M allele frequency was determined by receiver operating characteristic curve analysis in cohort A. Progression-free survival (PFS) was significantly shorter in the high- preT790M group (n = 12) than in the low-preT790M (n = 6) and negative (n = 26) groups (combined low-preT790M) (median: 6.9 vs. 13.8 months, P = 0.00073). These observations were validated in cohort B [median: 6.2 (n = 5) vs. 15.3 months (n = 17), P = 0.0029]. In 28 paired biopsies, Cobas detected post-progression T790M in 60% (3/5) of the high-preT790M, in 57% (4/7) of the low-preT790M, and in 56% (9/16) of the negative-preT790M groups.\n\n\n\nEGFR-mutated NSCLC with high preT790M had significantly shorter PFS on EGFR-TKIs. However, preT790M abundance may not necessarily confer post-TKI T790M resistance.",
"affiliations": "Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan; Internal Medicine III, Wakayama Medical University, Wakayama, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan.;Laboratory of Statistics, Graduate School of Medicine, Osaka City University, Osaka, Japan.;Internal Medicine III, Wakayama Medical University, Wakayama, Japan.;Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, Japan.;Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan.;Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, Japan.;Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan.;Department of Premier Preventive Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan.;Internal Medicine III, Wakayama Medical University, Wakayama, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan.;Internal Medicine III, Wakayama Medical University, Wakayama, Japan. Electronic address: ykoh@wakayama-med.ac.jp.;Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan; Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, Japan.",
"authors": "Matsumoto|Yoshiya|Y|;Sawa|Kenji|K|;Fukui|Mitsuru|M|;Oyanagi|Jun|J|;Yoshimoto|Naoki|N|;Suzumura|Tomohiro|T|;Watanabe|Tetsuya|T|;Kaneda|Hiroyasu|H|;Mitsuoka|Shigeki|S|;Asai|Kazuhisa|K|;Kimura|Tatsuo|T|;Yamamoto|Nobuyuki|N|;Hirata|Kazuto|K|;Koh|Yasuhiro|Y|;Kawaguchi|Tomoya|T|",
"chemical_list": "D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2019.10.029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "139()",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Droplet digital polymerase chain reaction; Epidermal growth factor receptor; Non-small cell lung cancer; Pretreatment T790M",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung; D066246:ErbB Receptors; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D011379:Prognosis; D047428:Protein Kinase Inhibitors; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "80-88",
"pmc": null,
"pmid": "31751804",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Predictive impact of low-frequency pretreatment T790M mutation in patients with EGFR-mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors.",
"title_normalized": "predictive impact of low frequency pretreatment t790m mutation in patients with egfr mutated non small cell lung cancer treated with egfr tyrosine kinase inhibitors"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-119823",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"dr... |
{
"abstract": "The infiltration and invasion of nerve trunks, nerve roots, and cranial nerves by lymphomatous malignant cells is defined as \"neurolymphomatosis\". It is mainly caused by lymphoma cells directly infiltrating the peripheral nerves, with a low incidence. Neurolymphomatosis is a rare condition of neoplastic endoneurial invasion, which is primary or secondary to non-Hodgkin's lymphoma and leukemia. We describe a case of primary peripheral neurolymphomatosis of multifocal involvement in a 77-year-old male patient. He presented with left lower limb pain and was diagnosed with CD20+ diffuse large B cell lymphoma (DLBCL). Magnetic resonance imaging (MRI), fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) computed tomography (CT), and nerve biopsy contributed to the diagnosis. Genomic profiling, programmed death ligand-1 (PD-L1) expression and tumor mutational burden (TMB) were also assessed. CDKN2A/CDKN2B deletions have been identified. PD-L1 expression assessed by 28-8 antibody was 1% positivity, and TMB of the sample was 11.6 muts/Mb. The patient responded well to rituximab combined with chemotherapy, however, he died after 3 cycles of chemotherapy due to severe lung infection and subsequent complication of respiratory failure. Here we report the clinical, radiological, pathological and molecular findings of the patient affected by multifocal neurolymphomatosis without systemic involvement of other organs.",
