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"abstract": "Gastrointestinal bleeding is an overwhelming complication of patients taking antithrombotic agents. These drugs pose a challenge to physicians in the management of bleeding to establish hemostasis without putting these patients at a higher risk for thromboembolism. This study aims to propose an algorithmic approach to four major groups of patients receiving antithrombotic agents (single antiplatelet agents, dual antiplatelet agents, anticoagulants and direct oral anticoagulants) to decide when and how these drugs should be held or restarted to offset between the risk of re-bleeding and thromboembolism. Four case-based algorithms are proposed in this article based on some relevant articles. Having designed four case-based algorithms, we are hoping to guide physicians who face a dilemma on the management of patients receiving antithrombotics when gastrointestinal bleeding occurs. Patients using antithrombotics referred for gastrointestinal bleeding were stratified into four groups based on the medication which is used as an antithrombotic agent and four algorithms were designed which are presented here. We have made an attempt to have a stepwise approach to four cases relevant to the study and have an evaluation on the management of their antithrombotic agents during an episode of gastrointestinal bleeding. It is widely accepted that antithrombotic agents should be restarted as soon as possible after the establishment of hemostasis in a patient taking antithrombotics referring for gastrointestinal bleeding. The time for resuming these drugs is different based on the severity of bleeding, the probability of thromboembolic events, and the nature of the antithrombotic medication which is used by the patient.",
"affiliations": "Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.",
"authors": "Sadeghi|Amir|A|;Zali|Mohammad Reza|MR|;Mohaghegh Shalmani|Hamid|H|;Ketabi Moghadam|Pardis|P|;Rajabnia Chenari|Mohsen|M|;Karimi|Mohammad Ali|MA|;Salari|Sina|S|;Asadzadeh-Aghdaei|Hamid|H|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nGastroenterol Hepatol Bed Bench\nGastroenterol Hepatol Bed Bench\nGHFBB\nGastroenterology and Hepatology From Bed to Bench\n2008-2258 2008-4234 Shaheed Beheshti University of Medical Sciences Tehran, Iran \n\nGHFBB-13-S8\nReview Article\nAn algorithmic approach to gastrointestinal bleeding in patients receiving antithrombotic agents \nSadeghi Amir 1 Zali Mohammad Reza 1 Mohaghegh Shalmani Hamid 1 Ketabi Moghadam Pardis 1 Rajabnia Chenari Mohsen 1 Karimi Mohammad Ali 1 Salari Sina 3 Asadzadeh-Aghdaei Hamid 2 \n1 \nGastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran\n\n\n2 \nBasic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran\n\n\n3 \nTaleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran \n\nReprint or Correspondence: Hamid Asadzadeh Aghdaei, MD. Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Disease, Shahid Beheshti University of Medical Sciences, Tehran, Iran. E-mail: hamid.assadzadeh@gmail.com, ORCID ID: 0000-0002-9382-9840\nWinter 2020 \n13 Suppl1 S8 S17\n28 5 2020 18 7 2020 ©2020 RIGLD, Research Institute for Gastroenterology and Liver Diseases This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Gastrointestinal bleeding is an overwhelming complication of patients taking antithrombotic agents. These drugs pose a challenge to physicians in the management of bleeding to establish hemostasis without putting these patients at a higher risk for thromboembolism. This study aims to propose an algorithmic approach to four major groups of patients receiving antithrombotic agents (single antiplatelet agents, dual antiplatelet agents, anticoagulants and direct oral anticoagulants) to decide when and how these drugs should be held or restarted to offset between the risk of re-bleeding and thromboembolism. Four case-based algorithms are proposed in this article based on some relevant articles. Having designed four case-based algorithms, we are hoping to guide physicians who face a dilemma on the management of patients receiving antithrombotics when gastrointestinal bleeding occurs. Patients using antithrombotics referred for gastrointestinal bleeding were stratified into four groups based on the medication which is used as an antithrombotic agent and four algorithms were designed which are presented here. We have made an attempt to have a stepwise approach to four cases relevant to the study and have an evaluation on the management of their antithrombotic agents during an episode of gastrointestinal bleeding. It is widely accepted that antithrombotic agents should be restarted as soon as possible after the establishment of hemostasis in a patient taking antithrombotics referring for gastrointestinal bleeding. The time for resuming these drugs is different based on the severity of bleeding, the probability of thromboembolic events, and the nature of the antithrombotic medication which is used by the patient.\n\nKey Words\nAlgorithmsGastrointestinal bleedingThromboembolic eventsAntithrombotic agents\n==== Body\nIntroduction\n Management of gastrointestinal (GI) bleeding for patients taking antithrombotic agents including antiplatelet drugs, anticoagulants and direct oral anticoagulants (DOACs) has always been challenging. Although there is a general agreement on the management of active bleeding in this situation, more studies are required to come to a consensus as to when and how antithrombotic agents should be reintroduced. To make restarting these antithrombotic agents justifiable in a patient with recent gastrointestinal bleeding, the risk of re-bleeding in contrast to the benefit of a decrease in the percentage of thrombotic events should be assessed individually. Base on the revised guidelines, the benefit of reinstating these agents outweigh the risk of withholding them for a long time (1,2). The risk of thromboembolism and also the risk of bleeding in patients on antithrombotic agents who referred for GI bleeding in this guideline review is stratified based on previous studies (2-4). The characteristics of a major GI bleeding is shown in table-1. It should be noted that one of these criteria is sufficient to label a bleeding event as a major bleeding (2,5). High-risk thromboembolic events are presented in table-2. One of the situations mentioned in table-2 is required to categorize a patient in the high-risk thromboembolic events (2,5,6). In the present study, we have attempted a case-based approach to the management of patients receiving antithrombotic agents who referred for gastrointestinal bleeding based on the risk stratification for GI bleeding and thromboembolism as depicted in table-1&2.\n\nTable 1 Characteristics of a major GI bleeding\n\nVomiting or passage of a large amount of fresh blood, maroon blood or black tarry stool through the rectum,\t\nShock and hemodynamic instability,\t\nA sudden drop in hemoglobin level to 6 gr/dl or less,\t\nRequiring transfusion of at least 4 units of packed RBCs,\t\nBleeding continuing for at least 3 days,\t\nA significant re-bleeding in 1 week,\t\nHigh risk stigmata of bleeding in endoscopy including lesions with active bleeding (spurting or oozing), non-bleeding visible vessels, adherent clots.\t\nTable 2 Patients of high-risk thromboembolic events\n\n\n\n\t\n\nAlgorithms\n\n\n\nPatients on dual antiplatelet therapy\n\n\n1. A 67-year-old man presented to the general gastroenterology clinic with complaints of profuse melena for 3 days. He had a history of coronary artery disease with earlier percutaneous coronary intervention with drug-eluting stent implantation 5 months before. Then, he was started on a dual antiplatelet therapy with aspirin and clopidogrel. On arrival, he was hemodynamically unstable with hypotension, tachycardia and clouding of consciousness. Before transfusion, Hb level was 5.9 gr/dl. Besides standard medical treatments, an examination with flexible endoscope was performed which was notable for a large ulcer with oozing in antrum. Esophagus, stomach and duodenum were all full of blood and blood clot. Initially, diluted epinephrine (1/10,000) was injected and then 2 endoscopic hemoclips were inserted and oozing stopped.\n\nAntiplatelet agents are used as primary and secondary preventive drugs of choice for arterial thrombosis in patients with certain medical conditions to prevent disastrous consequences in coronary artery, as well as cerebrovascular and peripheral vascular diseases. Dual antiplatelet therapy using aspirin (a non-selective cyclooxygenase inhibitor) plus a P2Y12 inhibitor such as clopidogrel, ticagrelor or prasugrel is suggested for especial situations in order to obtain a better antiplatelet effect than it is anticipated by single antiplatelet therapy (7). Patients with coronary artery disease with a history of stent placement are at risk for thrombosis and restenosis particularly during the first months of a drug-eluting stent placement and the first month of a bare-metal stent implantation. Generally, it is accepted that a combined antiplatelet therapy should be continued for 12 months in patients with a drug-eluting, and 1 month for those with a bare-metal stent.(8) GI bleeding is an overwhelming complication of dual antiplatelet therapy leading to withholding antiplatelet drugs. Generally, withholding both antiplatelet agents simultaneously is not recommended. The median time to coronary stent thrombosis is estimated as short as 7 days for the discontinuation of both drugs compared with 122 days for only clopidogrel withholding (9). Overall, it is recommended that aspirin be continued and Y2P12 inhibitors be omitted during an acute phase of a major GI bleeding because of an interaction between this class of medication with proton pump inhibitors (PPIs). Both PPIs and clopidogrel are metabolized by CY2C19 pathway (10). The point is when and how we can reintroduce these agents to offset the risk and benefit of restarting antiplatelet agents. The second drug is suggested to be reintroduced 3-5 days after discontinuation. Ticagrelor is preferably started 3 days after hemostasis but restarting of clopidogrel and prasugrel would be deferred up to 5 days. This difference is attributed to the mechanism of action of ticagrelor in contrast to clopidogrel and prasugrel which is a reversible P2Y12 receptor inhibitor with a platelet function returning of about 3–5 days after discontinuation. The latter drugs are irreversible inhibitors of P2Y13 receptor requiring at least 5-7 days for platelet function recovery (11-13) Studies have shown that initiation of antiplatelet agents in this stage would decrease the risk of restenosis although it does not increase the risk of re-bleeding (1,2). There is a general agreement on the continuation of these drugs if GI bleeding is minor (11). Vorapaxar, a new anti-platelet agent, is a protease-activated receptor (PAR-1) antagonist that inhibits thrombin receptor. It is indicated in patients with a history of myocardial infarction or peripheral arterial disease but is contraindicated in patients with a history of stroke, transient ischemic attack or intracranial hemorrhage because of the risk of intracranial hemorrhage. Besides these suggestions for acute phase of bleeding, it is suggested that antiplatelet agents be withdrawn for patients using them as primary prevention under supervision of a cardiologist as a long-term therapy. Trials in Japan on primary prevention of cardiovascular events by aspirin have not shown any benefit for aspirin in the reduction of cardiovascular events (14). It is in contrast to the study of Souk et al. which shows a protective effect even beyond cardiovascular benefits for aspirin usage as a primary prophylaxis for coronary artery diseases and cerebrovascular diseases in non-variceal GI bleedings (15). The present study is in line with the first approach and recommends discontinuation of aspirin as a primary prophylaxis if possible. It is also recommended that aspirin be prescribed with a lower dose. Furthermore, it is suggested that patients on ticagrelor or prasugrel as more potent antithrombotic agents but with a higher risk of bleeding be switched to the clopidogrel (16,6). PPI consumption and H.pylori eradication should be taken into consideration too. Initial usage of IV PPI after upper gastrointestinal bleeding is highly recommended by ESGE guideline and it is advised that PPI infusion be continued for 72 hours from gastrointestinal bleeding due to anti-platelet therapy. Oral PPI therapy should be considered after reinitiating antiplatelet therapy (17). Management of GI bleeding in patients receiving dual antiplatelet therapy has been depicted in figure-1. Based on the mentioned tips, the presented case whose clinical scenario and endoscopic findings were suggestive of a major bleeding (unstable hemodynamic and peptic ulcer disease with oozing) in the background of a high probability for thromboembolic events (implantation of drug-eluting stent in the last 5 months) drove us to withhold clopidogrel and continue aspirin. After resuscitation with IV fluids, endoscopic hemostasis was successfully performed. He was transferred to ICU and went on IV PPI therapy. Three days after hemostasis, he was not found to have an Hb drop and he continued to remain stable. A second-look endoscopy revealed inserted hemoclips without bleeding. He was sent to general gastroenterology ward and was restarted on clopidogrel after 5 days of index GI bleeding. H.pylori eradication was considered for him and he was advised to take oral PPI while taking dual antiplatelet therapy.\n\nFigure 1 The algorithm for the management of GI bleeding in patients taking dual antiplatelet therapy\n\n\nPatients on single antiplatelet therapy\n\n\n2. A 51-year-old woman was admitted to the emergency department with severe and non-stop hematemesis after a long episode of intractable vomiting unresponsive to antiemetic agents. Her past medical history was remarkable for diabetes mellitus and hypertension. So, she had been advised to take daily low-dose aspirin. On admission, she was noted to be orthostatic and hemodynamically unstable requiring packed cell transfusion. After resuscitation, she was transferred to the endoscopy unit which revealed a mallory weiss tearing with visible vessel in distal part of esophagus and a large amount of fresh blood in the stomach. An endoscopic hemoclip was inserted and no further bleeding was detected. \n\nThe management of a patient receiving single antiplatelet agent is somehow different from patients on dual antiplatelet drugs. A review of relevant studies shows that aspirin can safely be continued in minor GI bleedings. In contrast to minor bleedings, risk-benefit assessment of patients with major GI bleedings has proposed discontinuation of aspirin before endoscopy. Reinstating of aspirin 3-7 days after index bleeding has not added the risk of re-bleeding as well as thrombosis based on recent studies (18). Above that, findings have shown that platelet transfusion has not been improving the outcome of patients receiving single antiplatelet therapy (19). It is reflected in the study of Zakko et al. that platelet transfusion in this group of patients without thrombocytopenia has not reduced the risk of re-bleeding but has increased mortality rate (19). Similar to other patients with GI bleeding, these patients are also encouraged to eradicate H. Pylori infection and take PPI to reduce the risk of re-bleeding in near future (17). The algorithm for the management of GI bleeding in patients receiving single antiplatelet therapy is presented in figure-2. The presented patient had a major and life-threatening GI bleeding on aspirin. As evidenced in the previous studies, aspirin as a single antithrombotic agent be withheld during the acute phase of major GI bleeding. She was started on IV fluids and IV PPI infusion (17). An endoscopic hemostasis was considered as soon as possible after resuscitation. Then, our patient was sent to ICU. Having performed the hemostasis, aspirin was restarted in 3 days. A consultation with a cardiologist was demanded to evaluate the possibility of discontinuation of aspirin as a life-long primary preventive drug for cardiovascular and cerebrovascular events. She was discharged from hospital and was advised to take H. pylori eradication regimen and continue oral PPI as long as she was on aspirin (17).\n\nFigure 2 The algorithm for the management of GI bleeding in patients receiving single antiplatelet therapy\n\n\nPatients on warfarin \n\n\n3. A 76-year-old woman was referred to the hospital with complaints of hematemesis and melena for the last 2 days. A review of her record presented that she had an episode of transient ischemic attack 2 month before, and hypertension, congestive heart failure, atrial fibrillation and diabetes mellitus for several years. She was taking losartan, carvedilol, spironolactone, furosemide, warfarin and metformin. At the time of arrival, she was conscious and oriented to person, place and time but she was uncomfortable with weak peripheral pulses, irregular tachycardia and hypotension. Her laboratory results were hemoglobin 6.5 mg/dL, creatinine 0.8 mg/dL, INR=3.8. She was resuscitated by IV crystalloids, FFP and packed cell infusion and then she underwent an urgent endoscopy. A duodenal ulcer with a large adherent clot was detected in bulb. A successful hemostasis was achieved by one hemoclip. \n\nWarfarin is an accepted oral anticoagulant which inhibits coagulation cascade and prevents thromboembolic events. Besides the benefit of warfarin as an anticoagulant, the risk of bleeding remains a major concern particularly when restarted within 7 days from a bleeding event (20). Although a large number of anticoagulant agents under the name “direct oral anticoagulants (DOAC)” were introduced and approved for clinical usage, warfarin has still its place due to the possibility of strict dose adjustment according to the schedule of INR which is not feasible for DOACs (21). Based on the literature, warfarin should be stopped if bleeding occurred regardless of the severity of bleeding (22). The risk assessment of thromboembolism is navigating whether a bridging therapy with low molecular weight heparin (LMWH) is indicated or not. Patients of high-risk thromboembolic events are highly suggested to receive therapeutic dose of LMWH 48hrs of warfarin hold (23,24). Some authors believe that patients with high-risk stigmata of bleeding should be started on prophylactic dose of LMWH in 48hrs and then on a therapeutic dose in 72hrs (24). Reinitiating warfarin depends on the risk assessment of thromboembolism. Patients in high-risk thromboembolic events are suggested to initiate warfarin on day 3 after hemostasis but it may be postponed for 7 days for patients in low-risk thromboembolism (25). The crucial thing in the management of an acute episode of bleeding among patients receiving warfarin is warfarin reversal by vitamin K and FFP/PCC. In contrast to FFP, PCC does not require ABO matching and has faster onset of action and minimal risk of volume overload. So, usage of 4-factor PCC is superior to FFP in studies (26). Some authors believe that warfarin reversal should be taken into account for each patient with major bleeding regardless of the level of INR. On the other hand, some studies recommend a warfarin reversal in major bleedings with levels of INR more than 2.5 which is higher than the therapeutic level (27). The current guideline emphasizes the latter approach. Warfarin reversal in minor bleedings would only be indicated if the level of INR is higher than 2.5. It is strongly accepted that an urgent endoscopy for life-threatening GI bleedings should not be deferred until the correction of INR. Thus, there is no need to recheck INR after transfusion of required factors for an urgent endoscopy in major bleedings in contrast to endoscopies for minor bleedings which is highly recommended to be delayed up to an INR level of less than 2.5. The reason why vitamin K is usually added to the FFP/PCC for the reversal of warfarin in major bleedings is the short half-life of factor VIIa in these coagulation surrogates which makes oral/IV replacement of vitamin K a necessity to restore its endogenous source (26). Reversal of warfarin for clinically minor bleedings proceeds with FFP alone. Then, the result of endoscopy would provide us with complementary information about the cause of hemorrhage. In this regard, some of the patients with clinically minor bleedings belong to the group of patients with endoscopic high-risk stigmata of bleeding. Approach to this subset of patients should then be directed towards the mentioned approach for major bleedings (27). Findings have shown that a dose of vitamin K as low as 2.5 mg per day is potent for warfarin reversal. However, some other studies suggest a vitamin K dose of less than 5mg for patients categorized as high risk for thromboembolism and 5-10mg for those with low risk characteristics of thromboembolic events (28). We suggest the latter approach that is a low-dose vitamin K of less than 5mg in patients for high-risk thromboembolic events to reduce the risk of thromboembolism and 5-10mg in patients for low-risk thromboembolism. A comprehensive algorithm for the management of patients receiving warfarin referred for GI bleeding is shown in figure 3.\n\nFigure 3 An algorithm for the management of patients receiving warfarin referred for GI bleeding\n\n As reflected in the third case, the patient with AF in addition to risk factors including age>75, history of DM, CHF, HTN and a TIA in recent 3 months has CHA2DS2-Vasc score of 7 which makes her extremely potent for thromboembolism. On the other hand, an unstable hemodynamic in our patient signaled a life-threatening bleeding. This scenario urged for warfarin reversal by FFP and vitamin K, holding warfarin, an urgent endoscopy for hemostasis regardless of the level of INR after reversal, bridging with LMWH in 48 hours, and reinitiating warfarin after at least 3 days from hemostasis. This patient should be advised to have a tighter control of INR level since then, besides H.pylori eradication and long term usage of PPIs (29).\n\n\nPatients on direct oral anticoagulants\n\n\n4. An 18-year-old man with a history of pulmonary thromboembolism (PTE) 4 months ago. He is currently on rivaroxaban 20 mg/day. His physical examination and his vital signs are all normal. He undergoes an upper endoscopy which demonstrates mild erythema in body and antrum, several superficial clean-based ulcers in antrum and an eroding ulcer with non-bleeding visible vessel in bulb. A successful endoscopic therapy was performed and the patient was transferred to ICU.\n\nUsage of DOACs like dabigatran, as a direct thrombin inhibitor and apixaban, and rivaroxaban and edoxaban as direct factor Xa inhibitors, is of great interest among physicians and also patients requiring anticoagulant therapy, due to their dispensable monitoring which obviated the need for dose monitoring (30). Nevertheless, this benefit makes these drugs a greater threat for GI bleeding. Connolly et al. (2009) made a comparison between warfarin and dabigatran indicating an overall increased risk of major GI bleeding for dabigatran in contrast to warfarin (31). The same results have been found for rivaroxaban and apixaban (32). Other studies have indicated that making a comparison between bleeding tendency of warfarin and DOACs regardless of the age and comorbidities could result in a marked bias. As an example, elderly patients on warfarin due to AF have been at higher risk for bleeding in contrast to younger patients on apixaban (25). Thrombin time (TT) is a sensitive test for the effects of dabigatran. It is indicated that there is a correlation between plasma concentration of dabigatran and activated thromboplastin time. Normal TT shows the absence of dabigatran in the blood circulation, so there is no need to eliminate it or its antidote idarucizumab by dialysis (33). There are also some assays tracing anti-factor Xa for rivaroxaban and other drugs of this group which are not accessible to all laboratories and are not suggested. Although coagulation tests like thromboelastography are involved by DOACs, the results are not consistent with drug effect and drug concentration, so they are not used for the effect assessment of DOACs (34,35). In the acute phase of GI bleeding, these drugs should be discontinued. Major bleedings raise a major concern for hemostasis establishment in using DOACs, making drug reversal a necessity in acute phases of a severe GI bleeding. Unfortunately, platelet transfusion, desmopressin, cryoprecipitate, FFP and vitamin K have not been found to be effective in subsiding the effect of these drugs (7). Findings for the effect of PCC have been complicated. PCC has been thriving in the reduction of prolonged PT due to rivaroxaban but unsuccessful in normalizing dabigatran-induced abnormal TT and PTT (36). Idarucizumab (a potent monoclonal antibody directed against dabigatran) is the known antidote of dabigatran (37). Notably, the use of these antidotes should be avoided in minor bleedings due to the risk of thrombosis (38) but during an episode of a major bleeding, PCC and the antidote of dabigatran are suggested. Above that, dabigatran is known to be dialyzable and charcoal is to be considered for the last dose of DOACs ingested in the last 2-4 hours (9,39). Unlike GI bleedings on warfarin, bridging therapy is not recommended for an acute episode of GI bleeding in patients receiving DOACs. Based on the literature following hemostasis, DOACs are to be restarted in 3 days (1). Among them, apixaban has the lowest risk of bleeding so it is recommended that dabigatran and rivaroxaban be switched to apixaban 5 mg twice daily in patients with GI bleeding (39,40). Apixaban could be titrated to the lower dose of twice-daily 2.5 mg in patients with age>80, weight<60 kg and serum creatinine>1.5 mg/dl (39,41,42). DOACs clearance is prolonged in patients with reduced renal clearance especially dabigatran which is mostly (80%) cleared by the kidneys. Edoxaban, rivaroxaban and apixaban have 50%, 33% and 25% renal elimination, respectively. It is recommended that DOACs be used cautiously by patients with severe renal insufficiency (CrCl=15–29 mL/min), and no DOAC should be used by patients with CrCl <15 mL/min (43,44). The hepatic elimination of apixaban, rivaroxaban, edoxaban, and dabigatran is 75%, 65%, 50%, and 20% respectively. These drugs can be used in cirrhotic patients. The fact that they do not need to be monitored by INR makes them favorable for cirrhotic patients who have altered INR and other coagulation tests attributed to the cirrhosis. But, more studies are required to definitely confirm the safety of DOACs in cirrhotic patients (45). The approach to the GI bleeding in patients receiving DOACs is depicted in figure 4. \n\nFigure 4 The approach to the GI bleeding in patients receiving DOACs\n\nThe presented case is a young man with a history of recent PTE making him highly susceptible to thromboembolic events. He was admitted with a GI bleeding endoscopically high risk for bleeding. On admission after resuscitation with IV fluids and IV PPI, rivaroxaban was stopped and an endoscopic hemostasis was established urgently. The episode of bleeding had occurred at least 10 hours after the last dose of rivaroxaban was administered, so charcoal was not started. Rivaroxaban was restarted 3 days after hemostasis. Nevertheless, he was advised to substitute rivaroxaban with apixaban (5 mg twice-daily) or warfarin (with a strict dose adjustment based on INR level) under the supervision of his cardiologist. H.pylori eradication regimen and continuation of oral PPI therapy after discharge were ordered (17). \n\nConclusion\nManagement of GI bleeding which is commonly due to peptic ulcer diseases (duodenal ulcers more than gastric ulcers) (46) in patients receiving antithrombotic agents is of great importance for physicians. Hemostasis establishment in these patients who referred for major GI bleeding is challenging because reversal of anticoagulants and simultaneous discontinuation of antithrombotic agents leave patients prone to thromboembolism. In this study, we have tried to introduce 4 algorithms in the management of patients taking single antiplatelet agents, dual antiplatelet agents, warfarin and direct oral anticoagulants admitted with GI bleeding based on a comprehensive review of relevant articles. Stratification of patients for the severity of GI bleeding and probability of thromboembolism has been performed based on some previous studies (3,4). It has been tried that a step-wise approach be introduced indicating the best time for discontinuation and restarting of antithrombotics in patients with GI bleeding with regard to the risk of thromboembolic events and re-bleeding.\n\nConflict of interests\nThe authors declare that they have no conflict of interest.\n==== Refs\nReferences\n1 Scott MJ Veitch A Thachil J Reintroduction of anti-thrombotic therapy after a gastrointestinal haemorrhage: if and when? 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practice guidelines GUT 2018 67 405 17 29331946 \n10 Baghaei K Shokrzadeh L Jafari F Dabiri H Yamaoka Y Bolfion M Determination of Helicobacter pylori virulence by analysis of the cag pathogenicity island isolated from Iranian patients Dig Liver Dis 2009 41 634 8 19261552 \n11 Sung JJ Lau JY Ching JY Wu JC Lee YT Chiu PW Continuation of low-dose aspirin therapy in peptic ulcer bleeding a randomized trial Ann Intern Med 2010 152 1 9 19949136 \n12 Halvorsen S Storey RF Rocca B Sibbing D Ten Berg J Grove EL Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis Eur Heart J 2017 38 1455 62 27789570 \n13 Strate LL Gralnek IM ACG clinical guideline: management of patients with acute lower gastrointestinal bleeding Am J Gastroenterol 2016 111 459 74 26925883 \n14 Saito Y Okada S Ogawa H Soejima H Sakuma M Nakayama M Low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus: 10-year follow up of a randomized controlled trial Circulation 2017 135 659 70 27881565 \n15 Souk KM Tamim HM Abu Daya HA Rockey DC Barada KA Aspirin use for primary prophylaxis: Adverse outcomes in non-variceal upper gastrointestinal bleeding World J Gastrointest Surg 2016 8 501 7 27462392 \n16 Veitch AM Vanbiervliet G Gershlick AH Boustiere C Baglin TP Smith LA Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines GUT 2016 65 374 89 26873868 \n17 Ray WA Chung CP Murray KT Smalley WE Daugherty JR Dupont WD Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding Gastroenterology 2016 151 1105 12 27639805 \n18 Yusuf S Zhao F Mehta S Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation N Engl J Med 2001 345 494 502 11519503 \n19 Zakko L Rustagi T Douglas M Laine L No benefit from platelet transfusion for gastrointestinal bleeding in patients taking antiplatelete agents Clin Gastroenterol Hepatol 2017 15 46 52 27464591 \n20 Witt DM Delate T Garcia DA Clark NP Hylek EM Ageno W Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding Arch Intern Med 2012 172 1484 91 22987143 \n21 Qureshi W Mittal C Patsias I Garikapati K Kuchipudi A Cheema G Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation Am J Cardiol 2014 113 662 68 24355310 \n22 Tapaskar N Pang A Werner D A Sengupta N Resuming anticoagulation following hospitalization for gastrointestinal bleeding is associated with reduced thromboembolic events and improved mortality: results from a systematic review and meta-analysis Dig Dis Sci 2020 \n23 Granger CB Alexander JH McMurray JJ Lopes RD Hylek EM Hanna M apixaban versus warfarin in patients with atrial fibrillation The N Engl J Med 2011 365 981 92 21870978 \n24 Nagata N Sakurai T Moriyasu S Shimbo T Okubo H Watanabe K Impact of INR monitoring, reversal agent use, heparin bridging, and anticoagulant interruption on re-bleeding and thromboembolism in acute gastrointestinal bleeding PLoS One 2017 12 e0183423 28863196 \n25 Giugliano RP Ruff CT Braunwald E Murphy SA Wiviott SD Halperin JL Edoxaban versus warfarin in patients with atrial fibrillation N Engl J Med 2013 369 2093 104 24251359 \n26 Alizadeh AH Ranjbar M Ansari S MirArab A Alavian SM Mohammad K Seroprevalence of hepatitis B in Nahavand, Islamic Republic of Iran East Mediterr Health J. 2006 12 528 37 17333790 \n27 Abraham NS Singh S Alexander GC Heien H Haas LR Crown W Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study BMJ 2015 350 h1857 25910928 \n28 Shokrzadeh L Baghaei K Yamaoka Y Dabiri H Jafari F Sahebekhtiari N Analysis of 3'-end variable region of the cagA gene in Helicobacter pylori isolated from Iranian population J Gastroenterol Hepatol 2010 25 172 7 19793167 \n29 Desai J Kolb JM Weitz JI Aisenberg J Gastrointestinal bleeding with the new oral anticoagulants defining the issues and the management strategies Thromb Haemost 2013 110 205 12 23702623 \n30 Diep R Garcia D Should we monitor the direct oral anticoagulants? J thromb thrombolysis 2020 50 30 2 32323189 \n31 Connolly SJ Ezekowitz MD Yusuf S Eikelboom J Oldgren J Parekh A Dabigatran versus warfarin in patients with atrial fibrillation N Engl J Med 2009 361 1139 51 19717844 \n32 Patel MR Mahaffey KW Garg J Pan G Singer DE Hacke W Rivaroxaban versus warfarin in nonvalvular atrial fibrillation N Engl J Med 2011 365 883 91 21830957 \n33 Xu X Liang Q Dabigatran monitoring was influencec by thrombin time reagent with different thrombin concentrations Clin Appl Thromb Hemost 2019 25 1076029619867137 31364394 \n34 Halvorsen S Atar D Yang H De Caterina R Erol C Garcia D Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial Eur Heart J 20014 35 1864 72 \n35 Ikeda K Tachibana H Clinical implication of monitoring rivaroxaban and apixaban by using anti-factor Xa assay in patients with non-valvular atrial fibrillation J Arrhythm 2016 32 42 50 26949430 \n36 Erenberg ES Kamphuisen PW Sijpkens MK Meijers JC Buller HR Levi M Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, cross over study in healthy subjects Circulation 2011 124 1573 79 21900088 \n37 Pollack CV Jr Reilly PA van Ryn J Eikelboom JW Glund S Bernstein RA Idarucizumab for dabigatran reversal-full cohort analysis N Engl J Med 2017 377 431 41 28693366 \n38 Marano G Vaglio S Pupella S Liumbruno GM Franchini M How we treat bleeding associated with direct oral anticoagulants Blood Transfus 2016 14 465 73 27136433 \n39 Khadzhynov D Wagner F Formella S Wiegert E Moschetti V Slowinski T Effective elimination of dabigatran by hemodialysis A phase I single-center study in patients with end stage renal disease Thromb Haemost 2013 109 596 605 23389759 \n40 Kirchhof P Benussi S Kotecha D Ahlsson A Atar D Casadei B 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS Eur Heart J 2016 37 2893 962 27567408 \n41 Rottenstreich A Zacks N Kleinstern G Raccah BH Roth B Da'as N Direct-acting oral anticoagulant drug level monitoring in clinical patient management J Thromb Thrombolysis 2018 45 543 9 29532414 \n42 Martin K Beyer-Westendorf J Davidson BL Huisman MV Sandset PM Moll S Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH J Thromb Haemost 2016 14 1308 13 27299806 \n43 Moll S Martin KA Anticoagulant drug choice in patients who have had bariatric surgery presently, DOACs are not the preferred choice Thromb Res 2018 163 196 9 29395241 \n44 Heidbuchel H Verhamme P Alings M Antz M Diener HC Hacke W Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation EP Europace 2013 15 625 51 \n45 Elhosseiny S Moussawi HA Chalhoub JM Lafferty J Deeb L Direct oral anticoagulants in cirrhotic patients: current evidence and clinical observations Can J Gastroenterol Hepatol 2019 4383269 30792971 \n46 Sharifian A Tavakoli E Ashtari S Zali MR Endoscopic findings in upper gastrointestinal bleeding patients at Tehran’s Taleghani Hospital, Iran Govaresh 2016 21 260 65\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2008-2258",
"issue": "13(Suppl1)",
"journal": "Gastroenterology and hepatology from bed to bench",
"keywords": "Algorithms; Antithrombotic agents; Gastrointestinal bleeding; Thromboembolic events",
"medline_ta": "Gastroenterol Hepatol Bed Bench",
"mesh_terms": null,
"nlm_unique_id": "101525875",
"other_id": null,
"pages": "S8-S17",
"pmc": null,
"pmid": "33584999",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "11519503;23389759;19261552;21900088;28863196;27789570;26873868;21830957;17333790;27299806;26949430;23625942;27639805;32323189;30792971;26925883;19949136;24355310;29532414;27136433;32279174;27567408;27464591;16649384;28272736;28886622;26621548;23702623;25910928;29740754;21870978;24251359;31364394;24561548;29395241;26417980;29331946;22171905;28693366;22987143;19717844;27881565;19793167;27462392",
"title": "An algorithmic approach to gastrointestinal bleeding in patients receiving antithrombotic agents.",
"title_normalized": "an algorithmic approach to gastrointestinal bleeding in patients receiving antithrombotic agents"
} | [
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"companynumb": "IR-MACLEODS PHARMACEUTICALS US LTD-MAC2021032962",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
... |
{
"abstract": "An 80s male, with a medical history of hypertension, hyperuricemia, and atrial fibrillation, visited our emergency outpatient department with vomiting and diarrhea as the chief complaint in August 2017. The blood examination revealed a high level of inflammatory reaction. The plain abdominal CT revealed fluid retention contacting the small intestine and intraabdominal free gas. We diagnosed the case as a small intestinal perforation, following which we performed emergency surgery. The small intestine was perforated, and an abscess cavity was formed between the transverse mesocolon and mesentery proper. Thus, the abscess was removed, and about 30 cm of the small intestine, including the perforated site, was resected, followed by the reconstruction. The resected specimens revealed squamous cell carcinoma at the small intestinal perforated site. Lung squamous cell carcinoma was diagnosed by subsequent chest CT and immunostaining. We administered 3 courses of chemotherapy combined with carboplatin and albumin-bound paclitaxel. Although the effect was partially observed, interstitial pneumonia occurred, which was inferred to be drug-induced. The patient died in 195 days following the surgery. Herein, we reported a case of lung cancer, which was diagnosed on the detection of gastrointestinal perforation caused by a small intestinal metastasis.",
"affiliations": "Dept. of Gastroenterological Surgery, Sendai Kousei Hospital.",
"authors": "Odaka|Tetsuo|T|;Fujita|Shota|S|;Sato|Mamoru|M|;Sato|Ataru|A|;Kawasaki|Shuhei|S|;Shirasaki|Keiichi|K|;Ajiki|Takashi|T|;Yamauchi|Junichiro|J|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
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"issn_linking": "0385-0684",
"issue": "48(2)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D002294:Carcinoma, Squamous Cell; D006801:Humans; D007416:Intestinal Perforation; D008168:Lung; D008175:Lung Neoplasms; D008297:Male",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "285-287",
"pmc": null,
"pmid": "33597383",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Squamous Cell Carcinoma of the Lung from Gastrointestinal Perforation Due to Small Intestinal Metastasis.",
"title_normalized": "a case of squamous cell carcinoma of the lung from gastrointestinal perforation due to small intestinal metastasis"
} | [
{
"companynumb": "JP-PFIZER INC-2021297484",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "CARBOPLATIN"
},
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... |
{
"abstract": "Clozapine is a frequently prescribed atypical antipsychotic drug. Various case reports documented the successful recovery of acute antipsychotics toxicity in association with the administration of intralipid emulsion (ILE).\nThis study aimed to assess the adjuvant therapeutic role of SMOF Lipid administration on the outcomes of acute clozapine poisoning.\nForty patients with acute clozapine poisoning were randomly allocated into two equal groups. The control group received the standard supportive treatment only, whereas the intervention group received the standard supportive treatment plus SMOF Lipid 20% infusion. All patients were subjected to history taking, full clinical examination, and laboratory investigations. The study outcomes were evaluated.\nThe mean Glasgow Coma Scale (GCS) at 6 hours (13.1 ± 2.3 vs 9.2 ± 2, p < 0.001) and 12 hours (14.3 ± 1.5 vs 9.6 ± 2, p < 0.001) after admission was significantly higher in the intervention group compared to the control group. The intervention group showed a significantly lower frequency of prolonged QTc interval 12 hours after admission (p = 0.003), as well as a significantly shorter hospital stay (p < 0.001).\nSMOF Lipid infusion seemed to have improved GCS, the prolonged QTc interval, and shortened the length of hospital stay. Furthermore, there were no adverse effects related to its administration.",
"affiliations": "Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, 68782Tanta University, Tanta, Egypt.;Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, 68782Tanta University, Tanta, Egypt.;Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, 68782Tanta University, Tanta, Egypt.;Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, 68782Tanta University, Tanta, Egypt.",
"authors": "Elgazzar|Fatma M|FM|https://orcid.org/0000-0002-2353-9223;Elgohary|Mona S|MS|;Basiouny|Sara M|SM|;Lashin|Heba I|HI|https://orcid.org/0000-0001-9223-9008",
"chemical_list": "D000931:Antidotes; D014150:Antipsychotic Agents; D005217:Fat Emulsions, Intravenous; D005395:Fish Oils; D000069463:Olive Oil; D014280:Triglycerides; D013024:Soybean Oil; C000709826:SMOFlipid; D003024:Clozapine",
"country": "England",
"delete": false,
"doi": "10.1177/0960327120983873",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-3271",
"issue": "40(7)",
"journal": "Human & experimental toxicology",
"keywords": "Acute poisoning; SMOF lipid; antidote; clinical trial; clozapine",
"medline_ta": "Hum Exp Toxicol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000931:Antidotes; D014150:Antipsychotic Agents; D002648:Child; D002675:Child, Preschool; D003024:Clozapine; D003131:Combined Modality Therapy; D004534:Egypt; D005217:Fat Emulsions, Intravenous; D005260:Female; D005395:Fish Oils; D006801:Humans; D008297:Male; D000069463:Olive Oil; D011041:Poisoning; D013024:Soybean Oil; D016896:Treatment Outcome; D014280:Triglycerides; D055815:Young Adult",
"nlm_unique_id": "9004560",
"other_id": null,
"pages": "1053-1063",
"pmc": null,
"pmid": "33401984",
"pubdate": "2021-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Intravenous lipid emulsion as an adjuvant therapy of acute clozapine poisoning.",
"title_normalized": "intravenous lipid emulsion as an adjuvant therapy of acute clozapine poisoning"
} | [
{
"companynumb": "EG-MYLANLABS-2022M1001984",
"fulfillexpeditecriteria": "1",
"occurcountry": "EG",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": "4",
... |
{
"abstract": "B cell-depletion therapy based on rituximab is a therapeutic option for refractory disease in patients with systemic lupus erythematosus (SLE). The aim of this observational study was to document long-term effects on B cell function by following serum immunoglobulin levels in patients with SLE treated with rituximab in routine clinical practice.\n\n\n\nWe included 57 consecutive patients with SLE treated with rituximab and concomitant/sequential immunosuppressants and measured serum total IgG, IgM, and IgA and IgG anti-dsDNA antibodies, over a median of 48 months most recent followup. Flow cytometry was used prospectively to assess B cell phenotypes in 17 of 57 patients.\n\n\n\nTwelve patients (21%) had persistent IgM hypogammaglobulinemia (<0.4 gm/liter), and 4 of 57 (5%) had low IgG (<7 gm/liter) at the most recent followup (range 12-144 months). This was not associated with serious adverse events or high anti-double-stranded DNA (anti-dsDNA) antibodies (>1,000 IU/ml; normal <50 IU/ml). Factors predictive of low serum IgM included baseline serum IgM ≤0.8 gm/liter (receiver operator curve analysis) and subsequent therapy with mycophenolate mofetil (MMF; odds ratio 6.8, compared with other immunosuppressants). In patients maintaining normal IgM levels (9 of 17), the frequency of circulating IgD+CD27+ B cells was significantly higher (P = 0.05). At 12 months after rituximab, 7 of 30 SLE patients with baseline anti-dsDNA ≤1,000 IU/ml had lost seropositivity.\n\n\n\nLower baseline serum IgM levels and sequential therapy with MMF were predictive of IgM hypogammaglobulinemia after rituximab in SLE, but this was not associated with higher levels of anti-dsDNA antibodies or an increased risk of infections. This provides useful directions for clinicians regarding rituximab and sequential immunosuppressive treatment for patients with SLE.",
"affiliations": "University College London, Rayne Institute, London, UK.;Hospital General Universitario, Gregorio Marañón, Madrid, Spain.;University College London, Rayne Institute, London, UK.;University College London, Rayne Institute, London, UK.;University College London, Rayne Institute, London, UK.",
"authors": "Reddy|Venkat|V|;Martinez|Lina|L|;Isenberg|David A|DA|;Leandro|Maria J|MJ|;Cambridge|Geraldine|G|",
"chemical_list": "D018501:Antirheumatic Agents; D015415:Biomarkers; D007075:Immunoglobulin M; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1002/acr.22993",
"fulltext": "\n==== Front\nArthritis Care Res (Hoboken)Arthritis Care Res (Hoboken)10.1002/(ISSN)2151-4658ACRArthritis Care & Research2151-464X2151-4658John Wiley and Sons Inc. Hoboken 10.1002/acr.22993ACR22993Systemic Lupus ErythematosusSystemic Lupus ErythematosusPragmatic Treatment of Patients With Systemic Lupus Erythematosus With Rituximab: Long‐Term Effects on Serum Immunoglobulins Hypogammaglobulinemia After Rituximab in SLEReddy et alReddy Venkat \n1\nMartinez Lina \n2\nIsenberg David A. \n1\nLeandro Maria J. \n1\nCambridge Geraldine g.cambridge@ucl.ac.uk \n1\n1 University College London, Rayne InstituteLondonUK2 Hospital General Universitario, Gregorio MarañónMadridSpain* Address correspondence to Geraldine Cambridge, PhD, Rayne Building, 5 University Street, London, WC1E 6JF, UK. E‐mail: g.cambridge@ucl.ac.uk.24 4 2017 6 2017 69 6 10.1002/acr.v69.6857 866 08 3 2016 08 6 2016 12 7 2016 © 2016 The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Objective\nB cell–depletion therapy based on rituximab is a therapeutic option for refractory disease in patients with systemic lupus erythematosus (SLE). The aim of this observational study was to document long‐term effects on B cell function by following serum immunoglobulin levels in patients with SLE treated with rituximab in routine clinical practice.\n\nMethods\nWe included 57 consecutive patients with SLE treated with rituximab and concomitant/sequential immunosuppressants and measured serum total IgG, IgM, and IgA and IgG anti‐dsDNA antibodies, over a median of 48 months most recent followup. Flow cytometry was used prospectively to assess B cell phenotypes in 17 of 57 patients.\n\nResults\nTwelve patients (21%) had persistent IgM hypogammaglobulinemia (<0.4 gm/liter), and 4 of 57 (5%) had low IgG (<7 gm/liter) at the most recent followup (range 12–144 months). This was not associated with serious adverse events or high anti–double‐stranded DNA (anti‐dsDNA) antibodies (>1,000 IU/ml; normal <50 IU/ml). Factors predictive of low serum IgM included baseline serum IgM ≤0.8 gm/liter (receiver operator curve analysis) and subsequent therapy with mycophenolate mofetil (MMF; odds ratio 6.8, compared with other immunosuppressants). In patients maintaining normal IgM levels (9 of 17), the frequency of circulating IgD+CD27+ B cells was significantly higher (P = 0.05). At 12 months after rituximab, 7 of 30 SLE patients with baseline anti‐dsDNA ≤1,000 IU/ml had lost seropositivity.\n\nConclusion\nLower baseline serum IgM levels and sequential therapy with MMF were predictive of IgM hypogammaglobulinemia after rituximab in SLE, but this was not associated with higher levels of anti‐dsDNA antibodies or an increased risk of infections. This provides useful directions for clinicians regarding rituximab and sequential immunosuppressive treatment for patients with SLE.\n\nRosetrees TrustArthritis Research UK Clinical Research Fellowship(20488) source-schema-version-number2.0component-idacr22993cover-dateJune 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.1.2 mode:remove_FC converted:27.06.2017Dr. Reddy's work was supported by the Rosetrees Trust and by an Arthritis Research UK Clinical Research Fellowship (grant 20488). Dr. Cambridge's work was supported by the Rosetrees Trust.\n\nDrs. Leandro and Cambridge contributed equally to this work.\n\nDr. Isenberg has received advisory fees from Eli Lilly, Merck Serono, Pfizer, and UCB Pharma (less than $10,000 each). Dr. Leandro has received honoraria from Roche UK, Roche Brazil, and Roche Portugal, and support for attending conferences from Roche and Chugai UK (less than $10,000 each).\n==== Body\nINTRODUCTION\nHypogammaglobulinemia can be an important adverse outcome of B cell–depletion therapy with rituximab (a chimeric anti‐CD20 monoclonal antibody). Whereas transient hypogammaglobulinemia may not require specific therapy, some patients with B cell malignancies and autoimmune diseases 1 develop persistent hypogammaglobulinemia following rituximab, requiring intravenous immunoglobulin replacement therapy, particularly in the context of recurrent infections 2, 3, 4. Although antimicrobial antibody responses are relatively robust, the degree of response to challenge with influenza, pneumococcal, and tetanus immunogens after rituximab treatment may be impaired. This appears to relate to the degree and duration of B cell depletion in peripheral blood in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) 5, 6, 7.\n\nBox 1 Significance & Innovations\n\nIgG hypogammaglobulinemia was rare in systemic lupus erythematosus (SLE) patients at long‐term followup after multiple cycles of rituximab (RTX).\n\nRTX normalized raised IgG in the majority of patients.\n\nLow levels of serum total IgM presented in nearly one‐quarter of SLE patients and were associated with lower baseline levels, older age, and sequential therapy with mycophenolate mofetil.\n\nLow IgM was not associated with persistently high levels of anti–double‐stranded DNA or adverse events.\n\n\n\n\nB cell–depletion therapy based on rituximab is as yet unlicensed for SLE, but is used to treat early‐onset and refractory disease 8, 9, 10, 11. However, the probability of and factors associated with the incidence of persistent hypogammaglobulinemia after rituximab in the routine clinical setting has not been explored. Therefore, it is of direct clinical relevance to identify factors that may predict those at an increased risk of developing persistent hypogammaglobulinemia.\n\nBoth underlying disease and immunosuppressive therapies may affect serum Ig levels. In patients with SLE, hypergammaglobulinemia is often present; paradoxically, however, hypogammaglobulinemia similar to common variable immunodeficiency occasionally occurs and may relate to the presence of lymphocytotoxic autoantibodies 12, 13. Selective IgM and IgA deficiency has also been reported 14, 15. Hypogammaglobulinemia may be associated with older age, low IgG at baseline, nephritis 4, and treatment with immunosuppressants, including cyclophosphamide and mycophenolate mofetil (MMF) 16, 17, 18. A higher cumulative dose or repeated cycles of rituximab and concomitant or sequential use of immunosuppressants appear to increase the risk of persistent hypogammaglobulinemia in antineutrophil cytoplasmic antibody–associated vasculitis (AAV) and other autoimmune diseases 4. Importantly, long‐term persistence of hypogammaglobulinemia and associated adverse events is better appreciated in long‐term followup studies than short‐term clinical trials. Such information could therefore serve to identify those at a higher risk.\n\nB cell hyperactivity, characteristic of SLE, results in excessive production of both polyclonal and autoreactive antibodies 19, even before the onset of clinical disease 20, 21, 22. Elevated levels of IgG anti–double‐stranded DNA (anti‐dsDNA) antibodies are characteristic of SLE and considered pathogenic, but may occur independently of hypergammaglobulinemia 23, 24. Immune dysregulation in patients with SLE is at least partly related to changes in the interactions between immune cells within germinal centers and altered trafficking of peripheral blood lymphocytes 25, 26. Some abnormalities in the composition of peripheral B cell phenotypes appear to “improve” following rituximab, but this may also reflect naive B cell return, which recapitulates ontogeny 27, 28. Reduced levels of possibly protective natural antibodies of the IgM class have been suggested to be associated with development of anti‐dsDNA antibodies in a murine model of SLE 29.\n\nA study of the recovery of B cell subpopulations in patients with SLE who develop hypogammaglobulinemia may also relate to the extent of B cell depletion in the short term, and to the recovery of B cell subpopulations and/or clones in the long term, both of which may impact serum Ig levels. To this end, we investigated whether baseline serum Ig levels, concomitant/sequential immunosuppressants, and B cell phenotypes predict the development and/or persistence of hypogammaglobulinemia after rituximab. The relationship between serum Ig levels and anti‐ds DNA antibodies was also determined over the course of the study.\n\nPATIENTS AND METHODS\nPatients\nIn this cross‐sectional observational study, 57 consecutive patients with SLE, who met the revised American College of Rheumatology classification criteria 30 and were treated with rituximab, were included. All patients were attending University College London Hospitals (UCLH) and were treated according to clinical need. The specific indication for rituximab treatment in this cohort was persistent active disease refractory to conventional immunosuppressive therapies. Clinical notes and laboratory results of all SLE patients treated with rituximab from January 2000 until December 2012 were reviewed retrospectively. As this study was a clinical evaluation, it did not require hospital ethics committee approval, and results were compiled from anonymized files. In the cross‐sectional B cell phenotype study, collection of blood samples was approved by the UCLH Ethics Committee. Patients gave written informed consent according to the Declaration of Helsinki.\n\nAll patients had active disease refractory to hydroxychloroquine and at least 2 conventional immunosuppressants, including azathioprine (AZT), MMF, methotrexate (MTX), or cyclophosphamide (CYC). A majority of patients continued with low‐dose corticosteroids (prednisolone <10 mg/day), but in most cases the use of other immunosuppressants was stopped until evidence of B cell return (CD19+ cells >5/µl) or started only as required for optimal control of disease activity. A typical rituximab treatment cycle consisted of rituximab, 2 doses of 1 gm given 1–2 weeks apart in combination with 1 dose of intravenous cyclophosphamide (750 mg). The clinical response to rituximab in this cohort has been reported previously 31. Clinical and laboratory parameters were analyzed during the first cycle of rituximab (up to 12 months) and the most recent time point from all patients, some of whom had received multiple cycles of rituximab‐based treatment in combination with concomitant and/or subsequent therapy with immunosuppressants to determine longer‐term effects on the recovery of B cell subpopulations, serum Ig, and autoantibodies.\n\nClinical and laboratory indices\nSerum levels of IgG, IgM, and IgA, and IgG anti‐dsDNA antibody levels, were recorded from baseline (before the first infusion of rituximab) up to 12 months after rituximab, and also at most recent followup. Hypogammaglobulinemia was defined by serum IgG <7 gm/liter (normal range: 7–16 gm/liter), IgM <0.4 gm/liter (normal range 0.4–2.3 gm/liter); and IgA <0.7 gm/liter (normal range: 0.7–4.0 gm/liter).\n\nB cell immunophenotyping\nB cell phenotypes in whole blood were prospectively characterized by flow cytometry. Samples were stained with fluorescence‐tagged antibodies against CD19 (phycoerythrin [PE]–Cy7), IgD (fluorescein isothiocyanate), and CD27 (PE) (BD Biosciences). B cells were identified as CD19+ cells in the lymphocyte‐gated cells. B cell phenotypes were identified as follows: naive, IgD+CD27−, unswitched memory IgD+CD27+, switched memory IgD−CD27+, and double negative IgD−CD27−.\n\nStatistical analysis\nStatistical analysis was performed using Graph Pad Prism, version 5.01. Matched‐pairs signed rank test and the Mann‐Whitney U test were used to analyze differences in serum Ig between paired and unpaired data, respectively. Spearman's rank test was used to analyze correlations. Fisher's exact test was used to compare the proportions of patients in different groups. Receiver operator curve analysis was used to identify the cutoff value that distinguished patients developing low Ig. The odds ratio was used to express the effect of concomitant and/or subsequent immunosuppressants on the development of hypogammaglobulinemia.\n\nRESULTS\nPatient demographics\nClinical features, drug therapies prior to RTX and at most recent followup, and serology are shown for patients with low serum IgM and for those retaining normal levels of IgM in Supplementary Tables 1 and 2, respectively (available on the Arthritis Care & Research web site at http://onlinelibrary.wiley.com/doi/10.1002/acr.22993/abstract). Lupus nephritis was diagnosed in 29 of 57 patients (51%). Percentages of patients in each group were similar (7 of 12 [58%] in the low IgM group and 22 of 45 [49%] in the normal IgM group). Detailed patient demographics and clinical responses of this cohort of 57 patients have been previously described 31, 32, 33. The median age at the time of the first rituximab treatment cycle was 34 years (range 17–74 years). All patients had received previous treatment with at least 2 different immunosuppressants, not including corticosteroids, which were continued at a low dose (prednisolone <10 mg/day). The median duration of followup was 48 months (range 12–144 months).\n\nSerum total Ig and anti‐dsDNA antibodies in patients at 12‐month followup after rituximab\nAt baseline, 3 patients had low IgM, none had low IgA, and 1 had low IgG (Figure 1A, B, and C). Eleven patients had raised serum IgG levels (>16 gm/liter). At 12‐month followup after rituximab (n = 32), median baseline serum IgG level was 13.9 gm/liter, which was significantly reduced at 1, 2, 6, and 9 months after rituximab (P < 0.05 for all), but similar to baseline levels at 12 months (median 13.2 gm/liter) (Figure 1A). The median IgM levels, however, were significantly lower at all time points (Wilcoxon's matched‐pairs signed rank test; P < 0.005 for all), with the median serum IgM level at baseline (1.0 gm/liter) decreasing significantly to 0.71 gm/liter at 12 months (Figure 1B). The median baseline serum IgA level was 2.9 gm/liter, which fell at 1 and 3 months (P < 0.05) only (Figure 1C). The percentage change from baseline to 12 months of serum Ig and anti‐dsDNA is shown in Figure 2, and we noted a hierarchy in percent reduction from baseline with IgM > IgG > IgA (−18.4%, −2.8%, and 10.3%; Figure 2A, C, and D, respectively) and remarkable variations in IgG anti‐dsDNA levels (Figure 2B).\n\nFigure 1 Serum levels of IgG (A), IgM (B), and IgA (C) at intervals up to 12 months after treatment of patients with systemic lupus erythematosus with rituximab (n = 32). Box and whiskers represent median, interquartile range, and range. Differences between baseline and subsequent immunoglobulin levels of each class were calculated using Wilcoxon's matched‐pairs signed rank test. * = P < 0.05; ** = P < 0.005; *** = P < 0.0005; ns = not significant.\n\nFigure 2 Percentage change from baseline in immunoglobulin classes and anti–double‐stranded DNA (anti‐dsDNA) antibodies. Means and SDs of serum IgG (A), anti‐dsDNA autoantibodies (B), IgM (C), and IgA (D) at baseline and up to 12‐month followup after initial cycle of rituximab (administered at time 0) are expressed as a percentage of baseline (pre‐rituximab) levels.\n\nSerum Ig and anti‐dsDNA levels at 12 months after rituximab: relationship with baseline\nSerum IgM\nAt 12 months of followup, 25% of SLE patients (8 of 32) had serum IgM levels below the normal range. There was a significant difference between median baseline serum IgM levels in patients who developed low serum IgM levels at 12 months (8 of 32) and those who did not (P < 0.005) at 0.5 and 1.0 gm/liter, respectively (Figure 3A).\n\nFigure 3 Development of IgM hypogammaglobulinemia after rituximab: relationship with baseline serum IgM, sequential therapy, and B cell phenotype. A, Results for serum IgM were grouped on the basis of being within the normal range (0.4–2.3 gm/liter) at 12 months (indicated by shaded area) or <0.4 gm/liter at 12 months. Box and whiskers show median, interquartile range (IQR), and range with significance between baseline values in each group, calculated using the Mann‐Whitney U test. B, The number of patients who developed IgM hypogammaglobulinemia (IgM <0.4) and who had been treated with mycophenolate mofetil (MMF; 7 of 12) or with other immunosuppressants (7 of 43) following rituximab (RTX) are shown (odds ratio 6.8, 95% confidence interval 1.66–27.77). C, The frequency (%CD19+ B cells) of B cell subpopulations in samples available from patients with low (<0.4 gm/liter; n = 8) or serum IgM levels within the normal range (n = 9) after RTX. B cell subpopulations were defined using relative expression of IgD and CD27. Box and whiskers represent the median, IQR, and range of values and significance calculated using the Mann‐Whitney U test. Significance was at 5% level. ns = not significant; DN = double negative.\n\nSerum IgG\nOnly 1 patient had low serum IgG before treatment and at 12 months, and only 2 additional patients had levels <7 gm/liter. Figure 4A shows that in patients with IgG hypergammaglobulinemia pre‐rituximab (median 17.9 gm/liter), there was a significant reduction in median IgG levels between baseline and 12‐month followup in 11 of 32 patients (34%) (P < 0.01; Wilcoxon's matched‐pairs signed rank test), with levels normalizing in 8 patients. In those with baseline IgG within the normal range, there was no difference between baseline and levels at 12 months postrituximab.\n\nFigure 4 Fluctuations in serum IgG and anti–double‐stranded DNA (anti‐dsDNA) antibody levels in relation to baseline levels. A, Patients (n = 32) were grouped on the basis of whether their baseline serum IgG levels were within the normal range or greater than the upper limit of normal range (normal range 7–16 gm/liter; shaded area). Median and range for serum IgG levels for up to 12 months after rituximab (RTX) are shown. B, IgG anti‐dsDNA antibody levels in seropositive patients following RTX are shown for followup of 12 months. Upper limit of positive test was 50 IU/ml, and the shaded area indicates normal range. Results were stratified according to baseline anti‐dsDNA antibody levels of ≤1,000 IU/ml or >1,000 IU/ml. Significance between baseline in each group and 12‐month values were calculated using Wilcoxon's matched‐pairs signed rank test (significance level at 5%).\n\nSerum IgA\nSimilarly, there was a trend toward higher baseline median serum IgA levels, with a reduction in serum IgA levels when compared with baseline median serum IgA levels and with those who did not, at 3.7 gm/liter and 2.7 gm/liter (P = 0.06) (data not shown).\n\nAnti‐dsDNA antibodies\nAt 12 months, in 8 of 32 patients (19%), the levels of anti‐dsDNA fell to within the normal range, but median levels at baseline and 12‐month followup were similar (169 versus 100 IU/ml, not significant) (data not shown). In Figure 4B, patients were divided on the basis of having anti‐dsDNA titers ≤ or >1,000 IU/ml. In those with anti‐dsDNA levels >1,000 IU/ml, only 1 of 9 had levels that fell to within the normal range at 12 months compared with 7 of 23 (35%) who had levels ≤1,000 IU/ml at baseline. A significant reduction in median levels after 12 months in patients with titers ≤1,000 IU/ml, but not in those with titers >1,000 IU/ml, was also noted (Figure 4B).\n\nEffect of rituximab on serum Ig at most recent followup\nLow serum IgM was present in 12 of 57 patients (21%) (Figure 5B), with only 4 of 57 patients developing low IgG, all of whom had normal pretreatment levels (Figure 5A). Of 21 patients with raised serum IgG at pretreatment, 15 had normalized at the most recent followup. The demographics of the 12 patients developing low serum IgM levels following rituximab are shown in Supplementary Table 1 (available on the Arthritis Care & Research web site at http://onlinelibrary.wiley.com/doi/10.1002/acr.22993/abstract). Interestingly, at 12 months, 8 of 32 patients (25%) had low IgM, and at last followup a similar proportion, 12 of 57 (21%), had low IgM, suggesting that an accumulated rituximab dose was not necessarily related to development of low serum IgM.\n\nFigure 5 Changes between baseline serum Ig and anti–double‐stranded DNA (anti‐dsDNA) levels in systemic lupus erythematosus patients at the most recent (MR) followup. Paired serum Ig levels were available from 54 patients and anti‐dsDNA antibody levels from 40 patients. Shaded areas indicate the normal ranges used for each parameter. Values for serum levels of IgG (A), IgM (B), IgA (C), and anti‐dsDNA antibodies (D) at baseline and at MR followup (ranging from 12–144 months after initial rituximab treatment) are shown. Significance values shown were given by Wilcoxon's matched‐pairs signed rank tests for values at MR followup compared with baseline.\n\nThere was no difference in sex distribution compared with the whole cohort (data not shown), but they tended to be older (median age 43 years, range 22–59 years) compared with those maintaining normal IgM levels (median age 32 years, range 21–74 years) (Mann‐Whitney U test, P < 0.01). Three of 56 patients developed low IgA levels (Figure 5C). In 15 of 40 patients (38%), anti‐dsDNA levels normalized, with the majority (13 of 15) having had levels ≤1,000 IU/ml at baseline (Figure 5D). No serious adverse events were observed 31, 33, and none of the patients required intravenous Ig therapy.\n\nRelationship between low serum IgM and IgG anti‐dsDNA antibody levels\nWe did not find significant correlations between baseline serum IgM and anti‐dsDNA levels at baseline or maximal followup (data not shown). Further, median serum IgM levels in patients with anti‐dsDNA >1,000 IU/ml and those with levels ≤1,000 IU/ml (1.1 gm/liter and 0.9 gm/liter, respectively) were not significantly different (Mann‐Whitney U test; data not shown).\n\nPredictive factors for the development of low serum IgM after rituximab\nIgG hypogammaglobulinemia was present at long‐term followup in only 5% of SLE patients. As shown in Figure 3A, however, patients with serum IgM levels below 0.4 gm/liter at 12 months after rituximab had significantly lower baseline levels than those with IgM within the normal range at 1 year followup (P < 0.005). We employed receiver operating characteristic analysis (Supplementary Figure 1A, available on the Arthritis Care & Research web site at http://onlinelibrary.wiley.com/doi/10.1002/acr.22993/abstract) and found that a pretreatment serum IgM level ≤0.8 gm/liter was associated with a greater than 3‐fold likelihood ratio for the development of low IgM (<0.4 gm/liter) at 12 months, as well as at long‐term followup comparing those with low serum IgM (n = 12) and those with normal serum levels (n = 43) (Supplementary Figure 1B, available on the Arthritis Care & Research web site at http://onlinelibrary.wiley.com/doi/10.1002/acr.22993/abstract), with a significant area under the curve of 0.85 (95% confidence interval [95% CI] 0.7–1.0, P = 0.0002). This finding suggested that baseline serum IgM ≤0.8 gm/liter was associated with a greater than 4‐fold increase in the likelihood of developing low IgM (sensitivity 83%, specificity 80%). In accord with this cutoff value, at most recent followup, we found that 10 of 18 patients with serum IgM ≤0.8 gm/liter at baseline, and only 2 of 37 patients with levels >0.8 gm/liter, developed low IgM (P < 0.0001 by Fisher's exact test).\n\nEffect of sequential therapy with immunosuppressants\nThe results from our extended data at most recent followup showed that 12 of 57 patients developed low IgM, and 6 of these patients (50%) were treated with MMF at least 6 months after rituximab and 2 months before the time of analysis (Supplementary Table 1, available on the Arthritis Care & Research web site at http://onlinelibrary.wiley.com/doi/10.1002/acr.22993/abstract). In contrast, only 7 of 43 patients (16%) treated with other immunosuppressants, including AZT, MTX, and CYC, developed low IgM (Figure 3B). The odds ratio for the analysis was 6.8 (95% CI 1.66–27.77).\n\nB cell phenotypes in patients with low serum IgM levels\nWe found that the frequency of unswitched B cells (IgD+CD27+), but not other phenotypes, was significantly lower in patients who developed low IgM after rituximab when compared with those who did not (P < 0.05), although a trend for higher frequency of double negative (IgD−CD27−) memory B cell subpopulation was also apparent (n = 8) (Figure 3C). We found no significant difference between sex distribution or age, median times since last rituximab treatment (24 months in the low IgM group, 15 months in those with normal IgM), or in percentage of B cells, levels of C3, cumulative dose of rituximab, or anti‐dsDNA levels between the groups (Supplementary Tables 1 and 2, available on the Arthritis Care & Research web site at http://onlinelibrary.wiley.com/doi/10.1002/acr.22993/abstract) (data not shown).\n\nDISCUSSION\nIn this study, we found that lower baseline IgM levels were predictive of low serum IgM after rituximab and associated with a lower frequency of unswitched memory B cells. Sequential treatment with MMF after rituximab was also associated with low serum IgM. IgG hypogammaglobulinemia was rare, and the majority (71%) of those with raised serum IgG at baseline had normalized at maximum followup. Patients with low serum IgM did not experience serious adverse events. In the most recent published results of the cohort from which these patients were derived, we showed that the safety profile was favorable, and infusion related and hypersensitivity reactions were mostly mild to moderate 33.\n\nThere was a disparity in the dynamics of fluctuations between isotypes of serum Ig after rituximab. At 12 months and also at long‐term followup, median levels of serum IgG and IgA were not significantly different from those at baseline, with very few patients developing low levels of IgG or IgA. This contrasts with our experience in patients with RA in whom those with lower baseline serum Ig levels tended to develop persistent IgM and IgG hypergammaglobulinemia, resulting from an accumulation of incremental decreases after repeat cycles. The incidence of low IgM increased from 9.2% to 38.8% and that of IgG from 11.8% to 22.2% of RA patients, after 1 and 5 cycles, respectively 34. In patients with SLE, however, our results show that the incidences are much lower after repeat cycles, being for IgM 12 of 57 patients (21%), but only 4 of 57 patients (7%) developing low IgG, with all retaining IgG levels >5 gm, and therefore none were treated with intravenous immunoglobulin. Interestingly, at 12 months, 8 of 32 patients (25%) had low IgM, and at last followup a similar proportion, 12 of 57 patients (21%), had low IgM, suggesting that accumulated rituximab dose was not necessarily related to development of low serum IgM. An important factor influencing serum Ig levels is the balance between synthetic and catabolic rate of different Ig isotypes. IgG catabolism is greater in patients with SLE than in patients with RA, whereas IgM catabolism is greater in RA compared to patients with SLE 35.\n\nIn patients with AAV and thrombotic thrombocytopenic purpura, co‐therapies such as cyclophosphamide and plasmapheresis make it difficult to dissect the role of rituximab per se in the development of low serum Ig. None of our patients received plasmapheresis, but patients with SLE usually receive a single dose of 750 mg cyclophosphamide, which is substantially lower than that used in AAV. The comparison between patient groups was also confounded due to lower pre‐rituximab serum IgG levels in patients with AAV 4. Of direct clinical relevance, rituximab treatment did not result in significant reductions in serum IgG levels in those with low baseline IgG levels of <6 gm/liter 4. Even allowing for these limitations, we found that incidences of low IgG levels in SLE were markedly less frequent than in patients with AAV and RA.\n\nThere was no association between serum IgM levels, or with the development of low IgM, with levels of IgG anti‐dsDNA antibodies. Patients who developed low IgM however, had 2‐fold lower median levels of serum IgM before rituximab compared with those without IgM hypogammaglobulinemia at long‐term followup. Differential effects on Ig classes have also been described in patients with RA, as well as in patients with multiple myeloma treated with autologous hematopoietic stem cell transplant (HSCT) and rituximab maintenance therapy 36. Both groups of patients tend to develop low IgM, but not IgG and IgA. In contrast, some patients with refractory follicular lymphoma treated with rituximab and HSCT developed persistently low IgA and IgG with recovery of IgM levels 34, 37. Underlying disease can therefore influence the development of isotype‐specific hypogammaglobulinemia.\n\nSerum IgM is derived from both (short‐lived) newly generated perifollicular B cells (CD27−) and from CD27+ (unswitched) marginal zone B cells 38. Differences in specific co‐therapies or the regimen used may also therefore account for some of the disparity between the isotypes affected, depending on the parent B cells affected. Serum levels of IgA and IgG are largely maintained by long‐lived (CD20−) plasma cells, predominantly in the bone marrow. These are therefore not directly targeted by rituximab, and protective immunity is largely maintained, as in RA patients, for example (34,39). It is, however, difficult to differentiate the direct effects of rituximab preventing formation of new plasma cells from indirect effects through disease control.\n\nWe found no difference between time since last rituximab infusion or in cumulative rituximab dose in the subgroup of SLE patients studied for B cell phenotype. In SLE, MMF, but not AZT or hydroxychloroquine, treatment has been associated with reduced frequency of switched memory B cells and modest decreases in levels of serum Ig and of anti‐dsDNA antibodies 40, 41, 42. The composition of B cell subpopulations may vary between individuals with SLE and after rituximab; repopulation appears to recapitulate ontogeny, perhaps further influenced by antigen stimulation 43. We found that the frequency of unswitched (IgD+CD27+) B cells was significantly lower in patients who developed low IgM after rituximab when compared with those who did not. Relative levels of immunoglobulin may relate to the composition of B cell pools in bone marrow, lymphoid, and inflammatory tissues, which differ between individual patients. This is supported by the finding that patients who developed low IgM already had lower baseline levels 44. Unswitched (IgM‐committed) B cells are preferentially depleted by rituximab in vitro, suggesting a reduced threshold for survival and slow regeneration of unswitched B cells in SLE 45, 46, 47.\n\nOur results indicated a possible association between sequential treatment with MMF after rituximab and low serum IgM. MMF preferentially targets type II inosine monophosphate dehydrogenase, which is up‐regulated in activated lymphocytes (both B and T lymphocytes) 48, 49. Rituximab preferentially depletes naive and unswitched B cells, both of which are direct precursors for IgM production. Together with the potential removal of activated naive and memory cells by MMF, this may explain the profound effect of using a combination of rituximab and MMF on serum IgM levels. Co‐therapy with MMF has been associated with a higher rate of infections in clinical trial studies using ocrelizumab 50, and low Ig was noted in patients treated with a combination of MMF and atacicept 51. In the later study, low IgM levels in SLE patients treated with MMF alone in the placebo arm did not recover over the course of the study. Our data confirm that caution is needed when the combination of MMF, with judicious administration of the dose, and rituximab is being considered.\n\nIn contrast to IgM, serum IgA, after an initial decrease in median levels, started recovering as early as 2 months after rituximab, approaching baseline levels by 6 months. Early recovery in serum IgA levels suggests that the IgA plasma cell pool was rapidly replenished. It has previously been reported that circulating IgA+ plasmablasts can remain detectable early after rituximab, suggesting resistance to depletion of switched IgA+ precursor B cells, likely in the mucosal microenvironment and/or early regeneration 52. Serum IgG levels, despite showing a longer “lag” when compared with the recovery of serum IgA levels, was apparently also sustainable, attaining pretreatment levels in most patients by 12 months after rituximab. Indeed, rituximab treatment resulted in correction of hypergammaglobulinemia in most patients in our cohort. At long‐term followup, very few (5% of patients) had serum IgG levels below the lower limit of the normal range.\n\nPercentage change from baseline of dsDNA antibodies was highly variable between patients. Differences in patterns of fluctuations in anti‐dsDNA antibodies between patients implied a variable contribution from anti‐dsDNA committed B cell clones (CD20+) sensitive to B cell depletion, as well as from long‐lived (IgG) plasma cells (CD20−) 53. Autoantibody‐committed B cells are often preferentially removed by rituximab, as has also been shown in patients with RA 39, 54. A significant proportion of patients lost seropositivity to dsDNA at long‐term followup; however, there was little overall decrease in anti‐dsDNA antibodies in those patients with the highest baseline levels, suggesting the presence of a more entrenched autoreactive plasma cell pool.\n\nThe limitations of this study were that it was observational and from a single center, and that the data were not complete for all time points. However, clinical and laboratory results were available for the majority of patients at most recent followup (at least 54 of 57 patients); these results were complemented by prospective analysis of peripheral blood immunophenotyping of most patients who developed low serum IgM.\n\nOur results showed that hypogammaglobulinemia after rituximab was largely restricted to the IgM class, and was associated with low baseline levels and a lower frequency of unswitched B cells. The development of low serum IgM hypogammaglobulinemia was also associated with sequential MMF. Monitoring of serum Ig levels is an important adjunct to the selection of concomitant/sequential immunosuppressants after B cell–depletion therapy. Reassuringly, low IgM after rituximab was not associated in our patients with increased risk of infections. Nonetheless, it would be prudent to continue surveillance of the patients for potential adverse events.\n\nTaken together, the data presented provide new insights into the variability in biologic response, with rituximab providing useful information for the clinicians using rituximab for SLE.\n\nAUTHOR CONTRIBUTIONS\nAll authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Cambridge had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\n\nStudy conception and design\nReddy, Leandro, Cambridge.\n\nAcquisition of data\nReddy, Martinez, Isenberg, Leandro.\n\nAnalysis and interpretation of data\nReddy, Leandro, Cambridge.\n\nSupporting information\nSupplementary Table 1: Patients with low serum IgM (<0.4g/L) post‐rituximab (n=12) at most recent follow up. Demographics, ethnic origin, clinical features and drug therapy are shown for individual patients.\n\nClick here for additional data file.\n\n Supplementary Table 2: Patients with serum IgM within the normal range (0.4‐2.3g/L) post‐rituximab (n=45) at most recent follow up. Demographics, ethnic origin, clinical features and drug therapy are shown for individual patients.\n\nClick here for additional data file.\n\n Supplementary Table 3: Demographics and laboratory parameters of patients studied prospectively for B‐cell phenotype (Figure 3C). Number of cycles of rituximab, co‐therapies and serology (C3 and anti‐dsDNA antibodies) of 9 SLE patients with immunoglobulin levels within the normal range after rituximab and in 8 patients with SLE who developed low serum IgM levels after rituximab.\n\nClick here for additional data file.\n\n ACKNOWLEDGMENT\nThe authors wish to thank Gabriel Garcia, who was involved in the collection and processing of some of the blood samples and analysis of the FACS results.\n==== Refs\nREFERENCES\n1 \n\nMakatsori \nM \n, \n\nKiani‐Alikhan \nS \n, \n\nManson \nAL \n, \n\nVerma \nN \n, \n\nLeandor \nM. \n et al. Hypogammaglobulinaemia after rituximab treatment: incidence and outcomes . QJM \n2014 ;107 :821 –8 .\n24778295 \n2 \n\nBesada \nE \n, \n\nKoldingsnes \nW \n, \n\nNossent \nJC. \n\nSerum immunoglobulin levels and risk factors for hypogammaglobulinaemia during long‐term maintenance therapy with rituximab in patients with granulomatosis with polyangiitis . 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Arthritis Care Res (Hoboken) \n2017 ;69 :257 –62 .\n27110698 \n34 \n\nDe la Torre \nI \n, \n\nLeandro \nMJ \n, \n\nValor \nL \n, \n\nBecerra \nE \n, \n\nEdwards \nJC \n, \n\nCambridge \nG. \n\nTotal serum immunoglobulin levels in patients with RA after multiple B‐cell depletion cycles based on rituximab: relationship with B‐cell kinetics . Rheumatology (Oxford) \n2012 ;51 :833 –40 .\n22253030 \n35 \n\nLevy \nJ \n, \n\nBarnett \nEV \n, \n\nMacDonald \nNS \n, \n\nKlinenberg \nJR. \n\nAltered immunoglobulin metabolism in systemic lupus erythematosus and heumatoid arthritis . J Clin Invest \n1970 ;49 :708 –15 .\n5309797 \n36 \n\nLim \nSH \n, \n\nZhang \nY \n, \n\nWang \nZ \n, \n\nVaradarajan \nR \n, \n\nPeriman \nP \n, \n\nEsler \nWV. \n\nRituximab administration following autologous stem cell transplantation for multiple myeloma is associated with severe IgM deficiency . Blood \n2004 ;103 :1971 –2 .\n14976066 \n37 \n\nHicks \nLK \n, \n\nWoods \nA \n, \n\nBuckstein \nR \n, \n\nMangel \nJ \n, \n\nPennell \nN \n, \n\nZhang \nL \n, et al. Rituximab purging and maintenance combined with auto‐SCT: long‐term molecular remissions and prolonged hypogammaglobulinemia in relapsed follicular lymphoma . Bone Marrow Transplant \n2009 ;43 :701 –8 .\n19029963 \n38 \n\nWeill \nJC \n, \n\nWeller \nS \n, \n\nReynaud \nCA. \n\nHuman marginal zone B cells . Ann Rev Immunol \n2009 ;27 :267 –85 .\n19302041 \n39 \n\nCambridge \nG \n, \n\nPerry \nHC \n, \n\nNogueira \nL \n, \n\nSerre \nG \n, \n\nParsons \nHM \n, \n\nde la Torre \nI \n, et al. The effect of B‐cell depletion therapy on serological evidence of B‐cell and plasmablast activation in patients with rheumatoid arthritis over multiple cycles of rituximab treatment . J Autoimmun \n2014 ;50 :67 –76 .\n24365380 \n40 \n\nMino \nY \n, \n\nNaito \nT \n, \n\nShimoyama \nK \n, \n\nOgawa \nN \n, \n\nKawakami \nJ. \n\nEffective plasma concentrations of mycophenolic acid and its glucuronide in systemic lupus erythematosus patients in the remission‐maintenance phase . J Clin Pharm Ther \n2012 ;37 :217 –20 .\n21517926 \n41 \n\nEickenberg \nS \n, \n\nMickholz \nE \n, \n\nJung \nE \n, \n\nNofer \nJR \n, \n\nPavenstadt \nHJ \n, \n\nJacobi \nAM. \n\nMycophenolic acid counteracts B cell proliferation and plasmablast formation in patients with systemic lupus erythematosus . Arthritis Res Ther \n2012 ;14 :R110 .\n22571761 \n42 \n\nIsenberg \nDA. \n\nMeryl Streep and the problems of clinical trials . Arthritis Res Ther \n2012 ;14 :113 .\n22494430 \n43 \n\nVan Zelm \nMC \n, \n\nSzczepanski \nT \n, \n\nvan der Burg \nM \n, \n\nvan Dongen \nJJ. \n\nReplication history of B lymphocytes reveals homeostatic proliferation and extensive antigen–induced B cell expansion . 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B cell depletion therapy in systemic lupus erythematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response . Ann Rheum Dis \n2008 ;67 :1011 –6 .\n17962238 \n54 \n\nTeng \nYK \n, \n\nWheater \nG \n, \n\nHogan \nVE \n, \n\nStocks \nP \n, \n\nLevarht \nEW \n, \n\nHuizinga \nTW \n, et al. Induction of long‐term B‐cell depletion in refractory rheumatoid arthritis patients preferentially affects autoreactive more than protective humoral immunity . Arthritis Res Ther \n2012 ;14 :R57 .\n22409963\n\n",
"fulltext_license": "CC BY",
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"issue": "69(6)",
"journal": "Arthritis care & research",
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"medline_ta": "Arthritis Care Res (Hoboken)",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D015415:Biomarkers; D003430:Cross-Sectional Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007075:Immunoglobulin M; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
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"pages": "857-866",
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"pubdate": "2017-06",
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"references": "9324032;23740801;22032879;3541592;17312005;9802936;16188950;24889761;22409963;2679076;19029963;24057058;24365380;21532168;17276173;22325903;18250115;17008130;14976066;22253030;17500073;20948548;11905841;21517926;25916583;23740227;23241960;24296678;21125163;22494430;19302041;23064976;21398661;24884562;2865005;24554708;9099929;14561795;27110698;20829370;7906497;17412738;17962238;25556904;24831059;22571761;11526379;11067960;16447239;20525218;5309797;24778295;19935804",
"title": "Pragmatic Treatment of Patients With Systemic Lupus Erythematosus With Rituximab: Long-Term Effects on Serum Immunoglobulins.",
"title_normalized": "pragmatic treatment of patients with systemic lupus erythematosus with rituximab long term effects on serum immunoglobulins"
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"abstract": "A 29-year-old female with adult-onset Still's disease (AOSD) presented with progressive shortness of breath both on rest and on exertion, increased abdominal girth, and swelling in both legs. She was on oral prednisone and was recently started on canakinumab (interleukin-1 antagonist) for joint pain and rash of AOSD. Echocardiogram showed severely dilated right ventricle, dilated pulmonary artery, moderately reduced right ventricular systolic function, but with normal left ventricular systolic function. Computed tomography with contrast ruled out pulmonary embolism. Blood tests ruled out other rheumatologic diseases. The patient was diagnosed with right-sided heart failure likely secondary to AOSD. Right heart catheterization was needed but could not be performed because of severely dilated pulmonary artery. The patient was transferred to a higher center for further management and possible cardiopulmonary transplant.",
"affiliations": "Maimonides Medical Center, Brooklyn, NY, USA.;Maimonides Medical Center, Brooklyn, NY, USA.;Maimonides Medical Center, Brooklyn, NY, USA.;Maimonides Medical Center, Brooklyn, NY, USA.;Sri Aurobindo Institute of Medical Sciences, Indore, India.;Maimonides Medical Center, Brooklyn, NY, USA.",
"authors": "Sinha|Ankur|A|https://orcid.org/0000-0002-6245-3115;Patti|Ravikaran|R|;Ambesh|Paurush|P|;Obiagwu|Chukwudi|C|;Malhan|Namrita|N|;Chawla|Kabu|K|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961875726010.1177_2324709618757260Case ReportSevere Pulmonary Hypertension Due to Adult-Onset Still’s Disease https://orcid.org/0000-0002-6245-3115Sinha Ankur MBBS1Patti Ravikaran MBBS1Ambesh Paurush MBBS1Obiagwu Chukwudi MD1Malhan Namrita BDS2Chawla Kabu MD11 Maimonides Medical Center, Brooklyn, NY, USA2 Sri Aurobindo Institute of Medical Sciences, Indore, IndiaAnkur Sinha, MBBS, Department of Internal Medicine, Maimonides Medical Center, 4802 10th Avenue, Brooklyn, NY 11219, USA. Email: ansinha@maimonidesmed.org13 2 2018 Jan-Dec 2018 6 232470961875726030 12 2017 7 1 2018 © 2018 American Federation for Medical Research2018American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any 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).A 29-year-old female with adult-onset Still’s disease (AOSD) presented with progressive shortness of breath both on rest and on exertion, increased abdominal girth, and swelling in both legs. She was on oral prednisone and was recently started on canakinumab (interleukin-1 antagonist) for joint pain and rash of AOSD. Echocardiogram showed severely dilated right ventricle, dilated pulmonary artery, moderately reduced right ventricular systolic function, but with normal left ventricular systolic function. Computed tomography with contrast ruled out pulmonary embolism. Blood tests ruled out other rheumatologic diseases. The patient was diagnosed with right-sided heart failure likely secondary to AOSD. Right heart catheterization was needed but could not be performed because of severely dilated pulmonary artery. The patient was transferred to a higher center for further management and possible cardiopulmonary transplant.\n\npulmonary hypertensionadult-onset Still’s diseasecover-dateJanuary-December 2018\n==== Body\nIntroduction\nAdult-onset Still’s disease (AOSD) is a rare inflammatory autoimmune disease that is classically described by “Still’s triad” of fever, maculopapular rash, and arthritis, but it also has other atypical features like leukocytosis, elevated liver enzymes, and high serum ferritin levels.1 The etiology remains largely unknown.\n\nPulmonary arterial hypertension (PAH) is a disease characterized by progressive constriction of pulmonary arterioles, thereby causing an elevation in pulmonary arterial resistance and pressure. Although PAH has been reported with connective tissue disorders like systemic lupus erythematosus and systemic sclerosis, its association with AOSD is very rare.\n\nCase Report\nA 29-year-old female with AOSD presented with shortness of breath at rest. Her symptoms had progressed over 3 months. She complained of increased abdominal girth with swelling in both her legs. She had a history of poorly controlled AOSD with frequent flares leading to joint pain and rash. On discussion with the patient’s primary rheumatologist, we gathered that the patient had met criteria for diagnosis of AOSD (Yamaguchi criteria). The major criteria met were intermittent arthralgia lasting more than 4 weeks and leukocytosis as high as 13 000/mm with 91% neutrophils without evidence of infection. The minor criteria satisfying the diagnosis of AOSD were cervical lymphadenopathy on presentation, abnormal liver function tests (raised alkaline phosphatase to 138 U/L, aspartate aminotransferase of 75 U/L, and alanine aminotransferase of 60 U/L), a negative antinuclear antibody, and a negative rheumatoid factor. She met 5 criteria of AOSD with 2 major and 3 minor criteria. Workup for other rheumatologic conditions including systemic lupus erythematosus, systemic sclerosis, and CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome was negative. She was initially started on prednisone followed by conventional disease-modifying antirheumatoid drugs with little benefit. She had a previous trial of anakinra (interleukin-1 [IL] antagonist) as well as canakinumab (IL-1 antagonist) with no clinical improvement.\n\nOn admission, posteroanterior radiograph of the chest showed an enlarged cardiac silhouette with bilateral pleural effusions. Echocardiogram showed severely dilated pulmonary artery with dilated right ventricle. The estimated right ventricular systolic pressure was markedly elevated to 74.64 mm Hg, with moderately reduced right ventricular systolic function. Left ventricular systolic function was normal with an ejection fraction of 56% to 60%. The patient also had bilateral pleural effusion for which chest tubes were placed. Computed tomography with contrast ruled out pulmonary embolism, but the findings were significant for severely dilated pulmonary arterial trunk (Figures 1 and 2). Rheumatoid factor and antinuclear antibody were negative. Anti-dsDNA antibody was negative. The patient had evidence of active inflammation; serum ferritin was very high: 1167.5 ng/mL (normal 11-306 ng/mL in females). Complement levels were obtained, C3 level was low at 65 mg/dL (normal 80-180 mg/dL) and C4 level was normal at 11 mg/dL (normal 10-45). Erythrocyte sedimentation rate was 9 mm/h, and C-reactive protein was 1.43 mg/L.\n\nFigure 1. Computed tomography with contrast, coronal cut showing large pulmonary arterial trunk (arrow).\n\nFigure 2. Computed tomography with contrast, axial cut showing markedly dilated pulmonary trunk (arrow).\n\nThe patient was diagnosed with probable PAH with evidence of right heart failure. Right heart catheterization was considered, but could not be performed because of severely dilated pulmonary artery. Chest tubes were removed and the patient was transferred to a tertiary care center equipped to provide cardiopulmonary transplant.\n\nDiscussion\nAOSD is a clinical diagnosis, and an exclusion of other systemic disorders has to be carried out. The triad of fever, rash, and arthritis (Still’s triad) can be associated with macrophage activation syndrome, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and diffuse alveolar hemorrhage.1 The Yamaguchi criteria for diagnosis of AOSD2 are summarized in Table 1. Apart from these criteria, elevated ferritin levels can also aid in the diagnosis of AOSD.3\n\nTable 1. Yamaguchi Criteria for Diagnosis of AOSD.\n\nMajor criteria\t• Fever >39°C, lasting 1 week or longer\t\n\t• Arthralgia or arthritis, lasting 2 weeks or longer\t\n\t• Typical rash\t\n\t• Leukocytosis >10 000/mm with >80% polymorphonuclear cells\t\nMinor criteria\t• Sore throat\t\n\t• Recent development of significant lymphadenopathy\t\n\t• Hepatomegaly or splenomegaly\t\n\t• Abnormal liver function tests\t\n\t• Negative tests for antinuclear antibody and rheumatoid factor (IgM)\t\nExclusion criteria\t• Infections\t\n\t• Malignancies\t\n\t• Other rheumatic diseases\t\nFive or more criteria are required with 2 or more being major criteria for diagnosis of AOSD\t\nAbbreviations: AOSD, adult-onset Still’s disease; IgM, immunoglobulin M.\n\nAs high as 40% of patients with AOSD have evidence of cardiopulmonary manifestations. PAH has been documented with AOSD, but is exceedingly rare with only 9 cases reported in literature between 1990 and 2016.4 As per the updated clinical classification of pulmonary hypertension, PAH associated with connective tissue disorders are categorized as Group 1.5 The primary pathology is intimal proliferation and medial hypertrophy ultimately causing narrowing of the arteriolar lumen. The mechanism of damage in AOSD is not entirely known but the presence of inflammatory cells in the perivascular regions of the remodeled vessels favors an inflammatory pathology.6 AOSD involves an auto-inflammatory response, with dysregulation of several cytokines. These include IL-1, IL-6, IL-18, and tumor necrosis factor-α, and high levels of these cytokines have been observed in AOSD as well as idiopathic PAH.\n\nEchocardiography can suggest PAH with estimation of pulmonary artery pressure as well as right ventricular systolic pressure. Computed tomography scan of the chest may be performed to rule out interstitial lung involvement, or pathology favoring the diagnosis of other systemic diseases. Definitive diagnosis of PAH remains right heart catheterization with measurement of pulmonary capillary wedge pressure.\n\nSurvival after onset of PAH in patients with connective tissue diseases is shorter in comparison to idiopathic PAH.7 There have been no randomized clinical trials comparing treatment modalities for PAH secondary to AOSD and other connective tissue disorders, thus treatment is in the same lines as idiopathic PAH.8 Systemic inflammation plays a key role in the disease process of AOSD causing PAH. This is evident in studies that compared the use of anti-inflammatory/immunosuppressive therapy in conjunction with vasodilator therapies, and showed a significantly better response rate in comparison to vasodilator therapy alone.9\n\nTreatment of PAH is aimed at the primary cause of disease, but Group 1 PAH often needs advanced therapy. There are reports of clinical improvement of PAH with immunosuppressive therapy, and advanced therapy inclusive of endothelin receptor blockers, prostanoids, and phosphodiesterase-5 inhibitors have been associated with improvement in exercise tolerance and pulmonary hemodynamics.1 IL-1 receptor antagonists (anakinra) has been reported to cause rapid regression of disease.10 IL-6 inhibitor use (tocilizumab) has been proposed for AOSD based on the disease pathology. Suggested treatment modalities based on our literature review have been summarized in Table 2.\n\nTable 2. Suggested Treatment Modalities for PAH Due to AOSD Group 1 PAH.\n\nDrug Group\tMechanism of Action\tExample\t\nPrimary therapy\t\n Oral steroids\tImmunosuppressive\t• Prednisone\t\n DMARD\tImmunosuppressive\t• Methotrexate\t\n\t\t• Cyclosporine\t\nDrugs aimed at pulmonary hemodynamics\t\n Calcium channel blockers\tVasodilation, improved 5-year survival\t• Dihydropyridine\t\n\t\t• Diltiazem\t\n Prostaglandin analogs\tVasodilation\t• Epoprostenol (continuous IV)\t\n\t\t• Treprostinil (IV and subcutaneous)\t\n\t\t• Selexipab (oral)\t\n Endothelin antagonists\tVasodilation—as endothelin is vasoconstrictive and a mitogen\t• Bosentan (nonselective)\t\n\t\t• Ambisentan (selective)\t\n Nitric oxide–cyclic guanosine monophosphate enhancers\tVasodilation\t• Sildenafil\t\n\t\t• Tadafil\t\nCombination Therapy: May be needed for severe PAH. For Example, tadafil and ambisentan\t\nBiological agents aimed at AOSD\t\n Interleukin-1 antagonist\tCytokine blockade\t• Anakinra\t\n\t\t• Canakinumab\t\n Interleukin-6 antagonist\tCytokine blockade\t• Tocilizumab\t\nAbbreviations: PAH, pulmonary arterial hypertension; AOSD, adult-onset Still’s disease; DMARD, disease-modifying antirheumatic drug; IV, intravenous.\n\nLearning Points\nAOSD has been associated with PAH on rare occasions.\n\nPhysicians should keep a vigil watch for respiratory symptoms like shortness of breath, cough, and pleuritic chest pain in a patient with AOSD.\n\nSpecific therapy like anakinra and canakinumab should be attempted in addition to steroids.\n\nEarly referral to higher centers equipped in dealing with pulmonary hypertension, heart failure, and possible cardiopulmonary transplant can be lifesaving.\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\nEthical Approval: Ethical approval was not required as per institutional guidelines. Patient anonymity has been maintained throughout the article and images.\n\nInformed Consent: Informed consent was obtained.\n\nORCID iD: Ankur Sinha \nhttps://orcid.org/0000-0002-6245-3115\n==== Refs\nReferences\n1 \nEfthimiou P Kadavath S Mehta B. \nLife-threatening complications of adult-onset Still’s disease . Clin Rheumatol . 2014 ;33 :305 -314 . doi:10.1007/s10067-014-2487-4. 24435354 \n2 \nYamaguchi M Ohta A Tsunematsu T et al \nPreliminary criteria for classification of adult Still’s disease . J Rheumatol . 1992 ;19 :424 -430 .1578458 \n3 \nSchwarz-Eywill M Heilig B Bauer H Breitbart A Pezzutto A. \nEvaluation of serum ferritin as a marker for adult Still’s disease activity . Ann Rheum Dis . 1992 ;51 :683 -685 .1616341 \n4 \nWeatherald J Lategan J Helmersen D. \nPulmonary arterial hypertension secondary to adult-onset Still’s disease: response to cyclosporine and sildenafil over 15 years of follow-up . Respir Med Case Rep . 2016 ;19 :27 -30 . doi:10.1016/j.rmcr.2016.06.007. 27408785 \n5 \nSimonneau G Gatzoulis MA Adatia I et al \nUpdated clinical classification of pulmonary hypertension . J Am Coll Cardiol . 2013 :62 (25 suppl ):D34 -D41 . doi:10.1016/j.jacc.2013.10.029. 24355639 \n6 \nPrice LC Wort SJ Perros F et al \nInflammation in pulmonary arterial hypertension . Chest \n2012 ;141 :210 -221 .22215829 \n7 \nNgian GS Stevens W Prior D et al \nPredictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study . Arthritis Res Ther . 2012 ;14 :R213 .23039366 \n8 \nDistler O Pignone A. \nPulmonary arterial hypertension and rheumatic diseases—from diagnosis to treatment . Rheumatology (Oxford) . 2006 ;45 (suppl 4 ):iv22 -iv25 .16980719 \n9 \nJais X Launay D Yaici A et al \nImmunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases . Arthritis Rheum . 2008 ;58 :521 -531 .18240255 \n10 \nCampos M Schiopu E. \nPulmonary arterial hypertension in adult-onset Still’s disease: rapid response to anakinra . Case Rep Rheumatol . 2012 ;2012 :537613 . doi:10.1155/2012/537613. 22973530\n\n",
"fulltext_license": "CC BY",
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"journal": "Journal of investigative medicine high impact case reports",
"keywords": "adult-onset Still’s disease; pulmonary hypertension",
"medline_ta": "J Investig Med High Impact Case Rep",
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"title": "Severe Pulmonary Hypertension Due to Adult-Onset Still's Disease.",
"title_normalized": "severe pulmonary hypertension due to adult onset still s disease"
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"abstract": "BACKGROUND\nIntravitreal injection has become an efficient approach for delivering drugs at therapeutic levels to the posterior segment in retinal diseases. However, the increased frequency and number of intravitreal injections have raised concerns about their side effects. As manipulation during surgery is relatively simple, details of the procedure are easily overlooked. Iatrogenic crystalline lens injury is a rare complication caused by improper manipulation during surgical procedures. We report two cases of crystalline lens injury during intravitreal injection of triamcinolone acetonide (TA) with the hope of providing an insight into this treatment.\n\n\nMETHODS\nCase 1 was a 62-year-old woman with macular edema caused by central retinal vein occlusion in her right eye, and Case 2 was a 65-year-old man with macular edema caused by branch retinal vein occlusion in his right eye. In view of the patients' condition and economic constraints, an intravitreal injection of TA was administered. Due to inappropriate manipulation during surgery, the lens was injured. The site of lens injury and clinical manifestations were different in the two cases. Symptomatic treatment and continuous follow-up were carried out. The therapeutic effect following phacoemulsification of the cataract was satisfactory.\n\n\nCONCLUSIONS\nWell-defined surgical incision under proper anesthesia, sufficient patient information and proficient anatomical skills of the physician are mandatory to prevent this rare adverse event. Careful and meticulous phacoemulsification of the cataract is suggested.",
"affiliations": "Department of Ophthalmology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.;Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China.;Department of Ophthalmology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. liuxinquan1962@163.com.",
"authors": "Su|Jing|J|;Zheng|Li-Jun|LJ|;Liu|Xin-Quan|XQ|",
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"country": "United States",
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"doi": "10.12998/wjcc.v7.i22.3784",
"fulltext": "\n==== Front\nWorld J Clin CasesWJCCWorld Journal of Clinical Cases2307-8960Baishideng Publishing Group Inc jWJCC.v7.i22.pg378410.12998/wjcc.v7.i22.3784Case ReportIatrogenic crystalline lens injury during intravitreal injection of triamcinolone acetonide: A report of two cases Su Jing Department of Ophthalmology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaZheng Li-Jun Department of General Surgery, Shanghai Tenth People’s Hospital, Tongji University, Shanghai 200072, ChinaLiu Xin-Quan Department of Ophthalmology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. liuxinquan1962@163.comAuthor contributions: Su J was a major contributor in acquisition of the data, literature search and manuscript draft. Zheng LJ contributed to analysis of the data and preparation, revision of the manuscript. Liu XQ provided critical revision of the manuscript. All authors read and approved the final manuscript.\n\nSupported by Scientific Research Projects of Shanghai Municipal Health and Family Planning Commission, No. 201640049.\n\nCorresponding author: Xin-Quan Liu, MD, Chief Doctor, Department of Ophthalmology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, No. 725 South Wanping Road, Shanghai 200032, China. liuxinquan1962@163.com\n\nTelephone: +86-21-64385700\n\n26 11 2019 26 11 2019 7 22 3784 3791 26 5 2019 30 9 2019 15 10 2019 ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.2019This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.BACKGROUND\nIntravitreal injection has become an efficient approach for delivering drugs at therapeutic levels to the posterior segment in retinal diseases. However, the increased frequency and number of intravitreal injections have raised concerns about their side effects. As manipulation during surgery is relatively simple, details of the procedure are easily overlooked. Iatrogenic crystalline lens injury is a rare complication caused by improper manipulation during surgical procedures. We report two cases of crystalline lens injury during intravitreal injection of triamcinolone acetonide (TA) with the hope of providing an insight into this treatment.\n\nCASE SUMMARY\nCase 1 was a 62-year-old woman with macular edema caused by central retinal vein occlusion in her right eye, and Case 2 was a 65-year-old man with macular edema caused by branch retinal vein occlusion in his right eye. In view of the patients’ condition and economic constraints, an intravitreal injection of TA was administered. Due to inappropriate manipulation during surgery, the lens was injured. The site of lens injury and clinical manifestations were different in the two cases. Symptomatic treatment and continuous follow-up were carried out. The therapeutic effect following phacoemulsification of the cataract was satisfactory.\n\nCONCLUSION\nWell-defined surgical incision under proper anesthesia, sufficient patient information and proficient anatomical skills of the physician are mandatory to prevent this rare adverse event. Careful and meticulous phacoemulsification of the cataract is suggested.\n\nCrystalline lensIntravitreal injectionTriamcinolone acetonideIatrogenic injuryCase report\n==== Body\nCore tip: Iatrogenic crystalline lens injury is a rare complication caused by improper manipulation during surgical procedures. We report two cases of crystalline lens injury during intravitreal injection of triamcinolone acetonide. The site of lens injury and clinical manifestations were different in the two cases. Symptomatic treatment and continuous follow-up were carried out. We hope to provide an insight into this treatment.\n\nINTRODUCTION\nTriamcinolone acetonide (TA) is a type of glucocorticoid with long-lasting effects, which can inhibit cellular immunity, reduce inflammation and maintain the permeability of blood capillaries. It can also maintain the blood-retina barrier, limit fibrin exudation and inhibit the angiogenesis growth factor to prevent the formation of new blood vessels. Based on these features, TA is administered by intravitreal injection to treat vitreoretinal diseases at a local therapeutic and sustainable concentration. Although injection of Ozurdex has become the main treatment for macular edema in recent years[1], TA injection is an effective and inexpensive treatment and is still used in developing countries or regions. Recent research has indicated that intravitreal injection of TA is an efficient approach in the treatment of a variety of proliferative, edematous, neovascular and inflammatory ocular disorders[2-4]. Despite the efficacy of intravitreal TA injection, attention should be paid to its associated complications. These complications may be caused by the injection procedure or the side-effects of the corticosteroid. Long-term complications, such as cataract development and secondary glaucoma especially in the case of repeated injection, are attributed to the side effects of the corticosteroid. Immediate complications, such as conjunctival hemorrhage, retinal pigment epithelium tears, retinal detachment, vitreous hemorrhage and endophthalmitis, are due to the injection procedure. Iatrogenic crystalline lens injury is a rare complication of intravitreal TA injection, which occurs due to contact or penetration of the lens by the needle tip. We report two cases of iatrogenic crystalline lens injury during intravitreal injection of TA.\n\nCASE PRESENTATION\nChief complaints\nCase 1: A 62-year-old woman with a 5 mo history of central retinal vein occlusion in the right eye complained of severe vision impairment.\n\nCase 2: A 65-year-old man with macular edema caused by branch retinal vein occlusion in his right eye for 2 mo complained of visual deformity.\n\nHistory of present illness\nIn Case 1, the patient had received retinal photocoagulation therapy and treatment with oral Chinese medicine, but her condition did not improve. In Case 2, the patient experienced worsening visual disturbance for two weeks although he had received retinal photocoagulation therapy.\n\nHistory of past illness\nBoth patients had no remarkable history of illness.\n\nPhysical examination\nBoth patients had hyperopia. In Case 1, the eye axis was 22.15 mm and the spherical equivalent was 1.50 D. Her best-corrected visual acuity (BCVA) was 20/50 and the intraocular pressure (IOP) was 18 mmHg before injection. In Case 2, the eye axis was 21.68 mm and the spherical equivalent was 2.25 D. His BCVA was 20/100 and the IOP was 15 mmHg. Both patients had a shallow anterior chamber and the crystal lens was transparent on the whole under the slit lamp.\n\nImaging examinations\nIn Case 1, optical coherence tomography (OCT) revealed persistent cystoid macular and optic nerve edema (Figure 1A). In Case 2, OCT revealed cystoid macular edema and hemorrhage in the subtemporal quadrant of the retina.\n\nFigure 1 Case 1 optical coherence tomography imaging examinations. A: Before injection, optical coherence tomography (OCT) showed a serous retinal detachment and macular and optic nerve edema located at the outer retina; B: One month after injection, OCT showed that the macular edema was in remission, although the image was obscure; C: Seven months after injection, macular edema subsided significantly, but the macular membrane had formed.\n\nFINAL DIAGNOSIS\nMacular edema caused by retinal vein occlusion.\n\nTREATMENT\nIn China, anti-vascular therapy for macular edema secondary to retinal vein occlusion is not included in medical insurance. In view of the patients’ economic status and urgent desire for treatment, we treated the patients with intravitreal TA injection after informed consent related to treatment risk and associated complications was obtained. Briefly, 0.1 mL/4 mg TA was intravitreally injected under surface anesthesia into the superior temporal quadrant, 3.5 mm from the limbus of the cornea. All intravitreal injections were performed by the same right-handed resident.\n\nIn Case 1, on the first day after TA injection, slit lamp examination showed that the suspended TA particles formed a villiform opacity behind the posterior capsule. However, the lens cortex and core remained transparent (Figure 2A). There seemed to be a visible capsular channel perforation on the posterior capsule of the lens. The patient complained of blurred vision but no other discomfort. BCVA was fingers in front of the eyes and the IOP was 19 mmHg. The fundus was not observed. Follow-up after two weeks showed that the suspended TA particles behind the posterior capsule had a tendency to be absorbed (Figure 2B). The BCVA was enhanced to 20/166 and the IOP was 20 mmHg. One month later, the TA suspension behind the posterior capsule was further absorbed and the lens cortex and core remained transparent (Figure 2C). The BCVA was 20/133 and the IOP was 21 mmHg. Fuzzy fundus was observed and macular edema was alleviated (Figure 1B). The patient was subsequently lost to follow-up as she moved to another city. Eight months after the TA injection, she visited us again. The TA in the posterior capsule was mostly absorbed, limited rice crust opacity had formed and posterior subcapsular opacification was observed. A slow progressive opacity in the lens cortex and core was found (Figure 2D). OCT examination showed that macular edema had mostly subsided, but macular epiretinal membrane had appeared (Figure 1C). BCVA was enhanced to 20/100. However, the IOP rose to 32 mmHg without inflammation of the anterior and posterior chambers. She was prescribed timolol, brimonidine and latanoprost. The IOP was controlled to 21-25 mmHg. At 9 mo after intravitreal injection of TA, cataract surgery was performed with standard phacoemulsification devices. As rupture of the posterior capsule was predicted, we prepared for anterior vitrectomy before surgery. During the operation, the anterior chamber water pressure was reduced by keeping the height of the infusion bottle low. After annular tearing of the anterior capsule, only hydrodelineation was performed to prevent rupture of the posterior capsule or enlargement of the original tear. The nucleus and cortex were easily aspirated by an irrigation-aspiration probe with a low flow parameter due to the slight cataract. Posterior capsule holes were found during the process of removing the residual cortex and polishing the posterior capsule membrane. We were not sure whether the capsular tear was caused by the cataract surgery or needle puncture in the earlier intravitreal injection. In order to prevent further enlargement of the hole, polishing and irrigation-aspiration were stopped. This resulted in some cortical residues on the peripheral cortex and the posterior capsular surface. Fortunately, due to mild liquefaction of the vitreous body, vitreous exfoliation was inconspicuous despite rupture of the posterior capsule. We did not perform anterior vitrectomy and implanted the intraocular lens (IOL) directly into the ciliary sulcus. On the second day after surgery, there was no significant residual cortex in the pupil area, which did not affect the optic axis area.\n\nFigure 2 Case 1 slit lamp examinations. A: One day after injection, retroillumination showed that the suspended particles of triamcinolone acetonide (TA) formed a villiform opacity behind the posterior capsular; slit lamp examination showed a capsular channel perforation on the posterior capsule of the lens, but the lens cortex and core remained transparent; B: Two weeks after injection, retroillumination showed that the TA suspension behind the posterior capsule had a tendency to be absorbed; slit lamp examination showed that the lens cortex and core remained transparent; C: One month after injection, the TA suspension behind the posterior capsule was further absorbed; slit lamp examination showed that the lens cortex and core remained transparent; D: Eight months after injection, retroillumination showed that the TA particles were mostly absorbed, limited rice crust opacity had formed and posterior subcapsular opacification was found; slit lamp examination showed that the lens cortex and core had a slow progressive opacity; E: One week after cataract surgery, retroillumination showed that the posterior capsule had partial opacity in the upper quadrant of the nose, but no opacity in the pupil area; slit lamp examination showed that the intraocular lens was implanted in the sulcus.\n\nIn Case 2, on the first day after TA injection, the BCVA was 20/200 and the IOP was 42 mmHg. Lens opacity and expansion was observed under the slit lamp (Figure 3C). The image was blurred due to corneal edema. The IOP could not be controlled by anti-glaucoma medications in the following weeks. One week after injection, the patient underwent cataract surgery. The detailed procedure was the same as that in Case 1. The nucleus and cortex were removed by irrigation-aspiration using low flow parameters. A posterior capsule tear secondary to the injection was observed. Anterior vitrectomy was not performed as there was no obvious vitreous overflow. The IOL was then placed in the sulcus.\n\nFigure 3 Case 2 optical coherence tomography imaging examinations and slit lamp examinations. A: Before injection, optical coherence tomography (OCT) revealed cystoid macular edema; B: After cataract surgery, OCT revealed that macular edema had partially subsided; C: One day after injection, retroillumination showed the lens opacity and expansion. The image was blurred due to corneal edema; D: Four weeks after cataract surgery, retroillumination showed the remnants of the lens cortex in the upper quadrant.\n\nOUTCOME AND FOLLOW-UP\nIn Case 1, one week after surgery, the posterior capsule had partial opacity in the upper quadrant of the nose, but no opacity in the pupil area (Figure 2E). The patient’s BCVA increased to 20/33 and IOP was 15 mmHg without anti-glaucoma medications. Despite her improved eyesight, the patient still complained of sight deformation.\n\nIn Case 2, four weeks after surgery, BCVA was 20/50, and IOP was 16 mmHg without anti-glaucoma medications. Remnants of the lens cortex were found in the temporal quadrant (Figure 3D). Although not all the drugs were injected into the vitreous cavity, the macular edema partially subsided (Figure 3B).\n\nRegular follow-up visits were performed in both cases and no further complications were found. Both patients were satisfied with the final outcome and visual acuity.\n\nDISCUSSION\nIatrogenic crystalline lens injury due to needle tip contact or penetration is rare, with a reported incidence of 0.006%[5]. Only 4 cases have been reported. These four cases were all caused by intravitreal injection of dexamethasone into the crystalline lens[6-8]. In recent years, with the increase in Ozurdex injections, cases of iatrogenic lens injury have increased[9-11]. Due to the special suspending property of TA, the complication caused by TA implanted into the crystalline lens is unique. In our cases, the crystalline lens was injured, but cataract progression was not observed over the entire follow-up period. It was presumed that a small lens wound could heal spontaneously due to proliferation of the subcapsular epithelium which would seal the wound before the intraventricular passage of ions and fluid, leading to cataract progression[12]. The cataract remained stable in the superior-temporal quadrant without progress in Case 2. However, since we only monitored the patient for one week, a conclusion could not be drawn. As TA is composed of white suspended particles, feather-like turbidity formed, blocking the line of sight in Case 1 without cataract formation when TA was injected into the posterior capsule of the lens. Although not all TA injected into the posterior capsule of the lens was distributed in the vitreous cavity, it still played a role in the treatment of macular edema in Case 1. Although macular edema subsided, formation of the macular epiretinal membrane is rare. The reason for this requires further investigation.\n\nIn Case 1, the increase in IOP may be related to suspended TA particles which clogged the trabecular meshwork, which in turn was due to degeneration of the trabecular meshwork caused by steroid hormones. In Case 2, the increase in IOP was related to expansion of the lens caused by drug injection into the crystalline body. The experiences drawn from these two cases are as follows:\n\nThe injection site and angle\nThe site and the angle of the injection needle are important and are the main cause of lens injury. The needle used in intravitreal injection should puncture the pars plana corporis ciliaris, which is generally 3.5 mm-4 mm posterior to the limbus. In our two cases, we chose 3.5 mm using a caliper to measure from the limbus. We ignored the ocular axial length change in these cases. In Case 1, the eye axis was 22.15 mm, and in Case 2, the eye axis was 21.68 mm. Both cases had mild hyperopia with a short axial length. If the needle entry was performed according to the conventional 3.5 mm posterior to the limbus in short axial eyes, it would result in injection close to the ciliary body. On the one hand, injection close to the ciliary body would narrow the needle’s movable range and the needle could easily touch the lens. On the other hand, it might stimulate the ciliary body to cause pain, which will cause sudden movement of the operated eye, increase the difficulty of the operation and the risk of injury to adjacent structures. Therefore, the puncture site for intravitreal injection should be 4 mm posterior to the limbus, especially in hyperopia eyes.\n\nThe insert angle of the needle should be oblique toward the center of the optic nerve. It has been demonstrated that the angle between the posterior capsule of the crystalline lens and the retinal surface is 90°[5]. During surgery, in order to facilitate manipulation in the superior temporal quadrant, we asked the patient to look at his inferonasal quadrant during the operation. In such a position, the needling should be done perpendicular to the eyeball. If the needle is still at a fairly steep angle of less than 45°, it is more likely to damage the lens. Thus, the needle should be moved toward the optic nerve with a 90° angle after piercing the sclera.\n\nAnesthesia\nWe used surface anesthesia with alcaine eye drops. For some sensitive patients, this method is insufficient. Pain or tension during the operation may cause the patient to move their head or eyeball suddenly and results in lens injury. It is noteworthy that we used cotton swabs to displace the loose conjunctiva during the operation, and this may have led to a shift in the injection site location.\n\nDiameter of the needle\nThe recommended diameter of the needle is gauge 27 to reduce the risk of injury to ocular structures and wound leakage. In our procedure, we used 26 gauge needles. The thicker the needle, the greater the contact with the sclera, and greater strength for the injection is needed[13]. This caused movement of the eyeball due to local pain, and greater pressure resulted in a shorter distance between the needle and the lens.\n\nCONCLUSION\nAlthough intravitreal injection is a simple technique, it still requires a learning curve especially for young residents. Accurate selection of needle entry points and angles, appropriate anesthesia, stable head fixation, small-size injection needles and a comprehensive understanding of the patient’s condition before surgery are important to avoid complications. A careful preoperative evaluation and well-prepared cataract surgery can alleviate anatomical and functional damage.\n\nInformed consent statement: Informed written consent was obtained from the patient.\n\nConflict-of-interest statement: The authors declare that they have no conflict of interest.\n\nCARE Checklist (2016) statement: The manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: May 27, 2019\n\nFirst decision: September 9, 2019\n\nArticle in press: October 15, 2019\n\nSpecialty type: Medicine, Research and Experimental\n\nCountry of origin: China\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Meyer CH S-Editor: Zhang L L-Editor: Webster JR E-Editor: Liu JH\n==== Refs\n1 Schmitz K Maier M Clemens CR Höhn F Wachtlin J Lehmann F Bertelmann T Rüdiger K Horn M Bezatis A Spital G Meyer CH German Retinal Vein Occlusion Group Zuverlässigkeit und Sicherheit von intravitrealen Ozurdex-Injektionen Ophthalmologe 2014 111 44 52 23559321 \n2 Noma H Funatsu H Mimura T Shimada K Macular sensitivity and morphology after intravitreal injection of triamcinolone acetonide for macular edema with branch retinal vein occlusion Retina 2012 32 1844 1852 22653545 \n3 Campochiaro PA Wykoff CC Brown DM Boyer DS Barakat M Taraborelli D Noronha G Tanzanite Study Group Suprachoroidal Triamcinolone Acetonide for Retinal Vein Occlusion: Results of the Tanzanite Study Ophthalmol Retina 2018 2 320 328 31047241 \n4 Ghoraba HH Leila M Elgouhary SM Elgemai EEM Abdelfattah HM Ghoraba HH Heikal MA Safety of high-dose intravitreal triamcinolone acetonide as low-cost alternative to anti-vascular endothelial growth factor agents in lower-middle-income countries Clin Ophthalmol 2018 12 2383 2391 30538421 \n5 Meyer CH Rodrigues EB Michels S Mennel S Schmidt JC Helb HM Hager A Martinazzo M Farah ME Incidence of damage to the crystalline lens during intravitreal injections J Ocul Pharmacol Ther 2010 26 491 495 20874500 \n6 Taright N Guedira G Morfeq H Drimbea A Milazzo S Prevention of accidental injection of dexamethasone intravitreal implant into the crystalline lens J Fr Ophtalmol 2016 39 e211 e212 27566881 \n7 Abdolrahimzadeh S Parisi F Abdolrahimzadeh B Cruciani F Unusual choroidal vessels in neurofibromatosis type 1 observed with near-infrared reflectance and spectral domain optical coherence tomography Acta Ophthalmol 2016 94 e815 e816 27543268 \n8 Berarducci A Sian IS Ling R Inadvertent dexamethasone implant injection into the lens body management Eur J Ophthalmol 2014 24 620 622 24519508 \n9 Koller S Neuhann T Neuhann I Conspicuous crystalline lens foreign body after intravitreal injection Ophthalmologe 2012 109 1119 1121 23053335 \n10 Kurt A Durukan AH Küçükevcilioğlu M Accidental Intralenticular Injection of Ozurdex® for Branch Retinal Vein Occlusion: Intact Posterior Capsule and Resolution of Macular Edema Case Rep Ophthalmol Med 2019 2019 \n11 Baskan B Cıcek A Gulhan A Gundogan M Goktas S Ozurdex completely located inside a crystallized lens - Results of 14 months Am J Ophthalmol Case Rep 2016 4 38 40 29503921 \n12 Fagerholm PP Philipson BT Human traumatic cataract. A quantitative microradiographic and electron microscopic study Acta Ophthalmol (Copenh) 1979 57 20 32 419973 \n13 Kozak I Dean A Clark TM Falkenstein I Freeman WR Prefilled syringe needles versus standard removable needles for intravitreous injection Retina 2006 26 679 683 16829812\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "7(22)",