"affiliations": "Department of Respiratory Disease, Zhejiang Provincial People's Hospital, Hangzhou, China.;Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Department of Radiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK.;Department of Orthopedics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.",
"authors": "Peng|Ling|L|;Yang|Hanjin|H|;Zhao|Yilei|Y|;He|Jingsong|J|;Stebbing|Justin|J|;Chen|Bin|B|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/apm-21-2256",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2224-5820",
"issue": null,
"journal": "Annals of palliative medicine",
"keywords": "Neurolymphomatosis; case report; lymphoma; next generation sequencing (NGS); peripheral nerve",
"medline_ta": "Ann Palliat Med",
"mesh_terms": null,
"nlm_unique_id": "101585484",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34670378",
"pubdate": "2021-10-18",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Neurolymphomatosis of multifocal peripheral nerve involvement: a case report.",
"title_normalized": "neurolymphomatosis of multifocal peripheral nerve involvement a case report"
} | [
{
"companynumb": "CN-ROCHE-2977321",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "A 44-year-old man who was previously diagnosed with actinic cheilitis was prescribed imiquimod cream 5%, which resulted in thick hemorrhagic crusting of the lower lip after 4 applications. He subsequently noted the development of lichen planus lesions on his arms and legs for the first time in 15 years following imiquimod use. On follow-up he also was noted to have characteristic Wickham striae on his lower lip. Lichen planus is an autoimmune inflammatory condition in which autoreactive T lymphocytes attack keratinocytes. The mechanism of action for imiquimod is upregulation of IFN-alpha and IFN-beta. Treatment with clobetasol cream 0.05% led to resolution of his lichen planus lesions.",
"affiliations": "Division of Dermatology, University of Massachusetts Medical School, Worcester, MA 01605, USA. mark.scharf@umassmemorial.org",
"authors": "Domingues|Erik|E|;Chaney|Keri C|KC|;Scharf|Mark J|MJ|;Wiss|Karen|K|",
"chemical_list": "D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000893:Anti-Inflammatory Agents; D002990:Clobetasol; D000077271:Imiquimod",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-4162",
"issue": "89(6)",
"journal": "Cutis",
"keywords": null,
"medline_ta": "Cutis",
"mesh_terms": "D000276:Adjuvants, Immunologic; D000287:Administration, Topical; D000328:Adult; D000634:Aminoquinolines; D000893:Anti-Inflammatory Agents; D002613:Cheilitis; D002990:Clobetasol; D005500:Follow-Up Studies; D006801:Humans; D000077271:Imiquimod; D008010:Lichen Planus; D008046:Lip; D008297:Male; D016896:Treatment Outcome",
"nlm_unique_id": "0006440",
"other_id": null,
"pages": "276-7, 283",
"pmc": null,
"pmid": "22838091",
"pubdate": "2012-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Imiquimod reactivation of lichen planus.",
"title_normalized": "imiquimod reactivation of lichen planus"
} | [
{
"companynumb": "US-BAUSCH-BL-2020-020436",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMIQUIMOD"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nThe association of patient foramen ovale (PFO) and migraine headache (migraine) with aura (MA) is well established. Current research suggests a mechanistic link between platelet activation, paradoxical embolization and migraine in some patients.\n\n\nMETHODS\nClopidogrel, a platelet inhibitor, was added to existing migraine therapy, as a 4-week open-label trial in 15 women, aged 16-56 years, with severe migraine and documented right to left shunt (RLS).\n\n\nRESULTS\n13/15 had > 50% reduction or complete elimination of migraine symptoms. After completing the trial period, five responders remain on clopidogrel with ongoing benefit at 11.9 ± 4.5 months (6.5-20), one stopped clopidogrel because of side effects. Nine other responders underwent PFO closure and clopidogrel discontinuation. Eight of nine have had ongoing benefit.\n\n\nCONCLUSIONS\nClopidogrel may have a primary prophylactic role in migraine/RLS patients, but may also help select candidates who would benefit from PFO closure. A randomized clinical trial is being established.",
"affiliations": "Herbert and Sandi Feinberg Interventional Cardiology and Heart Valve Center, Columbia University Medical Center, New York-Presbyterian Hospital, Center for Interventional Cardiovascular Therapy, NY, USA.;Herbert and Sandi Feinberg Interventional Cardiology and Heart Valve Center, Columbia University Medical Center, New York-Presbyterian Hospital, Center for Interventional Cardiovascular Therapy, NY, USA.;Herbert and Sandi Feinberg Interventional Cardiology and Heart Valve Center, Columbia University Medical Center, New York-Presbyterian Hospital, Center for Interventional Cardiovascular Therapy, NY, USA rs2463@columbia.edu.",