"journal": "World journal of clinical cases",
"keywords": "Case report; Crystalline lens; Iatrogenic injury; Intravitreal injection; Triamcinolone acetonide",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "3784-3791",
"pmc": null,
"pmid": "31799305",
"pubdate": "2019-11-26",
"publication_types": "D002363:Case Reports",
"references": "27566881;23053335;419973;30538421;31047241;22653545;29503921;30809404;16829812;20874500;27543268;24519508;23559321",
"title": "Iatrogenic crystalline lens injury during intravitreal injection of triamcinolone acetonide: A report of two cases.",
"title_normalized": "iatrogenic crystalline lens injury during intravitreal injection of triamcinolone acetonide a report of two cases"
} | [
{
"companynumb": "CN-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-121216",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
... |
{
"abstract": "Preliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported.\n\n\n\nIn this double-blind, phase 3 trial, men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. Overall survival was assessed with a group sequential testing procedure and an O'Brien-Fleming-type alpha-spending function.\n\n\n\nAs of October 15, 2019, a total of 288 of 933 patients (31%) in the enzalutamide group and 178 of 468 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% confidence interval [CI], 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4 to 63.0) in the placebo group (hazard ratio for death, 0.73; 95% CI, 0.61 to 0.89; P = 0.001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the enzalutamide group and 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events.\n\n\n\nEnzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.).",
"affiliations": "From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.;From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.",
"authors": "Sternberg|Cora N|CN|;Fizazi|Karim|K|;Saad|Fred|F|;Shore|Neal D|ND|;De Giorgi|Ugo|U|;Penson|David F|DF|;Ferreira|Ubirajara|U|;Efstathiou|Eleni|E|;Madziarska|Katarzyna|K|;Kolinsky|Michael P|MP|;Cubero|Daniel I G|DIG|;Noerby|Bettina|B|;Zohren|Fabian|F|;Lin|Xun|X|;Modelska|Katharina|K|;Sugg|Jennifer|J|;Steinberg|Joyce|J|;Hussain|Maha|M|;|||",
"chemical_list": "D000726:Androgen Antagonists; D001549:Benzamides; D009570:Nitriles; D010919:Placebos; D010669:Phenylthiohydantoin; C540278:enzalutamide; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa2003892",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "382(23)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000726:Androgen Antagonists; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D004311:Double-Blind Method; D006801:Humans; D007610:Kallikreins; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010669:Phenylthiohydantoin; D010919:Placebos; D017430:Prostate-Specific Antigen; D064129:Prostatic Neoplasms, Castration-Resistant; D016019:Survival Analysis",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "2197-2206",
"pmc": null,
"pmid": "32469184",
"pubdate": "2020-06-04",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer.",
"title_normalized": "enzalutamide and survival in nonmetastatic castration resistant prostate cancer"
} | [
{
"companynumb": "FR-ASTELLAS-2018US017289",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRIMEBUTINE MALEATE"
},
"drugadditional": nul... |
{
"abstract": "Haematopoietic stem cell transplantation (HSCT) is used worldwide in various malignant and nonmalignant childhood diseases, including haematologic, genetic, autoimmune and metabolic disorders, and is the only curative treatment for many of these illnesses. The survival rates of many childhood diseases have been increased due to HSCT treatment. However, associated complications are still important for management. Central nervous system (CNS) complications in paediatric HSCT recipients can be associated with high morbidity and significantly contribute to mortality. Posterior reversible encephalopathy syndrome (PRES) is one of the most common CNS complications in patients with neurological symptoms following HSCT. Magnetic resonance imaging (MRI) is the modality of choice and shows typical bilateral vasogenic oedema at the posterior parts of the cerebral hemispheres; however, various atypical imaging manifestations can also occur. In this study, we retrospectively examined CNS complications in our paediatric HSCT recipients with a focus on the typical and atypical neuroimaging manifestations of PRES following HSCT.\n\n\n\nWe retrospectively reviewed the medical records of 300 consecutive paediatric HSCT recipients from January 2014 to November 2018. A total of 130 paediatric HSCT recipients who experienced neurological signs and symptoms and were evaluated with neuroimaging studies following HSCT were enrolled in the study. The timing of CNS complications was defined according to immune status, including the pre-engraftment period (< 30 days after HSCT), the early postengraftment period (30-100 days after HSCT), and the late postengraftment period (> 100 days after HSCT), which were defined as phases 1, 2 and 3, respectively.\n\n\n\nOverall, 130 paediatric HSCT recipients experienced neurological signs and symptoms and therefore underwent neuroimaging examinations. Among these 130 patients, CNS complications were present in 23 patients (17.6%, 23/130), including 13 (56.5%) females and 10 (43.5%) males with a median age of 8.0 years (range, 8 months to 18.0 years). Among these 23 patients, 14 cases of PRES (60.9%), 5 (21.7%) cases of leukoencephalopathy, 3 cases of acute subdural haemorrhage (ASDH) (13%) and 1 (4.3%) case of fungal CNS infection were identified by neuroimaging. On MRI, typical parietooccipital vasogenic oedema was present in 78.5% of the PRES cases (11/14). The following atypical neuroimaging manifestations were observed: isolated involvement of the bilateral frontal lobes in 1 case, isolated cerebellar vermis involvement in 1 case, and isolated basal ganglia involvement in 1 case. Restricted diffusion associated with cytotoxic damage was demonstrated in 2 of 14 cases, one of which also showed subacute cytotoxic injury with ADC pseudonormalization.\n\n\n\nPaediatric HSCT recipients presenting with CNS signs and symptoms should be evaluated by neuroimaging studies for timely diagnosis and early management. PRES is the most common CNS complication and may present with atypical MRI manifestations, which should not dissuade a PRES diagnosis in appropriate clinical settings.",
"affiliations": "Department of Radiology, Altınbas University School of Medicine Bahcelievler Medical Park Hospital, İstanbul, Turkey.;Department of Radiology, University of Health Sciences, Prof Dr Cemil Tascıoglu City Hospital, Istanbul, Turkey. drberrinerok@hotmail.com.;Department of Hematology, Altınbas University School of Medicine Bahcelievler Medical Park Hospital, İstanbul, Turkey.",
"authors": "Atça|Ali Önder|AÖ|0000-0002-7500-3316;Erok|Berrin|B|0000-0001-8036-547X;Aydoğdu|Selime|S|0000-0003-3380-3080",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12887-021-02890-y",
"fulltext": "\n==== Front\nBMC Pediatr\nBMC Pediatr\nBMC Pediatrics\n1471-2431\nBioMed Central London\n\n2890\n10.1186/s12887-021-02890-y\nResearch\nNeuroimaging findings of posterior reversible encephalopathy syndrome (PRES) following haematopoietic stem cell transplantation in paediatric recipients\nhttps://orcid.org/0000-0002-7500-3316\nAtça Ali Önder atcaali@hotmail.com\n\n1\nhttps://orcid.org/0000-0001-8036-547X\nErok Berrin drberrinerok@hotmail.com\n\n2\nhttps://orcid.org/0000-0003-3380-3080\nAydoğdu Selime selimea69@hotmail.com\n\n3\n1 grid.449305.f 0000 0004 0399 5023 Department of Radiology, Altınbas University School of Medicine Bahcelievler Medical Park Hospital, İstanbul, Turkey\n2 Department of Radiology, University of Health Sciences, Prof Dr Cemil Tascıoglu City Hospital, Istanbul, Turkey\n3 grid.449305.f 0000 0004 0399 5023 Department of Hematology, Altınbas University School of Medicine Bahcelievler Medical Park Hospital, İstanbul, Turkey\n11 10 2021\n11 10 2021\n2021\n21 4455 6 2021\n9 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\nHaematopoietic stem cell transplantation (HSCT) is used worldwide in various malignant and nonmalignant childhood diseases, including haematologic, genetic, autoimmune and metabolic disorders, and is the only curative treatment for many of these illnesses. The survival rates of many childhood diseases have been increased due to HSCT treatment. However, associated complications are still important for management. Central nervous system (CNS) complications in paediatric HSCT recipients can be associated with high morbidity and significantly contribute to mortality. Posterior reversible encephalopathy syndrome (PRES) is one of the most common CNS complications in patients with neurological symptoms following HSCT. Magnetic resonance imaging (MRI) is the modality of choice and shows typical bilateral vasogenic oedema at the posterior parts of the cerebral hemispheres; however, various atypical imaging manifestations can also occur. In this study, we retrospectively examined CNS complications in our paediatric HSCT recipients with a focus on the typical and atypical neuroimaging manifestations of PRES following HSCT.\n\nMethods\n\nWe retrospectively reviewed the medical records of 300 consecutive paediatric HSCT recipients from January 2014 to November 2018. A total of 130 paediatric HSCT recipients who experienced neurological signs and symptoms and were evaluated with neuroimaging studies following HSCT were enrolled in the study. The timing of CNS complications was defined according to immune status, including the pre-engraftment period (< 30 days after HSCT), the early postengraftment period (30–100 days after HSCT), and the late postengraftment period (> 100 days after HSCT), which were defined as phases 1, 2 and 3, respectively.\n\nResults\n\nOverall, 130 paediatric HSCT recipients experienced neurological signs and symptoms and therefore underwent neuroimaging examinations. Among these 130 patients, CNS complications were present in 23 patients (17.6%, 23/130), including 13 (56.5%) females and 10 (43.5%) males with a median age of 8.0 years (range, 8 months to 18.0 years). Among these 23 patients, 14 cases of PRES (60.9%), 5 (21.7%) cases of leukoencephalopathy, 3 cases of acute subdural haemorrhage (ASDH) (13%) and 1 (4.3%) case of fungal CNS infection were identified by neuroimaging. On MRI, typical parietooccipital vasogenic oedema was present in 78.5% of the PRES cases (11/14). The following atypical neuroimaging manifestations were observed: isolated involvement of the bilateral frontal lobes in 1 case, isolated cerebellar vermis involvement in 1 case, and isolated basal ganglia involvement in 1 case. Restricted diffusion associated with cytotoxic damage was demonstrated in 2 of 14 cases, one of which also showed subacute cytotoxic injury with ADC pseudonormalization.\n\nConclusion\n\nPaediatric HSCT recipients presenting with CNS signs and symptoms should be evaluated by neuroimaging studies for timely diagnosis and early management. PRES is the most common CNS complication and may present with atypical MRI manifestations, which should not dissuade a PRES diagnosis in appropriate clinical settings.\n\nKeywords\n\nHaematopoietic stem cell transplantation\nPosterior reversible encephalopathy syndrome\nCNS complications\nPRES\nMRI\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcIntroduction\n\nHaematopoietic stem cell transplantation (HSCT) refers to intravenous infusion of haematopoietic progenitor cells derived from bone marrow, umbilical cord blood or peripheral blood to restore the haematologic and immunologic functions of bone marrow. In autologous transplantation (AutoHSCT), the donor is the patient himself/herself before bone marrow ablation. On the other hand, in allogeneic transplantation (AlloHSCT), the donor is usually human leukocyte antigen (HLA)-compatible or may sometimes be a haploidentical (half matched, mismatched) donor. HSCT is used worldwide in many malignant and nonmalignant childhood diseases, including haematologic, genetic, autoimmune and metabolic disorders. The survival rates of these diseases have been increased with HSCT treatment [1, 2]. However, associated complications are still important for management, which can be related to chemotherapy- or radiotherapy-related toxicity or can be associated with the state of immunosuppression predisposing patients to infection. Before HSCT, some recipients are prepared with high doses of chemotherapy and frequently with accompanying total body irradiation (TBI). These regimens may be myeloablative or lower-intensity nonmyeloablative. After HSCT, a chemotherapy regimen is initiated to prevent graft rejection and graft versus host disease (GVHD). Central nervous system (CNS) complications in paediatric HSCT recipients can be associated with high morbidity and significantly contribute to mortality. Moreover, the presence of neuroimaging abnormalities is associated with higher mortality in paediatric HSCT recipients [3]. One of the most common CNS complications in patients with neurological symptoms following HSCT is posterior reversible encephalopathy syndrome (PRES). In PRES, magnetic resonance imaging (MRI) is the modality of choice and shows typical bilateral vasogenic oedema. The most common presentation is posterior encephalopathy in which lesions are located at the posterior parts of the cerebral hemispheres, namely, the occipitoparietal lobes [4–6]. However, it may also show a nonposterior distribution and can be associated with various atypical imaging findings. In this study, we retrospectively examined CNS complications that occurred in our paediatric HSCT recipients who presented with CNS signs and symptoms with a focus on the typical and atypical neuroimaging findings of PRES following HSCT.\n\nMethods\n\nWe retrospectively reviewed the medical records of 300 consecutive paediatric patients who underwent HSCT from January 2014 to November 2018. A total of 130 paediatric HSCT recipients who experienced neurological signs and symptoms and were evaluated with neuroimaging studies following HSCT were enrolled in the study and the following data of 23 patients who had CNS complications were recorded: patient demographics, indications for and types of HSCT, pre- and post-transplant drug regimens, the application of total body irradiation (TBI), the presenting neurological signs and symptoms, and neuroimaging findings.Imaging studies, including magnetic resonance (MR) imaging of the brain and/or computed tomography (CT) of the head, were retrospectively evaluated for the presence of any imaging abnormalities. CT was performed in 48 patients as a first-line imaging method to exclude haemorrhagic events. The CT images were obtained using 64 channel MDCT scanners (Philips Medical Systems, Brilliance 64, the Netherlands). MR imaging was performed in 96 cases with the Siemens 3 T MAGNETOM Skyra MRI scanner with a dedicated head coil. The pulse sequences were coronal FLAIR (TE/TR =125/10000 msec; TI = 2800 msec), axial T2 (TE/TR = 80/3000 msec), axial T1 (10/2000 msec), diffusion-weighted imaging (DWI) (TE/TR = 120/3500 msec) with apparent diffusion coefficient (ADC) maps and GRE (16/840 msec) sequences. In 14 cases, both CT and MRI were performed. In addition to pathological signal intensities on conventional MRI sequences (T1W, T2W and FLAIR), any pathological findings on DWI, GRE and contrast-enhanced T1W images were also recorded. The timing of CNS complications was defined according to immune status, including the pre-engraftment period (< 30 days after HSCT), the early postengraftment period (30–100 days after HSCT), and the late postengraftment period (> 100 days after HSCT), which were defined as phases 1, 2 and 3, respectively.\n\nResults\n\nThe study population included 130 paediatric HSCT recipients who experienced neurological signs and symptoms and therefore underwent neuroimaging examinations. Among these 130 patients, CNS complications were present in 23 patients (17.6%, 23/130). The patients included 13 (56.5%) females and 10 (43.5%) males with a median age of 8.0 years (range, 8 months to 18.0 years). The average age of the children at presentation was 8.40 ± 5.12 years. The underlying disorders for which HSCT was performed included acute lymphocytic leukaemia (ALL), acute myelogenous leukaemia (AML), lymphoma, thalassemia major, primary immune deficiencies, severe combined immune deficiency (SCID), Wiscott Aldrich syndrome (WA), haemophagocytic lymphohistiocytosis (HLH), sideroblastic anaemia (SA), aplastic anaemia (AA), Fanconi aplastic anaemia (FAA) and osteopetrosis. All of the patients underwent AlloHSCT. The sources of stem cells included bone marrow [n = 10], PBSCs [n = 9], bone marrow with PBSCs [n = 3] and bone marrow with cord blood [n = 1] from MSD [n = 4], MRD [n = 3], MUD [n = 10], and haploidentical donors [n = 6]. The preconditioning regimens were patient specific depending on the underlying disease and the types of donor and graft. All patients had received antibacterial, antifungal and antiviral prophylaxis. GVHD prophylaxis included calcineurin inhibitors, including cyclosporin A (CsA) (n = 18) and tacrolimus (n = 5) in combination with MTX with or without corticosteroids. The target serum concentration of CsA was determined to be 150–250 ng/mL for HSCT from MUT and haploidentical donors and 100–150 ng/mL for HSCT from MRT and MST donors. Five patients had received TBI (4 ALL, 1 lymphoma), and 7 patients had received chemotherapy (6 ALL, 1 AML) (Table 1). Twenty-three CNS complications included 14 cases of PRES (60.9%), 5 (21.7%) cases of leukoencephalopathy, 3 cases of acute subdural haemorrhage (SDH) (13%) and 1 (4.3%) case of fungal CNS infection (Tables 1, 2). The timing of the CNS complications is shown in Table 3. The most frequent neurological clinical signs and symptoms were headache followed by seizure, impaired consciousness and visual symptoms (Table 1). In PRES patients, the most frequent presentation was seizures, which were present in 71.4% of the PRES patients (10/14), followed by headache (50%) and visual symptoms (35,7%). While 6 cases of PRES occurred in phase 2, 5 cases were detected in phase 3, and 3 cases were detected in phase 1. Hypertension requiring antihypertensive treatment was present in 35.7% (5/14) of PRES cases at presentation. Of the 14 patients who developed PRES, 11 (78.5%) received cyclosporin A (CsA). In 4 (36.3%) of these cases, PRES developed when the CsA blood level was above the upper limit. In the remaining 7 (63.6%) patients, PRES occurred when the blood CsA level was within the normal range. Persistent signal changes were observed on follow-up MRI in 1 patient among the 4 patients who developed PRES and had a CsA blood level above the upper limit. Such changes were not observed in the patients whose CsA blood level was within the reference range, but this difference was not statistically significant (p > 0.05). On MRI, typical occipitoparietal vasogenic oedema was present in 78.5% of the PRES cases (11/14) (Table 4) (Fig. 1). The following atypical neuroimaging manifestations were identified: isolated involvement of bilateral frontal lobes in 1 case (Fig. 2), isolated cerebellar vermis involvement in 1 case (Fig. 3) and isolated basal ganglia involvement in 1 case (Fig. 4). MRI abnormalities were bilateral and almost symmetrical in all of the cases. Restricted diffusion associated with cytotoxic damage was demonstrated in 2 of 14 patients, one of whom had isolated cerebellar vermis involvement (Fig. 3). Unfortunately, she died 3 weeks after PRES onset due to acute pulmonary complications. The other patient presented with isolated basal ganglia involvement. In this patient, the lack of a dark signal on the ADC map despite increased signal intensity on DWI was considered ADC pseudonormalization rather than simple vasogenic oedema (Fig. 4). The median time of diagnosis from the day of first symptoms in PRES patients was 3 days for both typical and atypical presentations.While less delay was observed in the presentations with seizure and vomiting, the delay in diagnosis was more pronounced in patients with headache as an initial and dominant clinical finding. Follow-up imaging studies were performed in 9 of 14 patients with PRES. The other 5 patients died due to non-CNS complications. Among the 9 followed patients, reversibility was confirmed in 8 patients. In one patient with PRES who presented with basal ganglia involvement, persistent signal changes were detected 3 months after diagnosis. In this patient, the serum level of CsA was higher than the upper limit. In our patients with PRES, we did not detect haemorrhagic changes or pathologic contrast enhancement.Table 1 Demographics of the 23 patients who experienced CNS complications\n\nsex\tage\tdiagnosis\ttype of donor\tChemot-\nherapy\tRadio-\ntherapy\tGVHD prophylaxis\tSigns and symptoms\tCNS complications\tNeuroimaging findings of PFES\t\nMale\t10\tALL\tMUD\tyes\tno\tMTX + CsA\tseizure\tPRES\tParieto-occipital involvement\t\nMale\t12\tALL\tMUD\tyes\tno\tMTX + CsA\theadache\tSDH\tUnilateral left convexity\t\nFemale\t5\tMDS\tHaplo.\tno\tno\tMMF + TAC + CYC\timpaired consciousness, headache\tleukoencephalopathy\tSymmetrical periventricular T2W/FLAIR hyperintensity\t\nFemale\t0,75\tSCID\tHaplo.\tno\tno\tMMF + TAC + CYC\tNausea-\n\nvomiting\n\n\tSDH\tUnilateral right frontoparietal\t\nFemale\t9\tAA\tMRD\tno\tno\tMTX + CsA\tHeadache, impaired consciousness,\tFungal infection\tMultiple, small randomly distributed brain abscesses\t\nMale\t11\tAML\tHaplo.\tyes\tno\tMMF + TAC + CYC\tSeizure, Visual symptoms, headache\tPRES\tParieto-occipital involvement\t\nFemale\t7\tHLH\tHaplo.\tno\tno\tMMF + TAC + CYC\tHeadache\tPRES\tIsolated Cerebellum involvement\t\nFemale\t13\tFAA\tMUD\tno\tno\tMTX + CsA\tSeizure, Nausea- vomiting\tPRES\tParieto-occipital involvement\t\nMale\t15\tLymphoma\tMUD\tno\tTBI\tMTX + CsA\tSeizure, impaired consciousness\tPRES\tParieto-occipital involvement\t\nFemale\t8\tALL\tHaplo.\tyes\tTBI\tMTX + CsA + CYC\tNausea- vomiting\tleukoencephalopathy\tSymmetrical periventricular T2W/FLAIR hyperintensity\t\nFemale\t4\tSA\tMUD\tno\tno\tMTX + CsA\tHeadache, seizure\tleukoencephalopathy\tSymmetrical periventricular T2W/FLAIR hyperintensity\t\nMale\t7\tALL\tMUD\tyes\tTBI\tMTX + CsA\tHeadache, impaired consciousness\tleukoencephalopathy\tSymmetrical periventricular T2W/FLAIR hyperintensity\t\nFemale\t4\tTM\tMSD\tno\tno\tMTX + CsA\tHeadache,\n\nSeizure, visual symptoms\n\n\tPRES\tParieto-occipital involvement\t\nFemale\t8\tTM\tMSD\tno\tno\tMTX + CsA\tseizure\tPRES\tIsolated basal ganglia involvement\t\nFemale\t3\tTM\tMUD\tno\tno\tMTX + CsA\tVisual symptoms, headache\tPRES\tParieto-occipital involvement\t\nMale\t0,66\tOsteopetrosis\tMRD\tno\tno\tMTX + CsA\tNausea- vomiting\tSDH\tUnilateral left frontoparietal\t\nMale\t0,91\tWA\tHaplo.\tno\tno\tMMF + TAC + CYC\tSeizure\tPRES\tParieto-occipital involvement\t\nFemale\t17\tTM\tMRD\tno\tno\tMTX + CsA\tHeadache,\n\nNausea-\n\nvomiting\n\n\tPRES\tİsolated frontal involvement\t\nFemale\t5\tTM\tMUD\tno\tno\tMTX + CsA\tHeadache, seizure, impaired consciousness\tPRES\tParieto-occipital involvement\t\nMale\t14\tALL\tMUD\tyes\tTBI\tMTX + CsA\tseizure\tPRES\tParieto-occipital involvement\t\nMale\t13\tTM\tMSD\tno\tno\tMTX + CsA\tVisual symptoms, Nausea- vomiting, seizure\tPRES\tParieto-occipital involvement\t\nFemale\t18\tTM\tMUD\tno\tno\tMTX + CsA\timpaired consciousness, visual symptoms\tPRES\tParieto-occipital involvement\t\nMale\t8\tALL\tMSD\tyes\tTBI\tMTX + CsA\timpaired consciousness, headache\tleukoencephalopathy\tSymmetrical periventricular T2W/FLAIR hyperintensity\t\nCsA: CYC: MMF: MTX: TAC:\n\nTable 2 CNS Complications\n\n\tn\t%\t\nLeukoencephalopathy\t5\t21,7\t\nPRES\t14\t60.9\t\nFungal CNS infection\t1\t4.3\t\nSDH\t3\t13\t\n\nTable 3 Twenty-three CNS complications following HSCT in relation to the chronology of HSCT\n\n\tPhase 1\tPhase 2\tPhase 3\tNumber\t\nPRES\t3\t6\t5\t14\t\nLeukodystrophy\t\t1\t4\t5\t\nAcute Subdural haemorrhage\t3\t\t\t3\t\nFungal CNS infection\t\t\t1\t1\t\n\nTable 4 Encephalic locations in 14 PRES cases\n\nInvolvement of encephalic locations\t%\t\nTypical occipitoparietal involvement\t78.5%\t\nAtypical involvement\t21.5%\t\n-isolated bilateral frontal lobes\t7,16%\t\n-isolated basal ganglia\t7,16%\t\n-isolated cerebellar vermis\t7,16%\t\n\nFig. 1 An 11-year-old boy presenting with seizures and visual disturbances 3 months after undergoing allogeneic HSCT for acute myeloid leukaemia. a Axial and b) coronal FLAIR images demonstrating bilateral symmetrical parietal (a) and occipital (b) cortico-subcortical hyperintensity (black arrows). Note the prominent involvement of cortical grey matter (1a, white arrow). c DWI and d) an ADC map showing a high signal (arrows) representing the T2 shine-through effect but not true restricted diffusion. e Follow-up coronal FLAIR image demonstrating complete resolution of vasogenic oedema in the occipital lobes after 3 months\n\nFig. 2 A 17-year-old girl presenting with an altered level of consciousness 6 months after undergoing allogeneic HSCT for thalassemia major. a Axial T2W image showing bilateral frontal cortico-subcortical hyperintensity (arrows). b DWI and c) an ADC map showing a high signal (arrows) representing the T2 shine-through effect but not true restricted diffusion. d Axial T2W image demonstrating complete resolution of vasogenic oedema after 3 months\n\nFig. 3 A 7-year-old girl presenting with seizures and headache 37 days after undergoing allogeneic HSCT for haemophagocytic lymphohistiocytosis. a Axial T2W image showing abnormal cerebellar hyperintensity (arrows). b DWI and c) ADC images showing diffusion restriction (arrows). She died 3 weeks after PRES onset due to acute pulmonary GVHD\n\nFig. 4 A 17-year-old girl presenting with an altered level of consciousness 6 months after undergoing allogeneic HSCT for thalassemia major. a Coronal FLAIR image showing hyperintensity in the bilateral basal ganglia (arrows). b DWI showing increased signal intensity in the basal ganglia. c ADC map showing normal signal intensity, which was considered to be indicative of ADC pseudonormalization. d Follow-up coronal FLAIR image after 6 months demonstrating persistent hyperintensity associated with volume loss, suggesting cytotoxic injury\n\nLeukoencephalopathy was identified in 5 patients, which occurred in one patient during phase 2 and in the remaining patients during phase 3 (Table 3). On MRI, periventricular white matter hyperintensity on T2/FLAIR images with no diffusion restriction was present with normal preceding CT images. In the follow-up, total resolution of the MRI signal abnormalities was not observed in any of the cases (Fig. 5). Intracranial haemorrhage was identified in only 3 cases, all of which were acute SDH occurring in phase 1, and in the follow-up of these patients, total haemorrhage resolution was confirmed (Fig. 6). Fungal CNS infection was observed in one of the patients with a positive sputum culture for Aspergillus in the intensive care unit (ICU) (Fig. 7).Fig. 5 An 8-year-old girl presenting with headache, nausea and vomiting 5 months after undergoing allogeneic HSCT for ALL. a Axial CT of the head did not reveal any abnormalities. b Axial T2W image showing increased signal intensity in the periventricular white matter (b, arrows). d Follow-up axial T2W image 3 months after the first presentation shows persistent increased signal intensity in the periventricular white matter (c, arrows)\n\nFig. 6 A 9-month-old female girl presenting with nausea and vomiting 25 days after undergoing allogeneic HSCT for SCID. a Axial CT image showing acute hyperdense right frontoparietal SDH (arrow). b Follow-up axial CT image 1 month after the onset of acute SDH showing complete resolution\n\nFig. 7 A 9-year-old girl presenting with headache and impaired consciousness 5 months after undergoing allogeneic HSCT for aplastic anaemia. a Axial T2W image showing a cystic lesion with peripheral oedema in the left medial temporal region (arrow). b Axial T1w image showing hypointensity of the lesion. c, d Postcontrast axial T1W images showing ring enhancement of the same lesion and another similar lesion at the frontal convexity (d, arrow) compatible with a brain abscess\n\nDiscussion\n\nThe incidence of CNS complications following HSCT varies considerably in different studies depending on the patients’ demographic and clinical data, including pre-post-transplant drug regimens, the application of TBI, the degree of immune suppression or the development of GVHD. The rate is higher in patients with AlloHSCT than in patients with AutoHSCT and reaches up to 70% in some studies [7, 8]. In a recently conducted study by Hussein et al., which retrospectively evaluated 525 HSCT recipients, the prevalence was reported to be 13% [9]. In our study, the prevalence was 7.66% (23/300), which is similar to the rate of 8.67% (26/300) reported by Suxiang Liu et al. [10]. The prevalence among the recipients presenting with CNS signs and symptoms following HSCT in our study was 17.6% (23/130). Among these 23 patients, the most common clinical signs and symptoms were headache followed by seizure, visual symptoms and impaired consciousness. In our study, PRES was the most common CNS complication, which was observed in 4.6% of the 300 HSCT recipients (14/300) and was more frequent at < 100 days post-HSCT. Although different causes are responsible for PRES in paediatric patients, it is mostly described as a complication following various types of transplantation, and in many studies, it is the most common neuroimaging abnormality following HSCT. The incidence of PRES following allogenic HSCT in paediatric patients varies between 1.1–34% in different clinical studies in the literature and is affected by various factors, including the drugs used in the conditioning regimens and GVHD prophylaxis, the presence of HT, the level of immune suppression, underlying diseases, the type of transplantation, and the presence of triggering factors such as infections and GVHD [4, 11–13]. In a study retrospectively evaluating 35 paediatric HSCT recipients, the incidence of PRES was reported to be 17% (n = 6). In this study, all PRES patients were taking CNIs at the time of symptom onset, and the median time after HSCT to PRES onset was 21 days (phase 1) [14]. PRES is a clinical and radiologic diagnosis characterized by variable presentations with various combinations of acute neurological symptoms. In paediatric patients diagnosed with PRES, the most frequently reported primary presentation is seizures, as in our PRES patients [15]. The underlying pathophysiologic mechanism is controversial, and two main theories have been proposed. According to vasogenic theory, high blood pressure causes dysregulation of cerebrovascular autoregulation, resulting in cerebral vasodilation and oedema [5, 16]. However, arterial hypertension is not present in all patients with PRES. In our study, hypertension requiring antihypertensive treatment was present in 5 cases of PRES. On the other hand, according to cytotoxic theory, the cause is increased microvascular permeability as a result of direct toxic effects on endothelial cells [17]. The absence of increased blood pressure in many of the patients supports the cytotoxic theory, as in observed our cases. Immunosuppressive medications, such as CsA, TAC, and steroids, which are the most commonly used drugs for GVHD prophylaxis, can induce PRES in HSCT recipients [18–20]. On MRI, typical findings of cerebral vasogenic oedema as a result of extravasation of plasma proteins and cells into the extracellular space are demonstrated. In our patients, typical occipitoparietal vasogenic oedema was present in 78.5% of the PRES cases (11/14) (Fig. 1). In many studies, occipitoparietal involvement was predominantly reported to vary between 50 and 99% of their cases [15, 20]. Cerebral cortical (grey matter) involvement is observed in many patients, as in our cases [21, 22]. (Figs. 1 and 2). Despite being termed posterior, PRES can also show other distributions, mainly in watershed areas, which can be involved in combination or in isolation [23]. The uncommon locations observed in our patients were as follows: isolated involvement of the frontal lobes (Fig. 2), cerebellum (Fig. 3) and basal ganglia (Fig. 4). The term central PRES is used to describe isolated involvement of the basal ganglia, thalamus, brain stem and corpus callosum with a lack of cortico-subcortical involvement. The central variant of PRES was reported in 4% of cases in the study of McKinney et al. [24]. In the study of Raman et al. [25], the basal ganglia were involved in 22%, the brainstem in 9% and the thalamus in 4% of the cases. However, all of these cases also had lesions in the bilateral parietooccipital subcortical white matter. In our study, a central PRES variant with isolated involvement of the basal ganglia was observed in 1 patient (Fig. 4). In PRES, the lesions are usually symmetrical, as in our cases. However, purely unilateral cases of PRES have also been demonstrated in the literature [16, 24]. The symmetrical involvement and reversibility of the MRI findings in the patient with frontal involvement was compatible with PRES. In the patient with isolated basal ganglia and cerebellar vermis involvement presenting with restricted diffusion and the patient exhibiting the symmetrical basal ganglia involvement and restricted diffusion only in the basal ganglia and the vermis without extension to the cerebellar hemispheres, the findings suggested toxic metabolic aetiologies rather than vascular pathology. We excluded all other toxic metabolic aetiologies, including metabolic toxins (such as carbon monoxide), hypoglycaemia, hyperammonemia or hypoxia.\n\nIn PRES lesions, increased ADC values are characteristic and indicative of vasogenic oedema. DWI may be normal, or hyperintensity is often observed due to the T2 shine-through effect. However, true restricted diffusion may also present as an atypical finding in PRES lesions [26], which is important because higher ADC values are associated with reversibility, while decreased ADC values indicate cytotoxic injury and a poor prognosis [27]. In the study of McKinney et al. [24], 17.3% of the 76 patients with PRES had restricted diffusion, and in the study of Covarrubias et al. [28], 27% of 22 patients with PRES showed restricted diffusion. In the study of Hussein et al., the incidence of PRES in post-HSCT recipients was 3.2%, with the most frequent sites being the occipital and parietal regions in 88.2 and 82.4% of the patients, respectively. In their study, diffusion restriction was observed in 29.4% of the cases (n = 5), and no significant dark signal on ADC maps associated with pseudonormalization was noted in any of the 5 cases [9]. In our study, restricted diffusion was demonstrated in 2 of 14 PRES patients, one of whom showed isolated cerebellar vermiş involvement. Unfortunately, since the patient died from acute pulmonary complications 3 weeks after the onset of PRES, no follow-up MRI was available to determine whether the abnormal signals persisted (Fig. 3). The other patient presented with basal ganglia involvement, and an increased DWI signal was accompanied by normal ADC values indicating ADC pseudonormalization, which is a normal phase in the subacute stage of cytotoxic injury [29]. In the follow-up imaging studies of this patient, whose diagnosis was delayed, the latency period was characterized by volume loss and persistent signal changes, which is consistent with the association of restricted diffusion with persistent changes and a poor prognosis (Fig. 4).\n\nThe other reported atypical neuroimaging findings associated with PRES is accompanying haemorrhage and contrast enhancement, which were not present in our cases. Although PRES, as its names implies, is mostly reversible, residual sequelae formation can occur. In the follow-up, clinical recovery is usually observed earlier than disappearance of imaging findings and is usually associated with a good clinical outcome with early diagnosis and management.\n\nThe incidence of post-HSCT leukoencephalopathy was 1.6% in our study and was reported to be 1.9% in the study of Hussein S.A. et al. [14]. Four of our patients had CsA and MTX in their anti-GVHD regimen, 3 of whom had received TBI. In all 5 patients, CT images did not demonstrate any abnormality due to isodensity of the involved white matter, requiring further MRI studies to reveal hyperintensity on T2/FLAIR images with no diffusion restriction. In the follow-up images, a stable course was observed in all 5 cases; however, total resolution of the MRI signal abnormalities was not observed in any of the cases in our study (Fig. 5). Among our patients, intracranial haemorrhage was present in 3 patients, all of whom had acute SDH, and in the follow-up of these patients, total resolution of the haemorrhage was confirmed (Fig. 6). In the study of Hussein et al., the incidence of intracranial haemorrhage was reported to be 1.5% (n = 8), with 3/8 (37.5%) being SDH (36). We observed only one case of CNS infection, which occurred when the patient was followed in the intensive care unit, and multifocal invasive Aspergillosis was confirmed by sputum culture. MRI showed multiple randomly distributed enhanced rings surrounding small brain abscesses. Unfortunately, this patient died after a short time, and no CSF or histopathological confirmation was obtained prior to her death (Fig. 7).\n\nConclusion\n\nPaediatric HSCT recipients presenting with CNS signs and symptoms should be evaluated by neuroimaging studies for timely diagnosis and early management. PRES is the most common CNS complication and usually presents with typical clinical and imaging findings. However, atypical MRI manifestations may appear, which should not dissuade a PRES diagnosis in appropriate clinical settings with exclusion of other possibilities. Diffusion restriction is an important imaging finding that can be associated with residual changes and should be assessed in all MRI studies for these patients.\n\nMain points\n\n* Paediatric HSCT recipients presenting with CNS signs and symptoms should be evaluated by neuroimaging studies.\n\n* Variable neuroimaging presentations should not dissuade a PRES diagnosis in appropriate clinical settings following allogeneic HSCT in paediatric recipients.\n\n* In PRES, lower ADC values are associated with a poor prognosis, and normal ADC values in association with increased signal intensity on DWI should also be evaluated in terms of ADC pseudonormalization.\n\nAcknowledgements\n\nThe authors thank the Pediatric Stem Cell Transplantation Department of Altınbas University School of Medicine.\n\nAuthors’ contributions\n\nBE and AOA involved in the conception, wrote the protocol and designed the study, involved in data analysis and interpretation of results, drafted and reviewed the manuscript. SA contributed to the design and interpretation of results. BE critically reviewed the manuscript. All authors read and gave final approval of the version to be published and agreed to be accountable for all aspects of the work.\n\nFunding\n\nnone.\n\nAvailability of data and materials\n\nThe data sets used and/or analysed during the current study are available from the corresponding author upon reasonable request.\n\nDeclerations\n\nEthics approval and consent to participate\n\nEthics approval has been obtained from Bakırkoy Dr. Sadi Konuk Training and Research Hospital Research Ethics Committee. Written informed consent to participate were taken from the patients’ parents.\n\nConsent for publication\n\nWritten informed consent for publication has been taken from the patients’ parents.\n\nAll methods were performed in accordance with the relevant guidelines and regulations.\n\nCompeting interests\n\nnone.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAli Önder Atça and Berrin Erok are contributed equally as first authors.\n==== Refs\nReferences\n\n1. Nishiguchi T Mochizuki K Shakudo M Takeshita T Hino M Inoue Y CNS complications of hematopoietic stem cell transplantation Am J Roentgenol 2009 192 1003 1011 10.2214/AJR.08.1787 19304707\n2. Yoshida S Hayakawa K Yamamoto A Kuroda H Imashuku S The central nervous system complications of bone marrow transplantation in children Eur Radiol 2008 18 2048 2059 10.1007/s00330-008-1000-3 18491111\n3. Chen BT Ortiz AO Dagis A Torricelli C Parker P Openshaw H Brain imaging findings in symptomatic patients after allogeneic haematopoietic stem cell transplantation: correlation with clinical outcome Eur Radiol 2012 22 2273 2281 10.1007/s00330-012-2490-6 22618523\n4. Bartynski WS Zeigler ZR Shadduck RK Lister J Pretransplantation conditioning influence on the occurrence of cyclosporine or FK-506 neurotoxicity in allogeneic bone marrow transplantation (original research) AJNR Am J Neuroradiol 2004 25 2 261 269 14970028\n5. Straathof K Anoop P Allwood Z Silva J Nikolajeva O Chiesa R Long-term outcome following cyclosporine-related neurotoxicity in paediatric allogeneic haematopoietic stem cell transplantation (original research) Bone Marrow Transplant 2017 52 1 159 162 10.1038/bmt.2016.232 27643866\n6. Khan RB Sadighi ZS Zabrowski J Gajjar A Jeha S Imaging patterns and outcome of posterior reversible encephalopathy syndrome during childhood cancer treatment (original research) Pediatr Blood Cancer 2016 63 3 523 526 10.1002/pbc.25790 26469881\n7. Coley SC Jäger HR Szydlo RM Goldman JM CT and MRI manifestations of central nervous system infection following allogeneic bone marrow transplantation Clin Radiol 1999 54 6 390 397 10.1053/crad.1999.0200 10406341\n8. Levine DS Navarro OM Chaudry G Doyle JJ Blaser SI Imaging the complications of bone marrow transplantation in children RadioGraphics 2007 27 2 307 324 10.1148/rg.272065088 17374855\n9. Hussein SA Hammad M Abdalla A Patterns of central nervous system complications of post-hematopoietic stem cell transplant in pediatric oncology patients: a single institute experience Egypt J Radiol Nucl Med 2021 52 143 10.1186/s43055-021-00471-8\n10. Liu S Zheng D Xiao P Wang Y Zhai Z Lu J Li J Shaoyan H The related factors and the prognosis of nervous system complications on the pediatric patients with hematopoietic stem cell transplantation Blood 2018 132 5718 10.1182/blood-2018-99-117803\n11. Server A Bargalló N Fløisand Y Sponheim J Graus F Hald JK Imaging spectrum of central nervous system complications of hematopoietic stem cell and solid organ transplantation Neuroradiology 2017 59 2 105 126 10.1007/s00234-017-1804-4 28255902\n12. Zama D, Masetti R, Cordelli DM, Vendemini F, Giordano L, Milito G, et al. Risk factor analysis of posterior reversible encephalopathy syndrome after allogeneic hematopoietic SCT in children. Bone Marrow Transplant. 2014;49(12):1538–40.\n13. Masetti R Cordelli DM Zama D PRES in children undergoing hematopoietic stem cell or solid organ transplantation Pediatrics 2015 135 5 890 901 10.1542/peds.2014-2325 25917987\n14. Kapoor, Rajan; Simalti, Ashish; Kumar, Rajiv Yanamandra, Uday Das, Satyaranjan; Singh, Jasjit Nair, Velu. PRES in pediatric HSCT: a single-center experience, J Pediatr Hematol Oncol: August 2018 - Volume 40 - Issue 6 - p 433–437.\n15. Masetti R Cordelli DM Zama D PRES in children undergoing hematopoietic stem cell or solid organ transplantation (review) Pediatrics 2015 135 5 890 901 10.1542/peds.2014-2325 25917987\n16. Li XY, Huang K, Zhou DH, Li Y, Xu HG, Weng WJ, Xu LH, Fang JP. Severe hypertension is an independent risk factor for posterior reversible encephalopathy syndrome post-hematopoietic cell transplantation in children with thalassemia major. Clin Transplant. 2019;33(1):e13459.\n17. Johansson BB Eisenberg HM Suddith RL The blood-brain barrier in acute and chronic hypertension The cerebral microvasculature. Advances in experimental medicine and biology 1980 Boston, MA Springer\n18. Jennane S el Mahtat M Konopacki J Malfuson JV Doghmi K Mikdame M Cyclosporine-related posterior reversible encephalopathy syndrome after cord blood stem cell transplantation (case reports) Hematol Oncol Stem Cell Ther 2013 6 2 71 10.1016/j.hemonc.2013.05.002 23707936\n19. Hammerstrom AE Howell J Gulbis A Rondon G Champlin RE Popat U Tacrolimus-associated posterior reversible encephalopathy syndrome in hematopoietic allogeneic stem cell transplantation (original research) Am J Hematol 2013 88 4 301 305 10.1002/ajh.23402 23460378\n20. Fugate JE Rabinstein AA Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions (review) Lancet Neurol 2015 14 9 914 925 10.1016/S1474-4422(15)00111-8 26184985\n21. Mukherjee P McKinstry RC Reversible posterior leukoencephalopathy syndrome: evaluation with diffusion-tensor imaging (original research) Radiology 2001 219 756 765 10.1148/radiology.219.3.r01jn48756 11376265\n22. James M Provenzale, Jeffrey R. Petrella, Luiz Celso H. Cruz Jr, Jimmie C. Wong, Stefan Engelter, Daniel P. Barboriak. Quantitative assessment of diffusion abnormalities in posterior reversible encephalopathy syndrome (original reserch) Am J Neuroradiol 2001 22 1455 1461 11559490\n23. Bartynski WS Boardman JF Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome (original research) Am J Neuroradiol 2007 28 7 1320 1327 10.3174/ajnr.A0549 17698535\n24. Alexander M McKinney, James short, Charles L Truwit, Zeke J McKinney, Osman S Kozak, Karen S SantaCruz, et al. posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings (original research) AJR Am J Roentgenol 2007 189 4 904 912 10.2214/AJR.07.2024 17885064\n25. Raman R Devaramane R Jagadish GM Chowdaiah S Various imaging manifestations of posterior reversible encephalopathy syndrome (PRES) on magnetic resonance imaging (MRI) (original research) Pol J Radiol 2017 82 64 70 10.12659/PJR.899960 28243339\n26. Bartynski WS Tan HP Boardman JF Shapiro R Marsh JW Posterior reversible encephalopathy syndrome after solid organ transplantation (original research) AJNR Am J Neuroradiol 2008 29 5 924 930 10.3174/ajnr.A0960 18272559\n27. Lamy C Oppenheim C Mas JL Posterior reversible encephalopathy syndrome (review) Handb Clin Neurol 2014 121 1687 1701 10.1016/B978-0-7020-4088-7.00109-7 24365441\n28. Coverrubias DJ Luetmer PH Capmpeau NG Posterior reversible encephalopathy syndrome: prognostic utility of quantitative diffusion weighted MR images (original research) Am J Neuroradio 2002 23 1038 1048\n29. Duygulu G Özer T Kitiş Ö Çallı C Posterior reversibl ensefalopati sendromu (PRES): difüzyon ağırlıklı MRG bulguları posterior reversible encephalopathy syndrome (PRES): diffusion-weighted MR imaging findings Med J Kocaeli 2013 3 6 13\n\n",
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"journal": "BMC pediatrics",
"keywords": "CNS complications; Haematopoietic stem cell transplantation; MRI; PRES; Posterior reversible encephalopathy syndrome",
"medline_ta": "BMC Pediatr",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D059906:Neuroimaging; D054038:Posterior Leukoencephalopathy Syndrome; D012189:Retrospective Studies",
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"title": "Neuroimaging findings of posterior reversible encephalopathy syndrome (PRES) following haematopoietic stem cell transplantation in paediatric recipients.",
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"abstract": "Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system. Its treatment has focused on inflammation control as early as possible to avoid disability. Autologous hematopoietic stem cell transplantation (AHSCT) has been used for treating MS since 1996, with recent decisive results regarding benefits in long-term efficacy. Five patients followed up at an MS center in Belo Horizonte, Brazil, who had relapsing-remitting MS with high disease activity, underwent AHSCT between 2009 and 2011. They were evaluated clinically, with magnetic resonance imaging, and by the EDSS every six months after transplantation, up to July 2018. The patients were four women and one man, with ages ranging from 25-50 years, and time since disease onset ranging from 4-17 years at the time of the procedure. Four patients improved, one patient was stabilized, and all patients were free of disease activity after 5-9 years. Through improving patient selection and decreasing the time from disease onset, AHSCT could stop epitope spreading and disease progression. Despite multiple other therapeutic choices being approved for relapsing-remitting MS, AHSCT continues to be a treatment to consider for aggressive MS disease.",
"affiliations": "Universidade José do Rosário Vellano, Belo Horizonte, MG, Brasil.;Universidade José do Rosário Vellano, Belo Horizonte, MG, Brasil.;Universidade José do Rosário Vellano, Belo Horizonte, MG, Brasil.;Universidade José do Rosário Vellano, Belo Horizonte, MG, Brasil.;Ecoar Centro de Imagens, Belo Horizonte MG, Brasil.",
"authors": "Comini-Frota|Elizabeth R|ER|0000-0002-2702-0402;Marques|Bruna C C|BCC|;Torres|Caio|C|;Cohen|Karoline M S|KMS|;Miranda|Eduardo Carvalho|EC|",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "Nine-year follow up after hematopoietic stem cell transplantation in five multiple sclerosis patients.",
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"abstract": "We describe a 28-year-old Malaysian Australian man of Han Chinese descent with toxic epidermal necrolysis (TEN), occurring 2 weeks after commencing carbamazepine. He was subsequently found to be positive for human leukocyte antigen (HLA)-B*1502. Carbamazepine-induced Stevens-Johnson syndrome/TEN is strongly associated with the HLA-B*1502 allele, which is highly prevalent in Han Chinese, Malay, Thai and Indian populations. Prospective screening for the allele may prevent this cutaneous adverse drug reaction from occurring, but many neurologists and other medical practitioners are still unaware of the medico-legal risks of prescribing carbamazepine in susceptible populations and the availability of HLA-B*1502 testing. Performing HLA-B*1502 genotyping and avoiding carbamazepine in at-risk individuals has been proven to decrease incidences of drug-induced TEN. This test is widely available at most large pathology services in Australia, with results available within 2 weeks. The recommendation by regulatory bodies should be strengthened to ensure that the broad medical community is made more aware of this pertinent issue.",
"affiliations": "Department of Dermatology, St George Hospital Sydney, Gray Street, Kogarah, NSW 2217, Australia; University of New South Wales, High Street, Kensington, NSW 2052, Australia. Electronic address: jeremytck1989@gmail.com.;Department of Dermatology, St George Hospital Sydney, Gray Street, Kogarah, NSW 2217, Australia; University of New South Wales, High Street, Kensington, NSW 2052, Australia.;Department of Neurology, St George Hospital Sydney, Kogarah, NSW, Australia; University of New South Wales, High Street, Kensington, NSW 2052, Australia.",
"authors": "Tan|Jeremy C K|JC|;Murrell|Dedee F|DF|;Hersch|Mark I|MI|",
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"keywords": "Carbamazepine; Genetic screening; HLA-B*1502; Stevens–Johnson syndrome; Toxic epidermal necrolysis",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000328:Adult; D000483:Alleles; D000927:Anticonvulsants; D044466:Asians; D002220:Carbamazepine; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D059910:HLA-B15 Antigen; D006801:Humans; D015994:Incidence; D008297:Male; D011446:Prospective Studies; D013262:Stevens-Johnson Syndrome",
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"title": "Genetic screening for human leukocyte antigen alleles prior to carbamazepine treatment.",
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"abstract": "BACKGROUND\nThere are many adverse effects that have been described for isotretinoin. To the best of our knowledge, this is the first report of a possible association of oral isotretinoin intake with autoimmune thyroiditis and ocular myasthenia gravis (OMG).\n\n\nMETHODS\nA 19-year-old Caucasian male, who had used oral isotretinoin for severe acne disease for the previous six months, was referred to our clinic. He had a three-week history of diplopia and variable bilateral ptosis. Physical examination showed moderate periorbital edema and limitations of up- and down-gaze in the left eye. Laboratory findings and thyroid ultrasound were consistent with autoimmune thyroiditis. Antithyroid therapy did not relieve the clinical symptoms. Concomitant OMG was suspected. Variable ptosis and a positive response to oral prednisolone of 40 mg/day and pyridostigmine of 360 mg/day supported the diagnosis of concomitant autoimmune thyroiditis and OMG.\n\n\nCONCLUSIONS\nAutoimmune disorders may be triggered by oral isotretinoin treatment. Clinicians prescribing isotretinoin should be aware of the possible association between isotretinoin intake and concomitant autoimmune thyroiditis and OMG.",
"affiliations": "Eskisehir Osmangazi University Medical Faculty, Department of Ophthalmology, Eskisehir, Turkey.",
"authors": "Gursoy|Huseyin|H|;Cakmak|Idil|I|;Yildirim|Nilgun|N|;Basmak|Hikmet|H|",
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"fulltext": "\n==== Front\nCase Rep DermatolCase Rep DermatolCDECase Reports in Dermatology1662-6567S. 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 10.1159/000345680cde-0004-0256Published online: November, 2012Presumed Isotretinoin-Induced, Concomitant Autoimmune Thyroid Disease and Ocular Myasthenia Gravis: A Case Report Gursoy Huseyin *Cakmak Idil Yildirim Nilgun Basmak Hikmet Eskisehir Osmangazi University Medical Faculty, Department of Ophthalmology, Eskisehir, Turkey*Huseyin Gursoy Camlica Mahallesi, Natura Evleri L1D2, TR-26180 Tepebasi, Eskisehir (Turkey), E-Mail hhgursoy@hotmail.comSep-Dec 2012 16 9 2012 16 9 2012 4 3 256 260 Copyright © 2012 by S. Karger AG, Basel2012This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial-No-Derivative-Works License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Introduction\nThere are many adverse effects that have been described for isotretinoin. To the best of our knowledge, this is the first report of a possible association of oral isotretinoin intake with autoimmune thyroiditis and ocular myasthenia gravis (OMG).\n\nCase Presentation\nA 19-year-old Caucasian male, who had used oral isotretinoin for severe acne disease for the previous six months, was referred to our clinic. He had a three-week history of diplopia and variable bilateral ptosis. Physical examination showed moderate periorbital edema and limitations of up- and down-gaze in the left eye. Laboratory findings and thyroid ultrasound were consistent with autoimmune thyroiditis. Antithyroid therapy did not relieve the clinical symptoms. Concomitant OMG was suspected. Variable ptosis and a positive response to oral prednisolone of 40 mg/day and pyridostigmine of 360 mg/day supported the diagnosis of concomitant autoimmune thyroiditis and OMG.\n\nConclusion\nAutoimmune disorders may be triggered by oral isotretinoin treatment. Clinicians prescribing isotretinoin should be aware of the possible association between isotretinoin intake and concomitant autoimmune thyroiditis and OMG.\n\nKey words\nIsotretinoinOcular myasthenia gravisThyroiditis\n==== Body\nIntroduction\nIsotretinoin is a vitamin A synthetic analogue that has been widely used by dermatologists in the treatment of acne [1]. Among the many adverse effects of isotretinoin, eye dryness, corneal and retinal abnormalities, myalgia, true myopathy, psychiatric problems, and several autoimmune disorders have been described [2, 3, 4, 5, 6, 7, 8]. A literature review has revealed very few case reports of autoimmune disorders associated with isotretinoin intake. Isotretinoin-induced inflammatory bowel disease (IBD) was the most common of these autoimmune disorders [5]. Ulcerative colitis was the diagnosis in the majority of the cases. Some of the patients developed IBD after discontinuation of isotretinoin [7], while some developed IBD during the intake of isotretinoin [5]. There is only one report of an association between isotretinoin intake and immune-mediated diabetes mellitus [6]. In this case, it was concluded that latent autoimmune diabetes mellitus could be clinically revealed after isotretinoin use. Guillain-Barré syndrome, which is an autoimmune disease of the nervous system, has been reported in two patients taking oral isotretinoin, and both cases received intravenous immunoglobulin [8]. To the best of our knowledge, this is the first reported case of isotretinoin-induced autoimmune thyroiditis and ocular myasthenia gravis (OMG) resulting from use of isotretinoin.\n\nCase Presentation\nA 19-year-old Caucasian male was referred to our clinic, with a three-week history of diplopia and variable bilateral ptosis (fig. 1 and fig. 2). He had used oral isotretinoin (Roaccutane, Roche, Nutley, N.J., USA) at 1 mg/kg/day for severe acne disease, for the previous six months. No use of other medications or occurrence of any stressful events was recorded in his recent history. His complaints appeared within the last month of the successful acne treatment with isotretinoin. He first experienced a sudden onset of right eye ptosis, which recovered spontaneously within two weeks. Ptosis was worsened with fatigue. One week later, he noted left eye ptosis that was resolved within one week. Two weeks later, the right eye ptosis recurred and was accompanied by sudden onset of diplopia.\n\nThe ophthalmic, general medical and family histories for neuromuscular or autoimmune disorders were negative. He smoked 3–4 cigarettes per day. Physical examination showed moderate periorbital edema and limitations of up- and down-gaze in the left eye. Visual acuities were 10/10 in both eyes. Biomicroscopic and fundus examinations were normal.\n\nThyroid function tests revealed free T4 of 3.08 ng/dl (normal range 0.93–1.7 ng/dl), free T3 of 13.85 pg/ml (normal range 2.0–4.4 pg/ml) and thyroid-stimulating hormone (TSH) <0.005 mU/ml (normal range 0.27–4.2 IU/ml). The anti-thyroglobulin antibody level was normal, whereas TSH receptor antibody (TRAb) [40 U/l (normal <15 U/l)] and anti-thyroid-peroxidase antibody levels were elevated [492.2 IU/ml (normal 0–34 IU/ml)]. The creatine kinase activity and the hepatic enzyme levels were normal. The thyroid ultrasound showed moderately heterogeneous, reduced echogenicity, which was consistent with thyroiditis. Propylthiouracil (Propycil), at 200 mg/day, was prescribed by the endocrinologist. Orbital magnetic resonance imaging (MRI) and cerebral MRI indicated no pathology.\n\nNeurological consultation was requested to exclude OMG. The acetylcholine receptor antibody test, Tensilon test, and single fiber electromyography were normal. Computerized tomography of the chest showed no evidence of thymomas. In accordance with the clinical characteristics, oral pyridostigmine (Mestinon, Valeant Pharmaceuticals, Aliso Viejo, Calif., USA) at 180 mg/day was initiated.\n\nAt the second-month follow-up, diplopia still existed, but the patient was euthyroid and ptosis had disappeared. The patient showed limitation of down-gaze in the left eye. Forced duction tests were negative in both eyes. Botulinum toxin A (Botox, Allergan, Irvine, Calif., USA), at 2.5 units, was injected into the right inferior rectus muscle.\n\nAfter one month, variable ptosis recurred and diplopia persisted. In order to exclude myopathies the neurologist biopsied the left biceps brachii muscle. Ragged red fibers were seen in the samples, which was consistent with a mitochondrial cytopathy (MC). Pyridostigmine was stopped and oral Co-Enzyme Q10 (Co-Enzyme Q10, Life Time, Meridian, Idaho, USA) at 30 mg/day was initiated. Cardiac and neuromuscular disorders may be associated with MC, but were not detected in the patient. No clinical improvement was seen within one month; therefore, Co-Enzyme Q10 was discontinued.\n\nOral pyridostigmine at 360 mg/day and oral prednisolone (Deltacortril, Pfizer, New York, N.Y., USA) at 40 mg/day were initiated to treat the concomitant autoimmune thyroiditis and OMG. The clinical symptoms improved completely within one week.\n\nDiscussion\nRegarding the patient presented in this case report, there is a possible relationship between isotretinoin intake and concomitant autoimmune thyroiditis and OMG. The clinical symptoms did not reverse upon completion of the acne treatment, since the autoimmune reactions had already been triggered. It is reported that isotretinoin has immunomodulating effects that may induce some autoimmune diseases such as Crohn's disease, immune-mediated diabetes, and Guillain-Barré syndrome [5, 6, 7, 8, 9].\n\nGenetic predisposition and a variety of environmental factors have been found to influence the development of autoimmune diseases [10]. Drugs are one of the important environmental factors, which may be the trigger factor for the development of autoimmune diseases in genetically predisposed people [10]. It has been shown that isotretinoin is involved in induction of apoptosis, activation of T cells and B cells [9, 11, 12]. In our case, it is unclear how isotretinoin caused the development of autoimmune thyroiditis and OMG, but it is possible to suggest that isotretinoin triggered autoimmunity through its immunomodulating effects [9, 11, 12].\n\nMost screening tests for mitochondrial cytopathy are not sensitive, and in this case report, the observed ragged red fibers probably led to a false positive diagnosis [13]. The clinical and laboratory findings and the response to combined pyridostigmine and steroid treatment were consistent with concomitant autoimmune thyroiditis and OMG. The laboratory and thyroid ultrasound findings and moderate periorbital edema suggested thyroid eye disease (TED). Graves’ disease was the most likely etiology for the current TED, because TSH receptor antibody was elevated in addition to hormone levels, indicating hyperthyroidism [14]. Propylthiouracil was initiated accordingly. The patient was euthyroid at the next visit, but still complained of diplopia.\n\nPeriorbital swelling, eyelid retraction, proptosis, and restrictive and congestive ocular myopathy are common signs of TED [15]. In the present case, periorbital edema and laboratory findings supported TED. Diplopia, due to involvement of extraocular muscles, was a persistent finding and did not resolve until combined high-dose oral pyridostigmine and prednisolone was initiated. Diplopia could also be a consequence of autoimmune thyroiditis. However, normal orbital MRI and negative forced duction tests did not support a diagnosis of Graves’ ocular myopathy [15]. However, ptosis, which is not a feature of TED, was one of the presenting signs in the present case [15]. The spontaneous recovery of the ptosis at the second-month follow-up and the following recurrences of the ptosis were most likely due to the fluctuating nature of OMG.\n\nThe diagnostic and laboratory tests for OMG were negative. However, it has been reported that these tests may be negative in some OMG cases [16]. In the current case, the variable ptosis, the limitations of eye movements, and response to pyridostigmine were used to determine the diagnosis of OMG [16]. Steroids may be effective in both TED and OMG, supporting concomitant diagnosis of both diseases [17]. Epidemiological studies report that autoimmune thyroiditis occurs in 5–10% of OMG patients [18]. Although oral steroid and pyridostigmine relieved the symptoms, thyroid hormone levels must be checked during the follow-up. It is well known that diagnosis of OMG is a challenging process. Although a clinical diagnosis may be confirmed by laboratory testing, clinical findings of fluctuating and fatigable weakness leading to ptosis and diplopia are the most important elements of diagnosis [19]. In the present case, the emphasis was solely on TED, because of negative test results for OMG. This delayed the correct diagnosis. The entire clinical findings could not be explained by autoimmune thyroiditis. Variable ptosis and involvement of the extraocular muscles without any enlarged muscles, as observed by orbital MRI, supported the diagnosis of concomitant autoimmune thyroiditis and OMG [19].\n\nConclusions\nA case is reported of possible association between isotretinoin intake and autoimmune disorders. Autoimmune reactions may be triggered by oral isotretinoin treatment. Patients with acne should be assessed for autoimmune disorders or any predisposition to their development prior to treatment. Clinicians prescribing isotretinoin should be aware of the possible association between isotretinoin intake and concomitant autoimmune thyroiditis and OMG.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nDisclosure Statement\nThe authors declare that they have no financial conflict or competing interest.\n\nFig. 1 Limitation of up-gaze in the left eye at the first visit.\n\nFig. 2 Right ptosis at the first visit. Isotretinoin, thyroiditis and myasthenia gravis.\n==== Refs\nReferences\n1 Kraft J Freiman A Management of acne CMAJ 2011 183 E430 E435 21398228 \n2 Santodomingo-Rubido J Novascues EB Rubido-Crespo MJ Drug-induced ocular side-effects with isotretinoin Opthalmic Physiol Opt 2008 28 497 501 \n3 Chroni E Monastirli A Tsambaos D Neuromuscular adverse effects associated with systemic retinoid dermatotherapy: monitoring and treatment algorithm for clinicians Drug Saf 2010 33 25 34 20000864 \n4 Wooltorton E Accutane (isotretinoin) and psychiatric adverse effects CMAJ 2003 168 66 12515789 \n5 Papageorgiou NP Altman A Shoenfeld Y Inflammatory bowel disease: adverse effect of isotretinoin Isr Med Assoc J 2009 11 505 506 19891242 \n6 Dicembrini I Bardini G Rotella CM Association between oral isotretinoin therapy and unmasked latent immuno-mediated diabetes Diabetes Care 2009 38 8 e99 \n7 Passier JL Srivastava N van Puijenbroek EP Isotretinoin-induced inflammatory bowel disease Neth J Med 2006 64 52 54 16517990 \n8 Pritchard J Appleton R Howard R Hughes RA Guillain-Barré syndrome seen in users of isotretinoin BMJ 2004 328 1537 15217870 \n9 Shapiro PE Edelson RA Saturat JH Effects of retinoids on the immune system Retinoids. New Trends in Research and Therapy 1985 Basel Karger 225 235 \n10 D'Cruz D Autoimmune diseases associated with drugs, chemicals and environmental factors Toxicol Lett 2000 112-113 421 432 10720762 \n11 Ellis CN Krach KJ Uses and complications of isotretinoin therapy J Am Acad Dermatol 2001 45 S150 S157 11606947 \n12 Reddy D Siegel CA Sands BE Kane S Possible association between isotretinoin and inflammatory bowel disease Am J Gastroenterol 2006 101 1569 1573 16863562 \n13 Rifai Z Welle S Kamp C Thornton CA Ragged red fibers in normal aging and inflammatory myopathy Ann Neurol 1995 37 24 29 7818253 \n14 Paunkovic N Paunkovic J The diagnostic criteria of Graves’ disease and especially the thyrotropin receptor antibody; our own experience Hell J Nucl Med 2007 10 89 94 17684583 \n15 Maheshwari R Weis E Thyroid associated orbitopathy Indian J Ophthalmol 2012 60 87 93 22446901 \n16 Stojkovic T Béhin A Ocular myasthenia: diagnosis and treatment Rev Neurol (Paris) 2010 166 987 997 Review. Article in French 21075410 \n17 Widjaja A Rademaker J Gölkel C Holstein A Leifke E Wat N [Graves ophthalmopathy and ocular myasthenia] Ophthalmologe 2000 97 38 40 Article in German 10663788 \n18 Marinó M Ricciardi R Pinchera A Barbesino G Manetti L Chiovato L Braverman LE Rossi B Muratorio A Mariotti S Mild clinical expression of myasthenia gravis associated with autoimmune thyroid diseases J Clin Endocrinol Metab 1997 82 438 443 9024233 \n19 Juel VC Massey JM Myasthenia gravis Orphanet J Rare Dis 2007 2 44 17986328\n\n",
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"issue": "4(3)",
"journal": "Case reports in dermatology",
"keywords": "Isotretinoin; Ocular myasthenia gravis; Thyroiditis",
"medline_ta": "Case Rep Dermatol",
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"nlm_unique_id": "101517685",
"other_id": null,
"pages": "256-60",
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"pubdate": "2012-09",
"publication_types": "D002363:Case Reports",
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"title": "Presumed isotretinoin-induced, concomitant autoimmune thyroid disease and ocular myasthenia gravis: a case report.",
"title_normalized": "presumed isotretinoin induced concomitant autoimmune thyroid disease and ocular myasthenia gravis a case report"
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"abstract": "Patients with severe pulmonary arterial hypertension (PAH) in New York Heart Association (NYHA) functional class (FC) III/IV have a poor prognosis, despite survival benefits being demonstrated with intravenous epoprostenol. In this pilot study, the efficacy and safety of a triple combination therapy regimen in patients with severe PAH was investigated. Data from newly diagnosed NYHA FC III/IV PAH patients (n=19) initiated on upfront triple combination therapy (intravenous epoprostenol, bosentan and sildenafil) were collected retrospectively from a prospective registry. Significant improvements in 6-min walk distance and haemodynamics were observed after 4 months' triple combination therapy in 18 patients (p<0.01); 17 patients had improved to NYHA FC I or II. One patient was not included in the month 4 assessment (due to an emergency lung transplant in month 3). At the final evaluation (mean ± sd 32 ± 19 months), all 18 patients had sustained clinical and haemodynamic improvement. Overall survival estimates for the triple combination cohort were 100% at 1, 2 and 3 years. Expected survival calculated from the French equation was 75% (95% CI 68-82%), 60% (95% CI 50-70%) and 49% (95% CI 38-60%) at 1, 2 and 3 years, respectively. This pilot study provides preliminary evidence of the long-term benefits of upfront triple combination therapy in patients with severe PAH.",
"affiliations": "Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre APHP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Soins Intensifs, DHU Thorax Innovation, Hôpital de Bicêtre, Le Kremlin-Bicêtre INSERM U999, LabEx LERMIT, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson olivier.sitbon@bct.aphp.fr.;Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre APHP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Soins Intensifs, DHU Thorax Innovation, Hôpital de Bicêtre, Le Kremlin-Bicêtre INSERM U999, LabEx LERMIT, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson.;Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre APHP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Soins Intensifs, DHU Thorax Innovation, Hôpital de Bicêtre, Le Kremlin-Bicêtre INSERM U999, LabEx LERMIT, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson.;Univ. Lyon-1, Hospices Civils de Lyon, Centre de Référence des maladies pulmonaires rares, Centre de Compétences de l'Hypertension Pulmonaire, Hôpital Louis Pradel, Lyon.;Service de Pneumologie et d'oncologie thoracique, Hôpital Universitaire de Caen, Caen.;Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre APHP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Soins Intensifs, DHU Thorax Innovation, Hôpital de Bicêtre, Le Kremlin-Bicêtre INSERM U999, LabEx LERMIT, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson.;Service de Cardiologie, CHU, Grenoble.;Service de Cardiologie, CHU Gabriel-Montpied, Clermont-Ferrand.;Service de Cardiologie, Hôpital Haut-Lévêque, Pessac, France.;Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre APHP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Soins Intensifs, DHU Thorax Innovation, Hôpital de Bicêtre, Le Kremlin-Bicêtre INSERM U999, LabEx LERMIT, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson.;Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre APHP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Soins Intensifs, DHU Thorax Innovation, Hôpital de Bicêtre, Le Kremlin-Bicêtre INSERM U999, LabEx LERMIT, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson.;Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre APHP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Soins Intensifs, DHU Thorax Innovation, Hôpital de Bicêtre, Le Kremlin-Bicêtre INSERM U999, LabEx LERMIT, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson.;Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre APHP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Soins Intensifs, DHU Thorax Innovation, Hôpital de Bicêtre, Le Kremlin-Bicêtre INSERM U999, LabEx LERMIT, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson.",
"authors": "Sitbon|Olivier|O|;Jaïs|Xavier|X|;Savale|Laurent|L|;Cottin|Vincent|V|;Bergot|Emmanuel|E|;Macari|Elise Artaud|EA|;Bouvaist|Hélène|H|;Dauphin|Claire|C|;Picard|François|F|;Bulifon|Sophie|S|;Montani|David|D|;Humbert|Marc|M|;Simonneau|Gérald|G|",
"chemical_list": "D000959:Antihypertensive Agents; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D000068677:Sildenafil Citrate; D011464:Epoprostenol; D000077300:Bosentan",
"country": "England",
"delete": false,
"doi": "10.1183/09031936.00116313",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0903-1936",
"issue": "43(6)",
"journal": "The European respiratory journal",
"keywords": null,
"medline_ta": "Eur Respir J",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents; D000077300:Bosentan; D004359:Drug Therapy, Combination; D011464:Epoprostenol; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010879:Piperazines; D011379:Prognosis; D011687:Purines; D012042:Registries; D012189:Retrospective Studies; D000068677:Sildenafil Citrate; D013449:Sulfonamides; D013450:Sulfones; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8803460",
"other_id": null,
"pages": "1691-7",
"pmc": null,
"pmid": "24627535",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study.",
"title_normalized": "upfront triple combination therapy in pulmonary arterial hypertension a pilot study"
} | [
{
"companynumb": "FR-ACTELION-A-CH2018-179796",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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"activesubstancename": "BOSENTAN"
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{
"abstract": "The combination of hydroxychloroquine (HCQ) and azithromycin could represent a suitable treatment for SarS-CoV-2 positive pregnancies. The authors report one of the first cases of COVID-19 positive pregnant woman successfully treated with HCQ in April 2020.",
"affiliations": "Department of Obstetrics and Gynecology, New York Health and Hospitals/Lincoln, Bronx, NY USA. gsisti83@gmail.com.;Department of Woman, Child and General and Specialized Surgery, University of Campania \"Luigi Vanvitelli\", Naples, Italy. aschiattarella@gmail.com.;Department of Plastic Surgery, Cleveland Clinic, Ohio, USA. asisti6@gmail.com.",
"authors": "Sisti|Giovanni|G|;Schiattarella|Antonio|A|;Sisti|Andrea|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006886:Hydroxychloroquine; D017963:Azithromycin",
"country": "Italy",
"delete": false,
"doi": "10.23750/abm.v91i4.10216",
"fulltext": "\n==== Front\nActa Biomed\nActa Biomed\nActa Bio Medica : Atenei Parmensis\n0392-4203\n2531-6745\nMattioli 1885 Italy\n\n33525254\nACTA-91-123\n10.23750/abm.v91i4.10216\nCase Report\nTreatment of COVID-19 in pregnancy with hydroxychloroquine and azithromycin: a case report\nSisti Giovanni 1\nSchiattarella Antonio 2\nSisti Andrea 3\n1 Department of Obstetrics and Gynecology, New York Health and Hospitals/Lincoln, Bronx, NY, USA\n2 Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy.\n3 Department of Plastic Surgery, Cleveland Clinic, Ohio, USA\nCorresponding: Antonio Schiattarella, MD Department of Woman, Child and General and Specialized Surgery University of Campania “Luigi Vanvitelli” Largo Madonna Delle Grazie 1, 80138, Naples, Italy Phone: 0039 3921653275 Email: aschiattarella@gmail.com\n2020\n16 7 2020\n91 4 e202012313 7 2020\n15 7 2020\nCopyright: © 2020 ACTA BIO MEDICA SOCIETY OF MEDICINE AND NATURAL SCIENCES OF PARMA\n2020\nThis work is licensed under a Creative Commons Attribution 4.0 International License\nThe combination of hydroxychloroquine (HCQ) and azithromycin could represent a suitable treatment for SarS-CoV-2 positive pregnancies. The authors report one of the first cases of COVID-19 positive pregnant woman successfully treated with HCQ in April 2020. (www.actabiomedica.it)\n\nAzithromycin\nCOVID-19\nHydroxychloroquine\npregnancy\nSarS-CoV-2\n==== Body\nIntroduction\n\nSARS-CoV-2 is the new coronavirus responsible of the rapidly spreading COVID-19 pandemic [1]. This is a novel disease with no standard proven treatment available. SARS-CoV-2 usually attacks the lungs causing a wide range of symptoms ranging from mild dyspnea to severe shortness of breath requiring intubation. The underlying pathogenic mechanisms of the virus on the cells are unclear and only few hypotheses are currently available. Moreover, data on COVID-19 in pregnant women are lacking and the management is challenging. To date, (April 7, 2020), hydroxychloroquine (HCQ) has emerged as the most promising choice with its relatively low side effects, drug interactions and low cost [2]. HCQ has an in vitro and in vivo effect on the replication of SARS-CoV-2 virus. In addition, HCQ presents itself as particularly appealing for its possible safe use during pregnancy. HCQ is commonly used for other pathologies affecting pregnancy such as rheumatoid arthritis (RA), systemic lupus erythematous (SLE) and malaria.\n\nThe authors aim to report the successful use of HCQ in one pregnant symptomatic patient at 26 weeks of gestation, and hereby they present the details of the case, hoping to lead a new era in the response to this deadly virus.\n\nCase Report\n\nOn 3/29/2020 a middle aged woman G6P4014 at 26 weeks of pregnancy came to the emergency room complaining of mild dyspnea. The nasopharyngeal swab for SarS-CoV-2 quantitative reverse transcriptase (qRT)-PCR resulted positive. She did not meet criteria for admission, and she was discharged home with azithromycin 500 mg for the first day and other 2 days of azithromycin therapy (250 mg po daily) as outpatient therapy. On 04/01/2020 she came back to the hospital with complaints of dyspnea, shortness of breath, cough, subjective fever. The vital signs were stable, with maternal body temperature of 102.8 ºF. The chest X-ray showed bilateral patchy infiltrates (Fig. 1) and she was admitted to the hospital. On day 04/02/2020 HCQ 400 mg was started daily for other 5days. In addition, Azithromycin 500 mg was prescribed on 4/01/2020 followed by 250 mg daily for other 4 days. On 4/02/2020 a repeated nasopharyngeal swab for SarS-CoV-2 qRT-PCR resulted negative. On 4/04/2020 a bedside chest X-ray was performed and showed persistent patchy infiltrates (Fig. 2).\n\nFigure 1. Chest ray in PA (a) and LL (b) projections, performed on 04/01/2020 showed bilateral patchy infiltrates.\n\nFigure 2. Chest ray in PA, performed on 04/04/2020 showed persistent bilateral patchy infiltrates.\n\nThe labs showed a normocytic anemia compatible with the pregnancy status, no increase of white blood cell, elevated platelet (PLT) (662 K at discharge) and elevated AST/ALT 261/391 U/L. Gallstones were found during liver ultrasound examination. Daily fetal testing was negative, the patient did not exhibit any obstetrical complaint. On 4/05/2020 the EKG showed a prolonged QTc (479 ms), resolved with one dose of magnesium IV (1 gr/100 ml NS), with no chest symptoms.\n\nOn 4/6/2020, at day 6 of admission, the clinical condition improved, and the patient was discharged in stable clinical condition on day 7, with no fever, no increase white blood cell, and reassuring fetal status.\n\nDiscussion\n\nDuring the COVID-19 pandemic, on 03/28/2020, FDA authorized the emergency use of HCQ and chloroquine to treat hospitalized patients with COVID-19 [3]. This case report represents one of the first patients successfully treated with HCQ and azithromycin for COVID-19 during gestation until today, (April 7, 2020).\n\nOn day 3 of admission, the nasopharyngeal SarS-CoV-2 qRT-PCR result was negative and on day 6 the upper respiratory symptoms disappeared. She was discharged home in stable condition on day 7 of hospitalization. To date, the efficacy of HCQ and chloroquine have been suggested in both in vitro and in vivo studies. Lai and colleagues have demonstrated that chloroquine inhibits the replication of coronaviruses in vitro [4,5]. Chloroquine increases intracellular pH [5,6] and inhibits the quinone reductase-2, inhibition of MAP-kinase, interfering with ACE2 receptor glycosylation [4]. HCQ and chloroquine share a very similar molecular structure and mechanism of action, but in the clinical studies HCQ has been used rather than chloroquine, based on proven benefits. Indeed, HCQ seems more potent than chloroquine and it allows lower daily dose of HCQ with the same efficacy; HCQ also carries a better safety profile compared to chloroquine [7,8] To the best of our knowledge, in the current English literature, there is only 1 in vivo clinical study [9] regarding the use of HCQ on COVID-19 positive patients. This study was conducted in France and it did not include any pregnant patients. Gautret and colleagues [9] conducted an open-label, non-randomized study evaluating the use of HCQ on 20 COVID-19 positive patients admitted at “The Méditerranée Infection University Hospital Institute” in Marseille, France. Pregnant patients were excluded. The inclusion criteria comprised of being > 12 years of age and having a positive nasopharyngeal swab real-time reverse transcription-PCR for SarS-CoV-2. There were 20 patients treated with HCQ and 16 were control patients. Patients received 600mg daily of HCQ (200 mg TID) for a total of ten days. The primary endpoint was virological clearance at day-6 postinclusion. Of the 20 HCQ-treated patients, six patients received azithromycin (500mg on day 1 followed by 250 mg per day, the next four days) to prevent bacterial super-infection. The primary endpoint was viral clearance at day six. At day six, 70% of HCQ-treated patients achieved virological clearance compared to 12·5% in the control group, and 100% of HCQ and azithromycin combination-treated patients were virologically cured comparing with 57.1% in patients treated with HCQ only, and 12.5% in the control group. Details are shown in Table 1.\n\nTable 1. Clinical study on hydroxychloroquine treatment for COVID-19\n\nAuthor, Country\tNumber of patients/controls\tStudy design\tDaily dosage of HCQ (mg)\t% of patients with negative PCR at day 6/% of controls with negative PCR at day 6\tp-value\t\nGautret et al., France\t20/16\tCase control\t600\t70/12·5\t0.001\t\nHCQ = hydroxychloroquine\n\nGao and colleagues [10] in a recent research cite a “news briefing” on a large number of ongoing clinical trials in China. They state that more than 100 patients with COVID-19 had a better outcome with chloroquine compared to the control group, but these results have not yet been published in any peer-reviewed journal.\n\nIn our study we had the occurrence of prolonged QT interval at maternal EKG but the patient was asymptomatic and it promptly resolved with magnesium therapy. The association of HCQ with azithromycin is known to cause QTc prolongation and as a result routine daily EKG monitoring is necessary [11–14]. Daily EKG is recommended to monitor for increases in the QTc interval. Many international society guidelines [2,15,16] based on this limited in vitro and clinical evidence, considering the emergency need, already support the use of HCQ for COVID-19 patients, but there are not specifics for its use during pregnancy yet. HCQ has been used during pregnancy for rheumatoid arthritis (RA), systemic lupus erythematous (SLE) and malaria with excellent outcome and a good safety profile for the mother and her fetus [17,18].\n\nLiver dysfunction was found in severe COVID-19 disease [19,20] as a viral infection of liver cells but in our case, the increase of aminotransferase levels was mild and probably caused by gallstones.\n\nConclusion\n\nEvidence is evolving regarding the treatment of SARS-CoV-2. Recent evidence supports the combination of HCQ and azithromycin treatment for COVID positive patients. Our successful treatment of a COVID positive pregnant patient with HCQ, during April 2020, indicates this drug might be a useful treatment for SarS-CoV-2 during pregnancy. Further studies are needed to establish the real effectiveness and safety during gestation. In view of the above, guidelines for treatment of COVID-19 during pregnancy are urgently needed by the clinicians fighting this virus on the field.\n\nConflict of Interest\n\nEach author declares that there are no commercial associations that might pose a conflict of interest in connection with the article.\n==== Refs\nReferences\n\n1 Kickbusch I Leung GM Bhutta ZA Matsoso MP Ihekweazu C Abbasi K Covid-19: how a virus is turning the world upside down BMJ 2020 369 m1336 32245802\n2 Singh AK Singh A Shaikh A Singh R Misra A Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries Diabetes Metab Syndr 2020 14 3 241 6 32247211\n3 FDA Coronavirus (COVID-19) Update: Daily Roundup March 30, 2020 [Internet] https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-march-30-2020 2020\n4 Lu H Drug treatment options for the 2019-new coronavirus (2019-nCoV) Biosci Trends 2020 14 1 69 71 31996494\n5 Colson P Rolain J-M Raoult D Chloroquine for the 2019 novel coronavirus SARS-CoV-2 Int J Antimicrob Agents 2020 55 3 105923 32070753\n6 Wang M Cao R Zhang L Yang X Liu J Xu M Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Cell Res 2020 30 3 269 71 32020029\n7 Liu J Cao R Xu M Wang X Zhang H Hu H Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro Cell Discov 2020 6 16 32194981\n8 Yao X Ye F Zhang M Cui C Huang B Niu P In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Clin Infect Dis 2020\n9 Gautret P Lagier J-C Parola P Hoang VT Meddeb L Mailhe M Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Int J Antimicrob Agents 2020 105949 32205204\n10 Gao J Tian Z Yang X Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Biosci Trends 2020 14 1 72 3 32074550\n11 Chen C-Y Wang F-L Lin C-C Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia Clin Toxicol (Phila) 2006 44 2 173 5 16615675\n12 Choi Y Lim H-S Chung D Choi J-G Yoon D Risk Evaluation of Azithromycin-Induced QT Prolongation in Real-World Practice Biomed Res Int 2018 2018 1574806 30406128\n13 Yang Z Prinsen JK Bersell KR Shen W Yermalitskaya L Sidorova T Azithromycin Causes a Novel Proarrhythmic Syndrome Circ Arrhythm Electrophysiol 2017 10 4\n14 Ehud Chorin Matthew Dai Eric Shulman Lailt Wadhwani Roi Bar Cohen Chirag Barbhaiya Anthony Aizer Douglas Holmes Scott Bernstein Michael Soinelli David S Park Larry Chinitz Lior Jankelosn Ehud Chorin Matthew Dai Eric Shulman Lailt Wadhwani R LJ The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin 2020 21 1 1 9\n15 Alhazzani W Møller MH Arabi YM Loeb M Gong MN Fan E Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19) Intensive Care Med 2020\n16 multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia. [Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia] Zhonghua Jie He He Hu Xi Za Zhi 2020 43 3 185 8 32164085\n17 Ponticelli C Moroni G Hydroxychloroquine in systemic lupus erythematosus (SLE) Expert Opin Drug Saf 2017 16 3 411 9 27927040\n18 Fiehn C Ness T Weseloh C Specker C Hadjiski D Detert J [Safety management of the treatment with antimalarial drugs in rheumatology. Interdisciplinary recommendations based on a systematic literature search] Z Rheumatol 2020 79 2 186 94 32095892\n19 Bangash MN Patel J Parekh D COVID-19 and the liver: little cause for concern Lancet Gastroenterol Hepatol 2020 5 6 529 30 32203680\n20 Liu C Jiang ZC Shao CX Zhang HG Yue HM Chen ZH [Preliminary study of the relationship between novel coronavirus pneumonia and liver function damage: a multicenter study] Zhonghua Gan Zang Bing Za Zhi 2020 28 2 148 52\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0392-4203",
"issue": "91(4)",
"journal": "Acta bio-medica : Atenei Parmensis",
"keywords": null,
"medline_ta": "Acta Biomed",
"mesh_terms": "D000900:Anti-Bacterial Agents; D017963:Azithromycin; D000086382:COVID-19; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008875:Middle Aged; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious",
"nlm_unique_id": "101295064",
"other_id": null,
"pages": "e2020123",
"pmc": null,
"pmid": "33525254",
"pubdate": "2020-07-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32164085;32222812;32020029;32074550;31996494;32194981;32245802;32077660;30406128;32247211;32070753;28408648;32205204;32150618;16615675;32203680;32095892;27927040",
"title": "Treatment of COVID-19 in Pregnancy with Hydroxychloroquine and Azithromycin: a case report.",
"title_normalized": "treatment of covid 19 in pregnancy with hydroxychloroquine and azithromycin a case report"
} | [
{
"companynumb": "US-NOVARTISPH-NVSC2021US037779",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN"
},
"drugadditional": "3",
... |
{
"abstract": "Serotonin-specific reuptake inhibitors (SSRIs) are generally considered safe drugs but fatal adverse effects do sometimes occur, often as a consequence of interactions with other serotonin active drugs. Polypharmacy is usually a problem that the elderly encounter, but it can also have dire consequences for young people, especially when an underlying heart condition is present. Thus, failure to diagnose heart disease and the use of contraindicated medications can be a lethal combination, irrespective of age. Here we present a case of a young adult suffering from bipolar disorder who used a combination of two SSRIs (citalopram and fluoxetine) and a monoamine oxidase inhibitor (MAO; moclobemide) with tragic consequences. The deceased also suffered from undiagnosed hypertrophic cardiomyopathy and was carrier of a genotype that may have predisposed him to increased sensitivity to SSRIs. The apparent difficulty in establishing the manner of death in this case is also discussed.",
"affiliations": "1st Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece. goulas@med.auth.gr.;Department of Forensic Medicine and Toxicology, Medical School, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.;Department of Forensic Medicine and Toxicology, Medical School, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.;Department of Forensic Medicine and Toxicology, Medical School, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.;Department of Forensic Medicine and Toxicology, Medical School, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.;Department of Forensic Medicine and Toxicology, Medical School, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.;Department of Forensic Medicine and Toxicology, Medical School, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.",
"authors": "Goulas|Antonis|A|http://orcid.org/0000-0002-6189-594X;Raikos|Nikolaos|N|;Krokos|Diamantis|D|;Mastrogianni|Orthodoxia|O|;Orphanidis|Amvrosios|A|;Zisopoulos|Konstantinos|K|;Tsepa|Androniki|A|",
"chemical_list": "C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Serotonin Uptake Inhibitors; D005473:Fluoxetine; D015283:Citalopram",
"country": "United States",
"delete": false,
"doi": "10.1007/s12024-018-9960-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1547-769X",
"issue": "14(2)",
"journal": "Forensic science, medicine, and pathology",
"keywords": "Citalopram; Fatal intoxication; Fluoxetine; HTTLPR; Moclobemide",
"medline_ta": "Forensic Sci Med Pathol",
"mesh_terms": "D000328:Adult; D001714:Bipolar Disorder; D002312:Cardiomyopathy, Hypertrophic; D015283:Citalopram; D005473:Fluoxetine; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D000071184:Pharmacogenomic Variants; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Serotonin Uptake Inhibitors",
"nlm_unique_id": "101236111",
"other_id": null,
"pages": "225-228",
"pmc": null,
"pmid": "29488058",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23881890;12869766;15172079;21993870;16307209;11043674;25739526;11672964;21052868;21120513;26987318;23895108;23518607;9154246;2693835;24779425;10863884;29250824;15046013;26970020;22196068;24153159;12774892;18315446;15784664;22835221;21491099;28654193;11300508",
"title": "Fatal intoxication with antidepressants: a case with many culprits.",
"title_normalized": "fatal intoxication with antidepressants a case with many culprits"
} | [
{
"companynumb": "GR-ALEMBIC PHARMACUETICALS LIMITED-2018SCAL000846",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MOCLOBEMIDE"
},
"drug... |
{
"abstract": "To assess outcomes in patients treated with first-line bevacizumab-containing therapy for human epidermal growth factor receptor (HER)2-negative metastatic breast cancer (mBC) at a single centre with a homogenous standard-of-care.\n\n\n\nInformation on patient and disease characteristics, efficacy, and safety was extracted from computer-based records of all patients receiving first-line bevacizumab-paclitaxel at the Curie Institute, Paris, France, between 2008 and 2011.\n\n\n\nMedian progression-free survival in the 116 treated patients was 13.2 months; median overall survival was 38.4 months. Corresponding values were 9.0 and 18.8 months, respectively, in patients with triple-negative mBC, and 19.4 and 58.8 months, respectively, in patients receiving maintenance endocrine therapy. No new safety signals were seen.\n\n\n\nOutcomes in patients treated with bevacizumab-paclitaxel at our center were consistent with efficacy in prospective clinical trials, with notable activity in poor-prognosis disease. Maintenance endocrine or oral therapy with bevacizumab after paclitaxel discontinuation was associated with long-term disease control.",
"affiliations": "Department of Medical Oncology, Curie Institute, PSL Research University, Paris, France veronique.dieras@curie.fr.;Department of Medical Oncology, Curie Institute, PSL Research University, Paris, France.;Biostatistics Unit, Curie Institute, PSL Research University, Paris, France.;Biostatistics Unit, Curie Institute, PSL Research University, Paris, France.;Department of Medical Oncology, Curie Institute, PSL Research University, Paris, France.;Pharmacy Department, Curie Institute, PSL Research University, Paris, France.;Department of Medical Oncology, Curie Institute, PSL Research University, Paris, France.;Department of Medical Oncology, Curie Institute, PSL Research University, Paris, France.;Department of Medical Oncology, Curie Institute, PSL Research University, Paris, France.;Department of Medical Oncology, Curie Institute, PSL Research University, Paris, France.;Department of Medical Oncology, Curie Institute, PSL Research University, Paris, France.;Biostatistics Unit, Curie Institute, PSL Research University, Paris, France.;Biostatistics Unit, Curie Institute, PSL Research University, Paris, France.;Department of Medical Oncology, Curie Institute, PSL Research University, Paris, France.",
"authors": "Dieras|Veronique|V|;Pop|Simona|S|;Berger|Frederique|F|;Dujaric|Marie-Eglantine|ME|;Beuzeboc|Philippe|P|;Escalup|Laurence|L|;Bidard|François Clement|FC|;Cottu|Paul Henri|PH|;LE Tourneau|Christophe|C|;Piperno-Neumann|Sophie|S|;Laurence|Valerie|V|;Robain|Mathieu|M|;Asselain|Bernard|B|;Pierga|Jean-Yves|JY|",
"chemical_list": "D000068258:Bevacizumab; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D017239:Paclitaxel",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.11462",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "37(3)",
"journal": "Anticancer research",
"keywords": "Bevacizumab; HER2-negative; first-line; metastatic breast cancer; paclitaxel",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001943:Breast Neoplasms; D018572:Disease-Free Survival; D005260:Female; D005602:France; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel; D011379:Prognosis; D011446:Prospective Studies; D018719:Receptor, ErbB-2; D012189:Retrospective Studies; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "1403-1407",
"pmc": null,
"pmid": "28314310",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "First-line Bevacizumab and Paclitaxel for HER2-negative Metastatic Breast Cancer: A French Retrospective Observational Study.",
"title_normalized": "first line bevacizumab and paclitaxel for her2 negative metastatic breast cancer a french retrospective observational study"
} | [
{
"companynumb": "PHHY2017FR095108",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
"drug... |
{
"abstract": "Gastrointestinal toxicity is uncommon among patients treated with angiotensin II receptor antagonists. A 58-year-old man presented with nausea, vomiting and constant pain in the epigastrium that radiated to the flanks. He received treatment with valsartan (160 mg daily) for hypertension. The clinical, biochemical and radiological findings were compatible with a diagnosis of acute pancreatitis. After the patient achieved a clinical and biochemical recovery, the valsartan therapy was started again. Six weeks later, he returned to the hospital with an attack of pancreatitis. Subsequently, he returned with repeated attacks of pancreatitis twice, and the valsartan was discontinued. Ten months after the treatment, the patient had no complaints. When severe abdominal symptoms occur for no apparent reason during treatment with valsartan, a diagnosis of pancreatitis should be considered.",
"affiliations": "Department of Internal Medicine, Kocaeli University Medical Faculty, Turkey.",
"authors": "Can|Burak|B|;Sali|Mursel|M|;Batman|Adnan|A|;Yilmaz|Hasan|H|;Korkmaz|Ugur|U|;Celebi|Altay|A|;Senturk|Omer|O|;Hulagu|Sadettin|S|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.53.0667",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "53(7)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D047228:Angiotensin II Type 1 Receptor Blockers; D002760:Cholangiopancreatography, Endoscopic Retrograde; D049448:Cholangiopancreatography, Magnetic Resonance; D003937:Diagnosis, Differential; D006801:Humans; D006973:Hypertension; D008297:Male; D008875:Middle Aged; D019283:Pancreatitis, Acute Necrotizing; D016717:Sphincterotomy, Endoscopic; D013777:Tetrazoles; D014633:Valine; D000068756:Valsartan",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "703-5",
"pmc": null,
"pmid": "24694480",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Valsartan-induced acute pancreatitis.",
"title_normalized": "valsartan induced acute pancreatitis"
} | [
{
"companynumb": "TR-ACTAVIS-2015-11519",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALSARTAN"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nGiven the growing worldwide market of non-prescription drugs, monitoring their misuse in the context of self-medication represents a particular challenge in Public Health. The aim of this study was to investigate the prevalence of misuse, abuse, and dependence on non-prescription psychoactive drugs.\n\n\nMETHODS\nDuring one month, in randomly solicited community pharmacies, an anonymous questionnaire was offered to adults requesting paracetamol (control group), codeine combined with paracetamol in analgesics, or sedative H1 antihistamines. Responses about misuse (drug use not in agreement with the Patient Information Leaflet) abuse (excessive drug use having detrimental consequences), and dependence (established according to questions adapted from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria) on psychoactive drugs were compared to those of the paracetamol control group.\n\n\nRESULTS\n295 patients (mean age 48.5 years, 68.5% of women) having used one of the studied drugs during the previous month were included. Misuse and dependence to codeine analgesics concerned 6.8% and 17.8% of the patients exposed to these drugs, respectively, (n = 118), which was significantly higher than for paracetamol. 19.5% had used codeine analgesics daily for more than six months. Headache was the most frequent reason for persistent daily use. A high prevalence of persistent daily users of sedative H1 antihistamines was also observed. Whereas these drugs are recommended only for short treatment courses of occasional insomnia, 72.2% of the participants having taken doxylamine (n = 36) were daily users, predominantly for more than six months.\n\n\nCONCLUSIONS\nResults on misuse and dependence on non-prescription codeine analgesics suggest that chronic pain, in particular chronic cephalalgia, requires better medical care. In addition, as for hypnotics on prescription, persistent use of doxylamine for self-medication is not justified until an acceptable benefit-risk ratio for chronic sleep disturbance is shown by clinical data.",
"affiliations": "Equipe de Pharmacoépidémiologie, UMR1027 INSERM- Université de Toulouse III, Toulouse, France ; Centre d'Evaluation et d'Information sur la Pharmacodépendance (Addictovigilance Centre), Service de Pharmacologie Clinique, Hôpitaux de Toulouse, Toulouse, France.",
"authors": "Roussin|Anne|A|;Bouyssi|Annabelle|A|;Pouché|Lucie|L|;Pourcel|Laure|L|;Lapeyre-Mestre|Maryse|M|",
"chemical_list": "D000701:Analgesics, Opioid; D006634:Histamine H1 Antagonists; D004366:Nonprescription Drugs; D000082:Acetaminophen; D003061:Codeine",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0076499",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, USA 24098516PONE-D-13-0987610.1371/journal.pone.0076499Research ArticleMisuse and Dependence on Non-Prescription Codeine Analgesics or Sedative H1 Antihistamines by Adults: A Cross-Sectional Investigation in France Misuse and Dependence on Non-Prescription DrugsRoussin Anne \n1\n\n2\n\n*\nBouyssi Annabelle \n1\nPouché Lucie \n1\nPourcel Laure \n1\nLapeyre-Mestre Maryse \n1\n\n2\n\n1 \nEquipe de Pharmacoépidémiologie, UMR1027 INSERM- Université de Toulouse III, Toulouse, France\n\n2 \nCentre d’Evaluation et d’Information sur la Pharmacodépendance (Addictovigilance Centre), Service de Pharmacologie Clinique, Hôpitaux de Toulouse, Toulouse, France\nHsiao Chuhsing Kate Editor\nNational Taiwan University, Taiwan\n* E-mail: anne.roussin@univ-tlse3.frCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: AR MLM. Performed the experiments: AB L. Pouché L. Pourcel. Analyzed the data: AB L. Pouché L. Pourcel. Wrote the paper: AR MLM.\n\n2013 3 10 2013 8 10 e764996 3 2013 28 8 2013 © 2013 Roussin et al2013Roussin et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Background\nGiven the growing worldwide market of non-prescription drugs, monitoring their misuse in the context of self-medication represents a particular challenge in Public Health. The aim of this study was to investigate the prevalence of misuse, abuse, and dependence on non-prescription psychoactive drugs.\n\nMethod\nDuring one month, in randomly solicited community pharmacies, an anonymous questionnaire was offered to adults requesting paracetamol (control group), codeine combined with paracetamol in analgesics, or sedative H1 antihistamines. Responses about misuse (drug use not in agreement with the Patient Information Leaflet) abuse (excessive drug use having detrimental consequences), and dependence (established according to questions adapted from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria) on psychoactive drugs were compared to those of the paracetamol control group.\n\nResults\n295 patients (mean age 48.5 years, 68.5% of women) having used one of the studied drugs during the previous month were included. Misuse and dependence to codeine analgesics concerned 6.8% and 17.8% of the patients exposed to these drugs, respectively, (n = 118), which was significantly higher than for paracetamol. 19.5% had used codeine analgesics daily for more than six months. Headache was the most frequent reason for persistent daily use. A high prevalence of persistent daily users of sedative H1 antihistamines was also observed. Whereas these drugs are recommended only for short treatment courses of occasional insomnia, 72.2% of the participants having taken doxylamine (n = 36) were daily users, predominantly for more than six months.\n\nConclusions\nResults on misuse and dependence on non-prescription codeine analgesics suggest that chronic pain, in particular chronic cephalalgia, requires better medical care. In addition, as for hypnotics on prescription, persistent use of doxylamine for self-medication is not justified until an acceptable benefit-risk ratio for chronic sleep disturbance is shown by clinical data.\n\nThis work was supported by the Mission Interministérielle de la Lutte contre les Drogues et Toxicomanies (MILDT) (http://www.drogues.gouv.fr/) in relationship with the French Health Products Safety Agency (Afssaps)which has been renamed the Agence Nationale de Sécurité des Médicaments et Produits de Santé (ANSM) (http://www.ansm.sante.fr/Activites/Appels-a-projets-de-recherche). The reference grant number was: 0802707. The Scientific Commission of Afssaps has had a role in the study design by recommending to randomly select community pharmacies instead to use national sentinel network of pharmacies. Afssaps gave its agreement to publish results. However the funders did not have any role in data collection and analysis as well as preparation of the manuscript.\n==== Body\nIntroduction\nDrugs that can be obtained at community pharmacies without a medical prescription (non-prescription drugs) are considered to be safe enough when following the recommendations of use as presented in the Summary of Product Characteristics (SPC). Depending on the countries, patients can have free access to all or part of the non-prescription drugs in pharmacies (over-the-counter (OTC) drugs). In 2009, non-prescription drugs (not prescribed and prescribed) represented 44.9% of the drugs issued in community pharmacies in France [1]. According to Intercontinental Marketing Services (IMS) and the Association Française de l’Industrie Pharmaceutique pour une Automédication Responsable (AFIPA), in 2009 and in 2010, non-prescription drugs requested by patients without a medical prescription represented 14.1% of the total number of drug units issued in community pharmacies [2].\n\nAmong non-prescription drugs, those containing substances with a well-known potential of abuse and dependence (such as codeine) are not OTC in France, and the patients have to request them from the pharmacist. Throughout the world, problematic use of drugs containing substances with psychoactive properties used for self-medication have been recognized as an important issue in community pharmacies, particularly for opioids, anti-histamines with sedative properties, and sympathomimetics [3]–[7]. This concern was identified on the basis of the perception of the pharmacists and the knowledge of the general population about the potential problematic use of these drugs. However, there is a lack of quantitative data on misuse, abuse, and dependence on non-prescription drugs spontaneously requested by patients. Pharmacoepidemiological research on non-prescription drug use and safety are under-represented in comparison to prescription drugs. In a previous pilot study focusing on abuse of and dependence on self-medication, we have already demonstrated the feasibility to recruit patients through a regional network of community pharmacies, already involved in other studies or receiving pharmacy students for a six-month placement [8]. This study has demonstrated the feasibility and validity of a cross-sectional survey relying on an anonymous questionnaire given to patients seen in community pharmacies to investigate problematic use of psychoactive drugs used for self-medication or diversion.\n\nThe aim of the present study was to investigate the prevalence of misuse, abuse of, and dependence on codeine analgesics or on sedative H1 antihistamines for non-prescription drugs spontaneously requested by patients in community pharmacies and to identify reasons for persistent use, in comparison with non-prescription paracetamol.\n\nParticipants and Methods\nEthical Statement\nThis nationwide cross-sectional study was conducted during a one month period (from 15th February to 15th March 2009), relying on an anonymous questionnaire given to patients over 18 in community pharmacies. According to the French legislation on clinical research (Article 54 of the law n° 78-17 of January 6th 1978 and Public Health law of August 6th 2004), this study was submitted to the National Comité Consultatif sur le Traitement de l’Information en matière de Recherche dans le domaine de la Santé (CCTIRS) of the French Ministry of Research, which decided that no ethical approval was required since the patients remained anonymous. The National Council of the Pharmaceutical Order has been made aware of this study.\n\nSolicitation of Pharmacies\nThe number of pharmacies to be solicited has been calculated on the basis of the results obtained in a previous study [8]. The present survey was designed to get the highest rate of full adhesion to the protocol of the pharmacies which should accept to participate. As the pharmacies had to be solicited after a random selection based on the geographical national repartition, a low participation rate (between 5 to 10%) was anticipated. A total of 2,263 community pharmacies were solicited to participate, representing 10% of the pharmacies in each of the 22 administrative areas of the French metropolitan territory.\n\nThe pharmacies were asked to send their response by mail on their agreement to participate to the study. When they did not send back the invitation to join the study, they were asked to give their response during a telephone call from the study coordinator.\n\nStudied Drugs\nCodeine used for analgesia is combined with paracetamol and can be purchased at community pharmacies without a medical prescription in doses up to 20 mg of codeine per pill. Thirteen analgesic formulations of drugs containing codeine can be requested without limit of duration of use. These drugs are placed behind the dispensing counter in the pharmacies, and patients must request them from a member of the pharmacy staff.\n\nAmong sedative H1 antihistamines which have been included in the study, (alimemazine, chorphenamine, dimenhydrinate, doxylamine, oxomemazine, pheniramine, and promethazine), only alimemazine, doxylamine, and promethazine are indicated in the short-term treatment of sleeping disorder in adults. According to their SPC, they must not be used for longer than five days, in the context of self-medication.\n\nParacetamol was included as a control. It can be obtained by requesting it from a member of the Pharmacy staff without prescription with a maximum of 8 g per box.\n\nQuestionnaire and Data Collection\nPharmacies were randomly allocated to include patients requesting codeine combined with paracetamol, sedative H1 antihistamines, or paracetamol (with a list of all non-prescription products containing these substances). Therefore, one pharmacy had to distribute a questionnaire about only one category of the studied substances.\n\nWe asked pharmacists to offer the questionnaire to the first 12 patients requesting the studied drug during one month. Pharmacists had to explain the aim of the study to patients and to register the reasons for refusal to participate. In that case, the pharmacy staff had to offer the questionnaire to a new patient until the 12 questionnaires had been given during the study period.\n\nThe questionnaire recorded demographic information, patterns of drug use, criteria of misuse, abuse, and dependence. The misuse of paracetamol or codeine combined with paracetamol was determined when the drug was used in excessive doses (above maximal recommended doses of the majority of the SPCs of the brand drugs containing this association, i.e. 3 g/day and 120 mg/day for paracetamol and codeine phosphate, respectively), and when the use was regular (more than 10 days during the last month). For sedative H1 antihistamines, the SPC of most of the drugs specify that the treatment must not exceed five days. For this reason, misuse of the drugs containing sedative antihistamines was determined as soon as the patients declared that they used a product containing the substance for longer than five days, even when they did not use it in excessive doses.\n\nAbuse was defined as excess use of the drug, permanently or intermittently, with detrimental consequences on the patient’s health, or social or professional life.\n\nSubstance dependence was determined according to responses to questions adapted from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV criteria for problematic drug use) [9]. The patient was considered dependent when he or she met at least three criteria of physiological (tolerance and withdrawal symptoms) and/or psychological dependence (frequent use of higher doses than intended; persistent desire or unsuccessful efforts to control drug use; negative effects of the drug use on health, social, or professional life; continued drug use despite knowledge of negative effects, and a lot of time spent obtaining the drug). When the patients replied that if the drug was not available, they would not accept another drug proposed by the pharmacist and would go to another pharmacy to obtain the drug, it was considered that they spent a lot of time to obtain the drug.\n\nThe following data were also collected: purpose for taking the drug (including the use for other purpose than recommended), person who suggested their use (advice of a pharmacist, physician, or close family; after having seen an advertisement), whether the patient had informed his general practitioner (GP) about this consumption, and other drugs regularly used. Patients were free to fill out the questionnaire in the pharmacy or to take it away with prepaid envelopes to return it.\n\nData Analysis\nDescriptive statistics of the study population were calculated. Only the patients who had used one of the studied substances during the previous month were concerned by the questions on their patterns of use. We determined whether there were differences between each group of psychoactive substances and the control group. For continuous variables, differences were assessed using the Student’s t-test or a non-parametric test. Categorical data were described as percentages and compared using a Chi-squared test or Fisher’s exact test. Statistical analysis was conducted using SAS® 9.1 software.\n\nResults\nPatient Participation Rate\nDuring the one month study period, 915 questionnaires were offered in 145 pharmacies (6.4% of the solicited pharmacies). In order to get enough questionnaires filled in by regular users of each studied substance, the number of pharmacies having to offer the questionnaire to 12 patients on codeine (n = 82) was higher than for H1 antihistamines (n = 36), and paracetamol (n = 27).\n\nAs shown in Figure 1, only 9.9% (n = 91) of the solicited patients refused to get the questionnaire. The number of refusals was not statistically different between the studied substances. The reasons given by the patients for refusal were: time constraint (25), not interested (15), indiscrete questions (12), uncommon use (3), not fluent in French language (3), too long questionnaire (2). Among the 824 distributed questionnaires, 176 (21.4%) were completed inside the pharmacy. Among the other 648 patients who accepted the questionnaire, 231 (35.6%) returned it with the prepaid envelope. A total of 407 questionnaires were received, corresponding to a patient participation rate of 44.5%. Finally, 383 questionnaires were available for analysis, with a higher participation rate in the control group with paracetamol (Figure 1).\n\n10.1371/journal.pone.0076499.g001Figure 1 Patient participation rate.\nPatient participation rates were determined according to the modalities of completing the questionnaire inside or outside the pharmacy and according to the substances. (**p<0.01 vs control).\n\nPatient Characteristics\nThe mean age was 48.0±15.9 years old and the majority (66.1%) were women. No statistically significant difference in age and sex was observed between the three studied groups of substances (Table 1).\n\n10.1371/journal.pone.0076499.t001Table 1 Characteristics of the patients responding to the questionnaire and of users of the studied substances in the previous month.\n\tCodeine\tH1 antihistamines\tParacetamol (control)\tTotal\t\n\nNumber of patients (total sample)\n\t142\t110\t131\t383\t\nMean age (years) ± SD\t46.6±13.4\t48.9±15.6\t48.7±18.4\t48.0±15.9\t\nNumber of women\t94 (66.2%)\t70 (63.6%)\t89 (67.9%)\t253 (66.1%)\t\n\nNumber of patients (users in the previous month)\n\t118\t70\t107\t295\t\nMean age (years) ± SD\t46.1±12.4\t52.1±17.0\t48.7±18.7\t48.5±16.2\t\nNumber of women\t80 (67.8%)\t47 (67.4%)\t75 (70.1%)\t202 (68.5%)\t\n\nFirst use of the drug\n\t\nOn physician advice\t39 (33.1%)**\n\t16 (22.9%)***\n\t57 (53.3%)\t112 (38.0%)\t\nOn pharmacist advice\t39 (33.1%)*\n\t33 (47.1%)**\n\t21 (19.6%)\t93 (31.5%)\t\nOn close family advice\t30 (25.4%)\t19 (27.1%)*\n\t16 (15.0%)\t65 (22.0%)\t\nOn advertisement\t3 (2.5%)\t0 (0.0%)\t0 (0.0%)\t3 (1.0%)\t\nOther\t5 (4.2%)\t1 (1.4%)\t5 (4.7%)\t11 (3.7%)\t\nGP is aware of the use\t79 (66.9%)\t34 (48.6%)\t66 (61.7%)\t179 (60.7%)\t\n* p<0.05;\n\n** p<0.01;\n\n*** p<0.001 (comparison to the control group).\n\nPatients having used the Drug in the Previous Month\nA large majority of the participants (77%, n = 295) had used the drug during the previous month (Table 1). The mean age was 48.5±16.2 years old, and the majority (68.5%) were women. The patients had informed their GP about their use of the studied drug in 60.7% of cases. 38% had started use on medical advice. This rate was significantly less for codeine (33.1%) and sedative H1 antihistamines (22.9%) than for paracetamol (53.3%). In contrast, patients were significantly more numerous to have started the use of codeine (33.1%) and sedative H1 antihistamines (47.1%) than paracetamol (19.1%) on pharmaceutical advice. 22% had first purchased the drug following family advice and three percent after seeing an advertisement.\n\nMisuse, Abuse, Persistent use of, and Dependence on Paracetamol, Codeine Combined with Paracetamol in Analgesics and Sedative H1 Antihistamines\nFrequency of misuse, abuse of, and dependence on codeine or H1 antihistamines was compared to that observed in paracetamol users (Table 2).\n\n10.1371/journal.pone.0076499.t002Table 2 Problematic uses of codeine (combined with paracetamol), H1 antihistamines, and paracetamol (control) among the patients having used these drugs during the previous month.\n\tCodeine\tH1 antihistamines\tParacetamol (control)\t\n\t(N = 118)\t(N = 70)\t(N = 107)\t\nMisuse\t8 (6.8%)***\n\t26 (37.1%)***\n\t0 (0%)\t\nAbuse\t1 (0.85%)**\n\t0 (0%)\t0 (0%)\t\nDependence\t21 (17.8%)**\n\t1 (1.3%)\t4 (3.7%)\t\n** p<0.01;\n\n*** p<0.001 (comparison to the control group).\n\n1. Paracetamol\n1.1. Misuse, abuse, and persistent use of paracetamol\nNo patient having used paracetamol during the previous month (n = 107) declared a higher consumption than the maximal recommended dose, i.e. 4 g/day. However, the dose was unknown in 11 cases (10.3%), and four patients also used another brand drug containing paracetamol alone (two patients) or combined with codeine (two patients), without precision concerning the doses and duration of use. Whereas no misuse or abuse of paracetamol was observed, 19 patients were daily users (17.8% of the patients having used paracetamol during the previous month). Ten of them declared to have used paracetamol daily for more than six months (there were three missing data). The reasons for persistent use of paracetamol were to treat pain: 8 for musculoskeletal pain, 4 for headache pain, 1 for dental pain (no precision in 6 cases). Only one patient having a persistent use of paracetamol was qualified as dependent on this substance.\n\n1.2. Dependence on paracetamol\nAmong the 107 patients having used paracetamol for self-medication in the previous month, four (3.7%) were qualified as dependent on paracetamol. They were tolerant to the analgesic effects of paracetamol. They often used higher doses than intended and had a persistent desire to control drug use. All of them declared that it is the persistence of pain that led them to increase the doses they anticipated to take and also to have increased the doses of paracetamol to get the same effect as when they had begun using this drug. The description of the four cases of dependence is presented in Table 3.\n\n10.1371/journal.pone.0076499.t003Table 3 Cases of dependence on paracetamol purchased without prescription at the community pharmacy.\nN° of case\tSex/Age (years)\tDose of paracetamol (g)\tDuration of use (years)\tReason for use\tQuestionnaire returned in a prepaid envelope\tWithdrawal symptoms (except pain)\tWithdrawal causes rebound pain\tAssociated psychoactive drugs and analgesics\tGP is awa-re of the use\tAdverse effects\t\n1\tM/18\t>1.5 (daily)\t<0.5\ttoothache\tNo\t–\tyes\tno\tyes\tno\t\n2\tF/21\tmissing data\t10\tpain\tyes\t–\tyes\tno\tno\tno\t\n3\tF/50\t>3 (2 days/7)\t5\tmigraine\tyes\tno\tno\tno\tyes\tno\t\n4\tM/25\t>1 (3 days/7)\t15\theadache\tno\tno\tno\tibuprofen\tno\tno\t\n2. Codeine Combined with Paracetamol\n2.1. Misuse, abuse, and persistent use of codeine combined with paracetamol\nAmong the patients having used codeine combined with paracetamol during the previous month (n = 118), only one patient took maximal recommended doses (i.e. 4 g/day of paracetamol), but seven declared to increase sometimes or frequently the maximal recommended doses of the majority of brand drugs containing this association (i.e. 120 mg of codeine phosphate/day and 3 g of paracetamol/day). In addition, two patients reported the use of another brand drug containing codeine combined with paracetamol without specifying the dose. The description of the eight cases of misuse (6.8%) is presented in Table S1 (cases n° 1, 8, 10, 12, 13, 16, 22, and 23). Among these eight patients, six were qualified as dependent on codeine (cases n° 1, 8, 10, 12, 13, and 16). Only one patient (case n° 13) declared to use codeine in high doses for a reason other than treating pain. This 38 year-old woman had been using 200 mg of codeine phosphate and 4 g of paracetamol daily for three years, for anxiolytic effects and by habit. She declared to be dependent on codeine. Sometimes, she increases the doses, leading to an overdose of paracetamol. Another patient who misused codeine was considered as an abuser of codeine (case n° 1). This 38 year-old woman declared to have a daily consumption of codeine with intermittent use of higher doses than recommended ones for headaches. She declared suffering from deleterious consequences from her codeine consumption with a depressive mood and dependence on codeine.\n\nAmong the 118 patients, 30 (25.4%) had a daily consumption. Twenty three of them had used codeine combined with paracetamol daily for more than six months, mostly during a 2 to 5 year period (36.7%). Headache (migraine specified in nine cases) was the most frequent reason for this persistent use (for 15 patients). Musculoskeletal pain was the reason given by six patients, and the origin of pain was not specified in eight cases. One patient reported using codeine daily for three years only because of her dependence to this substance. Among the 30 persistent users of codeine combined with paracetamol, 11 were qualified as dependent on this association.\n\n2.2. Dependence on codeine combined with paracetamol\nDependence on codeine concerned 21 patients out of the 118 having used this substance for self-medication in the previous month (cases n° 1 to 21, Table S1). Ten patients presented three DSM-IV criteria of dependence, five presented four criteria, four presented five criteria, one presented six criteria, and one presented all seven criteria of dependence. Three patients declared to have a craving for codeine (cases n° 3, 10, and 13). Three patients declared the need to take codeine analgesics for reason additional to treating pain and without details (cases n° 2, 5, and 11). One person said that she used codeine for well being (case n° 10) and another one because of her dependence on codeine analgesics (case n° 13). Among the 21 cases of dependence on codeine analgesics, adverse effects were described by nine patients (Table S1). Adverse events were physical or psychological symptoms, for four and six patients, respectively. The physical symptoms declared were: constipation, nausea, vertigo, and stomach-ache. The psychological symptoms were: depressive mood, anxiety, tiredness, inattention, nervousness, and feeling sleepy.\n\nA large majority of patients dependent on codeine (18 out of 21 cases) declared that persistence of pain led them to increase the doses. As shown in Figure 2, the two items of dependence of DSM-IV the most frequently retrieved were the intake of doses of codeine higher than intended (55.9%), and the persistent desire, or the unsuccessful efforts to control the consumption of codeine analgesics (37.3%).\n\n10.1371/journal.pone.0076499.g002Figure 2 Positive responses to DSM-IV substance dependence items.\nResults are expressed as percentage of the patients having used non-prescription analgesic drugs containing codeine during the previous month.\n\n3. Sedative H1 Antihistamines\n3.1. Misuse, abuse, and persistent use of sedative H1 antihistamines\nWhereas no patient having used a sedative H1 antihistamine during the previous month (n = 70) took higher doses than recommended, 37.1% of them misused it. Concerning doxylamine, 26 patients (72.2%) out of the 36 who had used this drug during the previous month took the drug daily whereas it is recommended to stop consumption after 5 consecutive days and to obtain a physician’s advice when the insomnia persists. The description of the patients who misused doxylamine is presented in Table 4. The mean age was 59.6±14.7 years old, and the majority were women (n = 19).\n\n10.1371/journal.pone.0076499.t004Table 4 Cases of misuse of doxylamine (daily use for more than 5 consecutive days) purchased without prescription at the community pharmacy.\nN° of case\tSex/Age (years)\tDose used daily (mg)\tDuration of use (years)\tAssociatedpsychoactive drug\tAdverse event: reboundinsomnia associated towithdrawal\tHas tried todecrease dosesused but did notstop\tPersistent desire orunsuccessful efforts tocontrol doxylamine use\t\n1\tF/27\t30\t1.5\t\tyes\tno\tyes\t\n2\tF/69\t30\t<0.5\t\tyes\tyes\tyes\t\n3\tM/59\t15\t18\t\tyes\tyes\tyes\t\n4\tF/70\t15\t4\tclorazepate dipotassium- acepromazine-aceprometazine\tmissing data\tmissing data\tmissing data\t\n5\tF/81\t15\t2\t\tyes\tyes\tmissing data\t\n6\tM/35\t15\t0.5\t\tyes\tyes\tmissing data\t\n7\tF/51\t15\t0.5\t\tyes\tyes\tmissing data\t\n8\tF/42\t15\t0.5\t\tyes\tyes\tdesires to stop but it is not a major concern\t\n9\tF/56\t15\t<0.5\t\tyes\tyes\tyes\t\n10\tF/45\t15\t<0.5\t\tno\tno\tyes\t\n11\tM/45\t15\t<0.5\t\tyes\tyes\tmissing data\t\n12\tF/47\t15\t<0.5\tescitalopram and alprazolam\tyes\tno\tyes\t\n13\tF/MV\t15\t<0.5\t\tyes\tyes\tmissing data\t\n14\tF/59\t15\t<0.5\t\tno\tyes\tmissing data\t\n15\tF/88\t15\t0.5\tzopiclone\tyes\tno\tno\t\n16\tM/52\t7.5\t5\t\tyes\tyes\tyes\t\n17\tM/62\t7.5\t5\tzopiclone, meprobamate, and valproic acid\tno\tyes\tyes\t\n18\tM/62\t7.5\t2 to 5\t\tyes\tyes\tmissing data\t\n19\tF/82\t7.5\t2\t\tyes\tno\tno\t\n20\tF/66\t7.5\t2\t\tyes\tno\tmissing data\t\n21\tF/59\t7.5\t1.5\t\tyes\tno\tno\t\n22\tM/58\t7.5\t<0.5\t\tyes\tyes\tdesires to stop but it is not a major concern\t\n23\tF/72\t7.5\t<0.5\t\tyes\tno\tyes\t\n24\tF/82\t4\t2 to 5\t\tnever stopped\tyes\tmissing data\t\n25\tF/56\t4\t2\t\tno\tyes\tmissing data\t\n26\tF/65\tmissing data\t4\tvalerian-passiflora-hawthorn-horehound\tyes\tyes\tyes\t\nIn a large majority (20 out of 26) patients said that they experienced a rebound of insomnia when they did not take doxylamine or decreased the dose. No other adverse event was described by daily users except a 62 year-old man who declared to be tired upon awakening (case n° 17, Table 4). However, it was difficult to attribute this symptom to doxylamine, as this man was depressed and also used other substances which could account for this event (zopiclone, meprobamate and valproic acid). In 17 cases, patients declared that they had tried to decrease the dose but did not stop taking the drug. Ten patients had a persistent desire or made unsuccessful efforts to control doxylamine use (no precision in 11 cases). Six patients said that they would not accept another drug proposed by the pharmacist and would go to another pharmacy to obtain the drug (no response in two cases). Among the 26 patients who had taken doxylamine daily during the previous month, 16 had a daily consumption for more than six months, up to 18 years. In addition to the daily use of doxylamine, four patients also took another drug prescribed by the physician with hypnotic properties (alprazolam, meprobamate, association of clorazepate dipotassium-acepromazine and aceprometazine, or zopiclone).\n\n3.2. Dependence on H1 antihistamines\nOnly one patient presented three DSM-IV criteria of dependence on a drug and was a persistent user. This 55 year-old woman, declared having used doxylamine daily for sleeping for four years. She had a persistent desire to control the use of this drug. Withdrawal of doxylamine causes to her a rebound of insomnia. She was willing to spend a lot of time obtaining doxylamine. However, she did not perceive this consumption as deleterious for her health, or her social or professional life.\n\nDiscussion\nThis cross-sectional study, based on the responses to an anonymous self-questionnaire offered in a randomly selected sample of community pharmacies of the French territory, has highlighted misuse of non-prescription drugs containing codeine (combined with paracetamol) or sedative H1 antihistamine (doxylamine) spontaneously requested by patients. In addition, dependence on codeine (combined with paracetamol) was also observed. Misuse and dependence on codeine analgesics concerned 6.8% and 17.8% of the patients having used this substance during the previous month, respectively, and were significantly higher than for paracetamol. For 37.1% of patients having used a sedative H1 antihistamine during the previous month, misuse of doxylamine, the most frequently reported H1 antihistamine used, concerned 72.2% of the users of this substance.\n\nComparison with other Studies\nThe main findings obtained with drugs containing sedative H1 antihistamines concerned the high prevalence of misuse of doxylamine, i.e. a much longer use of this drug at normal dose than the recommended duration (which must not exceed five days). In our study, 72.2% of the patients who used doxylamine were daily users, and 61.5% for more than 6 months. Surprisingly, a majority of daily users of doxylamine (17 out of 26) reported informing the GP about this consumption which had started following his or her advice in 53.3% of the cases. In 4 cases out of 26, patients also used prescribed hypnotic drugs in addition to doxylamine, such as zolpidem and zopiclone.\n\nTo our knowledge, this study was the first one to investigate the reasons for the non-recommended persistent use of doxylamine. Except one patient who declared to be depressive and to use doxylamine by habit, the others reported using it for chronic sleeping problems. Data on the efficacy of persistent use of doxylamine or other first generation sedative H1 antihistamines in insomnia are scarce [10]–[12]. In a small size crossover trial design, daytime sedative effect with diphenhydramine administered twice a day was significantly higher than with placebo on day one [13]. However, tolerance to daytime sedative effect of diphenhydramine was complete after three days of administration. One randomized clinical trial of doxylamine (15 mg) versus zolpidem (10 mg), administered to 338 patients with common insomnia, has shown a similar efficacy in the two drugs with respect to sleep after two weeks of treatment; no withdrawal syndrome was observed for either drug [14]. However, data on the efficacy of longer treatment with doxylamine with respect to chronic insomnia are lacking. In our study, most persistent users of doxylamine declared to have a rebound of insomnia when they stopped or decreased the doses, and half of them reported having a persistent desire or spending a lot of time to obtain the drug. Whereas we did not find any report about the prevalence of dependence on doxylamine in the literature, cases of antihistamine abuse and dependence, especially diphenhydramine and dimenhydrinate, have been described [15]–[17]. Experimental studies performed on animals suggest the potential for abuse of and dependence on doxylamine. Doxylamine has been shown to produce a partial generalization to a 10 mg/kg cocaine training stimulus in rats [18]. Administration of doxylamine in association with diphenydramine produced complete cross-generalization with the training cue. Another reason for persistent use of doxylamine could be the low rate of adverse effects of this substance. Adverse effects of sedative antihistamines, including doxylamine, are, in particular, daytime drowsiness and altered vigilance or are associated to atropinic effects (dry mouth, constipation, and urinary retention). In our study, the population of users of doxylamine included may not have been large enough to highlight atropinic effects of doxylamine or daytime altered vigilance, even in daily users over several years. Only one of the 36 users of doxylamine during the previous month declared to be tired during awakening, but doxylamine was not the only factor potentially associated to this adverse event. A rebound of insomnia was described by 20 patients after stopping or following a lower dose of doxylamine. When observed after lowering dose of doxylamine, the rebound of sleep disturbance could correspond to a therapeutic failure. However, it was not possible to differentiate patients who experienced rebound of insomnia after withdrawal or after decreasing the doses. Therefore, it cannot be exluded that rebound of insomnia corresponds to psychological signs of withdrawal or to an anticipatory anxiety to experiment sleep disturbance when not taking the drug.\n\nThe most remarkable results obtained with codeine relate to dependence on this substance. In the literature, psychological criteria of dependence on codeine are less evoked than physiological dependence (tolerance and withdrawal symptoms) in non-cancer chronic pain patients (for a review, see for example, [19]). Surprisingly, physiological items of dependence were not the most frequently reported in our study in comparison with psychological ones. The high rate of dependence on codeine observed in this study (18% of users) seems correlated with persistence of pain, and was higher than that previously observed in one French area (7.5%) [8]. In our previous pilot study, the patient was considered dependent when three relevant behavioural criteria for established dependence concerning the harmful consequences of consumption were reported. Having taken into account the physiological criteria of dependence as well as the two other psychological criteria for dependence (often use of higher doses than intended and persistent desire or unsuccessful efforts at controling drug use) might have increased the rate of patients judged as dependent on codeine.\n\nWhereas the potential for abuse and dependence on codeine is established, data on the prevalence and incidence of persistent use or problematic use of this weak opioid by non-painful patients or patients with non-cancer chronic pain are very few. Only few patients became persistent users (0.3%) or probable problematic users (0.08%) in a recent Norwegian study on new users of codeine [20]. However, in Norway, codeine is not available without a medical prescription form in community pharmacies. In contrast, in Australia, where codeine analgesics can be obtained OTC, warnings have been recently given on dependence on codeine [21]. Between September 2005 and September 2010, 18% of all patients referred to the Drug and Alcohol Services at the Western Hospital of Melbourne were diagnosed with opioid dependence and had medical and psychiatric problems linked to their excessive use of codeine analgesics. All had some form of chronic pain, had initiated codeine analgesic use for acute pain (e.g., headache), and all described progressive use of analgesics because of psychogenic effects (e.g., “gave me energy”, “helped me forget”) [22]. Reasons for initiation and persistence of use of codeine are very similar to those reported in our study.\n\nStrengths and Limitations of the Study\nThe study has several strengths. Firstly, this is the first study giving quantitative data on misuse, abuse of, and dependence on non-prescription drugs spontaneously requested by patients in community pharmacies. Secondly, it was based on a nation-wide randomly selected sample of pharmacies in France. A previous study in one area had already demonstrated the feasibility to recruit patients in community pharmacies to investigate problematic use of psychoactive drugs used for self-medication [8]. Thirdly, we used a control (paracetamol alone available without prescription) to get a comparative evaluation of the extent of the problem of misuse, abuse and dependence with different drugs.\n\nThe study also has several limitations. The questionnaire was given to 915 adults over 18 spontaneously requesting the studied drugs, and 44.5% of them gave the completed questionnaire either to the pharmacists or send it to the study centre. Only one third of the patients who said they would complete the questionnaire outside the pharmacy returned it with the prepaid envelope. This rate was similar to that observed in two published studies: our previous pilot study [8] and a study on pharmacovigilance of non-prescription drugs performed in the UK [23]. These studies were, to our knowledge, the only ones in which staff explained the study and asked eligible subjects to complete the questionnaire outside the pharmacy.\n\nIn our study, response rate was lower for drugs containing psychoactive substances than for the control group. Therefore, patients most concerned with a problematic use of these drugs, could have had reserves to answer the questionnaire, and the results obtained might be an underestimation, for doxylamine as well as for codeine. However, in spite of this, statistically significant higher rates of misuse or dependence have been observed with doxylamine or codeine analgesics, in comparison to the paracetamol control group.\n\nFinally, our results cannot be extended to all the French population as children and adolescents were not included. It has been recently observed in California that most adolescent admissions in the addiction public system during 2006–2007 were for OTC drugs (32.1%), following stimulant prescription drugs (45.3%), whereas opioid prescription drugs (88.9%) were most common for adults [24]. Therefore, the number of patients with problematic uses of non-prescription drugs could have been even more elevated if young people have been included in our study.\n\nIn this study, paracetamol was used as a control. In contrast to patients dependent on codeine analgesics, the four patients presenting three DSM-IV items of dependence on paracetamol did not declare any psychoactive effects. Moreover, they did not describe any psychological symptoms when stopping use of paracetamol. Therefore, as the items of dependence for paracetamol were (i) tolerance, (ii) often used higher doses than intended and (iii) a persistent desire to control drug use, and as all the patients presented chronic pain, we conclude that it is pain itself and the anticipation of pain which lead to present items of dependence. As it has been clearly previously discussed by Lusher et al. [25], patients qualified as dependent on analgesics could present a pseudoaddiction (i.e. pain-related) or an analgesic addiction (when DSM-IV items are not related to persistence of pain but to other reasons such as well being, relaxation, euphoria,…).\n\nImplications for Public Health\nDrugs are classified in France according to their potential to impair driving performance. A pictogram corresponding to the highest level of risk (level 3) is indicated on the package of doxylamine drugs. A recent French study has shown that level 3 prescription drugs are associated with the highest risk of traffic accidents [26]. However, no data were available for non-prescription drugs. In Australia, an association between H1 antihistamine use and motor vehicle accidents has been evidenced in professional drivers and was independent from other potentially confounding factors such as age, alcohol intake, driving exposure, and sleepiness [27]. In a randomized, placebo-controlled clinical trial in a driving simulator, it was observed that sedative antihistamines impaired simulated driving performance to a similar degree as alcohol, and, surprisingly, is not associated with sleepiness [28]. Therefore, persistent doxylamine users could be at higher risk of impaired driving performance, even in absence of drowsiness/sleepiness during daytime. Sedative H1 antihistamines have also been identified as drugs used for chemical submission (i.e. psychoactive substances administered without the knowledge of a victim in order to induce incapacitation and thus facilitate criminal actions), probably because they cause impaired vigilance and drowsiness [29].\n\nUse of sedative H1 antihistamines was recently associated with an increased risk of mortality in comparison to non-users (HR (95% C.I.) = 4.57 (3.01 to 6.94)) in a matched cohort survival analysis performed in Pennsylvania, USA [30]. All pharmacological classes of hypnotics were associated with greater than threefold increased hazards of death, even when prescribed less than 18 pills/year; increase which was not attributable to pre-existing disease. These results could even have been underestimated as over-the-counter antihistamine sleep drugs were not included. Whereas this study did not investigate the pattern of use of sedative H1 antihistamines by the patients, it can be suspected that using higher doses than recommended ones, or having a persistent use, could worsen the associated risk of mortality.\n\nHalf of the codeine daily users reported headaches. Repeated use, without overuse, of single analgesics combined or not with opioids can lead to Medication Overuse Headache (MOH). Combination drugs containing codeine have been found to increase the risk of MOH in comparison with single analgesics [31]. Headache was also the reason for codeine use for 43.5% of the codeine-dependent patients. We did not have any information on past or present use by patients of illegal products (or legal but non-pharmaceutical products) with a potential of addiction. However, as it has been previously suggested, the need for the analgesic drug to treat headaches could result from its ability to help patients cope with life [32]. Since 2009, in England, changes in the Patient Information Leaflets and Labels on pharmaceutical products containing codeine or dihydrocodeine have been introduced to minimise the risk of overuse and addiction to these drugs. They state that the products are for short term use only, for the treatment of moderate, acute pain, and that the products can cause addiction or overuse headache if used continuously for more than three days [33]. To our knowledge, the impact of these changes in the information given to patients is still unknown.\n\nConclusion\nThis nationwide study has shown a high prevalence of persistent users of non-prescription codeine combined with paracetamol analgesics with significant differences observed for misuse, abuse, and dependence in comparison with paracetamol alone. Among the persistent users of codeine combined with paracetamol, one third were qualified dependent and presented more frequent psychological or behavioural criteria of dependence than physiological ones. Dependence on codeine mainly seemed associated with persistence of pain. Headache was the most frequent reason for persistent daily use of codeine analgesics. These results support the fact that chronic pain requires better medical care, in particular chronic cephalalgia, which in turn will help prevent drug-related chronic headaches.\n\nThe prevalence of persistent users of doxylamine was 72.2%. A rebound of insomnia upon drug cessation, and the fact that one third of the patients declared to have a persistent desire to control doxylamine use or to make unsuccessful efforts at it suggest that it could be difficult for patients to stop taking the drug. Therefore, more data on the risk of harm associated to doxylamine or other sedative H1 antihistamines used for self-medication are required, and, as for all pharmacological classes of hypnotics, persistent use of doxylamine for chronic sleeping problem remains questionable.\n\nOverall, the results obtained in the present study on the prevalence of problematic uses of codeine analgesics and doxylamine in non-prescription drugs in a French population sample of adults over 18 spontaneously requesting the studied drugs in pharmacy should help improve recommendations for medical care of cephalalgia and chronic sleeping problems. In addition, they also should help improve clinical management of patients dependent on these drugs.\n\nSupporting Information\nTable S1 \nCases of misuse and dependence on drugs containing codeine combined with paracetamol purchased without prescription at the community pharmacy.\n\n\n(DOCX)\n\nClick here for additional data file.\n\n We are grateful to the community pharmacies who have actively participated in the study. We also thank Virginia Clark, head of the English department at the Purpan School of Medicine for her helpful editing.\n==== Refs\nReferences\n1 Afssaps (2011) Analyse des ventes des médicaments aux officines et aux hôpitaux en France, 1999–2009. Rapport d’expertise, 11ème édition. Available: http://www.ansm.sante.fr/var/ansm_site/storage/original/application/6949f3707b826ada566544613ee8dafe.pdf. Accessed 10 September 2013.\n2 AFIPA. Les chiffres du marché de l’automédication en France. Available: http://www.afipa.org/1-afipa-automedication/119-l-automedication-responsable/327-les-chiffres-du-marche-de-l-automedication.aspx. Accessed 10 September 2013.\n3 \nMatheson C , Bond C , Pitcairn J (2002 ) Misuse of over-the-counter medicines from community pharmacies: a population survey of Scottish pharmacies . Pharm J \n269 : 66 –68 .\n4 \nPates R , McBride AJ , Li S , Ramadan R (2002 ) Misuse of over-the-counter medicines: a survey of community pharmacies in a South Wales health authority . Pharm J \n268 : 179 –182 .\n5 \nHughes GF , McElnay JC , Hughes CM , Mc Kenna P (1999 ) Abuse/misuse of non-prescription drugs . Pharm World Sci \n21 : 251 –255 .10658232 \n6 \nFleming GF , McElnay JC , Hughes CM (2004 ) Development of a community pharmacy-based model to identify and treat OTC drug abuse/misuse: a pilot study . Pharm World Sci \n26 : 282 –288 .15598070 \n7 \nWazaify M , Hughes CM , McElnay JC (2006 ) The implementation of a harm minimisation model for the identification and treatment of over-the-counter drug misuse and abuse in community pharmacies in Northern Ireland . Patient Educ Couns \n64 : 136 –141 .16431072 \n8 \nOrriols L , Gaillard J , Lapeyre-Mestre M , Roussin A (2009 ) Evaluation of abuse and dependence on drugs used for self-medication: a pharmacoepidemiological pilot study based on community pharmacies in France . Drug Saf \n32 : 859 –873 .19722729 \n9 American Psychiatric Association (2000) DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. Washington DC: American Psychiatric Association.\n10 \nMeolie AL , Rosen C , Kristo D , Kohrman M , Gooneratne N , et al (2005 ) Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence . J Clin Sleep Med \n1 : 173 –187 .17561634 \n11 \nMorin AK , Jarvis CI , Lynch AM (2007 ) Therapeutic options for sleep-maintenance and sleep-onset insomnia . Pharmacotherapy \n27 : 89 –110 .17192164 \n12 \nNo authors listed (2008 ) Sleep complaints: Whenever possible, avoid the use of sleeping pills . Prescrire Int \n97 : 206 –212 .\n13 \nRichardson GS , Roehrs TA , Rosenthal L , Koshorek G , Roth T (2002 ) Tolerance to daytime sedative effects of H1 antihistamines . J Clin Psychopharmacol \n22 : 511 –515 .12352276 \n14 \nSchadeck B , Chelly M , Ansellem D , Cohen A , Peraudeau P , et al (1996 ) Comparative efficacy of doxylamine (15 mg) and zolpidem (10 mg) for the treatment of common insomnia: a placebo-controlled study . La Semaine des hôpitaux de Paris \n72 : 428 –439 (article in French)..\n15 \nCraig DF , Mellor CS (1990 ) Dimenhydrinate dependence and withdrawal . CMAJ \n142 : 970 –973 .2328468 \n16 \nThomas A , Nallur DG , Jones N , Deslandes PN (2009 ) Diphenhydramine abuse and detoxification: a brief review and case report . J Psychopharmacol \n23 : 101 –105 .18308811 \n17 \nGracious B , Abe N , Sundberg J (2010 ) The importance of taking a history of over-the-counter medication use: a brief review and case illustration of “PRN” antihistamine dependence in a hospitalized adolescent . J Child Adolesc Psychopharmacol \n20 : 521 –524 .21186972 \n18 \nGauvin DV , Carl KL , Briscoe RJ , Vallett M , Holloway FA (1995 ) Cross-generalization between a cocaine cue and two antihistamines . Eur J Pharmacol \n294 : 281 –288 .8788442 \n19 \nVallejo R , Barkin RL , Wang VC (2011 ) Pharmacology of opioids in the treatment of chronic pain syndromes . Pain Physician \n14 : E343 –360 .21785485 \n20 \nSkurtveit S , Furu K , Borchgrevink P , Handal M , Fredheim O (2011 ) To what extent does a cohort of new users of weak opioids develop persistent or probable problematic opioid use? \nPain \n152 : 1555 –1561 .21450405 \n21 \nFrei MY , Nielsen S , Dobbin MD , Tobin CL (2010 ) Serious morbidity associated with misuse of over-the-counter codeine-ibuprofen analgesics: a series of 27 cases . Med J Aust \n193 : 294 –296 .20819050 \n22 \nMcDonough MA (2011 ) Misuse of codeine-containing combination analgesics . Med J Aust \n194 : 486 .\n23 \nSinclair HK , Bond CM , Hannaford PC , Grampian Pharmacy Network (1999 ) Pharmacovigilance of over-the-counter products based in community pharmacy: a feasible option? \nPharmacoepidemiol Drug Saf \n8 : 479 –491 .15073891 \n24 \nGonzales R , Brecht ML , Mooney L , Rawson RA (2011 ) Prescription and over-the-counter drug treatment admissions to the California public treatment system . J Subst Abuse Treat \n40 : 224 –229 .21193282 \n25 \nLusher J , Elander J , Bevan D , Telfer P , Burton B (2006 ) Analgesic addiction and pseudoaddiction in painful chronic illness . Clin J Pain \n22 : 316 –324 .16514333 \n26 Orriols L, Delorme B, Gadegbeku B, Tricotel A, Contrand B, et al. (2010) Prescription medicines and the risk of road traffic crashes: a French registry-based study. PLoS Med 7. doi: 10.1371/journal.pmed.1000366 \n\n27 \nHoward ME , Desai AV , Grunstein RR , Hukins C , Armstrong JG , et al (2004 ) Sleepiness, sleep-disordered breathing, and accident risk factors in commercial vehicle drivers . Am J Respir Crit CareMed \n170 : 1014 –1021 .\n28 \nWeiler JM , Woodworth G , Watson G (2000 ) Drug Effects on Driving Performance . Ann Intern Med \n133 : 657 –658 .\n29 \nDjezzar S , Questel F , Burin E , Dally S (2009 ) French Network of Centers for Evaluation and Information on Pharmacodependence (2009 ) Chemical submission: results of 4-year French inquiry . Int J Legal Med \n123 : 213 –219 .18925406 \n30 \nKripke DF , Langer RD , Kline LE (2012 ) Hypnotics’ association with mortality or cancer: a matched cohort study . BMJ Open \n2 : e000850 \ndoi:10.1136/bmjopen-2012-000850 \n\n31 \nBendtsen L , Birk S , Kasch H , Aegidius K , Sørensen PS , et al (2012 ) Reference programme: Diagnosis and treatment of headache disorders and facial pain. Danish Headache Society . J Headache \nPain13 Suppl 1S1 –29 .\n32 \nFerrari A , Cicero AF , Bertolini A , Leone S , Pasciullo G , et al (2006 ) Need for analgesics/drugs of abuse: a comparison between headache patients and addicts by the Leeds Dependence Questionnaire (LDQ) . Cephalalgia \n26 : 187 –193 .16426274 \n33 MHRA (No author listed) (2009) Over-the-counter painkillers containing codeine or dihydrocodeine. Drug Safety Update 3: 6. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON087912. Accessed 10 Sept 2013.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "8(10)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid; D003061:Codeine; D003430:Cross-Sectional Studies; D005260:Female; D005602:France; D006634:Histamine H1 Antagonists; D006801:Humans; D008297:Male; D008875:Middle Aged; D004366:Nonprescription Drugs; D015995:Prevalence; D012651:Self Medication; D019966:Substance-Related Disorders; D011795:Surveys and Questionnaires",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e76499",
"pmc": null,
"pmid": "24098516",
"pubdate": "2013",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "10658232;19722729;21186972;15317672;15598070;19536941;21125020;17561634;12352276;17192164;16426274;11033602;20819050;8788442;21534912;21785485;22371848;15073891;21193282;16514333;22270537;2328468;18308811;21450405;16431072;18925406",
"title": "Misuse and dependence on non-prescription codeine analgesics or sedative H1 antihistamines by adults: a cross-sectional investigation in France.",
"title_normalized": "misuse and dependence on non prescription codeine analgesics or sedative h1 antihistamines by adults a cross sectional investigation in france"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1005073",
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"occurcountry": "FR",
"patient": {
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"activesubstancename": "ALCOHOL"
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... |
{
"abstract": "Treatment rates for osteoporosis after a major osteoporotic fracture are unacceptably low. We evaluate the effectiveness of an ortho-geriatric team (OGT) in initiating pharmacologic therapy for osteoporosis post-hip fracture. The OGT was able to achieve a higher treatment rate for patients post-hip fracture in comparison to usual care provided by the primary care hospitalist. Potential reasons for delaying or not proceeding with drug therapy include patient concern regarding potential rare side effects of antiresorptive therapy including osteonecrosis of the jaw and atypical femoral fracture. These events however are rare, and in this study, only 3% of hip fractures were atypical femoral fractures.\n\n\n\nCurrently, a significant care gap for osteoporosis therapy exists post-hip fracture despite advances in pharmacologic therapy. We evaluate the effectiveness of the OGT at the Oakville Trafalgar Memorial Hospital (OTMH), Ontario, Canada, in reducing the care gap and initiating pharmacologic therapy in hip fracture patients prior to hospital discharge. We also evaluated the incidence of atypical femoral fracture (AFF) separately.\n\n\n\nA retrospective chart review of patients 59 years and older with a hip fracture admitted to OTMH from January 1, 2016, to February 1, 2017, was conducted. The primary outcome was the proportion of hip fracture patients discharged from the hospital with appropriate treatment for their underlying osteoporosis. A sub-analysis was completed reporting the incidence of AFF among older adults.\n\n\n\nA total of 197 patients with a hip fracture were identified, 134/197 (68%) patients were seen by the OGT, 98/134 (73%) of these patients were started on pharmacologic therapy prior to discharge, and 120/134 (89%) of patients seen by the OGT were on treatment within 3 months of discharge following assessment in the complex osteoporosis clinic. Sixty-three patients of the 197 (63/197) (32%) of the hip fracture patients were seen by a hospitalist, and treatment rates prior to discharge were 5%. Only 6/197 patients had experienced an AFF during the study period, and all patients with an atypical femoral fracture had been on long-term bisphosphonate therapy. All of the patients with an AFF had thigh or groin pain for several weeks to months prior to the development of the atypical femoral fracture, providing an opportunity to stop therapy and possibly prevent the development of a complete AFF.\n\n\n\nThe OGT was able to initiate anti-osteoporosis therapy in significantly more patients in comparison to usual care, and higher treatment rates are possible with an OGT.",
"affiliations": "McMaster University, Hamilton, Ontario, Canada. Aliya@mcmaster.ca.;McMaster University, Hamilton, Ontario, Canada.;Bone Research and Education Center, Oakville, Ontario, Canada.;McMaster University, Hamilton, Ontario, Canada.;Halton Healthcare Services, Oakville, Ontario, Canada.;Bone Research and Education Center, Oakville, Ontario, Canada.;McMaster University, Hamilton, Ontario, Canada.;Halton Healthcare Services, Oakville, Ontario, Canada.;Halton Healthcare Services, Oakville, Ontario, Canada.",
"authors": "Khan|Aliya A|AA|;AbuAlrob|Hajar|H|;Tariq|Farhan|F|;Tauqir|Madiha|M|;Zalzal|Paul|P|;M'Hiri|Iman|I|;Khan|Moin|M|;Ginty|Mark|M|;Weening|Brad|B|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "England",
"delete": false,
"doi": "10.1007/s11657-020-00861-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "16(1)",
"journal": "Archives of osteoporosis",
"keywords": "Atypical femoral fracture; Fracture liaison service; Hip fracture; Osteoporosis; Osteoporosis treatment",
"medline_ta": "Arch Osteoporos",
"mesh_terms": "D000368:Aged; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005264:Femoral Fractures; D006620:Hip Fractures; D006764:Hospitals, Community; D006801:Humans; D009864:Ontario; D010024:Osteoporosis; D058866:Osteoporotic Fractures; D012189:Retrospective Studies",
"nlm_unique_id": "101318988",
"other_id": null,
"pages": "8",
"pmc": null,
"pmid": "33409668",
"pubdate": "2021-01-06",
"publication_types": "D016428:Journal Article",
"references": "25222365;15746995;21599967;15490120;8166806;17566814;22883372;12366617;30976999;24511530;20634496;16331770;17033908;15045468;12030544;19421703;1636840;25481833;23060307;11730245;11991439;28099754;8950879;9875874;10527181;11172164;17476007;22398854;11420776;23426882;17074877;16913645;15542027;19016585;12904835;17415014;20536631;28138228;16391246;19257816;28668994;17641811;24535775;24956507;22836783;25051904;25414052;27956123;23712442;26789873;24030479;24314319;28717402;22829395;21847765;32266437;28236126;23572401;16823545",
"title": "Osteoporosis treatment rate following hip fracture in a community hospital.",
"title_normalized": "osteoporosis treatment rate following hip fracture in a community hospital"
} | [
{
"companynumb": "CA-AMGEN-CANSP2019003209",
"fulfillexpeditecriteria": "2",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "A 74-year-old morbidly obese man was scheduled for surgical repair of an incisional ventral hernia. Anaesthesia was induced with propofol and fentanyl, and maintained with desflurane. A second dose of fentanyl 0.2 mg, given before starting surgery, resulted in sinus bradycardia and mild decrease of arterial blood pressure. Atropine sulfate 0.5 mg was administered. One minute later, the ECG rhythm on the monitor changed to third degree atrioventricular block with a ventricular response rate of 40 beats/min associated with marked hypotension. Isoproterenol 0.02 mg reverted the atrioventricular block to sinus rhythm. Cardiac enzymes and ECG ruled out acute myocardial ischaemia. The surgical procedure and the recovery from anaesthesia were uneventful. The patient was discharged from the hospital on the fifth postoperative day. For the treatment of bradycardia atropine sulfate should be adjusted at least to lean body weight in order to avoid paradoxical heart rate response in patients with obesity.",
"affiliations": "Department of Medicine, Anaesthesiology and Intensive Care, University of Padova, Padova, Italy.;Department of Medicine, Anaesthesiology and Intensive Care, University of Padova, Padova, Italy.",
"authors": "Carron|Michele|M|;Veronese|Stefano|S|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D001285:Atropine; D000077335:Desflurane; D007530:Isoflurane; D005283:Fentanyl; D015742:Propofol",
"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": "D000368:Aged; D000768:Anesthesia, General; D000889:Anti-Arrhythmia Agents; D054537:Atrioventricular Block; D001285:Atropine; D001919:Bradycardia; D000077335:Desflurane; D005283:Fentanyl; D006801:Humans; D007530:Isoflurane; D008297:Male; D009767:Obesity, Morbid; D015742:Propofol",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25634857",
"pubdate": "2015-01-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10927998;21148651;12734175;16176118;16115264;23066004;9760293;3279717;1843448;21642950;20531173",
"title": "Atropine sulfate for treatment of bradycardia in a patient with morbid obesity: what may happen when you least expect it.",
"title_normalized": "atropine sulfate for treatment of bradycardia in a patient with morbid obesity what may happen when you least expect it"
} | [
{
"companynumb": "IT-TEVA-544530ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANITIDINE\\RANITIDINE HYDROCHLORIDE"
},
"drugadditio... |
{
"abstract": "We describe an extremely rare case of mediastinitis superinfected by emerging Achromobacter xylosoxidans. After mitral and aortic valves replacement, the patient first developed a Staphylococcus aureus mediastinitis, and five days after starting adapted antibiotic therapy, superficial pus analysis revealed the presence of Achromobacter xylosoxidans. This superinfection was considered superficial and focus was made on Staphylococcus aureus mediastinitis. Three weeks later, no more Staphylococcus aureus was found in pus samples and the sepsis seemed under control. Unfortunately, blood cultures were again positive for Achromobacter xylosoxidans three weeks later and the patient died from septic shock.",
"affiliations": "Department of Hospital Hygiene, CHU of Martinique, Fort-de-France, Martinique. Electronic address: karine.sanchez@chu-martinique.fr.;Department of Cardiothoracic Surgery, CHU of Martinique, Fort-de-France, Martinique.;Bacteriology Laboratory, CHU of Martinique, Fort-de-France, Martinique.;Department of Hospital Hygiene, CHU of Martinique, Fort-de-France, Martinique.;Department of Cardiothoracic Surgery, CHU of Martinique, Fort-de-France, Martinique.",
"authors": "Marion-Sanchez|Karine|K|;Lion|François|F|;Olive|Claude|C|;Cailleaux|Géraldine|G|;Roques|François|F|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2018.05.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "24(12)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Achromobacter xylosoxidans; Cardiac surgery; Mediastinitis; Staphylococcus aureus; Surinfection",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D042441:Achromobacter denitrificans; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001021:Aortic Valve; D017809:Fatal Outcome; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D008297:Male; D008480:Mediastinitis; D008943:Mitral Valve; D009894:Opportunistic Infections; D012772:Shock, Septic; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus; D015163:Superinfection; D013492:Suppuration",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "987-989",
"pmc": null,
"pmid": "29895453",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mediastinitis superinfected by Achromobacter xylosoxidans. A case report.",
"title_normalized": "mediastinitis superinfected by achromobacter xylosoxidans a case report"
} | [
{
"companynumb": "MQ-PFIZER INC-2018474503",
"fulfillexpeditecriteria": "1",
"occurcountry": "MQ",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRadio-chemotherapy is one of the steps of multidisciplinary management in locally advanced pancreatic cancer. The Epidermal Growth Factor Receptor (EGFR) plays an important role in the disease pathway. The purpose of this prospective study is to evaluate the feasibility and the efficacy of radiotherapy in combination with gemcitabine and EGFR targeting therapy for patients with locally advanced disease.\n\n\nMETHODS\nFrom November 2008 through January 2012, 34 patients were included in this study. In all cases an accurate pre-treatment staging including CT scan, Endoscopic Ultra-Sonography (EUS), 18F - fluorodeoxyglucose (18F-FDG) PET-CT and laparoscopy with peritoneal washing was performed. External beam radiation was delivered with a total dose of 50.4 Gy (1.8 Gy per fraction). Patients were treated using 3D- conformal radiotherapy, and the clinical target volume was the primary tumor and involved lymph nodes. Gemcitabine 300 mg/m(2) and Cetuximab were given weekly during radiation therapy.\n\n\nRESULTS\nTen patients (29.4 %) were excluded from the protocol because of the evidence of metastatic disease at the pre-treatment staging. Three patients refused radiochemotherapy. Twenty-one patients completed the therapy protocol. During the combined therapy grade 3-4 toxicities observed were only haematological (leukopenia 47,6 %, trombocytopenia 4.8 %, elevated gamma-GT 23.8 %, elevated alkaline phosphatase 4,8 %). Non-haematological toxicity grade 3-4 was never reported. Post-treatment workup showed partial response in five patients (24 %), stable disease in 11 patients (52 %) and disease progression in 5 patients (24 %). Two-year Local Control was 49 % (median, 18.6 months), 2-year Metastases Free Survival was 24 % (median, 10.8 months). One and two-year Overall Survival were 66 % and 28 % respectively, with a median survival time of 15.3 months.\n\n\nCONCLUSIONS\nThe combination of cetuximab and gemcitabine with concurrent radiation therapy provides a feasible and well tolerated treatment for locally advanced pancreatic cancer. Patients' selection is crucial in order to treat patients appropriately.",
"affiliations": "Radiotherapy Unit, Campus Bio-Medico University, Via A. del Portillo, 21, 00128, Rome, Italy. m.fiore@unicampus.it.;Radiotherapy Unit, Campus Bio-Medico University, Via A. del Portillo, 21, 00128, Rome, Italy. l.trodella@unicampus.it.;Department of General Surgery, Campus Bio-Medico University, Rome, Italy. s.valeri@unicampus.it.;Department of General Surgery, Campus Bio-Medico University, Rome, Italy. d.borzomati@unicampus.it.;Radiotherapy Unit, Campus Bio-Medico University, Via A. del Portillo, 21, 00128, Rome, Italy. b.floreno@unicampus.it.;Radiotherapy Unit, Campus Bio-Medico University, Via A. del Portillo, 21, 00128, Rome, Italy. e.ippolito@unicampus.it.;Radiotherapy Unit, Campus Bio-Medico University, Via A. del Portillo, 21, 00128, Rome, Italy. p.trecca@unicampus.it.;Radiotherapy Unit, Campus Bio-Medico University, Via A. del Portillo, 21, 00128, Rome, Italy. luca.trodella@unicampus.it.;Radiotherapy Unit, Campus Bio-Medico University, Via A. del Portillo, 21, 00128, Rome, Italy. r.dangelillo@unicampus.it.;Radiotherapy Unit, Campus Bio-Medico University, Via A. del Portillo, 21, 00128, Rome, Italy. s.ramella@unicampus.it.;Department of General Surgery, Campus Bio-Medico University, Rome, Italy. r.coppola@unicampus.it.",
"authors": "Fiore|Michele|M|;Trodella|Lucio|L|;Valeri|Sergio|S|;Borzomati|Domenico|D|;Floreno|Barnaba|B|;Ippolito|Edy|E|;Trecca|Pasquale|P|;Trodella|Luca Eolo|LE|;D'Angelillo|Rolando Maria|RM|;Ramella|Sara|S|;Coppola|Roberto|R|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D000068818:Cetuximab",
"country": "England",
"delete": false,
"doi": "10.1186/s13014-015-0564-8",
"fulltext": "\n==== Front\nRadiat OncolRadiat OncolRadiation Oncology (London, England)1748-717XBioMed Central London 56410.1186/s13014-015-0564-8ResearchProspective study of cetuximab and gemcitabine in combination with radiation therapy: feasibility and efficacy in locally advanced pancreatic head cancer Fiore Michele +393396854708m.fiore@unicampus.it Trodella Lucio l.trodella@unicampus.it Valeri Sergio s.valeri@unicampus.it Borzomati Domenico d.borzomati@unicampus.it Floreno Barnaba b.floreno@unicampus.it Ippolito Edy e.ippolito@unicampus.it Trecca Pasquale p.trecca@unicampus.it Trodella Luca Eolo luca.trodella@unicampus.it D’Angelillo Rolando Maria r.dangelillo@unicampus.it Ramella Sara s.ramella@unicampus.it Coppola Roberto r.coppola@unicampus.it Radiotherapy Unit, Campus Bio-Medico University, Via A. del Portillo, 21, 00128 Rome, Italy Department of General Surgery, Campus Bio-Medico University, Rome, Italy 15 12 2015 15 12 2015 2015 10 25531 7 2015 8 12 2015 © Fiore et al. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nRadio-chemotherapy is one of the steps of multidisciplinary management in locally advanced pancreatic cancer. The Epidermal Growth Factor Receptor (EGFR) plays an important role in the disease pathway. The purpose of this prospective study is to evaluate the feasibility and the efficacy of radiotherapy in combination with gemcitabine and EGFR targeting therapy for patients with locally advanced disease.\n\nMaterials and methods\nFrom November 2008 through January 2012, 34 patients were included in this study. In all cases an accurate pre-treatment staging including CT scan, Endoscopic Ultra-Sonography (EUS), 18F - fluorodeoxyglucose (18F-FDG) PET-CT and laparoscopy with peritoneal washing was performed. External beam radiation was delivered with a total dose of 50.4 Gy (1.8 Gy per fraction). Patients were treated using 3D- conformal radiotherapy, and the clinical target volume was the primary tumor and involved lymph nodes. Gemcitabine 300 mg/m2 and Cetuximab were given weekly during radiation therapy.\n\nResults\nTen patients (29.4 %) were excluded from the protocol because of the evidence of metastatic disease at the pre-treatment staging. Three patients refused radiochemotherapy. Twenty-one patients completed the therapy protocol. During the combined therapy grade 3–4 toxicities observed were only haematological (leukopenia 47,6 %, trombocytopenia 4.8 %, elevated gamma-GT 23.8 %, elevated alkaline phosphatase 4,8 %). Non-haematological toxicity grade 3–4 was never reported. Post-treatment workup showed partial response in five patients (24 %), stable disease in 11 patients (52 %) and disease progression in 5 patients (24 %). Two-year Local Control was 49 % (median, 18.6 months), 2-year Metastases Free Survival was 24 % (median, 10.8 months). One and two-year Overall Survival were 66 % and 28 % respectively, with a median survival time of 15.3 months.\n\nConclusions\nThe combination of cetuximab and gemcitabine with concurrent radiation therapy provides a feasible and well tolerated treatment for locally advanced pancreatic cancer. Patients’ selection is crucial in order to treat patients appropriately.\n\nKeywords\nPancreatic cancerRadiochemotherapyCetuximabPatient selectionissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nPancreatic Ductal Adenocarcinoma Cancer (PDAC) is the 10th most commonly diagnosed cancer and the 4th leading cause of cancer death in the U.S. The American Cancer Society estimates that 48,960 new cases and 40,560 deaths will occur in the U.S. in 2015 [1].\n\nThe only chance of cure and prolonged survival for PDAC patients (pts) is surgical resection. However, only 20 % of cases can be considered surgically resectable at diagnosis, while approximately 30 %-40 % of patients are affected by a locally advanced disease. The best therapeutic option for this large subset of patients has been the topic of the scientific debate in the last decade. A number of authors proposed neoadjuvant therapies for pancreatic cancer to better achieve tumor control and surgical radical resectability [2], as in several GI malignancies [3–5].\n\nConcomitant radio-chemotherapy (RCT) with gemcitabine has shown an improvement of local control and overall survival in the neoadjuvant setting [6].\n\nIn recent years preclinical data suggest that addition of Epidermal Growth Factor Receptor (EGFR) inhibitors can increase the activity of the use of gemcitabine and radiation in pancreatic cancer cell lines and tumors [7, 8].\n\nCetuximab, a monoclonal antibody that specifically binds to the EGFR, overexpressed in pancreatic cancer, has been shown in vivo and in vitro to enhance radiosensitivity, promote radiation induced apoptosis, decrease cell proliferation, inhibit radiation-induced damage repair and inhibit tumor angiogenesis [9].\n\nThe purpose of this study is to evaluate the feasibility and the efficacy of RCT with gemcitabine in combination with cetuximab for patients with locally advanced PDAC.\n\nMaterials and methods\nThe trial has been performed as a single-center one-armed phase II study.\n\nFrom November 2008 through January 2012, 34 consecutive patients affected by histologically proven pancreatic cancer fulfilling the inclusion criteria listed below were included in the study.\n\nOnly patients that met the following inclusion criteria were included in the treatment protocol: proven cytological or histological diagnosis of PDAC; age between 18 and 75 years; no previous RCT; 0-I ECOG performance status; adequate cardiac, liver and kidney function and a good bone marrow reserve. Patients were included if they had borderline resectable or unresectable pancreatic tumours. Definitions of borderline and unresectable disease were as per NCCN guidelines. Borderline resectable tumors were defined by venous involvement of the superior mesenteric vein (SMV) or portal vein (PV), gastroduodenal artery encasement, or abutment of the superior mesenteric artery (SMA) up to 180°. Unresectable disease was defined by greater than 180° of SMA involvement, SMV/PV occlusion that is not amenable to reconstruction, or aortic or inferior vena cava (IVC) invasion or encasement.\n\nThe exclusion criteria were: resectable and metastatic disease; previous or concomitant malignant disease; one or more of the following clinical conditions: infection, pregnancy or breast-feeding, liver failure, kidney failure, Pa O2 < 65 mmHg, Pa CO2 > 40 mmHg, mental disability.\n\nIn all cases a thorough pre-treatment staging was performed, including:clinical examination (ECOG performance status);\n\ncomplete blood tests and tumor markers (CEA, CA 19–9, CA 125);\n\nmultilayer CT scan (MS-CT) with and without contrast enhancement;\n\nendoscopic ultrasonography (EUS) with fine needle aspiration biopsy;\n\nlaparoscopy (LPS) with peritoneal washing;\n\nPET-CT with 18F-2-fluoro-2-deoxy-D-glucose (FDG).\n\n\n\nJaundiced patients underwent endoscopic biliary stenting before or during RCT.\n\nThe design of this study was approved by the Institutional Review Board.\n\nEach patient underwent CT-based planning before treatment. Each planning CT scan was obtained using a Simens 16-CT simulator (Siemens Medical System).\n\nRadiotherapy target volumes were established by CT scan and PET-CT scan. The Clinical Target Volume (CTV) included the tumor and involved lymph nodes (>1 cm on CT scan and PET positive). The Planning Target Volume (PTV) was defined by CTV with a safety margin of 1 cm in all directions to include organ motion and set-up errors. Patients were fixed during therapy by individual immobilization devices.\n\nExternal beam radiation was delivered to total dose of 50.4 Gy with fractionation of 1.8 Gy daily for 5 days a week. Patients were treated using 3D-conformal radiotherapy. Organs at risk for radiation-induced side effects were contoured on the planning CT and dose volume histograms (DVH) were calculated. Doses to the liver, kidneys and spine were not to exceed the stated dose tolerance guidelines used in the study. Maximum allowable radiation dose to the spinal cord was 40 Gy, no more than 50 % of the total liver volume was planned to receive more than 30 Gy (V30 < 50 %), and no more than 30 % and 50 % of the contralateral and ipsilateral kidney, respectively, were planned to receive more than 20 Gy (V20 < 30 % and 50 %). The minimal and maximal doses in the target volume were specified.\n\nAll treatments were delivered with a 15-MV linear accelerator (Varian Medical System) with a multifield isocentric technique using a multileaf collimator. Four axial fields were commonly placed, although non-coplanar techniques were also used. All fields were treated daily. A quality-control protocol was applied for all patients with the periodical acquisition of digital portal images to evaluate the precision of the set-up.\n\nSystemic therapy started the same day as radiation therapy and consisted of Gemcitabine 300 mg/m2 given weekly and Cetuximab given as loading dose 400 mg/m2 on day 1, and sequential Cetuximab 250 mg/m2∕week simultaneously with radiation.\n\nPatients were evaluated using a directed history and physical examination weekly during treatment.\n\nThe occurrence and nature of any adverse events were recorded according to the National Cancer Institute Common Toxicity Criteria (version 3.0) scale.\n\nApproximately 4 weeks after the completion of RCT, restaging consisting of clinical examination, laboratory test, tumor markers, CT scan, PET-CT scan was performed.\n\nThe tumor response was defined by CT scan and PET-CT scan according to the World Health Organization.\n\nThe study protocol was approved by the independent Ethics Committee of our University.\n\nResults\nPatients’ selection\nBetween November 2008 and January 2012, 34 patients (F:18; M:16) entered in the protocol. Twenty-four (70 %) patients were diagnosed based on cytology, ten (30 %) patients had histologically-confirmed positive biopsy. The median age was 68 years (range 36–75 years). All patients showed a good performance status (ECOG Score 0) and none of them had undergone previous chemotherapy or radiotherapy. In almost all cases the tumor was located in the head of the pancreas. Resectability status was accorded to the NCCN guidelines. Eighteen patients (86 %) had locally advanced unresectable tumors, three patients (14 %) had borderline resectable disease, on the basis of the involvement of less than 180 degrees of the superior mesenteric artery or involvement of the hepatic artery within 1 cm of the celiac axis. All patients underwent a diagnostic laparoscopy to verify occult peritoneal and/or hepatic metastases and to perform peritoneal washing. Laparoscopy was positive (presence of hepatic and/or peritoneal metastases and neoplastic cells in peritoneal washing) in 8 patients (23.5 %): neoplastic cells at peritoneal washing in 2 pts, histologically proven hepatic metastases in 3 pts, peritoneal carcinomatosis in 3 pts, unrecognized on CT scan. Moreover all patients performed PET-CT with 18F-2-fluoro-2-deoxy-D-glucose (FDG) resulting negative for distant disease in 32 patients (94.1 %) and positive disease in 2 (5.9 %): one patient with pulmonary metastasis, one patient with sovraclavear metastatic lymph node.\n\nAccording to the results of preoperative workup, 10 patients (29.4 %) had a metastatic disease and were therefore excluded from the protocol. Table 1 explains the results of the different staging methods for the 10 patients with metastatic disease.Table 1 Results of the different staging methods for the 10 patients with metastatic disease\n\nPatients\tCT scan\tPET-CT scan\tLaparoscopy\t\n1\t\t\tX\t\n2\t\t\tX\t\n3\t\t\tX\t\n4\t\t\tX\t\n5\t\t\tX\t\n6\t\t\tX\t\n7\tX\tX\t\t\n8\t\t\tX\t\n9\t\tX\t\t\n10\t\t\tX\t\n\n\nAfter pre-treatment selection 3 patients refused RCT. Thus 21 patients were treated.\n\nDemographic and clinical characteristics of these patients are listed in Table 2.Table 2 Enrolled patients’ characteristics\n\nCharacteristic\tNo of patients\n (N = 21)\t%\t\nAge (years)\t\t\n Median\t67\t\n Range\t43–75\t\nSex\t\t\t\n Male\t8\t38\t\n Female\t13\t62\t\nECOG performance status\t\t\t\n 0\t21\t100\t\n 1\t0\t0\t\nCA 19–9 at diagnosis, U/mL\t\t\n Median\t1028,15\t\n Range\t0–6688\t\nTumor localization\t\t\t\n Head\t21\t100\t\n Body/Tail\t0\t0\t\nResectability status\t\t\t\n Borderline resectable\t3\t14\t\n Unresectable\t18\t86\t\n\n\nTreatment-related toxicity\nAll twenty-one patients completed the therapy protocol.\n\nDuring RCT the most frequent all-grade toxicities were: haematological (anemia 76,2 %, leukopenia 80,9 %, thrombocytopenia 71,4 %), nausea (47,6 %), fatigue (47,6 %) and elevated gamma-GT levels (72,6 %).\n\nNo patient showed any clinical adverse events due to infusion of cetuximab. Three patients (14.3 %) had grade 1 acneiform rash and three patients (14.3 %) grade 2. Only one patient had grade 1 onychopathy.\n\nThe most common side effects during therapy were haematological events.\n\nG3 leukopenia and neutropenia occurred in 38,1 % and 19 % of patients respectively. Two patients (9,5 %) developed transient grade 4 leukopenia , and one patient grade 4 neutropenia not associated to fever. There were no cases of grade 3–4 anemia and grade 4 thrombocytopenia. Grade 3 trombocytopenia occurred in 4.8 % of patients.\n\nGastrointestinal toxicity consisted of nausea (33,3 % for grade 1 and 14,3 % for grade 2), vomiting (14,3 % for grade 1 and 4,8 % for grade 2) and diarrhoea (4,8 % for grade 1).\n\nFatigue and anorexia of grade 1 occurred in 38,1 % and 4,8 % of patients, and grade 2 in 9,5 % and 4,8 % of patients respectively.\n\nNo patients developed grade 3–4 elevated AST/ALT and total bilirubin. 4,8 % of patients had grade 2 of hyperbilirubinaemia and 14.3 % of patients grade 2 of hypertransaminasaemia.\n\nThree patients (19 %) had grade 3 of elevated gamma-GT and one patient (4,8 %) grade 4. Elevated alkaline phosphatase of grade 3 occurred in one patient (4,8 %).\n\nIn ten patients with hematologic grade 3–4 toxicity the treatment was interrupted (median time of interruptions was 5 days, range 2–8 days). Granulocyte colony stimulating factors were administered in three patients (14.2 %) with G4 leukopenia/neutropenia. There were no chemoradiation-associated deaths.\n\nThe toxicity data are summarized in Table 3.Table 3 Toxicity profile of chemoradiation with Cetuximab in all 21 patients\n\nToxicity\tGrade 1\tGrade 2\tGrade 3\tGrade 4\tAll grades\t\n\tNo. of events\t%\tNo. of events\t%\tNo. of events\t%\tNo. of events\t%\tNo. of events\t%\t\nHematologic\t\t\t\t\t\t\t\t\t\t\t\n Anemia\t10\t47,6\t6\t28,6\t0\t0\t0\t0\t16\t76,2\t\n Leukopenia\t2\t9,5\t5\t23,8\t8\t38,1\t2\t9,5\t17\t80,9\t\n Granulocytopenia\t5\t23,8\t8\t38,1\t4\t19\t1\t4,8\t18\t85,7\t\n Thrombocytopenia\t12\t57,2\t2\t9,5\t1\t4,8\t0\t0\t15\t71,4\t\nConstitutional\t\t\t\t\t\t\t\t\t\t\t\n Fatigue\t8\t38,1\t2\t9,5\t0\t0\t0\t0\t10\t47,6\t\n Anorexia\t1\t4,8\t1\t4,8\t0\t0\t0\t0\t2\t9,5\t\nGastrointestinal\t\t\t\t\t\t\t\t\t\t\t\n Nausea\t7\t33,3\t3\t14,3\t0\t0\t0\t0\t10\t47,6\t\n Vomiting\t3\t14,3\t1\t4,8\t0\t0\t0\t0\t4\t19\t\n Diarrhea\t1\t4,8\t0\t0\t0\t0\t0\t0\t1\t4,8\t\nLiver and biliary\t\t\t\t\t\t\t\t\t\t\t\n Elevated total bilirubin\t1\t4,8\t1\t4,8\t0\t0\t0\t0\t2\t9,5\t\n Elevated AST/ALT\t6\t28,6\t3\t14,3\t0\t0\t0\t0\t9\t4,3\t\n Elevated Alkaline phosphatase\t5\t23,8\t3\t14,3\t1\t4,8\t0\t0\t9\t4,3\t\n Elevated Gamma-GT\t6\t28,8\t5\t23,8\t4\t19\t1\t4,8\t16\t76,2\t\nAcneiform Rash\t3\t14,3\t3\t14,3\t0\t0\t0\t0\t6\t28,8\t\n\n\nTreatment efficacy\nAll patients enrolled were evaluated for clinical response. The average time of restaging after radiochemotherapy was 3.6 weeks (range 2.6-5 weeks).\n\nPost-treatment CT scan showed that 5 patients (24 %) had a partial response, in 11 patients (52 %) the disease resulted stable and 5 patients (24 %) experienced disease progression. If post-treatment PET-CT scan is considered, all patients showed a reduction in the value of SUVmax (Standard Uptake Value maximum).\n\nSeven patients (33.3 %) underwent surgical radical resection, and one patient (14.7 %) achieved a complete pathological response after combined radiochemotherapy.\n\nTwenty patients (95.2 %) received further sequential chemotherapy for a median of 4 months (range, 1 to 18 months). Fifteen patients received gemcitabine, four received other gemcitabine-based chemotherapy, and one received single-agent capecitabine. Eighteen (90 %) had no grade 3 or higher toxicity during chemotherapy. Two patients (10 %) experienced grade 3 gastrointestinal toxicities (eg, nausea, vomiting, and/or diarrhea) that required intravenous fluids but not hospitalization. Dose adjustments using standard dose-modification tables were based on the worst toxicity observed during the previous cycle.\n\nThe median follow-up was 23.3 months (range, 6 to 78 months).\n\nTwo-year Local Control (LC) was 49 % (median, 18.6 months; 95 % CI: 8.2–41), 2-year Metastases Free Survival (MFS) was 24 % (median, 10.8 months; 95 % CI: 3.2-31.9) [Figs. 1, 2].Fig. 1 Kaplan-Meier method for Local Control. The solid line represents the curve of Local Control; the dashed lines are the upper and lower limits of Local Control curve\n\nFig. 2 Kaplan-Meier method for Metasases Free Survival. The solid line represents the curve of Metastases Free Survival; the dashed lines are the upper and lower limits of the Metastases Free Survival curve\n\n\n\nOne-year Overall Survival (OS) and two-year OS were 66 % and 28 % respectively, with a median survival time of 15.3 months (95 % CI:10.8–22.5) [Fig. 3].Fig. 3 Kaplan-Meier method for Overall Survival. The solid line represents the curve of the Overall Survival; the dashed lines are the upper and lower limits of the Overall Survival curve\n\n\n\nThe initial site of progression was local in 3 patients, distant in 11 patients and local and at distant in two patients. Of patients who experienced local failure, three failed outside the radiotherapy fields at lomboaortic lymph nodes, two patients had ‘in-field’ recurrences. The systemic progression affected the liver in 6 patients, three patients showed peritoneal carcinomatosis (one patients experienced both liver and peritoneal progression), and two patients had lung and ovarian metastases. Four patients received palliative chemotherapy.\n\nAt the time of evaluation, three of the seven patients who underwent radical surgery are alive, two patients without evidence of disease, and one is continuing chemotherapy for distant progression.\n\nDiscussion\nThe optimal treatment strategy for locally advanced PDAC is still controversial, and despite considerable progress in oncology the poor prognosis of patients has not significantly improved. Thus there is clearly a need for additional therapeutic strategies. Improved biologic understanding of the disease and investigation of novel mechanism-based therapeutics are required to facilitate the development of more effective treatments with reduced toxicity. Modern radiotherapy has important roles in controlling local disease: to prevent disease symptoms, increase the possibility of resection, and extend survival. However, when combined with chemotherapy to maximize disease control, the effectiveness of treatment is limited by the radiation doses that can be given safely, due to the risk of toxicity in surrounding radiosensitive abdominal structures. In our opinion, the selection of patients affected by this disease is a crucial issue in the debate of integrated treatments. Advances in diagnostic imaging, with the improvement in the quality of computed tomography (CT) scanning, the input of PET-CT scan and the use of laparoscopy make it possible. For our diagnostic workup protocol we have combined imaging and laparoscopy to better select patients for radiochemotherapy and to select them for surgery after the combined modality.\n\nAfter preoperative staging, ten patients (29.4 %) had metastatic disease and were excluded from the protocol, while 24 patients (70.6 %) were enrolled for the combined therapy.\n\nOur diagnostic workup, including CT scan, PET-CT scan and laparoscopy, could be a model useful to clinicians who treat pancreatic cancer.\n\nBetter patient selection and multimodality treatment are crucial concepts to improve outcomes [10, 11]. Gemcitabine (difluorodeoxycytidine), an indipendent cytotoxic agent, is a nucleoside analog with potent radiosensitizing effects [6–8]. According to the results of randomized trials gemcitabine provides improvement in survival and clinical benefit compared with 5-fluorouracil (5-FU) treatment in advanced PDAC patients [12, 13]. For this superiority as both systemic therapy and potent radiosensitizing agent [14], we realized a protocol of treatment that included the use of preoperative gemcitabine-based chemoradiation. On basis of literature data a single agent should not be considered for locally advanced PDAC patients. Indeed therapies towards multiple targets may be more beneficial.\n\nNew therapeutic approaches involve the identification of a number of molecular targets that may be responsible of the resistance of cancer cells to radiation or to other cytotoxic agents. Among these EGFR has been a molecular target of considerable interest and investigation [9].\n\nCetuximab is a monoclonal antibody that specifically binds to the EGFR, thereby inhibiting downstream signal transduction pathways.\n\nBased on these considerations, we designed a clinical prospective protocol consisting of preoperative gemcitabine-based chemoradiation adding cetuximab to assess the feasibility and efficacy of this therapeutic strategy in patients with locally advanced pancreatic cancer.\n\nOur regimen of weekly cetuximab and gemcitabine delivered with concurrent radiation therapy resulted in a good profile of tolerability in patients with pancreatic cancer.\n\nCrane et al. [15] reported the results of a phase II trial of induction gemcitabine, oxaliplatin, and cetuximab followed by radiation (50.4 Gy) with concurrent capecitabine and cetuximab in 69 patients with locally advanced pancreatic cancer. Cetuximab (500 mg/m2) was started on day 1 of chemotherapy and was continued every 2 weeks during chemotherapy and chemoradiotherapy. Fifty-one patients (74 %) had unresectable tumors; 16 patients (23 %) had borderline resectable tumors due to vascular abutment, whereas 2 patients (3 %) had borderline resectable disease only on the basis of advanced regional adenopathy. Median follow-up was 16.3 months for all patients and 20.9 months for living patients; median progression-free survival (PFS) and OS were 12.5 and 19.2 months, respectively. In this study, six patients (8.7 %) had infusion reactions to cetuximab, and two of these were grade 3. Acneiform rash was 54 % and 3 % for grades 2 and 3, respectively; it correlated with improved survival. In our study only three patients (14.3 %) had grade 2 acneiform rash, no patient showed grade 3 toxicity. There was no correlation between acneiform rash and clinical outcomes.\n\nOur results agree with those of a phase I study evaluating cetuximab, gemcitabine and radiotherapy for locally advanced pancreatic cancer [16]. Recent results published by Arnoletti et al. have reported that the dose escalation was performed with gemcitabine (0–300 mg/m2) and cetuximab (400 mg/m2 loading dose and 250 mg/m2 weekly). The results of this study showed that 96 % of patients experienced grade 1–2 adverse events and 9 % had grade 3–4 adverse events. As in our study, there were not serious treatment-related events, and no patients deaths were associated to drug toxicity and to radiation schedule.\n\nIn two phase I studies reported both in abstract forms, the scheme of gemcitabine (300 mg/m2) and cetuximab (400 mg/m2 loading dose and 250 mg/m2∕week) with concurrent radiation therapy was tolerated and appeared to be effective [17, 18].\n\nOur results differ widely from those of another recently published phase I study, in which patients with locally unresectable pancreatic cancer were treated with gemcitabine (200 mg/m2 before dose escalation) plus cetuximab (400 mg/m2 loading dose followed by 250 mg/m2∕week) concurrent with radiation therapy (planned dose 50.4 Gy) [19] . Of the nine patients enrolled in this study, one was withdrawn before receiving the initial dose of cetuximab because of a decline in performance status; the remaining eight patients in which the tolerance to treatment was assessed presented a various baseline performance status. Five patients received more than the loading dose of cetuximab, and only one patient completed all doses of chemotherapy and radiotherapy.\n\nThe authors found a significant toxicity grade, including a high rate of infusion reactions, and they concluded that this combination should be approached with caution. This severe toxicity observed could be related to the traditional radiotherapy treatment volumes, which included primary tumor and prophylactic drainage nodes in the definition of clinical target volumes.\n\nIn our study, on the contrary, all patients completed the therapy protocol. We did not experience severe adverse events, included infusion reactions. The prophylactic use of chlorphenamine is likely to have prevented them.\n\nThe use of PET for target volume definition and delineation in GI tract tumors is only recently being investigated. In pancreatic cancer the interest is rapidly growing. Topkan et al. have compared CT- and PET/CT-based target volume delineation and the effects of these different modalities on 3D-conformal radiotherapy planning and radiation doses to critical organs. The authors demonstrated that PET-CT-based target volume contouring significantly increases the GTV (Gross Tumor Volume) and the PTV compared to CT-based contouring without increasing tissue toxicity in a clinically meaningful way. The authors utilized PET data and included the regional lymph nodes which appeared to be metabolically involved on PET scan but not on CT [20]. As this study suggests, the largest potential benefit of incorporating PET into RT planning for locally advanced pancreatic cancer may be the reduction in geographic misses associated with CT-based planning and the potential reduction in loco-regional treatment failure. On the basis of these considerations, we contoured small treatment volumes, including the pancreatic tumor and the involved lymph nodes. Radiation treatment volumes were defined not only based on the CT scan, as shown by the evidence in the literature, but also by using biological information obtained through PET-CT scan. In our cohort median PTV volume was 267.7 cc (range 130.6-797.6 cc). No patient developed grade 3–4 gastrointestinal toxicity. This may have been aided by limited-field radiotherapy.\n\nIn our study, RCT treatment, conducted on small volumes (only the areas biologically active) was safe and well tolerated with a manageable toxicity. None of 21 patients developed intestinal bleeding, a complication almost constant, variable from 3 % to 20 % [12, 13, 21–27]. At the same time the reduction of radiotherapy treatment volumes did not compromise the outcomes of survival and locoregional control. The median survival was 15.3 months, resulting improved in comparison with other studies of the literature [12, 13, 21–27]. Crane et al. retrospectively compared the efficacy of concurrent gemcitabine-based RCT with that of concurrent 5-FU-based RCT in patients with unresectable pancreatic cancer. Patients treated with gemcitabine had a median survival time of 11 months compared to 9 months of patients treated with 5-FU [12]. Brunner et al. published a retrospective analysis of patients treated with radiotherapy and 5-FU- or gemcitabine-based chemotherapy followed by additional chemotherapy with gemcitabine. In these patients the median survival time was 13 months [13]. In a prospective randomized study Li et al. investigated the efficacy of gemcitabine-concurrent RCT vs 5-FU based-RCT for locally advanced pancreatic cancer. The median survival was 14.5 months for gemcitabine-based RCT patients compared with 6.7 months for 5-FU-based RCT patients. The 1- and 2-year survival rate was 56 % and 15 % for gemcitabine-RCT compared with 31 % and 0 % for 5-FU-RCT, respectively [21]. In Huguet et al. trial, patients were treated with definitive gemcitabine-based chemoradiation if no progression was noted after initial induction chemotherapy. The median survival was 15 months [22]. In McGinn et al. study, weekly full-dose gemcitabine was administered concomitantly to involved-field irradiation, with a median survival time of 11.6 months [23]. In Muler et al. study [24] and in Kawakami et al. cohort [25] the median survival times were 12.9 months and 7.1 months, respectively. Goldstein et al. assessed the efficacy of a specific three-dimensional conformal radiotherapy technique with concurrent continuous infusion of 5-FU sandwiched between gemcitabine chemotherapy in patients with locally advanced pancreatic cancer. The median survival time in this study was 11.7 months, with the 1-year survival rate of 46.3 % [26]. Moreover, the results of SCALOP trial showed that the median overall survival was 15.2 months in the capecitabine-based RCT group and 13.4 in the gemcitabine-based RCT group [27].\n\nOur study demonstrated distant relapses as dominant treatment failure, emphasizing the need to find more effective systemic agents. The improvement of local control and, possibly, disease downstaging allowing surgical resection are important endpoints. The question remains how to improve local control without worsening the tolerability of the treatments. The use of modern radiation therapy procedures, such as contrast enhancement four-dimensional computed tomography (ce-4DCT), the radiation dose escalation of the primary tumor with intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) and better target selection could help to solve this problem.\n\nConclusions\nOur prospective study gives us the opportunity to emphasize, first of all, that in the treatment of pancreatic cancer, more than in others, the selection of patients, using the most modern imaging techniques and laparoscopy, is a crucial issue in order to treat these patients in the most appropriate way and to make appropriate assessments on patients’ compliance and response to therapies. To our knowledge, this is the first study in which this modality of patient selection is designed, allowing to exclude from locoregional treatment patients with early and rapidly progressive pancreatic cancer disease. Our diagnostic workup, including CT scan, PET-CT scan and laparoscopy, could be a model useful to clinicians who treat pancreatic cancer to improve patients' selection. Moreover, the combination of gemcitabine, cetuximab with concurrent radiation therapy, with smaller treatment volumes, is feasible and well tolerated, with encouraging results, that will allow to draw further studies combining systemic chemotherapy to radiotherapy dose intensified, in order to improve clinical outcomes.\n\nAbbreviations\n4DCTfour-dimensional Computed Tomography\n\n5-FU5-fluorouracil\n\nCTVClinical Target Volume\n\nEGFREpidermal Growth Factor Receptor\n\nEUSEndoscopic ultrasound\n\nGTVGross Tumor Volume\n\nIMRTIntensity Modulated Radiation Therapy\n\nLCLocal Control\n\nLPSlaparoscopy\n\nMFSMetastases Free Survival\n\nOSOverall Survival\n\nPDACPancreatic Ductal Adenocarcinoma Cancer\n\nPFSProgression Free Survival\n\nPTVPlanning Target Volume\n\nRCTRadio-Chemotherapy\n\nSUVStandard Uptake Value\n\nSBRTStereotactic Body Radiation Therapy\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nFM, TL, VS and CR are responsible for the study design. FM, FB, TP, TLE, VS collected the clinical data and drafted the manuscript. TL, CR, RS, DRM, BD revised the manuscript. FM, FB, TP, TLE, VS and IE were responsible for the treatment and evaluation of the patients. TL, CR, RS, DRM and BD provided oversight of the analysis of data and reviewing of the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgement\nWe thank Dr. Carlo Greco and Dr. Gennaro Nappo for their contribution to this study.\n\nDeclarations\nThe study protocol was approved by the independent Ethics Committee of Campus Bio-Medico University.\n==== Refs\nReferences\n1. Siegel RL Miller KD Jemal A Cancer Statistics, 2015 CA Cancer J Clin 2015 65 5 29 10.3322/caac.21254 25559415 \n2. Kleeff J Friess H Buchler MW Neoadjuvant therapy for pancreatic cancer Br J Surg 2007 94 261 262 10.1002/bjs.5737 17315287 \n3. Sauer R Becker H Hohenberger W Rodel C Wittekind C Fietkau R German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer N Engl J Med 2004 351 1731 1740 10.1056/NEJMoa040694 15496622 \n4. Mezhirr JJ Tang LH Coit DG Neoadjuvant therapy for locally advanced gastric cancer J Surg Oncol 2010 101 305 314 10.1002/jso.21483 20187070 \n5. Campbell NP Villaflor VM Neoadjuvant treatment of esophageal cancer World J Gastroenterol 2010 16 30 3793 3803 10.3748/wjg.v16.i30.3793 20698042 \n6. Loehrer PJ Sr Feng Y Cardenes H Wagner L Brell JM Cella D Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: An Eastern Cooperative Oncology Group Trial J Clin Oncol 2011 29 31 4105 4112 10.1200/JCO.2011.34.8904 21969502 \n7. Buchsbaum DJ Bonner JA Grizzle WE Stackhouse MA Carpenter M Hicklin DJ Treatment of pancreatic cancer xenografts with Erbitux (IMC-C225) anti-EGFR antibody, gemcitabine, and radiation Int J Radiat Oncol Biol Phys 2002 54 4 1180 1193 10.1016/S0360-3016(02)03788-4 12419447 \n8. Morgan MA Parsels LA Kollar LE Normolle DP Maybaum J Lawrence TS The combination of epidermal growth factor receptor inhibitors with gemcitabine and radiation in pancreatic cancer Clin Cancer Res 2008 14 16 5142 5149 10.1158/1078-0432.CCR-07-4072 18698032 \n9. Krempien R Muenter MW Huber PE Nill S Friess H Timke C Randomized phase II – study evaluating EGFR targeting therapy with Cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer – PARC: study protocol [ISRCTN56652283] BMC Cancer 2005 5 131 10.1186/1471-2407-5-131 16219105 \n10. Lawrence TS Chang EY Hahn TM Hertel LW Shewach DS Radiosensitization of pancreatic cancer cells by 2,2-difluoro-2-deoxycytidine Int J Radiat Oncol Biol Phys 1996 34 867 872 10.1016/0360-3016(95)02134-5 8598364 \n11. Lawrence TS Eisbruch A Shewach DS Gemcitabine-mediated radiosensitization Semin Oncol 1997 24 S7 S24 9194476 \n12. Crane CH Abbruzzese JL Evans DB Wolff RA Ballo MT Delclos M Is the therapeutic index better with gemcitabine-based chemoradiation than with 5–fluorouracil-based chemoradiation in locally advanced pancreatic cancer? Int J Radiat Oncol Biol Phys 2002 52 5 1293 1302 10.1016/S0360-3016(01)02740-7 11955742 \n13. Brunner TB Tinkl D Grabenbauer GG Meyer T Brueckl WM Sauer R Maintenance chemotherapy after chemoradiation improves survival of patients with locally advanced pancreatic carcinoma: a retrospective analysis of prospectively recruited patients Strahlenther Onkol 2006 182 4 210 215 10.1007/s00066-006-1524-x 16622622 \n14. Morgan MA Parsels LA Maybaum J Lawrence TS Improving gemcitabine-mediated radiosensitization using molecularly targeted therapy: A review Clin Cancer Res 2008 14 21 6744 6750 10.1158/1078-0432.CCR-08-1032 18980967 \n15. Crane CH Varadhachary GR Yordy JS Staerkel GA Javle MM Safran H Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4 (Dpc4) immunostaining with pattern of disease progression J Clin Oncol 2011 29 22 3037 3043 10.1200/JCO.2010.33.8038 21709185 \n16. Arnoletti JP Frolov A Eloubeidi M Keene K Posey J Wood T A phase I study evaluating the role of the anti-epidermal growth factor receptor (EGFR) antibody cetuximab as a radiosensitizer with chemoradiation for locally advanced pancreatic cancer Cancer Chemother Pharmacol 2011 67 4 891 897 10.1007/s00280-010-1383-0 20589377 \n17. Demols A Mahin C Maréchal R Delaunoit T Borbath I Hendlisz A Cetuximab plus chemoradiation combined therapy for locally advanced inoperable pancreatic adenocarcima: A phase I study J Clin Oncol Am Soc Clin Oncol Meeting Proc 2008 26 15S \n18. Munter M Timke C Abdollahi A Friess H Jaeger D Heeger S Final results of a phase II trial [PARC-Study ISRCTN56652283] for patients with primary inoperable locally advanced pancreatic cancer combining intensity modulated radiotherapy (IMRT) with cetuximab and gemcitabine J Clin Oncol Am Soc Clin Oncol Meeting Proc 2008 26 15S \n19. Chakravarthy AB Tsai CJ O'Brien N Lockhart AC Chan E Parikh A A phase I study of cetuximab in combination with gemcitabine and radiation for locally advanced pancreatic cancer Gastrointest Cancer Res 2012 5 112 118 23077684 \n20. Topkan E Yavuz AA Aydin M Onal C Yapar F Yavuz MN Comparison of CT and PET-CT based planning of radiation therapy in locally advanced pancreatic carcinoma J Exp Clin Cancer Res 2008 27 41 10.1186/1756-9966-27-41 18808725 \n21. Li CP Chao Y Chi KH Chan WK Teng HC Lee RC Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study Int J Radiat Oncol Biol Phys 2003 57 1 98 104 10.1016/S0360-3016(03)00435-8 12909221 \n22. Huguet F André T Hammel P Artru P Balosso J Selle F Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR Phase II and III studies J Clin Oncol 2007 25 3 326 331 10.1200/JCO.2006.07.5663 17235048 \n23. McGinn CJ Zalupski MM Shureiqi I Robertson JM Eckhauser FE Smith DC Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer J Clin Oncol 2001 19 4202 4208 11709563 \n24. Muler JH McGinn CJ Normolle D Lawrence T Brown D Hejna G Phase I trial using a time-to-event continual reassessment strategy for dose escalation of cisplatin combined with gemcitabine and radiation therapy in pancreatic cancer J Clin Oncol 2004 22 2 238 243 10.1200/JCO.2004.03.129 14665608 \n25. Kawakami H Uno T Isobe K Ueno N Aruga T Sudo K Toxicities and effects of involved-field irradiation with concurrent cisplatin for unresectable carcinoma of the pancreas Int J Radiat Oncol Biol Phys 2005 62 5 1357 1362 10.1016/j.ijrobp.2004.12.041 16029793 \n26. Goldstein D Van Hazel G Walpole E Underhill C Kotasek D Michael M Gemcitabine with a specific conformal 3D 5FU radiochemotherapy technique is safe and effective in the definitive management of locally advanced pancreatic cancer Br J Cancer 2007 97 4 464 471 10.1038/sj.bjc.6603900 17653074 \n27. Mukherjee S Hurt CN Bridgewater J Falk S Cummins S Wasan H Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial Lancet Oncol 2013 14 4 317 326 10.1016/S1470-2045(13)70021-4 23474363\n\n",
"fulltext_license": "CC BY",
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"journal": "Radiation oncology (London, England)",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D021441:Carcinoma, Pancreatic Ductal; D000068818:Cetuximab; D059248:Chemoradiotherapy; D003841:Deoxycytidine; D018572:Disease-Free Survival; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D020266:Radiotherapy, Conformal",
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"title": "Prospective study of cetuximab and gemcitabine in combination with radiation therapy: feasibility and efficacy in locally advanced pancreatic head cancer.",
"title_normalized": "prospective study of cetuximab and gemcitabine in combination with radiation therapy feasibility and efficacy in locally advanced pancreatic head cancer"
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"abstract": "We report a Chinese male patient with advanced stage lung squamous cell carcinoma who developed brain metastases after responding to treatment comprising six cycles of conventional chemotherapy with docetaxel and cisplatin. The patient was then treated with oral erlotinib (150 mg/day) and whole-brain radiation therapy followed by four cycles of docetaxel and carboplatin chemotherapy. The patient then received gefitinib (250 mg/day) as a maintenance therapy until the end of the follow-up period. In this patient, progression-free survival, defined as the interval from the initiation of first-line chemotherapy to the cessation of erlotinib due to progressive disease or death from any cause, was 3 months. Overall survival, defined as the interval from the initiation of first-line chemotherapy to death from any cause, was 75 months. Erlotinib was well tolerated in combination with whole-brain radiation therapy and a favorable objective response rate was observed. Furthermore, targeted drug treatment warrants consideration in patients with a negative epidermal growth factor receptor mutation status and male patients with a history of smoking.",
"affiliations": "Department of Thoracic Surgery, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, People's Republic of China.;Department of Thoracic Surgery, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, People's Republic of China.;Department of Thoracic Surgery, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, People's Republic of China.;Department of Thoracic Surgery, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, People's Republic of China.;Department of Medical Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, People's Republic of China.;Department of Thoracic Surgery, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, People's Republic of China.",
"authors": "Gao|Yuan|Y|;Song|PingPing|P|;Li|Hui|H|;Guo|HongBo|H|;Jia|Hui|H|;Zhang|BaiJiang|B|",
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"doi": "10.2147/OTT.S94108",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S94108ott-9-013Case ReportEpidermal growth factor receptor tyrosine kinase inhibitors with conventional chemotherapy for the treatment of non-small cell lung cancer Gao Yuan 1*Song PingPing 1*Li Hui 1Guo HongBo 1Jia Hui 2Zhang BaiJiang 11 Department of Thoracic Surgery, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, People’s Republic of China2 Department of Medical Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, People’s Republic of ChinaCorrespondence: BaiJiang Zhang, Department of Thoracic Surgery, Shandong Cancer Hospital and Institute, Jiyan Road 440, Jinan, Shandong 250117, People’s Republic of China, Email zhangbaijiang@sina.com* These authors contributed equally to this work\n\n2016 18 12 2015 9 13 20 © 2016 Gao et al. This work is published and licensed by Dove Medical Press Limited2016The 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.We report a Chinese male patient with advanced stage lung squamous cell carcinoma who developed brain metastases after responding to treatment comprising six cycles of conventional chemotherapy with docetaxel and cisplatin. The patient was then treated with oral erlotinib (150 mg/day) and whole-brain radiation therapy followed by four cycles of docetaxel and carboplatin chemotherapy. The patient then received gefitinib (250 mg/day) as a maintenance therapy until the end of the follow-up period. In this patient, progression-free survival, defined as the interval from the initiation of first-line chemotherapy to the cessation of erlotinib due to progressive disease or death from any cause, was 3 months. Overall survival, defined as the interval from the initiation of first-line chemotherapy to death from any cause, was 75 months. Erlotinib was well tolerated in combination with whole-brain radiation therapy and a favorable objective response rate was observed. Furthermore, targeted drug treatment warrants consideration in patients with a negative epidermal growth factor receptor mutation status and male patients with a history of smoking.\n\nKeywords\nEGFR tyrosine kinase inhibitorschemotherapynon-small cell lung cancer\n==== Body\nIntroduction\nLung cancer, of which non-small cell lung cancer (NSCLC) is the most common form, remains the leading cause of cancer-related mortality worldwide, and many NSCLC patients present with advanced disease at the time of initial diagnosis.1 Recent advancements in chemotherapy and targeted therapy have provided new treatment options for this disease.\n\nNSCLC research has increasingly focused on efforts to identify biomarkers that can predict increased clinical benefit from new agents in specific patient subgroups to enable clinicians make informed treatment decisions regarding the most appropriate initial treatment option for individual patients. The most promising biomarker to date is the epidermal growth factor receptor (EGFR) mutation status; recent data suggest that compared to patients with tumors lacking such mutations, patients with tumors harboring activating mutations in EGFR achieve a substantially increased benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs).2–7 Notably, EGFR mutations occur with greater frequency in Asian patients than in European patients, with typical mutation rates of ~30% and 8%, respectively.3,8,9 Therefore, approximately one in three Asian patients is positive for a biomarker predicting an exceptional response to EGFR TKI therapy. One such EGFR TKI is the orally administered targeted agent erlotinib, which inhibits the tyrosine kinase domain of EGFR. Erlotinib was approved for second-line use based on the positive results of the Phase III BR.21 trial,10 in which erlotinib, compared with best supportive care, improved overall survival. In Phase II studies, erlotinib has also been shown to have clinical benefit as a first-line therapy for advanced NSCLC, resulting in tumor response rates of 10%–20% and median survival durations of 10.9–12.9 months.11,12 However, despite important new additions to the therapeutic arsenal for NSCLC, the 5-year survival rate for patients with this disease remains disappointingly low, at <20%.13 The implementation of accurate EGFR mutation testing is a key component of biomarker-based treatment strategies in clinical practice; however, thus far, the selection or identification of patients with activating EGFR mutations based on clinical characteristics has been unsatisfactory.2,14\n\nUnfortunately, despite treatment advances, the prognosis of patients with advanced lung cancer remains poor, and the vast majority of patients die as a result of uncontrolled systemic disease. Among patients with NSCLC, ~20%–40% ultimately develop brain metastases.15,16 Treatment options for brain metastases from NSCLC include whole-brain radiation therapy (WBRT), stereotactic radiosurgery, surgical resection, or some combination of these three treatments. The median survival duration after WBRT strongly correlates with patient age, Eastern Cooperative Oncology Group performance status, and the number and location of the metastatic lesions, and it generally ranges from 3 to 6 months.17–21\n\nThe present study describes a 34-year-old male with NSCLC and brain metastases that were incidentally identified during a histopathological examination. This study also includes a review of the relevant literature to provide clinicians with information concerning a novel treatment program for NSCLC that achieved a longer overall survival. Written informed consent was obtained from the patient. The Research Ethics Committee of the Shandong Cancer Hospital and Institute approved this study.\n\nCase report\nA 34-year-old male was admitted to the local hospital in April 2007 complaining of hacking cough of unknown cause. The patient had no symptoms of bosom frowsty, chest pain, anhelation, fever, or weakness, and the patient had not experienced appetite or weight loss. However, the patient showed no evident improvement upon hospitalization. A chest computed tomography (CT) scan in May 2007 at the Affiliated Hospital of Binzhou Medical College (Binzhou, People’s Republic of China) revealed a mass in the hilum of the right lung, swollen lymph nodes in the mediastinum, and pleural effusion. Furthermore, fiberoptic bronchoscopy revealed the tumor pathology: moderately differentiated squamous cell carcinoma (SCC) in the middle and lower lobes of the lung. After 3 days, the patient visited the Chinese PLA General Hospital in Beijing, and an abdominal CT scan revealed a suspicious mass, which was considered to be either a metastatic tumor or an adenocarcinoma, in the right adrenal gland. Brain magnetic resonance imaging and bone emission CT showed no evidence of distant metastasis. The patient’s medical history was unremarkable, and SCC was staged as T4N2M0 (IIIB) according to the International Union Against Cancer 1997 Tumor Node Metastasis staging criteria.22 After several discussions, the oncologists chose not to perform surgery. The patient’s alanine aminotransferase level was between 2- and 2.5-fold above normal after admission to the hospital; therefore, treatments to protect the liver were initiated after the patient was admitted. The patient’s carcinoembryonic antigen level was 7.6 ng/mL, and carbohydrate antigen 19-9 (CA 19-9) level was 13.4 ng/mL. From May 28, 2007 to September 12, 2007, the patient received six cycles of adjuvant chemotherapy consisting of 300 mg of paclitaxel and 750 mg of dicycloplatin on day 1 of each 2-week cycle. The evident side effects of this adjuvant chemotherapy regimen were myelosuppression with grade 0–2 neutrocytopaenia and a grade 1 gastrointestinal reaction. The patient demonstrated a partial response (PR) after four cycles and a complete response (CR) after six cycles according to the chest CT scan, which showed a streaky or coarse reticular pattern of opacities in the upper right lobe under the pleura and small nodules in the right hilum (Figure 1). The patient did not receive any additional therapy until February 18, 2008, when a chest CT scan demonstrated lung cancer with mediastinal lymph node metastasis, a right lower lobe lesion (4.4×3.1 cm), and mediastinal lymph node enlargement. Brain CT showed abnormal enhancement in the right occipital lobe with evidence of metastatic disease. Abdominal ultrasound revealed medium-low echo in the right adrenal gland nodules and did not rule out adrenal metastasis. These findings indicated local recurrence and brain metastases. Therefore, from February 26, 2008 to June 14, 2008, the patient underwent six additional cycles of chemotherapy for progressive disease (PD) according to the following medication schedule: 1,000 mg of pemetrexed disodium on day 1; 50 mg of cisplatin on days 1 and 2; and 40 mg of cisplatin on day 3. This cycle was repeated every 2 weeks. For the first 12 cycles, 140 mg of cisplatin was administered on day 1. Grade 0–1 myelosuppression and grade 0–1 gastrointestinal reactions were observed. A potential PR was assessed after cycle 8, and the patient was evaluated after cycle 10 for stable disease (SD) (Figure 2). Beginning on March 7, 2008, sequential adjuvant radiotherapy was performed via 40 Gy/20 F irradiation of the whole brain and 60 Gy/20 F irradiation of the right occipital metastasis; no side effects were observed after the six cycles of maintenance radiotherapy. Oral erlotinib (150 mg/day) was administered from July 2008 to December 2009 (Figure 3). At the scheduled follow-up on December 7, 2009, the abdominal CT scan showed liver and adrenal metastases. On December 11, 2009, a brain magnetic resonance imaging scan revealed abnormal enhancement in the nodules of the right occipital lobe (ovular shape with a diameter of ~12 cm) with a history of suspected metastases, a right cerebellar lesion without abnormal enhancement, and a lesion with a slight increase in contrast compared with that of the original film. Emission CT showed no signs of bone metastases (Figure 4). From December 11, 2009 to January 3, 2010, the patient underwent retreatment according to chemotherapy cycles 1 and 2 using the following medications: 140 mg of docetaxel intravenously (iv) on day 1 and 500 mg of carboplatin iv on day 1. The patient experienced grade 0–2 side effects, bone marrow suppression, gastrointestinal reactions, nausea and vomiting. On January 22, 2010, an abdominal CT scan revealed multiple liver lesions (potential metastatic disease) and right adrenal metastases (4.6×3.7 cm). On December 7, 2009, a focused abdominal CT with contrast was performed to evaluate the patient for a PR. From January 23, 2010 to February 20, 2010, the patient was re-treated according to chemotherapy cycles 3 and 4 using the following medications: 140 mg of docetaxel iv on day 1 and 500 mg of carboplatin iv on day 1 (Figure 5). The patient experienced bone marrow suppression, grade 0–2 side effects, gastrointestinal reactions, nausea, and vomiting. Oral gefitinib treatment was initiated in June 2010 and continued until the patient died of pulmonary infection and cachexia in August 2013 (Figure 6).\n\nDiscussion\nErlotinib was initially used in combination with chemotherapy as a first-line treatment for advanced NSCLC but was found to be ineffective.23,24 This lack of efficacy could be explained by the hypothesis that a negative interaction occurs between EGFR TKIs and cytotoxic agents when they are administered concurrently and by the fact that no molecular biomarkers exist to identify appropriate patients for this combination treatment. Subsequently, several randomized studies, including the BR.21 and TRUST studies, have demonstrated the promising efficacy of erlotinib as a second-line or third-line treatment for patients with advanced NSCLC.10,25 As shown in the Iressa Pan-Asia Study (IPASS), a multicenter, Phase III, randomized study that examined the combination of gefitinib, carboplatin and paclitaxel as a first-line treatment for clinically selected patients in East Asia,2 EGFR-mutant lung cancer patients form a distinct subgroup exhibiting a superior clinical outcome in response to EGFR TKI treatment. Subsequently, two Japanese trials comparing first-line gefitinib therapy with chemotherapy for exclusively EGFR-mutant lung cancers confirmed the conclusion of the IPASS.5,6 However, no related studies on sequential intercalated combination regimens of chemotherapy and erlotinib have been reported. Importantly, activating EGFR mutations was found in only 30%–40% of Chinese patients with adenocarcinoma, and EGFR mutation testing was performed in only 10% of these patients; thus, the EGFR mutation status is unknown in most Chinese patients when decisions are made regarding the first-line treatment regimen.26 For these patients, a combination of chemotherapy and EGFR TKIs might be optimal. Although previous Phase III studies in unselected populations showed that the combination of chemotherapy and erlotinib did not improve survival compared with chemotherapy alone,23,24 sequential intercalated combination regimens of chemotherapy and erlotinib (the First-line Asian Sequential Tarceva and Chemotherapy Trial) significantly improved response and progression-free survival rates, especially in patients with adenocarcinoma.27\n\nOur patient with untreated stage IIIB NSCLC received six cycles of paclitaxel and dicycloplatin. During the subsequent follow-up, the patient attained disease control, defined as a CR or a PR according to the response evaluation criteria in solid tumors (RECIST).28 Pemetrexed disodium and cisplatin therapy was administered after the confirmation of PD according to the RECIST guidelines.28 This regimen was supplemented with WBRT and shrinking field cranial irradiation. Maintenance therapy with erlotinib was initiated immediately after attaining disease control using the appropriate traditional first-line chemotherapy. In the subsequent follow-up period, the emergence of new metastases and significant growth of the primary lesion indicated PD according to the RECIST guidelines.28 At that time, the patient was treated with traditional docetaxel and carboplatin chemotherapy. Thus, a sequential intercalated combination regimen of chemotherapy and erlotinib is a treatment option for patients with advanced NSCLC. When a patient experiences rapid NSCLC progression, such as PD according to the RECIST guidelines,28 we recommend first-line chemotherapy. When a patient is stable (CR, PR, or SD according to the RECIST guidelines28) or is experiencing slow progression (some cases of PD), we propose that erlotinib maintenance therapy should be administered.\n\nMost studies of EGFR TKIs have focused on patients with specific characteristics (eg, sex, smoking status, and histology) and activating EGFR mutations. Therefore, many studies have focused on patients with characteristics associated with the presence of activating EGFR mutations, especially those patients with histological evidence of adenocarcinoma. We did not perform EGFR mutation testing in this study because the majority of each biopsy specimen was used for pathologic testing and because of the associated cost and patient intolerance of this testing. However, some patients with lung SCC derive a clinical benefit from EGFR TKIs. In 2006, Achille et al reported a case of a white male former smoker with advanced lung SCC who responded to erlotinib.29 No EGFR mutations were found in that patient’s tumor tissue. The frequency of EGFR mutations is much lower in lung SCC patients and is reported to be between 0% and 5%.30–34 The largest lung SCC study to date was conducted by Miyamae et al;31 EGFR mutations were detected in 3.4% of the 87 lung SCC specimens by using SmartAmp2 and peptide nucleic acid-enriched sequencing methods. The current case did not appear to meet any of the suggested criteria for EGFR TKI therapy. EGFR mutation is a powerful predictor of the treatment response to EGFR TKIs.2,3,35–38 In the BR.21 study,39 patients harboring an EGFR mutation had a 23% reduced risk of death following erlotinib treatment compared with placebo (hazard ratio [HR]: 0.77). As stated in the review by Sun et al, 25% of lung cancers are not attributable to smoking, and a high proportion of Asian women are never-smokers but still develop lung cancer.39 In the Japanese cohort examined by Kawaguchi et al, 36.2% of the female lung SCC patients were never-smokers (n=991).40 Several risk factors such as environmental tobacco smoke, cooking oil vapors, and wood or coal burning are associated with lung cancer in never-smokers, and exposure to these risk factors is also common among Chinese men. Due to the retrospective nature of the present study, evaluating whether these factors contributed to our patient’s disease is difficult.41,42\n\nAlthough the mechanisms by which gefitinib and erlotinib inhibit EGFR function are similar, whether they possess comparative efficacy as a salvage therapy for NSCLC remains controversial.43 A series of case studies reported objective responses or SD in certain patients who received erlotinib after failing treatment with gefitinib for advanced NSCLC.44–47 However, two Phase II studies of erlotinib in such patients reported overall response rates of only 4%–10%.48,49 Erlotinib exhibited remarkable efficacy in combination with chemotherapy in NSCLC patients with brain metastases.49–51 EGFR TKIs exhibit excellent penetration of the blood–brain barrier because of their chemical structure and low molecular weight. In 2003, Cappuzzo et al49 first reported one CR and three PRs after 3 months of single-agent gefitinib treatment in four NSCLC patients with pretreated brain metastases. Furthermore, a multi-institutional Phase II study demonstrated that the overall survival of patients receiving WBRT with concurrent erlotinib therapy for the treatment of NSCLC was longer than that observed in historical controls and that this therapy particularly benefitted patients with EGFR mutations.21 Moreover, in our case, a significantly different response to gefitinib therapy was observed after attaining SD in response to erlotinib therapy and chemotherapy. However, we could not ascertain the mechanisms underlying the effectiveness of gefitinib in this case. In vitro studies indicated that the common mechanisms underlying TKI resistance (T790M and mesenchymal to epithelial transition factor [MET] amplification) were not inhibited by clinically achievable doses of gefitinib or erlotinib.52,53 Secondary T790M mutation and MET amplification have been commonly described as the mechanisms underlying acquired resistance to EGFR TKIs.52,53 If tumor progression occurs in patients with erlotinib-responsive NSCLC harboring EGFR mutations, the tumor cells have a high probability of becoming cross-resistant to gefitinib. However, other secondary mutations such as L747S and E884K have also been described; these mutations may result in differential responses to gefitinib and erlotinib.54 According to experimental studies, some irreversible and second-generation EGFR inhibitors can overcome the resistance induced by secondary T790M mutations.52,55,56 Currently, irreversible EGFR inhibitors and anti-MET therapeutics are being developed for the treatment of NSCLC. The results of clinical trials will determine whether these agents can be used to treat patients with acquired resistance to EGFR TKIs.57,58\n\nConclusion\nFor patients with advanced NSCLC, sequential intercalated combination regimens of chemotherapy and erlotinib could be considered. An assessment of concurrent erlotinib and radiation therapy for the initial treatment of brain metastases from NSCLC demonstrated that this combination was safe and well tolerated. However, these findings must be interpreted cautiously because they were only observed in one case and because a randomized, controlled trial has yet to be performed. Larger prospective, randomized clinical trials are needed to validate our findings and confirm these hypotheses.\n\nAcknowledgments\nThis work was partly supported by the Shandong Province Natural Science Foundation of China, as a part of the items outlined in Project No ZR211HM089.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 A complete response after six cycles of chemotherapy according to the contrast-enhanced chest computed tomography scan.\n\nNotes: Contrast-enhanced chest computed tomography scan showing a mass located in the hilum of the right lung (A). This mass exhibited evident shrinkage following six cycles of chemotherapy (B).\n\nFigure 2 A stable disease after six additional cycles of chemotherapy according to the contrast-enhanced chest computed tomography scan.\n\nNotes: Enhanced chest computed tomography scan on February 18, 2008, showing lung cancer with mediastinal lymph node metastasis, a right lower lobe lesion, and mediastinal lymph node enlargement (A). The lesion was significantly reduced and remained stable after six additional cycles of chemotherapy (B).\n\nFigure 3 Enhanced brain computed tomography scan showing that erlotinib treatment combined with whole-brain radiation therapy was effective for the patient.\n\nNotes: Enhanced brain computed tomography scan revealing metastasis in the right occipital lobe (A). This metastasis significantly shrank after erlotinib treatment combined with whole-brain radiation therapy until September 2009 (B).\n\nFigure 4 Abdominal computed tomography scan showed liver and adrenal metastases, and other lesions did not change significantly.\n\nNotes: Enhanced abdominal computed tomography scan showing liver and adrenal metastases (A, D). A brain magnetic resonance image revealed abnormal enhancement in nodules of the right occipital lobe with a history of suspected metastases and a right cerebellar lesion without abnormal enhancement (B). An enhanced chest computed tomography scan showed no significant change compared to the original film (C).\n\nFigure 5 A brain magnetic resonance image and an enhanced abdominal computed tomography showed no significant change from the previous month.\n\nNotes: An enhanced abdominal computed tomography scan revealing multiple liver lesions and right adrenal metastases (A, C). A brain magnetic resonance image showed no significant change from the previous month (B).\n\nFigure 6 Imaging findings after the patient received maintenance therapy with oral gefitinib.\n\nNotes: A brain magnetic resonance image and an enhanced abdominal computed tomography scan shown in a stable disease (B, C). An enhanced chest computed tomography scan showed no significant change compared to the original film (A).\n==== Refs\nReferences\n1 Ferlay J Shin HR Bray F Forman D Mathers C Parkin DM Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 Int J Cancer 2010 127 2893 2917 21351269 \n2 Mok TS Wu YL Thongprasert S Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma N Engl J Med 2009 361 947 957 19692680 \n3 Rosell R Moran T Queralt C Screening for epidermal growth factor receptor mutations in lung cancer N Engl J Med 2009 361 958 967 19692684 \n4 Zhu CQ da Cunha Santos G Ding K Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21 J Clin Oncol 2008 26 4268 4275 18626007 \n5 Mitsudomi T Morita S Yatabe Y Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial Lancet Oncol 2010 11 121 128 20022809 \n6 Maemondo M Inoue A Kobayashi K Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR N Engl J Med 2010 362 2380 2388 20573926 \n7 Cappuzzo F Ciuleanu T Stelmakh L Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study Lancet Oncol 2010 11 521 529 20493771 \n8 Shigematsu H Lin L Takahashi T Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers J Natl Cancer Inst 2005 97 339 346 15741570 \n9 Wu YL Zhong WZ Li LY Epidermal growth factor receptor mutations and their correlation with gefitinib therapy in patients with non-small cell lung cancer: a meta-analysis based on updated individual patient data from six medical centers in mainland China J Thorac Oncol 2007 2 430 439 17473659 \n10 Shepherd FA Rodrigues Pereira J Ciuleanu T Erlotinib in previously treated non-small-cell lung cancer N Engl J Med 2005 353 123 132 16014882 \n11 Giaccone G Gallegos Ruiz M Le Chevalier T Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study Clin Cancer Res 2006 12 6049 6055 17062680 \n12 Jackman DM Yeap BY Lindeman NI Phase II clinical trial of chemotherapy-naive patients > or =70 years of age treated with erlotinib for advanced non-small-cell lung cancer J Clin Oncol 2007 25 760 766 17228019 \n13 Jemal A Siegel R Xu J Ward E Cancer statistics, 2010 CA Cancer J Clin 2010 60 277 300 20610543 \n14 Lind JS Postmus PE Heideman DA Thunnissen EB Bekers O Smit EF Dramatic response to low-dose erlotinib of epidermal growth factor receptor mutation-positive recurrent non-small cell lung cancer after severe cutaneous toxicity J Thorac Oncol 2009 4 1585 1586 20009914 \n15 Mujoomdar A Austin JH Malhotra R Clinical predictors of metastatic disease to the brain from non-small cell lung carcinoma: primary tumor size, cell type, and lymph node metastases Radiology 2007 242 882 888 17229875 \n16 Barnholtz-Sloan JS Sloan AE Davis FG Vigneau FD Lai P Sawaya RE Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System J Clin Oncol 2004 22 2865 2872 15254054 \n17 Verger E Gil M Yaya R Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial Int J Radiat Oncol Biol Phys 2005 61 185 191 15629610 \n18 Sperduto PW Berkey B Gaspar LE Mehta M Curran W A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database Int J Radiat Oncol Biol Phys 2008 70 510 514 17931798 \n19 Gaspar L Scott C Rotman M Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials Int J Radiat Oncol Biol Phys 1997 37 745 751 9128946 \n20 Knisely JP Berkey B Chakravarti A A phase III study of conventional radiation therapy plus thalidomide versus conventional radiation therapy for multiple brain metastases (RTOG 0118) Int J Radiat Oncol Biol Phys 2008 71 79 86 18164847 \n21 McHaffie DR Chabot P Dagnault A Safety and feasibility of motexafin gadolinium administration with whole brain radiation therapy and stereotactic radiosurgery boost in the treatment of ≤6 brain metastases: a multi-institutional phase II trial J Neurooncol 2011 105 301 308 21523486 \n22 Mountain CF Revisions in the international system for staging lung cancer Chest 1997 111 1710 1717 9187198 \n23 Herbst RS Prager D Hermann R TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer J Clin Oncol 2005 23 5892 5899 16043829 \n24 Gatzemeier U Pluzanska A Szczesna A Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial J Clin Oncol 2007 25 1545 1552 17442998 \n25 Reck M van Zandwijk N Gridelli C Erlotinib in advanced non-small cell lung cancer: efficacy and safety findings of the global phase IV Tarceva Lung Cancer Survival Treatment study J Thorac Oncol 2010 5 1616 1622 20736854 \n26 Xue C Hu Z Jiang W National survey of the medical treatment status for non-small cell lung cancer (NSCLC) in China Lung Cancer 2012 77 371 375 22579298 \n27 Heymach JV Johnson BE Prager D Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer J Clin Oncol 2007 25 4270 4277 17878479 \n28 Goldie JH Coldman AJ A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate Cancer Treat Rep 1979 63 1727 1733 526911 \n29 Achille M Gallegos-Ruiz M Giaccone G Soria JC Response to erlotinib in first-line treatment of non-small-cell lung cancer in a white male smoker with squamous-cell histology Clin Lung Cancer 2006 8 214 216 17239298 \n30 Huang SF Liu HP Li LH High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan Clin Cancer Res 2004 10 8195 8203 15623594 \n31 Miyamae Y Shimizu K Hirato J Significance of epidermal growth factor receptor gene mutations in squamous cell lung carcinoma Oncol Rep 2011 25 921 928 21318227 \n32 Mu XL Li LY Zhang XT Gefitinib-sensitive mutations of the epidermal growth factor receptor tyrosine kinase domain in Chinese patients with non-small cell lung cancer Clin Cancer Res 2005 11 4289 4294 15958609 \n33 Ohtsuka K Ohnishi H Fujiwara M Abnormalities of epidermal growth factor receptor in lung squamous-cell carcinomas, adenosquamous carcinomas, and large-cell carcinomas: tyrosine kinase domain mutations are not rare in tumors with an adenocarcinoma component Cancer 2007 109 741 750 17238183 \n34 Qin BM Chen X Zhu JD Pei DQ Identification of EGFR kinase domain mutations among lung cancer patients in China: implication for targeted cancer therapy Cell Res 2005 15 212 217 15780185 \n35 Lynch TJ Bell DW Sordella R Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib N Engl J Med 2004 350 2129 2139 15118073 \n36 Paez JG Janne PA Lee JC EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy Science 2004 304 1497 1500 15118125 \n37 Pao W Miller V Zakowski M EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib Proc the Natl Acad Sci U S A 2004 101 13306 13311 \n38 Rosell R Viteri S Molina MA Benlloch S Taron M Epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in advanced nonsmall-cell lung cancer Curr Opin Oncol 2010 22 112 120 19949333 \n39 Sun S Schiller JH Gazdar AF Lung cancer in never smokers – a different disease Nat Rev Cancer 2007 7 778 790 17882278 \n40 Zhao Y Wang S Aunan K Seip HM Hao J Air pollution and lung cancer risks in China – a meta-analysis Sci Total Environ 2006 366 500 513 16406110 \n41 Kawaguchi T Takada M Kubo A Performance status and smoking status are independent favorable prognostic factors for survival in non-small cell lung cancer: a comprehensive analysis of 26,957 patients with NSCLC J Thorac Oncol 2010 5 620 630 20354456 \n42 Shao YY Lin CC Yang CH Gefitinib or erlotinib in the treatment of advanced non-small cell lung cancer Discov Med 2010 9 538 545 20587343 \n43 Kaira K Naito T Takahashi T Pooled analysis of the reports of erlotinib after failure of gefitinib for non-small cell lung cancer Lung Cancer 2010 68 99 104 19540616 \n44 Zhou ZT Xu XH Wei Q Lu MQ Wang J Wen CH Erlotinib in advanced non-small-cell lung cancer after gefitinib failure Cancer Chemother Pharmacol 2009 64 1123 1127 19322567 \n45 Wong AS Soong R Seah SB Evidence for disease control with erlotinib after gefitinib failure in typical gefitinib-sensitive Asian patients with non-small cell lung cancer J Thorac Oncol 2008 3 400 404 18379359 \n46 Vasile E Tibaldi C Chella A Falcone A Erlotinib after failure of gefitinib in patients with advanced non-small cell lung cancer previously responding to gefitinib J Thorac Oncol 2008 3 912 914 18670311 \n47 Cho BC Im CK Park MS Phase II study of erlotinib in advanced non-small-cell lung cancer after failure of gefitinib J Clin Oncol 2007 25 2528 2533 17577030 \n48 Lee DH Kim SW Suh C Yoon DH Yi EJ Lee JS Phase II study of erlotinib as a salvage treatment for non-small-cell lung cancer patients after failure of gefitinib treatment Ann Oncol 2008 19 2039 2042 18644828 \n49 Cappuzzo F Ardizzoni A Soto-Parra H Epidermal growth factor receptor targeted therapy by ZD 1839 (Iressa) in patients with brain metastases from non-small cell lung cancer (NSCLC) Lung Cancer 2003 41 227 231 12871787 \n50 Hotta K Kiura K Ueoka H Effect of gefitinib (‘Iressa’, ZD1839) on brain metastases in patients with advanced non-small-cell lung cancer Lung Cancer 2004 46 255 261 15474674 \n51 Ishida A Kanoh K Nishisaka T Gefitinib as a first line of therapy in non-small cell lung cancer with brain metastases Intern Med 2004 43 718 720 15468973 \n52 Kobayashi S Boggon TJ Dayaram T EGFR mutation and resistance of non-small-cell lung cancer to gefitinib N Engl J Med 2005 352 786 792 15728811 \n53 Bean J Brennan C Shih JY MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib Proc Natl Acad Sci U S A 2007 104 20932 20937 18093943 \n54 Costa DB Halmos B Kumar A BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations PLoS Med 2007 4 1669 1679 17973572 \n55 Costa DB Son K Cho BC Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib Clin Cancer Res 2008 14 7060 7067 18981003 \n56 Kwak EL Sordella R Bell DW Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib Proc Natl Acad Sci U S A 2005 102 7665 7670 15897464 \n57 Gonzales AJ Hook KE Althaus IW Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor Mol Cancer Ther 2008 7 1880 1889 18606718 \n58 Eskens FA Mom CH Planting AS A phase I dose escalation study of BIBW2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours Br J Cancer 2008 98 80 85 18026190\n\n",