"authors": "Spencer|Barbara T|BT|;Qureshi|Yasir|Y|;Sommer|Robert J|RJ|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine",
"country": "England",
"delete": false,
"doi": "10.1177/0333102414523845",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0333-1024",
"issue": "34(11)",
"journal": "Cephalalgia : an international journal of headache",
"keywords": "Clopidogrel; migraine headache; patent foramen ovale",
"medline_ta": "Cephalalgia",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000077144:Clopidogrel; D005260:Female; D054092:Foramen Ovale, Patent; D006801:Humans; D008875:Middle Aged; D020325:Migraine with Aura; D010975:Platelet Aggregation Inhibitors; D013988:Ticlopidine; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8200710",
"other_id": null,
"pages": "933-7",
"pmc": null,
"pmid": "24770421",
"pubdate": "2014-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "A retrospective review of clopidogrel as primary therapy for migraineurs with right to left shunt lesions.",
"title_normalized": "a retrospective review of clopidogrel as primary therapy for migraineurs with right to left shunt lesions"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/14/0040495",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditiona... |
{
"abstract": "Herbal remedies adulterated with glucocorticoids can cause Cushing's syndrome. We report a severe presentation of a 'herbal remedy' adulterated with glucocorticoids; causing a potentially fatal adrenal crisis precipitated by acute illness. Investigations were consistent with adrenal suppression and confirmed, after tablet analysis, to be due to a 'herbal remedy' containing synthetic betamethasone/dexamethasone. This case highlights the need for clinical vigilance and patient education about the potential risks associated with the use of unlicensed treatments and the role of tablet analysis in routine biochemistry.",
"affiliations": "Chemical Pathology, Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, UK.;Endocrinology and Diabetes, New Cross Hospital, Wolverhampton, UK.;Chemical Pathology, New Cross Hospital, Wolverhampton, UK.;Chemical Pathology, New Cross Hospital, Wolverhampton, UK.",
"authors": "Sensi|Harminder|H|;Buch|Harit|H|;Ford|Loretta|L|;Gama|Rousseau|R|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D006854:Hydrocortisone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228443",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(2)",
"journal": "BMJ case reports",
"keywords": "adrenal disorders; endocrine system",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D000309:Adrenal Insufficiency; D000359:Aftercare; D000893:Anti-Inflammatory Agents; D004340:Drug Contamination; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D007362:Intensive Care Units; D008875:Middle Aged; D010154:Pakistan; D008517:Phytotherapy; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30787026",
"pubdate": "2019-02-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29587734;29796686;19011006;27218272;28432185;25969663;11772128;21892916;18797616;28361161;15539672;12480390;15850848;22292789;20719838;25606172;24454289;2762789",
"title": "Acute adrenal failure: a potentially fatal consequence of an adulterated herbal remedy.",
"title_normalized": "acute adrenal failure a potentially fatal consequence of an adulterated herbal remedy"
} | [
{
"companynumb": "GB-RICON PHARMA, LLC-RIC201903-000172",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional... |
{
"abstract": "Acute generalized exanthematous pustulosis (AGEP) is seen uncommonly in children and sometimes shows atypical clinical features in this population. Patch testing can be used effectively in children for the confirmation of the culprit drug in cases of multiple drug use. Here, we report a rare, pediatric case of ceftriaxone-induced AGEP confirmed by patch testing with subsequent recurrence of the skin eruption.",
"affiliations": "Department of Dermatology, Marmara University School of Medicine, Istanbul, Turkey.;Department of Dermatology, Marmara University School of Medicine, Istanbul, Turkey.;Department of Dermatology, Marmara University School of Medicine, Istanbul, Turkey.;Division of Pediatric Infectious Diseases, Marmara University School of Medicine, Istanbul, Turkey.",
"authors": "Salman|Andac|A|https://orcid.org/0000-0002-6407-926X;Yucelten|Deniz|D|;Akin Cakici|Ozlem|O|;Kepenekli Kadayifci|Eda|E|",
"chemical_list": "D002443:Ceftriaxone; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13838",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "36(4)",
"journal": "Pediatric dermatology",
"keywords": "acute generalized exanthematous pustulosis; allergy; ceftriaxone; drug reaction; patch testing",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D002443:Ceftriaxone; D002675:Child, Preschool; D004342:Drug Hypersensitivity; D006801:Humans; D008297:Male; D008586:Meningitis, Pneumococcal; D008775:Methylprednisolone; D010328:Patch Tests; D011379:Prognosis; D035583:Rare Diseases; D012008:Recurrence; D018570:Risk Assessment; D016896:Treatment Outcome",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "514-516",
"pmc": null,
"pmid": "31050838",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acute generalized exanthematous pustulosis due to ceftriaxone: Report of a pediatric case with recurrence after positive patch test.",
"title_normalized": "acute generalized exanthematous pustulosis due to ceftriaxone report of a pediatric case with recurrence after positive patch test"
} | [
{
"companynumb": "TR-STRIDES ARCOLAB LIMITED-2019SP007327",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditio... |
{
"abstract": "Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.",
"affiliations": null,
"authors": "Ichikawa|Yoshihiko|Y|;Ghanefar|Mohsen|M|;Bayeva|Marina|M|;Wu|Rongxue|R|;Khechaduri|Arineh|A|;Naga Prasad|Sathyamangla V|SV|;Mutharasan|R Kannan|RK|;Naik|Tejaswitha Jairaj|TJ|;Ardehali|Hossein|H|",
"chemical_list": "C571883:ABCB8 protein, mouse; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D059005:Topoisomerase II Inhibitors; D064730:Dexrazoxane; D004317:Doxorubicin; D007501:Iron; D004250:DNA Topoisomerases, Type II; D003676:Deferoxamine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-9738",
"issue": "124(2)",
"journal": "The Journal of clinical investigation",
"keywords": null,
"medline_ta": "J Clin Invest",
"mesh_terms": "D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D003433:Crosses, Genetic; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D003676:Deferoxamine; D064730:Dexrazoxane; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D004452:Echocardiography; D006321:Heart; D006439:Hemodynamics; D006801:Humans; D007501:Iron; D015227:Lipid Peroxidation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria; D032383:Myocytes, Cardiac; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D059005:Topoisomerase II Inhibitors",
"nlm_unique_id": "7802877",
"other_id": null,
"pages": "617-30",
"pmc": null,
"pmid": "24382354",
"pubdate": "2014-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "14564513;19017630;2203071;11731422;20850381;17219451;12644586;12894526;12237336;22900902;22375032;9145923;9748552;9505340;21605084;6805506;19010377;19307704;23104132;8280612;8409700;9193323;11179439;17044806;20016527;8945928;15883202;9549639;14642395;15837802;17009097;12805055;4005257;2125530;7987999;17599610;14501028;17290056;9768818;11829750;21239834;18029550;12678762;17652819;16259955;6243966;11042600;18434588;17875725",
"title": "Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.",
"title_normalized": "cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation"
} | [
{
"companynumb": "US-JNJFOC-20140513047",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "To describe the clinical presentation, diagnosis, and outcomes of patients with biopsy-proven acute interstitial nephritis (AIN) related to fluoroquinolone (FQ) therapy.\n\n\n\nWe conducted a retrospective review of biopsy-proven AIN attributed to FQ use at Mayo Clinic's campus in Rochester, Minnesota, from January 1, 1993, through December 31, 2016. Cases were reviewed by a renal pathologist and attributed to FQ use by an expert nephrologist. We also reviewed and summarized all published case reports of biopsy-proven AIN that were attributed to FQ use.\n\n\n\nWe identified 24 patients with FQ-related biopsy-proven AIN at our institution. The most commonly prescribed FQ was ciprofloxacin in 17 patients (71%), and the median antibiotic treatment duration was 7 days (interquartile range [IQR], 5-12 days). The median time from the initiation of FQ to the diagnosis of AIN was 8.5 days (IQR, 3.75-20.75 days). Common clinical manifestations included fever (12; 50%), skin rash (5; 21%), and flank pain (2; 8%), and 9 (38%) had peripheral eosinophilia. However, 4 (17%) of the patients were asymptomatic at the time of diagnosis and AIN was suspected on the basis of routine laboratory monitoring. Most patients (17; 71%) recovered after the discontinuation of antibiotic therapy, and renal function returned to baseline at a median of 20.5 days (IQR, 11.75-27.25 days). Six patients (25%) required temporary hemodialysis, and 14 patients (58%) received corticosteroid therapy.\n\n\n\nThe onset of FQ-related AIN can be delayed, and a high index of suspicion is needed by physicians evaluating these patients. Overall outcomes are favorable, with recovery to baseline renal function within 3 weeks of discontinuing the offending drug.",