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"journal": "OncoTargets and therapy",
"keywords": "EGFR tyrosine kinase inhibitors; chemotherapy; non-small cell lung cancer",
"medline_ta": "Onco Targets Ther",
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"pages": "13-20",
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"pubdate": "2016",
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"references": "18670311;19692684;12871787;20009914;16043829;19322567;21523486;20573926;19949333;17473659;15254054;17442998;17931798;21318227;17973572;20610543;526911;17239298;17882278;15728811;15623594;20354456;17229875;15780185;15118125;18644828;15329413;18093943;17577030;18164847;15118073;17228019;19540616;20022809;18626007;9187198;15741570;18026190;9128946;21351269;16014882;22579298;18606718;15958609;18379359;20587343;15897464;15468973;18981003;19692680;20736854;16406110;17062680;17238183;17878479;15629610;15474674;20493771",
"title": "Epidermal growth factor receptor tyrosine kinase inhibitors with conventional chemotherapy for the treatment of non-small cell lung cancer.",
"title_normalized": "epidermal growth factor receptor tyrosine kinase inhibitors with conventional chemotherapy for the treatment of non small cell lung cancer"
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"abstract": "BACKGROUND\nCitomegalovirus (CMV) infects approximately 1% of live newborns. About 10% of the infants affected by congenital CMV infection are symptomatic at birth and up to 60% of these infants will develop permanent neurological disabilities. Depending on gestational age (GA) at the time of infection, the involvement of central nervous system (CNS) can lead to malformations of cortical development, calcifications, periventricular white matter lesions and cysts, ventriculomegaly and cerebellar hypoplasia.\n\n\nMETHODS\nWe report the MRI findings in a Caucasian female born at 32 weeks of post-menstrual age with post-birth diagnosis of congenital CMV infection showing an unusual and peculiar marked T2 hyperintensity of the inner part of olfactory bulbs in addition to the CMV related diffuse brain involvement. Despite the known extensively described fetal and neonatal Magnetic Resonance Imaging (MRI) findings in CMV infected fetuses and newborns, any in vivo MRI depiction of olfactory system damage have never been reported so far. Nevertheless, in murine studies CMV is known to infect the placenta during pregnancy showing particular tropism for neural stem cells of the olfactory system and previous neuropathologic study on CMV infected human fetal brains from 23 to 28 weeks of GA reported damage in the olfactory bulbs (OB) consisting in disseminated cytomegalic cells, inflammation, necrosis and neuronal and radial glial cell loss. Therefore, we assume an OB involvement and damage in congenital CMV infection.\n\n\nCONCLUSIONS\nTo our knowledge this is the first in vivo MRI evidence of OB damage in a newborn with congenital CMV infection that may give new insights on CMV infection.",
"affiliations": "Department of Neuroradiology, Careggi University Hospital, Largo Piero Palagi 1, Florence, Italy.;Division of Neonatology, Careggi University Hospital, Largo Piero Palagi 1, Florence, Italy.;Division of Neonatology, Careggi University Hospital, Largo Piero Palagi 1, Florence, Italy.;Division of Neonatology, Careggi University Hospital, Largo Piero Palagi 1, Florence, Italy.;Department Health Professions, U.O. Research and Development, Careggi University Hospital, Largo Piero Palagi 1, Florence, Italy.;Department Health Professions, U.O. Research and Development, Careggi University Hospital, Largo Piero Palagi 1, Florence, Italy.;Department of Emergency Radiology, Careggi University Hospital, Largo Brambilla 3, 50134, Florence, Italy.;Department of Neuroradiology, Careggi University Hospital, Largo Piero Palagi 1, Florence, Italy.;Division of Neonatology, Careggi University Hospital, Largo Piero Palagi 1, Florence, Italy.;Department of Neuroradiology, Careggi University Hospital, Largo Piero Palagi 1, Florence, Italy. scolae@aou-careggi.toscana.it.",
"authors": "Bianchi|Andrea|A|;Coviello|Caterina|C|;Leonardi|Valentina|V|;Luzzati|Michele|M|;Chiti|Stefano|S|;Ermini|Daniele|D|;Miele|Vittorio|V|;Fainardi|Enrico|E|;Dani|Carlo|C|;Scola|Elisa|E|http://orcid.org/0000-0001-9056-4122",
"chemical_list": null,
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"doi": "10.1186/s13052-021-01170-w",
"fulltext": "\n==== Front\nItal J Pediatr\nItal J Pediatr\nItalian Journal of Pediatrics\n1824-7288\nBioMed Central London\n\n1170\n10.1186/s13052-021-01170-w\nCase Report\nIn vivo magnetic resonance imaging evidence of olfactory bulbs changes in a newborn with congenital Citomegalovirus: a case report\nBianchi Andrea bianchia@aou-careggi.toscana.it\n\n1\nCoviello Caterina caterinacoviello83@yahoo.it\n\n2\nLeonardi Valentina valentinaleo83@yahoo.it\n\n2\nLuzzati Michele michele.luzzati@unifi.it\n\n2\nChiti Stefano chitis@aou-careggi.toscana.it\n\n3\nErmini Daniele erminid@aou-careggi.toscana.it\n\n3\nMiele Vittorio mielev@aou-careggi.toscana.it\n\n4\nFainardi Enrico fainardie@aou-careggi.toscana.it\n\n15\nDani Carlo carlo.dani@unifi.it\n\n26\nhttp://orcid.org/0000-0001-9056-4122\nScola Elisa scolae@aou-careggi.toscana.it\n\n1\n1 grid.24704.35 0000 0004 1759 9494 Department of Neuroradiology, Careggi University Hospital, Largo Piero Palagi 1, Florence, Italy\n2 grid.24704.35 0000 0004 1759 9494 Division of Neonatology, Careggi University Hospital, Largo Piero Palagi 1, Florence, Italy\n3 grid.24704.35 0000 0004 1759 9494 Department Health Professions, U.O. Research and Development, Careggi University Hospital, Largo Piero Palagi 1, Florence, Italy\n4 grid.24704.35 0000 0004 1759 9494 Department of Emergency Radiology, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy\n5 grid.8404.8 0000 0004 1757 2304 Department of Scienze Biomediche, Sperimentali E Cliniche, Neuroradiology, University of Florence, Viale Morgagni, 50 Florence, Italy\n6 grid.24704.35 0000 0004 1759 9494 Department of Neurosciences, Psychology, Drug Research and Child Health, Careggi University Hospital, Largo Piero Palagi 1, Florence, Italy\n16 11 2021\n16 11 2021\n2021\n47 22723 7 2021\n16 10 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nCitomegalovirus (CMV) infects approximately 1% of live newborns. About 10% of the infants affected by congenital CMV infection are symptomatic at birth and up to 60% of these infants will develop permanent neurological disabilities. Depending on gestational age (GA) at the time of infection, the involvement of central nervous system (CNS) can lead to malformations of cortical development, calcifications, periventricular white matter lesions and cysts, ventriculomegaly and cerebellar hypoplasia.\n\nCase presentation\n\nWe report the MRI findings in a Caucasian female born at 32 weeks of post-menstrual age with post-birth diagnosis of congenital CMV infection showing an unusual and peculiar marked T2 hyperintensity of the inner part of olfactory bulbs in addition to the CMV related diffuse brain involvement. Despite the known extensively described fetal and neonatal Magnetic Resonance Imaging (MRI) findings in CMV infected fetuses and newborns, any in vivo MRI depiction of olfactory system damage have never been reported so far. Nevertheless, in murine studies CMV is known to infect the placenta during pregnancy showing particular tropism for neural stem cells of the olfactory system and previous neuropathologic study on CMV infected human fetal brains from 23 to 28 weeks of GA reported damage in the olfactory bulbs (OB) consisting in disseminated cytomegalic cells, inflammation, necrosis and neuronal and radial glial cell loss. Therefore, we assume an OB involvement and damage in congenital CMV infection.\n\nConclusion\n\nTo our knowledge this is the first in vivo MRI evidence of OB damage in a newborn with congenital CMV infection that may give new insights on CMV infection.\n\nKeywords\n\nCongenital Citomegalovirus\nNewborn\nMagnetic resonance imaging\nOlfactory bulbs\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nCitomegalovirus (CMV) infects approximately 1% of live newborns. About 10% of the infants affected by congenital CMV infection are symptomatic at birth and up to 60% of these infants will develop permanent neurological disabilities [1, 2]. During pregnancy CMV may infect the placenta and may cause fetal growth retardation, severe brain malformations and sensorineural impairment [3]. Depending on gestational age (GA) at the time of infection, the involvement of central nervous system (CNS) can lead to malformations of cortical development, calcifications, periventricular white matter lesions and cysts, ventriculomegaly and cerebellar hypoplasia [4]. Fetal and neonatal Magnetic Resonance Imaging (MRI) findings in CMV infected fetuses and newborns have already been extensively described [5, 6] and CMV is known to show particular tropism for neural stem cells of the olfactory system [7]. Despite this, any in vivo MRI depiction of olfactory system damage have never been reported so far.\n\nCase presentation\n\nA Caucasian female was born at 32 weeks of GA to a 36-year-old woman via emergency cesarean section because of alterations in the fluximetric indices. TORCH screening performed during pregnancy resulted negative. Intrauterin growth retardation was evidenced since 26 weeks of GA. The APGAR scores were 7 and 8 at 1 and 5 min, respectively. Birth weight was 1210 g (6 th percentile), length was 39 cm (13 th percentile), and head circumference was 26 cm (1 th percentile). She was the second baby born to nonconsanguineous parents. The infant was admitted to the Neonatal Intensive Care Unit (NICU) because of respiratory distress syndrome and received nasal CPAP for 7 days. Physical examination at birth revealed generalized petechial rash and splenomegaly, and a complete blood count evidenced thrombocytopenia (22,000/mm3). Leukopenia (white blood cell count 4900/mm3) and anemia with 10.4 g/dL of hemoglobin were observed since the fifth day of life (DOL). The diagnosis of congenital CMV infection was proven by the detection, by polymerase chain reaction, of CMV DNA on a urine sample (32,000 copies/mL) and on blood sample (71,800 copies/ml). Cephalo-rachidian fluid also tested positive (390 copies/ml). Serological results revealed positive IgM and IgG antibodies anti-CMV. The mother did not performe CMV serology during pregnancy but preconceptional maternal immunity showed positive CMV-IgG and negative CMV-IgM. Thus, the infection was caused by maternal re-infection. Intravenous ganciclovir was started on sixth DOL and was switched to oral valganciclovir as soon as feeding tolerance was achieved (16 mg/kg twice a day). After the first week the infant developed cholestasis without signs of hepatitis. During the recovery the infant received numerous platelet and red blood cells transfusions. Granulocyte colony-stimulating factor (G-CSF) was administrated for the neutropenia. Since birth, clinical neurological evaluation revealed axial hypotonia and irritability alternating to lethargy. Serial cranial ultrasound showed periventricular cysts, lenticulostriate vasculopathy cysts and bilateral germinal matrix haemorrhage. MRI scan of the brain was acquired at 37 weeks GA. MRI scan was performed on a 1.5 Tesla scanner (Siemens Magnetom Aera Erlangen Germany, release VE11C). Axial and coronal T2-weighted images, volumetric isotropic sagittal T1 weighted Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) image, axial Diffusion Weighted Imaging Echo Planar Imaging Spin Echo (DWI EPI SE) image, volumetric axial Susceptibility Weighted Imaging (SWI) image, volumetric isotropic axial T2/T1 Weighted True Fast Imaging with Steady state free Procession (TrueFISP) image, were acquired.\n\nThe patient was sedated with Intranasal dexmedetomidine (2 mcg/kg) and continuously monitored for oxygen saturation and heart rate. MRI scan showed an immature aspect of the gyration of the cerebral hemispheres associated with a reduced myelination of the posterior arm of the internal capsule. T2-weighted sections revealed increased hyperintensity of the parieto-occipital and temporal white matter with cysts in the bilateral periventricular temporal region. Germinolytic cysts with hemosiderin deposit were depicted in the thalamocaudal notch region bilaterally. Interestingly, a market T2 hyperintensity of the inner part of olfactory bulbs was noticed (Figs. 1 and 2). Any abnormalities in the remaining cranial nerves weren’t found. She was given two CMV IgG transfusions without any improvement of thrombocytopenia, neutropenia and anaemia. Eye examination resulted negative for chorioretinitis and the hearing screen showed normal brain auditory evoked response. Due to long-lasting pancytopenia the infant was transferred to the haematological unit of the referral hospital on day thirty-eighth after birth. The parental informed consent for publication was obtained. Fig. 1 MRI coronal T2 weighted images: the OBs (squared white box) in the patient with CMV infection (row 1) showed abnormal T2 hyperintensity in the central portion in comparison with the physiological appearance (row 2) of OB of a newborn without CMV infection studied at the same corrected GA. CMV: Citomegalovirus, GA: gestational age; OB: olfactory bulb\n\nFig. 2 MR scan show an immature aspect of the gyration of the cerebral hemispheres associated with a reduced myelination (A and D, axial T2-weighted images; C, axial Diffusion Weighted Imaging DWI; E, volumetric axial-reformatted T1 weighted image). T2-weighted sections (A and D) revealed increased hyperintensity of the parieto-occipital and temporal white matter with cysts in the bilateral periventricular temporal region (white arrow in B, True Fast Imaging with steady state procession (TrueFISP) axial isotropic volumetric T2 weighted image) . Germinolytic cysts with hemosiderin deposit were depicted in the thalamocaudal notch region bilaterally (white arrow in F, axial Susceptibility Weighted Imaging (SWI))\n\nDiscussion and conclusions\n\nFetal and neonatal MRI findings in CMV infected fetuses and newborns have already been extensively described [5, 6]. Malformations of cortical development, calcifications, periventricular white matter lesions and cysts, ventriculomegaly and cerebellar hypoplasia occur according to GA at the time of infection [4]. Despite this, any in vivo MRI depiction of olfactory system damage has been never reported so far.\n\nNevertheless, previous neuropathologic study on CMV infected human fetal brains from 23 to 28 weeks of GA reported damage in the olfactory bulbs consisting in disseminated cytomegalic cells, inflammation, necrosis and neuronal and radial glial cell loss. Supporting this evidence, pronounced olfactory deficits were described in mouse model of CMV infection [8] occurring long before the auditory deficits. Additionally, studies on murine CMV showed that the placental CMV inoculation of embryos leads to olfactory bulbs infection. The virus enters via the apical cilia of olfactory sensory neurons (OSN) located in the nasal olfactory epithelium. The OSN project to olfactory bulbs (OB) where they form synapses with mitral/tufted cells whom axons directly connect with neurons of primary olfactory cortex. Additionally, CMV secondary spread systemically to blood through the myeloid cells that infiltrate the olfactory epithelium, become infected and then migrate in the superficial cervical lymph nodes [9]. In murine models OB infection was detected until 16 weeks after birth showing a longlasting persistence over time [8]. Interestingly the olfactory infection is a common, conserved route of mammalian herpesvirus entry to host [8, 10].\n\nOlfaction develops antenatally before audition and vision. Nevertheless, the assessment of olfactory function is challenging as no specific tests on in newborns are available. However, the early detection of olfactory deficits might be relevant, given its function in fetuses and newborns in learning of maternal odors, guiding feeding and social behaviors and maintaining a strong parent–infant bound [11].\n\nThe radial glial cells surrounding the periventricular germinal epithelium and the progenitor cells within the germinal areas (the Ventricular Zone (VZ) and the Subventricular Zone (SVZ)) are of utmost importance for fetal brain development. Previous neuropathological studies in human fetal brains showed that the radial glial cells surrounding the periventricular germinal epithelium are the main cellular target of CMV infection. Additionally, the presence of CMV-infected cells in the SVZ and in the VZ, and in cortical plate and subplate too, was also depicted. It was shown that CMV infects cells exhibiting the phenotypic characteristics of neural stem cells/progenitors [7, 8]. These findings may explain the severe cellular loss in the VZ and SVZ occurring in CMV infected brain human fetus [7] associated to the impairment of brain development. Interestingly, a connection between the OB and the periventricular area have been suggested in human fetal brain. In support of this, pathological studies in fetal brain demonstrated the presence of a rostral migratory stream of neuroblasts coming from the SVZ and connecting the anterior horn of the lateral ventricle and the OB. Additionally, an extension of the lateral ventricle reaching the olfactory bulb and probably closes during fetal development, was described in human brains [12–14]. Therefore, in human fetal brain a connection between the periventricular area, where CMV infects cells of the VZ and SVZ, and the OB is probably present and may contribute to the spread of CMV infection within the fetal CNS.\n\nThe MRI in vivo involvement of OB in CMV infected newborns hasn’t been described so far. A previous study showed the pattern of physiological MRI appearance of OB from birth to adult age [15]: in newborns at 15 days of median age the OB are depictable as two hypointense oval structures with a less hypointense central areas in T2- weighted images. The central part was interpreted as an area of axons and synaptic networks connected to primary olfactory area and to ganglionic eminence still with immature myelination and rich in extracellular matrix; this area undergoes progressive myelination, similar to cerebral white matter, reduction of the extracellular matrix and is no more detectable in children older than 2 years of age. In the patient described the central portion of the OB showed noticeable abnormal T2 hyperintensity, while the surrounding peripheral nerve portion was spared (Fig. 1). It can be assumed that the central part is highly susceptible to damage due to its immaturity. As no specific tests for olfactory functions on newborns are available, MRI still remain a unique test for the assessment of central olfactory system in newborns. The lack of confirmation of olfactory dysfunction is the main limitation in the case presented and it may be argued that the appearance of OB described is due to immaturity. Nevertheless, Fig. 1 shows the physiological appearance of OB in a newborn without CMV infection and studied at the same corrected GA, where any severe signal alteration in OB is present, therefore it is unlikely that the OB MRI appearance would be due to immaturity. Interestingly, any changes weren’t observed in the other cranial nerves, in particular in the optic nerves that are a true neocerebral extension, such as the olfactory nerves, suggesting a specific involvement of OB by CMV infection.\n\nConclusion\n\nDespite several neuroimaging studies on fetuses and newborns with congenital CMV infection, this is the first in vivo evidence of olfactory bulbs damage in a newborn with congenital CMV infection. In the future it would be interesting to assess the OB damage of congenital CMV infection in retrospective and prospective MRI studies. These observations may give new insights on CMV infection, prevention and control.\n\nAbbreviations\n\nCMV Citomegalovirus\n\nCNS Central Nervous System\n\nDOL day of life\n\nDWI Diffusion Weighted Imaging\n\nGA Gestational Age\n\nMRI Magnetic Resonance Imaging\n\nNICU Neonatal Intensive Care Unit\n\nOB olfactory bulbs\n\nOSN olfactory sensory neurons\n\nSVZ Subventricular Zone\n\nSWI Susceptibility Weighted Imaging\n\nTrueFISP True Fast Imaging with steady state procession\n\nVZ Ventricular Zone\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\n- AB gave a major contribution in drafting the text and figures, interpreted the MRI images and approved the final manuscript. - CC gave a major contribution in drafting the text, interpreted the clinical data and approved the final manuscript. - VL acquired and interpreted the clinical data, sedated and assisted the newborn during MRI examination and approved the final manuscript- ML acquired and interpreted the clinical data, assisted the newborn during recovery, acquired the informed parental consent and approved the final manuscript - SC acquired and interpreted the MRI data, contributed to the preparation of figures and approved the final manuscript - DE acquired and interpreted the MRI data, contributed to the preparation of figures and approved the final manuscript- VM revised the text critically, contributed to MRI data interpretation and approved the final manuscript- EF revised the text critically, contributed to MRI data interpretation and approved the final manuscript- CD concepted the work, revised the text critically and approved the final manuscript- ES gave a major contribution in concepting, drafting and revising the text critically, interpreted the MRI images and approved the final manuscript.\n\nFunding\n\nNo funding was received for the paper.\n\nAvailability of data and materials\n\nAny data or additional MRI images analyzed for this case report are available from the corresponding author on reasonable request.\n\nDeclarations\n\nConsent for publication\n\nParents give the informed consent to publication.\n\nCompeting interests\n\nThe authors declare that they have no competing interests and no disclosures.\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. Gaytant MA Steegers EA Semmekrot BA Merkus HM Galama JM Congenital cytomegalovirus infection: review of the epidemiology and outcome Obstet Gynecol Surv 2002 57 4 245 256 10.1097/00006254-200204000-00024 11961482\n2. Ross DS Dollard SC Victor M Sumartojo E Cannon MJ The epidemiology and prevention of congenital cytomegalovirus infection and disease: activities of the Centers for Disease Control and Prevention workgroup J Women's Health (Larchmt) 2006 15 3 224 229 10.1089/jwh.2006.15.224 16620180\n3. Griffiths PD Walter S Cytomegalovirus Curr Opin Infect Dis 2005 18 3 241 245 10.1097/01.qco.0000168385.39390.1b 15864102\n4. Barkovich AJ Lindan CE Congenital cytomegalovirus infection of the brain: imaging analysis and embryologic considerations AJNR Am J Neuroradiol 1994 15 4 703 715 8010273\n5. Doneda C Parazzini C Righini A Rustico M Tassis B Fabbri E Arrigoni F Consonni D Triulzi F Early cerebral lesions in cytomegalovirus infection: prenatal MR imaging Radiology 2010 255 2 613 621 10.1148/radiol.10090749 20413771\n6. Manara R Balao L Baracchini C Drigo P D’Elia R Ruga EM Brain magnetic resonance findings in symptomatic congenital cytomegalovirus infection Pediatr Radiol 2011 41 8 962 970 10.1007/s00247-011-2120-5 21597906\n7. Teissier N Fallet-Bianco C Delezoide AL Laquerrière A Marcorelles P Khung-Savatovsky S Nardelli J Cipriani S Csaba Z Picone O Golden JA Van Den Abbeele T Gressens P Adle-Biassette H Cytomegalovirus-induced brain malformations in fetuses J Neuropathol Exp Neurol 2014 73 2 143 158 10.1097/NEN.0000000000000038 24423639\n8. Lazarini F Katsimpardi L Levivien S Wagner S Gressens P Teissier N Lledo PM Congenital cytomegalovirus infection alters olfaction before hearing deterioration in mice J Neurosci 2018 38 49 10424 10437 10.1523/JNEUROSCI.0740-18.2018 30341181\n9. Farrell HE Bruce K Lawler C Stevenson PG Murine cytomegalovirus spread depends on the infected myeloid cell type J Virol 2019 93 15 e00540 e00519 10.1128/JVI.00540-19 31092580\n10. Farrell HE Lawler C Tan CS MacDonald K Bruce K Mach M Davis-Poynter N Stevenson PG Murine Cytomegalovirus Exploits Olfaction To Enter New Hosts mBio 2016 7 2 e00251 e00216 10.1128/mBio.00251-16 27118588\n11. Harding JE Cormack BE Alexander T Alsweiler JM Bloomfield FH Advances in nutrition of the newborn infant Lancet 2017 389 10079 1660 1668 10.1016/S0140-6736(17)30552-4 28443560\n12. Humphrey TJ The development of the olfactory and the accessory olfactory formations in human embryos and fetuses J Comp Neurol 1940 73 3 431 468 10.1002/cne.900730305\n13. Guerrero-Cázares H Gonzalez-Perez O Soriano-Navarro M Zamora-Berridi G García-Verdugo JM Quinoñes-Hinojosa A Cytoarchitecture of the lateral ganglionic eminence and rostral extension of the lateral ventricle in the human fetal brain J Comp Neurol 2011 519 6 1165 1180 10.1002/cne.22566 21344407\n14. Curtis MA Kam M Nannmark U Anderson MF Axell MZ Wikkelso C Holtås S van Roon-Mom WM Björk-Eriksson T Nordborg C Frisén J Dragunow M Faull RL Eriksson PS Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension Science 2007 315 5816 1243 1249 10.1126/science.1136281 17303719\n15. Schneider JF Floemer F Maturation of the olfactory bulbs: MR imaging findings AJNR Am J Neuroradiol 2009 30 6 1149 1152 10.3174/ajnr.A1501 19279285\n\n",
"fulltext_license": "CC BY",
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"issue": "47(1)",
"journal": "Italian journal of pediatrics",
"keywords": "Case report; Congenital Citomegalovirus; Magnetic resonance imaging; Newborn; Olfactory bulbs",
"medline_ta": "Ital J Pediatr",
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"title": "In vivo magnetic resonance imaging evidence of olfactory bulbs changes in a newborn with congenital Citomegalovirus: a case report.",
"title_normalized": "in vivo magnetic resonance imaging evidence of olfactory bulbs changes in a newborn with congenital citomegalovirus a case report"
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"abstract": "The aim of this study was to investigate long-term development of hearing in subjects who had received platinum-based chemotherapy in childhood or adolescence. Another aim was to assess the self-reported hearing loss handicap and compare it to audiometric measurements. Medical records from individuals diagnosed with childhood cancer and treated with platinum-based chemotherapy between 1985 and 2000 at the University Hospital in Lund Sweden were reviewed retrospectively. Fifteen subjects, who fulfilled the eligibility criteria set for the study, underwent a thorough audiometric evaluation. The results show that the hearing loss, in subjects with ototoxicity had increased after the end of treatment, to include also the lower frequencies. The largest deterioration in hearing thresholds, up to 55 dB HL, was found at frequencies above 2 kHz. The findings also reveal that the subjects have a considerably greater hearing loss handicap and disability than would be expected from the results of the audiometric evaluations. The conclusion of this study is that children and adolescence treated with platinum-based chemotherapy should have regular audiometric follow-up examinations, also many years after the end of treatment. Furthermore, assessments of self-reported hearing disability should be made during and after chemotherapy.",
"affiliations": "Department of Otorhinolaryngology, Head and Neck Surgery, Lund University, Lund, Sweden. einar-jon.einarsson@med.lu.se",
"authors": "Einarsson|Einar J|EJ|;Petersen|Hannes|H|;Wiebe|Thomas|T|;Fransson|Per A|PA|;Grenner|Jan|J|;Magnusson|Mås|M|;Moëll|Christer|C|",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents; D001301:Audiometry, Pure-Tone; D001309:Auditory Threshold; D002945:Cisplatin; D006233:Disabled Persons; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D034381:Hearing Loss; D006801:Humans; D008297:Male; D008499:Medical Records; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013548:Sweden; D055815:Young Adult",
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"references": null,
"title": "Long term hearing degeneration after platinum-based chemotherapy in childhood.",
"title_normalized": "long term hearing degeneration after platinum based chemotherapy in childhood"
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"abstract": "OBJECTIVE\nTrastuzumab therapy, the standard treatment for human epidermal growth factor receptor type-2 (HER2)-positive breast cancer, is associated with possible cardiotoxicity. We set out to retrospectively analyze the cardiac follow-up data of patients with breast cancer receiving trastuzumab treatment.\n\n\nMETHODS\nThe study involved 47 and 31 patients receiving adjuvant or palliative chemotherapy plus trastuzumab, respectively. Cardiovascular system assessments including echocardiography were regularly performed.\n\n\nRESULTS\nA significant heart abnormality was detected in 44.7% of the operable and 41.9% of metastatic cases. In the adjuvant setting, left ventricular ejection fraction changes occurred mostly during treatment and less frequently after its completion (40.4% vs. 19.4%), while in the palliative setting, 35.5% and 40% in the first and the second year of therapy. An asymptomatic atrial septum aneurysm was detected in 8.5% and 13% of the patients in the two groups.\n\n\nCONCLUSIONS\nTrastuzumab-related cardiotoxicity is mostly manifested in an asymptomatic decrease in left ventricular ejection fraction; hypertension, a high body mass index and left-sided irradiation are its predictors.",
"affiliations": "Department of Oncotherapy, University of Szeged, Szeged, Hungary.;Department of Oncotherapy, University of Szeged, Szeged, Hungary.;Department of Oncotherapy, University of Szeged, Szeged, Hungary.;Department of Oncotherapy, University of Szeged, Szeged, Hungary.;Department of Oncotherapy, University of Szeged, Szeged, Hungary.;Second Department of Medicine and Cardiology Center, University of Szeged, Szeged, Hungary.;Second Department of Medicine and Cardiology Center, University of Szeged, Szeged, Hungary.;Department of Oncotherapy, University of Szeged, Szeged, Hungary kahan.zsuzsanna@med.u-szeged.hu.",
"authors": "Valicsek|Erzsébet|E|;Kószó|Renáta|R|;Dobi|Ágnes|Á|;Uhercsák|Gabriella|G|;Varga|Zoltán|Z|;Vass|Andrea|A|;Jebelovszky|Éva|É|;Kahán|Zsuzsanna|Z|",
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"issue": "35(9)",
"journal": "Anticancer research",
"keywords": "BMI; Trastuzumab; cardiac dysfunction; hypertension; radiotherapy; risk factor",
"medline_ta": "Anticancer Res",
"mesh_terms": "D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D005260:Female; D006321:Heart; D006334:Heart Function Tests; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D010166:Palliative Care; D011159:Population Surveillance; D012307:Risk Factors; D000068878:Trastuzumab",
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"title": "Cardiac Surveillance Findings During Adjuvant and Palliative Trastuzumab Therapy in Patients with Breast Cancer.",
"title_normalized": "cardiac surveillance findings during adjuvant and palliative trastuzumab therapy in patients with breast cancer"
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"abstract": "CME:Heparin-Induced Thrombocytopenia Abstract. Heparin-induced thrombocytopenia (HIT) is a dangerous, potentially fatal, immunologically mediated side effect of heparin. Typically, five to ten days after heparin exposure there is a decrease in platelet count with a mean of 60 x 109/l. Due to an activation of thrombocytes by HIT antibodies, venous or more rarely arterial thromboses may occur. The diagnosis of HIT includes the calculation of the probability of a HIT using the 4T Score and the laboratory detection of HIT antibodies. The HIT therapy represents the immediate discontinuation of the heparin therapy as well as the beginning of an alternative therapeutic anticoagulation.",
"affiliations": "Wissenschaftliche Mitarbeiterin, Universitäres Zentrum für Hausarztmedizin beider Basel.;Universitäres Zentrum für Hausarztmedizin beider Basel.",
"authors": "Zehnder|Tonia|T|;Zeller|Andreas|A|",
"chemical_list": "D000906:Antibodies; D000925:Anticoagulants; D006493:Heparin",
"country": "Switzerland",
"delete": false,
"doi": "10.1024/1661-8157/a003365",
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"issue": "109(2)",
"journal": "Praxis",
"keywords": "HIT; Heparin; Thrombose; Thrombozytopenie; heparin; thrombocytopenia; thrombosis",
"medline_ta": "Praxis (Bern 1994)",
"mesh_terms": "D000906:Antibodies; D000925:Anticoagulants; D006493:Heparin; D006801:Humans; D013921:Thrombocytopenia; D013927:Thrombosis",
"nlm_unique_id": "101468093",
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"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
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"title": "CME:Heparin-Induced Thrombocytopenia.",
"title_normalized": "cme heparin induced thrombocytopenia"
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"companynumb": "CH-SA-2020SA063832",
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"abstract": "This was a retrospective study on the efficacy and drug resistance mutations selected at virological failure (VF) in prospectively-followed HIV-infected patients switched to dolutegravir plus rilpivirine (DTG+RPV) or lamivudine (DTG+3TC) while virologically suppressed (HIV-RNA <50 copies/mL). VF was defined as HIV-RNA >50 copies/mL in two consecutive determinations or in a single determination if followed by treatment modification, or >1000 copies/mL in a single determination. Totally, 374 patients were analysed (307 switched to DTG+3TC and 67 to DTG+RPV); 220 had documented historical resistance. The median (IQR) time with HIV-RNA <50 copies/mL before switch was 4.52 (1.93-8.14) years. VF occurred in 17 patients after a median of 1.74 (0.90-2.46) years of follow-up in the 3TC group [incidence rate (95% CI) 3.34 (2.08-5.37) per 100-PYFU] and in 2 patients after a median of 1.78 (1.10-2.99) years of follow-up in the RPV group [incidence rate (95% CI) 1.57 (0.4-6.28) per 100-PYFU]. The 48-week estimated probabilities to maintain virological suppression during treatment with a two-drug regimen were 97.8% (95% CI 95.1-99.0%) vs. 98.3% (95% CI 88.6-99.8%) in the 3TC versus RPV group (P = 0.311). At switch, patients with VF had undetectable HIV-RNA since 0.71 (0.23-1.07) years versus 1.49 (0.64-2.2) years in those without VF (P = 0.001). In the 3TC group, VF was not associated with the presence of historical resistance to nucleoside analogues, and DTG-resistant variants were not selected at VF. One VF to DTG+RPV occurred because of historical resistance to RPV, accompanied by newly selected G140A and Q148R mutations. VF was infrequent with these regimens and was negatively associated with duration of viral undetectability. Drug resistance mutations selected at failure of these regimens were those expected in case of failure of any regimen including DTG, 3TC or RPV, but the impact of resistance to NRTIs on efficacy of DTG+3TC seems lower than expected.",
"affiliations": "Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy.;Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy.;Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy.;Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy; Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy.;Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy; Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy.;Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy; University Hospital Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy.;Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy.;Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy.;Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy.;Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy.;Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy; Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy.;Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Stamira d'Ancona 20, 20127 Milan, Italy. Electronic address: nicola.gianotti@hsr.it.",
"authors": "Galizzi|Nadia|N|;Poli|Andrea|A|;Galli|Laura|L|;Muccini|Camilla|C|;Mastrangelo|Andrea|A|;Dell'Acqua|Raffaele|R|;Maillard|Myriam|M|;Bossolasco|Simona|S|;Cinque|Paola|P|;Lazzarin|Adriano|A|;Castagna|Antonella|A|;Gianotti|Nicola|N|",
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"issue": "55(3)",
"journal": "International journal of antimicrobial agents",
"keywords": "Dolutegravir; HIV; Integrase strand transfer inhibitor; Lamivudine; Rilpivirine; Two-drug regimen",
"medline_ta": "Int J Antimicrob Agents",
"mesh_terms": "D019380:Anti-HIV Agents; D024882:Drug Resistance, Viral; D015658:HIV Infections; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D019259:Lamivudine; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors; D000068696:Rilpivirine; D016896:Treatment Outcome",
"nlm_unique_id": "9111860",
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"pages": "105893",
"pmc": null,
"pmid": "31926287",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article",
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"title": "Retrospective study on the outcome of two-drug regimens based on dolutegravir plus one reverse transcriptase inhibitor in virologically-suppressed HIV-infected patients.",
"title_normalized": "retrospective study on the outcome of two drug regimens based on dolutegravir plus one reverse transcriptase inhibitor in virologically suppressed hiv infected patients"
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"companynumb": "IT-TEVA-2020-IT-1231142",
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"abstract": "Compartment syndrome is an ischemic change resulting from an increase in compartment pressure. Initially, patients present with direct tenderness and swelling, and the weak circulation secondary to compartment syndrome can eventually lead to motor and sensory impairment. If the increase in pressure results in neurological impairment, emergency intervention is required to decompress the compartment. Typically, compartment syndrome develops on forearms or lower legs. The gluteal compartment is rarely the location of compartment syndrome and only a few cases have been presented in the literature with trauma or hematoma. We have treated a patient with gluteal compartment syndrome who presented with no history of trauma or hemorrhage and present that case report here.",
"affiliations": "Department of Orthopaedic Surgery, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.;Department of Orthopaedic Surgery, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.;Department of Orthopaedic Surgery, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.",
"authors": "Kong|Gyu-Min|GM|;Kwon|Yong-Uk|YU|;Park|Jun-Ho|JH|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5371/hp.2015.27.4.278",
"fulltext": "\n==== Front\nHip PelvisHip PelvisHPHip & Pelvis2287-32602287-3279Korean Hip Society 10.5371/hp.2015.27.4.278Case ReportCompartment Syndrome of the Gluteus Medius Occurred without Bleeding or Trauma: A Case Report Kong Gyu-Min MDPhDKwon Yong-Uk MDPark Jun-Ho MDDepartment of Orthopaedic Surgery, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea.Address reprint request to Yong-Uk Kwon, MD. Department of Orthopaedic Surgery, Inje University Busan Paik Hospital, 75 Bokji-ro, Busanjin-gu, Busan 47392, Korea. TEL: +82-51-890-6257, FAX: +82-51-890-6619, slowsting@naver.com12 2015 30 12 2015 27 4 278 282 19 10 2015 22 11 2015 24 11 2015 Copyright © 2015 by Korean Hip Society2015This 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.Compartment syndrome is an ischemic change resulting from an increase in compartment pressure. Initially, patients present with direct tenderness and swelling, and the weak circulation secondary to compartment syndrome can eventually lead to motor and sensory impairment. If the increase in pressure results in neurological impairment, emergency intervention is required to decompress the compartment. Typically, compartment syndrome develops on forearms or lower legs. The gluteal compartment is rarely the location of compartment syndrome and only a few cases have been presented in the literature with trauma or hematoma. We have treated a patient with gluteal compartment syndrome who presented with no history of trauma or hemorrhage and present that case report here.\n\nGlutealCompartment syndromesAtraumaticNon-hemorrhagic\n==== Body\nCompartment syndrome is characterized by an increase of compartment pressure induced by any number of causes including trauma, bleeding and compression, and can result in pain, motor and sensory impairment, ischemic tissue necrosis and other symptoms. The most common causes of compartment syndrome are fracture (about 69%) and soft tissue injury1), and the most common site is the lower leg, followed by the forearm2). This condition is frequently associated with tibial shaft fractures in adults, and its incidence rate ranges between 2.7-11%2).\n\nThis syndrome rarely occurs in the pelvic region and is more common in the lower legs and forearms. Since Petrick3) first described the initial case of gluteal compartment syndrome, it has been rarely reported. In fact, gluteal compartment syndrome without trauma, has only previously been presented in three domestic case reports456). In these three domestic cases, however, bleeding and hematoma occurred following the administration of anti-platelet agents or low-molecular-weight heparins. This paper reports a rare case of compartment syndrome of the gluteus medius occurring in the absence of trauma and with no hematoma or bleeding observed during surgery and includes a brief review of the literature.\n\nCASE REPORT\nA 50-year old man visited our hospital with a chief complaint of widespread pain in the right thigh and waist. He was undergoing outpatient treatment at the internal medicine clinic due to a history of diabetes, tuberculosis, and hepatitis C virus infection (Child-Pugh score class B). The patient was observed lying down in a supine position after taking 20 ibuprofen pills in an attempted suicide gradually entered into a stupor. The patient was admitted through the emergency room 8 hours after losing consciousness. After regaining consciousness, he complained of right thigh and back pain with a visual analogue scale (VAS) score of 8. Before loss of consciousness, he had no trauma and did not undertake any intense exercise.\n\nThe patient was 180 cm tall, weighed 95 kg and was obese with a BMI of 29.32 kg/m2. The pain described above was present at rest, but did not increase with passive flexion of the hip and knee. Compared to the healthy left side, swelling was detected in the right thigh, but no trauma was noted such as febrile sense or petechiae on the skin. Although circulation was normal in the right distal limb, diminished sensation was observed in the right thigh (80% of heathy side medially and 20% of heathy side laterally). At the emergency room, compartment pressures measured using Whitesides technique were 20 mmHg on the medial side and 40 mmHg on the lateral side (Fig. 1).\n\nLaboratory findings included C-reactive protein 0.26 mg/dL (~0.5 mg/dL), lactate dehydrogenase 528 U/L (129-240 U/L), creatine phosphokinase 13,884 U/L (38-176 U/L), blood urea nitrogen 22 mg/dL (8-20) mg/dL, creatinine 1.32 mg/dL (0.6-1.2 mg/dL), and creatine kinase-MB 48.0 ng/mL (~0.5 ng/mL). All coagulation and bleeding parameters were normal with prothrombin time 14.0 sec (10.0-14.0 sec), international normalized ratio 1.28 (0.85-1.30), and activated partial thromboplastin time 40.3 sec (30-47 sec). A urine test revealed no ketone body, 3+ blood and 2+ protein. Although no deformed red blood cells were observed, both myoglobin and hemoglobin were detected in urine. Excluding swelling in the patient's hip and thigh (Fig. 2), no abnormal findings were observed on plain radiographs and computed tomography scans of the abdomen and lower leg at the time of admission. The patient underwent collaborative treatment with internal medicine after a diagnosis of liver cirrhosis and probable diagnosis of rhabdomyolysis, and sufficient amount of crystalloid fluid was given intravenously at the early stage. The initial compartment pressure measured using Whitesides technique was 40 mmHg on the right thigh. Although this was not a criterion for performing emergent fasciotomy, emergency surgery could be considered due to the severe pain and swelling of the thigh so a thorough follow-up was conducted. Until recovery to consciousness, the patient's position was not changed voluntarily or involuntarily. Pain (VAS 9) was intensified 8 hours after administration to the emergency room. The pain was localized to the right hip, and considerable pain was complained by the patient during passive range of motion exercises involving the hip. Diminished sensation below to 20% was noted over the calf and toes both medially and laterally. Flexor and extensor muscle strength on the ankle and toes was assessed as stage 1. Consequently, emergency fasciectomy and open release of the right hip were performed.\n\nOpen release was performed in a side-lying position. A 10-cm incision was made directly inferior to the greater trochanter and parallel to the posterior boarder of the greater trochanter at the height of the anterior superior iliac spine. The subcutaneous layer was dissected along the incision line, and a large volume of transudate was drained in this process. Compression caused by hematoma was not seen. Through an incision of the subcutaneous layer, the gluteus maximus fascia was exposed and then incised to the center of the greater trochanter. After the incision, decompression was achieved after a large volume of transudate was drained without any hematoma. There were no specific intraoperative findings in the vastus lateralis of the right thigh. Hematoma was not present in the three compartments of pelvic region (iliopsoas compartment, gluteus medius-minimus compartment, and gluteus maximus compartment)7), but severe swelling and ischemic change leading to a purple-black color were detected in the gluteus medius (Fig. 3). After fasciotomy, pain was improved and sensation was recovered in the affected legs by over 80% of the healthy side 48 hours after surgery. Muscle strength also improved to stage 3 or higher. On the third day post surgery, aseptic dressing and sufficient irrigation were performed in the operating room. Hip swelling gradually subsided and reperfusion was observed as the ischemia improved. On the fifth day post surgery, the incision site was sutured as ischemic changes were recovered (Fig. 4). Follow ups were continued for six months after surgery. Compartment syndrome was improved without loss of sensation and motor function and muscle weakness.\n\nDISCUSSION\nCompartment syndrome occurs when the tissue pressure within a muscle compartment exceeds the capillary perfusion pressure and results in decreased perfusion and ischemic changes. When the ischemic condition persists, the tissues and muscles undergo necrosis can lead to fibrosis in those muscle and tissues2). Trauma is the most common cause of compartment syndrome, and the calf is the most common area of onset1). Gluteal compartment syndrome is a rare condition that is caused by persistent compression of the hip subsequent to trauma, bleeding or hematoma, or is caused by remaining in the same position for a long period of time.\n\nThe diagnosis of acute compartment syndrome is typically made following clinical evaluation. In this case report, the first complaint of pain was delayed in the early phase because the patient was under a stupor due to drug overdose, and the location and boundary of the pain were unclear. After the patient regained consciousness, he complained of progressively intensifying pain. Aggravating pain and weakening sensation and motor function have been frequently associated with involuntary movement in patients with compartment syndrome8). Like in this review, as vague pain in the waist and thigh became definite pain in the hip over time, severe pain developed during involuntary movement of the hip. Before surgery, diminished sensation and muscle strength over the right leg is thought to be attributable to sciatic nerve compression caused by swelling and elevated compartment pressure in the hip and thigh regions.\n\nNotably, the patient's first complaint was pain in the right thigh and leg and not hip pain. For this reason, compartment pressure was measured in the thigh only because thigh compartment syndrome was more suspected. Careful assessement of the gluteal compartments was not made. The pelvic region is divided into three compartments, the iliopsoas, gluteus medius and minimus, and gluteus maximus, and thigh muscles are divided into anterior, posterior and adductor compartments. For these reasons, all compartments need to be evaluated separately on physical examination9), but a complete exam was not performed in the initial phase. In the diagnosis and evaluation of compartment syndrome of the lower limbs, the possibility of gluteal compartment syndrome should be taken into account in patients complaining of thigh and back pain.\n\nGluteal compartment syndrome is a very rare condition10). In the present case, compartment syndrome occurred in the right gluteus medius among the gluteus compartments without any traumatic event or hematoma. This could be attributed to gluteal compression caused by remaining in a lying down position for prolonged periods of time after decreased consciousness due to drug overdose in obese state with a BMI of 29 kg/m2 or higher. Since the gluteus medius muscles are relatively small compared to the gluteus maximus and there is no space between the gluteus medius and maximus muscles, compartment syndrome of the gluteus medius seems to occur. This review supports past research recommending that gluteal compartment syndrome can develop from continuous compression of the hip by maintaining limited movement or improper posture for prolonged periods of time due to medication or trauma.\n\nThis review highlights that gluteal compartment syndrome can be caused by remaining in a side-lying position for a long period of time in overweight patients. Therefore, even though a patient initially complains of pain in the waist and thigh without any trauma, a thorough clinical evaluation of the gluteal compartments, in addition to the femoral region is warranted. If compartment syndrome is suspected, sufficient examination of all compartments associated with the pain can lead to more prompt diagnosis and adequate treatment including rare gluteal compartment syndrome.\n\nFig. 1 Compartment pressure measuring tool using Whitesides technique.\nFig. 2 Direct tenderness and severe swelling were found in the patient's right leg. Circle: gluteus minimus, black triangle: gluteus medius, empty triangle: gluteus maximus.\nFig. 3 Ischemic change and loss of contractability of gluteus medius. Black arrow: gluteus medius, white arrow: vastus lateralis.\nFig. 4 Postoperative 5 days, at the second operation, the swelling of the gluteus medius subsided and ischemic changes were recovered. Black arrow: gluteus medius, white arrow: vastus lateralis.\n==== Refs\n1 Lee KB Lee SH Diagnosis and management of acute compartment syndrome J Korean Fract Soc 2015 28 93 101 \n2 Oh CW Lee HJ Acute compartment syndrome after trauma J Korean Fract Soc 2010 23 399 403 \n3 Petrik ME Stambough JL Rothman RH Posttraumatic gluteal compartment syndrome. A case report Clin Orthop Relat Res 1988 231 127 129 3370867 \n4 Chung KJ Chung YK Yoo JH Wang JS Sciatic nerve palsy complicating gluteal compartment syndrome due to rhabdomyolysis: a case report J Korean Orthop Assoc 2005 40 103 106 \n5 Choi DH Choi DW Awe SI Low molecular weight heparin associated intramuscular hematoma with compartment syndrome Korean J Med 2005 69 Suppl 3 S948 S951 \n6 Lee MJ Lee DK Spontaneous multi-stage gluteus muscular hemorrhage following long-term use of clopidogrel J Korean Neurol Assoc 2011 29 406 \n7 Ehlinger M Schneider L Lefebvre Y Jacquot X Cognet JM Simon P Exercise-induced acute bilateral isolated anterolateral compartment syndrome of the leg: a case report of a rare condition Rev Chir Orthop Reparatrice Appar Mot 2004 90 165 170 15107707 \n8 Browner BD Alberta FG Furey PC Goumas D Varma V Emergent care of musculoskeletal injuries Townsend CM Beauchamp RD Evers DM Mattox K Sabiston textbook of surgery 17th ed Philadelphia, PA W.B. Saunders 2004 554 557 \n9 Whitesides TE Haney TC Morimoto K Harada H Tissue pressure measurements as a determinant for the need of fasciotomy Clin Orthop Relat Res 1975 113 43 51 1192674 \n10 Owen CA Woody PR Mubarak SJ Hargens AR Gluteal compartment syndromes: a report of three cases and management utilizing the Wick catheter Clin Orthop Relat Res 1978 132 57 60 679554\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2287-3260",
"issue": "27(4)",
"journal": "Hip & pelvis",
"keywords": "Atraumatic; Compartment syndromes; Gluteal; Non-hemorrhagic",
"medline_ta": "Hip Pelvis",
"mesh_terms": null,
"nlm_unique_id": "101599815",
"other_id": null,
"pages": "278-82",
"pmc": null,
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"pubdate": "2015-12",
"publication_types": "D002363:Case Reports",
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"title": "Compartment Syndrome of the Gluteus Medius Occurred without Bleeding or Trauma: A Case Report.",
"title_normalized": "compartment syndrome of the gluteus medius occurred without bleeding or trauma a case report"
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"companynumb": "KR-PFIZER INC-2019094211",
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"abstract": "Recent studies have reported weight gain in virologically suppressed persons living with human immunodeficiency virus (PLWH) switched from older antiretroviral therapy (ART) to newer integrase strand transfer inhibitor (INSTI)-based regimens. In this study, we investigated whether weight gain differs among treatment-naive PLWH starting INSTI-based regimens compared to other ART regimens.\n\n\n\nAdult, treatment-naive PLWH in the Vanderbilt Comprehensive Care Clinic cohort initiating INSTI-, protease inhibitor (PI)-, and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART between January 2007 and June 2016 were included. We used multivariable linear mixed-effects models to generate marginal predictions of weights over time, adjusting for baseline clinical and demographic characteristics. We used restricted cubic splines to relax linearity assumptions and bootstrapping to generate 95% confidence intervals.\n\n\n\nAmong 1152 ART-naive PLWH, 351 initiated INSTI-based regimens (135 dolutegravir, 153 elvitegravir, and 63 raltegravir), 86% were male, and 49% were white. At ART initiation, median age was 35 years, body mass index was 25.1 kg/m2, and CD4+ T-cell count was 318 cells/μL. Virologic suppression at 18 months was similar between different ART classes. At all examined study time points, weight gain was highest among PLWH starting dolutegravir. At 18 months, PLWH on dolutegravir gained 6.0 kg, compared to 2.6 kg for NNRTIs (P < .05), and 0.5 kg for elvitegravir (P < .05). PLWH starting dolutegravir also gained more weight at 18 months compared to raltegravir (3.4 kg) and PIs (4.1 kg), though these differences were not statistically significant.\n\n\n\nTreatment-naive PLWH starting dolutegravir-based regimens gained significantly more weight at 18 months than those starting NNRTI-based and elvitegravir-based regimens.",
"affiliations": "Vanderbilt University Medical Center, Nashville, Tennessee.;Vanderbilt University Medical Center, Nashville, Tennessee.;Vanderbilt University Medical Center, Nashville, Tennessee.;Vanderbilt University Medical Center, Nashville, Tennessee.;Vanderbilt University Medical Center, Nashville, Tennessee.;Vanderbilt University Medical Center, Nashville, Tennessee.;Vanderbilt University Medical Center, Nashville, Tennessee.;Vanderbilt University Medical Center, Nashville, Tennessee.",
"authors": "Bourgi|Kassem|K|;Rebeiro|Peter F|PF|;Turner|Megan|M|;Castilho|Jessica L|JL|;Hulgan|Todd|T|;Raffanti|Stephen P|SP|;Koethe|John R|JR|;Sterling|Timothy R|TR|",
"chemical_list": "D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; C562325:dolutegravir",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciz407",
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"issn_linking": "1058-4838",
"issue": "70(7)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "HIV metabolic complications; integrase strand transfer inhibitors; treatment-naive adults with HIV; weight gain",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D005260:Female; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008297:Male; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D015430:Weight Gain",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1267-1274",
"pmc": null,
"pmid": "31100116",
"pubdate": "2020-03-17",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "24156897;22951353;23459863;28520615;24384588;25761868;24637543;25595743;20543657;26962236;27171741;23018438;28574967;26216031;29535090;24506429;19730111;19490182;23072344;20400883;26352511;28825943;29149237;22730929;29722811;19287299;12626890;25583168;20694301;30800425;8984340;26797215;16945078;25960080;27307508;25182245",
"title": "Greater Weight Gain in Treatment-naive Persons Starting Dolutegravir-based Antiretroviral Therapy.",
"title_normalized": "greater weight gain in treatment naive persons starting dolutegravir based antiretroviral therapy"
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"abstract": "To evaluate the prognosis and progression of spinal and bulbar muscular atrophy (SBMA), a rare X-linked motor neuron disorder caused by trinucleotide repeat expansion in the AR (androgen receptor) gene, after long-term androgen suppression with leuprorelin acetate treatment.\n\n\n\nIn the present natural history-controlled study, 36 patients with SBMA treated with leuprorelin acetate for up to 84 months (leuprorelin acetate-treated group; LT group) and 29 patients with SBMA with no specific treatment (non-treated group; NT group) were analysed. Disease progression was evaluated by longitudinal quantitative assessment of motor functioning using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the modified Norris score. In addition, we selected two major clinical endpoint events, namely the occurrence of pneumonia requiring hospitalisation and death, to evaluate disease prognosis following long-term leuprorelin acetate treatment.\n\n\n\nIn our analysis of the longitudinal disease progression using the random slope model, we observed a significant difference in the ALSFRS-R total score, the Limb Norris Score, and the Norris Bulbar Score (p=0.005, 0.026 and 0.020, respectively), with the LT group exhibiting a slower per-12-months decline compared with the NT group. As for the event analysis, the prognosis of the LT group was better in comparison to the NT group as for the event-free survival period (p=0.021).\n\n\n\nLong-term treatment with leuprorelin acetate appears to delay the functional decline and suppress the incidence of pneumonia and death in subjects with SBMA.",
"affiliations": "Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.;Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.;Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.;Biostatistics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.;Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.;Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.;Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.;Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.;Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.",
"authors": "Hashizume|Atsushi|A|;Katsuno|Masahisa|M|;Suzuki|Keisuke|K|;Hirakawa|Akihiro|A|;Hijikata|Yasuhiro|Y|;Yamada|Shinichiro|S|;Inagaki|Tomonori|T|;Banno|Haruhiko|H|;Sobue|Gen|G|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D016729:Leuprolide",
"country": "England",
"delete": false,
"doi": "10.1136/jnnp-2017-316015",
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"issn_linking": "0022-3050",
"issue": "88(12)",
"journal": "Journal of neurology, neurosurgery, and psychiatry",
"keywords": "neuromuscular; neuropharmacology; scales",
"medline_ta": "J Neurol Neurosurg Psychiatry",
"mesh_terms": "D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal; D018450:Disease Progression; D018572:Disease-Free Survival; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016729:Leuprolide; D008134:Long-Term Care; D008297:Male; D008875:Middle Aged; D009134:Muscular Atrophy, Spinal; D011014:Pneumonia; D011379:Prognosis",
"nlm_unique_id": "2985191R",
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"pages": "1026-1032",
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"pmid": "28780536",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy: natural history-controlled study.",
"title_normalized": "long term treatment with leuprorelin for spinal and bulbar muscular atrophy natural history controlled study"
} | [
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"companynumb": "JP-ABBVIE-17P-087-2079141-00",
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"activesubstancename": "LEUPROLIDE ACETATE"
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"abstract": "An ongoing outbreak of pneumonia associated with the severe acute respiratory coronavirus 2 (SARS-CoV-2) started in Wuhan, China, with cases now confirmed in multiple countries. The clinical course of patients remains to be fully characterized, clinical presentation ranges from asymptomatic infection to acute respiratory distress syndrome and acute renal failure, and no pharmacological therapies of proven efficacy yet exist. We report a case of SARS-CoV-2 infection in a renal transplant recipient with excellent outcome. This case states the importance of close monitoring of the concentration of cyclosporine in patients treated with lopinavir/ritonavir; the routine treatment of corticosteroid can be continued. This is a rare report of SARS-CoV-2 infection in a renal transplant recipient. Further data are needed to achieve better understanding of the impact of immunosuppressive therapy on the clinical presentation, severity, and outcome of SARS-CoV-2 infections in solid organ transplant recipients.",
"affiliations": "Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P.R. China.;Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P.R. China.;Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P.R. China.;Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P.R. China.;Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P.R. China.;Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P.R. China.;Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P.R. China.;Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P.R. China.;Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P.R. China.;Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P.R. China.;Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P.R. China.;Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, P.R. China.",
"authors": "Ning|Ling|L|https://orcid.org/0000-0002-7307-9827;Liu|Lei|L|;Li|Wenyuan|W|;Liu|Hongtao|H|;Wang|Jizhou|J|;Yao|Ziqin|Z|;Zhang|Shengyu|S|;Zhao|Desheng|D|;Nashan|Björn|B|;Shen|Aizong|A|;Liu|Lianxin|L|;Li|Lei|L|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D004338:Drug Combinations; D007166:Immunosuppressive Agents; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; D016572:Cyclosporine; D019438:Ritonavir",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15897",
"fulltext": null,
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"issn_linking": "1600-6135",
"issue": "20(7)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical decision-making; clinical research/practice; immunosuppressive regimens-maintenance; infection and infectious agents-viral; infectious disease; kidney transplantation/nephrology",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000073640:Betacoronavirus; D000086382:COVID-19; D002681:China; D018352:Coronavirus Infections; D016572:Cyclosporine; D004196:Disease Outbreaks; D004338:Drug Combinations; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D019520:Living Donors; D061466:Lopinavir; D008297:Male; D058873:Pandemics; D011024:Pneumonia, Viral; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019438:Ritonavir; D000086402:SARS-CoV-2; D014057:Tomography, X-Ray Computed; D066027:Transplant Recipients; D016896:Treatment Outcome",
"nlm_unique_id": "100968638",
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"pages": "1864-1868",
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"pubdate": "2020-07",
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"title": "Novel coronavirus (SARS-CoV-2) infection in a renal transplant recipient: Case report.",
"title_normalized": "novel coronavirus sars cov 2 infection in a renal transplant recipient case report"
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"abstract": "•Genomic tumor testing is an important tool in guiding treatment for gynecologic malignancies.•Targetable mutations may lead to new therapies in gynecologic cancer treatment.•Her2/neu mutations in serous ovarian carcinomas can be targeted with ERBB2 inhibitors.•Afatinib shows promising response rates in lung cancers carrying Her2/neu mutations.•Afatinib may be effective in serous ovarian tumors exhibiting Her2/neu or ERBB2 mutations.",
"affiliations": "Department of Gynecologic Oncology, NYU-Winthrop, Mineola, NY,USA.;School of Public Health, UC Berkeley, Berkeley, CA,USA.;Department of Gynecologic Oncology, UC Davis, Sacramento, CA,USA.;Department of Gynecologic Oncology, UC San Francisco, San Francisco, CA,USA.",
"authors": "Shepherd-Littlejohn|Amanda L|AL|;Hanft|Wyatt J|WJ|;Kennedy|Vanessa A|VA|;Alvarez|Edwin A|EA|",
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"doi": "10.1016/j.gore.2019.07.001",
"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(19)30063-310.1016/j.gore.2019.07.001Case ReportAfatinib use in recurrent epithelial ovarian carcinoma Shepherd-Littlejohn Amanda L. amanda.shepherd-littlejohn@nyulangone.orga⁎Hanft Wyatt J. beKennedy Vanessa A. cAlvarez Edwin A. da Department of Gynecologic Oncology, NYU-Winthrop, Mineola, NY,USAb School of Public Health, UC Berkeley, Berkeley, CA,USAc Department of Gynecologic Oncology, UC Davis, Sacramento, CA,USAd Department of Gynecologic Oncology, UC San Francisco, San Francisco, CA,USAe School of Medicine, UC Davis, Sacramento, CA,USA⁎ Corresponding author. 99 Gold Street, Apt. PH-C, Brooklyn, NY 11201,USA. amanda.shepherd-littlejohn@nyulangone.org03 7 2019 8 2019 03 7 2019 29 70 72 6 4 2019 27 6 2019 1 7 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Genomic tumor testing is an important tool in guiding treatment for gynecologic malignancies.\n\n• Targetable mutations may lead to new therapies in gynecologic cancer treatment.\n\n• Her2/neu mutations in serous ovarian carcinomas can be targeted with ERBB2 inhibitors.\n\n• Afatinib shows promising response rates in lung cancers carrying Her2/neu mutations.\n\n• Afatinib may be effective in serous ovarian tumors exhibiting Her2/neu or ERBB2 mutations.\n\n\n\nKeywords\nMolecular tumor testingTargeting agentsOvarian cancerHER2/neuERBB2Afatinib\n==== Body\n1 Patient case\n41 year old germline and somatic BRCA negative Caucasian female underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy for a pelvic mass at the age of 34. Pathology revealed a serous borderline tumor. The patient presented two years later with nausea, abdominal pain, and bloating. CT scan revealed a 3 cm mass on the anterior abdominal wall and a 2 cm mass at the vaginal cuff. She underwent a secondary optimal tumor debulking with implants removed from the anterior abdominal wall, rectum, sigmoid colon, vaginal cuff, and stomach. Pathology showed high grade serous carcinoma in all tumor implants. She received carboplatin (AUC 6) and nab-paclitaxel (260 mg/m2) every 3 weeks for a total of 6 cycles. Nab-paclitaxel was given after the patient had an allergic reaction to her first dose of paclitaxel. A year after completing chemotherapy, an increasing CA-125 and CT scan revealed intra-abdominal tumor recurrence. She underwent 3 cycles of carboplatin (AUC 6) and liposomal doxorubicin (50 mg/m2) with persistently elevated CA-125 levels. Her regimen was changed to 6 cycles of nab-paclitaxel (260 mg/m2) and bevacizumab (15 mg/m2) with normalization of her CA-125 level and no residual tumor. Nine months later, the patient presented with intra-abdominal recurrence. She was given 4 cycles of carboplatin (AUC 6) and gemcitabine (1000 mg/m2) and maintenance q3week topotecan (1.5 mg/m2). After a year, CA-125 levels started to rise and single agent liposomal doxorubicin was started with subsequent maintenance aromatase inhibitor, Letrozole. Patient was ineligible for clinical trials due to recurrence in the colon. She developed vaginal bleeding and had biopsy-confirmed recurrent high grade serous carcinoma at the vaginal cuff and sigmoid colon. Biopsies were sent for genetic sequencing which showed an activating HER2/neu alteration (ERBB2 G776_V777). Genomic results were discussed at a multi-disciplinary molecular tumor board and afatinib was recommended. The patient started on afatinib (40 mg PO daily) and had a significant decrease in her CA-125, decrease in the size of her vaginal tumor, and resolution of her bleeding. The patient experienced Grade 1 nausea and a Grade 2 dermatologic rash but was able to continue on afatinib. The patient had a progression free interval of ten months on afatinib. The decision was made to restart nab-paclitaxel (100 mg/m2) and bevacizumab (15 mg/m2) after an increase in CA-125. The patient has continued on maintenance nab-paclitaxel for the past six months and has had stable CA-125 levels.\n\n2 Discussion\nGreat efforts are being made to advance the treatment of ovarian cancer but this malignancy is still the 5th leading cause of cancer-related death among women in the United States (La Vecchia et al., 2017). Serous ovarian carcinomas (SOC) comprise 40% of ovarian neoplasms and are the most common form of this malignancy (La Vecchia et al., 2017). The lack of obvious symptoms until advanced stages and the high rate of recurrence greatly contribute to the low (36%) 5-year survival rate of patients with SOC (La Vecchia et al., 2017). In light of this data, new approaches to ovarian cancer treatment are necessary.\n\nPrimary surgical resection is considered the standard treatment for SOC, with adjuvant chemotherapy offered to patients with Stage 1C disease or greater (Kampan et al., 2015). The current standard chemotherapy regimen consists of intravenously administered paclitaxel (175 mg/m2) and carboplatin (AUC 5–7.5) q3 weeks for 6 cycles (Kampan et al., 2015). Approximately 60% of ovarian cancer patients will respond to initial treatment with combined paclitaxel-carboplatin, yet the median progression-free survival (PFS) is only 15 months (Kampan et al., 2015). The efficacy of platinum regimens is dependent on the treatment-free interval. Patients develop greater platinum resistance, and therefore lower response rates (RR), with shorter intervals between primary therapy and recurrence (Kampan et al., 2015).\n\nThe field of targeted therapies for the treatment of EOC has grown significantly in the last ten years. Anti-angiogenic agents are a large part of this expanding field, with bevacizumab being the most well studied.\n\nThe human epidermal growth factor receptor-2 gene (HER-2/ERBB2) represents another possible target for ovarian cancer based on its successful use in other malignancies. It encodes tyrosine kinase and is member of the ERBB receptor family. Dimerization of HER-2 and any of the ERBB receptors activates a series of signal transduction pathways involved in cellular proliferation, differentiation, and migration (Yan et al., 2014). Due to the nature of this receptor, protein overexpression, gene amplification, and gene mutations induce rapid tumor growth (Yan et al., 2014).\n\nHER-2 aberrations are common to many tumor types including breast, colon, endometrium, and lung. Observed frequency of HER-2 positivity in ovarian cancer varies with a range of 1.8–76% (Serrano-Olvera et al., 2006). Review of molecular tumor data from GOG-111 and GOG-9404 showed HER-2 overexpression in approximately 7% of EOC cases (Farley et al., 2009) and as high as 12% in serous histologies (Farley et al., 2009). In these clinical study populations, regardless of copy number, ERBB2 amplification was not correlated with tumor stage, tumor histology, overall survival (OS), or sensitivity to platinum-based chemotherapy (Farley et al., 2009).\n\nHER-2 overexpressing tumors are targetable using a variety of anti-ERBB2 drugs which are currently approved for breast, stomach, and lung cancers. Non-small cell lung cancer (NSCLC) is now treatable using afatinib. This ATP-competitive, aniline-quinazoline derivative binds and irreversibly inhibits signaling from EGFR, HER-2, and HER-4. Downregulating HER-2 and EGFR phosphorylation inhibits downstream signaling cascades and induces anti-proliferative effects through cell cycle G1 arrest and apoptotic cell death. Afatinib is approved as monotherapy for treatment of locally advanced or metastatic NSCLC having non-resistant EGFR mutations (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf, n.d.). As shown in the LUX-LUNG 3 trial, continuous daily dosing of afatinib, at 40–50 mg/day in the aforementioned NSCLC patient groups with EGFR mutation-positive Del19, was found to significantly increase RR and PFS in comparison to the standard six cycle cisplatin-pemetrexed chemotherapy regimen (Sequist et al., 2013).\n\nWith the impressive efficacy of HER-2 targeting therapies in breast, gastric, and lung cancers, attempts are being made to achieve similar efficacy for ovarian cancer. Trastuzumab, a HER-2 monoclonal antibody that binds the extracellular domain of EGFR, showed success in the treatment of HER-2 positive breast cancer. Due to its efficacy, the Gynecologic Oncology Group initiated a phase II trial of single agent trastuzumab for patients with recurrent or refractory ovarian carcinoma. Unfortunately, the low response rate of 7.3% limits the utility of this agent as a monotherapy (Bookman et al., 2003). Similarly, pertuzumab, another HER-2 antibody used in the treatment of breast cancers, was found to significantly increase RR and PFS when combined with gemcitabine in platinum-resistant ovarian cancers (Makhija et al., 2010).\n\nThe effectiveness of afatinib likely depends on a number of different clinical and molecular factors that have yet to be identified. As an example, the Carvajal-Hausdorf study identified cases of HER2 amplification showing differing levels of intracellular (ICD) and extracellular domains (ECD) (Carvajal-Hausdorf et al., 2017). Because HER2 targeted agents are directed against the HER2 ICD or ECD, these findings suggest that targeted HER2 agents may need to be tailored to the specific domain levels present.\n\nFor the patient in this case, afatinib was chosen as treatment due to the presence of an activating mutation in HER2. This use is an extrapolation of the results from the LUX-Lung trial in NSCLC. We have presented this case to demonstrate anecdotal effectiveness of targeting HER2/neu activation in patients with ovarian cancer and a HER2 activating tumor mutation.\n\n3 Conclusion\nCommercially available genomic sequencing can be used to guide individual treatment plans for primary or recurrent malignancies and should be based on the activating mutations present in the tumor. Her2/neu mutations are an effective target in lung cancers and afatinib is an effective targeting agent. Larger clinical trials are needed to assess the effectiveness of afatinib in ovarian cancer patients and to identify the specific sub-populations in which it may be most effective. Due to the rarity of this mutation in ovarian cancer, this may require a basket trial study that would assess use of afatinib or other HER2 targeting small molecule inhibitors in tumor types with activating HER2 mutation.\n\nDeclaration of Competing Interests\nDr. Amanda Shepherd-Littlejohn, Wyatt Hanft, Dr. Vanessa Kennedy, and Dr. Edwin Alvarez have no financial or personal conflicts of interest in producing this manuscript. Dr. Shepherd-Littlejohn, Wyatt Hanft, Dr. Kennedy, and Dr. Alvarez have nothing to disclose.\n\nAuthor contributions\nWyatt Hanft, MPH, conceived the idea, collected patient data, and wrote the first draft of the paper.\n\nDr. Amanda Shepherd-Littlejohn collected patient data, developed the discussion and contribution section of the paper, and edited the paper after the first draft. Dr. Shepherd-Littlejohn is also responsible for submission and is the corresponding author.\n\nDr. Vanessa Kennedy and Dr. Edwin Alvarez conceived the idea, were the final editors of the paper, and acted as mentors during the production of the manuscript.\n==== Refs\nReferences\nBookman M.A. Evaluation of monoclonal humanized anti-HER2 antibody, Trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group J. Clin. Oncol. 21 2 2003 283 290 12525520 \nCarvajal-Hausdorf D.E. Objective, domain-specific HER2 measurement in uterine and ovarian serous carcinomas and its clinical significance Gynecol. Oncol. 145 1 2017 154 158 28196634 \nFarley J. Associations between ERBB2 amplification and progression-free survival and overall survival in advanced stage, suboptimally-resected epithelial ovarian cancers: a Gynecologic Oncology Group Study Gynecol. Oncol. 113 3 2009 341 347 19272639 \nhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf \nKampan N.C. Paclitaxel and its evolving role in the Management of Ovarian Cancer Biomed. Res. Int. 2015 413076 \nLa Vecchia C. Ovarian cancer: epidemiology and risk factors Eur. J. Cancer Prev. 26 1 2017 55 62 26731563 \nMakhija S. Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer J. Clin. Oncol. 28 7 2010 1215 1223 19901115 \nSequist L.V. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations J. Clin. Oncol. 31 27 2013 3327 3334 23816960 \nSerrano-Olvera A. Prognostic, predictive and therapeutic implications of HER2 in invasive epithelial ovarian cancer Cancer Treat. Rev. 32 3 2006 180 190 16483720 \nYan M. HER2 aberrations in cancer: implications for therapy Cancer Treat. Rev. 40 6 2014 770 780 24656976\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-5789",
"issue": "29()",
"journal": "Gynecologic oncology reports",
"keywords": "Afatinib; ERBB2; HER2/neu; Molecular tumor testing; Ovarian cancer; Targeting agents",
"medline_ta": "Gynecol Oncol Rep",
"mesh_terms": null,
"nlm_unique_id": "101652231",
"other_id": null,
"pages": "70-72",
"pmc": null,
"pmid": "31360743",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports",
"references": "12525520;16483720;19272639;19901115;23816960;24656976;26137480;26731563;28196634",
"title": "Afatinib use in recurrent epithelial ovarian carcinoma.",
"title_normalized": "afatinib use in recurrent epithelial ovarian carcinoma"
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"abstract": "Alveolar echinococcosis is a rare but life-threatening infection caused by the parasite Echinococcus multilocularis. Its natural history is characterized by a slow parasitic growth over several years. Increased incidence and shorter development delay have been reported in immune-compromised patients. We report the reactivation of aborted lesions within 12 months of lung transplantation leading to a fast-growing aggressive hepatic lesion. Timely identification of alveolar echninococcosis allowed prompt albendazole treatment and radical surgery leading to a favorable outcome 42 months after transplantation. However, close clinical, serological and radiological monitoring is required to rule out relapses in the long term. The pre-existence of aborted self-limited lesions of alveolar echinococcosis and the possibility for their atypical rapid growth in patients undergoing profound immunosuppression should be known by healthcare providers, even if working in non-endemic areas.",
"affiliations": "Service de Pneumologie, Hôpital Louis Pradel, Hospices Civils de Lyon, 69500 Bron, France.;Unité de Sérologies Parasitaires et Fongiques, Laboratoire de Biologie Médicale, Centre Hospitalier Régional Universitaire, 25000 Besançon, France.;Service de Chirurgie Digestive et de Transplantation Hépatique, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69317 Lyon, France.;Service de Radiologie, Hôpital Edouard Herriot, Hospices Civils de Lyon, 69003 Lyon, France.;Institut des Agents Infectieux, Parasitologie Mycologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69317 Lyon, France.;Institut des Agents Infectieux, Parasitologie Mycologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69317 Lyon, France.;Service de Pneumologie, Hôpital Louis Pradel, Hospices Civils de Lyon, 69500 Bron, France.;Service de Pneumologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, 69317 Lyon, France.;Institut des Agents Infectieux, Parasitologie Mycologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69317 Lyon, France.",
"authors": "Dupont|Clarisse|C|;Grenouillet|Fréderic|F|0000-0001-6001-3135;Mabrut|Jean-Yves|JY|;Gay|Frédérique|F|;Persat|Florence|F|;Wallon|Martine|M|;Mornex|Jean-François|JF|;Philit|François|F|;Dupont|Damien|D|0000-0002-6992-1073",
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"doi": "10.3390/pathogens9090756",
"fulltext": "\n==== Front\nPathogens\nPathogens\npathogens\nPathogens\n2076-0817 MDPI \n\n10.3390/pathogens9090756\npathogens-09-00756\nCase Report\nFast-Growing Alveolar Echinococcosis Following Lung Transplantation\nDupont Clarisse 1 https://orcid.org/0000-0001-6001-3135Grenouillet Fréderic 23 Mabrut Jean-Yves 45 Gay Frédérique 6 Persat Florence 7 Wallon Martine 78 Mornex Jean-François 19 Philit François 10 https://orcid.org/0000-0002-6992-1073Dupont Damien 78* 1 Service de Pneumologie, Hôpital Louis Pradel, Hospices Civils de Lyon, 69500 Bron, France; clarisse.dupont@chu-lyon.fr (C.D.); jean-francois.mornex@chu-lyon.fr (J.-F.M.)\n2 Unité de Sérologies Parasitaires et Fongiques, Laboratoire de Biologie Médicale, Centre Hospitalier Régional Universitaire, 25000 Besançon, France; fgrenouillet@chu-besancon.fr\n3 UMR6249 CNRS-UBFC Chrono-Environnement, Université de Bourgogne-Franche-Comté, 25000 Besançon, France\n4 Service de Chirurgie Digestive et de Transplantation Hépatique, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69317 Lyon, France; jean-yves.mabrut@chu-lyon.fr\n5 Inserm, CRCL UMR1052, Université de Lyon, Université Lyon 1, 69373 Lyon, France\n6 Service de Radiologie, Hôpital Edouard Herriot, Hospices Civils de Lyon, 69003 Lyon, France; frederique.gay@chu-lyon.fr\n7 Institut des Agents Infectieux, Parasitologie Mycologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69317 Lyon, France; florence.persat@chu-lyon.fr (F.P.); martine.wallon@chu-lyon.fr (M.W.)\n8 Physiologie Intégrée du Système D’éveil, Centre de Recherche en Neurosciences de Lyon, INSERM U1028-CNRS UMR 5292, Centre Hospitalier Le Vinatier, Université de Lyon, Université Lyon 1, 69675 Bron, France\n9 INRAE, IVPC, UMR754, Université de Lyon, Université Lyon 1, 69007 Lyon, France\n10 Service de Pneumologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, 69317 Lyon, France; francois.philit@chu-lyon.fr\n* Correspondence: damien.dupont@chu-lyon.fr; Tel.: +33-4-72-00-15-20; Fax: +33-4-72-07-18-73\n16 9 2020 \n9 2020 \n9 9 75614 8 2020 14 9 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Alveolar echinococcosis is a rare but life-threatening infection caused by the parasite Echinococcus multilocularis. Its natural history is characterized by a slow parasitic growth over several years. Increased incidence and shorter development delay have been reported in immune-compromised patients. We report the reactivation of aborted lesions within 12 months of lung transplantation leading to a fast-growing aggressive hepatic lesion. Timely identification of alveolar echninococcosis allowed prompt albendazole treatment and radical surgery leading to a favorable outcome 42 months after transplantation. However, close clinical, serological and radiological monitoring is required to rule out relapses in the long term. The pre-existence of aborted self-limited lesions of alveolar echinococcosis and the possibility for their atypical rapid growth in patients undergoing profound immunosuppression should be known by healthcare providers, even if working in non-endemic areas.\n\nEchinococcus multilocularisparasiteliverlung transplantationimmunosuppression\n==== Body\n1. Introduction\nAlveolar echinococcosis (AE) is a rare but potentially life-threatening infection due to the accidental ingestion of the egg of the parasite Echinococcus multilocularis. It is encountered only in the northern hemisphere [1]. The natural history of infection in humans potentially follows three different scenarios depending on the immune status of the patient that has ingested E. multilocularis eggs: (i) seroconversion proving infection, either without associated liver damage (failure of parasite development) or presenting with a calcified lesion (aborted lesion) (ii) conventional AE in patients for whom the immune system partially controls the development of the parasite’s larva (metacestode), which will present clinical signs five to 15 years after infestation and (iii) uncontrolled hyperproliferation of the metacestode in immunodeficient patients [2]. An increased incidence of AE in immunosuppressed patients has been reported over the past decade, first in France then in Switzerland, where immunocompromised patients accounted, respectively, for 18% and 31% of newly-diagnosed AE cases [3,4,5]. Physicians are now confronted with this epidemiological shift and must now consider the risk of developing EA during an immunosuppressive regimen/pathology, either by de novo contamination or by reactivation of a preexisting lesion that has gone undetected [3,5]. Thus, small calcified lesions which were considered as aborted might represent a potential threat in this context, as they could play the role of a Trojan horse, leading to rapid metacestode proliferation.\n\n2. Case\nWe report an exceptionally fast growing and aggressive AE in a 41-year old Caucasian female veterinarian who underwent a right lung transplantation (LT) for pulmonary fibrosis. In addition to tacrolimus, mycophenolate and prednisolone started immediately post-transplantation, basiliximab—an interleukin 2 receptor antagonist—was required two months post-transplantation for persistent acute cellular rejection treated with intravenous methylprednisolone since one month post-transplantation. Ten months after transplantation, irregular hepatomegaly was detected associated with persisting pain in the right hypochondrium. An abdominal scan performed twelve months after transplantation revealed a 44 mm lesion in the hepatic segment IV with satellite nodules and necrotic adenomegaly suggesting cholangiocarcinoma (Figure 1).\n\nFortunately, a radiologist, experienced with alveolar echinococcosis, reoriented the diagnosis, based on the heterogeneous aspect of the lesion on the magnetic resonance imaging (MRI) and peripheral contrast and inflammatory perilesional variation and particularly multiple peripheral infracentrimetrical vesicles seen on axial T2-weighted MRI (Figure 1). A Positron Emission Tomography-Computed Tomography (PET/CT) scan confirmed the existence of a 45 mm by 35 mm hepatic lesion with a central hypodense region and a strong peripheral hypermetabolic rim (Standardized uptake values (SUV) max 5.3), persisting at 3 h (SUV max 7.7) and the absence of other associated lesions. Microscopic examination of a liver biopsy fragment showed necrosis and the presence of typical periodic acid-Schiff (PAS) positive thin lamellar layer. Blood tests with Em2+ and Em18 enzyme-linked immunosorbent assay (ELISA) (Bordier, Affinity Products, Crissier, Switzerland) gave positive results. Immunoblotting (Echinococcosis Western blot kit, LDBIO Diagnostics, Lyon, France) was also positive and supported the diagnosis of AE, showing the presence of 7-16-18-26/28 bands, characteristic pattern of E. multilocularis infection.\n\nTreatment by albendazole (400 mg bid orally) was immediately initiated. Hepatectomy and right adrenalectomy were performed 15 months post-transplantation with free resection margins. Pathological examination confirmed the diagnosis of AE [6], showing an unequivocal pseudotumoral lesion with numerous small vesicles and ill-defined borders, multiple areas of necrosis and granuloma surrounding slender parasitic PAS-positive layers [7]. At the last examination 42 months after transplantation, the patient was asymptomatic with unremarkable clinical examination and imaging (including 3 h 18-FDG post-injection PET/CT) and undetectable (Em2+) or weak and declining (Em18) serology levels.\n\nOral albendazole was uninterrupted since diagnosis. Regular monitoring of albendazole sulfoxide plasma levels allowed to reduce the daily posology to 200 mg bid in order to maintain concentrations within the target range (values ranging from 2.30 to 3.30 µmol/L). It was well-tolerated and not interacting with the immunosuppressive regimen.\n\nThe fast development of the parasitic lesion in our patient was confirmed by the retrospective Echinococcus serology of a serum sampled at the time of transplantation. It was found to be negative for first line tests (ELISA, Indirect Hemagglutination Assay) but immunoblotting showed the presence of a weak seven-band, compatible with aborted, self-limited alveolar echinococcosis. In support to this hypothesis, reexamination of abdominal computed tomography scans two months after transplantation revealed the presence of a small low density nodule within the liver, associated with a small central calcification (Figure 2).\n\nThe patient lives in a rural part of the French Massif Central region (France), a historic endemic zone for alveolar echinococcosis [8,9]. Direct interrogation at the time of diagnosis found exposure to several risk factors for AE prior to her transplantation and thereafter [10]: ownership of two dogs and four cats that were dewormed regularly but were free to roam outdoors and hunt unattended including in her unfenced garden visited by foxes; living in a house close to fields; vocational activities in the forest and growing leaf and root vegetables. She worked as a veterinarian for pets prior to transplantation but did not resume work before seven months post transplantation. She reported washing produces from her garden and good hand hygiene after handling and playing with dogs and cats. Alveolar echinococcosis has become less frequent in the Massif Central over the last two decades; therefore, this particular parasitic etiology was not at the forefront during differential diagnosis.\n\n3. Discussion\nHuman alveolar echinococcosis is characterized by the slow growth of lesions under normal circumstances, and clinical signs in immunocompetent hosts are usually not detected before five to 15 years post infection [11]. Increased susceptibility and shorter development times, averaging four years, have been reported in patients presenting with a variety of immunosuppressive conditions including solid cancer, chronic inflammatory disease, malignant hematological disorder, solid organ transplantation and AIDS [3]. Cases of fast growing lesions (less than three to four years) were published in kidney or heart transplant recipients [12,13], but there have been none so far in the context of lung transplantation, and of pre-existing presumptive aborted lesions. Aborted lesion is defined by the presence of a non-viable parasitic structure as evidenced by imaging, revealing a completely calcified lesion [2,14]. However, obtaining parasitological evidence of a non-viable and “dead” lesion is almost impossible for ethical reasons. Spontaneous death of the parasite in the aborted lesion is therefore presumed, but impossible to actually prove [10]. The profound immunosuppression required after lung transplantation and the drugs administered one month post transplantation to avoid acute cellular rejection, probably favored in our patient the rapid and aggressive reactivation of the aborted lesions, retrospectively found to be present two months post transplantation. The natural history of AE is the consequence of a balance between the growth of the metacestode and the host’s response, which depends on the genetic background of the host as well as on acquired disturbances of the Th1-related immune response. Th1-oriented immune response induces protective immunity, leading eventually to self-limited lesion. The laminated layer plays a major role in the induction of tolerance, driven by the Th2 response and anti-inflammatory cytokines, especially IL-10 and TGF-β [2,15]. Our patient received several immunosuppressive treatments that significantly impact on the Th1/Th2 balance and thus the host–parasite interaction, mainly tacrolimus—a calcineurin inhibitor known to inhibit the T-cell response and decrease the Th1/Th2 ratio—and basiliximab. A small lesion with central calcification, as observed in our patient, fits with the description of CT type IV lesion using Echinococcus multilocularis classification for computed tomography (EMUC-CT) [16]. Some authors hypothesize that this stage corresponds to the initial phase of the infection, with a strong immune response around the lesion to contain the infection, leading to the persistence of a self-limited dormant infection. Subsequently, this stage can evolve either towards an active infection (EMUC stage I to III) or involute, with necrosis and/or increased calcification [16,17]. They can have different aspects but usually include one or several small size calcifications. Active AE imaging patterns vary from small cystoid lesions to primarily circumscribed tumor-like or diffuse infiltrating lesions with various degrees of calcifications observed using a CT-scan. The pathognomonic honeycomb-like AE microcysts were shown using T2 weighted MRI [10,16]. The FDG–PET/CT often shows increased uptake of FDG surrounding AE lesions, higher than in other areas (as in our patient), and has thus become the preferred reference tool for assessing their metabolic activity [1,10]. These characteristic images, as well as the telltale signs of an active infection, and the possibility for both to exhibit atypical rapid growth in solid organ transplant should be known by healthcare providers [18], even if working in non-endemic areas. Interrogation is important to elicit recent or past long term residence in areas of parasite transmission and work- or life style-related risk factors. The worldwide extension of areas of active transmission and the possible resurgence in historic foci, should lead to an increased awareness, and to listing AE among the etiologies for liver lesions in national guidelines regarding transplantation and other contexts involving immunosuppression, wherever epidemiologically relevant.\n\nNot dismissing the existence of an alveolar echinococcosis is all the more important because it is a differential diagnosis of cholangiocarcinoma, or metastasis of cancer with the primary site being the liver. Chemotherapy that would have been prescribed for cancer etiologies, would facilitate parasitic invasion or reactivation.\n\nSearching for self-limited alveolar echinococcosis, or confirming active lesions in immunocompromised patients, requires both radiological and serological expertise. Serological work-up should systematically include immunoblotting in such patients to maximize sensitivity, since first line tests may be falsely negative in such context [1,3,19]. In immunocompromised patients, first-line techniques (ELISA) have significantly lowered sensitivity and Em-immunoblotting appears as the most sensitive test to diagnose AE [19]. Similarly, a recent review on laboratory-based approaches for AE diagnosis proposed the implementation of immunoblotting as a second line test in a patient with a compatible lesion shown by imaging techniques, but with negative serology using first-line ELISA [20]. This review also highlights the interest of histological examination and/or molecular techniques on liver biopsy, particularly in the same group of patients (negative serology but lesion shown with MRI/CT or ultrasonography). Even if liver biopsy is not recommended as a first line approach, fine-needle biopsy is a minimally invasive and effective diagnostic to confirm hepatic AE [6,21]. Moreover, liver biopsy is not associated with major complications in AE patients. Histological examination of tissue, showing characteristic PAS-positive metacestode layer allows for the diagnosis of AE, even if differential diagnosis with cystic echinococcosis is sometimes difficult. Thus, it should require the implementation of an immunohistochemistry assay using mAb Em2G11 staining [7,22].\n\nAE diagnosed in the context of immunosuppression has a poor prognosis overall [3]. In the case of our patient, both timely parasitostatic treatment and rapid radical surgery were decisive.\n\nClose clinical, serological and radiological post-intervention follow-up will remain essential; even after the end of treatment planned for two years post-alveolar echinococcosis surgery at the earliest [6], or until the serology becomes negative. It is even the more important in the case of our patient as she opted to continue to work as a veterinarian, providing care for mainly house pets, in an endemic alveolar echinococcosis area.\n\nClinicians attending to immunosuppressed patients living in endemic areas should not only be aware of the need to search for preexisting lesions, but also help prevent new cases of infections. Information should more specifically target dog owners [10] and could be relayed by veterinarians and pet groomers, with the support of educational flyers or posters addressing the need for regular deworming, for preventing roaming and for good hand hygiene after any contact.\n\nAcknowledgments\nWe thank Michelle Grange for language editing the manuscript.\n\nAuthor Contributions\nAll authors contributed to the manuscript conception and design. C.D., F.P. (François Philit), J.-F.M. and J.-Y.M. took care of the patient. Data collection and analysis were performed by M.W., D.D., F.P. (Florence Persat), F.G. (Fréderic Grenouillet) and F.G. (Frédérique Gay). The first draft of the manuscript was written by C.D., D.D. and M.W. and all authors commented on further versions of the manuscript. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nMornex JF reports grants, personal fees and non-financial support from CSL Behring, grants, personal fees and non-financial support from LFB Biomedicaments, personal fees and non-financial support from Actelion, personal fees from Roche, Boehringer, Ingelheim, GlaxoSmithKline, Novartis, Chiesi, Elivie, outside the submitted work. Grenouillet F, Mabrut JY, Wallon M, Persat F, Philit F, Gay F, Dupont C and Dupont D have no conflict of interest to report.\n\nFigure 1 Radiological findings at diagnosis. (a) Abdominal gray-scale ultrasound showing a heterogeneous mass lesion in the right lobe of the liver (white arrows). The lesion is generally hyperechoic with a central linear hypoechoic suggesting liquid component. There are also small hyperechoic nodules surrounding this main lesion. (b) Axial T2 weighted image after fat suppression demonstrates a tumor like hepatic mass (arrow), heterogeneous with a thick irregular border and central liquid component. (c) Axial and coronal (d) T1-weighted images with fat suppression, obtained after injection of gadolinium-based contrast agent showing a large heterogeneous tumor like mass in the liver (star), with intense peripheral enhancement and inflammation of adjacent liver. There are also satellite small hypointense vesicles with moderate peripheral contrast enhancement (arrows).\n\nFigure 2 Calcified lesion in the liver two months after transplantation: Axial unenhanced CT showing a small low-density nodule within the liver and the development of a small central calcification within the lesion (arrow).\n==== Refs\nReferences\n1. Wen H. Vuitton L. Tuxun T. Li J. Vuitton D.A. Zhang W. McManus D.P. Echinococcosis: Advances in the 21st Century Clin. Microbiol. Rev. 2019 32 e00075-18 10.1128/CMR.00075-18 30760475 \n2. Gottstein B. Wang J. Boubaker G. Marinova I. Spiliotis M. Müller N. Hemphill A. Susceptibility versus resistance in alveolar echinococcosis (larval infection with Echinococcus multilocularis) Veter Parasitol. 2015 213 103 109 10.1016/j.vetpar.2015.07.029 \n3. Chauchet A. Grenouillet F. Knapp J. Richou C. Delabrousse E. Dentan C. Millon L. Di Martino V. Contreras R. Deconinck E. Increased Incidence and Characteristics of Alveolar Echinococcosis in Patients With Immunosuppression-Associated Conditions Clin. Infect. Dis. 2014 59 1095 1104 10.1093/cid/ciu520 25034426 \n4. Geyer M. Wilpert J. Wiech T. Theilacker C. Stubanus M. Kramer-Zucker A. Fischer K.-G. Drognitz O. Frydrychowicz A. Kern W. Rapidly progressive hepatic alveolar echinococcosis in an ABO-incompatible renal transplant recipient Transpl. Infect. Dis. 2010 13 278 284 10.1111/j.1399-3062.2010.00583.x 20977568 \n5. Lachenmayer A. Gebbers D. Gottstein B. Candinas D. Beldi G. Elevated incidence of alveolar echinococcosis in immunocompromised patients Food Waterborne Parasitol. 2019 16 e00060 10.1016/j.fawpar.2019.e00060 32095630 \n6. Brunetti E. Kern P. Vuitton D.A. Writing Panel for the WHO-IWGE Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans Acta Trop. 2010 114 1 16 10.1016/j.actatropica.2009.11.001 19931502 \n7. Barth T. Herrmann T.S. Tappe D. Stark L. Grüner B. Buttenschoen K. Hillenbrand A. Juchems M. Henne-Bruns R. Kern P. Sensitive and Specific Immunohistochemical Diagnosis of Human Alveolar Echinococcosis with the Monoclonal Antibody Em2G11 PLoS Negl. Trop. Dis. 2012 6 e1877 10.1371/journal.pntd.0001877 23145198 \n8. Rapport Annuel D’activité Available online: https://cnr-echinococcoses-ccoms.univ-fcomte.fr/IMG/pdf/rapport_activite_cnr-e_2018-.pdf (accessed on 15 May 2020) \n9. Said-Ali Z. Grenouillet F. Knapp J. Bresson-Hadni S. Vuitton D.A. Raoul F. Richou C. Millon L. Giraudoux P. Francechino Network Detecting nested clusters of human alveolar echinococcosis Parasitology 2013 140 1693 1700 10.1017/S0031182013001352 23962413 \n10. Kern P. da Silva A.M. Akhan O. Müllhaupt B. Vizcaychipi K.A. Budke C. Vuitton D.A. The Echinococcoses: Diagnosis, Clinical Management and Burden of Disease Adv. Parasitol. 2017 96 259 369 10.1016/bs.apar.2016.09.006 28212790 \n11. Ammann R.W. Eckert J. Cestodes: Echinococcus Gastroenterol. Clin. N. Am. 1996 25 655 689 10.1016/S0889-8553(05)70268-5 \n12. Gaultier J.-B. Hot A. Mauservey C. Dumortier J. Coppéré B. Ninet J. Granulomatous liver disease as the presenting feature of alveolar echinococcosis in an hepatitis C infected cardiac transplant patient Rev. Med. Interne 2009 30 812 815 10.1016/j.revmed.2008.11.007 19193475 \n13. Gadby F. Quaesaet L. Eveilleau C. Payet-Charneau A. Couturaud F. Tromeur C. Pulmonary granuloma in an immunodepressed patient Rev. Mal. Respir. 2018 35 74 77 10.1016/j.rmr.2017.01.008 29395568 \n14. Vuitton D.A. McManus D.P. Rogan M. Romig T. Gottstein B. Naidich A. Tuxun T. Wen H. Da Silva A.M. The World Association of Echinococcosis International consensus on terminology to be used in the field of echinococcoses Parasite 2020 27 41 10.1051/parasite/2020024 32500855 \n15. Vuitton D.A. Gottstein B. Echinococcus multilocularisand Its Intermediate Host: A Model of Parasite-Host Interplay J. Biomed. Biotechnol. 2010 2010 923193 10.1155/2010/923193 20339517 \n16. Graeter T. Kratzer W. Oeztuerk S. Haenle M.M. Mason R.A. Hillenbrand A. Kull T. Barth T.F. Kern P. Gruener B. Proposal of a computed tomography classification for hepatic alveolar echinococcosis World J. Gastroenterol. 2016 22 3621 3631 10.3748/wjg.v22.i13.3621 27053854 \n17. Grimm J. Beck A. Nell J. Schmidberger J. Hillenbrand A. Beer A.J. Dezsényi B. Shi R. Beer M. Kern P. Combining Computed Tomography and Histology Leads to an Evolutionary Concept of Hepatic Alveolar Echinococcosis Pathogens 2020 9 634 10.3390/pathogens9080634 32759781 \n18. Dražilová S. Kinčeková J. Bena L. Zachar M. Švajdler M. Zavacký P. Jarcuska P. Alveolar echinococcosis in patient after cadaveric kidney transplantation Helminthologia 2011 48 229 10.2478/s11687-011-0032-4 \n19. Gottstein B. Lachenmayer A. Beldi G. Wang J. Merkle B. Vu X.L. Kurath U. Müller N. Diagnostic and follow-up performance of serological tests for different forms/courses of alveolar echinococcosis Food Waterborne Parasitol. 2019 16 e00055 10.1016/j.fawpar.2019.e00055 32095626 \n20. Siles-Lucas M. Casulli A. Conraths F.J. Müller N. Laboratory Diagnosis of Echinococcus spp. in Human Patients and Infected Animals Adv. Parasitol. 2017 96 159 257 10.1016/bs.apar.2016.09.003 28212789 \n21. Bulakci M. Ilhan M. Bademler S. Yilmaz E. Gulluoglu M. Bayraktar A. Asik M. Guloglu R. Efficacy of ultrasound-guided core-needle biopsy in the diagnosis of hepatic alveolar echinococcosis: A retrospective analysis Parasite 2016 23 19 10.1051/parasite/2016019 27101838 \n22. Reinehr M. Micheloud C. Grimm F. Kronenberg P.A. Grimm J. Beck A. Nell J. Meyer Zu Schwabedissen C. Furrer E. Müllhaupt B. Pathology of Echinococcosis: A Morphologic and Immunohistochemical Study on 138 Specimens With Focus on the Differential Diagnosis Between Cystic and Alveolar Echinococcosis Am. J. Surg. Pathol. 2020 44 43 54 10.1097/PAS.0000000000001374 31567204\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2076-0817",
"issue": "9(9)",
"journal": "Pathogens (Basel, Switzerland)",
"keywords": "Echinococcus multilocularis; immunosuppression; liver; lung transplantation; parasite",
"medline_ta": "Pathogens",
"mesh_terms": null,
"nlm_unique_id": "101596317",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32948027",
"pubdate": "2020-09-16",
"publication_types": "D002363:Case Reports",
"references": "23145198;31567204;27053854;32759781;26260407;20339517;19931502;23962413;32095626;19193475;25034426;30760475;27101838;28212789;29395568;32095630;8863045;20977568;32500855;28212790",
"title": "Fast-Growing Alveolar Echinococcosis Following Lung Transplantation.",
"title_normalized": "fast growing alveolar echinococcosis following lung transplantation"
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"abstract": "OBJECTIVE\nMycobacterium abscessus, and rapidly growing mycobacteria in general, are rare but increasing causes of central nervous system (CNS) infections. The aim of this study is to highlight the importance of considering these microorganism in the differential diagnosis of CNS infections, obtaining a prompt diagnosis, and improving clinical outcomes.\n\n\nMETHODS\nCase report and literature review.\n\n\nRESULTS\nWe report a case of meningeal infection in a patient who underwent decompressive craniectomy after a craniofacial trauma. The diagnosis was made analyzing a sample obtained during a second operation of cranioplasty. A regimen of amikacin, clarithromycin, and imipenem/cilastatin was started. In the following days, the patient experienced a variety of side effects. So, first clarithromycin was replaced with linezolid, then amikacin was stopped and cefoxitin added to the therapy and at the end all the antibiotics were withdrawn. The patient was discharged in good conditions and a clinical interdisciplinary follow-up was started. After 12 months, the patient is still doing well. After a literature analysis, 15 cases of M. abscessus CNS infections were identified. Various modes of acquisition, underlying disease and therapeutic schemes were evident.\n\n\nCONCLUSIONS\nConsidering the results of the literature analysis and the increasing incidence of M. abscessus, all specialists involved in the management of CNS infection should be aware of the importance of atypical microorganisms in differential diagnosis.",
"affiliations": "Department of Infectious Diseases, Catholic University of Rome, Rome, Italy.;Department of Neurosurgery, Catholic University of Rome, Largo A. Gemelli 8, 00168, Rome, Italy. stifano89@gmail.com.;Department of Infectious Diseases, Catholic University of Rome, Rome, Italy.;Department of Infectious Diseases, Catholic University of Rome, Rome, Italy.;Department of Infectious Diseases, Catholic University of Rome, Rome, Italy.;Department of Microbiology, Catholic University of Rome, Rome, Italy.;Department of Microbiology, Catholic University of Rome, Rome, Italy.;Department of Neurosurgery, Catholic University of Rome, Largo A. Gemelli 8, 00168, Rome, Italy.;Department of Neurosurgery, Catholic University of Rome, Largo A. Gemelli 8, 00168, Rome, Italy.;Department of Neurosurgery, Catholic University of Rome, Largo A. Gemelli 8, 00168, Rome, Italy.",
"authors": "Giovannenze|Francesca|F|;Stifano|Vito|V|http://orcid.org/0000-0002-5509-9592;Scoppettuolo|Giancarlo|G|;Damiano|Fernando|F|;Pallavicini|Federico|F|;Delogu|Giovanni|G|;Palucci|Ivana|I|;Rapisarda|Alessandro|A|;Sturdà|Cosimo|C|;Pompucci|Angelo|A|",
"chemical_list": "D001426:Bacterial Proteins; D018834:Chaperonin 60; C074119:heat-shock protein 65, Mycobacterium",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-018-1141-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "46(5)",
"journal": "Infection",
"keywords": "CNS infection; Meningeal infection; Mycobacterium abscessus complex",
"medline_ta": "Infection",
"mesh_terms": "D001426:Bacterial Proteins; D018834:Chaperonin 60; D015600:Glasgow Coma Scale; D020199:Hematoma, Subdural, Acute; D006801:Humans; D033162:Incidental Findings; D007432:Intraoperative Period; D008297:Male; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D000073358:Mycobacterium abscessus; D016133:Polymerase Chain Reaction; D014057:Tomography, X-Ray Computed; D014390:Tuberculosis, Meningeal",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "591-597",
"pmc": null,
"pmid": "29687315",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "10414479;8381805;18501854;26148928;11486298;26491178;17277290;26546993;27079354;28084211;1922723;15762284;15472442;25144796;27690688;21980068;10331831;11274327",
"title": "Incidental intraoperative diagnosis of Mycobacterium abscessus meningeal infection: a case report and review of the literature.",
"title_normalized": "incidental intraoperative diagnosis of mycobacterium abscessus meningeal infection a case report and review of the literature"
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"companynumb": "IT-MYLANLABS-2018M1083652",
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{
"abstract": "Ureaplasma urealyticum is a commensal of the female genital tract and can be detected as a pathogen in urethritis and vaginitis. Its importance as a respiratory pathogen beyond the field of neonatology remains controversial. We report a case of Ureaplasma-pneumonia in a recently lung-transplanted patient, with hyperammonemic syndrome. The 51-year-old lung-transplanted female was admitted to the intensive care unit with new-onset reduction of her mental state due to hyperammonemia. A diagnostic bronchoscopy showed purulent bronchitis and multiple superficial ulcerations of the bronchial mucosa. The DNA-PCR from bronchoalveolar lavage confirmed the presence of Ureaplasma urealyticum in low concentration (about 5 * 104 copies/ml), which was interpreted as evidence of infection and treated with Doxycycline intravenously. Ureaplasma was also identified by DNA-PCR in the biopsy specimens of the inflammatory enlarged mediastinal lymph nodes. Bilateral pleural effusions were found to be transudative and culturally sterile. Ureaplasma-pneumonia can cause fatal hyperammonemia in lung-transplant patients and should be considered in the differential diagnosis of every unclear hyperammonemia with normal liver function. The early identification and treatment of the infection leads to clinical and biochemical resolution.",
"affiliations": "Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistr.52, D-20246, Hamburg, Germany.;University Heart & Vascular Center Hamburg, Department of Cardiovascular Surgery, University Medical Center Hamburg-Eppendorf, Martinistr.52, D-20246, Hamburg, Germany.;Department of Internal Medicine, Gastroenterology, Infectiology and Tropical Diseases, University Medical Center Hamburg-Eppendorf, Martinistr.52, D-20246, Hamburg, Germany.;Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistr.52, D-20246, Hamburg, Germany.;Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistr.52, D-20246, Hamburg, Germany.;Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistr.52, D-20246, Hamburg, Germany.",
"authors": "Paparoupa|Maria|M|;Barten|Markus Johannes|MJ|;de Heer|Jocelyn|J|;Giessen|Hanna Sophie|HS|;Frings|Daniel|D|;Kluge|Stefan|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101080",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(19)30339-9\n10.1016/j.rmcr.2020.101080\n101080\nCase Report\nHyperammonemia by Ureaplasma urealyticum Pneumonia after Lung Transplantation\nPaparoupa Maria m.paparoupa@uke.dea∗ Barten Markus Johannes b de Heer Jocelyn c Giessen Hanna Sophie a Frings Daniel a Kluge Stefan a a Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistr.52, D-20246, Hamburg, Germany\nb University Heart & Vascular Center Hamburg, Department of Cardiovascular Surgery, University Medical Center Hamburg-Eppendorf, Martinistr.52, D-20246, Hamburg, Germany\nc Department of Internal Medicine, Gastroenterology, Infectiology and Tropical Diseases, University Medical Center Hamburg-Eppendorf, Martinistr.52, D-20246, Hamburg, Germany\n∗ Corresponding author. m.paparoupa@uke.de\n06 5 2020 \n2020 \n06 5 2020 \n30 10108030 10 2019 5 5 2020 © 2020 The Authors. Published by Elsevier Ltd.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Ureaplasma urealyticum is a commensal of the female genital tract and can be detected as a pathogen in urethritis and vaginitis. Its importance as a respiratory pathogen beyond the field of neonatology remains controversial. We report a case of Ureaplasma-pneumonia in a recently lung-transplanted patient, with hyperammonemic syndrome.\n\nThe 51-year-old lung-transplanted female was admitted to the intensive care unit with new-onset reduction of her mental state due to hyperammonemia. A diagnostic bronchoscopy showed purulent bronchitis and multiple superficial ulcerations of the bronchial mucosa. The DNA-PCR from bronchoalveolar lavage confirmed the presence of Ureaplasma urealyticum in low concentration (about 5 * 104 copies/ml), which was interpreted as evidence of infection and treated with Doxycycline intravenously. Ureaplasma was also identified by DNA-PCR in the biopsy specimens of the inflammatory enlarged mediastinal lymph nodes. Bilateral pleural effusions were found to be transudative and culturally sterile.\n\nUreaplasma-pneumonia can cause fatal hyperammonemia in lung-transplant patients and should be considered in the differential diagnosis of every unclear hyperammonemia with normal liver function. The early identification and treatment of the infection leads to clinical and biochemical resolution.\n\nKeywords\nAtypical pneumoniaImmunosuppressionHyperammonemic syndrome\n==== Body\n1 Introduction\nInfections are a major cause of early and late mortality after Lung Transplantation (LT) and chemoprophylaxis is an important component in the prevention of post-LT infections. According to a monocentric epidemiological study by Ji Hyun Yun et al., the most common bacterial infection in the first post-transplant month is the catheter-associated bacteremia. Bacterial pneumonia occurs typically between the second and the sixth month, as well as six months after transplantation. Multi-bacterial infections and multidrug-resistant pathogens are significantly likely to be detected. Fungal infections of the lung have been observed six months after transplantation and the most common viral agent of pneumonia was cytomegalovirus (CMV). Atypical pathogens, such as mycoplasma, were detected rarely and occurred over six months of transplantation time [1].\n\nUreaplasma urealyticum, Ureaplasma parvum and Mycoplasma hominis are known as \"genital mycoplasmas\". Ureaplasma urealyticum can be detected as a causative agent of urethritis and vaginitis, Ureaplasma parvum is usually saprophytic and can rarely cause urethritis and Mycoplasma hominis is considered to be facultative pathogenic [2].\n\nUreaplasma species is considered to be a low virulence commensal of the female genital tract. The clinical significance of Ureaplasma infections remains unclear. Ureaplasma colonization has a confirmed etiological association with infertility, stillbirth, premature birth, histological chorioamnionitis, and neonatal morbidities, including congenital pneumonia, meningitis, bronchopulmonary dysplasia, and perinatal death [[3], [4], [5], [6]]. Recently, Ureaplasma was divided into 2 different biovars and 14 different serotypes. Ureaplasma parvum is known as Biovar 1 and concludes the serotypes 1, 3, 6 and 14 and Ureaplasma urealyticum is known as Biovar 2 and contains the serotypes 2, 4, 5 and 7–13. The virulence of the serotypes and biovars remains controversial [7].\n\nThe importance of Ureaplasma species as an agent of pulmonary pathogenicity in adults is still under discussion and further investigations are required before recommendations to guide clinical practice can be made. We report a rare case of Ureaplasma-pneumonia in a recently lung-transplanted patient, being diagnosed in the setting of hyperammonemia.\n\n2 Case presentation\nThe intensive care acquisition of the 51-year-old female followed after a new-onset alteration of her mental state. Two weeks earlier, the patient underwent a double lung transplantation, due to a secondary lung fibrosis by rheumatoid arthritis. The postoperative course was uneventful. Suddenly, the patient developed agitation and was disoriented to place, time and person. In the context of cerebrospinal fluid (CSF) diagnostics, bacterial and viral pathogens of the central nervous system were excluded and neurological evaluation suggested that metabolic encephalopathy could be the cause of her symptoms.\n\nAt the point of intensive care admission, the patient was hemodynamically and respiratory stable, but not meaningfully contactable. Because of progressive reduction of her mental state, endotracheal intubation and mechanical ventilation had to be initiated. An emergency computed tomography of the brain was performed in order to exclude ischemic brain injury or intracranial hemorrhage. Although Posterior Reversible Encephalopathy Syndrome (PRES) could be ruled out by magnetic resonance imaging (MRI), current immunosuppression with Tacrolimus (12ng/ml by submission) was discontinued. Laboratory parameters were uneventful, except of an isolated hyperammonemia (serum ammonia 387 mmol/l, normal range 26–47 mmol/l). As all liver function parameters were normal, we hypothesized that hyperammonemia was unlikely linked to a hepatic dysfunction and started a targeted search for urease-producing microorganisms.\n\nThe bronchoscopy showed a pronounced purulent bronchitis and multiple white-yellow non flushable mucosal lines, as well as superficial ulcerations with necrotic mucosa, especially in the area of anastomosis in both sides. DNA-PCR (DNA-Polymerase Chain Reaction) of the extracted bronchoalveolar lavage (BAL) was positive for Ureaplasma urealyticum in low concentration (5 * 104 copies/ml). Based on the overall clinical presentation of the patient and the severity of bronchoscopic findings, we evaluated this evidence as an Ureaplasma urealyticum-induced infection, and initiated an antibiotic treatment with doxycycline 200mg once a day intravenously. All blood cultures obtained prior to antibiotic therapy were sterile after 5 days of incubation. More interestingly, Ureaplasma could be detected by DNA-PCR in the biopsy specimens of the inflammatory enlarged mediastinal lymph nodes.\n\nSeveral cultures of the bronchoalveolar lavage were negative for conventional bacteria, as well as for slow growing bacteria (such as Legionella pneumophila), mycobacteria and fungi. Pneumocystis jurovecii, Toxoplasma gondii, Aspergillus spp., Mycoplasma pneumoniae, Chlamydia spp. and Bordetella pertussis were negative. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Varicella-Zoster Virus (VZV) and Herpes Simplex Virus (HSV) were excluded by PCR in blood and BAL. Multiplex PCR of BAL samples was negative for respiratory viruses.\n\nUnder continuous renal replacement treatment, serum ammonia was rapidly eliminated, mental status was normal again and the patient could be extubated a few days later. Intermittent hemodialysis had to be performed, as bilateral pleural effusions persisted and renal retention parameters remained significantly high. The diagnostic puncture of the pleura confirmed transudate in both sides and no molecular or cultural evidence of Ureaplasma was detected. Fig. 1, Fig. 2 show the bilateral pleural effusions in conventional radiology and computed tomography, 10 days after submission to the intensive care unit.Fig. 1 Posteroanterior chest radiograph showing bilateral increased opacity of the lower fields, 10 days after submission to the intensive care unit.\n\nFig. 1Fig. 2 Thorax CT-scan with evidence of bilateral pleural effusions, 10 days after submission to the intensive care unit.\n\nFig. 2\n\n3 Discussion\nWe describe the unusual case of Ureaplasma-pneumonia after LT in an adult patient. Ureaplasma was detected in BAL samples and transbronchial biopsies of mediastinal lymph nodes. The concentration of microorganism was low (about 5 * 104 copies/ml) and its role as a respiratory pathogen remains unclear. However, taking account of the adequate response to doxycycline, and the absence of other pathogens, we believe that Ureaplasma-infection was present. Thus, we discuss our case in comparison to similar reports in immunosuppressed patients, especially lung-transplant recipients.\n\nUreaplasma-infections in immunosuppressed patients are often presented as co-infections with other atypical bacteria, such as Nocardia farcinica [8] and Mycoplasma hominis [9]. The likelihood of a co-infection in our case was ruled out by extensive molecular diagnostics.\n\nThe early identification of Ureaplasma was achieved, as unclear hyperammonemia occurred. Hyperammonemia with encephalopathy was the only clinical manifestation. Although bronchoscopy findings were pronounced, respiratory symptoms were absent. As liver function parameters were normal, we supposed that hyperammonemia was not linked to a liver dysfunction but to urease-producing microorganisms and performed a targeted search for urease-producing bacteria by extensive sampling and specific molecular investigations.\n\nThe appearance of atypical pneumonia in the early post-transplant period is very rare, as such a pulmonary infection occurs more often after six months of transplantation time [1]. There is some evidence that Ureaplasma-pneumonia in lung recipients can be a donor-derived opportunistic infection, which causes refractory hyperammonemia [10]. Transplantation experts suggest that a routine donor screening should be initiated for this reason [10]. Our case supports the theory of a donor-derived Ureaplasma-infection, as the elapsed time between LT and illness was very short.\n\nA similar case of Ureaplasma-pneumonia with hyperammonemia in a lung-transplant recipient has been recently described by Matson KM et al. [11]. The patient was treated with doxycycline, along with other measures to lower ammonia levels, and got clinically improved. Ureaplasma species were identified using 16S ribosomal RNA PCR/sequencing of pleural fluid, and by culture of bronchoalveolar lavage.\n\nParapneumonic pleural effusions with Ureaplasma-growth are often in immunosuppressed patients with Ureaplasma-pneumonia [8,9,11,12]. In our case, parapneumonic pleuritic involvement could be excluded, as bilateral pleural effusions were transudative and culturally sterile. However, our patient was already treated with antibiotics over 10 days before pleural puncture and microbial growth could have been eliminated for that reason. After a short period of volume recompensation, pleural effusions completely vanished.\n\nA refractory hyperammonemia following Ureaplasma-infection after LT has been already described in the literature [13]. The 65-year-old patient presented on day 7 after LT with refractory status epilepticus and normal computed tomography of the brain. Hyperammonemia >1000 μmol/l was detected and despite aggressive treatment, the patient developed global cerebral edema and died. Postmortem investigations revealed Ureaplasma parvum.\n\nA refractory hyperammonemia was not observed in our patient, as a continuous renal replacement therapy resulted in a rapid biochemical and clinical resolution of the disorder. An explanation for this outcome may have been the identification and successful treatment of the underlying cause of hyperammonemia early in the clinical course of the disease. A second reason could have been the absence of a disseminated Ureaplasma-infection. According to Bharat A et al. [14], disseminated Ureaplasma-infections with bacteremia can cause a fatal hyperammonemia in lung-transplant patients and empiric antimicrobial treatment, while awaiting microbiological confirmation, can be lifesaving in this condition.\n\n4 Conclusion\nUreaplasma-pneumonia can cause fatal hyperammonemia in lung-transplant patients, and should be considered as a differential diagnosis by every unclear hyperammonemia with normal liver function. This disorder may occur early in the post-transplant time, as it seems to be donor-derived. The early identification and treatment of the infection leads to clinical and biochemical resolution. However, disseminated Ureaplasma-infections in lung-recipients may lead to refractory hyperammonemia and death to due cerebral edema.\n\nEthics approval and consent to participate\nA case report is intended to develop information to be shared for educational purposes and do not meet the definition of “research”. Ethical approval was not necessary. Written informed consent was obtained from the legal guardian of the patient.\n\nConsent for publication\nWritten consent for publication was obtained from the legal guardian of the patient.\n\nFunding\nNot applicable.\n\nDeclaration of competing interest\nThe Authors have disclosed that they have no significant relationship with, or financial interest in, any commercial companies pertaining to this article.\n==== Refs\nReferences\n1 Yun J.H. Lee S.O. Jo K.W. Infections after lung transplantation: time of occurrence, sites, and microbiologic etiologies Korean J. Intern. Med. 30 4 2015 506 514 26161017 \n2 Nenoff P. Manos A. Ehrhard I. Non-viral sexually transmitted infections - epidemiology, clinical manifestations, diagnostics and therapy: Part 2: Chlamydia and mycoplasma Hautarzt 68 1 2017 50 58 27981387 \n3 Latino M.A. Botta G. Badino C. Association between genital mycoplasmas, acute chorioamnionitis and fetal pneumonia in spontaneous abortions J. Perinat. Med. 46 5 2018 503 508 28599391 \n4 Kotecha S. Hodge R. Schaber J.A. Pulmonary Ureaplasma urealyticum is associated with the development of acute lung inflammation and chronic lung disease in preterm infants Pediatr. Res. 55 1 2004 61 68 14605250 \n5 Skevaki C. Kafetzis D.A. Ureaplasma urealyticum airway colonization and pulmonary outcome in neonates Expert Rev. Anti Infect. Ther. 1 1 2003 183 191 15482111 \n6 Waites K.B. Crouse D.T. Cassell G.H. Systemic neonatal infection due to Ureaplasma urealyticum Clin. Infect. Dis. 17 Suppl 1 1993 S131 S135 8399903 \n7 Sung T.J. Ureaplasma infections in pre-term infants: recent information regarding the role of Ureaplasma species as neonatal pathogens Korean J. Pediatr. 53 12 2010 989 993 21253312 \n8 Canouï E. Blanc K. Loubinoux J. The value of molecular techniques to diagnose Ureaplasma urealyticum and Nocardia farcinica pleuropneumonia in a patient with diffuse large B-cell lymphoma Int. J. Infect. Dis. 64 2017 93 95 28951103 \n9 García-de-la-Fuente C. Miñambres E. Ugalde E. Post-operative mediastinitis, pleuritis and pericarditis due to Mycoplasma hominis and Ureaplasma urealyticum with a fatal outcome J. Med. Microbiol. 57 Pt 5 2008 656 657 18436601 \n10 Fernandez R. Ratliff A. Crabb D. Ureaplasma transmitted from donor lungs is pathogenic after lung transplantation Ann. Thorac. Surg. 103 2 2017 670 671 28109354 \n11 Matson K.M. Sonetti D.A. Successful treatment of Ureaplasma-induced hyperammonemia syndrome post-lung transplant Transpl. Infect. Dis. 21 1 2019 e13022 \n12 Deverrière G. Lemée L. Grangé S. Life-threatening pneumopathy and U urealyticum in a STAT3-deficient hyper-IgE syndrome patient Pediatrics 139 6 2017 \n13 McLaughlin D.C. Mallea J.M. Ng L.K. Hyperammonemia presenting as refractory status epilepticus after lung transplant in a patient positive for Ureaplasma parvum Indian J. Crit. Care Med. 22 6 2018 463 465 29962751 \n14 Bharat A. Cunningham S.A. Scott Budinger G.R. Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans Sci. Transl. Med. 7 284 2015 284re3\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "30()",
"journal": "Respiratory medicine case reports",
"keywords": "Atypical pneumonia; Hyperammonemic syndrome; Immunosuppression",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101080",
"pmc": null,
"pmid": "32420020",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "28951103;27981387;21253312;28599391;26161017;28109354;14605250;18436601;29962751;15482111;28562253;30403322;8399903;25904745",
"title": "Hyperammonemia by Ureaplasma urealyticum Pneumonia after Lung Transplantation.",
"title_normalized": "hyperammonemia by ureaplasma urealyticum pneumonia after lung transplantation"
} | [
{
"companynumb": "DE-ASTELLAS-2020US017625",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nAberrant vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) signaling have been shown to play a role in non-small-cell lung cancer (NSCLC) pathogenesis and are associated with decreased survival. We evaluated the clinical activity and tolerability of sunitinib malate (SU11248), an oral, multitargeted tyrosine kinase inhibitor that blocks the activity of receptors for VEGF and PDGF, as well as related tyrosine kinases in patients with previously treated, advanced NSCLC.\n\n\nMETHODS\nPatients with stage IIIB or IV NSCLC for whom platinum-based chemotherapy had failed received 50 mg/d of sunitinib for 4 weeks followed by 2 weeks of no treatment in 6-week treatment cycles. The primary end point was objective response rate (ORR); secondary end points included progression-free survival, overall survival, and safety.\n\n\nRESULTS\nOf the 63 patients treated with sunitinib, seven patients had confirmed partial responses, yielding an ORR of 11.1% (95% CI, 4.6% to 21.6%). An additional 18 patients (28.6%) experienced stable disease of at least 8 weeks in duration. Median progression-free survival was 12.0 weeks (95% CI, 10.0 to 16.1 weeks), and median overall survival was 23.4 weeks (95% CI, 17.0 to 28.3 weeks). Therapy was generally well tolerated.\n\n\nCONCLUSIONS\nSunitinib has promising single-agent activity in patients with recurrent NSCLC, with an ORR similar to that of currently approved agents and an acceptable safety profile. Further evaluation in combination with other targeted agents and chemotherapy in patients with NSCLC is warranted.",
"affiliations": "Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, CB# 7305, Chapel Hill, NC 27599, USA. socinski@med.unc.edu",
"authors": "Socinski|Mark A|MA|;Novello|Silvia|S|;Brahmer|Julie R|JR|;Rosell|Rafael|R|;Sanchez|Jose M|JM|;Belani|Chandra P|CP|;Govindan|Ramaswamy|R|;Atkins|James N|JN|;Gillenwater|Heidi H|HH|;Pallares|Cinta|C|;Tye|Lesley|L|;Selaru|Paulina|P|;Chao|Richard C|RC|;Scagliotti|Giorgio V|GV|",
"chemical_list": "D007211:Indoles; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; D002945:Cisplatin; D000077210:Sunitinib",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2007.13.9303",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "26(4)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung; D002423:Cause of Death; D002945:Cisplatin; D018450:Disease Progression; D004334:Drug Administration Schedule; D005221:Fatigue; D005260:Female; D006801:Humans; D007211:Indoles; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009325:Nausea; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D010146:Pain; D011505:Protein-Tyrosine Kinases; D011758:Pyrroles; D012074:Remission Induction; D013280:Stomatitis; D000077210:Sunitinib; D016896:Treatment Outcome",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "650-6",
"pmc": null,
"pmid": "18235126",
"pubdate": "2008-02-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "16014882;11208836;12531805;10856094;15761078;12538485;16757724;10655437;16330672;15117980;12748309;17167137;16731761;16103075;2702835;14713109;15169807;10811675;11740999;9052396;10780522",
"title": "Multicenter, phase II trial of sunitinib in previously treated, advanced non-small-cell lung cancer.",
"title_normalized": "multicenter phase ii trial of sunitinib in previously treated advanced non small cell lung cancer"
} | [
{
"companynumb": "ES-PFIZER INC-2005162012",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SUNITINIB MALATE"
},
"drugadditional": null,
... |
{
"abstract": "In this retrospective analysis of 36 patients with recurrent ovarian cancer (ROC) treated with platinum pemetrexed doublet ± bevacizumab, the median age was 54.5 years (47-60) and 33 (91.7%) had serous histology. The overall response rate [ORR = complete (CR)+partial (PR) response] was 83.3%. At a median follow-up of 16 months, the median PFS was 13.8 months (95% CI: 10.849-20.580) and median OS 30.6 months, (95% CI: 21.46 months-NR). The incidence of Grade 3/4 anemia, thrombocytopenia, neutropenia and non-hematological toxicity was 19.4%, 3.9%, 16.6%, and 8.3%. Platinum pemetrexed chemotherapy in ROC is safe and effective treatment option.",
"affiliations": "Department of Medical Oncology, CMC Vellore, Vellore, India.;Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.;Department of Pathology, CMC Vellore, Vellore, India.;Department of Gynecologic Oncology, CMC Vellore, Vellore, India.;Department of Gynecologic Oncology, CMC Vellore, Vellore, India.;Department of Radiotherapy, CMC Vellore, Vellore, India.;Department of Radiology, CMC Vellore, Vellore, India.;Department of Medical Oncology, CMC Vellore, Vellore, India.;Department of Medical Oncology, CMC Vellore, Vellore, India.;Department of Medical Oncology, CMC Vellore, Vellore, India.;Department of Biostatistics, CMC Vellore, Vellore, India.;Department of Medical Oncology, CMC Vellore, Vellore, India.",
"authors": "Joel|Anjana|A|0000-0002-6821-5900;John|George|G|;Daniel|Sherin|S|;Thomas|Vinotha|V|;Sebastian|Ajit|A|;Ramireddy|Jeba Karunya|JK|;Chandramohan|Anuradha|A|;John|Ajoy Oommen|AO|;Georgy|Josh Thomas|JT|0000-0002-7119-9710;Chacko|Raju Titus|RT|;Yadav|Bijesh|B|;Singh|Ashish|A|",
"chemical_list": "D000068437:Pemetrexed; D000068258:Bevacizumab; D016190:Carboplatin",
"country": "England",
"delete": false,
"doi": "10.1080/07357907.2021.1973021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-7907",
"issue": "39(10)",
"journal": "Cancer investigation",
"keywords": "Recurrent ovarian cancer; carboplatin; maintenance therapy; pemetrexed; platinum-sensitive ovarian cancer",
"medline_ta": "Cancer Invest",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D016190:Carboplatin; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D000068437:Pemetrexed; D012189:Retrospective Studies",
"nlm_unique_id": "8307154",
"other_id": null,
"pages": "893-901",
"pmc": null,
"pmid": "34486892",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Platinum-Pemetrexed Chemotherapy for Recurrent Ovarian Cancer (ROC): A Single Center Experience.",
"title_normalized": "platinum pemetrexed chemotherapy for recurrent ovarian cancer roc a single center experience"
} | [
{
"companynumb": "IN-ROCHE-3030518",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nto report on the possible correlation between incident retinal phototoxicity and the use of photosensitizing drugs.\n\n\nMETHODS\nfour patients were examined because of scotomas and visual loss after an incidental exposure to a strong light source. One patient (two eyes) was exposed to standard camera flash; one patient (one eye) had a brief exposure to welding light; one patient (two eyes) underwent uncomplicated phacoemulsifications with intraocular lens implantation. The fourth patient had a severe retinal phototoxicity following a secondary intraocular lens implantation. All four patients underwent a thorough assessment including history of systemic drug use. These patients had ophthalmologic evaluation including: best corrected visual acuity (ETDRS charts), fundus examination, fluorescein and indocyanine green angiographies and were followed for 1 year.\n\n\nRESULTS\non presentation, the mean visual acuity was 7.5/20 (range: 20/400-20/20). Fundus examination disclosed yellow-gray sub-retinal lesions in all affected eyes. Early phase fluorescein angiography showed one or multiple hypofluorescent spots surrounded by a halo of hyperfluorescent window defect. In the late phase, some of these spots leaked the fluorescein dye. Indocyanine green angiography demonstrated hypofluorescent spots throughout with ill-defined borders of hyperfluorescence observed during the late stages. The common finding in these four patients was the fact that they were all taking one or more photosensitizing drugs (hydrochlorothiazide, furosemide, allopurinol, and benzodiazepines). Three of the patients had a full visual recovery a few months after the phototoxicity. The fourth patient remained with a visual acuity of 20/60 12 months after the light exposure. Despite the visual recovery, non-homogeneous retinal pigment epithelial disturbances persisted in all affected eyes.\n\n\nCONCLUSIONS\nphototoxicity following incidental light exposure may occur in patients taking drugs of photosensitizing potential. Therefore, the thorough history of systemic drug ingestion should be obtained if patients have exposure to strong light sources.",
"affiliations": "Centre d'Imagerie-Laser Rabelais, Lyon, France. Dr.M.MAUGET-FAYSSE@wanadoo.fr",
"authors": "Mauget-Faÿsse|M|M|;Quaranta|M|M|;Francoz|N|N|;BenEzra|D|D|;Mauget-Fa|M|M|",
"chemical_list": "D017319:Photosensitizing Agents; D006852:Hydrochlorothiazide; D001569:Benzodiazepines; D000493:Allopurinol; D005665:Furosemide; D007208:Indocyanine Green",
"country": "Germany",
"delete": false,
"doi": "10.1007/s004170100307",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0721-832X",
"issue": "239(7)",
"journal": "Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie",
"keywords": null,
"medline_ta": "Graefes Arch Clin Exp Ophthalmol",
"mesh_terms": "D000368:Aged; D000493:Allopurinol; D001569:Benzodiazepines; D005260:Female; D005451:Fluorescein Angiography; D005665:Furosemide; D006801:Humans; D006852:Hydrochlorothiazide; D007208:Indocyanine Green; D008027:Light; D008297:Male; D008875:Middle Aged; D017319:Photosensitizing Agents; D011832:Radiation Injuries; D012160:Retina; D012607:Scotoma; D014792:Visual Acuity",
"nlm_unique_id": "8205248",
"other_id": null,
"pages": "501-8",
"pmc": null,
"pmid": "11521694",
"pubdate": "2001-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Incidental retinal phototoxicity associated with ingestion of photosensitizing drugs.",
"title_normalized": "incidental retinal phototoxicity associated with ingestion of photosensitizing drugs"
} | [
{
"companynumb": "FR-SA-200122475GDDC",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": null,
... |
{
"abstract": "As cervical metastases in esophagogastric junction cancer are extremely rare, the authors herein report a case. A 63-year-old woman presented with dysphagia since 6 months. Diagnostic endoscopy showed that the tumor was located at the esophagogastric junction and histopathological diagnosis of adenocarcinoma was offered. A subtotal gastrectomy was performed. Histopathological diagnosis was moderately differentiated adenocarcinoma, invading upto the serosa with metastases to perigastric nodes. The patient received chemotherapy of cisplatin and fluorouracil for one cycle and oral capecitabine for two cycles. Two years later, the patient presented with vaginal bleeding and magnetic resonance imaging of pelvis revealed a tumor of the cervix. Histopathological impression of the tumor was metastatic cervical adenocarcinoma and immunohistochemistry showed the tumor was cytokeratin, villin, and CDX2 were positive and cytokeratin 20, CA125, and CA199 were negative. The immunohistochemical profile was the same as that of primary.",
"affiliations": "Department of Oncology, The First Affiliated Hospital, Yangtze University, Jingzhou, Hubei, China.",
"authors": "Cai|Zhiqiang|Z|;Shu|Xiaoyan|X|;Li|Junchuan|J|;Yang|Jiyuan|J|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor",
"country": "India",
"delete": false,
"doi": "10.4103/0377-4929.107820",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0377-4929",
"issue": "55(4)",
"journal": "Indian journal of pathology & microbiology",
"keywords": null,
"medline_ta": "Indian J Pathol Microbiol",
"mesh_terms": "D000230:Adenocarcinoma; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002584:Cervix Uteri; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D008853:Microscopy; D008875:Middle Aged; D014594:Uterine Neoplasms",
"nlm_unique_id": "7605904",
"other_id": null,
"pages": "560-2",
"pmc": null,
"pmid": "23455807",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cervical metastasis of esophagogastric junction cancer.",
"title_normalized": "cervical metastasis of esophagogastric junction cancer"
} | [
{
"companynumb": "PHHY2013CN099662",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"dr... |
{
"abstract": "In recent years the the set of diagnostic tools in colorectal cancers has been extended by the assessment of the KRAS gene status. Currently it is a necessary step in order to qualify patients for the targeted therapy. The results of the analysis of several studies revealed a high rate of compliance of the KRAS gene mutational status in primary and metastatic tumors. In this paper we present a rare case of incompatibility of the KRAS mutations in the primary tumor located in the colon and metastatic changes in the liver.",
"affiliations": "Department of Gastrointestinal Cancer, Cancer Center-Institute, Warsaw, Poland. ekosakowska@coi.waw.pl",
"authors": "Kosakowska|Ewa Anna|EA|;Stec|Rafał|R|;Charkiewicz|Radosław|R|;Skoczek|Marta|M|;Chyczewski|Lech|L|",
"chemical_list": "C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins",
"country": "Poland",
"delete": false,
"doi": "10.2478/v10042-010-0078-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0239-8508",
"issue": "48(4)",
"journal": "Folia histochemica et cytobiologica",
"keywords": null,
"medline_ta": "Folia Histochem Cytobiol",
"mesh_terms": "D001483:Base Sequence; D015179:Colorectal Neoplasms; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins",
"nlm_unique_id": "8502651",
"other_id": null,
"pages": "597-602",
"pmc": null,
"pmid": "21478103",
"pubdate": "2010-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Molecular differences in the KRAS gene mutation between a primary tumor and related metastatic sites - case report and a literature review.",
"title_normalized": "molecular differences in the kras gene mutation between a primary tumor and related metastatic sites case report and a literature review"
} | [
{
"companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-137444",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"dr... |
{
"abstract": "To estimate the association of cefuroxime and moxifloxacin in relation to the occurrence of endophthalmitis following phacoemulsification cataract surgery.\n\n\n\nRetrospective clinical cohort study.\n\n\n\nWe studied patients with noncomplex phacoemulsification cataract surgery in Kaiser Permanente Northern California during 2014-2019. Data were obtained for acute, postoperative endophthalmitis within 90 days of phacoemulsification, including culture and antibiogram results, intracameral and topical antibiotic agent, and dose. In a post hoc analysis, we also examined preoperative anterior chamber depth (ACD) and postoperative anterior chamber volume (ACV).\n\n\n\nOf 216,141 surgeries, endophthalmitis occurred in 0.020% of moxifloxacin-injected eyes and 0.013% of cefuroxime eyes (relative risk 1.62 with 95% CI 0.82-3.20, P = .16). Of the 34 (0.016%) cases of endophthalmitis, cefuroxime 1 mg was injected into 13 eyes and moxifloxacin 0.1% into 21 eyes. Organisms with antibiograms were identified in 12 (35%) cases. Of these, bacteria recovered from cefuroxime-injected eyes were resistant to cefuroxime in all cases (4/4), with Enterococcus comprising half of these. In eyes injected with moxifloxacin 0.1%, 6 out of 7 organisms were sensitive to moxifloxacin injected with 0.1 mL and in 1 eye injected with 1 mL. Streptococcus was the most common organism recovered (6/9) in moxifloxacin-injected eyes. Preoperative ACD and postoperative calculated ACV were higher in eyes injected with moxifloxacin.\n\n\n\nEndophthalmitis cases with positive cultures were generally related to organism resistance in cefuroxime eyes but to sensitive organisms in moxifloxacin eyes. Moxifloxacin doses may have been insufficient in eyes with larger ACV.",
"affiliations": "From the Departments of Ophthalmology and Quality, Kaiser Permanente, Walnut Creek, California, USA (N.H.S.), Division of Research, Kaiser Permanente Northern California, Oakland, California (L.L, L.H.), Department of Ophthalmology, Kaiser Permanente San Rafael, California (J.A.C.). Electronic address: neal.shorstein@gmail.com.;From the Departments of Ophthalmology and Quality, Kaiser Permanente, Walnut Creek, California, USA (N.H.S.), Division of Research, Kaiser Permanente Northern California, Oakland, California (L.L, L.H.), Department of Ophthalmology, Kaiser Permanente San Rafael, California (J.A.C.).;From the Departments of Ophthalmology and Quality, Kaiser Permanente, Walnut Creek, California, USA (N.H.S.), Division of Research, Kaiser Permanente Northern California, Oakland, California (L.L, L.H.), Department of Ophthalmology, Kaiser Permanente San Rafael, California (J.A.C.).;From the Departments of Ophthalmology and Quality, Kaiser Permanente, Walnut Creek, California, USA (N.H.S.), Division of Research, Kaiser Permanente Northern California, Oakland, California (L.L, L.H.), Department of Ophthalmology, Kaiser Permanente San Rafael, California (J.A.C.).",
"authors": "Shorstein|Neal H|NH|;Liu|Liyan|L|;Carolan|James A|JA|;Herrinton|Lisa|L|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002444:Cefuroxime; D000077266:Moxifloxacin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajo.2021.02.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9394",
"issue": "227()",
"journal": "American journal of ophthalmology",
"keywords": null,
"medline_ta": "Am J Ophthalmol",
"mesh_terms": "D000867:Anterior Chamber; D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D001419:Bacteria; D002444:Cefuroxime; D009877:Endophthalmitis; D015818:Eye Infections, Bacterial; D005260:Female; D006801:Humans; D056965:Injections, Intraocular; D019654:Lens Implantation, Intraocular; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D018918:Phacoemulsification; D012189:Retrospective Studies; D017211:Treatment Failure",
"nlm_unique_id": "0370500",
"other_id": null,
"pages": "166-172",
"pmc": null,
"pmid": "33571472",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "32956857;29208819;18721703;18571078;27490050;25368512;32050222;30691922;26152124;26459998;31278356;29502614;28007104;24702755;17189795;25262563;26992840;16631049;24964171;18700925;26703490;17889778;28732619;17531690;16083841;31371152;24054967;12036640;12036639;26189384;26226062;31444079;27688910",
"title": "Endophthalmitis Prophylaxis Failures in Patients Injected With Intracameral Antibiotic During Cataract Surgery.",
"title_normalized": "endophthalmitis prophylaxis failures in patients injected with intracameral antibiotic during cataract surgery"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2021GSK054597",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFUROXIME SODIUM"
},
"drugadditiona... |
{
"abstract": "5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB) are benzofuran analogues of amphetamine and belong to the category of new psychoactive substances (NPS). Despite already published fatal 5- and 6-APB intoxication - in most cases, a combination of both substances - no sensitive method for the simultaneous detection and quantification of these new psychoactive compounds in human blood samples has yet been developed. Therefore, an easy and fast sample preparation-, as well as specific high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) method for the determination of both substances in blood, were established and validated. In a fatal intoxication in 2017 at the Institute of Forensic and Traffic Medicine in Heidelberg, Germany, concentrations of 850 ng/mL (5-APB) and 300 ng/mL (6-APB) were determined in peripheral blood. Besides, other body fluids (central blood, urine, bile), hair, and various tissues were examined to verify the presence of both compounds and to gain first insights into their distribution. In this publication, we show a method for the simultaneous determination of 5- and 6-APB in human samples by a chromatographic method and to investigate their distribution in the human body.",
"affiliations": "Institute of Forensic and Traffic Medicine, Heidelberg University Hospital, Voßstraße 2, 69115 Heidelberg, Germany.;Institute of Forensic and Traffic Medicine, Heidelberg University Hospital, Voßstraße 2, 69115 Heidelberg, Germany.;Institute of Forensic and Traffic Medicine, Heidelberg University Hospital, Voßstraße 2, 69115 Heidelberg, Germany.;Institute of Forensic and Traffic Medicine, Heidelberg University Hospital, Voßstraße 2, 69115 Heidelberg, Germany.;Institute of Forensic and Traffic Medicine, Heidelberg University Hospital, Voßstraße 2, 69115 Heidelberg, Germany.;Institute of Forensic and Traffic Medicine, Heidelberg University Hospital, Voßstraße 2, 69115 Heidelberg, Germany.",
"authors": "Hofmann|Vanessa|V|;Sundermann|Tom Richard|TR|;Landmann|Aysche|A|;Rechtsteiner|Stefanie|S|;Schmitt|Georg|G|;Bartel|Marc|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkab018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": null,
"journal": "Journal of analytical toxicology",
"keywords": "5-APB; 6-APB; HPLC-MS/MS; intoxication; new psychoactive substances (NPS)",
"medline_ta": "J Anal Toxicol",
"mesh_terms": null,
"nlm_unique_id": "7705085",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33576419",
"pubdate": "2021-02-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Simultaneous Determination of 5- and 6-APB in Blood, other Body Fluids, Hair, and Various Tissues by HPLC-MS/MS.",
"title_normalized": "simultaneous determination of 5 and 6 apb in blood other body fluids hair and various tissues by hplc ms ms"
} | [
{
"companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2022-03201",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPHETAMINE SULFATE"
},
... |
{
"abstract": "A 25-year-old woman, a never smoker with a history of heart-lung transplantation for World Health Organization group 1 pulmonary arterial hypertension performed 20 months prior to presentation, was evaluated for shortness of breath. Following transplantation, she was initiated on standard therapy of prednisone, tacrolimus, and azathioprine, along with routine antimicrobial prophylaxis. Her posttransplant course was complicated by persistent acute cellular rejection, as determined from a transbronchial biopsy specimen, without evidence of rejection in an endomyocardial biopsy specimen. The immunosuppressive medications were supplemented with pulse-dosed steroids, and the patient was transitioned from azathioprine to mycophenolate mofetil. Sirolimus was added 9 months prior to presentation. Three months prior to presentation, she was admitted for increasing oxygen requirements, shortness of breath, and bilateral infiltrates on the CT scans of the chest.",
"affiliations": "Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.;Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.;Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN. Electronic address: maldonado.fabien@mayo.edu.",
"authors": "Narotzky|Sarah|S|;Kennedy|Cassie Colleen|CC|;Maldonado|Fabien|F|",
"chemical_list": "D007166:Immunosuppressive Agents; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1378/chest.14-1443",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "147(5)",
"journal": "Chest",
"keywords": null,
"medline_ta": "Chest",
"mesh_terms": "D000328:Adult; D005260:Female; D016041:Heart-Lung Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D011183:Postoperative Complications; D011649:Pulmonary Alveolar Proteinosis; D012131:Respiratory Insufficiency; D020123:Sirolimus",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e185-e188",
"pmc": null,
"pmid": "25940262",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An unusual cause of respiratory failure in a 25-year-old heart and lung transplant recipient.",
"title_normalized": "an unusual cause of respiratory failure in a 25 year old heart and lung transplant recipient"
} | [
{
"companynumb": "US-PFIZER INC-202101872065",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAdefovir dipivoxil is a nucleotide analogue that is approved for treatment of chronic hepatitis B. Adefovir dipivoxil is associated with proximal tubular dysfunction, resulting in Fanconi syndrome, which can cause secondary hypophosphatemic osteomalacia. We describe a case of a patient with hypophosphatemic osteomalacia secondary to Fanconi syndrome induced by adefovir dipivoxil concomitantly with osteoporosis in whom clinical symptoms were improved by adding denosumab (a human monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand) to preceding administration of vitamin D3.\n\n\nMETHODS\nA 60-year-old Japanese man had been receiving low-dose adefovir dipivoxil (10 mg/day) to treat chronic hepatitis B for approximately 5 years. He presented to an orthopedic surgeon with severe pain of the right hip and no trauma history, and fracture of the neck of the right femur was identified. In addition, 99mTc-hydroxymethylene diphosphate scintigraphy revealed significantly abnormal uptake in the bilateral ribs, hips, and knees, and he was therefore referred to our university hospital for evaluation of multiple pathological fractures. We diagnosed hypophosphatemic osteomalacia due to Fanconi syndrome induced by adefovir dipivoxil therapy. Although we reduced the patient's adefovir dipivoxil dose and added calcitriol (active vitamin D3), he did not respond and continued to complain of bone pain. Several bone resorption markers and bone-specific alkaline phosphatase were also persistently elevated. Therefore, we added denosumab to vitamin D3 supplementation for treatment of excessive bone resorption. Two months after initiation of denosumab, his hip and knee pain was relieved, along with a decrease in serum alkaline phosphatase and some bone resorption markers.\n\n\nCONCLUSIONS\nAlthough denosumab is not generally an appropriate treatment for acquired Fanconi syndrome, it may be useful for patients who have hypophosphatemic osteomalacia due to adefovir dipivoxil-induced Fanconi syndrome associated with excessive bone resorption. However, clinicians should keep in mind that if denosumab is administered to patients with hypophosphatemic osteomalacia accompanied by excessive bone resorption, adequate vitamin D and/or phosphate supplementation should be done before administration of denosumab.",
"affiliations": "Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.;Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Shimotsuga, Tochigi, 321-0293, Japan. toshie@dokkyomed.ac.jp.;Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.;Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.;Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.;Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.;Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University, Mibu, Tochigi, Japan.;Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.;Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.",
"authors": "Kunii|Tomohisa|T|;Iijima|Toshie|T|http://orcid.org/0000-0002-4613-3744;Jojima|Teruo|T|;Shimizu|Masanori|M|;Kase|Masato|M|;Sakurai|Shintaro|S|;Kogai|Takahiko|T|;Usui|Isao|I|;Aso|Yoshimasa|Y|",
"chemical_list": "D000998:Antiviral Agents; D050071:Bone Density Conservation Agents; D063065:Organophosphonates; D000069448:Denosumab; D000225:Adenine; C106812:adefovir dipivoxil",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-019-2018-7",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 201810.1186/s13256-019-2018-7Case ReportDenosumab improves clinical manifestations of hypophosphatemic osteomalacia by adefovir-induced Fanconi syndrome: a case report Kunii Tomohisa t-kunii@dokkyomed.ac.jp 1http://orcid.org/0000-0002-4613-3744Iijima Toshie +81 282 86 1111toshie@dokkyomed.ac.jp 1Jojima Teruo jojima@dokkyomed.ac.jp 1Shimizu Masanori shimizum@dokkyomed.ac.jp 1Kase Masato k-masato@dokkyomed.ac.jp 1Sakurai Shintaro ssakurai@dokkyomed.ac.jp 1Kogai Takahiko tkogai@dokkyomed.ac.jp 2Usui Isao isaousui@dokkyomed.ac.jp 1Aso Yoshimasa yaso@dokkyomed.ac.jp 11 0000 0001 0702 8004grid.255137.7Department of Endocrinology and Metabolism, Dokkyo Medical University, Mibu, Shimotsuga, Tochigi, 321-0293 Japan 2 0000 0001 0702 8004grid.255137.7Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University, Mibu, Tochigi Japan 20 4 2019 20 4 2019 2019 13 9922 12 2018 18 2 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAdefovir dipivoxil is a nucleotide analogue that is approved for treatment of chronic hepatitis B. Adefovir dipivoxil is associated with proximal tubular dysfunction, resulting in Fanconi syndrome, which can cause secondary hypophosphatemic osteomalacia. We describe a case of a patient with hypophosphatemic osteomalacia secondary to Fanconi syndrome induced by adefovir dipivoxil concomitantly with osteoporosis in whom clinical symptoms were improved by adding denosumab (a human monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand) to preceding administration of vitamin D3.\n\nCase presentation\nA 60-year-old Japanese man had been receiving low-dose adefovir dipivoxil (10 mg/day) to treat chronic hepatitis B for approximately 5 years. He presented to an orthopedic surgeon with severe pain of the right hip and no trauma history, and fracture of the neck of the right femur was identified. In addition, 99mTc-hydroxymethylene diphosphate scintigraphy revealed significantly abnormal uptake in the bilateral ribs, hips, and knees, and he was therefore referred to our university hospital for evaluation of multiple pathological fractures. We diagnosed hypophosphatemic osteomalacia due to Fanconi syndrome induced by adefovir dipivoxil therapy. Although we reduced the patient’s adefovir dipivoxil dose and added calcitriol (active vitamin D3), he did not respond and continued to complain of bone pain. Several bone resorption markers and bone-specific alkaline phosphatase were also persistently elevated. Therefore, we added denosumab to vitamin D3 supplementation for treatment of excessive bone resorption. Two months after initiation of denosumab, his hip and knee pain was relieved, along with a decrease in serum alkaline phosphatase and some bone resorption markers.\n\nConclusions\nAlthough denosumab is not generally an appropriate treatment for acquired Fanconi syndrome, it may be useful for patients who have hypophosphatemic osteomalacia due to adefovir dipivoxil-induced Fanconi syndrome associated with excessive bone resorption. However, clinicians should keep in mind that if denosumab is administered to patients with hypophosphatemic osteomalacia accompanied by excessive bone resorption, adequate vitamin D and/or phosphate supplementation should be done before administration of denosumab.\n\nKeywords\nAdefovir dipivoxilFanconi syndromeOsteomalaciaOsteoporosisChronic hepatitis BDenosumabissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nAdefovir dipivoxil (ADV) is an acyclic nucleotide analogue of adenosine monophosphate that is widely used to treat chronic hepatitis B. There is considerable evidence that long-term administration of ADV, even at a low dose, causes renal tubular dysfunction due to nephrotoxicity [1–3]. Fanconi syndrome can be induced by generalized proximal tubular dysfunction due to ADV therapy, resulting in hypophosphatemic osteomalacia with pathological fractures [1–3].\n\nDenosumab is a human monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand (RANKL) that is employed for the treatment of osteoporosis [4]. In general, denosumab would not be considered appropriate for patients with hypophosphatemic osteomalacia due to Fanconi syndrome, because denosumab rapidly inhibits osteoclast-dependent bone and calcium resorption and subsequently induces hypocalcemia. However, we encountered a 60-year-old man with hypophosphatemic osteomalacia due to ADV-induced Fanconi syndrome in whom clinical manifestations improved after denosumab was added to vitamin D3 supplementation, as reported here.\n\nCase presentation\nA 60-year-old Japanese man was referred to our hospital for evaluation of severe bone pain and pathological fracture of the neck of the right femur. He had been receiving treatment for chronic hepatitis B with lamivudine (100 mg/day) and ADV (10 mg/day) since December 2006. In June 2013, he noticed low-back pain and then developed severe pain in the right hip. One month later, he also developed pain of the great toe during walking and was referred to an orthopedic surgeon at our hospital. Fracture of the neck of the right femur was found, despite no history of trauma (Fig. 1). In addition, 99mTc-hydroxymethylene diphosphate scintigraphy revealed significantly abnormal uptake in the bilateral ribs, hips, and knees (Fig. 2). In August 2013, he was referred to our outpatient clinic for evaluation of multiple pathological fractures.Fig. 1 Pelvic x-ray and computed tomography. The circles show a fracture of the right femoral neck\n\nFig. 2 99mTc-hydroxymethylene diphosphate scintigraphy showing increased uptake throughout the skeleton (ribs, hips, and knees)\n\n\n\nOn examination, his body mass index was 18.0 kg/m2, temperature was 36.7 °C, blood pressure was 151/86 mmHg, and pulse rate was 67 beats/min (regular). He had generalized bone pain and gait disturbance. His past medical history was appendicitis in 1967 and stomach polyps in 2011. In his family medical history, there was pancreatic cancer, but there was no liver disease. His regular medications were adefovir and ursodeoxycholic acid. He had smoked three packs of cigarettes per day for 30 years, but he had quit since 51 years old. He drinks 350 ml/day of beer. Laboratory tests showed marked elevation of alkaline phosphatase (ALP) (1223 U/L), as well as hypophosphatemia (1.9 mg/dl) and mild hypocalcemia (8.5 mg/dl). His serum creatinine was slightly elevated, whereas serum 1α,25(OH)2 vitamin D3 was relatively low at 26.4 pg/ml (reference range, 20.0–60.0 pg/ml) (Table 1).Table 1 Laboratory data on admission\n\n\t\t\tReference range\t\nChemistry\t\n AST\t12\tU/L\t13–30\t\n ALT\t7\tU/L\t10–42\t\n T-Bil\t0.5\tmg/dl\t0.4–1.5\t\n LDH\t141\tU/L\t124–222\t\n ALP\t1223\tU/L\t106–322\t\n ALP1\t3\t%\t\t\n ALP2 + ALP3\t91\t%\t\t\n ALP5\t6\t%\t\t\n LAP\t49\tU/L\t30–70\t\n gGTP\t12\tU/L\t13–64\t\n ChE\t267\tU/L\t215–464\t\n TP\t6.6\tg/dl\t6.6–8.1\t\n Alb\t4.1\tg/dl\t4.1–5.1\t\n BUN\t14\tmg/dl\t8.0–20.0\t\n Cre\t1.44\tmg/dl\t0.65–1.07\t\n eGFR\t40.2\tml/min/1.73m2\t\t\n UA\t1.5\tmg/dl\t3.7–7.0\t\n Na\t143\tmEq/L\t138–145\t\n K\t4\tmEq/L\t3.6–4.8\t\n Cl\t113\tmEq/L\t101–108\t\n Ca\t8.5\tmg/dl\t8.8–10.1\t\n IP\t1.9\tmg/dl\t2.7–4.6\t\n Glucose\t93\tmg/dl\t55–110\t\n HbA1c\t4.8\t%\t4.3–5.8\t\n CRP\t0.1\tmg/dl\t≤ 0.14\t\n Serum β2-microglobulin\t3.5\tmg/dl\t\t\nHepatitis marker\t\n Hbs-Ag\t250\tIU/ml\t< 0.05\t\n HBs-Ag\t0.4\tS/CO\t< 1.0\t\n HBe-Ab\t99.6\t%Inh\t< 50.0\t\nHematology\t\n WBC\t5200\t/μl\t3300–8600\t\n RBC\t447\t104/μl\t4.35–5.55\t\n Hb\t16.5\tg/dl\t13.7–16.8\t\n Hct\t47.6\t%\t40.7–50.1\t\n Plt\t16.3\t104/μl\t15.8–34.8\t\nBone metabolic parameters\t\n TRACP-5b\t781\tmU/dl\t170–590\t\n Bone ALP\t112\tμg/L\t3.7–20.9\t\n Deoxypyridinoline\t6.7\tnmol/mmol Cre\t2.1–5.4\t\n U-NTx\t216.1\tnmol BCE/mmol Cr\t13.0–66.2\t\n calcitonin\t16\tpg/ml\t< 9.52\t\n intact-PTH\t43.6\tpg/ml\t8.7–79.6\t\n PTHrP\t< 1.1\tpmol/L\t< 1.1\t\n 1,25(OH)2 Vit.D3\t26.4\tpg/ml\t20.0–60.0\t\n FGF23\t< 5\tpg/ml\t\t\nImmunology\t\n Antinuclear antibody\t20\ttimes\t< 20\t\n C3\t74\tmg/dl\t65–135\t\n C4\t13\tmg/dl\t13–53\t\n CH50\t41\tU/ml\t30–50\t\n IgG\t1031\tmg/dl\t680–1620\t\n IgA\t301\tmg/dl\t84–438\t\n IgM\t87\tmg/dl\t57–288\t\n IgE\t3\tIU/ml\t< 295\t\n Serum immunoelectrophoresis\tM protein (−)\t\t\n Urinary immunoelectrophoresis\tBJ protein (+)\t\t\nBlood gas analysis\t\n pH\t7.328\t\t7.350–7.450\t\n PCO2\t40.3\tmmHg\t35.0–45.0\t\n PO2\t110\tmmHg\t85.0–105.0\t\n HCO3-\t20.5\tmmol/L\t23.0–28.0\t\n BE\t−4.7\tmmol/L\t−4.6\t\n AG\t4.8\tmmol/L\t8.0–12.0\t\nUrinalysis\t\n pH\t6.5\t\t\t\n U-glucose\t100\tmg/dl\t\t\n U-blood\t–\t\t\t\n BJ-protein\t+\t\t\t\n U- total protein\t1.3\tg/g Cr\t\t\n Urinary NAG\t7.8\tIU/L\t0.3–11.5\t\n\t16.3\tIU/g Cr\t\t\n Urinary β2-microglobulin\t138,885\tμg/g Cr\t\t\n Na\t73\tmEq/L\t\t\n K\t24\tmEq/L\t\t\n Cl\t91\tmEq/L\t\t\n Ca\t29.4\tmg/dl\t\t\n IP\t43\tmg/dl\t\t\n UA\t30\tmg/dl\t\t\n Cre\t48\tmg/dl\t\t\n %TRP\t41.59\t%\t\t\n FEUA\t46.3\t%\t\t\nAbbreviations: AG Anion gap, Alb Albumin, ALP Alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, BCE Bone collagen equivalents, BE Base excess, BJ protein Bence-Jones protein, BUN Blood urea nitrogen, CH50 Total hemolytic complement, ChE Cholinesterase, Cre Creatinine, CRP C-reactive protein, eGFR Estimated glomerular filtration rate, FEUA Fractional excretion of uric acid, FGF23 Fibroblast growth factor 23, gGTP γ-Glutamyl transpeptidase, Hb Hemoglobin, HbA1c Hemoglobin A1c, HBe-Ab Hepatitis B e antigen antibody, Hbs-Ag Hepatitis B surface antigen, HCO3− Bicarbonate, Hct Hematocrit, Ig Immunoglobulin, IP inorganic phosphorus, LAP Leukocyte alkaline phosphatase, LDH Lactate dehydrogenase, NAG N-acetyl-β-D-glucosaminidase, NTx Cross-linked N-telopeptide of type I collagen, PCO2 Partial pressure of carbon dioxide, Plt Platelets, PO2 Partial pressure of oxygen, PTH Parathyroid hormone, PTHrP Parathyroid hormone-related protein, RBC Red blood cells, T-Bil Total bilirubin, TP Total protein, TRACP-5b Tartrate-resistant acid phosphatase 5b, %TRP Percentage tubular reabsorption of phosphate, UA Urinalysis, WBC White blood cells\n\n\n\nUrinalysis showed glycosuria (2+) and proteinuria (1+). Urinary β2-microglobulin was markedly elevated at 138,885 μg/g creatinine (Cr), and tubular reabsorption of phosphate was significantly decreased to 41.59% (reference range for percentage tubular reabsorption of phosphate, 80–94%) (Table 1). On the basis of these results, we diagnosed hypophosphatemic osteomalacia secondary to Fanconi syndrome caused by ADV therapy.\n\nDual-energy X-ray absorptiometry showed an extremely low bone mineral density with a mean lumbar T-score of − 3.6 SD. Several bone resorption markers were highly elevated (urinary cross-linked N-telopeptide of type I collagen, 216.1 nmol bone collagen equivalents/mmol; urinary deoxypyridinoline, 6.7 nmol/mmol Cr; serum tartrate-resistant acid phosphatase 5b, 781 mU/dl) (Table 1). Taken together, these findings suggested that the patient had excessive bone resorption combined with hypophosphatemic osteomalacia.\n\nTo treat his condition, we first reduced the dose of ADV from 10 mg daily to 10 mg every other day and administered calcitriol (1.0 μg/day) because he had both hypophosphatemia and mild hypocalcemia. In October 2013, he underwent prosthetic replacement of the head of the right femur. However, his generalized bone pain was not relieved by these measures, and several bone resorption markers remained very high, as did serum ALP despite treatment for osteomalacia. In June 2016, we added denosumab (60 mg subcutaneously), a human monoclonal antibody that inhibits RANKL, to ongoing vitamin D therapy in an attempt to suppress persistently high bone resorption. Two months after initiation of denosumab, his hip and knee pain were relieved, along with a decrease in serum ALP and several bone resorption markers (Figs. 3 and 4a–c). Urinary β2-microglobulin decreased gradually after addition of denosumab to vitamin D3. After 9 months of denosumab treatment, the patient’s mean lumbar T-score increased from − 2.0 SD to − 1.4 SD (Fig. 4d). We administered denosumab 60 mg every 6 months, and currently he continues to receive denosumab.Fig. 3 Clinical time course during treatments\n\nFig. 4 Changes in several bone metabolic markers after treatment with denosumab. a Urinary cross-linked N-telopeptide of type I collagen. b Serum tartrate-resistant acid phosphatase 5b. c Urinary deoxypyridinoline. d Bone mineral density of lumbar spine: T-score by dual-energy X-ray absorptiometry. Note: Time lines (x-axes) are different in each of the graphs\n\n\n\nDiscussion and conclusions\nWe present a case of a 60-year-old man who had hypophosphatemic osteomalacia secondary to acquired Fanconi syndrome caused by low-dose ADV therapy (10 mg/day). Osteomalacia is a metabolic bone disease characterized by a defective mineralization of the osteoid matrix synthesized by osteoblasts, leading to an accumulation of nonmineralized bone. Osteomalacia is usually associated with vitamin D deficiency or hypophosphatemia. Fanconi syndrome results from generalized dysfunction of the proximal renal tubules, which results in impaired reabsorption of amino acids, glucose, uric acid, bicarbonate, and phosphate, with increased urinary excretion of these solutes [5]. Thus, hypophosphatemic osteomalacia can occur in patients with Fanconi syndrome.\n\nADV is a nucleotide analogue of adenosine monophosphate that is widely used for the treatment of chronic hepatitis B. The mechanisms by which ADV induces nephrotoxicity remain to be determined, but ADV may impair tubular transport, increase apoptosis, or cause mitochondrial injury in the renal tubular epithelium [6]. It has been reported that ADV-related nephrotoxicity is dose-dependent, with a low dose of ADV (10 mg/day) generally being safe and well tolerated [7]. However, there is evidence that even low-dose ADV can induce nephrotoxicity, including Fanconi syndrome, especially in Asian patients [2, 3, 8, 9]. Recently, there has been an increase of reports regarding Fanconi syndrome associated with long-term ADV therapy, even at low doses, in patients from Japan and other Asian countries [8]. In addition, it has been suggested that the incidence of hypophosphatemic osteomalacia due to Fanconi syndrome associated with low-dose ADV therapy may be higher than previously thought [9].\n\nIn patients with ADV-induced Fanconi syndrome and/or hypophosphatemic osteomalacia, withdrawal or dose reduction of ADV should be performed immediately [5], and oral phosphate, calcium, or vitamin D3 should be added as necessary. In our patient, the dose of ADV was immediately reduced from 10 mg daily to 10 mg every other day. We also initiated treatment with calcitriol (1.0 μg/day) because our patient had hypophosphatemia and slightly low serum calcium and vitamin D3 levels. Generalized renal tubular injury caused by ADV inhibits 1α-hydroxylase activity with subsequent reduction of the 1,25-dihyroxyvitamin D3 level, leading to a decrease in intestinal calcium and phosphate absorption that can contribute to development of osteomalacia [3]. However, generalized bone pain was not relieved in our patient, and several bone resorption markers remained very high, despite ADV dose reduction and vitamin D3 supplementation. The serum level of bone-specific ALP also remained high.\n\nInterestingly, our patient had persistent elevation of bone resorption despite receiving treatment for osteomalacia. Previous studies have shown that bone resorption is occasionally increased in patients with hypophosphatemic osteomalacia because osteoclasts are unable to resorb nonmineralized osteoid [10]. Accordingly, our patient may have a mixed form of osteoporosis and osteomalacia (i.e., osteoporomalacia) [11]. Therefore, we added denosumab (anti-RANKL monoclonal antibody) to vitamin D3 supplementation in order to suppress bone resorption and treat his generalized bone pain. Two months after starting denosumab therapy, the patient’s hip and knee pain showed improvement, together with a decrease in serum bone-specific ALP and bone resorption markers.\n\nDenosumab is a human immunoglobulin G2 monoclonal antibody that inhibits bone resorption by targeting RANKL, which is involved in osteoclast differentiation [4]. Several studies have demonstrated that denosumab is effective for reducing the risk of fracture in women with postmenopausal osteoporosis [12]. Unlike bisphosphonates (another class of potent antiresorptive agents), denosumab does not cause more adverse events in patients with impaired kidney function, because renal insufficiency does not affect its pharmacokinetics or pharmacodynamics [13]. Thus, we chose denosumab for our patient because he had Fanconi syndrome with generalized proximal tubular dysfunction caused by ADV therapy.\n\nIn general, antiresorptive agents such as bisphosphonates and denosumab may not be appropriate for treating hypophosphatemic osteomalacia or other forms of osteomalacia, regardless of the degree of renal insufficiency and vitamin D level. Severe and prolonged hypocalcemia was reported after a single injection of denosumab (60 mg) in a patient with osteomalacia due to Fanconi syndrome [14], because calcium homeostasis is dependent on high bone turnover in osteomalacia. Monitoring of the serum calcium level also is mandatory to prevent severe hypocalcemia when denosumab is initiated in all forms of osteomalacia. Very recently, there was another case report of hypophosphatemia osteomalacia secondary to Fanconi syndrome in which bone pain was worsened by administration of denosumab [15]. Unlike in these reports, we observed that 2 months after initiation of denosumab, hip and knee pain of our patient was relieved along with a decrease in serum ALP and some bone resorption markers. We speculate that denosumab had worked well in our patient because of an adequate administration of vitamin D3 prior to denosumab. We speculate that denosumab may be an option for patients who have hypophosphatemic osteomalacia due to ADV-induced Fanconi syndrome with concurrent enhancement of bone resorption and/or osteoporosis. However, clinicians should keep in mind that if denosumab is administered to patients with hypophosphatemic osteomalacia accompanied by persistent excessive bone resorption despite treatment for osteomalacia, adequate vitamin D and/or phosphate supplementation should be done before administration of denosumab.\n\nAbbreviations\nADVAdefovir dipivoxil\n\nAGAnion gap\n\nAlbAlbumin\n\nALPAlkaline phosphatase\n\nALTalanine aminotransferase\n\nASTaspartate aminotransferase\n\nBCEBone collagen equivalents\n\nBEBase excess\n\nBJ proteinBence-Jones protein\n\nBUNBlood urea nitrogen\n\nCH50Total hemolytic complement\n\nChECholinesterase\n\nCreCreatinine\n\nCRPC-reactive protein\n\neGFREstimated glomerular filtration rate\n\nFEUAFractional excretion of uric acid\n\nFGF23Fibroblast growth factor 23\n\ngGTPγ-Glutamyl transpeptidase\n\nHbHemoglobin\n\nHbA1cHemoglobin A1c\n\nHBe-AbHepatitis B e antigen antibody\n\nHbs-AgHepatitis B surface antigen\n\nHCO3−Bicarbonate\n\nHctHematocrit\n\nIgImmunoglobulin\n\nLAPLeukocyte alkaline phosphatase\n\nLDHLactate dehydrogenase\n\nNTxCross-linked N-telopeptide of type I collagen\n\nPCO2Partial pressure of carbon dioxide\n\nPltPlatelets\n\nPO2Partial pressure of oxygen\n\nPTHParathyroid hormone\n\nPTHrPParathyroid hormone-related protein\n\nRANKLReceptor activator of nuclear factor-κB ligand\n\nRBCRed blood cells\n\nT-BilTotal bilirubin\n\nTPTotal protein\n\nTRACP-5bTartrate-resistant acid phosphatase 5b\n\n%TRPPercentage tubular reabsorption of phosphate\n\nUAUrinalysis\n\nWBCWhite blood cells\n\nAcknowledgements\nNot applicable.\n\nFunding\nWe did not receive any funding support for the publication of this case report.\n\nAvailability of data and materials\nThe datasets used and analyzed during this study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nTK, TI, and YA analyzed data and wrote the manuscript. TJ and MS carried out the clinical treatment and follow-up of the patient. MK and SS collected the data. TK and IU advised on and reviewed this report. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nIt was not required to submit the case to the institutional ethics committee.\n\nConsent for publication\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\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. Izzedine H Launay-Vacher V Deray G Antiviral drug-induced nephrotoxicity Am J Kidney Dis 2005 45 5 804 817 10.1053/j.ajkd.2005.02.010 15861345 \n2. Wong T Girgis CM Ngu MC Chen RC Emmett L Hypophosphatemic osteomalacia after low-dose adefovir dipivoxil therapy for hepatitis B J Clin Endocrinol Metab 2010 95 2 479 480 10.1210/jc.2009-2051 20133467 \n3. Girgis CM Wong T Ngu MC Emmett L Archer KA Hypophosphataemic osteomalacia in patients on adefovir dipivoxil J Clin Gastroenterol 2011 45 5 468 473 10.1097/MCG.0b013e3181e12ed3 20661153 \n4. Zaheer S LeBoff M Lewiecki EM Denosumab for the treatment of osteoporosis Expert Opin Drug Metab Toxicol 2015 11 3 461 470 10.1517/17425255.2015.1000860 25614274 \n5. Hall AM Bass P Unwin RJ Drug-induced renal Fanconi syndrome QJM 2014 107 261 269 10.1093/qjmed/hct258 24368854 \n6. Tanji N Tanji K Kambham N Markowitz GS Bell A Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion Hum Pathol 2001 32 7 734 740 10.1053/hupa.2001.25586 11486172 \n7. Izzedine H Hulot JS Launay-Vacher V Marcellini P Hadziyannis SJ Adefovir Dipivoxil International 438 Study Group. Renal safety of adefovir dipivoxil in patients with chronic hepatitis B: two double-blind, randomized, placebo-controlled studies Kidney Int 2004 66 3 1153 1158 10.1111/j.1523-1755.2004.00866.x 15327411 \n8. Eguchi H Tsuruta M Tani J Kuwahara R Hiromatsu Y Hypophosphatemic osteomalacia due to drug-induced Fanconi’s syndrome associated with adefovir dipivoxil treatment for hepatitis B Intern Med 2014 53 3 233 237 10.2169/internalmedicine.53.1213 24492692 \n9. Wang BF Wang Y Wang BY Sun FR Zhang D Osteomalacia and Fanconi’s syndrome caused by long-term low-dose adefovir dipivoxil J Clin Pharm Ther 2015 40 3 345 348 10.1111/jcpt.12259 25721615 \n10. Ros I Alvarez L Guañabens N Peris P Monegal A Hypophosphatemic osteomalacia: a report of five cases and evaluation of bone markers J Bone Miner Metab 2005 23 3 266 269 10.1007/s00774-004-0594-z 15838631 \n11. Bartl R Bartl C Drug-induced osteoporomalacia Bone disorders: biology, diagnosis, prevention, therapy 2017 Cham Springer 441 442 \n12. Cummings SR San Martin J McClung MR Siris ES Eastell R FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis N Engl J Med 2009 361 8 756 765 10.1056/NEJMoa0809493 19671655 \n13. Lipton A Fizazi K Stopeck AT Henry DH Brown JE Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials Eur J Cancer 2012 48 16 3082 3092 10.1016/j.ejca.2012.08.002 22975218 \n14. Shafqat H Alquadan KF Olszewski AJ Severe hypocalcemia after densumab in a patient with acquired Fanconi syndrome Osteoporos Int 2014 25 1187 1190 10.1007/s00198-013-2533-0 24158473 \n15. Chung T.-L. Chen N.-C. Chen C.-L. Severe hypophosphatemia induced by denosumab in a patient with osteomalacia and tenofovir disoproxil fumarate-related acquired Fanconi syndrome Osteoporosis International 2018 30 2 519 523 10.1007/s00198-018-4679-2 30171299\n\n",
"fulltext_license": "CC BY",
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"issue": "13(1)",
"journal": "Journal of medical case reports",
"keywords": "Adefovir dipivoxil; Chronic hepatitis B; Denosumab; Fanconi syndrome; Osteomalacia; Osteoporosis",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000998:Antiviral Agents; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D005198:Fanconi Syndrome; D006509:Hepatitis B; D006801:Humans; D017674:Hypophosphatemia; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates; D010018:Osteomalacia; D014055:Tomography, Emission-Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101293382",
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"pages": "99",
"pmc": null,
"pmid": "31003599",
"pubdate": "2019-04-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11486172;15327411;15838631;15861345;19671655;20133467;20661153;22975218;24158473;24368854;24492692;25614274;25721615;30171299",
"title": "Denosumab improves clinical manifestations of hypophosphatemic osteomalacia by adefovir-induced Fanconi syndrome: a case report.",
"title_normalized": "denosumab improves clinical manifestations of hypophosphatemic osteomalacia by adefovir induced fanconi syndrome a case report"
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"companynumb": "JP-GILEAD-2019-0404969",
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"activesubstancename": "LAMIVUDINE"
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"abstract": "BACKGROUND\nDimethyl fumarate (DMF) is approved for use in patients with relapsing-remitting multiple sclerosis (MS). Its mechanism of action is still not well understood, but besides the immunological pathways in MS, it may also affect the metabolism of normally functioning internal organs, tissues and cells.\n\n\nMETHODS\nWe report on the case of 29-year-old woman with satisfactorily-controlled type 1 diabetes (T1D), who was diagnosed as having MS. After administration of DMF she experienced intense, adverse gastro-intestinal reactions together with ketonuria up to 160 mg/dL. The highest ketone concentrations in the urine were observed approximately 2 h after each DMF dose and always with co-existing adverse reactions. Dose reduction did not improve symptoms and treatment had to be stopped. Twelve hours after the last dose of DMF all laboratory results returned to normal ranges and all gastro-intestinal adverse reactions were resolved within the following 24 h.\n\n\nCONCLUSIONS\nThis is a first report of ketonuria in a MS-patient with T1D treated with DMF. Patients with MS and co-existing metabolic diseases, which are not contraindicated for DMF treatment, represent a unique opportunity to address questions regarding the possible mechanisms of action of DMF on the cellular metabolism. The use of DMF in patients with metabolic diseases needs closer attention.",
"affiliations": "Department of Neurology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland. Electronic address: ewa26@mp.pl.;Department of Children's Diabetology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.",
"authors": "Krzystanek|Ewa|E|;Jarosz-Chobot|Przemyslawa|P|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069462:Dimethyl Fumarate",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2018.02.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "21()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "Adverse reaction; Diabetes mellitus; Dimethyl fumarate; Ketonuria; Multiple sclerosis",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000328:Adult; D003922:Diabetes Mellitus, Type 1; D000069462:Dimethyl Fumarate; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007662:Ketosis; D009103:Multiple Sclerosis",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "42-45",
"pmc": null,
"pmid": "29455073",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dimethyl fumarate in a patient with multiple sclerosis and type 1 diabetes mellitus: The importance of ketonuria.",
"title_normalized": "dimethyl fumarate in a patient with multiple sclerosis and type 1 diabetes mellitus the importance of ketonuria"
} | [
{
"companynumb": "PL-BIOGEN-2018BI00535692",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "INSULIN GLULISINE"
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{
"abstract": "Serious viral infections, due to delayed immune reconstitution, are a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Thus, many transplant centers prospectively track cellular immune recovery by evaluating absolute cell numbers and the phenotypic profile of reconstituting T cell subsets to identify individuals who are at highest risk of infection. Conventional assessments, however, fail to measure either the antigen specificity or functional capacity of reconstituting cells-both factors that correlate with endogenous antiviral protection. In this pilot study, we sought to address this limitation by prospectively investigating the tempo of endogenous immune reconstitution in a cohort of 23 pediatric HSCT patients using both quantitative (flow cytometry) and qualitative (IFNγ ELISpot) measures, which we correlated with either the presence or absence of infections associated with cytomegalovirus, adenovirus, Epstein-Barr virus, BK virus, human herpes virus 6, respiratory syncytial virus, parainfluenza, influenza, and human metapneumovirus. We present data spanning 12 months post-transplant demonstrating the influence of conditioning on immune recovery and highlighting the differential impact of active viral replication on the quantity and quality of reconstituting cells. Judicious use of standard (phenotypic) and novel (functional) monitoring strategies can help guide the clinical care and personalized management of allogenic HSCT recipients with infections.",
"affiliations": "Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston Methodist Hospital, Houston, Texas; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, and Medicine Baylor College of Medicine, Houston, Texas. Electronic address: swati.s.naik@gmail.com.;Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston Methodist Hospital, Houston, Texas; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.;Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston Methodist Hospital, Houston, Texas; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, and Medicine Baylor College of Medicine, Houston, Texas.;Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston Methodist Hospital, Houston, Texas; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.;Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston Methodist Hospital, Houston, Texas; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, and Medicine Baylor College of Medicine, Houston, Texas.;Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston Methodist Hospital, Houston, Texas; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, and Medicine Baylor College of Medicine, Houston, Texas.;Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston Methodist Hospital, Houston, Texas; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, and Medicine Baylor College of Medicine, Houston, Texas.;Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston Methodist Hospital, Houston, Texas; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, and Medicine Baylor College of Medicine, Houston, Texas.;Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston Methodist Hospital, Houston, Texas; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, and Medicine Baylor College of Medicine, Houston, Texas.",
"authors": "Naik|Swati|S|;Vasileiou|Spyridoula|S|;Aguayo-Hiraldo|Paibel|P|;Mukhi|Shivani|S|;Sasa|Ghadir|G|;Martinez|Caridad|C|;Krance|Robert A|RA|;Gottschalk|Stephen|S|;Leen|Ann|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2020.01.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "26(5)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Functional immune reconstitution; Viral infections",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D002648:Child; D020031:Epstein-Barr Virus Infections; D018380:Hematopoietic Stem Cell Transplantation; D004854:Herpesvirus 4, Human; D006801:Humans; D015166:Monitoring, Immunologic; D010865:Pilot Projects; D066027:Transplant Recipients",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "911-919",
"pmc": null,
"pmid": "31927102",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16151426;27207801;24914138;28783452;21057553;17311085;24146744;24406505;27385018;29297965;23092812;29211658;20399877;30993823;22314338;26908740;21236393;19747629;17934532;29542023;23178547;22210876;31481503;29678809",
"title": "Toward Functional Immune Monitoring in Allogeneic Stem Cell Transplant Recipients.",
"title_normalized": "toward functional immune monitoring in allogeneic stem cell transplant recipients"
} | [
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"abstract": "Pomalidomide dexamethasone is a standard of care for relapsed multiple myeloma (MM) patients who received at least two prior lines of therapy, including both lenalidomide and proteasome inhibitors (PI). We report here a real-life single-center series of 49 consecutive patients with relapsed and refractory MM treated with the triplet pomalidomide cyclophosphamide dexamethasone (PCD) combination. The median of prior lines of therapy was 3 and all patients were previously exposed to proteasome inhibitors and lenalidomide. The overall response rate was 76%, including 27% very good partial response or better. With a median follow-up of 16 months, the median progression-free survival (PFS) was 7.3 months and the median overall survival was not reached. Regarding safety, most frequent toxicity was hematologic, including 37% grade 3-4 cytopenias. Nine patients (18%) discontinued therapy due to adverse event. Our study confirms that PCD combination is feasible and results in favorable response rate and PFS in comparison with pomalidomide dexamethasone alone.",
"affiliations": "Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France.;Department of Hematology, Centre Hospitalier Universitaire, Nantes, France. cyrille.touzeau@chu-nantes.fr.",
"authors": "Trudel|Sabrina|S|;Tessoulin|Benoît|B|;Jullien|Maxime|M|;Blin|Nicolas|N|;Gastinne|Thomas|T|;Mahé|Béatrice|B|;Dubruille|Viviane|V|;Bonnet|Antoine|A|;Lok|Anne|A|;Chevallier|Patrice|P|;Peterlin|Pierre|P|;Garnier|Alice|A|;Guillaume|Thierry|T|;Le Bourgeois|Amandine|A|;Le Gouill|Steven|S|;Moreau|Philippe|P|;Touzeau|Cyrille|C|",
"chemical_list": "D011480:Protease Inhibitors; D013792:Thalidomide; D003907:Dexamethasone; D003520:Cyclophosphamide; C467566:pomalidomide; D000077269:Lenalidomide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-019-03649-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "98(6)",
"journal": "Annals of hematology",
"keywords": "Cyclophosphamide; Dexamethasone; Multiple myelomas; PCD; Pomalidomide; Relapse",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D003907:Dexamethasone; D004341:Drug Evaluation; D057915:Drug Substitution; D005260:Female; D006402:Hematologic Diseases; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D000077982:Progression-Free Survival; D011480:Protease Inhibitors; D012008:Recurrence; D012189:Retrospective Studies; D016879:Salvage Therapy; D013792:Thalidomide",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1441-1447",
"pmc": null,
"pmid": "30874851",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pomalidomide, cyclophosphamide, and dexamethasone for relapsed/refractory multiple myeloma patients in a real-life setting: a single-center retrospective study.",
"title_normalized": "pomalidomide cyclophosphamide and dexamethasone for relapsed refractory multiple myeloma patients in a real life setting a single center retrospective study"
} | [
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"companynumb": "FR-CELGENEUS-FRA-20190308962",
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"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
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{
"abstract": "BACKGROUND\nClostridium difficile is the most common cause of healthcare-associated infections and can have devastating morbidity and mortality. Traditional treatment algorithms involve intravenous metronidazole and enteric metronidazole or vancomycin. Fidaxomicin (DificidR) targets \"switch regions\" within RNA polymerases and effectively kills clostridium difficile bacteria and is typically administered orally primarily or through a naso/oro-gastric conduit.\n\n\nMETHODS\n55-year-old with a recent elective surgical procedure was hospitalized with multifocal pneumonia and subsequently developed clostridium difficile colitis. This patient failed the standard medical therapy for clostridium difficile colitis, decompensated and required surgical exploration, partial colectomy and mucous fistula creation. Following her surgery, her clinical condition improved and her colitis resolved with the antegrade administration of fidaxomicin through her mucous fistula.\n\n\nCONCLUSIONS\nFidaxomicin is a newer to market therapeutic agent that has been shown to be effective in the treatment of clostridium difficile colitis. Previously studies have shown benefit of oral fidaxomicin therapy for fulminant clostridium difficile but our study case report describes the index case of topical fidaxomicin through a mucous fistula.\n\n\nCONCLUSIONS\nIn our case of fulminant clostridium difficile colitis, Fidaxomicin administered in an antegrade fashion through a mucous fistula may have reduced the need for total colectomy in the treatment of fulminant clostridium difficile colitis.",
"affiliations": "George Washington University School of Medicine and Health Sciences, United States.;Department of General Surgery, George Washington University Hospital, United States. Electronic address: mdskancke@gwu.edu.;Department of General Surgery, George Washington University Hospital, United States.;Department of General Surgery, George Washington University Hospital, United States.",
"authors": "Arnott|Suzanne|S|;Skancke|Matthew|M|;Chen|Sheena|S|;Abell|Bruce|B|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2017.11.042",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(17)30620-X10.1016/j.ijscr.2017.11.042ArticleA case report of successful management of clostridium difficile colitis with antegrade Fidaxomicin through a mucous fistula obviating the need for subtotal colectomy Arnott Suzanne aSkancke Matthew mdskancke@gwu.edub⁎Chen Sheena bAbell Bruce ba George Washington University School of Medicine and Health Sciences, United Statesb Department of General Surgery, George Washington University Hospital, United States⁎ Corresponding author at: General Surgery Resident George Washington University Hospital 22nd & I Street, NW 6th Floor Suite 6B Washington, DC, United States mdskancke@gwu.edu27 11 2017 2018 27 11 2017 42 79 81 27 9 2017 22 11 2017 23 11 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• A novel case report of colon sparing treatment of clostridium difficile colitis.\n\n• Topical Fidaxomicin may be used to supplement treatment of resistant clostridium difficile colitis.\n\n• Antegrade administration of Fidaxomicin through a mucous fistula is feasible supplemental therapy.\n\n\n\nIntroduction\nClostridium difficile is the most common cause of healthcare-associated infections and can have devastating morbidity and mortality. Traditional treatment algorithms involve intravenous metronidazole and enteric metronidazole or vancomycin. Fidaxomicin (DificidR) targets “switch regions” within RNA polymerases and effectively kills clostridium difficile bacteria and is typically administered orally primarily or through a naso/oro-gastric conduit.\n\nPresentation of case\n55-year-old with a recent elective surgical procedure was hospitalized with multifocal pneumonia and subsequently developed clostridium difficile colitis. This patient failed the standard medical therapy for clostridium difficile colitis, decompensated and required surgical exploration, partial colectomy and mucous fistula creation. Following her surgery, her clinical condition improved and her colitis resolved with the antegrade administration of fidaxomicin through her mucous fistula.\n\nDiscussion\nFidaxomicin is a newer to market therapeutic agent that has been shown to be effective in the treatment of clostridium difficile colitis. Previously studies have shown benefit of oral fidaxomicin therapy for fulminant clostridium difficile but our study case report describes the index case of topical fidaxomicin through a mucous fistula.\n\nConclusion\nIn our case of fulminant clostridium difficile colitis, Fidaxomicin administered in an antegrade fashion through a mucous fistula may have reduced the need for total colectomy in the treatment of fulminant clostridium difficile colitis.\n\nKeywords\nFidaxomicinClostridium difficile colitis\n==== Body\n1 Introduction\nClostridium difficile (CD) is the most common cause of healthcare-associated infections with over half a million cases in the United States each year [1]. Oral fidaxomicin (DificidR) was approved by the FDA for the treatment of CD in 2011 and, in comparison to rectal vancomycin [2], [3], it targets “switch regions” within bacterial RNA polymerases. Fidaxomicin has been shown to effectively neutralizes CD species producing symptomatic cure and reduced recurrence. We present a case of fulminant CD colitis following treatment for hospital acquired multifocal pneumonia ultimately requiring an exploratory laparotomy and segmental colectomy. Following segmental colectomy, the patient was successfully treated with 10 days of antegrade fidaxomicin administered through the mucus fistula with subsequent stool polymerase chain reaction (PCR) testing showing remission of disease. The work in this case has been reported in line with the SCARE criteria [4].\n\n2 Case report\nA 55-year-old woman with a past medical history of hypertension, diabetes mellitus, prior transient ischemic attacks, and chronic kidney disease was admitted to the ICU for altered mental status after being found minimally responsive at home four postoperative days following an elective panniculectomy. Her initial workup was significant for a multi-focal pneumonia with concomitant acute kidney injury requiring initiation of hemodialysis. She was initially started on broad spectrum gram positive (vancomycin) and gram negative (piperacillin-tazobactam) coverage but on hospital day ten developed new onset watery diarrhea. Stool PCR testing was positive for CD and the patient was started on intravenous metronidazole (500 mg IV every six hours) and oral vancomycin (250 mg every six hours). After six days and despite double therapy, the patient’s disease progressed to fulminant CD colitis with advanced imaging showing pancolitis without evidence of megacolon or perforation. Rectal vancomycin (500 mg every six hours) and oral fidaxomicin (200 mg twice daily) were added however within two days the patient had decompensated, her leukocytosis had progressed to 54,000/ul, and she required multiple vasoactive medications to sustain a mean arterial pressure greater than 65 mmHg. The decision was made to proceed to the operating room for laparotomy and subtotal colectomy with an end ileostomy. The procedure was performed by a general surgeon with more than twenty years of experience with critical care surgery.\n\nDuring laparotomy, the right colon appeared edematous with evidence of significant inflammation with a transition point to healthy appearing colon distal to the hepatic flexure. Similarly, the small bowel appeared healthy proximal to the ileocecal valve. The ascending colon and small bowel extending 10 cm proximal to the ileocecal valve were resected leaving the patient in enteric discontinuity. The abdomen was then irrigated and a temporary abdominal closure vacuum dressing was placed and the patient was taken back to the ICU for continued resuscitation. While in the operating room, the resected colon and small bowel were opened on the back table revealing a significant burden of pseudomembranous disease within the ascending colon. Postoperative pathological analysis of the resected colon and small bowel confirmed our clinical suspicions identifying acute enterocolitis with transmural inflammation and luminal pseudo-membrane formation.\n\nThe patient remained hemodynamically stable overnight and was taken back to the operating room the following day for re-evaluation of the abdomen and potential abdominal closure. On second look, the terminal ileum and transverse colon appeared healthy without progression of clinical colitis. The terminal ileum and transverse colon stumps were externalized and matured following successful primary fascia closure (Fig. 1). Following the second operation, the mucus fistula developed new pseudomembranes consistent with persistent colitis. Over ten days, crushed fidaxomicin (200 mg twice daily) was administered through the mucous fistula by a red-rubber catheter in an antegrade fashion. During the ten-day course of antegrade fidaxomicin, the clinical burden of pseudomembranous disease on the mucous fistula receded, hemodynamic lability improved, and the leukocytosis cleared. Upon completion of the ten-day course of antegrade fidaxomicin by mucous fistula, repeat stool CD PCR studies from the mucous fistula were negative for CD.Fig. 1 Matured end ileostomy (A) and mucous fistula (B) following segmental right colectomy for fulminant clostridium difficile colitis. Note the presence of continued pseudomembranous disease on the mucous fistula prior to administration of antegrade fidaxomicin.\n\nFig. 1\n\n3 Discussion\nOver the last decade, there has been a notable increase in the severity of CD infections in addition to the discovery of new virulent strains [5]. With the high incidence and increased severity, the literature has proposed multiple new agents and strategies for managing CD infections that have failed to improve with metronidazole and vancomycin treatment alone [6]. Fidaxomicin was approved by the FDA for the treatment of CD in 2011 after it was shown to be non-inferior to rectal vancomycin in two large randomized controlled trials [7], [8]. While most of these initial patients only had mild to moderate illness, fidaxomicin has proven efficacy for symptomatic cure in addition to reducing disease recurrence compared to rectal vancomycin [3]. As a result, despite the higher cost of fidaxomicin, it has gained significant popularity for complicated CD infections [9].\n\nFidaxomicin is currently FDA approved for oral administration and has been demonstrated to have a 98–100% recovery when crushed and dispersed into various liquid vehicles [10]. Furthermore, multiple case reports have demonstrated successful medical management of severe CD colitis with crushed fidaxomicin through a nasogastric tube [11], [12]. Since CD colitis is a toxin mediated disease, postoperative antibiotics are usually also recommended even in the cases of subtotal colectomy which should in theory provide mechanical source control [13]. Given the morbidity of a subtotal colectomy, there has recently been a push towards bowel sparing treatment regimens, most notably being loop ileostomy with intraoperative colonic lavage and 10 days of vancomycin antegrade washes [14].\n\nWhile the initial administration of oral fidaxomicin in this case did not prevent the need for surgical intervention, it is possible that doses prior to surgery had not reached the affected colon secondary to the ileus from the patient’s inflammatory state. Following segmental resection, topical administration of fidaxomicin was possible, bypassing any prior absorption or transit issues with oral administration. Topical application of fidaxomicin has rarely been described in patients with severe disease requiring bowel resection. One prior case in the Czech Republic was described by Longin et al. where topical fidaxomicin 200 mg in small volume enemas was started after the patient failed to improve with metronidazole and vancomycin for eleven days after bowel resection. This patient eventually tested negative for CD by NAAT amplification and had successful gastrointestinal tract restoration after five months [15].\n\nIn this case, our patient failed to improve with intravenous metronidazole and rectal vancomycin alone, prompting the addition of oral fidaxomicin as a third agent for CD treatment. However, when the patient became hypotensive and refractory to resuscitation, surgical intervention was required. After the creation of her end-ileostomy and mucus fistula, crushed fidaxomicin successfully supplemented enteric vancomycin resulting in symptomatic and bacteriologic cure. This case report demonstrates a new administration route for fidaxomicin through mucous fistula that may prove effective in curing fulminant CD colitis obviating the need for subtotal colectomy.\n\nConflicts of interest\nWe have no conflicts of interest for this manuscript.\n\nFunding\nWe have no sources of funding for this research.\n\nEthical approval\nThe George Washington University IRB department does not require IRB approval for studies or analyses of less than 8 individuals. As this is a case report with one individual we believe this would be exempt from IRB approval provided that no identifying patient information is disclosed.\n\nConsent\nThe George Washington University Operative Consent form stipulates that patients “Agree to the appropriate disposal of any tissue or part removed from my body, to the taking of photographs during the procedure/operative/treatment for research, teaching, or scientific purposes as long as my identity is not disclosed.\" Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\nArnot, Suzanne − Manuscript production, study design, data analysis, patient care\n\nSkancke, Matthew − Manuscript production, study design, data analysis, patient care\n\nChen, Sheena − Study design, patient care\n\nAbell, Bruce − Manuscript production, study design, data analysis, patient care\n\nGuarantor\nMatthew Skancke and Bruce Abell\n==== Refs\nReferences\n1 Lessa F.C. Gould C.V. McDonald L.C. Current status of Clostridium difficile infection epidemiology Clin. Infect. Dis. 55 Suppl 2 2012 S65 70 22752867 \n2 Srivastava A. Talaue M. Liu S. New target for inhibition of bacterial RNA polymerase: switch region Curr. Opin. Microbiol. 14 5 2011 532 543 21862392 \n3 Nelson R.L. Suda K.J. Evans C.T. Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults Cochrane Database Syst. Rev. 3 2017 CD004610 28257555 \n4 Agha R.A. Fowler A.J. Saeta A. The SCARE Statement: Consensus-based surgical case report guidelines Int. J. Surg. 34 2016 180 186 27613565 \n5 Walters P.R. Zuckerbraun B.S. Clostridium difficile infection: clinical challenges and management strategies Crit. Care Nurse 34 4 2014 24 34 (quiz 35) 25086091 \n6 Fehér C. Soriano A. Mensa J. A review of experimental and off-Label therapies for clostridium difficile infection Infect Dis Ther 6 1 2017 1 35 27910000 \n7 Louie T.J. Miller M.A. Mullane K.M. Fidaxomicin versus vancomycin for Clostridium difficile infection N. Engl. J. Med. 364 5 2011 422 431 21288078 \n8 Cornely O.A. Crook D.W. Esposito R. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial Lancet Infect. Dis. 12 4 2012 281 289 22321770 \n9 Fehér C. Mensa J. A comparison of current guidelines of five international societies on clostridium difficile infection management Infect. Dis. Ther. 5 3 2016 207 230 27470257 \n10 Tousseeva A. Jackson J.D. Redell M. Stability and recovery of DIFICID(® ) (Fidaxomicin) 200-mg crushed tablet preparations from three delivery vehicles, and administration of an aqueous dispersion via nasogastric tube Drugs R. D. 14 4 2014 309 314 25424419 \n11 Maseda E. Hernandez-Gancedo C. Lopez-Tofiño A. Suarez-de-la Rica A. Garcia-Bujalance S. Gilsanz F. Use of fidaxomicin through a nasogastric tube for the treatment of septic shock caused by Clostridium difficile infection in a patient with oral cancer admitted to the Surgical Critical Care Unit Rev. Esp. Quimioter. 26 4 2013 375 377 http://www.ncbi.nlm.nih.gov/pubmed/24399354 24399354 \n12 Arends S. Defosse J. Diaz C. Wappler F. Sakka S.G. Successful treatment of severe Clostridium difficile infection by administration of crushed fidaxomicin via a nasogastric tube in a critically ill patient Int. J. Infect. Dis. 55 2017 27 28 28027991 \n13 van der Wilden G.M. Subramanian M.P. Chang Y. Antibiotic regimen after a total abdominal colectomy with ileostomy for fulminant clostridium difficile colitis: a multi-Institutional study Surg. Infect. (Larchmt) 16 4 2015 455 460 26069992 \n14 Neal M.D. Alverdy J.C. Hall D.E. Simmons R.L. Zuckerbraun B.S. Diverting loop ileostomy and colonic lavage: an alternative to total abdominal colectomy for the treatment of severe, complicated Clostridium difficile associated disease Ann. Surg. 254 3 2011 423-7-9 21865943 \n15 Bilek A. Longin P. Melichar A. Valeckova M. Local application of fidaxomicin in a patient with subtotal colectomy following recurring Clostridium difficile infection JMM Case Rep. 1 1 2014\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2210-2612",
"issue": "42()",
"journal": "International journal of surgery case reports",
"keywords": "Clostridium difficile colitis; Fidaxomicin",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "79-81",
"pmc": null,
"pmid": "29227855",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "28027991;25086091;27470257;26069992;21865943;21862392;28257555;27910000;22321770;25424419;27613565;21288078;24399354;22752867",
"title": "A case report of successful management of clostridium difficile colitis with antegrade Fidaxomicin through a mucous fistula obviating the need for subtotal colectomy.",
"title_normalized": "a case report of successful management of clostridium difficile colitis with antegrade fidaxomicin through a mucous fistula obviating the need for subtotal colectomy"
} | [
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"companynumb": "US-AXELLIA-001229",
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"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
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"abstract": "We conducted a phase I/II trial to assess the efficacy of cladribine, thiotepa and antithymocyte globulin as a reduced-intensity conditioning regimen for refractory or high-risk hematologic malignancy. The preparative regimen consisted of cladribine 5 mg/m(2)/day for 5 days, thiotepa 200 mg/m(2)/day for 3 days and ATG 3 mg/kg/day (day - 5) followed by allogeneic peripheral blood stem cell transplant. Twelve patients were transplanted from a human leukocyte antigen (HLA) matched family member. Two patients were treated at dose level I but both experienced grade IV dose limiting toxicities, and therefore the thiotepa dose was reduced to 133 mg/m(2)/day (dose level II). Only two of the next six patients experienced dose limiting toxicities. Median age was 46 years. At dose level II, the median time to neutrophil and platelet engraftment was 17 and 20 days, respectively. The incidence of acute and chronic graft-versus-host disease (GVHD) was 40% and 30%, respectively. Day + 100 non-relapse mortality was 0% and at 1 year was 20%. Median overall survival (OS) was 42 months and 2-year OS was 70%. Median progression-free survival (PFS) was 11 months and 2-year PFS was 40%. We conclude that the reduced-intensity conditioning regimen of cladribine, thiotepa and ATG achieved excellent donor chimerism with acceptable toxicity.",
"affiliations": "Department of Medicine, Mayo Clinic, Rochester, MN, USA.",
"authors": "Larsen|Jeremy T|JT|;Hogan|William J|WJ|;Micallef|Ivana N|IN|;Dispenzieri|Angela|A|;Gertz|Morie A|MA|;Inwards|David J|DJ|;Tun|Han W|HW|;Roy|Vivek|V|;Geyer|Susan M|SM|;Allred|Jacob B|JB|;Wu|Wenting|W|;Ansell|Stephen M|SM|;Elliott|Michelle A|MA|;Tefferi|Ayalew|A|;Porrata|Luis F|LF|;Gastineau|Dennis A|DA|;Lacy|Martha Q|MQ|;Litzow|Mark R|MR|",
"chemical_list": "D000961:Antilymphocyte Serum; D017338:Cladribine; D013852:Thiotepa",
"country": "United States",
"delete": false,
"doi": "10.3109/10428194.2012.753444",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "54(8)",
"journal": "Leukemia & lymphoma",
"keywords": null,
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000961:Antilymphocyte Serum; D000971:Antineoplastic Combined Chemotherapy Protocols; D017338:Cladribine; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D013852:Thiotepa; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1713-8",
"pmc": null,
"pmid": "23189958",
"pubdate": "2013-08",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "A phase I/II trial of reduced intensity allogeneic hematopoietic cell transplant for hematologic malignancies using cladribine, thiotepa and rabbit antithymocyte globulin.",
"title_normalized": "a phase i ii trial of reduced intensity allogeneic hematopoietic cell transplant for hematologic malignancies using cladribine thiotepa and rabbit antithymocyte globulin"
} | [
{
"companynumb": "US-JNJFOC-20130717621",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "Although pseudoseizures are a cause of drug toxicity (as escalating doses are used in an attempt to suppress seemingly intractable spells), in this brief report the exact converse is argued: namely, that a sub-group of pseudoseizures may arise as a reversible idiosyncratic toxic side-effect of GABAergic anticonvulsants. The term \"organic pseudoseizures\" is used to denote this group of medication related behavioural alterations.",
"affiliations": "Department of Medicine (Neurology), School of Biomedical Engineering, 6274 Coburg Road, Chemistry Building, Dalhousie University, Halifax, NS, B3H 4J3, Canada. weaver@chem3.chem.dal.ca",
"authors": "Weaver|Donald F|DF|",
"chemical_list": "D000927:Anticonvulsants; D018682:GABA Agents",
"country": "England",
"delete": false,
"doi": "10.1016/j.seizure.2003.10.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-1311",
"issue": "13(7)",
"journal": "Seizure",
"keywords": null,
"medline_ta": "Seizure",
"mesh_terms": "D000927:Anticonvulsants; D004569:Electroencephalography; D018682:GABA Agents; D006801:Humans; D012640:Seizures; D013001:Somatoform Disorders",
"nlm_unique_id": "9306979",
"other_id": null,
"pages": "467-9",
"pmc": null,
"pmid": "15324822",
"pubdate": "2004-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "\"Organic\" pseudoseizures as an unrecognized side-effect of anticonvulsant therapy.",
"title_normalized": "organic pseudoseizures as an unrecognized side effect of anticonvulsant therapy"
} | [
{
"companynumb": "CA-LUNDBECK-DKLU1105677",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VIGABATRIN"
},
"drugadditional": null,
... |
{
"abstract": "Cyclophosphamide (CYC) has long been considered a gold standard in inducing renal remission and preventing renal flares for patients with systemic lupus erythematosus (SLE). However, the rational use of CYC has not reached a consensus, such as the timing and length of treatment, the route of administration, and the ideal dosage. The objective of this study was to assess the efficacy and safety of short-interval lower-dose (SILD) intravenous (IV) CYC in the treatment of SLE. A total of 225 patients with lupus nephritis were randomly assigned to a 1-year trial, either the SILD group (12 fortnightly pulses at a fixed dose of 400 mg followed by 6 monthly pulses) or high-dose (HD) group (6 monthly pulses followed by two quarterly pulses at a dose of 0.5~1.0 g/m(2)). At 6 months of treatment, 28 % (30/107) of patients in the SILD group reached a complete remission (CR), and 51.4 % (55/107) were in partial remission (PR), as compared with 32.7 % (35/107) and 45.8 % (49/107) in the HD group, respectively. Serum albumin, 24-h urinary protein, and the scores of disease activity were significantly improved in both groups at 6 months and maintained at the end of clinical trial. However, the SILD group showed much less menstrual disturbances (11.5 %), gastrointestinal adverse effects (5.3 %), and leukopenia (9.7 %) than the HD group (28.6, 26.8, and 19.8 %, respectively) at the end of clinical trial. The efficacy of the short-interval lower-dose (SILD) IV CYC regimen in the treatment of lupus nephritis is equivalent to that of the high-dose (HD) regimen, whereas the incidence of adverse events is much lower in the SILD group.",
"affiliations": "Department of Rheumatology and Immunology, Peking University People's Hospital, 11 South Xizhimen Street, Beijing, 100044, People's Republic of China.",
"authors": "Zhang|X W|XW|;Li|Chun|C|;Ma|X X|XX|;Zhao|J X|JX|;An|Yuan|Y|;Liu|Shuang|S|;Li|Yan|Y|;Li|Z G|ZG|",
"chemical_list": "D007166:Immunosuppressive Agents; D012709:Serum Albumin; D003520:Cyclophosphamide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-014-2590-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "33(7)",
"journal": "Clinical rheumatology",
"keywords": null,
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000328:Adult; D003520:Cyclophosphamide; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D007275:Injections, Intravenous; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis; D008597:Menstrual Cycle; D008875:Middle Aged; D011446:Prospective Studies; D011507:Proteinuria; D012074:Remission Induction; D012709:Serum Albumin; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "939-45",
"pmc": null,
"pmid": "24744152",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D016449:Randomized Controlled Trial",
"references": "1585937;23263867;15485101;11315345;8164443;16221103;1948102;15082482;10215343;8770998;11479150;9324032;309095;2694209;11953978;1356175;11036121;11717709;7463697;12209517;12587819;866565;22087680;9306871;12465154;10499308;15593207;8569982",
"title": "Short-interval lower-dose intravenous cyclophosphamide as induction and maintenance therapy for lupus nephritis: a prospective observational study.",
"title_normalized": "short interval lower dose intravenous cyclophosphamide as induction and maintenance therapy for lupus nephritis a prospective observational study"
} | [
{
"companynumb": "CN-BAXTER-2015BAX018227",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nMethotrexate (MTX) has the potential to cause serious adverse reactions and even mortality. We analyzed the predisposing factors and outcome in patients with MTX-induced pancytopenia admitted into our unit from 1996 to 2015.\n\n\nMETHODS\nPatients were identified by departmental database search. Pancytopenia was defined as white blood cell count (WBC) < 3500 cells/mm3 , hemoglobin (Hb) < 11 g/dL and platelet count < 150 000 cells/mm3 . Severe pancytopenia was defined as WBC < 2000 cells/mm3 , Hb < 10 g/dL and platelet count < 50 000 cells/mm3 .\n\n\nRESULTS\nForty-six patients were included in the study (female = 35). Twenty-four had been under the care of either primary care physicians or orthopedic surgeons and presented to us with pancytopenia. Sixteen patients had severe pancytopenia. Disease distribution was as follows: rheumatoid arthritis 33, psoriasis eight, systemic sclerosis two and others three. The median dose of MTX was 10 mg/week and median duration of treatment was 11 months. The median cumulative dose was 750 mg. Symptoms at presentation included: oral mucositis (n = 37); fever (n = 24); diarrhea (n = 12), bleeding gums (n = 5) and purpura (n = 3). The potential risk factors were: hypoalbuminemia (n = 23), renal insufficiency (n = 14), dosing errors (n = 13) and non-supplementation of folates (n = 7). Thirteen patients died. WBC at admission was found to determine survival (P < 0.05).\n\n\nCONCLUSIONS\nIn patients on MTX, oral mucositis and fever can herald pancytopenia. MTX-induced pancytopenia is associated with high mortality. WBC at admission is the most important prognostic factor. There is need for increased awareness among physicians to minimize prescribing errors. A national guideline on monitoring of patients on MTX is desirable.",
"affiliations": "Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.;Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.;Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.;Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.;Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.;Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.;Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.;Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.;Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.",
"authors": "Ajmani|Sajal|S|;Preet Singh|Yogesh|Y|;Prasad|Shiva|S|;Chowdhury|Abhra|A|;Aggarwal|Amita|A|;Lawrence|Able|A|;Misra|Ramnath|R|;Mishra|Richa|R|;Agarwal|Vikas|V|",
"chemical_list": "D018501:Antirheumatic Agents; D015415:Biomarkers; D006454:Hemoglobins; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.13004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-1841",
"issue": "20(7)",
"journal": "International journal of rheumatic diseases",
"keywords": "drug induced pancytopenia; methotrexate; methotrexate toxicity",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D015415:Biomarkers; D016208:Databases, Factual; D005260:Female; D006454:Hemoglobins; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D010198:Pancytopenia; D010976:Platelet Count; D011565:Psoriasis; D012307:Risk Factors; D012595:Scleroderma, Systemic",
"nlm_unique_id": "101474930",
"other_id": null,
"pages": "846-851",
"pmc": null,
"pmid": "28261918",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Methotrexate-induced pancytopenia: a case series of 46 patients.",
"title_normalized": "methotrexate induced pancytopenia a case series of 46 patients"
} | [
{
"companynumb": "IN-MYLANLABS-2017M1052311",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "NUT midline carcinoma (NMC) is a rare, aggressive poorly differentiated carcinoma genetically defined by NUTM1 gene rearrangement. The purpose of this study was to determine the tumor mutational burden (TMB) and the expression of immunohistochemical (IHC) markers in NMCs that are generally used to identify patients that might benefit from checkpoint immunotherapy. Three cases in a 39-year-old male (case 1) and two 13-year-old females (cases 2, 3) were identified from departmental files, with confirmation by NUT IHC and 15q14 rearrangement by fluorescent in situ hybridization. Normal-tumor paired whole exome sequencing (WES) was applied to determine TMB. IHC for DNA mismatch repair proteins, Programmed cell death ligand 1, programmed cell death 1 (PD1), and CD8 was also performed. WES yielded a TMB of 7.61 and 1.52 per Mbp in the primary and pulmonary metastasis in case 1, respectively, and a TMB of 1.04 per Mbp in the primary tumor of case 2. Programmed cell death ligand 1 tumor proportion score was 20%, 1%, and 0% and combined positive score was 25, 5, and 0 in cases 1, 2, and 3, respectively; PD1 stain counts were 25, 52, and 35 per high-power field and the PD1/CD8 ratio was 95%, 95%, and 99% in cases 1, 2, and 3, respectively. The CD8 count per high-power field was 15, 33, and 30 per high-power field in cases 1, 2, and 3, respectively. Mismatch repair IHCs showed retained staining. Although the number of cases is limited, this study is the first to investigate checkpoint immunotherapy markers in NMCs and the results demonstrate no clear biomarker association. However, the results suggest that, if checkpoint therapy is under consideration, a comprehensive workup utilizing WES and IHC is warranted.",
"affiliations": "Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO.;Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO.;Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA.;Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO.;Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO.;Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO.",
"authors": "He|Mai|M|;Chernock|Rebecca|R|;Zhou|Shengmei|S|;Gondim|Mercia|M|;Dehner|Louis P|LP|;Pfeifer|John D|JD|",
"chemical_list": "D014408:Biomarkers, Tumor; D016827:CD8 Antigens; D000082082:Immune Checkpoint Inhibitors; C000630260:NUTM1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor",
"country": "United States",
"delete": false,
"doi": "10.1097/PAI.0000000000000781",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-4058",
"issue": "28(7)",
"journal": "Applied immunohistochemistry & molecular morphology : AIMM",
"keywords": null,
"medline_ta": "Appl Immunohistochem Mol Morphol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor; D016827:CD8 Antigens; D002277:Carcinoma; D053843:DNA Mismatch Repair; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms; D008297:Male; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D061026:Programmed Cell Death 1 Receptor; D000073359:Whole Exome Sequencing",
"nlm_unique_id": "100888796",
"other_id": null,
"pages": "495-500",
"pmc": null,
"pmid": "31180909",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Tumor Mutation Burden and Checkpoint Immunotherapy Markers in NUT Midline Carcinoma.",
"title_normalized": "tumor mutation burden and checkpoint immunotherapy markers in nut midline carcinoma"
} | [
{
"companynumb": "US-AMGEN-USASP2020169844",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": null,
... |
{
"abstract": "To test whether patients with MS on disease-modifying treatments (DMTs) are at a higher risk of acute or chronic hepatitis E virus (HEV) infections or extrahepatic manifestations, we monitored approximately 1,100 persons with MS (pwMS) during 3 years for HEV infection.\n\n\n\nThis is an observational case series study. All pwMS were followed in our MS center between January 2016 and December 2018 with at least annual standardized clinical and laboratory assessments. Patients with unexplained liver enzyme elevations were routinely screened for HEV infection.\n\n\n\nFour cases of acute HEV under DMT (fingolimod [n = 3]; dimethyl fumarate [n = 1]) were identified. Two presented with fulminant icteric hepatitis and one with a HEV-associated neurologic manifestation (neuralgic amyotrophy). No chronic HEV courses were observed. DMT was continued after clearing of HEV or normalization of liver function tests in all cases.\n\n\n\nHEV infection is an important differential diagnosis of drug-induced liver injury in pwMS under DMT. Our data do not suggest an increased incidence of acute HEV infections or chronification in pwMS. However, epidemiologic studies in immunomodulatory-treated patients are needed to further investigate HEV disease courses and extrahepatic manifestations.",
"affiliations": "From the Departments of Medicine, University Hospital Basel, Neurologic Clinic and Policlinic, Clinical Research and Biomedicine, University of Basel, Petersgraben, Switzerland.;From the Departments of Medicine, University Hospital Basel, Neurologic Clinic and Policlinic, Clinical Research and Biomedicine, University of Basel, Petersgraben, Switzerland.;From the Departments of Medicine, University Hospital Basel, Neurologic Clinic and Policlinic, Clinical Research and Biomedicine, University of Basel, Petersgraben, Switzerland.;From the Departments of Medicine, University Hospital Basel, Neurologic Clinic and Policlinic, Clinical Research and Biomedicine, University of Basel, Petersgraben, Switzerland.;From the Departments of Medicine, University Hospital Basel, Neurologic Clinic and Policlinic, Clinical Research and Biomedicine, University of Basel, Petersgraben, Switzerland.;From the Departments of Medicine, University Hospital Basel, Neurologic Clinic and Policlinic, Clinical Research and Biomedicine, University of Basel, Petersgraben, Switzerland.;From the Departments of Medicine, University Hospital Basel, Neurologic Clinic and Policlinic, Clinical Research and Biomedicine, University of Basel, Petersgraben, Switzerland. bernhard.decard@usb.ch.",
"authors": "Diebold|Martin|M|;Fischer-Barnicol|Bettina|B|;Tsagkas|Charidimos|C|;Kuhle|Jens|J|;Kappos|Ludwig|L|;Derfuss|Tobias|T|;Décard|Bernhard F|BF|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068717:Glatiramer Acetate; D000069462:Dimethyl Fumarate; D000068876:Fingolimod Hydrochloride; D000068556:Interferon beta-1a",
"country": "United States",
"delete": false,
"doi": "10.1212/NXI.0000000000000594",
"fulltext": "\n==== Front\nNeurol Neuroimmunol NeuroinflammNeurol Neuroimmunol NeuroinflammnnnNEURIMMINFLNeurology® Neuroimmunology & Neuroinflammation2332-7812Lippincott Williams & Wilkins Hagerstown, MD NEURIMMINFL201902088310.1212/NXI.00000000000005941441132142ArticleHepatitis E virus infections in patients with MS on oral disease-modifying treatment Diebold Martin MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for travel or speaker honoraria:\nReceived speaker honoraria from Biogen Switzerland used for research purposes exclusively.\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nResearch grant by fund of the University of Basel.\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nFischer-Barnicol Bettina MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for travel or speaker honoraria:\nreceived Speaker honoraria from biogen for her instituion (University Hospital basel), which were only used for research\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nTsagkas Charidimos MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for travel or speaker honoraria:\n(1) European Committee for Treatment and Research in Multiple Sclerosis (2)European Charcot Foundation\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nNONE\n\n\n\nResearch Support, Government Entities:\n(1)Swiss National Science Foundation,Grant number: 320030_156860 (2)University Basel, 3M1020\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nNONE\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nKuhle Jens MD, PhDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for travel or speaker honoraria:\nJK?s institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: Speaker honoraria: (1) Swiss MS Society (2) Biogen (3) Novartis (4) Roche (5) Genzyme Travel expenses: (1) Merck Serono (2) Novartis (3) Roche\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\n(1) Bayer AG (2) Biogen (3) Celgene (4) Genzyme (5) Merck (4) Novartis (5) Roche Pharma (Schweiz) AG\n\n\n\nResearch Support, Government Entities:\n(1) Swiss National Research Foundation\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\n(1) ECTRIMS Research Fellowship Programme (2) University of Basel (3) Swiss MS Society\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nKappos Ludwig MDScientific Advisory Boards:\nNONE\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nNONE\n\n\n\nEditorial Boards:\n(1)Multiple Sclerosis Journal, (2)Multiple Sclerosis and Related Disorders (3)Journal of Neurology member of the Editorial Board\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\n(1)Actelion, (2)Allmirall, (3)Bayer, (4) Baxalta, (5)Biogen, (6) CSL Behring,(7)Excemed, (8)Desitin, (9)GeNeuro SA, (10) Genzyme, (11)Japan Tobacco,(12)Merck, (13) Minoryx,(14)Mitsubishi Pharma, (15)Novartis, (16) Celgene,(17)Receptos/Celgene, (18)Roche, (19)sanofi-aventis,(20)Santhera,(21)Teva,\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\n(1)the Swiss MS Society, (2)the Swiss National Research Foundation, (3)the European Union, (4)Roche Research Foundations\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense fee payments, Technology or Inventions:\n(1) license fees for Neurostatus products paid directly to University Hospital Basel\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nDerfuss Tobias MDScientific Advisory Boards:\nScientific advisory boards for (1) Biogen (2) Novartis (3) Genzyme (4) Merck (5) Bayer (6) Octapharma (7) GeNeuro (8) Roche (9) Actelion (10) Celgene (11) MedDay\n\n\n\nGifts:\nNONE\n\n\n\nFunding for travel or speaker honoraria:\ntravel and speaker honoraria from (1) Biogen (2) Merck (3) Novartis (4) Genzyme (5) Roche\n\n\n\nEditorial Boards:\nMember of the Editorial board of Plos One\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nMy wife is an employee of Novartis.\n\n\n\nConsultancies:\nMember of steering committee in clinical trials by Novartis, Merck, Mitsubishi Pharma and GeNeuro\n\n\n\nSpeakers' Bureaus:\n(1) Biogen (2)Novartis (3) Merck (4) Genzyme (5) Roche\n\n\n\nOther activities:\nMember of the Executive board of ECTRIMS (non-profit entity)\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\n(1) Novartis (2) Biogen\n\n\n\nResearch Support, Government Entities:\n(1)PI of a projected funded by the Swiss National Foundation\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\n(1) Swiss MS Society\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nMy wife owns stocks options from Novartis\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nDécard Bernhard F. MDScientific Advisory Boards:\nBernhard D?card received for the institution (University Hospital Basel) fees from advisory boards or speaker fees from Biogen, Teva and Novartis, that were used exclusively for research support.\n\n\n\nGifts:\nNONE\n\n\n\nFunding for Travel or Speaker Honoraria:\nBernhard D?card received for the institution (University Hospital Basel) fees from advisory boards or speaker fees from Biogen, Teva and Novartis, that were used exclusively for research support. Dr. Bernhard D?card received travel support from Biogen and Genzyme.\n\n\n\nEditorial Boards:\nNONE\n\n\n\nPatents:\nNONE\n\n\n\nPublishing Royalties:\nNONE\n\n\n\nEmployment, Commercial Entity:\nNONE\n\n\n\nConsultancies:\nNONE\n\n\n\nSpeakers' Bureaus:\nNONE\n\n\n\nOther Activities:\nNONE\n\n\n\nClinical Procedures or Imaging Studies:\nNONE\n\n\n\nResearch Support, Commercial Entities:\nBernhard D?card received for the institution (University Hospital Basel) fees from advisory boards or speaker fees from Biogen, Teva and Novartis, that were used exclusively for research support.\n\n\n\nResearch Support, Government Entities:\nNONE\n\n\n\nResearch Support, Academic Entities:\nNONE\n\n\n\nResearch Support, Foundations and Societies:\nBD receives Research Support from the Swiss MS Society and the Bangerter-Rhyner Stiftung.\n\n\n\nStock/Stock Options/Board of Directors Compensation:\nNONE\n\n\n\nLicense Fee Payments, Technology or Inventions:\nNONE\n\n\n\nRoyalty Payments, Technology or Inventions:\nNONE\n\n\n\nStock/Stock Options, Research Sponsor:\nNONE\n\n\n\nStock/Stock Options, Medical Equipment & Materials:\nNONE\n\n\n\nLegal Proceedings:\nNONE\n\n\n\nFrom the Departments of Medicine, University Hospital Basel, Neurologic Clinic and Policlinic, Clinical Research and Biomedicine, University of Basel, Petersgraben, Switzerland.Correspondence Dr. Décard bernhard.decard@usb.chGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.\n\nThe Article Processing Charge was funded by the authors.\n\n11 7 2019 9 2019 11 7 2019 6 5 e59401 4 2019 23 5 2019 Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.2019American Academy of NeurologyThis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Objective\nTo test whether patients with MS on disease-modifying treatments (DMTs) are at a higher risk of acute or chronic hepatitis E virus (HEV) infections or extrahepatic manifestations, we monitored approximately 1,100 persons with MS (pwMS) during 3 years for HEV infection.\n\nMethods\nThis is an observational case series study. All pwMS were followed in our MS center between January 2016 and December 2018 with at least annual standardized clinical and laboratory assessments. Patients with unexplained liver enzyme elevations were routinely screened for HEV infection.\n\nResults\nFour cases of acute HEV under DMT (fingolimod [n = 3]; dimethyl fumarate [n = 1]) were identified. Two presented with fulminant icteric hepatitis and one with a HEV-associated neurologic manifestation (neuralgic amyotrophy). No chronic HEV courses were observed. DMT was continued after clearing of HEV or normalization of liver function tests in all cases.\n\nConclusion\nHEV infection is an important differential diagnosis of drug-induced liver injury in pwMS under DMT. Our data do not suggest an increased incidence of acute HEV infections or chronification in pwMS. However, epidemiologic studies in immunomodulatory-treated patients are needed to further investigate HEV disease courses and extrahepatic manifestations.\n\nOPEN-ACCESSTRUE\n==== Body\nHepatitis E virus (HEV) is the most common cause of hepatitis worldwide. Whereas HEV genotypes 1 and 2 are usually responsible for water-born outbreaks in developing countries, genotype 3 is endemic in Europe and North America and typically transmitted via the consumption of raw or undercooked pork meat and contaminated blood products. HEV IgG seroprevalence increases with age, and high rates have been reported in developed countries (IgG 20.4% in Switzerland) including hyperendemic regions such as southwest France, suggesting underestimation of the real impact of this disease in high-risk populations.1,2 Most HEV genotype 3 infections (>90%) are asymptomatic or show acute self-limiting courses, but chronic hepatitis and extrahepatic manifestations can occur. Chronic HEV infections, defined as persistence of positive HEV PCR for >6 months, are more frequent in immunocompromised patients. Patients with chronic HEV infection can develop rapid progression to liver cirrhosis.3\n\nTo date, more than 10 disease-modifying treatments (DMTs) are available for immunomodulation of MS. The use of highly effective DMTs may be associated with increasing risks for the development of infectious side effects. Whether persons with MS (pwMS) under DMTs are more susceptible for acute or chronic HEV infections or extrahepatic manifestations is unknown. Here, we describe the first case series of HEV infection in immunomodulatory-treated pwMS and discuss potential implications for the clinical management.\n\nMethods\nBetween January 2016 and December 2018, on average, 1,084 pwMS per year were regularly followed with standardized clinical and laboratory assessments at the MS outpatient center at the University Hospital Basel, Switzerland. Patients with unexplained liver enzyme elevations were routinely screened for HEV infection. We identified 4 pwMS with symptomatic or asymptomatic HEV infection (identified by simultaneously elevated HEV IgG and IgM and/or viremia4) in our regularly followed MS cohort (figure 1).\n\nFigure 1 (A) Clinical and laboratory courses of MS and hepatitis E virus (HEV) infection\nTime course of liver test results, key clinical features, and DMT in 4 persons with MS. Laboratory graphs depict courses of alanine transaminase, gamma-glutamyltransferase, and alkaline phosphatase (all shown in units/L). B, Extrahepatic HEV manifestation with neuralgic amyotrophy of the right shoulder (patient 4). High-resolution nerve ultrasound (Philips Affiniti 50G, linear 5–18 MHz probe) shows significant enlargements of C6 ventral nerve root (14.1 mm2 [B.a] right vs 11.1 mm2 left [not shown]) and proximal median nerve cross-sectional area (14.5 mm2 right [B.b] vs 11.5 mm2 left [not shown]) on the affected right side. Of note, the right median nerve further exhibited an enlarged hypoechoic fascicle (green circle B.b). A winged scapula was observed on clinical examination (B.c). ALAT = alanine transaminase; alk. phos. = alkaline phosphatase; GGT = gamma-glutamyltransferase.\n\nData availability\nAll 4 HEV patients signed an informed consent. Anonymized data not published within this article will be made available by request from any qualified investigator.\n\nResults\nPatient 1\nA 21-year-old woman was diagnosed with relapsing-remitting MS (RRMS) and treated with glatiramer acetate (GAA) for 23 months. Ten months after switching to fingolimod (FGL) due to disease activity on MRI, she developed asymptomatic elevation of liver enzymes, and an acute HEV infection was diagnosed by positive serology (see the table for patient details). FGL was not discontinued because the trend of liver enzymes suggested recovery from HEV. The patient remained stable at Expanded Disability Status Scale (EDSS) 1.5.\n\nTable Characteristics of MS and HEV infection\n\nPatient 2\nA 40-year-old man was diagnosed with RRMS and treated with FGL for 12 years without signs of clinical or MRI disease activity. He then presented with an acute icteric hepatic syndrome and significantly elevated liver enzymes. PCR and positive serology confirmed the diagnosis of an acute HEV infection. FGL was stopped and restarted 4 weeks after HEV PCR became negative. The patient remained stable at EDSS 3.5.\n\nPatient 3\nA 25-year-old woman was diagnosed with RRMS and received GAA for 8 years and natalizumab (NTZ) for 7 years. When her John Cunningham virus antibody status became positive, she was switched to FGL. After 4 years of FGL treatment, she developed an acute icteric hepatic syndrome with elevated liver enzymes. Positive PCR and serology confirmed the diagnosis of an acute HEV infection. FGL was discontinued for 6 weeks until HEV PCR was negative. The patient remained stable at EDSS 2.5.\n\nPatient 4\nA 48-year-old woman was initially diagnosed with a clinically isolated syndrome and treated with interferon-ß 1a intramuscular for 79 months. MS was diagnosed due to imaging and clinical disease activity, and she switched to dimethyl fumarate (DMF) at EDSS 3.5. After 2 months, she developed a painful shoulder syndrome with a subtle scapula alata on the right side (figure 2, B.c) accompanied by moderate liver enzyme elevations and a short-term drop of 45% in lymphocyte count (from 1,196 to 651 per μL). After detection of an acute HEV infection by positive serology, DMF treatment was suspended. Nerve ultrasound showed significant enlargements of the ventral nerve root C6 (figure 2, B.a) and the proximal median nerve with an enlarged hypoechoic fascicle (figure 2, B.b) on the affected side, suggesting a “forme fruste” of HEV-associated neuralgic amyotrophy (NA).5\n\nFigure 2 Diagnosis of HEV infection and practical considerations in patients with MS\nAdapted from EASL Clinical Practice Guidelines on hepatitis E virus infection 2018.4 HEV = hepatitis E virus. IgM = anti-HEV immunoglobulin M; IVIG = intravenous immunoglobulins; MS = multiple sclerosis.\n\nAfter normalization of liver enzymes, the patient was treated temporarily with NTZ and DMF before she stopped both treatments for personal reasons. She recovered well from NA, but developed new MS-associated symptoms with EDSS 4.0 in the subsequent year.\n\nDiscussion\nBetween 2016 and 2018, we identified 4 cases of HEV infections in our regularly followed monocentric cohort with approximately 1,100 pwMS. Although liver enzyme levels in immunosuppressed patients with acute HEV infections were reported to be lower than in immunocompetent patients,3,6 2/4 of our cases (both under FGL) developed fulminant icteric HEV courses with strongly elevated liver enzymes and evidence of viremia. On the other hand, patient 1 had a clinically asymptomatic HEV disease course under continued FGL and only minor liver function test elevations. Liver enzyme elevations in patient 4 were moderate, and HEV infection under DMF became symptomatic with a mild form of HEV-associated NA.5 In 3 cases, we temporarily discontinued and restarted a DMT after normalization of liver enzymes. Because drug-induced liver injury (DILI) is a common feature in a number of DMTs, our case series underlines the relevance of acute HEV infections as important differential diagnosis of DILI in pwMS and unexpected liver enzyme elevations (HEV diagnostic steps and practical considerations, figure 2). HEV infection in all 4 patients was not associated with concomitant signs of clinical or radiologic MS disease activity.\n\nLittle is known about the disease course—and eventual chronification—of HEV infections under immunomodulation. Bauer et al.7 described a series of 23 rheumatologic patients under immunosuppression without evidence of chronic HEV. However, immunocompromised solid organ transplant patients (especially under tacrolimus and with low lymphocyte counts) seem to have an elevated risk of persistent viremia and transition to chronic HEV infection.3 In our cases, duration of viremia, present in 2/4 cases, was short, and none developed a chronic HEV disease course.\n\nThe mechanism by which certain HEV strains cause extrahepatic and specifically neurologic injury, as NA in our case, remains elusive. Possible pathophysiologic concepts include direct affection of nervous tissue by the virus and immune-mediated damage to neural targets. PwMS under DMT might be more prone to direct neural infection and less susceptible for immune-mediated neurologic injury. In line with this hypothesis, in a recently published case-control study with 200 prospectively followed HEV infections, neurologic symptoms were observed in 22.6% of immunocompetent and only 3.2% of immunocompromised patients (p < 0.001).6\n\nCurrently, there are no data on prevalence, incidence, and disease course of HEV infections in pwMS. Although our data do not allow a precise epidemiologic evaluation of HEV in pwMS, in a cautious estimation, we may assume a minimal annual incidence of 0.12% in our patient population. The incidence of HEV infection varies geographically, and reliable data are scarce. Several studies in developed countries estimated annual incidence rates between 0.35% and 1.1% in healthy blood donors.8,9 The annual incidence in immunocompromised solid organ–transplanted patients was estimated to reach up to 3.2%.10 Even if oligo- or asymptomatic HEV infections may have remained undetected, our study does not suggest an increased overall risk for HEV infections in pwMS. With respect to a large proportion of oral treatments in our patient population, we cannot clarify whether certain DMTs or a treatment-associated lymphopenia may influence the susceptibility for symptomatic HEV infections. Systematic, prospective observations in larger MS cohorts may allow estimating an accurate prevalence of HEV-related liver and neurologic damage and their relation to specific DMTs.\n\nStudy funding\nNo targeted funding reported.\n\nDisclosure\nM. Diebold received grants from the University of Basel and speaker honoraria from Biogen Switzerland for the institution (University Hospital Basel) used exclusively for research purposes. B. Fischer-Barnicol and C. Tsagkas report no disclosures. J. Kuhle received speaker fees, research support, travel support, and/or served on advisory boards by ECTRIMS, Swiss MS Society, Swiss National Research Foundation (320030_160221), University of Basel, Bayer, Biogen, Genzyme, Merck, Novartis, Protagen AG, Roche, and Teva. L. Kappos' institution (University Hospital Basel) received and used exclusively for research support: steering committee, advisory board, and consultancy fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Celgene/Receptos, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Sanofi, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva; and grants from Bayer HealthCare, Biogen, F. Hoffmann-La Roche Ltd, Merck, Novartis, the European Union, the Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation. T. Derfuss serves on scientific advisory boards/steering committees/data safety monitoring boards for Novartis Pharmaceuticals, Merck, MedDay, Biogen, Sanofi Genzyme, GeNeuro, Mitsubishi Pharma, Teva Pharmaceuticals, and Bayer Schering Pharma; has received funding for travel and/or speaker honoraria from Biogen, Sanofi Genzyme, Novartis, and Merck; and receives research support from Biogen, Novartis Pharma, the European Union (ABIRISK project under grant agreement no. 115303), the Swiss National Foundation, and the Swiss MS Society. B.F. Décard received travel support and/or fees for the institution (University Hospital Basel) from advisory boards or speaker fees from Almirall, Biogen, Genzyme, Roche, Teva, and Novartis that were used exclusively for research support and receives research support from the Swiss MS Society and the Bangerter-Rhyner Stiftung. Go to Neurology.org/NN for full disclosures.\n\nAppendix Authors\n\n\nGlossary\nDILIdrug-induced liver injury\n\nDMFdimethyl fumarate\n\nFGLfingolimod\n\nGAAglatiramer acetate\n\nHEVhepatitis E virus\n\nNAneuralgic amyotrophy\n\nNTZnatalizumab\n\npwMSpersons with MS\n\nRRMSrelapsing-remitting MS\n==== Refs\nReferences\n1. Mansuy JM , Gallian P , Dimeglio C , et al \nA nationwide survey of hepatitis E viral infection in French blood donors . Hepatology \n2016 ;63 :1145 –1154 .27008201 \n2. Niederhauser C , Widmer N , Hotz M , et al \nCurrent hepatitis E virus seroprevalence in Swiss blood donors and apparent decline from 1997 to 2016 . Euro Surveill \n2018 ;23 .\n3. Kamar N , Garrouste C , Haagsma EB , et al \nFactors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants . Gastroenterology \n2011 ;140 :1481 –1489 .21354150 \n4. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu, European Association for the Study of the Liver . EASL Clinical Practice Guidelines on hepatitis E virus infection . J Hepatol \n2018 ;68 :1256 –1271 .29609832 \n5. van Eijk JJJ , Dalton HR , Ripellino P , et al \nClinical phenotype and outcome of hepatitis E virus-associated neuralgic amyotrophy . Neurology \n2017 ;89 :909 –917 .28768846 \n6. Abravanel F , Pique J , Couturier E , et al \nAcute hepatitis E in French patients and neurological manifestations . J Infect \n2018 ;77 :220 –226 .29966614 \n7. Bauer H , Luxembourger C , Gottenberg JE , et al \nOutcome of hepatitis E virus infection in patients with inflammatory arthritides treated with immunosuppressants: a French retrospective multicenter study . Medicine (Baltimore) \n2015 ;94 :e675 .25860212 \n8. Juhl D , Baylis SA , Blümel J , Görg S , Hennig H \nSeroprevalence and incidence of hepatitis E virus infection in German blood donors . Transfusion (Paris) \n2014 ;54 :49 –56 .\n9. Slot E , Hogema BM , Riezebos-Brilman A , Kok TM , Molier M , Zaaijer HL \nSilent hepatitis E virus infection in Dutch blood donors, 2011 to 2012 . Euro Surveill \n2013 ;18 :20550 .23929229 \n10. Legrand-Abravanel F , Kamar N , Sandres-Saune K , et al \nHepatitis E virus infection without reactivation in solid-organ transplant recipients, France . Emerg Infect Dis \n2011 ;17 :30 –37 .21192851\n\n",