"affiliations": "Division of Infectious Diseases, Mayo Clinic, Rochester, MN.;Division of Infectious Diseases, Mayo Clinic, Rochester, MN.;Division of Infectious Diseases, Mayo Clinic, Rochester, MN.;Divison of Nephrology, Mayo Clinic, Rochester, MN.;Division of Anatomic Pathology, Mayo Clinic, Rochester, MN.;Division of Infectious Diseases, Mayo Clinic, Rochester, MN.;Divison of Nephrology, Mayo Clinic, Rochester, MN.;Division of Infectious Diseases, Mayo Clinic, Rochester, MN; Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN. Electronic address: sohail.muhammad@mayo.edu.",
"authors": "Farid|Saira|S|;Mahmood|Maryam|M|;Abu Saleh|Omar M|OM|;Hamadah|Abdurrahman|A|;Nasr|Samih H|SH|;Garrigos|Zerelda Esquer|ZE|;Leung|Nelson|N|;Sohail|M Rizwan|MR|",
"chemical_list": "D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones",
"country": "England",
"delete": false,
"doi": "10.1016/j.mayocp.2017.08.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-6196",
"issue": "93(1)",
"journal": "Mayo Clinic proceedings",
"keywords": null,
"medline_ta": "Mayo Clin Proc",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D008297:Male; D008875:Middle Aged; D008910:Minnesota; D009395:Nephritis, Interstitial; D012189:Retrospective Studies",
"nlm_unique_id": "0405543",
"other_id": null,
"pages": "25-31",
"pmc": null,
"pmid": "29157532",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Manifestations and Outcomes of Fluoroquinolone-Related Acute Interstitial Nephritis.",
"title_normalized": "clinical manifestations and outcomes of fluoroquinolone related acute interstitial nephritis"
} | [
{
"companynumb": "US-MYLANLABS-2018M1006329",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALLOPURINOL"
},
"drugadditional": "3",
... |
{
"abstract": "We report the observation of a patient who presented with post-transplant Kaposi's sarcoma after a delay of eight months with a dual cutaneous and palatal localisation. The reduction in immunosuppressive treatment and the introduction of Rapamune® allowed good clinical progress initially with regression of the skin lesions. He subsequently presented later a skin relapse with visceral localisation. Chemotherapy was conducted based on weekly paclitaxel infusions allowing partial remission and maintenance of renal graft function with good clinical tolerance.",
"affiliations": "Faculté de médecine de Tunis, université de Tunis El Manar, 1007 Tunis, Tunisie; Service de médecine A, hôpital Charles-Nicolle, 1006 Tunis, Tunisie. Electronic address: amel.harzallah@fmt.utm.tn.;Faculté de médecine de Tunis, université de Tunis El Manar, 1007 Tunis, Tunisie; Service de médecine A, hôpital Charles-Nicolle, 1006 Tunis, Tunisie.;Faculté de médecine de Tunis, université de Tunis El Manar, 1007 Tunis, Tunisie; Service de médecine A, hôpital Charles-Nicolle, 1006 Tunis, Tunisie.;Faculté de médecine de Tunis, université de Tunis El Manar, 1007 Tunis, Tunisie; Service de médecine A, hôpital Charles-Nicolle, 1006 Tunis, Tunisie.;Faculté de médecine de Tunis, université de Tunis El Manar, 1007 Tunis, Tunisie; Service de médecine A, hôpital Charles-Nicolle, 1006 Tunis, Tunisie.;Faculté de médecine de Tunis, université de Tunis El Manar, 1007 Tunis, Tunisie; Service de médecine A, hôpital Charles-Nicolle, 1006 Tunis, Tunisie.;Service de médecine A, hôpital Charles-Nicolle, 1006 Tunis, Tunisie; Laboratoire de pathologie rénale LR00SP01, hôpital Charles-Nicolle, 1006 Tunis, Tunisie.;Faculté de médecine de Tunis, université de Tunis El Manar, 1007 Tunis, Tunisie; Service de médecine A, hôpital Charles-Nicolle, 1006 Tunis, Tunisie.;Faculté de médecine de Tunis, université de Tunis El Manar, 1007 Tunis, Tunisie; Service de médecine A, hôpital Charles-Nicolle, 1006 Tunis, Tunisie.",
"authors": "Harzallah|Amel|A|;Ounissi|Mondher|M|;Hajji|Meriem|M|;Chargui|Soumaya|S|;Hedri|Hafedh|H|;Abderrahim|Ezzeddine|E|;Ben Hamida|Fathi|F|;Bacha|Mongi|M|;Ben Abdallah|Taieb|T|",
"chemical_list": "D007166:Immunosuppressive Agents; D017239:Paclitaxel",
"country": "France",
"delete": false,
"doi": "10.1016/j.nephro.2020.10.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1769-7255",
"issue": "17(2)",
"journal": "Nephrologie & therapeutique",
"keywords": "Kaposi's sarcoma; Kidney transplantation; Paclitaxel; Sarcome de Kaposi; Transplantation rénale",
"medline_ta": "Nephrol Ther",
"mesh_terms": "D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D012514:Sarcoma, Kaposi",
"nlm_unique_id": "101248950",
"other_id": null,
"pages": "132-136",
"pmc": null,
"pmid": "33563572",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Successful treatment with paclitaxel of a visceral relapse of post-transplant Kaposi's sarcoma.",
"title_normalized": "successful treatment with paclitaxel of a visceral relapse of post transplant kaposi s sarcoma"
} | [
{
"companynumb": "TN-ACCORD-218827",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
"druga... |
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