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"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D056486:Chemical and Drug Induced Liver Injury; D003711:Demyelinating Diseases; D000069462:Dimethyl Fumarate; D057915:Drug Substitution; D005260:Female; D000068876:Fingolimod Hydrochloride; D000068717:Glatiramer Acetate; D016751:Hepatitis E; D016752:Hepatitis E virus; D006801:Humans; D007166:Immunosuppressive Agents; D000068556:Interferon beta-1a; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D055815:Young Adult",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D064888:Observational Study",
"references": "21192851;21354150;23441647;23929229;25860212;27008201;28768846;29609832;29966614;30180927",
"title": "Hepatitis E virus infections in patients with MS on oral disease-modifying treatment.",
"title_normalized": "hepatitis e virus infections in patients with ms on oral disease modifying treatment"
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"abstract": "With the recent introduction of more potent modern immunosuppressive regimens in solid-organ transplant, new types of viral infections such as adenovirus are emerging as a potential cause for graft dysfunction and loss. We report a case of 41-year-old male patient with end-stage renal disease from recurrent kidney stones who underwent kidney transplant from a deceased 12-year-old female donor. He developed adenoviral infection with acute cystitis, microscopic hematuria, and necrotizing interstitial nephritis associated with graft dysfunction within the first month of the postoperative period. Diagnosis was made by graft biopsy that showed more than 60% necrosis with tubulointerstitial hemorrhage, thrombotic microangiopathy, and histologic features suggestive of viral infection with negative Cytomegalovirus and polyomavirus stains in the graft and elevated adenovirus PCR in the blood. Simultaneously, the patient had very low absolute total lymphocyte count of 70 cells/μL during which he received supratherapeutic tacrolimus at whole blood trough levels and mycophenolate mofetil. This prompted the tapering of immunosuppression and the discontinuation of all antimicrobial drugs. Within a 2-week period, the immune reconstitution was sufficient for the clearance of the infection and the subsequent gradual recovery of graft function.",
"affiliations": "From the Rafik Hariri University Hospital, Beirut, Lebanon.",
"authors": "Saliba|Michelle|M|;Kfoury Assouf|Hala|H|;Abbas|Souodod|S|;Abi Hanna|Pierre|P|;Kamel|Gaby|G|;Barbari|Antoine|A|",
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"issue": "17(3)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
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"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000257:Adenoviridae Infections; D000328:Adult; D002648:Child; D005260:Female; D005335:Fever of Unknown Origin; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D011183:Postoperative Complications; D055031:Primary Graft Dysfunction",
"nlm_unique_id": "101207333",
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"pages": "411-413",
"pmc": null,
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"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Adenovirus Infection as a Cause of Fever of Unknown Origin and Allograft Dysfunction in a Kidney Transplant Recipient.",
"title_normalized": "adenovirus infection as a cause of fever of unknown origin and allograft dysfunction in a kidney transplant recipient"
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"abstract": "An unusual neurological syndrome occurred in 4 of 158 patients treated for osteogenic sarcoma with combination chemotherapy. There was an abrupt onset of focal cerebral deficits approximately ten days after chemotherapy with vincristine and high-dose methotrexate plus citrovorum factor rescue. The syndrome was short lived and always occurred early in the course of treatment. Prolonged neurological deficits remained in 2 patients. When similar chemotherapy was reinstituted in the 4 patients, no further neurological complications ensued. Possible causes include a leukoencephalopathy related to methotrexate or an embolic cerebral vasculopathy related to necrotic tumor microemboli emanating from the lungs.",
"affiliations": null,
"authors": "Allen|J C|JC|;Rosen|G|G|",
"chemical_list": "D014750:Vincristine; D002955:Leucovorin; D008727:Methotrexate",
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"abstract": "Coronary artery fistula is a relatively rare disorder with an incidence rate of 0.05-0.9%, and the majority of fistulae are detected incidentally. Most coronary artery fistulae are congenital, and the acquired variant is very rare. Herein, we present a possible acquired coronary artery to pulmonary artery fistula, most likely secondary to bronchiectasis in the adjacent lung. We will analyze the hemodynamic significance of the fistula in this case and also seek to understand the outcomes of various treatment modalities.\nA 56-year-old male patient presented with hypoxemia secondary to acute pulmonary edema during a hypertensive emergency. He developed myocardial ischemia after treatment with diuretics and nitroglycerin, due to shunting of blood from the right coronary artery to the right lower lobe branch of the right pulmonary artery, via the fistula. This resulted in coronary steal syndrome. Coronary angiogram confirmed the fistula connecting the right coronary artery to the right lower lobe branch of the right pulmonary artery. An attempt at coil embolization was unsuccessful due to the inability to advance the microcatheter beyond the fistula.\nThe majority of coronary artery fistulae are asymptomatic as they are hemodynamically not significant and are incidentally detected by coronary angiography, CT angiogram, echocardiogram or multi-detector row computed tomography (MDCT) with 3D reconstruction. The development of congenital fistula can be explained by the Hackensellner involution-persistence hypothesis, but the anatomy in this case and the bronchiectasis in the part of the lung adjacent to the fistula makes an acquired cause very likely due to local inflammation and the age of patient at initial diagnosis. An initial diagnosis of bronchiectasis was made at age 51, which was 5 years prior to the detection of the coronary artery fistula in this patient. Symptoms have been described mostly in the elderly and include chest pain, dyspnea, fatigue, syncope, and palpitations. Such symptomatic fistula should be treated either by percutaneous transluminal embolization or surgical ligation.\nThis is a unique case of acquired coronary to pulmonary artery fistula in the setting of bronchiectasis in a patient in which PTE was attempted and failed. More research is required to understand the pathophysiology of acquired fistula. The decision regarding the method of closure should be individualized and decided on a case by case basis.",
"affiliations": "Dept. of Internal Medicine, Brookdale Hospital Medical Center, Brooklyn, NY, USA.;Dept. of Pulmonary and Critical Care Medicine, Brookdale Hospital Medical Center, Brooklyn, NY, USA.;Dept. of Internal Medicine, Brookdale Hospital Medical Center, Brooklyn, NY, USA.;Dept. of Internal Medicine, Brookdale Hospital Medical Center, Brooklyn, NY, USA.;Dept. of Cardiology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA.;Dept. of Cardiology, Brookdale Hospital Medical Center, Brooklyn, NY, USA.",
"authors": "Narh|Joshua Tetteh|JT|;Zahid|Erum|E|;Shivaraj|Kiran|K|;Sahni|Sonu|S|;Kariyanna|Pramod Theetha|PT|;Khan|Abdullah|A|",
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"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30515-3\n10.1016/j.rmcr.2020.101301\n101301\nCase Report\nSteal and strain: A case of coronary artery fistula presenting with coronary steal syndrome and underlying bronchiectasis\nNarh Joshua Tetteh jnarh@bhmcny.orga∗ Zahid Erum b Shivaraj Kiran a Sahni Sonu a Kariyanna Pramod Theetha c Khan Abdullah d a Dept. of Internal Medicine, Brookdale Hospital Medical Center, Brooklyn, NY, USA\nb Dept. of Pulmonary and Critical Care Medicine, Brookdale Hospital Medical Center, Brooklyn, NY, USA\nc Dept. of Cardiology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA\nd Dept. of Cardiology, Brookdale Hospital Medical Center, Brooklyn, NY, USA\n∗ Corresponding author. Department of Internal Medicine, Brookdale University Hospital Medical Center, Address: 1 Brookdale Plaza, Brooklyn, NY, 11212 jnarh@bhmcny.org\n24 11 2020 \n2020 \n24 11 2020 \n31 10130123 9 2020 16 11 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nCoronary artery fistula is a relatively rare disorder with an incidence rate of 0.05–0.9%, and the majority of fistulae are detected incidentally. Most coronary artery fistulae are congenital, and the acquired variant is very rare. Herein, we present a possible acquired coronary artery to pulmonary artery fistula, most likely secondary to bronchiectasis in the adjacent lung. We will analyze the hemodynamic significance of the fistula in this case and also seek to understand the outcomes of various treatment modalities.\n\nCase presentation\nA 56-year-old male patient presented with hypoxemia secondary to acute pulmonary edema during a hypertensive emergency. He developed myocardial ischemia after treatment with diuretics and nitroglycerin, due to shunting of blood from the right coronary artery to the right lower lobe branch of the right pulmonary artery, via the fistula. This resulted in coronary steal syndrome. Coronary angiogram confirmed the fistula connecting the right coronary artery to the right lower lobe branch of the right pulmonary artery. An attempt at coil embolization was unsuccessful due to the inability to advance the microcatheter beyond the fistula.\n\nDiscussion\nThe majority of coronary artery fistulae are asymptomatic as they are hemodynamically not significant and are incidentally detected by coronary angiography, CT angiogram, echocardiogram or multi-detector row computed tomography (MDCT) with 3D reconstruction. The development of congenital fistula can be explained by the Hackensellner involution-persistence hypothesis, but the anatomy in this case and the bronchiectasis in the part of the lung adjacent to the fistula makes an acquired cause very likely due to local inflammation and the age of patient at initial diagnosis. An initial diagnosis of bronchiectasis was made at age 51, which was 5 years prior to the detection of the coronary artery fistula in this patient. Symptoms have been described mostly in the elderly and include chest pain, dyspnea, fatigue, syncope, and palpitations. Such symptomatic fistula should be treated either by percutaneous transluminal embolization or surgical ligation.\n\nConclusion\nThis is a unique case of acquired coronary to pulmonary artery fistula in the setting of bronchiectasis in a patient in which PTE was attempted and failed. More research is required to understand the pathophysiology of acquired fistula. The decision regarding the method of closure should be individualized and decided on a case by case basis.\n\nKeywords\nCoronary artery fistulaCoronary steal syndromeMyocardial ischemiaBronchiectasis\n==== Body\n1 Introduction\nCoronary artery fistula (CAF) is a rare congenital or acquired cardiopulmonary condition, that is defined as an abnormal vascular connection between one or more coronary arteries, either the pulmonary or systemic vascular network or a cardiac chamber without an interposing myocardial capillary bed [1]. CAF has been reported to have an incidence rate of 0.05–0.9% with the majority of cases being diagnosed during coronary angiography [2]. Furthermore, coronary-to-pulmonary artery fistula (CPAF) has been reported to make up 15–30% of all CAF cases, which are mostly detected by multi-detector row computed tomography (MDCT) with 3D reconstruction [3]. Typically, CAF is asymptomatic; however, symptomatic patients present with chronic dyspnea and angina caused by myocardial ischemia or ventricular volume overload from a left-to-right or left-to-left shunt, thus resulting in either coronary steal phenomenon or heart failure, respectively. Therapeutic strategies are largely based on expert opinion due to the paucity of retrospective studies and randomized trials [4]. There exists only a few reported cases of CPAF with underlying bronchiectasis with the pathophysiological relationship remaining unclear. Herein, we present a CAF patient with coronary steal syndrome and acute on chronic combined systolic and diastolic heart failure in the setting of bronchiectasis. We also aim to analyze the hemodynamics and also attempt to explain the anatomical changes associated with the CAF.\n\n2 Case presentation\nA 56-year-old Asian male with a past medical history of essential hypertension, chronic bronchiectasis, thoracic aortic aneurysm and remote history of smoking of 10 pack years presented to the emergency room with progressively worsening shortness of breath. At baseline patient experienced dyspnea only on exertion but eventually developed shortness of breath at rest which was associated with orthopnea. Initial vital signs on arrival were a blood pressure of 255/138 mmHg, heart rate was 153 beats/min, respiratory rate of 44 breaths/min, oxygen saturation 74% on room air. Physical examination findings revealed a middle-aged male with a BMI of 24 kg/m∧2, in respiratory distress, lung auscultation revealed decreased breath sounds at the bases with bibasilar crackles. Cardiac auscultation revealed continuous cardiac murmur, loudest at the left second intercostal space. Examination of extremities revealed prominent digital clubbing of the upper extremities.\n\nLaboratory analysis revealed troponin (0.079 ng/mL) and pro-B-type natriuretic peptide (pBNP; 417 pg/mL) levels. Arterial blood gas analysis showed hypoxemia and respiratory acidosis. The rest of laboratory findings as stated in Table 1. Initial EKG showed sinus tachycardia and left ventricular hypertrophy with repolarization changes in the anterior chest leads (Fig. 1).Table 1 Laboratory findings on arrival in the Emergency room.\n\nTable 1Hematology\tBiochemistry\t\nWCC x 10∧9/L\t13.5\tNa+\t136 mmol/L\tLDH\t1118 U/L\t\nNeutrophils %\t57.8\tK+\t4.2 mmol/L\tCRP\t1.6 U/L\t\nLymphocyte %\t33.0\tCl−\t95 mmol/L\tLactate\t5.8 mmol/L\t\nHgb g/dl\t15.8\tBUN\t27 mg/dl\tCPK\t199 U/L\t\nPlatelet x 10∧9/L\t280\tCr\t1.44 mg/dl\tTSH\t1.86 mIU/L\t\nESR mm\t9\tPhosphorus\t4.7 mg/dl\tALP\t108 U/L\t\n\tMagnesium\t2.6 mg/dl\tT-Bil\t0.6 mg/dl\t\nALT\t152 U/L\tD-Bil\t0.2 mg/dl\t\nAST\t232 U/L\t\t\t\nALP: Alkaline Phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea nitrogen; Cl: Chloride; CPK: Creatine kinase; Cr: Creatinine; CRP: C-reactive protein; D-Bil: Direct bilirubin; ESR: Erythrocyte sedimentation rate; Hgb: Hemoglobin; K: Potassium; LDH: Lactate dehydrogenase; Na: Sodium; T-Bil: Total Bilirubin; TSH: Thyroid stimulating hormone; WCC: White cell count.\n\nFig. 1 EKG on arrival in the ED, showing ischemic changes (T-wave inversion) in the inferior leads (II, III, aVF).\n\nFig. 1\n\nA portable anterior-posterior Chest x-ray showed possible left lower lung consolidation and cardiomegaly with a cardiothoracic ratio of 0.63. The patient was initiated on non-invasive positive pressure ventilation with bilevel positive airway pressure (BiPAP) support. However due to persistent hypoxia associated with worsening mental status patient was intubated and started on mechanical ventilation. Given elevated blood pressure, pBNP levels, and chest x-ray findings suggestive of pulmonary edema, nitroglycerin infusion was initiated for hypertensive emergency in conjunction with diuretics with an appropriate response. Repeat EKG revealed normal sinus rhythm with deep T-wave inversions in the inferior lateral leads (II, III, aVF, I, aVL, V4–V6) suggesting possible coronary ischemia (Fig. 2). Repeat troponin level was still elevated (1.32 ng/mL). Patient was initiated on treatment for non-ST-elevation myocardial infarction with dual anti-platelets, statin, and anticoagulant. The patient initially received empiric antibiotic therapy due to concerns for underlying pneumonia, Covid-19 testing by a nasopharyngeal swab test was found to be negative. Repeat chest x-ray showed a marked improvement in the pulmonary congestion after diuresis (Fig. 3).Fig. 2 EKG after normalization of blood pressure, showing ischemic changes (T-wave inversion) in the inferior leads.\n\nFig. 2Fig. 3 Chest x-ray showing improvement in pulmonary congestion after diuresis.\n\nFig. 3\n\nOf note the patient was known to the cardiology, pulmonary and cardiothoracic surgery service from prior admission in 2015 where he was worked up for chronic dyspnea. At that time CT angiogram of the chest revealed 4.8-cm aneurysmal dilatation of the ascending thoracic aorta and extensive bronchiectasis, primarily involving the right middle, upper, and left lower lobes (Fig. 4). Transthoracic echocardiogram (TTE) showed an aortic root diameter of 4.2 cm, an aortic valve opening of 1.65 cm, a left atrium diameter of 2.72 cm, an ejection fraction of 40–45%, left ventricular eccentric hypertrophy, an estimated peak pulmonary artery pressure of 50 mmHg, and normal right ventricular systolic function.Fig. 4 CT angiogram of the chest showing the dilated pulmonary artery.\n\nFig. 4\n\nCoronary angiography that was performed 8 months prior to this admission showed a coronary-to-pulmonary artery fistula (CPAF) between the right coronary artery and right lower lobe branch of the right pulmonary artery, which corresponded to the area of pulmonary bronchiectasis seen in computer tomography. At that time a multi-disciplinary team planned for the repair of the fistula on an outpatient basis but however, he was lost to follow-up.\n\nDuring the patient's current admission, repeat TTE showed left ventricular dilatation, and visual assessment displayed reduced systolic function and an ejection fraction in the range of 40–45% with diffuse hypokinesis. These changes were consistent with eccentric hypertrophy. Doppler parameters were consistent with abnormal left ventricular relaxation (grade 1 diastolic dysfunction) and a normal peak pulmonary artery pressure with normal right cardiac systolic function. Repeat coronary angiography performed during this admission also showed right coronary artery patency along with the previously detected fistula (Fig. 5). An attempt at coil embolization was unsuccessful due to the inability to advance the microcatheter beyond the fistula. After failed coil embolization, patient was transferred to the CCU in stable condition however 5 days thereafter he suffered a cardiac arrest and eventually passed away.Fig. 5 Coronary angiogram of the right coronary system in the right anterior oblique cranial view (left) and the left anterior oblique cranial view (right) showing the normal right coronary artery (blue arrows) and the right coronary-to-pulmonary artery fistula (red arrows). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 5\n\n3 Discussion\nHerein we report a unique case of CPAF with coronary steal syndrome and acute on chronic combined systolic and diastolic heart failure in the setting of bronchiectasis. This case helps us understand the unusual hemodynamics involved with CPAF, and provide a platform to further understand etiology and pathogenesis in this particular patient. To better understand CPAFs in general it is important to review the embryology. During embryogenesis, coronary arteries are formed from an island of cells around the heart which later develops into the primary capillary plexus. These cells, particularly the ones found around the aorta, penetrate the aorta and form the coronary ostia [5]. This occurs a few weeks after the division of the truncus arteriosus into the aorta and pulmonary artery; therefore, it is likely that penetration of the primary capillary plexus into the pulmonary artery may lead to anomalous origin of the left coronary artery from the pulmonary trunk. However, in our patient, the coronary ostia were in the normal aortic position but there was an abnormal connection between the coronary artery and one of the branches of the right pulmonary artery. The exact mechanism of this fistula formation remains unknown. However, a popular theory was proposed in 1955 by Hackensellner, in which the coronary fistula was suggested to be due to persistence of more than 2 out of 6 coronary analgens, 3 of which arise from the aorta and 3 from the pulmonary artery [6].\n\nCPAF may be explained anatomically by the proximity of the right coronary artery to the pulmonary trunk as well as to the right and left pulmonary arteries. Earlier studies have found that fistula termination was found in the pulmonary artery in up to 15–20% of cases, with the most common form being coronary-cameral fistula [7], where it is terminated either in the right atrium or ventricle. Among CPAF cases, 92% terminate in the pulmonary trunk, whereas the rest are divided between the right and left pulmonary arteries. When coronary artery origin is considered, fistulas arising from the left coronary artery are found to be more common (89%) when compared with the right coronary artery [[8], [9]]. This may be because the left coronary artery has a longer course that runs behind the pulmonary artery, thus increasing the chances of developing a fistula.\n\nHowever, as revealed in this case by coronary angiography, it is difficult to explain the formation of the congenital fistula between the right lower lobe branch of the right pulmonary artery and the proximal right coronary which makes it unique. Acquired coronary fistulas are extremely rare and are typically iatrogenic, but their development has also been described after myocardial infarction or penetrating trauma [10]. Our case is interesting because the fistula corresponded to the area of bronchiectasis in the adjacent lung (Fig. 6). A few reports of fistulas between the coronary artery and both the bronchial and pulmonary vasculatures have been reported but it is unclear if this is due to the formation of new connections via angiogenesis that are secondary to the intense recurrent inflammation associated with bronchiectasis or due to the opening of a pre-existing dormant fistula as a result of the vasodilation caused by the local inflammation [[11], [12], [13]].Fig. 6 CT scan of the chest showing bronchiectasis of the lung adjacent to the right side of the heart where the fistula is located.\n\nFig. 6\n\nAnother important aspect that this case demonstrates is the significance of hemodynamic abnormalities caused by CAFs. Cardiopulmonary hemodynamics in the setting of CAFs mainly depends on the size of the fistula and also the pressure gradient between its origin and termination. The difference in the high-pressure coronary artery and the low-pressure pulmonary artery eventually results in a left-to-right shunt and leads to pulmonary hypertension. However, in this case, we believe that the pulmonary hypertension was secondary to bronchiectasis, which is common. Uncontrolled hypertension was an added complication, which led to left ventricular hypertrophy, as shown by EKG and eccentric hypertrophy on TTE. When the patient received diuretics and nitroglycerin for the pulmonary edema that developed secondary to the hypertensive crisis, the venous return to the right side of the heart was compromised, which led to low pressure in the pulmonary artery and created a high gradient between the coronary and pulmonary arteries. This gradient diverted the blood from the coronary artery to the pulmonary artery, leading to coronary steal phenomenon. This was demonstrated by the T-wave inversion shown in the EKG, which over a period of time led to systolic heart failure due to the dominant right circulation.\n\nAngelini et al. [14] reported that coronary fistulas are considered significant if: 1. Significant flow is demonstrated in the fistula; 2. There is angiographic evidence of the receiving structure; 3. There are signs of volume overload in the cardiac chambers; 4. There is evidence of coronary steal phenomenon. The ratio of blood flow between the nutrient vessel and fistula will determine the significance of the fistula [15]. The presence of hypertension is well tolerated, but when there is an episode of relative hypotension, as seen in our patient, the flow is diverted into the fistulous tract, resulting in low flow to the distal nutrient vessel and leading to distal myocardial ischemia. In our patient, there was evidence of coronary steal, as shown by the EKG changes, as well as evidence of ongoing ischemia, as indicated by the elevated troponin levels. The absence of significant occlusion in the distal nutrient artery also suggested that the fistula was the cause of the ischemia.\n\nThe majority of coronary artery fistulas are asymptomatic and hemodynamically insignificant and are incidentally detected by CT angiogram studies, Doppler echocardiograms, MDCT, or coronary angiography [16]. Symptoms have been described mostly in the elderly and include chest pain, dyspnea, fatigue, syncope, and palpitations [[16], [17]]. The presence of symptoms depends on the size of the fistula, with larger fistulas resulting in pulmonary hypertension and coronary steal [18]. Our patient had symptoms of acute on chronic congestive heart failure and developed a myocardial infarction during admission, which we believe was caused by the coronary steal phenomenon because it is a known complication of coronary fistulas. Other complications that have been previously described include aneurysm of the fistula, fistula rupture, thrombosis, and endocarditis.\n\nTreatment of CAF is centered on closure which can be achieved via percutaneous transcatheter embolization (PTE) or surgical ligation. The fistula repair method depends on the complexity of the fistula anatomy as well as the presence of any underlying comorbidities that require intervention [19]. There is no consensus guidelines on a preferred repair method, but it is agreed that symptomatic and larger fistulas must be repaired. A Dutch study reported that cases with proximal fistulas, fistulas with termination away from the normal coronary artery, and older individuals are ideal candidates for PTE [20]. In contrast, those with larger fistulas, multiple fistulas, associated cardiac disease requiring surgical management, failure of PTE, tortuous fistulas, and large aneurysms are ideal candidates for surgical ligation [[21], [22]]. In our case, we attempted PTE for treatment of the fistula, but unfortunately the procedure was unsuccessful due to the inability to enter the distal end of the fistula, which is known to happen in up to 6% of patients [21].\n\n4 Conclusion\nCoronary artery fistulas are a relatively rare disorder and are typically discovered incidentally. Most of the cases are of congenital etiology, but acquired etiology has been described. This is a unique case of what we believe is an acquired fistula due to the adjacent lung inflammation secondary to bronchiectasis. Treatment is required when the fistula becomes hemodynamically significant, and the treatment method must be individualized and determined on a case-by-case basis.\n\nDeclaration of competing interest\nAll authors have no conflict of financial interest to disclose.\n\nDeclaration of competing interest\nThe authors have no conflicts of interest to disclose regarding this case report and review.\n\nAcknowledgements\nAll authors have equally contributed to this manuscript.\n==== Refs\nReferences\n1 Yun G. Nam T.H. Chun E.J. Coronary artery fistulas: pathophysiology, imaging findings, and management Radiographics 38 2018 688 703 29601265 \n2 Kim M.S. Jung J.I. Chun H.J. Coronary to pulmonary artery fistula: morphologic features at multidetector CT Int. J. Cardiovasc. Imag. 26 Suppl 2 2010 273 280 \n3 Izumi K. Hisata Y. Hazam S. Surgical repair for a coronary-pulmonary artery fistula with a saccular aneurysm of the coronary artery Ann. Thorac. Cardiovasc. Surg. 15 3 2009 194 197 19597399 \n4 Shin K.C. Shin M.S. Park J.W. Prophylactic and therapeutic embolization of the coronary-bronchial artery fistula in patient with bronchiectasis Int. J. Cardiol. 151 2 2011 e71 e73 20547428 \n5 Reese D.E. Mikawa T. Bader D.M. Development of the coronary vessel system Circ. Res. 91 9 2002 761 768 12411389 \n6 Hackensellner H.A. Ueber akgessorische, von der arteria pulmonalis abgehende herzgefaesse and ihre bedentung fuer das verstaendnis der formalen genese des ursprunges einer oder beider coronararterien von der lungenschlagader Frankfurt. Z Pathol. 66 1955 463 470 \n7 Dodge-Khatami A. Mavroudis C. Backer C.L. Congenital heart surgery nomenclature and database project: anomalies of the coronary arteries Ann. Thorac. Surg. 69 4 Suppl 2000 S270‐S297 10798435 \n8 Verdini D. Vargas D. Kuo A. Coronary-pulmonary artery fistulas: a systematic review J. Thorac. Imag. 31 6 2016 380‐390 \n9 Heifetz S.A. Robinowitz M. Mueller K.H. Virmani R. Total anomalous origin of the coronary arteries from the pulmonary artery Pediatr. Cardiol. 7 1 1986 11 18 3774577 \n10 Yu R. Sharma B. Franciosa J.A. Acquired coronary artery fistula to the left ventricle after acute myocardial infarction Am. J. Cardiol. 58 6 1986 557‐558 3751920 \n11 Bury R.W. Wojciuk J. Goode G.K. Multiple coronary artery fistulae associated with bronchiectasis: rarity or recognized phenomenon? Tex. Heart Inst. J. 37 3 2010 380 381 20548832 \n12 Lee S.T. Kim S.Y. Hur G. Coronary-to-bronchial artery fistula: demonstration by 64-multidetector computed tomography with retrospective electrocardiogram-gated reconstructions J. Comput. Assist. Tomogr. 32 3 2008 444 447 18520554 \n13 Abergel E. Aouate J.M. Geslin J. Lavergne T. Pernes J.M. Ourback P. Localized dilatation of the bronchi: a misunderstood etiology of coronaro-bronchial fistula Arch. Mal. Coeur. Vaiss. 83 2 1990 271 274 2106864 \n14 Angelini P. Villason S. Chan A.V. Diez J.G. Normal and anomalous coronary arteries in humans Angelini P. Coronary Artery Anomalies: A Comprehensive Approach 1999 Lippincott Williams & Wilkins Philadelphia 27 79 \n15 Morales A.R. Romanelli R. Boucek R.J. The mural left anterior descending coronary artery, strenuous exercise and sudden death Circulation 62 2 1980 230 237 7397963 \n16 Said S.A. Congenital solitary coronary artery fistulas characterized by their drainage sites World J. Cardiol. 2 1 2010 6 12 21160658 \n17 Dodd J.D. Ferencik M. Liberthson R.R. Evaluation of efficacy of 64-slice multidetector computed tomography in patients with congenital coronary fistulas J. Comput. Assist. Tomogr. 32 2 2008 265 270 18379314 \n18 Macchi R.J. Fabregas R.A. Chianelli H.O. Bourdet J.C. Lhez O. Stagnaro R. Anomalous communication of the left coronary artery with a peripheral branch of the right pulmonary artery Chest 69 4 1976 565 568 1261333 \n19 Reddy G. Davies J.E. Holmes D.R. Schaff H.V. Singh S.P. Alli O.O. Coronary artery fistulae Circ Cardiovasc Interv 8 11 2015 e003062 \n20 Said S.A. van der Werf T. Dutch survey of coronary artery fistulas in adults: congenital solitary fistulas Int. J. Cardiol. 106 3 2006 323‐332 16337040 \n21 Liu X. Zhang L. Qi Z. Fan M. Ge J. The characteristics of coronary-pulmonary artery fistulas and the effectivity of trans-catheter closure: a single center experience J. Thorac. Dis. 11 7 2019 2808 2815 31463109 \n22 Ahmed M.F. Mubin A. Sahni S. Multivessel coronary artery fistula presenting as coronary steal syndrome leading to cardiac arrest Cureus 12 5 2020 e8358\n\n",
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"keywords": "Bronchiectasis; Coronary artery fistula; Coronary steal syndrome; Myocardial ischemia",
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"title": "Steal and strain: A case of coronary artery fistula presenting with coronary steal syndrome and underlying bronchiectasis.",
"title_normalized": "steal and strain a case of coronary artery fistula presenting with coronary steal syndrome and underlying bronchiectasis"
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"abstract": "OBJECTIVE\nIn this study, by presenting four cases, we aimed to discuss the clinical presentation, diagnosis, therapy, and methods for prevention of Acanthamoeba keratitis (AK) and to emphasize that inflammatory dacryoadenitis can be seen together with it.\n\n\nMETHODS\nThis is a retrospective case series of four eyes of four wearers of hydrophilic soft contact lenses who developed AK. The diagnosis was based on clinical signs, disease course, and confocal microscopy results. In cases with dacryoadenitis, in addition to clinical findings, magnetic resonance imaging was used to establish the diagnosis.\n\n\nRESULTS\nAll of the cases were using their contact lenses without supervision of an ophthalmologist under inappropriate conditions such as swimming in a pool and during steam bath. The diagnosis was established, and the treatment was performed within the standard protocol for AK. Two of the patients had low visual acuity at the level of counting fingers with corneal scar, cataract, and glaucoma, whereas the other two healed with fewer complications and achieved better vision. Two of the 4 cases (50%) presented with dacryoadenitis accompanying the AK. Lacrimal gland swelling improved in conjunction with symptoms of keratitis without specific treatment for dacryoadenitis in these two cases.\n\n\nCONCLUSIONS\nDespite the improvements in diagnostic tests and treatment strategies for AK, the role of prevention becomes apparent because of the bad prognosis of this serious complication; thus, contact lens wearers should be aware of the importance of using lenses under ophthalmologist's supervision. In addition, we would like to emphasize that AK may be frequently associated with lacrimal gland inflammation.",
"affiliations": "Department of Ophthalmology (T.S.), Kadıköy Florence Nightingale Hospital, Istanbul Bilim University, Istanbul, Turkey; Department of Ophthalmology (S.A.K., A.A., S.F.A., S.A.), Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey; and Department of Ophthalmology (M.I.), Hacettepe University, Ankara, Turkey.",
"authors": "Sengor|Tomris|T|;Kurna|Sevda A|SA|;Altun|Ahmet|A|;Irkec|Murat|M|;Aki|Suat F|SF|;Aksoy|Sibel|S|",
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"title": "Contact Lens-Related Acanthamoeba Keratitis and Accompanying Dacryoadenitis.",
"title_normalized": "contact lens related acanthamoeba keratitis and accompanying dacryoadenitis"
} | [
{
"companynumb": "ALCN2016TR007697",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
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"activesubstancename": "ITRACONAZOLE"
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{
"abstract": "Preterm infants frequently receive red cell transfusions; however, the effect of transfusions on cognition is unclear. We evaluated the relationship between transfusions and cognitive outcomes in preterm infants enrolled in a randomized trial of erythropoiesis stimulating agents (ESAs).\n\n\n\nPreterm infants were randomized to ESAs or placebo during initial hospitalization, and transfusions recorded. Children were evaluated using standard developmental tests of cognition at 18-22 months (56 ESA, 24 placebo) and 3.5-4 years (39 ESA, 14 placebo).\n\n\n\nCognitive scores at 18-22 months were inversely correlated with transfusion volume (p = 0.02). Among those receiving ≥1 transfusion, cognitive scores were significantly higher in the ESA-treated group (p = 0.003). At 3.5-4 years, transfusions were not correlated with cognitive scores.\n\n\n\nIn the placebo group, transfused children had lower cognitive scores than did non-transfused children at 18-22 months. In the ESA group, cognitive scores did not differ by transfusion status, suggesting ESAs might provide neuroprotection.",
"affiliations": "Presbyterian Medical Group, Pediatrics, Albuquerque, NM, USA.;Iterative Consulting, Albuquerque, NM, USA.;Department of Pediatrics, University of New Mexico, Albuquerque, NM, USA.;Mind Research Network, Albuquerque, NM, USA.;Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.;American Academy of Pediatrics, Itasca, IL, USA.;University of Colorado, Aurora, CO, USA.;Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.;MEDNAX, Seattle, WA, USA.;Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.;CCTS, University of Utah, Salt Lake City, UT, USA.;Department of Pediatrics, University of Utah, Salt Lake City, UT, USA. robin.ohls@hsc.utah.edu.",
"authors": "Shah|Priya|P|;Cannon|Daniel C|DC|;Lowe|Jean R|JR|;Phillips|John|J|;Christensen|Robert D|RD|0000-0001-5872-582X;Kamath-Rayne|Beena|B|;Rosenberg|Adam|A|;Wiedmeier|Susan|S|;Patel|Shrena|S|;Winter|Sarah|S|;Baker|Shawna|S|;Ohls|Robin K|RK|0000-0003-2865-8878",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1038/s41372-021-00997-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0743-8346",
"issue": "41(6)",
"journal": "Journal of perinatology : official journal of the California Perinatal Association",
"keywords": null,
"medline_ta": "J Perinatol",
"mesh_terms": "D001803:Blood Transfusion; D003071:Cognition; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D019102:Infant, Very Low Birth Weight",
"nlm_unique_id": "8501884",
"other_id": null,
"pages": "1412-1418",
"pmc": null,
"pmid": "33911186",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "20437563",
"title": "Effect of blood transfusions on cognitive development in very low birth weight infants.",
"title_normalized": "effect of blood transfusions on cognitive development in very low birth weight infants"
} | [
{
"companynumb": "US-AMGEN-USASP2021204161",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ERYTHROPOIETIN"
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"drugadditional": "4",
... |
{
"abstract": "Thrombotic microangiopathies (TMAs) are systemic microvascular occlusive disorders. The present report describes a patient with relapsing-remitting multiple sclerosis who had been treated with interferon (IFN)-β1b therapy for eight years and developed TMA. The patient presented with headache, thrombocytopenia, renal dysfunction, severe hypertension, posterior reversible encephalopathy syndrome, and gastrointestinal involvement. After discontinuation of the medication and initiation of antihypertensive treatment, the patient rapidly improved. This is the first report of TMA with gastrointestinal involvement (intestinal TMA) induced by IFN-β. The new onset of hypertension or headache requires careful attention in cases of long-term administration of IFN-β1b.",
"affiliations": "Department of Neurology, The Jikei University School of Medicine, Japan.;Department of Neurology, The Jikei University School of Medicine, Japan.;Department of Neurology, The Jikei University School of Medicine, Japan.;Department of Neurology, The Jikei University School of Medicine, Japan.;Department of Neurology, The Jikei University School of Medicine, Japan.",
"authors": "Omoto|Shusaku|S|;Utsumi|Tomohiro|T|;Matsuno|Hiromasa|H|;Terasawa|Yuka|Y|;Iguchi|Yasuyuki|Y|",
"chemical_list": "D000959:Antihypertensive Agents; D016899:Interferon-beta",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.9326-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2915151710.2169/internalmedicine.9326-17Case ReportThrombotic Microangiopathy Presenting with Intestinal Involvement Following Long-term Interferon-β1b Treatment for Multiple Sclerosis Omoto Shusaku 1Utsumi Tomohiro 1Matsuno Hiromasa 1Terasawa Yuka 1Iguchi Yasuyuki 1\n1 Department of Neurology, The Jikei University School of Medicine, JapanCorrespondence to Dr. Shusaku Omoto, s-omoto@jikei.ac.jp\n\n20 11 2017 1 3 2018 57 5 741 744 6 4 2017 5 7 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Thrombotic microangiopathies (TMAs) are systemic microvascular occlusive disorders. The present report describes a patient with relapsing-remitting multiple sclerosis who had been treated with interferon (IFN)-β1b therapy for eight years and developed TMA. The patient presented with headache, thrombocytopenia, renal dysfunction, severe hypertension, posterior reversible encephalopathy syndrome, and gastrointestinal involvement. After discontinuation of the medication and initiation of antihypertensive treatment, the patient rapidly improved. This is the first report of TMA with gastrointestinal involvement (intestinal TMA) induced by IFN-β. The new onset of hypertension or headache requires careful attention in cases of long-term administration of IFN-β1b. \n\nthrombotic microangiopathyintestinal thrombotic microangiopathyinterferonmultiple sclerosisposterior reversible encephalopathy syndrome\n==== Body\nIntroduction\nThrombotic microangiopathies (TMAs) are microvascular occlusive disorders that induce systemic or intrarenal aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes. Acquired TMA syndrome is diverse and includes thrombotic thrombocytopenia purpura (TTP), Shiga toxin-mediated hemolytic uremic syndrome, drug-induced TMA, and complement-mediated TMA (1). The present report describes a patient with relapsing-remitting multiple sclerosis (RRMS) who had been treated with interferon (IFN)-β1b for eight years and presented with severe hypertension, posterior reversible encephalopathy syndrome (PRES), and gastrointestinal involvement due to drug-induced TMA.\n\nCase Report\nA 42-year-old woman was admitted to our hospital with headache, nausea, hypertension, and anemia. Eight years before this admission, the patient had been diagnosed with RRMS, which was maintained in remission with IFN-β1b at a dosage of 8 million IU every other day without other treatments. A health checkup 2 years before admission revealed mildly elevated systolic blood pressure (sBP) (140 mmHg), and 1 year later, her sBP was 150 mmHg. She had been experiencing severe headaches and nausea for one month before admission.\n\nOn admission, a physical examination showed severe arterial hypertension (226/138 mmHg) and tachycardia (116/min). She had headache and nausea but no edema. Laboratory investigations showed hemolytic anemia (hemoglobin 9.5 g/dL, elevated lactate dehydrogenase level 821 U/L, low haptoglobin level, and elevated reticulocytes), schistocytes, thrombopenia of 64×103/L, a slight increase in serum creatinine (0.86 mg/dL) compared with baseline (0.45 mg/dL), proteinuria (2.7 g/day), and a normal range of ADAMTS13 activity. Abdominal computed tomography and renal ultrasound were normal. Brain magnetic resonance imaging showed lesions with vasogenic edema involving the basal ganglia, brainstem, and bilateral cerebellum, suggesting PRES (Figure A-C). We ultimately diagnosed her with TMA associated with IFN-β1b because her hypertension had gradually progressed over two years with no signs of infection, malignancy, or autoimmune diseases.\n\nFigure. FLAIR brain images (A, B) on admission show hyperintense lesions in the bilateral basal ganglia (A), brainstem, and cerebellum (B). An ADC map (C) on admission shows increased values in the areas of FLAIR abnormalities. Coronal (D) and axial (E) sections of enhanced abdominal computed tomography on the 4th hospital day reveal diffuse wall thickening with intestinal mucosal enhancement and vasa recta engorgement (arrowhead) as well as dilation of the mesentery blood vessels (arrows) and ascites. Six days after initiation of antihypertensive therapy, the FLAIR hyperintense lesions in the bilateral basal ganglia are markedly decreased (F). FLAIR: fluid attenuated inversion recovery\n\nThe drug was withdrawn, and antihypertensive therapy was initiated with intravenous nicardipine infusion (2 mg/h). Her headache and nausea disappeared within a few days. On the 4th hospital day, the patient developed severe abdominal pain and nausea. Enhanced abdominal computed tomography showed marked intestinal edema, dilation of the mesentery blood vessels, and ascites (Figure D and E). These abnormalities were presumably caused by microangiopathy in mesentery blood vessels, as no evidence of potential causes such as ischemia or infection was found on clinical findings, laboratory data, or imaging. She had no fever, and her serum C-reactive protein and lactic acid levels were normal. A fecal culture was negative. The abdominal pain disappeared within a few days without specific treatment. Three weeks after the initiation of antihypertensive treatment, the laboratory abnormalities and elevated blood pressure returned to normal levels except for mild anemia (hemoglobin 9.8 mg/dL). The patient needed 2 antihypertensive drugs (nifedipine 40 mg/day and losartan 75 mg/day). PRES also improved, as seen on brain magnetic resonance imaging performed on the 6th hospital day (Figure F).\n\nDiscussion\nIFN-β is a widely prescribed immunomodulatory agent for RRMS and includes IFN-β1a and IFN-β1b. TMA induced by IFN-β1b is rare compared with that induced by IFN-β1a (2). Only one case in which IFN-β1b-induced TMA was described in detail has been reported among multiple sclerosis (MS) patients in Japan (3).\n\nSeveral mechanisms have been suggested to explain how IFN-β induces TMA. The pathogenesis of TMA may include a reduction in vascular endothelial growth factor (VEGF). A low level of VEGF inhibits appropriate renal endothelial formation and promotes the development of microvascular injury and TMA (4). In addition, VEGF is a major factor in the regulation of the production of endothelial nitric oxide. Nitric oxide plays a key role in maintaining local vasodilatation, reducing the risk for local thrombosis, and protecting endothelial cells from toxicity due to circulating cytokines, such as tumor necrosis factor-alpha, the circulating levels of which are elevated after injection of IFN (5, 6). Indeed, the inhibition of VEGF with the monoclonal VEGF antibody bevacizumab may cause TMA in patients with proteinuria and hypertension (4). A previous report showed that IFN-β inhibits the production of VEGF protein (7). For efficient angiogenesis, VEGF promotes phosphorylation-dependent ubiquitination and degradation of the IFN receptor and subsequent attenuation of IFN-α/β signaling (8).\n\nIn the present case, the patient's hypertension gradually progressed over two years. Systemic complications, such as hematological abnormalities and PRES due to intercurrent severe hypertension, probably developed just before admission and may have affected the disease status. In addition, microangiopathy itself presumably also affects the development of PRES. For instance, cisplatin has a cytotoxic effect on the vascular endothelium, leading to brain capillary leakage and acute blood-brain barrier disruption, which may trigger vasogenic edema (9). Indeed, previous reports have shown that some patients with PRES are normotensive (10).\n\nPlasma exchange is an essential treatment for acquired TTP, which is characterized by severe ADAMTS13 deficiency attributed mostly to the presence of autoantibodies to ADAMTS13. Because of the high mortality due to TTP, plasma exchange should be considered as an immediate intervention if a diagnosis of acquired TTP cannot be ruled out. However, plasma exchange is less effective for other types of TMA, according to evidence-based recommendations regarding the indication for apheresis advocated by the American Society for Apheresis (11). In the present case, discontinuation of IFN and best supportive care were selected as the initial treatment for TMA because we had high confidence in the diagnosis of drug-induced TMA, even though no specific diagnostic test exists for TMA, and the organ damage was not severe at admission, aside from PRES.\n\nLate-onset TMA following initiation of IFN therapy may reflect cumulative endothelial toxicity induced by IFN. Indeed, IFN-α and IFN-β therapies are known to directly cause TMA in a dose-dependent manner, and the IFN protein itself can directly damage small blood vessels, as shown in a transgenic mouse model of IFN toxicity (12). In particular, the duration of exposure to IFN-β for MS patients is longer than that of chronic myelocytic leukemia and hepatitis C virus patients treated with IFN-α (13). IFN acts as an immune modulator in MS but as an immune escalation factor in chronic myelocytic leukemia and hepatitis C virus. These differences may account for the delayed development of TMA in MS (13).\n\nTo our knowledge, this is the first report of TMA with gastrointestinal involvement (intestinal TMA: iTMA) induced by IFN-β. No pathologic criteria have been established for the diagnosis of iTMA. El-Bietar reported that the histopathological changes in iTMA after hematopoietic stem cell transplantation include mucosal hemorrhaging, loss of glands, endothelial cell swelling and separation, intraluminal schistocytes, fibrin, and microthrombi (14). The onset of iTMA occurred several days after admission in the present case, as the patient's platelet counts rapidly increased after the initiation of treatment. Rapid elevation of platelets due to platelet infusion causes deterioration of the clinical condition of TMA due to occlusive thrombosis in many organs (15).\n\nIn summary, we encountered a patient with RRMS who developed TMA following eight years of IFN-β1b therapy. After discontinuation of the medication and initiation of antihypertensive treatment, the patient rapidly improved. The new onset of hypertension or headache requires careful attention in cases of long-term administration of IFN-β1b. Routine monitoring of blood pressure and hematological tests may help detect TMA early in patients treated with IFN-β1b.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. George JN , Nester CM \nSyndromes of thrombotic microangiopathy . N Engl J Med \n371 : 654 -666 , 2014 .25119611 \n2. Vosoughi R , Marriott JJ \nThrombotic microangiopathy in Interferon Beta treated multiple sclerosis patients: review of literature and report of two new cases . Mult Scler Relat Disord \n3 : 321 -325 , 2014 .25876469 \n3. Nishio H , Tsukamoto T , Matsubara T , Okada Y , Takahashi R , Yanagita M \nThrombotic microangiopathy caused by interferon beta-1b for multiple sclerosis: a case report . CEN Case Rep \n5 : 179 -183 , 2016 .28508977 \n4. Eremina V , Jefferson JA , Kowalewska J , et al \nVEGF inhibition and renal thrombotic microangiopathy . N Engl J Med \n358 : 1129 -1136 , 2008 .18337603 \n5. Goldberg RJ , Nakagawa T , Johnson RJ , Thurman JM \nThe role of endothelial cell injury in thrombotic microangiopathy . Am J Kidney Dis \n56 : 1168 -1174 , 2010 .20843591 \n6. Kumpfel T , Then Bergh F , Pollmacher T , Holsboer F , Trenkwalder C \nAcute effects of interferon beta-1a on plasma cytokine levels in patients with MS . Neurology \n55 : 1231 -1233 , 2000 .11071509 \n7. Takano S , Ishikawa E , Matsuda M , Yamamoto T , Matsumura A \nInterferon-beta inhibits glioma angiogenesis through downregulation of vascular endothelial growth factor and upregulation of interferon inducible protein 10 . Int J Oncol \n45 : 1837 -1846 , 2014 .25175315 \n8. Zheng H , Qian J , Carbone CJ , Leu NA , Baker DP , Fuchs SY \nVascular endothelial growth factor-induced elimination of the type 1 interferon receptor is required for efficient angiogenesis . Blood \n118 : 4003 -4006 , 2011 .21832278 \n9. Ito Y , Arahata Y , Goto Y , et al \nCisplatin neurotoxicity presenting as reversible posterior leukoencephalopathy syndrome . AJNR Am J Neuroradiol \n19 : 415 -417 , 1998 .9541291 \n10. Covarrubias DJ , Luetmer PH , Campeau NG \nPosterior reversible encephalopathy syndrome: prognostic utility of quantitative diffusion-weighted MR images . AJNR Am J Neuroradiol \n23 : 1038 -1048 , 2002 .12063238 \n11. Schwartz J , Padmanabhan A , Aqui N , et al \nGuidelines on the Use of Therapeutic Apheresis in Clinical Practice-Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Seventh Special Issue . J Clin Apher \n31 : 149 -162 , 2016 .27322218 \n12. Kavanagh D , McGlasson S , Jury A , et al \nType I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature . Blood \n128 : 2824 -2833 , 2016 .27663672 \n13. Kundra A , Wang JC \nInterferon induced thrombotic microangiopathy (TMA): analysis and concise review . Crit Rev Oncol Hematol \n112 : 103 -112 , 2017 .28325251 \n14. El-Bietar J , Warren M , Dandoy C , et al \nHistologic features of intestinal thrombotic microangiopathy in pediatric and young adult patients after hematopoietic stem cell transplantation . Biol Blood Marrow Transplant \n21 : 1994 -2001 , 2015 .26150023 \n15. Harkness DR , Byrnes JJ , Lian EC , Williams WD , Hensley GT \nHazard of platelet transfusion in thrombotic thrombocytopenic purpura . JAMA \n246 : 1931 -1933 , 1981 .7197306\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(5)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "interferon; intestinal thrombotic microangiopathy; multiple sclerosis; posterior reversible encephalopathy syndrome; thrombotic microangiopathy",
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D000959:Antihypertensive Agents; D004334:Drug Administration Schedule; D005260:Female; D005767:Gastrointestinal Diseases; D006261:Headache; D006801:Humans; D006973:Hypertension; D016899:Interferon-beta; D007674:Kidney Diseases; D008134:Long-Term Care; D020529:Multiple Sclerosis, Relapsing-Remitting; D054038:Posterior Leukoencephalopathy Syndrome; D013921:Thrombocytopenia; D057049:Thrombotic Microangiopathies; D028761:Withholding Treatment",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "741-744",
"pmc": null,
"pmid": "29151517",
"pubdate": "2018-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21832278;27322218;26150023;28325251;28508977;12063238;25876469;9541291;27663672;25175315;11071509;7197306;25119611;18337603;20843591",
"title": "Thrombotic Microangiopathy Presenting with Intestinal Involvement Following Long-term Interferon-β1b Treatment for Multiple Sclerosis.",
"title_normalized": "thrombotic microangiopathy presenting with intestinal involvement following long term interferon 1b treatment for multiple sclerosis"
} | [
{
"companynumb": "JP-BAYER-2016-047613",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INTERFERON BETA-1B"
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"drugadditional": "1",
... |
{
"abstract": "Saprochaete clavata is a rare cause of fungaemia with deep organ involvement in patients with haematological malignancies with reported mortality rates of 60%-80%. We describe four cases of S clavata infection in a haematology unit over several months that were treated with voriconazole-based regimens. We also review the literature on factors that could contribute to earlier recognition and effective treatment of S clavata. We included all cases of culture-positive S clavata from sterile sites with associated signs of infection in patients undergoing treatment for a haematological malignancy. Isolates were identified by MALDI-TOF MS, and spectrum profiles were used to prepare clustering analysis of isolates. Susceptibility testing was performed using a commercial microtitre methods. Saprochaete clavata was isolated from the bloodstream in three cases and bronchial alveolar lavage (BAL) fluid in one case. Clustering analysis suggested strains of S clavata were clonal without evidence of divergence although a common source was not identified. Susceptibility testing yielded elevated MICs to fluconazole (8 mg/L) and echinocandins (>1-8 mg/L). All patients were treated with voriconazole-based regimens resulting in survival of 3/4 patients, who continued chemotherapy for their underlying malignancy without evidence of relapse. Saprochaete clavata is a rare but aggressive cause of breakthrough yeast infection in patients undergoing treatment for haematological malignancies, particularly patients with a prior history of echinocandin treatment. Timely initiation of appropriate treatment, aided by more rapid identification in microbiology laboratory, can reduce the risk of deep organ dissemination and patient death.",
"affiliations": "Department of Hematology and Oncology, Seràgnoli Institute of Hematology and Clinical Oncology, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Unit of Microbiology, Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Unit of Radiology, Department of Experimental, Scientific and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of Hematology and Oncology, Seràgnoli Institute of Hematology and Clinical Oncology, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of Hematology and Oncology, Seràgnoli Institute of Hematology and Clinical Oncology, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of Hematology and Oncology, Seràgnoli Institute of Hematology and Clinical Oncology, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Unit of Hemolymph-Pathology, Department of Hematology and Oncology, Seràgnoli Institute of Hematology and Clinical Oncology, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Unit of Hemolymph-Pathology, Department of Hematology and Oncology, Seràgnoli Institute of Hematology and Clinical Oncology, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of Hematology and Oncology, Seràgnoli Institute of Hematology and Clinical Oncology, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Department of Hematology and Oncology, Seràgnoli Institute of Hematology and Clinical Oncology, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.;Unit of Infectious Diseases, Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.",
"authors": "Stanzani|Marta|M|https://orcid.org/0000-0003-1569-3447;Cricca|Monica|M|;Sassi|Claudia|C|https://orcid.org/0000-0002-7864-2586;Sutto|Emanuele|E|;De Cicco|Gabriella|G|;Bonifazi|Francesca|F|;Bertuzzi|Clara|C|;Bacci|Francesco|F|;Paolini|Stefania|S|;Cavo|Michele|M|;Lewis|Russell E|RE|https://orcid.org/0000-0002-2002-4339",
"chemical_list": "D000935:Antifungal Agents; D065819:Voriconazole",
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.12978",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0933-7407",
"issue": "62(12)",
"journal": "Mycoses",
"keywords": "\nSaprochaete clavata\n; breakthrough IFI; echinocandins; fungaemia; haematological malignancies",
"medline_ta": "Mycoses",
"mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D004196:Disease Outbreaks; D005260:Female; D016469:Fungemia; D019337:Hematologic Neoplasms; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009894:Opportunistic Infections; D004718:Saccharomycetales; D065819:Voriconazole",
"nlm_unique_id": "8805008",
"other_id": null,
"pages": "1100-1107",
"pmc": null,
"pmid": "31365161",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Saprochaete clavata infections in patients undergoing treatment for haematological malignancies: A report of a monocentric outbreak and review of the literature.",
"title_normalized": "saprochaete clavata infections in patients undergoing treatment for haematological malignancies a report of a monocentric outbreak and review of the literature"
} | [
{
"companynumb": "IT-IBIGEN-2019.07892",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
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... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to investigate the association between general (GA), regional (RA), and local (LA) anesthetic techniques with respect to the development of delirium after vascular surgery. The authors hypothesized that patients undergoing GA for vascular surgery would have a higher incidence of postoperative delirium. The role of LA with respect to postoperative delirium in vascular surgery patients previously has not been reported.\n\n\nMETHODS\nRetrospective review.\n\n\nMETHODS\nTertiary referral center, university hospital.\n\n\nMETHODS\n500 patients undergoing vascular surgical procedures.\n\n\nMETHODS\nBased on the chosen anesthetic technique, all patients were divided into GA, RA, and LA groups, respectively. Exclusion criteria were patients with preoperative dementia or abnormal level of consciousness, patients undergoing open abdominal aneurysm repair surgery, and patients undergoing carotid endarterectomy. All anesthetic techniques were conducted according to routine institutional practices. Patients in both the RA and LA groups received intravenous sedation.\n\n\nRESULTS\nThree hundred ninety-six (79%) patients received GA, 73 (15%) RA, and 31 (6%) LA. The overall incidence of delirium was 19.4% and rates were similar among the 3 groups, with 73 (18.4%) patients in the GA group, 17 (23.2%) in the RA group, and 7 (22.5%) in the LA group (p = 0.56). Patients in the LA group were more likely to have emergency surgery and also had a higher incidence of previous cerebrovascular accidents or transient ischemic attacks. There was no significant difference with respect to either onset or duration of delirium among the 3 groups. Median length of hospital stay and in-hospital mortality were similar among the 3 groups.\n\n\nCONCLUSIONS\nDelirium rates after vascular surgery were similar with local, regional, or general anesthesia techniques. The presence of risk factors for the development of postoperative delirium should not influence the type of anesthesia provided.",
"affiliations": "Department of Anesthesia and Pain Management, Toronto General Hospital, Toronto, Canada.;Department of Anesthesia and Pain Management, Toronto General Hospital, Toronto, Canada.;Department of Anesthesia and Pain Management, Toronto General Hospital, Toronto, Canada.;Department of Anesthesia and Pain Management, Toronto General Hospital, Toronto, Canada.;Department of Anesthesia and Pain Management, Toronto General Hospital, Toronto, Canada.;Division of Vascular Surgery, University of Toronto, Toronto, Canada.;Department of Anesthesia and Pain Management, Toronto General Hospital, Toronto, Canada. Electronic address: george.djaiani@uhn.ca.",
"authors": "Ellard|Louise|L|;Katznelson|Rita|R|;Wasowicz|Marcin|M|;Ashworth|Alan|A|;Carroll|Jo|J|;Lindsay|Thomas|T|;Djaiani|George|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-0770",
"issue": "28(3)",
"journal": "Journal of cardiothoracic and vascular anesthesia",
"keywords": "delirium; type of anesthesia; vascular surgery",
"medline_ta": "J Cardiothorac Vasc Anesth",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000758:Anesthesia; D000765:Anesthesia, Conduction; D000768:Anesthesia, General; D000772:Anesthesia, Local; D016208:Databases, Factual; D003693:Delirium; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D012189:Retrospective Studies; D014656:Vascular Surgical Procedures",
"nlm_unique_id": "9110208",
"other_id": null,
"pages": "458-61",
"pmc": null,
"pmid": "24680130",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Type of anesthesia and postoperative delirium after vascular surgery.",
"title_normalized": "type of anesthesia and postoperative delirium after vascular surgery"
} | [
{
"companynumb": "CA-BAXTER-2014BAX040655",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
... |
{
"abstract": "To determine the plasma metformin concentration threshold associated with lactic acidosis and analyze the outcome in metformin-treated patients with lactic acidosis hospitalized in an emergency context.\n\n\n\nA retrospective, observational, single-center study.\n\n\n\nEmergency department and ICUs at Amiens University Hospital (Amiens, France).\n\n\n\nAll consecutive patients with data on arterial lactate and pH up to 12 hours before or after a plasma metformin assay within 24 hours of admission, over a 9.7-year period.\n\n\n\nNone.\n\n\n\nThe study population consisted of 194 metformin-treated diabetic patients (median age: 68.6; males: 113 [58.2%]); 163 (84%) had acute kidney injury, which was associated variously with dehydration (45.4%), sepsis (41.1%), cardiogenic shock (20.9%), and diabetic ketoacidosis (16%). Eighty-seven patients (44.8%) had lactic acidosis defined as an arterial blood pH less than 7.35 and a lactate concentration greater than or equal to 4 mM, and 38 of them (43.7%) died in the ICU. A receiver operating characteristic curve analysis showed that a metformin concentration threshold of 9.9 mg/L was significantly associated with the occurrence of lactic acidosis (specificity: 92.9%; sensitivity: 67.1%; area under the receiver operating characteristic curve: 0.83; p < 0.0001). Among lactic acidosis-positive patients, however, in-ICU death was less frequent when the metformin concentration was greater than or equal to 9.9 mg/L (33.9% vs 61.3% for < 9.9 mg/L; p = 0.0252). After adjustment for the Simplified Acute Physiology Score II, in-ICU death was positively associated with prothrombin activity less than 70% and negatively associated with the initiation of renal replacement therapy at admission.\n\n\n\nIn metformin-treated patients admitted in an emergency context, a plasma metformin concentration greater than or equal to 9.9 mg/L was strongly associated with the presence of lactic acidosis. This threshold may assist with the delicate decision of whether or not to initiate renal replacement therapy. Indeed, the outcome of lactic acidosis might depend on the prompt initiation of renal replacement therapy-especially when liver failure reduces lactate elimination.",
"affiliations": "Department of Clinical Pharmacology, Amiens University Hospital, Amiens, France.;Department of Clinical Pharmacology, Amiens University Hospital, Amiens, France.;Department of Clinical Pharmacology, Amiens University Hospital, Amiens, France.;Department of Clinical Pharmacology, Amiens University Hospital, Amiens, France.;Department of Clinical Pharmacology, Amiens University Hospital, Amiens, France.;MP3CV Laboratory, EA7517, University of Picardie Jules Verne, Amiens, France.;Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium.;Department of Endocrinology-Diabetology-Nutrition, Amiens University Hospital, Amiens, France.;Department of Clinical Pharmacology, Amiens University Hospital, Amiens, France.",
"authors": "Bennis|Youssef|Y|;Bodeau|Sandra|S|;Batteux|Benjamin|B|;Gras-Champel|Valérie|V|;Masmoudi|Kamel|K|;Maizel|Julien|J|;De Broe|Marc E|ME|;Lalau|Jean-Daniel|JD|;Lemaire-Hurtel|Anne-Sophie|AS|",
"chemical_list": "D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1097/CCM.0000000000004589",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-3493",
"issue": "48(12)",
"journal": "Critical care medicine",
"keywords": null,
"medline_ta": "Crit Care Med",
"mesh_terms": "D000140:Acidosis, Lactic; D000368:Aged; D004636:Emergency Service, Hospital; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008687:Metformin; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "0355501",
"other_id": null,
"pages": "e1194-e1202",
"pmc": null,
"pmid": "33003077",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "A Study of Associations Between Plasma Metformin Concentration, Lactic Acidosis, and Mortality in an Emergency Hospitalization Context.",
"title_normalized": "a study of associations between plasma metformin concentration lactic acidosis and mortality in an emergency hospitalization context"
} | [
{
"companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2020-06965",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "BACKGROUND\nSome studies have reported the development of moderate and severe de novo SpA-associated disease under vedolizumab (VDZ) treatment for IBD. Herein, we report a case series who developed severe enthesitis under VDZ therapy from a cohort of 90 treated cases.\n\n\nMETHODS\nIn a single Italian IBD Unit in which 90 cases were on VDZ therapy, we identified 11 cases who developed severe enthesitis. The onset of disease in relationship to VDZ initiation, clinical and sonographic imaging features, and outcomes (including therapy switches) was described.\n\n\nRESULTS\nA total of 11 cases, including 8 prior anti-TNF failures, with new-onset entheseal pathology were identified: multifocal (n = 4), unifocal (n = 6), and enthesitis/synovitis/dactylitis (n = 1). The mean duration of symptoms was 46 weeks (range 6-119), the mean CRP was 5.1 mg/dl, and the majority were HLA-B27 negative and showed good clinical response for gut disease. Clinical features and US showed severe enthesitis, including power Doppler change in 7 patients. All patients were initially treated with NSAIDs, and 5 patients underwent local steroid injections. At 12 months, 5/7 cases continued VDZ and 2 were switched to ustekinumab. At 12 months follow-up of 7 cases, 5 patients were in clinical remission and 2 patients had mild enthesitis with minimal increase of power Doppler signal. In addition, 4/7 severe patients developed marked post-inflammatory entheseal calcifications.\n\n\nCONCLUSIONS\nA predominant isolated severe enthesitis pattern of SpA may develop under VDZ therapy with severe disease in 8% of cases. Most cases continued VDZ therapy.",
"affiliations": "IBD Unit, IRCCS Sacro Cuore Don Calabria.;Rheumatology Unit, Sacro Cuore Don Calabria Cancer Care Center, Negrar, Italy.;IBD Unit, IRCCS Sacro Cuore Don Calabria.;IBD Unit, IRCCS Sacro Cuore Don Calabria.;Rheumatology Unit, Sacro Cuore Don Calabria Cancer Care Center, Negrar, Italy.;NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals Trust & The University of Leeds, Leeds, UK.",
"authors": "Ruscio|Mirko Di|MD|;Tinazzi|Ilaria|I|;Variola|Angela|A|;Geccherle|Andrea|A|;Marchetta|Antonio|A|;McGonagle|Dennis|D|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/keab135",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "60(12)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "enthesitis; inflammatory bowel disease; spondyloarthritis; ustekinumab; vedolizumab",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": null,
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "5809-5813",
"pmc": null,
"pmid": "33580246",
"pubdate": "2021-12-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prevalence and real-world management of vedolizumab-associated enthesitis in successfully treated IBD patients.",
"title_normalized": "prevalence and real world management of vedolizumab associated enthesitis in successfully treated ibd patients"
} | [
{
"companynumb": "IT-TAKEDA-2021TUS011395",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VEDOLIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "A 15-year-old female subject presented comatose, in respiratory failure and shock, after the intentional ingestion of ∼280 extended-release 200-mg carbamazepine tablets with a peak serum concentration of 138 µg/mL (583.74 µmol/L). The patient developed clinical seizures and an EEG pattern of stimulus-induced rhythmic, periodic, or ictal discharges, suggestive of significant cortical dysfunction. Due to the extremely high drug serum concentration and clinical instability, a combination of therapies was used, including lipid emulsion therapy, plasmapheresis, hemodialysis, continuous venovenous hemodiafiltration, and endoscopic intestinal decontamination. The patient's elevated serum lactate level with a high mixed venous saturation suggested possible mitochondrial dysfunction, prompting treatment with barbiturate coma to reduce cerebral metabolic demand. The serum carbamazepine concentration declined steadily, with resolution of lactic acidosis, no long-term end-organ damage, and return to baseline neurologic function. The patient was eventually discharged in her usual state of health. In the laboratory, we demonstrated in vitro that the active metabolite of carbamazepine hyperpolarized the mitochondrial membrane potential, supporting the hypothesis that the drug caused mitochondrial dysfunction. We thus successfully treated a life-threatening carbamazepine overdose with a combination of modalities. Future studies are required to validate this aggressive approach. The occurrence of mitochondrial dysfunction must be confirmed in patients with carbamazepine toxicity and the need to treat it validated.",
"affiliations": "Department of Global Pediatric Medicine and Division of Critical Care, St. Jude Children's Research Hospital, Memphis, Tennessee; and.;Divisions of Medicine Critical Care.;Emergency Medicine, and.;Neurology, Boston Children's Hospital, Boston, Massachusetts.;Neurology, Boston Children's Hospital, Boston, Massachusetts.;Neurology, Boston Children's Hospital, Boston, Massachusetts.;Emergency Medicine, and.;Divisions of Medicine Critical Care, daniel.kohane@childrens.harvard.edu.",
"authors": "Agulnik|Asya|A|;Kelly|Daniel P|DP|;Bruccoleri|Rebecca|R|;Yuskaitis|Christopher|C|;Ebrahimi-Fakhari|Darius|D|;Sahin|Mustafa|M|;Burns|Michele M|MM|;Kohane|Daniel S|DS|",
"chemical_list": "D001463:Barbiturates; D002220:Carbamazepine",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2016-1560",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "139(5)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000293:Adolescent; D001463:Barbiturates; D002220:Carbamazepine; D003128:Coma; D003131:Combined Modality Therapy; D003666:Decontamination; D062787:Drug Overdose; D005260:Female; D017583:Hemodiafiltration; D006801:Humans; D010956:Plasmapheresis; D006435:Renal Dialysis",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28557718",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Combination Clearance Therapy and Barbiturate Coma for Severe Carbamazepine Overdose.",
"title_normalized": "combination clearance therapy and barbiturate coma for severe carbamazepine overdose"
} | [
{
"companynumb": "PHHY2015US163102",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "BACKGROUND\nInflammatory myopathies are treated with glucocorticoids and other immunosuppressive medications. Intravenous immunoglobulin (IVIG) is increasingly used for refractory or severe cases; however, the evidence for their effectiveness is limited. We assessed effectiveness and safety of IVIG when used with other immunomodulatory agents in the treatment of inflammatory myopathies.\n\n\nMETHODS\nThis study reviewed records of patients diagnosed with dermatomyositis or polymyositis and treated with IVIG, from 2009 through 2016 in 1 tertiary medical center. Mixed-effects general linear regression models were applied to determine effectiveness of treatment on muscle strength, creatinine phosphokinase levels, and steroid dosage.\n\n\nRESULTS\nTwenty-three patients with dermatomyositis/polymyositis treated with IVIG were followed up for a mean of 31 (SD, ±25) months. During this period, a significant improvement in muscle strength was demonstrated, with a mean increase of 0.92 Medical Research Council scale points (β = 0.14; confidence interval [CI], 0.136-0.149; p < 0.0001), a significant reduction of creatinine phosphokinase levels and steroid dosage with a mean decrease of 1140 IU/L (β = -0.274; CI, -0.354 to -0.195; p < 0.0001), and 36 mg/d (β = -0.008; CI, -0.011 to -0.006; p < 0.0001), respectively. Overall, remission was observed in 10 patients (43.5%), and partial remission in 6 patients (26%), whereas 1 patient (17%) remained refractory to treatment, and 6 patients (27%) were lost to follow-up.\n\n\nCONCLUSIONS\nThe majority of patients with inflammatory myopathies experienced a clinical and laboratory improvement during IVIG treatment. In addition, a steroid-sparing effect was noticed in most patients. These results encourage the use of IVIG as an alternative treatment option for patients with limited responsiveness to conventional methods.",
"affiliations": "From the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv.;From the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv.",
"authors": "Ohad|Maayan|M|;Shemer|Asaf|A|;Lavie|Inbar|I|;Ozeri|David|D|;Shoenfeld|Yehuda|Y|;Kivity|Shaye|S|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors",
"country": "United States",
"delete": false,
"doi": "10.1097/RHU.0000000000001418",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1076-1608",
"issue": "27(8)",
"journal": "Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases",
"keywords": null,
"medline_ta": "J Clin Rheumatol",
"mesh_terms": "D003882:Dermatomyositis; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D009220:Myositis; D017285:Polymyositis",
"nlm_unique_id": "9518034",
"other_id": null,
"pages": "e616-e621",
"pmc": null,
"pmid": "32501943",
"pubdate": "2021-12-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intravenous Immunoglobulin for Inflammatory Myositis: Experience in a Tertiary Medical Center.",
"title_normalized": "intravenous immunoglobulin for inflammatory myositis experience in a tertiary medical center"
} | [
{
"companynumb": "IL-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326515",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
... |
{
"abstract": "Iatrogenic Cushing syndrome (CS) is a well-known complication of treating patients with systemic steroids. More rarely, it has been described in HIV-positive patients on ritonavir (RTV) while using the inhaled corticosteroid fluticasone, which is metabolized through the cytochrome P450 3A4 (CYP3A4) enzyme system. In the presence of RTV, a known CYP3A4 enzyme inhibitor, the interaction can result in impaired metabolism and systemic accumulation of inhaled fluticasone resulting in iatrogenic CS. Iatrogenic CS has been less often described with inhaled budesonide compared to inhaled fluticasone. Therefore, inhaled budesonide is often used as an alternative therapy for patients on RTV to avoid iatrogenic CS. We report the fifth case report of budesonide-induced iatrogenic CS in an HIV-positive patient on RTV. We highlight the importance of early recognition of the syndrome and distinguishing it from HIV lipodystrophy. Finally, we review the literature for cases of iatrogenic CS involving RTV and commonly used steroids.",
"affiliations": "1 Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA.;2 Riverside Shore Memorial Hospital, Onancock, VA, USA.;1 Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA.;1 Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA.",
"authors": "Colpitts|Lily|L|;Murray|Thomas B|TB|;Tahhan|Sami G|SG|;Boggs|Jody P|JP|",
"chemical_list": "D065692:Cytochrome P-450 CYP3A Inhibitors; D005938:Glucocorticoids; D017320:HIV Protease Inhibitors; D019819:Budesonide; D019438:Ritonavir",
"country": "United States",
"delete": false,
"doi": "10.1177/2325957417736612",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-9574",
"issue": "16(6)",
"journal": "Journal of the International Association of Providers of AIDS Care",
"keywords": "CYP3A4 metabolism; Cushing syndrome; HAART; budesonide; ritonavir",
"medline_ta": "J Int Assoc Provid AIDS Care",
"mesh_terms": "D000280:Administration, Inhalation; D019819:Budesonide; D003480:Cushing Syndrome; D065692:Cytochrome P-450 CYP3A Inhibitors; D003937:Diagnosis, Differential; D004347:Drug Interactions; D005260:Female; D005938:Glucocorticoids; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D039682:HIV-Associated Lipodystrophy Syndrome; D006801:Humans; D007049:Iatrogenic Disease; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive; D019438:Ritonavir",
"nlm_unique_id": "101603896",
"other_id": null,
"pages": "531-534",
"pmc": null,
"pmid": "29108449",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Iatrogenic Cushing Syndrome in a 47-Year-Old HIV-Positive Woman on Ritonavir and Inhaled Budesonide.",
"title_normalized": "iatrogenic cushing syndrome in a 47 year old hiv positive woman on ritonavir and inhaled budesonide"
} | [
{
"companynumb": "US-MYLANLABS-2018M1052995",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUDESONIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Sub-anaesthetic ketamine is of special interest for depression research due to its rapid and potent but short-lived antidepressant response (after-effect). The presented case is the first one in the literature which deals in detail with the transfer from ketamine's antidepressant action to ketamine addiction. A 50-year-old anaesthetic nurse, who had never been treated with antidepressants before, started with self-injecting ketamine racemate 50 mg IM once a week to cope with her major depression. She continuously stole ketamine from hospital stocks. Due to a gradually developing tolerance to ketamine's antidepressant action, she stepwise increased dose and frequency of ketamine self-injections up to daily 2 g IM (three-fold her anaesthetic dose) over six months. This was accompanied by the development of ketamine addiction, loss of consciousness, dissociative immobility, and amnesia. Inpatient detoxification treatment was characterized by a strong craving for ketamine and, later on, by the occurrence of a severe depressive episode remitting on venlafaxine. A 14-week follow-up documented a normal condition without any ketamine sequelae, such as craving, psychosis, depression, or cognitive abnormalities. Thus, awareness of ketamine addiction potential, even in patients who received ketamine for antidepressant purposes, is important.",
"affiliations": "a Head of the Department of Psychiatry, Psychotherapy and Psychosomatic Medicine , Evangelisches Krankenhaus Castrop-Rauxel, Academic Teaching Hospital of the University of Duisburg-Essen , Castrop-Rauxel , Germany.",
"authors": "Bonnet|Udo|U|",
"chemical_list": "D000928:Antidepressive Agents; D007649:Ketamine",
"country": "United States",
"delete": false,
"doi": "10.1080/02791072.2015.1072653",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0279-1072",
"issue": "47(4)",
"journal": "Journal of psychoactive drugs",
"keywords": "addiction; alcohol; antidepressant effect; ketamine; tolerance",
"medline_ta": "J Psychoactive Drugs",
"mesh_terms": "D000928:Antidepressive Agents; D003865:Depressive Disorder, Major; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D007649:Ketamine; D008875:Middle Aged; D012646:Self Administration; D019966:Substance-Related Disorders",
"nlm_unique_id": "8113536",
"other_id": null,
"pages": "276-85",
"pmc": null,
"pmid": "26317449",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long-Term Ketamine Self-Injections in Major Depressive Disorder: Focus on Tolerance in Ketamine's Antidepressant Response and the Development of Ketamine Addiction.",
"title_normalized": "long term ketamine self injections in major depressive disorder focus on tolerance in ketamine s antidepressant response and the development of ketamine addiction"
} | [
{
"companynumb": "DE-MYLANLABS-2015M1039961",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "KETAMINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCaudal epidural injection is one of the conventional treatments of chronic back pain. Even though spinal epidural hematoma after caudal epidural injection is rare but it can cause serious neurologic complication.\nAn 83-year-old woman taking cilostazol received caudal epidural steroid injection because of her chronic back pain. Six hours later, she experienced an acute hip pain which worsened with time.\n\n\nMETHODS\nMagnetic resonance image showed acute cord compression due to a spinal epidural hematoma at L2-S1 level with concomitant central canal compromise at L2/3, L3/4 level.\n\n\nMETHODS\nEmergency decompressive laminectomy and evacuation of the lumbar epidural hematoma were performed.\n\n\nRESULTS\nAll of her symptoms were resolved over the 72 hours following surgery.\n\n\nCONCLUSIONS\nContinuous vigilance after caudal epidural injection is important to prevent catastrophic neurologic deterioration with early detection and early treatment.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Gachon University Gil Medical Center, Incheon, South Korea.",
"authors": "Choi|Jung Ju|JJ|;Chang|Young Jin|YJ|;Jung|Wol Seon|WS|;Lee|Kyung Cheon|KC|;Kim|Ju Ho|JH|;Jo|Youn Yi|YY|",
"chemical_list": "D005343:Fibrinolytic Agents; D013256:Steroids; D013777:Tetrazoles; D000077407:Cilostazol",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000007127",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28614233MD-D-17-0240310.1097/MD.0000000000007127071273300Research ArticleClinical Case ReportDiscordant lumbar epidural hematoma after caudal steroid injection A case report (CARE-compliant)Choi Jung Ju MDChang Young Jin MDJung Wol Seon MDLee Kyung Cheon MDKim Ju Ho MDJo Youn Yi MD∗Hanaoka. Kazuo Department of Anesthesiology and Pain Medicine, Gachon University Gil Medical Center, Incheon, South Korea.∗ Correspondence: Youn Yi Jo, Department of Anesthesiology and Pain Medicine, Gachon University Gil Medical Center, 1198 Guwol-dong, Namdong-gu, Incheon 405-760, South Korea (e-mail: endless37@gilhospital.com).6 2017 16 6 2017 96 24 e712717 4 2017 10 5 2017 12 5 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nCaudal epidural injection is one of the conventional treatments of chronic back pain. Even though spinal epidural hematoma after caudal epidural injection is rare but it can cause serious neurologic complication.\n\nPatient concerns:\nAn 83-year-old woman taking cilostazol received caudal epidural steroid injection because of her chronic back pain. Six hours later, she experienced an acute hip pain which worsened with time.\n\nDiagnosis:\nMagnetic resonance image showed acute cord compression due to a spinal epidural hematoma at L2–S1 level with concomitant central canal compromise at L2/3, L3/4 level.\n\nInterventions:\nEmergency decompressive laminectomy and evacuation of the lumbar epidural hematoma were performed.\n\nOutcomes:\nAll of her symptoms were resolved over the 72 hours following surgery.\n\nLessons:\nContinuous vigilance after caudal epidural injection is important to prevent catastrophic neurologic deterioration with early detection and early treatment.\n\nKeywords\ncaudal epidural injectioncilostazollumbar epidural hematomaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nCaudal epidural injection is a procedure commonly applied to patients with chronic low back pain caused by disc herniation, radiculitis, or spinal stenosis.[1,2] This procedure is known to have low complication rate.[1] Clinical investigation of 257 cases of fluoroscopy-guided caudal block in 139 patients noted that 15.6% developed minor complications such as insomnia, transient headache, aggravation of back or leg pain, facial flushing, vasovagal reaction, or nausea, but no major complication was reported.[3] Other clinical studies reported complications that were confined to the anatomical structure of the injection site, such as cauda equina syndrome or intravascular injection during or after caudal injection.[4,5]\n\nEven though spinal epidural hematoma is a rare complication, but it is potentially catastrophic due to neurologic sequelae. In an analysis of 33,142 nonobstetric epidural blocks, spinal epidural hematoma occurred in 1/6628 cases.[6] Case reports described that in most case spinal epidural hematomas were localized in the site of injection.[7,8]\n\nTo our best knowledge, no previous reports have shown a lumbar epidural hematoma after caudal injection. We report an experience of lumbar epidural hematoma that is not matched with the injection site after caudal steroid injection.\n\n2 Case report\nThis report was approved by Institutional Review Board of Gil Hospital, and written informed consent was provided by the patient. An 83-year-old woman was diagnosed with lumbar spinal stenosis with bulging of the intervertebral discs from L2 to L5. She had a history of chronic back pain for over 10 years and took medicine without invasive interventions or operative procedures. She was pharmacologically treated with nonsteroidal antiinflammatory drugs and benzodiazepines for over 10 years. A physical exam showed a local tenderness around L5 and S1 vertebrae without motor or sensory deficits. She received a lumbar epidural steroid injection via interlaminar approach at L5/S1 level 7 months prior, which relieved her back pain for time. However, the recurrence of pain at the same spinal levels led to her admission to our hospital.\n\nHer medical history included type-2 diabetes, atrial fibrillation, and old CVA, for which she was taking cilostazol, a phosphodiesterase type 3 inhibitor. Laboratory findings showed normal electrolytes, hematocrit at 39.7%, platelets at 178,000/mm3, prothrombin time at 10.2 seconds, activated partial thromboplastin time at 33.2 seconds.\n\nA caudal epidural injection was performed under fluoroscopic guidance. The patient was asked to lie prone on a fluoroscopic table. A pillow was placed under the hips to tilt the pelvis and bring the sacral-hiatus into greater prominence. The sacro-coccygeal area was prepared using an iodine-based povidone solution and an alcohol solution. Three milliliter of 2% lidocaine was infiltrated using 25G needle to prevent puncture pain. We used a 22-gauge, 3.5-inch spinal needle. After penetrating 3 cm of skin, we checked the absence of blood in the syringe before advancing the needle. We injected 1 mL of contrast media before drug injection. After correctly positioning the needle, 0.2% lidocaine with 1 mg of dexamethasone in 15 mL total volume was injected. One hour after injection she experienced a reduction of back pain (Fig. 1). Three days after the caudal injection, the patient came to the outpatient clinic and complained of newly developed severe burning pain radiating into both hips, and difficulty standing. She complained that the symptom started about 6 hours after the caudal injection and worsened with time. A full neurological assessment revealed no weakness in the patient's trunk and lower limbs, and no other changes.\n\nFigure 1 Lateral (A) and antero-posterior (B) fluoroscopic images during caudal steroid injection.\n\nAn urgently checked lumbar spine magnetic resonance image (MRI) showed acute cord compression due to a spinal epidural hematoma at L2–S1 level with concomitant central canal compromise (severe at L2/3, L3/4 level) (Fig. 2). Emergency decompressive laminectomy and evacuation of the hematoma was performed uneventfully over 4 hours. Her symptoms resolved over the 72 hours following surgery. She had no further signs or symptoms of radiculopathy and returned to normal daily activity after 6 weeks.\n\nFigure 2 Magnetic resonance image shows spinal epidural hematoma in sagital T2-weighted image (A) and thecal sac compression by hematoma at axial T2-weighted image (B).\n\n3 Discussion\nWe describe an experience of discordant lumbar epidural hematoma after caudal steroid injection in a patient with chronic back pain. The frequency of spinal hematoma due to epidural steroid injections is unclear. Injected local anesthetics sometimes confuse and delay the diagnosis of epidural hematoma and might lead to the cord ischemia. Neurological impairment after epidural anesthesia is reported in 1/150,000, and 1/220,000 following spinal anesthesia.[9] A meta-analysis of 613 patients demonstrated that 29.7% of spinal hematoma was idiopathic, and anticoagulant therapy and vascular malformation were the 2nd and 3rd most common causes of spinal hematoma. Procedures at the spinal level itself frequently induced spinal hematoma without any further cause.[10]\n\nDrugs associated with coagulation such as anticoagulants, antiplatelet drugs, and thrombolytics are widely used for the treatment or prevention of stroke, myocardial infarction, pulmonary embolism, and deep vein thrombosis. Our patient had a history of cerebrovascular attack and was taking cilostazol, but no other anticoagulants. Cilostazol is a selective inhibitor of phosphodiesterase type 3 with therapeutic focus on increasing cyclic adenosine monophosphate. An increase in cyclic adenosine monophosphate increases the active form of protein kinase A, thereby directly inhibiting platelet aggregation, and producing a vasodilatory effect by inhibiting myosin light-chain kinase activation.[11] Cilostazol reduces the risk of stroke by 25.7% relative to aspirin, with significantly less hemorrhagic risk.[12] According to American Society of Interventional Pain Physicians (ASIPP) guidelines published in 2010, continued use of phosphodiesterase inhibitors, such as dipyridamole, dipyridamole plus aspirin, and cilostazol, does not increase the risk of spinal epidural hematoma after interventional procedures, and discontinuing the medication before the procedure is unnecessary.[13] A crossover study of 21 patients with peripheral arterial disease demonstrated that aspirin or clopidogrel alone significantly increased bleeding time, but not cilostazol alone. In combination therapy, cilostazole added to any aspirin/clopidogrel regimen did not prolong bleeding time above the significant increase of bleeding time caused by aspirin and clopidogrel.[14]\n\nHowever, despite the preinterventional normal laboratory values and not taking other anticoagulant, lumbar epidural hematoma still developed in this case. Thus, close observation is necessary for the patients even if cilostazole is the only medication taken.\n\nShanthanna and Park[15] reported an acute extradural hematoma at T10–12 following epidural steroid injection at L3–4 in a patient with spinal stenosis. They explained that tortuous and weakened blood vessels might be ruptured by the injectant. We observed discordant lumbar epidural hematoma separate from the injection site in a patient with long-term multilevel spinal stenosis. In the case of spinal stenosis, because of the narrow spinal canal, the neighboring structures including the venous epidural plexus are under pressure, and this increased pressure can result in veins in the epidural space becoming engorged and tortuous, leading to vessel wall thinning.\n\nEpidural hematoma requires rapid diagnosis and treatment. Rapid decompression surgeries in the case of epidural hematoma are necessary for neurological recovery.[16] If laminectomy is performed within 8 hours of neurological injury, neurological damage may be reversible.[17] Therefore, if epidural hematoma is suspected, it is important to immediately diagnose radiographically and to not delay surgical treatment. MRI is preferred as a fast, noninvasive method. The presence of epidural hematoma can be rapidly diagnosed by MRI, and its location and vascular malformation can be detected. The degree of cord compression can be confirmed and the timing of hematoma can be predicted.[18]\n\nIn our case, she experienced newly developed radiculopathy without motor weakness. Since we could not rule out epidural abscess or epidural hematoma, we confirmed using immediate MRI and proceeded with emergency surgery.\n\nIn conclusion, the cause of lumbar epidural hematoma following caudal steroid injection in this case was not clear. Possibilities included cilostazole, the underlying spinal stenosis, interventional violence, or a combination of all. In any event, it is important to prevent catastrophic cord injury with early detection and early treatment. Especially in the patients taking medications that can produce bleeding diathesis, close observation is mandatory.\n\nAbbreviation: MRI = magnetic resonance image.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Parr AT Manchikanti L Hameed H \nCaudal epidural injections in the management of chronic low back pain: a systematic appraisal of the literature . Pain Physician \n2012 ;15 :E159 –98 .22622911 \n[2] Lee SH Park JW Hwang BM \nAnaphylactic shock following nonionic contrast mediumduring caudal epidural injection . Korean J Pain \n2015 ;28 :280 –3 .26495083 \n[3] Botwin KP Gruber RD Bouchlas CG \nComplications of fluoroscopically guided caudal epidural injections . Am J Phys Med Rehabil \n2001 ;80 :416 –24 .11399002 \n[4] Bilir A Gulec S \nCauda equina syndrome after epidural steroid injection: a case report . J Manipulative Physiol Ther \n2006 ;29 : 492.e1-3 .\n[5] Park Y Lee JH Park KD \nUltrasound-guided vs. fluoroscopy-guided caudal epidural steroid injection for the treatment of unilateral lower lumbar radicular pain: a prospective, randomized, single-blind clinical study . Am J Phys Med Rehabil \n2013 ;92 :575 –86 .23636087 \n[6] Volk T Wolf A Van Aken H \nIncidence of spinal haematoma after epidural puncture: analysis from the German network for safety in regional anaesthesia . Eur J Anaesthesiol \n2012 ;29 :170 –6 .22374389 \n[7] Cullen DJ Bogdanov E Htut N \nSpinal epidural hematoma occurrence in the absence of known risk factors: a case series . J Clin Anesth \n2004 ;16 :376 –81 .15374560 \n[8] Williams KN Jackowski A Evans PJ \nEpidural haematoma requiring surgical decompression following repeated cervical epidural steroid injections for chronic pain . Pain \n1990 ;42 :97 –9 .\n[9] Horlocker TT \nRegional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy . Br J Anaesth \n2011 ;107 :96 –106 .\n[10] Kreppel D Antoniadis G Seeling W \nSpinal hematoma: a literature survey with meta-analysis of 613 patients . Neurosurg Rev \n2003 ;26 :1 –49 .12520314 \n[11] Kwon SU Cho YJ Koo JS \nCilostazol prevents the progression of the symptomatic intracranial arterial stenosis: the multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis . Stroke \n2005 ;36 :782 –6 .15746463 \n[12] Uchiyama S Shinohara Y Katayama Y \nBenefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2 . Cerebrovasc Dis \n2014 ;37 :296 –303 .24820203 \n[13] Horlocker TT Wedel DJ Rowlingson JC \nRegional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition) . Reg Anesth Pain Med \n2010 ;35 :64 –101 .20052816 \n[14] Comerota AJ \nEffect on platelet function of cilostazol, clopidogrel, and aspirin, each alone or in combination . Atheroscler Suppl \n2005 ;6 :13 –9 .16275168 \n[15] Shanthanna H Park J \nAcute epidural haematoma following epidural steroid injection in a patient with spinal stenosis . Anaesthesia \n2011 ;66 :837 –9 .21790519 \n[16] Li SL Wang DX Ma D \nEpidural hematoma after neuraxial blockade: a retrospective report from China . Anesth Analg \n2010 ;111 :1322 –4 .20705781 \n[17] Horlocker TT Wedel DJ Benzon H \nRegional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuroaxial Anesthesia and Anticoagulation) . Reg Anesth Pain Med \n2003 ;28 :172 –97 .12772135 \n[18] Neal JM Bermards CM Hadzic A \nASRA practice advisory on neurologic complications in regional anesthesia and pain medicine . Reg Anesth Pain Med \n2008 ;33 :404 –11 .18774509\n\n",
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"abstract": "Systemic capillary leak syndrome (SCLS) is an idiopathic vascular hyperpermeability that leads to profound hypotension, hypoalbuminemia, and hemoconcentration. Sixty years since its inauguration into literature, SCLS is still elusive, underdiagnosed, and profoundly dangerous. Few authors have documented anesthetic implications of classical acute SCLS, a form with complete recovery between exacerbations. However, minimal information is available about chronic SCLS, continuous generalized edema with or without exacerbations. Both forms are postulated to have similar pathogenesis, yet clinical differences are noteworthy, warranting variations in perioperative management. We present a patient with chronic SCLS who underwent general and regional anesthesia for elective surgery.",
"affiliations": "From the Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota.",
"authors": "Datta|Resham|R|;Panchamia|Jason K|JK|",
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"abstract": "Calcification in primary gastric cancer is very rare. In this report, we describe the computerized tomography (CT) changes in calcification in a patient with locally advanced signet-ring gastric cancer treated with chemotherapy.\n\n\n\nA 49-year-old man presented with 5 months' history of abdominal pain, anorexia, and rapid weight loss. He had undergone Billroth-II subtotal gastrectomy for a bleeding gastric ulcer 30 years ago. Abdominal CT showed irregular thickening of the gastric wall and miliary calcifications. Histologic examination of specimen obtained by endoscopic biopsy showed poorly differentiated calcified signet-ring gastric cancer. The patient was clinically staged T4N2M0 and treated with docetaxel, cisplatin, and fluorouracil (DCF)/oxaliplatin and S-1 (XLOX)/S-1. After five cycles of chemotherapy, the general condition of the patient improved and tumor markers (CEA, CA125, CA199) decreased. However, follow-up CT scans showed continuing increase in the calcification.\n\n\n\nTo conclude, in this case report we have described the dynamic changes in calcification in a gastric cancer patient receiving chemotherapy. One explanation for the observed increase in calcifications could be that the ischemic necrosis resulting from chemotherapy creates an alkaline environment, which promotes deposition of calcium salts. Our theory needs to be confirmed with histological evidence from a large series of patients. Nevertheless, we hope that these findings will improve understanding of the mechanism of calcification in gastric cancer.",
"affiliations": "Department of Oncology, Nanchang county people's hospital, Nanchang, China.;Department of Oncology, Nanchang county people's hospital, Nanchang, China.;Department of Oncology, Nanchang county people's hospital, Nanchang, China.;Department of Oncology, Nanchang county people's hospital, Nanchang, China.;Department of Oncology, Nanchang county people's hospital, Nanchang, China.;Department of Oncology, The Second Afiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, China. huanglongdoctor@163.com.",
"authors": "Wang|Ting|T|;Lu|Zhi-Yong|ZY|;Tu|Xin-Fei|XF|;Zhang|Shui-Hong|SH|;Huang|Fang|F|;Huang|Long|L|",
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"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 441510.1186/s12885-018-4415-5Case ReportComputerized tomography findings in calcified signet-ring gastric cancer receiving chemotherapy: a case report Wang Ting 339749005@qq.com 3Lu Zhi-Yong 906631671@qq.com 3Tu Xin-Fei 350827320@qq.com 3Zhang Shui-Hong 459429257@qq.com 3Huang Fang huanglongdoctor@163.com 3Huang Long 0086 20 13699549060huanglongdoctor@163.com 1231 0000 0001 2182 8825grid.260463.5Department of Oncology, The Second Afiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, China 2 JiangXi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, Jiangxi China 3 Department of Oncology, Nanchang county people’s hospital, Nanchang, China 27 4 2018 27 4 2018 2018 18 47420 10 2017 20 4 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\nCalcification in primary gastric cancer is very rare. In this report, we describe the computerized tomography (CT) changes in calcification in a patient with locally advanced signet-ring gastric cancer treated with chemotherapy.\n\nCase presentation\nA 49-year-old man presented with 5 months’ history of abdominal pain, anorexia, and rapid weight loss. He had undergone Billroth-II subtotal gastrectomy for a bleeding gastric ulcer 30 years ago. Abdominal CT showed irregular thickening of the gastric wall and miliary calcifications. Histologic examination of specimen obtained by endoscopic biopsy showed poorly differentiated calcified signet-ring gastric cancer. The patient was clinically staged T4N2M0 and treated with docetaxel, cisplatin, and fluorouracil (DCF)/oxaliplatin and S-1 (XLOX)/S-1. After five cycles of chemotherapy, the general condition of the patient improved and tumor markers (CEA, CA125, CA199) decreased. However, follow-up CT scans showed continuing increase in the calcification.\n\nConclusions\nTo conclude, in this case report we have described the dynamic changes in calcification in a gastric cancer patient receiving chemotherapy. One explanation for the observed increase in calcifications could be that the ischemic necrosis resulting from chemotherapy creates an alkaline environment, which promotes deposition of calcium salts. Our theory needs to be confirmed with histological evidence from a large series of patients. Nevertheless, we hope that these findings will improve understanding of the mechanism of calcification in gastric cancer.\n\nKeywords\nGastric cancerCalcificationComputerized tomographyChemotherapyPrognosishttp://dx.doi.org/10.13039/501100001809National Natural Science Foundation of China81460393issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nGastric cancer is one of the commonest malignancies [1]. Calcification in primary gastric cancer is uncommon and is seen in less than 3% of cases [2]; most of these tumors are adenocarcinomas containing pools of mucin.\n\nIn general, calcifications within malignancies are circumscribed and round in shape, with diameter ranging from 5 to 100 μm [3]. Calcifications may be seen in tumors of the thyroid, thymus, and pancreas, or in meningiomas, and are especially common in tumors of the female reproductive system (ovary, endometrium) and breast [3–8].\n\nGastric carcinoma with calcification characteristically occurs in relatively young patients [9, 10]. In most previous reports of calcified gastric cancer, the focus has been on imaging findings and pathological features; the patients generally received surgical resection and so the authors could not observe the progression of the calcification.\n\nIn this report, we present the serial computerized tomography (CT) features of a locally advanced calcified signet-ring cell gastric cancer that showed partial response to chemotherapy.\n\nCase presentation\nA 49-year-old man visited to our hospital in December 2016 with complaints of abdominal pain, anorexia, and rapid weight loss for 5 months. He had undergone Billroth-II subtotal gastrectomy 30 years earlier for treatment of a bleeding gastric ulcer. Abdominal CT scan revealed irregular thickening of the gastric walls and miliary calcifications. Histopathological examination of specimen obtained by endoscopic biopsy showed poorly differentiated signet-ring cell cancer with calcifications (Fig. 1). Tumor markers were elevated (CEA 6.21 ng/mL, CA125 115.80 u/mL, and CA199 659.93 u/mL). Serum calcium and phosphorus levels were within the normal range. The clinical stage was T4N2M0. A tumor at this stage is inoperable, and so the patient was started on chemotherapy with docetaxel, cisplatin, and fluorouracil (DCF). He received three cycles of DCF, but in March 2017 the chemotherapy protocol was changed to XLOX (oxaliplatin and S-1) because of toxic response. After five cycles of chemotherapy (3 cycles of DCF + 2 cycles of XLOX) the symptoms of abdominal pain and anorexia were relieved, and CEA, CA125, and CA199 decreased to 1.90 ng/mL, 112.80 u/mL, and 344.32 u/mL, respectively. Abdominal CT showed reduction in gastric wall thickening. However, the calcifications had increased (Fig. 2). The patient refused further chemotherapy and was lost to follow-up for 2 months.Fig. 1 Histopathological examination shows signet-ring cells and psammoma bodies. A, B (× 100); C (× 200); D (× 400)\n\nFig. 2 Serial abdominal CT scans show continuous increase in the calcifications (arrow) since starting chemotherapy\n\n\n\nIn July 2017, the patient returned to the hospital with complaints of epigastric pain and abdominal distention. Abdominal CT showed progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria and increased calcifications (Fig. 2). The patient was started on palliative oral chemotherapy with S-1.\n\nDiscussion and conclusions\nCalcification in stomach cancer is rare, and there have been few reports since the initial description by Fukuda in 1922 [11]. Based on the imaging and pathologic characteristics, calcification can be of three types: mucous calcification, psammomatous calcification, or heterotropic ossification. Mucous calcification is seen within the mucin pools that are characteristic of advanced diffuse mucinous adenocarcinoma, whereas psammomatous calcification is seen within glandular lumina and stroma of non-mucin-producing intestinal carcinomas [12]. Heterotropic ossification refers to the calcification seen in primary and metastatic well-differentiated adenocarcinoma [10]. Of these, mucous calcification is relatively common. Almost all cases of mucous calcification are seen in adenocarcinomas or signet-ring cell carcinomas with large amounts of mucus secretion. The patient reported in this study also had signet-ring cell gastric cancer. The reason for the calcification in stomach cancer is still unclear. Psammomatous and non-psammomatous calcification may be induced by osteopontin protein produced by macrophages [13]. Murayama et al. have reported a case of gastric cancer that was found to produce a parathyroid hormone (PTH)-like substance; the authors suggested that this may have a role in the pathogenesis of psammomatous calcification [14]. The alkaline environment in the mucin pools may also promote calcification. Mucin is a similar cartilage calcification tendency of glycoprotein. Alkaline environment has accelerated the calcium salt deposits.\n\nWhether the degree of calcification is related to the response to chemotherapy and prognosis is still unclear. Patients with mucinous gastric cancer and diffuse calcifications tend to be relatively young, and therefore survival may be better in them than in those having gastric cancer without calcification [10]. Among patients with serous adenocarcinoma of the ovary, those with calcification have significantly better survival than those without calcification. However, in papillary carcinoma of the thyroid the presence of calcification and the number of calcifications were not found to have any prognostic significance [15]. The significance of calcification in gastric adenocarcinoma is not known.\n\nThe general condition of our patient improved after five cycles of chemotherapy: symptoms subsided and abdominal CT and serum tumor markers showed improvement; however, the amount of calcification increased. Luca et al. reported a patient with calcified signet-ring cell gastric cancer in whom the calcification decreased gradually following chemotherapy. However, in our patient, serial abdominal CT scans showed continuous increase in the calcifications since starting chemotherapy. This may have been because of dystrophic calcification in chemotherapy-induced areas of ischemic necrosis. Mainly due to protein denaturation after more combined with phosphate, and the calcium ions internal flow after cellular damage form calcium phosphate [16]. Another possibility is that chemotherapy created an alkaline environment in the tumor [17]. Chemotherapy results in areas of ischemia and necrosis. Poor blood supply leads to decrease in cellular respiration and carbon dioxide production, which results in a relative alkalinity. Calcium salts, being poorly soluble in alkaline solutions, get deposited in the tissues [17, 18].\n\nTo conclude, in this case report we have described the dynamic changes in calcification in a gastric cancer patient receiving chemotherapy. One explanation for the observed increase in calcifications could be that the ischemic necrosis resulting from chemotherapy creates an alkaline environment, which promotes deposition of calcium salts. Our theory needs to be confirmed with histological evidence from a large series of patients. Nevertheless, we hope that these findings will improve understanding of the mechanism of calcification in gastric cancer.\n\nAbbreviations\nCA125Carbohydrate antigen 125\n\nCA199Carbohydrate antigen 199\n\nCEACarcinoembryonic antigen\n\nCTComputerized tomography\n\nDCFDocetaxel + cisplatin + fluorouracil\n\nRECISTResponse evaluation criteria in solid tumors\n\nS-1Tegafur-gimeracil-oteracil potassium capsule\n\nXLOXOxaliplatin + S-1\n\nFunding\nThis work was supported by grants from the National Natural Science Foundation of China (81460393), the Natural Science Foundation of JiangXi Province, China (20151BAB215020) to Long Huang, and the Project of Health Department of Jiang Xi Province Science and Technology Plan (20184039) to Ting Wang. The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.\n\nAvailability of data and materials\nAll data related to the current case report are available from the corresponding author upon request.\n\nAuthors’ contributions\nTW and ZYL participated in the treatment of the patient, drafting, and revision of the manuscript. XFT, SHZ, and FH participated in the treatment of the patient. LH participated in the analysis and interpretation of the data, as well as in the drafting and revision of the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nReports describing the case of a single patient are exempt from review by the Ethics Committee of the Second Affiliated Hospital of Nanchang University. Authors obtained written informed consent and publication consent from the patient.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and the accompanying images. A copy of the written consent is available for review by the editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Siegel RL Miller KD Jemal A Cancer statistics, 2017 CA Cancer J Clin 2017 67 1 7 30 10.3322/caac.21387 28055103 \n2. Park MS Yu JS Kim MJ Yoon SY Kim SH Noh TW Mucinous versus nonmucinous gastric carcinoma: differentiation with helical CT Radiology 2002 223 2 540 546 10.1148/radiol.2232010905 11997565 \n3. Olsen JL Penney DP Averill KA Fine structural studies of a human thyroid adenoma, with special reference to psammoma bodies Hum Pathol 1977 8 103 111 10.1016/S0046-8177(77)80070-1 191347 \n4. Johannessen JV Sobrinho-Simoes M The origin and significance of thyroid psammoma bodies Lab Investig 1980 43 287 296 7401638 \n5. Kepes J Electron microscopic studies of meningiomas Am J Pathol 1961 39 499 510 13752576 \n6. Budka H Hyaline inclusions (pseudopsammoma bodies) in meningiomas: immunocytochemical demonstration of epithel-like secretion of secretory component and immunoglobulins a and M Acta Neuropathol 1982 56 294 298 10.1007/BF00691261 6283779 \n7. Cameron RI McCluggage WG Extensive psammomatous calcification of the uterus and cervix associated with a uterine serous carcinoma J Clin Pathol 2004 57 888 890 10.1136/jcp.2004.017004 15280415 \n8. Frenczy A Talens M Zoghby M Hussain SS Ultrastructural studies on morphogenesis of psammoma bodies in ovarian serous neoplasia Cancer 1977 39 2451 2459 10.1002/1097-0142(197706)39:6<2451::AID-CNCR2820390623>3.0.CO;2-7 872045 \n9. Niwa Y Goto H Hayakawa T Early gastric cancer with psammomatous calcification Hepato-Gastroenterology 1998 45 1527 1530 9840099 \n10. Balestreri L Canzonieri V Morassut S Calcified gastric cancer-CT findings before and after chemotherapy. Case report and discussion of the pathogenesis of this type of calcification Clin Imaging 1997 21 122 125 10.1016/S0899-7071(96)00010-1 9095387 \n11. Fukuda T A case of adenocarcinoma of the stomach with deposit of calcified granules Iji shinbun (Med News) 1922 1088 201 209 \n12. Imai T Murayama H Arima S Heterotopic ossification and psammomatous calcification in gastric carcinoma: case report and review of literature Acta Pathol Jap 1979 29 975 984 \n13. Kawahara K Niguma T Yoshino T Gastric carcinoma with psammomatous calcification after Billroth II reconstruction: case report and literature review Pathol Int 2001 51 718 722 10.1046/j.1440-1827.2001.01257.x 11696176 \n14. Murayama H Kamio A Imai T Gastric carcinoma with psammomatous calcification: report of case with reference to calculogenesis Cancer 1982 49 788 796 10.1002/1097-0142(19820215)49:4<788::AID-CNCR2820490431>3.0.CO;2-O 7055786 \n15. Rosai J Carcangiu ML DeLellis RA Papillary carcinoma. In: atlas of tumor pathology, 3rd series, fascicle 5, “tumor of the thyroid” 1992 Washington D.C Armed Forces Institute of Pathology 65 121 \n16. Gutiérrezd OA Asteinza M Loscos JM Endoscopic ultrasonography features of calcified gastric cancer Hepato-gastroenterol 2001 48 37 303 304 \n17. Rotondo A Grassi R Smaltino F Calcified gastric cancer: report of a case and review of literature Brit J Radiol 1986 59 700 405 407 10.1259/0007-1285-59-700-405 3008900 \n18. D'Altorio RA Calcification in a gastric mucinous adenocarcinoma Am J Dig Dis 1973 18 419 422 10.1007/BF01071993 4349584\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "18(1)",
"journal": "BMC cancer",
"keywords": "Calcification; Chemotherapy; Computerized tomography; Gastric cancer; Prognosis",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D018279:Carcinoma, Signet Ring Cell; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
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"pages": "474",
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"pmid": "29699526",
"pubdate": "2018-04-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Computerized tomography findings in calcified signet-ring gastric cancer receiving chemotherapy: a case report.",
"title_normalized": "computerized tomography findings in calcified signet ring gastric cancer receiving chemotherapy a case report"
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"abstract": "Spontaneous coronary artery dissection is a rare and often fatal condition of pregnancy. The long-term morbidity is unknown, but a small cohort of patients develop severe ventricular dysfunction as a consequence. We describe a 37-week gestation parturient who presented with cardiogenic shock secondary to spontaneous left main coronary artery dissection. Despite rapid diagnosis, stabilisation with an intra-aortic balloon pump and prompt transfer to a tertiary centre for emergency caesarean delivery and coronary artery bypass grafting, the patient developed a severe postoperative dilated ischaemic cardiomyopathy. There is little information about the long-term outcomes and the specific anaesthesia management of combined emergency caesarean delivery and cardiac surgery in pregnancy for spontaneous coronary artery dissection. Therefore, we outline our multidisciplinary management of this critically ill pregnant woman.",
"affiliations": "Department of Anaesthesia, Austin Hospital, Heidelberg, Victoria, Australia. laurence.weinberg@austin.org.au",
"authors": "Weinberg|L|L|;Ong|M|M|;Tan|C O|CO|;McDonnell|N J|NJ|;Lo|C|C|;Chiam|E|E|",
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"issue": "41(2)",
"journal": "Anaesthesia and intensive care",
"keywords": null,
"medline_ta": "Anaesth Intensive Care",
"mesh_terms": "D000328:Adult; D002585:Cesarean Section; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease; D004630:Emergencies; D005260:Female; D006801:Humans; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular",
"nlm_unique_id": "0342017",
"other_id": null,
"pages": "251-5",
"pmc": null,
"pmid": "23530793",
"pubdate": "2013-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous coronary artery dissection in pregnancy requiring emergency caesarean delivery followed by coronary artery bypass grafting.",
"title_normalized": "spontaneous coronary artery dissection in pregnancy requiring emergency caesarean delivery followed by coronary artery bypass grafting"
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"abstract": "OBJECTIVE\nCardioversion can rapidly and effectively restore sinus rhythm in patients with persistent atrial fibrillation. Since 2011 dabigatran has been available as an alternative to warfarin to prevent thromboembolic events in patients with non-valvular atrial fibrillation undergoing cardioversion. We studied time to cardioversion, risk of adverse events, and risk of readmission with atrial fibrillation after cardioversion according to anticoagulation therapy.\n\n\nRESULTS\nThrough the nationwide Danish registries we included 1,230 oral anticoagulation naïve patients with first time non-valvular atrial fibrillation and first time cardioversion from 2011 to 2012; 37% in the dabigatran group (n = 456), and 63% in the warfarin group (n = 774). Median time to cardioversion was 4.0 (interquartile range [IQR] 2.9 to 6.5) and 6.9 (IQR 3.9 to 12.1) weeks in the dabigatran and warfarin groups respectively, and the adjusted odds ratio of cardioversion within the first 4 weeks was 2.3 (95% confidence interval [CI] 1.7 to 3.1) in favor of dabigatran. The cumulative incidence of composite endpoint of stroke, bleeding or death were 2.0% and 1.0% at 30 weeks in the warfarin and dabigatran groups respectively, with an adjusted hazard ratio of 1.33 (95% CI 0.33 to 5.42). Cumulative incidence of readmission with atrial fibrillation after 30 weeks were 9% and 11% in the warfarin and dabigatran groups, respectively, and an adjusted hazard ratio of 0.66 (95% CI 0.41 to 1.08).\n\n\nCONCLUSIONS\nAnticoagulation treatment with dabigatran allows shorter time to cardioversion for atrial fibrillation than warfarin, and appears to be an effective and safe alternative treatment strategy to warfarin.",
"affiliations": "Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.;Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.;Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark; The Heart Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.;Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.;Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.;Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.;Institute of Health, Science and Technology, Aalborg University, Aalborg, Denmark.;Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; The Danish Heart Foundation, Copenhagen, Denmark.",
"authors": "Pallisgaard|Jannik Langtved|JL|;Lindhardt|Tommi Bo|TB|;Hansen|Morten Lock|ML|;Schjerning|Anne-Marie|AM|;Olesen|Jonas Bjerring|JB|;Staerk|Laila|L|;Torp-Pedersen|Christian|C|;Gislason|Gunnar Hilmar|GH|",
"chemical_list": "D000925:Anticoagulants; D000991:Antithrombins; D014859:Warfarin; D000069604:Dabigatran",
"country": "United States",
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"doi": "10.1371/journal.pone.0141377",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2651358910.1371/journal.pone.0141377PONE-D-15-23761Research ArticleCardioversion and Risk of Adverse Events with Dabigatran versus Warfarin—A Nationwide Cohort Study Cardioversion with Dabigatran versus WarfarinPallisgaard Jannik Langtved \n1\n\n2\n*Lindhardt Tommi Bo \n1\n\n2\nHansen Morten Lock \n1\n\n3\nSchjerning Anne-Marie \n1\nOlesen Jonas Bjerring \n1\nStaerk Laila \n1\n\n2\nTorp-Pedersen Christian \n4\nGislason Gunnar Hilmar \n1\n\n2\n\n5\n\n6\n\n1 \nDepartment of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark\n\n2 \nFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark\n\n3 \nThe Heart Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark\n\n4 \nInstitute of Health, Science and Technology, Aalborg University, Aalborg, Denmark\n\n5 \nThe National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark\n\n6 \nThe Danish Heart Foundation, Copenhagen, Denmark\nWu Wen-Chih Hank Editor\nProvidence VA Medical Center and Brown University, UNITED STATES\nCompeting Interests: The study was supported by an unrestricted research grant from Boehringer-Ingelheim. The sponsor had no influence on the study design, interpretation of results or the decision to submit the paper for publication. Dr. Gislason is supported by an unrestricted clinical research scholarship from the Novo Nordisk Foundation. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.\n\nConceived and designed the experiments: JLP TBL MLH GHG. Analyzed the data: JLP TBL MLH AMS JBO LS CTP GHG. Contributed reagents/materials/analysis tools: JLP CTP GHG. Wrote the paper: JLP TBL MLH AMS JBO LS CTP GHG.\n\n* E-mail: jannikjannik@gmail.com29 10 2015 2015 10 10 e01413772 6 2015 6 10 2015 © 2015 Pallisgaard et al2015Pallisgaard et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Aim\nCardioversion can rapidly and effectively restore sinus rhythm in patients with persistent atrial fibrillation. Since 2011 dabigatran has been available as an alternative to warfarin to prevent thromboembolic events in patients with non-valvular atrial fibrillation undergoing cardioversion. We studied time to cardioversion, risk of adverse events, and risk of readmission with atrial fibrillation after cardioversion according to anticoagulation therapy.\n\nMethods and Results\nThrough the nationwide Danish registries we included 1,230 oral anticoagulation naïve patients with first time non-valvular atrial fibrillation and first time cardioversion from 2011 to 2012; 37% in the dabigatran group (n = 456), and 63% in the warfarin group (n = 774). Median time to cardioversion was 4.0 (interquartile range [IQR] 2.9 to 6.5) and 6.9 (IQR 3.9 to 12.1) weeks in the dabigatran and warfarin groups respectively, and the adjusted odds ratio of cardioversion within the first 4 weeks was 2.3 (95% confidence interval [CI] 1.7 to 3.1) in favor of dabigatran. The cumulative incidence of composite endpoint of stroke, bleeding or death were 2.0% and 1.0% at 30 weeks in the warfarin and dabigatran groups respectively, with an adjusted hazard ratio of 1.33 (95% CI 0.33 to 5.42). Cumulative incidence of readmission with atrial fibrillation after 30 weeks were 9% and 11% in the warfarin and dabigatran groups, respectively, and an adjusted hazard ratio of 0.66 (95% CI 0.41 to 1.08).\n\nConclusion\nAnticoagulation treatment with dabigatran allows shorter time to cardioversion for atrial fibrillation than warfarin, and appears to be an effective and safe alternative treatment strategy to warfarin.\n\nThe study was supported by an unrestricted research grant from Boehringer-Ingelheim. The sponsor had no influence on the study design, interpretation of results or the decision to submit the paper for publication. Dr. Gislason is supported by an unrestricted clinical research scholarship from the Novo Nordisk Foundation. Data AvailabilityDue to ethical restrictions, relevant data are available upon request. Interested researchers may submit requests for de-identified data to jannikjannik@gmail.com.Data Availability\nDue to ethical restrictions, relevant data are available upon request. Interested researchers may submit requests for de-identified data to jannikjannik@gmail.com.\n==== Body\nIntroduction\nAtrial fibrillation is the most frequent cardiac arrhythmia with a prevalence of about 1–2% in the general population.[1] Cardioversion can be used to restore sinus rhythm in patients with persistent atrial fibrillation, but requires oral anticoagulation for at least 3 weeks in patients with atrial fibrillation duration above 48 hours. In non-anticoagulated patients the peri-procedural risk of a stroke event associated with cardioversion is between 5 and 7%, but treatment with warfarin reduces incidence of thromboembolic events to between 0.5 and 1.6%,[2–5] hence international guidelines recommend at least 3 consecutive weeks of effective anticoagulation before cardioversion, followed by at least 4 weeks of anticoagulation.[1,6] Since August 22, 2011 dabigatran has been an alternative to warfarin in Denmark as oral anticoagulation therapy in patients with non-valvular atrial fibrillation requiring cardioversion.[7,8] The main objective of this study was to investigate the time to cardioversion in anticoagulation naïve patients with first-time atrial fibrillation, according to initiated anticoagulation therapy with either dabigatran or warfarin. Further, we assessed the risk of cardiovascular adverse events or death and the risk of readmission with atrial fibrillation after cardioversion according to anticoagulation treatment strategy.\n\nMethods\nIn Denmark all residents are at birth or immigration provided with a permanent and unique civil registration number that enables individual level linkage between administrative registries.\n\nThe Danish National Patient Register holds information on all discharges from hospitals in Denmark since 1978.[9] Each hospitalization is at discharge coded with one primary and, if appropriate, one or more secondary diagnoses according to the International Classification of Diseases, the 8th revision (ICD-8) until 1994 and the 10th revision (ICD-10) thereafter.\n\nData on pharmacy prescriptions claims were identified from the Danish Registry of Medicinal Product Statistics that keeps records on all drug prescriptions dispensed from Danish pharmacies since 1995. Each drug dispensing is registered according to an international classification of drugs, the Anatomical Therapeutic Chemical (ATC) system, as well as the date of dispensing, quantity dispensed, strength, formulation, and affiliation of the physician issuing the prescription. The partial reimbursement of drug expenses by the Danish health care system requires all pharmacies to register each drug dispensing in the National Prescription Registry.\n\nCauses of death were obtained from the National Causes of Death Register, in which both underlying and immediate causes of death are recorded using the International Classification of Diseases (ICD).[10],[9]\n\nStudy population and follow up\nInclusion criteria were: First time discharge coding diagnosis with non-valvular atrial fibrillation between August 22, 2011 and December 31, 2012, no prior anticoagulation treatment and cardioversion performed after anticoagulation treatment initiation. Both in and outpatients were eligible to enter the study. Valid data on onset date of atrial fibrillation and type of atrial fibrillation (paroxysmal, persistent or permanent) was not available in this study, because of this first day of anticoagulation treatment was chosen as day of entry in the study. Patients who received warfarin entered the warfarin group, and patients receiving dabigatran were assigned to the dabigatran group regardless of treatment dosage. We excluded patients with prior anticoagulation treatment or treated with other anticoagulation than dabigatran or warfarin.\n\nPatients were followed until end of study (December 31. 2012), change of anticoagulation treatment regime, time of death, or date of an endpoint of interest.\n\nStudy cohort\nNewly onset atrial fibrillation after August 22, 2011 was identified using ICD-10 codes for atrial fibrillation. Non-valvular atrial fibrillation was identified excluding patients with a diagnosis of rheumatic valvular disease by using ICD-8 and ICD-10 codes, or a history with prosthetic heart valve replacement, using the specific Nordic procedure codes for valve replacements. Study start was the date of a claimed prescription of dabigatran or warfarin using ATC codes. Information on age and gender came from the Danish Civil Registration System. Comorbidities were identified using ICD-8 and ICD-10 codes for: heart failure, chronic kidney disease, peripheral arterial disease, stroke, ischemic heart disease, chronic pulmonary obstructive disease, bleeding, liver disease and cancer. Glucose lowering medication and antihypertensive drugs were identified by ATC codes and used as proxies for diabetes mellitus and hypertension, respectively The method used to identify hypertension in this study has a positive predictive value of 80.0%, and a specificity of 94.7%.[11] ATC codes were also used to identify: concomitant drug: verapamil, amiodarone, dronedarone, flecainide, digoxin, non-steroidal anti-inflammatory drugs (NSAID), antiplatelet and acetylsalicylic acid (Appendix 1). Cardioversion and trans esophageal echocardiogram was identified by Danish national non-surgical procedure codes. Analyzing for non-inferiority between warfarin and dabigatran treatment between warfarin and dabigatran treatment, would have required approximately 30.000 patients which was not possible with current study design.\n\nStudy outcomes\nThe study outcome was time between date of claimed prescription of dabigatran or warfarin to date of cardioversion and proportion of patients undergoing cardioversion within the first 4 weeks All procedure of cardioversions are registered holding information on the time and date the cardioversion was performed (Appendix 1). The risk of readmission with atrial fibrillation within thirty weeks from cardioversion and the risk of a composite endpoint of stroke, major bleeding and death within thirty weeks after cardioversion were analyzed. Stroke and bleeding were identified using ICD-10 codes, and information on death came from National Causes of Death Register. (Appendix 1)\n\nStatistical analysis\nBaseline characteristics were presented as medians with interquartile range (IQR) or frequencies and percentages. Differences between baseline characteristics were compared by Chi-square, Fishers, or Kruskal-Wallis test as appropriate. Time from claimed prescription of anticoagulation treatment to date of cardioversion was graphically as medians with IQR in a jitter plot and tested for significance by Welch Two Sample t-test. Chance of cardioversion within the first 4 weeks was analyzed with multivariable logistic regression analysis adjusted for age, sex, comorbidities and concomitant drugs. Predicted probabilities of cardioversion within the first 4 weeks were calculated for an average person of both men and women, using results from the baseline table and the odds ratio. Risk of a composite event and risk of readmission with atrial fibrillation were presented as cumulative incidences curves with 95% CI, and as time dependent Cox proportional-hazard analyses adjusted for age, sex, comorbidities and concomitant drugs. The mean follow up time was 28.9 weeks in the dabigatran group and 33.6 weeks in the warfarin group; hence, a 30 weeks follow-up period was chosen. Sensitivity analyses were completed with age and sex matched groups excluding patients with ischemic heart disease and chronic heart failure and analysis for treatment bias to warfarin and dabigatran was performed. P-value of <0.05 was considered significant. For data management and analysis we used R version 3.1.1 (The R Foundation for Statistical Computing).\n\nEthics\nIn Denmark, retrospective register studies do not require approval from the ethics committees. The Danish Data Protection Agency approved this study (Ref.no: 2007-58-0015 / GEH-2014-013 and I-Suite no: 02731) and data were made available to us in an anonymized format such that individuals could not be identified.\n\nResults\nDuring the study period 1,230 patients were eligible to enter the study cohort, with 37% in the dabigatran group (n = 456), and 63% in the warfarin group (n = 774). Only 27 patients (2.3%) changed OAC regime in the follow up period. Selection of the study cohort is depicted in Fig 1. Chronic heart failure, hypertension and ischemic heart disease, antiplatelet usage was predominant in the warfarin group (Table 1).\n\n10.1371/journal.pone.0141377.g001Fig 1 Flowchart of the patient population.\n10.1371/journal.pone.0141377.t001Table 1 Baseline characteristics of patients by anticoagulation treatment status.\nCharacteristic\tDabigatran\tWarfarin\tp–value †\n\t\nNumber\t456\t774\t\t\nAge, * y (IQR)\t66.3 (59.3–72.6)\t67.4 (60.8–72.5)\t0.046\t\nMen, %\t332 (72.8)\t569 (73.5)\t0.838\t\nStroke, (%)\t27 (5.9)\t45 (5.8)\t1.000\t\nChronic Heart Failure, (%)\t50 (11.0)\t148 (19.1)\t<0.001\t\nDiabetes Mellitus, (%)\t42 (9.2)\t96 (12.4)\t0.105\t\nLiver disease, (%)\t4 (0.9)\t10 (1.3)\t0.589\t\nBleeding, (%)\t42 (9.2)\t67 (8.7)\t0.821\t\nHypertension, (%)\t291 (63.8)\t546 (70.5)\t0.017\t\nIschemic Heart Disease, (%)\t38 (8.3)\t107 (13.8)\t0.005\t\nPeripheral arterial disease, (%)\t5 (1.1)\t17 (2.2)\t0.187\t\nAny Cancer, (%)\t45 (9.9)\t93 (12.0)\t0.290\t\nChronic Kidney Disease, (%)\t10 (2.2)\t24 (3.1)\t0.375\t\nChronic Obstructive Pulmonary Disease, (%)\t31 (6.8)\t43 (5.6)\t0.447\t\nPercutaneous Coronary Intervention, (%)\t20 (4.4)\t49 (6.3)\t0.192\t\nCoronary Artery Bypass Grafting, (%)\t8 (1.8)\t22 (2.8)\t0.316\t\nCHA2DS2-VASc, n (%)\t\t\t0.103\t\n 0\t68 (14.9)\t83 (10.7)\t\t\n 1\t125 (27.4)\t181 (23.4)\t\t\n 2\t133 (29.2)\t247 (31.9)\t\t\n 3\t88 (19.3)\t176 (22.7)\t\t\n ≥ 4\t42 (9.2)\t87 (11.2)\t\t\nVerapamil, (%)\t15 (3.3)\t25 (3.2)\t1.000\t\nAmiodarone, (%)\t26 (5.7)\t38 (4.9)\t0.595\t\nFlecainide, (%)\t5 (1.1)\t3 (0.4)\t0.155\t\nAcetylsalicylic acid, (%)\t129 (28.3)\t252 (32.6)\t0.106\t\nDigoxin, (%)\t160 (35.1)\t269 (34.8)\t0.950\t\nAntiplatelet, ‡ (%)\t14 (4.7)\t53 (10.2)\t0.008\t\nNSAID, § (%)\t64 (14.0)\t123 (15.9)\t0.427\t\n* Continuous variables are presented as median (interquartile range [IQR])\n\n† The P value is for the comparison between groups and is based on the Fisher’s exact test or Chi-Square test for categorical variables and Kruskal-Wallis for continuous variables.\n\n‡ Clopidogrel, presugrel or ticagrelor.\n\n§ Diclofenac, ibuprofen, celecoxib, rofecoxib, naproxen.\n\nTime to cardioversion and cardioversion within the first 4 weeks\nThe median time to cardioversion were 4.0 (IQR 2.9 to 6.5) and 6.9 (IQR 3.9 to 12.1) weeks in the dabigatran and warfarin groups respectively (Fig 2). Significantly more patients in the dabigatran group (n = 229; 50%) underwent cardioversion within the first 4 weeks, compared to the warfarin group (n = 207; 27%), p<0.005. The adjusted odds ratio of cardioversion within the first 4 weeks was 2.3 (95% CI 1.7 to 3.1) in favor of dabigatran treatment, with transesophageal echocardiogram performed prior to the cardioversion in 26 (6%) and 40 (5%) in the dabigatran and warfarin group, respectively (Table 2). Predicted probability of cardioversion within the first 4 weeks in 66 years old men with hypertension were 43.8% and 25.4% in the dabigatran and warfarin group respectively, and 47.1% and 27.9% for a 66 years old woman with hypertension (Table 2).\n\n10.1371/journal.pone.0141377.g002Fig 2 Jitter plot with weeks from claimed prescription of anticoagulation treatment, to cardioversion in the two groups, with median weeks and interquartile range (IQR).\nOne dot represents one patient.\n\n10.1371/journal.pone.0141377.t002Table 2 Cardioversion within the first four weeks.\n\tDabigatran\tWarfarin\tP—Value\t\nIncidence of Cardioversion within the first four weeks, (%)*\n\t229/456 (50%)\t207/774 (27%)\t<0.005\t\nOdds ratio and 95% CI of cardioversion within the first four weeks, †\n\t2.3 (1.7–3.1)\t1 (ref.)\t<0.005\t\nTransesophageal echocardiogram, (%) ‡\n\t26 (6%)\t40 (5%)\t0.696\t\nPredicted probability of cardioversion within the first four weeks\t\t\n66 years old men with hypertension, §\n\t43.8%\t25.4%\t\t\n66 years old women with hypertension, §\n\t47.1%\t27.9%\t\t\n* The P value is for the comparison between groups and is based on the Chi-Square test\n\n† Odds ratio was adjusted for age, sex, diabetes, ischemic heart disease, chronic heart failure, liver disease, bleeding, cancer, chronic kidney disease, chronic obstructive pulmonary disease, stroke, peripheral arterial disease, dronedarone, amiodarone, flecainide, verapamil, antiplatelets, NSAID and acetylsalicylic acid.\n\n‡ Fisher's exact test.\n\n§ Predicted probabilities are calculated from for characteristics of an average person of both sexes as found in Table 1.\n\nComposite safety endpoint\nThe composite endpoint of stroke, major bleeding or death within 30 weeks after cardioversion occurred in 3 (0.7%; Bleed 0, Stroke 1; Death 2) in the dabigatran group and in 13 (1.4%; Bleed 0, Stroke 1, Death 12) patients warfarin groups. Of the 465 patients in the dabigatran group, nine patients switched to warfarin treatment and were censored at the day switching to warfarin. In the warfarin group 18 changed to dabigatran and was censored at the day switching to dabigatran (Table 1). There was an even distribution of cumulative incidence over time with 2.0% and 1.0% after 30 weeks in the warfarin and dabigatran groups, respectively (Fig 3). The time dependent Cox regression analysis found a hazard ratio (HR) of 1.33 (95% CI 0.33 to 5.42) for the composite endpoint in the warfarin group compared to the dabigatran group.\n\n10.1371/journal.pone.0141377.g003Fig 3 Cumulative incidence and patients at risk within 30 weeks from cardioversion with dabigatran and warfarin treatment.\nLeft: Composite endpoint of stroke, bleeding and death. Right: Readmission with atrial fibrillation. Shades represent 95% confidence intervals. At risk table represents number of patients at risk of event at given time.\n\nReadmission with atrial fibrillation\nReadmission with atrial fibrillation within 30 weeks after cardioversion was experienced by 38 (8.3%) in the dabigatran group and by 59 (7.6%) patients in and warfarin group. The cumulative incidences of readmission with atrial fibrillation after 30 weeks were 9% and 11% in the warfarin and dabigatran groups, respectively (Fig 3). In the time dependent adjusted Cox regression analysis, there was no significant difference between the two groups regarding frequency of readmission with atrial fibrillation with a HR 0.66 (95% CI 0.41 to 1.08).\n\nSensitivity analysis\nIn a sensitivity analysis we excluded patients with either ischemic heart disease or chronic heart failure, and propensity score matched the dabigatran group to the warfarin group with age and sex. The results were similar to the unmatched population, both regarding time to cardioversion (weeks (IQR) 3.9 (2.5 to 5.9) for dabigatran and 6.5 (3.6 to 11.9) for warfarin; p<0.005), chance of cardioversion within the first 4 weeks (OR (95%CI) 3.1 (2.3 to 4.2)), risk of composite events (HR (95%CI) 1.0(0.6 to 1.6)), and risk readmission with atrial fibrillation (HR (95%CI): 0.8 (0.1 to 4.5)).\n\nDiscussion\nIn this nationwide study we investigated time to cardioversion according to oral anticoagulation treatment in patients with first-time atrial fibrillation. The main results of the study were that dabigatran allows shorter time to cardioversion than warfarin, and appears to be as effective and safe treatment strategy. This suggests that dabigatran might be favored over warfarin in patients where cardioversion is intended. This study is, to our knowledge, the first to investigate time to cardioversion in a real life population treated with dabigatran, whereas prior studies have been either randomised controlled trial or post hoc analysis with focus on rivaroxaban or apixaban.\n\nThe X-VeRT (eXplore the efficacy and safety of once-daily oral rivaroxaban for the prevention of caRdiovascular events in patients with non valvular aTrial fibrillation scheduled for cardioversion) study was a clinical trial, of patients with non-valvular atrial fibrillation randomized to rivaroxaban or warfarin prior to cardioversion. The duration of rivaroxaban and warfarin treatment prior to cardioversion was 3 and 4 weeks respectively.[12]\n\nIn a post hoc analysis of the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, the time from study entry to cardioversion was analyzed in patients randomized to with either warfarin or apixaban treatment. The duration of apixaban and warfarin treatment prior to cardioversion was 36 and 35 weeks, respectively.[13]\n\nIn a post hoc analysis of the RE-LY (The Randomized Evaluation of Long-Term Anticoagulation Therapy) trial the risk for cardiovascular complications with either warfarin or dabigatran treatment were analyzed in patients who underwent cardioversion.[8] Time to cardioversion was not investigated in this study. The variation between the results found in our study, the X-VeRT study and the ARISTOTLE post hoc analysis can be explained by difference in both selection of study cohorts and in study designs.\n\nIn both the RE-LY and ARISTOTLE post hoc analyses, and in the X-VeRT study the rates of stroke and systemic embolism at 30 days was <1% and did not differ whether the patient was treated with a novel oral anticoagulant (NOAC) or a vitamin K antagonist. The rates of major bleeding ranged from 0.2% to 1.7% in the NOAC groups, and ranged from 0.3% to 0.6% in the Vitamin K antagonist groups.[8,12,13] All-cause mortality rates were 0.5% in the NOAC groups and 0.6% in the warfarin groups in the X-VeRT study and ARISTOTLE trial. And in the post hoc RE-LY trial seven died but this was not specified by group. In our study 0.7% in the dabigatran group and 1.4% in the warfarin group had a composite event of stroke, bleeding or all-cause mortality with no significant difference, making our findings comparable to the prior studies. The duration of atrial fibrillation episode increase the risk of recurrent atrial fibrillation in patients with intermitting atrial fibrillation.[14]\n\nDespite three weeks longer duration of time to cardioversion in the warfarin group compared with the dabigatran group, the cumulative incidence of readmissions with atrial fibrillation was similar in the two groups. Similar results were found in the ACUTE (Assessment of Cardioversion Using Trans-esophageal Echocardiograph) study, where one group had only 3 days to cardioversion versus 31 days in the comparing group, but the same maintenance of sinus rhythm was found after 8 weeks in the two groups.[15] This suggests that the duration of atrial fibrillation time periods investigated in our and the ACUTE study are not long enough to increase the risk of recurrent episodes.\n\nThe post hoc analysis of both the ARISTOTLE and RE-LY study both investigated the safety of cardioversion in patients already in anticoagulation treatment; whereas the aim of the X-VeRT study was to investigate the safety of anticoagulation treatment in patients scheduled for elective cardioversion. Our results are therefore more comparable to the X-VeRT study than the two post hoc analyses, since approximately 50% of the patients in the dabigatran group in our study received cardioversion already within 4 weeks.\n\nLimitations\nThe main limitation is inherited in the observational design of the study and lack of clinical information. In addition information regarding the date of referral to cardioversion was unavailable, and intention of anticoagulation treatment regarding cardioversion was also unknown. Exact referral date to cardioversion would have made our study more comparable to randomized controlled trials. Furthermore, the treatment groups were not randomly assigned to either dabigatran or warfarin, increasing risk of selection bias to the groups, although this risk was limited according to our preliminary analysis as described previously.\n\nConclusion\nIn this nationwide study, we found time to cardioversion shortened by 3 weeks with warfarin compared with dabigatran treatment, with more twice the chance of cardioversion within the first 4 weeks. We found no difference regarding risk of subsequent death, stroke, bleeding, or readmission with atrial fibrillation within 30 weeks after cardioversion.\n\nAppendix\n10.1371/journal.pone.0141377.t003Appendix 1 ICD-10 codes\t\nAtrial Fibrillation\tI48\t\nRheumatic Heart Valve Disease\tI05, I06, I080, I069, I081, I082, I083, DT823A,I068, I080A, I082A, I081A\t\nStroke\tI63, I64, DG458, DG459\t\nBleeding\tI60, I61, I690, I691, N02, R31, K228F, K251,K252, K254, K256, K260, K262, K264, K266,K270, K272, K274, K625, K633, K638B,K638C, K850, K922\t\nChronic Heart Failure\tI50, J819\t\nIschemic Heart Disease\tI21, I22\t\nAtherosclerosis\tI74\t\nCancer\tC\t\nChronic Kidney Disease\tI12, E102, E112, E132, E142, N03, N04, N05,N06, N07, N08, N11, N13, N14, N18, N19, N25,N26, N27, N28, N29, N391, Q61.\t\nChronic Obstructive Pulmonary Disease\tJ42, J43, J44\t\nLiver disease\tK7\t\nATC\t\nWarfarin\tB01AA03\t\nMarcoumar\tB01AA04\t\nDabigatran\tB01AE07\t\nRivaoxaban\tB01AF01\t\nDiabetes Mellitus\tA10\t\nHypertension as usage of two different drugs classes.\tC09, C03AA, C03C, C07A C02AB\t\nVerapamil\tC08DA\t\nAmiodarone\tC01BD\t\nFleccanide\tC01BC\t\nAcetylsalicylic acid\tB01AC\t\nNSAID\tM01AB05, M01AE01, M01AH01, M01AH02, M01AE02\t\nAntiplatelet\tB01AC04, B01AC24, B10AC22\t\nDigoxine\tC01AA\t\nProcedure Codes\t\nCardioversion\tBFFA0, BFFA00, BFFA01, BFFA04\t\nTransesophageal echocardiogram\tUXUC81, UXUC81C\t\nPercutaneous Coronary Intervention\tKFNG00, KFNG02, KFNG05, KFNG10, KFNG12, KFNG20, KFNG30, KFNG40, KFNG96\t\nCoronary Artery Bypass Grafting\tKFNA00, KFNA10, KFNA20, KFNA96, KFNB00, KFNB96, KFNC10, KFNC20, KFNC30, KFNC40, KFNC50, KFNC60, KFNC96, KFND10, KFND20, KFND96, KFNE00, KFNE10, KFNE20, KFNE96,\t\nProsthetic Valve Replacement\tKFKD00, KFMA20, KFMA32A, KFMD00, KFMD33, KFMD96\n==== Refs\nReferences\n1 \nJanuary CT , Wann LS , Alpert JS , Calkins H , Cigarroa JE , Cleveland JC , et al\n2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation . Journal of the American College of Cardiology . 2014 ;64 :e1 –e76 .24685669 \n2 \nBjerkelund CJ , Orning OM . The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation . The American Journal of Cardiology . 1969 ;23 :208 –216 .4180019 \n3 \nArnold AZ , Mick MJ , Mazurek RP , Loop FD , Trohman RG . Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter . Journal of the American College of Cardiology . 1992 ;19 :851 –855 .1545081 \n4 \nKlein AL , Grimm RA , Jasper SE , Murray RD , Apperson-Hansen C , Lieber EA , et al\nACUTE Steering and Publications Committee for the ACUTE Investigators. Efficacy of transesophageal echocardiography-guided cardioversion of patients with atrial fibrillation at 6 months: a randomized controlled trial . Am Heart J . 2006 ;151 :380 –389 .16442904 \n5 \nStellbrink C , Nixdorff U , Hofmann T , Lehmacher W , Daniel WG , Hanrath P , et al\nSafety and Efficacy of Enoxaparin Compared With Unfractionated Heparin and Oral Anticoagulants for Prevention of Thromboembolic Complications in Cardioversion of Nonvalvular Atrial Fibrillation The Anticoagulation in Cardioversion using Enoxaparin (ACE) Trial . Circulation . 2004 ;109 :997 –1003 .14967716 \n6 \nCamm AJ , Lip GYH , Caterina RD , Savelieva I , Atar D , Hohnloser SH , et al\n2012 focused update of the ESC Guidelines for the management of atrial fibrillation An update of the 2010 ESC Guidelines for the management of atrial fibrillationDeveloped with the special contribution of the European Heart Rhythm Association . Europace . 2012 ;14 :1385 –1413 .22923145 \n7 \nHijazi Z , Hohnloser SH , Oldgren J , Andersson U , Connolly SJ , Eikelboom JW , et al\nEfficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis . Circulation . 2014 ;129 :961 –970 .24323795 \n8 \nNagarakanti R , Ezekowitz MD , Oldgren J , Yang S , Chernick M , Aikens TH , et al\nDabigatran Versus Warfarin in Patients With Atrial Fibrillation An Analysis of Patients Undergoing Cardioversion . Circulation . 2011 ;123 :131 –136 .21200007 \n9 \nAndersen TF , Madsen M , Jørgensen J , Mellemkjoer L , Olsen JH . The Danish National Hospital Register. A valuable source of data for modern health sciences . Dan Med Bull . 1999 ;46 :263 –268 .10421985 \n10 \nKildemoes HW , Sørensen HT , Hallas J . The Danish National Prescription Registry . Scand J Public Health . 2011 ;39 :38 –41 .21775349 \n11 \nOlesen JB , Lip GYH , Hansen ML , Hansen PR , Tolstrup JS , Lindhardsen J , et al\nValidation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study . BMJ [Internet] . 2011 [cited 2013 Jun 13];342 Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031123/\n\n12 \nCappato R , Ezekowitz MD , Klein AL , Camm AJ , Ma C- S , Heuzey J-Y Le , et al, on behalf of the X-VeRT Investigators . Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation . Eur Heart J . 2014 ;35 :3346 –3355 .25182247 \n13 \nFlaker G , Lopes RD , Khatib SM Al -, Hermosillo AG , Hohnloser SH , Tinga B , et al\nEfficacy and Safety of Apixaban in Patients After Cardioversion for Atrial Fibrillation: Insights From the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) . Journal of the American College of Cardiology . 2014 ;63 :1082 –1087 .24211508 \n14 \nWijffels MCEF , Kirchhof CJHJ , Dorland R , Allessie MA . Atrial Fibrillation Begets Atrial Fibrillation A Study in Awake Chronically Instrumented Goats . Circulation . 1995 ;92 :1954 –1968 .7671380 \n15 \nAsher CR , Klein AL . The ACUTE trial . Transesophageal echocardiography to guide electrical cardioversion in atrial fibrillation. Assessment of Cardioversion Using Transesophageal Echocardiography . Cleveland Clinic Journal of Medicine . 2002 ;69 :713 –718 .12222975\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "10(10)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000925:Anticoagulants; D000991:Antithrombins; D001281:Atrial Fibrillation; D015331:Cohort Studies; D000069604:Dabigatran; D003718:Denmark; D005260:Female; D005500:Follow-Up Studies; D006739:Hospital Administration; D006801:Humans; D015994:Incidence; D008297:Male; D012042:Registries; D012306:Risk; D013923:Thromboembolism; D013997:Time Factors; D014859:Warfarin",
"nlm_unique_id": "101285081",
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"pages": "e0141377",
"pmc": null,
"pmid": "26513589",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12222975;21200007;4180019;21282258;21775349;22923145;24323795;24211508;24685669;14967716;1545081;7671380;10421985;16442904;25182247",
"title": "Cardioversion and Risk of Adverse Events with Dabigatran versus Warfarin-A Nationwide Cohort Study.",
"title_normalized": "cardioversion and risk of adverse events with dabigatran versus warfarin a nationwide cohort study"
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"abstract": "To evaluate treatment outcomes following radioactive iodine (RAI) treatment with a cumulative dose of ≥≥600 mCi in differentiated thyroid carcinoma (DTC) patients, a retrospective review of medical records was done in 176 DTC patients with a cumulative dose of ≥600 mCi from January 1993 to December 2013. All patients were followed up for at least 2 years after receiving 600 mCi of I-131 treatment. Remission criteria were no clinical and imaging evidence of disease and low serum thyroglobulin levels during thyroid-stimulating hormone suppression of <0.2 ng/ml or of <1 ng/ml after stimulation in the absence of interfering antibodies. A total of 176 patients were included in the study: 137 - papillary thyroid cancer, 29 - follicular thyroid cancer, 9 - mixed papillary and follicular thyroid cancer, and 1 - Hurthle cell carcinoma. Most of the patients (118, 67%) had locoregional metastasis, whereas 48 patients (27%) had distant metastases at presentation. The median cumulative dose was 900 mCi (range: 600-2200 mCi). The mean follow-up period was 82.84 ± 42.41 months. Only 16 patients (9.1%) met remission criteria at the end of treatment. The rest of patients (160, 90.9%) were not remitted: stable disease in 94 (53.4%), at least 1 metastasis without I-131 uptake in 34 (19.3%), progressive disease in 21 (11.9%), and death during the whole follow-up period in 11 (6.3%). Two patients (1.1%) developed second primary malignancy. Eighteen cases were suspected of bone marrow suppression (14 cases [7.9%] had anemia and 5 cases [2.8%] had neutropenia). Seven patients (3.9%) developed permanent salivary gland dysfunction. Although the complications after receiving RAI treatment with a cumulative dose of ≥≥600 mCi were low and not severe, the patients with remission were in <10%. Our study suggests that the decision to administer further treatments should be made on an individual basis because beneficial effects may be controversial.",
"affiliations": "Department of Radiology, Division of Nuclear Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Department of Radiology, Division of Nuclear Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.",
"authors": "Kaewput|Chalermrat|C|;Pusuwan|Pawana|P|",
"chemical_list": null,
"country": "Austria",
"delete": false,
"doi": "10.4103/wjnm.WJNM_49_20",
"fulltext": "\n==== Front\nWorld J Nucl Med\nWorld J Nucl Med\nWJNM\nWorld Journal of Nuclear Medicine\n1450-1147\n1607-3312\nWolters Kluwer - Medknow India\n\nWJNM-20-54\n10.4103/wjnm.WJNM_49_20\nOriginal Article\nOutcomes following I-131 treatment with cumulative dose exceeding or equal to 600 mCi in differentiated thyroid carcinoma patients\nKaewput Chalermrat\nPusuwan Pawana\nDepartment of Radiology, Division of Nuclear Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand\nAddress for correspondence: Dr. Chalermrat Kaewput, Department of Radiology, Division of Nuclear Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. E-mail: aung_med@hotmail.com\nJan-Mar 2021\n22 8 2020\n20 1 5460\n16 4 2020\n18 6 2020\n26 6 2020\nCopyright: © 2020 World Journal of Nuclear Medicine\n2020\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nTo evaluate treatment outcomes following radioactive iodine (RAI) treatment with a cumulative dose of ≥≥600 mCi in differentiated thyroid carcinoma (DTC) patients, a retrospective review of medical records was done in 176 DTC patients with a cumulative dose of ≥600 mCi from January 1993 to December 2013. All patients were followed up for at least 2 years after receiving 600 mCi of I-131 treatment. Remission criteria were no clinical and imaging evidence of disease and low serum thyroglobulin levels during thyroid-stimulating hormone suppression of <0.2 ng/ml or of <1 ng/ml after stimulation in the absence of interfering antibodies. A total of 176 patients were included in the study: 137 – papillary thyroid cancer, 29 – follicular thyroid cancer, 9 – mixed papillary and follicular thyroid cancer, and 1 – Hurthle cell carcinoma. Most of the patients (118, 67%) had locoregional metastasis, whereas 48 patients (27%) had distant metastases at presentation. The median cumulative dose was 900 mCi (range: 600–2200 mCi). The mean follow-up period was 82.84 ± 42.41 months. Only 16 patients (9.1%) met remission criteria at the end of treatment. The rest of patients (160, 90.9%) were not remitted: stable disease in 94 (53.4%), at least 1 metastasis without I-131 uptake in 34 (19.3%), progressive disease in 21 (11.9%), and death during the whole follow-up period in 11 (6.3%). Two patients (1.1%) developed second primary malignancy. Eighteen cases were suspected of bone marrow suppression (14 cases [7.9%] had anemia and 5 cases [2.8%] had neutropenia). Seven patients (3.9%) developed permanent salivary gland dysfunction. Although the complications after receiving RAI treatment with a cumulative dose of ≥≥600 mCi were low and not severe, the patients with remission were in <10%. Our study suggests that the decision to administer further treatments should be made on an individual basis because beneficial effects may be controversial.\n\n600 mCi\ncumulative dose\ndifferentiated thyroid cancer\nradioiodine therapy\n==== Body\nINTRODUCTION\n\nDistant metastases occur in <10% of patients with papillary and follicular carcinoma but represent the most frequent cause of thyroid cancer-related death. Treatment of distant metastasis (DM) patients is based on radioiodine and locoregional therapies. One-third of DM patients have no I-131 uptake and die because of radioiodine refractory (RR).[1] According to the American Thyroid Association (ATA) 2015, radioiodine refractory is classified in four ways: (i) the malignant/metastatic tissue does not ever concentrate RAI, (ii) the tumor tissue loses the ability to concentrate RAI after previous evidence of RAI-avid disease, (iii) RAI is concentrated in some lesions but not in the others, and (iv) metastatic disease progresses despite significant concentration of RAI.[2] These conditions have led to the development of targeted therapy and tyrosine kinase inhibitors, which have shown clinical activity in Phase III trials.[34] However, these drugs have significant toxicities. The previous study of Durante et al.[5] revealed that most remission is obtained with cumulative activity equal to or lower than 600 mCi (22 GBq). The cumulative activities of I-131 larger than 600 mCi are associated with an increased risk of cancer and leukemia. The aim of our study was to study the outcomes and complications in differentiated thyroid carcinoma (DTC) patients who received RAI treatment with a cumulative dose exceeding or equal to 600 mCi.\n\nMATERIALS AND METHODS\n\nPatients\n\nA retrospective study of DTC patients who received RAI treatment with a cumulative dose exceeding or equal to 600 mCi in the Division of Nuclear Medicine, Faculty of Medicine Siriraj Hospital, from January 1993 to December 2013 was performed. Each patient was reclassified in accordance with the seventh edition (AJCC 2009) of the TNM staging system for DTC. The 2009 ATA initial risk stratification system was used in evaluation of the risk of recurrence at initiation in each patient (low-risk patients were defined as having intrathyroidal DTC with no evidence of extrathyroidal extension, vascular invasion, or metastases; intermediate-risk patients demonstrated either microscopic extrathyroidal extension, cervical node metastases, RAI-avid disease in the neck outside the thyroid bed, vascular invasion, or aggressive tumor histology; high-risk patients had gross extrathyroidal extension, incomplete tumor resection, distant metastases, or inappropriate post-operative serum thyroglobulin (Tg) values). From the medical folder, age at diagnosis, gender, histopathological type, tumor invasion, radioiodine uptake of postoperative thyroid remnant, radioiodine doses, follow-up period, and outcome of treatment after receiving RAI treatment with a cumulative dose exceeding or equal to 600 mCi were recorded. Patients who were lost to follow-up or died within the first 2 years were excluded. The study was approved by Siriraj Ethics Committee for Human Experiment for retrospective reviews of patient medical records, and the need for informed consent was waived (COA no. Si 106/2015). The patient characteristics are described in Table 1.\n\nTable 1 Baseline demographic and clinical characteristics (n=176)\n\nCharacteristics\tn (%)\t\nGender (female)\t116 (65.9)\t\nAge at diagnosis (years), mean±SD\t43.22±17.68\t\n24-h I-131 uptake, median (range) (%)\t3.3 (0.2-35.1)\t\nHistologic cell type\t\t\n PTC\t137 (77.8)\t\n FTC\t29 (16.5)\t\n Mixed papillary and follicular cell carcinoma\t9 (5.1)\t\n Hurthle cell carcinoma\t1 (0.6)\t\nMetastasis\t\t\n No\t10 (5.7)\t\n Locoregional metastasis\t118 (67.0)\t\n Distant metastasis (mediastinal node, lung, and bone metastasis)\t48 (27.3)\t\nTotal I-131 dose, median (range) (mCi)\t900 (600-2200)\t\nFollow-up period (months), mean±SD\t82.84±42.41\t\nPTC: Papillary thyroid carcinoma, FTC: Follicular cell carcinoma, SD: Standard deviation\n\nOutcome of treatment\n\nAll patients were followed up for at least 2 years (mean follow-up period was 82.84 ± 42.41 months). Follow-up included whole-body scan (WBS) after RAI treatment and other imaging modalities such as ultrasound (US), computed tomography (CT), or magnetic resonance imaging, and subsequent thyroid-stimulating hormone (TSH), Tg, and Tg antibody (TgAb) measurements were used for detection of metastatic site. Using these, parameter status on follow-up was classified as remission and nonremission.\n\nRemission was defined according to:\n\nNo clinical evidence of disease\n\nNo imaging evidence of tumor by RAI imaging (no uptake at thyroid bed and no uptake outside the thyroid bed on posttreatment WBS and no imaging evidence of tumor on a recent diagnostic or posttreatment WBS) and/or neck US. The images were interpreted by an experienced nuclear medicine physician and a diagnostic radiologist\n\nLow serum Tg levels during TSH suppression (<0.2 ng/ml) or after stimulation (<1 ng/ml) without interfering TgAb (<40 IU/mL).\n\nNonremission was defined as three groups:\n\nStable disease (SD) was classified as unaltered Tg levels, persistent uptake in the previous foci without progression or new metastatic foci\n\nProgressive disease (PD) was established as increasing consecutive Tg levels and/or detection of new metastatic foci\n\nAt least 1 metastasis without I-131 uptake.\n\nComplications from radioiodine treatment were described as:\n\nSecond primary malignancy (SPM) was clarified as solid or hematologic malignancies that occurred after receiving a cumulative dose exceeding or equal to 600 mCi of I-131. Histological results were obtained for all SPMs to exclude the possibility of metastases\n\nBone marrow suppression was clarified as abnormal of any series of complete blood count on the follow-up period after receiving a cumulative dose exceeding or equal to 600 mCi of I-131. The bone marrow suppression was classified according to the WHO classification as described below:\n\nNeutropenia is diagnosed if absolute neutrophil count (ANC) <1,500 cell/mm 3\n\nMild neutropenia ANC 1000–1500 cell/mm 3\n\nModerate neutropenia ANC 500–1000 cell/mm 3\n\nSevere neutropenia ANC <500 cell/mm 3\n\nAnemia is diagnosed if hemoglobin (Hb) <11 g/ml\n\nGrade 1 (mild) Hb 9.5–10.9 g/ml\n\nGrade 2 (moderate) Hb 8.0–9.4 g/ml\n\nGrade 3 (serious) Hb 6.5–7.9 g/ml\n\nGrade 4 (life-threatening) Hb <6.5 g/ml\n\nThrombocytopenia is diagnosed if platelet count <100,000/μl\n\nSalivary gland dysfunction was clarified as dry mouth, lack of taste, or sialadenitis that patient complained as shown in the medical record on the follow-up after radioiodine treatment. Sialadenitis was clinically diagnosed by swelling in the region of major salivary glands with or without pain with spontaneous resolution and without clinical signs of bacterial or viral infection.\n\nStatistical analysis\n\nContinuous variables were presented as mean and standard deviation. Categorical variables were presented as counts with percentage. P < 0.05 was considered statistically significant. Remission outcomes were analyzed using multiple logistic regression for univariate and multivariate analyses. All analyses were conducted using the SPSS software (version 22.0, IBM Corporation, Armonk, NY, USA).\n\nRESULTS\n\nTotal number of DTC patients referred to the Division of Nuclear Medicine, Faculty of Medicine Siriraj Hospital, during period January 1993 up to December 2013. Among the 227 DTC patients who received a cumulative dose of ≥600 mCi of I-131, 51 patients were excluded due to lost to follow-up within the first 2 years. Then, 176 patients were enrolled in the study (116 women, mean age: 43.22 ± 17.68 years, range: 9–85 years). The total therapeutic dose ranged from 600 to 2200 mCi. The most common primary tumor histology type was papillary thyroid carcinoma in 137 cases (77.8%). The mean follow-up period was 82.84 ± 42.41 months. Patients and outcomes following I-131 treatment with a cumulative dose exceeding or equal to 600 mCi on the last follow-up are described in Figure 1.\n\nFigure 1 Flowchart of the population and outcomes following I-131 treatment with a cumulative dose exceeding or equal to 600 mCi\n\nRemission\n\nSixteen patients (9.1%) were diagnosed as being disease free at the end of the follow-up period (12 females with mean age at diagnosis of remission cases of 41.1 ± 16.5 years, mean total therapeutic dose of 795.6 ± 136.4 mCi, mean 24-h I-131 uptake of 3.5% ± 2.4%). Low, intermediate, and high risks of recurrent disease were observed in 5, 10, and 1 case, respectively. The mean period of follow-up was 92.8 ± 35.7 months, as described in Table 2. The univariate and multivariate analyses of significant prognostic factor comparison between the remission and nonremission groups are described in Table 3.\n\nTable 2 Remission cases following radioactive iodine treatment with cumulative dose ≥600 mCi\n\nPatient number\tAge at diagnosis\tGender\t24-h I-131 uptake before RAI Rx\tDiagnosis (site of metastasis)\tRisk of recurrence (at initiation)\tTotal dose (mCi)\tF/U period (months)\tComments\t\n1\t67\tMale\t1.06\tPTC\tLow\t600\t77\tPersistent uptake at thyroid bed since the second dose\t\n2\t22\tFemale\t2.3\tPTC\tLow\t810\t(113)\tPersistent uptake at thyroid bed since the first dose\t\n3\t41\tFemale\t7.9\tMixed PTC and FTC\tLow\t710\t(199)\t\t\n4\t15\tMale\t2.37\tFTC\tLow\t930\t(37)\t\t\n5\t37\tFemale\t3.5\tFTC\tLow\t980\t(114)\t\t\n6\t26\tFemale\t6.5\tPTC (CLN)\tIntermediate\t900\t102\t\t\n7\t30\tMale\t2.9\tPTC (CLN)\tIntermediate\t930\t158\t\t\n8\t33\tFemale\t1\tPTC (CLN)\tIntermediate\t600\t89\t\t\n9\t37\tFemale\t2.37\tPTC (CLN)\tIntermediate\t800\t47\t\t\n10\t60\tFemale\t2.5\tPTC (CLN)\tIntermediate\t800\t75\t\t\n11\t70\tFemale\t7.11\tPTC with vascular and capsular invasion\tIntermediate\t750\t99\t\t\n12\t63\tFemale\t1.66\tPTC (CLN)\tIntermediate\t600\t97\t\t\n13\t37\tFemale\t6.5\tPTC (CLN)\tIntermediate\t1100\t102\t\t\n14\t36\tFemale\t1.57\tPTC (CLN)\tIntermediate\t900\t41\t\t\n15\t32\tMale\t7.14\tPTC (CLN)\tIntermediate\t750\t82\t\t\n16\t53\tMale\t4.6\tFTC (bone)\tHigh\t800\t151\t\t\nPTC: Papillary thyroid carcinoma, FTC: Follicular cell carcinoma, RAI: Radioactive iodine, CLN: Cervical lymph node\n\nTable 3 Univariate and multivariate analyses of significant prognostic factors for remission cases (n=16)\n\nCharacteristics\tRemission, n (%)\tNonremission, n (%)\tP\tCrude\tAdjusted\t\n\t\t\nORs (95% CI)\tP\tORs (95% CI)\tP\t\nAge (years), mean±SD\t41.1±16.5\t43.4±17.9\t0.62\t\t\t\t\t\n <55\t12 (9.4)\t116 (90.6)\t0.55\tReference\t\tReference\t\t\n ≥55\t4 (8.3)\t44 (91.7)\t\t0.88 (0.27-2.87)\t0.83\t0.96 (0.25-3.67)\t0.96\t\nGender\t\t\t\t\t\t\t\t\n Female\t11 (9.5)\t105 (90.5)\t0.80\tReference\t\tReference\t\t\n Male\t5 (8.3)\t55 (91.7)\t\t0.87 (0.29-2.62)\t0.80\t1.07 (0.30-3.83)\t0.92\t\nRAIU (%), mean±SD\t3.5±2.4\t5.2±5.6\t0.24\t\t\t\t\t\n ≤1.9\t5 (9.6)\t47 (90.4)\t0.31\tReference\t\tReference\t\t\n 2-3.9\t6 (18.2)\t27 (81.8)\t\t2.09 (0.58-7.50)\t0.26\t2.33 (0.55-9.77)\t0.25\t\n ≥4\t5 (8.2)\t56 (91.8)\t\t0.84 (0.23-3.08)\t0.79\t0.77 (0.19-3.16)\t0.71\t\nCell type\t\t\t\t\t\t\t\t\n PTC\t12 (8.8)\t125 (91.2)\t0.96\tReference\t\tReference\t\t\n FTC\t3 (10.3)\t26 (89.7)\t\t1.20 (0.32-4.56)\t0.79\t2.59 (0.33-20.51)\t0.37\t\n Others\t1 (10.0)\t9 (90.0)\t\t1.16 (0.14-9.93)\t0.89\t0.91 (0.07-11.06)\t0.94\t\nRisk of recurrence\t\t\t\t\t\t\t\t\n Low\t5 (45.5)\t6 (54.5)\t<0.001\tReference\t\tReference\t\t\n Intermediate\t10 (8.5)\t107 (91.5)\t\t0.11 (0.03-0.43)\t0.002\t0.05 (0.01-0.49)\t0.01\t\n High\t1 (2.1)\t47 (97.9)\t\t0.03 (0.00-0.26)\t0.002\t0.01 (0.00-0.17)\t0.003\t\nMetastasis\t\t\t\t\t\t\t\t\n No\t5 (14.3)\t30 (85.7)\t0.24\tReference\t\tReference\t\t\n Yes\t11 (7.8)\t5 (92.2)\t\t0.51 (0.16-1.57)\t0.24\t4.45 (0.50-39.66)\t0.18\t\nOR: Odds ratio, CI: Confidence interval, SD: Standard deviation, RAIU: Radioactive iodine uptake, PTC: Papillary thyroid carcinoma, FTC: Follicular cell carcinoma\n\nNonremission\n\nThere were 160 nonremission cases (105 females with mean age at diagnosis of 43.4 ± 17.9 ng/ml, mean total therapeutic dose of 944.01 ± 236.9 mCi, mean 24-h I-131 uptake of 5.2% ± 5.6%). Low, intermediate, and high risks of recurrent disease were observed in 6, 107, and 47 cases, respectively. The mean period of follow-up was 83.7 ± 43.6 months. Ninety-four cases (53.4%) had SD, 34 (19.3%) had at least 1 metastasis without I-131 uptake, and 21 (11.9%) had PD. Death was found in 11 cases (6.3%), 1 died from pneumonia sepsis, 1 case was secondary malignancy related (non-Hodgkin lymphoma [NHL]), and the rest 9 cases died from an unknown cause. There was no significant difference in the mean survival time of death group (73.5 ± 39.7 months) and alive group (84.9 ± 42.7 months), P = 0.39.\n\nAmong the 160 cases of nonremission cases, DM was found in 117 patients (73.1%), including 34 cases of bone, 32 cases within lungs, and 51 cases within mediastinum. Locoregional metastasis was found in 23 cases.\n\nComplications\n\nThere were 2 patients (1.1%) of SPM, 18 patients (10.2%) of suspected bone marrow suppression, and 7 patients (3.9%) of salivary gland dysfunction.\n\nSecond primary malignancy\n\nTwo of 176 patients developed SPM following I-131 treatment with a cumulative dose exceeding or equal to 600 mCi. These included 1 case of NHL and 1 case of invasive ductal carcinoma of the breast. The first case was a 65-year-old man with PTC and cervical lymph node (LN) metastasis who was diagnosed with NHL 20 months after the cumulative activity of I-131 of 600 mCi. He presented with abdominal pain and gastric ulcer, as seen on the gastroscopy. His pathological report from gastric biopsy revealed NHL. Finally, he died from NHL. The second case was a 63-year-old woman with PTC and cervical LN metastasis who was found invasive ductal carcinoma of the right breast 2 years after the cumulative activity of I-131 of 600 mCi. She underwent right total mastectomy with sentinel LN biopsy and completed a session of chemotherapy. Then, she was in a complete remission of breast cancer.\n\nBone marrow suppression\n\nAt least 6 months after RAI treatment with a cumulative dose of 600 mCi, 18 cases (10.2%) were suspected of bone marrow suppression. Thirteen cases (7.4%) developed anemia, four patients (2.3%) had neutropenia, and the remaining one case (0.5%) had anemia with neutropenia.\n\nAnemia\n\nFourteen cases had anemia after RAI treatment with a cumulative dose of 600 mCi (10 female [78.5%], mean age at diagnosis: 47.07 ± 16.99 years, mean Hb: 10.11 ± 0.83 g/ml). Eight cases were recovery after 6-month follow-up and the rest six cases had persistent anemia (mean follow-up period of 20.14 ± 9.13 months). Six cases with persistent anemia were 3 cases of grade I and 3 cases of Grade II anemia. Two cases of Grade II anemia, one was found lower gastrointestinal bleeding and one was proven of iron-deficiency anemia. The remaining four cases were not found the definite cause of persistent anemia.\n\nNeutropenia\n\nFive cases had mild neutropenia after RAI treatment with a cumulative dose of 600 mCi (4 females, mean age at diagnosis: 27 ± 4.42 years, mean ANC: 1,233.4 ± 207.63 cell/mm3). Four cases were recovery and 1 case had persistent mild neutropenia (mean follow-up period of 13.2 ± 4.96 months). The case with persistent mild neutropenia was a 27-year-old female PTC patient with cervical node, bilateral lungs, and bone metastases. She was found mild neutropenia (ANC: 1,070 cell/mm3) after receiving the fourth session of I-131 therapy (cumulative dose of 600 mCi). After 15-month follow-up, ANC was slightly increased with the level of 1400 cell/mm 3 without clinical symptom. This case also had persistent Grade I anemia without a definite cause.\n\nSalivary gland dysfunction\n\nSeven cases were classified as salivary gland dysfunction. Three of seven cases had dry mouth with diagnosed as xerostomia and the rest four cases had sialadenitis. From these seven patients, three cases complained about salivary gland dysfunction before the cumulative activity of I-131 of 600 mCi (1 case after 150 mCi, 1 case after 210 mCi, and 1 case after 300 mCi). All of the seven cases had persistent symptoms.\n\nDISCUSSION\n\nThe outcomes of DTC patients are excellent, with long-term disease survival rates approaching 90% over 20 years following appropriate treatment. Despite the overall excellent outcome, some DTC patients have DM with worse prognosis and are frequently unresponsive to conventional therapy requiring multiple doses of RAI therapy.[6] One-third of the DM patients have no I-131 uptake and die because of RR. The previous study of Wassermann et al. found that patients were classified as progressive RR had a worse prognosis which could justify molecular targeted therapy. In contrast, cases of nonprogressive RR found prolonged survival times which should be managed with “wait and see.”[7] Our study found high incidences of nonremission cases (91.9%) after RAI treatment with a cumulative dose of ≥600 mCi, and most of the cases had SD (53.4%). The previous study of Nasreen et al.[8] revealed a higher incidence of disease-free patients (36%) and rather low incidence of nondisease-free group (35%) after receiving a cumulative dose of ≥600 mCi I-131 as compared to our study. It is possible due to different remission criteria in their study and shorter period of follow-up in our study. Another reason was that most of the patients in their study had TNM Stage I (45%) which has high chance to be in remission. Martins-Filho et al. found that disease status was positively associated with TNM stage by multiple logistic regression analysis. Patients with higher staging (III and IV), above 45 years of age, and aggressive variants have a worse prognosis, greater chances of local recurrence, and distant metastases and require higher and more RAI doses.[9] Our study shows similar results that the mean cumulative dose in the nonremission group was significantly higher than that in the remission group.\n\nNonremission cases in our study reveal multiple metastatic sites including bone, lung, mediastinal, and some of locoregional metastasis. DM is associated with mortality having five times greater probability of death than patients having no metastasis or local metastasis.[8] Although there were 73.1% of nonremission patients who have DM in our study, we were not able to evaluate the impact on overall survival since the mean follow-up time was below 10 years. A longer follow-up time is necessary in order to evaluate the impact of this information on patient management.\n\nIn the remission group, we found that the risk of recurrence at initiation was inversely associated with remission in both univariate and multivariate analyses. Between the remission and nonremission groups, mean age at diagnosis and mean 24-h I-131 uptake before RAI treatment had no statistical differences. The previous study of Liu et al. revealed similar results that intermediate and high risks, as well as tumor Stage T3 or T4 and LN metastasis, were significantly associated with unsuccessful outcomes.[10]\n\nIn our study, remission cases with low risk of recurrence at initiation, the total body scan of all patients revealed persistent 1–2 uptake lesions at anterior neck region on planar images which were suspected of persistent thyroid remnant. Then, they received RAI treatment until a cumulative dose of ≥600 mCi. All of these lesions might be possible due to paratracheal node metastasis rather than residual thyroid remnant because most of the thyroid remnant should be destroyed by RAI ablation.[11] However, we cannot conclude this hypothesis because we did not perform single-photon emission CT/CT in all cases as routine protocol, and then, we did not have complete data. We also found that remission DTC patients with cervical node metastasis had metastatic foci of ≤2 lesions. One remission case with high risk of recurrence had only 1 metastatic focus at the left proximal femur since the first WBS. All of our findings suggested an important observation that I-131 treatment is possible effective in patients with few metastatic sites (≤2 foci) which have high chance to be in remission.\n\nSecond primary malignancy\n\nThe use of radioiodine therapy has raised concern about the potential for the development of SPM, especially in patients with a cumulative dose exceeding 600 mCi. Rubino et al. found a correlation between RAI dose and SPM (mean follow-up: 13 years).[12] In our study, we found only 2 cases (1.1%) of SPM which included 1 case of IDC of the breast and 1 case of NHL after receiving I-131 treatment with a cumulative dose exceeding 600 mCi. In the previous study of Lin et al. revealed higher results in which there were 6.1% of secondary malignancy who was treated with I-131 cumulative dose ≥600 mCi.[13] In the previous study of Nasreen et al., they also showed similar results. They reported two patients (2.78%) with SPM after receiving a cumulative dose of ≥600 mCi: one of leukemia and the other of carcinoid tumor.[8] The lower incidence of SPM in our study than that in other populations is possible from different ethnicities and different malignancy types.\n\nThe cancer, found in our study, was not commonly found in the previous study. Second primary cancers associated with RAI treatment included bone and soft-tissue, colorectal, salivary gland cancer and leukemia.[12] In the previous study, cancer of salivary glands and leukemia are close in terms of incidence risk estimates because salivary glands receive a much higher absorbed dose and greater sensitivity of bone marrow to the stochastic effects of radiation.[13] However, some studies revealed an association between thyroid cancer and breast cancer, as seen in our study.[14]\n\nBone marrow suppression\n\nBone marrow suppression may occur within 1 month of radioiodine therapy and is usually transient. Severe bone marrow suppression seldom occurs when the radiation dose to blood is <200 cGy.[15] Bone marrow suppression occurs most often in patients who have the following risks: receive a large cumulative amount of radioiodine, receive external beam therapy in addition to I-131, have large functioning tumors that produce a high concentration of I-131, and have extensive bone metastasis.[16] In our study, we found 18 patients with suspected bone marrow suppression after receiving 600 mCi of RAI treatment, of which most of them (14 cases) had anemia. Six of 14 cases had persistent anemia for at least 6-month follow-up. Many medical conditions cause anemia such as active bleeding, iron-deficiency anemia, chronic disease, or poor nutrition. Most of the anemic patients were women who have more prevalence of anemia as compared to men. Causes of anemia in women are multiple. In majority, the cause of anemia in women is the iron-deficiency type, which occurs due to deficiency of iron, resulting in impaired formation of Hb. Women suffer from chronic blood loss due to monthly menstrual cycles, which always leads to chronic anemia. In addition, it is possible due to thalassemia or chronic disease.[17] About 1% of Thai population are affected with thalassemic disease and about 30%–40% of population are carriers of at least one of abnormal gene.[18] As there is no detail, we cannot conclude the definite cause of anemia in our study. However, the anemic patients in our study did not require blood transfusion. Otherwise, several studies have demonstrated that high-dose RAI treatment associated with leukopenia and thrombocytopenia rather than anemia.[192021]\n\nSalivary gland dysfunction\n\nIodine is greatly concentrated in the thyroid gland by carrier-mediated mechanism, but similar uptake is found in other organs, including the salivary and lacrimal glands. The concentration of secreted iodide in saliva has been reported to vary from 20 to 100 times of that in a serum. Therefore, the salivary glands can receive a substantial radiation-absorbed dose from I-131 treatment.[22] Sialadenitis and xerostomia have been considered as transient side effects of radioiodine therapy. The previous study of Ko et al. demonstrated that the risk of salivary gland secretion impairment significantly increased with increasing administered doses.[23] Alexander et al. reported that 42.9% of patients undergoing radioiodine therapy suffered from reduced salivary gland function more than 1 year after the last radioiodine application and persistent xerostomia occurred in 4.4%.[21] The previous study of Solans revealed that 32.9% of patients reported subjective xerostomia which persisted to the second year of follow-up in 20.3% of cases and was still present more than 3 years after the last dose of RAI treatment in 15.2% of cases.[24] Our study found only 7 cases of permanent salivary gland dysfunction (1.7% of xerostomia and 2.2% of sialadenitis), in which the incidence is relatively low as compared to the previous studies. It is possible due to preventive protocol in our institution such as encourage patients to suck sour/lemon candies 24 h after RAI therapy and drink plenty of water during admission.\n\nThere are some limitations to our study. First, there is a relatively short follow-up period which limits the ability for overall survival analysis and because of the long latency of radiation-induced cytogenetic change to malignancy. Second, a retrospective cohort study is typically lower in statistical quality. A multicenter, international origin dataset is needed to validate our results. Third, the identification of salivary glands dysfunction using the patient's record instead of image measurements. The information regarding whether or not patients received protection for salivary glands was not available from the database, although such protection is routinely offered during treatment in our center.\n\nCONCLUSION\n\nAlthough the complications after I-131 treatment with a cumulative dose exceeding or equal to 600 mCi in DTC patients were low and not severe, the patients with remission were in <10%. Our study suggests that the decision to administer further treatments should be made on an individual basis because beneficial effects may be controversial.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Mazzaferri EL Kloos RT Clinical review 128: Current approaches to primary therapy for papillary and follicular thyroid cancer J Clin Endocrinol Metab 2001 86 1447 63 11297567\n2 Bryan RH Eric KA Keith CB Gerard MD Susan JM Yuri E 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer Thyroid 2015 26 76 80\n3 Brilli L Pacini F Targeted therapy in refractory thyroid cancer: Current achievements and limitations Future Oncol 2011 7 657 68 21568681\n4 Thomas L Lai SY Dong W Feng L Dadu R Regone RM Sorafenib in metastatic thyroid cancer: A systematic review Oncologist 2014 19 251 8 24563075\n5 Durante C Haddy N Baudin E Leboulleux S Hartl D Travagli JP Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: Benefits and limits of radioiodine therapy J Clin Endocrinol Metab 2006 91 2892 9 16684830\n6 Palme CE Waseem Z Raza SN Eski S Walfish P Freeman JL Management and outcome of recurrent well-differentiated thyroid carcinoma Arch Otolaryngol Head Neck Surg 2004 130 819 24 15262757\n7 Wassermann J Bernier M Spano J Lepoutre-lussey C Buffet C Simon J Outcomes and prognostic factors in radioiodine refractory differentiated thyroid carcinomas Oncologist 2016 21 50 8 26675742\n8 Nasreen F Nahar N Sultana S Alam F Outcome of well-differentiated thyroid carcinoma patients receiving a cumulative doses of ≥600 mCi (22GBq) of I-131 Bangladesh J Nucl Med 2014 17 114 9\n9 Martins-Filho R Ward LS Amorim BJ Santos AO Lima MCL Ramos CD Cumulative doses of radioiodine in the treatment of differentiated thyroid carcinoma: Knowing when to stop Arq Bras Endocrinol Metabol 2010 54 807 12 21340173\n10 Liu N Meng Z Jia Q Tan J Zhang G Zheng W Multiple-factor analysis of the first radioactive iodine therapy in post-operative patients with differentiated thyroid cancer for achieving a disease-free status Sci Rep 2016 6 34915 27721492\n11 Karam M Gianoukakis A Feustel PJ Cheema A Postal ES Cooper JA Influence of diagnostic and therapeutic doses on thyroid remnant ablation rates Nucl Med Commun 2003 24 489 95 12717064\n12 Rubino C de Vathaire F Dottorini ME Hall P Schvartz C Couette JE Second primary malignancies in thyroid cancer patients Br J Cancer 2003 89 1638 44 14583762\n13 Lin JD Kuo SF Huang BY Lin SF Chen ST The efficacy of radioactive iodine for the treatment of well-differentiated thyroid cancer with distant metastasis Nucl Med Commun 2018 39 1091 6 30180044\n14 Joseph KR Edirimanne S Eslick GD The association between breast cancer and thyroid cancer: A meta-analysis Breast Cancer Res Treat 2015 152 173 81 26058757\n15 Benua RS Cicale NR Sonenberg M Rawson RW The relation of radioiodine dosimetry to results and complications in the treatment of metastatic thyroid cancer Am J Roentgenol Radium Ther Nucl Med 1962 87 171 82\n16 de Vathaire F Schlumberger M Delisle MJ Francese C Challeton C de la Genardiére E Leukaemias and cancers following iodine-131 administration for thyroid cancer Br J Cancer 1997 75 734 9 9043033\n17 Chaparro CM Suchdev PS Anemia epidemiology, pathophysiology, and etiology in low- and middle-income countries Ann N Y Acad Sci 2019 1450 15 31 31008520\n18 Panich V Pornpatkul M Sriroongrueng W The problem of thalassemia in Thailand Southeast Asian J Trop Med Public Health 1992 23 Suppl 2 1 6\n19 Molinaro E Leboeuf R Shue B Martorella AJ Fleisher M Larson S Mild decreases in white blood cell and platelet counts are present one year after radioactive iodine remnant ablation Thyroid 2009 19 1035 41 19772430\n20 Prinsen HT Helselink EN Brouwers AH Plukker JT Sluiter WJ Links TP Bone marrow function after I-131 therapy in patients with differentiated thyroid carcinom J Clin Endocrinol Metabol 2015 100 3911 7\n21 Alexander C Bader JB Schaefer A Finke C Kirsch CM Intermediate and long-term side effects of high-dose radioiodine therapy for thyroid carcinoma J Nucl Med 1998 39 1551 4 9744341\n22 Myant NB Iodine metabolism of salivary glands Ann N Y Acad Sci 1960 85 208 14 14425579\n23 Ko KY Kao CH Lin CL Huang WS Yen RF I-131 treatment for thyroid cancer and the risk of developing salivary and lacrimal gland dysfunction and a secondary primary malignancy: A nationwide population-based cohort study Eur J Nucl Mol Imaging 2015 42 1172 8\n24 Solans R Bosch JA Galofré P Porta F Roselló J Selva-O'Callagan A Salivary and lacrimal gland dysfunction (sicca syndrome) after radioiodine therapy J Nucl Med 2001 42 738 43 11337569\n\n",
"fulltext_license": "CC BY-NC-SA",
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"issue": "20(1)",
"journal": "World journal of nuclear medicine",
"keywords": "600 mCi; cumulative dose; differentiated thyroid cancer; radioiodine therapy",
"medline_ta": "World J Nucl Med",
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"pubdate": "2021",
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"title": "Outcomes following I-131 treatment with cumulative dose exceeding or equal to 600 mCi in differentiated thyroid carcinoma patients.",
"title_normalized": "outcomes following i 131 treatment with cumulative dose exceeding or equal to 600 mci in differentiated thyroid carcinoma patients"
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"abstract": "BACKGROUND\nBevacizumab combined with chemotherapy has become the first-line therapy in advanced nonsquamous non-small-cell lung cancer (NSCLC). However, few studies have focused on cisplatin/pemetrexed with bevacizumab as the first-line therapy to treat advanced nonsquamous NSCLC. Importantly, whether the epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements can influence the efficacy of bevacizumab in combination with chemotherapy is very interesting. Herein, we report three cases with different types of gene drives in advanced nonsquamous NSCLC.\n\n\nMETHODS\nIn the first case, a patient presented with wild-type EGFR and negative ALK rearrangement. In the second case, a patient presented with wild-type EGFR and positive ALK rearrangement. In the third case, a patient presented with negative ALK rearrangement and mutated EGFR in exon 19.\n\n\nCONCLUSIONS\nWe speculate that bevacizumab in combination with cisplatin/pemetrexed as the first-line therapy is well tolerated and results in a clinically meaningful treatment benefit, irrespective of the gene drive type in advanced nonsquamous NSCLC. However, more data are needed to confirm the relationship.",
"affiliations": "Department of Oncology, School of Medicine, Shandong University; Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China.;Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China.;Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China.;Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China.",
"authors": "Wang|Haiyong|H|;Zhu|Hui|H|;Kong|Li|L|;Yu|Jinming|J|",
"chemical_list": null,
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"doi": "10.2147/OTT.S101241",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOncoTargets and TherapyOncoTargets and therapy1178-6930Dove Medical Press 10.2147/OTT.S101241ott-9-4639Case SeriesEfficacy of cisplatin/pemetrexed with bevacizumab to treat advanced lung adenocarcinoma with different drive genes: case report and literature review Wang Haiyong 12Zhu Hui 2Kong Li 2Yu Jinming 21 Department of Oncology, School of Medicine, Shandong University2 Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Jinming Yu, Department of Radiation Oncology, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, 440 Ji Yan Road, Jinan, Shandong, 250117, People’s Republic of China, Tel +86 531 8798 4777, Fax +86 531 8798 4079, Email sdyujinming@126.com2016 26 7 2016 9 4639 4644 © 2016 Wang et al. This work is published and licensed by Dove Medical Press Limited2016The 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.Background\nBevacizumab combined with chemotherapy has become the first-line therapy in advanced nonsquamous non-small-cell lung cancer (NSCLC). However, few studies have focused on cisplatin/pemetrexed with bevacizumab as the first-line therapy to treat advanced nonsquamous NSCLC. Importantly, whether the epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements can influence the efficacy of bevacizumab in combination with chemotherapy is very interesting. Herein, we report three cases with different types of gene drives in advanced nonsquamous NSCLC.\n\nCase presentation\nIn the first case, a patient presented with wild-type EGFR and negative ALK rearrangement. In the second case, a patient presented with wild-type EGFR and positive ALK rearrangement. In the third case, a patient presented with negative ALK rearrangement and mutated EGFR in exon 19.\n\nConclusion\nWe speculate that bevacizumab in combination with cisplatin/pemetrexed as the first-line therapy is well tolerated and results in a clinically meaningful treatment benefit, irrespective of the gene drive type in advanced nonsquamous NSCLC. However, more data are needed to confirm the relationship.\n\nKeywords\ncase reportslung cancercisplatin/pemetrexedbevacizumab\n==== Body\nIntroduction\nNon-small-cell lung cancer (NSCLC) is one of the most common carcinomas in the world.1 Patients with advanced NSCLC have a poor prognosis, with 4–6 months median progression-free survival (PFS) and 8–10 months median overall survival (OS).2–4 Chemotherapy is the preferred option for advanced NSCLC, and platinum-based doublet chemotherapy is the internationally recognized standard for treating advanced NSCLC.5,6 However, the efficacy of traditional chemotherapy has reached a plateau. With the development of molecular biology and cellular biology, targeted therapies bring hope to patients with NSCLC. Patients harboring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements may benefit from treatment with tyrosine kinase inhibitors or ALK inhibitors.7,8 In addition, bevacizumab, one of the most widely used drugs of targeted therapy, has been the first-line therapy in combination with chemotherapy in advanced nonsquamous NSCLC.9 However, few studies have focused on the combination of bevacizumab with pemetrexed/cisplatin. In addition, the correlation between EGFR mutations or ALK rearrangements and the efficacy of bevacizumab in combination with chemotherapy has been problematic in clinical practice. In our study, we share three case reports. In the first case, a patient presented with no EGFR mutations and ALK rearrangements. In the second case, we present a patient who has no EGFR mutations but has ALK rearrangements. While in the third case, we present a patient who has EGFR mutations but has no ALK rearrangements.\n\nCase reports\nThis study was approved by the Ethics Committee of Shandong Cancer Hospital, and all patients signed informed consent forms for procedures to be performed and the reporting of their results.\n\nCase 1\nA 69-year-old man presented to Shandong Cancer Hospital. The right lung mass was found by computed tomography (CT) scan 9 months ago, when the patient underwent a routine physical examination (Figure 1A). CT-guided percutaneous needle biopsy of the lung mass proved adenocarcinoma, and the gene detection showed that the EGFR was wild type and the ALK rearrangement was negative. The patient received bevacizumab (7.5 mg/kg), cisplatin (75 mg/m2), and pemetrexed (500 mg/m2) administered every 3 weeks. During the treatment, digestive tract reaction and myelotoxicity were well tolerated. Chest CT showed significant shrinkage of the primary mass after two cycles of therapy (Figure 1B). Interestingly, after four cycles of therapy, the lung mass showed further shrinkage, as evidenced by CT scan (Figure 1C). In addition, the expression of carcinoembryonic antigen was reduced progressively in the course of treatment (Table 1).\n\nCase 2\nA 52-year-old woman also presented to Shandong Cancer Hospital. Multiple lung nodules and multiple brain metastases were found in the patient by CT scan and magnetic resonance imaging scan, respectively (Figures 2A and 3A). CT-guided percutaneous needle biopsy of the mass proved adenocarcinoma, and the gene detection showed that the EGFR was wild type and the ALK rearrangement was positive. This patient also received bevacizumab (7.5 mg/kg), cisplatin (75 mg/m2), and pemetrexed (500 mg/m2) administered every 3 weeks. During the treatment, digestive tract reaction and myelotoxicity were well tolerated. Chest CT showed significant shrinkage of the major lung nodule after two cycles of therapy (Figure 2B). Importantly, brain magnetic resonance imaging showed that the major brain metastasis mass almost disappeared after two cycles of therapy (Figure 3B). Similarly, after four cycles of therapy, the major lung nodule showed further shrinkage as seen from CT scan (Figure 2C), and the brain metastasis mass also almost disappeared (Figure 3C). In addition, the expression of carcinoembryonic antigen was reduced progressively in the course of treatment (Table 1).\n\nCase 3\nA 58-year-old woman also presented to Shandong Cancer Hospital. The left lung mass was found by CT scan 3 months ago (Figure 4A). CT-guided percutaneous needle biopsy of the lung mass proved adenocarcinoma, and the gene detection showed that a deletion mutation in the exon 19 of the EGFR and the ALK rearrangement was negative. She also received bevacizumab (7.5 mg/kg), cisplatin (75 mg/m2), and pemetrexed (500 mg/m2) administered every 3 weeks. During the treatment, digestive tract reaction and myelotoxicity were also well tolerated. Chest CT showed significant shrinkage of the major lung nodule after two cycles of therapy (Figure 4B). Similarly, after four cycles of therapy, the major lung nodule showed further shrinkage as seen from CT scan (Figure 4C). The expression of carcinoembryonic antigen was also reduced progressively in the course of treatment (Table 1).\n\nDiscussion\nThe vascular endothelial growth factor pathway is well established as one of the key regulators in tumor angiogenesis, which is a fundamental event in tumor growth and metastatic dissemination.10,11 Bevacizumab, a recombinant humanized IgG1 monoclonal antibody, can inhibit tumor angiogenesis and suppress tumor growth and metastasis by specifically binding with vascular endothelial growth factor, thereby blocking the biological effects of vascular endothelial growth factor.12 In addition, bevacizumab can increase the concentration of chemotherapeutic drug by promoting tumor vascular stabilization, reducing tissue gap pressure, and increasing vascular permeability, thus enhancing the efficacy of chemotherapy.13\n\nAt present, bevacizumab showed encouraging efficacy as the first-line therapy for patients with nonsquamous NSCLC in some studies (Table 2). The Eastern Cooperative Oncology Group 4599, a Phase III clinical study of III/IV nonsquamous NSCLC, compared the efficacy of carboplatin/paclitaxel and carboplatin/paclitaxel plus bevacizumab and showed that the median OS was extended by 2 months and the median PFS was extended by 1.7 months, respectively.14 The AVAiL compared the efficacy of cisplatin/gemcitabine and cisplatin/gemcitabine plus bevacizumab for advanced NSCLC and showed that the hazard ratio for PFS was 0.75 in the low-dose group and 0.82 in the high-dose group compared with placebo, respectively.15 Reynolds et al evaluated the combination of nab-paclitaxel, carboplatin, and bevacizumab in advanced (stage IIIB/IV) nonsquamous NSCLC and showed the response rate was 31% with a stable disease rate of 54%. The median PFS was 9.8 months, and the median OS was 16.8 months.16 The SAiL study, an open-label, single-group, Phase IV study from centers in 40 countries, assessed the safety and efficacy of first-line bevacizumab combined with standard chemotherapy regimens in clinical practice and confirmed the manageable safety profile of first-line bevacizumab in combination with various standard chemotherapy regimens for the treatment of advanced nonsquamous NSCLC.17 Interestingly, these studies considered mainly White patients as the research subjects. In fact, bevacizumab was also efficacious in Asian populations by subgroup analyses of the AVAiL and SAiL studies. In addition, the randomized Phase II JO19907 study compared the efficacy and safety of first-line carboplatin/paclitaxel alone with carboplatin/paclitaxel plus bevacizumab in Japanese patients with advanced nonsquamous NSCLC. The results showed that the hazard ratio for PFS was 0.61 with carboplatin/paclitaxel plus bevacizumab versus carboplatin/paclitaxel alone.18 Importantly, the Phase III BEYOND trial was undertaken to confirm the efficacy of first-line bevacizumab plus platinum doublet chemotherapy in a Chinese patient population, and the results showed that the PFS was prolonged by 2.7 months and the OS was also prolonged by 6.6 months in patients with carboplatin/paclitaxel plus bevacizumab versus carboplatin/paclitaxel plus placebo.19 After reviewing the earlier research, we can find that bevacizumab combined with chemotherapy has been used as the first-line therapy status for advanced nonsquamous lung cancer. However, two problems should be paid attention. First, bevacizumab can prolong survival only in combination with paclitaxel, and the survival benefits to patients were not found in combination with gemcitabine. This can be attributed to the fact that paclitaxel can trigger inflammation in the body, thus promoting the formation of tumor blood vessels.20,21 Interestingly, bevacizumab, an antiangiogenic drug, not only can reverse these negative factors but also can augment the treatment effect of paclitaxel. Second, pemetrexed, an effective therapeutic agent in the treatment of NSCLC, is a novel metabolic antagonist capable of inhibiting multiple enzymes involved in folate metabolism. At present, cisplatin plus pemetrexed therapy has been used as a standard therapeutic strategy for patients with advanced nonsquamous NSCLC.22 However, few studies have focused on cisplatin/pemetrexed with bevacizumab as the first-line therapy to treat advanced nonsquamous NSCLC. Similar studies have been analyzed, and we found the application of combination of pemetrexed/oxaliplatin and bevacizumab in patients with stage IV NSCLC and showed that the objective response rate was 55.3%. The median PFS and OS were 6.2 months and 14.6 months, respectively.23 However, in this study, the application of bevacizumab is combined with oxaliplatin and not with cisplatin. In addition, Barlesi et al24 demonstrated that in patients with nonsquamous NSCLC who had achieved disease control with platinum-based chemotherapy plus bevacizumab, bevacizumab plus pemetrexed maintenance was associated with a significant PFS benefit compared with bevacizumab alone. However, the study was not from the People’s Republic of China, and the study did not carry out subgroup analysis according to different gene mutation types. Hirai et al25 also retrospectively evaluated the feasibility of cisplatin/pemetrexed/bevacizumab therapy as a first-line chemotherapeutic strategy for patients with advanced nonsquamous NSCLC and clarified the effectiveness and tolerability of cisplatin/pemetrexed/bevacizumab therapy in patients with nonsquamous NSCLC. However, the study was also not from the People’s Republic of China, and the dose of bevacizumab was 15 mg/kg in this study. In our study, we mainly proved the effectiveness of cisplatin/pemetrexed/bevacizumab therapy in Chinese patients with nonsquamous NSCLC, irrespective of the gene drive type. In addition, the dose of bevacizumab that all the patients received was 7.5 mg/kg in our study. However, these are just a few case reports, and it requires a larger, randomized controlled trial to verify.\n\nThe discovery of EGFR mutations or ALK rearrangements has led to altered treatments for patients with NSCLC who harbor these drivers. Agents that inhibit the tyrosine kinase-binding sites have demonstrated improved PFS versus chemotherapy. However, the correlation between EGFR mutations or ALK rearrangements and the efficacy of bevacizumab in combination with chemotherapy warrants further analysis. The BEYOND trial showed the significance of high EGFR tyrosine kinase inhibitor in both arms after progression, but overall postprogression treatments were balanced in the EGFR mutation-positive group. EGFR mutation-positive tumor status seemed to be prognostic for a better prognosis regardless of treatment. The median PFS was 12.4 months with carboplatin/paclitaxel plus bevacizumab and 7.9 months with carboplatin/paclitaxel plus placebo in EGFR mutation-positive tumors and 8.3 months and 5.6 months in wild-type tumors, respectively.19 Interestingly, another study showed that ALK-positive patients had a significantly longer PFS on pemetrexed compared with EGFR or KRAS mutant patients in NSCLC. This conclusion suggested that pemetrexed should be preferentially considered for the treatment of ALK-positive lung adenocarcinoma.26 In our study, we chose three patients with different types of gene drives and found that the disease in the three patients was controlled. However, we also found the disease remission of the first patient is relatively slow compared to the other two patients. This phenomenon may be due to different driving genes. Of course, more clinical studies are needed for further clarification.\n\nThere are still some limitations in our report. First, at present, the patients in our report are still in the maintenance therapy, and the exact PFS or OS was not observed due to a short span of time. Second, in our report, we mainly evaluated the changes of the main mass in the lung. In fact, different degrees of lymph node metastasis were found in the three patients before treatment, and all these lymph node metastases get relieved to some extent after treatment.\n\nConclusion\nIn summary, based on the three cases and previous studies, cisplatin/pemetrexed/bevacizumab therapy can serve as a primary therapeutic strategy for patients with advanced nonsquamous NSCLC and with or without EGFR mutations or ALK rearrangements. More clinical studies are needed to further validate our hypothesis.\n\nAcknowledgments\nThis work was supported by the special fund for Scientific Research in Public Interest (201402011).\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Case 1.\n\nNotes: (A) Prior to therapy, chest CT scan shows a primary mass (arrow) in the right lung. (B) After two cycles of therapy, chest CT scan shows significant shrinkage of the mass (arrow). (C) After four cycles of therapy, chest CT scan shows further shrinkage of the mass (arrow), although not obvious.\n\nAbbreviation: CT, computed tomography.\n\nFigure 2 Case 2.\n\nNotes: (A) Prior to therapy, chest CT scan shows a major lung nodule (arrow) in the right lung. (B) After two cycles of therapy, chest CT scan shows significant shrinkage of the mass (arrow). (C) After four cycles of therapy, chest CT scan shows further shrinkage of the mass (arrow).\n\nAbbreviation: CT, computed tomography.\n\nFigure 3 Case 2.\n\nNotes: (A) Prior to therapy, brain MRI scan shows major brain metastasis nodules (arrow). (B and C) After two or four cycles of therapy, brain MRI scan shows significant shrinkage of the major brain metastasis nodules (arrow).\n\nAbbreviation: MRI, magnetic resonance imaging.\n\nFigure 4 Case 3.\n\nNotes: (A) Prior to therapy, chest CT scan shows a major lung mass (arrow) in the right lung. (B) After two cycles of therapy, chest CT scan shows significant shrinkage of the mass (arrow). (C) After four cycles of therapy, chest CT scan shows further shrinkage of the mass (arrow).\n\nAbbreviation: CT, computed tomography.\n\nTable 1 Clinical characteristics of different patients during the course of treatment\n\nVariable\tCase 1\tCase 2\tCase 3\t\nAge, years\t69\t52\t58\t\nSex\tMale\tFemale\tFemale\t\nStage\tIV\tIV\tIV\t\nSmoking\tYes\tNo\tNo\t\nPrimary tumor size (cm)\t\t\t\t\n Before treatment\t6.0×4.7\t1.8×1.2\t2.7×2.3\t\n After two cycles of therapy\t4.4×3.7\tShow not clear\t1.8×1.0\t\n After four cycles of therapy\t4.2×3.3\tShow not clear\t1.0×0.7\t\nPathological type\tAdenocarcinoma\tAdenocarcinoma\tAdenocarcinoma\t\nGene type\t\t\t\t\n EGFR\tWild type\tWild type\tExon 19 mutation\t\n ALK\tNegative\tPositive\tNegative\t\nCEA (ng/mL)\t\t\t\t\n Before treatment\t419.2\t119.9\t8.62\t\n After two cycles of therapy\t244.9\t25.03\t3.48\t\n After four cycles of therapy\t189.2\t14.63\t1.72\t\nResponse\t\t\t\t\n After two cycles of therapy\tPR\tCR\tPR\t\n After four cycles of therapy\tSD\tSD\tSD\t\nAbbreviations: EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; CEA, carcinoembryonic antigen; PR, progressive disease; CR, complete response; SD, stable disease.\n\nTable 2 Randomized controlled trials of bevacizumab plus chemotherapy\n\nStudy ID\tPublished year\tChemotherapy regimens\tResults\tResearch type\t\nSandler et al14\t2006\tPaclitaxel/carboplatin\tThe median survival was 12.3 months and 10.3 months (P=0.003). The median PFS was 6.2 months and 4.5 months (P<0.001)\tProspective study\t\nReck et al15\t2009\tCisplatin/gemcitabine\tThe PFS was 6.7 months and 6.1 months (P=0.003)\tProspective study\t\nReynolds et al16\t2009\tPaclitaxel/carboplatin\tMedian PFS was 9.8 months, and median survival was 16.8 months\tProspective study\t\nCrinò et al17\t2010\tPlatinum-based chemotherapy\tConfirm the manageable safety profile of first-line bevacizumab in combination with various standard chemotherapy regimens\tProspective study\t\nNiho et al18\t2012\tCarboplatin/paclitaxel\tThe median PFS was 6.9 months and 5.9 months (P=0.0090). Median OS was >22 months in both treatment groups (P=0.9526)\tProspective study\t\nZhou et al19\t2015\tCarboplatin/paclitaxel\tOS was 24.3 months and 17.7 months (P=0.0154). Median PFS was 12.4 months and 7.9 months (P<0.001)\tProspective study\t\nMir et al23\t2012\tPemetrexed/oxaliplatin\tThe median PFS and OS were 6.2 months and 14.6 months, respectively\tProspective study\t\nAbbreviations: PFS, progression-free survival; OS, overall survival.\n==== Refs\nReferences\n1 Jemal A Bray F Center MM Ferlay J Ward E Forman D Global cancer statistics CA Cancer J Clin 2011 61 2 69 90 21296855 \n2 Liu KJ Guan ZZ Liang Y A double-blind, randomized phase II study of dicycloplatin plus paclitaxel versus carboplatin plus paclitaxel as first-line therapy for patients with advanced non-small-cell lung cancers Arch Med Sci 2014 10 4 717 724 25276156 \n3 Stinchcombe TE Socinski MA Current treatments for advanced stage non-small cell lung cancer Proc Am Thorac Soc 2009 6 2 233 241 19349493 \n4 Hotta K Matsuo K Ueoka H Kiura K Tabata M Tanimoto M Addition of platinum compounds to a new agent in patients with advanced non-small-cell lung cancer: a literature based meta-analysis of randomised trials Ann Oncol 2004 15 12 1782 1789 15550583 \n5 Schiller JH Harrington D Belani CP Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer N Engl J Med 2002 346 2 92 98 11784875 \n6 Ohe Y Ohashi Y Kubota K Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan Ann Oncol 2007 18 2 317 323 17079694 \n7 Perez-Soler R Chachoua A Hammond LA Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer J Clin Oncol 2004 22 16 3238 3247 15310767 \n8 Kris MG Natale RB Herbst RS Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial JAMA 2003 290 16 2149 2158 14570950 \n9 Cohen MH Gootenberg J Keegan P Pazdur R FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer Oncologist 2007 12 6 713 718 17602060 \n10 Ferrara N Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications Semin Oncol 2002 29 suppl 16 10 14 12516033 \n11 Bergers G Benjamin LE Tumorigenesis and the angiogenic switch Nat Rev Cancer 2003 3 6 401 410 12778130 \n12 Jenab-Wolcott J Giantonio BJ Bevacizumab. current indications and future development for management of solid tumors Expert Opin Biol Ther 2009 9 4 507 517 19344286 \n13 Willett GG Boucher Y di Tomaso E Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer Nat Med 2004 10 2 145 147 14745444 \n14 Sandler A Gray R Perry MC Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer N Engl J Med 2006 355 24 2542 2550 17167137 \n15 Reck M von Pawel J Zatloukal P Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil J Clin Oncol 2009 27 8 1227 1234 19188680 \n16 Reynolds C Barrera D Jotte R Phase II trial of nanoparticle albumin-bound paclitaxel, carboplatin, and bevacizumab in first-line patients with advanced nonsquamous non-small cell lung cancer J Thorac Oncol 2009 4 12 1537 1543 19887966 \n17 Crinò L Dansin E Garrido P Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study Lancet Oncol 2010 11 8 733 740 20650686 \n18 Niho S Kunitoh H Nokihara H Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non squamous non-small-cell lung cancer. JO19907 Study Group Lung Cancer 2012 76 3 362 367 22244743 \n19 Zhou C Wu YL Chen G BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer J Clin Oncol 2015 33 19 2197 2204 26014294 \n20 Roodhart JM He H Daenen LG Notch1 regulates angio-supportive bone marrow-derived cells in mice: relevance to chemoresistance Blood 2013 122 1 143 153 23690447 \n21 Volk-Draper L Hall K Griggs C Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner Cancer Res 2014 74 19 5421 5434 25274031 \n22 Scagliotti GV Parikh P von Pawel J Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer J Clin Oncol 2008 26 21 3543 3551 18506025 \n23 Mir O Boudou-Rouquette P Giroux J Pemetrexed, oxaliplatin and bevacizumab as first-line treatment in patients with stage IV non-small cell lung cancer Lung Cancer 2012 77 1 104 109 22364783 \n24 Barlesi F Scherpereel A Rittmeyer A Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089) J Clin Oncol 2013 31 24 3004 3011 23835708 \n25 Hirai F Seto T Inamasu E Feasibility of cisplatin/pemetrexed with 15 mg/kg bevacizumab for the treatment of patients with advanced non-squamous non-small cell lung cancer Oncol Lett 2015 9 6 2577 2582 26137109 \n26 Camidge DR Kono SA Lu X Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed J Thorac Oncol 2011 6 4 774 780 21336183\n\n",
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"journal": "OncoTargets and therapy",
"keywords": "bevacizumab; case reports; cisplatin/pemetrexed; lung cancer",
"medline_ta": "Onco Targets Ther",
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"pages": "4639-44",
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"title": "Efficacy of cisplatin/pemetrexed with bevacizumab to treat advanced lung adenocarcinoma with different drive genes: case report and literature review.",
"title_normalized": "efficacy of cisplatin pemetrexed with bevacizumab to treat advanced lung adenocarcinoma with different drive genes case report and literature review"
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"abstract": "Mucorales organisms are an uncommon cause of invasive fungal infections after solid organ transplantation but are associated with great morbidity and mortality. We report a fatal case of disseminated Cunninghamella infection early after heart transplantation. The patient developed graft dysfunction and elevated markers of myocyte injury and autopsy revealed fulminant fungal myocarditis. This case highlights the need for a high index of suspicion in immunocompromised patients who are not improving with standard antimicrobial therapy.",
"affiliations": "Division of Infectious Disease, Department of Medicine, Tufts Medical Center, Boston, MA, USA.;Division of Cardiology, Department of Medicine, Tufts Medical Center, Boston, MA, USA.;Division of Cardiology, Department of Medicine, Tufts Medical Center, Boston, MA, USA.;Division of Infectious Disease, Department of Medicine, Tufts Medical Center, Boston, MA, USA.;Division of Cardiology, Department of Medicine, Tufts Medical Center, Boston, MA, USA.;Department of Pathology, Tufts Medical Center, Boston, MA, USA.;Division of Infectious Disease, Department of Medicine, Tufts Medical Center, Boston, MA, USA.;Division of Cardiology, Department of Medicine, Tufts Medical Center, Boston, MA, USA.;Division of Cardiology, Department of Medicine, Tufts Medical Center, Boston, MA, USA.",
"authors": "Margoles|Lindsay|L|;DeNofrio|David|D|;Patel|Ayan R|AR|;Golan|Yoav|Y|;Vest|Amanda R|AR|;Arkun|Knarik|K|;Boucher|Helen W|HW|;Kiernan|Michael S|MS|;Upshaw|Jenica N|JN|http://orcid.org/0000-0001-5801-5481",
"chemical_list": "D000935:Antifungal Agents",
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"doi": "10.1111/tid.12820",
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"issue": "20(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "fungal infections; heart transplantation; mucormycosis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000935:Antifungal Agents; D020093:Cunninghamella; D017809:Fatal Outcome; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D016867:Immunocompromised Host; D000072742:Invasive Fungal Infections; D008172:Lung Diseases, Fungal; D008297:Male; D008875:Middle Aged; D009091:Mucormycosis; D032342:Muscle Cells; D009205:Myocarditis; D009894:Opportunistic Infections",
"nlm_unique_id": "100883688",
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"title": "Disseminated mucormycosis masquerading as rejection early after orthotopic heart transplantation.",
"title_normalized": "disseminated mucormycosis masquerading as rejection early after orthotopic heart transplantation"
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"abstract": "CMV infection is one of the most common opportunistic infection in kidney transplant patients. If not treated, it is associated with increased mortality and graft loss. It can present as viremia or CMV disease in the form of CMV syndrome or tissue invasive CMV disease. The cutaneous presentation of CMV disease is a rare finding. Its identification is vital as cutaneous CMV infection can signal systemic infection and poor prognosis. In our case, 46-year-old male who was a post renal allograft recipient (RAR) presented as a protuberant growth over the medial side of the left ankle. On skin biopsy, nucleomegaly and inclusion bodies were seen in the epithelial cells. Immunohistochemistry was positive for CMV infection. Patient was treated with Ganciclovir, however, he succumbed to death because of severe sepsis due to secondary bacterial infection. Thus, CMV disease should always be kept in mind in immunocompromised patients like post RAR patients who present with cutaneous features like ulcerative lesions or fungating growth.",
"affiliations": "Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India.;Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India.;Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India.;Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India.;Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India.;Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India.;Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India.;Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India.;Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India.;Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India.",
"authors": "Bhandari|Gaurav|G|;Tiwari|Vaibhav|V|https://orcid.org/0000-0003-0128-0959;Gupta|Anurag|A|;Jain|Sunila|S|;Gupta|Pallav|P|;Bhargava|Vinant|V|;Malik|Manish|M|;Gupta|Ashwani|A|;Bhalla|Anil Kumar|AK|;Rana|Devender Singh|DS|",
"chemical_list": "D000998:Antiviral Agents; D015774:Ganciclovir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13590",
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"issue": "23(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "CMV; sepsis; skin infection; transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000998:Antiviral Agents; D003586:Cytomegalovirus Infections; D015774:Ganciclovir; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections",
"nlm_unique_id": "100883688",
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"references": null,
"title": "CMV presenting as a skin growth in renal transplant patient.",
"title_normalized": "cmv presenting as a skin growth in renal transplant patient"
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"abstract": "Hyperprogressive disease (HPD) has been recently proposed as a new pattern of progression in patients treated with immune checkpoint inhibitors (ICIs). Until now, no biological marker has been found to predict this accelerated tumour growth. We describe the case of a 62-year-old women who experienced a marked increase in absolute eosinophil count (AEC) concurrently with a huge radiological progression after the first nivolumab dose in absence of other immune-related adverse events (irAEs). Further investigations are needed to establish the role of early hypereosinophilia as a marker of progression and to identify patients who might not benefit from ICI treatment.",
"affiliations": "Medical Oncology Unit B, Policlinico Umberto I, \"Sapienza\" University of Rome, Viale Regina Elena 324, 00161, Rome, Italy. mario.occhipinti@uniroma1.it.;Medical Oncology Unit, Sant' Andrea Hospital, \"Sapienza\" University of Rome, Rome, Italy.;Medical Oncology Unit, Sant' Andrea Hospital, \"Sapienza\" University of Rome, Rome, Italy.;Medical Oncology Unit, Sant' Andrea Hospital, \"Sapienza\" University of Rome, Rome, Italy.",
"authors": "Occhipinti|Mario|M|http://orcid.org/0000-0002-7169-5343;Falcone|Rosa|R|;Onesti|Concetta Elisa|CE|;Marchetti|Paolo|P|",
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"fulltext": "\n==== Front\nDrug Saf Case RepDrug Saf Case RepDrug Safety - Case Reports2199-11622198-977XSpringer International Publishing Cham 295361857810.1007/s40800-018-0078-zCase ReportHyperprogressive Disease and Early Hypereosinophilia After Anti-PD-1 Treatment: A Case Report http://orcid.org/0000-0002-7169-5343Occhipinti Mario mario.occhipinti@uniroma1.it 1Falcone Rosa 2Onesti Concetta Elisa 2Marchetti Paolo 231 grid.7841.aMedical Oncology Unit B, Policlinico Umberto I, “Sapienza” University of Rome, Viale Regina Elena 324, 00161 Rome, Italy 2 grid.7841.aMedical Oncology Unit, Sant’ Andrea Hospital, “Sapienza” University of Rome, Rome, Italy 3 0000 0004 1758 0179grid.419457.aIstituto Dermopatico dell’Immacolata-IRCCS, Rome, Italy 13 3 2018 13 3 2018 12 2018 5 12© The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Hyperprogressive disease (HPD) has been recently proposed as a new pattern of progression in patients treated with immune checkpoint inhibitors (ICIs). Until now, no biological marker has been found to predict this accelerated tumour growth. We describe the case of a 62-year-old women who experienced a marked increase in absolute eosinophil count (AEC) concurrently with a huge radiological progression after the first nivolumab dose in absence of other immune-related adverse events (irAEs). Further investigations are needed to establish the role of early hypereosinophilia as a marker of progression and to identify patients who might not benefit from ICI treatment.\n\nissue-copyright-statement© The Author(s) 2018\n==== Body\nKey Points\n\nHyperprogressive disease (HPD) is a novel pattern of response during immune checkpoint inhibitor (ICI) treatment. Immune-related eosinophilia is a biological immune-related adverse effect with anti-programmed death 1 (anti-PD-1) or anti-programmed death ligand 1 (anti-PD-L1).\t\nIn this case report, anti-PD-1 administration resulted in a marked increase in absolute eosinophil count (AEC) concurrently with a huge radiological progression.\t\nEarly hypereosinophilia may be a negative predictive factor of ICIs treatment.\t\n\n\n\nIntroduction\nAnti-programmed death 1 (anti-PD-1) and anti-programmed death ligand 1 (anti-PD-L1) monoclonal antibodies (mAbs) are immune checkpoint inhibitors (ICIs) capable of restoring immunity against tumours and improving survival in several tumour types [1]. Nevertheless, some patients seem to not benefit from immunotherapy and, indeed, it seems that ICIs accelerate the drive towards progression. In fact, Champiat et al. documented a new pattern of rapid progression in patients treated with ICIs: hyperprogressive disease (HPD). It is defined as a RECIST (Response Evaluation Criteria In Solid Tumors) progression at the first evaluation and as a ≥ 2-fold increase of the tumour growth rate (TGR) between the reference (prior to treatment onset) and the experimental (between baseline and the first tumour evaluation) periods [2]. Kato et al. reported that patients with mouse double minute 2 homolog (MDM2) family amplifications appear to be at risk of accelerated progression after immunotherapy [3]. At present, biomarkers for outcome during immune-checkpoint blockade are not available and further research is strongly needed as these may influence individual treatment choice. Absolute eosinophil count (AEC) has been recently investigated as a new potential biomarker of outcome in patients affected by melanoma. An increase in the eosinophil count has been correlated with an improved overall survival in metastatic melanoma patients treated with ipilimumab, and recently it has been studied in patients during anti-PD-1/anti-PD-L1 treatment [4–8]. Bernard-Tessier et al. proposed immune-related eosinophilia as a new biological immune-related adverse effect with anti-PD-1 or anti-PD-L1 [8]. It has been defined as a clinically significant increase of AEC over 500 per mm3, in two samples at different times, during anti-PD1 or anti-PD-L1 treatment. We describe here the first case of a patient who experienced dramatic hyperprogressive disease and early elevation of AEC after the first dose of anti-PD-1 treatment.\n\nCase Report\nIn March 2015, a 60-year-old Caucasian female never smoker presented to the emergency department with fever and persistent cough. The chest X-ray and the subsequent CT scan showed a hilar lung mass on the upper left lobe, multiple hilar, para-tracheal, subcarinal and prevascular lymphadenopathies, bone pelvis and vertebral lesions. The histological examination, obtained by bronchoscopy, revealed a non-small-cell lung cancer (NSCLC), CK7+ and TTF1+ adenocarcinoma, EGFR wt, PD-L1 negative, ALK and ROS1 not rearranged. She was staged as cT3N3M1b (stage IV) according to the American Joint Committee on Cancer Staging Manual, 7th edition [9].\n\nFrom April 2015 to August 2015, the patient underwent first-line platinum 75 mg/m2 plus pemetrexed 500 mg/m2 chemotherapy given every 3 weeks for six cycles. The CT scan performed on August 2015 revealed a complete response on the lung mass and on lymphadenopathies and a bone stable disease. The patient continued maintenance treatment with pemetrexed until July 2016 when the surveillance CT scan showed an oligoprogression on the right adrenal gland with a 4-cm mass (SUV 25). In September 2016, the patient underwent right adrenalectomy (histological examination: NSCLC metastases) and continued maintenance pemetrexed until November 2016. The CT scan performed on December 2016 revealed disease progression on bone metastases, lymphadenopathies and a recurrence on the adrenalectomy site.\n\nThe patient started second-line treatment with docetaxel 75 mg/m2 plus nintedanib 200 mg twice a day every 3 weeks. She experienced AST/ALT grade 2 (G2) elevation and neutropenia grade 1 (G1). After the third cycle, the CT scan showed disease progression with new abdominal lymphadenopathies.\n\nAdministration of nivolumab 3 mg/kg every 2 weeks was started on 29 March 2017 and the patient had a good clinical status. One week after the first dose, laboratory tests revealed a marked increase in AEC of 10.7 × 103 (0.0–0.8) and moderate anaemia (Hb 8.4 g/dL). There were no other perturbations in laboratory tests (blood chemistry and endocrinological functions). The patient experienced fatigue (G1), no fever, no rash or any other immune-related adverse events (irAEs); stool sample was negative for parasites and heart evaluation was negative for any damage. A thorax CT scan, performed in order to exclude an eosinophilic pneumonia, revealed a lung recurrence on the upper left lobe (1.2 × 2 cm). The patient continued clinical observation and received the second nivolumab dose on 12 April 2017. A week later, the patient developed progressive fatigue and appetite loss; AEC was still increasing (12.3 × 103). The patient was hospitalized for severe anaemia and worsening clinical status. A CT scan was performed on 27 April with evidence of a further increase of the lung mass on upper left lobe (7.2 × 2.7 cm vs 1.2 × 2 cm), pleural effusion, several liver metastases and peritoneal carcinomatosis; because of the severe rapidly progressive anaemia, a gastroscopy was carried out showing multiple neoplastic gastric ulcerative lesions (Fig. 1). Despite the AEC decreasing (1.1 × 103), nivolumab treatment was discontinued as a result of clinical deterioration and radiological progression disease. The patient died 2 months after the last nivolumab dose.Fig.1 Endoscopic findings of multiple neoplastic gastric ulcerative lesions\n\n\n\n\nDiscussion\nHyperprogressive disease (HPD) has been observed in 9% of patients treated with anti-PD-1/PD-L1 [2]. It is associated with older age (≥ 65 years old) and worse overall survival. Tumour disease growth acceleration could be linked to the blockade of PD-1/PD-L1 signalling in combination with genetic cell alterations such as MDM2 family amplification. Kato et al. identified, among 155 patients during treatment with ICIs, a time-to-treatment failure (TTF) < 2 months in all six patients with MDM2/MDM4 amplification [3]. Moreover, mechanisms of adaptive resistance and tumour escape such as up-regulation of alternative immune checkpoints have been observed [10].\n\nIn literature, increase in AEC during treatment with ICIs has been reported as a favourable biomarker in metastatic melanoma patients [6, 7]. Recently, Bernard-Tessier et al. reported the first case series of immune-related eosinophilia during anti-PD-1/PD-L1 treatment, showing kinetics leucocyte changes restricted to the eosinophils lineage [8]. ICIs can lead to interferon (IFN)-γ elevation, which in turn activates JAK-STAT signalling, leading to the production of interferon-inducible chemokines [11, 12]. In particular, activation of the STAT1 pathway by IFN-γ, associated with the signalling triggered by tumour necrosis factor (TNF), is responsible for the induction of IFN-inducible chemokines CXCL9, CXCL10 and CXCL11 attracting TH1 cells [13]. In an animal tumour model study, authors observed that tumour-infiltrating eosinophils, activated by TH1 response, secrete chemokines, guiding CD8+ T cells to the tumour, resulting in tumour rejection and prolonged survival [14]. In addition, IFN-γ inhibits STAT6 signalling, influencing the TH2 response [13, 15]. The presence of an activated TH2 eosinophil response could sustain M2-like macrophages in tumours and promote an immunosuppressive and pro-tumour environment [16]. Hence, the activation and polarization of eosinophil response could predict tumour growth or tumour rejection.\n\nIn our case, the patient experienced dramatic hyperprogressive disease after the first dose of nivolumab according to Kato’s criteria, as TTF < 2 months, > 50% increase in tumour burden compared with pre-immunotherapy imaging and > 2-fold increase in progression pace (Fig. 2). Concurrently, she reported a marked increase in AEC. At that time, there was no clinical evidence of allergic manifestation, signs of parasitic infection, or other irAEs. No other medications were started before or after the first perfusion of nivolumab. Conversely to literature findings, we observed a negative association between the increase in AEC and the outcome.Fig.2 Changes in absolute eosinophil counts during nivolumab treatment. Arrows show nivolumab dose administration\n\n\n\n\nConclusions\nIn summary, this case reports an early eosinophilia after the first nivolumab infusion, spontaneously recovered. It occurred simultaneously with clinical deterioration of the patient and the radiologic finding of hyperprogressive disease. No other medical conditions could explain the aetiology of hypereosinophilia and only the time relation with nivolumab administration may suggest the causality. We can’t demonstrate the link between the early hypereosinophilia and the pattern of hyperprogression. Prospective studies are needed to determine the precise role of changes in AEC during treatment with ICIs and to clarify if the early presentation of hypereosinophilia may be a predictive factor of ICIs failure and of radiological and clinical hyperprogression.\n\nFunding\nMario Occhipinti, Rosa Falcone, Concetta Elisa Onesti and Paolo Marchetti declare that they have no sources of funding to disclose.\n\nConflicts of interest\nMario Occhipinti, Rosa Falcone, Concetta Elisa Onesti and Paolo Marchetti declare that they have no conflicts of interest to disclose.\n\nEthical approval\nAll procedures were in accordance with the 1964 Helsinki Declaration (and its amendments). No approval by ethical committee or institutional review board was required.\n\nInformed consent\nThe patient died in June 2017. Written informed consent was obtained from the husband of the patient for publication of the case.\n==== Refs\nReferences\n1. Lipson EJ Forde PM Hammers HJ Emens LA Taube JM Topalian SL Antagonists of PD-1 and PD-L1 in cancer treatment Semin Oncol 2015 42 4 587 600 10.1053/j.seminoncol.2015.05.013 26320063 \n2. Champiat S Dercle L Ammari S Hyperprogressive disease (HPD) is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1 Clin Cancer Res. 2017 23 8 1920 1928 10.1158/1078-0432.CCR-16-1741 27827313 \n3. Kato S Goodman A Walavalkar V Barkauskas DA Sharabi A Kurzrock R Hyper-progressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate Clin Cancer Res. 2017 23 15 4242 4250 10.1158/1078-0432.CCR-16-3133 28351930 \n4. Delyon J Mateus C Lefeuvre D Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival Ann Oncol. 2013 24 6 1697 1703 10.1093/annonc/mdt027 23439861 \n5. Moreira A Leisgang W Schuler G Heinzerling L Eosinophilic count as a biomarker for prognosis of melanoma patients and its importance in the response to immunotherapy Immunotherapy 2017 9 2 115 121 10.2217/imt-2016-0138 28128709 \n6. Weide B Martens A Hassel JC Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab Clin Cancer Res. 2016 22 22 5487 5496 10.1158/1078-0432.CCR-16-0127 27185375 \n7. Gaba L, Victoria I, Pineda E, et al. Changes in blood eosinophilia during anti-PD1 therapy as a predictor of long term disease control in metastatic melanoma. ASCO Meet Abstr. 2015;33(15_suppl):9069.\n8. Bernard-Tessier A Jeanville P Champiat S Immune-related eosinophilia induced by anti-programmed death 1 or death-ligand 1 antibodies Eur J Cancer 2017 81 135 137 10.1016/j.ejca.2017.05.017 28624693 \n9. Edge SB Byrd DR Compton CC Frits AG Greene FL Trotti A AJCC cancer staging manual 2010 7 New York Springer \n10. Koyama S Akbay EA Li YY Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints Nat Commun. 2016 7 10501 10.1038/ncomms10501 26883990 \n11. Peng W Liu C Xu C PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines Cancer Res. 2012 72 20 5209 5218 10.1158/0008-5472.CAN-12-1187 22915761 \n12. Schindler C Levy DE Decker T JAK-STAT signaling: from interferons to cytokines J Biol Chem. 2007 282 28 20059 20063 10.1074/jbc.R700016200 17502367 \n13. Liu LY Bates ME Jarjour NN Busse WW Bertics PJ Kelly EA Generation of Th1 and Th2 chemokines by human eosinophils: evidence for a critical role of TNF-α J Immunol. 2007 179 7 4840 4848 10.4049/jimmunol.179.7.4840 17878383 \n14. Carretero R Sektioglu IM Garbi N Salgado OC Beckhove P Hämmerling GJ Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8+ T cells Nat Immunol. 2015 16 6 609 617 10.1038/ni.3159 25915731 \n15. Huang Z Xin J Coleman J IFN- γ suppresses STAT6 phosphorylation by inhibiting its recruitment to the IL-4 receptor J Immunol. 2005 174 3 1332 1337 10.4049/jimmunol.174.3.1332 15661890 \n16. Wu D Molofsky AB Liang HE Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis Science 2011 332 6026 243 247 10.1126/science.1201475 21436399\n\n",
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"abstract": "Apatinib, one of the novel oral antiangiogenic agents, shows survival benefits in treating advanced or metastatic gastric adenocarcinoma. However, its efficacy in treating advanced head and neck neoplasms has not been reported. Herein, three elderly men with advanced head and neck neoplasms were treated with apatinib and S-1. Their initial diagnoses were hypopharyngeal carcinoma, metastatic squamous cell carcinoma of head and neck, and squamous cell carcinoma of the pyriform sinus. All patients underwent repeated chemotherapy but developed disease progression. As they refused radiotherapy due to its serious adverse reaction, apatinib was administered at a dose of 425 mg daily and S-1 at 60 mg twice daily. Thirty days after apatinib administration, the patients achieved partial response according to the Response Evaluation Criteria in Solid Tumors 1.1 standard. Mild toxicity or drug-related side effect was observed during the treatment. Therefore, apatinib and S-1 could be the new treatment option for advanced head and neck neoplasms. However, clinical trials are required to confirm their efficacy and safety.",
"affiliations": "Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.;Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.",
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"abstract": "Myocardial injury or infarction in the setting of anaphylaxis can be due to anaphylaxis itself, known as Kounis syndrome, or as a result of treatment with epinephrine. Myocardial ischemia caused by therapeutic doses of epinephrine in the setting of anaphylaxis is a rare event attributed to coronary artery vasospasm. A 41-year-old female with past medical history of recurrent costochondritis, chronic thrombocytopenia, and nonspecific palindromic rheumatism presented to the emergency department with perioral numbness, flushing and throat tightness after a meal containing fish and almonds. Intramuscular epinephrine was ordered but inadvertently administered intravenously, after which she developed sharp, substernal chest pain and palpitations. Electrocardiogram showed normal sinus rhythm with QT interval prolongation. Troponin peaked at 1.41 ng/mL. She was given 324 mg of aspirin in the emergency department. Transthoracic echocardiogram showed normal ejection fraction with lateral wall motion abnormality. We present a case of a patient with no significant risk factors for coronary artery disease who developed myocardial injury following inadvertent IV administration of a therapeutic dose of epinephrine for an anaphylactic-like reaction. The development of myocardial injury after epinephrine is rare, with only six reported cases in literature and just one after intravenous administration. This is the first described case of known myocardial injury without ST-T wave changes on electrocardiogram . The proposed mechanism is an alpha-1 receptor-mediated coronary vascular spasm resulting in myocardial ischemia. The aim of this case is to raise awareness of the potential for acute myocardial injury after inadvertent intravenous administration of epinephrine for anaphylaxis, even in patients with no known risk factors for coronary artery disease, as well as to demonstrate that this clinical scenario can present regardless of troponin elevation and without ST-T wave ECG changes.",
"affiliations": "Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.;Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, USA.;Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, USA.;Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, USA.",
"authors": "Zakka|Katerina|K|https://orcid.org/0000-0003-1498-6424;Gadi|Sneha|S|;Koshlelashvili|Nikoloz|N|;Maleque|Noble M|NM|https://orcid.org/0000-0002-9829-4662",
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"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X SAGE Publications Sage UK: London, England \n\n10.1177/2050313X20933104\n10.1177_2050313X20933104\nCase Report\nAcute myocardial injury after administration of intravenous epinephrine for allergic reaction\nhttps://orcid.org/0000-0003-1498-6424Zakka Katerina 1 Gadi Sneha 2 Koshlelashvili Nikoloz 2 https://orcid.org/0000-0002-9829-4662Maleque Noble M 2 1 Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA\n2 Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA, USA\nNoble M Maleque, Department of Internal Medicine, Emory University School of Medicine, 550 Peachtree St NE Atlanta, GA 30308, USA. Email: mmnoble@emory.edu\n17 6 2020 \n2020 \n8 2050313X2093310405 9 2019 13 5 2020 © The Author(s) 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Myocardial injury or infarction in the setting of anaphylaxis can be due to anaphylaxis itself, known as Kounis syndrome, or as a result of treatment with epinephrine. Myocardial ischemia caused by therapeutic doses of epinephrine in the setting of anaphylaxis is a rare event attributed to coronary artery vasospasm. A 41-year-old female with past medical history of recurrent costochondritis, chronic thrombocytopenia, and nonspecific palindromic rheumatism presented to the emergency department with perioral numbness, flushing and throat tightness after a meal containing fish and almonds. Intramuscular epinephrine was ordered but inadvertently administered intravenously, after which she developed sharp, substernal chest pain and palpitations. Electrocardiogram showed normal sinus rhythm with QT interval prolongation. Troponin peaked at 1.41 ng/mL. She was given 324 mg of aspirin in the emergency department. Transthoracic echocardiogram showed normal ejection fraction with lateral wall motion abnormality. We present a case of a patient with no significant risk factors for coronary artery disease who developed myocardial injury following inadvertent IV administration of a therapeutic dose of epinephrine for an anaphylactic-like reaction. The development of myocardial injury after epinephrine is rare, with only six reported cases in literature and just one after intravenous administration. This is the first described case of known myocardial injury without ST-T wave changes on electrocardiogram . The proposed mechanism is an alpha-1 receptor-mediated coronary vascular spasm resulting in myocardial ischemia. The aim of this case is to raise awareness of the potential for acute myocardial injury after inadvertent intravenous administration of epinephrine for anaphylaxis, even in patients with no known risk factors for coronary artery disease, as well as to demonstrate that this clinical scenario can present regardless of troponin elevation and without ST-T wave ECG changes.\n\nMyocardial injuryepinephrineanaphylaxisallergic reactioncover-dateJanuary-December 2020typesetterts1\n==== Body\nBackground\nMyocardial injury in the setting of anaphylaxis can be due to the anaphylaxis itself in an entity known as Kounis syndrome or epinephrine treatment.1 Kounis syndrome is an acute coronary syndrome occurring in association with conditions that involve mast cell activation and in turn chemical mediators that induce coronary vasospasm resulting in myocardial ischemia and infarction.1 Myocardial ischemia caused by therapeutic doses of epinephrine in the setting of anaphylaxis is a rare event and is thought to be due to coronary artery vasospasm.2 In addition to coronary artery vasospasm, mast cell–derived mediators and epinephrine can cause platelet aggregation leading to thrombotic occlusion of coronary arteries.3\n\nEpinephrine is lifesaving in the treatment of anaphylaxis. It is recommended to give an intramuscular injection of epinephrine 1:1000 up to a maximum dose of 0.5 mg over 5 minutes and to repeat doses after 15 minutes if there is no clinical improvement.4 Epinephrine is considered safe for the management of anaphylaxis when given at the correct dose by the intramuscular (IM) route. The intravenous (IV) route of administration is less often used in anaphylaxis. The majority of cardiovascular adverse events occur when epinephrine is given intravenously or incorrectly dosed.5 We report a case in which a therapeutic dose of intravenous epinephrine was used to treat anaphylaxis-like symptoms resulting in an increase in cardiac biomarkers and regional wall motion abnormalities on resting transthoracic echocardiogram but without changes in the electrocardiogram, likely as a result of epinephrine-induced coronary vasospasm.\n\nCase description\nA 41-year-old female presented to the emergency department (ED) with anaphylaxis-like symptoms shortly after eating fish and almonds. This was the second ED visit within two days for the same complaint. During her previous visit, she was treated with prednisone 60 mg, famotidine 20 mg, and diphenhydramine 25 mg in the ED with clinical improvement, and was discharged on cetirizine 10 mg daily, prednisone 20 mg daily, and famotidine 20 mg daily. Complete blood count was pertinent for mild thrombocytopenia (platelet count = 125,000/microliter). Basic metabolic panel was unremarkable. Electrocardiogram (ECG) (Figure 1) showed normal sinus rhythm, and chest X-ray was unremarkable for an acute cardiopulmonary process. During her second visit to the ED for the same complaint, the patient had facial flushing but no rash or shortness of breath. She reported nausea, perioral numbness, flushing, tingling, and throat tightness. She denied any chest pain, cough, swelling, or loss of consciousness.\n\nFigure 1. Electrocardiogram (ECG) at presentation (17:55 pm). Normal sinus rhythm. Normal ECG. Vent. Rate 80 bpm, PR interval 134 ms, QRS duration 88 ms, QT/QTc 404/465 ms, P-R-T axes 74 88 45.\n\nHer past medical history is pertinent to costochondritis, chronic thrombocytopenia, and a nonspecific palindromic rheumatism. She has a history of mild allergic reaction to trimethoprim-sulfamethoxazole and H1 N1 vaccine, but never to food. She has no history of asthma, seasonal allergies or eczema. Family history was pertinent to early cardiac death in a cousin, but no atopy. She has no history of tobacco or drug use and drinks alcohol on social occasions.\n\nHer vital signs upon presentation were the following: blood pressure 137/92 mm Hg, heart rate 90 beats per minute (bpm), temperature 36.2°C, respiratory rate 17 breaths/minute, oxygen saturation of 100% on room air, and a body mass index of 19.2 kg/m2. Physical examination revealed a well-appearing woman of stated age in no respiratory distress. She had no swelling in the eyelids/lips/cheeks/tongue, no drooling, no stridor, and no voice changes. Cardiovascular and pulmonary examination was normal. There was no rash on examination of her skin. The rest of the examination was otherwise normal. She was given prednisone 60 mg and diphenhydramine 25 mg, and IM epinephrine was ordered as initial therapy but she was inadvertently administered IV epinephrine (0.3 mg). Shortly after this dose, she developed sharp central chest pain and palpitations, with a maximum heart rate of 99 bpm. Results of an ECG revealed normal sinus rhythm, QTc prolongation, and no ST-T wave changes (Figure 2). She received one dose of aspirin (324 mg). Increased severity of her chest pain improved over the course of two hours, after which she described her chest pain as similar to that of her previous episodes of costochondritis. She denied any previous chest pain with exertion. In addition to the previous lab tests performed, a serum TSH, d-dimer, lipid panel, and urinalysis were performed and were normal. Her labs were significant for mild thrombocytopenia (platelets = 131,000), glucose 149 mg/dL, and troponin 0.05 ng/mL (normal: < 0.03 ng/mL). Serial troponins were performed with peak troponin of 1.41 ng/mL (Table 1). A third ECG was performed, which demonstrated normal sinus rhythm with sinus arrhythmia, rightward axis, and no ST-T wave changes (Figure 3).\n\nFigure 2. ECG after IV administration of epinephrine (18:26 pm). Normal sinus rhythm. Prolonged QT. Abnormal ECG. Vent. Rate 91 bpm, PR interval 122 ms, QRS duration 98 ms, QT/QTc 392/482 ms, P-R-T axes 83 87 50.\n\nTable 1. Troponin trend.\n\nTime\tTroponin I (ng/mL) (normal value < 0.03)\t\n18:40 pm\t0.05\t\n22:09 pm\t0.98\t\n00:09 am\t1.04\t\n04:32 am\t1.30\t\n06:32 am\t1.41 (peak)\t\n08:04 am\t1.34\t\nFigure 3. ECG after IV administration of epinephrine (08:23 am). Normal sinus rhythm with sinus arrhythmias. Rightward axis. Borderline ECG. Vent. Rate 86 bpm, PR interval 134 ms, QRS duration 88 ms, QT/QTc 362/433 ms, P-R-T axes 75 91 72.\n\nThe patient was admitted to hospital for observation. Due to the patient’s age, lack of cardiac risk factors, close correlation between her symptoms and the administration of epinephrine, and ECG with no ST-T wave changes, the consulting cardiology team concluded that plaque rupture was unlikely to be the etiology of the patient’s symptoms. She was started on aspirin 81 mg daily. A transthoracic echocardiogram (TTE) was done twenty hours after symptoms started to evaluate for structural heart disease that may have predisposed the patient. Her cardiac echocardiogram showed a normal left ventricular size measuring 4.9 cm, low-normal left ventricular ejection fraction (50%), elevated right atrial pressure (dilated inferior vena cava, with respiratory size variation less than 50%), and left ventricle lateral wall abnormality (Figure 4;. https://www.youtube.com/watch?v=soLXgVLXppU).\n\nFigure 4. Transthoracic echocardiogram (TTE) video clip demonstrating left ventricle lateral wall abnormality.\n\nThe left ventricle’s mid-inferolateral segment and mid-anterolateral segment were akinetic, and the mid-inferior segment was hypokinetic. Given these findings, a coronary computed tomography angiography (CCTA) or nuclear perfusion stress test was recommended; however, the patient declined testing and was discharged home with plans to do further workup in the outpatient setting.\n\nDiscussion\nEpinephrine-induced myocardial ischemia in the setting of treatment of anaphylaxis has been reported on rare occasions. To date, six cases were reported where therapeutic doses of epinephrine had caused myocardial infarction.1 Out of these reports one was after IV injection, two after IM injection, and three after subcutaneous injection. It has been suggested that patients with multiple risk factors for coronary artery disease (CAD) may be more susceptible to complications of epinephrine injection.6 However, the six case reports were of relatively young individuals without risk factors for CAD, as was the case in this report. The patients of the six case reports all developed myocardial infarction after the use of epinephrine with ST wave changes detected on ECG, which was not seen in our patient.\n\nExperimentally, epinephrine is known to induce spasm in susceptible patients, and has been used to diagnose Prinzmetal’s angina.7 Epinephrine has a high affinity for beta-1/beta-2 receptors at low doses and alpha-1/alpha-2 receptors at higher doses in cardiac and smooth muscles of the vascular walls.8 Stimulation of beta-1/beta-2 receptors leads to increased cardiac contractility, rate, and dilates coronary arteries, whereas alpha-1/alpha-2 receptors mediate vasoconstriction including that of the coronary vasculature.8\n\nThis patient is a 41-year-old relatively healthy female who did not have any modifiable or non-modifiable risk factors for CAD. She developed chest pain few minutes after administration of epinephrine. There were no ECG changes; however, cardiac biomarkers increased and left ventricle lateral wall abnormalities were seen on echocardiogram. Mechanisms of microvascular myocardial infarction with non-obstructive coronary arteries involve microvascular coronary spasm, Takotsubo syndrome, myocarditis, and coronary thromboembolism.9 We believe this temporal relationship is more in favor of epinephrine as the cause of chest pain and myocardial injury rather than Kounis syndrome since the patient was treated for anaphylaxis in a previous admission with antihistamines, and her chest pain did not begin until after administration of epinephrine. The patient denied chest pain with her allergic symptoms, and the nature of the chest pain changed dramatically after the administration of epinephrine into a “sharp, pressing” pain. The postulated mechanism is an alpha-1 receptor-mediated coronary vascular spasm. In addition, it is unlikely that the patient experienced coronary vasospasm secondary to Takotsubo since the characteristic apical left ventricle ballooning10 was not seen on initial TTE. Furthermore, Takotsubo is associated with electrocardiogram changes mimicking a myocardial infarction of the anterior wall,10 which also was not seen in our patient.”\n\nThe most likely cause of the anaphylaxis-like reaction was the fish and/or almonds due to the temporal relationship of the symptoms beginning shortly after ingestion. The use of epinephrine in this case is debatable as there were no respiratory symptoms at presentation. However, some authors have suggested that emergency physicians should be treating more patients with anaphylaxis with the use of epinephrine.11 Although most documented adverse events have been associated with IV administration,12 opinions differ on the use of IV epinephrine for anaphylaxis. Brown et al. used it successfully in anaphylaxis secondary to insect stings.13 It is also considered to be a preferred route in some instances where an IV line is in place (e.g. during surgery), but potential lethal arrhythmias have been seen with IV epinephrine, thus careful monitoring is encouraged.14 Overall, the recommendation is to use IM epinephrine as the preferred route of administration. Although IM epinephrine was ordered in our case, IV epinephrine was inadvertently given. Ultimately, this patient did well clinically and will likely not have any permanent sequelae. Patient had repeat echocardiogram one month post discharge with the resolution of wall motion abnormality, and a nuclear stress test showed no coronary ischemia six months post discharge.\n\nPatients at the risk of developing coronary artery spasms following the administration of epinephrine is an area that is understudied. Old age, preexisting CAD, and the use of beta blocker were some of the risk factors for epinephrine-induced myocardial ischemia reported in the literature.11,15,16 Even though myocardial injury could occur on rare occasions with therapeutic doses of epinephrine, this should not discourage the early use of epinephrine as a lifesaving medication in anaphylaxis. The physician should be made aware of this potential adverse effect of epinephrine in this clinical setting and take the remediable steps if necessary.\n\nConclusion\nThis case report describes the first reported case of cardiac complications with IV epinephrine without ischemic findings on electrocardiogram. Epinephrine is still the mainstay of the treatment of anaphylaxis but we hope physicians will be aware of this potential adverse effect, which can occur in patients with no risk factors for CAD in the acute setting.\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\nEthics approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent for patient information and images to be published was provided by the patient on 8 September 2018. Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iDs: Katerina Zakka \nhttps://orcid.org/0000-0003-1498-6424\n\nNoble M Maleque \nhttps://orcid.org/0000-0002-9829-4662\n==== Refs\nReferences\n1 \nJayamali WD Herath H Kulathunga A. \nMyocardial infarction during anaphylaxis in a young healthy male with normal coronary arteries—is epinephrine the culprit?\n\nBMC Cardiovasc Disord \n2017 ; 17 (1 ): 237 .28870153 \n2 \nSenthilkumaran S David SS Jena NN , et al\nEpinephrine-induced myocardial infarction in severe anaphylaxis: is beta-blocker a bad actor or bystander?\n\nAm J Emerg Med \n2013 ; 31 (9 ): 1410 .\n3 \nTummala K Maniyal VK Chandrashekaran R , et al\nCardiac anaphylaxis: a case of acute ST-segment elevation myocardial infarction after IM epinephrine for anaphylactic shock\n. Am J Emerg Med \n2013 ; 31 (7 ): 1157 .\n4 \nSimons FER Ardusso LRF Bilò MB , et al\nWorld allergy organization guidelines for the assessment and management of anaphylaxis\n. World Allergy Organ J \n2011 ; 4 (2 ): 13 –37\n.23268454 \n5 \nWood JP Traub SJ Lipinski C. \nSafety of epinephrine for anaphylaxis in the emergency setting\n. World J Emerg Med \n2013 ; 4 (4 ): 245 –251\n.25215127 \n6 \nRubio Caballero JA Oteo DomÃ-nguez JF Maicas Bellido C , et al\n[An adrenaline-induced vasospasm as the form of presentation of variant angina]\n. Rev Esp Cardiol \n1999 ; 52 (4 ): 273 –276\n.10217970 \n7 \nYasue H Touyama M Kato H , et al\nPrinzmetal’s variant form of angina as a manifestation of alpha-adrenergic receptor-mediated coronary artery spasm: documentation by coronary arteriography\n. Am Heart J \n1976 ; 91 (2 ): 148 –155\n.813507 \n8 \nOvergaard CB Dzavik V. \nInotropes and vasopressors: review of physiology and clinical use in cardiovascular disease\n. Circulation \n2008 ; 118 (10 ): 1047 –1056\n.18765387 \n9 \nVidal-Perez R Abou Jokh Casas C Agra-Bermejo RM , et al\nMyocardial infarction with non-obstructive coronary arteries: a comprehensive review and future research directions\n. World J Cardiol \n2019 ; 11 (12 ): 305 –315\n.31908730 \n10 \nGianni M Dentali F Grandi AM , et al\nApical ballooning syndrome or takotsubo cardiomyopathy: a systematic review\n. European Heart Journal \n2006 ; 27 (13 ): 1523 –1529\n.16720686 \n11 \nMcLean-Tooke AP Bethune CA Fay AC , et al\nAdrenaline in the treatment of anaphylaxis: what is the evidence?\n\nBMJ \n2003 ; 327 (7427 ): 1332 –1335\n.14656845 \n12 \nCampbell RL Bellolio MF Knutson BD , et al\nEpinephrine in anaphylaxis: higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine\n. J Allergy Clin Immunol Pract \n2015 ; 3 (1 ): 76 –80\n.25577622 \n13 \nBrown SG Blackman KE Stenlake V , et al\nInsect sting anaphylaxis; prospective evaluation of treatment with intravenous adrenaline and volume resuscitation\n. Emerg Med J \n2004 ; 21 (2 ): 149 –154\n.14988337 \n14 \nKarns JL. \nEpinephrine-induced potentially lethal arrhythmia during arthroscopic shoulder surgery: a case report\n. AANA J \n1999 ; 67 (5 ): 419 –421\n.10876433 \n15 \nLieberman P Simons FE. \nAnaphylaxis and cardiovascular disease: therapeutic dilemmas\n. Clin Exp Allergy \n2015 ; 45 (8 ): 1288 –1295\n.25711241 \n16 \nLang DM. \nAnaphylactoid and anaphylactic reactions. Hazards of beta-blockers\n. Drug Saf \n1995 ; 12 (5 ): 299 –304\n.7669259\n\n",
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"title": "Acute myocardial injury after administration of intravenous epinephrine for allergic reaction.",
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"abstract": "Haemophagocytic lymphohistiocytosis (HLH) is an uncommon but serious systemic inflammatory response with high mortality rates. It can be triggered by malignancy or infectious agents, often in the context of immunosuppression. Literature covering HLH in heart transplantation (HTx) is scarce.\nA 25-year-old male with a history of celiac disease underwent HTx at Sahlgrenska Hospital in 2011 due to giant cell myocarditis and was treated with tacrolimus, mycophenolate mofetil (MMF), and prednisolone. He developed several episodes of acute cellular rejections (ACR) during the first 3 post-HTx years, which subsided after addition of everolimus. In May 2017, the patient was admitted to the hospital due to fever without focal symptoms. He had an extensive inflammatory reaction, but screening for infectious agents was negative. Haemophagocytic lymphohistiocytosis was discussed early, but first dismissed since two bone marrow biopsies revealed no signs of haemophagocytosis. Increasing levels of soluble IL-2 were considered confirmative of the diagnosis. Even with intense immunosuppressant treatment, the patient deteriorated and died in progressive multiorgan failure within 2 weeks of the symptom onset.\nA 25-year-old HTx recipient with an extensive inflammatory response, fulfilled criteria for HLH, but the diagnosis was delayed due to normal bone marrow biopsies. A background with autoimmune reactivity and immunosuppressive therapy may have contributed to HLH, but the actual trigger was not identified. Haemophagocytic lymphohistiocytosis can occur in HTx recipients in the absence of malignancy, identifiable infectious triggers and signs of haemophagocytosis. Early diagnosis and intervention are likely to be of importance for a favourable outcome.",
"affiliations": "Department of Transplant Institute, Sahlgrenska University Hospital, SE-413 25, Gothenburg, Sweden.;Department of Transplant Institute, Sahlgrenska University Hospital, SE-413 25, Gothenburg, Sweden.;Department of Transplant Institute, Sahlgrenska University Hospital, SE-413 25, Gothenburg, Sweden.",
"authors": "Danielsson|Christian|C|0000-0003-3184-1833;Karason|Kristjan|K|0000-0002-2802-1191;Dellgren|Göran|G|0000-0003-4961-9704",
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"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119 Oxford University Press \n\n10.1093/ehjcr/ytaa070\nytaa070\nCase Reports\nOther\nHaemophagocytic lymphohistiocytosis after heart transplantation: a case report\nhttp://orcid.org/0000-0003-3184-1833Danielsson Christian y1 http://orcid.org/0000-0002-2802-1191Karason Kristjan y1y2 http://orcid.org/0000-0003-4961-9704Dellgren Göran y1y3y4 Cameli Matteo Handling Editor Nistor Dan Octavian Editor Miglioranza Marcelo Haertel Editor Simovic Stefan Editor Patel Peysh A. Editor y1 \nDepartment of Transplant Institute, Sahlgrenska University Hospital, SE-413 25, Gothenburg, Sweden\ny2 \nDepartment of Cardiology, Sahlgrenska University Hospital, SE-413 25, Gothenburg, Sweden\ny3 \nDepartment of Cardiothoracic Surgery, Sahlgrenska University Hospital, SE-413 25, Gothenburg, Sweden\ny4 \nDepartment of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 90 Gothenburg, Sweden\n Corresponding author. Tel: +46 31 342 26 21, Email: christian.danielsson@vgregion.se\n6 2020 \n03 5 2020 \n03 5 2020 \n4 3 1 4\n20 9 2019 29 10 2019 12 3 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.2020 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nHaemophagocytic lymphohistiocytosis (HLH) is an uncommon but serious systemic inflammatory response with high mortality rates. It can be triggered by malignancy or infectious agents, often in the context of immunosuppression. Literature covering HLH in heart transplantation (HTx) is scarce.\n\nCase summary\nA 25-year-old male with a history of celiac disease underwent HTx at Sahlgrenska Hospital in 2011 due to giant cell myocarditis and was treated with tacrolimus, mycophenolate mofetil (MMF), and prednisolone. He developed several episodes of acute cellular rejections (ACR) during the first 3 post-HTx years, which subsided after addition of everolimus. In May 2017, the patient was admitted to the hospital due to fever without focal symptoms. He had an extensive inflammatory reaction, but screening for infectious agents was negative. Haemophagocytic lymphohistiocytosis was discussed early, but first dismissed since two bone marrow biopsies revealed no signs of haemophagocytosis. Increasing levels of soluble IL-2 were considered confirmative of the diagnosis. Even with intense immunosuppressant treatment, the patient deteriorated and died in progressive multiorgan failure within 2 weeks of the symptom onset.\n\nDiscussion\nA 25-year-old HTx recipient with an extensive inflammatory response, fulfilled criteria for HLH, but the diagnosis was delayed due to normal bone marrow biopsies. A background with autoimmune reactivity and immunosuppressive therapy may have contributed to HLH, but the actual trigger was not identified. Haemophagocytic lymphohistiocytosis can occur in HTx recipients in the absence of malignancy, identifiable infectious triggers and signs of haemophagocytosis. Early diagnosis and intervention are likely to be of importance for a favourable outcome.\n\nHeart transplantationHaemophagocytic syndromeHaemophagocytic LymphohistiocytosisCase reportSwedish Heart and Lung Foundation20160671ALF/LUAALFGBG-21431Sahlgrenska Academy and University Hospital\n==== Body\nLearning points\nHaemophagocytic lymphohistiocytosis (HLH) is an uncommon but serious systemic inflammatory response with high mortality rates.\n\nHaemophagocytic lymphohistiocytosis can occur in heart transplant recipients in the absence of malignancy, identifiable infectious triggers and signs of haemophagocytosis.\n\nOn suspicion of HLH a bone marrow biopsy should be performed according to the HLH 2004 protocol, but a negative find is not sufficient to rule out the diagnosis.\n\n\n\n\nIntroduction\nHaemophagocytic lymphohistiocytosis (HLH), or haemophagocytic syndrome, is an uncommon but serious systemic inflammatory response with mortality rates of around 50% when occurring in recipients of solid organ transplants.1 It can occur as a primary form where genetic factors contribute to a dysfunctional immune system, or as a secondary reactive variant, when infections or malignancy may act as triggers, often in the context of immunosuppression. It is characterized by a dysfunctional activation of morphologically benign histiocytes with subsequent haemophagocytosis. Clinical manifestations include high fever, pancytopenia, and hepatosplenomegaly, while common laboratory findings consist of high levels of ferritin, hypertriglyceridaemia, and increased soluble CD25 (α-chain of IL-2 receptor).2,3\n\nTimeline\n2011–2013\tOrthotopic heart transplantation due to giant cell myocarditis.\t\n\tSeveral episodes of treatment-requiring acute cellular rejections (ACR) leading to more potent immunosuppressive regimen.\t\n\tPacemaker due to 3rd degree atrioventricular block.\t\n2017\t\nBeginning of May\tFever and malaise at home, initially interpreted as common cold.\t\n8–14 May\tProgressing symptoms and admission to local infection clinic.\t\n\tHaemophagocytic lymphohistiocytosis (HLH) suspected but bone marrow biopsy is negative shifting diagnostic focus.\t\n14 May\tProgressing renal and heart failure. Transported to Sahlgrenska University Hospital for myocardial biopsies.\t\n15 May\tMyocardial biopsies without signs of ACR. Haemophagocytic lymphohistiocytosis once again suspected leading to a second bone marrow biopsy.\t\n16 May\tClinical deterioration, empiric HLH treatment is added.\t\n\tSecond bone marrow biopsy negative but results from IL 2-receptor analysis considered confirmative of HLH diagnosis.\t\n17 May\tMassive organ failure and intense treatment efforts. Patient dies.\t\nCase presentation\nA 25-year-old male with a history of celiac disease underwent heart transplantation at the Sahlgrenska University Hospital in 2011 due to giant cell myocarditis. He was placed on an immunosuppressive regimen comprised of tacrolimus, MMF, and prednisolone. Rejection surveillance with endomyocardial biopsies was performed according to a protocol during the first year and, thereafter, only on indication. During the first 3 post-transplant years the patient developed several treatment-requiring episodes of acute cellular rejections, but this subsided when the immunosuppressive maintenance protocol was intensified with everolimus. In 2013, a routine electrocardiogram revealed atrioventricular (AV) block III and the patient received a pacemaker. Over the following years, there were no further significant complications and graft function remained essentially intact.\n\nIn the beginning of May 2017, the patient developed a fever without any focal symptoms. After a week at home without improvement, he was admitted to the local infection clinic and underwent extensive screening for potential infectious causes. Laboratory tests showed an extensive inflammatory reaction, but screening for a wide array of viral causes with real-time PCR, as well as bacterial cultures, were negative. Electrocardiogram from May 2017 revealed a biological sinus tachycardia with a rate of 108 and supraventricular extrasystoles. Further, a QRS morphology consistent with right bundle branch block (RBBB) and left anterior fascicular block (LAFB), and high QRS amplitudes in the limb leads indicating left ventricular hypertrophy. Initial chest X-rays were unremarkable, and an abdominal ultrasound showed no signs of organomegaly. Serum concentrations of immunosuppressive drugs were adequate. In the absence of an apparent infectious cause, intravenous hydrocortisone was added to the treatment to counteract the inflammation.\n\nDue to the presence of pancytopenia [Hb 97 g/L (134–170), WBC 2.1 × 109/L,3–7 platelet count 139 × 109/L (145–348)], elevated ferritin levels [1378 µg/L (30–400)], hypertriglyceridaemia [4.1 mmol/L (0.45–2.6)] and decreased fibrinogen [1.37 g/L (1.8–3.8)], also HLH was considered a differential diagnosis at this early stage. However, since a bone marrow biopsy showed no obvious signs of haemophagocytosis the investigative focus shifted towards other possible explanations. Empiric treatment with wide spectrum antibiotics (cefotaxime) was initiated. Despite the current treatment, the patient’s condition continued to deteriorate. Due to worsening heart and renal function the patient was transferred to the local cardiology clinic, and owing to a growing suspicion of an acute allograft rejection, he was transported to the Sahlgrenska University Hospital for further evaluation and treatment.\n\nAt the Sahlgrenska hospital, echocardiography showed impaired systolic graft function (ejection fraction = 35%) but myocardial biopsies showed no signs of rejection. Persisting pancytopenia and further elevation of ferritin and triglycerides once again highlighted HLH. A second bone marrow sample still revealed no signs of haemophagocytosis, but the levels of soluble IL-2 where clearly elevated [6000 U/mL (45–1100)], which was considered confirmative of HLH. Due to respiratory deterioration the patient was transferred to the cardiothoracic intensive care unit and received mechanical ventilation. He was treated with intravenous betamethasone and human immunoglobulin (KIOVIG). Herpes simplex (HSV) 1 virus was detected with PCR analyses of serum (log 2.48) and treatment with acyclovir was added. At this stage, the patient exhibited severe deterioration with the development of pulmonary oedema and circulatory shock. He was placed in veno-venous extracorporeal membrane oxygenation (ECMO), but a progressive multiorgan failure could not be reversed and the patient died 2 weeks after the initial onset of symptoms.\n\nDiscussion\nWe describe a case of HLH in a heart transplant recipient with a fatal outcome. Haemophagocytic lymphohistiocytosis is a rare disorder and only a handful of case studies in heart transplanted patients have been reported previously.1,4–6,8 In our case, a timely diagnosis was challenging and response to treatment was poor. We therefore believe that our experience can add to the existing base of knowledge.\n\nThe first diagnostic guidelines for HLH where published in 1991 and have since then developed into the HLH-2004 protocol (Table 1), which today is the most widely used diagnostic guideline in clinical practice for adults.7 On suspicion, the diagnostic importance of finding haemophagocytosis in bone marrow samples has been emphasized, also in heart transplant recipients.1 Even though our patient at an early stage fulfilled five of eight criteria, sufficient for identifying HLH, the diagnosis was delayed due to negative bone marrow biopsies shifting the focus to other serious conditions more frequently occurring in this patient population. The presence of haemophagocytosis in bone marrow has actually been shown to have a limited predictive value for the HLH diagnosis,9 but may still be of importance to rule out other causes of cytopenias.10 Burns et al.4 describes similar problems with identifying the underlying cause behind the HLH in their case, although it is described as almost certainly infection associated. Reactive HLH is most often associated with virus infections, where the strongest aetiological connection has been drawn to herpes viruses, especially Epstein-Barr virus (EBV).4 Previous cases of HLH in heart transplanted patients reaffirm this.5,8 However, in our case the only viral analysis with positive outcome was a HSV-1 PCR, but since the log was only 2.18, we find it unlikely to be the trigger.\n\n\nTable 1 Diagnostic criteria for reactive haemophagocytic lymphohistiocytosis according to the HLH 2004 protocol\n\n\n\nFever\n\n\n\n\t\n\nSplenomegaly\n\n\n\t\n\n\nCytopenia affecting ≥ 2 lineages of peripheral blood cells:\n\nAnaemia (haemoglobin < 90 g/L)\n\n\nThrombocytopenia (<100 × 109/L)\n\n\nNeutropenia (<1.0 × 109/L)\n\n\n\n\n\n\t\n\n\nHypertriglyceridaemia (<3.0 mmol/L, fasting value) and/or hypofibrinogenaemia (1.5 g/L)\n\n\n\t\n\n\nHyperferritinemia (≥500 mg/L)\n\n\n\t\n\nLow or absent natural killer cell activity\n\n\n\t\n\n\nElevated soluble IL-2 receptor levels(>2400 U/mL)\n\n\n\t\n\nHaemophagocytosis in bone marrow, spleen or lymph nodes\n\n\n\t\nAt least five out of the eight criteria must be fulfilled for the diagnosis. No evidence of malignancy must be present.\n\nThe table also shows which diagnostic criteria the patient in this case report fulfilled (italics).\n\nThe rarity of HLH, the lack of specific laboratory or clinical tests and the variability in clinical manifestation often contribute to a diagnostic delay. Most cases of HLH do however warrant an early and aggressive treatment for favourable outcomes. Upon high clinical suspicion of HLH, treatment should therefore begin early, even though diagnostic tests are not finished. The main principle of HLH treatment is to supress life-threatening inflammation, and the current recommendation for induction therapy comprises betamethasone and etoposide. It is also essential to try to identify and treat any underlying triggering condition. Prophylactic treatment for opportunistic infections, immunoglobulin supplementation, and careful monitoring for improvement or deterioration are needed. If the patient recovers after an 8-week induction period, the HLH treatment can be weaned off. In case of no improvement, treatment continues as a bridge to allogeneic haematopoietic stem cell transplantation.11\n\nIn summary, even though the patient in an early stage fulfilled necessary criteria to identify HLH, a definitive diagnosis was delayed due to the absence of haemophagocytosis in a bone marrow biopsy (Figure 1). Moreover, neither biopsies nor other investigations could provide an answer to the underlying cause, leaving us unaware of what essentially triggered the HLH. Thus, it is important to be aware that HLH may occur in the absence of malignancy, an apparent infectious trigger or signs of haemophagocytosis in a bone marrow biopsy. When the diagnosis was set, the patient was in such a deteriorated state that we were not sure if he could survive the addition of etoposide to his treatment. Perhaps a definitive diagnosis could have been achieved earlier if diagnostics according to the HLH-2004 protocol had been adhered more thoroughly as soon as HLH was suspected. Even so, the severity and quick progress of the HLH in our patient leaves us with the question if treatment would have been effective even if initiated at an earlier stage.\n\nFigure 1 (A) Haematoxylin and eosin stain, scale bar 50 µm. Ordinary bone marrow with normal distribution of haematopoietic cells. No sign of malignancy. (B) CD68 stain, scale bar 100 µm. Bone marrow with normal number of histiocytes/macrophages.\n\nLead author biography\nChristian Danielsson was born in 1988, Gothenburg, Sweden. He studied medicine at the Sahlgrenska Academy, University of Gothenburg where he got his medical degree in 2017. The following year, he worked at the Thoracic section of the Transplantation Clinic at the Sahlgrenska University Hospital. This is where he developed an interest in cardiac transplantation. He is currently doing his internship at the same hospital.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nFunding\nSwedish Heart and Lung Foundation (20160671); and ALF/LUA research grant (ALFGBG-21431) from the Sahlgrenska Academy and University Hospital.\n\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\n\nConsent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance. \n\n\nConflict of interest: G.D. has a research grant from Astellas regarding an immunosuppressive study in lung transplantation (ScanCLAD study), and a research grant from Abbott regarding an LVAD destination study (SweVAD study), but none applicable to this study. There are no financial conflicts of interest disclosures from any of the authors.\n\nSupplementary Material\nytaa070_Supplementary_Slide_Set Click here for additional data file.\n==== Refs\nReferences\n1 \nMasri K , Mahon N , Rosario A , Mirza I , Keys TF , Ratliff NB , Starling RC. \nReactive hemophagocytic syndrome associated with disseminated histoplasmosis in a heart transplant recipient\n. J Heart Lung Transplant 2003 ;22 :487 –491\n.12681429 \n2 \nJanka G , Zur Stadt U. \nFamilial and acquired hemophagocytic lymphohistiocytosis\n. Hematol Am Soc Hematol Educ Program 2005 ;2005 :82 –88\n.\n3 \nFilipovich AH. \nHemophagocytic lymphohistiocytosis (HLH) and related disorders\n. Hematol Am Soc Hematol Educ Program 2009 ;2009 :127 –131\n.\n4 \nBurns BF , Walley VM , Davies RA , Auclair F , Bormanis J. \nHemophagocytic syndrome complicating cardiac transplantation\n. Cardiovasc Pathol 1998 ;7 :47 –50\n.25989963 \n5 \nReuland AK , Engelhardt M , Meyer PT , Stroh AL , Lübbert M , Finke J , Schmitt-Gräff A , Zirlik A , Wäsch R. \nAggressive plasmablastic lymphoproliferation complicated by hemophagocytic syndrome 12 years after heart transplant\n. Leuk Lymphoma 2012 ;53 :1845 –1848\n.22335533 \n6 \nThomas G , Hraiech S , Dizier S , Weiller PJ , Ene N , Serratrice J , Secq V , Ambrosi P , Drancourt M , Roch A , Papazian L. \nDisseminated Mycobacterium lentiflavum responsible for hemophagocytic lymphohistocytosis in a man with a history of heart transplantation\n. J Clin Microbiol 2014 ;52 :3121 –3123\n.24871221 \n7 \nHenter JI , Horne A , Aricó M , Egeler RM , Filipovich AH , Imashuku S , Ladisch S , McClain K , Webb D , Winiarski J , Janka G. \nHLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis\n. Pediatr Blood Cancer 2007 ;48 :124 –131\n.16937360 \n8 \nPucci A , Grasso M , Arbustini E. \nMyocardial involvement due to a disseminated human cytomegalovirus infection in a heart transplant recipient. A case report\n. G Ital Cardiol 1989 ;19 :230 –233\n.2550305 \n9 \nHo C , Yao X , Tian L , Li FY , Podoltsev N , Xu ML. \nMarrow assessment for hemophagocytic lymphohistiocytosis demonstrates poor correlation with disease probability\n. Am J Clin Pathol 2014 ;141 :62 –71\n.24343738 \n10 \nLehmberg K , Nichols KE , Henter JI , Girschikofsky M , Greenwood T , Jordan M , Kumar A , Minkov M , Rosée Weitzman LP ; Study Group on Hemophagocytic Lymphohistiocytosis Subtypes of the Histiocyte Society. \nConsensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies\n. Haematologica 2015 ;100 :997 –1004\n.26314082 \n11 \nJordan MB , Allen CE , Weitzman S , Filipovich AH , McClain KL. \nHow I treat hemophagocytic lymphohistiocytosis\n. Blood 2011 ;118 :4041 –4052\n.21828139\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "4(3)",
"journal": "European heart journal. Case reports",
"keywords": "Case report; Haemophagocytic Lymphohistiocytosis; Haemophagocytic syndrome; Heart transplantation",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "1-4",
"pmc": null,
"pmid": "32617508",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": "22335533;25989963;16937360;24871221;21828139;12681429;2550305;24343738;26314082;16304363;20008190",
"title": "Haemophagocytic lymphohistiocytosis after heart transplantation: a case report.",
"title_normalized": "haemophagocytic lymphohistiocytosis after heart transplantation a case report"
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"companynumb": "SE-MYLANLABS-2020M1066442",
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"activesubstancename": "EVEROLIMUS"
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"abstract": "The purpose of this article was to report the efficacy of intravitreal bevacizumab to resolve secondary angle-closure glaucoma caused by biliary tract carcinoma metastasis to the iris.\n\n\n\nA 52-year-old white woman who was under systemic chemotherapy for biliary tract carcinoma presented with a metastatic tumor in the left iris. At presentation, her visual acuity was at the 20/50 level. The tumor was occupying the nasal half of the iris, and had already occupied 5.5 clock hours of the angle, resulting in intraocular pressure elevation to 34 mm Hg. Several small clumps of tumor seeds were also observed on the iris and along the angle. Her intraocular pressure remained high despite full medical therapy with dorzolamide, timolol, brimonidine, and oral acetozolamide. Because of the vascularized nature of the tumor, antivascular endothelial growth factor (anti-VEGF) treatment with 3 repeated injections of bevacizumab (1.25 mg/0.05 mL) was applied 1-month apart. Bevacizumab treatment resulted in an abrupt decrease in tumor mass and disappearance of tumoral seeds from the anterior chamber. The patient's vision improved to 20/20, and intraocular pressure decreased to normal levels.\n\n\n\nAnti-VEGF treatment with intravitreal bevacizumab can restore sight and achieve intraocular pressure control in metastatic iris tumors complicated with secondary glaucoma. Anti-VEGF drugs are viable alternatives for the treatment of secondary angle-closure glaucoma induced by metastatic iris tumors and can prevent enucleation of these eyes.",
"affiliations": "Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, NY.;Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, NY.",
"authors": "Aydin|Rukiye|R|;Tezel|Tongalp H|TH|",
"chemical_list": "D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/IJG.0000000000000959",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1057-0829",
"issue": "27(6)",
"journal": "Journal of glaucoma",
"keywords": null,
"medline_ta": "J Glaucoma",
"mesh_terms": "D000230:Adenocarcinoma; D020533:Angiogenesis Inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001661:Biliary Tract Neoplasms; D005260:Female; D015812:Glaucoma, Angle-Closure; D006801:Humans; D007429:Intraocular Pressure; D058449:Intravitreal Injections; D015811:Iris Neoplasms; D008875:Middle Aged; D009366:Neoplasm Seeding; D041623:Tomography, Optical Coherence; D014065:Tonometry, Ocular; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity",
"nlm_unique_id": "9300903",
"other_id": null,
"pages": "e113-e116",
"pmc": null,
"pmid": "29613980",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Use of Intravitreal Bevacizumab for the Treatment of Secondary Glaucoma Caused by Metastatic Iris Tumor.",
"title_normalized": "use of intravitreal bevacizumab for the treatment of secondary glaucoma caused by metastatic iris tumor"
} | [
{
"companynumb": "US-TEVA-2018-US-930477",
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"actiondrug": "5",
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"activesubstancename": "FLUOROURACIL"
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"abstract": "A 61-year-old woman was introduced for consultation with a chief complaint of frequent vomiting. CT revealed a pancreatic body cancer approximately 40mm in size; an invading stenosis from the horizontal part of the duodenum to the jejunum, superior mesenteric artery, and portal vein, splenic vein obstruction, lymphadenopathy, and some ascitic fluid. We diagnosed a passage disorder due to the invasive stenosis from the horizontal part of the duodenum of the pancreatic body cancer to the jejunum, and subsequently performed a duodenum and jejunum bypass operation. We controlled cancer pain with opioid analgesia, and S-1 monotherapy was chosen as the primary chemotherapy. A tendency to increase and the cancer pain of the tumor was aggravated when 5 courses took effect, so gemcitabine plus nab-paclitaxel(GEM plus nab-PTX)therapy was chosen as the second-line chemotherapy because of adverse Grade 3 events due to difficulties with S-1 internal use. We tapered off the opioid analgesia dosage because the cancer pain was relieved after 1 course. The imaging top indicated stable disease at the end of 5 courses, but the pain was relieved so opioid pain killers were unnecessary. Foreign continuation is under treatment with 10-course GEM plus nab-PTX therapy after initial diagnosis. Currently, the patient has undergone 5 courses of S-1 for approximately 18 months, and has achieved stable disease. The only adverse events were nausea, fatigue, Grade 1 malaise, and Grade 2 alopecia, as detected with imaging.",
"affiliations": "Dept. of Surgery, Hasuda Hospital.",
"authors": "Kaneko|Jun|J|;Kamiya|Ayako|A|;Kobayashi|Kenta|K|;Takatsuno|Yasushi|Y|;Kondoh|Ito|I|;Maejima|Kentaro|K|;Isogai|Jun|J|;Hasegawa|Kumi|K|;Endo|Takeshi|T|;Maejima|Shizuaki|S|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; C056507:gemcitabine; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "45(3)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "563-565",
"pmc": null,
"pmid": "29650939",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Successful Treatment with Gemcitabine plus Nab-Paclitaxel Therapy for Nonresected Pancreatic Body Cancer(Stage IVb).",
"title_normalized": "a case of successful treatment with gemcitabine plus nab paclitaxel therapy for nonresected pancreatic body cancer stage ivb"
} | [
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"companynumb": "JP-TEVA-2018-JP-929555",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
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{
"abstract": "A case of successful suicide from overdose of amitriptyline, perphenazine, and midazolam is described. Postmortem findings were inadequate to explain the death. Sudden cardiac arrest suggested that the death from overdose probably resulted from drug cardiotoxicity. The physicians should be aware of this serious complication when prescribing a combination of these potential lethal drugs. A limited supply should be given to depressed patients.",
"affiliations": null,
"authors": "Kasantikul|V|V|;Kasantikul|D|D|",
"chemical_list": "D011619:Psychotropic Drugs; D000639:Amitriptyline; D010546:Perphenazine; D008874:Midazolam",
"country": "Thailand",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0125-2208",
"issue": "72(2)",
"journal": "Journal of the Medical Association of Thailand = Chotmaihet thangphaet",
"keywords": null,
"medline_ta": "J Med Assoc Thai",
"mesh_terms": "D000639:Amitriptyline; D003645:Death, Sudden; D005260:Female; D006801:Humans; D008874:Midazolam; D008875:Middle Aged; D010546:Perphenazine; D011619:Psychotropic Drugs; D013405:Suicide",
"nlm_unique_id": "7507216",
"other_id": null,
"pages": "109-11",
"pmc": null,
"pmid": "2738485",
"pubdate": "1989-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Death following intentional overdose of psychotropic drugs.",
"title_normalized": "death following intentional overdose of psychotropic drugs"
} | [
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"companynumb": "TH-MYLANLABS-2018M1096912",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PERPHENAZINE"
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{
"abstract": "OBJECTIVE\nTo report the outcomes of intravitreal methotrexate (MTX) injections to rescue eyes with relapsed primary intraocular lymphoma (PIOL).\n\n\nMETHODS\nRetrospective case series of patients with ocular relapse of PIOL who had initially received systemic chemotherapy (all five cases) and external beam radiotherapy (EBRT) to brain and orbits (two cases). Injections of MTX (400 µg/0.1 mL) were given one time per week for 1 month, every other week for 4 months, followed by a maintenance phase of one injection one time per month for 8 months (total of 20 injections in a year).\n\n\nRESULTS\nFrom April 2008 to February 2016, there were nine eyes of five patients (three men; average age at first presentation 62 years) treated with our rescue protocol of intravitreal MTX injections. Ocular relapse occurred at a mean interval of 15 months (range 5-34 months) after the completion of initial systemic treatment. At mean follow-up of 31 months (range 5-104 months), tumour control was achieved in eight out of nine eyes (89%); one eye failed, with persistent retinal infiltrates despite increasing the frequency of injections, resulting in severe keratopathy. The only other complication occurred in one eye, developing cystoid macular oedema from MTX injections that resolved with topical anti-inflammatory medications and reduced frequency of MTX. There were no cases of reduced vision or ocular relapse, but two patients died (one of central nervous system lymphoma).\n\n\nCONCLUSIONS\nIntravitreal MTX was a safe and effective treatment modality for relapsed PIOL after systemic chemotherapy and radiotherapy, achieving local tumour control in 89%, and hence represents an optimal choice. However, given the rare nature of PIOL, larger collaborative studies with longer follow-up are needed to corroborate this.",
"affiliations": "Ocular Oncology Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK.;Ocular Oncology Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK.;Department of Medical Oncology, St Bartholomew's Hospital, London, UK.;Ocular Oncology Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK.;Ocular Oncology Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK.;Ocular Oncology Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK.;Ocular Oncology Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK mandeep.sagoo1@nhs.net.",
"authors": "Mohammad|Mona|M|http://orcid.org/0000-0002-8318-1171;Andrews|Richard M|RM|;Plowman|P Nicholas|PN|;Hay|Gordon|G|;Arora|Amit K|AK|;Cohen|Victoria M L|VML|;Sagoo|Mandeep S|MS|http://orcid.org/0000-0003-1530-3824",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bjophthalmol-2020-317199",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1161",
"issue": null,
"journal": "The British journal of ophthalmology",
"keywords": "Not applicable; Retina; Vitreous",
"medline_ta": "Br J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "0421041",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33087316",
"pubdate": "2020-10-21",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcomes of intravitreal methotrexate to salvage eyes with relapsed primary intraocular lymphoma.",
"title_normalized": "outcomes of intravitreal methotrexate to salvage eyes with relapsed primary intraocular lymphoma"
} | [
{
"companynumb": "GB-PFIZER INC-2020430793",
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"occurcountry": "GB",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
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"drugadditional": "3",... |
{
"abstract": "BACKGROUND\nWhile peripheral neuropathy is a common side effect of platinum-based chemotherapy, central nervous system (CNS) toxicity, such as encephalopathy or seizures, appears to be rare. This manuscript describes the only reported case of nonconvulsive status epilepticus associated with cisplatin in a cervical cancer patient who does not have other underlying medical conditions.\n\n\nMETHODS\nThe patient is a 54-year-old Chinese female with recurrent stage IIIB moderately differentiated squamous cell carcinoma of the cervix who was being treated with cisplatin and topotecan. During the sixth cycle of this regimen, the patient presented with mental status changes. While imaging and laboratory values were within normal limits, the patient's EEG revealed nonconvulsive status epilepticus. After appropriate intervention, she made a complete recovery with no further seizures. The patient currently remains on antiepileptic therapy, but is no longer receiving cisplatin.\n\n\nCONCLUSIONS\nPatients who present with new onset seizures should primarily be evaluated for underlying medical conditions. Among patients who are suspected to have CNS side effects associated with platinum use, we recommend avoidance of platinum agents in future chemotherapeutic regimens. Although rare, providers should be aware of the potential for CNS toxicity associated with this drug class.",
"affiliations": "Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1155 Herman Pressler, CPB6.3279, Houston, TX, 77030-3721, USA. llholman@mdanderson.org.;Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, 159 Tianzhou Road, Xuhui Area, Shanghai, 200030, China. renyulan79@126.com.;Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1155 Herman Pressler, CPB6.3279, Houston, TX, 77030-3721, USA. swestin@mdanderson.org.",
"authors": "Holman|Laura L|LL|;Ren|Yulan|Y|;Westin|Shannon N|SN|",
"chemical_list": "D019772:Topotecan; D017239:Paclitaxel; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-015-1755-2",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 26474752175510.1186/s12885-015-1755-2Case ReportStatus epilepticus associated with platinum chemotherapy in a patient with cervical cancer: a case report Holman Laura L. llholman@mdanderson.org 1Ren Yulan renyulan79@126.com 2Westin Shannon N. (713) 794-4314swestin@mdanderson.org 11 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Unit 1362, 1155 Herman Pressler, CPB6.3279, Houston, TX 77030-3721 USA 2 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, 159 Tianzhou Road, Xuhui Area, Shanghai, 200030 China 17 10 2015 17 10 2015 2015 15 7281 6 2014 9 10 2015 © Holman et al. 2015Open 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\nWhile peripheral neuropathy is a common side effect of platinum-based chemotherapy, central nervous system (CNS) toxicity, such as encephalopathy or seizures, appears to be rare. This manuscript describes the only reported case of nonconvulsive status epilepticus associated with cisplatin in a cervical cancer patient who does not have other underlying medical conditions.\n\nCase presentation\nThe patient is a 54-year-old Chinese female with recurrent stage IIIB moderately differentiated squamous cell carcinoma of the cervix who was being treated with cisplatin and topotecan. During the sixth cycle of this regimen, the patient presented with mental status changes. While imaging and laboratory values were within normal limits, the patient’s EEG revealed nonconvulsive status epilepticus. After appropriate intervention, she made a complete recovery with no further seizures. The patient currently remains on antiepileptic therapy, but is no longer receiving cisplatin.\n\nConclusion\nPatients who present with new onset seizures should primarily be evaluated for underlying medical conditions. Among patients who are suspected to have CNS side effects associated with platinum use, we recommend avoidance of platinum agents in future chemotherapeutic regimens. Although rare, providers should be aware of the potential for CNS toxicity associated with this drug class.\n\nKeywords\nPlatinum chemotherapySeizureNeurotoxicityCervical cancerissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nPlatinum analogs are chemotherapeutic agents used to treat a wide variety of malignancies. Members of this drug class commonly prescribed for gynecologic malignancies include cisplatin and carboplatin. These medications work by covalently binding to DNA to produce intrastrand and interstrand crosslinks. The formation of these DNA adducts leads to inhibition of transcription and replication, as well as cell-cycle arrest [1].\n\nThe most common side effects associated with platinum agents are nephrotoxicity, myelosuppression, nausea and vomiting, and hypersensitivity reactions. Neurotoxicity is also reported, though the frequency varies widely among the drugs in this class. While up to 60 % of patients receiving cisplatin have neurotoxicity, only 4-5 % of patients who receive carboplatin experience this side effect [2].\n\nPeripheral neuropathy is the most common neurological toxicity associated with platinum agents. Patients with platinum-induced peripheral neuropathy can experience paresthesia in a “glove and stocking” distribution, loss of vibratory sensation, and loss of proprioception that can severely affect activities of daily living and quality of life. Ototoxicity, in the form of hearing loss or tinnitus, is also a well-described neurological side effect associated with cisplatin. Encephalopathy, transient blindness, aphasia, and seizures are reported to be associated with platinum use, but appear to be exceedingly rare in the absence of brain pathology, laboratory abnormalities, or medication overdose [3–5].\n\nIn this paper, we report a case of status epilepticus associated with cisplatin in a patient with recurrent cervical carcinoma.\n\nCase presentation\nThe patient is a 54-year-old female with recurrent stage IIIB moderately differentiated squamous cell carcinoma of the cervix. Patient had no relevant prior medical or family history. Her initial treatment included one cycle of oxaliplatin and tegafur followed by intensity-modulated radiotherapy (IMRT) and vaginal brachytherapy. At completion of her radiation, the patient received five cycles of taxane and platinum-based chemotherapy with a complete response. She remained without evidence of disease for two years, when she was diagnosed with a recurrence in her retroperitoneal and thoracic lymph nodes. Oxaliplatin and paclitaxel were initiated, but discontinued after one cycle due to vague “mental status changes.” She underwent brain imaging at that time that was within normal limits. She was then treated with radiation to the retroperitoneal lymph nodes followed by immunotherapy with dendritic cell and cytokine-induced killer cell transfusions resulting in a partial response. The patient was then initiated on an oral taxane for two cycles with persistent disease. She then presented to our institution and was dispositioned to topotecan (0.75 mg/m2) daily on cycle days one, two, and three and cisplatin (50 mg/m2) on cycle day 1, administered every three weeks. The patient tolerated the first five cycles without incident and achieved an objective tumor response. However, on day two of cycle six, she developed altered mental status and was not responding appropriately to questions or commands. She was brought to the emergency room where vital signs and laboratory values, including complete blood count, complete metabolic panel, and urinalysis, were within normal limits. Neurological examination revealed no focal deficits. She underwent CT and MRI of the brain, which were also within normal limits. However, electroencephalogram (EEG) revealed the presence of nonconvulsive seizures (NCS). She was given a one-time dose of lorazepam with significant improvement in her mental status. The patient was also initiated on levetiracetam. A repeat EEG three days later noted resolution of the seizure activity. After this episode, the patient was transitioned to topotecan and bevacizumab with no further seizures to date. Please reference Table 1 for timeline of events.Table 1 Timeline of events\n\nDate\tKey Event\t\nJuly 2011\tDiagnosis of Cervical Cancer\t\nAugust 2011 – January 2012\tPrimary Treatment\t\n-oxaliplatin/tegafur\t\n-IMRT/brachytherapy\t\n-Paclitaxel/platinum\t\nJanuary 2013\tRecurrence of disease\t\nJanuary 2013 – October 2013\tTreatment for Recurrence\t\n-oxaliplatin/paclitaxel\t\n- tumor-directed radiation\t\n- dendritic cell immunotherapy\t\n- taxane therapy\t\nOctober 2013\tProgression of disease/consultation at MD Anderson Cancer Center\t\nOctober 2013\tInitiation of topotecan/cisplatin\t\nOctober 2013 – January 2014\tCycles #1–5 of topotecan/cisplatin\t\nFebruary 2014\tCycle #6 of topotecan/cisplatin\t\nSEIZURE ACTIVITY\t\n\n\nConclusions\nThis case describes the unusual presentation of a patient in nonconvulsive status epilepticus attributed to cisplatin use. As the patient had normal laboratory and imaging findings without convulsions, the diagnosis was somewhat more challenging. Interestingly, the patient reported a history of vague mental status changes with platinum use in the past. On further questioning, it appears that her symptoms at that time were very similar to her current presentation. However, she did not undergo EEG evaluation or further neurological work-up.\n\nWhile central nervous system (CNS) disorders are not frequently associated with platinum use, cases have been reported [3–6]. Posterior reversible encephalopathy syndrome (PRES) is the most commonly described platinum-associated CNS toxicity in the literature [7]. PRES can occur in a wide variety of clinical settings, including eclampsia, sepsis, autoimmune disease, and medication-related toxicity. Symptoms of PRES typically involve headache, visual changes, seizures, and encephalopathy. PRES is diagnosed by clinical presentation as well as brain MRI, where white matter edema of the posterior cerebral hemispheres is typically seen. When PRES is associated with platinum drugs, symptoms have been reported to occur within a few hours of cisplatin administration and typically resolve in a few days [6].\n\nSeveral authors have described the presence of seizures after platinum administration not attributable to PRES, including two cases of status epilepticus [7–9]. However, almost all of these patients had laboratory derangements such as hypomagnesemia or renal insufficiency, or imaging abnormalities such as brain metastases, which could lower the seizure threshold. In the absence of other medical factors that could potentiate them, seizures associated with platinum chemotherapy appear to be exceedingly rare. This manuscript describes the only reported case of nonconvulsive status epilepticus related to cisplatin use in a cervical cancer patient without other underlying medical conditions.\n\nThe etiology of platinum-induced CNS toxicity is unknown, though heavy metal toxicity or demylinization have been proposed [7]. Overdose of platinum agents can certainly also cause these disorders. However, reports have noted CNS toxicity with these drugs at a wide range of doses and in combination with various chemotherapeutic agents. As platinum agents do not typically cross the blood-brain barrier, patients should be protected from most CNS side effects at doses in the therapeutic range. It is unclear why this is not true for all patients.\n\nIn conclusion, CNS toxicity appears to be a rare but serious side effect of administration of platinum-containing drugs. Patients who present with CNS symptoms should primarily be evaluated for other underlying medical conditions. However, if platinum-based chemotherapy is suspected as the etiology, we suggest the use of alternative chemotherapeutic regimens in the future.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nAbbreviations\nCNSCentral nervous system\n\nEEGElectroencephalogram\n\nIMRTIntensity-modulated radiotherapy\n\nNCSNonconvulsive seizures\n\nPRESPosterior reversible encephalopathy syndrome\n\nCompeting interests\n\nThe authors have no conflicts of interest to report.\n\nAuthors’ contributions\n\nLLH participated in the conception and coordination of the report and drafted the manuscript. YR aided with coordination of the report and helped to draft the manuscript. SNW participated in the conception of the report, coordinated the report, and helped to draft the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThis study was supported by funds from an NIH T32 CA101642 to LLH and an NIH K12 Calabresi Scholar Award (K12 CA088084) to SNW.\n==== Refs\nReferences\n1. Maccio A Madeddu C Cisplatin : an old drug with a newfound efficacy -- from mechanisms of action to cytotoxicity Expert Opin Pharmacother. 2013 14 1839 57 10.1517/14656566.2013.813934 23876094 \n2. McWhinney SR Goldberg RM McLeod HL Platinum neurotoxicity pharmacogenetics Mol Cancer Ther. 2009 8 10 6 10.1158/1535-7163.MCT-08-0840 19139108 \n3. Sharief U Perry DJ Delayed reversible posterior encephalopathy syndrome following chemotherapy with oxaliplatin Clin Colorectal Cancer. 2009 8 163 5 10.3816/CCC.2009.n.026 19632931 \n4. Verschraegen C Conrad CA Hong WK Subacute encephalopathic toxicity of cisplatin Lung Cancer. 1995 13 305 9 10.1016/0169-5002(95)00503-X 8719070 \n5. Berman IJ Mann MP Seizures and transient cortical blindness associated with cis-platinum (II) diamminedichloride (PDD) therapy in a thirty-year-old man Cancer. 1980 45 764 6 10.1002/1097-0142(19800215)45:4<764::AID-CNCR2820450425>3.0.CO;2-G 7188878 \n6. Lamy C Oppenheim C Mas JL Posterior reversible encephalopathy syndrome Handb Clin Neurol. 2014 121 1687 701 10.1016/B978-0-7020-4088-7.00109-7 24365441 \n7. Steeghs N de Jongh FE Sillevis Smitt PA van den Bent MJ Cisplatin-induced encephalopathy and seizures Anticancer Drugs. 2003 14 443 6 10.1097/00001813-200307000-00009 12853886 \n8. Philip PA Carmichael J Harris AL Convulsions and transient cortical blindness after cisplatin BMJ. 1991 302 416 10.1136/bmj.302.6773.416 2004162 \n9. Mead GM Arnold AM Green JA Macbeth FR Williams CJ Whitehouse JM Epileptic seizures associated with cisplatin administration Cancer Treat Rep. 1982 66 1719 22 6889460\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "15()",
"journal": "BMC cancer",
"keywords": null,
"medline_ta": "BMC Cancer",
"mesh_terms": "D002945:Cisplatin; D005260:Female; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel; D012640:Seizures; D013226:Status Epilepticus; D019772:Topotecan; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "728",
"pmc": null,
"pmid": "26474752",
"pubdate": "2015-10-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "12853886;7188878;6889460;2004162;24365441;19139108;19632931;23876094;8719070",
"title": "Status epilepticus associated with platinum chemotherapy in a patient with cervical cancer: a case report.",
"title_normalized": "status epilepticus associated with platinum chemotherapy in a patient with cervical cancer a case report"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US08203",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "We retrospectively analyzed the safety and efficacy of a myeloablative conditioning regimen with fludarabine (FLU) in unrelated cord blood transplantation (UCBT) of 30 pediatric patients with hematologic malignancies. The conditioning regimen consisted of FLU, busulfan (BU) and cyclophosphamide (CY). All of the patients received Cyclosporine (CSA) and mycophenolate mofetil (MMF) as graft versus host disease (GVHD) prophylaxis. We achieved high engraftment rates (96.7%) and rapid hematopoietic reconstitution. Acute GVHD occurred in 12 cases of the 29 engraftment patients (41.4%), and 6 cases (20.7%) were of grade III-IV. Chronic GVHD only occurred in 1 of 28 evaluable patients (3.6%). Twenty-three patients (76.7%) became infected, and 3 cases (10.0%) died of severe infections. Cytomegalovirus (CMV) reactivation occurred in 70.0% of the patients, but no CMV diseases were observed, nor did any patients die of CMV infection. The cumulative incidence of relapse (6.7%) was significantly reduced, and none of the acute lymphoblastic leukemia (ALL) patients relapsed. The 3-year overall survival (OS) and event-free survival (EFS) rates were 73.3% and 70.0%, respectively. The 3-year OS and EFS of the ALL patients was 75.0%. This conditioning regimen demonstrates good results and security in UCBT, especially in acute lymphoblastic leukemia.",
"affiliations": null,
"authors": "Tong|J|J|;Sun|Z|Z|;Liu|H|H|;Geng|L|L|;Ding|K|K|;Wang|X|X|;Zheng|C|C|;Tang|B|B|;Zhu|X|X|;Yao|W|W|;Song|K|K|;Liu|X|X|",
"chemical_list": "D019653:Myeloablative Agonists; D014740:Vidarabine; C024352:fludarabine",
"country": "Slovakia",
"delete": false,
"doi": "10.4149/neo_2014_073",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2685",
"issue": "61(5)",
"journal": "Neoplasma",
"keywords": null,
"medline_ta": "Neoplasma",
"mesh_terms": "D000293:Adolescent; D002648:Child; D036101:Cord Blood Stem Cell Transplantation; D005260:Female; D006086:Graft vs Host Disease; D006801:Humans; D008297:Male; D019653:Myeloablative Agonists; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012008:Recurrence; D019172:Transplantation Conditioning; D014740:Vidarabine",
"nlm_unique_id": "0377266",
"other_id": null,
"pages": "593-600",
"pmc": null,
"pmid": "25030443",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A myeloablative conditioning regimen with fludarabine demonstrates good results in UCBT for 30 pediatric patients with hematologic malignancies, especially acute lymphoblastic leukemia.",
"title_normalized": "a myeloablative conditioning regimen with fludarabine demonstrates good results in ucbt for 30 pediatric patients with hematologic malignancies especially acute lymphoblastic leukemia"
} | [
{
"companynumb": "CN-SA-2014SA149037",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report the development of morbilliform rash and serotonin toxicity after the addition of milnacipran to a patient's medication therapy.\n\n\nMETHODS\nA 57-year-old white female presented to the emergency department because of a full-body morbilliform rash, which appeared 9 days after initiation of milnacipran 50 mg twice daily. In the emergency department the patient's vital signs were: heart rate 121 beats/min, blood pressure 180/100 mm Hg, and temperature 38.9 °C. The patient reported diarrhea, nausea, dizziness, restlessness, and increased muscle pain. Her history included recurrent breast cancer first diagnosed in 1999, hypertension, fibromyalgia, depression, osteopenia, gastroesophageal reflux disease, insomnia, and endometriosis. Her home medications included milnacipran, fluoxetine, alprazolam, zolpidem, zoledronic acid, anastrozole, doxepin, ranitidine, levocetirizine, doxazosin, tramadol, vitamin D, and ferrous gluconate. The patient's increased heart rate, blood pressure, and temperature, as well as restlessness, self-reported diarrhea and nausea, and self-reported increase in muscle pain, indicated serotonin toxicity. Milnacipran, fluoxetine, and tramadol were discontinued, while doxepin was continued. Treatment consisted of acetaminophen, diphenhydramine, methylprednisolone, promethazine, and hydralazine 10 mg intravenously. The following morning all vital signs were within normal limits and the patient's diarrhea, nausea, dizziness, restlessness, and muscle pain resolved. She was discharged the following morning. The rash had resolved after day 2 of hospital discharge, which was the fourth day after discontinuation of milnacipran.\n\n\nCONCLUSIONS\nGiven the patient's symptoms, the timing of symptom onset, the patient's history, and findings on physical examination, as well as use of the Naranjo probability scale, milnacipran was deemed the probable cause of the morbilliform reaction and serotonin toxicity. Only 1 case report of rash and 2 case reports of serotonin syndrome associated with milnacipran have been reported.\n\n\nCONCLUSIONS\nIt is important to increase awareness of the possibility of developing morbilliform rash and serotonin toxicity with milnacipran therapy, as both conditions can be associated with poor outcomes if not detected early and treated appropriately.",
"affiliations": "College of Pharmacy, University of Tennessee, Knoxville, TN, USA.",
"authors": "Huskey|Amanda M|AM|;Thomas|Cassandra C|CC|;Waddell|James Aubrey|JA|",
"chemical_list": "D000928:Antidepressive Agents; D003521:Cyclopropanes; D000078764:Milnacipran",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1R474",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "47(7-8)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000928:Antidepressive Agents; D003521:Cyclopropanes; D005076:Exanthema; D005260:Female; D006801:Humans; D008875:Middle Aged; D000078764:Milnacipran; D020230:Serotonin Syndrome",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "e32",
"pmc": null,
"pmid": "23837199",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Occurrence of milnacipran-associated morbilliform rash and serotonin toxicity.",
"title_normalized": "occurrence of milnacipran associated morbilliform rash and serotonin toxicity"
} | [
{
"companynumb": "US-ACTAVIS-2014-10526",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOCETIRIZINE"
},
"drugadditional": null,
... |
{
"abstract": "Rituximab targets the CD20 antigen expressed on B-lymphocytes and is used to treat recurrent minimal change disease, but experience of its use in pregnancy is limited. We describe a 28-year-old Caucasian female, with recurrent nephrotic syndrome secondary to minimal change disease. She had failed to respond to non-teratogenic alternative therapies. The patient was successfully maintained in remission with rituximab during two consecutive pregnancies. Rituximab (1 g) was administered at 14+6 weeks 14 weeks and 6 days during Pregnancy 1 and 500 mg administered at 23+4 weeks 23 weeks and 4 days of Pregnancy 2. Rituximab had no apparent effect on infant B-cell development in either pregnancy, as neonatal lymphocyte titres were within normal range. There were no maternal complications in either pregnancy. Neither infant encountered infection-related complications. Although rituximab administration during pregnancy appeared safe, evidence of placental transfer is reported with neonatal B-cell depletion, thus alternatives with known safety profiles in pregnancy should be considered before rituximab administration.",
"affiliations": "Department of Nephrology and Obstetrics, King's College Hospital NHS Foundation Trust, London, UK.;Department of Nephrology and Obstetrics, King's College Hospital NHS Foundation Trust, London, UK.;Department of Nephrology and Obstetrics, King's College Hospital NHS Foundation Trust, London, UK.",
"authors": "Holden|Francesca|F|;Bramham|Kate|K|;Clark|Katherine|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1753495X18813739",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1753-495X",
"issue": "13(3)",
"journal": "Obstetric medicine",
"keywords": "Rituximab; minimal change nephropathy; pregnancy",
"medline_ta": "Obstet Med",
"mesh_terms": null,
"nlm_unique_id": "101464191",
"other_id": null,
"pages": "145-147",
"pmc": null,
"pmid": "33093868",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": "18596903;21098742;28315862;15089769;20937725;17515892;26860320;24751753;20947541;17437503;19877045;10845926;28387313;24480824;16570081;24777675;22772325;28264814",
"title": "Rituximab for the maintenance of minimal change nephropathy - A report of two pregnancies.",
"title_normalized": "rituximab for the maintenance of minimal change nephropathy a report of two pregnancies"
} | [
{
"companynumb": "GB-CELLTRION INC.-2019GB018897",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Thrombotic thrombocytopenic purpura (TTP) is acquired in the majority of cases. Traditional therapy consists of plasma exchange (PEX), as well as the administration of certain immunosuppressive agents including steroids. A standard dose of rituximab (RTX) at 375 mg/m2 weekly for 4 consecutive weeks was recently demonstrated to have significant activity in patients with acquired TTP. To date, clinicians have limited experience using low-dose RTX. In the present study, 2 patients were treated with low-dose RTX at 100 mg weekly for 4 consecutive weeks as a salvage therapy following failure to respond to PEX and other immunosuppressive agents. Prior to RTX therapy, the patients had severely deficient ADAMTS13 activity and detectable anti-ADAMTS13 inhibitors. The patients achieved complete remission and presented long-term stabilization during follow-up. Repeated detection during follow-up demonstrated that the patients had 100% ADAMTS13 activity and undetectable anti-ADAMTS13 antibodies. Although further investigation in a prospective clinical trial is required, the use of low-dose RTX seems to be as effective as a standard dose for patients with relapsing or refractory acquired TTP.",
"affiliations": "Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China ; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China.;Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China ; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China.;Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China ; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China.;Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China ; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China.;Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China ; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China.",
"authors": "Tong|Hong-Yan|HY|;Ye|L I|LI|;Ye|Xing-Nong|XN|;Lu|DE-Min|DM|;Li|Ying|Y|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/etm.2015.2797",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-0981",
"issue": "10(6)",
"journal": "Experimental and therapeutic medicine",
"keywords": "ADAMTS13; low dose; rituximab; thrombotic thrombocytopenic purpura",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "2295-2298",
"pmc": null,
"pmid": "26668631",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": "2062330;12588343;15933059;21636861;20934383;20546023;11389047;20130241;22624596;15710595;16409158;22566601;22878941;23432850;18403395;21926591",
"title": "Long-term remission induced by low-dose rituximab for relapsed and refractory thrombotic thrombocytopenic purpura: A report of two cases.",
"title_normalized": "long term remission induced by low dose rituximab for relapsed and refractory thrombotic thrombocytopenic purpura a report of two cases"
} | [
{
"companynumb": "PHHY2015CN154746",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"d... |
{
"abstract": "Therapy with sulfonylurea is preferable to insulin in the majority of individuals with KCNJ11 mutations, but not all of these people achieve target levels of HbA1c in long-term follow-up. We aimed to compare sulfonylurea therapy with insulin treatment in two sulfonylurea-sensitive individuals with a KCNJ11 mutation who had poorly controlled permanent neonatal diabetes mellitus.\n\n\n\nWe report on two individuals with a KCNJ11 mutation (p.R201H) who are currently aged 35 (SVK1) and 21 years (SVK2). These individuals were switched from insulin to sulfonylurea in 2005. Data from the first 4 (SVK2) and 8 years (SVK1) of the follow-up showed improved diabetes control and increased quality of life for both individuals. During the following years, however, both individuals failed to retain good diabetes control (HbA1c ≤ 53 mmol/mol; 7.0%). We therefore changed the therapy to a combination of insulin and sulfonylurea in both individuals, or to insulin monotherapy in SVK1, and compared the effects on HbA1c with those of sulfonylurea monotherapy. HbA1c levels in both individuals worsened after adding insulin to sulfonylurea [67 mmol/mol (8.3%) vs 77 mmol/mol (9.2%) in SVK1 and 106 mmol/mol (11.8%) vs 110±19 mmol/mol (12.2±1.7%) in SVK2], and after switching to only insulin therapy in SVK1 [57 mmol/mol (7.4%) vs 62 mmol/mol (7.8%)] when compared with sulfonylurea monotherapy.\n\n\n\nOur data show that sulfonylurea monotherapy might be preferable to insulin in people with permanent neonatal diabetes mellitus sensitive to sulfonylurea even when HbA1c is above target.",
"affiliations": "DIABGENE Laboratory, Institute of Experimental Endocrinology, Biomedical Research Center of Slovak Academy of Sciences, Bratislava, Slovakia.;Department of Pediatrics, Children Faculty Hospital, Kosice, Slovakia.;Children Diabetes Centre at the Department of Paediatrics, Medical Faculty of Comenius University and Children Faculty Hospital, Bratislava, Slovakia.;DIABGENE Laboratory, Institute of Experimental Endocrinology, Biomedical Research Center of Slovak Academy of Sciences, Bratislava, Slovakia.;First Department of Internal Medicine, Medical Faculty of Safarik University, Kosice, Slovakia.;Outpatient Diabetes Clinic DIAHELP, Pardubice, Czech Republic.;DIABGENE Laboratory, Institute of Experimental Endocrinology, Biomedical Research Center of Slovak Academy of Sciences, Bratislava, Slovakia.;DIABGENE Laboratory, Institute of Experimental Endocrinology, Biomedical Research Center of Slovak Academy of Sciences, Bratislava, Slovakia.",
"authors": "Stanik|J|J|0000-0002-0538-1274;Dankovcikova|A|A|;Barak|L|L|;Skopkova|M|M|;Palko|M|M|;Divinec|J|J|;Klimes|I|I|;Gasperikova|D|D|",
"chemical_list": "D006442:Glycated Hemoglobin A; D007004:Hypoglycemic Agents; D007328:Insulin; C489474:Kir6.2 channel; D024661:Potassium Channels, Inwardly Rectifying; D005905:Glyburide",
"country": "England",
"delete": false,
"doi": "10.1111/dme.13575",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0742-3071",
"issue": "35(3)",
"journal": "Diabetic medicine : a journal of the British Diabetic Association",
"keywords": null,
"medline_ta": "Diabet Med",
"mesh_terms": "D000328:Adult; D003920:Diabetes Mellitus; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D005260:Female; D005905:Glyburide; D006442:Glycated Hemoglobin A; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D008297:Male; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying; D055815:Young Adult",
"nlm_unique_id": "8500858",
"other_id": null,
"pages": "386-391",
"pmc": null,
"pmid": "29278452",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D003160:Comparative Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Sulfonylurea vs insulin therapy in individuals with sulfonylurea-sensitive permanent neonatal diabetes mellitus, attributable to a KCNJ11 mutation, and poor glycaemic control.",
"title_normalized": "sulfonylurea vs insulin therapy in individuals with sulfonylurea sensitive permanent neonatal diabetes mellitus attributable to a kcnj11 mutation and poor glycaemic control"
} | [
{
"companynumb": "SK-SA-2018SA051200",
"fulfillexpeditecriteria": "1",
"occurcountry": "SK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INSULIN HUMAN"
},
"drugadditional": "3",
"... |
{
"abstract": "To describe a case of primary melanoma of the prostate gland, then review the published literature of similar cases.\n\n\n\nPresentation of the clinical course of a 42-year-old man diagnosed with primary melanoma of the prostate after presenting with gross hematuria. Review of published literature.\n\n\n\nPrimary melanoma of the genitourinary tract is a very rare disease, representing less than 1% of all melanomas in men. Only 6 cases of primary melanomas have been previously reported in the English literature.\n\n\n\nThe current report emphasizes the importance of a multidisciplinary approach and adherence to treatment principles in cutaneous melanoma. With complete surgical extirpation (including extended pelvic lymphadenectomy as needed), close surveillance using 18F-FDG PET/CT, and aggressive systemic treatment in patients with good performance status, cure can be achieved.",
"affiliations": "Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: rl8402@gmail.com.;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.;Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: jfward@mdanderson.org.",
"authors": "Li|Roger|R|;Zhang|Miao|M|;Duplisea|Jonathan J|JJ|;Troncoso|Patricia|P|;Ward|John F|JF|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.urology.2018.08.035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4295",
"issue": "123()",
"journal": "Urology",
"keywords": null,
"medline_ta": "Urology",
"mesh_terms": "D000328:Adult; D006801:Humans; D008297:Male; D008545:Melanoma; D011471:Prostatic Neoplasms",
"nlm_unique_id": "0366151",
"other_id": null,
"pages": "16-19",
"pmc": null,
"pmid": "30195014",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Detection and Treatment of Primary Prostatic Melanoma.",
"title_normalized": "detection and treatment of primary prostatic melanoma"
} | [
{
"companynumb": "US-PFIZER INC-2019024919",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DACARBAZINE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nAsparaginase treatment is standard in all pediatric acute lymphoblastic leukemia (ALL) regimens, whereas in adults, it is either excluded or administered for a shorter duration. Several adult ALL protocols are adapting pediatric regimens, but the optimal implementation of asparaginase is not well studied, considering its potential higher toxicity. We studied a pegaspargase dosing strategy based on its pharmacokinetic characteristics in adults.\n\n\nMETHODS\nBetween 2004 and 2009, 51 adults age 18 to 57 years with newly diagnosed ALL were treated with a regimen adapted from a pediatric trial that included six doses of intravenous pegaspargase at 2,000 IU/m(2) per dose. Intervals between doses were longer than 4 weeks and rationally synchronized with other chemotherapy drugs to prevent overlapping toxicities. Pegaspargase was administered with steroids to reduce hypersensitivity. Asparaginase-related toxicities were monitored after 173 pegaspargase doses.\n\n\nRESULTS\nThe most common grade 3/4 asparaginase-related toxicities were lengthy hyperbilirubinemia and transaminitis, occasionally resulting in subsequent treatment delays. All toxicities resolved spontaneously. Forty-five percent of patients were able to receive all six doses of pegaspargase, and 61% received ≥ three doses. In only 20% of patients, the drug was discontinued after pegaspargase-related serious toxicity. Ninety-six percent achieved complete remission, almost all within 4 weeks, and a low induction death rate was seen. Seven-year disease-free and overall survival were 58% and 51%, respectively.\n\n\nCONCLUSIONS\nOur dose and schedule of pegaspargase, based on its pharmacokinetics, and our detailed toxicity profile could be applied for safer adaptation of pediatric ALL protocols in adults.",
"affiliations": "Dan Douer, Matthew A. Lunning, Patrick W. Burke, Jae H. Park, and Martin S. Tallman, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Ibrahim Aldoss, Laleh Ramezani, Lisa Mark, Janice Vrona, Vinod Pullarkat, and Ann M. Mohrbacher, Keck School of Medicine, University of Southern California; and Vassilios I. Avramis, Children's Hospital of Los Angeles, University of Southern California, Los Angeles, CA.",
"authors": "Douer|Dan|D|;Aldoss|Ibrahim|I|;Lunning|Matthew A|MA|;Burke|Patrick W|PW|;Ramezani|Laleh|L|;Mark|Lisa|L|;Vrona|Janice|J|;Park|Jae H|JH|;Tallman|Martin S|MS|;Avramis|Vassilios I|VI|;Pullarkat|Vinod|V|;Mohrbacher|Ann M|AM|",
"chemical_list": "D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2013.50.2708",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "32(9)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D056486:Chemical and Drug Induced Liver Injury; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D006932:Hyperbilirubinemia; D060828:Induction Chemotherapy; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D011092:Polyethylene Glycols; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D018805:Sepsis; D016896:Treatment Outcome",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "905-11",
"pmc": null,
"pmid": "24516026",
"pubdate": "2014-03-20",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia.",
"title_normalized": "pharmacokinetics based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia"
} | [
{
"companynumb": "US-SERVIER-S19002098",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "3",
"d... |
{
"abstract": "We report a case of an 86-year-old woman admitted to the hospital with rhabdomyolysis and acute kidney injury 3 weeks after starting sitagliptin while on long-term atorvastatin therapy. She also had low levels of 25-hydroxyvitamin D and mild chronic kidney disease, which may have contributed to the development of rhabdomyolysis. A review of the literature reveals four previous reports of this drug interaction in elderly patients, some with underlying kidney disease.",
"affiliations": "Department of Medicine/Nephrology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.;Department of Medicine/Nephrology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.;Department of Medicine/Nephrology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.;Department of Medicine/Nephrology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA.;Department of Medicine/Nephrology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 10461, USA. michal.melamed@einstein.yu.edu.",
"authors": "Buttar|Rupinder Singh|RS|;Batra|Jasveen|J|;Kreimerman|Jacqueline|J|;Aleta|Melissa|M|;Melamed|Michal L|ML|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014807:Vitamin D; D000069059:Atorvastatin; C104450:25-hydroxyvitamin D; D000068900:Sitagliptin Phosphate",
"country": "United States",
"delete": false,
"doi": "10.1007/s11606-017-4115-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-8734",
"issue": "32(10)",
"journal": "Journal of general internal medicine",
"keywords": "acute kidney injury; drug interaction; rhabdomyolysis; sitagliptin; statins; vitamin D",
"medline_ta": "J Gen Intern Med",
"mesh_terms": "D058186:Acute Kidney Injury; D000369:Aged, 80 and over; D000069059:Atorvastatin; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012206:Rhabdomyolysis; D000068900:Sitagliptin Phosphate; D014807:Vitamin D",
"nlm_unique_id": "8605834",
"other_id": null,
"pages": "1156-1159",
"pmc": null,
"pmid": "28707259",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19178510;25838999;22968766;21199268;227925;11991950;19046202;22587686;7888298;21468365;24407560;23077137;26423691;22323613;17468348;22985909;19249953;22023482;19204138",
"title": "Rhabdomyolysis and AKI with Atorvastatin and Sitagliptin Use in the Setting of Low 25-Hydroxyvitamin D Levels.",
"title_normalized": "rhabdomyolysis and aki with atorvastatin and sitagliptin use in the setting of low 25 hydroxyvitamin d levels"
} | [
{
"companynumb": "US-009507513-1606USA014115",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SITAGLIPTIN PHOSPHATE"
},
"drugadditional": ... |
{
"abstract": "BACKGROUND\nChronic lymphoid leukemia (CLL) is a hematological malignant disease, associated with a clonal B cell proliferation. The incidence is 4400 new cases per year in France. The prevalence increases with age with a median age at diagnostic of 65 years. Renal involvement is rare and estimated at 1.2% of patients with CLL. Renal pathological diagnoses associated with CLL are variable and are not always related to the hematological disease. We report here on cases of patients with CLL who underwent a renal biopsy over the past 16 years in Marseille.\n\n\nMETHODS\nAll cases of renal biopsies performed in patients with CLL between2000 and 2016 in Marseille were included. Pathological analysis was performed by the same experimented pathologist. Data were collected at the time of biopsy and after treatment.\n\n\nRESULTS\nTen patients were included in this study. The reason for renal biopsy was acute kidney injury or the onset of nephrotic syndrome. We report on 4 cases of membranous nephropathy, 1 minimal change disease, 1 cryglobulinemia-related membrano-proliferative glomerulonephritis, 1 light chain amyloidosis, 1 fibrillary glomerulonephritis, 1 interstitial monoclonal infiltration and one case of non-specific tubular lesions. Only one patient was treated before the biopsy, 7 patients received a specific hematological treatment of CLL because of its renal involvement. Renal and hematological responses were variable.\n\n\nCONCLUSIONS\nRenal involvement of CLL is rare and is not mentioned in the Binet classification. Yet, it can be severe, with acute kidney injury or nephrotic syndrome, and can lead to the initiation of a specific treatment. The most frequent presentation this series was secondary MN, which differs from previous series.",
"affiliations": "Médecine interne, hôpital de la Timone (AP-HM), Aix-Marseille université, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France; Centre de néphrologie et de transplantation rénale, hôpital de la Conception (AP-HM), Aix-Marseille université, 13385 Marseille cedex 05, France.;Laboratoire d'anatomo-pathologie, hôpital de la Timone (AP-HM), Aix-Marseille université, 13385 Marseille cedex 05, France.;Médecine interne, hôpital de la Timone (AP-HM), Aix-Marseille université, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France.;Médecine interne, hôpital de la Timone (AP-HM), Aix-Marseille université, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France.;Service de néphrologie, hôpital d'instructions des armées Saint-Anne, 83000 Toulon, France.;Service de néphrologie, hôpital européen, 13385 Marseille cedex 05, France.;Médecine interne, hôpital de la Conception (AP-HM), 13385 Marseille cedex 05France.;Service de néphrologie, résidence du Parc, 13009 Marseille, France.;Service de néphrologie, hôpital Henri-Duffaut, 84000 Avignon, France.;Médecine interne, hôpital de la Timone (AP-HM), Aix-Marseille université, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France.;Médecine interne, hôpital de la Timone (AP-HM), Aix-Marseille université, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France.;Centre de néphrologie et de transplantation rénale, hôpital de la Conception (AP-HM), Aix-Marseille université, 13385 Marseille cedex 05, France.;Centre de néphrologie et de transplantation rénale, hôpital de la Conception (AP-HM), Aix-Marseille université, 13385 Marseille cedex 05, France.;Médecine interne, hôpital de la Timone (AP-HM), Aix-Marseille université, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France. Electronic address: jharle@ap-hm.fr.",
"authors": "Vial|R|R|;Daniel|L|L|;Devos|M|M|;Bouchacourt|B|B|;Cazajous|G|G|;Sichez|H|H|;Mazodier|K|K|;Lankester|M|M|;Gobert|P|P|;Seguier|J|J|;Swiader|L|L|;Sallée|M|M|;Jourde-Chiche|N|N|;Harlé|J-R|JR|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.revmed.2018.05.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0248-8663",
"issue": "39(8)",
"journal": "La Revue de medecine interne",
"keywords": "Amylose AL; Chronic lymphoid leukemia membranous nephropathy; Glomérulonéphrite extramembraneuse; Glomérulonéphrite membrano-proliferative; Infiltration lymphoïde interstitielle; Leucémie lymphoïde chronique; Light chain amyloidosis; Membrano-proliferative glomerulonephritis; Monoclonal interstitial infiltration",
"medline_ta": "Rev Med Interne",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000369:Aged, 80 and over; D000686:Amyloidosis; D005260:Female; D005602:France; D005921:Glomerulonephritis; D015433:Glomerulonephritis, Membranous; D006801:Humans; D007668:Kidney; D007674:Kidney Diseases; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D017254:Leukemic Infiltration; D008297:Male; D008875:Middle Aged; D009402:Nephrosis, Lipoid; D009404:Nephrotic Syndrome; D010257:Paraneoplastic Syndromes; D012189:Retrospective Studies",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "612-617",
"pmc": null,
"pmid": "29891261",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Chronic lymphoid leukemia and renal complication: Report on 10 cases from Marseille over 16 years.",
"title_normalized": "chronic lymphoid leukemia and renal complication report on 10 cases from marseille over 16 years"
} | [
{
"companynumb": "FR-ROCHE-2175139",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CHLORAMBUCIL"
},
"drugadditional": "3",
"dru... |
{
"abstract": "OBJECTIVE\nTo further assess preclinical and early clinical evidence that imatinib mesylate, a platelet-derived growth factor receptor (PDGFR) inhibitor, modulates taxane activity in prostate cancer and bone metastases, a randomized study was conducted.\n\n\nMETHODS\nMen with progressive castration-resistant prostate cancer with bone metastases (n = 144) were planned for equal randomization to i.v. 30 mg/m(2) docetaxel on days 1, 8, 15, and 22 every 42 days with 600 mg imatinib daily or placebo, for an improvement in median progression-free survival from 4.5 to 7.5 months (two-sided alpha = 0.05 and beta = 0.20). Secondary end points included differential toxicity and bone turnover markers, tumor phosphorylated PDGFR (p-PDGFR) expression, and modulation of p-PDGFR in peripheral blood leukocytes.\n\n\nRESULTS\nAccrual was halted early because of adverse gastrointestinal events. Among 116 evaluable men (57 docetaxel + imatinib; 59 docetaxel + placebo), respective median times to progression were 4.2 months (95% confidence interval, 3.1-7.5) and 4.2 months (95% confidence interval, 3.0-6.8; P = 0.58, log-rank test). Excess grade 3 toxicities (n = 23) in the docetaxel + imatinib group were principally fatigue and gastrointestinal. Tumor p-PDGFR expression was observed in 12 of 14 (86%) evaluable bone specimens. In peripheral blood leukocytes, p-PDGFR reduction was more likely in docetaxel + imatinib-treated patients compared with docetaxel + placebo (P < 0.0001), as were reductions in urine N-telopeptides (P = 0.004) but not serum bone-specific alkaline phosphatase (P = 0.099).\n\n\nCONCLUSIONS\nThese clinical and translational results question the value of PDGFR inhibition with taxane chemotherapy in prostate cancer bone metastases and are at variance with the preclinical studies. This discordance requires explanation.",
"affiliations": "Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. pmathew@mdanderson.org",
"authors": "Mathew|Paul|P|;Thall|Peter F|PF|;Bucana|Corazon D|CD|;Oh|William K|WK|;Morris|Michael J|MJ|;Jones|Donnah M|DM|;Johnson|Marcella M|MM|;Wen|Sijin|S|;Pagliaro|Lance C|LC|;Tannir|Nizar M|NM|;Tu|Shi-Ming|SM|;Meluch|Anthony A|AA|;Smith|Lon|L|;Cohen|Lorenzo|L|;Kim|Sun-Jin|SJ|;Troncoso|Patricia|P|;Fidler|Isaiah J|IJ|;Logothetis|Christopher J|CJ|",
"chemical_list": "D001549:Benzamides; D010879:Piperazines; D010919:Placebos; D011743:Pyrimidines; D043823:Taxoids; D000077143:Docetaxel; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-07-1269",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "13(19)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D001859:Bone Neoplasms; D002369:Castration; D015331:Cohort Studies; D018572:Disease-Free Survival; D000077143:Docetaxel; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010879:Piperazines; D010919:Placebos; D011471:Prostatic Neoplasms; D011743:Pyrimidines; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D043823:Taxoids",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "5816-24",
"pmc": null,
"pmid": "17908974",
"pubdate": "2007-10-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Platelet-derived growth factor receptor inhibition and chemotherapy for castration-resistant prostate cancer with bone metastases.",
"title_normalized": "platelet derived growth factor receptor inhibition and chemotherapy for castration resistant prostate cancer with bone metastases"
} | [
{
"companynumb": "US-PFIZER INC-2019261591",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
... |
{
"abstract": "Resnik E, LeFevre CA. Fulminant Clostridium difficile colitis associated with paclitaxel and carboplatin chemotherapy. Pseudomembranous colitis is commonly associated with the use of antibiotics. Some antineoplastic agents even without associated antibiotic use can predispose patients to developing infection with Clostridium difficile. The infection is usually mild; however, in rare cases severe forms of pseudomembranous colitis may be encountered. A 66 year-old female with stage IIIC suboptimally debulked epithelial ovarian cancer was treated with paclitaxel and carboplatin. the patient developed fulminant C. difficile colitis three weeks after the second cycle of chemotherapy. Severe symptoms began 24 h prior to admission; however, mild nausea and diarrhea had been present for a week despite self-treatment with over-the-counter Imodium and Pepto-Bismol. Her last antibiotic use was seven weeks previously. The patient was hospitalized immediately for aggressive treatment. Notwithstanding all the efforts, her condition continued to deteriorate and she expired. Severe C. difficile colitis can be life threatening. Patients undergoing chemotherapy who develop significant diarrhea should be evaluated for C. difficile. Prompt diagnosis and intervention prior to onset of severe symptoms can potentially improve the outcome.",
"affiliations": "Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.",
"authors": "Resnik|E.|E|;Lefevre|C. A.|CA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1046/j.1525-1438.1999.99065.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1048-891X",
"issue": "9(6)",
"journal": "International journal of gynecological cancer : official journal of the International Gynecological Cancer Society",
"keywords": null,
"medline_ta": "Int J Gynecol Cancer",
"mesh_terms": null,
"nlm_unique_id": "9111626",
"other_id": null,
"pages": "512-514",
"pmc": null,
"pmid": "11240821",
"pubdate": "1999-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fulminant Clostridium difficile colitis associated with paclitaxel and carboplatin chemotherapy.",
"title_normalized": "fulminant clostridium difficile colitis associated with paclitaxel and carboplatin chemotherapy"
} | [
{
"companynumb": "US-PFIZER INC-2017538398",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "A 69-year-old man was diagnosed with diffuse large B-cell lymphoma (DLBCL) negative for Epstein-Barr virus-encoded small nuclear RNA 1 (EBER-1) in October 2011, when he was also diagnosed as having a human T-cell leukemia virus type-I (HTLV-1) carrier. He achieved complete response after six courses of R-CHOP therapy. In February 2015, the patient had high fever and markedly elevated serum lactate dehydrogenase (LDH) level. Bone marrow examination revealed infiltration of CD4-positive T-cell malignancy. Based on the tentative diagnosis of adult T-cell leukemia/lymphoma, modified LSG15 therapy was initiated. His symptoms and serum LDH level quickly improved after the start of treatment. During the treatment, HTLV-1 proviral DNA integration was reported negative, allowing his final diagnosis to be peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Despite discontinuation of chemotherapy in the middle of the second course due to the patient's preference, complete remission was reached. He remains in clinical remission at 28 months after the treatment discontinuation. Discordant lymphoma of DLBCL and PTCL-NOS in HTLV-1 carrier has not been well characterized and will be discussed with a literature review.",
"affiliations": "Aozora Clinic.;Department of Hematology, National Hospital Organization Tokyo Medical Center.;Department of Hematology, National Hospital Organization Tokyo Medical Center.;Department of Hematology, National Hospital Organization Tokyo Medical Center.;Department of Hematology, National Hospital Organization Tokyo Medical Center.",
"authors": "Sumiya|Chieko|C|;Kagoo|Toshiya|T|;Yokoyama|Akihiro|A|;Yano|Takahiro|T|;Ueno|Hironori|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.62.1400",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "62(9)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Diffuse large B-cell lymphoma; Discordant lymphoma; Human T-cell leukemia virus type-I carrier; Peripheral T-cell lymphoma not otherwise specified",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D020031:Epstein-Barr Virus Infections; D004854:Herpesvirus 4, Human; D015368:Human T-lymphotropic virus 1; D006801:Humans; D015458:Leukemia, T-Cell; D016403:Lymphoma, Large B-Cell, Diffuse; D016411:Lymphoma, T-Cell, Peripheral; D008297:Male",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "1400-1405",
"pmc": null,
"pmid": "34615800",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Discordant lymphoma of diffuse large B-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified in a human T-cell leukemia virus type-I carrier.",
"title_normalized": "discordant lymphoma of diffuse large b cell lymphoma and peripheral t cell lymphoma not otherwise specified in a human t cell leukemia virus type i carrier"
} | [
{
"companynumb": "JP-BAXTER-2021BAX040952",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nOsimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is selective for both epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. Almost all patients who initially respond to an epidermal growth factor receptor tyrosine kinase inhibitor subsequently report disease progression. Epidermal growth factor receptor-dependent resistance mechanisms, bypass pathway activation, and histological transformation have been reported with osimertinib therapy.\n\n\nMETHODS\nWe report a case of a 64-year-old Asian man with epidermal growth factor receptor T790M-positive adenocarcinoma that transformed to epidermal growth factor receptor T790M-negative large-cell neuroendocrine carcinoma after osimertinib therapy. A prompt rebiopsy revealed a rare mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitor, and subsequently treatment with carboplatin and etoposide was effective.\n\n\nCONCLUSIONS\nDespite the promising emergence of circulating tumoral DNA testing, this case report emphasizes the importance of rebiopsy of a progressive epidermal growth factor receptor-mutant tumor.",
"affiliations": "Department of Respiratory Medicine, Yokkaichi Municipal Hospital, 2-2-37, Shibata, Yokkaichi-shi, Mie, 510-0822, Japan. miyazaki.sin1@gmail.com.;Department of Respiratory Medicine, Yokkaichi Municipal Hospital, 2-2-37, Shibata, Yokkaichi-shi, Mie, 510-0822, Japan.;Department of Respiratory Medicine, Yokkaichi Municipal Hospital, 2-2-37, Shibata, Yokkaichi-shi, Mie, 510-0822, Japan.;Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan.;Department of Respiratory Medicine, Yokkaichi Municipal Hospital, 2-2-37, Shibata, Yokkaichi-shi, Mie, 510-0822, Japan.;Department of Pharmacy, Yokkaichi Municipal Hospital, 2-2-37, Shibata, Yokkaichi-shi, Mie, 510-0822, Japan.;Department of Pharmacy, Yokkaichi Municipal Hospital, 2-2-37, Shibata, Yokkaichi-shi, Mie, 510-0822, Japan.;Department of Pathology, Yokkaichi Municipal Hospital, 2-2-37, Shibata, Yokkaichi-shi, Mie, 510-0822, Japan.;Department of Respiratory Medicine, Yokkaichi Municipal Hospital, 2-2-37, Shibata, Yokkaichi-shi, Mie, 510-0822, Japan.",
"authors": "Miyazaki|Shinichi|S|;Kuno|Yasumasa|Y|;Hayai|Shunsaku|S|;Teramachi|Ryo|R|;Yamashita|Ryo|R|;Saito|Yusuke|Y|;Higuchi|Kosuke|K|;Nara|Yoshiharu|Y|;Ikeda|Takuya|T|",
"chemical_list": "D000178:Acrylamides; D000814:Aniline Compounds; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-020-02447-0",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2447\n10.1186/s13256-020-02447-0\nCase Report\nAn EGFR T790M-mutated lung adenocarcinoma undergoing large-cell neuroendocrine carcinoma transformation after osimertinib therapy: a case report\nMiyazaki Shinichi miyazaki.sin1@gmail.com 1 Kuno Yasumasa kuno@movie.ocn.ne.jp 1 Hayai Shunsaku shayai0816@yahoo.co.jp 1 Teramachi Ryo coolryokun@yahoo.co.jp 2 Yamashita Ryo bluenature1215@gmail.com 1 Saito Yusuke yusukesaito1013@gmail.com 3 Higuchi Kosuke okusuribennkyouyou@yahoo.co.jp 3 Nara Yoshiharu pathology@yokkaichihp01.jp 4 Ikeda Takuya ikedat@yokkaichihp01.jp 1 1 grid.417360.70000 0004 1772 4873Department of Respiratory Medicine, Yokkaichi Municipal Hospital, 2-2-37, Shibata, Yokkaichi-shi, Mie 510-0822 Japan \n2 grid.27476.300000 0001 0943 978XDepartment of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560 Japan \n3 grid.417360.70000 0004 1772 4873Department of Pharmacy, Yokkaichi Municipal Hospital, 2-2-37, Shibata, Yokkaichi-shi, Mie 510-0822 Japan \n4 grid.417360.70000 0004 1772 4873Department of Pathology, Yokkaichi Municipal Hospital, 2-2-37, Shibata, Yokkaichi-shi, Mie 510-0822 Japan \n7 8 2020 \n7 8 2020 \n2020 \n14 12225 11 2019 6 7 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\nOsimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is selective for both epidermal growth factor receptor tyrosine kinase inhibitor–sensitizing and T790M resistance mutations. Almost all patients who initially respond to an epidermal growth factor receptor tyrosine kinase inhibitor subsequently report disease progression. Epidermal growth factor receptor–dependent resistance mechanisms, bypass pathway activation, and histological transformation have been reported with osimertinib therapy.\n\nCase presentation\nWe report a case of a 64-year-old Asian man with epidermal growth factor receptor T790M-positive adenocarcinoma that transformed to epidermal growth factor receptor T790M-negative large-cell neuroendocrine carcinoma after osimertinib therapy. A prompt rebiopsy revealed a rare mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitor, and subsequently treatment with carboplatin and etoposide was effective.\n\nConclusions\nDespite the promising emergence of circulating tumoral DNA testing, this case report emphasizes the importance of rebiopsy of a progressive epidermal growth factor receptor–mutant tumor.\n\nKeywords\nEpidermal growth factor receptorT790MOsimertinibLarge-cell neuroendocrine carcinomaTransformationissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nLung cancer is the most common cause of cancer mortality worldwide. Non-small-cell lung cancer (NSCLC) accounts for 85% of cases and includes adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma. The epidermal growth factor receptor (EGFR) gene is one of the most important oncogenes in NSCLC. Mutations in EGFR tyrosine kinase are observed in 51.4% of advanced NSCLC adenocarcinoma cases in Asian populations compared, with approximately 20% among the white population [1]. EGFR mutations are more common in nonsmokers and women. Osimertinib therapy is the first-line treatment for patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. It is also effective against tumors that harbor the T790M EGFR mutation responsible for 50% of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) [2]. Almost all patients who initially respond to an EGFR TKI subsequently report disease progression. EGFR-dependent resistance mechanisms (such as the C797S point mutation), bypass pathway activation (such as mesenchymal–epithelial transition factor amplification), and histological transformation (such as small cell carcinoma) have been reported with osimertinib therapy [3]. We report a rare case of a patient in whom EGFR T790M-positive adenocarcinoma transformed into large-cell neuroendocrine carcinoma (LCNEC) after osimertinib therapy.\n\nCase presentation\nA 64-year-old Asian man with a 46–pack-year smoking history was referred to our department for progressive exertional dyspnea over the course of 1 week. An extensive workup demonstrated a right middle lobe mass, right hilar lymphadenopathy, bilateral pulmonary nodules, and right pleural effusion with pleural nodules, as well as nodules in the peritoneum, mesentery, and omentum (Fig. 1). Histopathological and molecular analyses of transbronchial biopsy specimens from the right middle lobe revealed adenocarcinoma; the malignant epithelial cells were positive for carcinoembryonic antigen (CEA) and negative for synaptophysin (Fig. 2), and they harbored an exon 19 deletion mutation in EGFR. The patient was initially treated with afatinib, which resulted in a partial response.\nFig. 1 Clinical history of the patient. A rebiopsy was performed from the right pleural metastasis (white arrow)\n\nFig. 2 a–c Histopathological results of the biopsy specimen. a Hematoxylin and eosin staining. b Carcinoembryonic antigen staining (CEA). c Synaptophysin staining. Original magnification, × 100. d–f Histology of pleural biopsy specimen. d Hematoxylin and eosin staining. e CEA staining. f synaptophysin staining. Original magnification, × 100\n\n\n\nSeventeen months later, computed tomography (CT) revealed progression of the primary lesion in the right middle lobe and new metastasis to the right pleura. Five cycles of carboplatin (CBDCA) and pemetrexed (PEM) were administered as second-line treatment, which subsequently stabilized the disease. Although one cycle of maintenance therapy with PEM was administered, the lesions of the right middle lobe and pleura progressed. Over the next 7 months, neither six cycles of docetaxel treatment nor afatinib rechallenge was effective. A liquid biopsy revealed EGFR-T790M mutation, and the patient received osimertinib therapy. Although this maintained the stable disease status for 4 months, rapid progression of the right pleural metastasis occurred subsequently. A CT-guided biopsy of the pleura was performed, and LCNEC characterized by positive CEA and synaptophysin staining was identified by histologic examination (Fig. 2). Molecular analysis revealed the EGFR exon 19 deletion without T790M mutation. Thus, a combination of CBDCA and etoposide (VP-16) was initiated, and the patient had stable disease for 3 months. After three cycles of CBDCA and VP-16, the right pleural metastasis progressed, and the treatment was changed to amrubicin (AMR). After one cycle of AMR, he developed superior vena cava syndrome, and he died 41 months after the initial presentation.\n\nDiscussion\nWe report a case of a patient with EGFR T790M-positive adenocarcinoma that transformed to EGFR T790M-negative LCNEC after osimertinib therapy. EGFR exon 19 deletion was identified in both the adenocarcinoma and LCNEC. To the best of our knowledge, this is the fourth description of adenocarcinoma transformation to LCNEC after osimertinib therapy [4–6]. One recent study investigating the mechanisms of resistance to osimertinib in 73 consecutive patients reported only small cell lung cancer (SCLC) transformation in 4 patients [7]. LCNEC shares several clinical characteristics and genomic features with SCLC [8], and, similarly to cases of adenocarcinoma transforming to SCLC [9], the underlying mechanism leading to neuroendocrine differentiation may be the inactivation of retinoblastoma 1 (RB1) and tumor protein 53 (TP53). Inactivation of RB1 and TP53 was observed in pretransformed and post-transformed EGFR-mutant lung adenocarcinoma [9]. However, RB1 loss alone is not sufficient to drive SCLC transformation [10], indicating that other changes must occur in tumors to promote SCLC transformation. The preferential APOBEC (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like)-induced hypermutation was observed in transformed SCLCs, whereas EGFR T790M-positive lung adenocarcinoma had rare APOBEC-associated mutations. The APOBEC mutational process may induce SCLC transformation through genomic instability.\n\nSeveral demographic and pathological factors are associated with EGFR mutation prevalence. EGFR mutations tend to be more common among patients with an adenocarcinoma histology and among nonsmokers [11]. Among Asian populations, the average incidences of EGFR mutations were 31% overall, 47% among patients with adenocarcinoma, and 56% among nonsmokers. Among white populations, the average incidences of EGFR mutations were 7% overall, 13% among patients with adenocarcinoma, and 35% among nonsmokers. The reason for the high frequency of EGFR mutations in Asian patients is unclear, and genome-wide association studies may identify loci that are specifically related to EGFR-targeted carcinogenesis [12]. A multicenter phase II study on cisplatin-etoposide chemotherapy for LCNEC demonstrated that the major efficacy endpoints were similar to those of SCLC [13], and researchers have recommended platinum-etoposide chemotherapy treatment [14]. In 2018, Horn et al. reported that the addition of atezolizumab to chemotherapy in the first-line treatment of extensive stage SCLC increased overall survival and progression-free survival significantly compared with chemotherapy alone [15]. These data suggest that adding an immune checkpoint inhibitor to etoposide-platinum in the front-line setting improves prognosis for patients with LCNEC. At the time we treated our patient, however, addition of atezolizumab to chemotherapy was not approved, owing to the restrictions of the national health insurance system in Japan.\n\nAlthough rebiopsy has a pivotal role in investigating mechanisms of resistance to EGFR TKIs, it is not always feasible. Previous studies have reported that the rate of rebiopsy is approximately 50% [16, 17]; the reasons for not performing a rebiopsy were inaccessible tumors (5%), deterioration in performance status (4%), and patient refusal (22%) [18]. In the present study, rebiopsy revealed that transformation to LCNEC was the mechanism underlying the resistance to EGFR TKI and subsequently led to effective treatment of our patient (Fig. 3).\nFig. 3 Treatment algorism for advanced epidermal growth factor receptor–mutant patients with non-small-cell lung cancer\n\n\n\nConclusions\nWe report a case of a patient in whom EGFR T790M-positive adenocarcinoma transformed into LCNEC after osimertinib therapy. Rebiopsy of the tumor after disease progression was instrumental in determining the mechanism of osimertinib resistance and led to effective treatment.\n\nAbbreviations\nAMRAmrubicin\n\nAPOBECApolipoprotein B mRNA editing enzyme catalytic polypeptide-like\n\nCBDCACarboplatin\n\nCEACarcinoembryonic antigen\n\nCTComputed tomography\n\nEGFREpidermal growth factor receptor\n\nLCNECLarge-cell neuroendocrine carcinoma\n\nNSCLCNon-small-cell lung cancer\n\nPEMPemetrexed\n\nRB1Retinoblastoma 1\n\nSCLCSmall cell lung cancer\n\nTKITyrosine kinase inhibitor\n\nTP53Tumor protein 53\n\nVP-16Etoposide\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\nSM cared for the patient, performed the clinical reasoning, and wrote the article. YK, SH, RT, RY, and TI cared for the patient. YN made the pathological diagnosis and contributed microscopic pictures. YS and KH helped in preparing the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThere was no funding for this case report.\n\nAvailability of data and materials\nData are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nNone declared.\n==== Refs\nReferences\n1. Shi Y Au JS Thongprasert S A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER) J Thorac Oncol 2014 9 154 162 10.1097/JTO.0000000000000033 24419411 \n2. Jänne PA Yang JC Kim DW AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer N Engl J Med 2015 372 1689 1699 10.1056/NEJMoa1411817 25923549 \n3. Minari R Bordi P Tiseo M Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance Transl Lung Cancer Res 2016 5 695 708 10.21037/tlcr.2016.12.02 28149764 \n4. Ricordel C Llamas-Gutierrez F Chiforeanu D Large cell neuroendocrine lung carcinoma transformation as an acquired resistance mechanism to osimertinib J Thorac Oncol 2017 12 e184 e186 10.1016/j.jtho.2017.07.019 29074211 \n5. Baglivo S Ludovini V Sidoni A Large cell neuroendocrine carcinoma transformation and EGFR-T790M mutation as coexisting mechanisms of acquired resistance to EGFR-TKIs in lung cancer Mayo Clin Proc 2017 92 1304 1311 10.1016/j.mayocp.2017.03.022 28778263 \n6. Moriguchi S Uruga H Fujii T Transformation of epidermal growth factor receptor T790M mutation-positive adenosquamous carcinoma of the lung to small cell carcinoma and large-cell neuroendocrine carcinoma following osimertinib therapy: an autopsy case report Respirol Case Rep 2019 7 e00402 30828454 \n7. Mehlman C Cadranel J Rousseau-Bussac G Resistance mechanisms to osimertinib in EGFR-mutated advanced non-small-cell lung cancer: a multicentric retrospective French study Lung Cancer 2019 137 149 156 10.1016/j.lungcan.2019.09.019 31600593 \n8. Miyoshi T Umemura S Matsumura Y Genomic profiling of large-cell neuroendocrine carcinoma of the lung Clin Cancer Res 2017 23 757 765 10.1158/1078-0432.CCR-16-0355 27507618 \n9. Lee JK Lee J Kim S Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas J Clin Oncol 2017 35 3065 3074 10.1200/JCO.2016.71.9096 28498782 \n10. Niederst MJ Sequist LV Poirier JT RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer Nat Commun 2015 6 6377 10.1038/ncomms7377 25758528 \n11. Sekine I Yamamoto N Nishio K Emerging ethnic differences in lung cancer therapy Br J Cancer 2008 99 1757 1762 10.1038/sj.bjc.6604721 18985035 \n12. Mitsudomi T Molecular epidemiology of lung cancer and geographic variations with special reference to EGFR mutations Transl Lung Cancer Res 2014 3 205 211 25806302 \n13. Le Treut J Sault MC Lena H Multicentre phase II study of cisplatin-etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study Ann Oncol 2013 24 1548 1552 10.1093/annonc/mdt009 23406729 \n14. Derks JL van Suylen RJ Thunnissen E Chemotherapy for pulmonary large cell neuroendocrine carcinomas: does the regimen matter? Eur Respir J 2017 49 1601838 10.1183/13993003.01838-2016 28572122 \n15. Horn L Mansfield AS Szczęsna A First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer N Engl J Med 2018 379 2220 2229 10.1056/NEJMoa1809064 30280641 \n16. Kawamura T Kenmotsu H Taira T Rebiopsy for patients with non-small-cell lung cancer after epidermal growth factor receptor-tyrosine kinase inhibitor failure Cancer Sci 2016 107 1001 1005 10.1111/cas.12963 27145431 \n17. Ichihara E Hotta K Kubo T Clinical significance of repeat rebiopsy in detecting the EGFR T790M secondary mutation in patients with non-small cell lung cancer Oncotarget 2018 9 29525 29531 10.18632/oncotarget.25705 30034635 \n18. Zhou J Zhao C Zhao J Re-biopsy and liquid biopsy for patients with non-small cell lung cancer after EGFR-tyrosine kinase inhibitor failure Thorac Cancer 2019 10 957 965 10.1111/1759-7714.13035 30887673\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "14(1)",
"journal": "Journal of medical case reports",
"keywords": "Epidermal growth factor receptor; Large-cell neuroendocrine carcinoma; Osimertinib; T790M; Transformation",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000178:Acrylamides; D000077192:Adenocarcinoma of Lung; D000814:Aniline Compounds; D018278:Carcinoma, Neuroendocrine; D002289:Carcinoma, Non-Small-Cell Lung; D066246:ErbB Receptors; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "122",
"pmc": null,
"pmid": "32762742",
"pubdate": "2020-08-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31600593;28778263;27507618;23406729;24419411;29074211;25923549;28572122;27145431;28498782;30887673;28149764;25806302;18985035;30280641;30034635;25758528;30828454",
"title": "An EGFR T790M-mutated lung adenocarcinoma undergoing large-cell neuroendocrine carcinoma transformation after osimertinib therapy: a case report.",
"title_normalized": "an egfr t790m mutated lung adenocarcinoma undergoing large cell neuroendocrine carcinoma transformation after osimertinib therapy a case report"
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